FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Smith, GP AF Smith, Gideon P. TI Intradermal sodium thiosulfate for exophytic calcinosis cutis of connective tissue disease SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Letter C1 Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. RP Smith, GP (reprint author), Massachusetts Gen Hosp, Dept Dermatol, 50 Staniford St,Suite 200, Boston, MA 02114 USA. EM gpsmith@partners.org NR 5 TC 1 Z9 1 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD SEP PY 2013 VL 69 IS 3 BP E146 EP E147 DI 10.1016/j.jaad.2013.03.022 PG 3 WC Dermatology SC Dermatology GA 207OM UT WOS:000323611100012 PM 23957995 ER PT J AU Stricker, NH Salat, DH Foley, JM Zink, TA Kellison, IL McFarland, CP Grande, LJ McGlinchey, RE Milberg, WP Leritz, EC AF Stricker, Nikki H. Salat, David H. Foley, Jessica M. Zink, Tyler A. Kellison, Ida L. McFarland, Craig P. Grande, Laura J. McGlinchey, Regina E. Milberg, William P. Leritz, Elizabeth C. TI Decreased White Matter Integrity in Neuropsychologically Defined Mild Cognitive Impairment Is Independent of Cortical Thinning SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Diffusion tensor imaging; Aging; Neuropsychological tests; Magnetic resonance imaging; Memory; Executive function ID SURFACE-BASED ANALYSIS; DIFFUSION TENSOR MRI; ALZHEIMERS-DISEASE; SPATIAL STATISTICS; BLOOD-PRESSURE; AD DEMENTIA; POSTERIOR CINGULATE; MEMORY PERFORMANCE; AFRICAN-AMERICANS; VASCULAR FACTORS AB Improved understanding of the pattern of white matter changes in early and prodromal Alzheimer's disease (AD) states such as mild cognitive impairment (MCI) is necessary to support earlier preclinical detection of AD, and debate remains whether white matter changes in MCI are secondary to gray matter changes. We applied neuropsychologically based MCI criteria to a sample of normally aging older adults; 32 participants met criteria for MCI and 81 participants were classified as normal control (NC) subjects. Whole-head high resolution T1 and diffusion tensor imaging scans were completed. Tract-Based Spatial Statistics was applied and a priori selected regions of interest were extracted. Hippocampal volume and cortical thickness averaged across regions with known vulnerability to AD were derived. Controlling for cortical thickness, the MCI group showed decreased average fractional anisotropy (FA) and decreased FA in parietal white matter and in white matter underlying the entorhinal and posterior cingulate cortices relative to the NC group. Statistically controlling for cortical thickness, medial temporal FA was related to memory and parietal FA was related to executive functioning. These results provide further support for the potential role of white matter integrity as an early biomarker for individuals at risk for AD and highlight that changes in white matter may be independent of gray matter changes. C1 [Stricker, Nikki H.; Foley, Jessica M.; Zink, Tyler A.; Kellison, Ida L.; McFarland, Craig P.; Grande, Laura J.] VA Boston Healthcare Syst, Psychol Serv, Boston, MA USA. [Stricker, Nikki H.; Grande, Laura J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Salat, David H.; Leritz, Elizabeth C.] VA Boston Healthcare Syst, Neuroimaging Res Vet Ctr, Boston, MA USA. [Foley, Jessica M.; McGlinchey, Regina E.; Milberg, William P.; Leritz, Elizabeth C.] VA Boston Healthcare Syst, GRECC, Boston, MA USA. [Salat, David H.] Massachusetts Gen Hosp, Athinoula Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Salat, David H.; Foley, Jessica M.; McGlinchey, Regina E.; Milberg, William P.; Leritz, Elizabeth C.] Harvard Univ, Sch Med, Boston, MA USA. [Leritz, Elizabeth C.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. RP Stricker, NH (reprint author), VA Boston Med Ctr 116B, 150 S Huntington Ave, Jamaica Plain, MA 02130 USA. EM stricker@bu.edu RI McGlinchey, Regina/R-1971-2016 FU National Institute of Neurologic Disorders and Stroke [K23NS062148]; National Institute of Nursing Research [R01NR010827]; National Institute on Aging [P60AG08812, P01AG004390]; Medical Research Service VA Merit Review Awards; Gilbert Foundation/AFAR Research Grant FX This work was supported by the National Institute of Neurologic Disorders and Stroke (grant numbers K23NS062148); the National Institute of Nursing Research (grant number R01NR010827), the National Institute on Aging (grant numbers P60AG08812, P01AG004390); and by Medical Research Service VA Merit Review Awards to William Milberg and Regina McGlinchey. This research was conducted while Nikki Stricker was a Gilbert Foundation/AFAR Research Grant recipient. The authors thank Marge Ahlquist for her assistance with BP collection and phlebotomy on all participants. The authors report no conflicts of interest. NR 87 TC 8 Z9 9 U1 2 U2 9 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD SEP PY 2013 VL 19 IS 8 BP 925 EP 937 DI 10.1017/S1355617713000660 PG 13 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 209AQ UT WOS:000323725800009 PM 23809097 ER PT J AU Linden, PA Morgan, JA Couper, GS AF Linden, Philip A. Morgan, Jeffrey A. Couper, Gregory S. TI Seven-year disease-free survival after radical pneumonectomy for a pulmonary artery sarcoma SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article C1 [Linden, Philip A.] Univ Hosp Case Med Ctr, Case Western Reserve Sch Med, Div Thorac & Esophageal Surg, Cleveland, OH 44106 USA. [Morgan, Jeffrey A.] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA. [Couper, Gregory S.] Brigham & Womens Hosp, Div Cardiac Surg, Boston, MA 02115 USA. [Couper, Gregory S.] Harvard Univ, Sch Med, Boston, MA USA. RP Linden, PA (reprint author), Univ Hosp Case Med Ctr, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM philip.linden@uhhospitals.org NR 3 TC 0 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD SEP PY 2013 VL 146 IS 3 BP E17 EP E18 DI 10.1016/j.jtcvs.2013.04.022 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 207MV UT WOS:000323605800004 PM 23764412 ER PT J AU Dahlberg, SE Schiller, JH Bonomi, PB Sandler, AB Brahmer, JR Ramalingam, SS Johnson, DH AF Dahlberg, Suzanne E. Schiller, Joan H. Bonomi, Philip B. Sandler, Alan B. Brahmer, Julie R. Ramalingam, Suresh S. Johnson, David H. TI Body Mass Index and Its Association with Clinical Outcomes for Advanced Non-Small-Cell Lung Cancer Patients Enrolled on Eastern Cooperative Oncology Group Clinical Trials SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Body mass index; Weight; Obesity; Non-small-cell lung cancer; Advanced disease; First-line therapy; Phase III; Chemotherapy; Bevacizumab ID HAZARDS REGRESSION-MODEL; EPIDEMIOLOGIC EVIDENCE; WEIGHT-LOSS; US ADULTS; OBESITY; RISK; MORTALITY; SURVIVAL; COHORT; MEN AB Introduction: Obesity increases the risk of death from many adverse health outcomes and has also been linked with cancer outcomes. The impact of obesity on outcomes of advanced non-small-cell lung cancer patients is unclear. Methods: The authors evaluated the association of body mass index (BMI) and outcomes in 2585 eligible patients enrolled in three consecutive first-line trials conducted by the Eastern Cooperative Oncology Group. BMI was categorized as underweight (BMI < 18.5kg/m(2)), normal weight (BMI: 18.5 to < 25kg/m(2)), overweight (BMI: 25 to < 30kg/m(2)), and obese (BMI 30kg/m(2)). In addition to analyzing overall and progression-free survival, reasons for treatment discontinuation were also assessed by BMI group. Results: Of the patients enrolled, 4.6% were underweight, 44.1% were normal weight, 34.3% of patients were classified as overweight, and 16.9% were obese. Nonproportional hazards existed for obese patients relative to the other three groups of patients, with a change in overall survival hazard occurring at approximately 16 months. In multivariable Cox models, obese patients had superior outcomes earlier on study compared with normal/overweight patients 0.86 (HR=0.86, p=0.04; 95% CI: 0.75-0.99), but later experienced increased hazard (HR=1.54, p< 0.001; 95% CI: 1.22-1.94), indicating a time effect while undergoing treatment. Conclusion: Data from these three trials suggest differential outcomes associated with BMI, and additional studies of the mechanisms underlying this observation, as well as dietary and lifestyle interventions, are warranted to help optimize therapy. C1 [Dahlberg, Suzanne E.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Schiller, Joan H.] Univ Texas SW Med Ctr Dallas, Div Hematol Oncol, Dallas, TX 75390 USA. [Bonomi, Philip B.] Rush Univ, Dept Med Oncol, Med Ctr, Chicago, IL 60612 USA. [Sandler, Alan B.] Oregon Hlth & Sci Univ, Div Hematol & Med Oncol, Portland, OR 97201 USA. [Brahmer, Julie R.] Johns Hopkins Univ, Dept Med Oncol, Baltimore, MD USA. [Ramalingam, Suresh S.] Emory Univ, Dept Hematol & Med Oncol, Winship Canc Inst, Atlanta, GA 30322 USA. Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. RP Dahlberg, SE (reprint author), Dana Farber Canc Inst, Dept Biostat & Computat Biol, CLSB 11007,450 Brookline Ave, Boston, MA 02215 USA. EM dahlberg@jimmy.harvard.edu FU Public Health Service Grants from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services [CA23318, CA66636, CA21115, CA49957, CA21076, CA49883, CA16116] FX This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M. D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA49957, CA21076, CA49883, CA16116 and from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. NR 44 TC 17 Z9 17 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD SEP PY 2013 VL 8 IS 9 BP 1121 EP 1127 DI 10.1097/JTO.0b013e31829cf942 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 205FS UT WOS:000323429100007 PM 23887169 ER PT J AU De Martino, RR Goodney, PP Nolan, BW Robinson, WP Farber, A Patel, VI Stone, DH Cronewett, JL AF De Martino, Randall R. Goodney, Philip P. Nolan, Brian W. Robinson, William P. Farber, Alik Patel, Virendra I. Stone, David H. Cronewett, Jack L. CA Vasc Study Grp New England TI Optimal selection of patients for elective abdominal aortic aneurysm repair based on life expectancy SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT William J. Von Liebig Forum at the Rapid Session of the Vascular Annual Meeting of the Society-for-Vascular-Surgery (SVS) / Peripheral-Vascular-Surgery-Society Session CY JUN 07-09, 2012 CL National Harbor, MD SP Soc Vasc Surg (SVS), Peripheral Vasc Surg Soc ID RANDOMIZED CONTROLLED-TRIAL; PRACTICE GUIDELINES; MORTALITY; VALIDATION; MANAGEMENT; SURGERY; COHORT; SCORE AB Objective: Elective abdominal aortic aneurysm (AAA) repair is beneficial when rupture is likely during a patient's expected lifetime. The purpose of this study was to identify predictors of long-term mortality after elective AAA repair for moderately sized AAAs (<6.5-cm diameter) to identify patients unlikely to benefit from surgery. Methods: We analyzed 2367 elective infrarenal AAA (<6.5 cm) repairs across 21 centers in New England from 2003 to 2011. Our main outcome measure was 5-year life-table survival. Cox proportional hazards analysis was used to describe associations between patient characteristics and 5-year survival. Results: During the study period, 1653 endovascular AAA repairs and 714 open AAA repairs were performed. Overall, 5-year survival rates were similar by procedure type (75% endovascular repair, 80% open repair; P = .14). Advanced age >= 75 years (hazard ratio [HR], 2.0; P < .01) and age >80 years (HR, 2.6; P < .01), coronary artery disease (HR, 1.4; P < .04), unstable angina or recent myocardial infarction (HR, 4.6; P < .01), oxygen-dependent chronic obstructive pulmonary disease (HR, 2.7; P < .01), and estimated glomerular filtration rate <30 mL/min/1.73 m(2) (HR, 2.8; P < .01) were associated with poor survival. Aspirin (HR, 0.8; P < .03) and statin (HR, 0.7; P < .01) use were associated with improved survival. We used these risk factors to develop risk strata for low-risk, medium-risk, and high-risk groups with survival, respectively, of 85%, 69%, and 43% at 5 years (P < .001). Conclusions: More than 75% of patients with moderately sized AAAs who underwent elective repair in our region survived 5 years, but 4% were at high risk for 5-year mortality. Patients with multiple risk factors, especially age >80 years, unstable angina, oxygen-dependent chronic obstructive pulmonary disease, and estimated glomerular filtration rate <30 mL/min/1.73 m(2), are unlikely to achieve sufficient long-term survival to benefit from surgery, unless their AAA rupture risk is very high. C1 [De Martino, Randall R.; Goodney, Philip P.; Nolan, Brian W.; Stone, David H.; Cronewett, Jack L.] Dartmouth Hitchcock Med Ctr, Vasc Surg Sect, Lebanon, NH 03766 USA. [Robinson, William P.] Univ Massachusetts, Sch Med, Div Vasc & Endovasc Surg, Worcester, MA USA. [Farber, Alik] Boston Univ, Med Ctr, Sect Vasc & Endovasc Surg, Boston, MA USA. [Patel, Virendra I.] Massachusetts Gen Hosp, Div Vasc & Endovasc Surg, Boston, MA 02114 USA. RP De Martino, RR (reprint author), Dartmouth Hitchcock Med Ctr, Vasc Surg Sect, 1 Med Ctr Dr,3V, Lebanon, NH 03766 USA. EM randall.r.de.martino@hitchcock.org FU AHRQ HHS [R21 HS021581]; NHLBI NIH HHS [K08 HL105676] NR 22 TC 16 Z9 16 U1 1 U2 8 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 SEP PY 2013 VL 58 IS 3 BP 589 EP 595 DI 10.1016/j.jvs.2013.03.010 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 207QG UT WOS:000323616800003 PM 23642927 ER PT J AU Nabzdyk, LP Kuchibhotla, S Guthrie, P Chun, M Auster, ME Nabzdyk, C Deso, S Andersen, N Gnardellis, C LoGerfo, FW Veves, A AF Nabzdyk, Leena Pradhan Kuchibhotla, Sarada Guthrie, Patrick Chun, Maggie Auster, Michael E. Nabzdyk, Christoph Deso, Steven Andersen, Nicholas Gnardellis, Charalambos LoGerfo, Frank W. Veves, Aristidis TI Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID ANIMAL-MODELS; SUBSTANCE-P; CONNECTION; EAR; INFLAMMATION; INHIBITION; NEUROPATHY; RECEPTORS; REPAIR; CELLS AB Objective: The present study is designed to understand the contribution of peripheral vascular disease and peripheral neuropathy to the wound-healing impairment associated with diabetes. Using a rabbit model of diabetic neuroischemic wound healing, we investigated rate of healing, leukocyte infiltration, and expression of cytokines, interleukin-8 and interleukin-6, and neuropeptides, substance P, and neuropeptide Y. Methods: Diabetes was induced in New Zealand White rabbits by administering alloxan while control rabbits received saline. Ten days later, animals in both groups underwent surgery. One ear served as a sham, and the other was made ischemic (ligation of central + rostral arteries) or neuroischemic (ischemia + resection of central + rostral nerves). Four 6-mm punch biopsy wounds were created in both ears and wound healing was followed for 10 days using computerized planimetry. Results: Nondiabetic sham and ischemic wounds healed significantly more rapidly than diabetic sham and ischemic wounds. Healing was slowest in neuroischemic wounds, irrespective of diabetic status. A high M1/M2 macrophage ratio and a high proinflammatory cytokine expression, both indicators of chronic proinflammatory state, and low neuropeptide expression were seen in preinjury diabetic skin. Postinjury, in diabetic wounds, the M1/M2 ratio remained high, the reactive increase in cytokine expression was low, and neuropeptide expression was further decreased in neuroischemic wounds. Conclusions: This rabbit model illustrates how a combination of a high M1/M2 ratio, a failure to mount postinjury cytokine response as well as a diminished neuropeptide expression, contribute to wound-healing impairment in diabetes. The addition of neuropathy to ischemia leads to equivalently severe impaired wound-healing irrespective of diabetes status, suggesting that in the presence of ischemia, loss of neuropeptide function contributes to the impaired healing associated with diabetes. C1 [Nabzdyk, Leena Pradhan; Guthrie, Patrick; Chun, Maggie; Nabzdyk, Christoph; Deso, Steven; Andersen, Nicholas; LoGerfo, Frank W.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Vasc & Endovasc Surg, Dept Surg,Med Sch, Boston, MA 02215 USA. [Kuchibhotla, Sarada; Auster, Michael E.; Veves, Aristidis] Harvard Univ, Beth Israel Deaconess Med Ctr, Joslin Beth Israel Deaconess Foot Ctr, Dept Surg,Med Sch, Boston, MA 02215 USA. [Kuchibhotla, Sarada; Auster, Michael E.; Veves, Aristidis] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Microcirculat Lab, Boston, MA 02215 USA. [Gnardellis, Charalambos] Technol Educ Inst Messolonghi, Mesolongion, Greece. RP Veves, A (reprint author), Beth Israel Deaconess Med Ctr, 1 Deaconess Rd,PA 321A, Boston, MA 02215 USA. EM aveves@bidmc.harvard.edu FU NIH [R01 1R01NS066205-01]; William J. von Liebig Foundation FX This work was funded in part by (1) NIH R01 1R01NS066205-01 (MPI) to Drs Veves and Pradhan Nabzdyk; and (2) William J. von Liebig Foundation award to Dr LoGerfo. NR 24 TC 16 Z9 16 U1 2 U2 13 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 SEP PY 2013 VL 58 IS 3 BP 766 EP + DI 10.1016/j.jvs.2012.11.095 PG 22 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 207QG UT WOS:000323616800028 ER PT J AU Conrad, MF Kwolek, CJ Mukhopadhyay, S Patel, VI Cambria, RP AF Conrad, Mark F. Kwolek, Christopher J. Mukhopadhyay, Shankha Patel, Virendra I. Cambria, Richard P. TI Late Aortic Remodeling Persists in the Stented Segment After Endovascular Repair of Acute Complicated Type B Aortic Dissection SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 40th Annual Meeting of the New-England-Society-for-Vascular-Surgery CY SEP 27-29, 2013 CL Stowe, VT SP New England Soc Vasc Surg C1 [Conrad, Mark F.; Kwolek, Christopher J.; Mukhopadhyay, Shankha; Patel, Virendra I.; Cambria, Richard P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2013 VL 58 IS 3 BP 849 EP 849 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 207QG UT WOS:000323616800047 ER PT J AU Patel, VI Lancaster, RT Ergul, E Conrad, MF Bertges, D Schermerhorn, M Goodney, P Cambria, RP AF Patel, Virendra I. Lancaster, Robert T. Ergul, Emel Conrad, Mark F. Bertges, Daniel Schermerhorn, Marc Goodney, Phillip Cambria, Richard P. TI Postoperative Renal Dysfunction Independently Predicts Late Mortality in Patients Undergoing Aortic Reconstruction SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 40th Annual Meeting of the New-England-Society-for-Vascular-Surgery CY SEP 27-29, 2013 CL Stowe, VT SP New England Soc Vasc Surg C1 [Patel, Virendra I.; Lancaster, Robert T.; Ergul, Emel; Conrad, Mark F.; Cambria, Richard P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bertges, Daniel] Flether Allan Med Ctr, Burlington, VT USA. [Schermerhorn, Marc] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Goodney, Phillip] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2013 VL 58 IS 3 BP 852 EP 852 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 207QG UT WOS:000323616800054 ER PT J AU Patel, VI Mukhopadhyay, S Conrad, MF Brewster, DC LaMuraglia, GM Watkins, MT Kwolek, CJ Cambria, RP AF Patel, Virendra I. Mukhopadhyay, Shankha Conrad, Mark F. Brewster, David C. LaMuraglia, Glenn M. Watkins, Michael T. Kwolek, Christopher J. Cambria, Richard P. TI Predictors of Increased Length of Stay Following Endovascular AAA Repair SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 40th Annual Meeting of the New-England-Society-for-Vascular-Surgery CY SEP 27-29, 2013 CL Stowe, VT SP New England Soc Vasc Surg C1 [Patel, Virendra I.; Mukhopadhyay, Shankha; Conrad, Mark F.; Brewster, David C.; LaMuraglia, Glenn M.; Watkins, Michael T.; Kwolek, Christopher J.; Cambria, Richard P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2013 VL 58 IS 3 BP 855 EP 855 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 207QG UT WOS:000323616800064 ER PT J AU Vierthaler, L Goodney, PP Schanzer, A Patel, VI Cronenwett, JL Bertges, DJ AF Vierthaler, Luke Goodney, Philip P. Schanzer, Andres Patel, Virenda I. Cronenwett, Jack L. Bertges, Daniel J. CA Vasc Study Grp New England TI Determinants of Amputation-Free Survival After Peripheral Vascular Intervention for Critical Limb Ischemia SO JOURNAL OF VASCULAR SURGERY LA English DT Meeting Abstract CT 40th Annual Meeting of the New-England-Society-for-Vascular-Surgery CY SEP 27-29, 2013 CL Stowe, VT SP New England Soc Vasc Surg C1 [Vierthaler, Luke; Bertges, Daniel J.] Univ Vermont, Coll Med, Burlington, VT USA. [Goodney, Philip P.; Cronenwett, Jack L.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Schanzer, Andres] Univ Massachusetts, Med Ctr, Worcester, MA USA. [Patel, Virenda I.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD SEP PY 2013 VL 58 IS 3 BP 855 EP 855 PG 1 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 207QG UT WOS:000323616800063 ER PT J AU Barczynski, M Randolph, GW Cernea, CR Dralle, H Dionigi, G Alesina, PF Mihai, R Finck, C Lombardi, D Hartl, DM Miyauchi, A Serpell, J Snyder, S Volpi, E Woodson, G Kraimps, JL Hisham, AN AF Barczynski, Marcin Randolph, Gregory W. Cernea, Claudio R. Dralle, Henning Dionigi, Gianlorenzo Alesina, Piero F. Mihai, Radu Finck, Camille Lombardi, Davide Hartl, Dana M. Miyauchi, Akira Serpell, Jonathan Snyder, Samuel Volpi, Erivelto Woodson, Gayle Kraimps, Jean Louis Hisham, Abdullah N. CA Int Neural Monitoring Study Grp TI External branch of the superior laryngeal nerve monitoring during thyroid and parathyroid surgery: International Neural Monitoring Study Group standards guideline statement SO LARYNGOSCOPE LA English DT Article DE Superior laryngeal nerve; external branch of the superior laryngeal nerve; nerve identification; nerve stimulation; nerve monitoring; thyroid and parathyroid surgery ID IN-VIVO MODEL; CRICOTHYROID MUSCLE; SURGICAL ANATOMY; PARALYSIS; IDENTIFICATION; INJURY; NECK; ELECTROMYOGRAPHY; RECOGNITION; ANESTHESIA AB Intraoperative neural monitoring (IONM) during thyroid surgery has gained widespread acceptance as an adjunct to the gold standard of visual identification of the recurrent laryngeal nerve (RLN). Contrary to routine dissection of the RLN, most surgeons tend to avoid rather than routinely expose and identify the external branch of the superior laryngeal nerve (EBSLN) during thyroidectomy or parathyroidectomy. IONM has the potential to be utilized for identification of the EBSLN and functional assessment of its integrity; therefore, IONM might contribute to voice preservation following thyroidectomy or parathyroidectomy. We reviewed the literature and the cumulative experience of the multidisciplinary International Neural Monitoring Study Group (INMSG) with IONM of the EBSLN. A systematic search of the MEDLINE database (from 1950 to the present) with predefined search terms (EBSLN, superior laryngeal nerve, stimulation, neuromonitoring, identification) was undertaken and supplemented by personal communication between members of the INMSG to identify relevant publications in the field. The hypothesis explored in this review is that the use of a standardized approach to the functional preservation of the EBSLN can be facilitated by application of IONM resulting in improved preservation of voice following thyroidectomy or parathyroidectomy. These guidelines are intended to improve the practice of neural monitoring of the EBSLN during thyroidectomy or parathyroidectomy and to optimize clinical utility of this technique based on available evidence and consensus of experts. C1 [Barczynski, Marcin] Jagiellonian Univ, Coll Med, Dept Endocrine Surg, Chair Gen Surg 3, PL-31202 Krakow, Poland. [Randolph, Gregory W.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Div Thyroid & Parathyroid Surg,Massachusetts Eye, Boston, MA 02115 USA. [Randolph, Gregory W.] Harvard Univ, Sch Med, Dept Surg, Div Surg Oncol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Cernea, Claudio R.] Univ Sao Paulo, Sch Med, Dept Head & Neck Surg, Sao Paulo, Brazil. [Dralle, Henning] Univ Halle Wittenberg, Dept Gen Visceral & Vasc Surg, D-06108 Halle, Germany. [Dionigi, Gianlorenzo] Univ Insubria, Endocrine Surg Res Ctr, Dept Surg Sci, Varese Como, Italy. [Alesina, Piero F.] Univ Duisburg Essen, Acad Teaching Hosp, Kliniken Essen Mitte, Dept Surg, Essen, Germany. [Alesina, Piero F.] Univ Duisburg Essen, Acad Teaching Hosp, Kliniken Essen Mitte, Ctr Minimally Invas Surg, Essen, Germany. [Mihai, Radu] John Radcliffe Hosp, Dept Endocrine Surg, Oxford OX3 9DU, England. [Finck, Camille] Univ Liege, Dept Otorhinolaryngol, Liege, Belgium. [Lombardi, Davide] Univ Brescia, Dept Otorhinolaryngol, Brescia, Italy. [Hartl, Dana M.] Inst Gustave Roussy, Dept Head & Neck Oncol, Villejuif, France. [Miyauchi, Akira] Kuma Hosp, Dept Surg, Kobe, Hyogo, Japan. [Serpell, Jonathan] Monash Univ, Alfred Hosp, Endocrine Surg Unit, Melbourne, Vic 3181, Australia. [Snyder, Samuel] Scott & White Mem Hosp & Clin, Texas A&M Hlth Sci Ctr, Coll Med, Dept Surg, Temple, TX USA. [Volpi, Erivelto] Fac Med Sci Santa Casa, Dept Surg, Sao Paulo, Brazil. [Woodson, Gayle] So Illinois Univ, Sch Med, Dept Surg, Div Otolaryngol, Springfield, IL 62794 USA. [Kraimps, Jean Louis] Univ Poitiers, Jean Bernard Hosp, Dept Endocrine Surg, Poitiers, France. [Hisham, Abdullah N.] Putrajaya Hosp, Dept Breast & Endocrine Surg, Putrajaya, Malaysia. RP Barczynski, M (reprint author), Jagiellonian Univ, Coll Med, Dept Endocrine Surg, Chair Gen Surg 3, 37 Pradnicka St, PL-31202 Krakow, Poland. EM marbar@mp.pl RI Czarniecka, Agnieszka/I-5137-2014; Cernea, Claudio/F-5610-2016; Iacobone, Maurizio/K-8714-2016; Moriondo, Andrea/L-2936-2016; Bacuzzi, Alessandro/K-3120-2016 OI Czarniecka, Agnieszka/0000-0003-1249-7205; Moriondo, Andrea/0000-0002-9423-5446; Chiofalo, Maria Grazia/0000-0002-1519-1378; dionigi, gianlorenzo/0000-0003-0864-6087; Bacuzzi, Alessandro/0000-0002-4108-156X NR 48 TC 43 Z9 44 U1 1 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD SEP PY 2013 VL 123 SU 4 BP S1 EP S14 DI 10.1002/lary.24301 PG 14 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 208TH UT WOS:000323702000001 PM 23832799 ER PT J AU Aquino, AE Sene-Fiorese, M Paolillo, FR Duarte, FO Oishi, JC Pena, AA Duarte, ACGO Hamblin, MR Bagnato, VS Parizotto, NA AF Aquino, Antonio E., Jr. Sene-Fiorese, Marcela Paolillo, Fernanda R. Duarte, Fernanda O. Oishi, Jorge C. Pena, Airton A., Jr. Duarte, Ana C. G. O. Hamblin, Michael R. Bagnato, Vanderlei S. Parizotto, Nivaldo A. TI Low-level laser therapy (LLLT) combined with swimming training improved the lipid profile in rats fed with high-fat diet SO LASERS IN MEDICAL SCIENCE LA English DT Article DE Exercise; Metabolism; LLLT; Photobiomodulation; Obesity; Dyslipidemia ID MUSCLE PERFORMANCE; ADIPOSE-TISSUE; EXERCISE; EXPRESSION; OBESITY; LIVER; RESTRICTION; ADAPTATION; METABOLISM; DISEASE AB Obesity and associated dyslipidemia is the fastest growing health problem throughout the world. The combination of exercise and low-level laser therapy (LLLT) could be a new approach to the treatment of obesity and associated disease. In this work, the effects of LLLT associated with exercises on the lipid metabolism in regular and high-fat diet rats were verified. We used 64 rats divided in eight groups with eight rats each, designed: SC, sedentary chow diet; SCL, sedentary chow diet laser, TC, trained chow diet; TCL, trained chow diet laser; SH, sedentary high-fat diet; SHL, sedentary high-fat diet laser; TH, trained high-fat diet; and THL, trained high-fat diet laser. The exercise used was swimming during 8 weeks/90 min daily and LLLT (GA-Al-As, 830 nm) dose of 4.7 J/point and total energy 9.4 J per animal, applied to both gastrocnemius muscles after exercise. We analyzed biochemical parameters, percentage of fat, hepatic and muscular glycogen and relative mass of tissue, and weight percentage gain. The statistical test used was ANOVA, with post hoc Tukey-Kramer for multiple analysis between groups, and the significant level was p < 0.001, p < 0.01, and p < 0.05. LLLT decreased the total cholesterol (p < 0.05), triglycerides (p < 0.01), low-density lipoprotein cholesterol (p < 0.05), and relative mass of fat tissue (p < 0.05), suggesting increased metabolic activity and altered lipid pathways. The combination of exercise and LLLT increased the benefits of exercise alone. However, LLLT without exercise tended to increase body weight and fat content. LLLT may be a valuable addition to a regimen of diet and exercise for weight reduction and dyslipidemic control. C1 [Aquino, Antonio E., Jr.; Sene-Fiorese, Marcela; Paolillo, Fernanda R.; Bagnato, Vanderlei S.] Univ Sao Paulo, Opt Grp, Inst Phys Sao Carlos IFSC, Sao Carlos, SP, Brazil. [Aquino, Antonio E., Jr.; Duarte, Fernanda O.; Oishi, Jorge C.; Pena, Airton A., Jr.; Duarte, Ana C. G. O.] Fed Univ Sao Carlos UFSCar, Phys Educ & Motor Human Dept, Lab Nutr & Metab Appl Exercise, Sao Carlos, SP, Brazil. [Aquino, Antonio E., Jr.; Bagnato, Vanderlei S.; Parizotto, Nivaldo A.] Fed Univ Sao Carlos UFSCar, Biotechnol Post Grad Program, Sao Carlos, SP, Brazil. [Sene-Fiorese, Marcela] Univ Camilo Castelo Branco, Dept Phys Educ, BR-13690970 Sao Paulo, Brazil. [Hamblin, Michael R.; Parizotto, Nivaldo A.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.; Parizotto, Nivaldo A.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Parizotto, Nivaldo A.] Fed Univ Sao Carlos UFSCar, Dept Phys Therapy, Electrothermophototherapy Lab, Sao Carlos, SP, Brazil. [Aquino, Antonio E., Jr.; Parizotto, Nivaldo A.] Fed Univ Sao Carlos UFSCar, BR-13565905 Sao Paulo, Brazil. RP Aquino, AE (reprint author), Fed Univ Sao Carlos UFSCar, Via Washington Luis,Km 235, BR-13565905 Sao Paulo, Brazil. EM spydera@ig.com.br; parizoto@ufscar.br RI Bagnato, Vanderlei/C-3133-2012; Optica e fotonica, Inct/I-2419-2013; PARIZOTTO, Nivaldo/D-5347-2014; USP, CePOF/J-3608-2015; Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016; Sene-Fiorese, Marcela/G-4557-2012; OI PARIZOTTO, Nivaldo/0000-0003-1774-9053; Sene-Fiorese, Marcela/0000-0003-3886-4667; Hamblin, Michael/0000-0001-6431-4605 FU NIAID NIH HHS [R01 AI050875] NR 45 TC 8 Z9 8 U1 0 U2 7 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0268-8921 J9 LASER MED SCI JI Lasers Med. Sci. PD SEP PY 2013 VL 28 IS 5 BP 1271 EP 1280 DI 10.1007/s10103-012-1223-z PG 10 WC Engineering, Biomedical; Surgery SC Engineering; Surgery GA 209GF UT WOS:000323742200008 PM 23151893 ER PT J AU Neumeister, A Normandin, MD Pietrzak, RH Piomelli, D Zheng, MQ Gujarro-Anton, A Potenza, MN Bailey, CR Lin, SF Najafzadeh, S Ropchan, J Henry, S Corsi-Travali, S Carson, RE Huang, Y AF Neumeister, A. Normandin, M. D. Pietrzak, R. H. Piomelli, D. Zheng, M-Q Gujarro-Anton, A. Potenza, M. N. Bailey, C. R. Lin, S-F Najafzadeh, S. Ropchan, J. Henry, S. Corsi-Travali, S. Carson, R. E. Huang, Y. TI Increased OMAR MA1 DV in PTSD SO MOLECULAR PSYCHIATRY LA English DT Editorial Material C1 [Neumeister, A.; Corsi-Travali, S.] NYU, Sch Med, Dept Psychiat & Radiol, Mol Imaging Program, New York, NY 10012 USA. [Neumeister, A.; Corsi-Travali, S.] NYU, Dept Psychiat, Langone Med Ctr, Steven & Alexandra Cohen Vet Ctr Study Posttrauma, New York, NY 10016 USA. [Normandin, M. D.; Zheng, M-Q; Lin, S-F; Najafzadeh, S.; Ropchan, J.; Henry, S.; Carson, R. E.; Huang, Y.] Yale Univ, Sch Med, Dept Diagnost Radiol, Positron Emiss Tomog Ctr, New Haven, CT 06510 USA. [Normandin, M. D.] Harvard Univ, Ctr Adv Med Imaging Sci, Div Nucl Med & Mol Imaging, Dept Radiol,Sch Med,Massachusetts Gen Hosp, Boston, MA USA. [Pietrzak, R. H.] Natl Ctr Posttraumat Stress Disorder, Dept Vet Affairs, Clin Neurosci Div, West Haven, CT USA. [Pietrzak, R. H.; Potenza, M. N.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Piomelli, D.; Gujarro-Anton, A.] Univ Calif Irvine, Dept Anat & Biol, Irvine, CA USA. [Potenza, M. N.] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA. [Potenza, M. N.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. [Bailey, C. R.] Johns Hopkins Sch Med, Baltimore, MD USA. RP Neumeister, A (reprint author), NYU, Sch Med, Dept Psychiat & Radiol, Mol Imaging Program, New York, NY 10012 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2013 VL 18 IS 9 BP 953 EP 953 DI 10.1038/mp.2013.94 PG 1 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 207JS UT WOS:000323595300001 ER PT J AU Neumeister, A Normandin, MD Pietrzak, RH Piomelli, D Zheng, MQ Gujarro-Anton, A Potenza, MN Bailey, CR Lin, SF Najafzadeh, S Ropchan, J Henry, S Corsi-Travali, S Carson, RE Huang, Y AF Neumeister, A. Normandin, M. D. Pietrzak, R. H. Piomelli, D. Zheng, M. Q. Gujarro-Anton, A. Potenza, M. N. Bailey, C. R. Lin, S. F. Najafzadeh, S. Ropchan, J. Henry, S. Corsi-Travali, S. Carson, R. E. Huang, Y. TI Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study SO MOLECULAR PSYCHIATRY LA English DT Article DE brain imaging; cannabinoid receptors; OMAR; PET; PTSD ID CHRONIC UNPREDICTABLE STRESS; ENDOCANNABINOID SYSTEM; TRAUMA EXPOSURE; IN-VIVO; MEMORY; PTSD; DEPRESSION; AMYGDALA; BINDING; RATS AB Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1-selective radioligand [C-11] OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [C-11] OMAR, which measures the volume of distribution (V-T) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [C-11] OMAR V-T values (F(2,53) 7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53) 5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively-OMAR V-T, anandamide and cortisol-correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor-mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder. C1 [Neumeister, A.; Corsi-Travali, S.] NYU, Sch Med, Dept Psychiat & Radiol, Mol Imaging Program, New York, NY 10016 USA. [Neumeister, A.; Corsi-Travali, S.] NYU, Dept Psychiat, Langone Med Ctr, Steven & Alexandra Cohen Vet Ctr Study Posttrauma, New York, NY 10016 USA. [Normandin, M. D.; Zheng, M. Q.; Lin, S. F.; Najafzadeh, S.; Ropchan, J.; Henry, S.; Carson, R. E.; Huang, Y.] Yale Univ, Sch Med, Dept Diagnost Radiol, Positron Emiss Tomog Ctr, New Haven, CT 06510 USA. [Normandin, M. D.] Harvard Univ, Ctr Adv Med Imaging Sci, Div Nucl Med & Mol Imaging, Sch Med,Dept Radiol,Massachusetts Gen Hosp, Boston, MA USA. [Pietrzak, R. H.] US Dept Vet Affairs, Natl Ctr Posttraumat Stress Disorder, Clin Neurosci Div, West Haven, CT USA. [Pietrzak, R. H.; Potenza, M. N.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Piomelli, D.; Gujarro-Anton, A.] Univ Calif Irvine, Dept Anat & Biol, Irvine, CA USA. [Potenza, M. N.] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT USA. [Potenza, M. N.] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. [Bailey, C. R.] Johns Hopkins Sch Med, Baltimore, MD USA. RP Neumeister, A (reprint author), NYU, Sch Med, Dept Psychiat & Radiol, Mol Imaging Program, 1 Pk Ave,8th Floor,Room 225, New York, NY 10016 USA. EM alexander.neumeister@nyumc.org RI Carson, Richard/H-3250-2011; Normandin, Marc/C-6728-2015 OI Carson, Richard/0000-0002-9338-7966; Normandin, Marc/0000-0003-1645-523X FU National Institutes of Health [R21MH096105, R21MH085627, R01MH096876]; National Center for Research Resources (NCRR) [UL1 RR024139]; National Center for Advancing Translational Science (NCATS); National Institutes of Health (NIH); NIH roadmap for Medical Research FX We acknowledge the excellent work of the staff of the Yale PET Center and the nursing support from Brenda Breault, RN, BSN, Cynthia D'Amico, RN, BSN, Michelle San Pedro, RN, CCRC, Jamie Cyr, RN, CCRN and Deborah Campbell, RN for their contributions with patient care during the PET scans. The project described was supported by the National Institutes of Health through the following awards: R21MH096105, R21MH085627 and R01MH096876. This publication was also made possible by CTSA Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Science (NCATS), components of the National Institutes of Health (NIH), and NIH roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. NR 64 TC 65 Z9 66 U1 4 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2013 VL 18 IS 9 BP 1034 EP 1040 DI 10.1038/mp.2013.61 PG 7 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 207JS UT WOS:000323595300014 PM 23670490 ER PT J AU Eran, A Li, JB Vatalaro, K McCarthy, J Rahimov, F Collins, C Markianos, K Margulies, DM Brown, EN Calvo, SE Kohane, IS Kunkel, LM AF Eran, A. Li, J. B. Vatalaro, K. McCarthy, J. Rahimov, F. Collins, C. Markianos, K. Margulies, D. M. Brown, E. N. Calvo, S. E. Kohane, I. S. Kunkel, L. M. TI Comparative RNA editing in autistic and neurotypical cerebella SO MOLECULAR PSYCHIATRY LA English DT Article DE A-to-I; autism; epigenetics; human cerebellum; neurodevelopment; RNA editing ID PRE-MESSENGER-RNA; SPECTRUM DISORDERS; PREFRONTAL CORTEX; RECEPTOR CHANNELS; BRAIN-DEVELOPMENT; ADAR DEAMINASES; ENZYME ADAR2; ADENOSINE; TRANSCRIPTOME; MODULATION AB Adenosine-to-inosine (A-to-I) RNA editing is a neurodevelopmentally regulated epigenetic modification shown to modulate complex behavior in animals. Little is known about human A-to-I editing, but it is thought to constitute one of many molecular mechanisms connecting environmental stimuli and behavioral outputs. Thus, comprehensive exploration of A-to-I RNA editing in human brains may shed light on gene-environment interactions underlying complex behavior in health and disease. Synaptic function is a main target of A-to-I editing, which can selectively recode key amino acids in synaptic genes, directly altering synaptic strength and duration in response to environmental signals. Here, we performed a high-resolution survey of synaptic A-to-I RNA editing in a human population, and examined how it varies in autism, a neurodevelopmental disorder in which synaptic abnormalities are a common finding. Using ultra-deep (>1000 x) sequencing, we quantified the levels of A-to-I editing of 10 synaptic genes in postmortem cerebella from 14 neurotypical and 11 autistic individuals. A high dynamic range of editing levels was detected across individuals and editing sites, from 99.6% to below detection limits. In most sites, the extreme ends of the population editing distributions were individuals with autism. Editing was correlated with isoform usage, clusters of correlated sites were identified, and differential editing patterns examined. Finally, a dysfunctional form of the editing enzyme adenosine deaminase acting on RNA B1 was found more commonly in postmortem cerebella from individuals with autism. These results provide a population-level, high-resolution view of A-to-I RNA editing in human cerebella and suggest that A-to-I editing of synaptic genes may be informative for assessing the epigenetic risk for autism. C1 [Eran, A.; Brown, E. N.; Kohane, I. S.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Eran, A.; Vatalaro, K.; McCarthy, J.; Rahimov, F.; Collins, C.; Markianos, K.; Kunkel, L. M.] Boston Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Li, J. B.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Rahimov, F.; Collins, C.; Kunkel, L. M.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Markianos, K.; Margulies, D. M.; Kohane, I. S.; Kunkel, L. M.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Margulies, D. M.] Correlagen Diagnost, Waltham, MA USA. [Margulies, D. M.; Kohane, I. S.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA USA. [Brown, E. N.] Harvard Univ, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neurosci Stat Res Lab,Med Sch, Boston, MA USA. [Brown, E. N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Calvo, S. E.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Kunkel, L. M.] Manton Ctr Orphan Dis Res, Boston, MA USA. RP Kohane, IS (reprint author), Boston Childrens Hosp, Dept Pediat, 300 Longwood Ave,Enders 144, Boston, MA 02115 USA. EM Isaac_kohane@harvard.edu; kunkel@enders.tch.harvard.edu FU National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD, USA [HHSN275200900011C, N01-HD-9-0011]; NIH [1R01MH085143-01]; [MH068855]; [NIH-P30-HD18655] FX We thank Oliver St Lawrence, Jamie Jett, Benjamin Boese and Tim Harkins at 454, our wonderful lab mates, Professor David Bartel, Thutrang Nguyen, Eran Mick and Elena Helman for their tremendous help. Human tissue was obtained from the National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD, USA contract HHSN275200900011C, re. no. N01-HD-9-0011, and from The Harvard Brain Tissue Resource Center, through the Autism Tissue Program. The Harvard Brain Tissue Resource Center is supported by grant MH068855. The Molecular Genetics Core Facility at Children's Hospital Boston Intellectual and Developmental Disabilities Research Center (IDDRC) is supported by grant NIH-P30-HD18655. This study was generously supported by the Nancy Lurie Marks Family Foundation, The Roche Applied Science Sequencing Grant Program, Autism Speaks, Simons Foundation and the NIH Grant 1R01MH085143-01. NR 74 TC 13 Z9 13 U1 0 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 EI 1476-5578 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2013 VL 18 IS 9 BP 1041 EP 1048 DI 10.1038/mp.2012.118 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 207JS UT WOS:000323595300015 PM 22869036 ER PT J AU Roberts, SA Lawrence, MS Klimczak, LJ Grimm, SA Fargo, D Stojanov, P Kiezun, A Kryukov, GV Carter, SL Saksena, G Harris, S Shah, RR Resnick, MA Getz, G Gordenin, DA AF Roberts, Steven A. Lawrence, Michael S. Klimczak, Leszek J. Grimm, Sara A. Fargo, David Stojanov, Petar Kiezun, Adam Kryukov, Gregory V. Carter, Scott L. Saksena, Gordon Harris, Shawn Shah, Ruchir R. Resnick, Michael A. Getz, Gad Gordenin, Dmitry A. TI An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers SO NATURE GENETICS LA English DT Article ID DNA-POLYMERASE-ZETA; SINGLE-STRANDED-DNA; BREAST-CANCER; HOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE; SOMATIC MUTATIONS; PROSTATE-CANCER; GENOMIC DNA; IN-VIVO; CELLS AB Recent studies indicate that a subclass of APOBEC cytidine deaminases, which convert cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction, may induce mutation clusters in human tumors. We show here that throughout cancer genomes APOBEC-mediated mutagenesis is pervasive and correlates with APOBEC mRNA levels. Mutation clusters in whole-genome and exome data sets conformed to the stringent criteria indicative of an APOBEC mutation pattern. Applying these criteria to 954,247 mutations in 2,680 exomes from 14 cancer types, mostly from The Cancer Genome Atlas (TCGA), showed a significant presence of the APOBEC mutation pattern in bladder, cervical, breast, head and neck, and lung cancers, reaching 68% of all mutations in some samples. Within breast cancer, the HER2-enriched subtype was clearly enriched for tumors with the APOBEC mutation pattern, suggesting that this type of mutagenesis is functionally linked with cancer development. The APOBEC mutation pattern also extended to cancer-associated genes, implying that ubiquitous APOBEC-mediated mutagenesis is carcinogenic. C1 [Roberts, Steven A.; Resnick, Michael A.] Natl Inst Environm Hlth Sci, Mol Genet Lab, Durham, NC USA. [Lawrence, Michael S.; Stojanov, Petar; Kiezun, Adam; Kryukov, Gregory V.; Carter, Scott L.; Saksena, Gordon; Getz, Gad] Broad Inst MIT & Harvard, Cambridge, MA USA. [Klimczak, Leszek J.; Grimm, Sara A.; Fargo, David] Natl Inst Environm Hlth Sci, Durham, NC USA. [Kryukov, Gregory V.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Harris, Shawn; Shah, Ruchir R.] SRA Int Inc, Durham, NC USA. [Getz, Gad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Getz, Gad] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Gordenin, DA (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, Durham, NC USA. EM gadgetz@broadinstitute.org; gordenin@niehs.nih.gov RI Kryukov, Gregory/A-9592-2008; OI Gordenin, Dmitry/0000-0002-8399-1836 FU Intramural Research Program of the US National Institutes of Health; National Institute of Environmental Health Sciences [ES065073, GS-23F-9806H, HHSN273201000086U]; National Human Genome Research Institute [U54HG003067] FX We would like to thank J. Taylor, P. Wade and D. Zaykin for helpful discussions and critical reading of the manuscript. The results published here are in part based on data generated by the TCGA project established by the National Cancer Institute and the National Human Genome Research Institute (database of Genotypes and Phenotypes (dbGaP) accession phs000178.v8.p7). The work was supported in part by the Intramural Research Program of the US National Institutes of Health, the National Institute of Environmental Health Sciences (project ES065073 to M.A.R.; contract GS-23F-9806H and order HHSN273201000086U to R.R.S.) and by the National Human Genome Research Institute (grant U54HG003067 to G.G.). NR 51 TC 235 Z9 239 U1 4 U2 30 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 SEP PY 2013 VL 45 IS 9 BP 970 EP + DI 10.1038/ng.2702 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 209ID UT WOS:000323748200005 PM 23852170 ER PT J AU Lee, SH Ripke, S Neale, BM Faraone, SV Purcell, SM Perlis, RH Mowry, BJ Thapar, A Goddard, ME Witte, JS Absher, D Agartz, I Akil, H Amin, F Andreassen, OA Anjorin, A Anney, R Anttila, V Arking, DE Asherson, P Azevedo, MH Backlund, L Badner, JA Bailey, AJ Banaschewski, T Barchas, JD Barnes, MR Barrett, TB Bass, N Battaglia, A Bauer, M Bayes, M Bellivier, F Bergen, SE Berrettini, W Betancur, C Bettecken, T Biederman, J Binder, EB Black, DW Blackwood, DHR Bloss, CS Boehnke, M Boomsma, DI Breen, G Breuer, R Bruggeman, R Cormican, P Buccola, NG Buitelaar, JK Bunney, WE Buxbaum, JD Byerley, WF Byrne, EM Caesar, S Cahn, W Cantor, RM Casas, M Chakravarti, A Chambert, K Choudhury, K Cichon, S Cloninger, CR Collier, DA Cook, EH Coon, H Cormand, B Corvin, A Coryell, WH Craig, DW Craig, IW Crosbie, J Cuccaro, ML Curtis, D Czamara, D Datta, S Dawson, G Day, R De Geus, EJ Degenhardt, F Djurovic, S Donohoe, GJ Doyle, AE Duan, JB Dudbridge, F Duketis, E Ebstein, RP Edenberg, HJ Elia, J Ennis, S Etain, B Fanous, A Farmer, AE Ferrier, IN Flickinger, M Fombonne, E Foroud, T Frank, J Franke, B Fraser, C Freedman, R Freimer, NB Freitag, CM Friedl, M Frisen, L Gallagher, L Gejman, PV Georgieva, L Gershon, ES Geschwind, DH Giegling, I Gill, M Gordon, SD Gordon-Smith, K Green, EK Greenwood, TA Grice, DE Gross, M Grozeva, D Guan, WH Gurling, H De Haan, L Haines, JL Hakonarson, H Hallmayer, J Hamilton, SP Hamshere, ML Hansen, TF Hartmann, AM Hautzinger, M Heath, AC Henders, AK Herms, S Hickie, IB Hipolito, M Hoefels, S Holmans, PA Holsboer, F Hoogendijk, WJ Hottenga, JJ Hultman, CM Hus, V Ingason, A Ising, M Jamain, S Jones, EG Jones, I Jones, L Tzeng, JY Kahler, AK Kahn, RS Kandaswamy, R Keller, MC Kennedy, JL Kenny, E Kent, L Kim, Y Kirov, GK Klauck, SM Klei, L Knowles, JA Kohli, MA Koller, DL Konte, B Korszun, A Krabbendam, L Krasucki, R Kuntsi, J Kwan, P Landen, M Langstrom, N Lathrop, M Lawrence, J Lawson, WB Leboyer, M Ledbetter, DH Lee, PH Lencz, T Lesch, KP Levinson, DF Lewis, CM Li, J Lichtenstein, P Lieberman, JA Lin, DY Linszen, DH Liu, CY Lohoff, FW Loo, SK Lord, C Lowe, JK Lucae, S MacIntyre, DJ Madden, PAF Maestrini, E Magnusson, PKE Mahon, PB Maier, W Malhotra, AK Mane, SM Martin, CL Martin, NG Mattheisen, M Matthews, K Mattingsdal, M McCarroll, SA McGhee, KA McGough, JJ McGrath, PJ McGuffin, P McInnis, MG McIntosh, A McKinney, R McLean, AW McMahon, FJ McMahon, WM McQuillin, A Medeiros, H Medland, SE Meier, S Melle, I Meng, F Meyer, J Middeldorp, CM Middleton, L Milanova, V Miranda, A Monaco, AP Montgomery, GW Moran, JL Moreno-De-Luca, D Morken, G Morris, DW Morrow, EM Moskvina, V Muglia, P Muhleisen, TW Muir, WJ Muller-Myhsok, B Murtha, M Myers, RM Myin-Germeys, I Neale, MC Nelson, SF Nievergelt, CM Nikolov, I Nimgaonkar, V Nolen, WA Nothen, MM Nurnberger, JI Nwulia, EA Nyholt, DR O'Dushlaine, C Oades, RD Olincy, A Oliveira, G Olsen, L Ophoff, RA Osby, U Owen, MJ Palotie, A Parr, JR Paterson, AD Pato, CN Pato, MT Penninx, BW Pergadia, ML Pericak-Vance, MA Pickard, BS Pimm, J Piven, J Posthuma, D Potash, JB Poustka, F Propping, P Puri, V Quested, DJ Quinn, EM Ramos-Quiroga, JA Rasmussen, HB Raychaudhuri, S Rehnstrom, K Reif, A Ribases, M Rice, JP Rietschel, M Roeder, K Roeyers, H Rossin, L Rothenberger, A Rouleau, G Ruderfer, D Rujescu, D Sanders, AR Sanders, SJ Santangelo, SL Sergeant, JA Schachar, R Schalling, M Schatzberg, AF Scheftner, WA Schellenberg, GD Scherer, SW Schork, NJ Schulze, TG Schumacher, J Schwarz, M Scolnick, E Scott, LJ Shi, JX Shilling, PD Shyn, SI Silverman, JM Slager, SL Smalley, SL Smit, JH Smith, EN Sonuga-Barke, EJS St Clair, D State, M Steffens, M Steinhausen, HC Strauss, JS Strohmaier, J Stroup, TS Sutcliffe, JS Szatmari, P Szelinger, S Thirumalai, S Thompson, RC Todorov, AA Tozzi, F Treutlein, J Uhr, M van den Oord, EJCG Van Grootheest, G Van Os, J Vicente, AM Vieland, VJ Vincent, JB Visscher, PM Walsh, CA Wassink, TH Watson, SJ Weissman, MM Werge, T Wienker, TF Wijsman, EM Willemsen, G Williams, N Willsey, AJ Witt, SH Xu, W Young, AH Yu, TW Zammit, S Zandi, PP Zhang, P Zitman, FG Zollner, S Devlin, B Kelsoe, JR Sklar, P Daly, MJ O'Donovan, MC Craddock, N Sullivan, PF Smoller, JW Kendler, KS Wray, NR AF Lee, S. Hong Ripke, Stephan Neale, Benjamin M. Faraone, Stephen V. Purcell, Shaun M. Perlis, Roy H. Mowry, Bryan J. Thapar, Anita Goddard, Michael E. Witte, John S. Absher, Devin Agartz, Ingrid Akil, Huda Amin, Farooq Andreassen, Ole A. Anjorin, Adebayo Anney, Richard Anttila, Verneri Arking, Dan E. Asherson, Philip Azevedo, Maria H. Backlund, Lena Badner, Judith A. Bailey, Anthony J. Banaschewski, Tobias Barchas, Jack D. Barnes, Michael R. Barrett, Thomas B. Bass, Nicholas Battaglia, Agatino Bauer, Michael Bayes, Monica Bellivier, Frank Bergen, Sarah E. Berrettini, Wade Betancur, Catalina Bettecken, Thomas Biederman, Joseph Binder, Elisabeth B. Black, Donald W. Blackwood, Douglas H. R. Bloss, Cinnamon S. Boehnke, Michael Boomsma, Dorret I. Breen, Gerome Breuer, Rene Bruggeman, Richard Cormican, Paul Buccola, Nancy G. Buitelaar, Jan K. Bunney, William E. Buxbaum, Joseph D. Byerley, William F. Byrne, Enda M. Caesar, Sian Cahn, Wiepke Cantor, Rita M. Casas, Miguel Chakravarti, Aravinda Chambert, Kimberly Choudhury, Khalid Cichon, Sven Cloninger, C. Robert Collier, David A. Cook, Edwin H. Coon, Hilary Cormand, Bru Corvin, Aiden Coryell, William H. Craig, David W. Craig, Ian W. Crosbie, Jennifer Cuccaro, Michael L. Curtis, David Czamara, Darina Datta, Susmita Dawson, Geraldine Day, Richard De Geus, Eco J. Degenhardt, Franziska Djurovic, Srdjan Donohoe, Gary J. Doyle, Alysa E. Duan, Jubao Dudbridge, Frank Duketis, Eftichia Ebstein, Richard P. Edenberg, Howard J. Elia, Josephine Ennis, Sean Etain, Bruno Fanous, Ayman Farmer, Anne E. Ferrier, I. Nicol Flickinger, Matthew Fombonne, Eric Foroud, Tatiana Frank, Josef Franke, Barbara Fraser, Christine Freedman, Robert Freimer, Nelson B. Freitag, Christine M. Friedl, Marion Frisen, Louise Gallagher, Louise Gejman, Pablo V. Georgieva, Lyudmila Gershon, Elliot S. Geschwind, Daniel H. Giegling, Ina Gill, Michael Gordon, Scott D. Gordon-Smith, Katherine Green, Elaine K. Greenwood, Tiffany A. Grice, Dorothy E. Gross, Magdalena Grozeva, Detelina Guan, Weihua Gurling, Hugh De Haan, Lieuwe Haines, Jonathan L. Hakonarson, Hakon Hallmayer, Joachim Hamilton, Steven P. Hamshere, Marian L. Hansen, Thomas F. Hartmann, Annette M. Hautzinger, Martin Heath, Andrew C. Henders, Anjali K. Herms, Stefan Hickie, Ian B. Hipolito, Maria Hoefels, Susanne Holmans, Peter A. Holsboer, Florian Hoogendijk, Witte J. Hottenga, Jouke-Jan Hultman, Christina M. Hus, Vanessa Ingason, Andres Ising, Marcus Jamain, Stephane Jones, Edward G. Jones, Ian Jones, Lisa Tzeng, Jung-Ying Kaehler, Anna K. Kahn, Rene S. Kandaswamy, Radhika Keller, Matthew C. Kennedy, James L. Kenny, Elaine Kent, Lindsey Kim, Yunjung Kirov, George K. Klauck, Sabine M. Klei, Lambertus Knowles, James A. Kohli, Martin A. Koller, Daniel L. Konte, Bettina Korszun, Ania Krabbendam, Lydia Krasucki, Robert Kuntsi, Jonna Kwan, Phoenix Landen, Mikael Langstrom, Niklas Lathrop, Mark Lawrence, Jacob Lawson, William B. Leboyer, Marion Ledbetter, David H. Lee, Phil H. Lencz, Todd Lesch, Klaus-Peter Levinson, Douglas F. Lewis, Cathryn M. Li, Jun Lichtenstein, Paul Lieberman, Jeffrey A. Lin, Dan-Yu Linszen, Don H. Liu, Chunyu Lohoff, Falk W. Loo, Sandra K. Lord, Catherine Lowe, Jennifer K. Lucae, Susanne MacIntyre, Donald J. Madden, Pamela A. F. Maestrini, Elena Magnusson, Patrik K. E. Mahon, Pamela B. Maier, Wolfgang Malhotra, Anil K. Mane, Shrikant M. Martin, Christa L. Martin, Nicholas G. Mattheisen, Manuel Matthews, Keith Mattingsdal, Morten McCarroll, Steven A. McGhee, Kevin A. McGough, James J. McGrath, Patrick J. McGuffin, Peter McInnis, Melvin G. McIntosh, Andrew McKinney, Rebecca McLean, Alan W. McMahon, Francis J. McMahon, William M. McQuillin, Andrew Medeiros, Helena Medland, Sarah E. Meier, Sandra Melle, Ingrid Meng, Fan Meyer, Jobst Middeldorp, Christel M. Middleton, Lefkos Milanova, Vihra Miranda, Ana Monaco, Anthony P. Montgomery, Grant W. Moran, Jennifer L. Moreno-De-Luca, Daniel Morken, Gunnar Morris, Derek W. Morrow, Eric M. Moskvina, Valentina Muglia, Pierandrea Muehleisen, Thomas W. Muir, Walter J. Mueller-Myhsok, Bertram Murtha, Michael Myers, Richard M. Myin-Germeys, Inez Neale, Michael C. Nelson, Stan F. Nievergelt, Caroline M. Nikolov, Ivan Nimgaonkar, Vishwajit Nolen, Willem A. Noethen, Markus M. Nurnberger, John I. Nwulia, Evaristus A. Nyholt, Dale R. O'Dushlaine, Colm Oades, Robert D. Olincy, Ann Oliveira, Guiomar Olsen, Line Ophoff, Roel A. Osby, Urban Owen, Michael J. Palotie, Aarno Parr, Jeremy R. Paterson, Andrew D. Pato, Carlos N. Pato, Michele T. Penninx, Brenda W. Pergadia, Michele L. Pericak-Vance, Margaret A. Pickard, Benjamin S. Pimm, Jonathan Piven, Joseph Posthuma, Danielle Potash, James B. Poustka, Fritz Propping, Peter Puri, Vinay Quested, Digby J. Quinn, Emma M. Antoni Ramos-Quiroga, Josep Rasmussen, Henrik B. Raychaudhuri, Soumya Rehnstroem, Karola Reif, Andreas Ribases, Marta Rice, John P. Rietschel, Marcella Roeder, Kathryn Roeyers, Herbert Rossin, Lizzy Rothenberger, Aribert Rouleau, Guy Ruderfer, Douglas Rujescu, Dan Sanders, Alan R. Sanders, Stephan J. Santangelo, Susan L. Sergeant, Joseph A. Schachar, Russell Schalling, Martin Schatzberg, Alan F. Scheftner, William A. Schellenberg, Gerard D. Scherer, Stephen W. Schork, Nicholas J. Schulze, Thomas G. Schumacher, Johannes Schwarz, Markus Scolnick, Edward Scott, Laura J. Shi, Jianxin Shilling, Paul D. Shyn, Stanley I. Silverman, Jeremy M. Slager, Susan L. Smalley, Susan L. Smit, Johannes H. Smith, Erin N. Sonuga-Barke, Edmund J. S. St Clair, David State, Matthew Steffens, Michael Steinhausen, Hans-Christoph Strauss, John S. Strohmaier, Jana Stroup, T. Scott Sutcliffe, James S. Szatmari, Peter Szelinger, Szabocls Thirumalai, Srinivasa Thompson, Robert C. Todorov, Alexandre A. Tozzi, Federica Treutlein, Jens Uhr, Manfred van den Oord, Edwin J. C. G. Van Grootheest, Gerard Van Os, Jim Vicente, Astrid M. Vieland, Veronica J. Vincent, John B. Visscher, Peter M. Walsh, Christopher A. Wassink, Thomas H. Watson, Stanley J. Weissman, Myrna M. Werge, Thomas Wienker, Thomas F. Wijsman, Ellen M. Willemsen, Gonneke Williams, Nigel Willsey, A. Jeremy Witt, Stephanie H. Xu, Wei Young, Allan H. Yu, Timothy W. Zammit, Stanley Zandi, Peter P. Zhang, Peng Zitman, Frans G. Zoellner, Sebastian Devlin, Bernie Kelsoe, John R. Sklar, Pamela Daly, Mark J. O'Donovan, Michael C. Craddock, Nicholas Sullivan, Patrick F. Smoller, Jordan W. Kendler, Kenneth S. Wray, Naomi R. CA Cross-Disorder Grp Psychiat Genomi Int Inflammatory Bowel Dis Genetic TI Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs SO NATURE GENETICS LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; AUTISM SPECTRUM DISORDERS; MAJOR DEPRESSIVE DISORDER; BIPOLAR DISORDER; COMMON SNPS; CROHNS-DISEASE; SCHIZOPHRENIA; RISK; ASSOCIATION AB Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 +/- 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 +/- 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 +/- 0.06 s.e.), and ADHD and major depressive disorder (0.32 +/- 0.07 s.e.), low between schizophrenia and ASD (0.16 +/- 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders. C1 [Lee, S. Hong; Mowry, Bryan J.; Byrne, Enda M.; Visscher, Peter M.; Wray, Naomi R.] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Anttila, Verneri; Raychaudhuri, Soumya; Daly, Mark J.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Anttila, Verneri; Raychaudhuri, Soumya; Daly, Mark J.] Harvard Univ, Sch Med, Boston, MA USA. [Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Perlis, Roy H.; Bergen, Sarah E.; Chambert, Kimberly; McCarroll, Steven A.; Moran, Jennifer L.; O'Dushlaine, Colm; Raychaudhuri, Soumya; Rossin, Lizzy; Scolnick, Edward; Daly, Mark J.; Smoller, Jordan W.] Broad Inst MIT & Harvard, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. [Purcell, Shaun M.; Ruderfer, Douglas; Sklar, Pamela] Icahn Sch Med Mt Sinai, Dept Psychiat, Div Psychiat Genom, New York, NY USA. [Perlis, Roy H.; Bergen, Sarah E.; Lee, Phil H.; Smoller, Jordan W.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Mowry, Bryan J.] Queensland Ctr Mental Hlth Res, Wacol, Qld, Australia. [Thapar, Anita; Fraser, Christine; Georgieva, Lyudmila; Gordon-Smith, Katherine; Grozeva, Detelina; Hamshere, Marian L.; Holmans, Peter A.; Jones, Ian; Kirov, George K.; Moskvina, Valentina; Nikolov, Ivan; Owen, Michael J.; Williams, Nigel; Zammit, Stanley; O'Donovan, Michael C.; Craddock, Nicholas] Cardiff Univ, Sch Med, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales. [Thapar, Anita; Fraser, Christine; Georgieva, Lyudmila; Jones, Ian; Kirov, George K.; Nikolov, Ivan; Owen, Michael J.; Williams, Nigel; Zammit, Stanley; O'Donovan, Michael C.; Craddock, Nicholas] Cardiff Univ, Sch Med, Inst Psychol Med & Clin Neurosci, Cardiff CF10 3AX, S Glam, Wales. [Goddard, Michael E.] Dept Environm & Primary Ind Victoria, Biosci Res Div, Melbourne, Vic, Australia. [Goddard, Michael E.] Univ Melbourne, Fac Land & Environm, Melbourne, Vic, Australia. [Witte, John S.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Absher, Devin; Myers, Richard M.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Agartz, Ingrid; Andreassen, Ole A.; Djurovic, Srdjan; Mattingsdal, Morten; Melle, Ingrid] Univ Oslo, Inst Clin Med, KG Jebsen Ctr Psychosis Res, Oslo, Norway. [Agartz, Ingrid] Diakonhjemmet Hosp, Dept Res, Oslo, Norway. [Akil, Huda; Meng, Fan; Thompson, Robert C.; Watson, Stanley J.] Univ Michigan, Mol & Behav Neurosci Inst, Mol Psychiat Lab, Ann Arbor, MI 48109 USA. [Amin, Farooq] Emory Univ, Atlanta Vet Affairs Med Ctr, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. [Andreassen, Ole A.; Melle, Ingrid] Oslo Univ Hosp, Div Mental Hlth & Addict, Oslo, Norway. [Anjorin, Adebayo; Bass, Nicholas; Choudhury, Khalid; Gurling, Hugh; Kandaswamy, Radhika; Krasucki, Robert; Lawrence, Jacob; McQuillin, Andrew; Pimm, Jonathan; Puri, Vinay] UCL, Mental Hlth Sci Unit, London, England. [Anney, Richard; Cormican, Paul; Corvin, Aiden; Donohoe, Gary J.; Gallagher, Louise; Gill, Michael; Kenny, Elaine; Morris, Derek W.; Quinn, Emma M.] Univ Dublin Trinity Coll, Dept Psychiat, Dublin 2, Ireland. [Arking, Dan E.; Chakravarti, Aravinda] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Asherson, Philip; Breen, Gerome; Collier, David A.; Craig, Ian W.; Farmer, Anne E.; Kuntsi, Jonna; Lewis, Cathryn M.; McGuffin, Peter] Kings Coll London, Inst Psychiat, MRC, Social Genet & Dev Psychiat SGDP Ctr, London, England. [Azevedo, Maria H.; Oliveira, Guiomar] Univ Coimbra, Fac Med, Coimbra, Portugal. [Backlund, Lena; Frisen, Louise; Osby, Urban; Schalling, Martin] Karolinska Inst, Ctr Mol Med, Dept Mol Med & Surg, Stockholm, Sweden. [Badner, Judith A.; Gershon, Elliot S.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [Bailey, Anthony J.] Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. [Banaschewski, Tobias] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Child & Adolescent Psychiat & Psychotherapy, Mannheim, Germany. [Barchas, Jack D.] Cornell Univ, Weill Med Coll, Dept Psychiat, New York, NY 10021 USA. [Barnes, Michael R.] GlaxoSmithKline, London, England. [Barrett, Thomas B.] Portland VA Med Ctr, Portland, OR USA. [Battaglia, Agatino] Stella Maris Inst Child & Adolescent Neuropsychia, Pisa, Italy. [Bauer, Michael] Carl Gustav Carus Univ Hosp, Dept Psychiat & Psychotherapy, Dresden, Germany. [Bayes, Monica] Parc Cient Barcelona, Ctr Nacl Anal Genom, Barcelona, Spain. [Bellivier, Frank; Etain, Bruno; Jamain, Stephane; Leboyer, Marion] Hop Henri Mondor, INSERM, U955, F-94010 Creteil, France. [Bellivier, Frank] Univ Paris 07, Paris, France. [Bellivier, Frank] Grp Hosp St Louis, AP HP, Dept Psychiat, Paris, France. [Bellivier, Frank; Etain, Bruno; Jamain, Stephane; Leboyer, Marion] Fdn FondaMental, ENBREC European Network Bipolar Res Expert Ctr Gr, Creteil, France. [Bergen, Sarah E.; Hultman, Christina M.; Kaehler, Anna K.; Landen, Mikael; Langstrom, Niklas; Lichtenstein, Paul; Magnusson, Patrik K. E.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Berrettini, Wade; Elia, Josephine; Lohoff, Falk W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Betancur, Catalina] INSERM, U952, Paris, France. [Betancur, Catalina] CNRS, Unite Mixte Rech UMR 7224, Paris, France. [Betancur, Catalina] Univ Paris 06, Paris, France. [Bettecken, Thomas; Binder, Elisabeth B.; Czamara, Darina; Holsboer, Florian; Ising, Marcus; Kohli, Martin A.; Lucae, Susanne; Mueller-Myhsok, Bertram; Uhr, Manfred] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol & Adul, Boston, MA 02114 USA. [Black, Donald W.; Coryell, William H.; Potash, James B.; Wassink, Thomas H.] Univ Iowa, Dept Psychiat, Iowa City, IA 52242 USA. [Blackwood, Douglas H. R.; MacIntyre, Donald J.; McGhee, Kevin A.; McIntosh, Andrew; McLean, Alan W.; Muir, Walter J.; Pickard, Benjamin S.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh, Midlothian, Scotland. [Bloss, Cinnamon S.; Schork, Nicholas J.; Smith, Erin N.] Scripps Translat Sci Inst, La Jolla, CA USA. [Bloss, Cinnamon S.] Scripps Hlth, La Jolla, CA USA. [Boehnke, Michael; Flickinger, Matthew; Guan, Weihua; Kwan, Phoenix; Scott, Laura J.; Zhang, Peng; Zoellner, Sebastian] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Boehnke, Michael; Flickinger, Matthew; Guan, Weihua; Kwan, Phoenix; Scott, Laura J.; Zhang, Peng; Zoellner, Sebastian] Univ Michigan, Sch Publ Hlth, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Boomsma, Dorret I.; De Geus, Eco J.; Hottenga, Jouke-Jan; Middeldorp, Christel M.; Willemsen, Gonneke] Vrije Univ Amsterdam, Dept Biol Psychol, Amsterdam, Netherlands. [Boomsma, Dorret I.; De Geus, Eco J.; Penninx, Brenda W.; Smit, Johannes H.; Van Grootheest, Gerard; Willemsen, Gonneke] EMGO Inst Hlth & Care Res, Amsterdam, Netherlands. [Boomsma, Dorret I.; De Geus, Eco J.; Hottenga, Jouke-Jan; Middeldorp, Christel M.; Penninx, Brenda W.] Neurosci Campus Amsterdam, Amsterdam, Netherlands. [Breen, Gerome] Natl Inst Heath Res, Biomed Res Ctr Mental Hlth, London, England. [Breen, Gerome] Maudsley Natl Hlth Serv NHS Trust, London, England. [Breen, Gerome] Inst Psychiat, London, England. [Breuer, Rene; Frank, Josef; Meier, Sandra; Rietschel, Marcella; Strohmaier, Jana; Treutlein, Jens; Witt, Stephanie H.] Heidelberg Univ, Med Fac Mannheim, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, Mannheim, Germany. [Bruggeman, Richard] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, Groningen, Netherlands. [Buccola, Nancy G.] Louisiana State Univ, Sch Nursing, Hlth Sci Ctr, New Orleans, LA USA. [Buitelaar, Jan K.; Franke, Barbara] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Dept Cognit Neurosci, NL-6525 ED Nijmegen, Netherlands. [Bunney, William E.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92717 USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Psychiat, Seaver Autism Ctr Res & Treatment, New York, NY USA. [Byerley, William F.; Hamilton, Steven P.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Byerley, William F.] NCIRE Northern Calif Inst Q Res & Educ, San Francisco, CA USA. [Caesar, Sian; Gordon-Smith, Katherine; Jones, Lisa] Univ Birmingham, Dept Psychiat, Birmingham, W Midlands, England. [Cahn, Wiepke; Kahn, Rene S.] Univ Med Ctr, Rudolf Magnus Inst Neurosci, Dept Psychiat, Utrecht, Netherlands. [Cantor, Rita M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Casas, Miguel; Antoni Ramos-Quiroga, Josep; Ribases, Marta] Hosp Univ Vall Hebron, CIBERSAM Ctr Invest Biomed Area Salud Mental, Dept Psychiat, Barcelona, Spain. [Casas, Miguel; Antoni Ramos-Quiroga, Josep] Univ Autonoma Barcelona, Dept Psychiat & Legal Med, E-08193 Barcelona, Spain. [Cichon, Sven; Degenhardt, Franziska; Herms, Stefan; Muehleisen, Thomas W.; Noethen, Markus M.] Univ Bonn, Dept Genom, Life & Brain Ctr, Bonn, Germany. [Cichon, Sven] Res Ctr Julich, Inst Neurosci & Med INM 1, Julich, Germany. [Cichon, Sven; Degenhardt, Franziska; Mattheisen, Manuel; Muehleisen, Thomas W.; Noethen, Markus M.; Propping, Peter; Schumacher, Johannes] Univ Bonn, Inst Human Genet, Bonn, Germany. [Cichon, Sven; Herms, Stefan] Univ Basel, Div Med Genet, Dept Biomed, Basel, Switzerland. [Cloninger, C. Robert; Heath, Andrew C.; Madden, Pamela A. F.; Pergadia, Michele L.; Todorov, Alexandre A.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Cook, Edwin H.] Univ Illinois, Dept Psychiat, Inst Juvenile Res, Chicago, IL 60612 USA. [Coon, Hilary; McMahon, William M.] Univ Utah, Dept Psychiat, Salt Lake City, UT USA. [Cormand, Bru] Univ Barcelona, Fac Biol, Dept Genet, Barcelona, Spain. [Cormand, Bru] Biomed Network Res Ctr Rare Dis CIBERER, Barcelona, Spain. [Cormand, Bru] Univ Barcelona IBUB, Inst Biomed, Barcelona, Spain. [Craig, David W.; Szelinger, Szabocls] Translat Genom Res Inst, Phoenix, AZ USA. [Crosbie, Jennifer; Schachar, Russell] Univ Toronto, Hosp Sick Children, Neurosci & Mental Hlth Program, Toronto, ON M5G 1X8, Canada. [Cuccaro, Michael L.; Pericak-Vance, Margaret A.] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA. [Curtis, David] Univ London, East London NHS Fdn Trust, London, England. [Czamara, Darina; Mueller-Myhsok, Bertram] Munich Cluster Syst Neurol SyNergy, Munich, Germany. [Datta, Susmita] UCL, Genet Inst, London, England. [Dawson, Geraldine] Autism Speaks, New York, NY USA. [Dawson, Geraldine] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Dawson, Geraldine; Piven, Joseph] Univ N Carolina, Carolina Inst Dev Disabil, Chapel Hill, NC USA. [Day, Richard; Matthews, Keith] Univ Dundee, Ninewells Hosp & Med Sch, Med Res Inst, Div Neurosci, Dundee DD1 9SY, Scotland. [Djurovic, Srdjan] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Doyle, Alysa E.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Duan, Jubao; Gejman, Pablo V.; Sanders, Alan R.] NorthShore Univ Hlth Syst, Dept Psychiat & Behav Sci, Evanston, IL USA. [Duan, Jubao; Gejman, Pablo V.; Sanders, Alan R.] Univ Chicago, Evanston, IL USA. [Dudbridge, Frank] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England. [Duketis, Eftichia; Freitag, Christine M.; Poustka, Fritz] Goethe Univ Frankfurt, Dept Child & Adolescent Psychiat Psychosomat & Ps, D-60054 Frankfurt, Germany. [Ebstein, Richard P.] Natl Univ Singapore, Dept Psychol, Singapore 117548, Singapore. [Edenberg, Howard J.] Indiana Univ Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. [Edenberg, Howard J.; Foroud, Tatiana; Koller, Daniel L.; Nurnberger, John I.] Indiana Univ Sch Med, Dept Med & Mol Genet, Indianapolis, IN 46202 USA. [Elia, Josephine] Univ Penn, AI Dupont Hosp Children, Philadelphia, PA 19104 USA. [Ennis, Sean] Univ Coll Med Sci, Sch Med, Dublin, Ireland. [Etain, Bruno; Jamain, Stephane; Leboyer, Marion] Univ Paris Est, Fac Med, Creteil, France. [Etain, Bruno; Jamain, Stephane; Leboyer, Marion] Hop H Mondor A Chenevier, AP HP, Dept Psychiat, Creteil, France. [Fanous, Ayman] Georgetown Univ, Sch Med, Dept Psychiat, Washington, DC USA. [Fanous, Ayman; Neale, Michael C.; Kendler, Kenneth S.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Ferrier, I. Nicol; Parr, Jeremy R.; Young, Allan H.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Fombonne, Eric] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Fombonne, Eric] Oregon Hlth & Sci Univ, Inst Dev & Disabil, Portland, OR 97201 USA. [Freedman, Robert; Olincy, Ann] Univ Colorado Denver, Dept Psychiat, Aurora, CO USA. [Freimer, Nelson B.; Loo, Sandra K.; Nelson, Stan F.; Ophoff, Roel A.; Smalley, Susan L.] Univ Calif Los Angeles, Dept Neurobehav Genet, Los Angeles, CA USA. [Friedl, Marion; Giegling, Ina; Hartmann, Annette M.; Konte, Bettina; Rujescu, Dan] Univ Halle, Dept Psychiat, Halle, Germany. [Geschwind, Daniel H.; Lowe, Jennifer K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Geschwind, Daniel H.; Lowe, Jennifer K.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Ctr Autism Res & Treatment, Los Angeles, CA 90095 USA. [Gordon, Scott D.; Henders, Anjali K.; Martin, Nicholas G.; Medland, Sarah E.; Montgomery, Grant W.; Nyholt, Dale R.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Green, Elaine K.] Univ Plymouth, Dept Biomed & Biol Sci, Plymouth PL4 8AA, Devon, England. [Greenwood, Tiffany A.; McKinney, Rebecca; Nievergelt, Caroline M.; Shilling, Paul D.; Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Grice, Dorothy E.] Icahn Sch Med Mt Sinai, Div Tics OCD & Related Disorders, New York, NY USA. [Grice, Dorothy E.; Silverman, Jeremy M.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA. [Gross, Magdalena; Hoefels, Susanne; Maier, Wolfgang] Univ Bonn, Dept Psychiat, Bonn, Germany. [Guan, Weihua] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [De Haan, Lieuwe] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1012 WX Amsterdam, Netherlands. [Haines, Jonathan L.] Vanderbilt Univ, Med Ctr, Ctr Human Genet Res, Nashville, TN USA. [Hakonarson, Hakon] Childrens Hosp Philadelphia, Ctr Appl Genom, Div Human Genet, Philadelphia, PA 19104 USA. [Hakonarson, Hakon] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Hallmayer, Joachim] Stanford Univ, Sch Med, Dept Psychiat, Stanford, CA 94305 USA. [Hamshere, Marian L.; Holmans, Peter A.; Moskvina, Valentina] Cardiff Univ, Biostat & Bioinformat Unit, Cardiff, S Glam, Wales. [Hansen, Thomas F.; Ingason, Andres; Olsen, Line; Rasmussen, Henrik B.; Werge, Thomas] Copenhagen Univ Hosp, Inst Biol Psychiat, Roskilde, Denmark. [Hansen, Thomas F.; Ingason, Andres; Mattheisen, Manuel; Olsen, Line; Rasmussen, Henrik B.; Werge, Thomas] iPSYCH, Lundbeck Initiat Integrat Psychiat Res, Roskilde, Denmark. [Hautzinger, Martin] Univ Tubingen, Dept Clin & Dev Psychol, Tubingen, Germany. [Hickie, Ian B.] Univ Sydney, Brain & Mind Res Inst, Sydney, NSW 2006, Australia. [Hipolito, Maria; Lawson, William B.; Nwulia, Evaristus A.] Howard Univ, Coll Med, Dept Psychiat & Behav Sci, Washington, DC USA. [Hoogendijk, Witte J.] Erasmus MC, Dept Psychiat, Rotterdam, Netherlands. [Hus, Vanessa] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [Jones, Edward G.] Univ Calif Davis, Ctr Neurosci, Davis, CA 95616 USA. [Tzeng, Jung-Ying] N Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Keller, Matthew C.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Kennedy, James L.] Ctr Addict & Mental Hlth, Psychiat Neurogenet Sect, Toronto, ON, Canada. [Kent, Lindsey] Univ St Andrews, Sch Med, St Andrews, Fife, Scotland. [Kim, Yunjung; Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Klauck, Sabine M.] German Canc Res Ctr, Div Mol Genome Anal, Heidelberg, Germany. [Klei, Lambertus; Devlin, Bernie] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Knowles, James A.; Medeiros, Helena; Pato, Carlos N.; Pato, Michele T.] Univ So Calif, Keck Sch Med, Dept Psychiat, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Korszun, Ania] Queen Mary Univ London, Wolfson Inst Preventit Med, London, England. [Krabbendam, Lydia; Myin-Germeys, Inez; Van Os, Jim] Maastricht Univ, Med Ctr, South Limburg Mental Hlth Res & Teaching Network, Dept Psychiat & Neuropsychol, Maastricht, Netherlands. [Landen, Mikael] Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden. [Lathrop, Mark] Ctr Natl Genotypage, Evry, France. [Ledbetter, David H.; Martin, Christa L.] Geisinger Hlth Syst, Autism & Dev Med Inst, Danville, PA USA. [Lencz, Todd; Malhotra, Anil K.] Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Div North Shore, Dept Psychiat,Div Res, Glen Oaks, NY USA. [Lencz, Todd; Malhotra, Anil K.] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA. [Lencz, Todd; Malhotra, Anil K.] Yeshiva Univ, Albert Einstein Coll Med, Dept Psychiat & Behav Sci, Bronx, NY USA. [Lesch, Klaus-Peter] Univ Wurzburg, ADHD Clin Res Unit, Dept Psychiat Psychosomat & Psychotherapy, Div Mol Psychiat, D-97070 Wurzburg, Germany. [Lesch, Klaus-Peter] Maastricht Univ, Sch Mental Hlth & Neurosci MHENS, Dept Psychiat & Psychol, Maastricht, Netherlands. [Levinson, Douglas F.] Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Li, Jun] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Lieberman, Jeffrey A.; McGrath, Patrick J.] Columbia Univ, New York State Psychiat Inst, New York, NY USA. [Lin, Dan-Yu] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Linszen, Don H.] Univ Amsterdam, Acad Med Ctr, Dept Psychiat, NL-1105 AZ Amsterdam, Netherlands. [Liu, Chunyu] Univ Illinois, Dept Psychiat, Inst Human Genet, Chicago, IL 60612 USA. [Loo, Sandra K.; Smalley, Susan L.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Lord, Catherine] Weill Cornell Med Coll, Ctr Autism & Developing Brain, White Plains, NY USA. [Maestrini, Elena] Univ Bologna, Dept Pharm & Biotechnol, Bologna, Italy. [Mahon, Pamela B.; Schulze, Thomas G.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Mane, Shrikant M.] Yale Ctr Genome Anal, Orange, CT USA. [Mattheisen, Manuel] Aarhus Univ, Dept Biomed, Aarhus, Denmark. [Mattheisen, Manuel] Univ Bonn, Dept Genom Math, Bonn, Germany. [Mattingsdal, Morten] Sorlandet Hosp, Kristiansand, Norway. [McGough, James J.] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst, Los Angeles, CA 90095 USA. [McInnis, Melvin G.; Zhang, Peng; Zoellner, Sebastian] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA. [McIntosh, Andrew; McLean, Alan W.; Muir, Walter J.; Pickard, Benjamin S.] Univ Edinburgh, Mol Med Ctr, Edinburgh, Midlothian, Scotland. [McMahon, Francis J.] NIMH, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Meyer, Jobst] Univ Trier, Dept Neurobehav Genet, Trier, Germany. [Middleton, Lefkos] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London, England. [Milanova, Vihra] Alexander Univ Hosp, Psychiat Clin 1, Dept Psychiat, Sofia, Bulgaria. [Miranda, Ana] Univ Valencia, Dept Dev & Educ Psychol, Valencia, Spain. [Monaco, Anthony P.] Univ Oxford, Ctr Human Genet, Wellcome Trust, Oxford, England. [Monaco, Anthony P.] Tufts Univ, Off President, Medford, MA 02155 USA. [Moreno-De-Luca, Daniel; Sanders, Stephan J.; State, Matthew] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Morken, Gunnar] St Olavs Hosp, Dept Psychiat, Trondheim, Norway. [Morken, Gunnar] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway. [Morrow, Eric M.] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA. [Morrow, Eric M.] Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Muglia, Pierandrea; Tozzi, Federica] GlaxoSmithKline Res & Dev Ltd, Neurosci Ctr Excellence Drug Discovery, Verona, Italy. [Muehleisen, Thomas W.] Univ Bonn, Life & Brain Ctr, Bonn, Germany. [Murtha, Michael; Sanders, Stephan J.; State, Matthew; Willsey, A. Jeremy] Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. [Nimgaonkar, Vishwajit] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Nimgaonkar, Vishwajit] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Nolen, Willem A.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9713 AV Groningen, Netherlands. [Nurnberger, John I.] Indiana Univ Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. [Oades, Robert D.] Univ Duisburg Essen, Clin Child & Adolescent Psychiat & Psychotherapy, Essen, Germany. [Oliveira, Guiomar] Ctr Hosp Coimbra, Pediat Hosp, Res & Clin Training Dept, Coimbra, Portugal. [Oliveira, Guiomar] Univ Coimbra, Coimbra, Portugal. [Ophoff, Roel A.] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA. [Ophoff, Roel A.] Univ Med Ctr Utrecht, Dept Psychiat, Utrecht, Netherlands. [Palotie, Aarno; Rehnstroem, Karola] Sanger Inst, Cambridge, England. [Paterson, Andrew D.] Hosp Sick Children, Program Genet & Genom Biol, Toronto, ON M5G 1X8, Canada. [Paterson, Andrew D.; Xu, Wei] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Penninx, Brenda W.; Smit, Johannes H.; Van Grootheest, Gerard] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, Dept Funct Genom, Amsterdam, Netherlands. [Posthuma, Danielle] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands. [Posthuma, Danielle] Erasmus Univ, Med Ctr, Dept Child & Adolescent Psychiat, Rotterdam, Netherlands. [Quested, Digby J.] Univ Oxford, Acad Dept Psychiat, Oxford, England. [Reif, Andreas] Univ Wurzburg, Dept Psychiat, Wurzburg, Germany. [Ribases, Marta] Vall dHebron Res Inst, Psychiat Genet Unit, Barcelona, Spain. [Rice, John P.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Roeder, Kathryn] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. [Roeyers, Herbert; Sonuga-Barke, Edmund J. S.] Univ Ghent, Dept Expt Clin & Hlth Psychol, B-9000 Ghent, Belgium. [Rothenberger, Aribert] Univ Med Gottingen, Gottingen, Germany. [Rouleau, Guy] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada. [Sanders, Stephan J.; State, Matthew; Willsey, A. Jeremy] Yale Univ, Dept Genet, New Haven, CT USA. [Sanders, Stephan J.] Yale Univ, Program Neurogenet, New Haven, CT USA. [Santangelo, Susan L.] Maine Med Ctr, Dept Psychiat, Portland, ME 04102 USA. [Santangelo, Susan L.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Sergeant, Joseph A.] Vrije Univ Amsterdam, Dept Clin Neuropsychol, Amsterdam, Netherlands. [Schatzberg, Alan F.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Palo Alto, CA 94304 USA. [Scheftner, William A.] Rush Univ, Med Ctr, Rush Ambulatory Behav Hlth, Chicago, IL 60612 USA. [Schellenberg, Gerard D.] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA USA. [Scherer, Stephen W.] Hosp Sick Children, Ctr Appl Genom, Toronto, ON M5G 1X8, Canada. [Schork, Nicholas J.; Smith, Erin N.] Scripps Res Inst, La Jolla, CA 92037 USA. [Schulze, Thomas G.] Univ Gottingen, Dept Psychiat & Psychotherapy, D-37073 Gottingen, Germany. [Schwarz, Markus] Psychiat Ctr Nordbaden, Wiesloch, Germany. [Shi, Jianxin] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Shyn, Stanley I.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Slager, Susan L.] Mayo Clin, Rochester, MN USA. [Sonuga-Barke, Edmund J. S.] Univ Southampton, Dev Brain & Behav Lab, Acad Unit Psychol, Southampton, Hants, England. [St Clair, David] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Steffens, Michael] Fed Inst Drugs & Med Devices BfArM, Res Dept, Bonn, Germany. [Steinhausen, Hans-Christoph] Aalborg Univ Hosp, Res Unit Child & Adolescent Psychiat, Aalborg, Denmark. [Steinhausen, Hans-Christoph] Univ Basel, Basel, Switzerland. [Steinhausen, Hans-Christoph] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [Strauss, John S.; Vincent, John B.] Ctr Addict & Mental Hlth, Mol Neuropsychiat & Dev Lab, Toronto, ON, Canada. [Stroup, T. Scott] Columbia Univ, Dept Psychiat, New York, NY USA. [Sutcliffe, James S.] Vanderbilt Univ, Vanderbilt Brain Inst, Nashville, TN 37235 USA. [Szatmari, Peter] Univ Toronto, Dept Psychiat, Toronto, ON, Canada. [Szatmari, Peter] Hosp Sick Children, Neurosci & Mental Hlth Program, Toronto, ON M5G 1X8, Canada. [Szatmari, Peter] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Thirumalai, Srinivasa] Oxford Hlth NHS Fdn Trust, Marlborough House Secure Unit, Milton Keynes, Bucks, England. [van den Oord, Edwin J. C. G.] Virginia Commonwealth Univ, Ctr Biomarker Res & Personalized Med, Richmond, VA USA. [Vicente, Astrid M.] Inst Nacl Saude Dr Ricardo Jorge, Lisbon, Portugal. [Vicente, Astrid M.] BioFIG Ctr Biodivers Funct & Integrat Genom, Lisbon, Portugal. [Vicente, Astrid M.] Inst Gulbenkian Ciencias, Lisbon, Portugal. [Vieland, Veronica J.] Nationwide Childrens Hosp, Battelle Ctr Math Med, Columbus, OH USA. [Visscher, Peter M.] Univ Queensland, Diamantina Inst, Brisbane, Qld, Australia. [Walsh, Christopher A.] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Walsh, Christopher A.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Walsh, Christopher A.] Harvard Univ, Sch Med, Dept Neurol, Ctr Life Sci, Boston, MA 02115 USA. [Walsh, Christopher A.] Harvard Univ, Sch Med, Dept Pediat, Ctr Life Sci, Boston, MA 02115 USA. [Weissman, Myrna M.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Werge, Thomas] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark. [Wienker, Thomas F.] Univ Bonn, Inst Med Biometry, Bonn, Germany. [Wijsman, Ellen M.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Wijsman, Ellen M.] Univ Washington, Dept Med, Seattle, WA USA. [Young, Allan H.] Kings Coll London, Inst Psychiat, Ctr Affect Disorders, London, England. [Yu, Timothy W.] Harvard Univ, Childrens Hosp Boston, Sch Med, Div Genet, Boston, MA USA. [Zandi, Peter P.] Johns Hopkins Univ, Dept Mental Hlth, Baltimore, MD USA. [Zitman, Frans G.] Leiden Univ, Med Ctr, Dept Psychiat, Leiden, Netherlands. [Kelsoe, John R.] Vet Affairs San Diego Healthcare Syst, Special Treatment & Evaluat Program, Dept Psychiat, San Diego, CA USA. [Kendler, Kenneth S.] Virginia Commonwealth Univ, Dept Human & Mol Genet, Richmond, VA USA. [Kendler, Kenneth S.] Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. RP Wray, NR (reprint author), Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. EM naomi.wray@uq.edu.au RI Herms, Stefan/J-1949-2014; Stroup, Thomas/F-9188-2014; Magnusson, Patrik/C-4458-2017; Lesch, Klaus-Peter/J-4906-2013; Vicente, Astrid/F-8692-2014; Miranda, Ana/G-8619-2015; Cormand, Bru/H-5338-2015; Montgomery, Grant/B-7148-2008; Zhang, Peng/N-2920-2014; Mattheisen, Manuel/B-4949-2012; Paterson, Andrew/A-4088-2011; Melle, Ingrid /B-4858-2011; Schumacher, Johannes/F-4970-2015; Ruderfer, Douglas/M-5795-2016; Lohoff, Falk/M-7951-2016; Lencz, Todd/J-3418-2014; BELLIVIER, FRANK/H-5197-2012; McQuillin, Andrew/C-1623-2008; Franke, Andre/B-2151-2010; Nyholt, Dale/C-8384-2013; Monaco, Anthony/A-4495-2010; Bailey, Anthony/J-2860-2014; Liu, Chang/B-7249-2009; Thompson, Richard/J-8879-2014; Binder, Elisabeth/K-8905-2014; Myin-Germeys, Inez /L-5106-2014; Lee, Sang Hong/A-2569-2011; Breen, Gerome/A-5540-2010; Hansen, Thomas/O-5965-2014; Wray, Naomi/C-8639-2015; Holmans, Peter/F-4518-2015; Sutcliffe, James/C-1348-2012; van Grootheest, Gerard/C-6942-2014; Kahler, Anna/J-2874-2012; Franke, Barbara/D-4836-2009; Morrow, Eric/J-2767-2013; McGuffin, Peter/A-1565-2012; Sonuga-Barke, Edmund/D-9137-2011; McIntosh, Andrew/B-9379-2008; Kuntsi, Jonna/G-9750-2011; Nolen, Willem/E-9006-2014; Scherer, Stephen /B-3785-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; OI Goddard, Michael/0000-0001-9917-7946; Schachar, Russell/0000-0002-2015-4395; Zammit, Stanley/0000-0002-2647-9211; Herms, Stefan/0000-0002-2786-8200; Stroup, Thomas/0000-0002-3123-0672; Morris, Derek/0000-0002-3413-570X; Myin-Germeys, Inez/0000-0002-3731-4930; Jamain, Stephane/0000-0002-4321-4100; Greenwood, Tiffany/0000-0002-6080-6503; KELLER, MATTHEW/0000-0002-6075-9882; Nurnberger, John/0000-0002-7674-1767; Gill, Michael/0000-0003-0206-5337; Medland, Sarah/0000-0003-1382-380X; Pickard, Benjamin/0000-0002-2374-6329; Steffens, Michael/0000-0002-6445-8593; de Geus, Eco/0000-0001-6022-2666; Martin, Nicholas/0000-0003-4069-8020; Betancur, Catalina/0000-0002-3327-4804; McMahon, Francis/0000-0002-9469-305X; Corvin, Aiden/0000-0001-6717-4089; MacIntyre, Donald J/0000-0001-6963-1335; O'Donovan, Michael/0000-0001-7073-2379; Hamilton, Steven/0000-0001-8106-6260; Barnes, Michael/0000-0001-9097-7381; Backlund, Lena/0000-0001-9399-5024; Gallagher, Louise/0000-0001-9462-2836; Donohoe, Gary/0000-0003-3037-7426; Sanders, Stephan/0000-0001-9112-5148; Andreassen, Ole A./0000-0002-4461-3568; Oliveira, Guiomar/0000-0002-7049-1277; Yu, Timothy/0000-0003-2988-7701; Thapar, Anita/0000-0002-3689-737X; Etain, Bruno/0000-0002-5377-1488; Visscher, Peter/0000-0002-2143-8760; Gearry, Richard/0000-0002-2298-5141; Faraone, Stephen/0000-0002-9217-3982; Edenberg, Howard/0000-0003-0344-9690; Nievergelt, Caroline/0000-0001-5766-8923; Buxbaum, Joseph/0000-0001-8898-8313; Bruggeman, Richard/0000-0002-3238-8471; Weissman, Myrna/0000-0003-3490-3075; Palmieri, Orazio/0000-0002-0019-7929; Anney, Richard/0000-0002-6083-407X; Agartz, Ingrid/0000-0002-9839-5391; Nothen, Markus/0000-0002-8770-2464; Ribases, Marta/0000-0003-1039-1116; Lesch, Klaus-Peter/0000-0001-8348-153X; Willsey, Arthur/0000-0002-9922-3612; Vicente, Astrid/0000-0001-7134-8037; Craig, Ian/0000-0002-4063-1005; Bergen, Sarah/0000-0002-5888-0034; Anttila, Verneri/0000-0002-0073-4675; Laukens, Debby/0000-0002-1984-5850; Wijsman, Ellen/0000-0002-2725-6669; Matthews, Keith/0000-0002-4478-5888; lichtenstein, paul/0000-0003-3037-5287; Miranda, Ana/0000-0001-6998-5686; Cormand, Bru/0000-0001-5318-4382; Montgomery, Grant/0000-0002-4140-8139; Zhang, Peng/0000-0003-1182-1392; Mattheisen, Manuel/0000-0002-8442-493X; Paterson, Andrew/0000-0002-9169-118X; Melle, Ingrid /0000-0002-9783-548X; Schumacher, Johannes/0000-0001-9217-6457; Ruderfer, Douglas/0000-0002-2365-386X; Lencz, Todd/0000-0001-8586-338X; McQuillin, Andrew/0000-0003-1567-2240; Franke, Andre/0000-0003-1530-5811; Monaco, Anthony/0000-0001-7480-3197; Bailey, Anthony/0000-0003-4257-972X; Lee, Sang Hong/0000-0001-9701-2718; Breen, Gerome/0000-0003-2053-1792; Hansen, Thomas/0000-0001-6703-7762; Wray, Naomi/0000-0001-7421-3357; Holmans, Peter/0000-0003-0870-9412; Sutcliffe, James/0000-0001-5200-6007; van Grootheest, Gerard/0000-0003-4350-6661; Franke, Barbara/0000-0003-4375-6572; McGuffin, Peter/0000-0002-9888-2907; McIntosh, Andrew/0000-0002-0198-4588; Scherer, Stephen /0000-0002-8326-1999; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Buccola, Nancy/0000-0003-1378-4636; Ramos-Quiroga, Josep Antoni/0000-0003-1622-0350; Escott-Price, Valentina/0000-0003-1784-5483; Kent, Lindsey/0000-0002-5315-3399; Moran, Jennifer/0000-0002-5664-4716 FU Australian Research Council [FT0991360, DE130100614]; Australian National Health and Medical Research Council [613608, 1011506, 1047956]; National Institute of Mental Health (NIMH) [U01 MH085520]; Netherlands Scientific Organization (NOW) [480-05-003]; Dutch Brain Foundation; VU University FX This research was directly supported by the Australian Research Council (FT0991360 and DE130100614) and the Australian National Health and Medical Research Council (613608, 1011506 and 1047956). The PGC Cross-Disorder Group is supported by National Institute of Mental Health (NIMH) grant U01 MH085520. Statistical analyses were carried out on the Genetic Cluster Computer (see URLs), which is financially supported by the Netherlands Scientific Organization (NOW; 480-05-003; principal investigator D.P.) along with a supplement from the Dutch Brain Foundation and VU University. Numerous (> 100) grants from government agencies along with substantial private and foundation support worldwide enabled the collection of phenotype and genotype data, without which this research would not be possible; grant numbers are listed in primary PGC publications or in the Supplementary Note. NR 64 TC 407 Z9 409 U1 27 U2 235 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 SEP PY 2013 VL 45 IS 9 BP 984 EP + DI 10.1038/ng.2711 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 209ID UT WOS:000323748200007 ER PT J AU Miron, VE Boyd, A Zhao, JW Yuen, TJ Ruckh, JM Shadrach, JL van Wijngaarden, P Wagers, AJ Williams, A Franklin, RJM Ffrench-Constant, C AF Miron, Veronique E. Boyd, Amanda Zhao, Jing-Wei Yuen, Tracy J. Ruckh, Julia M. Shadrach, Jennifer L. van Wijngaarden, Peter Wagers, Amy J. Williams, Anna Franklin, Robin J. M. Ffrench-Constant, Charles TI M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination SO NATURE NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; GADOLINIUM CHLORIDE; PROGENITOR CELLS; GENE-EXPRESSION; ACTIVIN-A; REPAIR; IDENTIFICATION; MONOCYTES; INJURY; BETA AB The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia and macrophages, which can be polarized to distinct functional phenotypes: pro-inflammatory (M1) and anti-inflammatory or immunoregulatory (M2). We found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 cell conditioned media and impaired in vivo following intra-lesional M2 cell depletion. M2 cell densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger mouse and in multiple sclerosis lesions that normally show remyelination. Blocking M2 cell-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Thus, our results indicate that M2 cell polarization is essential for efficient remyelination and identify activin-A as a therapeutic target for CNS regeneration. C1 [Miron, Veronique E.; Boyd, Amanda; Yuen, Tracy J.; Williams, Anna; Ffrench-Constant, Charles] Univ Edinburgh, Multiple Sclerosis Soc Ctr Translat Res, MRC Ctr Regenerat Med, Edinburgh, Midlothian, Scotland. [Zhao, Jing-Wei; Yuen, Tracy J.; Ruckh, Julia M.; van Wijngaarden, Peter; Franklin, Robin J. M.] Univ Cambridge, Dept Vet Med, MRC Cambridge Stem Cell Inst, Wellcome Trust, Cambridge, England. [Shadrach, Jennifer L.; Wagers, Amy J.] Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Shadrach, Jennifer L.; Wagers, Amy J.] Joslin Diabet Ctr, Cambridge, MA USA. RP Miron, VE (reprint author), Univ Edinburgh, Multiple Sclerosis Soc Ctr Translat Res, MRC Ctr Regenerat Med, Edinburgh, Midlothian, Scotland. EM vmiron@staffmail.ed.ac.uk RI Zhao, Jing-Wei/A-6887-2012; Zhao, Jing-Wei/L-9964-2014 OI Zhao, Jing-Wei/0000-0002-1135-9743 FU UK Multiple Sclerosis Society; Wellcome Trust; Multiple Sclerosis Society of Canada FX We thank the UK Multiple Sclerosis Tissue Bank for providing human brain tissue, F. Roncaroli (Imperial College London) for neuropathological diagnosis of lesions and R. Nicholas (Imperial College London) for providing clinical history of patients. We also thank W. Mungall, J. Huang, M. Harrisingh, A. Jarjour, M. Bechler, M. Swire, A.-C. Nunes-Fonseca, D. Morrison, and C. Watkins for technical assistance. This work was funded by the UK Multiple Sclerosis Society (R.J.M.F. and C.ff.-C.) and the Wellcome Trust (A.W. and C.ff.-C.), and V.E.M. holds a post-doctoral fellowship from the Multiple Sclerosis Society of Canada. NR 48 TC 290 Z9 296 U1 7 U2 92 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2013 VL 16 IS 9 BP 1211 EP U75 DI 10.1038/nn.3469 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 207KN UT WOS:000323597500012 PM 23872599 ER PT J AU Stoll, G Pietilainen, OPH Linder, B Suvisaari, J Brosi, C Hennah, W Leppa, V Torniainen, M Ripatti, S Ala-Mello, S Plottner, O Rehnstrom, K Tuulio-Henriksson, A Varilo, T Tallila, J Kristiansson, K Isohanni, M Kaprio, J Eriksson, JG Raitakari, OT Lehtimaki, T Jarvelin, MR Salomaa, V Hurles, M Stefansson, H Peltonen, L Sullivan, PF Paunio, T Lonnqvist, J Daly, MJ Fischer, U Freimer, NB Palotie, A AF Stoll, Georg Pietilainen, Olli P. H. Linder, Bastian Suvisaari, Jaana Brosi, Cornelia Hennah, William Leppa, Virpi Torniainen, Minna Ripatti, Samuli Ala-Mello, Sirpa Plottner, Oliver Rehnstrom, Karola Tuulio-Henriksson, Annamari Varilo, Teppo Tallila, Jonna Kristiansson, Kati Isohanni, Matti Kaprio, Jaakko Eriksson, Johan G. Raitakari, Olli T. Lehtimaki, Terho Jarvelin, Marjo-Riitta Salomaa, Veikko Hurles, Matthew Stefansson, Hreinn Peltonen, Leena Sullivan, Patrick F. Paunio, Tiina Lonnqvist, Jouko Daly, Mark J. Fischer, Utz Freimer, Nelson B. Palotie, Aarno TI Deletion of TOP3 beta, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders SO NATURE NEUROSCIENCE LA English DT Article ID FRAGILE-X-SYNDROME; MENTAL-RETARDATION PROTEIN; GENOME-WIDE ASSOCIATION; HIDDEN-MARKOV MODEL; SNP GENOTYPING DATA; VELOCARDIOFACIAL SYNDROME; FOUNDER POPULATION; DIGEORGE-SYNDROME; SCHIZOPHRENIA; RNA AB Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high-impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We found that the enrichment of a rare chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enabled the detection of association between TOP3B and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3 beta revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was catalytically active on RNA. The recruitment of TOP3 beta to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome. Our results indicate a previously unknown role for TOP3 beta in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders. C1 Univ Wurzburg, Dept Biochem, D-97070 Wurzburg, Germany. [Pietilainen, Olli P. H.; Ripatti, Samuli; Rehnstrom, Karola; Tallila, Jonna; Hurles, Matthew; Peltonen, Leena; Palotie, Aarno] Wellcome Trust Sanger Inst, Cambridge, England. [Hennah, William; Leppa, Virpi; Ripatti, Samuli; Kaprio, Jaakko; Paunio, Tiina; Palotie, Aarno] Inst Mol Med Finland, Helsinki, Finland. [Pietilainen, Olli P. H.; Varilo, Teppo; Peltonen, Leena; Paunio, Tiina] Natl Inst Hlth & Welf, Publ Hlth Genom Unit, Helsinki, Finland. [Suvisaari, Jaana; Hennah, William; Torniainen, Minna; Tuulio-Henriksson, Annamari; Kaprio, Jaakko; Lonnqvist, Jouko] Natl Inst Hlth & Welf, Dept Mental Hlth, Helsinki, Finland. [Suvisaari, Jaana; Hennah, William; Torniainen, Minna; Tuulio-Henriksson, Annamari; Kaprio, Jaakko; Lonnqvist, Jouko] Natl Inst Hlth & Welf, Substance Abuse Serv, Helsinki, Finland. [Ala-Mello, Sirpa; Lonnqvist, Jouko] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. [Plottner, Oliver] Roche Diagnost GmbH, Pharma Res & Early Dev, Penzberg, Germany. [Isohanni, Matti] Univ Oulu, Dept Psychiat, Inst Clin Med, Oulu, Finland. [Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Eriksson, Johan G.] Natl Inst Hlth & Welf Chron Dis Epidemiol & Preve, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland. [Eriksson, Johan G.] Vaasa Cent Hosp, Vaasa, Finland. [Eriksson, Johan G.] Folkhalsan Res Ctr, Helsinki, Finland. [Eriksson, Johan G.] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland. [Raitakari, Olli T.] Univ Turku, Dept Clin Physiol Nucl Med, Turku, Finland. [Raitakari, Olli T.] Turku Univ Hosp, FIN-20520 Turku, Finland. [Raitakari, Olli T.] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Raitakari, Olli T.] Turku Univ, Cent Hosp, Turku, Finland. [Lehtimaki, Terho] Univ Tampere, Dept Clin Chem, FIN-33101 Tampere, Finland. [Lehtimaki, Terho] Tampere Univ Hosp, Tampere, Finland. [Jarvelin, Marjo-Riitta] Imperial Coll London, Dept Epidemiol & Biostat, London, England. [Jarvelin, Marjo-Riitta] Imperial Coll London, MRC HPA Ctr Environm & Hlth, London, England. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Children Young People & Families, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Salomaa, Veikko] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Stefansson, Hreinn] deCODE Genet, Reykjavik, Iceland. [Peltonen, Leena] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Psychiat & Epidemiol, Chapel Hill, NC USA. [Paunio, Tiina] Univ Helsinki, Cent Hosp, Dept Psychiat, Helsinki, Finland. [Daly, Mark J.] Massachusetts Gen Hosp, Anal & Translat Genet Unit, Boston, MA 02114 USA. [Daly, Mark J.; Palotie, Aarno] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Freimer, Nelson B.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Ctr Neurobehav Genet, Los Angeles, CA 90024 USA. RP Freimer, NB (reprint author), Univ Wurzburg, Dept Biochem, D-97070 Wurzburg, Germany. EM utz.fischer@biozentrum.uni-wuerzburg.de; nfreimer@mednet.ucla.edu RI Ripatti, Samuli/H-9446-2014; Fischer, Utz/A-4090-2016; OI Ripatti, Samuli/0000-0002-0504-1202; Kristiansson, Kati/0000-0003-4688-107X; Eriksson, Johan/0000-0002-2516-2060; Kaprio, Jaakko/0000-0002-3716-2455; Varilo, Teppo/0000-0002-5839-8854 FU Wellcome Trust [WT089062, WT098051]; Academy of Finland [200923, 251704, 136635, 128504, 132071]; Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]; EuroHead project [LSM-CT-2004-504837]; European Community's Seventh Framework Programme; ENGAGE Consortium [HEALTH-F4-2007-201413]; EU/SYNSYS-Synaptic Systems [242167]; National Alliance for Research in Schizophrenia and Depression; Sigrid Juselius Foundation; Biomedicum Helsinki Foundation; Jalmari and Rauha Ahokas Foundation; Paivikki and Sakari Sohlberg Foundation; Orion Farmos Research Foundation; US National Institutes of Health [RL1MH083268, P30NS062691]; DFG [FOR 855] FX We thank R. Durbin for providing genotype data from the 173 individuals who constitute the sub-isolate population sample, C. Sabatti for helpful suggestions, and B. Laggerbauer and A. Hirmer for critically reading the manuscript. This work was supported by The Wellcome Trust (grant numbers WT089062 and WT098051 to A.P.), the Academy of Finland (project grants 200923 and 251704 to A. P., 136635 to V.S., 128504 to W.H., and 132071 to M.I.), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers 213506 and 129680 to A.P. and J. K.), the EuroHead project (LSM-CT-2004-504837), the European Community's Seventh Framework Programme (FP7/2007-2013), the ENGAGE Consortium (grant agreement HEALTH-F4-2007-201413), EU/SYNSYS-Synaptic Systems (grant number 242167 to A.P.), the National Alliance for Research in Schizophrenia and Depression, Sigrid Juselius Foundation (to J. L. and A. P.), the Biomedicum Helsinki Foundation (to O.P.H.P.), the Jalmari and Rauha Ahokas Foundation (to O.P.H.P.), the Paivikki and Sakari Sohlberg Foundation (to A. P.), the Orion Farmos Research Foundation (to W.H.), grants RL1MH083268 and P30NS062691 from the US National Institutes of Health (to N.B.F.), and grants of the RVZ-network and the DFG (FOR 855) to U.F. NR 61 TC 43 Z9 43 U1 0 U2 19 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2013 VL 16 IS 9 BP 1228 EP U99 DI 10.1038/nn.3484 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 207KN UT WOS:000323597500014 PM 23912948 ER PT J AU Polack, PO Friedman, J Golshani, P AF Polack, Pierre-Olivier Friedman, Jonathan Golshani, Peyman TI Cellular mechanisms of brain state-dependent gain modulation in visual cortex SO NATURE NEUROSCIENCE LA English DT Article ID BARREL CORTEX; CORTICAL NETWORKS; IN-VIVO; GABAERGIC NEURONS; BEHAVIORAL STATE; BASAL FOREBRAIN; ACETYLCHOLINE; NOREPINEPHRINE; ACTIVATION; NEOCORTEX AB Visual cortical neurons fire at higher rates to visual stimuli during locomotion than during immobility, while maintaining orientation selectivity. The mechanisms underlying this change in gain are not understood. We performed whole-cell recordings from layer 2/3 and layer 4 visual cortical excitatory neurons and from parvalbumin-positive and somatostatin-positive inhibitory neurons in mice that were free to rest or run on a spherical treadmill. We found that the membrane potential of all cell types became more depolarized and (with the exception of somatostatin-positive interneurons) less variable during locomotion. Cholinergic input was essential for maintaining the unimodal membrane potential distribution during immobility, whereas noradrenergic input was necessary for the tonic depolarization associated with locomotion. Our results provide a mechanism for how neuromodulation controls the gain and signal-to-noise ratio of visual cortical neurons during changes in the state of vigilance. C1 [Polack, Pierre-Olivier; Friedman, Jonathan; Golshani, Peyman] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [Polack, Pierre-Olivier; Golshani, Peyman] W Los Angeles Vet Affairs Med Ctr, Dept Neurol, Los Angeles, CA 90073 USA. RP Golshani, P (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. EM pgolshani@mednet.ucla.edu OI Polack, Pierre-Olivier/0000-0003-1716-6595 FU US National Institutes of Health [KO8 NS0562101]; Whitehall Foundation [2012-05-83]; Veterans Affairs Merit Review Award [1I01BX001524-01A1] FX We acknowledge R. Gruver for technical assistance on visual stimulation, Z. Peng and C. Houser for histology, and D. Contreras, M. Einstein, T. Indersmitten, M. Javaherian, C. Kaba, S. Mahon, A. Silva and S. Singh for their thoughtful comments on the manuscript. This work was supported by the US National Institutes of Health (KO8 NS0562101), the Whitehall Foundation (grant 2012-05-83) and a Veterans Affairs Merit Review Award (1I01BX001524-01A1). NR 53 TC 125 Z9 125 U1 0 U2 35 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2013 VL 16 IS 9 BP 1331 EP U227 DI 10.1038/nn.3464 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 207KN UT WOS:000323597500026 PM 23872595 ER PT J AU Hall, FM Kopans, DB Sadowsky, NL Homer, MJ AF Hall, Ferris M. Kopans, Daniel B. Sadowsky, Norman L. Homer, Marc J. TI Development of Wire Localization for Occult Breast Lesions: Boston Remembrances SO RADIOLOGY LA English DT Editorial Material ID END RETRACTABLE WIRE; PREOPERATIVE LOCALIZATION; CURVED-END; MAMMOGRAPHY; EXCISION C1 [Hall, Ferris M.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Kopans, Daniel B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Sadowsky, Norman L.] Massachusetts Gen Hosp, Dept Radiol, Brookline, MA USA. [Homer, Marc J.] Tufts Med Ctr, Dept Radiol, Boston, MA USA. RP Hall, FM (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA. EM fhall@bidmc.harvard.edu NR 20 TC 5 Z9 6 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 SEP PY 2013 VL 268 IS 3 BP 622 EP 627 DI 10.1148/radiol.13121943 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 205CR UT WOS:000323419300003 PM 23970507 ER PT J AU Huo, YL Wischgoll, T Choy, JS Sola, S Navia, JL Teague, SD Bhatt, DL Kassab, GS AF Huo, Yunlong Wischgoll, Thomas Choy, Jenny Susana Sola, Srikanth Navia, Jose L. Teague, Shawn D. Bhatt, Deepak L. Kassab, Ghassan S. TI CT-based Diagnosis of Diffuse Coronary Artery Disease on the Basis of Scaling Power Laws SO RADIOLOGY LA English DT Article ID CROSS-SECTIONAL AREA; INTRAVASCULAR ULTRASOUND; MYOCARDIAL-INFARCTION; VASCULAR TREE; FLOW; ATHEROSCLEROSIS; MORPHOMETRY; PROGRESSION; SIZE; MASS AB Purpose: To provide proof of concept for a diagnostic method to assess diffuse coronary artery disease (CAD) on the basis of coronary computed tomography (CT) angiography. Materials and Methods: The study was approved by the Cleveland Clinic Institutional Review Board, and all subjects gave informed consent. Morphometric data from the epicardial coronary artery tree, determined with CT angiography in 120 subjects (89 patients with metabolic syndrome and 31 ageand sex-matched control subjects) were analyzed on the basis of the scaling power law. Results obtained in patients with metabolic syndrome and control subjects were compared statistically. Results: The mean lumen cross-sectional area (ie, lumen cross-sectional area averaged over each vessel of an epicardial coronary artery tree) and sum of intravascular volume in patients with metabolic syndrome (0.039 cm(2) +/- 0.015 [standard deviation] and 2.71 cm(3) +/- 1.75, respectively) were significantly less than those in control subjects (0.054 cm(2) +/- 0.015 and 3.29 cm(3) +/- 1.77, respectively; P < .05). The length-volume power law showed coefficients of 27.0 cm(-4/3) +/- 9.0 (R-2 = 0.91 6 0.08) for patients with metabolic syndrome and 19.9 cm(-4/3) +/- 4.3 (R-2 = 0.92 6 0.07) for control subjects (P < .05). The probability frequency shows that more than 65% of patients with metabolic syndrome had a coefficient of 23 or more for the length-volume scaling power law, whereas approximately 90% of the control subjects had a coefficient of less than 23. Conclusion: The retrospective scaling analysis provides a quantitative rationale for diagnosis of diffuse CAD. (C) RSNA, 2013 C1 [Huo, Yunlong; Choy, Jenny Susana; Kassab, Ghassan S.] Indiana Univ Purdue Univ Indianapolis, Dept Biomed Engn, Indianapolis, IN 46202 USA. [Teague, Shawn D.] Indiana Univ Purdue Univ Indianapolis, Dept Radiol, Indianapolis, IN 46202 USA. [Kassab, Ghassan S.] Indiana Univ Purdue Univ Indianapolis, Dept Surg, Indianapolis, IN 46202 USA. [Kassab, Ghassan S.] Indiana Univ Purdue Univ Indianapolis, Dept Cellular & Integrat Physiol, Indianapolis, IN 46202 USA. [Wischgoll, Thomas] Wright State Univ, Dept Elect & Comp Engn, Dayton, OH 45435 USA. [Sola, Srikanth; Navia, Jose L.] Cleveland Clin, Dept Cardiovasc Surg, Cleveland, OH 44106 USA. [Bhatt, Deepak L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Kassab, GS (reprint author), Indiana Univ Purdue Univ Indianapolis, Dept Biomed Engn, Indianapolis, IN 46202 USA. EM gkassab@iupui.edu RI Huo, Yunlong/N-8155-2013; OI Huo, Yunlong/0000-0003-4121-3224 FU National Institutes of Health [HL-092048] FX This research was supported by the National Institutes of Health (grant HL-092048). NR 30 TC 6 Z9 6 U1 0 U2 6 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 SEP PY 2013 VL 268 IS 3 BP 694 EP 701 DI 10.1148/radiol.13122181 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 205CR UT WOS:000323419300009 PM 23616633 ER PT J AU Wong, HJ Sistrom, CL Benzer, TI Halpern, EF Morra, DJ Gazelle, GS Ferris, TG Weilburg, JB AF Wong, Hannah J. Sistrom, Chris L. Benzer, Theodore I. Halpern, Elkan F. Morra, Dante J. Gazelle, G. Scott Ferris, Timothy G. Weilburg, Jeffrey B. TI Use of Imaging in the Emergency Department: Physicians Have Limited Effect on Variation SO RADIOLOGY LA English DT Article ID HEAD COMPUTED-TOMOGRAPHY; LOGISTIC-REGRESSION; RISK TOLERANCE; PATIENT; TRENDS; TRAUMA; INJURY; OUTCOMES; STATES; CARE AB Purpose: To quantify interphysician variation in imaging use during emergency department (ED) visits and examine the contribution of factors to this variation at the patient, visit, and physician level. Materials and Methods: This study was HIPAA compliant and approved by the institutional review board of Partners Healthcare System (Boston, Mass), with waiver of informed consent. In this retrospective study of 88 851 consecutive ED visits during 2011 at a large urban teaching hospital, a hierarchical logistic regression model was used to identify multiple predictors for the probability that low- or high-cost imaging would be ordered during a given visit. Physician-specific random effects were estimated to articulate (by odds ratio) and quantify (by intraclass correlation coefficient [ICC]) interphysician variation. Results: Patient-and visit-level factors found to be statistically significant predictors of imaging use included measures of ED busyness, prior ED visit, referral source to the ED, and ED arrival mode. Physician-level factors (eg, sex, years since graduation, annual workload, and residency training) did not correlate with imaging use. The remaining amount of interphysician variation was very low (ICC, 0.97% for low-cost imaging; ICC, 1.07% for high-cost imaging). These physician-specific odds ratios of imaging estimates were moderately reliable at 0.78 (95% confidence interval [CI]: 0.77, 0.79) for low-cost imaging and 0.76 (95% CI: 0.74, 0.78) for high-cost imaging. Conclusion: After careful and comprehensive case-mix adjustment by using hierarchical logistic regression, only about 1% of the variability in ED imaging utilization was attributable to physicians. (C) RSNA, 2013 C1 [Wong, Hannah J.] York Univ, Sch Hlth Policy & Management, Toronto, ON M3J 2R7, Canada. [Benzer, Theodore I.; Morra, Dante J.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Halpern, Elkan F.; Gazelle, G. Scott] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Sistrom, Chris L.; Ferris, Timothy G.; Weilburg, Jeffrey B.] Massachusetts Gen Hosp, Phys Org, Boston, MA 02114 USA. [Gazelle, G. Scott] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Sistrom, CL (reprint author), Univ Florida, Dept Radiol, Ctr Hlth, 1600 Archer Rd,POB 100374, Gainesville, FL 32610 USA. EM sistrc@radiology.ufl.edu OI Wong, Hannah/0000-0002-9740-0312 FU National Decision Support Company; Ameritox; Radiological Society of North America FX H.J.W. No relevant conflicts of interest to disclose. C.L.S. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: money paid to author for consultancy from the National Decision Support Company. Other relationships: none to disclose. T.I.B. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: author is employed by the Massachusetts General Hospital as an attending physician; money paid to author for expert testimony from various legal firms. Other relationships: none to disclose. E.F.H. Financial activities related to the present article: none to disclose. Financial activities not related to the present article: money paid to author for consultancy from Hologic; money paid to author for expert testimony from Ameritox; money paid to author for travel/accommodations/meeting expenses unrelated to activities listed from Radiological Society of North America. Other relationships: none to disclose. D.J.M. No relevant conflicts of interest to disclose. G.S.G. No relevant conflicts of interest to disclose. T.G.F. No relevant conflicts of interest to disclose. J.B.W. No relevant conflicts of interest to disclose. NR 32 TC 6 Z9 6 U1 0 U2 2 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 SEP PY 2013 VL 268 IS 3 BP 779 EP 789 DI 10.1148/radiol.13130972 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 205CR UT WOS:000323419300019 PM 23801769 ER PT J AU Kulkarni, NM Uppot, RN Eisner, BH Sahani, DV AF Kulkarni, Naveen M. Uppot, Raul N. Eisner, Brian H. Sahani, Dushyant V. TI Radiation Dose Reduction at Multidetector CT Response SO RADIOLOGY LA English DT Letter C1 [Kulkarni, Naveen M.; Uppot, Raul N.; Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Eisner, Brian H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kulkarni, NM (reprint author), Massachusetts Gen Hosp, Dept Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. EM dsahani@partners.org NR 3 TC 0 Z9 0 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 SEP PY 2013 VL 268 IS 3 BP 926 EP 926 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 205CR UT WOS:000323419300039 PM 24137708 ER PT J AU Kuhlthau, K Kovacs, E Hall, T Clemmons, T Orlich, F Delahaye, J Sikora, D AF Kuhlthau, Karen Kovacs, Erica Hall, Trevor Clemmons, Traci Orlich, Felice Delahaye, Jennifer Sikora, Darryn TI Health-related quality of life for children with ASD: Associations with behavioral characteristics SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Health-related quality of life; Behavior ID AUTISM SPECTRUM DISORDERS; INTELLECTUAL DISABILITY; PSYCHOMETRIC PROPERTIES; PSYCHIATRIC-PROBLEMS; ASPERGER-SYNDROME; CONCEPTUAL-MODEL; PARENT REPORT; RATING-SCALE; ADOLESCENTS; CHECKLIST AB This paper examines health-related quality of life (HRQoL) of children age 6-11 years with an autism spectrum disorder (ASD) using the Child Health and Illness Profile - Child Edition (CHIP-CE). We further examine associations of HRQoL scores with measures of behavior using regression models. Overall HRQoL scores are lower than those for normative samples. We find that both externalizing and internalizing behaviors (measured with the Child Behavior Checklist) are correlated with HRQoL as are several of the subscales of the aberrant behavior checklist. These results suggest that some potentially modifiable aspects of ASD, in particular ASD-related and aberrant behaviors, are associated with HRQoL. These associations are suggestive of the potential for improvements in behaviors in some domains having the potential to improve HRQoL. Future studies should determine whether improvements in behaviors are associated with improvements in HRQoL. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Kuhlthau, Karen] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02114 USA. [Kuhlthau, Karen; Delahaye, Jennifer] Massachusetts Gen Hosp, Ctr Child & Adolescent Hlth Res & Policy, Boston, MA 02114 USA. [Kovacs, Erica] Columbia Univ, Med Ctr, New York, NY 10027 USA. [Orlich, Felice] Seattle Childrens Hosp, Seattle, WA USA. [Sikora, Darryn] Providence Neurodev Ctr Children Providence Hlth, Providence, RI USA. RP Kuhlthau, K (reprint author), Harvard Univ, Sch Med, Dept Pediat, 100 Cambridge St,15th Floor, Boston, MA 02114 USA. EM kkuhlthau@partners.org NR 41 TC 9 Z9 9 U1 4 U2 25 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD SEP PY 2013 VL 7 IS 9 BP 1035 EP 1042 DI 10.1016/j.rasd.2013.04.006 PG 8 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA 204IG UT WOS:000323358400004 ER PT J AU de Lacy, AM Rattner, DW Adelsdorfer, C Tasende, MM Fernandez, M Delgado, S Sylla, P Martinez-Palli, G AF de Lacy, Antonio M. Rattner, David W. Adelsdorfer, Cedric Tasende, Marta M. Fernandez, Maria Delgado, Salvadora Sylla, Patricia Martinez-Palli, Graciela TI Transanal natural orifice transluminal endoscopic surgery (NOTES) rectal resection: "down-to-up" total mesorectal excision (TME)-short-term outcomes in the first 20 cases SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article DE MANOS; Minimally invasive surgery; NOTES; Rectal cancer; Transanal ID LOW ANTERIOR RESECTION; RANDOMIZED CLINICAL-TRIAL; DOUBLE-STAPLING TECHNIQUE; ANASTOMOTIC LEAKAGE; COLON-CANCER; RISK-FACTORS; SURGICAL COMPLICATIONS; OPEN COLECTOMY; MICROSURGERY; CLASSIFICATION AB The transanal minilaparoscopy-assisted natural orifice transluminal endoscopic surgery (NOTES) approach holds significant promise as a safe and less morbid alternative to conventional low anterior rectal resection. Previous reports have shown satisfactory short-term oncologic results. We evaluated the safety and short-term outcomes in rectal cancer subjects who underwent transanal minilaparoscopy-assisted natural orifice surgery total mesorectal excision (TME) rectal resection. Twenty selected patients with rectal cancer were enrolled onto a prospective study of minilaparoscopy-assisted natural orifice surgery TME rectal resection. The study endpoints were safety of access (intra- or postoperative morbidity) and adequacy of oncological resection criteria; intact TME; distal and circumferential margins; and number of lymph nodes retrieved. All procedures were successfully completed with the transanal NOTES and minilaparoscopy technique. The mean age was 65 +/- A 10 years; 55 % of patients were male; the mean body mass index was 25.3 +/- A 3.8 kg/m(2). Thirty-five percent of tumors were in the distal rectum, 50 % in midrectum, and 15 % in proximal rectum. Coloanal anastomoses were hand sewn in 65 % and stapled in 35 %. Mean operative time was 235 +/- A 56 min. There were no procedure-related complications. Pathologic analysis demonstrated negative distal and circumferential margins in all patients. An average of 15.9 +/- A 4.3 lymph nodes were retrieved. The mesorectal fascia was intact in all the specimens. This study demonstrates that transanal NOTES with minilaparoscopic assistance in the hands of a specialized team is safe; meets the oncologic requirements for high-quality rectal cancer surgery; and may offer advantages over pure laparoscopic approaches for visualizing and dissecting out the distal mesorectum. Minilaparoscopic assistance allows one to compensate for the limitations of current NOTES instrumentation to ensure the safety and adequacy of oncologic resection in these difficult cases. Careful patient selection, a specialized team, and long-term outcome evaluation are critical before this procedure can be considered for routine clinical use. C1 [de Lacy, Antonio M.; Adelsdorfer, Cedric; Tasende, Marta M.; Fernandez, Maria; Delgado, Salvadora] Univ Barcelona, Dept Gastrointestinal Surg, Inst Digest & Metab Dis ICMDM, Hosp Clin,IDIBAPS,CIBERehd,Ctr Esther Koplowitz, Barcelona, Spain. [Rattner, David W.; Sylla, Patricia] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Martinez-Palli, Graciela] Hosp Clin Barcelona, Dept Anesthesiol, Barcelona, Spain. RP de Lacy, AM (reprint author), Univ Barcelona, Dept Gastrointestinal Surg, Inst Digest & Metab Dis ICMDM, Hosp Clin,IDIBAPS,CIBERehd,Ctr Esther Koplowitz, Barcelona, Spain. EM alacy@clinic.ub.es NR 38 TC 72 Z9 74 U1 1 U2 20 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 J9 SURG ENDOSC JI Surg. Endosc. PD SEP PY 2013 VL 27 IS 9 BP 3165 EP 3172 DI 10.1007/s00464-013-2872-0 PG 8 WC Surgery SC Surgery GA 207RN UT WOS:000323621500014 PM 23519489 ER PT J AU Sylla, P Bordeianou, LG Berger, D Han, KS Lauwers, GY Sahani, DV Sbeih, MA Lacy, AM Rattner, DW AF Sylla, Patricia Bordeianou, Liliana G. Berger, David Han, Kyung S. Lauwers, Gregory Y. Sahani, Dushyant V. Sbeih, Mohammed A. Lacy, Antonio M. Rattner, David W. TI A pilot study of natural orifice transanal endoscopic total mesorectal excision with laparoscopic assistance for rectal cancer SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article DE Transanal; TME; NOTES; Rectal cancer; Laparoscopy ID RANDOMIZED CONTROLLED-TRIAL; LOW ANTERIOR RESECTION; COLORECTAL SURGERY; RECTOSIGMOID RESECTION; NOTES SURVIVAL; OPEN COLECTOMY; PORCINE MODEL; COLON-CANCER; MICROSURGERY; OUTCOMES AB The objective of this pilot study was to evaluate the feasibility and safety of natural orifice endoscopic transanal total mesorectal excision (TME) with laparoscopic assistance in a cohort study of five patients with stage I and IIA rectal cancer. Five eligible patients with node-negative rectal cancer located 4-12 cm from the anal verge were enrolled in an IRB-approved pilot study. All patients underwent transanal endoscopic TME with laparoscopic assistance, hand-sewn coloanal anastomosis, and a diverting loop ileostomy. Primary and secondary end points included adequacy of the mesorectal excision and 30-day postoperative complications, respectively. Between November 2011 and May 2012, three males and two females underwent transanal endoscopic TME with laparoscopic assistance. Patient mean age and BMI were 48.6 +/- A 9.8 years and 25.7 +/- A 2.3 kg/m(2), respectively. Tumors were located an average of 5.7 +/- A 2.4 cm from the anal verge and preoperatively staged as T1N0M0 (2), T2N0M0 (1), and T3N0M0 (2). Mean operative time was 274.6 +/- A 85.4 min with no intraoperative complications. Partial intersphincteric resection was performed in conjunction with transanal endoscopic TME in three patients. Pathologic examination of TME specimens demonstrated complete mesorectal excision in all cases with negative proximal, distal, and radial margins. Mean length of hospital stay was 5.2 +/- A 2.6 days and three minor complications occurred, including one ileus and two cases of transient urinary dysfunction. At a mean early follow-up of 5.4 +/- A 2.3 months, all patients remain disease-free. In this pilot study of five patients with rectal cancer, transanal endoscopic TME with laparoscopic assistance is feasible and safe, and is a promising alternative to open and laparoscopic TME. Evaluation of long-term functional and oncologic outcomes of this approach is needed before widespread adoption can be recommended. C1 [Sylla, Patricia; Bordeianou, Liliana G.; Berger, David; Sbeih, Mohammed A.; Rattner, David W.] Massachusetts Gen Hosp, Div Gastrointestinal Surg, Dept Surg, Boston, MA 02114 USA. [Han, Kyung S.] Natl Canc Ctr, Ctr Colorectal Canc Res Inst & Hosp, Goyang 411769, Gyeonggi, South Korea. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sahani, Dushyant V.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Lacy, Antonio M.] Univ Barcelona, Dept Gastrointestinal Surg, Inst Digest & Metab Dis, E-08036 Barcelona, Spain. RP Sylla, P (reprint author), Massachusetts Gen Hosp, Div Gastrointestinal Surg, Dept Surg, 15 Parkman St,Wang 460, Boston, MA 02114 USA. EM psylla@partners.org FU Center for Integration of Medicine and Innovative Technology (CIMIT), DoD [W82XWH-07-02-0011] FX We acknowledge Dr. Allan Goldstein for his contribution as a medical monitor for the study. This study was funded by a Grant from the Center for Integration of Medicine and Innovative Technology (CIMIT), DoD award W82XWH-07-02-0011. This study is registered with www.clinicaltrials.gov as NCT01340755. NR 37 TC 58 Z9 64 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 J9 SURG ENDOSC JI Surg. Endosc. PD SEP PY 2013 VL 27 IS 9 BP 3396 EP 3405 DI 10.1007/s00464-013-2922-7 PG 10 WC Surgery SC Surgery GA 207RN UT WOS:000323621500041 PM 23572214 ER PT J AU McLemore, EC Coker, AM Devaraj, B Chakedis, J Maawy, A Inui, T Talamini, MA Horgan, S Peterson, MR Sylla, P Ramamoorthy, S AF McLemore, Elisabeth C. Coker, Alisa M. Devaraj, Bikash Chakedis, Jeffrey Maawy, Ali Inui, Tazo Talamini, Mark A. Horgan, Santiago Peterson, Michael R. Sylla, Patricia Ramamoorthy, Sonia TI TAMIS-assisted laparoscopic low anterior resection with total mesorectal excision in a cadaveric series SO SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES LA English DT Article DE Colorectal cancer; Endoscopy; Gastrointestinal cancer; Surgical ID TRANSANAL ENDOSCOPIC MICROSURGERY; RECTAL-CANCER; SPHINCTER PRESERVATION; SURGERY; MODEL; PROCTECTOMY; EXPERIENCE; ACCESS; SWINE AB To demonstrate the feasibility of an innovative technique for the surgical management of rectal cancer, we performed transanal minimally invasive surgery assisted low anterior resection with total mesorectal excision (TAMIS-assisted LAR with TME) in a cadaver model. Transanal LAR via natural orifice transluminal endoscopic surgery has been reported in cadaveric series using rigid transanal platforms. This procedure has not been described using a combination of a single incision laparoscopy and TAMIS transanal endoscopic platform. We describe the first cadaveric series of TAMIS-assisted LAR with TME. TAMIS-assisted LAR with TME was successfully performed in five fresh human cadavers. The procedure was performed using the mini-Gelpoint single incision platform and the Gelpoint Path TAMIS platform (Applied Medical, Rancho Santa Margarita, CA). The variables recorded were age, body mass index (BMI), operative time, complications, and specimen length. The grade of the TME was determined by evaluation of the specimen by photo documentation by a gastrointestinal pathologist. All cadavers were male with a mean age of 71 +/- A 8 years and mean BMI of 28 +/- A 3 kg/m(2). The mean operative time was 200 +/- A 55 min (range 128-249 min). The quality of the TME was grade I (complete) with intact mesorectum in all five cases. The mean specimen length was 36.8 +/- A 3.4 cm. TAMIS-assisted LAR with TME was feasible. A high-quality TME can be achieved using this innovative technique. Transanal endoscopic total mesorectal dissection may revolutionize the surgical management of rectal cancer. However, multicenter clinical trials are needed to further evaluate the oncologic safety and surgical outcomes of transanal endoscopic TME using various platforms before widespread application of this new technique. C1 [McLemore, Elisabeth C.; Coker, Alisa M.; Devaraj, Bikash; Chakedis, Jeffrey; Maawy, Ali; Inui, Tazo; Talamini, Mark A.; Horgan, Santiago; Ramamoorthy, Sonia] Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA. [McLemore, Elisabeth C.] Univ Calif San Diego, Med Ctr, Moores Canc Ctr, San Diego, CA 92103 USA. [Peterson, Michael R.] Univ Calif San Diego, Dept Pathol, San Diego, CA 92103 USA. [Sylla, Patricia] Massachusetts Gen Hosp, Dept Surg, Div Gastrointestinal Surg, Boston, MA 02114 USA. RP McLemore, EC (reprint author), Univ Calif San Diego, Med Ctr, Moores Canc Ctr, 3855 Hlth Sci Dr 0987, San Diego, CA 92103 USA. EM emclemore@ucsd.edu FU University of California San Diego Moores Cancer Center; Ethicon Endosurgery and Olympus FX This research was funded by Applied Medical and The University of California San Diego Moores Cancer Center. Educational grants from Ethicon Endosurgery and Olympus provide additional funding to support research, education and training conducted at the UC San Diego Center for the Future of Surgery. NR 29 TC 18 Z9 22 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0930-2794 J9 SURG ENDOSC JI Surg. Endosc. PD SEP PY 2013 VL 27 IS 9 BP 3478 EP 3484 DI 10.1007/s00464-013-2889-4 PG 7 WC Surgery SC Surgery GA 207RN UT WOS:000323621500053 PM 23494511 ER PT J AU Yeh, DD Imam, AM Truong, SH McLaughlin, EL Klein, EN Avery, LL Velmahos, GC AF Yeh, D. Dante Imam, Ayesha M. Truong, Shani H. McLaughlin, Erin L. Klein, Eric N. Avery, Laura L. Velmahos, George C. TI Incidental Findings in Trauma Patients: Dedicated Communication with the Primary Care Physician Ensures Adequate Follow-Up SO WORLD JOURNAL OF SURGERY LA English DT Article ID CT; PREVALENCE AB Frequent use of computed tomography (CT) in trauma patients results in frequent detection of non-trauma-related incidental findings (IFs). Inpatient documentation and disclosure at discharge are infrequent, even when they are potentially serious. We aimed to not only identify the incidence of IFs but also to evaluate the effectiveness of an intervention to trigger follow-up. In this before-after study, all trauma patients evaluated by the trauma surgery service who underwent CT were admitted for > 24 h, had at least one IF requiring follow-up, and had a primary care physician (PCP) employed in our health care system were identified. The historical control period was from January 2006 to December 2008. The intervention period was from December 2011 to September 2012. Intervention consisted of notifying the PCP via email or postal letter. The outcome of interest-the rate of follow-up-was compared between both groups. During the historical period, 364 (20.5 %) of 1,774 eligible trauma patients had 434 IFs requiring follow-up. During the study period, 197 (26 %) of 692 trauma patients had 212 IFs requiring follow-up. Overall, 91 % of study patients with postdischarge PCP follow-up had documented follow-up of the IF. There was a significant improvement in the rate of follow-up in the study group compared to that of the control group (51 vs. 11 %; p < 0.0001). Detection of IFs is common in trauma patients. A dedicated effort of communicating the presence of an IF to the patient's PCP triggered a follow-up for 91 % of patients who saw their PCP after hospital discharge. C1 [Yeh, D. Dante; Imam, Ayesha M.; Truong, Shani H.; McLaughlin, Erin L.; Klein, Eric N.; Velmahos, George C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Avery, Laura L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Yeh, DD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM dyeh2@partners.org NR 9 TC 4 Z9 4 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD SEP PY 2013 VL 37 IS 9 BP 2081 EP 2085 DI 10.1007/s00268-013-2092-8 PG 5 WC Surgery SC Surgery GA 204MM UT WOS:000323369400009 PM 23703640 ER PT J AU Oursler, KK Tate, JP Gill, TM Crothers, K Brown, TT Crystal, S Womack, J Leaf, DA Sorkin, JD Justice, AC AF Oursler, Krisann K. Tate, Janet P. Gill, Thomas M. Crothers, Kristina Brown, Todd T. Crystal, Stephen Womack, Julie Leaf, David A. Sorkin, John D. Justice, Amy C. TI Association of the Veterans Aging Cohort Study Index with Exercise Capacity in HIV-Infected Adults SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ADVANCED HEART-FAILURE; 6-MINUTE WALK TEST; PEAK OXYGEN-UPTAKE; ANTIRETROVIRAL THERAPY; FUNCTIONAL STATUS; PHYSICAL FUNCTION; AEROBIC CAPACITY; SKELETAL-MUSCLE; MORTALITY AB Physical disability is a major priority in aging, affecting morbidity, mortality, and quality of life. Despite the large number of adults aging with HIV, our understanding of the physiologic and clinical risk factors for disability is limited. Our goal is to determine whether the Veterans Aging Cohort Study (VACS) Index, based on routine clinical blood tests, could serve as a point of care screening tool to identify HIV-infected adults at high risk for physical disability. HIV-infected adults enrolled in the VACS participated in a cross-sectional exercise study with established measures of strength and endurance. The VACS Index was calculated using recent clinical laboratory values and age; a higher score reflects greater mortality risk. Statistical analyses included correlation and linear regression models adjusted for muscle mass. Fifty-five HIV-infected adults, predominantly African-American men, were included with age mean +/- SD of 52 +/- 7 years. Median (IQR) CD4 cell count was 356 cells/mm(3) (212-527). The VACS Index was inversely correlated with quadriceps strength (r = -0.45, p < 0.01), grip strength (r = -0.28, p = 0.04), and 6-min walk distance (r = -0.27, p = 0.05). A 20-point increase in VACS Index score was associated with a 10% lower leg strength (p < 0.01), which remained significant after adjustment for muscle cross-sectional area (p = 0.02). The VACS Index explained 31% of the variance in specific leg strength. In this group of middle-aged adults with well-controlled HIV infection the VACS Index was significantly associated with upper and lower extremity strength. The VACS Index may be valuable for identification of patients at high risk for disability due to muscle weakness. C1 [Oursler, Krisann K.; Sorkin, John D.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Oursler, Krisann K.; Sorkin, John D.] Baltimore VA Med Ctr, Geriatr Res Educ & Clin Ctr, Baltimore, MD 21201 USA. [Tate, Janet P.; Justice, Amy C.] Yale Univ, Sch Med & Publ Hlth, New Haven, CT USA. [Tate, Janet P.; Justice, Amy C.] VA Connecticut Healthcare Syst, New Haven, CT USA. [Gill, Thomas M.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Crothers, Kristina] Univ Washington, Seattle, WA 98195 USA. [Brown, Todd T.] Johns Hopkins Sch Med, Baltimore, MD USA. [Crystal, Stephen] Rutgers State Univ, Ctr Hlth Serv Res Pharmacotherapy Chron Dis Manag, Inst Hlth, New Brunswick, NJ 08903 USA. [Womack, Julie] Yale Univ, Sch Nursing, New Haven, CT 06536 USA. [Leaf, David A.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Leaf, David A.] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. RP Oursler, KK (reprint author), Baltimore VA Med Ctr, BT GRECC 18, 10 North Greene St, Baltimore, MD 21201 USA. EM koursler@grecc.umaryland.edu OI Crothers, Kristina/0000-0001-9702-0371 FU National Institute on Aging (NIA) [K23 AG024896]; NIA University of Maryland Claude D. Pepper Older Americans Independence Center [P60-AG12583]; Baltimore VA Geriatric Research, Clinical and Education Center; NIA [K24AG021507, P30AG021342]; NHLBI [R01 HL090342]; NINR [K01 NR013437]; CTSA NCRR [UL1 RR024139]; NIAAA [U10-AA13566, U24-AA020794]; U.S. Department of Veterans Affairs FX Disclosure of Funding: National Institute on Aging (NIA) K23 AG024896 (Dr. Oursler), NIA University of Maryland Claude D. Pepper Older Americans Independence Center P60-AG12583 (Drs. Oursler and Sorkin), Baltimore VA Geriatric Research, Clinical and Education Center (Drs. Oursler and Sorkin), NIA K24AG021507 and P30AG021342 (Dr. Gill), NHLBI R01 HL090342 (Dr. Crothers), NINR K01 NR013437 and CTSA NCRR UL1 RR024139 (Dr. Womack), and NIAAA U10-AA13566 and U24-AA020794 and in kind by the U.S. Department of Veterans Affairs (Dr. Justice). NR 44 TC 10 Z9 10 U1 0 U2 1 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD SEP PY 2013 VL 29 IS 9 BP 1218 EP 1223 DI 10.1089/aid.2012.0388 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 204NL UT WOS:000323372600007 PM 23705911 ER PT J AU Berger, D Williams, EC Bryson, CL Rubinsky, AD Bradley, KA AF Berger, Douglas Williams, Emily C. Bryson, Chris L. Rubinsky, Anna D. Bradley, Katharine A. TI Alcohol questionnaires and HDL: Screening scores as scaled markers of alcohol consumption SO ALCOHOL LA English DT Article DE HDL cholesterol; Alcohol; Alcohol screening questionnaire ID PRIMARY-CARE PATIENTS; IDENTIFICATION TEST AUDIT; USE DISORDERS; PROBLEM DRINKING; RISK-FACTORS; HEALTH; DEPRESSION; VALIDATION; DEPENDENCE; SEVERITY AB Improving the quality of alcohol-related care requires practical approaches to assessing alcohol consumption to guide management and monitor outcomes. Given the increasing use of alcohol screening questionnaires to identify alcohol misuse it would be ideal if scores on screening questionnaires were also indicators of average alcohol consumption. However, the questionnaires were not designed for this purpose and include dimensions of drinking that may not reflect average consumption (e.g. heavy episodic drinking, alcohol-related problems). In a general population sample, scores on the AUDIT-C screen correlated with reports of alcohol consumption in detailed interviews, but the relationship is unknown for clinical populations and other questionnaires. Serum high-density lipoprotein cholesterol (HDL) is a biomarker routinely obtained in clinical care and is known to rise with average alcohol consumption. This cross-sectional study of 11,175 male U.S. Veterans Affairs patients enrolled in a primary care study used HDL as an objective biomarker to evaluate whether average alcohol consumption increased as scores increased on 3 brief alcohol screens - the AUDIT-C, AUDIT Question #3 (a single-item screen), and the CAGE questionnaire. Mean HDL progressively increased as screening scores increased for the AUDIT-C and AUDIT Question #3: about 12 mg/dL from the lowest to the highest scores. The association was much weaker for the CAGE questionnaire. Results were minimally affected by adjustment for covariates (e.g. age, race, medical comorbidity, smoking, medication count, and depression) but the association was modified (p = 0.008) and mildly attenuated by adherent use of lipid-lowering medications. This study using HDL as a biomarker of average alcohol consumption adds to evidence that some alcohol screening scores may also serve as scaled markers of average alcohol consumption. Published by Elsevier Inc. C1 [Berger, Douglas; Bryson, Chris L.] Dept Vet Affairs VA Puget Sound Hlth Care Syst, Gen Med Serv, Seattle, WA USA. [Berger, Douglas; Bryson, Chris L.; Bradley, Katharine A.] Univ Washington, Dept Med, Seattle, WA USA. [Williams, Emily C.; Bryson, Chris L.; Rubinsky, Anna D.; Bradley, Katharine A.] Dept Vet Affairs VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Northwest Ctr Excellence, Seattle, WA USA. [Williams, Emily C.; Bradley, Katharine A.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Rubinsky, Anna D.; Bradley, Katharine A.] Vet Affairs VA Puget Sound Hlth Care Syst, Ctr Excellence Substance Abuse Treatment & Educ, Seattle, WA USA. [Bradley, Katharine A.] Grp Hlth Res Inst, Seattle, WA USA. RP Berger, D (reprint author), VA Puget Sound, Gen Internal Med Sect, 1660 S Columbian Way,S-123 PCC, Seattle, WA 98108 USA. EM douglas.berger@va.gov FU VA HSRD IAC [05-206] FX This project was funded by VA HSR&D IAC Grant 05-206. The funding organization had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. NR 45 TC 4 Z9 4 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 J9 ALCOHOL JI Alcohol PD SEP PY 2013 VL 47 IS 6 BP 439 EP 445 DI 10.1016/j.alcohol.2013.07.001 PG 7 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 204IY UT WOS:000323360200003 PM 23886863 ER PT J AU Yabroff, KR Short, PF Machlin, S Dowling, E Rozjabek, H Li, CY McNeel, T Ekwueme, DU Virgo, KS AF Yabroff, K. Robin Short, Pamela F. Machlin, Steven Dowling, Emily Rozjabek, Heather Li, Chunyu McNeel, Timothy Ekwueme, Donatus U. Virgo, Katherine S. TI Access to Preventive Health Care for Cancer Survivors SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID 2ND PRIMARY CANCERS; UNITED-STATES; MEDICAL-CARE; BREAST; MAINTENANCE AB Background: Access to health care, particularly effective primary and secondary preventive care, is critical for cancer survivors, in order to minimize the adverse sequelae of cancer and its treatment. Purpose: The goal of the study was to evaluate the association between cancer survivorship and access to primary and preventive health care. Methods: Cancer survivors (n=4960) and individuals without a cancer history (n=64,431) aged >= 18 years, from the 2008-2010 Medical Expenditure Panel Survey (MEPS), were evaluated. Multiple measures of access and preventive services use were compared. The association between cancer survivorship and access and preventive services was evaluated with multivariate logistic regression models, stratified by age group (18-64 years and >= 65 years), controlling for the effects of age, gender, race/ethnicity, education, marital status, and comorbidities. Data were analyzed in 2013. Results: Cancer survivors aged >= 65 years had equivalent or greater access and preventive services use than individuals without a cancer history, in adjusted analyses. However, among those aged 18-64 years with private health insurance, cancer survivors were more likely than other individuals to have a usual source of care and to use preventive services, whereas uninsured or publicly insured cancer survivors were generally less likely to have a usual source of care and to use preventive services than were uninsured or publicly insured adults without a cancer history. Conclusions: Although access and preventive care use in cancer survivors is generally equivalent or greater compared to that of other individuals, disparities for uninsured and publicly insured cancer survivors aged 18-64 years suggest that improvements in survivor care are needed. Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Yabroff, K. Robin; Rozjabek, Heather] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Machlin, Steven] Agcy Healthcare Res & Qual, Ctr Financing Access & Cost Trends, Rockville, MD USA. [McNeel, Timothy] Informat Management Serv Inc, Calverton, MD USA. [Short, Pamela F.] Penn State Univ, Ctr Hlth Care & Policy Res, University Pk, PA 16802 USA. [Dowling, Emily] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Li, Chunyu; Ekwueme, Donatus U.] CDC, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Virgo, Katherine S.] Intramural Res Dept, Hlth Serv Res Program, Amer Canc Soc, Natl Home Off, Atlanta, GA USA. RP Yabroff, KR (reprint author), NCI, Hlth Serv & Econ Branch, 9609 Med Ctr Dr,3E436, Rockville, MD 20850 USA. EM yabroffr@mail.nih.gov NR 28 TC 10 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2013 VL 45 IS 3 BP 304 EP 312 DI 10.1016/j.amepre.2013.04.021 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 202CU UT WOS:000323191900008 ER PT J AU LaRowe, SD Kalivas, PW Nicholas, JS Randall, PK Mardikian, PN Malcolm, RJ AF LaRowe, Steven D. Kalivas, Peter W. Nicholas, Joyce S. Randall, Patrick K. Mardikian, Pascale N. Malcolm, Robert. J. TI A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID NUCLEUS-ACCUMBENS; RECEPTOR AGONIST; SEEKING BEHAVIOR; RELAPSE; REINSTATEMENT; INDIVIDUALS; VALIDITY; LY379268 AB Background: There remains no FDA approved medication for the treatment of cocaine dependence. Preclinical studies and early pilot clinical investigations have suggested that N-acetylcysteine (NAC) may be useful in the treatment of the disorder. Objective: The present report assessed the efficacy of NAC in the treatment of cocaine dependence. Methods: Cocaine-dependent volunteers (n = 111) were randomized to receive daily doses of 1,200 mg of NAC, 2,400 mg of NAC, or placebo. Participants were followed for 8 weeks (up to three visits weekly). At each of these visits, urine samples were collected, along with self-reports of cocaine use. Urine samples were assessed for quantitative levels of benzoylecognine (ie, cocaine metabolite). Results: Overall, the primary results for the clinical trial were negative. However, when considering only subjects who entered the trial having already achieved abstinence, results favored the 2,400 mg NAC group relative to placebo, with the 2,400 mg group having longer times to relapse and lower craving ratings. Conclusion: While the present trial failed to demonstrate that NAC reduces cocaine use in cocaine-dependent individuals actively using, there was some evidence it prevented return to cocaine use in individuals who had already achieved abstinence from cocaine. Scientific Significance: N-acetylcysteine may be useful as a relapse prevention agent in abstinent cocaine-dependent individuals. C1 [LaRowe, Steven D.] Ralph H Johnson VAMC, Charleston, SC USA. [LaRowe, Steven D.; Randall, Patrick K.; Mardikian, Pascale N.; Malcolm, Robert. J.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Kalivas, Peter W.; Nicholas, Joyce S.] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Nicholas, Joyce S.] Med Univ S Carolina, Dept Med, Div Biostat & Epidemiol, Charleston, SC 29425 USA. RP LaRowe, SD (reprint author), Med Univ S Carolina, Dept Psychiat, Ctr Drug & Alcohol Programs, Charleston, SC 29425 USA. EM larowe@musc.edu FU NIDA NIH HHS [DA0199903, P50 DA015369, R01 DA003906, R01 DA012513] NR 32 TC 30 Z9 32 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SEP PY 2013 VL 22 IS 5 BP 443 EP 452 DI 10.1111/j.1521-0391.2013.12034.x PG 10 WC Substance Abuse SC Substance Abuse GA 202DV UT WOS:000323194600004 PM 23952889 ER PT J AU Nocente, R Vitali, M Balducci, G Enea, D Kranzler, HR Ceccanti, M AF Nocente, Roberto Vitali, Mario Balducci, Giuseppe Enea, Domenico Kranzler, Henry R. Ceccanti, Mauro TI Varenicline and neuronal nicotinic acetylcholine receptors: A new approach to the treatment of co-occurring alcohol and nicotine addiction? SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID SHORT-SLEEP MICE; PARTIAL AGONIST VARENICLINE; RANDOMIZED CONTROLLED-TRIAL; ETHANOL-INDUCED DEFICITS; SMOKING-CESSATION; CROSS-TOLERANCE; DRUG-DEPENDENCE; LONG-SLEEP; TOBACCO DEPENDENCE; INDUCED REDUCTION AB Background and Objectives: Alcohol and nicotine dependence are serious public health problems worldwide. They are associated with substantial morbidity and mortality, as well as adverse social effects and increased healthcare costs. Although efficacious treatments are available for these disorders, additional therapeutic options are required to ensure greater treatment utilization. In this paper, we describe the empirical basis on which varenicline, a nicotinic partial agonist approved for smoking cessation, may also have utility in the treatment of alcohol addiction. Methods: We sought to identify papers examining nicotine dependence, alcohol dependence, smoking, alcohol, and varenicline for possible inclusion in the present review. We identified over 600 papers through Pubmed/Medline, PsychINFO, and Google Scholar. We found 12 papers taking into consideration the following criteria: original language English, varenicline effect on alcohol consumption. Results: Animal studies have shown that varenicline reduces alcohol consumption. Two recent studies showed that varenicline also reduces alcohol consumption in humans. Both nicotine and alcohol interact with alpha 4 beta 2 and alpha 3 beta 4 nicotinic acetylcholine (ACh) receptors located in the ventral tegmental area of the brain, inducing dopamine (DA) release at the nucleus accumbens. Varenicline binds to nicotinic ACh receptors, where it has partial agonist effects, producing a moderate and constant level of DA release both in the mesolimbic pathway and in the prefrontal cortex. Conclusions and Scientific Significance: Through these effects, varenicline may reduce alcohol craving, seeking, and consumption, in addition to promoting smoking cessation. Additional studies are needed to confirm the efficacy of varenicline in the treatment of alcohol dependence. C1 [Nocente, Roberto; Vitali, Mario; Balducci, Giuseppe; Enea, Domenico; Ceccanti, Mauro] Univ Roma La Sapienza, Dept Clin Med, I-00100 Rome, Italy. [Vitali, Mario] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Kranzler, Henry R.] Univ Penn, Dept Psychiat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Kranzler, Henry R.] Philadelphia VAMCPhiladelphia, MIRECC VISN4, Philadelphia, PA USA. RP Ceccanti, M (reprint author), Univ Roma La Sapienza, Dept Clin Med, Viale Univ 37, I-00100 Rome, Italy. EM mauro.ceccanti@uniroma1.it OI CECCANTI, Mauro/0000-0001-9981-8715 NR 74 TC 13 Z9 14 U1 0 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SEP PY 2013 VL 22 IS 5 BP 453 EP 459 DI 10.1111/j.1521-0391.2013.12037.x PG 7 WC Substance Abuse SC Substance Abuse GA 202DV UT WOS:000323194600005 PM 23952890 ER PT J AU Yule, AM Wilens, TE Martelon, MK Simon, A Biederman, J AF Yule, Amy M. Wilens, Timothy E. Martelon, Mary Kate Simon, Andrew Biederman, Joseph TI Does exposure to parental substance use disorders increase substance use disorder risk in offspring? A 5-year follow-up study SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID DRUG-USE; PREVENTION PROGRAMS; GENDER-DIFFERENCES; ALCOHOL; ADOLESCENTS; ABUSE; DEPENDENCE; CHILDREN; DRINKING; GIRLS AB Background: This study examined the impact of exposure to parental substance use disorders (SUD) (alcohol or drug abuse or dependence) on the development of SUD in offspring. Methods: The original sample was derived from pediatric and psychiatric ascertained females 6-17 years old with (N = 140) and without Attention Deficit Hyperactivity Disorder (ADHD; N = 122). At baseline, these groups had 143 and 131 biological siblings and 274 and 238 parents, respectively. All subjects and their family members were comprehensively and blindly assessed by structured psychiatric interviews for psychopathology and substance use. The female probands and their siblings were reassessed after a follow-up period of 5 years. Results: At follow-up the mean age of offspring was 17.9 +/- 4.20 years. Independently of ADHD, familial risk, and socioeconomic status, exposure to maternal drug use disorders, but not paternal drug use disorders, was significantly associated with the development of a drug use disorder in offspring (OR: 7.04; p = 0.03). There was a significant association between exposure to parental SUD during adolescence (relative to preschool or latency years) and SUD in offspring (OR: 3.61; p = 0.03). Conclusions: Exposure to maternal drug use disorders during adolescent years increased the risk for the development of a drug use disorder in a sample of females with and without ADHD and their siblings. Exposure to parental SUD during adolescence specifically increases the risk of SUD development in offspring. C1 [Yule, Amy M.; Wilens, Timothy E.; Martelon, Mary Kate; Simon, Andrew; Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, 55 Parkman St,YAW 6A, Boston, MA 02114 USA. EM twilens@partners.org NR 36 TC 11 Z9 12 U1 2 U2 26 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SEP PY 2013 VL 22 IS 5 BP 460 EP 465 DI 10.1111/j.1521-0391.2013.12048.x PG 6 WC Substance Abuse SC Substance Abuse GA 202DV UT WOS:000323194600006 PM 23952891 ER PT J AU Suzuki, J Meyer, F Wasan, AD AF Suzuki, Joji Meyer, Fremonta Wasan, Ajay D. TI Characteristics of medical inpatients with acute pain and suspected non-medical use of opioids SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID CHRONIC NONCANCER PAIN; SUBSTANCE MISUSE; VALIDATION; MANAGEMENT; RISK; HOSPITALIZATION; PHYSICIANS; ADDICTION; THERAPY; SOCIETY AB Objective: The purpose of this study was to characterize medical inpatients with acute pain suspected of non-medical opioid use. Method: Medical inpatients treated with opioids for acute pain referred for psychiatric consultation were administered questionnaires including the Screener and Opioid Assessment for Pain Patients (SOAPP) and the Hospital Misuse Checklist (HMC), developed for this study. Results: The nine subjects referred for evaluation of possible non-medical opioid use, compared to the 23 subjects referred for other reasons, were younger (37.7 vs. 51.3, t = 2.81, p = .012), more likely to score positive on the SOAPP (100% vs. 47.8%, Fisher's p < .05) and report lifetime histories of any substance use disorder (SUD) (88.9% vs. 30.4%, chi(2) = 9.7, p = .002). No differences were found on items on the HMC. Conclusions: The results of this preliminary study indicate that medical inpatients with suspected non-medical use of opioids resemble chronic pain outpatients misusing opioids. Further research is needed to better characterize this patient population and to validate the HMC measure. C1 [Suzuki, Joji; Meyer, Fremonta; Wasan, Ajay D.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Suzuki, Joji; Meyer, Fremonta; Wasan, Ajay D.] Harvard Univ, Sch Med, Boston, MA USA. [Meyer, Fremonta] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. [Wasan, Ajay D.] Brigham & Womens Hosp, Dept Anesthesia Perioperat & Pain Med, Boston, MA 02115 USA. RP Suzuki, J (reprint author), Brigham & Womens Hosp, Dept Psychiat, 75 Francis St, Boston, MA 02115 USA. EM jsuzuki2@partners.org NR 24 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SEP PY 2013 VL 22 IS 5 BP 515 EP 520 DI 10.1111/j.1521-0391.2013.12016.x PG 6 WC Substance Abuse SC Substance Abuse GA 202DV UT WOS:000323194600015 PM 23952900 ER PT J AU Xie, ZC AF Xie, Zhongcong TI Cancer Prognosis: Can Anesthesia Play a Role? SO ANESTHESIOLOGY LA English DT Editorial Material ID RETROSPECTIVE ANALYSIS; INDUCED APOPTOSIS; ISOFLURANE; SURGERY; RECURRENCE; INCREASES; BREAST; BRAIN C1 [Xie, Zhongcong] Massachusetts Gen Hosp, Geriatr Anesthesia Res Unit, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. [Xie, Zhongcong] Harvard Univ, Sch Med, Charlestown, MA USA. RP Xie, ZC (reprint author), Massachusetts Gen Hosp, Geriatr Anesthesia Res Unit, Dept Anesthesia Crit Care & Pain Med, Charlestown, MA USA. EM zxie@partners.org FU National Institutes of Health, Bethesda, Maryland [R21AG038994, R01GM088801, R01 AG041274]; Alzheimer's Association, Chicago, Illinois; Cure Alzheimer's Fund, Wellesley, Massachusetts FX This research was supported by R21AG038994, R01GM088801, and R01 AG041274 from National Institutes of Health, Bethesda, Maryland, Investigator-initiated Research grant from Alzheimer's Association, Chicago, Illinois, and Cure Alzheimer's Fund, Wellesley, Massachusetts (to Dr. Xie). The authors are not supported by, nor maintain any financial interest in, any commercial activity that may be associated with the topic of this article. NR 17 TC 3 Z9 3 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD SEP PY 2013 VL 119 IS 3 BP 501 EP 503 DI 10.1097/ALN.0b013e31829e4819 PG 3 WC Anesthesiology SC Anesthesiology GA 205CX UT WOS:000323420000008 PM 23756456 ER PT J AU Kharasch, ED Rosow, CE AF Kharasch, Evan D. Rosow, Carl E. TI Assessing the Utility of the Utility Function SO ANESTHESIOLOGY LA English DT Editorial Material ID MODEL; PHARMACODYNAMICS; PHARMACOKINETICS C1 [Kharasch, Evan D.] Washington Univ, Dept Anesthesiol, Div Clin & Translat Res, St Louis, MO 63130 USA. [Kharasch, Evan D.] Washington Univ, Div Clin & Translat Res, Dept Biochem & Mol Biophys, St Louis, MO USA. [Rosow, Carl E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. RP Kharasch, ED (reprint author), Washington Univ, Dept Anesthesiol, Div Clin & Translat Res, St Louis, MO 63130 USA. EM kharasch@wustl.edu FU National Institutes of Health (Bethesda, Maryland) [R01-DA14211, R01-DA02931] FX Funding was provided by the National Institutes of Health (Bethesda, Maryland) Grants R01-DA14211 and R01-DA02931 (to Dr. Kharasch). The authors declare no competing interests. NR 14 TC 1 Z9 1 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD SEP PY 2013 VL 119 IS 3 BP 504 EP 506 DI 10.1097/ALN.0b013e31829ce70b PG 3 WC Anesthesiology SC Anesthesiology GA 205CX UT WOS:000323420000009 PM 23770599 ER PT J AU Wanderer, JP Anderson-Dam, J Levine, W Bittner, EA AF Wanderer, Jonathan P. Anderson-Dam, John Levine, Wilton Bittner, Edward A. TI Development and Validation of an Intraoperative Predictive Model for Unplanned Postoperative Intensive Care SO ANESTHESIOLOGY LA English DT Article ID INDIVIDUALIZING RISK; UNIT ADMISSION; SYSTEM; TRANSFUSION; MORTALITY; NOMOGRAM; REMINDER; OUTCOMES; SURGERY; IMPACT AB Background: The allocation of intensive care unit (ICU) beds for postoperative patients is a challenging daily task that could be assisted by the real-time detection of ICU needs. The goal of this study was to develop and validate an intraoperative predictive model for unplanned postoperative ICU use. Methods: With the use of anesthesia information management system, postanesthesia care unit, and scheduling data, a data set was derived from adult in-patient noncardiac surgeries. Unplanned ICU admissions were identified (4,847 of 71,996; 6.7%), and a logistic regression model was developed for predicting unplanned ICU admission. The model performance was tested using bootstrap validation and compared with the Surgical Apgar Score using area under the curve for the receiver operating characteristic. Results: The logistic regression model included 16 variables: age, American Society of Anesthesiologists physical status, emergency case, surgical service, and 12 intraoperative variables. The area under the curve was 0.905 (95% CI, 0.900-0.909). The bootstrap validation model area under the curves were 0.513 at booking, 0.688 at 3h before case end, 0.738 at 2h, 0.791 at 1h, and 0.809 at case end. The Surgical Apgar Score area under the curve was 0.692. Unplanned ICU admissions had more ICU-free days than planned ICU admissions (5 vs. 4; P < 0.001) and similar mortality (5.6 vs. 6.0%; P = 0.248). Conclusions: The authors have developed and internally validated an intraoperative predictive model for unplanned postoperative ICU use. Incorporation of this model into a real-time data sniffer may improve the process of allocating ICU beds for postoperative patients. C1 [Wanderer, Jonathan P.; Anderson-Dam, John; Levine, Wilton; Bittner, Edward A.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Wanderer, JP (reprint author), Vanderbilt Univ, Dept Anesthesiol, Vanderbilt Clin, 1301 Med Ctr Dr,Suite 4648, Nashville, TN 37212 USA. EM jonathan.wanderer@vanderbilt.edu NR 21 TC 8 Z9 8 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD SEP PY 2013 VL 119 IS 3 BP 516 EP 524 DI 10.1097/ALN.0b013e31829ce8fd PG 9 WC Anesthesiology SC Anesthesiology GA 205CX UT WOS:000323420000011 PM 23756454 ER PT J AU Sigakis, MJG Bittner, EA Wanderer, JP AF Sigakis, Matthew J. G. Bittner, Edward A. Wanderer, Jonathan P. TI Validation of a Risk Stratification Index and Risk Quantification Index for Predicting Patient Outcomes: In-hospital Mortality, 30-day Mortality, 1-year Mortality, and Length-of-stay SO ANESTHESIOLOGY LA English DT Article ID CLINICAL COMORBIDITY INDEX; CARDIAC RISK; ADMINISTRATIVE DATA; ACCURACY; MORBIDITY; SYSTEM; CARE AB Background: External validation of published risk stratification models is essential to determine their generalizability. This study evaluates the performance of the Risk Stratification Indices (RSIs) and 30-day mortality Risk Quantification Index (RQI). Methods: 108,423 adult hospital admissions with anesthetics were identified (2006-2011). RSIs for mortality and length-of-stay endpoints were calculated using published methodology. 91,128 adult, noncardiac inpatient surgeries were identified with administrative data required for RQI calculation. Results: RSI in-hospital mortality and RQI 30-day mortality Brier scores were 0.308 and 0.017, respectively. RSI discrimination, by area under the receiver operating curves, was excellent at 0.966 (95% CI, 0.963-0.970) for in-hospital mortality, 0.903 (0.896-0.909) for 30-day mortality, 0.866 (0.861-0.870) for 1-yr mortality, and 0.884 (0.882-0.886) for length-of-stay. RSI calibration, however, was poor overall (17% predicted in-hospital mortality vs. 1.5% observed after inclusion of the regression constant) as demonstrated by calibration plots. Removal of self-fulfilling diagnosis and procedure codes (20,001 of 108,423; 20%) yielded similar results. RQIs were calculated for only 62,640 of 91,128 patients (68.7%) due to unmatched procedure codes. Patients with unmatched codes were younger, had higher American Society of Anesthesiologists physical status and 30-day mortality. The area under the receiver operating curve for 30-day mortality RQI was 0.888 (0.879-0.897). The model also demonstrated good calibration. Performance of a restricted index, Procedure Severity Score + American Society of Anesthesiologists physical status, performed as well as the original RQI model (age + American Society of Anesthesiologists + Procedure Severity Score). Conclusion: Although the RSIs demonstrated excellent discrimination, poor calibration limits their generalizability. The 30-day mortality RQI performed well with age providing a limited contribution. C1 [Sigakis, Matthew J. G.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. Vanderbilt Univ, Dept Anesthesia, Nashville, TN 37235 USA. RP Sigakis, MJG (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Gray Bigelow 444,55 Fruit St, Boston, MA 02114 USA. EM msigakis@partners.org NR 39 TC 11 Z9 11 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD SEP PY 2013 VL 119 IS 3 BP 525 EP 540 DI 10.1097/ALN.0b013e31829ce6e6 PG 16 WC Anesthesiology SC Anesthesiology GA 205CX UT WOS:000323420000012 PM 23770598 ER PT J AU Leffert, LR Schwamm, LH AF Leffert, Lisa R. Schwamm, Lee H. TI Neuraxial Anesthesia in Parturients with Intracranial Pathology: A Comprehensive Review and Reassessment of Risk SO ANESTHESIOLOGY LA English DT Review ID CHIARI-I MALFORMATION; VENOUS SINUS THROMBOSIS; LUMBAR EPIDURAL ANALGESIA; CESAREAN-SECTION; MOYAMOYA-DISEASE; SPINAL-ANESTHESIA; ARTERIOVENOUS-MALFORMATIONS; LUMBOPERITONEAL SHUNT; OBSTETRIC ANESTHESIA; DURAL PUNCTURE AB Parturients with intracranial lesions are often assumed to have increased intracranial pressure, even in the absence of clinical and radiographic signs. The risk of herniation after an inadvertent dural puncture is frequently cited as a contraindication to neuraxial anesthesia. This article reviews the relevant literature on the use of neuraxial anesthesia in parturients with known intracranial pathology, and proposes a framework and recommendations for assessing risk of neurologic deterioration, with epidural analgesia or anesthesia, or planned or inadvertent dural puncture. The authors illustrate these concepts with numerous case examples and provide guidance for the practicing anesthesiologist in determining the safety of neuraxial anesthesia. C1 [Leffert, Lisa R.] Massachusetts Gen Hosp, Dept Crit Care Anesthesia & Pain Med, Boston, MA 02114 USA. [Leffert, Lisa R.; Schwamm, Lee H.] Harvard Univ, Sch Med, Boston, MA USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Leffert, LR (reprint author), Massachusetts Gen Hosp, Dept Crit Care Anesthesia & Pain Med, GRB 444,55 Fruit St, Boston, MA 02114 USA. EM lleffert@partners.org OI Schwamm, Lee/0000-0003-0592-9145 NR 119 TC 10 Z9 10 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD SEP PY 2013 VL 119 IS 3 BP 703 EP 718 DI 10.1097/ALN.0b013e31829374c2 PG 16 WC Anesthesiology SC Anesthesiology GA 205CX UT WOS:000323420000033 PM 23584382 ER PT J AU Thanassoulis, G Peloso, GM O'Donnell, CJ AF Thanassoulis, George Peloso, Gina M. O'Donnell, Christopher J. TI Genomic Medicine for Improved Prediction and Primordial Prevention of Cardiovascular Disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Editorial Material DE atherosclerosis; cholesterol; genetics; genomics; myocardial infarction; prediction; prevention; risk ID CORONARY-HEART-DISEASE; GENETIC RISK SCORE; MENDELIAN RANDOMIZATION; TRIAL; ASSOCIATION C1 [Thanassoulis, George] McGill Univ, Ctr Hlth, Montreal, PQ H3A 2T5, Canada. [Peloso, Gina M.; O'Donnell, Christopher J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst, Framingham, MA USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM odonnellc@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999, ZIA HL006002-06] NR 21 TC 5 Z9 5 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD SEP PY 2013 VL 33 IS 9 BP 2049 EP 2050 DI 10.1161/ATVBAHA.113.301814 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 203UY UT WOS:000323320700002 PM 23946465 ER PT J AU Suidan, GL Brill, A De Meyer, SF Voorhees, JR Cifuni, SM Cabral, JE Wagner, DD AF Suidan, Georgette L. Brill, Alexander De Meyer, Simon F. Voorhees, Jaymie R. Cifuni, Stephen M. Cabral, Jessica E. Wagner, Denisa D. TI Endothelial Von Willebrand Factor Promotes Blood-Brain Barrier Flexibility and Provides Protection From Hypoxia and Seizures in Mice SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE blood-brain barrier; blood vessels; claudin-5; endothelium; hypoxia; seizures; von Willebrand factor ID INDUCED STATUS EPILEPTICUS; TEMPORAL-LOBE EPILEPSY; WEIBEL-PALADE BODIES; REOXYGENATION STRESS; LITHIUM-PILOCARPINE; TIGHT JUNCTIONS; IN-VIVO; PERMEABILITY; EXPRESSION; CELLS AB Objective-Aberrant blood-brain barrier (BBB) permeability is a hallmark pathology of many central nervous system diseases. von Willebrand factor (VWF) is stored in endothelial Weibel-Palade bodies from where it is released on activation into plasma and basement membrane. The role of VWF in endothelial homeostasis is unclear. The goal of this study was to assess the role of VWF in disease models associated with increased BBB permeability. Approach and Results-We did not find any differences in BBB permeability to Evans blue dye at baseline between wild-type and VWF-/- animals. We next used 2 models presenting with increased BBB permeability, hypoxia/reoxygenation and pilocarpine-induced status epilepticus, to assess the response of VWF-/- animals. In both models, VWF-/- mice maintained a tighter BBB than wild-type mice. VWF-/- mice fared worse in both conditions, with approximate to 100% of VWF-/- mice dying within 120 minutes after pilocarpine administration, whereas >80% of wild-type animals survived. Investigation into the status of tight junction proteins revealed that VWF-/- mice expressed more claudin-5 at baseline. In vitro work confirmed that the presence of subendothelial VWF is inhibitory to claudin-5 expression. Conclusions-VWF deficiency confers partial preservation of BBB integrity after hypoxia/reoxygenation and seizures. Surprisingly, this decrease in BBB permeability did not result in protection of animals because they demonstrated more severe pathology in both models compared with wild-type animals. These data suggest that a rigid BBB is detrimental (to the organism) during certain disease states and that VWF release may provide desired flexibility under stress. C1 [Suidan, Georgette L.; Brill, Alexander; De Meyer, Simon F.; Voorhees, Jaymie R.; Cifuni, Stephen M.; Wagner, Denisa D.] Immune Dis Inst, Boston, MA USA. [Suidan, Georgette L.; Brill, Alexander; De Meyer, Simon F.; Voorhees, Jaymie R.; Cifuni, Stephen M.; Cabral, Jessica E.; Wagner, Denisa D.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Wagner, Denisa D.] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Suidan, Georgette L.; Brill, Alexander; De Meyer, Simon F.; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [De Meyer, Simon F.] KU Leuven Kulak, Lab Thrombosis Res, Kortrijk, Belgium. RP Wagner, DD (reprint author), Boston Childrens Hosp, Program Cellular & Mol Med, 3 Blackfan Circle,3rd Floor, Boston, MA 02115 USA. EM Denisa.Wagner@childrens.harvard.edu FU National Heart, Lung and Blood Institute of the National Institutes of Health [R01 HL041002]; National Research Service Award from theNational Institutes of Neurological Disease and Stroke of the National Institutes of Health [1F32NS073245] FX This work was generously supported by the National Heart, Lung and Blood Institute of the National Institutes of Health grant R01 HL041002 (to D.D. Wagner) and a National Research Service Award from the National Institutes of Neurological Disease and Stroke of the National Institutes of Health grant 1F32NS073245 (to G.L. Suidan). S.F. De Meyer was a postdoctoral fellow of the Research Foundation Flanders (Fonds voor Wetenschappelijk Onderzoek Vlaanderen). NR 65 TC 14 Z9 16 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD SEP PY 2013 VL 33 IS 9 BP 2112 EP 2120 DI 10.1161/ATVBAHA.113.301362 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 203UY UT WOS:000323320700012 PM 23825365 ER PT J AU Gilbar, PJ Seger, AC AF Gilbar, Peter J. Seger, Andrew C. TI Accidental intrathecal administration of bortezomib: Preventing fatalities SO ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Gilbar, Peter J.] Toowoomba Hosp, Canc Serv, Toowoomba, Qld, Australia. [Gilbar, Peter J.] Toowoomba Hosp, Palliat Care Serv, Toowoomba, Qld, Australia. [Seger, Andrew C.] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, Boston, MA 02115 USA. [Seger, Andrew C.] Dana Farber Canc Inst, Ctr Patient Safety, Boston, MA 02115 USA. RP Gilbar, PJ (reprint author), Toowoomba Hosp, Canc Serv, Toowoomba, Qld, Australia. RI Gilbar, Peter/H-4737-2011 OI Gilbar, Peter/0000-0001-7748-1891 NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1743-7555 J9 ASIA-PAC J CLIN ONCO JI Asia-Pac. J. Clin. Oncol. PD SEP PY 2013 VL 9 IS 3 BP 290 EP 291 DI 10.1111/ajco.12020 PG 2 WC Oncology SC Oncology GA 203UK UT WOS:000323319000012 PM 23176407 ER PT J AU Mercer, E Norton, T Woo, S Treister, N Dodson, TB Solomon, DH AF Mercer, E. Norton, T. Woo, S. Treister, N. Dodson, T. B. Solomon, D. H. TI Ninety-One Osteoporosis Patients Affected with Bisphosphonate-Related Osteonecrosis of the Jaw: A Case Series SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE Osteoporosis; Bisphosphonate; Osteonecrosis of the jaw; Risk factor ID RISK-FACTORS; ASSOCIATION; PREVENTION AB Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) presents with necrotic bone in the mouth in the setting of BP exposure. It has been studied in cancer patients taking high-dose BP, but BRONJ has also been noted in patients taking lower-dose BP for osteoporosis. The purpose of this study was to characterize the phenotypes and outcomes in a large series of patients with osteoporosis and BRONJ in the setting of BP exposure. We conducted a retrospective case series. The sample was composed of subjects with BRONJ and osteoporosis. Subjects with a history of BP treatment for myeloma or metastatic cancer to the bones were excluded. Descriptive statistics were computed for the study variables. Ninety-one cases of BRONJ met the inclusion criteria. Subjects had a median age of 71 years and were predominantly female (94.5 %). The median time of BP exposure was 60 months (range 2-120). Most subjects were treated with alendronate (82.4 %). The mandible was involved more frequently (58.2 %) than the maxilla (37.3 %). Subjects commonly (65.9 %), but not universally, reported pain. For subjects with treatment outcome data (n = 0), most reported improvement (80.0 %). Although BRONJ is an uncommon condition, the absolute number of cases is fairly large due to the very large number of patients taking BPs for osteoporosis. The findings of this study confirm that BRONJ primarily affects the mandible, a substantial minority present without pain, and patients typically improve with treatment. C1 [Mercer, E.; Norton, T.; Solomon, D. H.] Brigham & Womens Hosp, Div Rheumatol, Boston, MA 02115 USA. [Woo, S.; Treister, N.] Brigham & Womens Hosp, Div Oral Med & Dent, Boston, MA 02115 USA. [Dodson, T. B.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Solomon, D. H.] Brigham & Womens Hosp, Div Pharmacoepidemiol, Boston, MA 02115 USA. RP Solomon, DH (reprint author), Brigham & Womens Hosp, Div Rheumatol, 75 Francis St,PBB-B3, Boston, MA 02115 USA. EM dsolomon@partners.org FU NIH [DE-R21-018750, AR-K24-055989]; Center for Applied Clinical Investigation, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital; Amgen; Lilly; CORRONA FX This study was supported by NIH Grants DE-R21-018750 and AR-K24-055989 as well as by the Center for Applied Clinical Investigation, Department of Oral and Maxillofacial Surgery, Massachusetts General Hospital. N. Treister receives royalties from Medscape and Up to Date, serves on the Data Safety Committee for Falk Pharmaceuticals, and served on advisory boards for Pfizer and Merck in the past 3 years. T. B. Dodson is a member of the American Association of Oral and Maxillofacial Surgeons' Task Force on Bisphosphonate-Related Osteonecrosis of the Jaw. D. H. Solomon has received salary support from research grants to his institution in the past 3 years from Amgen, Lilly, and CORRONA, unrelated to the current project. He has served in unpaid roles on two Pfizer-sponsored trials and one Novartis-sponsored trial on unrelated topics. He receives royalties from Up to Date. NR 19 TC 4 Z9 4 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD SEP PY 2013 VL 93 IS 3 BP 241 EP 248 DI 10.1007/s00223-013-9747-1 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 202QM UT WOS:000323233500006 PM 23756612 ER PT J AU Al-Obaidi, AK Nelson, BD Al Badawi, G Hicks, MHR Guarino, AJ AF Al-Obaidi, Abdul Kareem Nelson, Brett D. Al Badawi, Ghazwan Hicks, Madelyn Hsiao-Rei Guarino, Anthony J. TI Child mental health and service needs in Iraq: beliefs and attitudes of primary school teachers SO CHILD AND ADOLESCENT MENTAL HEALTH LA English DT Article DE Iraq; children; mental health; school-based mental health services; conflict ID PROGRAM; DISORDERS; CONFLICT; CENTERS; NIGERIA; VIEWS AB Objective: To survey Iraqi primary school teachers' beliefs and attitudes about mental health and behavioural problems of children. Methods: From 10 primary schools in Baghdad, 148 teachers were surveyed using a closed-response questionnaire to assess beliefs and attitudes regarding students' mental health and behavioural problems, needs, resources and limitations to teaching. Results: Disruptive behaviours were rated as main problems by the largest proportions of teachers. In-service training on 'identifying students with social, emotional, or behavioural problems' and 'effective behaviour management' was rated very important by 70% of teachers. Most teachers received no training on mental health during their teaching career. There was low reported availability of a wide range of school-based mental health resources. Conclusions: Teachers in Iraq report substantial mental health and behavioural problems in primary school children and identify high unmet need for school-based mental health programmes and training. C1 [Al-Obaidi, Abdul Kareem] IIE, New York, NY 10018 USA. [Al-Obaidi, Abdul Kareem; Al Badawi, Ghazwan] Al Mustansyria Med Coll, Baghdad, Iraq. [Nelson, Brett D.] Massachusetts Gen Hosp, Harvard Humanitarian Initiat, Dept Pediat, Div Global Hlth, Boston, MA 02114 USA. [Hicks, Madelyn Hsiao-Rei] Kings Coll London, Inst Psychiat, Hlth Serv & Populat Res Dept, London, England. [Guarino, Anthony J.] Ctr Interprofess Studies & Innovat MGH Inst Hlth, Boston, MA USA. RP Al-Obaidi, AK (reprint author), IIE, 5 W 37th St 12, New York, NY 10018 USA. EM kareemobaidi@gmail.com FU Iraq Scholars Rescue Project of the Institute of International Education (IIE) (NY, USA); Harvard Humanitarian Initiative (MA, USA); Brigham and Women's Hospital Department of Emergency Medicine (MA, USA) FX The authors thank the Iraqi teachers for their time in participating in this study, and the referee for valuable suggestions. The authors also acknowledge and appreciate the support of the Iraq Scholars Rescue Project of the Institute of International Education (IIE) (NY, USA), the Harvard Humanitarian Initiative (MA, USA) and the Brigham and Women's Hospital Department of Emergency Medicine (MA, USA). NR 48 TC 0 Z9 0 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1475-357X J9 CHILD ADOL MENT H-UK JI Child Adolesc. Ment. Health PD SEP PY 2013 VL 18 IS 3 SI SI BP 171 EP 179 DI 10.1111/j.1475-3588.2012.00670.x PG 9 WC Psychology, Clinical; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 204QP UT WOS:000323383400008 ER PT J AU Collins, E Gilkeson, G AF Collins, Erin Gilkeson, Gary TI Hematopoetic and mesenchymal stem cell transplantation in the treatment of refractory systemic lupus erythematosus - Where are we now? SO CLINICAL IMMUNOLOGY LA English DT Review DE Lupus; Stem cell transplantation ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; COLLAGEN-INDUCED ARTHRITIS; AUTOIMMUNE-DISEASES; T-CELLS; INDOLEAMINE 2,3-DIOXYGENASE; HEALTHY DONORS; IN-VITRO; MECHANISMS; MICE AB Cell based therapies are of increasing interest in the treatment of systemic lupus due to their potential for long term suppression or cure of disease. Two methods for stem cell transplantation are currently being investigated/performed for treatment of lupus. Autologous hematopoetic stem cell transplantation is used in patients refractory to standard therapy. The morbidity and mortality of the procedure limit its use to select patients. Results indicate 50% long term disease free survival. The technical difficulty of the procedure requires it to be performed only in experienced centers. Mesenchymal stem cell transplants are a new emerging therapy for the treatment of lupus. Studies in murine models of lupus provide evidence of efficacy with safety. Limited uncontrolled trials in humans provide evidence of efficacy as well. Controlled trials are needed to assess the efficacy of both these therapies compared to standard therapy. Published by Elsevier Inc. C1 Med Univ S Carolina, Div Rheumatol, Charleston, SC 29425 USA. Ralph H Johnson VAMC, Med Res Serv, Charleston, SC USA. RP Gilkeson, G (reprint author), 96 Jonathan Lucas St,Suite 912, Charleston, SC 29425 USA. EM Gilkeson@musc.edu NR 58 TC 6 Z9 7 U1 0 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD SEP PY 2013 VL 148 IS 3 BP 328 EP 334 DI 10.1016/j.clim.2013.01.009 PG 7 WC Immunology SC Immunology GA 202CX UT WOS:000323192200005 PM 23411031 ER PT J AU Walsh, CO Milliren, CE Feldman, HA Taveras, EM AF Walsh, Carolyn O. Milliren, Carly E. Feldman, Henry A. Taveras, Elsie M. TI Sensitivity and Specificity of Obesity Diagnosis in Pediatric Ambulatory Care in the United States SO CLINICAL PEDIATRICS LA English DT Article DE pediatric obesity; diagnosis; sensitivity and specificity; health care surveys ID EXPERT COMMITTEE RECOMMENDATIONS; OVERWEIGHT; PREVENTION; CHILDREN; TRENDS AB Objective. We examined the sensitivity and specificity of an obesity diagnosis in a nationally representative sample of pediatric outpatient visits. Methods. We used the 2005 to 2009 National Ambulatory Medical Care and National Hospital Ambulatory Medical Care surveys. We included visits with children 2 to 18 years, yielding a sample of 48 145 database visits. We determined 3 methods of identifying obesity: documented body mass index (BMI) 95th percentile; International Classification of Diseases, Ninth Revision (ICD-9) code; and positive answer to the question, Does the patient now have obesity? Using BMI as the gold standard, we calculated the sensitivity and specificity of a clinical obesity diagnosis. Results. Among the 19.5% of children who were obese by BMI, 7.0% had an ICD-9 code and 15.2% had a positive response to questioning. The sensitivity of an obesity diagnosis was 15.4%, and the specificity was 99.2%. Conclusions. The sensitivity of the obesity diagnosis in pediatric ambulatory visits is low. Efforts are needed to increase identification of obese children. C1 [Walsh, Carolyn O.] Boston Childrens Hosp, Boston Med Ctr, Boston, MA USA. [Milliren, Carly E.; Feldman, Henry A.] Boston Childrens Hosp, Boston, MA USA. [Taveras, Elsie M.] Harvard Univ, Sch Med, Boston, MA 02214 USA. [Taveras, Elsie M.] Massachusetts Gen Hosp, Boston, MA 02214 USA. RP Taveras, EM (reprint author), Harvard Univ, Sch Med, Div Gen Pediat, Dept Pediat, 175 Cambridge St,5th Floor,CPZD 579B, Boston, MA 02214 USA. EM etaveras@partners.org FU Boston Combined Residency Program in Pediatrics Fred Lovejoy Research and Education Fund FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was funded by a grant from the Boston Combined Residency Program in Pediatrics Fred Lovejoy Research and Education Fund to Carolyn O. Walsh. NR 17 TC 4 Z9 4 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD SEP PY 2013 VL 52 IS 9 BP 829 EP 835 DI 10.1177/0009922813488648 PG 7 WC Pediatrics SC Pediatrics GA 205ZN UT WOS:000323484400005 PM 23676286 ER PT J AU Guanci, MM AF Guanci, Mary McKenna TI Ventriculitis of the Central Nervous System SO CRITICAL CARE NURSING CLINICS OF NORTH AMERICA LA English DT Article DE Intraventricular catheter; Cerebral spinal fluid; External ventricular drain; Shunt ID INFECTIONS AB An infection of the ventricular system of the brain is referred to as ventriculitis. The signs and symptoms of ventriculitis include the triad of altered mental status, fever, and headache, as seen in the patient with meningitis. Identifying the organism responsible is important in determining the cause and in planning a treatment strategy. Nurses have a pivotal role in the early identification and management of the patient with ventriculitis. C1 Massachusetts Gen Hosp, Neurosci Intens Care, Boston, MA 02474 USA. RP Guanci, MM (reprint author), Massachusetts Gen Hosp, Neurosci Intens Care, 55 Fruit St, Boston, MA 02474 USA. EM mguanci@partners.org NR 16 TC 1 Z9 1 U1 0 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0899-5885 J9 CRIT CARE NURS CLIN JI Crit. Care Nurs. Clin. N. Am. PD SEP PY 2013 VL 25 IS 3 BP 399 EP + DI 10.1016/j.ccell.2013.04.005 PG 9 WC Nursing SC Nursing GA 205YY UT WOS:000323482100006 PM 23981456 ER PT J AU Florez, JC AF Florez, Jose C. TI Pharmacogenetic Perturbations in Humans as a Tool to Generate Mechanistic Insight SO DIABETES LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; RISK; PATHWAYS; DISEASE; TRAITS C1 [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM jcflorez@partners.org FU NIDDK NIH HHS [R01 DK088214, R01 DK072041] NR 13 TC 2 Z9 2 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2013 VL 62 IS 9 BP 3019 EP 3021 DI 10.2337/db13-0871 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205DG UT WOS:000323421000006 PM 23970522 ER PT J AU Lauritzen, HPMM Brandauer, J Schjerling, P Koh, HJ Treebak, JT Hirshman, MF Galbo, H Goodyear, LJ AF Lauritzen, Hans P. M. M. Brandauer, Josef Schjerling, Peter Koh, Ho-Jin Treebak, Jonas T. Hirshman, Michael F. Galbo, Henrik Goodyear, Laurie J. TI Contraction and AICAR Stimulate IL-6 Vesicle Depletion From Skeletal Muscle Fibers In Vivo SO DIABETES LA English DT Article ID ACTIVATED PROTEIN-KINASE; FATTY-ACID OXIDATION; MESSENGER-RNA EXPRESSION; STAGE RENAL-DISEASE; GLUCOSE-UPTAKE; LIVING MICE; T-TUBULES; MITOCHONDRIAL BIOGENESIS; INTERLEUKIN-6 RELEASE; PLASMA INTERLEUKIN-6 AB Recent studies suggest that interleukin 6 (IL-6) is released from contracting skeletal muscles; however, the cellular origin, secretion kinetics, and signaling mechanisms regulating IL-6 secretion are unknown. To address these questions, we developed imaging methodology to study IL-6 in fixed mouse muscle fibers and in live animals in vivo. Using confocal imaging to visualize endogenous IL-6 protein in fixed muscle fibers, we found IL-6 in small vesicle structures distributed throughout the fibers under basal (resting) conditions. To determine the kinetics of IL-6 secretion, intact quadriceps muscles were transfected with enhanced green fluorescent protein (EGFP)-tagged IL-6 (IL-6-EGFP), and 5 days later anesthetized mice were imaged before and after muscle contractions in situ. Contractions decreased IL-6-EGFP-containing vesicles and protein by 62% (P < 0.05), occurring rapidly and progressively over 25 min of contraction. However, contraction-mediated IL-6-EGFP reduction was normal in muscle-specific AMP-activated protein kinase (AMPK) 2-inactive transgenic mice. In contrast, the AMPK activator AICAR decreased IL-6-EGFP vesicles, an effect that was inhibited in the transgenic mice. In conclusion, resting skeletal muscles contain IL-6-positive vesicles that are expressed throughout myofibers. Contractions stimulate the rapid reduction of IL-6 in myofibers, occurring through an AMPK2-independent mechanism. This novel imaging methodology clearly establishes IL-6 as a contraction-stimulated myokine and can be used to characterize the secretion kinetics of other putative myokines. C1 [Lauritzen, Hans P. M. M.; Koh, Ho-Jin; Hirshman, Michael F.; Goodyear, Laurie J.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Lauritzen, Hans P. M. M.; Koh, Ho-Jin; Hirshman, Michael F.; Goodyear, Laurie J.] Harvard Univ, Sch Med, Boston, MA USA. [Brandauer, Josef] Gettysburg Coll, Dept Hlth Sci, Gettysburg, PA 17325 USA. [Schjerling, Peter] Bispebjerg Hosp, Inst Sports Med, Dept Orthoped Surg M, DK-2400 Copenhagen, Denmark. [Schjerling, Peter] Univ Copenhagen, Ctr Hlth Aging, Fac Hlth Sci, Copenhagen, Denmark. [Treebak, Jonas T.] Univ Copenhagen, Novo Nordisk Fdn, Fac Hlth Sci, Ctr Basic Metab Res, Copenhagen, Denmark. [Galbo, Henrik] Copenhagen Univ Hosp, Rigshosp, Dept Rheumatol, Copenhagen, Denmark. [Galbo, Henrik] Copenhagen Univ Hosp, Rigshosp, Inst Inflammat Res, Copenhagen, Denmark. RP Goodyear, LJ (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM laurie.goodyear@joslin.harvard.edu RI Treebak, Jonas/B-4521-2017; OI Treebak, Jonas/0000-0003-1488-7012; Schjerling, Peter/0000-0001-7138-3211 FU National Institutes of Health (NIH) [R01AR45670, R01DK68626]; DERC at the Joslin Diabetes Center [P30DK036836]; Weimann Foundation; Beckett Foundation; Danish National Research Foundation; NIH [T32-DK-07260-29]; Gettysburg College Professional Development grant; Novo Nordisk Foundation Center for Basic Metabolic Research FX This project was supported by the National Institutes of Health (NIH) grants R01AR45670 and R01DK68626 (L.J.G.) and the DERC P30DK036836 at the Joslin Diabetes Center. H.P.M.M.L. was supported by the Weimann Foundation, the Beckett Foundation, and the Danish National Research Foundation. J.B. was supported by an NIH Training grant (T32-DK-07260-29) and a Gettysburg College Professional Development grant. J.T.T. was supported by the Novo Nordisk Foundation Center for Basic Metabolic Research. No other potential conflicts of interest relevant to this article were reported. NR 56 TC 15 Z9 16 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2013 VL 62 IS 9 BP 3081 EP 3092 DI 10.2337/db12-1261 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205DG UT WOS:000323421000015 PM 23761105 ER PT J AU Hayes, MG Urbanek, M Hivert, MF Armstrong, LL Morrison, J Guo, C Lowe, LP Scheftner, DA Pluzhnikov, A Levine, DM McHugh, CP Ackerman, CM Bouchard, L Brisson, D Layden, BT Mirel, D Doheny, KF Leya, MV Lown-Hecht, RN Dyer, AR Metzger, BE Reddy, TE Cox, NJ Lowe, WL AF Hayes, M. Geoffrey Urbanek, Margrit Hivert, Marie-France Armstrong, Loren L. Morrison, Jean Guo, Cong Lowe, Lynn P. Scheftner, Douglas A. Pluzhnikov, Anna Levine, David M. McHugh, Caitlin P. Ackerman, Christine M. Bouchard, Luigi Brisson, Diane Layden, Brian T. Mirel, Daniel Doheny, Kimberly F. Leya, Marysa V. Lown-Hecht, Rachel N. Dyer, Alan R. Metzger, Boyd E. Reddy, Timothy E. Cox, Nancy J. Lowe, William L., Jr. CA HAPO Study Cooperative Res Grp TI Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies SO DIABETES LA English DT Article ID GESTATIONAL DIABETES-MELLITUS; FASTING GLUCOSE-LEVELS; INCREASED RISK; OUTCOME HAPO; VARIANTS; LOCI; HYPERGLYCEMIA; MTNR1B; POPULATION; PATHOPHYSIOLOGY AB Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at approximate to 28 weeks' gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy. C1 [Hayes, M. Geoffrey; Urbanek, Margrit; Armstrong, Loren L.; Scheftner, Douglas A.; Ackerman, Christine M.; Layden, Brian T.; Leya, Marysa V.; Lown-Hecht, Rachel N.; Metzger, Boyd E.; Lowe, William L., Jr.] Northwestern Univ, Dept Med, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. [Hivert, Marie-France] Univ Sherbrooke, Dept Med, Div Endocrinol, Sherbrooke, PQ J1K 2R1, Canada. [Hivert, Marie-France] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Morrison, Jean; Pluzhnikov, Anna; Cox, Nancy J.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Reddy, Timothy E.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC USA. [Lowe, Lynn P.; Dyer, Alan R.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Levine, David M.; McHugh, Caitlin P.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Bouchard, Luigi] Univ Sherbrooke, Dept Biochem, Sherbrooke, PQ J1K 2R1, Canada. [Bouchard, Luigi; Brisson, Diane] Chicoutimi Hosp, ECOGENE & Lipid Clin 21, Saguenay, PQ, Canada. [Mirel, Daniel] Broad Inst, Cambridge, MA USA. [Doheny, Kimberly F.] Johns Hopkins Univ, Inst Med Genet, Ctr Inherited Dis Res, Baltimore, MD USA. [Guo, Cong; Reddy, Timothy E.] Duke Univ, Inst Genome Sci & Policy, Durham, NC USA. RP Hayes, MG (reprint author), Northwestern Univ, Dept Med, Feinberg Sch Med, Div Endocrinol Metab & Mol Med, Chicago, IL 60611 USA. EM ghayes@northwestern.edu FU National Institutes of Health (NIH) [HD-34242, HD-34243, HG-004415, CA-141688]; Institutes of Health Research-INMD [110791]; American Diabetes Association FX This study was supported by National Institutes of Health (NIH) grants HD-34242, HD-34243, HG-004415, and CA-141688, Institutes of Health Research-INMD (Funding Reference Number 110791), and by the American Diabetes Association. NR 50 TC 20 Z9 20 U1 1 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD SEP PY 2013 VL 62 IS 9 BP 3282 EP 3291 DI 10.2337/db12-1692 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 205DG UT WOS:000323421000037 PM 23903356 ER PT J AU Fishman, MN Srinivas, S Hauke, RJ Amato, RJ Esteves, B Cotreau, MM Strahs, AL Slichenmyer, WJ Bhargava, P Kabbinavar, FF AF Fishman, M. N. Srinivas, S. Hauke, R. J. Amato, R. J. Esteves, B. Cotreau, M. M. Strahs, A. L. Slichenmyer, W. J. Bhargava, P. Kabbinavar, F. F. TI Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Dose escalation; Maximum tolerated dose; Pharmacokinetics; Renal cell carcinoma; Tivozanib; Temsirolimus ID ENDOTHELIAL GROWTH-FACTOR; RECEPTOR TYROSINE KINASES; INTERFERON-ALPHA; ANTITUMOR ACTIVITIES; TARGETED THERAPY; SOLID TUMORS; III TRIAL; SUNITINIB; EVEROLIMUS; INHIBITOR AB Background: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor. Patients and methods: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5 mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3 + 3 dose-escalation design and subsequent expansion cohort. Results: Of 27 patients treated, 20 patients had received >= 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5 mg/d plus temsirolimus 25 mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade >= 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus. Conclusions: In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Fishman, M. N.] H Lee Moffitt Canc Ctr & Res Inst, Dept Genitourinary Oncol, Tampa, FL USA. [Srinivas, S.] Stanford Med Ctr, Dept Oncol, Stanford, CA USA. [Hauke, R. J.] Nebraska Canc Specialists, Omaha, NE USA. [Amato, R. J.] Univ Texas Hlth Sci Ctr Houston, Div Oncol, Houston, TX 77030 USA. [Esteves, B.; Bhargava, P.] AVEO Pharmaceut Inc, Dept Clin Res, Cambridge, MA USA. [Cotreau, M. M.] AVEO Pharmaceut Inc, Dept Clin Pharmacol, Cambridge, MA USA. [Strahs, A. L.] AVEO Pharmaceut Inc, Dept Biometr, Cambridge, MA USA. [Slichenmyer, W. J.] AVEO Pharmaceut Inc, Cambridge, MA USA. [Bhargava, P.] Dana Farber Canc Inst, Dept Med Oncol Solid Tumor Oncol, Boston, MA 02115 USA. [Kabbinavar, F. F.] Univ Calif Los Angeles, Inst Urol Oncol, Los Angeles, CA 90095 USA. RP Kabbinavar, FF (reprint author), Univ Calif Los Angeles, Inst Urol Oncol, 924 Westwood Blvd,Suite 1050, Los Angeles, CA 90095 USA. EM FKabbina@mednet.ucla.edu FU AVEO Pharmaceuticals, Inc. FX This work (ClinicalTrials.gov Identifier: NCT00563147) was supported by AVEO Pharmaceuticals, Inc. AVEO and Astellas Pharma Inc are parties to a collaboration agreement for the co-development of tivozanib. Through the roles of B. Esteves, M. M. Cotreau, A. L. Strahs, W.J. Slichenmyer and P. Bhargava (current/former employees of AVEO) as authors, the study sponsor has participated in all aspects of study conduct and manuscript development. NR 36 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 IS 13 BP 2841 EP 2850 DI 10.1016/j.ejca.2013.04.019 PG 10 WC Oncology SC Oncology GA 194JD UT WOS:000322627300009 PM 23726267 ER PT J AU Ruderfer, DM Chambert, K Moran, J Talkowski, M Chen, ES Gigek, C Gusella, JF Blackwood, DH Corvin, A Gurling, HM Hultman, CM Kirov, G Magnusson, P O'Donovan, MC Owen, MJ Pato, C St Clair, D Sullivan, PF Purcell, SM Sklar, P Ernst, C AF Ruderfer, Douglas M. Chambert, Kim Moran, Jennifer Talkowski, Michael Chen, Elizabeth S. Gigek, Carolina Gusella, James F. Blackwood, Douglas H. Corvin, Aiden Gurling, Hugh M. Hultman, Christina M. Kirov, George Magnusson, Patrick O'Donovan, Michael C. Owen, Michael J. Pato, Carlos St Clair, David Sullivan, Patrick F. Purcell, Shaun M. Sklar, Pamela Ernst, Carl TI Mosaic copy number variation in schizophrenia SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE schizophrenia; copy number variation; mosaic; SNP microarrays ID BIPOLAR DISORDER; GENOME; RISK; ASSOCIATION; ABERRATIONS; VARIANTS; DNA AB Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n = 3518; control, n = 4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects. C1 [Ruderfer, Douglas M.; Chambert, Kim; Moran, Jennifer; Purcell, Shaun M.] Broad Inst, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Ruderfer, Douglas M.; Purcell, Shaun M.; Sklar, Pamela] Mt Sinai Sch Med, Dept Psychiat, Div Psychiat Genom, New York, NY USA. [Ruderfer, Douglas M.; Purcell, Shaun M.] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA. [Talkowski, Michael; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Talkowski, Michael; Gusella, James F.] Harvard Univ, Sch Med, Dept Genet & Neurol, Boston, MA USA. [Chen, Elizabeth S.; Gigek, Carolina; Ernst, Carl] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. [Blackwood, Douglas H.] Univ Edinburgh, Div Psychiat, Sch Mol & Clin Med, Edinburgh, Midlothian, Scotland. [Corvin, Aiden] Univ Dublin Trinity Coll, Dept Psychiat, Neuropsychiat Genet Res Grp, Dublin 2, Ireland. [Corvin, Aiden] Univ Dublin Trinity Coll, Inst Mol Med, Dublin 2, Ireland. [Gurling, Hugh M.] UCL, Sch Med, Mol Psychiat Lab, Dept Mental Hlth Sci,Windeyer Inst Med Sci, London W1N 8AA, England. [Hultman, Christina M.; Magnusson, Patrick] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Hultman, Christina M.] Uppsala Univ, Dept Neurosci, Uppsala, Sweden. [Kirov, George; O'Donovan, Michael C.; Owen, Michael J.] Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff CF10 3AX, S Glam, Wales. [Pato, Carlos] Univ So Calif, Ctr Genom Psychiat, Los Angeles, CA USA. [St Clair, David] Univ Aberdeen, Inst Med Sci, Aberdeen, Scotland. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Ernst, C (reprint author), McGill Univ, 6875 LaSalle Blvd,Frank Common Bldg Room 2101-2, Verdun, PQ H4H 1R3, Canada. EM carl.ernst@mcgill.ca RI Ruderfer, Douglas/M-5795-2016; OI Ruderfer, Douglas/0000-0002-2365-386X; Corvin, Aiden/0000-0001-6717-4089; O'Donovan, Michael/0000-0001-7073-2379; Moran, Jennifer/0000-0002-5664-4716; Chen, Elizabeth/0000-0002-3573-0164 FU Medical Research Council [G0800509] NR 17 TC 6 Z9 6 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD SEP PY 2013 VL 21 IS 9 BP 1007 EP 1011 DI 10.1038/ejhg.2012.287 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 203HA UT WOS:000323281400018 PM 23321615 ER PT J AU Arbizu, J Prieto, E Martinez-Lage, P Marti-Climent, JM Garcia-Granero, M Lamet, I Pastor, P Riverol, M Gomez-Isla, MT Penuelas, I Richter, JA Weiner, MW AF Arbizu, Javier Prieto, E. Martinez-Lage, P. Marti-Climent, J. M. Garcia-Granero, M. Lamet, I. Pastor, P. Riverol, M. Gomez-Isla, M. T. Penuelas, I. Richter, J. A. Weiner, M. W. CA Alzheimer's Dis Neuroimaging TI Automated analysis of FDG PET as a tool for single-subject probabilistic prediction and detection of Alzheimer's disease dementia SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE FDG; PET; Alzheimer's disease; Mild cognitive impairment; Dementia; Prediction ID MILD COGNITIVE IMPAIRMENT; BRAIN GLUCOSE-METABOLISM; GRAY-MATTER VOLUME; F-18-FDG PET; APOE GENOTYPE; ASSOCIATION WORKGROUPS; DIAGNOSTIC GUIDELINES; NATIONAL INSTITUTE; MRI; MCI AB To introduce, evaluate and validate a voxel-based analysis method of F-18-FDG PET imaging for determining the probability of Alzheimer's disease (AD) in a particular individual. The subject groups for model derivation comprised 80 healthy subjects (HS), 36 patients with mild cognitive impairment (MCI) who converted to AD dementia within 18 months, 85 non-converter MCI patients who did not convert within 24 months, and 67 AD dementia patients with baseline FDG PET scan were recruited from the AD Neuroimaging Initiative (ADNI) database. Additionally, baseline FDG PET scans from 20 HS, 27 MCI and 21 AD dementia patients from our institutional cohort were included for model validation. The analysis technique was designed on the basis of the AD-related hypometabolic convergence index adapted for our laboratory-specific context (AD-PET index), and combined in a multivariable model with age and gender for AD dementia detection (AD score). A logistic regression analysis of different cortical PET indexes and clinical variables was applied to search for relevant predictive factors to include in the multivariable model for the prediction of MCI conversion to AD dementia (AD-Conv score). The resultant scores were stratified into sixtiles for probabilistic diagnosis. The area under the receiver operating characteristic curve (AUC) for the AD score detecting AD dementia in the ADNI database was 0.879, and the observed probability of AD dementia in the six defined groups ranged from 8 % to 100 % in a monotonic trend. For predicting MCI conversion to AD dementia, only the posterior cingulate index, Mini-Mental State Examination (MMSE) score and apolipoprotein E4 genotype (ApoE4) exhibited significant independent effects in the univariable and multivariable models. When only the latter two clinical variables were included in the model, the AUC was 0.742 (95 % CI 0.646 - 0.838), but this increased to 0.804 (95 % CI 0.714 - 0.894, bootstrap p = 0.027) with the addition of the posterior cingulate index (AD-Conv score). Baseline clinical diagnosis of MCI showed 29.7 % of converters after 18 months. The observed probability of conversion in relation to baseline AD-Conv score was 75 % in the high probability group (sixtile 6), 34 % in the medium probability group (merged sixtiles 4 and 5), 20 % in the low probability group (sixtile 3) and 7.5 % in the very low probability group (merged sixtiles 1 and 2). In the validation population, the AD score reached an AUC of 0.948 (95 % CI 0.625 - 0.969) and the AD-Conv score reached 0.968 (95 % CI 0.908 - 1.000), with AD patients and MCI converters included in the highest probability categories. Posterior cingulate hypometabolism, when combined in a multivariable model with age and gender as well as MMSE score and ApoE4 data, improved the determination of the likelihood of patients with MCI converting to AD dementia compared with clinical variables alone. The probabilistic model described here provides a new tool that may aid in the clinical diagnosis of AD and MCI conversion. C1 [Arbizu, Javier; Prieto, E.; Marti-Climent, J. M.; Penuelas, I.; Richter, J. A.] Univ Navarra Clin, Dept Nucl Med, Pamplona 31008, Spain. [Martinez-Lage, P.; Lamet, I.; Pastor, P.; Riverol, M.; Gomez-Isla, M. T.] Univ Navarra Clin, Dept Neurol, Pamplona 31008, Spain. [Garcia-Granero, M.] Univ Navarra, Sch Sci, Dept Biochem & Genet, Pamplona 31008, Spain. [Weiner, M. W.] San Francisco VA Med Ctr, CIND, San Francisco, CA 94121 USA. RP Arbizu, J (reprint author), Univ Navarra Clin, Dept Nucl Med, Ave Pio 12 36, Pamplona 31008, Spain. EM jarbizu@unav.es RI Saykin, Andrew/A-1318-2007; Pastor, Pau/C-9834-2009; Prieto, Elena/N-2142-2014; Jack, Clifford/F-2508-2010 OI Saykin, Andrew/0000-0002-1376-8532; Pastor, Pau/0000-0002-7493-8777; Prieto, Elena/0000-0002-3609-1210; Jack, Clifford/0000-0001-7916-622X FU Government of Spain, Institute of Health Carlos III, the Ministry of Health [01/0809]; Ministry of Science and Innovation CIBERNED (Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas) [ADE 10/00028, CB06/05/0077]; Alzheimer's Disease Neuroimaging Initiative (ADNI; National Institutes of Health) [U01 AG024904]; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering; Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd; Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; Takeda Pharmaceutical Company; Canadian Institutes of Health Research; NIH [P30 AG010129, K01 AG030514] FX This work was supported in part by the Government of Spain, Institute of Health Carlos III, the Ministry of Health grant 01/0809, and the Ministry of Science and Innovation grant ADE 10/00028, and CB06/05/0077 CIBERNED (Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas).; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; National Institutes of Health grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research provides funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study was coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuroimaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129 and K01 AG030514. NR 40 TC 15 Z9 16 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD SEP PY 2013 VL 40 IS 9 BP 1394 EP 1405 DI 10.1007/s00259-013-2458-z PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 200GO UT WOS:000323056300014 PM 23715905 ER PT J AU Pae, M Wu, DY AF Pae, Munkyong Wu, Dayong TI Immunomodulating effects of epigallocatechin-3-gallate from green tea: mechanisms and applications SO FOOD & FUNCTION LA English DT Review ID REGULATORY T-CELLS; INFLAMMATORY-BOWEL-DISEASE; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; COLLAGEN-INDUCED ARTHRITIS; NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; 67-KDA LAMININ RECEPTOR; CENTRAL-NERVOUS-SYSTEM; GROWTH-FACTOR-BETA AB Consuming green tea or its active ingredient, epigallocatechin-3-gallate (EGCG), has been shown consistently to benefit the healthy functioning of several body systems. In the immune system specifically, accumulating evidence has revealed an immunomodulating effect of green tea/EGCG. Several types of immune cells in both the innate and adaptive immune systems are known to be affected in varying degrees by green tea/EGCG. Among them, the dramatic effect on T cell functions has been repeatedly demonstrated, including T cell activation, proliferation, differentiation, and production of cytokines. In particular, dysregulated T cell function with respect to different subsets of CD4(+) T cells is a critical pathogenic factor in the development of autoimmune inflammatory diseases. Recent studies have shown that EGCG affects the differentiation of naive CD4(+) T cells into different effector subsets in a way that would be expected to favorably impact autoimmunity. Consistent with these findings, studies using animal models of autoimmune diseases have reported disease improvement in animals treated with green tea/EGCG. Altogether, these studies identify and support the use of EGCG as a potential therapeutic agent in preventing and ameliorating T cell-mediated autoimmune diseases. Given the paucity of information in human studies, the translational value of these findings needs to be verified in future research. C1 [Pae, Munkyong] Harvard Univ, Sch Med, Joslin Diabet Ctr, Cellular & Mol Physiol Sect, Boston, MA 02115 USA. [Wu, Dayong] Tufts Univ, Nutr Immunol Lab, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Pae, M (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Cellular & Mol Physiol Sect, Boston, MA 02115 USA. EM dayong.wu@tufts.edu FU USDA National Institute of Food and Agriculture [2010-65200-20360]; USDA [58-1950-0-014] FX This project is supported by the USDA National Institute of Food and Agriculture grant 2010-65200-20360 and the USDA contract #58-1950-0-014. The authors would like to thank Stephanie Marco for her assistance in the preparation of the manuscript. NR 159 TC 16 Z9 23 U1 4 U2 35 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 2042-6496 EI 2042-650X J9 FOOD FUNCT JI Food Funct. PD SEP PY 2013 VL 4 IS 9 BP 1287 EP 1303 DI 10.1039/c3fo60076a PG 17 WC Biochemistry & Molecular Biology; Food Science & Technology SC Biochemistry & Molecular Biology; Food Science & Technology GA 204GP UT WOS:000323353500001 PM 23835657 ER PT J AU Militsakh, ON Sanderson, JA Lin, D Wax, MK AF Militsakh, Oleg N. Sanderson, Jeremy A. Lin, Derrick Wax, Mark K. TI Rehabilitation of a parotidectomy patient-A systematic approach SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Review DE Facial nerve; facial paralysis; parotidectomy; frey's syndrome; free flap; microvascular reconstruction; nerve graft; neurorrhaphy; parotid surgery ID FACIAL-NERVE FUNCTION; QUALITY-OF-LIFE; GRACILIS MUSCLE TRANSPLANTATION; FREE TISSUE TRANSFER; CROSS-FACE NERVE; FREYS-SYNDROME; PARALYZED FACE; SUPERFICIAL PAROTIDECTOMY; VESTIBULAR SCHWANNOMA; RECONSTRUCTION AB Parotidectomy is a common surgical procedure. Resultant contour defect, Frey's syndrome, and facial nerve rehabilitation deserve special consideration. Microsurgical techniques provide unparallel advantage for reconstruction of large-volume defects. Same-stage reconstruction of the defect is advocated and often beneficial to the patient. The importance of full communication between the extirpative and reconstructive surgeon cannot be underscored. Often, institutional and personal biases must be overcome to provide best quality care for the patient. This article provides a comprehensive review of the medical literature on the subject and contrives a systematic approach to the use of various reconstructive techniques. (c) 2012 Wiley Periodicals, Inc. C1 [Militsakh, Oleg N.] Univ Nebraska Med Ctr, Div Head & Neck Surg, Dept Otolaryngol, Omaha, NE 68198 USA. [Militsakh, Oleg N.; Sanderson, Jeremy A.] Nebraska Methodist Hosp, Omaha, NE 68198 USA. [Sanderson, Jeremy A.] Univ Nebraska Med Ctr, Dept Plast Surg, Omaha, NE 68198 USA. [Lin, Derrick] Massachusetts Eye & Ear Infirm, Dept Otol, Boston, MA 02114 USA. [Lin, Derrick] Massachusetts Eye & Ear Infirm, Dept Laryngol, Boston, MA 02114 USA. [Wax, Mark K.] Oregon Hlth & Sci Univ, Dept Otolaryngol, Portland, OR 97201 USA. RP Militsakh, ON (reprint author), Univ Nebraska Med Ctr, Div Head & Neck Surg, Dept Otolaryngol, Omaha, NE 68198 USA. EM omilitsakh@unmc.edu OI Militsakh, Oleg/0000-0002-5759-5960 NR 97 TC 1 Z9 1 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD SEP PY 2013 VL 35 IS 9 BP 1349 EP 1361 DI 10.1002/hed.23095 PG 13 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 203TS UT WOS:000323317000027 PM 22907838 ER PT J AU Volandes, AE Barry, MJ Wood, F Elwyn, G AF Volandes, Angelo E. Barry, Michael J. Wood, Fiona Elwyn, Glyn TI Audio-video decision support for patients: the documentary genre as a basis for decision aids SO HEALTH EXPECTATIONS LA English DT Article DE decision aids; decision making; documentary films; objectivity; truth; video ID LIFE; BEHAVIOR; ASTHMA AB Objective Decision support tools are increasingly using audio-visual materials. However, disagreement exists about the use of audio-visual materials as they may be subjective and biased. Methods This is a literature review of the major texts for documentary film studies to extrapolate issues of objectivity and bias from film to decision support tools. Results The key features of documentary films are that they attempt to portray real events and that the attempted reality is always filtered through the lens of the filmmaker. The same key features can be said of decision support tools that use audio-visual materials. Three concerns arising from documentary film studies as they apply to the use of audio-visual materials in decision support tools include whose perspective matters (stakeholder bias), how to choose among audio-visual materials (selection bias) and how to ensure objectivity (editorial bias). Discussion Decision science needs to start a debate about how audio-visual materials are to be used in decision support tools. Simply because audio-visual materials may be subjective and open to bias does not mean that we should not use them. Conclusion Methods need to be found to ensure consensus around balance and editorial control, such that audio-visual materials can be used. C1 [Volandes, Angelo E.; Barry, Michael J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gen Med Unit, Boston, MA USA. [Wood, Fiona; Elwyn, Glyn] Cardiff Univ, Dept Med, Sch Med, Cardiff CF10 3AX, S Glam, Wales. RP Volandes, AE (reprint author), Massachusetts Gen Hosp, Gen Med Unit, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM avolandes@partners.org RI Elwyn, G./L-4292-2015; OI Elwyn, Glyn/0000-0002-0917-6286 FU Agency for Healthcare Research and Quality [K08HS018780] FX Dr. Volandes was supported by grant number K08HS018780 from the Agency for Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency for Healthcare Research and Quality. NR 25 TC 3 Z9 3 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1369-6513 J9 HEALTH EXPECT JI Health Expect. PD SEP PY 2013 VL 16 IS 3 BP E80 EP E88 DI 10.1111/j.1369-7625.2011.00727.x PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 200DZ UT WOS:000323049300008 PM 22032516 ER PT J AU Leonardi, S Truffa, AAM Neely, ML Tricoci, P White, HD Gibson, CM Wilson, M Stone, GW Harrington, RA Bhatt, DL Mahaffey, KW AF Leonardi, Sergio Truffa, Adriano A. M. Neely, Megan L. Tricoci, Pierluigi White, Harvey D. Gibson, C. Michael Wilson, Matthew Stone, Gregg W. Harrington, Robert A. Bhatt, Deepak L. Mahaffey, Kenneth W. TI A novel approach to systematically implement the universal definition of myocardial infarction: insights from the CHAMPION PLATFORM trial SO HEART LA English DT Article ID ACUTE CORONARY SYNDROMES; PLATELET INHIBITION; CARDIAC TROPONIN; INTERVENTION; ELEVATION; CANGRELOR; OUTCOMES; PCI; PROGNOSIS; STRATEGY AB Objective To reassess the efficacy of cangrelor efficacy using the universal definition of myocardial infarction (MI). Design We adopted a novel approach to systematically implement the universal definition of MI. Two physicians blinded to treatment allocation reviewed plots of CK-MB and troponin values in relation to time of randomisation and percutaneous coronary intervention (PCI) to identify patients with stable or falling biomarkers pre-PCI (ie, primary cohort), and those with post-PCI CK-MB elevations. Setting The CHAMPION PLATFORM trial. Patients Non-ST-elevation acute coronary syndromes (95%) and stable angina patients (5%). Interventions Cangrelor versus placebo. Main outcome measures The efficacy of cangrelor compared with placebo using the reclassified events (type 4a MI) and the original clinical events committee-adjudicated (CEC PCI-MI) results was investigated. Results Of 5295 patients, 3406 (64.4%) were in the primary cohort. Type 4a MI occurred in 4.3% (226 events/5295 patients) while original CEC PCI-MI occurred in 6.5% (344 events/5295 patients), a significant difference (p<0.0001). Using the reclassified MI events, the primary composite endpoint of death, MI, or ischaemia-driven revascularisation through 48h occurred in 5.4% of patients (4.9% cangrelor, 6.0% placebo; OR 0.80; 95% CI 0.63 to 1.02) as opposed to 7.5% of the primary analyses (7.0% cangrelor, 8.0% placebo; OR 0.87; 95% CI 0.71 to 1.07). Conclusions Systematic, strict implementation of the universal MI definition with emphasis on baseline assessment may enhance discrimination in detecting PCI-MI and may allow for more rigorous assessment of interventions in patients undergoing early PCI. C1 [Leonardi, Sergio; Truffa, Adriano A. M.; Neely, Megan L.; Tricoci, Pierluigi; Wilson, Matthew; Mahaffey, Kenneth W.] Duke Univ Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Leonardi, Sergio] Fdn IRCCS Policlin San Matteo, Dept Cardiol, Pavia, Italy. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand. [Gibson, C. Michael] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Stone, Gregg W.] Columbia Univ Med Ctr, New York, NY USA. [Stone, Gregg W.] Cardiovasc Res Fdn, New York, NY USA. [Harrington, Robert A.] Stanford Univ, Stanford, CA 94305 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. RP Leonardi, S (reprint author), Duke Clin Res Inst, 2400 Pratt St,Room 0311 Terrace Level, Durham, NC 27705 USA. EM sergio.leonardi@duke.edu OI Leonardi, Sergio/0000-0002-4800-6132 FU Medicines Company; Duke Clinical Research Institute FX The CHAMPION PLATFORM trial was funded by The Medicines Company. The current analyses were funded by the Duke Clinical Research Institute. The sponsors had no role in the conception and design of the present study. The analyses were performed by the Duke Clinical Research Institute statistical team and independently confirmed by the Sponsor. NR 22 TC 14 Z9 15 U1 0 U2 5 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 EI 1468-201X J9 HEART JI Heart PD SEP 1 PY 2013 VL 99 IS 17 BP 1282 EP 1287 DI 10.1136/heartjnl-2012-303103 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 201SH UT WOS:000323162800012 PM 23434768 ER PT J AU Nielsen, JB Pietersen, A Graff, C Lind, B Struijk, JJ Olesen, MS Haunso, S Gerds, TA Ellinor, PT Kober, L Svendsen, JH Holst, AG AF Nielsen, Jonas Bille Pietersen, Adrian Graff, Claus Lind, Bent Struijk, Johannes Jan Olesen, Morten Salling Haunso, Stig Gerds, Thomas Aalexander Ellinor, Patrick Thomas Kober, Lars Svendsen, Jesper Hastrup Holst, Anders Gaarsdal TI Risk of atrial fibrillation as a function of the electrocardiographic PR interval: Results from the Copenhagen ECG Study SO HEART RHYTHM LA English DT Article DE Atrial fibrillation; Gender differences; PR interval; Electrocardiography; General population; Marquette 12SL validation ID 1ST-DEGREE ATRIOVENTRICULAR-BLOCK; BLOOD-PRESSURE; ATHEROSCLEROSIS RISK; HEART-FAILURE; COHORT; POPULATION; STROKE; MORTALITY; DIAGNOSIS; VALIDITY AB BACKGROUND Prolongation of the PR interval has been associated with an increased risk of incident atrial fibrillation (AF). OBJECTIVE To determine if there was a nonlinear relation between PR interval duration and the risk of AF. METHODS We included 288,181 individuals, corresponding to one third of the population in the greater region of Copenhagen. These individuals had a digital electrocardiogram (ECG) recorded in a general practitioner's core facility from 2001 to 2010. Data on drug use, comorbidity, and outcomes were collected from Danish registries. RESULTS During a median follow-up period of 5.7 years, 11,087 developed AF. Having a PR interval >= 95th percentile (>= 196 ms for women, >= 204 ms for men) was associated with an increased risk of AF as evidenced by a multivariable-adjusted hazard ratio (HR) of 1.18 (95% confidence interval [CI] 1.06-1.30, P = .001) for women and 1.30 (1.17-1.44, P < .001) for men compared with the respective reference groups (PR interval between 40th and 60th percentile). Having a short PR interval <5th percentile (<= 121 ms for women, <= 129 ms for men) was also associated with an increased risk of AF for women (HR 1.32, 950/0 CI 1.12-1.56, P = .001), but this was not significant for men (HR 1.09, 950/0 CI 0.92-1.29, P = .33). CONCLUSION In this Large ECG study, we found an increased risk of AF for Longer PR intervals for both women and men. With respect to short PR intervals, we also observed an increased risk of AF for women. C1 [Nielsen, Jonas Bille; Olesen, Morten Salling; Haunso, Stig; Svendsen, Jesper Hastrup; Holst, Anders Gaarsdal] Danish Natl Res Fdn Ctr Cardiac Arrhythmia DARC, Copenhagen, Denmark. [Nielsen, Jonas Bille; Olesen, Morten Salling; Haunso, Stig; Svendsen, Jesper Hastrup; Holst, Anders Gaarsdal] Univ Copenhagen, Rigshosp, Ctr Heart, Mol Cardiol Lab, DK-2100 Copenhagen, Denmark. [Pietersen, Adrian; Lind, Bent] Copenhagen Gen Practitioners Lab, Copenhagen, Denmark. [Graff, Claus; Struijk, Johannes Jan] Aalborg Univ, Dept Hlth Sci & Technol, Aalborg, Denmark. [Haunso, Stig; Gerds, Thomas Aalexander] Univ Copenhagen, Dept Biostat, Copenhagen, Denmark. [Kober, Lars; Svendsen, Jesper Hastrup] Univ Copenhagen, Fac Hlth Sci, Dept Med & Surg, Copenhagen, Denmark. [Ellinor, Patrick Thomas] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Ellinor, Patrick Thomas] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Nielsen, JB (reprint author), Rigshosp, Dept Cardiol, Mol Cardiol Lab, 9312 Juliane Mariesvej 20, DK-2100 Copenhagen, Denmark. EM jonas.bille.nielsen@gmail.com RI Graff, Claus/D-1601-2010; OI Struijk, Johannes/0000-0002-8713-1913; Svendsen, Jesper Hastrup/0000-0001-8466-8515 FU University of Copenhagen; Danish National Research Foundation; Danish Council for Independent Research [11-107456]; John and Birthe Meyer Foundation; Foundation of 17-12-1981; Beckett Foundation; Copenhagen Medical Society (OMSK) FX This study was supported by the University of Copenhagen, the Danish National Research Foundation, The Danish Council for Independent Research (Grant No 11-107456), The John and Birthe Meyer Foundation, The Foundation of 17-12-1981, The Beckett Foundation, and the Copenhagen Medical Society (OMSK). NR 32 TC 24 Z9 27 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD SEP PY 2013 VL 10 IS 9 BP 1249 EP 1256 DI 10.1016/j.hrthm.2013.04.012 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 206CQ UT WOS:000323494600007 PM 23608590 ER PT J AU Goldberger, JJ Schliamser, JE Kadish, AH Subacius, H Shalaby, A Schaechter, A Levine, J AF Goldberger, Jeffrey J. Schliamser, Jorge E. Kadish, Alan H. Subacius, Haris Shalaby, Alaa Schaechter, Andi Levine, Joseph TI Should an Improvement in Left Ventricular Systolic Function Preclude ICD Generator Replacement? Reply SO HEART RHYTHM LA English DT Letter ID CARDIOMYOPATHY C1 [Goldberger, Jeffrey J.; Schliamser, Jorge E.; Kadish, Alan H.; Subacius, Haris; Schaechter, Andi] Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. [Goldberger, Jeffrey J.; Schliamser, Jorge E.; Kadish, Alan H.; Subacius, Haris; Schaechter, Andi] Northwestern Univ, Feinberg Sch Med, Div Cardiol, Chicago, IL USA. [Kadish, Alan H.] Touro Coll, Brooklyn, NY USA. [Kadish, Alan H.] New York Med Coll, Valhalla, NY 10595 USA. [Shalaby, Alaa] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Levine, Joseph] St Francis Hosp, Ctr Heart, Roslyn, NY USA. RP Goldberger, JJ (reprint author), Northwestern Univ, Feinberg Sch Med, Ctr Cardiovasc Innovat, Chicago, IL 60611 USA. EM j-goldberger@northwestern.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1547-5271 J9 HEART RHYTHM JI Heart Rhythm PD SEP PY 2013 VL 10 IS 9 BP E77 EP E78 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 206CQ UT WOS:000323494600004 PM 23872694 ER PT J AU Chang, WT Ahlfors, SP Lin, FH AF Chang, Wei-Tang Ahlfors, Seppo P. Lin, Fa-Hsuan TI Sparse current source estimation for MEG using loose orientation constraints SO HUMAN BRAIN MAPPING LA English DT Article DE inverse problem; l(1)-norm; convex optimization; MEG; EEG; orientation constraint ID SURFACE-BASED ANALYSIS; CORTICAL ACTIVITY; HUMAN BRAIN; EEG; MAGNETOENCEPHALOGRAPHY; RECONSTRUCTION; LOCALIZATION AB Spatially focal source estimates for magnetoencephalography (MEG) and electroencephalography (EEG) data can be obtained by imposing a minimum (1)-norm constraint on the distribution of the source currents. Anatomical information about the expected locations and orientations of the sources can be included in the source models. In particular, the sources can be assumed to be oriented perpendicular to the cortical surface. We introduce a minimum (1)-norm estimation source modeling approach with loose orientation constraints ((LOC)-L-1), which integrates the estimation of the orientation, location, and strength of the source currents into a cost function to jointly model the residual error and the (1)-norm of the source estimates. Evaluation with simulated MEG data indicated that the (LOC)-L-1 method can provide low spatial dispersion, high localization accuracy, and high source detection rates. Application to somatosensory and auditory MEG data resulted in physiologically reasonable source distributions. The proposed (LOC)-L-1 method appears useful for incorporating anatomical information about the source orientations into sparse source estimation of MEG data. Hum Brain Mapp 34:2190-2201, 2013. (c) 2011 Wiley Periodicals, Inc. C1 [Chang, Wei-Tang; Lin, Fa-Hsuan] Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. [Ahlfors, Seppo P.; Lin, Fa-Hsuan] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Ahlfors, Seppo P.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Lin, Fa-Hsuan] Aalto Univ, Sch Sci, Dept Biomed Engn & Computat Sci, Espoo, Finland. RP Lin, FH (reprint author), Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. EM fhlin@ntu.edu.tw RI Lin, Fa-Hsuan/G-6988-2012; Ahlfors, Seppo/P-3644-2016 OI Lin, Fa-Hsuan/0000-0002-9539-1731; FU National Institutes of Health [R01HD040712, R01NS037462, R01NS048279, R01NS057500, P41RR014075, R01MH083744, R21DC010060, R21EB007298]; National Science Council, Taiwan [NSC 98-2320-B-002-004-MY3, NSC 100-2325-B-002-046]; Ministry of Economic Affairs [100-EC-17-A-19-S1-175]; National Health Research Institute [NHRI-EX100-9715EC]; Academy of Finland (FiDiPro program) FX Contract grant sponsor: National Institutes of Health Grants; Contract grant numbers: R01HD040712, R01NS037462, R01NS048279, R01NS057500, P41RR014075, R01MH083744, R21DC010060, R21EB007298; Contract grant sponsor: National Science Council, Taiwan; Contract grant numbers: NSC 98-2320-B-002-004-MY3, NSC 100-2325-B-002-046; Contract grant sponsor: Ministry of Economic Affairs; Contract grant number: 100-EC-17-A-19-S1-175; Contract grant sponsor: National Health Research Institute; Contract grant number: NHRI-EX100-9715EC; Contract grant sponsor: Academy of Finland (FiDiPro program). NR 29 TC 4 Z9 4 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD SEP PY 2013 VL 34 IS 9 BP 2190 EP 2201 DI 10.1002/hbm.22057 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 203UZ UT WOS:000323320800016 PM 22438263 ER PT J AU Krebs, CE Karkheiran, S Powell, JC Cao, M Makarov, V Darvish, H Di Paolo, G Walker, RH Shahidi, GA Buxbaum, JD De Camilli, P Yue, ZY Paisan-Ruiz, C AF Krebs, Catharine E. Karkheiran, Siamak Powell, James C. Cao, Mian Makarov, Vladimir Darvish, Hossein Di Paolo, Gilbert Walker, Ruth H. Shahidi, Gholam Ali Buxbaum, Joseph D. De Camilli, Pietro Yue, Zhenyu Paisan-Ruiz, Coro TI The Sac1 Domain of SYNJ1 Identified Mutated in a Family with Early-Onset Progressive Parkinsonism with Generalized Seizures SO HUMAN MUTATION LA English DT Article DE homozygosity mapping; whole-exome sequencing; SYNJ1; autosomal recessive Parkinsonism AB This study aimed to elucidate the genetic causes underlying early-onset Parkinsonism (EOP) in a consanguineous Iranian family. To attain this, homozygosity mapping and whole-exome sequencing were performed. As a result, a homozygous mutation (c.773G>A; p.Arg258Gln) lying within the NH2-terminal Sac1-like inositol phosphatase domain of polyphosphoinositide phosphatase synaptojanin 1 (SYNJ1), which has been implicated in the regulation of endocytic traffic at synapses, was identified as the disease-segregating mutation. This mutation impaired the phosphatase activity of SYNJ1 against its Sac1 domain substrates in vitro. We concluded that the SYNJ1 mutation identified here is responsible for the EOP phenotype seen in our patients probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions. Our finding not only opens new avenues of investigation in the synaptic dysfunction mechanisms associated with Parkinsonism, but also suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.(C) 2013 Wiley Periodicals, Inc. C1 [Krebs, Catharine E.; Powell, James C.; Walker, Ruth H.; Yue, Zhenyu; Paisan-Ruiz, Coro] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY USA. [Karkheiran, Siamak] Univ Tehran Med Sci, Hazrat Rasool Hosp, Movement Disorders Clin, Tehran, Iran. [Cao, Mian; De Camilli, Pietro] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Cell Biol, New Haven, CT 06510 USA. [Cao, Mian; De Camilli, Pietro] Yale Univ, Sch Med, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT USA. [Makarov, Vladimir] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY USA. [Darvish, Hossein] Shahid Beheshti Univ Med Sci, Dept Med Genet, Tehran, Iran. [Di Paolo, Gilbert] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, Med Ctr, Dept Pathol & Cell Biol, New York, NY USA. [Walker, Ruth H.] James J Peters Vet Affairs Med Ctr, Dept Neurol, Bronx, NY USA. [Shahidi, Gholam Ali] Univ Tehran Med Sci, Hazrat Rasool Hosp, Dept Neurol, Tehran, Iran. [Buxbaum, Joseph D.] Mt Sinai Schoool Med, Seaver Autism Ctr Res & Treatment, New York, NY USA. [Buxbaum, Joseph D.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY USA. [Buxbaum, Joseph D.; Yue, Zhenyu] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY USA. [Buxbaum, Joseph D.; Paisan-Ruiz, Coro] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY USA. [Buxbaum, Joseph D.; Paisan-Ruiz, Coro] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY USA. [Buxbaum, Joseph D.; Yue, Zhenyu; Paisan-Ruiz, Coro] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY USA. RP Paisan-Ruiz, C (reprint author), Icahn Sch Med Mt Sinai, Dept Neurol, 1 Gustave L Levy Pl, New York, NY USA. EM coro.paisan-ruiz@mssm.edu RI Paisan-Ruiz, Coro/C-2912-2009; OI Buxbaum, Joseph/0000-0001-8898-8313 FU Parkinson's Disease Foundation; Ellison Foundation; Michael J. Fox Foundation; NIH/NINDS [R01NS060809, R01NS072359, R37NS036251, R01NS079388]; NIMH [R01MH095797] FX Contract grant sponsors: The Parkinson's Disease Foundation; Ellison Foundation; Michael J. Fox Foundation; NIH/NINDS (R01NS060809, R01NS072359, R37NS036251, R01NS079388); NIMH (R01MH095797). NR 53 TC 72 Z9 74 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1059-7794 J9 HUM MUTAT JI Hum. Mutat. PD SEP PY 2013 VL 34 IS 9 BP 1200 EP 1207 DI 10.1002/humu.22372 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 200YZ UT WOS:000323109200004 PM 23804563 ER PT J AU Young, RH Teilum, D Talerman, A AF Young, Robert H. Teilum, Dorthe Talerman, Aleksander TI History of Gynecological Pathology XXV. Dr Gunnar Teilum SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Gunnar Teilum; Historical essay; Histopathology ID ENDODERMAL SINUS TUMORS; YOLK-SAC-TUMOR; ALPHA-FETOPROTEIN; CLASSIFICATION; CARCINOMA; OVARY; MESONEPHROMA; TESTIS C1 [Teilum, Dorthe] Rigshospitalet, Sect Breast Surg, Copenhagen, Denmark. [Young, Robert H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs, Boston, MA USA. RP Young, RH (reprint author), Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. EM rhyoung@partners.org NR 33 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD SEP PY 2013 VL 32 IS 5 BP 520 EP 527 DI 10.1097/PGP.0b013e31827ddd42 PG 8 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA 203OQ UT WOS:000323302900013 PM 23902928 ER PT J AU Trivedi, MH Bandelow, B Demyttenaere, K Papakosts, GI Szamosi, J Earley, W Eriksson, H AF Trivedi, Madhukar H. Bandelow, Borwin Demyttenaere, Koen Papakosts, George I. Szamosi, Johan Earley, Willie Eriksson, Hans TI Evaluation of the effects of extended release quetiapine fumarate monotherapy on sleep disturbance in patients with major depressive disorder: a pooled analysis of four randomized acute studies SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Atypical antipsychotic; major depressive disorder; monotherapy; quetiapine XR; sleep disturbance ID ASTERISK-D REPORT; DOUBLE-BLIND; XR MONOTHERAPY; INSOMNIA; SYMPTOMS; EFFICACY; TOLERABILITY; ANXIETY; SCALE; RISK AB Effects of once-daily extended-release quetiapine fumarate (quetiapine XR) monotherapy on sleep quality and disturbance in patients with major depressive disorder (MDD) were evaluated. Pooled data from four 6- or 8-wk placebo-controlled quetiapine XR (50-300 mg/d) monotherapy studies (D1448C00001; D1448C00002; D1448C00003; D1448C00004) were analysed. Primary efficacy end-point was change from randomization in Montgomery Asberg Depression Rating Scale (MADRS) score. Post hoc analyses of secondary end-points were conducted for change from randomization in: MADRS item 4 (reduced sleep); Hamilton Rating Scale for Depression (HAMD) items 4 (insomnia-early), 5 (insomnia-middle), 6 (insomnia-late) and sleep disturbance factor (items 4+5+6) scores; Pittsburgh Sleep Quality Index (PSQI) global scores. MADRS total score change was also evaluated in patients experiencing high and low baseline sleep disturbance (HAMD sleep disturbance factor scores >= 4 and <4, respectively). In total, 1808 patients were randomized to quetiapine XR or placebo across four studies. At last assessment, quetiapine XR reduced MADRS item 4, HAMD items 4, 5 and 6, HAMD sleep disturbance factor score and PSQI global scores from baseline vs. placebo (p<0.001). For those experiencing high sleep disturbance (n=865, quetiapine XR; n=514, placebo), quetiapine XR improved MADRS total score vs. placebo at all visits (p<0.001). For those with low sleep disturbance (n=252, quetiapine XR; n=121, placebo), quetiapine XR improved MADRS total score vs. placebo at weeks 2 (p<0.001), 4 and 6 (both p<0.05). In conclusion, quetiapine XR (50-300 mg/d) monotherapy improved symptoms of sleep disturbance vs. placebo in patients with MDD, including those with either high or low baseline sleep disturbance levels. C1 [Trivedi, Madhukar H.] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Bandelow, Borwin] Univ Goettingen, Dept Psychiat & Psychotherapy, Gottingen, Germany. [Demyttenaere, Koen] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Papakosts, George I.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Szamosi, Johan; Eriksson, Hans] AstraZeneca, R&D, Sodertalje, Sweden. [Earley, Willie] AstraZeneca, Wilmington, DE USA. RP Trivedi, MH (reprint author), Univ Texas SW Med Ctr Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM madhukar.trivedi@utsouthwestern.edu RI Bandelow, Borwin/E-7295-2011 OI Bandelow, Borwin/0000-0003-2511-3768 FU AstraZeneca Pharmaceuticals; AstraZeneca FX These studies were supported by AstraZeneca Pharmaceuticals and were registered at ClinicalTrials.gov (D1448C00001 study identifier number NCT00320268; D1448C00002 study identifier number NCT00321490; D1448C00003 study identifier number NCT00326144; D1448C00004 study identifier number NCT00351169). We thank Jocelyn Woodcock, MPhil, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca. NR 40 TC 5 Z9 5 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD SEP PY 2013 VL 16 IS 8 BP 1733 EP 1744 DI 10.1017/S146114571300028X PG 12 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 201TQ UT WOS:000323166300004 PM 23673347 ER PT J AU Reimer, B Fried, R Mehler, B Joshi, G Bolfek, A Godfrey, KM Zhao, N Goldin, R Biederman, J AF Reimer, Bryan Fried, Ronna Mehler, Bruce Joshi, Gagan Bolfek, Anela Godfrey, Kathryn M. Zhao, Nan Goldin, Rachel Biederman, Joseph TI Brief Report: Examining Driving Behavior in Young Adults with High Functioning Autism Spectrum Disorders: A Pilot Study Using a Driving Simulation Paradigm SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE Driving behavior; High functioning autism spectrum disorder; Distraction; Cognitive workload; Driving simulation ID 3 AGE-GROUPS; ATTENTION; IMPACT; DRIVERS; PERFORMANCE; VALIDATION; VALIDITY; CHILDREN; TASK AB Although it is speculated that impairments associated with autism spectrum disorder (ASD) will adversely affect driving performance, little is known about the actual extent and nature of the presumed deficits. Ten males (18-24 years of age) with a diagnosis of high functioning autism and 10 age matched community controls were recruited for a driving simulation experiment. Driving behavior, skin conductance, heart rate, and eye tracking measurements were collected. The high functioning ASD participants displayed a nominally higher and unvaried heart rate compared to controls. With added cognitive demand, they also showed a gaze pattern suggestive of a diversion of visual attention away from high stimulus areas of the roadway. This pattern deviates from what is presumed to be optimal safe driving behavior and appears worthy of further study. C1 [Reimer, Bryan; Mehler, Bruce; Godfrey, Kathryn M.; Zhao, Nan] Univ New England, MIT, Transportat Ctr, AgeLab, Cambridge, MA 02139 USA. [Fried, Ronna; Joshi, Gagan; Bolfek, Anela; Goldin, Rachel; Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Fried, Ronna; Joshi, Gagan; Bolfek, Anela; Goldin, Rachel; Biederman, Joseph] Massachusetts Gen Hosp, Clin & Res Program Adult ADHD, Boston, MA 02114 USA. [Fried, Ronna; Joshi, Gagan; Bolfek, Anela; Goldin, Rachel; Biederman, Joseph] Harvard Univ, Dept Psychiat, Sch Med, Boston, MA 02114 USA. RP Reimer, B (reprint author), Univ New England, MIT, Transportat Ctr, AgeLab, 77 Massachusetts Ave,Room E40-291, Cambridge, MA 02139 USA. EM reimer@mit.edu RI Mehler, Bruce/E-4538-2017; Reimer, Bryan/G-6431-2010 OI Mehler, Bruce/0000-0001-5929-4179; Reimer, Bryan/0000-0003-4850-8738 NR 29 TC 13 Z9 14 U1 1 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD SEP PY 2013 VL 43 IS 9 BP 2211 EP 2217 DI 10.1007/s10803-013-1764-4 PG 7 WC Psychology, Developmental SC Psychology GA 202XD UT WOS:000323253100020 PM 23338532 ER PT J AU Hung, AY Ahveninen, J Cheng, YW AF Hung, An-Yi Ahveninen, Jyrki Cheng, Yawei TI Atypical mismatch negativity to distressful voices associated with conduct disorder symptoms SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE Conduct disorder (CD); distressful voices; impulsivity; juvenile delinquents; mismatch negativity (MMN) ID CALLOUS-UNEMOTIONAL TRAITS; SHORT-TERM PLASTICITY; AUDITORY-CORTEX; ANTISOCIAL-BEHAVIOR; PREFRONTAL LESIONS; ADOLESCENTS; BRAIN; IMPULSIVITY; CHILDHOOD; CHILDREN AB Background: Although a general consensus holds that emotional reactivity in youth with conduct disorder (CD) symptoms arises as one of the main causes of successive aggression, it remains to be determined whether automatic emotional processing is altered in this population. Methods: We measured auditory event-related potentials (ERP) in 20 young offenders and 20 controls, screened for DSM-IV criteria of CD and evaluated using the youth version of Hare Psychopathy Checklist (PCL:YV), State-Trait Anxiety Inventory (STAI) and Barrett Impulsiveness Scale (BIS-11). In an oddball design, sadly or fearfully spoken deviant' syllables were randomly presented within a train of emotionally neutral standard' syllables. Results: In young offenders meeting with CD criteria, the ERP component mismatch negativity (MMN), presumed to reflect preattentive auditory change detection, was significantly stronger for fearful than sad syllables. No MMN differences for fearful versus sad syllables were observed in controls. Analyses of nonvocal deviants, matched spectrally with the fearful and sad sounds, supported our interpretation that the MMN abnormalities in juvenile offenders were related to the emotional content of sounds, instead of purely acoustic factors. Further, in the young offenders with CD symptoms, strong MMN amplitudes to fearful syllables were associated with high impulsive tendencies (PCL:YV, Factor 2). Higher trait and state anxiety, assessed by STAI, were positively correlated with P3a amplitudes to fearful and sad syllables, respectively. The differences in group-interaction MMN/P3a patterns to emotional syllables and nonvocal sounds could be speculated to suggest that there is a distinct processing route for preattentive processing of species-specific emotional information in human auditory cortices. Conclusions: Our results suggest that youths with CD symptoms may process distressful voices in an atypical fashion already at the preattentive level. This auditory processing abnormality correlated with increased impulsivity and anxiety. Our results may help to shed light on the neural mechanisms of aggression. C1 [Hung, An-Yi; Cheng, Yawei] Natl Yang Ming Univ, Inst Neurosci, Taipei 112, Taiwan. [Hung, An-Yi; Cheng, Yawei] Natl Yang Ming Univ, Brain Res Ctr, Taipei 112, Taiwan. [Ahveninen, Jyrki] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp,Dept Radiol, Charlestown, MA USA. [Cheng, Yawei] Natl Yang Ming Univ Hosp, Dept Rehabil, Yilan, Taiwan. RP Cheng, YW (reprint author), Natl Yang Ming Univ, Inst Neurosci, 155,Sec 2,St Linong, Taipei 112, Taiwan. EM ywcheng2@ym.edu.tw FU National Science Council [NSC 99-2314-B-010-037-MY3, NSC 100-2628-H-010-001-MY3]; National Yang-Ming University Hospital [RD2011-005]; Ministry of Education; Ministry of Education, Aim for the Top University Plan; National Institutes of Health [R01MH083744, R21DC010060, R01HD040712, R01NS037462] FX The study was funded by National Science Council (NSC 99-2314-B-010-037-MY3; NSC 100-2628-H-010-001-MY3) and National Yang-Ming University Hospital (RD2011-005), and was also supported by a grant from the Ministry of Education (A grant from Ministry of Education, Aim for the Top University Plan). Author J.A. was supported by National Institutes of Health Awards R01MH083744, R21DC010060, R01HD040712, and R01NS037462. None of the authors have any conflicts of interest. The authors would like to thank Dr. Sharon Furtak for proofreading the whole article and Dr. Wei-Tang Chang for the MMN scalp potential analyses. NR 64 TC 10 Z9 11 U1 3 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9630 EI 1469-7610 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD SEP PY 2013 VL 54 IS 9 BP 1016 EP 1027 DI 10.1111/jcpp.12076 PG 12 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 202XI UT WOS:000323253700011 PM 23701279 ER PT J AU Chiu, CJ Wray, LA Lu, FH Beverly, EA AF Chiu, Ching-Ju Wray, Linda A. Lu, Feng-Hwa Beverly, Elizabeth A. TI BMI Change Patterns and Disability Development of Middle-aged Adults with Diabetes: A Dual Trajectory Modeling Approach SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE weight; physical function; diabetes; group-based modeling ID BODY-MASS INDEX; WEIGHT CHANGE; OLDER-ADULTS; SELF-REPORT; GLYCEMIC CONTROL; SAS PROCEDURE; TYPE-2; DIAGNOSIS; HEALTH; IMPACT AB Few longitudinal studies have examined associations between body mass index (BMI) changes in adults with diabetes and the development of disability. To investigate association patterns between BMI and disability in middle-aged adults with diabetes. Retrospective cohort design with data from the 1992-2006 Health and Retirement Study (HRS). A group-based joint trajectory method identified distinct BMI change trajectories and their link to subsequent disability trajectories. U.S. nationally representative adults aged 51-61 who reported a diagnosis of diabetes in the 1992 HRS (N = 1,064). BMI and self-reported disability score were the main variables. Sociodemographic, clinical, behavioral, and diabetes-related factors were also examined. Four distinct weight trajectories (stable normal weight, 28.7 %; stable overweight, 46.2 %; loss and regain obese, 18.0 %; weight cumulating morbidly obese, 7.1 %) and three disability trajectories (little or low increase, 34.4 %; moderate increase, 45.4 %; chronic high increase, 20.2 %) best characterized the long-term patterns of BMI and disability change in middle-aged adults with diabetes. Adults in stable normal weight had the highest probability of being in the little/low increase disability group; however, one in five adults in that group progressed into chronic high disability, a higher proportion compared to the stable overweight group. Although there were various ways in which the two trajectories were linked, the beneficial impacts of optimizing weight in adults with diabetes were supported. In addition, the complexity of diabetes control in those with relatively normal weight was highlighted from this study. (C) Society of General Internal Medicine 2013 C1 [Chiu, Ching-Ju; Lu, Feng-Hwa] Natl Cheng Kung Univ, Coll Med, Inst Gerontol, Tainan 70101, Taiwan. [Wray, Linda A.] Penn State Univ, Dept Biobehav Hlth, University Pk, PA 16802 USA. [Lu, Feng-Hwa] Natl Cheng Kung Univ Hosp, Dept Family Med, Tainan 70428, Taiwan. [Beverly, Elizabeth A.] Harvard Univ, Sch Med, Joslin Diabet Med Ctr, Boston, MA USA. RP Chiu, CJ (reprint author), Natl Cheng Kung Univ, Coll Med, Inst Gerontol, 1 Univ Rd, Tainan 70101, Taiwan. EM cjchiu@mail.ncku.edu.tw FU Office of Research and Development at National Cheng Kung University [D100-35B19] FX This work was supported by Office of Research and Development at National Cheng Kung University (D100-35B19). We acknowledge the valuable editorial help provided by Kaileen Yeh and Siao-Ling Lee. The earlier version of this paper was presented at the 5th Annual Research Retreat of the Penn State Institute for Diabetes and Obesity. NR 33 TC 5 Z9 5 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2013 VL 28 IS 9 BP 1150 EP 1156 DI 10.1007/s11606-013-2399-z PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 202XR UT WOS:000323254700014 PM 23463456 ER PT J AU Smith, KJ Wateska, A Nowalk, MP Raymund, M Lee, BY Zimmerman, RK Fine, MJ AF Smith, Kenneth J. Wateska, Angela Nowalk, M. Patricia Raymund, Mahlon Lee, Bruce Y. Zimmerman, Richard K. Fine, Michael J. TI Cost-Effectiveness of Procalcitonin-Guided Antibiotic Use in Community Acquired Pneumonia SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE cost-effectiveness analysis; procalcitonin; community-acquired pneumonia ID RANDOMIZED-CONTROLLED-TRIAL; LOW-RISK PATIENTS; LENGTH-OF-STAY; CRITICAL PATHWAY; REDUCE DURATION; CARE; THERAPY; IMPLEMENTATION; METAANALYSIS; COHORT AB Although prior randomized trials have demonstrated that procalcitonin-guided antibiotic therapy effectively reduces antibiotic use in patients with community-acquired pneumonia (CAP), uncertainties remain regarding use of procalcitonin protocols in practice. To estimate the cost-effectiveness of procalcitonin protocols in CAP. Decision analysis using published observational and clinical trial data, with variation of all parameter values in sensitivity analyses. Hypothetical patient cohorts who were hospitalized for CAP. Procalcitonin protocols vs. usual care. Costs and cost per quality adjusted life year gained. When no differences in clinical outcomes were assumed, consistent with clinical trials and observational data, procalcitonin protocols cost $10-$54 more per patient than usual care in CAP patients. Under these assumptions, results were most sensitive to variations in: antibiotic cost, the likelihood that antibiotic therapy was initiated less frequently or over shorter durations, and the likelihood that physicians were nonadherent to procalcitonin protocols. Probabilistic sensitivity analyses, incorporating procalcitonin protocol-related changes in quality of life, found that protocol use was unlikely to be economically reasonable if physician protocol nonadherence was high, as observational study data suggest. However, procalcitonin protocols were favored if they decreased hospital length of stay. Procalcitonin protocol use in hospitalized CAP patients, although promising, lacks physician nonadherence and resource use data in routine care settings, which are needed to evaluate its potential role in patient care. (C) Society of General Internal Medicine 2013 C1 [Smith, Kenneth J.; Wateska, Angela; Lee, Bruce Y.; Fine, Michael J.] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. [Nowalk, M. Patricia; Raymund, Mahlon; Zimmerman, Richard K.] Univ Pittsburgh, Sch Med, Dept Family Med, Pittsburgh, PA 15213 USA. [Fine, Michael J.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ & Promot, Pittsburgh, PA USA. RP Smith, KJ (reprint author), Univ Pittsburgh, Sch Med, Dept Med, 200 Meyran Ave,Suite 200, Pittsburgh, PA 15213 USA. EM smithkj2@upmc.edu OI Smith, Kenneth J/0000-0001-8088-566X; Zimmerman, Richard/0000-0001-5941-6092 FU NIAID [R01AI 076256] FX Supported by the NIAID (R01AI 076256) NR 29 TC 13 Z9 13 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2013 VL 28 IS 9 BP 1157 EP 1164 DI 10.1007/s11606-013-2400-x PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 202XR UT WOS:000323254700015 PM 23463457 ER PT J AU Yoon, J Rose, DE Canelo, I Upadhyay, AS Schectman, G Stark, R Rubenstein, LV Yano, EM AF Yoon, Jean Rose, Danielle E. Canelo, Ismelda Upadhyay, Anjali S. Schectman, Gordon Stark, Richard Rubenstein, Lisa V. Yano, Elizabeth M. TI Medical Home Features of VHA Primary Care Clinics and Avoidable Hospitalizations SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE medical home; avoidable hospitalizations; access; care coordination ID HEALTH-CARE; SENSITIVE CONDITIONS; ILLNESS; ACCESS; RATES AB As the Veterans Health Administration (VHA) reorganizes providers into the patient-centered medical home, questions remain whether this model of care can demonstrate improved patient outcomes and cost savings. We measured adoption of medical home features by VHA primary care clinics prior to widespread implementation of the patient-centered medical home and examined if they were associated with lower risk and costs of potentially avoidable hospitalizations. Secondary patient data was linked to clinic administrative and survey data. Patient and clinic factors in the baseline year (FY2009) were used to predict patient outcomes in the follow-up year. 2,853,030 patients from 814 VHA primary care clinics Patient outcomes were measured by hospitalizations for an ambulatory care sensitive condition (ACSC) and their costs and identified through diagnosis and procedure codes from inpatient records. Clinic adoption of medical home features was obtained from the American College of Physicians Medical Home BuilderA (R). The overall mean home builder score in the study clinics was 88 (SD = 13) or 69 %. In adjusted analyses an increase of 10 points in the medical home adoption score in a clinic decreased the odds of an ACSC hospitalization for patients by 3 % (P = 0.032). By component, higher access and scheduling (P = 0.004) and care coordination and transitions (P = 0.020) component scores were related to lower risk of an ACSC hospitalization, and higher population management was related to higher risk (P = 0.023). Total medical home features was not related to ACSC hospitalization costs among patients with at least one (P = 0.074). Greater adoption of medical home features by VHA primary care clinics was found to be significantly associated with lower risk of avoidable hospitalizations with access and scheduling and care coordination/transitions in care as key factors. (C) Society of General Internal Medicine 2013 C1 [Yoon, Jean; Upadhyay, Anjali S.] VA Palo Alto Hlth Care Syst, Hlth Econ Resource Ctr, Menlo Pk, CA 94025 USA. [Yoon, Jean] VA Palo Alto Hlth Care Syst, Ctr Hlth Care Evaluat, Menlo Pk, CA USA. [Rose, Danielle E.; Canelo, Ismelda; Rubenstein, Lisa V.; Yano, Elizabeth M.] VA Greater Los Angeles, Ctr Ctr Excellence Study Healthcare Provider Beha, Sepulveda, CA USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Rubenstein, Lisa V.] RAND Corp, Santa Monica, CA USA. [Yano, Elizabeth M.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Schectman, Gordon; Stark, Richard] Vet Hlth Adm, Patient Care Serv, Washington, DC USA. RP Yoon, J (reprint author), VA Palo Alto Hlth Care Syst, Hlth Econ Resource Ctr, 795 Willow Rd 152 MPD, Menlo Pk, CA 94025 USA. EM jean.yoon@va.gov FU Department of Veterans Affairs, Veterans Health Administration Office of Research and Development, Health Services Research and Development [IIR 09-082]; VA HSR&D Senior Research Career Scientist Award [RCS 05-195] FX This work was supported by the Department of Veterans Affairs, Veterans Health Administration Office of Research and Development, Health Services Research and Development (grant #: IIR 09-082). Dr. Yano's effort was covered by a VA HSR&D Senior Research Career Scientist Award (Project #RCS 05-195). The authors wish to acknowledge Belinda Black MSPH, Office of Patient Care Services, Veterans Health Administration for administering the clinic survey and Michael Barr MD, MBA, FACP, American College of Physicians for providing valuable comments. Preliminary results from this study were presented at the Academy Health Annual Research Meeting, June 24-26, 2012, in Orlando, FL and the VA Health Services Research and Development Meeting, July 17-19, in Washington, DC. NR 21 TC 15 Z9 15 U1 0 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2013 VL 28 IS 9 BP 1188 EP 1194 DI 10.1007/s11606-013-2405-5 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 202XR UT WOS:000323254700019 PM 23529710 ER PT J AU Cronholm, PF Shea, JA Werner, RM Miller-Day, M Tufano, J Crabtree, BF Gabbay, R AF Cronholm, Peter F. Shea, Judy A. Werner, Rachel M. Miller-Day, Michelle Tufano, Jim Crabtree, Benjamin F. Gabbay, Robert TI The Patient Centered Medical Home: Mental Models and Practice Culture Driving the Transformation Process SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE patient-centered care; primary health care; delivery of health care; workplace; program evaluation ID PRIMARY-CARE; HEALTH-CARE; IMPROVEMENT; QUALITY AB The Patient-Centered Medical Home (PCMH) has become a dominant model of primary care re-design. The PCMH model is a departure from more traditional models of healthcare delivery and requires significant transformation to be realized. To describe factors shaping mental models and practice culture driving the PCMH transformation process in a large multi-payer PCMH demonstration project. Individual interviews were conducted at 17 primary care practices in South Eastern Pennsylvania. A total of 118 individual interviews were conducted with clinicians (N = 47), patient educators (N = 4), office administrators (N = 12), medical assistants (N = 26), front office staff (N = 7), nurses (N = 4), care managers (N = 11), social workers (N = 4), and other stakeholders (N = 3). A multi-disciplinary research team used a grounded theory approach to develop the key constructs describing factors shaping successful practice transformation. Three central themes emerged from the data related to changes in practice culture and mental models necessary for PCMH practice transformation: 1) shifting practice perspectives towards proactive, population-oriented care based in practice-patient partnerships; 2) creating a culture of self-examination; and 3) challenges to developing new roles within the practice through distribution of responsibilities and team-based care. The most tension in shifting the required mental models was displayed between clinician and medical assistant participants, revealing significant barriers towards moving away from clinician-centric care. Key factors driving the PCMH transformation process require shifting mental models at the individual level and culture change at the practice level. Transformation is based upon structural and process changes that support orientation of practice mental models towards perceptions of population health, self-assessment, and the development of shared decision-making. Staff buy-in to the new roles and responsibilities driving PCMH transformation was described as central to making sustainable change at the practice level; however, key barriers related to clinician autonomy appeared to interfere with the formation of team-based care. (C) Society of General Internal Medicine 2013 C1 [Cronholm, Peter F.] Univ Penn, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. [Cronholm, Peter F.] Univ Penn, Ctr Publ Hlth Initiat, Philadelphia, PA 19104 USA. [Cronholm, Peter F.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Shea, Judy A.; Werner, Rachel M.] Univ Penn, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Werner, Rachel M.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Miller-Day, Michelle] Chapman Univ, Dept Commun Studies, Orange, CA USA. [Tufano, Jim] Univ Washington, Sch Med, Dept Biomed Informat & Med Educ, Seattle, WA USA. [Crabtree, Benjamin F.] UMDNJ Robert Wood Johnson Med Sch, Dept Family Med & Community Hlth, New Brunswick, NJ USA. [Gabbay, Robert] Penn State Coll Med, Penn State Milton S Hershey Med Ctr, Penn State Hershey Diabet Inst, Diabet Program, Hershey, PA USA. RP Cronholm, PF (reprint author), Univ Penn, Dept Family Med & Community Hlth, 141 Anat & Chem Bldg,3620 Hamilton Walk, Philadelphia, PA 19104 USA. EM peter.cronholm@uphs.upenn.edu FU Agency for Healthcare Research and Quality [5R18HS019150]; Aetna Foundation FX This project was supported by a grant from the Agency for Healthcare Research and Quality (5R18HS019150) and funds from Aetna Foundation. NR 30 TC 25 Z9 25 U1 5 U2 30 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2013 VL 28 IS 9 BP 1195 EP 1201 DI 10.1007/s11606-013-2415-3 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 202XR UT WOS:000323254700020 PM 23539283 ER PT J AU Ganzini, L Denneson, LM Press, N Bair, MJ Helmer, DA Poat, J Dobscha, SK AF Ganzini, Linda Denneson, Lauren M. Press, Nancy Bair, Matthew J. Helmer, Drew A. Poat, Jennifer Dobscha, Steven K. TI Trust is the Basis for Effective Suicide Risk Screening and Assessment in Veterans SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE depression; post-traumatic stress disorder; qualitative methods; screening; suicide; veterans ID CARE AB To reduce suicides among Veterans, the Department of Veterans Affairs (VA) has designated suicide risk assessments for Veterans who screen positive for depression or post-traumatic stress disorder as a national performance goal. Many VA Medical Centers (VAMCs) are using brief suicidal ideation screens, administered in non-mental health ambulatory care settings, as the first step in the assessment process. To explore Veterans' perceptions of the suicide screening and risk assessment process, the barriers and facilitators to disclosing suicidal thoughts, and perceptions of possible consequences of revealing suicidal thoughts. Investigators recorded one semi-structured interview with each Veteran. Transcripts were analyzed using a modified grounded theory approach. Thirty-four Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans who screened positive for suicidal ideation in non-mental health ambulatory care settings in 2009 and 2010. Veterans accepted the need to assess suicide risk. They increasingly experienced attempts to suppress and avoid thoughts of suicide as burdensome and exhausting. Despite this, Veterans often failed to disclose severe and pervasive suicidal thoughts when screened because: (1) they considered suicidal thoughts as shameful and a sign of weakness; (2) they believed suicidal thoughts were private and not to be divulged to strangers; (3) they worried that disclosure would lead to unwanted hospitalization or medication recommendations; and (4) the templated computer reminder process was perceived as perfunctory and disrespectful. In contrast, admitting and discussing thoughts of suicide with a health provider who focused on building a relationship, demonstrated genuineness and empathy, offered information on the rationale for suicide risk assessment, and used straightforward and understandable language, all promoted trust that resulted in more honest disclosure of suicidal thoughts. In ambulatory care settings, both provider behaviors and system modifications may lead to more honest disclosure of suicidal thoughts. (C) Society of General Internal Medicine 2013 C1 [Ganzini, Linda; Denneson, Lauren M.; Dobscha, Steven K.] Portland VA Med Ctr, Portland Ctr Study Chron Comorbid Phys & Mental D, Portland, OR 97207 USA. [Ganzini, Linda; Denneson, Lauren M.; Dobscha, Steven K.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Press, Nancy] Oregon Hlth & Sci Univ, Dept Publ Hlth, Portland, OR 97201 USA. [Press, Nancy; Poat, Jennifer] Oregon Hlth & Sci Univ, Dept Nursing, Portland, OR 97201 USA. [Bair, Matthew J.] Richard L Roudebush Vet Adm Med Ctr, Indianapolis, IN 46202 USA. [Helmer, Drew A.] W Haven Vet Affairs Med Ctr, West Haven, CT USA. [Helmer, Drew A.] VA New Jersey Hlth Care Syst, War Related Illness & Injury Study Ctr, E Orange, NJ USA. RP Ganzini, L (reprint author), Portland VA Med Ctr, Portland Ctr Study Chron Comorbid Phys & Mental D, POB 1034 RD 66, Portland, OR 97207 USA. EM linda.ganzini@va.gov FU Department of Veterans Affairs, Veterans Health Administration, and Health Services Research and Development Service [DHI-08-096] FX We gratefully acknowledge the assistance of Michael Martin; Megan Crutchfield, MPH; and Monica Huffman, BS. This material is based upon work supported by the Department of Veterans Affairs, Veterans Health Administration, and Health Services Research and Development Service Project DHI-08-096. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. NR 17 TC 18 Z9 18 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2013 VL 28 IS 9 BP 1215 EP 1221 DI 10.1007/s11606-013-2412-6 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 202XR UT WOS:000323254700023 PM 23580131 ER PT J AU Jena, AB Prasad, V AF Jena, Anupam B. Prasad, Vinay TI Duty Hour Reform in a Shifting Medical Landscape SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article ID MYOCARDIAL-INFARCTION; PATIENT SAFETY; RESIDENT; SUPERVISION; EMERGENCY; WORK; MORTALITY; EDUCATION; ERROR; CARE AB The circumstances that led to the death of Libby Zion in 1984 prompted national discussions about the impact of resident fatigue on patient outcomes. Nearly 30 years later, national duty hour reforms largely motivated by patient safety concerns have demonstrated a negligible impact of duty hour reductions on patient mortality. We suggest that the lack of an impact of duty hour reforms on patient mortality is due to a different medical landscape today than existed in 1984. Improvements in quality of care made possible by computerized order entry, automated medication checks, inpatient pharmacists, and increased resident supervision have, among other systemic changes, diminished the adverse impact that resident fatigue is able to have on patient outcomes. Given this new medical landscape, advocacy towards current and future duty hour reforms may be best justified by evidence of the impact of duty hour reform on resident wellbeing, education, and burnout. C1 [Jena, Anupam B.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Jena, Anupam B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jena, Anupam B.] Natl Bur Econ Res, Cambridge, MA 02138 USA. [Prasad, Vinay] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Jena, AB (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM jena@hcp.med.harvard.edu; vinayak.prasad@nih.gov NR 23 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2013 VL 28 IS 9 BP 1238 EP 1240 DI 10.1007/s11606-013-2439-8 PG 3 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 202XR UT WOS:000323254700028 PM 23568191 ER PT J AU Cassese, T Kaplan, E Douglas, V Dhaliwal, G AF Cassese, Todd Kaplan, Elizabeth Douglas, Vanja Dhaliwal, Gurpreet TI Getting to the Right Question SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Editorial Material DE diagnostic reasoning; clinical problem solving; history-taking; weakness ID PRIMARY SJOGRENS-SYNDROME; HYPOKALEMIC PERIODIC PARALYSIS; RESPIRATORY ARREST; PHYSICIANS; DIAGNOSIS; ACIDOSIS C1 [Cassese, Todd] Quinnipiac Univ, Dept Med Sci, Frank H Netter MD Sch Med, Hamden, CT 06518 USA. [Kaplan, Elizabeth] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Douglas, Vanja] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA. [Dhaliwal, Gurpreet] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, San Francisco, CA USA. RP Cassese, T (reprint author), Quinnipiac Univ, Dept Med Sci, Frank H Netter MD Sch Med, 275 Mt Carmel Ave, Hamden, CT 06518 USA. EM todd.cassese@quinnipiac.edu NR 15 TC 1 Z9 1 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD SEP PY 2013 VL 28 IS 9 BP 1242 EP 1246 DI 10.1007/s11606-012-2254-7 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 202XR UT WOS:000323254700030 PM 23184311 ER PT J AU Bell, ME Larsen, SE Goodman, LA Dutton, MA AF Bell, Margret E. Larsen, Sadie E. Goodman, Lisa A. Dutton, Mary Ann TI Comparison of Victims' Reports and Court Records of Intimate Partner Violence Perpetrators' Criminal Case Outcomes SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE intimate partner violence; domestic violence; criminal court; legal ID PROSECUTION AB Intimate partner violence (IPV) victims often report feeling confused and uninformed about court proceedings, including even about the final disposition of the case against their partner. This is problematic because victims' decisions in responding to subsequent abuse may be significantly influenced by their beliefs about the outcomes of prior court experiences. Also, researchers often rely on victim report of court case outcomes; discrepancies between women's reports and official records may account for some of the conflicting findings in the empirical literature. In the current study, we compared the reports of case outcome given by 81 women recruited immediately after the final hearing of an IPV-related criminal case against their perpetrator with court records of case outcome. Findings revealed a fair level of agreement between women's reports and court files that was significantly different from the level of agreement expected by chance, but far from perfect. Level of agreement increased substantially when cases involving suspended sentences were removed. In reviewing these findings, we discuss the extent to which results can or cannot be interpreted as reflecting the accuracy of women's knowledge and review their implications for IPV researchers and court systems. C1 [Bell, Margret E.] VA Boston Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, Boston, MA 02130 USA. [Bell, Margret E.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Larsen, Sadie E.] Clement J Zablocki VA Med Ctr, Milwaukee, WI USA. [Larsen, Sadie E.] Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI 53226 USA. [Goodman, Lisa A.] Boston Coll, Dept Counseling Dev & Educ Psychol, Lynch Sch Educ, Chestnut Hill, MA 02167 USA. [Dutton, Mary Ann] Georgetown Univ, Dept Psychiat, Washington, DC USA. RP Bell, ME (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 150 S Huntington Ave,116B-3, Boston, MA 02130 USA. EM margret.bell@va.gov NR 9 TC 0 Z9 0 U1 1 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD SEP PY 2013 VL 28 IS 14 BP 2966 EP 2977 DI 10.1177/0886260513488693 PG 12 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA 205HC UT WOS:000323433000009 PM 23708777 ER PT J AU Vranceanu, AM Merker, VL Park, E Plotkin, SR AF Vranceanu, Ana-Maria Merker, Vanessa L. Park, Elyse Plotkin, Scott R. TI Quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis: a systematic review of the literature SO JOURNAL OF NEURO-ONCOLOGY LA English DT Review DE Neurofibromatosis 1; Neurofibromatosis 2; Schwannomatosis; Quality of life ID TYPE-1; DISORDERS; CANCER; COHORT AB The aim of this study was to review the literature on quality of life among adult patients with neurofibromatosis 1, neurofibromatosis 2 and schwannomatosis, and to identify the specific aspects of quality of life that were studied and reported in this population. We also set out to report predictors of quality of life. Published research reports were included if they described quality of life in this population and met methodological quality according to a list of predefined criteria. Eight studies (7 in NF1, 1 in NF2, 0 in schwannomatosis), conducted between 2001 and 2013, met inclusion criteria. The methodological quality of the eight studies was mostly high according to ratings by predefined criteria. Most studies reported that patients with NF experience decreased quality of life when compared to the general population. Visibility and disease severity were strong predictors of skin-specific quality of life in NF1 patients. However, the majority of findings regarding predictors of quality of life were weak or inconclusive. Given the decreased quality of life in NF patients, it is important to examine more comprehensively the psychosocial factors in this population, especially in patients with NF2 and schwannomatosis. Mind body interventions that address these domains may provide comprehensive and efficacious long term treatment. C1 [Vranceanu, Ana-Maria; Park, Elyse] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Merker, Vanessa L.; Plotkin, Scott R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Merker, Vanessa L.; Plotkin, Scott R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. RP Vranceanu, AM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Yawkey 9E,55 Fruit St, Boston, MA 02114 USA. EM avranceanu@partners.org; splotkin@partners.org OI Merker, Vanessa/0000-0002-4542-5227 NR 22 TC 9 Z9 9 U1 2 U2 24 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD SEP PY 2013 VL 114 IS 3 BP 257 EP 262 DI 10.1007/s11060-013-1195-2 PG 6 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 203EZ UT WOS:000323275000001 PM 23817811 ER PT J AU Cahill, ME Remmers, C Jones, KA Xie, Z Sweet, RA Penzes, P AF Cahill, Michael E. Remmers, Christine Jones, Kelly A. Xie, Zhong Sweet, Robert A. Penzes, Peter TI Neuregulin1 signaling promotes dendritic spine growth through kalirin SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE environmental enrichment; ERBB4; NRG1; plasticity; schizophrenia; synapse ID CENTRAL-NERVOUS-SYSTEM; PARVALBUMIN-POSITIVE INTERNEURONS; GDP/GTP EXCHANGE FACTOR; LONG-TERM POTENTIATION; DEVELOPMENTAL PROFILE; BEHAVIORAL PHENOTYPES; SURFACE EXPRESSION; PREFRONTAL CORTEX; TYROSINE KINASE; RECEPTOR ERBB4 AB The biological functions of the neuregulin 1 (NRG1) and ERBB4 genes have received much recent attention due to several studies showing associations between these genes and schizophrenia. Moreover, reduced forebrain dendritic spine density is a consistent feature of schizophrenia. It is thus important to understand the mechanisms whereby NRG1 and erbB4 modulate spine morphogenesis. Here, we show that long-term incubation with NRG1 increases both spine size and density in cortical pyramidal neurons. NRG1 also enhances the content of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors in spines. Knockdown of ERBB4 expression prevented the effects of NRG1 on spine size, but not on spine density. The effects of NRG1 and erbB4 on spines were mediated by the RacGEF kalirin, a well-characterized regulator of dendritic spines. Finally, we show that environmental enrichment, known to promote spine growth, robustly enhances the levels of erbB4 protein in the forebrain. These findings provide a mechanistic link between NRG1 signaling and spine morphogenesis. C1 [Cahill, Michael E.; Remmers, Christine; Jones, Kelly A.; Xie, Zhong; Penzes, Peter] Northwestern Univ, Feinberg Sch Med, Dept Physiol, Chicago, IL 60611 USA. [Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Translat Neurosci Program, Pittsburgh, PA USA. [Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Sweet, Robert A.] VA Pittsburgh Healthcare Syst, Educ & Clin Ctr, VISN Mental Illness Res 4, Pittsburgh, PA USA. [Penzes, Peter] Northwestern Univ, Feinberg Sch Med, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. RP Penzes, P (reprint author), 303 E Chicago Ave, Chicago, IL 60611 USA. EM p-penzes@northwestern.edu RI Xie, Zhong/B-6829-2011; Penzes, Peter/L-3987-2016 OI Xie, Zhong/0000-0002-8348-4455; Penzes, Peter/0000-0001-5449-1640 FU NIH-NIMH [R01MH071316, R01MH097216]; National Alliance for Research on Schizophrenia and Depression (NARSAD); Ruth L. Kirschstein National Research Service Awards [1F31AG031621-01A2, 1F31MH085362]; NIH [R01 MH 071533, R01 AG027224]; VHA [I01 BX000452] FX This study was supported by grants from NIH-NIMH (R01MH071316, R01MH097216), National Alliance for Research on Schizophrenia and Depression (NARSAD) to P. P., Ruth L. Kirschstein National Research Service Awards 1F31AG031621-01A2 to M. E. C and 1F31MH085362 to K.A.J, and research grants from NIH (R01 MH 071533, R01 AG027224) and from the VHA (I01 BX000452) to RAS. All experiments involving animals were done according to the Institutional Animal Care and Use Committee of Northwestern University. M. E. C, C. R, K.A.J., Z.X. performed research and analyzed results. M. E. C., C. R., and P. P. wrote the manuscript, and P. P. and R. A. S. contributed resources necessary to complete this study. NR 54 TC 15 Z9 15 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2013 VL 126 IS 5 BP 625 EP 635 DI 10.1111/jnc.12330 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 204TV UT WOS:000323393400008 PM 23742124 ER PT J AU Mocco, J O'Kelly, C Arthur, A Meyers, PM Hirsch, JA Woo, HH Rasmussen, PA Albuquerque, FC Turk, A Tarr, R Fiorella, D AF Mocco, J. O'Kelly, Cian Arthur, Adam Meyers, Phil M. Hirsch, Joshua A. Woo, Henry H. Rasmussen, Peter A. Albuquerque, Felipe C. Turk, Aquilla Tarr, Rob Fiorella, David TI Randomized clinical trials: the double edged sword SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Editorial Material DE Arteriovenous Malformation ID ACUTE ISCHEMIC-STROKE; BRAIN ARTERIOVENOUS-MALFORMATIONS; ENDOVASCULAR TREATMENT; ONYX; VERTEBROPLASTY; EMBOLIZATION; FRACTURES; THERAPY C1 [Mocco, J.] Vanderbilt Univ Sch Med, Dept Neurosurg, Nashville, TN USA. [O'Kelly, Cian] Univ Edmonton, Dept Neurosurg, Edmonton, AB, Canada. [Arthur, Adam] Semmes Murphey Neurol & Spine Inst, Dept Neurosurg, Memphis, TN USA. [Arthur, Adam] Mid South Imaging & Therapeut, Memphis, TN USA. [Meyers, Phil M.] Columbia Univ, Coll Phys & Surg, Neurol Inst, Dept Neurosurg & Radiol,New York Presbyterian Hos, New York, NY USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Woo, Henry H.] SUNY Stony Brook, Dept Neurosurg, Cerebrovasc Ctr, Stony Brook, NY 11794 USA. [Rasmussen, Peter A.] Cleveland Clin Fdn, Dept Neurosurg, Cleveland, OH 44195 USA. [Albuquerque, Felipe C.] Barrow Neurol Inst, Dept Neurosurg, Phoenix, AZ 85013 USA. [Turk, Aquilla] Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. RP Fiorella, D (reprint author), SUNY Stony Brook, Dept Neurosurg, Cerebrovasc Ctr, Stony Brook, NY 11794 USA. EM David.Fiorella@sbumed.org OI Arthur, Adam/0000-0002-1536-1613 NR 16 TC 9 Z9 9 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2013 VL 5 IS 5 BP 387 EP 390 DI 10.1136/neurintsurg-2013-010882 PG 4 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 201UO UT WOS:000323168700013 PM 23935169 ER PT J AU Hirsch, JA Barr, JD Zoarski, GH AF Hirsch, Joshua A. Barr, John D. Zoarski, Gregg H. TI Sacroplasty: beyond the beginning SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID COMPRESSION FRACTURES; VERTEBRAL AUGMENTATION; VERTEBROPLASTY C1 [Hirsch, Joshua A.] Massachusetts Gen Hosp, Dept NeuroEndovasc Program, Boston, MA 02114 USA. [Barr, John D.] Calif Ctr Neurointervent Surg, La Jolla, CA USA. [Zoarski, Gregg H.] Christiana Hosp, Newark, DE USA. RP Hirsch, JA (reprint author), Massachusetts Gen Hosp, Dept NeuroEndovasc Program, Boston, MA 02114 USA. EM hirsch@snisonline.org NR 14 TC 2 Z9 2 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2013 VL 5 IS 5 BP 395 EP 395 DI 10.1136/neurintsurg-2012-010434 PG 1 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 201UO UT WOS:000323168700016 PM 22753269 ER PT J AU Manchikanti, L Pampati, V Hirsch, JA AF Manchikanti, Laxmaiah Pampati, Vidyasagar Hirsch, Joshua A. TI Analysis of utilization patterns of vertebroplasty and kyphoplasty in the Medicare population SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID INTERVENTIONAL PAIN MANAGEMENT; VERTEBRAL COMPRESSION FRACTURES; UNITED-STATES; RANDOMIZED-TRIAL; PERFECT STORM; TRENDS; AUGMENTATION; GUIDELINES; DISCOURSE; FALLACIES AB Objective To determine the pattern of utilization of vertebral augmentation procedures including vertebroplasty and kyphoplasty of the lumbar and thoracic spine in the Medicare population in the USA. Methods This analysis was performed using a standard 5% national sample of the Centers for Medicare and Medicaid Services physician outpatient billing claims from 2001 to 2008 and the Physician/Supplier Procedure Summary Master File for 2009 and 2010. Overall characteristics of utilization patterns for vertebral augmentation procedures were evaluated using multiple variables. Results From 2002 to 2010, vertebroplasty procedures decreased overall by 24.6% with an average annual decrease of 3.5% per 100000 Medicare population; from 2006 to 2010 the declines were 42.4% overall and 12.9% annually. From 2006 to 2010, kyphoplasty procedures increased overall by 0.8% with an annual average increase of 0.2% per 100000 Medicare population. Conclusion Analysis of growth patterns of vertebroplasty and kyphoplasty in the Medicare population from 2002 to 2010 illustrates a lack of growth of kyphoplasty and a decline in vertebroplasty procedures. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY 42003 USA. [Manchikanti, Laxmaiah] Univ Louisville, Dept Anesthesiol & Perioperat Med, Louisville, KY 40292 USA. [Pampati, Vidyasagar] Pain Management Ctr Paducah, Dept Stat, Paducah, KY 42003 USA. [Hirsch, Joshua A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept NeuroIntervent Radiol, Boston, MA USA. RP Manchikanti, L (reprint author), Pain Management Ctr Paducah, 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.com FU American Society of Interventional Pain Physicians (ASIPP) FX The data from the Centers for Medicare and Medicaid Services (CMS) were purchased for $16 000 by the American Society of Interventional Pain Physicians (ASIPP). There was no other funding. Internal resources were used in preparing this manuscript. NR 28 TC 9 Z9 9 U1 1 U2 2 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2013 VL 5 IS 5 BP 467 EP 472 DI 10.1136/neurintsurg-2012-010337 PG 6 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 201UO UT WOS:000323168700031 PM 22773335 ER PT J AU Deipolyi, AR Hirsch, JA Oklu, R AF Deipolyi, Amy R. Hirsch, Joshua A. Oklu, Rahmi TI Bilateral inferior petrosal sinus sampling with desmopressin SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Article ID DEPENDENT CUSHINGS-SYNDROME; CORTICOTROPIN-RELEASING HORMONE; DIFFERENTIAL-DIAGNOSIS; ACTH; STIMULATION; PITUITARY AB In this technical note, the use of desmopressin to stimulate pituitary adrenocorticotropic hormone secretion in place of the commercially available corticotropin releasing hormone (CRH) in bilateral inferior petrosal sinus sampling is described. Although the use of CRH is the standard of practice, it is currently unavailable in the USA and desmopressin provides reliable results with no additional observed side effects. C1 [Deipolyi, Amy R.; Oklu, Rahmi] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Radiol, Div Vasc Imaging & Intervent, Boston, MA 02115 USA. [Hirsch, Joshua A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Radiol, Div Intervent Neuroradiol, Boston, MA 02115 USA. RP Oklu, R (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Vasc Imaging & Intervent, 55 Fruit St,GRB 290A, Boston, MA 02114 USA. EM roklu@partners.org OI Deipolyi, Amy/0000-0003-3144-386X FU NIBIB NIH HHS [L30 EB012342] NR 13 TC 3 Z9 4 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2013 VL 5 IS 5 BP 487 EP 488 DI 10.1136/neurintsurg-2012-010437 PG 2 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 201UO UT WOS:000323168700035 PM 22735860 ER PT J AU Deipolyi, AR Hirsch, JA Oklu, R AF Deipolyi, Amy R. Hirsch, Joshua A. Oklu, Rahmi TI Caution during use of desmopressin in IPSS SO JOURNAL OF NEUROINTERVENTIONAL SURGERY LA English DT Letter DE Technology ID DEPENDENT CUSHINGS-SYNDROME; DIFFERENTIAL-DIAGNOSIS; DISEASE C1 [Deipolyi, Amy R.; Oklu, Rahmi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Deipolyi, AR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 55 Fruit St,GRB 290A, Boston, MA 02114 USA. EM rahmioklu@gmail.com OI Deipolyi, Amy/0000-0003-3144-386X FU NIBIB NIH HHS [L30 EB012342] NR 8 TC 2 Z9 2 U1 1 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1759-8478 J9 J NEUROINTERV SURG JI J. NeuroInterventional Surg. PD SEP PY 2013 VL 5 IS 5 BP E28 EP E28 DI 10.1136/neurintsurg-2012-010579 PG 1 WC Neuroimaging; Surgery SC Neurosciences & Neurology; Surgery GA 201UO UT WOS:000323168700002 PM 23155116 ER PT J AU Cirnigliaro, CM Fountaine, MF Emmons, R Kirshblum, SC Asselin, P Spungen, AM Bauman, WA AF Cirnigliaro, Christopher M. La Fountaine, Michael F. Emmons, Racine Kirshblum, Steven C. Asselin, Pierre Spungen, Ann M. Bauman, William A. TI Prediction of limb lean tissue mass from bioimpedance spectroscopy in persons with chronic spinal cord injury SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Spinal cord injury; Bioimpedance spectroscopy; Lean tissue mass; Extracellular volume; Intracellular volume; Dual-energy X-ray absorptiometry ID X-RAY ABSORPTIOMETRY; SKELETAL-MUSCLE MASS; FAT-FREE MASS; RESTING ENERGY-EXPENDITURE; BODY-COMPOSITION; BIOELECTRICAL-IMPEDANCE; HEMODIALYSIS-PATIENTS; MEN; WATER; MODEL AB Background: Bioimpedance spectroscopy (BIS) is a non-invasive, simple, and inexpensive modality that uses 256 frequencies to determine the extracellular volume impedance (ECVRe) and intracellular volume impedance (ICVRi) in the total body and regional compartments. As such, it may have utility as a surrogate measure to assess lean tissue mass (LTM). Objective: To compare the relationship between LTM from dual-energy X-ray absorptiometry (DXA) and BIS impedance values in spinal cord injury (SCI) and able-bodied (AB) control subjects using a cross-sectional research design. Methods: In 60 subjects (30 AB and 30 SCI), a total body DXA scan was used to obtain total body and leg LTM. BIS was performed to measure the impedance quotient of the ECVRe and ICVRi in the total body and limbs. Results: BIS-derived ECVRe yielded a model for LTM in paraplegia, tetraplegia, and control for the right leg (RL) (R-2 = 0.75, standard errors of estimation (SEE) = 1.02 kg, P < 0.0001; R-2 = 0.65, SEE = 0.91 kg, P = 0.0006; and R-2 = 0.54, SEE = 1.31 kg, P < 0.0001, respectively) and left leg (LL) (R-2 = 0.76, SEE = 1.06 kg, P < 0.0001; R-2 = 0.64, SEE = 0.83 kg, P = 0.0006; and R-2 = 0.54, SEE = 1.34 kg, P < 0.0001, respectively). The ICVRi was similarly predictive of LTM in paraplegia, tetraplegia, and AB controls for the RL (R-2 = 0.85, SEE = 1.31 kg, P < 0.0001; R-2 = 0.52, SEE = 0.95 kg, P = 0.003; and R-2 = 0.398, SEE = 1.46 kg, P = 0.0003, respectively) and LL (R-2 = 0.62, SEE = 1.32 kg, P = 0.0003; R-2 = 0.57, SEE = 0.91 kg, P = 0.002; and R-2 = 0.42, SEE = 1.31 kg, P = 0.0001, respectively). Conclusion: Findings demonstrate that the BIS-derived impedance quotients for ECVRe and ICVRi may be used as surrogate markers to track changes in leg LTM in persons with SCI. C1 [Cirnigliaro, Christopher M.; La Fountaine, Michael F.; Asselin, Pierre; Spungen, Ann M.; Bauman, William A.] James J Peters VA Med Ctr, Natl Ctr Excellence Med Consequences Spinal Cord, Bronx, NY USA. [La Fountaine, Michael F.; Spungen, Ann M.; Bauman, William A.] James J Peters VA Med Ctr, Med & Spinal Cord Injury Serv, Bronx, NY USA. [La Fountaine, Michael F.] Seton Hall Univ, S Orange, NJ 07079 USA. [La Fountaine, Michael F.; Spungen, Ann M.; Bauman, William A.] Icahn Sch Med Mt Sinai, New York, NY USA. [Emmons, Racine] William Paterson Univ, Wayne, NJ USA. [Kirshblum, Steven C.] Kessler Inst Rehabilitat, W Orange, NJ 07052 USA. [Kirshblum, Steven C.] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Phys Med & Rehabil, Newark, NJ 07103 USA. RP Cirnigliaro, CM (reprint author), Kessler Inst Rehabilitat, Rm L052m,1199 Pleasant Valley Way, W Orange, NJ 07052 USA. EM christopher.cirnigliaro@va.gov FU James J. Peters VA Medical Center, Bronx, NY; Department of Veterans Affairs Rehabilitation Research & Development (RRD) Service; Kessler Institute for Rehabilitation, West Orange, NJ; RR&D National Center of Excellence for the Medical Consequences of Spinal Cord Injury [B2648C, B4162C] FX The authors thank the James J. Peters VA Medical Center, Bronx, NY, the Department of Veterans Affairs Rehabilitation Research & Development (RR&D) Service, and the Kessler Institute for Rehabilitation, West Orange, NJ for their support. This work was funded by a RR&D National Center of Excellence for the Medical Consequences of Spinal Cord Injury (#B2648C & B4162C). NR 45 TC 1 Z9 1 U1 1 U2 6 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD SEP PY 2013 VL 36 IS 5 SI SI BP 443 EP 453 DI 10.1179/2045772313Y.0000000108 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 203YL UT WOS:000323330700006 PM 23941792 ER PT J AU Wecht, JM Zhu, C Weir, JP Yen, C Renzi, C Galea, M AF Wecht, Jill M. Zhu, Carolyn Weir, Joseph P. Yen, Christina Renzi, Christopher Galea, Marinella TI A prospective report on the prevalence of heart rate and blood pressure abnormalities in veterans with spinal cord injuries SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Spinal cord injuries; Bradycardia; Tachycardia; Hypotension; Hypertension; Tetraplegia; Paraplegia; Autonomic function; Cardiovascular disease; Veterans ID REMAINING AUTONOMIC FUNCTION; PULSE-WAVE VELOCITY; INTERNATIONAL STANDARDS; ARTERIAL STIFFNESS; CHRONIC HYPOTENSION; ORTHOSTATIC HYPOTENSION; CARDIOVASCULAR-DISEASE; COGNITIVE PERFORMANCE; NEUROLOGICAL LEVEL; PHYSICAL-ACTIVITY AB Objective: Decentralized autonomic cardiovascular regulation may lead to increased prevalence of heart rate (HR) and blood pressure (BP) abnormalities in veterans with SCI. In addition, comorbid medical conditions and prescription medication use may increase HR and BP abnormalities. These abnormalities include bradycardia, and tachycardia, hypotension, hypertension as well as autonomic dysreflexia and orthostatic hypotension; the prevalence of which is unknown. Design: HR and BP data were measured during a routine annual physical examination in 64 veterans with SCI. Measurements of HR and BP were recorded in the seated and supine positions to document the influence of body position and to document intra-subject variability in these assessments. Results: All subjects were chronically injured (20 +/- 14 years), 33 subjects were tetraplegic (T: C3-C8), nine had high paraplegia (HP: T1-T6), and 22 had low paraplegia (LP: T7-L2). Regardless of position, the prevalence of bradycardia was increased in the T group, whereas prevalence of tachycardia was increased in the HP and LP groups. Systolic hypotension was more common in the T and HP groups than the LP group and positional effects were most evident in the T group. Systolic hypertension was comparable in the T and HP groups but was twice as prevalent in the LP group. Increased prevalence of individuals with three or more medical conditions and prescribed three or more medications which might influence HR and BP was observed. Conclusion: Decentralized autonomic regulation, comorbid medical conditions, and prescription medication use in veterans with SCI result in HR and BP abnormalities; our data suggest that these abnormalities vary depending on the level of injury and orthostatic positioning. C1 [Wecht, Jill M.; Yen, Christina; Renzi, Christopher] James J Peters VAMC, Ctr Excellence, Bronx, NY USA. [Wecht, Jill M.; Galea, Marinella] James J Peters VAMC, Med Serv, Bronx, NY USA. Mt Sinai Sch Med, Dept Med, New York, NY USA. [Wecht, Jill M.; Galea, Marinella] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. [Zhu, Carolyn] Mt Sinai Sch Med, Dept Geriatr & Palliat Care, New York, NY USA. [Zhu, Carolyn; Weir, Joseph P.] Univ Kansas, Dept Hlth Sport & Exercise Sci, Lawrence, KS 66045 USA. RP Wecht, JM (reprint author), James J Peters VA Med Ctr, Ctr Excellence Med Consequences Spinal Cord Injur, Rm 7A 13,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM JM.Wecht@va.gov FU Veterans Affairs Rehabilitation Research and Development Service [B6999R] FX This research was supported by the Veterans Affairs Rehabilitation Research and Development Service (Grant no. B6999R). NR 45 TC 4 Z9 4 U1 1 U2 10 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD SEP PY 2013 VL 36 IS 5 SI SI BP 454 EP 462 DI 10.1179/2045772313Y.0000000109 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 203YL UT WOS:000323330700007 PM 23941793 ER PT J AU Zhu, C Galea, M Livote, E Signor, D Wecht, JM AF Zhu, Carolyn Galea, Marinella Livote, Elayne Signor, Dan Wecht, Jill M. TI A retrospective chart review of heart rate and blood pressure abnormalities in veterans with spinal cord injury SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Review DE Spinal cord injuries; Cardiac arrhythmias; Hypotension; Hypertension; Orthostatic hypotension; Autonomic dysreflexia; Tetraplegia; Paraplegia ID CARDIOVASCULAR-DISEASE RISK; CONTINGENT NEGATIVE-VARIATION; INTERNATIONAL STANDARDS; DEPRESSIVE SYMPTOMS; ARTERIAL STIFFNESS; AUTONOMIC DYSREFLEXIA; COGNITIVE PERFORMANCE; HYPERTENSIVE SUBJECTS; NEUROLOGICAL LEVEL; FOLLOW-UP AB Objective: Autonomic impairment may lead to increased prevalence of heart rate (HR) and blood pressure (BP) abnormalities in veterans with spinal cord injury (SCI). In addition, comorbid medical conditions and prescription medication use may influence these abnormalities, including bradycardia, and tachycardia, hypotension, hypertension as well as autonomic dysreflexia (AD), and orthostatic hypotension (OH). Design: A retrospective review of clinical and administrative datasets in veterans with SCI and compared the prevalence rates between clinical values and ICD-9 diagnostic codes in individuals with tetraplegia (T: C1-C8), high paraplegia (HP: T1-T6), and low paraplegia (LP: T7 and below). Results: The prevalence of clinical values indicative of a HR >= 80 beats per minute was higher in the HP compared to the LP and T groups. A systolic BP (SBP) <= 110 mmHg was more common in the T compared to the HP and LP groups, whereas the prevalence of a SBP >= 140 mmHg was increased in the LP compared to the HP and T groups. Diagnosis of hypertension was 39-60% whereas the diagnosis of hypotension was less than 1%. Diagnosis of AD and OH was highest in the T group, but remained below 10%, regardless of categorical lesion level. Antihypertensive medications were commonly prescribed (55%), and patients on these medications were less likely to have high BP. The odds ratio of higher SBP and DBP increased with age and body mass index (BMI). Conclusion: In veterans with SCI, the prevalence of HR and BP abnormalities varied depending on level of lesion, age, BMI, and prescription medication use. C1 [Zhu, Carolyn; Livote, Elayne; Signor, Dan] James J Peters VAMC, Dept Geriatr & Palliat Med, Bronx, NY USA. [Galea, Marinella; Wecht, Jill M.] James J Peters VAMC, Med Serv, Bronx, NY USA. [Wecht, Jill M.] James J Peters VAMC, Ctr Excellence, Bronx, NY USA. [Wecht, Jill M.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Galea, Marinella; Wecht, Jill M.] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. RP Wecht, JM (reprint author), James J Peters VA Med Ctr, Room 1E-02,130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM JM.Wecht@va.gov FU Veterans Affairs Rehabilitation Research and Development Service [B6999R] FX This research was supported by the Veterans Affairs Rehabilitation Research and Development Service (Grant # B6999R). NR 59 TC 6 Z9 6 U1 2 U2 10 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD SEP PY 2013 VL 36 IS 5 SI SI BP 463 EP 475 DI 10.1179/2045772313Y.0000000145 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 203YL UT WOS:000323330700008 PM 23941794 ER PT J AU Bauman, WA La Fountaine, MF Cirnigliaro, CM Kirshblum, SC Spungen, AM AF Bauman, William A. La Fountaine, Michael F. Cirnigliaro, Christopher M. Kirshblum, Steven C. Spungen, Ann M. TI Low-dose baclofen therapy raised plasma insulin-like growth factor-1 concentrations, but not into the normal range in a predictable and sustained manner in men with chronic spinal cord injury SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Baclofen; Gamma-aminobutyric acid; Insulin-like growth factor-1; Testosterone; Spinal cord injuries; Paraplegia; Tetraplegia; Spasticity ID GAMMA-AMINOBUTYRIC-ACID; RESTING ENERGY-EXPENDITURE; HORMONE-SECRETION; BODY-COMPOSITION; TESTOSTERONE; STIMULATION; INDIVIDUALS; INVOLVEMENT; DISCORDANT; FAILURE AB Objective: To evaluate, whether once-daily oral baclofen administration increases and/or sustains plasma insulin-like growth factor-1 (IGF-1) concentration in 11 men with chronic spinal cord injury (SCI) and IGF-1 deficiency (i.e. <250 ng/ml). Design: Prospective, open-label, dose titration study. Baclofen was administered at 20 mg/day for 8 weeks; then increased to 40 mg/day for another 8 weeks. Plasma IGF-1 and self-reported side effects were measured at baseline and every other week for the duration of the study. Results: The subjects were 43 +/- 12 years old, had duration of injury of 20 +/- 12 years; eight subjects had a complete motor injury, and eight had paraplegia. Nine of 11 subjects completed the 20 mg/day treatment and 5 subjects completed the 40 mg/day treatment. Plasma IGF-1 levels improved with each baclofen dose; however, only one subject increased from baseline and remained above the targeted physiological range of 250 ng/ml throughout treatment. A significant increase in IGF-1concentration was observed between baseline and week 2 (154 +/- 63 vs. 217 +/- 69 ng/ml; P < 0.05), weeks 8 and 10 (188 +/- 95 vs. 228 +/- 93 ng/ml; P < 0.05), and weeks 8 and 16 (188 +/- 95 vs. 259 +/- 92 ng/ml; P < 0.05). No serious side effects were observed at 20 mg/day; the 40 mg/day dose was less well tolerated. Conclusion: Baclofen was not effective at sustaining plasma IGF-1 concentrations in the physiological range in men with chronic SCI. C1 [Bauman, William A.; La Fountaine, Michael F.; Cirnigliaro, Christopher M.; Spungen, Ann M.] James J Peters VA Med Ctr, VA RR&D Natl Ctr Excellence Med Consequences Spin, Bronx, NY 10468 USA. [Bauman, William A.; Spungen, Ann M.] James J Peters VA Med Ctr, Med Serv, Bronx, NY 10468 USA. [Bauman, William A.; Spungen, Ann M.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Bauman, William A.; Spungen, Ann M.] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. [La Fountaine, Michael F.] Seton Hall Univ, Sch Hlth & Med Sci, Dept Phys Therapy, S Orange, NJ 07079 USA. [Kirshblum, Steven C.] Kessler Inst Rehabil, W Orange, NJ USA. [Kirshblum, Steven C.] Univ Med & Dent New Jersey, Dept Phys Med & Rehabil, Newark, NJ 07103 USA. RP Bauman, WA (reprint author), James J Peters VA Med Ctr, Natl Ctr Excellence Med Consequences Spinal Cord, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM william.bauman@va.gov FU James J. Peters VA Medical Center, Bronx, NY; Department of Veterans Affairs Rehabilitation Research & Development Service; Kessler Institute for Rehabilitation, West Orange, NJ; Veteran Affairs Rehabilitation Research & Development National Center of Excellence for the Medical Consequences of Spinal Cord Injury [B4162-C, B9212-C] FX The authors thank the James J. Peters VA Medical Center, Bronx, NY, the Department of Veterans Affairs Rehabilitation Research & Development Service, and Kessler Institute for Rehabilitation, West Orange, NJ for their support. This work was funded by the Veteran Affairs Rehabilitation Research & Development National Center of Excellence for the Medical Consequences of Spinal Cord Injury (No.'s B4162-C & B9212-C). NR 37 TC 2 Z9 2 U1 0 U2 1 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD SEP PY 2013 VL 36 IS 5 SI SI BP 476 EP 482 DI 10.1179/2045772312Y.0000000061 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 203YL UT WOS:000323330700009 PM 23941795 ER PT J AU Evans, CT Rogers, TJ Chin, A Johnson, S Smith, B Weaver, FM Burns, SP AF Evans, Charlesnika T. Rogers, Thea J. Chin, Amy Johnson, Stuart Smith, Bridget Weaver, Frances M. Burns, Stephen P. TI Antibiotic prescribing trends in the emergency department for veterans with spinal cord injury and disorder 2002-2007 SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Physician's practice patterns; Spinal cord injuries; Antibiotic prescribing patterns; Antibiotic resistance; Veterans; Clinical guidelines ID RESPIRATORY-TRACT INFECTIONS; UNITED-STATES; ADULTS; RESISTANCE; BRONCHITIS; PROVIDERS; SETTINGS AB Objective: Clinical guidelines exist to promote antibiotic stewardship, particularly in ambulatory care settings such as the emergency department (ED). However, there is limited evidence on prescribing practice for persons with spinal cord injury and disorder (SCI/D). The goal of this study was to assess trends in antibiotic prescribing in the ED setting for persons with SCI/D. Design: A retrospective dynamic cohort study design. Setting: ED visits that did not result in same day hospitalization over 6 years (fiscal year (FY) 2002-FY2007) in Department of Veterans Affairs (VA) facilities Participants: Veterans with SCI/D. Outcome measures: VA clinical and administrative databases were used to identify the cohort and to obtain demographics, diagnoses, and medications. The rate of antibiotic prescribing for ED visits was defined as the number of antibiotics/total ED visits. Results: Veterans with SCI/D had 21 934 ED visits and 5887 antibiotics prescribed over the study period (rate of 268.4 prescriptions/1000 visits). The antibiotic prescribing rate increased from 238.8/1000 visits in FY2002 to 310.8/1000 visits in FY2007 (P < 0.0001). This increase in the rate of prescribing was seen across all patient demographics and factors assessed. Conclusion: Although clinical guidelines for judicious use of antibiotics in persons with SCI/D have been disseminated to providers, antibiotic prescribing in an ED setting is high and continuing to rise in this population. C1 [Evans, Charlesnika T.; Rogers, Thea J.; Chin, Amy; Smith, Bridget; Weaver, Frances M.] Northwestern Univ, Feinberg Sch Med, Dept Vet Affairs VA, Ctr Management Complex Chron Care, Chicago, IL 60611 USA. [Evans, Charlesnika T.; Rogers, Thea J.; Chin, Amy; Smith, Bridget; Weaver, Frances M.; Burns, Stephen P.] Northwestern Univ, Feinberg Sch Med, Spinal Cord Injury Qual Enhancement Res Initiat S, Chicago, IL 60611 USA. [Evans, Charlesnika T.] Northwestern Univ, Feinberg Sch Med, Inst Healthcare Studies, Chicago, IL 60611 USA. [Johnson, Stuart; Smith, Bridget; Weaver, Frances M.] Loyola Univ, Med Ctr, Dept Med, Maywood, IL 60153 USA. [Burns, Stephen P.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Burns, Stephen P.] Univ Washington, Seattle, WA 98195 USA. RP Evans, CT (reprint author), Edward J Hines Jr VA Hosp 151H, 5th Ave & Roosevelt Rd,POB 5000,Room D302, Hines, IL 60141 USA. EM Charlesnika.Evans@va.gov NR 23 TC 3 Z9 3 U1 0 U2 8 PU MANEY PUBLISHING PI LEEDS PA STE 1C, JOSEPHS WELL, HANOVER WALK, LEEDS LS3 1AB, W YORKS, ENGLAND SN 1079-0268 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD SEP PY 2013 VL 36 IS 5 SI SI BP 492 EP 498 DI 10.1179/2045772312Y.0000000076 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 203YL UT WOS:000323330700011 PM 23941797 ER PT J AU Doran, KM Ragins, KT Iacomacci, AL Cunningham, A Jubanyik, KJ Jenq, GY AF Doran, Kelly M. Ragins, Kyle T. Iacomacci, Andrea L. Cunningham, Alison Jubanyik, Karen J. Jenq, Grace Y. TI The Revolving Hospital Door Hospital Readmissions Among Patients Who Are Homeless SO MEDICAL CARE LA English DT Article DE homelessness; readmissions; hospital quality ID CASE-MANAGEMENT PROGRAM; HEART-FAILURE; RESPITE CARE; HEALTH-CARE; COSTS; ADULTS AB Background: National attention is increasingly focused on hospital readmissions. Little prior research has examined readmissions among patients who are homeless.Objective: The aim of the study was to determine 30-day hospital readmission rates among patients who are homeless and examine factors associated with hospital readmissions in this population.Methods: We conducted a retrospective chart review of patients who were homeless and hospitalized at a single urban hospital from May-August 2012. Homelessness was identified by an electronic medical record flag and confirmed by manual chart review. The primary outcome was all-cause hospital readmission to the study hospital within 30 days of hospital discharge. Patient-level and hospitalization-level factors associated with risk for readmission were examined using generalized estimating equations.Results: There were 113 unique patients who were homeless and admitted to the hospital a total of 266 times during the study period. The mean age was 49 years, 27.4% of patients were women, and 75.2% had Medicaid. Half (50.8%) of all hospitalizations resulted in a 30-day hospital inpatient readmission and 70.3% resulted in either an inpatient readmission, observation status stay, or emergency department visit within 30 days of hospital discharge. Most readmissions occurred early after hospital discharge (53.9% within 1 week, 74.8% within 2 weeks). Discharge to the streets or shelter versus other living situations was associated with increased risk for readmission in multivariable analyses.Conclusions: Patients who were homeless had strikingly high 30-day hospital readmission rates. These findings suggest the urgent need for further research and interventions to improve postdischarge care for patients who are homeless. C1 [Doran, Kelly M.] Yale Univ, Sch Med, Robert Wood Johnson Fdn, Clin Scholars Program, New Haven, CT USA. [Doran, Kelly M.] US Dept Vet Affairs, New Haven, CT USA. [Doran, Kelly M.; Jubanyik, Karen J.] Yale Univ, Sch Med, Dept Emergency Med, New Haven, CT USA. [Ragins, Kyle T.] Yale Univ, Sch Med, New Haven, CT USA. [Iacomacci, Andrea L.] Yale New Haven Med Ctr, Dept Clin Effectiveness, New Haven, CT 06504 USA. [Cunningham, Alison] Columbus House Inc, New Haven, CT USA. [Jenq, Grace Y.] Yale Univ, Sch Med, Dept Med, Sect Geriatr, New Haven, CT 06510 USA. RP Doran, KM (reprint author), Bellevue Hosp Ctr, Dept Emergency Med, 1st Ave & 27th St,Room A345, New York, NY 10016 USA. EM kmdoran@gmail.com NR 24 TC 11 Z9 11 U1 1 U2 24 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 SEP PY 2013 VL 51 IS 9 BP 767 EP 773 DI 10.1097/MLR.0b013e31829fafbb PG 7 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 205AE UT WOS:000323411600004 PM 23929401 ER PT J AU Lazaridou, A Astrakas, L Mintzopoulos, D Khanchiceh, A Singhal, A Moskowitz, M Rosen, B Tzika, A AF Lazaridou, Asimina Astrakas, Loukas Mintzopoulos, Dionyssios Khanchiceh, Azadeh Singhal, Aneesh Moskowitz, Michael Rosen, Bruce Tzika, Aria TI fMRI as a molecular imaging procedure for the functional reorganization of motor systems in chronic stroke SO MOLECULAR MEDICINE REPORTS LA English DT Article DE functional magnetic resonance imaging; stroke; brain; dynamical causal modeling ID RANDOMIZED CONTROLLED-TRIAL; ROBOT-ASSISTED THERAPY; MAGNETIC-RESONANCE; RECOVERY; REHABILITATION; STIMULATION; CONNECTIVITY; CORTEX; PLASTICITY; MRI AB Previous brain imaging studies suggest that stroke alters functional connectivity in motor execution networks. Moreover, current understanding of brain plasticity has led to new approaches in stroke rehabilitation. Recent studies showed a significant role of effective coupling of neuronal activity in the SMA (supplementary motor area) and M1 (primary motor cortex) network for motor outcome in patients after stroke. After a subcortical stroke, functional magnetic resonance imaging (fMRI) during movement reveals cortical reorganization that is associated with the recovery of function. The aim of the present study was to explore connectivity alterations within the motor-related areas combining motor fMRI with a novel MR-compatible hand-induced robotic device (MR_CHIROD) training. Patients completed training at home and underwent serial MR evaluation at baseline and after 8 weeks of training. Training at home consisted of squeezing a gel exercise ball with the paretic hand at similar to 75% of maximum strength for 1 h/day, 3 days/week. The fMRI analysis revealed alterations in M1, SMA, PMC (premotor cortex) and Cer (cerebellum) in both stroke patients and healthy controls after the training. Findings of the present study suggest that enhancement of SMA activity could benefit M1 dysfunction in stroke survivors. These results also indicate that connectivity alterations between motor areas might assist the counterbalance of a functionally abnormal M1 in chronic stroke survivors and possibly other patients with motor dysfunction. C1 [Lazaridou, Asimina; Astrakas, Loukas; Mintzopoulos, Dionyssios; Tzika, Aria] Massachusetts Gen Hosp, NMR Surg Lab, Boston, MA 02114 USA. [Lazaridou, Asimina; Astrakas, Loukas; Mintzopoulos, Dionyssios; Tzika, Aria] Harvard Univ, Sch Med, Shriners Burn Inst, Boston, MA 02114 USA. [Lazaridou, Asimina; Astrakas, Loukas; Mintzopoulos, Dionyssios; Moskowitz, Michael; Rosen, Bruce; Tzika, Aria] Northeastern Univ, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02115 USA. [Khanchiceh, Azadeh] Northeastern Univ, Boston, MA 02115 USA. [Singhal, Aneesh] Harvard Univ, Sch Med, Dept Neurol, Stroke Res Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Tzika, A (reprint author), Massachusetts Gen Hosp, NMR Surg Lab, Dept Surg, Room 261,51 Blossom St, Boston, MA 02114 USA. EM atzika@hms.harvard.edu RI Astrakas, Loukas/F-5918-2011 FU National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health [R21 EB004665-01A2] FX This study was supported in part by a grant from the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health (grant no. R21 EB004665-01A2) to Dr A. Aria Tzika. We thank Dr Mavroidis, the principal investigator of the subcontract to Northeastern University, for construction of the MR_CHIROD. Thanks is extended to Ann Power Smith Ph.D. of Write Science Right for editorial assistance. NR 47 TC 4 Z9 5 U1 2 U2 19 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1791-2997 J9 MOL MED REP JI Mol. Med. Rep. PD SEP PY 2013 VL 8 IS 3 BP 775 EP 779 DI 10.3892/mmr.2013.1603 PG 5 WC Oncology; Medicine, Research & Experimental SC Oncology; Research & Experimental Medicine GA 205RS UT WOS:000323463100011 PM 23900349 ER PT J AU Ramirez-Ortiz, ZG Pendergraft, WF Prasad, A Byrne, MH Iram, T Blanchette, CJ Luster, AD Hacohen, N El Khoury, J Means, TK AF Ramirez-Ortiz, Zaida G. Pendergraft, William F., III Prasad, Amit Byrne, Michael H. Iram, Tal Blanchette, Christopher J. Luster, Andrew D. Hacohen, Nir El Khoury, Joseph Means, Terry K. TI The scavenger receptor SCARF1 mediates the clearance of apoptotic cells and prevents autoimmunity SO NATURE IMMUNOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; EVOLUTIONARILY CONSERVED RECOGNITION; ENDOTHELIAL-CELLS; INNATE IMMUNITY; SURFACE CALRETICULIN; ENGULFMENT RECEPTOR; FUNGAL PATHOGENS; TYROSINE KINASE; C-ELEGANS; GOOD MEAL AB The clearance of apoptotic cells is critical for the control of tissue homeostasis; however, the full range of receptors on phagocytes responsible for the recognition of apoptotic cells remains to be identified. Here we found that dendritic cells (DCs), macrophages and endothelial cells used the scavenger receptor SCARF1 to recognize and engulf apoptotic cells via the complement component C1q. Loss of SCARF1 impaired the uptake of apoptotic cells. Consequently, in SCARF1-deficient mice, dying cells accumulated in tissues, which led to a lupus-like disease, with the spontaneous generation of autoantibodies to DNA-containing antigens, activation of cells of the immune system, dermatitis and nephritis. The discovery of such interactions of SCARF1 with C1q and apoptotic cells provides insight into the molecular mechanisms involved in the maintenance of tolerance and prevention of autoimmune disease. C1 [Ramirez-Ortiz, Zaida G.; Pendergraft, William F., III; Prasad, Amit; Byrne, Michael H.; Iram, Tal; Blanchette, Christopher J.; Luster, Andrew D.; Hacohen, Nir; El Khoury, Joseph; Means, Terry K.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA USA. [Ramirez-Ortiz, Zaida G.; Pendergraft, William F., III; Prasad, Amit; Byrne, Michael H.; Iram, Tal; Blanchette, Christopher J.; Luster, Andrew D.; Hacohen, Nir; El Khoury, Joseph; Means, Terry K.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Charlestown, MA USA. [Ramirez-Ortiz, Zaida G.; Pendergraft, William F., III; Prasad, Amit; Byrne, Michael H.; Iram, Tal; Blanchette, Christopher J.; Luster, Andrew D.; Hacohen, Nir; El Khoury, Joseph; Means, Terry K.] Harvard Univ, Sch Med, Charlestown, MA USA. [Pendergraft, William F., III] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Pendergraft, William F., III; Hacohen, Nir; Means, Terry K.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Iram, Tal] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. [El Khoury, Joseph] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Means, TK (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA USA. EM means.terry@mgh.harvard.edu FU National Institute of Allergy and Infectious Diseases [R01-AI084884, U24 AI082660, T32-AI007061]; National Institute of Arthritis, Musculoskeletal and Skin Diseases [K01-AR051367]; National Institute of Diabetes and Digestive and Kidney Diseases [F32-DK097891]; Lupus Research Institute; Alliance for Lupus Research; American Society of Nephrology FX We thank Y.F. Peng (University of Washington) for Mfge8-/- mice; M. Michalak (University of Alberta) for K41 (calreticulin-sufficient) and K42 (calreticulin-deficient) MEFs; and M.J. Shlomchik and P. Mundel and members of their laboratories for technical assistance and discussions. Supported by the National Institute of Allergy and Infectious Diseases (R01-AI084884 to T. K. M.; U24 AI082660 to J.E.K.; and T32-AI007061 to Z.G.R.-O.), the National Institute of Arthritis, Musculoskeletal and Skin Diseases (K01-AR051367 to T. K. M.), the National Institute of Diabetes and Digestive and Kidney Diseases (F32-DK097891 to W. F. P.), the Lupus Research Institute (T. K. M. and N.H.), the Alliance for Lupus Research (T. K. M. and N.H.) and the American Society of Nephrology (W.F.P.). NR 50 TC 53 Z9 53 U1 4 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 SEP PY 2013 VL 14 IS 9 BP 917 EP + DI 10.1038/ni.2670 PG 12 WC Immunology SC Immunology GA 204OS UT WOS:000323377700009 PM 23892722 ER PT J AU Overstreet, MG Gaylo, A Angermann, BR Hughson, A Hyun, YM Lambert, K Acharya, M Billroth-MacLurg, AC Rosenberg, AF Topham, DJ Yagita, H Kim, M Lacy-Hulbert, A Meier-Schellersheim, M Fowell, DJ AF Overstreet, Michael G. Gaylo, Alison Angermann, Bastian R. Hughson, Angela Hyun, Young-Min Lambert, Kris Acharya, Mridu Billroth-MacLurg, Alison C. Rosenberg, Alexander F. Topham, David J. Yagita, Hideo Kim, Minsoo Lacy-Hulbert, Adam Meier-Schellersheim, Martin Fowell, Deborah J. TI Inflammation-induced interstitial migration of effector CD4(+) T cells is dependent on integrin alpha(V) SO NATURE IMMUNOLOGY LA English DT Article ID DELAYED-TYPE HYPERSENSITIVITY; IN-VIVO; DENDRITIC CELLS; LEUKOCYTE MIGRATION; INFLUENZA INFECTION; LYMPH-NODES; V INTEGRINS; FIBRONECTIN; EXPRESSION; MOTILITY AB Leukocytes must traverse inflamed tissues to effectively control local infection. Although motility in dense tissues seems to be integrin independent and based on actomyosin-mediated protrusion and contraction, during inflammation, changes to the extracellular matrix (ECM) may necessitate distinct motility requirements. Indeed, we found that the interstitial motility of T cells was critically dependent on Arg-Gly-Asp (RGD)-binding integrins in the inflamed dermis. Inflammation-induced deposition of fibronectin was functionally linked to higher expression of integrin alpha(V) on effector CD4(+) T cells. By intravital multiphoton imaging, we found that the motility of CD4(+) T cells was dependent on alpha(V) expression. Selective blockade or knockdown of alpha(V) arrested T helper type 1 (T(H)1) cells in the inflamed tissue and attenuated local effector function. Our data demonstrate context-dependent specificity of lymphocyte movement in inflamed tissues that is essential for protective immunity. C1 [Overstreet, Michael G.; Gaylo, Alison; Hughson, Angela; Hyun, Young-Min; Lambert, Kris; Billroth-MacLurg, Alison C.; Topham, David J.; Kim, Minsoo; Fowell, Deborah J.] Univ Rochester, Aab Inst Biomed Sci, David H Smith Ctr Vaccine Biol & Immunol, Rochester, NY 14627 USA. [Overstreet, Michael G.; Gaylo, Alison; Hyun, Young-Min; Billroth-MacLurg, Alison C.; Topham, David J.; Kim, Minsoo; Fowell, Deborah J.] Univ Rochester, Dept Microbiol & Immunol, Rochester, NY USA. [Angermann, Bastian R.; Meier-Schellersheim, Martin] NIAID, Computat Biol Unit, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Acharya, Mridu; Lacy-Hulbert, Adam] Massachusetts Gen Hosp, Dept Pediat, Program Dev Immunol, Boston, MA 02114 USA. [Acharya, Mridu; Lacy-Hulbert, Adam] Harvard Univ, Sch Med, Boston, MA USA. [Rosenberg, Alexander F.] Univ Rochester, Med Ctr, Div Allergy Immunol & Rheumatol, Rochester, NY 14642 USA. [Yagita, Hideo] Juntendo Univ, Dept Immunol, Tokyo, Japan. RP Fowell, DJ (reprint author), Univ Rochester, Aab Inst Biomed Sci, David H Smith Ctr Vaccine Biol & Immunol, Rochester, NY 14627 USA. EM deborah_fowell@urmc.rochester.edu OI Lacy-Hulbert, Adam/0000-0003-2162-0156 FU US National Institutes of Health [AI072690, AI088427, HL018208, HL087088, AI089079]; American Heart Association [11SDG7520018]; National Institute of Allergy and Infectious Diseases FX We thank N. Killeen (University of California, San Francisco) for WT15 mice; R. Locksley (University of California, San Francisco) for IFN-gamma reporter mice (Yeti mice); M. Nussenzweig (The Rockefeller University) for CD11c-YFP mice; R. Hynes (MIT) for Itga5fl/fl mice; B. Leon and F. Lund (University of Alabama) for H. polygyrus-infected tissue; R. Germain and J. Egen for technical assistance; K. Kasischke, L. Callahan, E. Brown and the University of Rochester Medical Center Multiphoton Core for support; Kihong Lim for technical assistance; J. Miller and S. Georas for comments on the manuscript; and members of the Fowell and Kim laboratories for discussions and support. Supported by the US National Institutes of Health (AI072690 and AI088427 to D. J. F.; HL018208 and HL087088 to M. K.; and AI089079 to M.G.O.), the American Heart Association (11SDG7520018 to Y.-M.H.) and the intramural program of the National Institute of Allergy and Infectious Diseases (B. R. A. and M.M.-S.). NR 55 TC 36 Z9 36 U1 0 U2 20 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 SEP PY 2013 VL 14 IS 9 BP 949 EP + DI 10.1038/ni.2682 PG 12 WC Immunology SC Immunology GA 204OS UT WOS:000323377700012 PM 23933892 ER PT J AU Brent, GA Kogai, T AF Brent, Gregory A. Kogai, Takahiko TI CANCER Novel target to enhance radioiodine uptake in thyroid cancer SO NATURE REVIEWS ENDOCRINOLOGY LA English DT Editorial Material AB The sodium-iodide symporter mediates iodide uptake, but its activity is reduced by the overexpression of pituitary tumour-transforming gene 1 protein-binding factor (PBF) in thyroid tumours. A recent study shows that inhibiting PBF phosphorylation enhances radioiodine uptake in thyroid cancer models. C1 [Brent, Gregory A.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA 90073 USA. [Kogai, Takahiko] Dokkyo Med Univ, Dept Infect Control & Clin Lab Med, Mibu, Tochigi 3210293, Japan. RP Brent, GA (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM gbrent@ucla.edu FU NCI NIH HHS [R01 CA89364] NR 10 TC 3 Z9 4 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5029 J9 NAT REV ENDOCRINOL JI Nat. Rev. Endocrinol. PD SEP PY 2013 VL 9 IS 9 BP 508 EP 509 DI 10.1038/nrendo.2013.132 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 202LQ UT WOS:000323218200003 PM 23817292 ER PT J AU Blomberg, BA Akers, SR Saboury, B Mehta, NN Cheng, G Torigian, DA Lim, E Del Bello, C Werner, TJ Alavi, A AF Blomberg, Bjoern A. Akers, Scott R. Saboury, Babak Mehta, Nehal N. Cheng, Gang Torigian, Drew A. Lim, Esther Del Bello, Catherine Werner, Thomas J. Alavi, Abass TI Delayed time-point F-18-FDG PET CT imaging enhances assessment of atherosclerotic plaque inflammation SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article DE atherosclerosis; fluorine-18 fluorodeoxyglucose; multiple time-point imaging; positron emission tomography ID POSITRON-EMISSION-TOMOGRAPHY; VASCULAR INFLAMMATION; FLUORODEOXYGLUCOSE UPTAKE; LARGE ARTERIES; FDG-PET; RISK; RESOLUTION; WALL AB Objective The aim of this study was to determine the ideal circulation time of fluorine-18 fluorodeoxyglucose (F-18-FDG) in order to detect and quantify atherosclerotic plaque inflammation with PET computed tomography (CT) imaging.Methods Fifteen patients underwent multiple time-point imaging at approximate to 60, 120, and 180 min after F-18-FDG administration. For each time point, global assessment of aortic and carotid F-18-FDG uptake was determined qualitatively by visual assessment and semiquantitatively by calculation of the mean and maximum standardized uptake values (SUV) and the corresponding target-to-background ratio (TBR).Results Delayed imaging achieved significant improvement in visualization of atherosclerotic plaque inflammation [Friedman's (2) statistic (d.f.=2, n=15)=24.13, P<0.001, Kendall's W=0.80]. This observation was confirmed by semiquantitative image analysis. At 1 h, the aortic and carotid SUVmean-calculated TBR was 1.05 [95% confidence interval (CI)=0.98, 1.11] and 0.88 (95% CI=0.81, 0.96), respectively. At 3 h, the TBR significantly increased to 1.57 (95% CI=1.28, 1.86; P=0.001) for the aorta and to 1.61 (95% CI=1.36, 1.87; P<0.001) for the carotid arteries. SUVmax-calculated TBRs showed a similar increase over time.Conclusion One- and 2-h F-18-FDG PET CT imaging is suboptimal for global assessment of atherosclerotic plaque inflammation compared with imaging at 3 h. Our data support the utilization of 3-h delayed imaging to obtain optimal data for the detection and quantification of atherosclerotic plaque inflammation in human arteries. C1 [Blomberg, Bjoern A.; Saboury, Babak; Torigian, Drew A.; Alavi, Abass] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Blomberg, Bjoern A.; Saboury, Babak; Torigian, Drew A.; Werner, Thomas J.; Alavi, Abass] Hosp Univ Penn, Dept Radiol, Philadelphia, PA 19104 USA. [Akers, Scott R.; Cheng, Gang; Lim, Esther; Del Bello, Catherine] Philadelphia VA Med Ctr, Dept Radiol, Philadelphia, PA USA. [Mehta, Nehal N.] NHLBI, Bethesda, MD 20892 USA. [Blomberg, Bjoern A.] Univ Utrecht, Sch Med, Univ Med Ctr Utrecht, Utrecht, Netherlands. RP Alavi, A (reprint author), 3400 Spruce St, Philadelphia, PA 19104 USA. EM abass.alavi@uphs.upenn.edu FU United States Department of Veterans Affairs (VISN 4 CPPF Grant) FX This study was supported in part by a grant from the United States Department of Veterans Affairs (VISN 4 CPPF Grant). NR 29 TC 11 Z9 12 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0143-3636 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD SEP PY 2013 VL 34 IS 9 BP 860 EP 867 DI 10.1097/MNM.0b013e3283637512 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 202QA UT WOS:000323232000004 PM 23799532 ER PT J AU Fazeli, PK Ackerman, KE Pierce, L Guereca, G Bouxsein, M Misra, M AF Fazeli, P. K. Ackerman, K. E. Pierce, L. Guereca, G. Bouxsein, M. Misra, M. TI Sclerostin and Pref-1 have differential effects on bone mineral density and strength parameters in adolescent athletes compared with non-athletes SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE Adolescent athletes; Bone strength; Pref-1; Sclerostin ID PREADIPOCYTE FACTOR-I; QUANTITATIVE COMPUTED-TOMOGRAPHY; VAN-BUCHEM-DISEASE; POSTMENOPAUSAL WOMEN; ANOREXIA-NERVOSA; SERUM SCLEROSTIN; DISTAL RADIUS; MARROW FAT; PHYSICAL-ACTIVITY; GENDER AB Excessive exercise can have detrimental effects on bone; however, the mechanisms leading to bone loss are not well understood. Sclerostin and preadipocyte factor (Pref)-1 are two hormones which inhibit bone formation. The present study demonstrates that these hormones may have differential effects in athletes as compared to non-athletes. Exercise activity is common in female adolescents, however, excessive exercise can have detrimental effects on bone mineral density (BMD). Mechanisms underlying this decrease in bone mass are not well understood. We investigated the effects of sclerostin, a potent inhibitor of bone formation via WNT signaling inhibition, and Pref-1, a suppressor of osteoblast differentiation, on BMD, bone turnover markers and bone strength in adolescent athletes. We studied 50 adolescents between 15-21 years of age: 17 amenorrheic athletes (AA), 17 eumenorrheic athletes (EA), and 16 nonathletic controls (NA). We measured spine and hip BMD by dual energy x-ray absorptiometry and estimated failure load and stiffness at the distal radius and tibia using micro-finite element analysis. We also measured fasting sclerostin, Pref-1, N-terminal propeptide of type 1 procollagen, and C-terminal collagen cross-links levels. Sclerostin levels were higher in AA and EA compared with NA (AA: 0.42 +/- 0.15 ng/mL, EA: 0.44 +/- 0.09 ng/mL, NA: 0.33 +/- 0.14 ng/mL; p = 0.047). In EA, sclerostin was positively associated with lumbar spine (LS) BMD and its Z-score (R = 0.52, p = 0.03 and R = 0.55, p = 0.02, respectively) whereas in NA, sclerostin was inversely associated with LS BMD (R = -0.61, p = 0.01). Pref-1 levels were similar in all three groups and there were significant inverse associations between Pref-1, BMD, and estimated bone strength in NA. Sclerostin and Pref-1 may have differential effects on bone in adolescent athletes compared to non-athletes. C1 [Fazeli, P. K.; Ackerman, K. E.; Pierce, L.; Guereca, G.; Misra, M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Bouxsein, M.] Beth Israel Deaconess Med Ctr, Ctr Adv Orthopaed Studies, Boston, MA 02215 USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Endocrine Unit, BUL 457,55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org FU NIH [1 R01 HD060827-01A1, K23 DK094820-01, UL1 RR025758-03]; Harvard Clinical and Translational Science Center, from the National Center for Research Resources FX We thank the research nurses and bionutritionists at the Clinical Research Center of Massachusetts General Hospital and our subjects, without whom this study would not have been possible. The project described was supported by NIH Grant nos 1 R01 HD060827-01A1 (Misra), K23 DK094820-01 (Fazeli), and UL1 RR025758-03, Harvard Clinical and Translational Science Center, from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health. NR 37 TC 12 Z9 12 U1 0 U2 6 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD SEP PY 2013 VL 24 IS 9 BP 2433 EP 2440 DI 10.1007/s00198-013-2353-2 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 200IV UT WOS:000323062700007 PM 23579340 ER PT J AU Shargorodsky, J Bleier, BS Holbrook, EH Cohen, JM Busaba, N Metson, R Gray, ST AF Shargorodsky, Josef Bleier, Benjamin S. Holbrook, Eric H. Cohen, Jeffrey M. Busaba, Nicolas Metson, Ralph Gray, Stacey T. TI Outcomes Analysis in Epistaxis Management: Development of a Therapeutic Algorithm SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Article DE epistaxis; nasal packing; bleeding ID ANTERIOR EPISTAXIS; POSTERIOR EPISTAXIS; CHEMICAL CAUTERY; ARTERY LIGATION; TRIAL AB Objective This study explored the outcomes of epistaxis treatment modalities to optimize management and enable the development of a therapeutic algorithm. Study Design Case series with chart review. Setting Tertiary care hospital. Subjects and Methods Adult patients presenting between 2005 and 2011 with epistaxis underwent cauterization, tamponade, and/or proximal vascular control. Outcomes of treatment modalities were compared. Multivariate logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for coagulopathy, hypertension, and bleeding site. Results The population included 147 patients (94 men, 53 women). For initial epistaxis, nondissolvable packing demonstrated the highest initial treatment failure rate of 57.4% (OR, 3.37; 95% CI, 1.33-8.59 compared with cautery). No significant differences were noted among initial posterior epistaxis treatment modalities. Length of nondissolvable pack placement for 3, 4, or 5 days had no significant impact on recurrence. Among patients who failed initial management, those who next underwent cautery or proximal vascular control required a significantly shorter inpatient stay of 5.3 vs 6.8 days compared with those who underwent packing (OR, 0.16; 95% CI, 0.04-0.68). There were no treatment failures following surgical arterial ligation. Conclusion Initial management of anterior epistaxis with chemical cautery had a higher success rate and a lower number of total required interventions than did nondissolvable packing. Duration of packing did not affect recurrence. In patients who failed initially, progression to cautery or proximal vascular control led to significantly shorter inpatient stays than did packing. C1 [Shargorodsky, Josef; Bleier, Benjamin S.; Holbrook, Eric H.; Cohen, Jeffrey M.; Busaba, Nicolas; Metson, Ralph; Gray, Stacey T.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Shargorodsky, Josef; Bleier, Benjamin S.; Holbrook, Eric H.; Busaba, Nicolas; Gray, Stacey T.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol Head & Neck Surg, Boston, MA 02114 USA. RP Shargorodsky, J (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM Josef_Shargorodsky@meei.harvard.edu FU Arthrocare FX Benjamin S. Bleier is a consultant for and has received a research grant from Arthrocare, is a consultant for Gyrus, and has 2 patents (one for drug delivery to the central nervous system, the other for treatment of sinusitis with P-gp inhibitors) with the Massachusetts Eye and Ear Infirmary. NR 24 TC 7 Z9 8 U1 0 U2 9 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD SEP PY 2013 VL 149 IS 3 BP 390 EP 398 DI 10.1177/0194599813492949 PG 9 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 206BA UT WOS:000323489500008 PM 23764960 ER PT J AU Gandhi, NR Tate, JP Rodriguez-Barradas, MC Rimland, D Goetz, MB Gibert, C Brown, ST Mattocks, K Justice, AC AF Gandhi, Neel R. Tate, Janet P. Rodriguez-Barradas, Maria C. Rimland, David Goetz, Matthew Bidwell Gibert, Cynthia Brown, Sheldon T. Mattocks, Kristin Justice, Amy C. TI Validation of an algorithm to identify antiretroviral-naive status at time of entry into a large, observational cohort of HIV-infected patients SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE HIV-1; antiretroviral therapy; cohort studies; HIV infections; epidemiology; HIV infections/drug therapy; pharmacoepidemiology ID IMMUNODEFICIENCY-VIRUS-INFECTION; FRENCH-HOSPITAL-DATABASE; MYOCARDIAL-INFARCTION; HIV-1-INFECTED PATIENTS; THERAPY; RISK; MORTALITY; AIDS; AGE; COLLABORATION AB Purpose Large, observational HIV cohorts play an important role in answering questions which are difficult to study in randomized trials; however, they often lack detailed information regarding previous antiretroviral treatment (ART). Knowledge of ART treatment history is important when ascertaining the long-term impact of medications, co-morbidities, or adverse reactions on HIV outcomes. Methods We performed a retrospective study to validate a prediction algorithm for identifying ART-naive patients using the Veterans Aging Cohort Study's Virtual Cohortan observational cohort of 40594 HIV-infected veterans nationwide. Medical records for 3070 HIV-infected patients were reviewed to determine history of combination ART treatment. An algorithm using Virtual Cohort laboratory data was used to predict ART treatment status and compared to medical record review. Results Among 3070 patients' medical records reviewed, 1223 were eligible for analysis. Of these, 990 (81%) were ART naive at cohort entry based on medical record review. The prediction algorithm's sensitivity was 86%, specificity 47%, positive predictive value (PPV) 87%, and negative predictive value 45%, using a viral load threshold of <400 copies/ml. Sensitivity analysis revealed that PPV would be maximized by increasing the viral load threshold, whereas sensitivity would be maximized by lowering the viral load threshold. Conclusions A prediction algorithm using available laboratory data can be used to accurately identify ART-naive patients in large, observational HIV cohorts. Use of this algorithm will allow investigators to accurately limit analyses to ART-naive patients when studying the contribution of ART to outcomes and adverse events. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Gandhi, Neel R.] Albert Einstein Coll Med, Div Gen Internal Med, Bronx, NY 10467 USA. [Gandhi, Neel R.] Montefiore Med Ctr, Bronx, NY 10467 USA. [Gandhi, Neel R.] Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. [Gandhi, Neel R.] Emory Univ, Rollins Sch Publ Hlth, Dept Global Hlth, Atlanta, GA 30322 USA. [Gandhi, Neel R.] Emory Univ, Rollins Sch Publ Hlth, Dept Infect Dis, Atlanta, GA 30322 USA. [Tate, Janet P.; Justice, Amy C.] Yale Univ, Sch Med, Dept Med, Gen Internal Med Sect, New Haven, CT 06510 USA. [Tate, Janet P.; Justice, Amy C.] VA Connecticut Healthcare Syst, New Haven, CT USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Infect Dis Sect, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Michael E DeBakey VA Med Ctr, Dept Med, Houston, TX USA. [Rodriguez-Barradas, Maria C.] Baylor Coll Med, Houston, TX 77030 USA. [Rimland, David] Emory Univ, Sch Med, Dept Med, Infect Dis Sect, Atlanta, GA 30322 USA. [Rimland, David] Atlanta VA Med Ctr, Atlanta, GA USA. [Goetz, Matthew Bidwell] VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, Los Angeles, CA USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Gibert, Cynthia] Washington DC VA Med Ctr, Infect Dis Sect, Washington, DC USA. [Gibert, Cynthia] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Brown, Sheldon T.] James J Peters VA Med Ctr, Dept Med, Infect Dis Sect, New York, NY USA. [Brown, Sheldon T.] Mt Sinai Sch Med, New York, NY USA. [Mattocks, Kristin] VA Cent Western Massachusetts Hlth Care Syst, Quantitat Hlth Sci & Psychiat, Leeds, MA USA. [Mattocks, Kristin] Univ Massachusetts, Med Ctr, Worcester, MA USA. RP Gandhi, NR (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, 1518 Clifton Rd NE,CNR 3031, Atlanta, GA 30322 USA. EM neelgandhi@alumni.williams.edu OI Goetz, Matthew/0000-0003-4542-992X FU National Institutes of Health: NIAAA [U10-AA13566]; NIA [R01-AG029154, K23 AG024896]; Doris Duke Charitable Foundation Clinical Scientist Development Award [2007070]; Training Program in Environmental Epidemiology [T32 ES07069]; Centers for AIDS Research at Albert Einstein/Montefiore [AI-51519]; Emory University [P30 AI050409] FX This work was financially supported by National Institutes of Health: NIAAA (U10-AA13566), and NIA (R01-AG029154; K23 AG024896). Dr. Gandhi is the recipient of the Doris Duke Charitable Foundation Clinical Scientist Development Award (2007070). Dr. Tate was supported by the Training Program in Environmental Epidemiology funded under grant no. T32 ES07069. This work was also facilitated by the Centers for AIDS Research at Albert Einstein/Montefiore (AI-51519) and at Emory University (P30 AI050409). NR 24 TC 6 Z9 6 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD SEP PY 2013 VL 22 IS 9 BP 1019 EP 1025 DI 10.1002/pds.3476 PG 7 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 202WF UT WOS:000323250600013 PM 23836591 ER PT J AU Galsky, MD Xie, W Nakabayashi, M Ross, RW Fennessy, FM Tempany, CM Choueiri, TK Khine, K Kantoff, PW Taplin, ME Oh, WK AF Galsky, M. D. Xie, W. Nakabayashi, M. Ross, R. W. Fennessy, F. M. Tempany, C. M. Choueiri, T. K. Khine, K. Kantoff, P. W. Taplin, M-E Oh, W. K. TI Analysis of the correlation between endorectal MRI response to neoadjuvant chemotherapy and biochemical recurrence in patients with high-risk localized prostate cancer SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE neoadjuvant chemotherapy; endorectal MRI; intermediate end points ID RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; RADIATION-THERAPY; FREE SURVIVAL; ANTIGEN ERA; PHASE-II; MEN; DOCETAXEL; TRIAL AB BACKGROUND: Intermediate end points are desirable to expedite the integration of neoadjuvant systemic therapy into the treatment strategy for high-risk localized prostate cancer. Endorectal magnetic resonance imaging at 1.5 Tesla (1.5T erMRI) response has been utilized as an end point in neoadjuvant trials but has not been correlated with clinical outcomes. METHODS: Data were pooled from two trials exploring neoadjuvant chemotherapy in high-risk localized prostate cancer. Trial 1 explored docetaxel for 6 months and Trial 2 explored docetaxel plus bevacizumab for 4.5 months, both before radical prostatectomy. erMRI was done at baseline and end of chemotherapy. 1.5T erMRI response, based upon T2W sequences, was recorded. Multivariable Cox regression was undertaken to evaluate the association between clinical parameters and biochemical recurrence. RESULTS: There were 53 evaluable patients in the combined analysis: 20 (33%) achieved a PSA response, 16 (27%) achieved an erMRI partial response and 24 (40%) achieved an erMRI minor response. Median follow-up was 4.2 years, and 33 of 53 evaluable (62%) patients developed biochemical recurrence. On multivariable analysis, PSA response did not correlate with biochemical recurrence (hazard ratio = 0.58, 95% confidence interval (CI) 0.25-1.33) and paradoxically erMRI response was associated with a significantly shorter time to biochemical recurrence (hazard ratio = 2.47, 95% CI 1.00-6.13). CONCLUSIONS: Response by 1.5T erMRI does not correlate with a decreased likelihood of biochemical recurrence in patients with high-risk localized prostate cancer treated with neoadjuvant docetaxel and may be associated with inferior outcomes. These data do not support the use of 1.5T erMRI response as a primary end point in neoadjuvant chemotherapy trials. C1 [Galsky, M. D.; Oh, W. K.] Mt Sinai Sch Med, Tisch Canc Inst, Dept Med, New York, NY 10029 USA. [Xie, W.; Nakabayashi, M.; Ross, R. W.; Fennessy, F. M.; Tempany, C. M.; Choueiri, T. K.; Khine, K.; Kantoff, P. W.; Taplin, M-E] Dana Farber Canc Inst, Dept Solid Tumor Oncol, Boston, MA 02115 USA. RP Galsky, MD (reprint author), Mt Sinai Sch Med, Tisch Canc Inst, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM Matthew.galsky@mssm.edu FU NCI NIH HHS [R01 CA111288]; NIBIB NIH HHS [P41 EB015898] NR 21 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD SEP PY 2013 VL 16 IS 3 BP 266 EP 270 DI 10.1038/pcan.2013.15 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 201NK UT WOS:000323148100008 PM 23712318 ER PT J AU Patenaude, AF Tung, N Ryan, PD Ellisen, LW Hewitt, L Schneider, KA Tercyak, KP Aldridge, J Garber, JE AF Patenaude, Andrea F. Tung, Nadine Ryan, Paula D. Ellisen, Leif W. Hewitt, Larissa Schneider, Katherine A. Tercyak, Kenneth P. Aldridge, Julie Garber, Judy E. TI Young adult daughters of BRCA1/2 positive mothers: What do they know about hereditary cancer and how much do they worry? SO PSYCHO-ONCOLOGY LA English DT Article DE BRCA1; 2; hereditary breast; ovarian cancer; mutation carriers; preventive oncology; psychoeducational intervention; cancer risk ID BREAST-CANCER; EVENT SCALE; PROPHYLACTIC SURGERY; MUTATION CARRIERS; FAMILY-HISTORY; RISK; WOMEN; CHILDREN; IMPACT; PERCEPTIONS AB Objective The objectives of this study are to determine (i) what daughters, ages 18-24years, of BRCA1/2 mutation carriers understand about their 50% chance of carrying a BRCA1/2 mutation and about risk reduction or management options for mutation carriers, (ii) the extent and nature of daughters' cancer-related distress, and (iii) the effects of knowing mother's mutation status on daughters' future plans. Methods A total of 40 daughters, currently aged 18-24years, of mothers who tested positive for a mutation in BRCA1/2 were invited by mail to participate (with contact information supplied by their mothers). Daughters participated in a qualitative telephone interview about the impact of learning their mother's mutation status on their understanding of their own cancer risks and their cancer-related distress, and their knowledge of screening strategies, risk-reducing surgery, current health status, and future plans. Participants also completed study-specific demographic and family history questionnaires, the Brief Symptom Inventory-18, Impact of Event Scale (with hereditary predisposition to breast/ovarian cancer as the event), and the Breast Cancer Genetic Counseling Knowledge Questionnaire. Results Daughters' genetic knowledge is suboptimal; gaps and misconceptions were common. Over 1/3 of the daughters reported high cancer-related distress, despite normal levels of general distress. Disclosed genetic information raised future concerns, especially regarding childbearing. Conclusion Targeted professional attention to this high-risk cohort of young women is critical to inform the next generation of daughters of BRCA1/2 mutation carriers and encourage recommended screening by age 25years. Improved uptake of screening and risk reduction options could improve survival, and psychoeducation could reduce cancer-related distress. Copyright (c) 2013 John Wiley & Sons, Ltd. C1 [Patenaude, Andrea F.; Hewitt, Larissa; Schneider, Katherine A.; Aldridge, Julie; Garber, Judy E.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Tung, Nadine] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Ryan, Paula D.; Ellisen, Leif W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Patenaude, Andrea F.; Tung, Nadine; Ellisen, Leif W.; Aldridge, Julie; Garber, Judy E.] Harvard Univ, Sch Med, Boston, MA USA. [Tercyak, Kenneth P.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Ryan, Paula D.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. RP Patenaude, AF (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM andrea_patenaude@dfci.harvard.edu FU US Department of Defense Congressionally Directed Medical Research Breast Cancer Research Program [BC084061:W81XWH-09-1-0217] FX This study was funded by the US Department of Defense Congressionally Directed Medical Research Breast Cancer Research Program, Grant #BC084061:W81XWH-09-1-0217. NR 37 TC 7 Z9 7 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD SEP PY 2013 VL 22 IS 9 BP 2024 EP 2031 DI 10.1002/pon.3257 PG 8 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 205NQ UT WOS:000323451500013 PM 23417902 ER PT J AU Gilleland, J Reed-Knight, B Brand, S Griffin, A Wasilewski-Masker, K Meacham, L Mertens, A AF Gilleland, Jordan Reed-Knight, Bonney Brand, Sarah Griffin, Anya Wasilewski-Masker, Karen Meacham, Lillian Mertens, Ann TI Assessment of family psychosocial functioning in survivors of pediatric cancer using the PAT2.0 SO PSYCHO-ONCOLOGY LA English DT Article DE cancer; oncology; survivorship; pediatrics; psychology; family functioning ID ASSESSMENT-TOOL PAT2.0; RISK; DIAGNOSIS; DISTRESS; SERVICES; IMPACT AB Background: This study aimed to examine clinical validity and utility of a screening measure for familial psychosocial risk, the Psychosocial Assessment Tool 2.0 (PAT2.0), among pediatric cancer survivors participating in long-term survivorship care. Methods: Caregivers (N = 79) completed the PAT2.0 during their child's survivorship appointment. Caregivers also reported on family engagement in outpatient mental health treatment. Medical records were reviewed for treatment history and oncology provider initiated psychology consults. Results: The internal consistency of the PAT2.0 total score in this survivorship sample was strong. Psychology was consulted by the oncology provider to see 53% of participant families, and families seen by psychology had significantly higher PAT2.0 total scores than families without psychology consults. PAT2.0 total scores and corresponding subscales were higher for patients, parents, and siblings enrolled in outpatient mental health services since treatment completion. Results were consistent with psychosocial risk categories presented within the Pediatric Psychosocial Preventative Health Model. Fifty-one percent of families presenting for survivorship care scored in the "universal" category, 34% scored in the "targeted" category, and 15% scored in the "clinical" category. Conclusions: Data indicate that the overall proportions of families experiencing "universal", "targeted", and "clinical" levels of familial distress may be constant from the time of diagnosis into survivorship care. Overall, the PAT2.0 demonstrated strong psychometric properties among survivors of pediatric cancer and shows promise as a psychosocial screening measure to facilitate more effective family support in survivorship care. Copyright (C) 2013 John Wiley & Sons, Ltd. C1 [Gilleland, Jordan; Griffin, Anya; Wasilewski-Masker, Karen; Meacham, Lillian; Mertens, Ann] Childrens Healthcare Atlanta, Aflac Canc & Blood Disorders Ctr, Atlanta, GA USA. [Gilleland, Jordan; Wasilewski-Masker, Karen; Meacham, Lillian; Mertens, Ann] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. [Reed-Knight, Bonney] Univ Georgia, Dept Psychol, Athens, GA 30602 USA. [Brand, Sarah] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gilleland, J (reprint author), Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA. EM jordan.gilleland@choa.org NR 19 TC 4 Z9 4 U1 0 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1057-9249 J9 PSYCHO-ONCOLOGY JI Psycho-Oncol. PD SEP PY 2013 VL 22 IS 9 BP 2133 EP 2139 DI 10.1002/pon.3265 PG 7 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 205NQ UT WOS:000323451500028 PM 23529924 ER PT J AU Jung, M AF Jung, Minsoo TI Associations of Physical and Sexual Health with Suicide Attempts Among Female Sex Workers in South Korea SO SEXUALITY AND DISABILITY LA English DT Article DE Suicide; Female sex workers; Sexually transmitted disease; South Korea ID SELF-RATED HEALTH; TRANSMITTED INFECTIONS; DEPRESSIVE SYMPTOMS; MENTAL-HEALTH; RISK-FACTORS; CHINA; COMMUNITY; PREVALENCE; MORTALITY; IDEATION AB This study investigated suicidal behavior prevalence and its association with physical and sexual health, and behavior-related factors among female sex workers in South Korea. Using time location sampling, we recruited 1,083 sex workers for an interviewer-administered questionnaire regarding sexual behavior, sociodemographics, and self-rated health (SRH) status. Participants were also tested for sexually transmitted diseases (STDs). We used binary logistic regression analysis to define suicide attempt factors. Around 28 % of sex workers in the sample reported that they had attempted suicide in the past year. Suicide attempts were independently associated with drinking alcohol almost every day, not using condom regularly, STD infection experience, and unfavorable SRH status. Higher suicide attempt likelihood was associated with poor sexual and physical health, but there was no significant association with the number of customers per week. We thus need to revive STD screening programs provided by the government and to support mental health programs. C1 [Jung, Minsoo] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02215 USA. [Jung, Minsoo] Dongduk Womens Univ, Dept Hlth Sci, Seoul, South Korea. RP Jung, M (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 450 Brookline Ave,LW 601, Boston, MA 02215 USA. EM minsoo_jung@dfci.harvard.edu OI Jung, Minsoo/0000-0003-3317-6507 NR 41 TC 1 Z9 1 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0146-1044 J9 SEX DISABIL JI Sex. Disabil. PD SEP PY 2013 VL 31 IS 3 BP 275 EP 286 DI 10.1007/s11195-013-9305-9 PG 12 WC Rehabilitation SC Rehabilitation GA 203AV UT WOS:000323263500007 ER PT J AU Ananthakrishnan, AN Oxford, EC Nguyen, DD Sauk, J Yajnik, V Xavier, RJ AF Ananthakrishnan, A. N. Oxford, E. C. Nguyen, D. D. Sauk, J. Yajnik, V. Xavier, R. J. TI Genetic risk factors for Clostridium difficile infection in ulcerative colitis SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; TOXIN-A; DIARRHEA; HOST; VARIANTS; OUTCOMES; BURDEN; HEALTH; QUEBEC; EPIDEMIOLOGY AB Background Patients with inflammatory bowel disease (IBD) are at higher risk for Clostridium difficile infection (CDI). Disruption of gut microbiome and interaction with the intestinal immune system are essential mechanisms for pathogenesis of both CDI and IBD. Whether genetic polymorphisms associated with susceptibility to IBD are also associated with risk of CDI is unknown. Aims To use a well-characterised and genotyped cohort of patients with UC to (i) identify clinical risk factors for CDI; (ii) examine if any of the IBD genetic risk loci were associated with CDI; and (iii) to compare the performance of predictive models using clinical and genetic risk factors in determining risk of CDI. Methods We used a prospective registry of patients from a tertiary referral hospital. Medical record review was performed to identify all ulcerative colitis (UC) patients within the registry with a history of CDI. All patients were genotyped on the Immunochip. We examined the association between the 163 risk loci for IBD and risk of CDI using a dominant genetic model. Model performance was examined using receiver operating characteristics curves. Results The study included 319 patients of whom 29 developed CDI (9%). Female gender and pancolitis were associated with increased risk, while use of anti-TNF was protective against CDI. Six genetic polymorphisms including those at TNFRSF14 [Odds ratio (OR) 6.0, P-value 0.01] were associated with increased risk while 2 loci were inversely associated. On multivariate analysis, none of the clinical parameters retained significance after adjusting for genetics. Presence of at least one high-risk locus was associated with an increase in risk for CDI (20% vs. 1%) (P=6x10(-9)). Compared to 11% for a clinical model, the genetic loci explained 28% of the variance in CDI risk and had a greater AUROC. Conclusion Host genetics may influence susceptibility to Clostridium difficile infection in patients with ulcerative colitis. C1 [Ananthakrishnan, A. N.; Nguyen, D. D.; Sauk, J.; Yajnik, V.; Xavier, R. J.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ananthakrishnan, A. N.; Nguyen, D. D.; Sauk, J.; Yajnik, V.; Xavier, R. J.] Harvard Univ, Sch Med, Boston, MA USA. [Oxford, E. C.] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Xavier, R. J.] MGH, Ctr Computat & Integrat Biol, Boston, MA USA. [Xavier, R. J.] Broad Inst, Cambridge, MA USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org FU National Institutes of Health (NIH) [P30 DK043351, K23 DK097142, U01 DK062432, R01 DK064869] FX This work is supported by a grant from the National Institutes of Health (NIH) (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. Ananthakrishnan is supported in part by a grant from the National Institutes of Health (K23 DK097142). Xavier is supported by grants U01 DK062432 & R01 DK064869 from the NIH. NR 49 TC 16 Z9 17 U1 0 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD SEP PY 2013 VL 38 IS 5 BP 522 EP 530 DI 10.1111/apt.12425 PG 9 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 199GH UT WOS:000322982000008 PM 23848254 ER PT J AU Davidson, TM Price, M McCauley, JL Ruggiero, KJ AF Davidson, Tatiana M. Price, Matthew McCauley, Jenna L. Ruggiero, Kenneth J. TI Disaster Impact Across Cultural Groups: Comparison of Whites, African Americans, and Latinos SO AMERICAN JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Article DE Disaster impact; Cultural groups; PTSD; Depression ID STRESSFUL LIFE EVENTS; HURRICANE-KATRINA; PSYCHOLOGICAL DISTRESS; PTSD; RACE; RESOURCES; ETHNICITY; COMMUNICATION; RESILIENCE; CHECKLIST AB The current study extends knowledge regarding the differential impact of natural disasters among White, African American, and Latino survivors of Hurricane Ike through its use of a large, regional sample recruited via representative sampling procedures to examine the associations between cultural identification and disaster impact, including loss, damage, and negative mental health outcomes. Consistent with previous research, results indicated disparities between cultural groups with regard to disaster exposure. Additionally, type of disaster impact was differentially associated with PTSD and depression status dependent on cultural group. Specifically, the extent of personal disaster exposure, property damage, and loss of services made significant contributions to PTSD status among White survivors. African-Americans were more likely than White and Latino Ike survivors to endorse post-disaster PTSD and depression and endorsement of depression was predicted by severity of property damage. With respect to Latino respondents, only the extent of personal disaster exposure significantly contributed to both PTSD and depression status. Implications of the current findings are discussed with regard to future disaster preparedness and response efforts and the implementation and evaluation of community-based disaster resources. C1 [Davidson, Tatiana M.; Price, Matthew; McCauley, Jenna L.] Med Univ S Carolina, Natl Crime Victims Res & Treatment Ctr, Charleston, SC 29425 USA. [Ruggiero, Kenneth J.] Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. RP Davidson, TM (reprint author), Med Univ S Carolina, Natl Crime Victims Res & Treatment Ctr, 67 President St IOP 2 South,MSC 861, Charleston, SC 29425 USA. EM davidst@musc.edu FU NIMH NIH HHS [R34 MH077149, R34 MH77149] NR 50 TC 6 Z9 6 U1 4 U2 28 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0562 J9 AM J COMMUN PSYCHOL JI Am. J. Community Psychol. PD SEP PY 2013 VL 52 IS 1-2 BP 97 EP 105 DI 10.1007/s10464-013-9579-1 PG 9 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA 194QE UT WOS:000322647000008 PM 23709270 ER PT J AU Kazamel, M Cutter, G Claussen, G Alsharabati, M Oh, SJ Lu, L King, PH AF Kazamel, Mohamed Cutter, Gary Claussen, Gwendolyn Alsharabati, Mohammad Oh, Shin J. Lu, Liang King, Peter H. TI Epidemiological features of amyotrophic lateral sclerosis in a large clinic-based African American population SO AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION LA English DT Article DE Motor neuron disease; race; phenotype; gender effect ID MOTOR-NEURON DISEASE; PROGNOSIS; ALS AB Our objective was to identify the main clinical and epidemiological features of ALS in a large cohort of African American (AA) patients and compare them to Caucasian (CA) patients in a clinic-based population. We retrospectively identified 207 patients who were diagnosed with ALS based on the revised El Escorial criteria (60 AA and 147 CA subjects). Patients were seen in the Neuromuscular Division at the University Medical Center. We compared epidemiological and clinical features of these two groups, focusing on age of onset and diagnosis, clinical presentation and survival. Results showed that AA patients had a significantly younger age of disease onset (55 years vs. 61 years for CA, p = 0.011) and were diagnosed at an earlier age (56 years vs. 62 years, p = 0.012). In younger ALS patients (< 45 years of age), there was a significant difference in gender frequency, with females predominating in the AA population and males in the CA population (p = 0.025). In a multivariable Cox proportional hazard model, survival rates were not different between the groups. In both groups, survival significantly increased with younger age. In conclusion, AA patients presented at an earlier age, but there was no difference in survival compared to CA patients. A gender reversal occurred in younger ALS patients, with AA patients more likely to be female and CA patients more likely to be male. C1 [Kazamel, Mohamed; Claussen, Gwendolyn; Alsharabati, Mohammad; Oh, Shin J.; Lu, Liang; King, Peter H.] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL USA. [Cutter, Gary] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL USA. [King, Peter H.] Univ Alabama Birmingham, Dept Cell Dev & Integrat Biol, Birmingham, AL USA. [King, Peter H.] Univ Alabama Birmingham, Dept Genet, Birmingham, AL USA. [Oh, Shin J.; Lu, Liang; King, Peter H.] Birmingham VA Med Ctr, Birmingham, AL USA. RP King, PH (reprint author), 1720 7th Ave S,SC 260, Birmingham, AL 35294 USA. EM pking@uab.edu FU National Institutes of Health; Department of Veterans Affairs FX Funding was provided by the National Institutes of Health (PHK and LL), and Department of Veterans Affairs (PHK). NR 16 TC 7 Z9 8 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8421 J9 AMYOTROPH LA SCL FR JI Amyotroph. Lateral Scher. Frontotemp. Degenerat. PD SEP PY 2013 VL 14 IS 5-6 BP 334 EP 337 DI 10.3109/21678421.2013.770030 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 196NR UT WOS:000322782800002 PM 23458155 ER PT J AU Fondell, E O'Reilly, EJ Fitzgerald, KC Falcone, GJ McCullough, ML Park, Y Kolonel, LN Ascherio, A AF Fondell, Elinor O'Reilly, Eilis J. Fitzgerald, Kathryn C. Falcone, Guido J. McCullough, Marjorie L. Park, Yikyung Kolonel, Laurence N. Ascherio, Alberto TI Magnesium intake and risk of amyotrophic lateral sclerosis: Results from five large cohort studies SO AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION LA English DT Article DE Amyotrophic lateral sclerosis; motor neuron disease; longitudinal cohort studies; epidemiology; magnesium ID FOOD FREQUENCY QUESTIONNAIRE; SOCIETY CANCER PREVENTION; BASE-LINE CHARACTERISTICS; DIETARY-INTAKE; DISEASE; DISORDERS; HEALTH; PATHOGENESIS; ASSOCIATION; SURVIVAL AB A low magnesium intake has been suggested to be associated with amyotrophic lateral sclerosis (ALS) in pathological and case-control studies, but prospective studies in humans are lacking. The relation between dietary intake of magnesium and ALS risk was explored in five large prospective cohort studies (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study), comprising over 1,050,000 males and females contributing 1093 cases of ALS during a mean of 15 years of follow-up. Cox proportional hazards models were used within each cohort, and cohort-specific estimates were subsequently pooled using a random-effects model. Results demonstrated that dietary magnesium intake was not associated with ALS risk, relative risk 1.07, 95% confidence interval 0.88-1.31 comparing the highest quintile of intake with the lowest. This finding does not support a protective effect of magnesium intake on ALS risk. Further analyses should explore magnesium intake in combination with heavy metal exposure and genetic variants affecting magnesium absorption. C1 [Fondell, Elinor; O'Reilly, Eilis J.; Fitzgerald, Kathryn C.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Falcone, Guido J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Falcone, Guido J.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [McCullough, Marjorie L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Park, Yikyung] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kolonel, Laurence N.] Univ Hawaii, Program Epidemiol, Ctr Canc, Honolulu, HI 96822 USA. [Ascherio, Alberto] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Fondell, E (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 655 Huntington Ave, Boston, MA 02115 USA. EM efondell@hsph.harvard.edu RI Falcone, Guido/L-2287-2016; OI Falcone, Guido/0000-0002-6407-0302; Park, Yikyung/0000-0002-6281-489X FU National Institute of Neurological Diseases and Stroke [RO1 NS045893]; National Cancer Institute [PO1 CA87969, PO1 CA055075] FX This work was supported by a grant from the National Institute of Neurological Diseases and Stroke (RO1 NS045893) and by grants from the National Cancer Institute (PO1 CA87969 and PO1 CA055075). NR 37 TC 2 Z9 2 U1 0 U2 6 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 2167-8421 J9 AMYOTROPH LA SCL FR JI Amyotroph. Lateral Scher. Frontotemp. Degenerat. PD SEP PY 2013 VL 14 IS 5-6 BP 356 EP 361 DI 10.3109/21678421.2013.803577 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 196NR UT WOS:000322782800006 PM 23777266 ER PT J AU Specht, MC Miller, CL Skolny, MN Jammallo, LS O'Toole, J Horick, N Isakoff, SJ Smith, BL Taghian, AG AF Specht, Michelle C. Miller, Cynthia L. Skolny, Melissa N. Jammallo, Lauren S. O'Toole, Jean Horick, Nora Isakoff, Steven J. Smith, Barbara L. Taghian, Alphonse G. TI Residual Lymph Node Disease After Neoadjuvant Chemotherapy Predicts an Increased Risk of Lymphedema in Node-Positive Breast Cancer Patients SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID SURGICAL ADJUVANT BREAST; QUALITY-OF-LIFE; AXILLARY DISSECTION; ARM LYMPHEDEMA; BIOPSY; CARCINOMA; COMPLICATIONS; SURGERY; EDEMA; WOMEN AB Axillary lymph node dissection (ALND) is recommended for patients with clinically node-positive breast cancer and carries a risk of lymphedema > 30 %. Patients with node-positive breast cancer may consider neoadjuvant chemotherapy, which can reduce node positivity. We sought to determine if neoadjuvant chemotherapy reduced the risk of lymphedema in patients undergoing ALND for node-positive breast cancer. The 229 patients who underwent unilateral ALND and chemotherapy were divided into two groups: 30 % (68/229) had neoadjuvant and 70 % (161/229) had adjuvant chemotherapy. Prospective arm volumes were measured via perometry preoperatively and at 3- to 7-month intervals after surgery. Lymphedema was defined as relative volume change (RVC) a parts per thousand yen10 %, > 3 months from surgery. Kaplan-Meier curves and multivariate regression models were used to identify risk factors for lymphedema. Fifteen percent (10/68) of neoadjuvant patients compared with 23 % (37/161) of adjuvant patients developed RVC a parts per thousand yen10 % (hazard ratio = 0.76, p = 0.39). For all patients, body mass index was significantly associated with lymphedema (p = 0.0003). For neoadjuvant patients, residual lymph node disease after chemotherapy was associated with a ninefold greater risk of lymphedema compared to those without residual disease (p = 0.038). Patients who underwent neoadjuvant chemotherapy did not have a statistically significant reduction in risk of lymphedema. Among patients who receive neoadjuvant chemotherapy, residual lymph node disease predicted a greater risk of lymphedema. These patients should be closely monitored for lymphedema and possible early intervention for the condition. C1 [Specht, Michelle C.; Smith, Barbara L.] Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. [Miller, Cynthia L.; Skolny, Melissa N.; Jammallo, Lauren S.; Taghian, Alphonse G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [O'Toole, Jean] Massachusetts Gen Hosp, Dept Phys & Occupat Therapy, Boston, MA 02114 USA. [Horick, Nora] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Isakoff, Steven J.] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. RP Specht, MC (reprint author), Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. EM ataghian@partners.org NR 47 TC 6 Z9 6 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD SEP PY 2013 VL 20 IS 9 BP 2835 EP 2841 DI 10.1245/s10434-012-2828-y PG 7 WC Oncology; Surgery SC Oncology; Surgery GA 194WQ UT WOS:000322663800007 PM 23689935 ER PT J AU Schmidt, B Chang, KK Maduekwe, UN Look-Hong, N Rattner, DW Lauwers, GY Mullen, JT Yang, HK Yoon, SS AF Schmidt, Benjamin Chang, Kevin K. Maduekwe, Ugwuji N. Look-Hong, Nicole Rattner, David W. Lauwers, Gregory Y. Mullen, John T. Yang, Han-Kwang Yoon, Sam S. TI D2 Lymphadenectomy with Surgical Ex Vivo Dissection into Node Stations for Gastric Adenocarcinoma Can Be Performed Safely in Western Patients and Ensures Optimal Staging SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article ID PRESERVING TOTAL GASTRECTOMY; RANDOMIZED CONTROLLED-TRIAL; MARUYAMA INDEX SURGERY; DUTCH D1-D2 TRIAL; CANCER SURGERY; UNITED-STATES; LYMPH-NODES; MORBIDITY; MORTALITY; RESECTION AB The AJCC recommends examination of > 16 nodes to stage gastric adenocarcinoma. D2 lymphadenectomy (LAD) followed by surgical ex vivo dissection (SEVD) into nodal stations is standard at many high-volume Asian centers, but potential increases in morbidity and mortality have slowed adoption of D2 LAD in some Western centers. A total of 331 patients with gastric adenocarcinoma who underwent surgical resection at one Western institution from 1995 to 2010 were examined. Median age of patients was 69 years old, 65 % were male, and 84 % were white. D1 LAD was performed in 285 patients (86 %) and D2 LAD in 46 patients (14 %), with SEVD being performed in 17 patients (37 %) in the D2 group. D2 LAD with or without SEVD was performed much more commonly between 2006 and 2010. For the D1, D2 without SEVD, and D2 with SEVD groups, the median number of examined nodes and percentage with > 16 examined nodes were 16 and 51 %, 27 and 93 %, and 40 and 100 %, respectively. Major complications occurred in 16 % of the D1 group and 17 % of the D2 group (p > 0.05), and 30-day mortality was 3 % for the D1 group and 0 % for the D2 group. D2 LAD was a positive prognostic factor for overall survival on univariate (p = 0.027) and multivariate analyses (p = 0.005), but there were several possible confounding variables. D2 LAD at our Western institution was performed with low morbidity and no mortality. Optimal staging occurred after D2 LAD combined with SEVD, where a median of 40 nodes were examined and all patients had > 16 examined nodes. C1 [Schmidt, Benjamin; Chang, Kevin K.; Maduekwe, Ugwuji N.; Look-Hong, Nicole; Rattner, David W.; Mullen, John T.; Yoon, Sam S.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Lauwers, Gregory Y.] Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Yang, Han-Kwang] Univ Seoul, Coll Med, Dept Surg, Seoul Natl Univ Hosp, Seoul, South Korea. RP Yoon, SS (reprint author), Mem Sloan Kettering Canc Ctr, Gastr & Mixed Tumor Serv, 1275 York Ave, New York, NY 10021 USA. EM yoons@mskcc.org NR 35 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD SEP PY 2013 VL 20 IS 9 BP 2991 EP 2999 DI 10.1245/s10434-013-3019-1 PG 9 WC Oncology; Surgery SC Oncology; Surgery GA 194WQ UT WOS:000322663800029 PM 23760588 ER PT J AU Ogiso, S Conrad, C Araki, K Basso, V Gayet, B AF Ogiso, Satoshi Conrad, Claudius Araki, Kenichiro Basso, Valeria Gayet, Brice TI Posterior Approach for Laparoscopic Pancreaticoduodenectomy to Prevent Replaced Hepatic Artery Injury SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article AB Laparoscopic pancreaticoduodenectomy (PD) has become more popular despite its complexity and tendency for higher morbidity.1 Replaced right hepatic artery (RRHA) and replaced common hepatic artery (RCHA), both originating from the superior mesenteric artery (SMA), are the most significant and relatively common vascular anomalies in patients undergoing PD, occurring in 8.6-21 and 0.4-4.5 % of cases, respectively.2 (,) 3 An inadvertent injury to theses arteries may result in an intra- or postoperative bleeding, hepatic or bile duct ischemia, and consequent leakage or delayed stricture in the bilioenteric anastomosis.2 (-) 4 Therefore, preservation of these aberrant hepatic arteries is essential unless their resection is oncologically indicated.2 We describe a posterior approach that can be advantageous in laparoscopic PD for patients with a RRHA or RCHA. The posterior approach was used in 81 laparoscopic PDs at the Institute Mutualiste Montsouris between 1994 and 2012.5 In brief, retropancreatic dissection is performed to complete kocherization and expose the posterolateral aspect of the SMA. The origin of the RRHA or RCHA can then be identified and dissected. After division of the pancreatic neck, the portal vein and RRHA or RCHA are separated off the pancreatic neck. In case of the RCHA, the gastroduodenal artery originating from the RCHA is divided during this dissection. The video shows a secure procedure to preserve a RCHA in laparoscopic PD by early identification and dissection of the aberrant artery via the posterior approach. The posterior approach can help to prevent inadvertent RRHA or RCHA injury in laparoscopic PD. C1 [Ogiso, Satoshi; Conrad, Claudius; Araki, Kenichiro; Basso, Valeria; Gayet, Brice] Paris Descartes Univ, Inst Mutualiste Montsouris, Dept Digest Pathol, Paris, France. [Ogiso, Satoshi] Kyoto Univ, Grad Sch Med, Dept Surg, Div Hepatopancreatobiliary & Transplant Surg, Kyoto, Japan. [Conrad, Claudius] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Gayet, B (reprint author), Paris Descartes Univ, Inst Mutualiste Montsouris, Dept Digest Pathol, Paris, France. EM brice.gayet@imm.fr NR 5 TC 7 Z9 8 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD SEP PY 2013 VL 20 IS 9 BP 3120 EP 3120 DI 10.1245/s10434-013-3058-7 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 194WQ UT WOS:000322663800046 PM 23793363 ER PT J AU Liang, QL Benavides, GA Vassilopoulos, A Gius, D Darley-Usmar, V Zhang, JH AF Liang, Qiuli Benavides, Gloria A. Vassilopoulos, Athanassios Gius, David Darley-Usmar, Victor Zhang, Jianhua TI Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts SO BIOCHEMICAL JOURNAL LA English DT Article DE apoptosis; autophagy; c-Jun; c-Jun N-terminal kinase (JNK); sirtuin 3 ID OXIDATIVE STRESS; DEPENDENT DEACETYLASE; LYSINE ACETYLATION; CELLULAR BIOENERGETICS; MONITORING AUTOPHAGY; CALORIE RESTRICTION; SKELETAL-MUSCLE; SIRTUINS; LC3; PROTEIN AB Sirt3 (sirtuin 3) is an NAD-dependent deacetylase localized to mitochondria. Sirt3 expression is increased in mouse muscle and liver by starvation, which could protect against the starvation-dependent increase in oxidative stress and protein damage. Damaged proteins and organelles depend on autophagy for removal and this is critical for cell survival, but the role of Sirt3 is unclear. To examine this, we used Sirt3-KO (knockout) mouse embryonic fibroblast cells, and found that, under basal conditions, Sirt3-KO cells exhibited increased autophagy flux compared with WT (wild-type) cells. In response to nutrient deprivation, both WT and KO cells exhibited increased basal and ATP-linked mitochondrial respiration, indicating an increased energy demand. Both cells exhibited lower levels of phosphorylated mTOR (mammalian target of rapamycin) and higher autophagy flux, with KO cells exhibiting lower maximal mitochondrial respiration and reserve capacity, and higher levels of autophagy than WT cells. KO cells exhibit higher phospho-JNK (c-Jun N-terminal kinase) and phospho-c-Jun than WT cells under starvation conditions. However, inhibition of JNK activity in Sirt3-KO cells did not affect LC3-I (light chain 3-I) and LC3-II levels, indicating that Sirt3-regulated autophagy is independent of the JNK pathway. Caspase 3 activation and cell death are significantly higher in Sirt3-KO cells compared with WT cells in response to nutrient deprivation. Inhibition of autophagy by chloroquine exacerbated cell death in both WT and Sirt3-KO cells, and by 3-methyadenine exacerbated cell death in Sirt3-KO cells. These data suggest that nutrient deprivation-induced autophagy plays a protective role in cell survival, and Sirt3 decreases the requirement for enhanced autophagy and improves cellular bioenergetics. C1 [Liang, Qiuli; Benavides, Gloria A.; Darley-Usmar, Victor; Zhang, Jianhua] Univ Alabama Birmingham, Ctr Free Rad Biol, Birmingham, AL 35294 USA. [Liang, Qiuli; Benavides, Gloria A.; Darley-Usmar, Victor; Zhang, Jianhua] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Liang, Qiuli; Zhang, Jianhua] Birmingham VA Med Ctr, Dept Vet Affairs, Birmingham, AL 35233 USA. [Vassilopoulos, Athanassios; Gius, David] Northwestern Univ, Feinberg Sch Med, Dept Radiat Oncol, Chicago, IL 60611 USA. RP Zhang, JH (reprint author), Univ Alabama Birmingham, Ctr Free Rad Biol, Birmingham, AL 35294 USA. EM zhanja@uab.edu OI Zhang, Jianhua/0000-0002-2128-9574 FU National Institutes of Health [NIHR01-NS064090]; Veterans Affairs merit award FX This work was supported by the National Institutes of Health [grant number NIHR01-NS064090] and a Veterans Affairs merit award (to J.Z.). NR 52 TC 17 Z9 18 U1 0 U2 11 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD SEP 1 PY 2013 VL 454 BP 249 EP 257 DI 10.1042/BJ20130414 PN 2 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 202CL UT WOS:000323191000009 PM 23767918 ER PT J AU Barth, MJ Goldman, S Smith, L Perkins, S Shiramizu, B Gross, TG Harrison, L Sanger, W Geyer, MB Giulino-Roth, L Cairo, MS AF Barth, Matthew J. Goldman, Stanton Smith, Lynette Perkins, Sherrie Shiramizu, Bruce Gross, Thomas G. Harrison, Lauren Sanger, Warren Geyer, Mark B. Giulino-Roth, Lisa Cairo, Mitchell S. TI Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukaemia: a Children's Oncology Group report SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE non-Hodgkin lymphoma; rituximab; pharmacokinetics; pediatric; CD20 ID NON-HODGKINS-LYMPHOMA; SERUM CONCENTRATIONS; RISK; IDEC-C2B8; LEUKEMIA AB The ANHL01P1 trial was undertaken to determine pharmacokinetics and safety following the addition of rituximab to French-American-British/Lymphome Malins de Burkitt (FAB/LMB96) chemotherapy in 41 children and adolescents with Stage III/IV mature B-cell lymphoma/leukaemia. Patients received rituximab (375mg/m(2)) days -2 and 0 of two induction cycles and day 0 of two consolidation cycles. Highest peak levels were achieved following the second dose of each induction cycle [299 +/- 19 and 384 +/- 25 mu g/ml (Group-B); 245 +/- 31 and 321 +/- 32g/ml (Group-C)] with sustained troughs and t1/2 of 26-29d. Rituximab can be safely added to FAB chemotherapy with high early rituximab peak/trough levels and a long t1/2. C1 [Barth, Matthew J.] SUNY Coll Buffalo, Div Pediat Hematol Oncol, Buffalo, NY 14222 USA. [Goldman, Stanton] Med City Childrens Hosp, Div Pediat Hematol Oncol, Dallas, TX USA. [Smith, Lynette] Univ Nebraska, Coll Publ Hlth, Dept Biostat, Omaha, NE 68182 USA. [Perkins, Sherrie] Univ Utah, Dept Pathol, Salt Lake City, UT USA. [Shiramizu, Bruce] Univ Hawaii, Div Pediat Hematol Oncol, Honolulu, HI 96822 USA. [Gross, Thomas G.] Ohio State Univ, Div Pediat Hematol Oncol Blood & Marrow Transplan, Columbus, OH 43210 USA. [Harrison, Lauren; Cairo, Mitchell S.] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Sanger, Warren] Univ Nebraska Med Ctr, Dept Cytogenet, Omaha, NE USA. [Geyer, Mark B.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. [Giulino-Roth, Lisa] Weill Cornell Med Coll, Dept Pediat, Div Pediat Hematol Oncol, New York, NY USA. [Giulino-Roth, Lisa] Mem Sloan Kettering Canc Ctr, Dept Pediat, New York, NY 10021 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Med, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Pathol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Microbiol, Valhalla, NY 10595 USA. [Cairo, Mitchell S.] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. RP Cairo, MS (reprint author), New York Med Coll, Munger Pavil,50 Plaza West, Valhalla, NY 10595 USA. EM mitchell_cairo@nymc.edu OI Geyer, Mark/0000-0001-5248-9117 FU Division of Cancer Treatment, National Cancer Institute; National Institutes of Health, Department of Health and Human Services (COG) [CA98543-09, CA98413-09]; Pediatric Cancer Research Foundation; Doris Duke Charitable Foundation FX Funding was provided by The Division of Cancer Treatment, National Cancer Institute, and National Institutes of Health, Department of Health and Human Services (COG) (CA98543-09 and CA98413-09), Pediatric Cancer Research Foundation and the Doris Duke Charitable Foundation. NR 14 TC 10 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2013 VL 162 IS 5 BP 678 EP 683 DI 10.1111/bjh.12434 PG 6 WC Hematology SC Hematology GA 201QQ UT WOS:000323158400012 PM 23802659 ER PT J AU Yiu, G Marra, KV Wagley, S Krishnan, S Sandhu, H Kovacs, K Kuperwaser, M Arroyo, JG AF Yiu, Glenn Marra, Kyle V. Wagley, Sushant Krishnan, Sheela Sandhu, Harpal Kovacs, Kyle Kuperwaser, Mark Arroyo, Jorge G. TI Surgical outcomes after epiretinal membrane peeling combined with cataract surgery SO BRITISH JOURNAL OF OPHTHALMOLOGY LA English DT Article DE Epiretinal Membrane; Membrane Peeling; Vitrectomy; Phacoemulsification; Combined Surgery ID PARS-PLANA VITRECTOMY; INTRAOCULAR-LENS IMPLANTATION; NONVITRECTOMIZING VITREOUS SURGERY; INTERNAL LIMITING MEMBRANE; CYSTOID MACULAR EDEMA; COMBINED PHACOEMULSIFICATION; VITREORETINAL DISEASES; DIABETIC-RETINOPATHY; COEXISTING CATARACT; NUCLEAR SCLEROSIS AB Objective To compare functional and anatomical outcomes after idiopathic epiretinal membrane (ERM) peeling combined with phacoemulsification and intraocular lens implantation versus ERM peeling alone. Methods A retrospective, non-randomised comparative case series study was conducted of 81 eyes from 79 patients who underwent ERM peeling at the Beth Israel Deaconess Medical Center between 2001 and 2010. Eyes that underwent combined surgery for ERM and cataracts (group 1) were compared with those that had ERM peeling alone (group 2) with respect to best-corrected visual acuity at 6months and 1year after surgery, postoperative central macular thickness (CMT) as measured on optical coherence tomography, and rates of complications, including elevated intraocular pressure (IOP), ERM recurrence and need for reoperation. Results Mean logMAR visual acuity improved significantly in both groups at 6months (p<0.001) and 1year (p<0.001) after surgery. There was no statistical difference between the two groups in visual acuity improvement at 6months (p=0.108) or 1year (p=0.094). Mean CMT of both groups also significantly decreased after surgery (p=0.002), with no statistical difference in CMT reduction between the two groups, but a trend toward less CMT reduction in group 1 (p=0.061). The rates of complications, including IOP elevation, ERM recurrence and frequency of reoperation, were similar in the two groups, with non-statistical trends toward greater ERM recurrence (p=0.084) and need for reoperation (p=0.096) in those that had combined surgery. Conclusions Combined surgery for ERMs and cataracts may potentially be as effective as membrane peeling alone with respect to visual and anatomical outcomes. Further studies are necessary to determine if there may be greater ERM recurrence or need for reoperation after combined surgery. C1 [Yiu, Glenn; Sandhu, Harpal; Arroyo, Jorge G.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA USA. [Marra, Kyle V.; Wagley, Sushant; Kuperwaser, Mark; Arroyo, Jorge G.] Harvard Univ, Sch Med, Dept Ophthalmol, Beth Israel Deaconess Med Ctr, Boston, MA USA. [Krishnan, Sheela] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Kovacs, Kyle] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Arroyo, JG (reprint author), Beth Israel Deaconess Med Ctr, Retina Serv, 330 Brookline Ave,CC-5, Boston, MA 02215 USA. EM jarroyo@bidmc.harvard.edu OI Marra, Kyle/0000-0003-3517-7140 NR 33 TC 8 Z9 8 U1 0 U2 8 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0007-1161 EI 1468-2079 J9 BRIT J OPHTHALMOL JI Br. J. Ophthalmol. PD SEP PY 2013 VL 97 IS 9 BP 1197 EP 1201 DI 10.1136/bjophthalmol-2013-303189 PG 5 WC Ophthalmology SC Ophthalmology GA 201SO UT WOS:000323163500024 PM 23832965 ER PT J AU Dorsey, ER Darwin, KC Nichols, PE Kwok, JH Bennet, C Rosenthal, LS Bombard, Y Shoulson, I Oster, E AF Dorsey, E. R. Darwin, K. C. Nichols, P. E. Kwok, J. H. Bennet, C. Rosenthal, L. S. Bombard, Y. Shoulson, I. Oster, E. TI Knowledge of the Genetic Information Nondiscrimination act among individuals affected by Huntington disease SO CLINICAL GENETICS LA English DT Article DE genetic discrimination; Genetic Information Non-discrimination Act; health policy; Huntington disease ID INTERNATIONAL RESPOND-HD; DISCRIMINATION; STIGMA; RISK AB The Genetic Information Nondiscrimination Act (GINA) of 2008 was the first US legislation to address genetic discrimination. We sought to assess understanding of GINA among individuals affected by the autosomal dominant condition, Huntington disease (HD). We conducted a cross-sectional survey of individuals with varying risk of HD to assess their familiarity with GINA. As a control, individuals were surveyed about their familiarity with the Health Insurance Portability and Accountability Act (HIPAA). Those who reported familiarity with GINA were asked about their knowledge of specific provisions of the legislation. The survey was offered to 776 participants and completed by 410 (response rate 53%). Respondents across all groups were less familiar with GINA (41% slightly, somewhat, or very familiar) than with HIPAA (65%; p<0.0001). Of individuals with or at risk for HD who reported some familiarity with GINA, less than half correctly identified GINA's protections, and less than 15% correctly identified its limitations. Thus, among individuals affected by HD, familiarity with and knowledge of GINA are low. The effectiveness of the legislation may be limited by this lack of knowledge. C1 [Dorsey, E. R.; Darwin, K. C.; Nichols, P. E.; Rosenthal, L. S.] Johns Hopkins Med, Dept Neurol, Baltimore, MD USA. [Kwok, J. H.] Univ Calif Berkeley, Dept Econ, Berkeley, CA 94720 USA. [Bennet, C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Bombard, Y.] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Bombard, Y.] Mem Sloan Kettering Canc Ctr, Ctr Hlth Policy & Outcomes, New York, NY 10021 USA. [Shoulson, I.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Oster, E.] Univ Chicago, Booth Sch Business, Chicago, IL 60637 USA. RP Dorsey, ER (reprint author), 600 North Wolfe St,Meyer 6-181D, Baltimore, MD 21287 USA. EM ray.dorsey@jhmi.edu FU Robert Wood Johnson Foundation Physician Faculty Scholar Award; CHDI Foundation, Inc.; Neubauer family FX This study was funded by a Robert Wood Johnson Foundation Physician Faculty Scholar Award (E.R.D.). CHDI Foundation, Inc. funded the Huntington Study Group COHORT study from which participants for this report were drawn. We also acknowledge funding from the Neubauer family (E.O.). NR 21 TC 4 Z9 4 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD SEP PY 2013 VL 84 IS 3 BP 251 EP 257 DI 10.1111/cge.12065 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 199FJ UT WOS:000322979600011 PM 23167775 ER PT J AU Fernandez-Feo, M Wei, G Blumenkranz, G Dewhirst, FE Schuppan, D Oppenheim, FG Helmerhorst, EJ AF Fernandez-Feo, M. Wei, G. Blumenkranz, G. Dewhirst, F. E. Schuppan, D. Oppenheim, F. G. Helmerhorst, E. J. TI The cultivable human oral gluten-degrading microbiome and its potential implications in coeliac disease and gluten sensitivity SO CLINICAL MICROBIOLOGY AND INFECTION LA English DT Article DE Coeliac disease; degradation; gliadin; oral bacteria; proteases ID ACTINOMYCES-ODONTOLYTICUS; INTESTINAL MICROBIOTA; PROLYL ENDOPROTEASE; ENZYME THERAPY; SPRUE; ENDOCARDITIS; DEGRADATION AB Coeliac disease is characterized by intestinal inflammation caused by gluten, proteins which are widely contained in the Western diet. Mammalian digestive enzymes are only partly capable of cleaving gluten, and fragments remain that induce toxic responses in patients with coeliac disease. We found that the oral microbiome is a novel and rich source of gluten-degrading organisms. Here we report on the isolation and characterization of the cultivable resident oral microbes that are capable of cleaving gluten, with special emphasis on the immunogenic domains. Bacteria were obtained by a selective culturing approach and enzyme activities were characterized by: (i) hydrolysis of paranitroanilide-derivatized gliadin-derived tripeptide substrates; (ii) gliadin degradation in-gel (gliadin zymography); (iii) gliadin degradation in solution; (iv) proteolysis of the highly immunogenic -gliadin-derived 33-mer peptide. For selected strains pH activity profiles were determined. The culturing strategy yielded 87 aerobic and 63 anaerobic strains. Species with activity in at least two of the four assays were typed as: Rothia mucilaginosa HOT-681, Rothia aeria HOT-188, Actinomyces odontolyticus HOT-701, Streptococcus mitis HOT-677, Streptococcus sp. HOT-071, Neisseria mucosa HOT-682 and Capnocytophaga sputigena HOT-775, with Rothia species being active in all four assays. Cleavage specificities and substrate preferences differed among the strains identified. The approximate molecular weights of the enzymes were similar to 75kD (Rothia spp.), similar to 60kD (A.odontolyticus) and similar to 150kD (Streptococcus spp.). In conclusion, this study identified new gluten-degrading microorganisms in the upper gastrointestinal tract. A cocktail of the most active oral bacteria, or their isolated enzymes, may offer promising new treatment modalities for coeliac disease. C1 [Fernandez-Feo, M.; Wei, G.; Blumenkranz, G.; Oppenheim, F. G.; Helmerhorst, E. J.] Boston Univ, Dept Periodontol & Oral Biol, Henry M Goldman Sch Dent Med, Boston, MA 02118 USA. [Dewhirst, F. E.] Forsyth Inst, Dept Microbiol, Cambridge, MA USA. [Dewhirst, F. E.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Schuppan, D.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Gastroenterol, Boston, MA 02215 USA. [Schuppan, D.] Johannes Gutenberg Univ Mainz, Div Mol & Translat Med, D-55122 Mainz, Germany. RP Helmerhorst, EJ (reprint author), Boston Univ, Dept Periodontol & Oral Biol, Henry M Goldman Sch Dent Med, 700 Albany St,CABR W202A, Boston, MA 02118 USA. EM helmer@bu.edu OI Wei, Guoxian/0000-0001-5115-3697; Helmerhorst, Eva/0000-0002-4803-3018 FU National Institutes of Health [AI087803, DE007652, DE016937, AI078385] FX The studies were funded by grants from the National Institutes of Health: AI087803 (EJH), DE007652 (FO), DE016937 (FED) and AI078385 (DS). NR 28 TC 26 Z9 27 U1 2 U2 55 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1198-743X J9 CLIN MICROBIOL INFEC JI Clin. Microbiol. Infect. PD SEP PY 2013 VL 19 IS 9 BP E386 EP E394 DI 10.1111/1469-0691.12249 PG 9 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 202GE UT WOS:000323201300002 PM 23714165 ER PT J AU Webster, CM Wu, LF Douglas, D Soukas, AA AF Webster, Christopher M. Wu, Lianfeng Douglas, Denzil Soukas, Alexander A. TI A non-canonical role for the C. elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2 SO DEVELOPMENT LA English DT Article DE Target of rapamycin (TOR); TOR complex 2 (TORC2); Dosage compensation complex (DCC); Rictor; Metabolism; Growth; Aging; C. elegans; Epigenetics; dpy-21 ID CAENORHABDITIS-ELEGANS; X-CHROMOSOME; MTOR COMPLEX; TRANSCRIPTION FACTOR; HISTONE H4; LIFE-SPAN; MOTIF PHOSPHORYLATION; KINASE; AKT; CHROMATIN AB The target of rapamycin complex 2 (TORC2) pathway is evolutionarily conserved and regulates cellular energetics, growth and metabolism. Loss of function of the essential TORC2 subunit Rictor (RICT-1) in Caenorhabditis elegans results in slow developmental rate, reduced brood size, small body size, increased fat mass and truncated lifespan. We performed a rict-1 suppressor RNAi screen of genes encoding proteins that possess the phosphorylation sequence of the AGC family kinase SGK, a key downstream effector of TORC2. Only RNAi to dpy-21 suppressed rict-1 slow developmental rate. DPY-21 functions canonically in the ten-protein dosage compensation complex (DCC) to downregulate the expression of X-linked genes only in hermaphroditic worms. However, we find that dpy-21 functions outside of its canonical role, as RNAi to dpy-21 suppresses TORC2 mutant developmental delay in rict-1 males and hermaphrodites. RNAi to dpy-21 normalized brood size and fat storage phenotypes in rict-1 mutants, but failed to restore normal body size and normal lifespan. Further dissection of the DCC via RNAi revealed that other complex members phenocopy the dpy-21 suppression of rict-1, as did RNAi to the DCC effectors set-1 and set-4, which methylate histone 4 on lysine 20 (H4K20). TORC2/rict-1 animals show dysregulation of H4K20 mono- and tri-methyl silencing epigenetic marks, evidence of altered DCC, SET-1 and SET-4 activity. DPY-21 protein physically interacts with the protein kinase SGK-1, suggesting that TORC2 directly regulates the DCC. Together, the data suggest non-canonical, negative regulation of growth and reproduction by DPY-21 via DCC, SET-1 and SET-4 downstream of TORC2 in C. elegans. C1 [Webster, Christopher M.; Wu, Lianfeng; Douglas, Denzil; Soukas, Alexander A.] Massachusetts Gen Hosp, Dept Med, Ctr Human Genet, Res & Diabet Unit, Boston, MA 02114 USA. [Webster, Christopher M.; Wu, Lianfeng; Douglas, Denzil; Soukas, Alexander A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Soukas, AA (reprint author), Massachusetts Gen Hosp, Dept Med, Ctr Human Genet, Res & Diabet Unit, Boston, MA 02114 USA. EM asoukas@chgr.mgh.harvard.edu FU New Scholar in Aging Award from the Ellison Medical Foundation; National Institutes of Health (NIH) Career Development Award [K08DK087941]; Charles H. Hood Foundation Child Health Research Award; NIH Office of Research Infrastructure Programs [P40 OD010440] FX This work was supported by a New Scholar in Aging Award from the Ellison Medical Foundation [A.S.]; a National Institutes of Health (NIH) Career Development Award [K08DK087941 to A.S.]; and the Charles H. Hood Foundation Child Health Research Award [A.S.]. Some C. elegans strains were provided by the Caenorhabditis Genetics Center, which is funded by NIH Office of Research Infrastructure Programs [P40 OD010440]. Deposited in PMC for release after 12 months. NR 46 TC 5 Z9 12 U1 3 U2 16 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD SEP 1 PY 2013 VL 140 IS 17 BP 3601 EP 3612 DI 10.1242/dev.094292 PG 12 WC Developmental Biology SC Developmental Biology GA 200BN UT WOS:000323041400012 PM 23884442 ER PT J AU Wheeler, S Moore, K Forsberg, CW Riley, K Floyd, JS Smith, NL Boyko, EJ AF Wheeler, S. Moore, K. Forsberg, C. W. Riley, K. Floyd, J. S. Smith, N. L. Boyko, E. J. TI Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy SO DIABETOLOGIA LA English DT Article DE Cohort study; Diabetes mellitus; Monotherapy; Mortality; Oral hypoglycaemic medication; Pharmacoepidemiology; Veterans ID ALL-CAUSE MORTALITY; ADVERSE CARDIOVASCULAR OUTCOMES; PROPENSITY SCORE METHODS; POPULATION-BASED COHORT; MYOCARDIAL-INFARCTION; PHARMACOLOGICAL-TREATMENT; CLINICAL-TRIALS; HEART-FAILURE; RISK; MELLITUS AB Despite oral hypoglycaemic medications being the most commonly used pharmacological treatments for type 2 diabetes, research is limited on their comparative safety, particularly their effects on overall mortality. We compared mortality risk with monotherapy initiation of four oral hypoglycaemic medications in a nationwide cohort of US veterans with type 2 diabetes. We identified new users of oral hypoglycaemic medication monotherapy between 2004 and 2009 who received care for at least 1 year from the Veterans Health Administration. Patients were followed until initial monotherapy discontinuation, addition of another diabetes pharmacotherapy, death or end of follow-up. Mortality HRs were estimated using Cox regression adjusted for potential confounding factors. Among new users of metformin, sulfonylureas and rosiglitazone (185,360 men, 7,812 women), 4,256 (2.2%) died during follow-up. Average duration of medication use ranged from 1.4 to 1.7 years. Significantly higher mortality risk was seen for glibenclamide (known as glyburide in the USA and Canada) (HR 1.38, 95% CI 1.27, 1.50) or glipizide (HR 1.55, 95% CI 1.43, 1.67) compared with metformin monotherapy, and for glipizide compared with rosiglitazone (HR 1.27, 95% CI 1.01, 1.59) or glibenclamide monotherapy (HR 1.12, 95% CI 1.02, 1.23). A significant sex-rosiglitazone interaction was seen (p = 0.034) compared with metformin monotherapy, with women having a higher HR (HR 4.36, 95% CI 1.34, 14.20) than men (HR 1.19, 95% CI 0.95, 1.49). Significantly higher mortality was associated with glibenclamide, glipizide and rosiglitazone use compared with metformin, and with glipizide use compared with rosiglitazone or glibenclamide. The potential for residual confounding by indication should be considered in interpreting these results. C1 [Wheeler, S.; Boyko, E. J.] VA Puget Sound Hlth Care Syst, Gen Med Serv, Seattle, WA 98108 USA. [Moore, K.; Forsberg, C. W.; Riley, K.; Smith, N. L.; Boyko, E. J.] VA Puget Sound Hlth Care Syst, Epidemiol Res & Informat Ctr, Seattle, WA 98108 USA. [Floyd, J. S.] Univ Washington, Dept Med, Seattle, WA USA. [Smith, N. L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, N. L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Boyko, E. J.] VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Boyko, EJ (reprint author), VA Puget Sound Hlth Care Syst, 1660 South Columbian Way, Seattle, WA 98108 USA. EM eboyko@uw.edu RI Floyd, James/G-7563-2015 FU ERIC of VA Puget Sound in Seattle; National Heart, Lung and Blood Institute [T32 HL007902] FX This work was supported by the ERIC of VA Puget Sound in Seattle, and by facilities and services provided by the Diabetes Research Center (DK-17047) at the University of Washington. VA Puget Sound Health Care System provided support for the involvement of E. J. Boyko, N. L. Smith and S. Wheeler in this research. J. S. Floyd was supported by National Heart, Lung and Blood Institute training grant T32 HL007902. NR 42 TC 16 Z9 16 U1 0 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2013 VL 56 IS 9 BP 1934 EP 1943 DI 10.1007/s00125-013-2958-1 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 200HV UT WOS:000323059800011 PM 23797633 ER PT J AU Geng, T Hu, W Broadwater, MH Snider, JM Bielawski, J Russo, SB Schwacke, JH Ross, J Cowart, LA AF Geng, T. Hu, W. Broadwater, M. H. Snider, J. M. Bielawski, J. Russo, S. B. Schwacke, J. H. Ross, J. Cowart, L. A. TI Fatty acids differentially regulate insulin resistance through endoplasm reticulum stress-mediated induction of tribbles homologue 3: a potential link between dietary fat composition and the pathophysiological outcomes of obesity SO DIABETOLOGIA LA English DT Article DE Animal model; Diet-induced obesity; ER stress; Insulin resistance; NEFA; Trib3 ID COA DEHYDROGENASE-DEFICIENCY; PALMITATE-INDUCED APOPTOSIS; SKELETAL-MUSCLE CELLS; METABOLICALLY HEALTHY; GLUCOSE-HOMEOSTASIS; LIPID-METABOLISM; SATURATED-FAT; TRB3; ACTIVATION; CERAMIDE AB Previous studies have shown that saturated fatty acids cause insulin resistance (IR) that is prevented by unsaturated fatty acids. Tribbles homologue 3 (TRIB3) is a putative endogenous inhibitor of insulin signalling, but its role in insulin signalling is controversial. This study aimed to determine whether fatty acids regulate IR via TRIB3. We treated HepG2 cells with saturated and unsaturated fatty acids and evaluated TRIB3 expression. We then tested whether regulation of TRIB3 occurred through endoplasmic reticulum (ER) stress, and whether modulating TRIB3 and ER stress marker genes was necessary and/or sufficient for regulation of insulin signalling. To test the in vivo significance of this mechanism, we fed mice obesogenic diets with different fatty acid profiles and assessed physiological variables of diabetes, ER stress markers and Trib3 expression in the liver. Our data show that fatty acids differentially regulate IR through ER stress-mediated induction of TRIB3. Intriguingly, a standard and widely used obesogenic diet high in unsaturated fats failed to induce ER stress, TRIB3 or IR. However, an alternative obesogenic diet with lower unsaturated fat recapitulated the cell studies by causing ER stress, TRIB3 induction and IR. This study revealed a novel mechanism linking dietary fat composition to IR. Given the emerging roles for ER stress in non-alcoholic liver disease, we conclude that dietary fat composition rather than total amount may mediate hepatic pathology associated with obesity. C1 [Geng, T.; Hu, W.; Broadwater, M. H.; Snider, J. M.; Bielawski, J.; Russo, S. B.; Schwacke, J. H.; Ross, J.; Cowart, L. A.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Broadwater, M. H.] NOAA, Ctr Coastal Environm Hlth & Biomol Res, Charleston, SC 29412 USA. [Cowart, L. A.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29403 USA. RP Cowart, LA (reprint author), Med Univ S Carolina, Dept Biochem & Mol Biol, 173 Ashley Ave, Charleston, SC 29425 USA. EM cowartl@musc.edu FU VA Merit award; COBRE in Lipidomics in Pathobiology FX This work was supported by a VA Merit award and the COBRE in Lipidomics in Pathobiology, both to L. A. Cowart NR 48 TC 13 Z9 15 U1 0 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2013 VL 56 IS 9 BP 2078 EP 2087 DI 10.1007/s00125-013-2973-2 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 200HV UT WOS:000323059800027 PM 23820633 ER PT J AU Franks, PW Christophi, CA Jablonski, KA Delahanty, LM Horton, ES Knowler, WC Florez, JC AF Franks, P. W. Christophi, C. A. Jablonski, K. A. Delahanty, L. M. Horton, E. S. Knowler, W. C. Florez, J. C. CA Diabet Prevention Program Res Grp TI RETRACTED ARTICLE: Common variation in PPARGC1A/B and progression to diabetes or change in metabolic traits following preventive interventions: the Diabetes Prevention Program (vol 59, pg 2672, 2010) SO DIABETOLOGIA LA English DT Correction C1 [Franks, P. W.] Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, Malmo, Sweden. [Franks, P. W.] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Franks, P. W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Franks, P. W.; Christophi, C. A.; Jablonski, K. A.] Washington Univ, Diabet Prevent Program Coordinating Ctr, Ctr Biostat, Rockville, MD 20852 USA. [Delahanty, L. M.; Florez, J. C.] Massachusetts Gen Hosp, Dept Med, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Horton, E. S.; Florez, J. C.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Knowler, W. C.] Natl Inst Diabet & Digest & Kidney Dis, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ USA. [Florez, J. C.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. RP Franks, PW (reprint author), Washington Univ, Diabet Prevent Program Coordinating Ctr, Ctr Biostat, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM paul.franks@med.lu.se NR 1 TC 1 Z9 1 U1 6 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD SEP PY 2013 VL 56 IS 9 BP 2102 EP 2102 DI 10.1007/s00125-013-2911-3 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 200HV UT WOS:000323059800033 ER PT J AU Bortsov, AV Platts-Mills, TF Peak, DA Jones, JS Swor, RA Domeier, RM Lee, DC Rathlev, NK Hendry, PL Fillingim, RB McLean, SA AF Bortsov, A. V. Platts-Mills, T. F. Peak, D. A. Jones, J. S. Swor, R. A. Domeier, R. M. Lee, D. C. Rathlev, N. K. Hendry, P. L. Fillingim, R. B. McLean, S. A. TI Pain distribution and predictors of widespread pain in the immediate aftermath of motor vehicle collision SO EUROPEAN JOURNAL OF PAIN LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; WHIPLASH-ASSOCIATED DISORDERS; PERITRAUMATIC DISTRESS INVENTORY; LOW-BACK-PAIN; NECK PAIN; TRAFFIC COLLISIONS; RISK-FACTORS; INJURY; SCALE; ONSET AB Background: Musculoskeletal pain is common after motor vehicle collision (MVC). The study objective was to evaluate distribution of pain and predictors of widespread musculoskeletal pain in the early aftermath (within 48 h) of collision. Methods: European American adults aged 18-65 years presenting to the emergency department (ED) after collision who were discharged to home after evaluation were eligible. Evaluation included an assessment of reported pre-collision psychological characteristics, crash characteristics, current pain severity and location, and current psychological symptoms. Adjusted risk ratios were estimated using generalized linear models. Results: Among 890 participants included in the study, 589/890 (66%) had pain in three or more regions, and 192/890 (22%) had widespread musculoskeletal pain (pain in seven or more regions). In adjusted analyses, the presence of widespread pain was strongly associated with depressive and somatic symptoms prior to collision, pain catastrophizing, and acute psychological symptoms, and was not associated with most collision characteristics (road speed limit, extent of vehicle damage, collision type, driver vs. passenger, airbag deployment). The reported number of body regions that struck an object during the collision was associated with both reported pre-collision depressive symptoms and with widespread pain. Conclusion: More than one in five individuals presenting to the ED in the hours after MVC have widespread pain. Widespread pain is strongly associated with patient characteristics known to be modulated by supraspinal mechanisms, suggesting that stress-induced hyperalgesia may influence acute widespread pain after collision. C1 [Bortsov, A. V.; McLean, S. A.] Univ N Carolina, Dept Anesthesiol, Chapel Hill, NC 27599 USA. [Platts-Mills, T. F.; McLean, S. A.] Univ N Carolina, Dept Emergency Med, Chapel Hill, NC USA. [Peak, D. A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Jones, J. S.] Spectrum Hlth Hosp, Dept Emergency Med, Grand Rapids, MI USA. [Swor, R. A.] William Beaumont Hosp, Dept Emergency Med, Royal Oak, MI 48072 USA. [Domeier, R. M.] St Joseph Mercy Hosp, Dept Emergency Med, Ann Arbor, MI 48104 USA. [Lee, D. C.] N Shore Univ Hosp, Dept Emergency Med, Manhasset, NY USA. [Rathlev, N. K.] Baystate Med Ctr, Dept Emergency Med, Springfield, MA 01199 USA. [Hendry, P. L.] Univ Florida & Shands Jacksonville, Dept Emergency Med, Coll Med, Jacksonville, FL USA. [Fillingim, R. B.] Univ Florida, Coll Dent, Dept Community Dent & Behav Sci, Gainesville, FL USA. RP McLean, SA (reprint author), Univ N Carolina, Dept Anesthesiol, Chapel Hill, NC 27599 USA. EM smclean@aims.unc.edu OI McLean, Samuel/0000-0001-9482-3582 FU National Institute of Arthritis, Musculoskeletal, and Skin Diseases [R01 AR056328]; National Center for Research Resources [KL2 RR025746] FX Funding for this study was provided by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (R01 AR056328: Samuel A. McLean). Dr. Platts-Mills is supported by Award Number KL2 RR025746 from the National Center for Research Resources. NR 35 TC 13 Z9 13 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1090-3801 J9 EUR J PAIN JI Eur. J. Pain PD SEP PY 2013 VL 17 IS 8 BP 1243 EP 1251 DI 10.1002/j.1532-2149.2013.00285.x PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 195SJ UT WOS:000322723600016 PM 23335385 ER PT J AU Gola, S Keshri, GK Gupta, A AF Gola, Shefali Keshri, Gaurav Km Gupta, Asheesh TI Hepatic metabolism of ibuprofen in rats under acute hypobaric hypoxia SO EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY LA English DT Article DE Acute hypobaric hypoxia; Hepatic metabolism; Pharmacokinetics; Ibuprofen; CYP2C9 level ID HIGH-ALTITUDE HEADACHE; CHRONIC INTERMITTENT HYPOXIA; LONG-TERM EXPOSURE; HEALTHY-VOLUNTEERS; DRUG-METABOLISM; STEREOSELECTIVE METABOLISM; CLINICAL PHARMACOKINETICS; LIVER MICROSOMES; DOWN-REGULATION; UP-REGULATION AB Hypobaric hypoxia induced at high altitude causes a subnormal oxygen concentration in cells which affects the drug metabolic and pharmacokinetic (PK) capacity of the body. The metabolism and PK of drugs like ibuprofen may be impaired under hypoxia and may require a different than usual therapeutic dose regimen to ensure safe therapy. The present investigation was undertaken to evaluate the effect of acute hypobaric hypoxia (AHH) on hepatic metabolism and PK of ibuprofen in rats. Animals were exposed to simulated altitude of 7620 m (similar to 25,000 ft) for AHH exposure (6 and 24 h) in a decompression chamber and were administrated with single dose of ibuprofen (80 mg/kg body weight, p.o.). The results showed that GST activity was significantly reduced at 6 h (15%) and 24 h (23%) (p < 0.05) in hypoxic group as compared to normoxic. A significant increase by 20-24% (p < 0.05) in AST level was observed after AHH exposure. LDH activity also exhibited significant increase (p < 0.05) after 24 h of AHH. A significant down-regulated CYP2C9 level and mild histopathological changes were observed after 24 h of AHH. Furthermore, PK variables viz, elimination half-life (T1/2) and mean residence time (MRT) of ibuprofen exhibited significant increase by 42% and 51% (p < 0.05) respectively after 24 h of AHH. Thus, results suggest that AHH exposure of 24 h significantly affects phase II conjugation pathway, CYP2C9 level, AST level, liver histology and PK parameters. This asserts that AHH can impair disposition of ibuprofen however, it requires further investigation under chronic hypobaric hypoxic conditions. (c) 2012 Elsevier GmbH. All rights reserved. C1 [Gola, Shefali; Keshri, Gaurav Km; Gupta, Asheesh] DRDO, Def Inst Physiol & Allied Sci, Delhi 110054, India. RP Gupta, A (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, BAR 416,40 Blossom St, Boston, MA 02114 USA. EM asheeshgupta2001@gmail.com FU Defence Institute of Physiology and Allied Sciences (DIPAS), DRDO, Ministry of Defence, Government of India FX This study was supported and funded by the Defence Institute of Physiology and Allied Sciences (DIPAS), DRDO, Ministry of Defence, Government of India. The authors are grateful to Director, DIPAS for providing kind support and encouragement to the study. NR 55 TC 1 Z9 3 U1 2 U2 16 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0940-2993 J9 EXP TOXICOL PATHOL JI Exp. Toxicol. Pathol. PD SEP PY 2013 VL 65 IS 6 BP 751 EP 758 DI 10.1016/j.etp.2012.11.001 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA 198NO UT WOS:000322929800006 PM 23218936 ER PT J AU Golden-Mason, L Rosen, HR AF Golden-Mason, Lucy Rosen, Hugo R. TI Natural killer cells: multifaceted players with key roles in hepatitis C immunity SO IMMUNOLOGICAL REVIEWS LA English DT Review DE innate immunity; liver; human; interferon ID HUMAN NK-CELLS; PLASMACYTOID-DENDRITIC-CELLS; ACTIVATED STELLATE CELLS; INHIBITORY RECEPTOR GENES; B-ASSOCIATED TRANSCRIPT-3; VIRUS ENVELOPE PROTEIN; INDUCED LIVER-INJURY; HLA-E EXPRESSION; COMPLEX CLASS-I; T-CELLS AB Natural killer cells (NKs) are involved in every stage of hepatitis C viral (HCV) infection, from protection against HCV acquisition and resolution in the acute phase to treatment-induced clearance. In addition to their direct antiviral actions, NKs are involved in the induction and priming of appropriate downstream T-cell responses. In the setting of chronic HCV, overall NK cell levels are decreased, subset distribution is altered, and changes in NK receptor (NKR) expression have been demonstrated, although the contribution of individual NKRs to viral clearance or persistence remains to be clarified. Enhanced NK cell cytotoxicity accompanied by insufficient interferon- production may promote liver damage in the setting of chronic infection. Treatment-induced clearance is associated with activation of NK cells, and it will be of interest to monitor NK cell responses to triple therapy. Activated NK cells also have anti-fibrotic properties, and the same hepatic NK cell populations that are actively involved in control of HCV may also be involved in control of HCV-associated liver damage. We still have much to learn, in particular: how do liver-derived NKs influence the outcome of HCV infection? Do NK receptors recognize HCV-specific components? And, are HCV-specific memory NK populations generated? C1 [Golden-Mason, Lucy; Rosen, Hugo R.] UCD, Dept Med, Hepatitis Ctr C, Div Gastroenterol & Hepatol, Aurora, CO USA. [Golden-Mason, Lucy; Rosen, Hugo R.] UCD, Integrated Program Immunol, Denver, CO USA. [Golden-Mason, Lucy; Rosen, Hugo R.] NJH, Denver, CO USA. [Rosen, Hugo R.] Denver VA Med Ctr, Denver, CO USA. RP Rosen, HR (reprint author), Div GI Hepatol B 158, Acad Off Bldg 1,12631 E 17th Ave,Rm 7614,POB 6511, Aurora, CO 80045 USA. EM hugo.rosen@ucdenver.edu FU HCV Center Grant [U19 AI 1066328]; VA Merit Review [RO1 DK60590, RO1 DK071560] FX This work was supported by the following grants to H. R. R.: U19 AI 1066328 (HCV Center Grant); VA Merit Review; RO1 DK60590 and RO1 DK071560. The authors declare no conflicts of interest. NR 187 TC 27 Z9 29 U1 2 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD SEP PY 2013 VL 255 IS 1 SI SI BP 68 EP 81 DI 10.1111/imr.12090 PG 14 WC Immunology SC Immunology GA 201OM UT WOS:000323150900006 PM 23947348 ER PT J AU Clark, RB Cervantes, JL Maciejewski, MW Farrokhi, V Nemati, R Yao, XD Anstadt, E Fujiwara, M Wright, KT Riddle, C La Vake, CJ Salazar, JC Finegold, S Nichols, FC AF Clark, Robert B. Cervantes, Jorge L. Maciejewski, Mark W. Farrokhi, Vahid Nemati, Reza Yao, Xudong Anstadt, Emily Fujiwara, Mai Wright, Kyle T. Riddle, Caroline La Vake, Carson J. Salazar, Juan C. Finegold, Sydney Nichols, Frank C. TI Serine Lipids of Porphyromonas gingivalis Are Human and Mouse Toll-Like Receptor 2 Ligands SO INFECTION AND IMMUNITY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; BIOLOGICAL-ACTIVITIES; MULTIPLE-SCLEROSIS; BONE LOSS; LIPOPOLYSACCHARIDE; ATHEROSCLEROSIS; RECOGNITION; ACTIVATION; FLAVOLIPIN; FIMBRIAE AB The total cellular lipids of Porphyromas gingivalis, a known periodontal pathogen, were previously shown to promote dendritic cell activation and inhibition of osteoblasts through engagement of Toll-like receptor 2 (TLR2). The purpose of the present investigation was to fractionate all lipids of P. gingivalis and define which lipid classes account for the TLR2 engagement, based on both in vitro human cell assays and in vivo studies in mice. Specific serine-containing lipids of P. gingivalis, called lipid 654 and lipid 430, were identified in specific high-performance liquid chromatography fractions as the TLR2-activating lipids. The structures of these lipids were defined using tandem mass spectrometry and nuclear magnetic resonance methods. In vitro, both lipid 654 and lipid 430 activated TLR2-expressing HEK cells, and this activation was inhibited by anti-TLR2 antibody. In contrast, TLR4-expressing HEK cells failed to be activated by either lipid 654 or lipid 430. Wild-type (WT) or TLR2-deficient (TLR2(-/-)) mice were injected with either lipid 654 or lipid 430, and the effects on serum levels of the chemokine CCL2 were measured 4 h later. Administration of either lipid 654 or lipid 430 to WT mice resulted in a significant increase in serum CCL2 levels; in contrast, the administration of lipid 654 or lipid 430 to TLR2(-/-) mice resulted in no increase in serum CCL2. These results thus identify a new class of TLR2 ligands that are produced by P. gingivalis that likely play a significant role in mediating inflammatory responses both at periodontal sites and, potentially, in other tissues where these lipids might accumulate. C1 [Clark, Robert B.; Cervantes, Jorge L.; Anstadt, Emily; Fujiwara, Mai; Wright, Kyle T.; Riddle, Caroline; La Vake, Carson J.; Salazar, Juan C.] Univ Connecticut, Sch Med, Dept Pediat, Dept Immunol, Farmington, CT 06032 USA. [Clark, Robert B.; Cervantes, Jorge L.; Anstadt, Emily; Fujiwara, Mai; Wright, Kyle T.; Riddle, Caroline; La Vake, Carson J.; Salazar, Juan C.] Univ Connecticut, Sch Med, Dept Med, Farmington, CT USA. [Maciejewski, Mark W.] Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT USA. [Farrokhi, Vahid; Nemati, Reza; Yao, Xudong] Univ Connecticut, Dept Chem, Storrs, CT USA. [Finegold, Sydney] VA Greater Los Angeles Healthcare Syst, Div Infect Dis, Los Angeles, CA USA. [Nichols, Frank C.] Univ Connecticut, Sch Dent Med, Dept Oral Hlth & Diagnost Sci, Farmington, CT 06032 USA. RP Nichols, FC (reprint author), Univ Connecticut, Sch Dent Med, Dept Oral Hlth & Diagnost Sci, Farmington, CT 06032 USA. EM Nichols@nso.uchc.edu FU NIH [1 R01 DE021055-01A1]; National MS Society [RG4070-A-6]; NIAID [AI090166] FX This work was supported by NIH 1 R01 DE021055-01A1 (F.C.N.), National MS Society RG4070-A-6 (R.B.C.), and NIAID AI090166 (J.C.S.). NR 53 TC 11 Z9 11 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD SEP PY 2013 VL 81 IS 9 BP 3479 EP 3489 DI 10.1128/IAI.00803-13 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 201NM UT WOS:000323148300042 PM 23836823 ER PT J AU Salgado, CD Sepkowitz, KA John, JF Cantey, JR Attaway, HH Freeman, KD Sharpe, PA Michels, HT Schmidt, MG AF Salgado, Cassandra D. Sepkowitz, Kent A. John, Joseph F. Cantey, J. Robert Attaway, Hubert H. Freeman, Katherine D. Sharpe, Peter A. Michels, Harold T. Schmidt, Michael G. TI The Environment and Healthcare-Acquired Infections: Why Accurate Reporting and Evaluation of Biological Plausibility Are Important Reply SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Letter ID COPPER; SURFACES; UNIT C1 [Salgado, Cassandra D.; Cantey, J. Robert] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Sepkowitz, Kent A.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [John, Joseph F.] Ralph H Johnson VA, Dept Med, Charleston, SC USA. [Attaway, Hubert H.; Schmidt, Michael G.] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. [Freeman, Katherine D.] Extrapolate, Delray Beach, FL USA. [Sharpe, Peter A.] Sharpe & Associates, W Orange, NJ USA. [Michels, Harold T.] Copper Dev Assoc, New York, NY USA. RP Salgado, CD (reprint author), Med Univ S Carolina, Div Infect Dis, 135 Rutledge Ave, Charleston, SC 29425 USA. EM salgado@musc.edu NR 8 TC 1 Z9 1 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD SEP 1 PY 2013 VL 34 IS 9 BP 997 EP 999 DI 10.1086/671938 PG 3 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 195LD UT WOS:000322702900020 PM 23917920 ER PT J AU Tzika, AA Fontes-Oliveira, CC Shestov, AA Constantinou, C Psychogios, N Righi, V Mintzopoulos, D Busquets, S Lopez-Soriano, FJ Milot, S Lepine, F Mindrinos, MN Rahme, LG Argiles, JM AF Tzika, A. Aria Fontes-Oliveira, Cibely Cristine Shestov, Alexander A. Constantinou, Caterina Psychogios, Nikolaos Righi, Valeria Mintzopoulos, Dionyssios Busquets, Silvia Lopez-Soriano, Francisco J. Milot, Sylvain Lepine, Francois Mindrinos, Michael N. Rahme, Laurence G. Argiles, Josep M. TI Skeletal muscle mitochondrial uncoupling in a murine cancer cachexia model SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE skeletal muscle; cancer cachexia; mitochondria; peroxisome proliferator-activated receptor gamma co-activator-1 beta; uncoupling protein 3; nuclear magnetic resonance spectroscopy; gas chromatography/mass spectrometry; adenosine triphosphate; tricarboxylic acid ID MAGNETIC-RESONANCE-SPECTROSCOPY; PLACEBO-CONTROLLED TRIAL; IN-VIVO; GENE-EXPRESSION; BURN-TRAUMA; PROTEIN-DEGRADATION; OXIDATIVE STRESS; P-31 NMR; MOLECULAR-MECHANISMS; PGC-1 COACTIVATORS AB Approximately half of all cancer patients present with cachexia, a condition in which disease-associated metabolic changes lead to a severe loss of skeletal muscle mass. Working toward an integrated and mechanistic view of cancer cachexia, we investigated the hypothesis that cancer promotes mitochondrial uncoupling in skeletal muscle. We subjected mice to in vivo phosphorous-31 nuclear magnetic resonance (P-31 NMR) spectroscopy and subjected murine skeletal muscle samples to gas chromatography/mass spectrometry (GC/MS). The mice used in both experiments were Lewis lung carcinoma models of cancer cachexia. A novel 'fragmented mass isotopomer' approach was used in our dynamic analysis of C-13 mass isotopomer data. Our P-31 NMR and GC/MS results indicated that the adenosine triphosphate (ATP) synthesis rate and tricarboxylic acid (TCA) cycle flux were reduced by 49% and 22%, respectively, in the cancer-bearing mice (p<0.008; t-test vs. controls). The ratio of ATP synthesis rate to the TCA cycle flux (an index of mitochondrial coupling) was reduced by 32% in the cancer-bearing mice (p=0.036; t-test vs. controls). Genomic analysis revealed aberrant expression levels for key regulatory genes and transmission electron microscopy (TEM) revealed ultrastructural abnormalities in the muscle fiber, consistent with the presence of abnormal, giant mitochondria. Taken together, these data suggest that mitochondrial uncoupling occurs in cancer cachexia and thus point to the mitochondria as a potential pharmaceutical target for the treatment of cachexia. These findings may prove relevant to elucidating the mechanisms underlying skeletal muscle wasting observed in other chronic diseases, as well as in aging. C1 [Tzika, A. Aria; Constantinou, Caterina; Psychogios, Nikolaos; Righi, Valeria; Mintzopoulos, Dionyssios] Massachusetts Gen Hosp, NMR Surg Lab, Dept Surg, Boston, MA 02114 USA. [Tzika, A. Aria; Constantinou, Caterina; Psychogios, Nikolaos; Righi, Valeria; Mintzopoulos, Dionyssios; Rahme, Laurence G.] Harvard Univ, Sch Med, Shriners Burn Inst, Boston, MA 02114 USA. [Tzika, A. Aria; Psychogios, Nikolaos; Righi, Valeria; Mintzopoulos, Dionyssios] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Boston, MA 02114 USA. [Fontes-Oliveira, Cibely Cristine; Busquets, Silvia; Lopez-Soriano, Francisco J.; Argiles, Josep M.] Univ Barcelona, Fac Biol, Canc Res Grp, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. [Shestov, Alexander A.] Univ Minnesota, Sch Med, Dept Radiol, Ctr Magnet Resonance Res, Minneapolis, MN 55455 USA. [Constantinou, Caterina; Rahme, Laurence G.] Massachusetts Gen Hosp, Dept Surg, Mol Surg Lab, Boston, MA 02114 USA. [Mindrinos, Michael N.] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. [Milot, Sylvain; Lepine, Francois] Univ Quebec, INRS Inst Armand Frappier, Laval, PQ H7V 1B7, Canada. RP Tzika, AA (reprint author), Massachusetts Gen Hosp, NMR Surg Lab, Dept Surg, 51 Blossom St,Room 261, Boston, MA 02114 USA. EM atzika@hms.harvard.edu; jargiles@ub.edu OI Busquets, Silvia/0000-0002-9319-3555; Psychogios, Nikolaos/0000-0002-2747-6012; Righi, Valeria/0000-0003-2394-8462; Constantinou, Caterina/0000-0003-3589-0739; Fontes-Oliveira, Cibely/0000-0003-1112-6015 FU Shriners Hospital for Children research grants [8893, 8892]; Alban Scholarship Programme [E05D059293BR] FX This study was supported in part by Shriners Hospital for Children research grants (no. 8893) to A. Aria Tzika and (no. 8892) to Laurence G. Rahme. Cibely C. Fontes-Oliveira was supported by an Alban Scholarship Programme (E05D059293BR). We thank Ann Power Smith of Write Science Right for editorial assistance. NR 111 TC 17 Z9 17 U1 1 U2 15 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD SEP PY 2013 VL 43 IS 3 BP 886 EP 894 DI 10.3892/ijo.2013.1998 PG 9 WC Oncology SC Oncology GA 190XD UT WOS:000322375900023 PM 23817738 ER PT J AU Chang, JJ Woods, M Lindsay, RJ Doyle, EH Griesbeck, M Chan, ES Robbins, GK Bosch, RJ Altfeld, M AF Chang, J. Judy Woods, Matt Lindsay, Robert J. Doyle, Erin H. Griesbeck, Morgane Chan, Ellen S. Robbins, Gregory K. Bosch, Ronald J. Altfeld, Marcus TI Higher Expression of Several Interferon-Stimulated Genes in HIV-1-Infected Females After Adjusting for the Level of Viral Replication SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV-1; innate immunity; type I Interferon; Toll-like receptors; T cells; sex differences; immune activation; dendritic cells; pathogenesis ID PLASMACYTOID DENDRITIC CELLS; HIV-1 INFECTION; SEX-DIFFERENCES; IMMUNE ACTIVATION; VIRUS BURDEN; RNA LEVELS; T-CELLS; RESPONSES; AIDS; PROGRESSION AB Background. Clinical studies have shown faster disease progression and stronger immune activation in human immunodeficiency virus (HIV)-1-infected females when compared with males for the same level of HIV-1 replication. Here we determine whether the elevated levels of HIV-1-induced interferon-alpha (IFN-alpha) production observed in females are associated with higher interferon-stimulated gene (ISG) expression levels in T cells, hence suggesting type-I IFN as a mechanism for the higher HIV-1-associated immune activation observed. Methods. T-cell and dendritic cell populations were isolated from treatment-naive chronically HIV-1-infected individuals enrolled in the Adult Clinical Trials Group 384 by fluorescence-activated cell sorting. The expression of 98 genes involved in Toll-like receptor and type I IFN signaling pathways were quantified using Nanostring technology. Results. Several ISGs were significantly correlated with HIV-1 viral load and/or CD4(+) T-cell count. Higher expression levels of a subset of these ISGs were observed in cells derived from females as compared to males after adjusting for viral load and were correlated to higher levels of T-cell activation. Conclusion. These data show that higher IFN-alpha production is associated with higher ex vivo expression of several ISGs in females. This might contribute to higher levels of immune activation and the observed faster HIV-1 disease progression in females for a given level of viral replication. C1 [Chang, J. Judy; Woods, Matt; Lindsay, Robert J.; Doyle, Erin H.; Griesbeck, Morgane; Altfeld, Marcus] Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA. [Chang, J. Judy; Woods, Matt; Lindsay, Robert J.; Doyle, Erin H.; Griesbeck, Morgane; Altfeld, Marcus] MIT, Cambridge, MA 02139 USA. [Chang, J. Judy; Woods, Matt; Lindsay, Robert J.; Doyle, Erin H.; Griesbeck, Morgane; Altfeld, Marcus] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Ellen S.; Bosch, Ronald J.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Robbins, Gregory K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. RP Altfeld, M (reprint author), Massachusetts Gen Hosp, Ragon Inst MGH MIT & Harvard, 9th Floor,400 Technol Sq, Cambridge, MA 02139 USA. EM maltfeld@partners.org OI Doyle, Erin/0000-0001-9380-2819 FU National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIAID) [R01 AI078784]; National Health and Medical Research Council of Australia [519578]; Phillip T. and Susan M. Ragon Foundation; NIAID [AI38855, AI27659, AI38858, AI25879, AI27666, AI68634, AI68636]; Agouron/Pfizer; Bristol Myers Squibb; GlaxoSmithKline FX These studies were supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIAID; R01 AI078784) and fellowships awarded to J. J. C. from the National Health and Medical Research Council of Australia (519578) and the Phillip T. and Susan M. Ragon Foundation. ACTG 384 was supported in part by NIAID (grants AI38855, AI27659, AI38858, AI25879, AI27666, AI68634, AI68636) and by Agouron/Pfizer, Bristol Myers Squibb, and GlaxoSmithKline. NR 34 TC 24 Z9 24 U1 0 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 1 PY 2013 VL 208 IS 5 BP 830 EP 838 DI 10.1093/infdis/jit262 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 198YB UT WOS:000322958900015 PM 23757341 ER PT J AU Fitz-Gibbon, S Tomida, S Chiu, BH Nguyen, L Du, C Liu, MH Elashoff, D Erfe, MC Loncaric, A Kim, J Modlin, RL Miller, JF Sodergren, E Craft, N Weinstock, GM Li, HY AF Fitz-Gibbon, Sorel Tomida, Shuta Chiu, Bor-Han Lin Nguyen Du, Christine Liu, Minghsun Elashoff, David Erfe, Marie C. Loncaric, Anya Kim, Jenny Modlin, Robert L. Miller, Jeff F. Sodergren, Erica Craft, Noah Weinstock, George M. Li, Huiying TI Propionibacterium acnes Strain Populations in the Human Skin Microbiome Associated with Acne SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID STREPTOLYSIN-S; STAPHYLOCOCCUS-AUREUS; ESCHERICHIA-COLI; BODY HABITATS; BACTERIA; SEQUENCE; STREPTOCOCCUS; RESISTANCE; DIVERSITY; GENES AB The human skin microbiome has important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that although the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne, and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may have roles in determining virulence properties of P. acnes strains, and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain-level analysis of the human microbiome to define the role of commensals in health and disease. C1 [Fitz-Gibbon, Sorel; Tomida, Shuta; Chiu, Bor-Han; Lin Nguyen; Du, Christine; Li, Huiying] Univ Calif Los Angeles, David Geffen Sch Med, Crump Inst Mol Imaging, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Du, Christine; Elashoff, David; Loncaric, Anya; Kim, Jenny; Modlin, Robert L.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Liu, Minghsun; Modlin, Robert L.; Miller, Jeff F.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. [Erfe, Marie C.; Craft, Noah] Univ Calif Los Angeles, David Geffen Sch Med, Harbor UCLA Med Ctr, Ctr Immunotherapeut Res,Los Angeles Biomed Res In, Los Angeles, CA 90095 USA. [Kim, Jenny; Sodergren, Erica; Weinstock, George M.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Dermatol, Los Angeles, CA USA. [Li, Huiying] Washington Univ, Genome Inst, St Louis, MO USA. [Fitz-Gibbon, Sorel; Tomida, Shuta] UCLA DOE Inst Genom & Prote, Los Angeles, CA USA. RP Li, HY (reprint author), Univ Calif Los Angeles, 4339 CNSI,570 Westwood Plaza,Bldg 114, Los Angeles, CA 90095 USA. EM huiying@mednet.ucla.edu OI Modlin, Robert/0000-0003-4720-031X FU NIH [U54HG004968]; NIH/NIAMS [UH2AR057503] FX We thank G Kasimatis, B Shi, EE Curd, R Yan, M Wong, and J Liu for comments and technical support. We thank C Lee for performing statistical analyses in the initial phase. We also thank Z Guo and CS Miller for critical reading of the manuscript. This research was funded as one of the Demonstration Projects by the NIH Human Microbiome Project (HMP). It was supported by grant UH2AR057503 from NIH/NIAMS and grant U54HG004968 from NIH. NR 43 TC 106 Z9 111 U1 8 U2 80 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2013 VL 133 IS 9 BP 2152 EP 2160 DI 10.1038/jid.2013.21 PG 9 WC Dermatology SC Dermatology GA 202GY UT WOS:000323203300013 PM 23337890 ER PT J AU Hettmer, S Teot, LA van Hummelen, P MacConaill, L Bronson, RT Dall'Osso, C Mao, JH McMahon, AP Gruber, PJ Grier, HE Rodriguez-Galindo, C Fletcher, CD Wagers, AJ AF Hettmer, Simone Teot, Lisa A. van Hummelen, Paul MacConaill, Laura Bronson, Roderick T. Dall'Osso, Claudia Mao, Junhao McMahon, Andrew P. Gruber, Peter J. Grier, Holcombe E. Rodriguez-Galindo, Carlos Fletcher, Christopher D. Wagers, Amy J. TI Mutations in Hedgehog pathway genes in fetal rhabdomyomas SO JOURNAL OF PATHOLOGY LA English DT Article DE fetal rhabdomyoma; hedgehog signalling; PTCH1 ID INTERGROUP RHABDOMYOSARCOMA; GORLIN-SYNDROME; MOUSE MODEL; EMBRYONAL RHABDOMYOSARCOMA; TUMORS AB Ligand-independent, constitutive activation of Hedgehog signalling in mice expressing a mutant, activated SmoM2 allele results in the development of multifocal, highly differentiated tumours that express myogenic markers (including desmin, actin, MyoD and myogenin). The histopathology of these tumours, commonly classified as rhabdomyosarcomas, more closely resembles human fetal rhabdomyoma (FRM), a benign tumour that can be difficult to distinguish from highly differentiated rhabdomyosarcomas. We evaluated the spectrum of Hedgehog (HH) pathway gene mutations in a cohort of human FRM tumours by targeted Illumina sequencing and fluorescence in situ hybridization testing for PTCH1. Our studies identified functionally relevant aberrations at the PTCH1 locus in three of five FRM tumours surveyed, including a PTCH1 frameshift mutation in one tumour and homozygous deletions of PTCH1 in two tumours. These data suggest that activated Hedgehog signalling contributes to the biology of human FRM. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Hettmer, Simone; Dall'Osso, Claudia; Wagers, Amy J.] Harvard Univ, Howard Hughes Med Inst, Dept Stem Cell & Regenerat Biol, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Hettmer, Simone; Wagers, Amy J.] Joslin Diabet Ctr, Cambridge, MA USA. [Hettmer, Simone; Grier, Holcombe E.; Rodriguez-Galindo, Carlos] Boston Childrens Hosp, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hettmer, Simone; Grier, Holcombe E.; Rodriguez-Galindo, Carlos] Boston Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Teot, Lisa A.] Boston Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [van Hummelen, Paul; MacConaill, Laura] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Bronson, Roderick T.] Tufts Univ, Sch Vet, Dept Biomed Sci, North Grafton, MA USA. [Mao, Junhao] Univ Massachusetts, Sch Med, Worcester, MA USA. [McMahon, Andrew P.] Univ So Calif, Keck Sch Med, Dept Stem Cell Biol & Regenerat Med, Los Angeles, CA 90033 USA. [Gruber, Peter J.] Univ Utah, Sch Med, Div Cardiothorac Surg, Salt Lake City, UT USA. [Fletcher, Christopher D.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Hettmer, S (reprint author), Boston Childrens Hosp, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. EM simone.hettmer@childrens.harvard.edu FU Harvard Stem Cell Institute; National Institutes of Health (NIH) [NIH DP2 OD004345, NIH NS033642]; PALS Bermuda/St. Baldrick's and the Alex's Lemonade Stand Foundation FX We thank C Namgyal, T Bowman and C Unitt in the DF/HCC research pathology core for help with DNA isolation and IHC; C Zhang and R Lee in the DF/HCC cytogenetics core for PTCH1 FISH testing; R Ehrlich, M Ducar, A Sunkavalli and M Hanna in the DFCI Center for Cancer Genome Discovery (CCGD) for assistance with OncoPanel v. 1 sequencing; and D Tchessalova for animal colony maintenance/technical assistance. MuTect was made available through the generosity of Kristian Cibulskis and the Cancer Genome Analysis Program at the Broad Institute, Inc. This work was funded in part by the Harvard Stem Cell Institute, the National Institutes of Health (NIH; Grant Nos NIH DP2 OD004345 to AJW and NIH NS033642 to APM) and PALS Bermuda/St. Baldrick's and the Alex's Lemonade Stand Foundation (to SH). Content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies. NR 21 TC 11 Z9 12 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 J9 J PATHOL JI J. Pathol. PD SEP PY 2013 VL 231 IS 1 BP 44 EP 52 DI 10.1002/path.4229 PG 9 WC Oncology; Pathology SC Oncology; Pathology GA 196GM UT WOS:000322761500006 PM 23780909 ER PT J AU Steenbergen, RDM Ongenaert, M Snellenberg, S Trooskens, G van der Meide, WF Pandey, D Bloushtain-Qimron, N Polyak, K Meijer, CJLM Snijders, PJF Van Criekinge, W AF Steenbergen, Renske D. M. Ongenaert, Mate Snellenberg, Suzanne Trooskens, Geert van der Meide, Wendy F. Pandey, Deeksha Bloushtain-Qimron, Noga Polyak, Kornelia Meijer, Chris J. L. M. Snijders, Peter J. F. Van Criekinge, Wim TI Methylation-specific digital karyotyping of HPV16E6E7-expressing human keratinocytes identifies novel methylation events in cervical carcinogenesis SO JOURNAL OF PATHOLOGY LA English DT Article DE human papillomavirus; DNA methylation; biomarkers; epigenetic reprogramming; cervical cancer ID RANDOMIZED CONTROLLED-TRIAL; SQUAMOUS-CELL CARCINOMA; HUMAN-PAPILLOMAVIRUS; INTRAEPITHELIAL NEOPLASIA; DNA METHYLATION; GENE-EXPRESSION; UP-REGULATION; HIGH-RISK; CANCER; PHOSPHATASE AB Transformation of epithelial cells by high-risk human papillomavirus hrHPV) types can lead to anogenital carcinomas, particularly cervical cancer, and oropharyngeal cancers. This process is associated with DNA methylation alterations, often affecting tumour suppressor gene expression. This study aimed to comprehensively unravel genome-wide DNA methylation events linked to a transforming hrHPV-infection, which is driven by deregulated expression of the viral oncogenes E6 and E7 in dividing cells. Primary human keratinocytes transduced with HPV16E6E7 and their untransduced counterparts were subjected to methylation-specific digital karyotyping MSDK) to screen for genome-wide DNA-methylation changes at different stages of HPV-induced transformation. Integration of the obtained methylation profiles with genome-wide gene expression patterns of cervical carcinomas identified 34 genes with increased methylation in HPV-transformed cells and reduced expression in cervical carcinomas. For 12 genes CLIC3, CREB3L1, FAM19A4, LFNG, LHX1, MRC2, NKX2-8, NPTX-1, PHACTR3, PRDM14, SOST and TNFSF13) specific methylation in HPV-containing cell lines was confirmed by semi-quantitative methylation-specific PCR. Subsequent analysis of FAM19A4, LHX1, NKX2-8, NPTX-1, PHACTR3 and PRDM14 in cervical tissue specimens showed increasing methylation levels for all genes with disease progression. All six genes were frequently methylated in cervical carcinomas, with highest frequencies (up to 100%) seen for FAM19A4, PHACTR3 and PRDM14. Analysis of hrHPV-positive cervical scrapes revealed significantly increased methylation levels of the latter three genes in women with high-grade cervical disease compared to controls. In conclusion, MSDK analysis of HPV16-transduced keratinocytes at different stages of HPV-induced transformation resulted in the identification of novel DNA methylation events, involving FAM19A4, LHX1, NKX2-8, PHACTR3 and PRDM14 genes in cervical carcinogenesis. These genes may provide promising triage markers to assess the presence of (pre)cancerous cervical lesions in hrHPV-positive women. Copyright (c) 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. C1 [Steenbergen, Renske D. M.; Snellenberg, Suzanne; van der Meide, Wendy F.; Pandey, Deeksha; Meijer, Chris J. L. M.; Snijders, Peter J. F.] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands. [Ongenaert, Mate; Trooskens, Geert; Van Criekinge, Wim] Univ Ghent, BioBix, Dept Math Modelling Stat & Bioinformat, B-9000 Ghent, Belgium. [Ongenaert, Mate] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium. [Bloushtain-Qimron, Noga; Polyak, Kornelia] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Steenbergen, RDM (reprint author), VUmc Canc Ctr Amsterdam, Dept Pathol, Unit Mol Pathol, POB 7057, NL-1007 MB Amsterdam, Netherlands. EM r.steenbergen@vumc.nl OI Ongenaert, Mate/0000-0001-7520-871X FU Dutch Cancer Society [VU2007-3771] FX The authors thank W Verlaat, L de Strooper and S Bach for excellent technical assistance and Dr SM Wilting for critical reading of the manuscript. This study was supported by the Dutch Cancer Society (Grant No. VU2007-3771). NR 47 TC 20 Z9 20 U1 1 U2 18 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3417 J9 J PATHOL JI J. Pathol. PD SEP PY 2013 VL 231 IS 1 BP 53 EP 62 DI 10.1002/path.4210 PG 10 WC Oncology; Pathology SC Oncology; Pathology GA 196GM UT WOS:000322761500007 PM 23674368 ER PT J AU Park, SH Wang, DJJ Duong, TQ AF Park, Sung-Hong Wang, Danny J. J. Duong, Timothy Q. TI Balanced steady state free precession for arterial spin labeling MRI: Initial experience for blood flow mapping in human brain, retina, and kidney SO MAGNETIC RESONANCE IMAGING LA English DT Article DE Blood flow; Arterial spin labeling; Pseudo-continuous arterial spin labeling; Balanced steady state free precession; fMRI; Retina; Kidney ID SINGLE-SHOT RARE; RADIO-FREQUENCY; DYNAMIC MRI; MOUSE MODEL; SSFP FMRI; PERFUSION; RESOLUTION; INVERSION; QUANTIFICATION; QUANTITATION AB We implemented pseudo-continuous ASL (pCASL) with 2D and 3D balanced steady state free precession (bSSFP) readout for mapping blood flow in the human brain, retina, and kidney, free of distortion and signal dropout, which are typically observed in the most commonly used echo-planar imaging acquisition. High resolution functional brain imaging in the human visual cortex was feasible with 3D bSSFP pCASL. Blood flow of the human retina could be imaged with pCASL and bSSFP in conjunction with a phase cycling approach to suppress the banding artifacts associated with bSSFP. Furthermore, bSSFP based pCASL enabled us to map renal blood flow within a single breath hold. Control and test-retest experiments suggested that the measured blood flow values in retina and kidney were reliable. Because there is no specific imaging tool for mapping human retina blood flow and the standard contrast agent technique for mapping renal blood flow can cause problems for patients with kidney dysfunction, bSSFP based pCASL may provide a useful tool for the diagnosis of retinal and renal diseases and can complement existing imaging techniques. (c) 2013 Elsevier Inc. All rights reserved. C1 [Park, Sung-Hong] Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, Taejon 305701, South Korea. [Park, Sung-Hong; Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Res Imaging Inst, San Antonio, TX 78229 USA. [Wang, Danny J. J.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Duong, Timothy Q.] Univ Texas Hlth Sci Ctr San Antonio, Dept Ophthalmol, San Antonio, TX 78229 USA. [Duong, Timothy Q.] South Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Park, SH (reprint author), Korea Adv Inst Sci & Technol, Dept Bio & Brain Engn, 291 Daehak Ro, Taejon 305701, South Korea. EM sunghongpark@kaist.ac.kr; duongt@uthscsa.edu RI Duong, Timothy/B-8525-2008; Park, Sung-Hong/B-3393-2012 OI Park, Sung-Hong/0000-0002-1731-0668 FU VA MERIT; KUSTAR-KAIST Institute; [R01 EY014211]; [R01 EY018855]; [R01 MH080892]; [R01-EB014922]; [R01 NS081077] FX This work is supported in part by R01 EY014211, R01 EY018855, and VA MERIT to TQD, by R01 MH080892, R01-EB014922 and R01 NS081077 to DJW, and by KUSTAR-KAIST Institute to SHP. NR 44 TC 13 Z9 13 U1 0 U2 18 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD SEP PY 2013 VL 31 IS 7 BP 1044 EP 1050 DI 10.1016/j.mri.2013.03.024 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 198TG UT WOS:000322944600002 PM 23664680 ER PT J AU Wallace, GC Dixon-Mah, YN Vandergrift, WA Ray, SK Haar, CP Mittendorf, AM Patel, SJ Banik, NL Giglio, P Das, A AF Wallace, Gerald C. Dixon-Mah, Yaenette N. Vandergrift, W. Alex, III Ray, Swapan K. Haar, Catherine P. Mittendorf, Amber M. Patel, Sunil J. Banik, Naren L. Giglio, Pierre Das, Arabinda TI Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma SO METABOLIC BRAIN DISEASE LA English DT Review DE Glioblastoma; ALK; MET; AKT ID ANAPLASTIC LYMPHOMA KINASE; HEPATOCYTE GROWTH-FACTOR; C-MET; MALIGNANT GLIOMAS; TYROSINE KINASE; STEM-CELLS; RECURRENT GLIOBLASTOMA; FACTOR/SCATTER FACTOR; TRANSCRIPTION FACTOR; GENETIC PATHWAYS AB Glioblastoma is the most common aggressive, highly glycolytic, and lethal brain tumor. In fact, it is among the most commonly diagnosed lethal malignancies, with thousands of new cases reported in the United States each year. Glioblastoma's lethality is derived from a number of factors including highly active pro-mitotic and pro-metastatic pathways. Two factors increasingly associated with the intracellular signaling and transcriptional machinery required for such changes are anaplastic lymphoma kinase (ALK) and the hepatocyte growth factor receptor (HGFR or, more commonly MET). Both receptors are members of the receptor tyrosine kinase (RTK) family, which has itself gained much attention for its role in modulating mitosis, migration, and survival in cancer cells. ALK was first described as a vital oncogene in lymphoma studies, but it has since been connected to many carcinomas, including non-small cell lung cancer and glioblastoma. As the receptor for HGF, MET has also been highly characterized and regulates numerous developmental and wound healing events which, when upregulated in cancer, can promote tumor progression. The wealth of information gathered over the last 30 years regarding these RTKs suggests three downstream cascades that depend upon activation of STAT3, Ras, and AKT. This review outlines the significance of ALK and MET as they relate to glioblastoma, explores the significance of STAT3, Ras, and AKT downstream of ALK/MET, and touches on the potential for new chemotherapeutics targeting ALK and MET to improve glioblastoma patient prognosis. C1 [Wallace, Gerald C.; Dixon-Mah, Yaenette N.; Vandergrift, W. Alex, III; Haar, Catherine P.; Mittendorf, Amber M.; Patel, Sunil J.; Banik, Naren L.; Giglio, Pierre; Das, Arabinda] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA. [Wallace, Gerald C.; Dixon-Mah, Yaenette N.; Vandergrift, W. Alex, III; Haar, Catherine P.; Mittendorf, Amber M.; Patel, Sunil J.; Banik, Naren L.; Giglio, Pierre; Das, Arabinda] Med Univ S Carolina, MUSC Brain & Spine Tumor Program, Charleston, SC 29425 USA. [Ray, Swapan K.] Univ S Carolina, Sch Med, Dept Pathol Microbiol & Immunol, Columbia, SC 29208 USA. [Banik, Naren L.] Ralph H Johnson VA Med Ctr, Charleston, SC 29425 USA. RP Das, A (reprint author), Med Univ S Carolina, Dept Neurosci, 96 Jonathan Lucas St, Charleston, SC 29425 USA. EM dasa@musc.edu FU National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS) [NS31622, NS-38146, NS-57811, NS-41088]; State of South Carolina Spinal Cord Injury Research Project (SCSCIRF); VA [1I01BX001262-01A2]; Pfizer, Inc.; Jerry Zucker Fund for Brain Tumor Research of the MUSC Foundation FX Completion of this project was made possible by funding from the National Institutes of Health (NIH) and National Institute of Neurological Disorders and Stroke (NINDS): (NS31622, NS-38146, NS-57811, and NS-41088), the State of South Carolina Spinal Cord Injury Research Project (SCSCIRF), VA (1I01BX001262-01A2), Pfizer, Inc., and the Jerry Zucker Fund for Brain Tumor Research of the MUSC Foundation. NR 92 TC 2 Z9 2 U1 3 U2 19 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7490 J9 METAB BRAIN DIS JI Metab. Brain Dis. PD SEP PY 2013 VL 28 IS 3 BP 355 EP 366 DI 10.1007/s11011-013-9401-7 PG 12 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 197XK UT WOS:000322885700003 PM 23543207 ER PT J AU Bodhankar, S Chen, YX Vandenbark, AA Murphy, SJ Offner, H AF Bodhankar, Sheetal Chen, Yingxin Vandenbark, Arthur A. Murphy, Stephanie J. Offner, Halina TI IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke SO METABOLIC BRAIN DISEASE LA English DT Article DE MCAO; Inflammatory cells; Regulatory B-cells; IL-10 ID REGULATORY T-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ACUTE ISCHEMIC-STROKE; MURINE EXPERIMENTAL STROKE; BRAIN-INJURY; B10 CELLS; NEUROLOGIC DEFICITS; RAT-BRAIN; IN-VIVO; IL-10 AB Clinical stroke induces inflammatory processes leading to cerebral injury. IL-10 expression is elevated during major CNS diseases and limits inflammation in the brain. Recent evidence demonstrated that absence of B-cells led to larger infarct volumes and increased numbers of activated T-cells, monocytes and microglial cells in the brain, thus implicating a regulatory role of B-cell subpopulations in limiting CNS damage from stroke. The aim of this study was to determine whether the IL-10-producing regulatory B-cell subset can limit CNS inflammation and reduce infarct volume following ischemic stroke in B-cell deficient (mu MT-/-) mice. Five million IL-10-producing B-cells were obtained from IL-10-GFP reporter mice and transferred i.v. to mu MT(-/-)mice. After 24 h following this transfer, recipients were subjected to 60 min of middle cerebral artery occlusion (MCAO) followed by 48 h of reperfusion. Compared to vehicle-treated controls, the IL-10(+) B-cell-replenished mu MT(-/-)mice had reduced infarct volume and fewer infiltrating activated T-cells and monocytes in the affected brain hemisphere. These effects in CNS were accompanied by significant increases in regulatory T-cells and expression of the co-inhibitory receptor, PD-1, with a significant reduction in the proinflammatory milieu in the periphery. These novel observations provide the first proof of both immunoregulatory and protective functions of IL-10-secreting B-cells in MCAO that potentially could impart significant benefit for stroke patients in the clinic. C1 [Bodhankar, Sheetal; Vandenbark, Arthur A.; Offner, Halina] Portland VA Med Ctr, VA Med Ctr, Portland, OR 97239 USA. [Bodhankar, Sheetal; 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. [Chen, Yingxin; Murphy, Stephanie J.; Offner, Halina] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Offner, H (reprint author), Portland VA Med Ctr, VA Med Ctr, R&D-31,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM offnerva@ohsu.edu FU NIH/NINDS [1RO1 NS075887]; Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development FX The authors wish to thank Melissa Barber for assistance with manuscript preparation. This work was supported by NIH/NINDS 1RO1 NS075887. This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government. NR 63 TC 31 Z9 34 U1 0 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0885-7490 J9 METAB BRAIN DIS JI Metab. Brain Dis. PD SEP PY 2013 VL 28 IS 3 BP 375 EP 386 DI 10.1007/s11011-013-9413-3 PG 12 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 197XK UT WOS:000322885700005 PM 23640015 ER PT J AU Crist, RC Clarke, TK Ang, A Ambrose-Lanci, LM Lohoff, FW Saxon, AJ Ling, W Hillhouse, MP Bruce, RD Woody, G Berrettini, WH AF Crist, Richard C. Clarke, Toni-Kim Ang, Alfonso Ambrose-Lanci, Lisa M. Lohoff, Falk W. Saxon, Andrew J. Ling, Walter Hillhouse, Maureen P. Bruce, R. Douglas Woody, George Berrettini, Wade H. TI An Intronic Variant in OPRD1 Predicts Treatment Outcome for Opioid Dependence in African-Americans SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE pharmacogenetics; methadone; buprenorphine; treatment outcome ID METHADONE-MAINTENANCE; RANDOMIZED-TRIAL; RECEPTOR GENE; ALCOHOL DEPENDENCE; HEROIN-ADDICTION; DRUG-DEPENDENCE; RHESUS-MONKEYS; CLINICAL-TRIAL; DELTA; BUPRENORPHINE AB Although buprenorphine and methadone are both effective treatments for opioid dependence, their efficacy can vary significantly among patients. Genetic differences may explain some of the variability in treatment outcome. Understanding the interactions between genetic background and pharmacotherapy may result in more informed treatment decisions. This study is a pharmacogenetic analysis of the effects of genetic variants in OPRD1, the gene encoding the delta-opioid receptor, on the prevalence of opioid-positive urine tests in African-Americans (n = 77) or European-Americans (n = 566) undergoing treatment for opioid dependence. Patients were randomly assigned to treatment with either methadone or buprenorphine/naloxone (Suboxone) over a 24-week open-label clinical trial, in which illicit opioid use was measured by weekly urinalysis. In African-Americans, the intronic SNP rs678849 predicted treatment outcome for both medications. Methadone patients with the CC genotype were less likely to have opioid-positive urine tests than those in the combined CT and TT genotypes group (relative risk (RR) = 0.52, 95% confidence interval (CI) = 0.44-0.60, p = 0.001). In the buprenorphine treatment group, however, individuals with the CC genotype were more likely to have positive opioid drug screens than individuals in the combined CT and TT genotypes group (RR = 2.17, 95% CI = 1.95-2.68, p = 0.008). These findings indicate that the genotype at rs678849 predicts African-American patient response to two common treatments for opioid dependence, suggesting that matching patients to treatment type based on the genotype at this locus may improve overall treatment efficacy. This observation requires confirmation in an independent population. C1 [Crist, Richard C.; Clarke, Toni-Kim; Ambrose-Lanci, Lisa M.; Lohoff, Falk W.; Berrettini, Wade H.] Univ Penn, Sch Med, Ctr Neurobiol & Behav, Dept Psychiat, Philadelphia, PA 19104 USA. [Ang, Alfonso; Ling, Walter; Hillhouse, Maureen P.] Univ Calif Los Angeles, Integrated Subst Abuse Programs, Los Angeles, CA USA. [Saxon, Andrew J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Bruce, R. Douglas] Yale Univ, Sch Med, New Haven, CT USA. [Woody, George] Univ Penn, Perelman Sch Med, Treatment Res Inst, Philadelphia, PA 19104 USA. RP Crist, RC (reprint author), Univ Penn, Sch Med, Ctr Neurobiol & Behav, Translat Res Labs,Dept Psychiat, 125 South 31st St,Room 2109, Philadelphia, PA 19104 USA. EM crist@mail.med.upenn.edu RI Lohoff, Falk/M-7951-2016; OI Clarke, Toni-Kim/0000-0002-7745-6351 FU Pfizer; Pamlab; Guidepoint Global LLC; Genome Canada; Genome Quebec; Reckitt Benckiser Pharmaceuticals; Gilead Sciences; Merck Co.; Bristol Myers Squibb; Boehringer Ingelheim; Abbott Laboratories; Pfizer, Inc. FX Falk Lohoff received research grant support from Pfizer. Issued to University of Pennsylvania and also scientific advisor or paid consultant to Pamlab. Guidepoint Global LLC, Genome Canada, and Genome Quebec. Andrew Saxon is a paid consultant to Reckitt Benckiser Pharmaceuticals; Walter Ling is a paid consultant to Reckitt Benckiser Pharmaceuticals; R Douglas Bruce received research grant support from Gilead Sciences, Merck & Co., Bristol Myers Squibb, Boehringer Ingelheim, Reckitt Benckiser Pharmaceuticals, Abbott Laboratories, Pfizer, Inc., and honorarium from Reckitt Benckiser Pharmaceuticals; the remaining authors declare no conflict of interest. NR 54 TC 14 Z9 14 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2013 VL 38 IS 10 BP 2003 EP 2010 DI 10.1038/npp.2013.99 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 201TI UT WOS:000323165500019 PM 23612435 ER PT J AU Tritos, NA Eppakayala, S Swearingen, B Hedley-Whyte, ET Miller, KK Nachtigall, LB Grinspoon, SK Biller, BMK Klibanski, A AF Tritos, Nicholas A. Eppakayala, Samatha Swearingen, Brooke Hedley-Whyte, E. Tessa Miller, Karen K. Nachtigall, Lisa B. Grinspoon, Steven K. Biller, Beverly M. K. Klibanski, Anne TI Pathologic and clinical features of pituitary adenomas showing TSH immunoreactivity SO PITUITARY LA English DT Article DE Growth hormone; Hyperthyroidism; Acromegaly; Pituitary adenoma; Pituitary apoplexy; Thyrotropin ID THYROID-HORMONE; TUMORS; MANAGEMENT; RESISTANCE; DIAGNOSIS; APOPLEXY AB Patients with thyrotropin-secreting pituitary adenomas may present with mass effect, hypopituitarism, and/or hyperthyroidism. The spectrum of pathologic and clinical features of patients whose tumors demonstrate beta-thyrotropin immunoreactivity (beta-TSH IR) has not been characterized. To characterize the phenotype of patients with pituitary adenomas with positive beta-TSH IR, we conducted a retrospective analysis of patient records of all adult patients (n = 1,223) undergoing pituitary surgery in our institution over one decade (1999-2009). The search identified 166 adults with tumors which had beta-TSH IR. These patients were individually matched to 166 patients whose tumors revealed no beta-TSH IR. Clinical, pathological, imaging and biochemical data were extracted. 332 patients, aged 51.4 +/- A 15.1 years [150 women (45 %) and 182 men (55 %)], with pituitary adenomas (mean tumor diameter +/- A SD: 22.7 +/- A 9.0 mm) were studied. The degree of beta-TSH IR was associated with the presence of central hyperthyroidism (p < 0.0001) or goiter (p = 0.0217). Patients whose tumors expressed more extensive beta-TSH IR were less likely to develop pituitary apoplexy than those without beta-TSH IR (p = 0.0428). In addition, the degree of beta-TSH IR correlated with the presence of immunoreactivity for beta-FSH (p < 0.0001), beta-LH (p < 0.0001), alpha subunit (p < 0.0001), and GH (p = 0.0036). Conclusions: Pituitary adenomas expressing beta-TSH IR were more likely to demonstrate immunoreactivity for beta-FSH, beta-LH, GH or alpha subunit. Patients with such tumors were more likely to exhibit hyperthyroidism and goiter, but less likely to develop pituitary apoplexy than patients without beta-TSH IR. These findings suggest that beta-TSH IR is associated with specific phenotypic features in patients with pituitary adenomas. C1 [Tritos, Nicholas A.; Eppakayala, Samatha; Miller, Karen K.; Nachtigall, Lisa B.; Grinspoon, Steven K.; Biller, Beverly M. K.; Klibanski, Anne] Massachusetts Gen Hosp, Dept Med, Neuroendocrine Unit, Boston, MA 02114 USA. [Tritos, Nicholas A.; Swearingen, Brooke; Hedley-Whyte, E. Tessa; Miller, Karen K.; Nachtigall, Lisa B.; Grinspoon, Steven K.; Biller, Beverly M. K.; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Swearingen, Brooke] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Hedley-Whyte, E. Tessa] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Tritos, NA (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM ntritos@partners.org NR 23 TC 2 Z9 2 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X J9 PITUITARY JI Pituitary PD SEP PY 2013 VL 16 IS 3 BP 287 EP 293 DI 10.1007/s11102-012-0419-3 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 195LS UT WOS:000322704500001 PM 22869255 ER PT J AU Melmed, S Casanueva, FF Klibanski, A Bronstein, MD Chanson, P Lamberts, SW Strasburger, CJ Wass, JAH Giustina, A AF Melmed, S. Casanueva, F. F. Klibanski, A. Bronstein, M. D. Chanson, P. Lamberts, S. W. Strasburger, C. J. Wass, J. A. H. Giustina, A. TI A consensus on the diagnosis and treatment of acromegaly complications SO PITUITARY LA English DT Article DE Acromegaly; Consensus; Complications; Diagnosis; Treatment ID QUALITY-OF-LIFE; SECRETING PITUITARY-ADENOMAS; PREOPERATIVE OCTREOTIDE TREATMENT; SOMATOSTATIN ANALOG TREATMENT; HORMONE RECEPTOR ANTAGONIST; INTERACTING-PROTEIN GENE; GAMMA-KNIFE RADIOSURGERY; SLOW-RELEASE LANREOTIDE; GROWTH-FACTOR-I; SLEEP-APNEA AB In March 2011, the Acromegaly Consensus Group met to revise and update the guidelines on the diagnosis and treatment of acromegaly complications. The meeting was sponsored by the Pituitary Society and the European Neuroendocrinology Association and included experts skilled in the management of acromegaly. Complications considered included cardiovascular, endocrine and metabolic, sleep apnea, bone diseases, and mortality. Outcomes in selected, related clinical conditions were also considered, and included pregnancy, familial acromegaly and invasive macroadenomas. The need for a new disease staging model was considered, and design of such a tool was proposed. C1 [Melmed, S.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Casanueva, F. F.] Univ Santiago de Compostela, Div Endocrinol CHUS, Dept Med, Santiago De Compostela, Spain. [Klibanski, A.] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Klibanski, A.] Harvard Univ, Sch Med, Boston, MA USA. [Bronstein, M. D.] Univ Sao Paulo, Sch Med, Div Endocrinol & Metab, Neuroendocrine Unit, Sao Paulo, Brazil. [Chanson, P.] Univ Paris 11, Fac Med, Orsay, France. [Chanson, P.] Hop Bicetre, AP HP, Serv Endocrinol & Malad Reprod, Le Kremlin Bicetre, France. [Chanson, P.] INSERM, U693, F-94275 Le Kremlin Bicetre, France. [Lamberts, S. W.] Erasmus MC, Dept Internal Med, Div Endocrinol, Rotterdam, Netherlands. [Strasburger, C. J.] Charite Campus Mitte, Dept Endocrinol, Berlin, Germany. [Wass, J. A. H.] Churchill Hosp, Dept Endocrinol, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Giustina, A.] Univ Brescia, Dept Med & Surg Sci, Brescia, Italy. RP Melmed, S (reprint author), Cedars Sinai Med Ctr, Dept Med, 8700 Beverly Blvd,Room 2015, Los Angeles, CA 90048 USA. EM Shlomo.Melmed@cshs.org FU Pituitary Society; European Neuroendocrine Association; Ipsen FX The authors thank all participants in the Eighth Acromegaly Consensus Group meeting: Ariel Barkan (USA), Albert Beckers (Belgium), Paolo Beck-Peccoz (Italy), John Bevan (UK), Nienke Biermasz (The Netherlands), Jens Bollerslev (Norway), Vivien Bonert (USA), Francoise Borson-Chazot (France), John Carmichael (USA), Philippe Caron (France), Jens Christiansen (Denmark), David Clemmons (USA), Renato Cozzi (Italy), Maria Vittoria Davi (Italy), Diego Ferone (Italy), Maria Fleseriu (USA), Monica Gadelha (Brazil), Yona Greenman (Israel), Ashley Grossman (UK), Ken Ho (Australia), David Kleinberg (USA), Marta Korbonits (UK), Monica Marazuela Azpiroz (Spain), Gherardo Mazziotti (Italy), Moises Mercado (Mexico), Mark Molitch (USA), Lisa Nachtigall (USA), Stephan Petersenn (Germany), Vera Popovic-Brkic (Serbia), Roberto Salvatori (USA), Janet Schlechte (USA), Michael Sheppard (UK), Gunther Stalla (Germany), Peter Trainer (UK), Mary Lee Vance (USA), Aart Van der Lely (The Netherlands), and Susan Webb (Spain). This study was sponsored by the Pituitary Society and the European Neuroendocrine Association and was supported by an unrestricted grant from Ipsen. We acknowledge the editorial assistance provided by Martin Gilmour of ESP Bioscience (Crowthorne, UK), supported by Ipsen, during the preparation of this manuscript. NR 116 TC 100 Z9 104 U1 7 U2 23 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X J9 PITUITARY JI Pituitary PD SEP PY 2013 VL 16 IS 3 BP 294 EP 302 DI 10.1007/s11102-012-0420-x PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 195LS UT WOS:000322704500002 PM 22903574 ER PT J AU Biller, BMK Ji, HJ Ahn, H Savoy, C Siepl, EC Popovic, V Coculescu, M Roemmler, J Gavrila, C Cook, DM Strasburger, CJ AF Biller, Beverly M. K. Ji, Hyi-Jeong Ahn, Hyunji Savoy, Conrad Siepl, E. Christine Popovic, Vera Coculescu, Mihail Roemmler, Josefine Gavrila, Catalin Cook, David M. Strasburger, Christian J. TI 12-Month effects of once-weekly sustained-release growth hormone treatment in adults with GH deficiency SO PITUITARY LA English DT Article DE Weekly; Sustained-release GH; LB03002; Adult GH deficiency; Long-term safety ID SACCHAROMYCES-CEREVISIAE; DOUBLE-BLIND; EFFICACY; ANTIBODIES; CHILDREN; SAFETY AB The weekly sustained-release recombinant human GH formulation LB03002, showed beneficial effects in GH-deficient (GHD) adults in a previous 26-week double-blind study. Prior studies of long-acting GH preparations in adults have only been conducted for 6 or 8 months, so the effects of longer-term use are unknown; this is important to address, as replacement is given for many years in GHD adults. This open-label, 26-week study extension evaluated longer-term safety and efficacy of LB03002 over 52 weeks in adults with GHD who had previously been randomized to GH, and provides additional safety and efficacy data over 26 weeks in the cohort who had previously been randomized to placebo. Of 147 adults with GHD who completed a preceding study, 136 patients continued in this open-label study to receive LB03002 over an additional 26 weeks. This represented a continuation of long-acting GH for 26 weeks in the cohort who took this medication in the prior study (LB03002 Throughout group), and describes the first use of long-acting GH in the cohort that was randomized to placebo in the prior study (Switched to LB03002 group). The LB03002 dose was adjusted according to serum insulin-like growth factor-I (IGF-I) levels. LB03002 treatment demonstrated mean significant decreases from baseline in fat mass (FM) for both 26 (Switched group, P = 0.001) and 52 weeks (Throughout group, P = 0.002) of 1.11 (1.95) kg and 1.06 (3.16) kg, respectively. Prolonged GH treatment was effective in sustaining the increase in lean body mass (LBM), serum IGF-I and IGFBP-3 levels achieved during the first 26 weeks. Long-term treatment with the sustained-release weekly GH preparation over both 26 and 52 weeks in adults with GHD demonstrated a sustained reduction of FM with a favorable safety profile. This study extends prior knowledge about long-acting GH because it reports the most prolonged treatment of adults with any long-acting GH preparation, thereby confirming the value and safety of such agents for long-term GH replacement. C1 [Biller, Beverly M. K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ji, Hyi-Jeong; Ahn, Hyunji] LG Life Sci Ltd, Seoul 110062, South Korea. [Savoy, Conrad; Siepl, E. Christine] Biopartners GmbH, CH-6340 Baar, Switzerland. [Popovic, Vera] Univ Belgrade, Belgrade 11000, Serbia. [Coculescu, Mihail] Natl Inst Endocrinol CI Parhon, Bucharest 011863, Romania. [Roemmler, Josefine] Univ Munich, D-80336 Munich, Germany. [Gavrila, Catalin] SANA Med Ctr, Bucharest 011025, Romania. [Cook, David M.] Oregon Hlth & Sci Univ, Portland, OR 97239 USA. [Strasburger, Christian J.] Charite, D-10117 Berlin, Germany. RP Ahn, H (reprint author), LG Life Sci Ltd, Seoul 110062, South Korea. EM ahnhj@lgls.com FU LG Life Sciences, Ltd., Korea; Biopartners, GmbH, Switzerland FX H.J.J. and H. A. are employees of LG Life Sciences, Ltd.; C. S. and E. C. S. are employees of Biopartners, GmbH.; B. M. K. B. and C.J.S. received consulting fees from LG Life Sciences, Ltd., Korea, and Biopartners, GmbH, Switzerland.; V. P., M. C., J.R., C. G., and D. M. C. have nothing to declare. NR 13 TC 8 Z9 8 U1 0 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X J9 PITUITARY JI Pituitary PD SEP PY 2013 VL 16 IS 3 BP 311 EP 318 DI 10.1007/s11102-012-0422-8 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 195LS UT WOS:000322704500004 PM 22915288 ER PT J AU Zada, G Tirosh, A Huang, AP Laws, ER Woodmansee, WW AF Zada, Gabriel Tirosh, Amir Huang, Abel P. Laws, Edward R. Woodmansee, Whitney W. TI The postoperative cortisol stress response following transsphenoidal pituitary surgery: a potential screening method for assessing preserved pituitary function SO PITUITARY LA English DT Article DE Pituitary neoplasm; Transsphenoidal; Cortisol; Hypopituitarism; Hormone replacement; Stress response; Surgery ID ADRENAL AXIS; OPEN CHOLECYSTECTOMY; ADENOMAS; ILLNESS AB The ability to reliably identify patients with new hypocortisolemia acutely following pituitary surgery is critical. We aimed to quantify the postoperative cortisol stress response following selective transsphenoidal adenomectomy, as a marker for postoperative preservation of functional pituitary gland. Records of 208 patients undergoing transsphenoidal operations for pituitary lesions were reviewed. Patients with Cushing's Disease, preoperative adrenal insufficiency, and those receiving intraoperative steroids were excluded. To quantify the postoperative stress response, the a dagger cortisol index was defined as the postoperative day (POD) 1 morning cortisol minus the preoperative morning cortisol level. The incidence of new hypocortisolemia requiring glucocorticoid replacement upon hospital discharge was also recorded. Fifty-two patients met inclusion criteria. The mean preoperative, POD1, and POD2 cortisol levels were 16.5, 29.2, and 21.8 mu g/dL, respectively. Morning fasting cortisol levels on POD1 ranged from 4.2 to 73.0 mu g/dL. The a dagger cortisol index ranged from -19.0 to +56.2 (mean +12.7 mu g/dL). Five patients (9.6 %) developed new hypocortisolemia on POD 1-3 requiring glucocorticoid replacement; only one required long-term replacement. The mean a dagger cortisol in patients requiring postoperative glucocorticoids was -2.8 mu g/dL, compared with +14.4 mu g/dL in patients without evidence of adrenal insufficiency (p = 0.005). Of the 32 patients (61.5 %) with a a dagger cortisol > 25 mu g/dL, none developed postoperative adrenal insufficiency. The postoperative cortisol stress response, as quantified by the a dagger cortisol index, holds potential as a novel and complimentary screening method to predict preservation of normal pituitary function and acute development of new ACTH deficiency following transsphenoidal pituitary surgery. C1 [Zada, Gabriel] Los Angeles Cty USC Med Ctr, Keck Sch Med, Dept Neurosurg, Los Angeles, CA USA. [Zada, Gabriel] USC Dept Neurosurg, Los Angeles, CA 90089 USA. [Tirosh, Amir; Woodmansee, Whitney W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA USA. [Huang, Abel P.] Natl Taiwan Univ Hosp, Dept Surg, Yun Lin Branch, Yunlin, Taiwan. [Laws, Edward R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurosurg, Boston, MA 02115 USA. RP Zada, G (reprint author), USC Dept Neurosurg, 1200 North State St,Suite 5046, Los Angeles, CA 90089 USA. EM gzada@usc.edu FU NIDDK NIH HHS [T32 DK007529] NR 20 TC 3 Z9 3 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1386-341X EI 1573-7403 J9 PITUITARY JI Pituitary PD SEP PY 2013 VL 16 IS 3 BP 319 EP 325 DI 10.1007/s11102-012-0423-7 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 195LS UT WOS:000322704500005 PM 22915289 ER PT J AU Kamran, SC Shinagare, AB Howard, SAH Nishino, M Hornick, JL Krajewski, KM Ramaiya, NH AF Kamran, Sophia Constance Shinagare, Atul Bhanudas Howard, Stephanie Anne Holler Nishino, Mizuki Hornick, Jason Laurence Krajewski, Katherine Margaret Ramaiya, Nikhil Himmatsinh TI Intrathoracic malignant peripheral nerve sheath tumors: imaging features and implications for management SO RADIOLOGY AND ONCOLOGY LA English DT Article DE malignant peripheral nerve sheath tumors; chest; neurofibromatosis; imaging; malignant triton tumor ID RADIOLOGIC-PATHOLOGICAL CORRELATION; VON-RECKLINGHAUSENS-DISEASE; NEUROFIBROMATOSIS TYPE-I; TRITON TUMORS; DIFFERENTIATION; BENIGN; TYPE-1; SURVIVAL; MRI AB Background. The aim of the study was to analyze the clinical and imaging characteristics of primary intrathoracic malignant peripheral nerve sheath tumors (MPNSTs). Patients and methods. In this institutional review board (IRB)-approved retrospective study, clinical and imaging features of 15 patients (eight men; mean age 50 years [range 18-83)] with pathologically proven malignant peripheral nerve sheath tumors seen from January 1999 to December 2011 were analyzed. Imaging features (CT in 15, MRI in 5 and PET/CT in 4) of primary tumors were evaluated by three radiologists and correlated with clinical management. Results. Of the 15 tumors, six were located in the mediastinum (two each in anterior, middle and posterior mediastinum), four in chest wall, two were paraspinal, and three in the lung. Four patients had neurofibromatosis-1 (NF1); four tumors had heterologous rhabdomyoblastic differentiation (malignant triton tumor). Masses typically were elongated along the direction of nerves, with mean size of 11 cm. The masses were hypo- or isodense to muscles on CT, isointense on T1-weighted images, hyperintense on T2-weighted images and intensely fluorodeoxyglucose (FDG) avid (mean standardized uptake value [SUV](max) of 10.5 [range 4.4-23.6]). Necrosis and calcification was seen in four tumors each. Finding of invasion of adjacent structures on imaging led to change in management in seven patients; patients with invasion received chemoradiation. Conclusions. Intrathoracic MPNSTs appear as large elongated masses involving mediastinum, lung or chest wall. Radiological identification of invasion of adjacent structures is crucial and alters therapy, with patients with invasion receiving neoadjuvant or adjuvant chemoradiation. C1 [Kamran, Sophia Constance; Shinagare, Atul Bhanudas; Howard, Stephanie Anne Holler; Nishino, Mizuki; Krajewski, Katherine Margaret; Ramaiya, Nikhil Himmatsinh] Dana Farber Canc Inst, Dept Imaging, Boston, MA 02115 USA. [Kamran, Sophia Constance; Shinagare, Atul Bhanudas; Howard, Stephanie Anne Holler; Nishino, Mizuki; Krajewski, Katherine Margaret; Ramaiya, Nikhil Himmatsinh] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Hornick, Jason Laurence] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kamran, Sophia Constance; Shinagare, Atul Bhanudas; Howard, Stephanie Anne Holler; Nishino, Mizuki; Hornick, Jason Laurence; Krajewski, Katherine Margaret; Ramaiya, Nikhil Himmatsinh] Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Shinagare, AB (reprint author), Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02115 USA. EM ashinagare@partners.org OI Kamran, Sophia/0000-0001-9283-6515 FU National Institutes of Health [1K23CA157631] FX No potential conflicts of interest were disclosed. In financial disclosures the authors stated that the investigator Mizuki Nishino (MN) had been supported by 1K23CA157631 (NCI) from the National Institutes of Health. NR 23 TC 5 Z9 5 U1 0 U2 2 PU ASSOC RADIOLOGY & ONCOLOGY PI LJUBLJANA PA INST ONCOLOGY, ZALOSKA CESTA 2, LJUBLJANA, 1000, SLOVENIA SN 1318-2099 J9 RADIOL ONCOL JI Radiol. Oncol. PD SEP PY 2013 VL 47 IS 3 BP 230 EP 238 DI 10.2478/raon-2013-0047 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 199BB UT WOS:000322968000005 PM 24133387 ER PT J AU Batt, RE Yeh, J AF Batt, Ronald E. Yeh, John TI Mullerianosis: Four Developmental (Embryonic) Mullerian Diseases SO REPRODUCTIVE SCIENCES LA English DT Article DE adenomyosis; endocervicosis; endometriosis; endosalpingiosis; choristoma; mullerian choristoma; mullerianosis ID UTERUS-LIKE MASS; FLORID CYSTIC ENDOSALPINGIOSIS; OTHERWISE-NORMAL-UTERUS; ACCESSORY UTERINE MASS; URINARY-BLADDER; URETERAL ENDOMETRIOSIS; TETHERED CORD; ORIGIN; TISSUE; PATHOGENESIS AB The theory of mullerianosis predicts that embryonic mullerian tissue, misplaced during organogenesis, results in the formation of 4 benign mullerian diseasesdevelopmental adenomyosis, endometriosis, endosalpingiosis, and endocervicosis(developmental mullerian diseases) that will be identified in human female fetuses, infants, children, adolescents, and adults. Direct evidence is presented to support the existence of developmental adenomyosis, developmental endometriosis, and developmental endocervicosis in human female fetuses along with strong circumstantial evidence supporting the existence of all 4 developmental mullerian diseases in human female infants, children, adolescents, and adults. This evidence throws light upon the pathogenesis of rare mullerian lesions whose pathogenesis remains inexplicable by classical and modern theories. Furthermore, this research has scientific and clinical relevance: scientific relevance because it opens up a new field of comparative researchthe 4 developmental mullerian diseases complement the 4 acquired mullerian diseases; clinical relevance because it identifies rare mullerian diseases curable by complete surgical excision. C1 [Batt, Ronald E.] SUNY Buffalo, Dept Obstet Gynecol, Sch Med & Biomed Sci, Buffalo, NY 14260 USA. [Yeh, John] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA USA. RP Batt, RE (reprint author), Women & Childrens Hosp, 219 Bryant St, Buffalo, NY 14222 USA. EM rbatt@buffalo.edu NR 67 TC 7 Z9 11 U1 2 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD SEP PY 2013 VL 20 IS 9 BP 1030 EP 1037 DI 10.1177/1933719112472736 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 201YZ UT WOS:000323180300004 PM 23314961 ER PT J AU Ovrutsky, AR Merkel, PA Schonteich, E Bai, XY Kinney, W Iseman, MD Kartalija, M Knight, V Chan, ED AF Ovrutsky, Alida R. Merkel, Patricia A. Schonteich, Eric Bai, Xiyuan Kinney, William Iseman, Michael D. Kartalija, Marinka Knight, Vijaya Chan, Edward D. TI Patients with non-tuberculous mycobacterial lung disease have elevated transforming growth factor-beta following ex vivo stimulation of blood with live Mycobacterium intracellulare SO SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE Non-tuberculous mycobacteria; Mycobacterium avium complex; Marfan syndrome; interferon-gamma; fibrillin-1 ID INTERFERON-GAMMA; MARFANS-SYNDROME; CYTOKINE PRODUCTION; AVIUM INFECTION; TGF-BETA; EXPRESSION; COMPLEX; ALPHA AB We previously found that a subset of patients with pulmonary non-tuberculous mycobacterial (pNTM) disease were taller, leaner, and had a higher prevalence of pectus excavatum and scoliosis than uninfected controls. Additionally, whole blood of pNTM patients stimulated ex vivo with live Mycobacterium intracellulare produced significantly less interferon-gamma (IFN gamma) compared to that of uninfected controls. Since IFN. production can be suppressed by transforming growth factor-beta (TGF beta), an immunosuppressive cytokine, we measured basal and M. intracellulare-stimulated blood levels of TGF beta in a group of 20 pNTM patients and 20 uninfected controls. In contrast to the IFN. findings, we found that stimulated blood from pNTM patients produced significantly higher levels of TGF beta compared to controls. Since pNTM patients frequently possess body features that overlap with Marfan syndrome (MFS), and increased TGF beta expression is important in the pathogenesis of MFS, we posit that a yet-to-be-identified syndrome related to MFS predisposes certain individuals to develop pNTM disease. C1 [Ovrutsky, Alida R.; Bai, Xiyuan; Kinney, William; Kartalija, Marinka; Chan, Edward D.] Denver Vet Affairs Med Ctr, Aurora, CO USA. [Ovrutsky, Alida R.; Merkel, Patricia A.; Bai, Xiyuan; Kinney, William; Iseman, Michael D.; Knight, Vijaya; Chan, Edward D.] Natl Jewish Hlth, Dept Med, Aurora, CO USA. [Ovrutsky, Alida R.; Merkel, Patricia A.; Bai, Xiyuan; Kinney, William; Iseman, Michael D.; Knight, Vijaya; Chan, Edward D.] Natl Jewish Hlth, Dept Acad Affairs, Aurora, CO USA. [Schonteich, Eric] Natl Jewish Hlth, Complement Lab, Aurora, CO USA. [Iseman, Michael D.; Chan, Edward D.] Univ Colorado Denver, Div Pulm Sci & Crit Care Med, Aurora, CO USA. RP Chan, ED (reprint author), Natl Jewish Hlth, D509,Neustadt Bldg,1400 Jackson St, Denver, CO 80206 USA. EM chane@njhealth.org FU NCRR NIH HHS [UL1 RR025780] NR 29 TC 4 Z9 4 U1 0 U2 3 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0036-5548 EI 1651-1980 J9 SCAND J INFECT DIS JI Scand. J. Infect. Dis. PD SEP PY 2013 VL 45 IS 9 BP 711 EP 714 DI 10.3109/00365548.2013.800947 PG 4 WC Infectious Diseases SC Infectious Diseases GA 202TP UT WOS:000323242800009 PM 23808720 ER PT J AU Libby, P Nahrendorf, M Swirski, FK AF Libby, Peter Nahrendorf, Matthias Swirski, Filip K. TI Monocyte heterogeneity in cardiovascular disease SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE Myocardial infarction; Atherosclerosis; Acute coronary syndromes; Inflammation; Mononuclear phagocytes; Innate immunity ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY-DISEASE; STEM-CELL PROLIFERATION; HEMATOPOIETIC STEM; GENE-EXPRESSION; ATHEROSCLEROTIC LESIONS; INFLAMMATORY MONOCYTES; CD14+CD16+ MONOCYTES; CD16(+) MONOCYTES; SPLENIC RESERVOIR AB Only a few decades ago, students of the pathophysiology of cardiovascular disease paid little heed to the involvement of inflammation and immunity. Multiple lines of evidence now point to the participation of innate and adaptive immunity and inflammatory signaling in a variety of cardiovascular conditions. Hence, interest has burgeoned in this intersection. This review will focus on the contribution of innate immunity to both acute injury to the heart muscle itself, notably myocardial infarction, and to chronic inflammation in the artery wall, namely atherosclerosis, the cause of most myocardial infarctions. Our discussion of the operation of innate immunity in cardiovascular diseases will focus on functions of the mononuclear phagocytes, with special attention to emerging data regarding the participation of different functional subsets of these cells in cardiovascular pathophysiology. C1 [Libby, Peter] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,Dept Med, Boston, MA 02115 USA. [Nahrendorf, Matthias; Swirski, Filip K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02115 USA. RP Libby, P (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc Med,Dept Med, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM plibby@rics.bwh.harvard.edu FU NHLBI NIH HHS [R01 HL080472] NR 69 TC 30 Z9 31 U1 4 U2 22 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD SEP PY 2013 VL 35 IS 5 BP 553 EP 562 DI 10.1007/s00281-013-0387-3 PG 10 WC Immunology; Pathology SC Immunology; Pathology GA 200YT UT WOS:000323108500003 PM 23839097 ER PT J AU Lee, DH Kim, JY Lee, MK Lee, C Min, JH Jeong, DH Lee, JW Chu, SH Meyerhardt, JA Ligibel, J Jones, LW Kim, NK Jeon, JY AF Lee, Dong Hoon Kim, Ji Young Lee, Mi Kyung Lee, Choae Min, Ji-Hee Jeong, Duck Hyoun Lee, Ji-Won Chu, Sang Hui Meyerhardt, Jeffrey A. Ligibel, Jennifer Jones, Lee W. Kim, Nam Kyu Jeon, Justin Y. TI Effects of a 12-week home-based exercise program on the level of physical activity, insulin, and cytokines in colorectal cancer survivors: a pilot study SO SUPPORTIVE CARE IN CANCER LA English DT Article DE Colorectal cancer; Exercise; Insulin resistance; IGFs; Cytokine ID RANDOMIZED CONTROLLED-TRIAL; GROWTH-FACTOR-I; POSTMENOPAUSAL WOMEN; BREAST-CANCER; IGF-I; FACTOR BINDING-PROTEIN-3; AEROBIC EXERCISE; PROSTATE-CANCER; COLON-CANCER; SERUM-LEVELS AB The purposes of this study are to examine (1) the feasibility and efficacy of two different home-based exercise protocols on the level of physical activity (PA), and (2) the effect of increased PA via home-based exercise program on biomarkers of colorectal cancer. Seventeen patients (age 55.18 +/- 13.3 years) with stage II-III colorectal cancer completed the 12-week home-based exercise program. Subjects were randomized into either casually intervened home-based exercise group (CIHE) or intensely intervened home-based exercise group (IIHE). The primary outcome was the level of PA. Furthermore, insulin, homeostasis model assessment of insulin resistance, insulin-like growth factor axis, and adipocytokines were measured. Both CIHE and IIHE program significantly increased the level of PA at 12 weeks compared to its level at baseline (CIHE, 10.00 +/- 8.49 vs. 46.07 +/- 45.59; IIHE, 12.08 +/- 11.04 vs. 35.42 +/- 27.42 MET hours per week). Since there was no difference in PA change between groups (p = 0.511), the data was combined in analyzing the effects of increased PA on biomarkers. Increase in PA significantly reduced insulin (6.66 +/- 4.58 vs. 4.86 +/- 3.48 mu U/ml, p = 0.006), HOMA-IR (1.66 +/- 1.23 vs. 1.25 +/- 1.04, p = 0.017), and tumor necrosis alpha-alpha (TNF-alpha 4.85 +/- 7.88 vs. 2.95 +/- 5.38 pg/ml, p = 0.004), and significantly increased IGF-1 (135.39 +/- 60.15 vs. 159.53 ng/ml, p = 0.007), IGF binding protein (IGFBP)-3 (2.67 +/- 1.48 vs. 3.48 +/- 1.00 ng/ml, p = 0.013), and adiponectin (6.73 +/- 3.07 vs. 7.54 +/- 3.96 mu g/ml, p = 0.015). CIHE program was as effective as IIHE program in increasing the level of PA, and the increase in PA resulted in significant change in HOMA-IR, IGF-1 axis, TNF-alpha, and adiponectin levels in stage II-III colorectal cancer survivors. C1 [Lee, Dong Hoon; Kim, Ji Young; Lee, Mi Kyung; Lee, Choae; Min, Ji-Hee; Jeon, Justin Y.] Yonsei Univ, Dept Sport & Leisure Studies, Coll Educ, Seoul 120749, South Korea. [Jeong, Duck Hyoun; Kim, Nam Kyu] Yonsei Univ, Dept Surg, Coll Med, Seoul 120749, South Korea. [Lee, Ji-Won] Yonsei Univ, Dept Family Med, Coll Med, Seoul 120749, South Korea. [Chu, Sang Hui] Yonsei Univ, Dept Clin Nursing Sci, Nursing Policy & Res Inst, Biobehav Res Ctr,Coll Nursing, Seoul 120749, South Korea. [Meyerhardt, Jeffrey A.; Ligibel, Jennifer] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jones, Lee W.] Duke Univ, Med Ctr, Durham, NC USA. [Jeon, Justin Y.] Yonsei Univ, Dept Sport & Leisure Studies, Seoul 120749, South Korea. RP Jeon, JY (reprint author), Yonsei Univ, Dept Sport & Leisure Studies, 134 Seodaemun Gu, Seoul 120749, South Korea. EM jjeon@yonsei.ac.kr OI Kim, Nam-Kyu/0000-0003-0639-5632 FU National Research Foundation of Korea (NRF) [2011-0004892]; National R & D program for Cancer Control, Ministry of Health and Welfare, Republic of Korea [1120230] FX National Research Foundation of Korea (NRF) (No. 2011-0004892 to J.Y.J.) and the National R & D program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1120230 to N.K.K). NR 41 TC 24 Z9 24 U1 0 U2 17 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0941-4355 EI 1433-7339 J9 SUPPORT CARE CANCER JI Support. Care Cancer PD SEP PY 2013 VL 21 IS 9 BP 2537 EP 2545 DI 10.1007/s00520-013-1822-7 PG 9 WC Oncology; Health Care Sciences & Services; Rehabilitation SC Oncology; Health Care Sciences & Services; Rehabilitation GA 194IY UT WOS:000322626600021 PM 23636649 ER PT J AU Dehghan, S Seto, J Liu, EB Walsh, MP Dyer, DW Chodosh, J Seto, D AF Dehghan, Shoaleh Seto, Jason Liu, Elizabeth B. Walsh, Michael P. Dyer, David W. Chodosh, James Seto, Donald TI Computational analysis of four human adenovirus type 4 genomes reveals molecular evolution through two interspecies recombination events SO VIROLOGY LA English DT Article DE Adenovirus; Molecular evolution; Recombination; Zoonosis ID ACUTE RESPIRATORY-DISEASE; US MILITARY RECRUITS; DNA-REPLICATION; ANTIGENIC RELATIONSHIPS; IN-VIVO; EPIDEMIC KERATOCONJUNCTIVITIS; CHIMPANZEE ADENOVIRUSES; GENETIC-VARIABILITY; BINDING PROTEIN; SUBGENUS-B AB Computational analysis of human adenovirus type 4 (HAdV-E4), a pathogen that is the only HAdV member of species E, provides insights into its zoonotic origin and molecular adaptation. Its genome encodes a domain of the major capsid protein, hexon, from HAdV-B16 recombined into the genome chassis of a simian adenovirus. Genomes of two recent field strains provide a clue to its adaptation to the new host: recombination of a NF-I binding site motif, which is required for efficient viral replication, from another HAdV genome. This motif is absent in the chimpanzee adenoviruses and the HAdV-E4 prototype, but is conserved amongst other HAdVs. This is the first report of an interspecies recombination event for HAdVs, and the first documentation of a lateral partial gene transfer from a chimpanzee AdV. The potential for such recombination events are important when considering chimpanzee adenoviruses as candidate gene delivery vectors for human patients. (C) 2013 Elsevier Inc. All rights reserved. C1 [Dehghan, Shoaleh] American Univ, Dept Chem, Washington, DC 20016 USA. [Dehghan, Shoaleh; Seto, Jason; Liu, Elizabeth B.; Walsh, Michael P.; Seto, Donald] George Mason Univ, Sch Syst Biol, Bioinformat & Computat Biol Program, Manassas, VA 20110 USA. [Dyer, David W.] Univ Oklahoma, Hlth Sci Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. [Chodosh, James] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Howe Lab,Dept Ophthalmol, Boston, MA 02114 USA. RP Seto, D (reprint author), George Mason Univ, Sch Syst Biol, Bioinformat & Computat Biol Program, 10900 Univ Blvd,MSN 5B3, Manassas, VA 20110 USA. EM dseto@gmu.edu FU Department of Defense; U.S. Army Medical Research and Material Command [DAMD17-03-2-0089]; EOS Project; HQ USAF Surgeon General Office, Directorate of Modernization (SGR); Defense Threat Reduction Agency (DTRA); Global Emerging Infections Surveillance and Response System (GEIS); Division of the Armed Forces Health Surveillance Center, Silver Spring, MD; Office of the Provost at George Mason University; NIH [EY013124]; Research to Prevent Blindness Senior Scientific Investigator Award FX Genome sequencing was completed with support from the Department of Defense through which one of the authors (D.S.: 2002 to 2004) was affiliated with the U.S. Air Force Surgeon General Office, Directorate of Modernization (SGR) and the U.S. Air Force Epidemic Outbreak Surveillance (EOS) Program (Falls Church, VA), specifically by a grant from the U.S. Army Medical Research and Material Command (DAMD17-03-2-0089). Additional support was provided through the EOS Project, which was funded by HQ USAF Surgeon General Office, Directorate of Modernization (SGR), and the Defense Threat Reduction Agency (DTRA). One of the HAdV-E4 field strains was obtained from and collected with the support of the Global Emerging Infections Surveillance and Response System (GEIS), a Division of the Armed Forces Health Surveillance Center, Silver Spring, MD (www.afhsc.mil). D.S. thanks Clark Tibbetts (EOS; 2001 to 2005) and David Metzgar for earlier discussions on type 4 HAdVs, as well as the Office of the Provost at George Mason University for funding a Sabbatical Study Leave; Lilian Coralia Lopez Rojas Desjardins for providing a unique writing environment in Antigua (Guatemala); and Professor James Chodosh, his research group, and the Massachusetts Eye and Ear Infirmary, Harvard Medical School (Boston, MA) for providing a stimulating intellectual environment.; JC was supported by NIH grant EY013124 and a Research to Prevent Blindness Senior Scientific Investigator Award. NR 89 TC 14 Z9 16 U1 1 U2 12 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2013 VL 443 IS 2 BP 197 EP 207 DI 10.1016/j.virol.2013.05.014 PG 11 WC Virology SC Virology GA 195FC UT WOS:000322686700002 PM 23763770 ER PT J AU Lewandrowski, K Lee-Lewandrowski, E Croker, B Gregory, K Lewandrowski, N AF Lewandrowski, Kent Lee-Lewandrowski, Elizabeth Croker, Benjamin Gregory, Kimberly Lewandrowski, Nicole TI Financial Viability of Point-of-Care Laboratory Testing in a Primary Care Setting in the United States SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract C1 [Lee-Lewandrowski, Elizabeth; Croker, Benjamin; Gregory, Kimberly; Lewandrowski, Nicole] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2013 VL 140 SU 1 MA 38 BP 38 EP 38 PG 1 WC Pathology SC Pathology GA V40HA UT WOS:000209468500039 ER PT J AU Zhang, SS Hart, JA Husain, AN Wagner, AJ Hornick, JL AF Zhang, Sharon S. Hart, John A. Husain, Aliya N. Wagner, Andrew J. Hornick, Jason L. TI Identification of SDHA (Subunit A of the Succinate Dehydrogenase) Mutation in Patient With Carney-Stratakis Syndrome SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract C1 [Zhang, Sharon S.] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. [Hart, John A.; Husain, Aliya N.; Wagner, Andrew J.] Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2013 VL 140 SU 1 MA 185 BP 185 EP 185 PG 1 WC Pathology SC Pathology GA V40HA UT WOS:000209468500186 ER PT J AU Lewandrowski, K Croker, B Gregory, K Lewandrowski, N Lee-Lewandrowski, E AF Lewandrowski, Kent Croker, Benjamin Gregory, Kimberly Lewandrowski, Nicole Lee-Lewandrowski, Elizabeth TI Patient Satisfaction With Point-of-Care Laboratory Testing: Report of a Quality Improvement Program in an Ambulatory Practice of an Academic Medical Center SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract C1 [Lewandrowski, Kent; Croker, Benjamin; Gregory, Kimberly; Lewandrowski, Nicole] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 EI 1943-7722 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD SEP PY 2013 VL 140 SU 1 MA 199 BP 199 EP 199 PG 1 WC Pathology SC Pathology GA V40HA UT WOS:000209468500200 ER PT J AU Lai, A Tran, T Nguyen, HM Fleischmann, J Beenhouwer, DO Graber, CJ AF Lai, Andrew Thuong Tran Nguyen, Hien M. Fleischmann, Jacob Beenhouwer, David O. Graber, Christopher J. TI Outpatient Parenteral Antimicrobial Therapy at Large Veterans Administration Medical Center SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article AB Objectives: To evaluate our outpatient parenteral antimicrobial therapy (OPAT) program to determine its impact on infection management in a facility notable for high patient comorbidity and a large catchment area that includes most of Southern California. Study Design: Retrospective chart review. Methods: We reviewed all episodes of patients receiving OPAT from our institution from 2006 through 2009 for patient utilization characteristics and assessment of complications. Results: A total of 333 patients received 393 courses of OPAT for a mean of 21.1 days. Diabetes mellitus (53.5%), psychiatric disease (39%), and chronic kidney disease (31%) were common; more than half the patients lived more than 20 miles from our medical center. Osteomyelitis (39.7%) and bacteremia (19.3%) accounted for the majority of OPAT indications. Staphylococcus aureus (36.4%) was the most frequent infecting organism, and vancomycin (37.4%) was the most frequently prescribed medication. Complications including hospital readmission, adverse drug reactions, or line- related complications were noted in 96 of 393 (24.4%) episodes, but most were minor, reversible, or not directly related to the OPAT given. Serious line- related complications that required hospital readmission were noted in only 6 (1.5%) episodes. OPAT was completed as planned in 313 (79.6%) episodes; end-stage renal disease was associated with OPAT noncompletion in multivariable analysis (odds ratio = 2.20, P = .047). We estimated that OPAT saved our medical center $4 million per year. Conclusions: Despite our patients' high level of comorbidity and our facility's large catchment area, we were able to deliver OPAT successfully and safely with significant cost savings. C1 [Lai, Andrew] Huntington Hosp, Dept Med, Pasadena, CA USA. [Thuong Tran; Fleischmann, Jacob; Beenhouwer, David O.; Graber, Christopher J.] VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, 11301 Wilshire Blvd,111-F, Los Angeles, CA 90073 USA. [Thuong Tran] VA Greater Los Angeles Healthcare Syst, Serv Pharm, Los Angeles, CA 90073 USA. [Nguyen, Hien M.] Kaiser Permanente Northwest, Portland, OR USA. [Fleischmann, Jacob; Beenhouwer, David O.; Graber, Christopher J.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Graber, CJ (reprint author), VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, 11301 Wilshire Blvd,111-F, Los Angeles, CA 90073 USA. EM christopher.graber@va.gov NR 14 TC 0 Z9 0 U1 0 U2 0 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD SEP PY 2013 VL 19 IS 9 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA V44PB UT WOS:000209759800003 ER PT J AU Kostic, AD Chun, E Meyerson, M Garrett, WS AF Kostic, Aleksandar D. Chun, Eunyoung Meyerson, Matthew Garrett, Wendy S. TI Microbes and Inflammation in Colorectal Cancer SO CANCER IMMUNOLOGY RESEARCH LA English DT Article ID ENTEROTOXIGENIC BACTEROIDES-FRAGILIS; FAMILIAL ADENOMATOUS POLYPOSIS; COLITIS-ASSOCIATED CANCER; T-BET DEFICIENCY; COLON-CANCER; HELICOBACTER-PYLORI; ESCHERICHIA-COLI; INTESTINAL INFLAMMATION; GUT MICROBIOTA; TUMOR-GROWTH AB Over the past decade, there has been a renaissance in research on physiologic interactions between humans and their resident microbiota, the vast numbers of bacteria, fungi, and viruses that live within and on the body. The burgeoning interest in what constitutes the human microbiome has also focused on the contribution of microbes to carcinogenesis. Given the microbiomes of malignancies arising at mucosal sites, the microbiota may prove as influential as stromal cells and immune cells in the tumor microenvironment. Herein, we focus on the interconnections of microbes and inflammation in colorectal carcinogenesis. (C) 2013 AACR. C1 [Kostic, Aleksandar D.; Meyerson, Matthew; Garrett, Wendy S.] Broad Inst Harvard & MIT, Canc Program & Infect Dis Initiat, Cambridge, MA USA. [Chun, Eunyoung; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Cambridge, MA 02138 USA. [Meyerson, Matthew; Garrett, Wendy S.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Meyerson, Matthew; Garrett, Wendy S.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. [Meyerson, Matthew; Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Garrett, WS (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM wgarrett@hsph.harvard.edu OI Kostic, Aleksandar/0000-0002-0837-4360 NR 99 TC 17 Z9 17 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2326-6066 EI 2326-6074 J9 CANCER IMMUNOL RES JI Cancer Immunol. Res. PD SEP PY 2013 VL 1 IS 3 BP 150 EP 157 DI 10.1158/2326-6066.CIR-13-0101 PG 8 WC Oncology; Immunology SC Oncology; Immunology GA AM7FI UT WOS:000340029700002 PM 24777677 ER PT J AU Merchant, FM Sayadi, O Moazzami, K Puppala, D Armoundas, AA AF Merchant, Faisal M. Sayadi, Omid Moazzami, Kasra Puppala, Dheeraj Armoundas, Antonis A. TI T-Wave Alternans as an Arrhythmic Risk Stratifier: State of the Art SO CURRENT CARDIOLOGY REPORTS LA English DT Article DE Repolarization alternans; Arrhythmia risk stratification; Arrhythmia prevention; Sudden cardiac death; T-wave alternans ID SUDDEN CARDIAC DEATH; IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR; LONG-QT SYNDROME; CALCIUM TRANSIENT ALTERNANS; CONGESTIVE-HEART-FAILURE; REPOLARIZATION ALTERNANS; ELECTRICAL ALTERNANS; MECHANICAL ALTERNANS; ACTION-POTENTIALS; VENTRICULAR TACHYARRHYTHMIAS AB Microvolt level T-wave alternans (MTWA), a phenomenon of beat-beat variability in the repolarization phase of the ventricles, has been closely associated with an increased risk of ventricular tachyarrhythmic events (VTE) and sudden cardiac death (SCD) during medium-and long-term follow-up. Recent observations also suggest that heightened MTWA magnitude may be closely associated with short-term risk of impending VTE. At the subcellular and cellular level, perturbations in calcium transport processes likely play a primary role in the genesis of alternans, which then secondarily lead to alternans of action potential morphology and duration (APD). As such, MTWA may play a role not only in risk stratification but also more fundamentally in the pathogenesis of VTE. In this paper, we outline recent advances in understanding the pathogenesis of MTWA and also the utility of T-wave alternans testing for clinical risk stratification. We also highlight emerging clinical applications for MTWA. C1 [Merchant, Faisal M.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Sayadi, Omid; Moazzami, Kasra; Puppala, Dheeraj; Armoundas, Antonis A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. RP Armoundas, AA (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, 149 13th St, Charlestown, MA 02129 USA. EM aarmoundas@partners.org FU NIA [1R21AG035128]; Integration of Medicine and Innovative Technology (CIMIT); American Heart Association [12POST9310001]; Deane Institute for Integrative Research in Atrial Fibrillation and Stroke; Cardiovascular Research Society FX The work was supported by NIA grant 1R21AG035128, by a Fellowship and a Science Award from the Center for Integration of Medicine and Innovative Technology (CIMIT), a Post-doctoral Fellowship (#12POST9310001) from the American Heart Association and the Deane Institute for Integrative Research in Atrial Fibrillation and Stroke and the Cardiovascular Research Society. NR 91 TC 6 Z9 6 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3782 EI 1534-3170 J9 CURR CARDIOL REP JI Curr. Cardiol. Rep. PD SEP PY 2013 VL 15 IS 9 AR 398 DI 10.1007/s11886-013-0398-7 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT6YQ UT WOS:000345083400007 PM 23881581 ER PT J AU Selby, VN Teerlink, JR AF Selby, Van N. Teerlink, John R. TI What's New in the Treatment of Acute Heart Failure? SO CURRENT CARDIOLOGY REPORTS LA English DT Article DE Acute heart failure; Drug therapy; Clinical trials; Vasodilators; Inotropes; Ultrafiltration; Diuretics; Nitroglycerin; Sodium nitroprusside; Nesiritide; Dobutamine; Milrinone; Levosimendan; Omecamtiv mecarbil; Serelaxin; Istaroxime; Ularitide; Cenderitide; Aliskiren; Rolofylline; Tezosentan; Cinaciguat ID ACUTE MYOCARDIAL-INFARCTION; NATIONAL REGISTRY ADHERE; RANDOMIZED CONTROLLED-TRIALS; CARDIAC MYOSIN ACTIVATOR; SODIUM-NITROPRUSSIDE; NATRIURETIC PEPTIDE; INTRAVENOUS NESIRITIDE; OMECAMTIV MECARBIL; RENAL IMPAIRMENT; DOUBLE-BLIND AB Acute heart failure is associated with substantial morbidity and mortality. Goals of treatment are decongestion, correction of hemodynamic abnormalities, symptom relief, and reducing long-term morbidity and mortality. Loop diuretics are a first-line agent for treatment of volume overload, with ultrafiltration reserved for those who do not respond to pharmacologic therapy. In patients with normal or elevated blood pressure, vasodilators are used to correct hemodynamics and reverse central volume redistribution, although no currently available agent has been shown to improve outcomes. Intravenous inotropes and inodilators are associated with frequent adverse effects and are reserved for patients with hypotension and evidence of inadequate perfusion. Novel drugs designed to maximize hemodynamic benefits while minimizing adverse effects are under investigation, with several agents showing promise in clinical studies. C1 [Selby, Van N.] Univ Calif San Francisco, Div Cardiol, San Francisco, CA 94143 USA. [Teerlink, John R.] San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA 94121 USA. RP Teerlink, JR (reprint author), San Francisco VA Med Ctr, Cardiol Sect, 4150 Clement St,Cardiol 111C, San Francisco, CA 94121 USA. EM john.teerlink@ucsf.edu FU Amgen; Cytokinetics; Corthera; Novartis FX John R. Teerlink has been consultant for Amgen, Cytokinetics, Corthera, Novartis, and St. Jude, and has received grant support from Amgen, Cytokinetics, Corthera, and Novartis. NR 56 TC 5 Z9 5 U1 4 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3782 EI 1534-3170 J9 CURR CARDIOL REP JI Curr. Cardiol. Rep. PD SEP PY 2013 VL 15 IS 9 AR 393 DI 10.1007/s11886-013-0393-z PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA AT6YQ UT WOS:000345083400002 PM 23881577 ER PT J AU Bosch, A Ellis, H Tao, J Castel, P Ibrahim, Y Bergamaschi, A Prat, A Scaltriti, M Baselga, J AF Bosch, A. Ellis, H. Tao, J. Castel, P. Ibrahim, Y. Bergamaschi, A. Prat, A. Scaltriti, M. Baselga, J. TI PI3K pathway inhibitors sensitize to anti-estrogen therapy as a result of increased estrogen receptor levels and signaling SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Bosch, A.; Ellis, H.; Castel, P.; Scaltriti, M.; Baselga, J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Tao, J.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Ibrahim, Y.] Vall dHebron Inst Oncol, Expt Therapeut, Barcelona, Spain. [Bergamaschi, A.] Univ Illinois, Urbana, IL 61801 USA. [Prat, A.] Vall dHebron Inst Oncol, Translat Genom, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA38 BP S17 EP S17 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600043 ER PT J AU Brastianos, PK Carter, SL Santagata, S Taylor-Weiner, A Stemmer-Rachamimov, A Louis, DL Baselga, J Beroukhim, R Getz, G Hahn, WC AF Brastianos, P. K. Carter, S. L. Santagata, S. Taylor-Weiner, A. Stemmer-Rachamimov, A. Louis, D. L. Baselga, J. Beroukhim, R. Getz, G. Hahn, W. C. TI Genomic characterization of brain metastases and paired primary tumors reveals patterns of clonal evolution SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Brastianos, P. K.] Massachusetts Gen Hosp, Ctr Canc, Div Med Oncol, Boston, MA USA. [Carter, S. L.; Taylor-Weiner, A.; Getz, G.] Broad Inst Harvard & MIT, Canc Program, Boston, MA USA. [Santagata, S.] Brigham & Womens Hosp, Pathol, Boston, MA 02115 USA. [Stemmer-Rachamimov, A.; Louis, D. L.] Massachusetts Gen Hosp, Pathol, Boston, MA 02114 USA. [Baselga, J.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Beroukhim, R.; Hahn, W. C.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA4 BP S3 EP S3 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600009 ER PT J AU Brose, MS Cabanillas, ME Cohen, EEW Wirth, L Sherman, SI Riehl, T Yue, H Sherman, E AF Brose, M. S. Cabanillas, M. E. Cohen, E. E. W. Wirth, L. Sherman, S. I. Riehl, T. Yue, H. Sherman, E. TI An open-label, multi-center phase 2 study of the BRAF inhibitor vemurafenib in patients with metastatic or unresectable papillary thyroid cancer (PTC) positive for the BRAF V600 mutation and resistant to radioactive iodine (NCT01286753, NO25530) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Brose, M. S.] Univ Penn, Abramson Canc Ctr, Hematol Oncol, Philadelphia, PA 19104 USA. [Cabanillas, M. E.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. [Cohen, E. E. W.] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA. [Wirth, L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Sherman, S. I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Endocrine Disorders, Houston, TX 77030 USA. [Riehl, T.] Genentech Inc, Prod Dev, San Francisco, CA 94080 USA. [Yue, H.] Genentech Inc, Biostat, San Francisco, CA 94080 USA. [Sherman, E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NR 0 TC 3 Z9 3 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA28 BP S13 EP S13 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600033 ER PT J AU de Koning, HJ Plevritis, SK Meza, R ten Haaf, K Munshi, VN Pinsky, PF Hazelton, WD Feuer, EJ McMahon, PM AF de Koning, H. J. Plevritis, S. K. Meza, R. ten Haaf, K. Munshi, V. N. Pinsky, P. F. Hazelton, W. D. Feuer, E. J. McMahon, P. M. CA CISNET Lung Modeling Grp TI Benefits and harms of computed tomography lung cancer screening programs for high risk populations - using evidence from the 2 largest randomized controlled trials on lung cancer screening worldwide SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [de Koning, H. J.; ten Haaf, K.] Erasmus MC, Publ Hlth, Rotterdam, Netherlands. [Plevritis, S. K.] Stanford Univ, Stanford, CA 94305 USA. [Meza, R.] Univ Michigan, Ann Arbor, MI 48109 USA. [Munshi, V. N.; McMahon, P. M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Pinsky, P. F.; Feuer, E. J.; CISNET Lung Modeling Grp] NCI, Bethesda, MD 20892 USA. [Hazelton, W. D.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA14 BP S7 EP S7 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600019 ER PT J AU Nabors, L Fink, K Mikkelsen, T Grujicic, D Tarnawski, R Nam, D Perry, J Markivskyy, A Picard, M Reardon, D AF Nabors, L. Fink, K. Mikkelsen, T. Grujicic, D. Tarnawski, R. Nam, D. Perry, J. Markivskyy, A. Picard, M. Reardon, D. TI A randomized phase II study investigating cilengitide added to standard chemoradiotherapy in patients with newly diagnosed glioblastoma with unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter: Initial report of the CORE study SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Nabors, L.] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. [Fink, K.] Baylor Univ, Med Ctr, Neurooncol Associates, Dallas, TX USA. [Mikkelsen, T.] Henry Ford Hlth Syst, Dept Neurol, Detroit, MI USA. [Mikkelsen, T.] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI USA. [Grujicic, D.] Clin Ctr Serbia, Inst Neurosurg, Belgrade, Serbia. [Tarnawski, R.] Maria Sklodowska Curie Mem Canc Ctr, Gliwice, Poland. [Tarnawski, R.] Radiotherapy & Chemotherapy Clin, Inst Oncol Gliwice Branch, Gliwice, Poland. [Nam, D.] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurosurg, Seoul, South Korea. [Perry, J.] Sunnybrook Hlth Sci Ctr, Div Neurol, Toronto, ON M4N 3M5, Canada. [Markivskyy, A.] Merck KGaA, Global Clin Dev Unit Oncol, Darmstadt, Germany. [Picard, M.] Merck KGaA, Global Clin Dev Ctr Oncol, Darmstadt, Germany. [Reardon, D.] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RI Tarnawski, Rafal/N-7526-2016 NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA40 BP S17 EP S18 PG 2 WC Oncology SC Oncology GA V40HV UT WOS:000209470600045 ER PT J AU Ou, S Gadgeel, S Chiappori, A Riely, G Lee, R Garcia, L Tatsuno, M Tanaka, T Gandhi, L AF Ou, S. Gadgeel, S. Chiappori, A. Riely, G. Lee, R. Garcia, L. Tatsuno, M. Tanaka, T. Gandhi, L. TI Safety and efficacy analysis of RO5424802/CH5424802 in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients who have failed crizotinib in a dose-finding phase I study (AF-002JG, NCT01588028) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Ou, S.] Chao Family Comprehens Canc Ctr, Med Hematol Oncol, Orange, CA USA. [Gadgeel, S.] Karmanos Canc Inst, Med Hematol Oncol, Detroit, MI USA. [Chiappori, A.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Med Hematol Oncol, Tampa, FL 33612 USA. [Riely, G.] Mem Sloan Kettering Canc Ctr, Med Hematol Oncol, New York, NY 10021 USA. [Lee, R.] Hoffmann La Roche Inc, Nutley, NJ 07110 USA. [Garcia, L.] Chugai Pharmaceut USA LLC, Clin Res, Berkeley Hts, NJ USA. [Tatsuno, M.; Tanaka, T.] Chugai Pharmaceut Co Ltd, Tokyo, Japan. [Gandhi, L.] Dana Farber Canc Inst, Med Med Oncol, Boston, MA 02115 USA. NR 0 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA44 BP S19 EP S19 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600049 ER PT J AU Penson, RT Huang, H Tewari, KS Long, HJ Ramondetta, LM Landrum, LM Oaknin, A Reid, TJA Leitao, MM Sill, M AF Penson, R. T. Huang, H. Tewari, K. S. Long, H. J. Ramondetta, L. M. Landrum, L. M. Oaknin, A. Reid, T. J. A. Leitao, M. M. Sill, M. TI Patient reported outcomes in a practice changing randomized trial of bevacizumab in the treatment of advanced cervical cancer: A Gynecologic Oncology Group study SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Penson, R. T.] Massachusetts Gen Hosp, Med Hem Oncol, Boston, MA 02114 USA. [Huang, H.; Sill, M.] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Tewari, K. S.] Univ Calif Med Ctr Irvine, Gynecol Oncol, Orange, CA USA. [Long, H. J.] Mayo Clin, Med Oncol, Rochester, MN USA. [Ramondetta, L. M.] Univ Texas MD Anderson Canc Ctr, Gynecol Oncol, Houston, TX 77030 USA. [Landrum, L. M.] Univ Oklahoma, Hlth Sci Ctr, Gynecol Oncol, Oklahoma City, OK USA. [Oaknin, A.] Paseo de Vall Hebron, GEICO, Barcelona, Spain. [Reid, T. J. A.] Univ Cincinnati, Gynecol Oncol, Cincinnati, OH USA. [Leitao, M. M.] Mem Sloan Kettering Canc Ctr, Gynecol Oncol, New York, NY 10021 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA42 BP S18 EP S18 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600047 ER PT J AU Ranson, M Pao, W Kim, DW Kim, SW Ohe, Y Felip, E Planchard, D Ghiorghiu, S Cantarini, M Janne, PA AF Ranson, M. Pao, W. Kim, D. W. Kim, S. W. Ohe, Y. Felip, E. Planchard, D. Ghiorghiu, S. Cantarini, M. Jaenne, P. A. TI Preliminary results from a Phase I study with AZD9291: An irreversible inhibitor of epidermal growth factor receptor (EGFR) activating and resistance mutations in non-small cell lung cancer (NSCLC) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Ranson, M.] Univ Manchester Christie Hosp NHS Trust, Dept Med Oncol, Manchester, Lancs, England. [Pao, W.] Vanderbilt Ingram Canc Ctr, Div Hematol & Oncol, Nashville, TN USA. [Kim, D. W.] Seoul Natl Univ Hosp, Dept Internal Med, Seoul 110744, South Korea. [Kim, S. W.] Asan Med Ctr, Dept Oncol, Seoul, South Korea. [Ohe, Y.] Natl Canc Ctr Hosp East, Div Thorac Oncol, Kashiwa, Chiba, Japan. [Felip, E.] Hosp Univ Vall dHebron, Dept Oncol, Barcelona, Spain. [Planchard, D.] Inst Gustave Roussy, Dept Med Oncol, Villejuif, France. [Ghiorghiu, S.; Cantarini, M.] AstraZeneca, Dept Global Med Dev, Macclesfield, Cheshire, England. [Jaenne, P. A.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. NR 0 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA33 BP S15 EP S15 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600038 ER PT J AU Schadendorf, D Hodi, FS Robert, C Weber, JS Margolin, K Hamid, O Chen, TT Berman, DM Wolchok, JD AF Schadendorf, D. Hodi, F. S. Robert, C. Weber, J. S. Margolin, K. Hamid, O. Chen, T. T. Berman, D. M. Wolchok, J. D. TI Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Schadendorf, D.] Univ Hosp Essen, Dermatol, Essen, Germany. [Hodi, F. S.] Dana Farber Canc Inst, Med Oncol, Boston, MA 02115 USA. [Robert, C.] Inst Gustave Roussy, Dermatol, Villejuif, France. [Weber, J. S.] Univ S Florida, H Lee Moffitt Canc Ctr, Cutaneous Oncol, Tampa, FL 33682 USA. [Margolin, K.] Univ Washington, Med Oncol, Seattle, WA 98195 USA. [Hamid, O.] Angeles Clin & Res Inst, Melanoma Program Oncol Res, Los Angeles, CA USA. [Chen, T. T.] Bristol Myers Squibb Co, GBS, Wallingford, CT 06492 USA. [Berman, D. M.] Bristol Myers Squibb Co, Global Clin Res, Lawrenceville, NJ USA. [Wolchok, J. D.] Mem Sloan Kettering Canc Ctr, Med, New York, NY 10021 USA. NR 0 TC 8 Z9 9 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA24 BP S11 EP S11 PG 1 WC Oncology SC Oncology GA V40HV UT WOS:000209470600029 ER PT J AU Wildiers, H Kim, SB Gonzalez-Martin, A LoRusso, PM Ferrero, JM Smitt, M Yu, R Leung, A Krop, IE AF Wildiers, H. Kim, S. B. Gonzalez-Martin, A. LoRusso, P. M. Ferrero, J. M. Smitt, M. Yu, R. Leung, A. Krop, I. E. TI T-DM1 for HER2-positive metastatic breast cancer (MBC): Primary results from TH3RESA, a phase 3 study of T-DM1 vs treatment of physician's choice SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract C1 [Wildiers, H.] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium. [Kim, S. B.] Univ Ulsan, Coll Med, Dept Oncol, Asan Med Ctr, Seoul, South Korea. [Gonzalez-Martin, A.] Ctr Oncol MD Anderson Int Espana, Dept Med Oncol, Madrid, Spain. [LoRusso, P. M.] Wayne State Univ, Dept Internal Med, Karmanos Canc Inst, Detroit, MI 48202 USA. [Ferrero, J. M.] Ctr Antoine Lacassagne, Dept Med Oncol, F-06054 Nice, France. [Smitt, M.; Yu, R.; Leung, A.] Genentech Inc, San Francisco, CA 94080 USA. [Krop, I. E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 EI 1879-0852 J9 EUR J CANCER JI Eur. J. Cancer PD SEP PY 2013 VL 49 SU 3 MA LBA15 BP S7 EP S8 PG 2 WC Oncology SC Oncology GA V40HV UT WOS:000209470600020 ER PT J AU Arnardottir, ES Janson, C Bjornsdottir, E Benediktsdottir, B Juliusson, S Kuna, SK Pack, AI Gislason, T AF Arnardottir, Erna Sif Janson, Christer Bjornsdottir, Erla Benediktsdottir, Bryndis Juliusson, Sigurdur Kuna, Sam K. Pack, Allan I. Gislason, Thorarinn TI Is frequent nocturnal sweating a symptom of obstructive sleep apnea? SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Sleep disorders; Sleep studies; Apnoea / Hypopnea C1 [Arnardottir, Erna Sif; Bjornsdottir, Erla; Benediktsdottir, Bryndis; Gislason, Thorarinn] Landspitali, Dept Resp Med & Sleep, Reykjavik, Iceland. [Arnardottir, Erna Sif; Bjornsdottir, Erla; Benediktsdottir, Bryndis; Gislason, Thorarinn] Univ Iceland, Fac Med, Reykjavik, Iceland. [Arnardottir, Erna Sif; Kuna, Sam K.; Pack, Allan I.] Univ Penn, Sch Med, Dept Med, Div Sleep Med, Philadelphia, PA 19104 USA. [Janson, Christer] Uppsala Univ, Dept Med Sci Resp Med & Allergol, Uppsala, Sweden. [Juliusson, Sigurdur] Landspitali, Dept Otolaryngol, Reykjavik, Iceland. [Kuna, Sam K.] Philadelphia Vet Affairs Med Ctr, Pulm Crit Care & Sleep Sect, Philadelphia, PA USA. EM ernasif@landspitali.is; christer.janson@medsci.uu.se; erlabjo@gmail.com; brynben@hi.is; sjul@landspitali.is; Samuel.Kuna@va.gov; Allan.Pack@uphs.upenn.edu; thorarig@landspitali.is NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 4672 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370403316 ER PT J AU Cohen, I LaPrad, A Adam, O Peles, Z Brown, R Solway, J Fredberg, J AF Cohen, Inon LaPrad, Adam Adam, Ori Peles, Zachi Brown, Robert Solway, Julian Fredberg, Jeffrey TI Determination of total lung capacity (TLC) without body plethysmography SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE COPD - diagnosis; Lung function testing; Primary care C1 PulmOne Adv Med Devices Ltd, IL-4355332 Raanana, Israel. Massachusetts Gen Hosp, Sect Pulm & Crit Care, Dept Med, Boston, MA 02115 USA. Univ Chicago, Dept Med, Sect Pulm & Crit Care, Dept Pediat, Chicago, IL 60637 USA. Univ Chicago, Pulm Med Serv, Chicago, IL 60637 USA. Harvard Univ, Sch Publ Hlth, Dept Enviromental Hlth, Boston, MA 02115 USA. EM inon@pulm-one.com; adam@pulm-one.com; ori@pulm-one.com; zachi@pulm-one.com; rbrown5@partners.org; jsolway@medicine.bsd.uchicago.edu; jfredber@hsph.harvard.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 4832 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370400187 ER PT J AU Delcroix, M Channick, R Galie, N Ghofrani, HA Jansa, P Le Brun, FO Mehta, S Perchenet, L Pulido, T Sastry, BKS Sitbon, O Souza, R Torbicki, A Simonneau, G Rubin, L AF Delcroix, Marion Channick, Richard Galie, Nazzareno Ghofrani, Hossein-Ardeschir Jansa, Pavel Le Brun, Franck-Olivier Mehta, Sanjay Perchenet, Loic Pulido, Tomas Sastry, B. K. S. Sitbon, Olivier Souza, Rogerio Torbicki, Adam Simonneau, Gerald Rubin, Lewis TI Is 6-minute walk distance (6MWD) associated with long-term outcomes in pulmonary arterial hypertension (PAH)? Results from SERAPHIN SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Pulmonary hypertension; Treatments; Exercise C1 [Delcroix, Marion] Univ Hosp Gasthuisberg, Dept Pneumol, Leuven, Belgium. [Channick, Richard] Massachusetts Gen Hosp, Pulm & Crit Care, Boston, MA 02114 USA. [Galie, Nazzareno] Univ Bologna, Inst Cardiol, Bologna, Italy. [Ghofrani, Hossein-Ardeschir] Univ Hosp Giessen, Dept Internal Med 2, Pulm Hypertens Div, Giessen, Germany. [Jansa, Pavel] Charles Univ Prague, Dept Med 2, Fac Med 1, Clin Dept Cardiol & Angiol, Prague, Czech Republic. [Le Brun, Franck-Olivier; Perchenet, Loic] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Mehta, Sanjay] Univ Western Ontario, Dept Med, Victoria Hosp, Div Respirol,London Hlth Sci Ctr, London, ON, Canada. [Pulido, Tomas] Natl Inst Cardiol, Cardiopulm Dept, Mexico City, DF, Mexico. [Sastry, B. K. S.] CARE Hosp, Dept Cardiol, Hyderabad, Andhra Pradesh, India. [Sitbon, Olivier; Simonneau, Gerald] Univ Paris 11, CHU Bicetre, Le Kremlin Bicetre, France. [Souza, Rogerio] Univ Sao Paulo, Sch Med, Dept Pulm, Inst Heart, Sao Paulo, Brazil. [Torbicki, Adam] ECZ Otwock, Ctr Postgrad Med Educ, Dept Pulm Circulat & Thromboembol Dis, Otwock, Poland. [Rubin, Lewis] Univ Calif San Diego, Div Pulm & Crit Care Med, San Diego, CA 92103 USA. EM marion.delcroix@uz.kuleuven.ac.be; rchannick@partners.org; nazzareno.galie@unibo.it; Ardeschir.Ghofrani@innere.med.uni-giessen.de; jansapavel@yahoo.com; franck-olivier.le-brun@actelion.com; Sanjay.Mehta@lhsc.on.ca; loic.perchenet@actelion.com; tpulido@prodigy.net.mx; bkssastry@hotmail.com; olivier.sitbon@bct.aphp.fr; souza.rogerio@me.com; adam.torbicki@ecz-otwock.pl; gerald.simonneau@bct.aphp.fr; ljr@lewisrubinmd.com NR 0 TC 0 Z9 0 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 2594 PG 2 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370402659 ER PT J AU Funke, M Knudsen, L Matthieu, S Fontaine, B Chun, J Ochs, M Tager, AM AF Funke, Manuela Knudsen, Lars Matthieu, Stephanie Fontaine, Benjamin Chun, Jerold Ochs, M. Tager, Andrew M. TI The role of the lysophosphatidic acid (LPA) receptor 1 in developmental alveolarization SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Lung growth/development; Congenital lesion/malformation; Animal models C1 [Funke, Manuela] Univ Hosp Bern, Inselspital, Dept Pulm Med, CH-3010 Bern, Switzerland. [Knudsen, Lars; Matthieu, Stephanie] Hannover Med Sch, Inst Funct & Appl Anat, Biomed Res Endstage & Obstruct Lung Dis Hannover, D-30625 Hannover, Germany. [Fontaine, Benjamin; Tager, Andrew M.] Harvard Univ, Sch Med, Pulm & Crit Care Unit, Boston, MA 02129 USA. [Fontaine, Benjamin; Tager, Andrew M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02129 USA. [Chun, Jerold] Indiana Univ Sch Med, Dept Obstet & Gynecol, Indianapolis, IN 46202 USA. [Chun, Jerold] Scripps Res Inst, Dept Mol Biol, Dorris Neurosci Ctr, La Jolla, CA 92037 USA. EM manuela.funke-chambour@insel.ch; knudsen.lars@mh-hannover.de; stefanie.matthieu@googlemail.com; BAFONTAINE@partners.org; jchun@scripps.edu; AMTAGER@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 2826 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370400354 ER PT J AU Ghofrani, HA Channick, R Delcroix, M Galie, N Jansa, P Le Brun, FO Mehta, S Mittelholzer, C Pulido, T Sastry, BKS Sitbon, O Souza, R Torbicki, A Rubin, L Simonneau, G AF Ghofrani, Hossein-Ardeschir Channick, Richard Delcroix, Marion Galie, Nazzareno Jansa, Pavel Le Brun, Franck-Olivier Mehta, Sanjay Mittelholzer, Camilla Pulido, Tomas Sastry, B. K. S. Sitbon, Olivier Souza, Rogerio Torbicki, Adam Rubin, Lewis Simonneau, Gerald TI Effect of macitentan on morbidity and mortality in pulmonary arterial hypertension: A randomised controlled trial (SERAPHIN) SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Pulmonary hypertension; Treatments C1 [Ghofrani, Hossein-Ardeschir] Univ Hosp Giessen, Dept Internal Med 2, Pulm Hypertens Div, Giessen, Germany. [Channick, Richard] Massachusetts Gen Hosp, Pulm & Crit Care, Boston, MA 02114 USA. [Delcroix, Marion] Univ Hosp Gasthuisberg, Dept Pneumol, Leuven, Belgium. [Galie, Nazzareno] Univ Bologna, Inst Cardiol, Bologna, Italy. [Jansa, Pavel] Charles Univ Prague, Clin Dept Cardiol & Angiol, Fac Med 1, Dept Med 2, Prague, Czech Republic. [Le Brun, Franck-Olivier; Mittelholzer, Camilla] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Mehta, Sanjay] Univ Western Ontario, Dept Med, Div Respirol, London Hlth Sci Ctr, London, ON, Canada. [Pulido, Tomas] Natl Inst Cardiol, Cardiopulm Dept, Mexico City, DF, Mexico. [Sastry, B. K. S.] CARE Hosp, Dept Cardiol, Hyderabad, Andhra Pradesh, India. [Sitbon, Olivier; Simonneau, Gerald] Univ Paris 11, CHU Bicetre, Le Kremlin Bicetre, France. [Souza, Rogerio] Univ Sao Paulo, Sch Med, Inst Heart, Dept Pulm, Sao Paulo, Brazil. [Torbicki, Adam] ECZ Otwock, Dept Pulm Circulat & Thromboembol Dis, Ctr Postgrad Med Educ, Otwock, Poland. [Rubin, Lewis] Univ Calif San Diego, Div Pulm & Crit Care Med, San Diego, CA 92103 USA. EM ArdeschirGhofrani@innere.med.uni-giessen.de; rchannick@partners.org; marion.delcroix@uz.kuleuven.ac.be; nazzareno.galie@unibo.it; jansapavel@yahoo.com; franck-olivierle-brun@actelion.com; Sanjay.Mehta@lhsc.on.ca; camilla.mittelholzer@actelion.com; tpulido@prodigy.net.mx; bkssastry@hotmail.com; oliviersitbon@bct.aphp.fr; souza.rogerio@me.com; adam.torbicki@ecz-otwock.pl; Ijr@lewisrubinmd.com; gerald.simonneau@bct.aphp.fr NR 0 TC 0 Z9 0 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 2443 PG 2 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370400180 ER PT J AU Hansbro, P Beckett, E Stevens, R Jarnicki, A Wark, P Foster, P AF Hansbro, Philip Beckett, Emma Stevens, Richard Jarnicki, Andrew Wark, Peter Foster, Paul TI A short-term model of COPD identifies a role for mast cell tryptase SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Smoking; Animal models; Inflammation C1 [Hansbro, Philip; Beckett, Emma; Jarnicki, Andrew; Wark, Peter; Foster, Paul] Univ Newcastle, Immunol, Newcastle, NSW 2300, Australia. [Hansbro, Philip; Jarnicki, Andrew; Wark, Peter; Foster, Paul] Hunter Med Res Inst, Immunol, Newcastle, NSW, Australia. [Stevens, Richard] Harvard Univ, Sch Med, Med, Boston, MA USA. [Stevens, Richard] Brigham & Womens Hosp, Med, Boston, MA 02115 USA. Sydney Med Sch, Woolcock Inst Med Res, Sydney, NSW, Australia. Vrije Univ Med Ctr, Mol Cell Biol, Amsterdam, Netherlands. St Josephs Healthcare, Firestone Inst Resp Heatlh, Hamilton, ON, Canada. Univ Texas MD Anderson Canc Ctr, Pulm Med, Houston, TX 77030 USA. Massachusetts Gen Hosp, Med, Boston, MA 02114 USA. [Wark, Peter] John Hunter Hosp, Resp & Sleep Med, Newcastle, NSW, Australia. EM Philip.Hansbro@newcastle.edu.au; Emma.Beckett@uon.edu.au; rstevens@rics.bwh.harvard.edu; Andrew.Jarnicki@newcastle.edu.au; Peter.Wark@hnehealth.nsw.gov.au; Paul.Foster@newcastle.edu.au NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 2241 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370404502 ER PT J AU Jansa, P Channick, R Delcroix, M Galie, N Ghofrani, HA Hunche, E Mehta, S Mittelholzer, C Pulido, T Sastry, BKS Sitbon, O Souza, R Torbicki, A Simonneau, G Rubin, L AF Jansa, Pavel Channick, Richard Delcroix, Marion Galie, Nazzareno Ghofrani, Hossein-Ardeschir Hunche, Elke Mehta, Sanjay Mittelholzer, Camilla Pulido, Tomas Sastry, B. K. S. Sitbon, Olivier Souza, Rogerio Torbicki, Adam Simonneau, Gerald Rubin, Lewis TI Impact of macitentan on the health-related quality of life (HRQoL) in pulmonary arterial hypertension (PAH): Results from a long-term randomised controlled trial SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Pulmonary hypertension; Treatments; Quality of life C1 [Jansa, Pavel] Charles Univ Prague, Clin Dept Cardiol & Angiol, Fac Med 1, Dept Med 2, Prague, Czech Republic. [Channick, Richard] Massachusetts Gen Hosp, Pulm & Crit Care, Boston, MA 02114 USA. [Delcroix, Marion] Univ Hosp Gasthuisberg, Dept Pneumol, Leuven, Belgium. [Galie, Nazzareno] Univ Bologna, Inst Cardiol, Bologna, Italy. [Ghofrani, Hossein-Ardeschir] Univ Hosp Giessen, Pulm Hypertens Div, Dept Internal Med 2, Giessen, Germany. [Hunche, Elke; Mittelholzer, Camilla] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Mehta, Sanjay] Univ Western Ontario, Dept Med, Div Respirol, London Hlth Sci Ctr,Victoria Hosp, London, ON, Canada. [Pulido, Tomas] Natl Inst Cardiol, Cardiopulm Dept, Mexico City, DF, Mexico. [Sastry, B. K. S.] CARE Hosp, Dept Cardiol, Hyderabad, Andhra Pradesh, India. [Sitbon, Olivier; Simonneau, Gerald] Univ Paris 11, CHU Bicetre, F-94275 Le Kremlin Bicetre, France. [Souza, Rogerio] Univ Sao Paulo, Sch Med, Dept Pulm, Inst Heart, Sao Paulo, Brazil. [Torbicki, Adam] ECZ Otwock, Dept Pulm Circulat & Thromboembol Dis, Ctr Postgrad Med Educ, Otwock, Poland. [Rubin, Lewis] Univ Calif San Diego, Div Pulm & Crit Care Med, San Diego, CA 92103 USA. EM jansapavel@yahoo.com; rchannick@partners.org; marion.delcroix@uz.kuleuven.ac.be; nazzareno.galie@unibo.it; Ardeschir.Ghofrani@innere.med.uni-giessen.de; Elke.Hunsche@actelion.com; Sanjay.Mehta@lhsc.on.ca; camilla.mittelholzer@actelion.com; tpulido@prodigy.net.mx; bkssastry@hotmail.com; olivier.sitbon@bct.aphp.fr; souza.rogerio@me.com; adam.torbicki@ecz-otwock.pl; gerald.simonneau@bct.aphp.fr; ljr@lewisrubinmd.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 2472 PG 2 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370403363 ER PT J AU Larose, TL Langhammer, A Chen, Y Camargo, CA Romundstad, P Mai, XM AF Larose, Tricia L. Langhammer, Arnulf Chen, Yue Camargo, Carlos A., Jr. Romundstad, Pal Mai, Xiao-Mei TI Serum 25-hydroxyvitamin D levels and lung function in adults with asthma: The HUNT study SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Spirometry; Asthma - mechanism; Rhinitis C1 [Larose, Tricia L.; Langhammer, Arnulf; Romundstad, Pal; Mai, Xiao-Mei] Norwegian Univ Sci & Technol, Fac Med, Publ Hlth & Gen Practice, N-7034 Trondheim, Norway. [Chen, Yue] Univ Ottawa, Epidemiol & Community Med, Ottawa, ON, Canada. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Emergency Med, Boston, MA USA. EM tricia.larose@ntnu.no; arnulf.langhammer@ntnu.no; Yue.Chen@uottawa.ca; ccamargo@partners.org; pal.romundstad@ntnu.no; xiao-mei.mai@ntnu.no NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 7028 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370402680 ER PT J AU Pinto-Plata, V Divo, M Tesfaigzi, Y Peterson, H Calhoum, V Holloway, D Wang, YY Owen, C Celli, B AF Pinto-Plata, Victor Divo, Miguel Tesfaigzi, Yohannes Peterson, Hans Calhoum, Vince Holloway, Dustin Wang, Yaoyu Owen, Caroline Celli, Bartolome TI Plasma metabolomic signature in COPD patients: Associations to proteomic profile and clinical outcomes SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Biomarkers; COPD - mechanism; Monitoring C1 [Pinto-Plata, Victor; Divo, Miguel; Owen, Caroline; Celli, Bartolome] Harvard Univ, Brigham & Womens Hosp, Sch Med, Pulm Crit Care Med, Boston, MA 02115 USA. [Tesfaigzi, Yohannes; Peterson, Hans; Calhoum, Vince] Lovelace Resp Res Inst, Pulm Res, Albuquerque, NM USA. [Holloway, Dustin; Wang, Yaoyu] Dana Farber Canc Inst, Ctr Canc Computac Biol, Boston, MA 02115 USA. EM vpinto@copdnet.org; mdivo@copdnet.org; YTesfaig@lrri.org; HPeterse@lrri.org; vcalhoun@mrn.org; holloway@jimmy.harvard.edu; yewang@jimmy.harvard.edu; cowen1@partners.org; bcelli@copdnet.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 4253 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370401470 ER PT J AU Riaz, H Riaz, I Abir, T Badshah, M Milton, A AF Riaz, Hans Riaz, Irbaz Abir, Tanvir Badshah, Maaz Milton, Abul TI Vitamin D as a supplementary agent in the treatment of pulmonary tuberculosis: A systematic review and meta-analysis of randomized controlled trials SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Tuberculosis - management C1 [Riaz, Hans] Dow Univ Hlth Sci, Internal Med, Karachi, Sindh, Pakistan. [Riaz, Irbaz] Univ Arizona, Internal Med, Tucson, AZ USA. [Abir, Tanvir] Univ Western Sydney, Sch Med, Sydney, NSW, Australia. [Badshah, Maaz] Mt Sinai Sch Med, James J Peters VA Med Ctr, Internal Med, New York, NY USA. [Milton, Abul] Univ Newcastle, Ctr Clin Epidemiol & Biostat, Newcastle, NJ USA. EM harisriaz73@yahoo.com; sipra.irbaz@gmail.com; abir_tanvir100@yahoo.com.au; maazbadshah501@hotmail.com; milton.hasnat@newcastle.edu.au NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 567 PG 1 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370400438 ER PT J AU Sitbon, O Channick, R Delcroix, M Galie, N Ghofrani, HA Jansa, P Le Brun, FO Mehta, S Perchenet, L Pulido, T Sastry, BKS Souza, R Torbicki, A Rubin, L Simonneau, G AF Sitbon, Olivier Channick, Richard Delcroix, Marion Galie, Nazzareno Ghofrani, Hossein-Ardeschir Jansa, Pavel Le Brun, Franck-Olivier Mehta, Sanjay Perchenet, Loic Pulido, Tomas Sastry, B. K. S. Souza, Rogerio Torbicki, Adam Rubin, Lewis Simonneau, Gerald TI Effect of macitentan on haemodynamics in SERAPHIN, a randomised controlled trial in pulmonary arterial hypertension (PAH) SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Pulmonary hypertension; Treatments C1 [Sitbon, Olivier; Simonneau, Gerald] Univ Paris 11, CHU Bicetre, Le Kremlin Bicetre, France. [Channick, Richard] Massachusetts Gen Hosp, Pulm & Crit Care, Boston, MA 02114 USA. [Delcroix, Marion] Univ Hosp Gasthuisberg, Dept Pneumol, Leuven, Belgium. [Galie, Nazzareno] Univ Bologna, Inst Cardiol, Bologna, Italy. [Ghofrani, Hossein-Ardeschir] Univ Hosp Giessen, Dept Internal Med 2, Pulm Hypertens Div, Giessen, Germany. [Jansa, Pavel] Charles Univ Prague, Clin Dept Cardiol & Angiol, Fac Med 1, Dept Med 2, Prague, Czech Republic. [Le Brun, Franck-Olivier; Perchenet, Loic] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Mehta, Sanjay] Univ Western Ontario, Dept Med, Div Respirol, London Hlth Sci Ctr,Victoria Hosp, London, ON, Canada. [Pulido, Tomas] Natl Inst Cardiol, Cardiopulm Dept, Mexico City, DF, Mexico. [Sastry, B. K. S.] CARE Hosp, Dept Cardiol, Hyderabad, Andhra Pradesh, India. [Souza, Rogerio] Univ Sao Paulo, Sch Med, Inst Heart, Dept Pulm, Sao Paulo, Brazil. [Torbicki, Adam] ECZ Otwock, Ctr Postgrad Med Educ, Dept Pulm Circulat & Thromboembol Dis, Otwock, Poland. [Rubin, Lewis] Univ Calif San Diego, Div Pulm & Crit Care Med, San Diego, CA 92103 USA. EM olivier.sitbon@bct.aphp.fr; rchannick@partners.org; marion.delcroix@uz.kuleuven.ac.be; nazzareno.galie@unibo.it; ardeschir.ghofrani@innere.med.uni-giessen.de; jansapavel@yahoo.com; franck-olivier.le-brun@actelion.com; sanjay.mehta@lhsc.on.ca; loic.perchenet@actelion.com; tpulido@prodigy.net.mx; bkssastry@hotmail.com; souza.rogerio@me.com; adam.torbicki@ecz-otwock.pl; ljr@lewisrubinmd.com; gerald.simonneau@bct.aphp.fr NR 0 TC 0 Z9 0 U1 1 U2 1 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 3863 PG 2 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370403348 ER PT J AU Varraso, R Chiuve, S Fung, T Barr, G Hu, F Willett, W Camargo, C AF Varraso, Raphaelle Chiuve, Stephanie Fung, Teresa Barr, Graham Hu, Frank Willett, Walter Camargo, Carlos, Jr. TI Prospective cohort study of the alternate healthy eating index-2010 and risk of chronic obstructive pulmonary disease in US women and men SO EUROPEAN RESPIRATORY JOURNAL LA English DT Meeting Abstract DE Epidemiology; COPD - mechanism C1 [Varraso, Raphaelle] INSERM, Ctr Res Epidemiol & Populat Hlth CESP, Resp & Environm Epidemiol Team, U1018, Villejuif, France. [Varraso, Raphaelle] Univ Paris Sud, UMRS 1018, Villejuif, France. [Chiuve, Stephanie] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Chiuve, Stephanie] Harvard Univ, Sch Med, Boston, MA USA. [Chiuve, Stephanie; Fung, Teresa; Hu, Frank; Willett, Walter] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Fung, Teresa] Simmons Coll, Dept Nutr, Boston, MA 02115 USA. [Barr, Graham] Dept Med, New York, NY USA. [Barr, Graham] Dept Epidemiol, Div Gen Med, New York, NY USA. [Hu, Frank; Willett, Walter; Camargo, Carlos, Jr.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Hu, Frank; Willett, Walter; Camargo, Carlos, Jr.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Camargo, Carlos, Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM raphaelle.varraso@inserm.fr; schiuve@hsph.harvard.edu; teresa.fung@simmons.edu; rgb9@columbia.edu; nhbfh@channing.harvard.edu; WWILLETT@hsph.harvard.edu; CCAMARGO@PARTNERS.ORG RI Varraso, Raphaelle/R-8740-2016 OI Varraso, Raphaelle/0000-0002-3338-7825 NR 0 TC 0 Z9 0 U1 0 U2 0 PU EUROPEAN RESPIRATORY SOC JOURNALS LTD PI SHEFFIELD PA 442 GLOSSOP RD, SHEFFIELD S10 2PX, ENGLAND SN 0903-1936 EI 1399-3003 J9 EUR RESPIR J JI Eur. Resp. J. PD SEP 1 PY 2013 VL 42 SU 57 MA 1610 PG 2 WC Respiratory System SC Respiratory System GA V38VH UT WOS:000209370401167 ER PT J AU Afeiche, M Gaskins, A Toth, T Tanrikut, C Hauser, R Chavarro, J AF Afeiche, M. Gaskins, A. Toth, T. Tanrikut, C. Hauser, R. Chavarro, J. TI MEAT INTAKE AND SEMEN PARAMETERS AMONG MEN ATTENDING A FERTILITY CLINIC SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Afeiche, M.; Gaskins, A.; Chavarro, J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Toth, T.] Massachusetts Gen Hosp, Vincent Mem Obstet & Gynecol Serv, Boston, MA 02114 USA. [Toth, T.; Tanrikut, C.] Harvard Univ, Sch Med, Boston, MA USA. [Tanrikut, C.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Hauser, R.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-98 BP S30 EP S31 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500099 ER PT J AU Akopians, AL Rosales, M Janzen, D Memarzadeh, S AF Akopians, A. L. Rosales, M. Janzen, D. Memarzadeh, S. TI DISTRIBUTION OF CD44 (CLUSTER OF DIFFERENTIATION-44) POSITIVE ENDOMETRIAL EPITHELIAL PROGENITORS IN HUMAN ENDOMETRIOSIS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Akopians, A. L.; Rosales, M.; Janzen, D.; Memarzadeh, S.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90095 USA. [Memarzadeh, S.] Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Los Angeles, CA USA. [Memarzadeh, S.] VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-745 BP S363 EP S364 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501520 ER PT J AU Barton, SE Poorvu, PD London, WB Duncan, CN Lehmann, LE Marcus, KJ AF Barton, S. E. Poorvu, P. D. London, W. B. Duncan, C. N. Lehmann, L. E. Marcus, K. J. TI EFFECTIVENESS OF LEUPROLIDE ACETATE FOR MENSTRUAL SUPRESSION AND RATES OF ACUTE OVARIAN FAILURE IN POSTMENARCHAL GIRLS UNDERGOING STEM CELL TRASPLANTATION (SCT). SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Barton, S. E.] Brigham & Womens Hosp, Div Reprod Med Obstet & Gynecol, Boston, MA 02115 USA. [Barton, S. E.; London, W. B.; Duncan, C. N.; Lehmann, L. E.] Harvard Univ, Sch Med, Boston, MA USA. [Poorvu, P. D.; Marcus, K. J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol,Boston Childrens Hosp,Dana Farb, Boston, MA 02115 USA. [London, W. B.] Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Program, Boston, MA 02115 USA. [Duncan, C. N.; Lehmann, L. E.] Childrens Hosp, Dana Farber Canc Inst, 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-154 BP S46 EP S46 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500154 ER PT J AU Brady, PC Imudia, AN Awonuga, AO Wright, DL Styer, AK Toth, TL AF Brady, P. C. Imudia, A. N. Awonuga, A. O. Wright, D. L. Styer, A. K. Toth, T. L. TI PREGNANCIES OF UNKNOWN LOCATION: A MINIMALLY INVASIVE DIAGNOSTIC APPROACH WITH KARMAN ASPIRATION SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Brady, P. C.; Imudia, A. N.; Wright, D. L.; Styer, A. K.; Toth, T. L.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Imudia, A. N.; Wright, D. L.; Styer, A. K.; Toth, T. L.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Fertil Ctr, Boston, MA 02114 USA. [Awonuga, A. O.] Wayne State Univ, Div Reprod Endocrinol & Infertil, Detroit, MI 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-537 BP S304 EP S304 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501316 ER PT J AU Charlton, BM Wu, K Giovannucci, E Fuchs, CS Rosner, BA Michels, KB AF Charlton, B. M. Wu, K. Giovannucci, E. Fuchs, C. S. Rosner, B. A. Michels, K. B. TI A PROSPECTIVE STUDY ON ORAL CONTRACEPTIVE USE AND COLORECTAL CANCER SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Charlton, B. M.; Giovannucci, E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Wu, K.; Giovannucci, E.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Giovannucci, E.; Rosner, B. A.] Brigham & Womens Hosp, Dept Med, Charming Div Network Med, Boston, MA 02115 USA. [Giovannucci, E.; Rosner, B. A.] Harvard Univ, Sch Med, Boston, MA USA. [Fuchs, C. S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Michels, K. B.] Harvard Univ, Brigham & Womens 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-186 BP S56 EP S57 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500186 ER PT J AU Dimitriadis, I Batsis, M Petrozza, JC Wright, DL Souter, I AF Dimitriadis, I. Batsis, M. Petrozza, J. C. Wright, D. L. Souter, I. TI ARE INFERTILE WOMEN CONCEIVING WITH IN-VITRO FERTILIZATION (IVF) AT HIGHER RISK FOR ADVERSE PREGNANCY OUTCOMES THAN THOSE CONCEIVING WITH OVULATION INDUCTION/INTRAUTERINE INSEMINATION (OI/IUI)? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Dimitriadis, I.; Batsis, M.; Petrozza, J. C.; Wright, D. L.; Souter, I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Obstet Gynecol Reprod Endocrinol & Infertil Div,F, Boston, MA USA. [Dimitriadis, I.] Tufts Med Ctr, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-1190 BP S491 EP S491 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554502200 ER PT J AU Gaskins, AJ Afeiche, M Tanrikut, C Petrozza, JC Hauser, R Chavarro, JE AF Gaskins, A. J. Afeiche, M. Tanrikut, C. Petrozza, J. C. Hauser, R. Chavarro, J. E. TI PHYSICAL AND SEDENTARY ACTIVITIES IN RELATION TO SEMEN QUALITY. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Gaskins, A. J.; Afeiche, M.; Chavarro, J. E.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Tanrikut, C.; Petrozza, J. C.] Massachusetts Gen Hosp, Fertil Ctr, Boston, MA 02114 USA. [Hauser, R.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-405 BP S123 EP S123 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500402 ER PT J AU Goldman, RH Imudia, AN Awonuga, AO Wright, DL Styer, AK Toth, TL AF Goldman, R. H. Imudia, A. N. Awonuga, A. O. Wright, D. L. Styer, A. K. Toth, T. L. TI IMPACT OF SUPRAPHYSIOLOGIC SERUM ESTRADIOL LEVEL ON CLINICAL PREGNANCY AND MISCARRIAGE RATES FOLLOWING IVF CYCLES SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Goldman, R. H.; Imudia, A. N.; Wright, D. L.; Styer, A. K.; Toth, T. L.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Awonuga, A. O.] Wayne State Univ, Sch Med, Div Reprod Endocrinol & Infertil, Detroit, MI 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-532 BP S302 EP S302 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501311 ER PT J AU Goldman, RH Batsis, M Petrozza, JC Souter, IC AF Goldman, R. H. Batsis, M. Petrozza, J. C. Souter, I. C. TI INDIVIDUALIZED PREDICTIONS FOR CLINICAL PREGNANCY (CPR), MULTIPLE PREGNANCY (MPR), AND SPONTANEOUS ABORTION RATES (SABR) FOLLOWING OVULATION INDUCTION/INTRAUTERINE INSEMINATION (OI/IUI) SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Goldman, R. H.; Batsis, M.; Petrozza, J. C.; Souter, I. C.] Massachusetts Gen Hosp, Boston, MA 02114 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-366 BP S112 EP S112 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500363 ER PT J AU Karmon, AE Toth, TL Afeiche, M Tanrikut, C Hauser, R Chavarro, JE AF Karmon, A. E. Toth, T. L. Afeiche, M. Tanrikut, C. Hauser, R. Chavarro, J. E. TI ALCOHOL AND CAFFEINE INTAKE IN RELATION TO SEMEN PARAMETERS AMONG FERTILITY PATIENTS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Karmon, A. E.; Toth, T. L.; Tanrikut, C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Karmon, A. E.; Toth, T. L.; Tanrikut, C.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Afeiche, M.; Hauser, R.; Chavarro, J. E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-37 BP S12 EP S12 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500038 ER PT J AU Kim, HJ Adams, J Pau, CT Welt, CK AF Kim, H. -J. Adams, J. Pau, C. T. Welt, C. K. TI POLYCYSTIC OVARY MORPHOLOGY: AGE-BASED CRITERIA. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Kim, H. -J.] Konkuk Univ, Sch Med, Chungju, Chungcheongbuk, South Korea. [Adams, J.; Pau, C. T.; Welt, C. K.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-123 BP S38 EP S38 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500124 ER PT J AU Liu, J Lee, GY Toner, M Biggers, JD AF Liu, J. Lee, G. Y. Toner, M. Biggers, J. D. TI BOVINE PREIMPLANTATION EMBRYO CULTURE: IS A SEQUENTIAL PROTOCOL NECESSARY? SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Liu, J.; Lee, G. Y.; Toner, M.; Biggers, J. D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Liu, J.; Lee, G. Y.; Toner, M.; Biggers, J. D.] Shriners Hosp Children, Boston, MA USA. [Biggers, J. D.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-380 BP S256 EP S257 PG 3 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501160 ER PT J AU Maas, KH Su, HI Hall, JE Chang, RJ Joffe, H AF Maas, K. H. Su, H. I. Hall, J. E. Chang, R. J. Joffe, H. TI ANTI-MULLERIAN HORMONE LEVELS FLUCTUATE AFTER DEPOT GNRH AGONIST EXPOSURE IN HEALTHY REPRODUCTIVE-AGED WOMEN. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Maas, K. H.; Su, H. I.; Chang, R. J.] Univ Calif San Diego, Dept Reprod Med, La Jolla, CA 92093 USA. [Hall, J. E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Reprod Endocrine Unit,Dept Med, Boston, MA USA. [Joffe, H.] Harvard Univ, Sch Med, Dept Psychiat, Ctr Womens Mental Hlth,Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-383 BP S117 EP S117 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500380 ER PT J AU Melamed, A Elias, KM Stanic, AK AF Melamed, A. Elias, K. M. Stanic, A. K. TI OVARIAN TORSION IN PATIENTS UNDERGOING FERTILITY TREATMENT: A SINGLE INSTITUTION CASE SERIES SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Melamed, A.; Elias, K. M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Melamed, A.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Stanic, A. K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Fertil Ctr,Vincent Dept Obstet & Gynecol, Boston, MA 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-855 BP S394 EP S394 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554501628 ER PT J AU Souter, I Karmon, A Batsis, M Thatcher, M Wright, D AF Souter, I. Karmon, A. Batsis, M. Thatcher, M. Wright, D. TI SHOULD INFERTILE WOMEN WITH NORMAL TSH LEVELS (< 5.0MIU/L) STRIVE FOR A STRICTER PRECONCEPTION TSH CUT-OFF? THE EFFECTS OF A LOWER TSH THRESHOLD ON THE OUTCOME OF IN-VITRO FERTILIZATION (IVF) CYCLES. SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Souter, I.; Karmon, A.; Batsis, M.; Thatcher, M.; Wright, D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Obstet Gynecol Reprod Endocrinol & Infertil Div, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-1338 BP S533 EP S533 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554502347 ER PT J AU Souter, I Batsis, M Chiu, YH Afeiche, M Hauser, R Chavarro, J AF Souter, I. Batsis, M. Chiu, Y. -H. Afeiche, M. Hauser, R. Chavarro, J. TI THE ASSOCIATION OF PROTEIN INTAKE (PI) AND ANTRAL FOLLICLE COUNT (AFC) AMONG WOMEN UNDERGOING INFERTILITY TREATMENTS SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Souter, I.; Batsis, M.; Hauser, R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Obstet Gynecol Reprod Endocrinol & Infertil Div, Boston, MA USA. [Batsis, M.; Chiu, Y. -H.; Afeiche, M.; Hauser, R.; Chavarro, J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Chavarro, J.] Harvard Univ, Brigham & Womens 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-40 BP S12 EP S13 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500041 ER PT J AU Stanic, AK Karmon, AE McLellan, ST Dickinson, KA Toth, TL Wright, DL AF Stanic, A. K. Karmon, A. E. McLellan, S. T. Dickinson, K. A. Toth, T. L. Wright, D. L. TI PREDICTORS OF CLINICAL TWIN GESTATION AFTER TWO EMBRYO TRANSFER IN FRESH IVF CYCLES SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Stanic, A. K.; Karmon, A. E.; McLellan, S. T.; Dickinson, K. A.; Toth, T. L.; Wright, D. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Fertil Ctr,Vincent Dept Obstet & Gynecol, Boston, MA 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA P-1239 BP S505 EP S505 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554502249 ER PT J AU Stanic, AK Kim, M Rueda, BR Styer, AK AF Stanic, A. K. Kim, M. Rueda, B. R. Styer, A. K. TI THE IMPACT OF DENDRITIC CELL DEPLETION ON THE ESTABLISHMENT OF ENDOMETRIOSIS-LIKE LESIONS IN A MURINE MODEL SO FERTILITY AND STERILITY LA English DT Meeting Abstract CT International-Federation-of-Fertility-Societies 21st World Congress on Fertility and Sterility / 69th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 12-17, 2013 CL Boston, MA SP Int Federat Fertil Soc, Amer Soc Reprod Med C1 [Stanic, A. K.; Kim, M.; Rueda, B. R.; Styer, A. K.] Harvard Univ, Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Vincent Ctr Reprod Biol,Sch Med, Boston, MA 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 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD SEP PY 2013 VL 100 IS 3 SU S MA O-70 BP S22 EP S22 PG 1 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA AQ1PY UT WOS:000342554500071 ER PT J AU Hasegawa, K Chiba, T Hagiwara, Y Watase, H Tsugawa, Y Brown, DFM Camargo, CA AF Hasegawa, Kohei Chiba, Takuyo Hagiwara, Yusuke Watase, Hiroko Tsugawa, Yusuke Brown, David F. M. Camargo, Carlos A., Jr. CA Japanese Emergency Med Network TI Quality of Care for Acute Asthma in Emergency Departments in Japan: A Multicenter Observational Study SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Article DE Acute asthma; Quality of care; Guidelines; Hospitalization; Emergency department AB BACKGROUND: Little is known about the quality of acute asthma care in emergency departments (EDs) outside of North America. OBJECTIVE: We evaluated concordance of acute asthma management in Japanese EDs with recommendations in the 2007 National Institutes of Health asthma guidelines and investigated whether guideline concordance was associated with risk of hospital admission. METHODS: We conducted a multicenter chart review study in 23 EDs across Japan. We identified ED patients aged 18 to 54 years with acute asthma between 2009 and 2011. Concordance with evidence-based guideline recommendations was evaluated by using item-by-item quality measures and composite concordance scores both at patient and ED levels. These scores ranged from 0 to 100. RESULTS: Among 1380 patients, the median age was 35 years and 11% were hospitalized. Overall guideline concordance score was suboptimal both at the patient level (mean +/- SD, 72 +/- 14) and ED level (mean +/- SD, 72 +/- 6). Specifically, asthma care at the patient level was suboptimal in several areas: inhaled anticholinergics in ED (2%), systemic corticosteroid in ED (56%) and at discharge (36%), and peak flow assessment (9%). A multivariable model that adjusted for severity at presentation and several ED characteristics showed that higher guideline concordance was associated with significantly lower risk of hospital admission (odds ratio, 0.70 per 10-unit increase in composite score; 95% CI, 0.62-0.79 per 10-unit increase in composite score). CONCLUSION: The management of acute asthma in Japanese EDs is suboptimal. Greater concordance with guideline-recommended management might reduce unnecessary hospitalizations. Knowledge translation initiatives are warranted to increase adherence with best practice in acute asthma management. (C) 2013 American Academy of Allergy, Asthma & Immunology C1 [Hasegawa, Kohei; Brown, David F. M.; Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Chiba, Takuyo] Obama Municipal Hosp, Dept Emergency Med, Obama, Fukui, Japan. [Hagiwara, Yusuke] Tokyo Metropolitan Childrens Med Ctr, Dept Pediat Emergency & Crit Care Med, Fuchu, Tokyo, Japan. [Watase, Hiroko] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [Tsugawa, Yusuke] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Tsugawa, Yusuke] St Lukes Life Sci Inst, Ctr Clin Epidemiol, Tokyo, Japan. RP Hasegawa, K (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, 326 Cambridge St,Ste 410, Boston, MA 02114 USA. EM khasegawa1@partners.org FU St Luke's Life Science Institute (Tokyo, Japan); National Institutes of Health [U01 AI-87881] FX Supported by a grant from St Luke's Life Science Institute (Tokyo, Japan) and by National Institutes of Health grant U01 AI-87881 (C.A.C.). The study sponsor had no involvement in the study design; in the collection, analysis, and interpretation of data; in the writing of the article; or in the decision to submit the article for publication. NR 38 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD SEP-OCT PY 2013 VL 1 IS 5 BP 509 EP U238 DI 10.1016/j.jaip.2013.05.001 PG 10 WC Allergy; Immunology SC Allergy; Immunology GA V38WX UT WOS:000209374600014 PM 24565623 ER PT J AU Leung, J Guyer, A Banerji, A AF Leung, John Guyer, Autumn Banerji, Aleena TI IgE-mediated hypersensitivity to ondansetron and safe use of palonosetron SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE LA English DT Letter C1 [Leung, John; Guyer, Autumn; Banerji, Aleena] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Rheumatol Immunol & Allergy, Boston, MA USA. RP Banerji, A (reprint author), Allergy Associates, 55 Fruit St,Cox 2, Boston, MA 02114 USA. EM abanerji@partners.org NR 11 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 2213-2198 EI 2213-2201 J9 J ALLER CL IMM-PRACT JI J. Allergy Clin. Immunol.-Pract. PD SEP-OCT PY 2013 VL 1 IS 5 BP 526 EP 527 DI 10.1016/j.jaip.2013.05.004 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA V38WX UT WOS:000209374600020 PM 24565629 ER PT J AU Elson, LC Barr, CJ Chandran, SE Hansen, VJ Malchau, H Kwon, YM AF Elson, Leah C. Barr, Christopher J. Chandran, Shaun E. Hansen, Viktor Johannes Malchau, Henrik Kwon, Young-Min TI Are Morbidly Obese Patients Undergoing Total Hip Arthroplasty at an Increased Risk For Component Malpositioning? SO JOURNAL OF ARTHROPLASTY LA English DT Article DE obesity; total hip arthroplasty; component malpositioning AB Acetabular cup positioning is a critical factor in determining adverse clinical outcomes in THA. This evaluation was performed to determine if morbid obesity (BMI >= 35 kg/m(2)) is a contributing risk factor to cup malpositioning. Two groups of patients were obtained from a local arthroplasty registry and match-controlled for gender, age, and diagnosis (n = 211 morbidly obese; n = 211 normal). Intraoperative data and postoperative AP pelvis and cross-table lateral radiographs were obtained for each patient. The Martell Hip Analysis Suite was used to calculate cup positioning (successful positioning defined as 30 degrees-45 degrees of abduction, and 5 degrees-25 degrees of anteversion), as well as varus-valgus alignment of the femoral stem. There was a significant correlation between morbid obesity with respect to underanteversion; using multivariate analysis, there was a trend toward a combined underanteversion/overabduction of the acetabular cup. Of all variables considered, high BMI was the most significant risk factor leading to malpositioning. (C) 2013 Elsevier Inc. All rights reserved. C1 [Elson, Leah C.; Barr, Christopher J.; Chandran, Shaun E.; Hansen, Viktor Johannes; Malchau, Henrik; Kwon, Young-Min] Massachusetts Gen Hosp, Dept Orthopaed Surg, Harris Orthopaed Lab, Boston, MA 01248 USA. RP Kwon, YM (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St,GRJ 1126, Boston, MA 01248 USA. OI Malchau, Henrik/0000-0002-4291-2441 NR 16 TC 21 Z9 21 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD SEP PY 2013 VL 28 IS 8 SU S BP 41 EP 44 DI 10.1016/j.arth.2013.05.035 PG 4 WC Orthopedics SC Orthopedics GA V40OJ UT WOS:000209487600011 PM 23910510 ER PT J AU Choi, HR Beecher, B Bedair, H AF Choi, Ho-Rim Beecher, Benjamin Bedair, Hany TI Mortality After Septic Versus Aseptic Revision Total Hip Arthroplasty: A Matched-Cohort Study SO JOURNAL OF ARTHROPLASTY LA English DT Article DE total hip arthroplasty; septic revision; mortality AB Mortality rates after revision total hip arthroplasty (THA) for periprosthetic sepsis were investigated in 93 patients and compared to 93 patients, matched for age, gender, year of surgery, who underwent revision for aseptic failures. The mortality rate was 33% (31/93) in the septic group and 22% (20/93) in the aseptic group at 5 and 6 year follow-up, respectively (P = 0.10). Patients in the septic group died on average 6 years earlier (74 versus 80 yrs; P < 0.05) than those in the aseptic group. Charlson Comorbidity Index (CCI) was an independent predictor of mortality among the both groups (P < 0.05), while age (P < 0.01) was a predictor of mortality only in the aseptic group. While revision THA for sepsis alone did not predict increased mortality, a 33% mortality rate at five years in patients with an average age of 66 years and earlier death by 6 years compared to aseptic revisions is alarming. (C) 2013 Elsevier Inc. All rights reserved. C1 [Choi, Ho-Rim; Beecher, Benjamin; Bedair, Hany] Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02114 USA. RP Bedair, H (reprint author), Massachusetts Gen Hosp, Dept Orthoped Surg, 55 Fruit St,Yawkey 3B, Boston, MA 02114 USA. NR 21 TC 9 Z9 10 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD SEP PY 2013 VL 28 IS 8 SU S BP 56 EP 58 DI 10.1016/j.arth.2013.02.041 PG 3 WC Orthopedics SC Orthopedics GA V40OJ UT WOS:000209487600015 PM 23937921 ER PT J AU Choi, HR Kwon, YM Freiberg, AA Malchau, H AF Choi, Ho-Rim Kwon, Young-Min Freiberg, Andrew A. Malchau, Henrik TI Comparison of One-Stage Revision With Antibiotic Cement Versus Two-Stage Revision Results for Infected Total Hip Arthroplasty SO JOURNAL OF ARTHROPLASTY LA English DT Article DE total hip arthroplasty; infection; one-stage revision; two-stage revision; comparison AB Eighty three patients of infected total hip arthroplasty (THA) treated by implant removal and staged revision were retrospectively analyzed. Clinical characteristics and treatment outcomes were compared between three groups: 17 one-stage revisions (one-stage group), 44 two-stage revisions with second stage reimplantation (two-stage reimplanted group), and 22 planned two-stage but no reimplantation (two-stage non-reimplanted group). The rate of infection control was 82% (14/17) in the one-stage group, 75% (33/44) in the two-stage reimplanted group, and 68% (15/22) in the two-stage non-reimplanted group (P = 0.60). The mean of latest Harris hip score was 77, 60, and 58 (P = 0.14), and the UCLA activity score was 4.0, 4.2, and 3.6 (P = 0.74) for each group, respectively. Results of this study suggest that one-stage revision arthroplasty can be a treatment option in selected cases of infected THA with a satisfactory infection control rate and functional outcomes comparable to those of two-stage revision. (C) 2013 Elsevier Inc. All rights reserved. C1 [Choi, Ho-Rim; Kwon, Young-Min; Malchau, Henrik] Massachusetts Gen Hosp, Dept Orthoped Surg, Harris Orthoped Lab, Boston, MA 02114 USA. [Freiberg, Andrew A.] Massachusetts Gen Hosp, Dept Orthoped Surg, Adult Reconstruct Serv, Boston, MA 02114 USA. RP Malchau, H (reprint author), Massachusetts Gen Hosp, Dept Orthoped Surg, Harris Orthoped Lab, 55 Fruit St,GRJ 1126, Boston, MA 02114 USA. OI Malchau, Henrik/0000-0002-4291-2441 NR 23 TC 12 Z9 12 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD SEP PY 2013 VL 28 IS 8 SU S BP 66 EP 70 DI 10.1016/j.arth.2013.02.037 PG 5 WC Orthopedics SC Orthopedics GA V40OJ UT WOS:000209487600017 PM 23972299 ER PT J AU Bedair, H Tetrault, M Choi, HR Mayle, R Bashyal, R Abbot, D Eberhardt, J Sporer, S Della Valle, C AF Bedair, Hany Tetrault, Matthew Choi, Ho-Rim Mayle, Robert Bashyal, Ravi Abbot, Daniel Eberhardt, Jamie Sporer, Scott Della Valle, Craig CA Revision Total Hip Arthroplasty St TI A Comparison of Modular Tapered Versus Modular Cylindrical Stems for Complex Femoral Revisions SO JOURNAL OF ARTHROPLASTY LA English DT Article DE revision total hip arthroplasty; modular femoral components; hip replacement complications; tapered modular stems; cylindrical modular stems; femoral revisions AB The effect of distal geometry in modular stems in revision THA remains unclear. The purpose of this study is to compare femoral revisions with modular tapered versus modular cylindrical stems in high-grade defects. A multicenter review of 105 femoral revisions with Paprosky III/IV defects using modular titanium stems (61 tapered; 44 cylindrical) was performed with an average follow-up of 5 years. Demographic data was comparable between groups. The tapered group had more IIIB and IV defects (51% vs. 20%; P < .01). The failure rate for component osseointegration was 1.6% in the tapered group and 15.9% in the cylindrical group (P = <. 01). The rate of femoral component re-revision for any reason was 4.9% in the tapered group and 22.7% in the cylindrical group (P=. 013). Modular tapered stems were associated with lower rates of stem failure and improved bone ongrowth compared to cylindrical stems despite being used in femurs with greater defects. (C) 2013 Elsevier Inc. All rights reserved. C1 [Bedair, Hany; Choi, Ho-Rim; Bashyal, Ravi; Eberhardt, Jamie] Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. [Tetrault, Matthew; Mayle, Robert; Abbot, Daniel; Sporer, Scott; Della Valle, Craig] Rush Univ, Med Ctr, Dept Orthopaed Surg, Chicago, IL 60612 USA. [Sporer, Scott] Cadence Hlth, Dept Orthopaed Surg, Winfield, IL USA. RP Bedair, H (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, 55 Fruit St, Boston, MA 02114 USA. OI Tetreault, Matthew/0000-0003-3584-9285 NR 11 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0883-5403 EI 1532-8406 J9 J ARTHROPLASTY JI J. Arthroplast. PD SEP PY 2013 VL 28 IS 8 SU S BP 71 EP 73 DI 10.1016/j.arth.2013.04.052 PG 3 WC Orthopedics SC Orthopedics GA V40OJ UT WOS:000209487600018 ER PT J AU Agboola, F McCarthy, T Biddinger, PD AF Agboola, Foluso McCarthy, Tara Biddinger, Paul D. TI Impact of Emergency Preparedness Exercise on Performance SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Article DE exercise evaluation; emergency preparedness exercise; hospital preparedness; performance; emergency preparedness AB The aim of this study was to investigate whether prior participation in preparedness exercises was predictive of better performance on objective measures of response. We conducted a statewide tabletop exercise that focused on a hazardous materials (HAZMAT) scenario and assessed performance using our developed evaluation tool. The evaluative score was analyzed in relation to the number of HAZMAT exercises in the past 3 years, participation in prior CHEMPACK-specific exercise, hospital size, teaching status of the hospital, preparedness training experience, and participants years of experience in preparedness activities. Hospitals that had participated in more exercises in the past 3 years performed significantly better than hospitals that had participated in fewer exercises. No significant differences were found between the performance of hospitals in relation to size, teaching status, preparedness training experience, and participants' years of experience in preparedness activities. Our results suggest that more frequent participation in exercises may result in improved overall response. C1 [Agboola, Foluso; McCarthy, Tara; Biddinger, Paul D.] Harvard Univ, Sch Publ Hlth, Div Policy Translat & Leadership Dev, 677 Huntington Ave, Boston, MA 02115 USA. [Biddinger, Paul D.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Biddinger, Paul D.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Agboola, F (reprint author), Harvard Univ, Sch Publ Hlth, Div Policy Translat & Leadership Dev, 677 Huntington Ave, Boston, MA 02115 USA. EM fagboola@hsph.harvard.edu FU US Centers for Disease Control and Prevention (CDC) Preparedness and Emergency Response Research Center [5PO1TP000307-04] FX The authors acknowledge the funding support from the US Centers for Disease Control and Prevention (CDC) grant number 5PO1TP000307-04 Preparedness and Emergency Response Research Center-Linking Assessment to Measurement and Performance in Public Health Emergency Preparedness Exercises. The content of this publication as well as the views and discussions expressed in this article are solely those of the authors and do not necessarily represent the views of any partner organizations, the CDC, or the US Department of Health & Human Services, nor does mention of trade names, commercial practices, or organizations imply endorsement by the US government. The authors acknowledge the work and commitment of their partners from the Massachusetts Department of Public Health. NR 24 TC 7 Z9 7 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1078-4659 EI 1550-5022 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD SEP-OCT PY 2013 VL 19 SU 2 BP S77 EP S83 DI 10.1097/PHH.0b013e31828ecd84 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V43KM UT WOS:000209680300018 PM 23903400 ER PT J AU Orellana, G Alvarado, L Munoz-Neira, C Avila, R Mendez, MF Slachevsky, A AF Orellana, Gricel Alvarado, Luis Munoz-Neira, Carlos Avila, Rodrigo Mendez, Mario F. Slachevsky, Andrea TI Psychosis-Related Matricide Associated With a Lesion of the Ventromedial Prefrontal Cortex SO JOURNAL OF THE AMERICAN ACADEMY OF PSYCHIATRY AND THE LAW LA English DT Article ID LATE-ONSET SCHIZOPHRENIA; PSYCHOPATHY; DELUSIONS; BRAIN; NEUROPSYCHIATRY; CONFABULATION; VIOLATIONS; RETRIEVAL; JUDGMENT; INJURY AB Matricide, the killing of a mother by her biological child, is a rare event. We report a case of matricide associated with a woman who sustained a right ventromedial prefrontal lesion during surgery for nasal polyposis that was performed when she was 40 years old. After her surgery, she developed psychotic symptoms associated with the emergence of antisocial behavior. She committed matricide 22 years later. Neuropsychological evaluation showed decreased frontal-executive deficits, and magnetic resonance imaging revealed a lesion in the right gyrus rectus area of the ventromedial prefrontal region. This case suggests that a secondary psychotic syndrome associated with a lesion in the frontal neural network, which is disturbed in psychopathy, could facilitate homicidal behavior. Furthermore, this case has legal implications for the prosecution of murder associated with a brain lesion. C1 [Orellana, Gricel] Univ Chile, Fac Med, Dept Psiquiatria Oriente, Santiago, Chile. [Alvarado, Luis] Univ Chile, Fac Ciencias Sociales, Dept Psicol, Santiago, Chile. [Alvarado, Luis] Univ Chile, Fac Med, Dept Psiquiatria Oriente, Santiago, Chile. [Munoz-Neira, Carlos; Slachevsky, Andrea] Hosp Salvador, Unidad Neurol Cognit & Demencias, Serv Neurol, Santiago, Chile. [Avila, Rodrigo] Hosp Salvador, Serv Psiquiatria, Santiago, Chile. [Mendez, Mario F.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Mendez, Mario F.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Mendez, Mario F.] VA Greater Los Angeles Healthcare Ctr, Los Angeles, CA USA. [Slachevsky, Andrea] Univ Chile, Dept Neurol Oriente, Santiago, Chile. [Slachevsky, Andrea] Univ Chile, Programa Farmacol Mol & Clin, ICBM, Fac Med, Santiago, Chile. [Slachevsky, Andrea] Clin Alemana, Santiago, Chile. RP Slachevsky, A (reprint author), Univ Chile, Ctr Invest Avanzada Educ, Periodista Jose Carrasco Tapia 75, Santiago, Chile. EM aslachevsky@me.com RI Alvarado, L./F-7134-2014 OI Alvarado, L./0000-0002-8219-9476 FU NIA NIH HHS [R01AG034499-03] NR 42 TC 1 Z9 1 U1 6 U2 11 PU AMER ACAD PSYCHIATRY & LAW PI BLOOMFIELD PA ONE REGENCY DR, PO BOX 30, BLOOMFIELD, CT 06002 USA SN 1093-6793 EI 1943-3662 J9 J AM ACAD PSYCHIATRY JI J. Am. Acad. Psychiatry Law PD SEP 1 PY 2013 VL 41 IS 3 BP 401 EP 406 PG 6 WC Law; Psychiatry SC Government & Law; Psychiatry GA AN8LT UT WOS:000340856400010 PM 24051593 ER PT J AU Greysen, SR Horwitz, LI Covinsky, KE Gordon, K Ohl, ME Justice, AC AF Greysen, S. Ryan Horwitz, Leora I. Covinsky, Kenneth E. Gordon, Kirsha Ohl, Michael E. Justice, Amy C. TI Does Social Isolation Predict Hospitalization and Mortality Among HIV+ and Uninfected Older Veterans? SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE social isolation; outcomes of care; mortality; aging; hospitalization; HIV/AIDS ID LONG-TERM-CARE; ALCOHOL-CONSUMPTION; AFRICAN-AMERICANS; FOLLOW-UP; ADULTS; SUPPORT; HEALTH; COHORT; WOMEN; RISK AB Objectives To compare levels of social isolation in aging veterans with and without the human immunodeficiency virus (HIV) and determine associations with hospital admission and mortality. Design Longitudinal data analysis. Setting The Veterans Aging Cohort Study (VACS), at eight VA Medical Centers nationally. Participants Veterans aged 55 and older enrolled in VACS from 2002 to 2008 (N = 1,836). Measurements A Social Isolation Score (SIS) was created using baseline survey responses about relationship status; number of friends and family and frequency of visits; and involvement in volunteer work, religious or self-help groups, and other community activities. Scores were compared according to age and HIV status, and multivariable regression was used to assess effects of SIS on hospital admission and all-cause mortality. Results Mean SIS was higher for HIV-positive (HIV+) individuals, with increasing difference according to age (P = .01 for trend). Social isolation was also more prevalent for HIV+ (59%) than uninfected participants (51%, P < .001). In multivariable regression analysis of HIV+ and uninfected groups combined, adjusted for demographic and clinical features, isolation was independently associated with greater risk of incident hospitalization (hazard rate (HR) = 1.25, 95% confidence interval (CI) = 1.09-1.42) and risk of all-cause mortality (HR=1.28, 95% CI = 1.06-1.54). Risk estimates calculated for HIV+ and uninfected groups separately were not significantly different. Conclusion Social isolation is associated with greater risk of hospitalization and death in HIV+ and uninfected older veterans. Despite similar effects in both groups, the population-level effect of social isolation may be greater in those who are HIV+ because of the higher prevalence of social isolation, particularly in the oldest individuals. C1 [Greysen, S. Ryan] Univ Calif San Francisco, Div Hosp Med, San Francisco, CA 94113 USA. [Horwitz, Leora I.; Justice, Amy C.] Yale Univ, Sch Med, Div Gen Internal Med, New Haven, CT USA. [Covinsky, Kenneth E.] Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94113 USA. [Covinsky, Kenneth E.] San Francisco VA Med Ctr, San Francisco, CA USA. [Gordon, Kirsha; Justice, Amy C.] W Haven Vet Affairs Med Ctr, West Haven, CT USA. [Ohl, Michael E.] Univ Iowa, Sch Med, Div Infect Dis, Iowa City, IA 52242 USA. RP Greysen, SR (reprint author), Univ Calif San Francisco, Div Hosp Med, 533 Parnassus Ave,Box 0131, San Francisco, CA 94113 USA. EM Ryan.Greysen@ucsf.edu OI Horwitz, Leora/0000-0003-1800-6040 FU Robert Wood Johnson Foundation; U.S. Department of Veterans Affairs; National Institute on Aging [K08 AG038336]; American Federation for Aging FX The authors would like to thank the Robert Wood Johnson Foundation Clinical Scholars program and U.S. Department of Veterans Affairs for funding support. Dr. Horwitz is supported by the National Institute on Aging (K08 AG038336) and the American Federation for Aging Research through the Paul B. Beeson Career Development Award Program. NR 57 TC 10 Z9 11 U1 1 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2013 VL 61 IS 9 BP 1456 EP 1463 DI 10.1111/jgs.12410 PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 216TL UT WOS:000324307200003 PM 23927911 ER PT J AU Bouchard, R Chong, T Pugazhenthi, S AF Bouchard, Ron Chong, Thomas Pugazhenthi, Subbiah TI Laser Capture Microdissection of Neurons from Differentiated Human Neuroprogenitor Cells in Culture SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Neuroscience; Issue 79; Neurobiology; Cellular Biology; Cells; Cultured; Neurons; Central Nervous System; Neurodegenerative Diseases; Human neuroprogenitor cells; neuronal differentiation; neuronal markers; astrocytes; laser capture microdissection; PEN membrane slides; cell culture AB Neuroprogenitor cells (NPCs) isolated from the human fetal brain were expanded under proliferative conditions in the presence of epidermal growth factor (EGF) and fibroblast growth factor (FGF) to provide an abundant supply of cells. NPCs were differentiated in the presence of a new combination of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), dibutyryl cAMP (DBC) and retinoic acid on dishes coated with poly-L-lysine and mouse laminin to obtain neuron-rich cultures. NPCs were also differentiated in the absence of neurotrophins, DBC and retinoic acid and in the presence of ciliary neurotrophic factor (CNTF) to yield astrocyte-rich cultures. Differentiated NPCs were characterized by immunofluorescence staining for a panel of neuronal markers including NeuN, synapsin, acetylcholinesterase, synaptophysin and GAP43. Glial fibrillary acidic protein (GFAP) and STAT3, astrocyte markers, were detected in 10-15% of differentiated NPCs. To facilitate cell-type specific molecular characterization, laser capture microdissection was performed to isolate neurons cultured on polyethylene naphthalate (PEN) membrane slides. The methods described in this study provide valuable tools to advance our understanding of the molecular mechanism of neurodegeneration. C1 [Bouchard, Ron; Chong, Thomas; Pugazhenthi, Subbiah] Denver VA Med Ctr, Endocrinol Sect, Denver, CO 80220 USA. [Bouchard, Ron; Chong, Thomas; Pugazhenthi, Subbiah] Univ Colorado Denver Sch Med, Dept Med, Denver, CO 80204 USA. RP Pugazhenthi, S (reprint author), Denver VA Med Ctr, Endocrinol Sect, Denver, CO 80220 USA. EM Subbiah.Pugazhenthi@ucdenver.edu FU Merit Review grant from the Veterans Administration [NEUD-004-07F] FX This work was supported by Merit Review grant (NEUD-004-07F) from the Veterans Administration (to S.P). NR 15 TC 0 Z9 0 U1 0 U2 1 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD SEP PY 2013 IS 79 AR UNSP e50487 DI 10.3791/50487 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RI UT WOS:000209228100011 PM 24084642 ER PT J AU Gfrerer, L Dougherty, M Liao, EC AF Gfrerer, Lisa Dougherty, Max Liao, Eric C. TI Visualization of Craniofacial Development in the sox10: kaede Transgenic Zebrafish Line Using Time-lapse Confocal Microscopy SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Developmental Biology; Issue 79; Craniofacial Abnormalities; Jaw Abnormalities; Cleft Palate; Craniofacial Abnormalities; Maxillofacial Abnormalities; Reconstructive Surgical Procedures; Developmental Biology; Embryology; Congenital; Hereditary; Neonatal Diseases and Abnormalities; Craniofacial development; cranial neural crest; confocal microscopy; fate mapping; cell lineage analysis; sox10; kaede; photoconversion; zebrafish; palate AB Vertebrate palatogenesis is a highly choreographed and complex developmental process, which involves migration of cranial neural crest (CNC) cells, convergence and extension of facial prominences, and maturation of the craniofacial skeleton. To study the contribution of the cranial neural crest to specific regions of the zebrafish palate a sox10: kaede transgenic zebrafish line was generated. Sox10 provides lineage restriction of the kaede reporter protein to the neural crest, thereby making the cell labeling a more precise process than traditional dye or reporter mRNA injection. Kaede is a photo-convertible protein that turns from green to red after photo activation and makes it possible to follow cells precisely. The sox10: kaede transgenic line was used to perform lineage analysis to delineate CNC cell populations that give rise to maxillary versus mandibular elements and illustrate homology of facial prominences to amniotes. This protocol describes the steps to generate a live time-lapse video of a sox10: kaede zebrafish embryo. Development of the ethmoid plate will serve as a practical example. This protocol can be applied to making a time-lapse confocal recording of any kaede or similar photoconvertible reporter protein in transgenic zebrafish. Furthermore, it can be used to capture not only normal, but also abnormal development of craniofacial structures in the zebrafish mutants. C1 [Gfrerer, Lisa; Dougherty, Max; Liao, Eric C.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. RP Gfrerer, L (reprint author), Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. EM lisa.gfrerer@gmail.com NR 15 TC 2 Z9 2 U1 1 U2 6 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD SEP PY 2013 IS 79 AR UNSP e50525 DI 10.3791/50525 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RI UT WOS:000209228100013 PM 24121214 ER PT J AU Matsumoto, H Miller, JW Vavvas, DG AF Matsumoto, Hidetaka Miller, Joan W. Vavvas, Demetrios G. TI Retinal Detachment Model in Rodents by Subretinal Injection of Sodium Hyaluronate SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Medicine; Issue 79; Photoreceptor Cells; Rodentia; Retinal Degeneration; Retinal Detachment; animal models; Neuroscience; ophthalmology; retina; mouse; photoreceptor cell death; retinopathy; age-related macular degeneration (AMD) AB Subretinal injection of sodium hyaluronate is a widely accepted method of inducing retinal detachment (RD). However, the height and duration of RD or the occurrence of subretinal hemorrhage can affect photoreceptor cell death in the detached retina. Hence, it is advantageous to create reproducible RDs without subretinal hemorrhage for evaluating photoreceptor cell death. We modified a previously reported method to create bullous and persistent RDs in a reproducible location with rare occurrence of subretinal hemorrhage. The critical step of this modified method is the creation of a self-sealing scleral incision, which can prevent leakage of sodium hyaluronate after injection into the subretinal space. To make the self-sealing scleral incision, a scleral tunnel is created, followed by scleral penetration into the choroid with a 30 G needle. Although choroidal hemorrhage may occur during this step, astriction with a surgical spear reduces the rate of choroidal hemorrhage. This method allows a more reproducible and reliable model of photoreceptor death in diseases that involve RD such as rhegmatogenous RD, retinopathy of prematurity, diabetic retinopathy, central serous chorioretinopathy, and age-related macular degeneration (AMD). C1 [Matsumoto, Hidetaka; Miller, Joan W.; Vavvas, Demetrios G.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Cambridge, MA 02138 USA. RP Matsumoto, H (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Cambridge, MA 02138 USA. EM hide-m@gunma-u.ac.jp; Demetrios_Vavvas@meei.harvard.edu OI Vavvas, Demetrios/0000-0002-8622-6478 FU Bausch & Lomb Vitreoretinal Fellowship; National Eye Institute [EY014104]; Research to Prevent Blindness Foundation; Lions Eye Research Fund FX We thank Wendy Chao for her support in critical review. This work was supported by Bausch & Lomb Vitreoretinal Fellowship (HM), National Eye Institute grant EY014104 (JWM), Research to Prevent Blindness Foundation (DGV), Lions Eye Research Fund (DGV), and a generous donation of the Yeatts family (JWM and DGV). NR 25 TC 3 Z9 3 U1 0 U2 1 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD SEP PY 2013 IS 79 AR UNSP e50660 DI 10.3791/50660 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RI UT WOS:000209228100038 ER PT J AU Tassa, C Liong, M Hilderbrand, S Sandler, JE Reiner, T Keliher, EJ Weissleder, R Shaw, SY AF Tassa, Carlos Liong, Monty Hilderbrand, Scott Sandler, Jason E. Reiner, Thomas Keliher, Edmund J. Weissleder, Ralph Shaw, Stanley Y. TI Microfluidic On-chip Capture-cycloaddition Reaction to Reversibly Immobilize Small Molecules or Multi-component Structures for Biosensor Applications SO JOVE-JOURNAL OF VISUALIZED EXPERIMENTS LA English DT Article DE Chemistry; Issue 79; Organic Chemicals; Macromolecular Substances; Chemistry and Materials (General); Surface Plasmon Resonance; Bioorthogonal Chemistry; Diels-Alder Cycloaddition Reaction; Small Molecule Immobilization; Binding Kinetics; Immobilized Nanoparticles AB Methods for rapid surface immobilization of bioactive small molecules with control over orientation and immobilization density are highly desirable for biosensor and microarray applications. In this Study, we use a highly efficient covalent bioorthogonal [4+2] cycloaddition reaction between trans-cyclooctene (TCO) and 1,2,4,5-tetrazine (Tz) to enable the microfluidic immobilization of TCO/Tz-derivatized molecules. We monitor the process in real-time under continuous flow conditions using surface plasmon resonance (SPR). To enable reversible immobilization and extend the experimental range of the sensor surface, we combine a non-covalent antigen-antibody capture component with the cycloaddition reaction. By alternately presenting TCO or Tz moieties to the sensor surface, multiple capture-cycloaddition processes are now possible on one sensor surface for on-chip assembly and interaction studies of a variety of multi-component structures. We illustrate this method with two different immobilization experiments on a biosensor chip; a small molecule, AP1497 that binds FK506-binding protein 12 (FKBP12); and the same small molecule as part of an immobilized and in situ-functionalized nanoparticle. C1 [Tassa, Carlos; Liong, Monty; Hilderbrand, Scott; Sandler, Jason E.; Reiner, Thomas; Keliher, Edmund J.; Weissleder, Ralph; Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu; Shaw.Stanley@mgh.harvard.edu OI Reiner, Thomas/0000-0002-7819-5480 FU NIH (NHLBI) [HHSN268201000044C] FX We acknowledge funding from NIH (NHLBI Contract No. HHSN268201000044C to R.W., S.H. and S.Y.S.). NR 24 TC 0 Z9 0 U1 3 U2 18 PU JOURNAL OF VISUALIZED EXPERIMENTS PI CAMBRIDGE PA 1 ALEWIFE CENTER, STE 200, CAMBRIDGE, MA 02140 USA SN 1940-087X J9 JOVE-J VIS EXP JI J. Vis. Exp. PD SEP PY 2013 IS 79 AR UNSP e50772 DI 10.3791/50772 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V36RI UT WOS:000209228100050 PM 24084440 ER PT J AU Kalapatapu, RK Delucchi, KL Lasher, BA Vinogradov, S Batki, SL AF Kalapatapu, Raj K. Delucchi, Kevin L. Lasher, Brooke A. Vinogradov, Sophia Batki, Steven L. TI Alcohol Use Biomarkers Predicting Cognitive Performance: A Secondary Analysis in Veterans With Alcohol Dependence and Posttraumatic Stress Disorder SO MILITARY MEDICINE LA English DT Article ID SUBSTANCE USE DISORDERS; GAMMA-GLUTAMYL-TRANSFERASE; LIVER-FUNCTION; NEUROPSYCHOLOGICAL IMPAIRMENT; ABUSING PATIENTS; TREATMENT ENTRY; DEPRESSION; ABUSERS; DICHOTOMIZATION; ABILITIES AB Objective: We conducted a secondary analysis of baseline data from a recently completed pharmacological pilot clinical trial among 30 veterans with alcohol dependence and posttraumatic stress disorder (PTSD). This trial included baseline measures of alcohol use biomarkers, both indirect (carbohydrate-deficient transferrin, GGT [gamma-glutamyltransferase], mean corpuscular volume, AST [aspartate aminotransferase], alanine aminotransferase) and direct (ethyl glucuronide, ethyl sulfate), as well as neurocognitive measures (Trail Making Test parts A and B, Hopkins Verbal Learning Test-Revised, Balloon Analogue Risk Task, Delay Discounting Task). Methods: Two regression models were estimated and tested for each neurocognitive measure (dependent measure). The first model included the alcohol use biomarker alone as the predictor. The second model included the alcohol use biomarker along with the following 3 additional predictors: Beck Depression Inventory, Clinician-Administered PTSD Scale, and receiving medications. Results: In both models, the indirect biomarkers, such as GGT and AST, significantly predicted performance on the Hopkins Verbal Learning Test-Revised %Retention. GGT alone significantly predicted performance on the Trail Making Test part A. Conclusions: Indirect alcohol use biomarkers may have a specific role in identifying those veterans with alcohol dependence and PTSD who have impaired cognitive performance. However, direct alcohol use biomarkers may not share such a role. C1 [Kalapatapu, Raj K.; Delucchi, Kevin L.; Vinogradov, Sophia; Batki, Steven L.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Kalapatapu, Raj K.; Lasher, Brooke A.; Vinogradov, Sophia; Batki, Steven L.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Lasher, Brooke A.; Vinogradov, Sophia; Batki, Steven L.] Northern Calif Inst Res & Educ, San Francisco, CA 94121 USA. RP Kalapatapu, RK (reprint author), Univ Calif San Francisco, Dept Psychiat, 401 Parnassus Ave, San Francisco, CA 94143 USA. FU Department of Defense [W81XWH-05-2-0094]; National Center for Research Resources; National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI [UL1 RR024131]; [K23DA034883] FX This study was supported by the Department of Defense Grant Number W81XWH-05-2-0094 (PI: Batki), which was given by the Northern California Institute for Research and Education, and with resources of the Veterans Affairs Medical Center, San Francisco, California. Dr. Kalapatapu is currently funded by K23DA034883. This project was also supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1 RR024131. NR 62 TC 2 Z9 2 U1 6 U2 10 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD SEP PY 2013 VL 178 IS 9 BP 974 EP 980 DI 10.7205/MILMED-D-13-00097 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA AN7UC UT WOS:000340805500013 PM 24005546 ER PT J AU Spangler, M Hawley, H Barnes, N Saxena, S AF Spangler, Mikayla Hawley, Heather Barnes, Nicole Saxena, Shailendra TI A Review of Guidelines and Pharmacologic Options for Asthma Treatment, With a Focus on Exercise-Induced Bronchoconstriction SO PHYSICIAN AND SPORTSMEDICINE LA English DT Article DE asthma; treatment; quick relief; long-term control; exacerbation; exercise-induced asthma ID ACTING BETA-AGONISTS; METAANALYSIS AB Asthma affects millions of individuals worldwide. Exercise-induced bronchoconstriction is common in patients diagnosed with asthma, but may also occur in patients without chronic asthma. Patients with isolated exercise-induced bronchoconstriction may require pretreatment with inhaled short-acting beta-agonists prior to exercise. Patients diagnosed with asthma can achieve good control of the symptoms of exercise-induced bronchoconstriction with appropriate treatment of underlying chronic asthma. Current guidelines suggest staging patients with asthma based on severity of symptoms and initiating therapy according to their stage. Pharmacotherapy for asthma management consists of both quick-relief medications (short-acting beta-agonists) as well as maintenance, or long-term control, medications (inhaled corticosteroids, long-acting beta-agonists, leukotriene receptor antagonists, cromolyn, and theophylline). C1 [Spangler, Mikayla] Creighton Univ, Sch Pharm & Hlth Profess, Omaha, NE 68178 USA. [Spangler, Mikayla] Creighton Univ, Sch Med, Dept Family Practice, Omaha, NE 68178 USA. [Hawley, Heather] William S Middleton Mem Vet Adm Med Ctr, PGY Ambulatory Care Pharm Resident 2, Madison, WI USA. [Barnes, Nicole] San Antonio Mil Med Ctr, San Antonio, TX USA. [Saxena, Shailendra] Creighton Univ, Sch Med, Dept Family Practice, Omaha, NE USA. RP Spangler, M (reprint author), Creighton Univ, Sch Pharm & Hlth Profess, Omaha, NE 68178 USA. NR 18 TC 4 Z9 4 U1 0 U2 3 PU JTE MULTIMEDIA PI WEST CONSHOHOCKEN PA 18 ELIZABETH ST, STE 110, WEST CONSHOHOCKEN, PA 19428 USA SN 0091-3847 J9 PHYSICIAN SPORTSMED JI Physician Sportsmed. PD SEP PY 2013 VL 41 IS 3 BP 50 EP 57 DI 10.3810/psm.2013.09.2024 PG 8 WC Primary Health Care; Orthopedics; Sport Sciences SC General & Internal Medicine; Orthopedics; Sport Sciences GA AR2FA UT WOS:000343397800005 PM 24113702 ER PT J AU Schunemann, HJ Tugwell, P Reeves, BC Akl, EA Santesso, N Spencer, FA Shea, B Wells, G Helfand, M AF Schuenemann, Holger J. Tugwell, Peter Reeves, Barnaby C. Akl, Elie A. Santesso, Nancy Spencer, Frederick A. Shea, Beverley Wells, George Helfand, Mark TI Non-randomized studies as a source of complementary, sequential or replacement evidence for randomized controlled trials in systematic reviews on the effects of interventions (vol 4, pg 49, 2013) SO RESEARCH SYNTHESIS METHODS LA English DT Correction C1 [Schuenemann, Holger J.; Akl, Elie A.; Santesso, Nancy] McMaster Univ, Dept Clin Epidemiol & Biostat, Hamilton, ON L8S 4K1, Canada. [Schuenemann, Holger J.; Spencer, Frederick A.] McMaster Univ, Dept Med, Hamilton, ON L8S 4K1, Canada. [Tugwell, Peter; Shea, Beverley] Ottawa Hosp, Ottawa Hosp Res Inst, Clin Epidemiol Unit, Ottawa, ON, Canada. [Tugwell, Peter; Wells, George] Univ Ottawa, Dept Med, Ottawa, ON, Canada. [Tugwell, Peter] Ctr Global Hlth, Inst Populat Hlth, Ottawa, ON, Canada. [Reeves, Barnaby C.] Univ Bristol, Bristol Royal Infirm, Bristol Heart Inst, Bristol, Avon, England. [Akl, Elie A.] Amer Univ Beirut, Dept Internal Med, Beirut, Lebanon. [Helfand, Mark] Oregon Hlth & Sci Univ, Portland VA Med Ctr, Portland, OR 97201 USA. [Helfand, Mark] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Wells, George] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON K1N 6N5, Canada. RP Schunemann, HJ (reprint author), McMaster Univ, Dept Clin Epidemiol & Biostat, Hlth Sci Ctr, Room 2C10B,1280 Main St West, Hamilton, ON L8S 4K1, Canada. EM schuneh@mcmaster.ca NR 1 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1759-2879 EI 1759-2887 J9 RES SYNTH METHODS JI Res. Synth. Methods PD SEP PY 2013 VL 4 IS 3 BP 289 EP 289 PG 1 WC Mathematical & Computational Biology; Multidisciplinary Sciences SC Mathematical & Computational Biology; Science & Technology - Other Topics GA V38ZP UT WOS:000209381600011 ER PT J AU Wang, HE Wells, JM Rizk, DV AF Wang, Henry E. Wells, James M. Rizk, Dana V. TI Bullous Lesions After Use of a Commercial Therapeutic Hypothermia Temperature Management System: A Possible Burn Injury? SO THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT LA English DT Article AB Therapeutic hypothermia (TH) is a novel technique for improving the likelihood of survival with good neurologic outcome after cardiopulmonary arrest. While commercial temperature management systems (TMS) are intended to facilitate cooling of the body during TH, their operation also involves body exposure to heat. We describe the case of a 72-year-old female postarrest patient who underwent TH using a commercial water-circulating TMS and concurrent continuous renal replacement therapy. The patient developed bullous lesions on the thigh and torso suspected to constitute a scald burn injury from the TMS. Clinicians must be aware of this important adverse event when providing TH, especially in the setting of concurrent hemodialysis therapy. C1 [Wang, Henry E.] Univ Alabama Birmingham, Dept Emergency Med, Sch Med, Birmingham, AL 35249 USA. [Wells, James M.] Univ Alabama Birmingham, Dept Med, Sch Med, Div Pulm & Crit Care Med, Birmingham, AL 35249 USA. [Wells, James M.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Rizk, Dana V.] Univ Alabama Birmingham, Dept Med, Sch Med, Div Nephrol, Birmingham, AL 35249 USA. RP Wang, HE (reprint author), Univ Alabama Birmingham, Dept Emergency Med, 619 19th St South OHB 251, Birmingham, AL 35249 USA. EM hwang@uabmc.edu NR 22 TC 3 Z9 3 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-7658 EI 2153-7933 J9 THER HYPOTHERMIA TEM JI Ther. Hypothermia Temp. Manag. PD SEP 1 PY 2013 VL 3 IS 3 BP 147 EP 150 DI 10.1089/ther.2013.0013 PG 4 WC Critical Care Medicine SC General & Internal Medicine GA V38PI UT WOS:000209354900010 ER PT J AU Guanci, MM AF Guanci, Mary McKenna TI University of Pennsylvania web question: Has anyone determined the best practice for the patient who may have been cooled after a code and then codes again? Are you recooling the patient? How long should the patient be recooled? SO THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Guanci, MM (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 2153-7658 EI 2153-7933 J9 THER HYPOTHERMIA TEM JI Ther. Hypothermia Temp. Manag. PD SEP 1 PY 2013 VL 3 IS 3 BP 152 EP 152 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA V38PI UT WOS:000209354900012 ER PT J AU Kinnaman, KA Mannix, RC Comstock, RD Meehan, WP AF Kinnaman, Karen A. Mannix, Rebekah C. Comstock, R. Dawn Meehan, William P., III TI Management strategies and medication use for treating paediatric patients with concussions SO ACTA PAEDIATRICA LA English DT Article DE Concussion; Medication management; Paediatric patient ID TRAUMATIC BRAIN-INJURY; POST-CONCUSSION; SPORT; PHYSICIANS; KNOWLEDGE; PROVIDERS; MEDICINE AB Aim: To assess management strategies for paediatric patients suffering from concussions. Methods: A 17-item questionnaire was distributed to 1305 section members of the American Academy of Pediatrics Sections on Adolescent Health, Sports Medicine and Fitness, Community Pediatrics and School Health. The use of medications, neuropsychological testing, neuroimaging and published guidelines in concussion management was queried. Results: Two hundred and twenty respondents (17%) completed the questionnaire, of which 64% had been an attending for greater than 10 years. A majority of respondents (92%) managed patients with concussions, with 26% treating more than 24 patients per year. Most paediatricians (84%) reported using a published guideline. The majority of respondents (89%) manage the symptoms of concussed patients with medications, most commonly acetaminophen (62%) or nonsteroidal anti-inflammatory medications (54%). The use of prescriptions medications such as tricyclic antidepressants (23%), amantadine (10%) and methylphenidate (8%) was also commonly reported. Paediatricians treating > 16 patients per year with concussion were more likely to prescribe tricyclic antidepressants, stimulants and agents used for sleep disturbance. Conclusion: Paediatricians nationwide routinely use medications when managing patients with concussions. The pharmacological agents used differ according to number of patients treated per year. In addition, most paediatricians use published guidelines in concussion management. C1 [Kinnaman, Karen A.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Kinnaman, Karen A.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Mannix, Rebekah C.; Meehan, William P., III] Harvard Univ, Sch Med, Boston Childrens Hosp, Div Emergency Med, Boston, MA USA. [Mannix, Rebekah C.] Harvard Univ, Sch Med, Boston Childrens Hosp, Brain Injury Ctr, Boston, MA USA. [Comstock, R. Dawn] Colorado Sch Publ Hlth, Dept Epidemiol, Aurora, CO USA. [Meehan, William P., III] Harvard Univ, Sch Med, Div Sports Med, Boston Childrens Hosp, Boston, MA USA. [Meehan, William P., III] Harvard Univ, Sch Med, Sports Concuss Clin, Boston Childrens Hosp, Boston, MA USA. [Meehan, William P., III] Micheli Ctr Sports Injury & Prevent, Waltham, MA USA. RP Kinnaman, KA (reprint author), Brigham & Womens Hosp, Dept Emergency Med, 75 Francis St,Neville House 2nd Floor, Boston, MA 02115 USA. EM kkinnaman@partners.org NR 22 TC 11 Z9 11 U1 0 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD SEP PY 2013 VL 102 IS 9 BP E424 EP E428 DI 10.1111/apa.12315 PG 5 WC Pediatrics SC Pediatrics GA 193YV UT WOS:000322598300010 PM 23750873 ER PT J AU Choe, MS Ortiz-Mantilla, S Makris, N Gregas, M Bacic, J Haehn, D Kennedy, D Pienaar, R Caviness, VS Benasich, AA Grant, PE AF Choe, Myong-sun Ortiz-Mantilla, Silvia Makris, Nikos Gregas, Matt Bacic, Janine Haehn, Daniel Kennedy, David Pienaar, Rudolph Caviness, Verne S., Jr. Benasich, April A. Grant, P. Ellen TI Regional Infant Brain Development: An MRI-Based Morphometric Analysis in 3 to 13 Month Olds SO CEREBRAL CORTEX LA English DT Article DE brain development; infant; MRI; volumetric analysis ID CEREBRAL WHITE-MATTER; AUTISM SPECTRUM DISORDERS; MAGNETIC-RESONANCE; SEXUAL-DIMORPHISM; NEONATAL BRAIN; TOPOGRAPHIC PARCELLATION; HEMISPHERIC-ASYMMETRY; VOLUMETRIC-ANALYSIS; CAUDATE-NUCLEUS; EARLY-CHILDHOOD AB Elucidation of infant brain development is a critically important goal given the enduring impact of these early processes on various domains including later cognition and language. Although infants whole-brain growth rates have long been available, regional growth rates have not been reported systematically. Accordingly, relatively less is known about the dynamics and organization of typically developing infant brains. Here we report global and regional volumetric growth of cerebrum, cerebellum, and brainstem with gender dimorphism, in 33 cross-sectional scans, over 3 to 13 months, using T-1-weighted 3-dimensional spoiled gradient echo images and detailed semi-automated brain segmentation. Except for the midbrain and lateral ventricles, all absolute volumes of brain regions showed significant growth, with 6 different patterns of volumetric change. When normalized to the whole brain, the regional increase was characterized by 5 differential patterns. The putamen, cerebellar hemispheres, and total cerebellum were the only regions that showed positive growth in the normalized brain. Our results show region-specific patterns of volumetric change and contribute to the systematic understanding of infant brain development. This study greatly expands our knowledge of normal development and in future may provide a basis for identifying early deviation above and beyond normative variation that might signal higher risk for neurological disorders. C1 [Choe, Myong-sun; Haehn, Daniel; Pienaar, Rudolph; Grant, P. Ellen] Harvard Univ, Sch Med, Childrens Hosp Boston, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. [Choe, Myong-sun; Grant, P. Ellen] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Newborn Med,Dept Med, Boston, MA USA. [Choe, Myong-sun; Makris, Nikos; Kennedy, David; Caviness, Verne S., Jr.] Harvard Univ, Sch Med, Dept Neurol, Ctr Morphometr Anal,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Gregas, Matt; Bacic, Janine] Harvard Univ, Sch Med, Dept Neurol, Clin Res Program,Childrens Hosp Boston, Boston, MA 02115 USA. [Choe, Myong-sun; Pienaar, Rudolph; Grant, P. Ellen] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA USA. [Haehn, Daniel; Pienaar, Rudolph; Grant, P. Ellen] Harvard Univ, Sch Med, Dept Radiol, Div Neuroradiol,Childrens Hosp Boston, Boston, MA 02115 USA. [Ortiz-Mantilla, Silvia; Benasich, April A.] Rutgers State Univ, Ctr Mol & Behav Neurosci, Dept Neurosci, Newark, NJ 07102 USA. [Kennedy, David] Univ Massachusetts, Sch Med, Dept Psychiat, Child & Adolescent NeuroDev Initiat CANDI, Worcester, MA 01655 USA. RP Grant, PE (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston, MA 02115 USA. EM ellen.grant@childrens.harvard.edu OI Benasich, April A/0000-0002-5137-776X FU Thrasher Research Fund; Santa Fe Institute Consortium; William Randolph Hearst Fund of Harvard University; NIH [K23NS042758, R21EB008547]; NSF [SBE-0542013]; Elizabeth H. Solomon Center for Neurodevelopmental Research FX This research was supported by the Thrasher Research Fund, the Santa Fe Institute Consortium, the William Randolph Hearst Fund of Harvard University, NIH K23NS042758, NIH R21EB008547 and by NSF #SBE-0542013 (to the Temporal Dynamics of Learning Center) with additional funding from the Elizabeth H. Solomon Center for Neurodevelopmental Research. NR 105 TC 15 Z9 15 U1 1 U2 21 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD SEP PY 2013 VL 23 IS 9 BP 2100 EP 2117 DI 10.1093/cercor/bhs197 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 194VP UT WOS:000322661100008 PM 22772652 ER PT J AU Paintlia, AS Paintlia, MK Singh, AK Singh, I AF Paintlia, Ajaib S. Paintlia, Manjeet K. Singh, Avtar K. Singh, Inderjit TI Modulation of Rho-Rock signaling pathway protects oligodendrocytes against cytokine toxicity via PPAR--dependent mechanism SO GLIA LA English DT Article DE lovastatin; EAE; MS; oligodendrocyte progenitors; PPAR-; RhoA-ROCK; survival; differentiation ID CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ACTIVATED RECEPTOR-GAMMA; NECROSIS-FACTOR-ALPHA; COA REDUCTASE INHIBITOR; N-ACETYL CYSTEINE; ENDOTHELIAL-CELLS; IN-VITRO; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); DEMYELINATING DISEASES AB We earlier documented that lovastatin (LOV)-mediated inhibition of small Rho GTPases activity protects vulnerable oligodendrocytes (OLs) in mixed glial cell cultures stimulated with Th1 cytokines and in a murine model of multiple sclerosis (MS). However, the precise mechanism of OL protection remains unclear. We here employed genetic and biochemical approaches to elucidate the underlying mechanism that protects LOV treated OLs from Th1 (tumor necrosis factor-alpha) and Th17 (interleukin-17) cytokines toxicity in in vitro. Cytokines enhanced the reactive oxygen species (ROS) generation and mitochondrial membrane depolarization with corresponding lowering of glutathione (reduced) level in OLs and that were reverted by LOV. In addition, the expression of ROS detoxifying enzymes (catalase and superoxide-dismutase 2) and the transactivation of peroxisome proliferators-activated receptor (PPAR)-alpha/-beta/-gamma including PPAR-gamma coactivator-1 alpha were enhanced by LOV in similarly treated OLs. Interestingly, LOV-mediated inhibition of small Rho GTPases, i.e., RhoA and cdc42, and Rho-associated kinase (ROCK) activity enhanced the levels of PPAR ligands in OLs via extracellular signal regulated kinase (1/2)/p38 mitogen-activated protein kinase/cytoplasmic phospholipase 2/cyclooxygenase-2 signaling cascade activation. Small hairpin RNA transfection-based studies established that LOV mainly enhances PPAR-alpha and less so of PPAR-beta and PPAR-gamma transactivation that enhances ROS detoxifying defense in OLs. In support of this, the observed LOV-mediated protection was lacking in PPAR-alpha-deficient OLs exposed to cytokines. Collectively, these data provide unprecedented evidence that LOV-mediated inhibition of the Rho-ROCK signaling pathway boosts ROS detoxifying defense in OLs via PPAR-alpha-dependent mechanism that has implication in neurodegenerative disorders including MS. C1 [Paintlia, Ajaib S.; Paintlia, Manjeet K.; Singh, Inderjit] Med Univ S Carolina, Dept Pediat, Darby Childrens Res Inst, Charleston, SC 29425 USA. [Singh, Avtar K.] Ralph H Johnson VA Med Ctr, Dept Pathol & Lab Med, Charleston, SC USA. RP Singh, I (reprint author), Med Univ S Carolina, Dept Pediat, 173 Ashley Ave, Charleston, SC 29425 USA. EM singhi@musc.edu FU National Institutes of Health [NS-22576, NS-37766, C06 RR018823]; Department of Veterans Affairs [VA-1BX001072, VA-BX001999] FX Grant sponsor: National Institutes of Health; Grant numbers: NS-22576, NS-37766, and C06 RR018823; Grant sponsor: Department of Veterans Affairs; Grant numbers: VA-1BX001072 and VA-BX001999. NR 67 TC 10 Z9 10 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0894-1491 J9 GLIA JI Glia PD SEP PY 2013 VL 61 IS 9 BP 1500 EP 1517 DI 10.1002/glia.22537 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 190ID UT WOS:000322331700009 PM 23839981 ER PT J AU Sparks, TN Cheng, YW Phan, N Caughey, AB AF Sparks, Teresa N. Cheng, Yvonne W. Ngoc Phan Caughey, Aaron B. TI Does risk of preeclampsia differ by twin chorionicity? SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE Chorionicity; multiple gestation; preeclampsia; twins ID PREGNANCIES; ZYGOSITY; OUTCOMES AB Objective: Examine whether dichorionic (DC) and monochorionic (MC) twins exhibit different rates and severity of preeclampsia. Methods: Retrospective cohort study of 695 twin pregnancies from 2002 to 2007. DC pregnancies were compared to MC pregnancies, with the primary outcome of interest being development of preeclampsia, and the secondary outcome being severity of preeclampsia. Chi square test compared proportions and multivariable analyses controlled for potential confounders. Results: Any preeclampsia developed in 21.1% (104/492) of DC and 10.8% (22/203) of MC pregnancies (p = 0.001), mild preeclampsia in 13.8% (68/492) of DC and 4.9% (10/203) of MC pregnancies (p = 0.001) and severe preeclampsia in 7.3% (36/492) of DC and 5.9% (12/203) of MC pregnancies (p = 0.506). DC pregnancies showed higher odds of mild preeclampsia compared to MC pregnancies (aOR 5.85, 95% CI 1.31-26.13) after controlling for several potential confounders including gestational age at delivery. Conclusions: A statistically significant larger proportion of women with DC twins developed any preeclampsia, and specifically mild preeclampsia, compared to those with MC twins. Additionally, after controlling for several potential confounders, women with DC pregnancies demonstrated higher odds of developing mild preeclampsia compared to those with MC pregnancies. Mechanisms of preeclampsia development may differ by twin chorionicity. C1 [Sparks, Teresa N.] Massachusetts Gen Hosp, Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. [Cheng, Yvonne W.] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Ngoc Phan] Kaiser San Francisco, San Francisco, CA USA. [Caughey, Aaron B.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. RP Sparks, TN (reprint author), Brigham & Womens Hosp, Dept Obstet & Gynecol, 75 Francis St,ASB1-3, Boston, MA 02115 USA. EM tsparks@partners.org OI Sparks, Teresa/0000-0002-8593-2186 FU UCSF Women's Reproductive Health Research Career Development Award, NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development [K12 HD001262] FX Dr Yvonne Cheng is supported by the UCSF Women's Reproductive Health Research Career Development Award, NIH, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12 HD001262). NR 23 TC 8 Z9 8 U1 0 U2 7 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD SEP PY 2013 VL 26 IS 13 BP 1273 EP 1277 DI 10.3109/14767058.2013.777701 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 194RO UT WOS:000322650600004 PM 23425367 ER PT J AU Prather, AA Epel, ES Cohen, BE Neylan, TC Whooley, MA AF Prather, Aric A. Epel, Elissa S. Cohen, Beth E. Neylan, Thomas C. Whooley, Mary A. TI Gender differences in the prospective associations of self-reported sleep quality with biomarkers of systemic inflammation and coagulation: Findings from the Heart and Soul Study SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE Sleep; Inflammation; Gender; Coronary heart disease ID C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; RISK-FACTOR; TESTOSTERONE REPLACEMENT; HYPOGONADAL MEN; WHITEHALL-II; OLDER-ADULTS; DURATION; HEALTH; WOMEN AB Systemic inflammation is proposed as a putative mechanism underlying the link between poor sleep and cardiovascular disease. The aim of present study was to investigate the cross-sectional and prospective associations of self-reported sleep quality with biomarkers of inflammation and coagulation implicated in coronary heart disease (CHD) and to explore whether these associations differed between men and women. To this end, measures of sleep quality and markers of inflammation, including circulating levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (CRP), and fibrinogen were assessed at baseline in 980 participants with established CHD and 626 at 5-year follow-up. In the sample as a whole, subjective sleep quality was unrelated to inflammatory markers in cross-sectional and prospective analyses. However, in gender stratified analyses, adjusting for age, ethnicity, education, body mass index, and regular snoring, poorer subjective sleep quality at baseline was prospectively associated with 5-year increases in IL-6 (b = 0.14, SE = 0.05, p = 0.003), CRP (b = 0.21, SE = 0.09, p = 0.02), and fibrinogen (b = 18.02, SE = 7.62, p = 0.02) in women but not men. These associations remained independent of lifestyle/psychosocial factors, medical comorbidities, medication use, and cardiac function. Women who reported baseline sleep disturbances characterized by a tendency to wake up too early in the morning also showed significant 5-year increases in circulating IL-6 that withstood covariate adjustment. Further research is necessary to elucidate the pathways that underlie gender-specific associations between subjective sleep quality and markers of inflammation and coagulation as this may help clarify gender disparities in CHD. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Prather, Aric A.; Epel, Elissa S.; Cohen, Beth E.; Neylan, Thomas C.; Whooley, Mary A.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94118 USA. [Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Cohen, Beth E.; Neylan, Thomas C.; Whooley, Mary A.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Prather, AA (reprint author), Univ Calif San Francisco, Dept Psychiat, 3333 Calif St,Suite 465, San Francisco, CA 94118 USA. EM prathera@chc.ucsf.edu FU NIH/NHLBI [K08 HL112961]; Robert Wood Johnson Foundation Health and Society Scholars fellowship; Department of Veterans Affairs, Washington DC; National Heart, Lung and Blood Institute, Bethesda, MD [R01 HL079235]; American Federation for Aging Research (Paul Beeson Scholars Program), New York, NY; Robert Wood Johnson Foundation, Princeton, NJ; Ischemia Research and Education Foundation, South San Francisco, CA FX This research was supported in part by NIH/NHLBI Grant K08 HL112961 and a Robert Wood Johnson Foundation Health and Society Scholars fellowship to Dr. Prather. The Heart and Soul Study was funded by the Department of Veterans Affairs, Washington DC, the National Heart, Lung and Blood Institute (R01 HL079235), Bethesda, MD, the American Federation for Aging Research (Paul Beeson Scholars Program), New York, NY, the Robert Wood Johnson Foundation (Faculty Scholars Program), Princeton, NJ, and the Ischemia Research and Education Foundation, South San Francisco, CA. NR 57 TC 21 Z9 21 U1 2 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD SEP PY 2013 VL 47 IS 9 BP 1228 EP 1235 DI 10.1016/j.psychires.2013.05.004 PG 8 WC Psychiatry SC Psychiatry GA 191LF UT WOS:000322413800015 PM 23746737 ER PT J AU Gupta, A Avci, P Sadasivam, M Chandran, R Parizotto, N Vecchio, D de Melo, WCMA Dai, TH Chiang, LY Hamblin, MR AF Gupta, Asheesh Avci, Pinar Sadasivam, Magesh Chandran, Rakkiyappan Parizotto, Nivaldo Vecchio, Daniela de Melo, Wanessa C. M. A. Dai, Tianhong Chiang, Long Y. Hamblin, Michael R. TI Shining light on nanotechnology to help repair and regeneration SO BIOTECHNOLOGY ADVANCES LA English DT Review DE Liposomes; Low level laser (or light) therapy; Nanomaterials; Nanoparticles; Photodynamic therapy; Phototherapy; Repair and regeneration; Stem cells ID LOW-LEVEL-LASER; MESENCHYMAL STEM-CELLS; WALLED CARBON NANOTUBES; SUBFOVEAL CHOROIDAL NEOVASCULARIZATION; 2-PHOTON PHOTODYNAMIC THERAPY; BLADDER-CARCINOMA CELLS; HELIUM-NEON LASER; OF-THE-ART; IN-VITRO; DRUG-DELIVERY AB Phototherapy can be used in two completely different but complementary therapeutic applications. While low level laser (or light) therapy (LLLT) uses red or near-infrared light alone to reduce inflammation, pain and stimulate tissue repair and regeneration, photodynamic therapy (PDT) uses the combination of light plus non-toxic dyes (called photosensitizers) to produce reactive oxygen species that can kill infectious microorganisms and cancer cells or destroy unwanted tissue (neo-vascularization in the choroid, atherosclerotic plaques in the arteries). The recent development of nanotechnology applied to medicine (nanomedicine) has opened a new front of advancement in the field of phototherapy and has provided hope for the development of nanoscale drug delivery platforms for effective killing of pathological cells and to promote repair and regeneration. Despite the well-known beneficial effects of phototherapy and nanomaterials in producing the killing of unwanted cells and promoting repair and regeneration, there are few reports that combine all three elements i.e. phototherapy, nanotechnology and, tissue repair and regeneration. However, these areas in all possible binary combinations have been addressed by many workers. The present review aims at highlighting the combined multi-model applications of phototherapy, nanotechnology and, reparative and regeneration medicine and outlines current strategies, future applications and limitations of nanoscale-assisted phototherapy for the management of cancers, microbial infections and other diseases, and to promote tissue repair and regeneration. (c) 2012 Elsevier Inc. All rights reserved. C1 [Gupta, Asheesh; Avci, Pinar; Sadasivam, Magesh; Chandran, Rakkiyappan; Parizotto, Nivaldo; Vecchio, Daniela; de Melo, Wanessa C. M. A.; Dai, Tianhong; Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Gupta, Asheesh; Vecchio, Daniela; Dai, Tianhong; Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Gupta, Asheesh] Def Inst Physiol & Allied Sci, Delhi, India. [Sadasivam, Magesh; Chandran, Rakkiyappan] Amity Univ Uttar Pradesh, Amity Inst Nanotechnol, Noida, India. [Parizotto, Nivaldo] Univ Fed Sao Carlos, BR-13560 Sao Carlos, SP, Brazil. [de Melo, Wanessa C. M. A.] Univ Sao Paulo, Sao Carlos, SP, Brazil. [Chiang, Long Y.] Univ Massachusetts, Dept Chem, Lowell, MA USA. [Hamblin, Michael R.] Harvard MIT Div Hlth Sci & Technol, Cambridge, MA USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu RI PARIZOTTO, Nivaldo/D-5347-2014; OI PARIZOTTO, Nivaldo/0000-0003-1774-9053; Hamblin, Michael/0000-0001-6431-4605 FU US NIH [R01AI050875]; BOYSCAST Fellowship (Department of Science and Technology, Government of India); [R01CA137108] FX This work was supported by the US NIH (R01AI050875 to MRH). Long Y Chiang was supported by R01CA137108. Asheesh Gupta was supported by BOYSCAST Fellowship 2010-11 (Department of Science and Technology, Government of India). NR 261 TC 24 Z9 24 U1 2 U2 122 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0734-9750 J9 BIOTECHNOL ADV JI Biotechnol. Adv. PD SEP-OCT PY 2013 VL 31 IS 5 SI SI BP 607 EP 631 DI 10.1016/j.biotechadv.2012.08.003 PG 25 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 186QJ UT WOS:000322058900011 PM 22951919 ER PT J AU Weathington, NM Mallampalli, RK AF Weathington, Nathaniel M. Mallampalli, Rama K. TI New insights on the function of SCF ubiquitin E3 ligases in the lung SO CELLULAR SIGNALLING LA English DT Review DE Protein degradation; Proteolysis; Lung; Inflammation ID F-BOX PROTEINS; NF-KAPPA-B; ALLOSTERIC INHIBITOR; MULTIPLE-MYELOMA; MITOTIC ARREST; BETA-TRCP; K-ATPASE; DEGRADATION; CANCER; PROTEASOME AB Recent developments in pulmonary cell biology have shown that the maintenance of protein concentrations, proteostasis, is an integral process of all biologic systems. The balance of available protein is the sum total of three key elements of cell metabolism: production by transcription and translation, compartmentalization through processing and sorting, and proteolytic degradation of proteins at any stage of their life-span. Considerable advances are constantly made in each of these three essential fields, and our appreciation for the diversity of mechanisms of protein degradation has expanded greatly in the last decade. The ubiquitin proteasome system (UPS) has emerged as the predominant protein degradation pathway in eukaryotes, with the large cullin-RING family of E3 ligases responsible for ubiquitination of a broad array of proteins to be degraded. The Skip-Cullin-F-box (SCF) ubiquitin E3 ligase superfamily is the largest family of cullin-RING ligases, with interchangeable F-box proteins orchestrating the trafficking proteins for ubiquitination and degradation. We will discuss the best characterized and most recent developments in the role of this intriguing family of proteins in normal physiology and disorders of the lungs. (c) 2013 Elsevier Inc. All rights reserved. C1 [Weathington, Nathaniel M.; Mallampalli, Rama K.] Univ Pittsburgh, Acute Lung Injury Ctr Excellence, Dept Med, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. [Mallampalli, Rama K.] Vet Affairs Pittsburgh Healthcare Syst, Med Specialty Serv Line, Pittsburgh, PA USA. RP Mallampalli, RK (reprint author), Univ Pittsburgh, UPMC Montefiore, Dept Med, NW 628, Pittsburgh, PA 15213 USA. EM mallampallirk@upmc.edu FU BLRD VA [I01 BX002200]; NHLBI NIH HHS [R01 HL097376, R01 HL081784, R01 HL098174, R01 HL096376, R01 HL068135] NR 43 TC 3 Z9 3 U1 0 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD SEP PY 2013 VL 25 IS 9 BP 1792 EP 1798 DI 10.1016/j.cellsig.2013.05.003 PG 7 WC Cell Biology SC Cell Biology GA 189WK UT WOS:000322298800008 PM 23680451 ER PT J AU Faje, AT Fazeli, PK Katzman, D Miller, KK Breggia, A Rosen, CJ Mendes, N Misra, M Klibanski, A AF Faje, Alexander T. Fazeli, Pouneh K. Katzman, Debra Miller, Karen K. Breggia, Anne Rosen, Clifford J. Mendes, Nara Misra, Madhusmita Klibanski, Anne TI Inhibition of Pref-1 (preadipocyte factor 1) by oestradiol in adolescent girls with anorexia nervosa is associated with improvement in lumbar bone mineral density SO CLINICAL ENDOCRINOLOGY LA English DT Article ID MESENCHYMAL STEM-CELLS; FACTOR-I LEVELS; ADIPOCYTE DIFFERENTIATION; GROWTH-HORMONE; MARROW FAT; POTENTIAL MECHANISM; WOMEN; PROTEIN; ESTROGEN; OSTEOPOROSIS AB Objective Adolescents with anorexia nervosa (AN) are amenorrheic and have decreased bone mass accrual and low bone mineral density (BMD). The regulation of mesenchymal stem cell differentiation is an important factor governing bone formation. Preadipocyte factor 1 (Pref-1), an inhibitor of adipocyte and osteoblast differentiation, is elevated in states of oestrogen deficiency. In this study, we aim to (i) investigate effects of transdermal oestradiol on Pref-1 in adolescent girls with AN, and (ii) examine associations of changes in Pref-1 with changes in lumbar BMD and bone turnover markers. Design Adolescent girls with AN and normal-weight controls were studied cross-sectionally. Girls with AN were examined longitudinally in a double-blind study and received transdermal oestradiol (plus cyclic medroxyprogesterone) or placebo for 12 months. Patients Sixty-nine girls (44 with AN, 25 normal-weight controls) 13-18 years were studied at baseline; 22 AN girls were followed prospectively. Measurements Pref-1 levels, bone formation and resorption markers, and BMD. Results Pref-1 levels decreased in girls with AN after treatment with transdermal oestradiol compared with placebo (-0.015 +/- 0.016 vs 0.060 +/- 0.026 ng/ml, P = 0.01), although at baseline, levels did not differ in AN vs controls (0.246 +/- 0.015 vs 0.267 +/- 0.022 ng/ml). Changes in Pref-1 over 12 months correlated inversely with changes in lumbar BMD (r = -0.48, P = 0.02) and positively with changes in CTX (r = 0.73, P = 0.006). Conclusions For the first time, we show that Pref-1 is negatively regulated by oestradiol in adolescent girls with AN. Inhibition of Pref-1 may mediate the beneficial effects of transdermal oestradiol replacement on BMD in girls with AN. C1 [Faje, Alexander T.; Fazeli, Pouneh K.; Miller, Karen K.; Mendes, Nara; Misra, Madhusmita; Klibanski, Anne] Massachusetts Gen Hosp Children, Neuroendocrine Unit, Boston, MA USA. [Faje, Alexander T.; Fazeli, Pouneh K.; Miller, Karen K.; Mendes, Nara; Misra, Madhusmita; Klibanski, Anne] Harvard Univ, Sch Med, Boston, MA USA. [Katzman, Debra] Hosp Sick Children, Div Adolescent Med, Toronto, ON M5G 1X8, Canada. [Breggia, Anne; Rosen, Clifford J.] Maine Med Ctr Res Inst, Portland, ME USA. [Misra, Madhusmita] Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA USA. RP Klibanski, A (reprint author), Massachusetts Gen Hosp, BUL 457, Neuroendocrine Unit, 55 Fruit St, Boston, MA 02114 USA. EM aklibanski@partners.org RI Mendes Estella, Nara/A-1469-2015 FU NIH [R01 DK062249, 1 UL1 RR025758-01] FX We thank the staff at the Clinical Research Center of Massachusetts General and the Clinical Investigation Unit at the Hospital for Sick Children for their nursing and bionutrition support. This study was supported by NIH grants R01 DK062249 and 1 UL1 RR025758-01. NR 46 TC 9 Z9 9 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD SEP PY 2013 VL 79 IS 3 BP 326 EP 332 DI 10.1111/cen.12144 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 188IO UT WOS:000322186700007 PM 23331192 ER PT J AU Pedersen, BS Konstantinopoulos, PA Spillman, MA De, S AF Pedersen, Brent S. Konstantinopoulos, Panagiotis A. Spillman, Monique A. De, Subhajyoti TI Copy neutral loss of heterozygosity is more frequent in older ovarian cancer patients SO GENES CHROMOSOMES & CANCER LA English DT Article ID STRAND-BREAK REPAIR; TUMOR-SUPPRESSOR GENES; CELLULAR SENESCENCE; AGE; DNA; PATHWAYS; EXPRESSION; MORTALITY; PATTERNS; SURVIVAL AB Loss of heterozygosity (LOH) is a common type of genomic alterations in ovarian cancer. Analyzing 74,415 copy neutral LOH events in 513 serous ovarian adenocarcinomas samples from the Cancer Genome Atlas, we report that the frequency of LOH events increases with age. Similar trend is observed for LOH involving chromosome 17, which is frequently implicated in ovarian cancer. The results are consistent when we analyze data from the Boston high-gradeserouscancer cohort. We further show that germ line and somatic mutations in BRCA1 (in chromosome 17) and BRCA2 (in chromosome 13) loci are not necessary to establish the pattern. We also report significant age-related changes in expression patterns for several genes in the homologous recombination (HR) pathway, such as BRCA1, RAD50, RAD52, XRCC2, XRCC3, and MRE11A in these patient samples. Furthermore, we develop a metric for pathway-level imbalance, and show that increased imbalance in the HR pathway, i.e., increase in expression of some HR genes and decrease in expression of others, is common and correlates significantly with the frequency of LOH events in the patient samples. Taken together, it is highly likely that aging and deregulation of HR pathway contribute to the increased incidence of copy-neutral LOH in ovarian cancer patients. (c) 2013 Wiley Periodicals, Inc. C1 [Pedersen, Brent S.; Spillman, Monique A.; De, Subhajyoti] Univ Colorado, Sch Med, Dept Med, Aurora, CO 80045 USA. [Konstantinopoulos, Panagiotis A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Spillman, Monique A.] Univ Colorado, Sch Med, Dept Obstet & Gynecol, Aurora, CO USA. [De, Subhajyoti] Univ Colorado, Ctr Canc, Mol Oncol Program, Aurora, CO USA. RP De, S (reprint author), Univ Colorado, Sch Med, Dept Med, 12700 E 19th Ave,Mailstop 8617, Aurora, CO 80045 USA. EM subhajyoti.de@ucdenver.edu FU NCI Physical Sciences Oncology Center pilot [NCI U54CA143798]; American Cancer Society [57-001-53] FX Supported by: NCI Physical Sciences Oncology Center pilot; Grant number: NCI U54CA143798; and the American Cancer Society; Grant number: ACS IRG #57-001-53. NR 34 TC 11 Z9 11 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD SEP PY 2013 VL 52 IS 9 BP 794 EP 801 DI 10.1002/gcc.22075 PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 183MN UT WOS:000321819800002 PM 23716468 ER PT J AU Lombaert, H Grady, L Polimeni, JR Cheriet, F AF Lombaert, Herve Grady, Leo Polimeni, Jonathan R. Cheriet, Farida TI FOCUSR: Feature Oriented Correspondence Using Spectral Regularization-A Method for Precise Surface Matching SO IEEE TRANSACTIONS ON PATTERN ANALYSIS AND MACHINE INTELLIGENCE LA English DT Article DE Registration; surface fitting; spectral methods; graph theory ID HUMAN CEREBRAL-CORTEX; SHAPE-ANALYSIS; COORDINATE SYSTEM; REGISTRATION; ALGORITHM; DIFFUSION; FRAMEWORK; IMAGES; GRAPHS; MESHES AB Existing methods for surface matching are limited by the tradeoff between precision and computational efficiency. Here, we present an improved algorithm for dense vertex-to-vertex correspondence that uses direct matching of features defined on a surface and improves it by using spectral correspondence as a regularization. This algorithm has the speed of both feature matching and spectral matching while exhibiting greatly improved precision (distance errors of 1.4 percent). The method, FOCUSR, incorporates implicitly such additional features to calculate the correspondence and relies on the smoothness of the lowest-frequency harmonics of a graph Laplacian to spatially regularize the features. In its simplest form, FOCUSR is an improved spectral correspondence method that nonrigidly deforms spectral embeddings. We provide here a full realization of spectral correspondence where virtually any feature can be used as an additional information using weights on graph edges, but also on graph nodes and as extra embedded coordinates. As an example, the full power of FOCUSR is demonstrated in a real-case scenario with the challenging task of brain surface matching across several individuals. Our results show that combining features and regularizing them in a spectral embedding greatly improves the matching precision (to a submillimeter level) while performing at much greater speed than existing methods. C1 [Lombaert, Herve] McGill Univ, Ctr Intelligent Machines, Montreal, PQ H2J 2K9, Canada. [Grady, Leo] HeartFlow Inc, R&D, Redwood City, CA USA. [Polimeni, Jonathan R.] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Sch Med,Dept Radiol, Charlestown, MA USA. [Cheriet, Farida] Ecole Polytech Montreal, Dept Comp Engn, Montreal, PQ, Canada. RP Lombaert, H (reprint author), McGill Univ, Ctr Intelligent Machines, 4239 Rue St Denis, Montreal, PQ H2J 2K9, Canada. RI Polimeni, Jonathan/P-1395-2014 OI Polimeni, Jonathan/0000-0002-1348-1179 FU Alexander Graham Bell Canada Graduate Scholarships of the Natural Sciences and Engineering Research Council of Canada (NSERC) FX The authors would especially like to thank Bruce Fischl and Martin Reuter for their helpful comments, the anonymous reviewers for their valuable comments and suggestions, Gareth Funka-Lea for supporting this project, as well as the financial support from the Alexander Graham Bell Canada Graduate Scholarships of the Natural Sciences and Engineering Research Council of Canada (NSERC). NR 74 TC 19 Z9 20 U1 1 U2 28 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0162-8828 EI 1939-3539 J9 IEEE T PATTERN ANAL JI IEEE Trans. Pattern Anal. Mach. Intell. PD SEP PY 2013 VL 35 IS 9 BP 2143 EP 2160 DI 10.1109/TPAMI.2012.276 PG 18 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 186GB UT WOS:000322029000008 PM 23868776 ER PT J AU Konukoglu, E Glocker, B Criminisi, A Pohl, KM AF Konukoglu, Ender Glocker, Ben Criminisi, Antonio Pohl, Kilian M. TI WESD-Weighted Spectral Distance for Measuring Shape Dissimilarity SO IEEE TRANSACTIONS ON PATTERN ANALYSIS AND MACHINE INTELLIGENCE LA English DT Article DE Shape distance; spectral distance; Laplace operator; Laplace spectrum; segmentations; label maps; medical images ID ONE HEAR; SURFACES; DOMAINS; DRUM AB This paper presents a new distance for measuring shape dissimilarity between objects. Recent publications introduced the use of eigenvalues of the Laplace operator as compact shape descriptors. Here, we revisit the eigenvalues to define a proper distance, called Weighted Spectral Distance (WESD), for quantifying shape dissimilarity. The definition of WESD is derived through analyzing the heat trace. This analysis provides the proposed distance with an intuitive meaning and mathematically links it to the intrinsic geometry of objects. We analyze the resulting distance definition, present and prove its important theoretical properties. Some of these properties include: 1) WESD is defined over the entire sequence of eigenvalues yet it is guaranteed to converge, 2) it is a pseudometric, 3) it is accurately approximated with a finite number of eigenvalues, and 4) it can be mapped to the [0, 1) interval. Last, experiments conducted on synthetic and real objects are presented. These experiments highlight the practical benefits of WESD for applications in vision and medical image analysis. C1 [Konukoglu, Ender] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Cambridge, MA 02144 USA. [Glocker, Ben; Criminisi, Antonio] Microsoft Res Cambridge, Cambridge CB3 0FB, England. [Pohl, Kilian M.] Univ Penn, Philadelphia, PA 19104 USA. RP Konukoglu, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Cambridge, MA 02144 USA. EM ender.konukoglu@gmail.com OI Glocker, Ben/0000-0002-4897-9356 FU Institute for Translational Medicine and Therapeutics (ITMAT) Transdisciplinary Program; [UL1RR024134] FX The authors would like to thank the support in part by Grant Number UL1RR024134 and by the Institute for Translational Medicine and Therapeutics (ITMAT) Transdisciplinary Program. NR 43 TC 12 Z9 12 U1 0 U2 12 PU IEEE COMPUTER SOC PI LOS ALAMITOS PA 10662 LOS VAQUEROS CIRCLE, PO BOX 3014, LOS ALAMITOS, CA 90720-1314 USA SN 0162-8828 J9 IEEE T PATTERN ANAL JI IEEE Trans. Pattern Anal. Mach. Intell. PD SEP PY 2013 VL 35 IS 9 BP 2284 EP 2297 DI 10.1109/TPAMI.2012.275 PG 14 WC Computer Science, Artificial Intelligence; Engineering, Electrical & Electronic SC Computer Science; Engineering GA 186GB UT WOS:000322029000017 PM 23868785 ER PT J AU Zanartu, M Ho, JC Mehta, DD Hillman, RE Wodicka, GR AF Zanartu, Matias Ho, Julio C. Mehta, Daryush D. Hillman, Robert E. Wodicka, George R. TI Subglottal Impedance-Based Inverse Filtering of Voiced Sounds Using Neck Surface Acceleration SO IEEE TRANSACTIONS ON AUDIO SPEECH AND LANGUAGE PROCESSING LA English DT Article DE Accelerometer; ambulatory monitoring; glottal airflow; glottal source; inverse filtering; neck vibration; vocal folds; voice production ID DOMAIN ACOUSTIC MODEL; GLOTTAL AIR-FLOW; VOCAL-TRACT; LINEAR PREDICTION; WAVE-FORM; RESPIRATORY SYSTEM; SPEECH SYNTHESIS; TRANSMISSION; SPEAKERS; SIGNALS AB A model-based inverse filtering scheme is proposed for an accurate, non-invasive estimation of the aerodynamic source of voiced sounds at the glottis. The approach, referred to as subglottal impedance-based inverse filtering (IBIF), takes as input the signal from a lightweight accelerometer placed on the skin over the extrathoracic trachea and yields estimates of glottal airflow and its time derivative, offering important advantages over traditional methods that deal with the supraglottal vocal tract. The proposed scheme is based on mechano-acoustic impedance representations from a physiologically-based transmission line model and a lumped skin surface representation. A subject-specific calibration protocol is used to account for individual adjustments of subglottal impedance parameters and mechanical properties of the skin. Preliminary results for sustained vowels with various voice qualities show that the subglottal IBIF scheme yields comparable estimates with respect to current aerodynamics-based methods of clinical vocal assessment. A mean absolute error of less than 10% was observed for two glottal airflow measures-maximum flow declination rate and amplitude of the modulation component-that have been associated with the pathophysiology of some common voice disorders caused by faulty and/or abusive patterns of vocal behavior (i.e., vocal hyperfunction). The proposed method further advances the ambulatory assessment of vocal function based on the neck acceleration signal, that previously have been limited to the estimation of phonation duration, loudness, and pitch. Subglottal IBIF is also suitable for other ambulatory applications in speech communication, in which further evaluation is underway. C1 [Zanartu, Matias] Univ Tecn Federico Santa Maria, Dept Elect Engn, Valparaiso 2390123, Chile. [Ho, Julio C.; Wodicka, George R.] Purdue Univ, Weldon Sch Biomed Engn, W Lafayette, IN 47901 USA. [Mehta, Daryush D.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Mehta, Daryush D.; Hillman, Robert E.] Massachusetts Gen Hosp, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Hillman, Robert E.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Hillman, Robert E.] Harvard Mit Div Hlth Sci & Technol, Boston, MA 02114 USA. [Wodicka, George R.] Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47901 USA. RP Zanartu, M (reprint author), Univ Tecn Federico Santa Maria, Dept Elect Engn, Valparaiso 2390123, Chile. EM matias.zanartu@usm.cl; hoj@purdue.edu; dmehta@seas.harvard.edu; hillman.robert@mgh.harvard.edu; wodicka@purdue.edu RI Zanartu, Matias/I-3133-2012 OI Zanartu, Matias/0000-0001-5581-4392 FU UTFSM; CONICYT FONDECYT [11110147]; Institute of Laryngology and Voice Restoration FX This work was supported by UTFSM, CONICYT FONDECYT under Grant 11110147, the Institute of Laryngology and Voice Restoration, and the Institute of Laryngology and Voice Restoration. The associate editor coordinating the review of this manuscript and approving it for publication was Soren Holdt Jensen. NR 66 TC 9 Z9 9 U1 0 U2 9 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1558-7916 EI 1558-7924 J9 IEEE T AUDIO SPEECH JI IEEE Trans. Audio Speech Lang. Process. PD SEP PY 2013 VL 21 IS 9 BP 1929 EP 1939 DI 10.1109/TASL.2013.2263138 PG 11 WC Acoustics; Engineering, Electrical & Electronic SC Acoustics; Engineering GA 184QC UT WOS:000321906800005 PM 25400531 ER PT J AU Wright, JL Plymate, S D'Oria-Cameron, A Bain, C Haugk, K Xiao, LR Lin, DW Stanford, JL McTiernan, A AF Wright, Jonathan L. Plymate, Stephen D'Oria-Cameron, Andrea Bain, Carolyn Haugk, Kathy Xiao, Liren Lin, Daniel W. Stanford, Janet L. McTiernan, Anne TI A study of caloric restriction versus standard diet in overweight men with newly diagnosed prostate cancer: A randomized controlled trial SO PROSTATE LA English DT Article DE obesity; prostate cancer; diet; randomized ID IGF-BINDING PROTEIN-3; DIABETES PREVENTION PROGRAM; BODY-MASS INDEX; WEIGHT-LOSS; RADICAL PROSTATECTOMY; LIFE-STYLE; CLINICAL-TRIAL; GROWTH-FACTORS; UNITED-STATES; RISK-FACTOR AB INTRODUCTION. Obese men have an increased risk of prostate cancer (PCa)-specific mortality. Potential mechanisms include insulin and related proteins. We investigate whether a short-term caloric restriction diet in overweight/obese men with newly diagnosed PCa can lead to measurable changes in patient anthropometrics and insulin-related proteins. METHODS. Overweight and obese PCa patients choosing active surveillance or radical prostatectomy were randomized to a 6-week, caloric-restricted diet or to continue their current diet. Changes from baseline to end of study in anthropometrics, dietary constituents and serum proteins (insulin, c-peptide, IGF-1, adiponectin, IGF-BP3) were compared between the intervention and control groups using a Generalized Estimating Equation model. RESULTS. Nineteen patients were randomized to the intervention (N=10) or control (N=9) group. Men in the intervention group had a 1.7% (3.7lbs) mean decline in weight versus 1.0% (2.0lbs) in controls (P<0.05), and a reduced intake of calories, total and saturated fat, protein and starch (all P<0.1 compared to controls). There was a significant difference (P=0.002) in mean serum IGFBP-3 between the intervention (+2.8%) and control group (-6.9%). Other biomarkers changed with the diet intervention to a degree similar to previous weight loss studies but were not statistically significant compared with controls. CONCLUSION. In this small pilot study, a 6-week caloric restricted diet in men with newly diagnosed PCa produced changes in weight, diet and serum proteins possibly related to prognosis. These results support larger-scale trials testing longer-term weight loss effects on potential PCa progression biomarkers. Prostate 73: 1345-1351, 2013. (c) 2013 Wiley Periodicals, Inc. C1 [Wright, Jonathan L.; Lin, Daniel W.] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Wright, Jonathan L.; D'Oria-Cameron, Andrea; Bain, Carolyn; Xiao, Liren; Lin, Daniel W.; Stanford, Janet L.; McTiernan, Anne] Fred Hutchison Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Wright, Jonathan L.; Lin, Daniel W.] VA Puget Sound Hlth Care Syst, Urol Sect, Seattle, WA USA. [Plymate, Stephen] Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. [Plymate, Stephen; Haugk, Kathy] VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev, Seattle, WA USA. [Plymate, Stephen; Haugk, Kathy] VA Puget Sound Hlth Care Syst, GRECC, Seattle, WA USA. [Stanford, Janet L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP Wright, JL (reprint author), Fred Hutchison Canc Res Ctr, 1100 Fairview Ave North,M4-B874, Seattle, WA 98109 USA. EM jlwright@u.washington.edu FU NIH; National Cancer Institute [P50CA097186]; Fred Hutchinson Cancer Research Center FX Grant sponsor: NIH; Grant sponsor: National Cancer Institute; Grant number: P50CA097186; Grant sponsor: Fred Hutchinson Cancer Research Center. NR 40 TC 5 Z9 6 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-4137 J9 PROSTATE JI Prostate PD SEP PY 2013 VL 73 IS 12 BP 1345 EP 1351 DI 10.1002/pros.22682 PG 7 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 186AH UT WOS:000322013100010 PM 23775525 ER PT J AU Long, TJ Takeno, M Sprenger, CC Plymate, SR Ratner, BD AF Long, Thomas J. Takeno, Marc Sprenger, Cynthia C. Plymate, Stephen R. Ratner, Buddy D. TI Capillary Force Seeding of Sphere-Templated Hydrogels for Tissue-Engineered Prostate Cancer Xenografts SO TISSUE ENGINEERING PART C-METHODS LA English DT Article ID SCAFFOLDS; PROLIFERATION AB Biomaterial-based tissue-engineered tumor models are now widely used in cancer biology studies. However, specific methods for efficient and reliable cell seeding into these and tissue-engineering constructs used for regenerative medicine often remain poorly defined. Here, we describe a capillary force-based method for seeding the human prostate cancer cell lines M12 and LNCaP C4-2 into sphere-templated poly(2-hydroxyethyl methacrylate) hydrogels. The capillary force seeding method improved the cell number and distribution within the porous scaffolds compared to well-established protocols such as static and centrifugation seeding. Seeding efficiency was found to be strongly dependent on the rounded cell diameter relative to the pore diameter and pore interconnect size, parameters that can be controllably modulated during scaffold fabrication. Cell seeding efficiency was evaluated quantitatively using a PicoGreen DNA assay, which demonstrated some variation in cell retention using the capillary force method. When cultured within the porous hydrogels, both cell lines attached and proliferated within the network, but histology showed the formation of a necrotic zone by 7 days likely due to oxygen and nutrient diffusional limitations. The necrotic zone thickness was decreased by dynamically culturing cells in an orbital shaker. Proliferation analysis showed that despite a variable seeding efficiency, by 7 days in culture, scaffolds contained a roughly consistent number of cells as they proliferated to fill the pores of the scaffold. These studies demonstrate that sphere-templated polymeric scaffolds have the potential to serve as an adaptable cell culture substrate for engineering a three-dimensional prostate cancer model. C1 [Long, Thomas J.; Takeno, Marc; Ratner, Buddy D.] Univ Washington, Dept Bioengn, Seattle, WA 98195 USA. [Sprenger, Cynthia C.; Plymate, Stephen R.] Univ Washington, Dept Med, Seattle, WA 98195 USA. [Plymate, Stephen R.] Vet Affairs Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA USA. RP Ratner, BD (reprint author), Univ Washington, Dept Bioengn, Box 355061,3720 15th Ave NE, Seattle, WA 98195 USA. EM ratner@uweb.engr.washington.edu FU Nanotechnology and Physical Science in Cancer Research Training Program NIH [T32CA138312, TMEN-U54CA126540, PO1 CA085859]; Veterans Affairs Research Service FX This work was supported by the Nanotechnology and Physical Science in Cancer Research Training Program NIH T32CA138312 (T.J.L. and B. D. R.), TMEN-U54CA126540 (S. R. P.), PO1 CA085859 (S. R. P.), and the Veterans Affairs Research Service (S.R.P.). NR 22 TC 5 Z9 5 U1 0 U2 14 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3384 J9 TISSUE ENG PART C-ME JI Tissue Eng. Part C-Methods PD SEP PY 2013 VL 19 IS 9 BP 738 EP 744 DI 10.1089/ten.tec.2012.0388 PG 7 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 187KS UT WOS:000322117900008 PM 23373788 ER PT J AU Taylor, DJ Bramoweth, AD Grieser, EA Tatum, JI Roane, BM AF Taylor, Daniel J. Bramoweth, Adam D. Grieser, Emily A. Tatum, Jolyn I. Roane, Brandy M. TI Epidemiology of Insomnia in College Students: Relationship With Mental Health, Quality of Life, and Substance Use Difficulties SO BEHAVIOR THERAPY LA English DT Article DE insomnia; college; psychosocial; hypnotic; stimulant ID MOTOR-VEHICLE ACCIDENTS; INDIRECT COSTS; SLEEP; POPULATION; DEPRESSION; INVENTORY; INSTRUMENT; DISORDERS; PATTERNS; CRITERIA AB The purpose of this study was to evaluate the prevalence and correlates of insomnia using rigorous diagnostic criteria and a comprehensive assessment battery. In a large sample (N=1,074) of college students (mean age 20.39 years), participants were asked to complete a week-long sleep diary and comprehensive questionnaire packet assessing recommended daytime functioning domains (i.e., fatigue, quality of life, depression, anxiety, stress, academic performance, substance use) during the academic year. A significant portion of this sample of college students met proposed DSM-5 criteria for chronic insomnia (9.5%). The chronic insomnia group reported significantly worse sleep, fatigue, depression, anxiety, stress, and quality of life, and greater hypnotic and stimulant use for sleep problems. There were no differences between groups on excessive daytime sleepiness, academic performance, or substance use. This was a rigorous and comprehensive assessment of the prevalence and psychosocial correlates of insomnia. Insomnia is a significant problem in college students and should be regularly assessed. More research is also needed to guide treatment in this population. C1 [Taylor, Daniel J.] Univ N Texas, Denton, TX 76203 USA. [Bramoweth, Adam D.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Roane, Brandy M.] Univ N Texas, Hlth Sci Ctr, Denton, TX 76203 USA. RP Taylor, DJ (reprint author), Univ N Texas, Dept Psychol, 1155 Union Circle 311280, Denton, TX 76203 USA. EM djtaylor@unt.edu FU PHS HHS [A1085558] NR 49 TC 30 Z9 30 U1 10 U2 88 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 0005-7894 J9 BEHAV THER JI Behav. Therapy PD SEP PY 2013 VL 44 IS 3 BP 339 EP 348 PG 10 WC Psychology, Clinical SC Psychology GA 176PR UT WOS:000321317100001 PM 23768662 ER PT J AU Bonner, LM Lanto, AB Bolkan, C Watson, GS Campbell, DG Chaney, EF Zivin, K Rubenstein, LV AF Bonner, Laura M. Lanto, Andy B. Bolkan, Cory Watson, G. Stennis Campbell, Duncan G. Chaney, Edmund F. Zivin, Kara Rubenstein, Lisa V. TI Help-Seeking from Clergy and Spiritual Counselors Among Veterans with Depression and PTSD in Primary Care SO JOURNAL OF RELIGION & HEALTH LA English DT Article DE Depression; PTSD; Clergy ID POSTTRAUMATIC-STRESS-DISORDER; MENTAL-HEALTH PROFESSIONALS; SOCIAL SUPPORT; QUALITY IMPROVEMENT; COLLABORATION; SETTINGS; SYMPTOMS; SUICIDE; NEED AB Little is known about the prevalence or predictors of seeking help for depression and PTSD from spiritual counselors and clergy. We describe openness to and actual help-seeking from spiritual counselors among primary care patients with depression. We screened consecutive VA primary care patients for depression; 761 Veterans with probable major depression participated in telephone surveys (at baseline, 7 months, and 18 months). Participants were asked about (1) openness to seeking help for emotional problems from spiritual counselors/clergy and (2) actual contact with spiritual counselors/clergy in the past 6 months. At baseline, almost half of the participants, 359 (47.2 %), endorsed being "very" or "somewhat likely" to seek help for emotional problems from spiritual counselors; 498 (65.4 %) were open to a primary care provider, 486 (63.9 %) to a psychiatrist, and 409 (66.5 %) to another type of mental health provider. Ninety-one participants (12 %) reported actual spiritual counselor/clergy consultation. Ninety-five (10.3 %) participants reported that their VA providers had recently asked them about spiritual support; the majority of these found this discussion helpful. Participants with current PTSD symptoms, and those with a mental health visit in the past 6 months, were more likely to report openness to and actual help-seeking from clergy. Veterans with depression and PTSD are amenable to receiving help from spiritual counselors/clergy and other providers. Integration of spiritual counselors/clergy into care teams may be helpful to Veterans with PTSD. Training of such providers to address PTSD specifically may also be desirable. C1 [Bonner, Laura M.] Educ & Clin Ctr GRECC, VA Puget Sound Geriatr Res, Seattle, WA 98018 USA. [Bonner, Laura M.] Hlth Serv Res & Dev HSR&D, Seattle, WA 98018 USA. [Bonner, Laura M.; Watson, G. Stennis; Chaney, Edmund F.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Lanto, Andy B.; Chaney, Edmund F.; Rubenstein, Lisa V.] VA Greater Los Angeles, Los Angeles, CA USA. [Bolkan, Cory] Washington State Univ, Vancouver, WA USA. [Watson, G. Stennis] Univ Washington, Seattle, WA 98195 USA. [Campbell, Duncan G.] Univ Montana, Missoula, MT 59812 USA. [Zivin, Kara] VA Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Rubenstein, Lisa V.] Univ Calif Los Angeles, Los Angeles, CA USA. [Rubenstein, Lisa V.] RAND Corp, Los Angeles, CA USA. RP Bonner, LM (reprint author), Educ & Clin Ctr GRECC, VA Puget Sound Geriatr Res, GRECC S 182,1660 S Columbian Way, Seattle, WA 98018 USA. EM Laura.bonner@va.gov NR 28 TC 9 Z9 9 U1 1 U2 21 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0022-4197 J9 J RELIG HEALTH JI J. Relig. Health PD SEP PY 2013 VL 52 IS 3 BP 707 EP 718 DI 10.1007/s10943-012-9671-0 PG 12 WC Public, Environmental & Occupational Health; Religion SC Public, Environmental & Occupational Health; Religion GA 174DC UT WOS:000321132600002 PM 23297184 ER PT J AU Warren, KE Poussaint, TY Vezina, G Hargrave, D Packer, RJ Goldman, S Wen, PY Pollack, IF Zurakowski, D Kun, LE Prados, MD Rutkowski, S Kieran, MW AF Warren, Katherine E. Poussaint, Tina Y. Vezina, Gilbert Hargrave, Darren Packer, Roger J. Goldman, Stewart Wen, Patrick Y. Pollack, Ian F. Zurakowski, David Kun, Larry E. Prados, Michael D. Rutkowski, Stefan Kieran, Mark W. TI Challenges with defining response to antitumor agents in pediatric neuro-oncology: A report from the response assessment in pediatric neuro-oncology (RAPNO) working group SO PEDIATRIC BLOOD & CANCER LA English DT Article DE brain; imaging; pediatric; RANO; response; tumor ID INTRINSIC PONTINE GLIOMAS; HIGH-GRADE GLIOMAS; INTEROBSERVER VARIABILITY; CHEMOTHERAPY; CHILDREN; CRITERIA; CARBOPLATIN; ONCOLOGY; SURVIVAL; THERAPY AB Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro-Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations. Pediatr Blood Cancer 2013;60:1397-1401. (c) 2013 Wiley Periodicals, Inc. C1 [Warren, Katherine E.] NCI, Bethesda, MD 20892 USA. [Poussaint, Tina Y.; Zurakowski, David] Childrens Hosp, Boston, MA 02115 USA. [Vezina, Gilbert; Packer, Roger J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Hargrave, Darren] Great Ormond St Hosp Sick Children, London WC1N 3JH, England. [Goldman, Stewart] Lurie Childrens Hosp Chicago, Chicago, IL USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pollack, Ian F.] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Kun, Larry E.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Prados, Michael D.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Rutkowski, Stefan] Univ Med Ctr, Hamburg, Germany. [Kieran, Mark W.] Dana Farber Childrens Hosp Canc Ctr, Boston, MA USA. RP Warren, KE (reprint author), NCI, Pediat Oncol Branch, Bldg 10 Room 1-5750,9000 Rockville Pike, Bethesda, MD 20892 USA. EM warrenk@mail.nih.gov RI Hargrave, Darren/H-1066-2014; OI Hargrave, Darren/0000-0001-8219-9807; Kieran, Mark/0000-0003-2184-7692 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research NR 25 TC 16 Z9 16 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2013 VL 60 IS 9 BP 1397 EP 1401 DI 10.1002/pbc.24562 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 181XM UT WOS:000321703900068 PM 23625747 ER PT J AU Friedmann, AM Wolfson, JA Hudson, MM Weinstein, HJ Link, MP Billett, A Larsen, EC Yock, T Donaldson, SS Marcus, K Krasin, MJ Howard, SC Metzger, ML AF Friedmann, Alison M. Wolfson, Julie A. Hudson, Melissa M. Weinstein, Howard J. Link, Michael P. Billett, Amy Larsen, Eric C. Yock, Torunn Donaldson, Sarah S. Marcus, Karen Krasin, Matthew J. Howard, Scott C. Metzger, Monika L. TI Relapse after treatment of pediatric hodgkin lymphoma: Outcome and role of surveillance after end of therapy SO PEDIATRIC BLOOD & CANCER LA English DT Article DE childhood; Hodgkin lymphoma; outcome; pediatric; relapse; surveillance ID INVOLVED-FIELD RADIATION; POSITRON-EMISSION-TOMOGRAPHY; PROSPECTIVE CLINICAL-TRIAL; FOLLOW-UP; PET SCANS; DISEASE; CHILDREN; UTILITY; VAMP AB Background The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additional therapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well defined. Procedures We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history, physical examination, laboratory tests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse. Results Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse and timing (whether detected at a routine visit or an extra visit) did not impact survival. Conclusions In pediatric HL, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted. Pediatr Blood Cancer 2013;160:1458-1463. (c) 2013 Wiley Periodicals, Inc. C1 [Friedmann, Alison M.; Weinstein, Howard J.; Yock, Torunn] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wolfson, Julie A.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Hudson, Melissa M.; Krasin, Matthew J.; Howard, Scott C.; Metzger, Monika L.] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. [Link, Michael P.; Donaldson, Sarah S.] Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. [Billett, Amy; Marcus, Karen] Dana Farber Canc Inst, Boston, MA 02115 USA. [Larsen, Eric C.] Maine Childrens Canc Program, Scarborough, ME USA. RP Friedmann, AM (reprint author), Massachusetts Gen Hosp, Dept Pediat Hematol Oncol, Yawkey 8B,55 Fruit St, Boston, MA 02114 USA. EM afriedmann@partners.org RI Howard, Scott/K-3401-2013; OI Howard, Scott/0000-0003-2244-1686; Wolfson, Julie/0000-0002-3711-2239 FU National Institutes of Health Cancer Support Core Grant [CA-21765]; American Lebanese Syrian Associated Charities (ALSAC) FX Grant sponsor: National Institutes of Health Cancer Support Core Grant; Grant number: CA-21765; Grant sponsor: American Lebanese Syrian Associated Charities (ALSAC) NR 18 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2013 VL 60 IS 9 BP 1458 EP 1463 DI 10.1002/pbc.24568 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 181XM UT WOS:000321703900078 PM 23677874 ER PT J AU Salzmann, TC Garcia, LA Celis, V Martinez, OC Jou, C DeTorres, C Graupera, JM Rodriguez-Galindo, C Astigarraga, I Alsina, L Perez-Martinez, A Martinez-Gallo, M Colobran, R Chiang, S Schlums, H Entesarian, M Henter, JI Bryceson, Y AF Cardesa Salzmann, Teresa Alonso Garcia, Laura Celis, Veronica Cruz Martinez, Ofelia Jou, Cristina DeTorres, Carmen Mora Graupera, Jaume Rodriguez-Galindo, Carlos Astigarraga, Itziar Alsina, Laia Perez-Martinez, Antonio Martinez-Gallo, Monica Colobran, Roger Chiang, Samuel Schlums, Heinrich Entesarian, Miriam Henter, Jan-Inge Bryceson, Yenan TI IMPAIRED CYTOTOXIC LYMPHOCYTE DEGRANULATION IN A PATIENT WITH LANGERHANS CELL HISTIOCYTOSIS COMPLICATED BY A HEMOPHAGOCYTIC SYNDROME SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Cardesa Salzmann, Teresa; Alonso Garcia, Laura; Celis, Veronica; Cruz Martinez, Ofelia; Jou, Cristina; DeTorres, Carmen; Mora Graupera, Jaume] Hosp St Joan de Deu, Dept Pediat Oncol, Barcelona, Spain. [Cardesa Salzmann, Teresa; Alonso Garcia, Laura; Celis, Veronica; Cruz Martinez, Ofelia; Jou, Cristina; DeTorres, Carmen; Mora Graupera, Jaume] Hosp St Joan de Deu, Pediat Pathol Dept, Barcelona, Spain. [Rodriguez-Galindo, Carlos] Dana Farber, Pediat Hematol & Oncol Dept, Boston, MA USA. [Astigarraga, Itziar] Hosp Univ Cruces, Pediat Hematol Oncol Dept, Bilbao, Spain. [Alsina, Laia] Hosp St Joan de Deu, Allergy & Clin Immunol Dept, Barcelona, Spain. [Perez-Martinez, Antonio] Hosp Nino Jesus Madrid, Dept Pediat, Madrid, Spain. [Martinez-Gallo, Monica; Colobran, Roger] Hosp Valle De Hebron, Dept Immunol, Barcelona, Spain. [Chiang, Samuel; Schlums, Heinrich; Entesarian, Miriam; Henter, Jan-Inge; Bryceson, Yenan] Karolinska Inst, Dept Immunol, S-10401 Stockholm, Sweden. RI Astigarraga, I/I-1215-2014 OI Astigarraga, I/0000-0002-5012-0137 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2013 VL 60 IS 9 BP E73 EP E73 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 181XM UT WOS:000321703900015 ER PT J AU Chang, WT Nummenmaa, A Witzel, T Ahveninen, J Huang, S Tsai, KWK Chu, YH Polimeni, JR Belliveau, JW Lin, FH AF Chang, Wei-Tang Nummenmaa, Aapo Witzel, Thomas Ahveninen, Jyrki Huang, Samantha Tsai, Kevin Wen-Kai Chu, Ying-Hua Polimeni, Jonathan R. Belliveau, John W. Lin, Fa-Hsuan TI Whole-head rapid fMRI acquisition using echo-shifted magnetic resonance inverse imaging SO NEUROIMAGE LA English DT Article DE Echo-shifting; Inverse imaging; fMRI; Parallel imaging ID SURFACE-BASED ANALYSIS; SIGNAL-TO-NOISE; FUNCTIONAL MRI; PHYSIOLOGICAL NOISE; VISUAL-CORTEX; TIME-SERIES; SPIN ECHOES; BOLD FMRI; SENSITIVITY; SENSE AB The acquisition time of BOLD contrast functional MRI (fMRI) data with whole-brain coverage typically requires a sampling rate of one volume in 1-3 s. Although the volumetric sampling time of a few seconds is adequate for measuring the sluggish hemodynamic response (HDR) to neuronal activation, faster sampling of fMRI might allow for monitoring of rapid physiological fluctuations and detection of subtle neuronal activation timing information embedded in BOLD signals. Previous studies utilizing a highly accelerated volumetric MR inverse imaging (InI) technique have provided a sampling rate of one volume per 100 ms with 5 mm spatial resolution. Here, we propose a novel modification of this technique, the echo-shifted lid, which allows TE to be longer than TR, to measure BOLD fMRI at an even faster sampling rate of one volume per 25 ms with whole-brain coverage. Compared with conventional EPI, echo-shifted InI provided an 80-fold speedup with similar spatial resolution and less than 2-fold temporal SNR loss. The capability of echo-shifted InI to detect HDR timing differences was tested empirically. At the group level (n = 6), echo-spaced InI was able to detect statistically significant HDR timing differences of as low as 50 ms in visual stimulus presentation. At the level of individual subjects, significant differences in HDR timing were detected for 400 ms stimulus-onset differences. Our results also show that the temporal resolution of 25 ms is necessary for maintaining the temporal detecting capability at this level. With the capabilities of being able to distinguish the timing differences in the millisecond scale, echo-shifted InI could be a useful fMRI tool for obtaining temporal information at a time scale closer to that of neuronal dynamics. (C) 2013 Elsevier Inc. All rights reserved. C1 [Chang, Wei-Tang; Tsai, Kevin Wen-Kai; Chu, Ying-Hua; Lin, Fa-Hsuan] Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. [Chang, Wei-Tang; Nummenmaa, Aapo; Witzel, Thomas; Ahveninen, Jyrki; Huang, Samantha; Polimeni, Jonathan R.; Belliveau, John W.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA USA. [Lin, Fa-Hsuan] Aalto Univ, Sch Sci, Dept Biomed Engn & Computat Sci, Espoo, Finland. RP Lin, FH (reprint author), Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. EM fhlin@ntu.edu.tw RI Lin, Fa-Hsuan/G-6988-2012; Polimeni, Jonathan/P-1395-2014; Witzel, Thomas/P-1402-2014 OI Lin, Fa-Hsuan/0000-0002-9539-1731; Polimeni, Jonathan/0000-0002-1348-1179; FU National Institutes of Health (NIH) [R01DA14178, R01MH083744, R21DC010060, R01HD040712, R01NS037462, P41 RR14075, R01EB006847, RO1EB000790, R21EB007298]; Mental Illness and Neuroscience Discovery Institute (MIND) [NSC 100-2917-I-564-027, NSC 101-2628-B-002-005-MY3, 100-EC-17-A-19-S1-175, NHRI-EX102-10247EI]; Academy of Finland [127624]; Finnish Cultural Foundation; Finnish Foundation for Technology Promotion; NIH/National Center for Research Resources [S10RR014978, S10RR021110, S10RR019307, S10RR023401] FX We appreciate the technical support by Mary T. O'Hara and Lawrence T. White at the Athinoula A. Martinos Center for Biomedical Imaging. This work was also supported in part by An-Yi Hung and Stephanie Rossi. Additionally, this work was supported by National Institutes of Health (NIH) Grants R01DA14178, R01MH083744, R21DC010060, R01HD040712, R01NS037462, P41 RR14075, R01EB006847, RO1EB000790, R21EB007298, the Mental Illness and Neuroscience Discovery Institute (MIND), NSC 100-2917-I-564-027 (National Science Council, Taiwan), NSC 101-2628-B-002-005-MY3 (National Science Council, Taiwan), 100-EC-17-A-19-S1-175 (Ministry of Economic Affairs, Taiwan), NHRI-EX102-10247EI (National Health Research Institute, Taiwan), and the Academy of Finland (the FiDiPro program and grant 127624), the Finnish Cultural Foundation, and the Finnish Foundation for Technology Promotion. The research environment was supported by NIH/National Center for Research Resources Shared Instrumentation Grants S10RR014978, S10RR021110, S10RR019307, and S10RR023401. NR 65 TC 11 Z9 11 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2013 VL 78 BP 325 EP 338 DI 10.1016/j.neuroimage.2013.03.040 PG 14 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 165MV UT WOS:000320488900032 PM 23563228 ER PT J AU Lin, FH Witzel, T Raij, T Ahveninen, J Tsai, KWK Chu, YH Chang, WT Nummenmaa, A Polimeni, JR Kuo, WJ Hsieh, JC Rosen, BR Belliveau, JW AF Lin, Fa-Hsuan Witzel, Thomas Raij, Tommi Ahveninen, Jyrki Tsai, Kevin Wen-Kai Chu, Yin-Hua Chang, Wei-Tang Nummenmaa, Aapo Polimeni, Jonathan R. Kuo, Wen-Jui Hsieh, Jen-Chuen Rosen, Bruce R. Belliveau, John W. TI fMRI hemodynamics accurately reflects neuronal timing in the human brain measured by MEG SO NEUROIMAGE LA English DT Article DE Neurovascular coupling; Hemodynamics; Neuronal timing; Inverse imaging; Latency; BOLD ID TIME-RESOLVED FMRI; SURFACE-BASED ANALYSIS; EVENT-RELATED FMRI; FUNCTIONAL MRI; VISUAL-CORTEX; CORTICAL SURFACE; SENSORY STIMULATION; COORDINATE SYSTEM; MENTAL ROTATION; SIGNALS AB Neuronal activation sequence information is essential for understanding brain functions. Extracting such timing information from blood oxygenation level dependent (BOLD) fMRI is confounded by interregional neurovascular differences and poorly understood relations between BOLD and electrophysiological response delays. Here, we recorded whole-head BOLD fMRI at 100 ms resolution and magnetoencephalography (MEG) during a visuomotor reaction-time task. Both methods detected the same activation sequence across five regions, from visual towards motor cortices, with linearly correlated interregional BOLD and MEG response delays. The smallest significant interregional BOLD delay was 100 ms; all delays >= 400 ms were significant. Switching the order of external events reversed the sequence of BOLD activations, indicating that interregional neurovascular differences did not confound the results. This may open new avenues for using fMRI to follow rapid activation sequences in the brain. (C) 2013 Elsevier Inc. All rights reserved. C1 [Lin, Fa-Hsuan; Tsai, Kevin Wen-Kai; Chu, Yin-Hua; Chang, Wei-Tang] Natl Taiwan Univ, Inst Biomed Engn, Taipei 106, Taiwan. [Lin, Fa-Hsuan; Nummenmaa, Aapo] Aalto Univ, Sch Sci, Dept Biomed Engn & Computat Sci, Espoo, Finland. [Witzel, Thomas; Raij, Tommi; Ahveninen, Jyrki; Chang, Wei-Tang; Nummenmaa, Aapo; Polimeni, Jonathan R.; Rosen, Bruce R.; Belliveau, John W.] Harvard Univ, Sch Med, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol,Massachusetts Gen Hosp, Charlestown, MA USA. [Kuo, Wen-Jui; Hsieh, Jen-Chuen] Natl Yang Ming Univ, Inst Neurosci, Taipei 112, Taiwan. [Hsieh, Jen-Chuen] Natl Yang Ming Univ, Inst Brain Sci, Taipei 112, Taiwan. RP Lin, FH (reprint author), Natl Taiwan Univ, Inst Biomed Engn, 1,Sec 4,Roosevelt Rd, Taipei 106, Taiwan. EM fhlin@ntu.edu.tw RI Lin, Fa-Hsuan/G-6988-2012; Polimeni, Jonathan/P-1395-2014; Witzel, Thomas/P-1402-2014 OI Lin, Fa-Hsuan/0000-0002-9539-1731; Polimeni, Jonathan/0000-0002-1348-1179; FU United States National Institutes of Health (NIH) [R01HD040712, R01NS037462, R01NS048279, P41RR014075, R01MH083744, R21DC010060, R21EB007298]; National Center for Research Resources; National Science Council, Taiwan [NSC 101-2628-B-002-005-MY3, NSC 100-2325-B-002-046]; National Health Research Institute, Taiwan [NHRI-EX102-10247EI]; Academy of Finland [127624] FX We are grateful for access to the MEG imaging resources at the Veteran General Hospital, Taipei, Taiwan, and the MRI resources at the National Yang-Ming University and National Taiwan University Hospital, Taipei, Taiwan. We also thank Academician Riitta Hari for comments, Chih-Che Chou and Yen-Hsiang Wang for technical support, and Nichole Eusemann for language editing. This work was supported by grants from the United States National Institutes of Health (NIH) (R01HD040712, R01NS037462, R01NS048279, P41RR014075, R01MH083744, R21DC010060, R21EB007298), National Center for Research Resources, National Science Council, Taiwan (NSC 101-2628-B-002-005-MY3, NSC 100-2325-B-002-046), National Health Research Institute, Taiwan (NHRI-EX102-10247EI), and Academy of Finland (127624 and the FiDiPro program). NR 67 TC 9 Z9 9 U1 0 U2 15 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 SEP PY 2013 VL 78 BP 372 EP 384 DI 10.1016/j.neuroimage.2013.04.017 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 165MV UT WOS:000320488900036 PM 23591071 ER PT J AU Bertsimas, D Cacchiani, V Craft, D Nohadani, O AF Bertsimas, D. Cacchiani, V. Craft, D. Nohadani, O. TI A hybrid approach to beam angle optimization in intensity-modulated radiation therapy SO COMPUTERS & OPERATIONS RESEARCH LA English DT Article DE Beam angle optimization; Intensity-modulated radiation therapy; Heuristic algorithm; Simulated annealing; Gradient descent; Linear programming; Computational experiments ID ORIENTATION OPTIMIZATION; ROBUST OPTIMIZATION; RADIOTHERAPY DESIGN; DOSE OPTIMIZATION; GENETIC ALGORITHM; PENCIL BEAM; SELECTION; IMRT; CANCER AB Intensity-Modulated Radiation Therapy is the technique of delivering radiation to cancer patients by using non-uniform radiation fields from selected angles, with the aim of reducing the intensity of the beams that go through critical structures while reaching the dose prescription in the target volume. Two decisions are of fundamental importance: to select the beam angles and to compute the intensity of the beams used to deliver the radiation to the patient. Often, these two decisions are made separately: first, the treatment planners, on the basis of experience and intuition, decide the orientation of the beams and then the intensities of the beams are optimized by using an automated software tool. Automatic beam angle selection (also known as Beam Angle Optimization) is an important problem and is today often based on human experience. In this context, we face the problem of optimizing both the decisions, developing an algorithm which automatically selects the beam angles and computes the beam intensities. We propose a hybrid heuristic method, which combines a simulated annealing procedure with the knowledge of the gradient. Gradient information is used to quickly find a local minimum, while simulated annealing allows to search for global minima. As an integral part of this procedure, the beam intensities are optimized by solving a Linear Programming model. The proposed method presents a main difference from previous works: it does not require to have on input a set of candidate beam angles. Indeed, it dynamically explores angles and the only discretization that is necessary is due to the maximum accuracy that can be achieved by the linear accelerator machine. Experimental results are performed on phantom and real-life case studies, showing the advantages that come from our approach. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Bertsimas, D.] MIT, Ctr Operat Res, Cambridge, MA 02139 USA. [Cacchiani, V.] Univ Bologna, DEIS, Bologna, Italy. [Craft, D.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Craft, D.] Harvard Univ, Sch Med, Boston, MA USA. [Nohadani, O.] Purdue Univ, Sch Ind Engn, W Lafayette, IN 47907 USA. RP Cacchiani, V (reprint author), Univ Bologna, DEIS, Bologna, Italy. EM dbertsim@MIT.EDU; valentina.cacchiani@unibo.it; dcraft@partners.org; nohadani@purdue.edu RI Nohadani, Omid/N-8177-2013 NR 32 TC 12 Z9 12 U1 1 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0305-0548 J9 COMPUT OPER RES JI Comput. Oper. Res. PD SEP PY 2013 VL 40 IS 9 SI SI BP 2187 EP 2197 DI 10.1016/j.cor.2012.06.009 PG 11 WC Computer Science, Interdisciplinary Applications; Engineering, Industrial; Operations Research & Management Science SC Computer Science; Engineering; Operations Research & Management Science GA 159ZK UT WOS:000320085600004 ER PT J AU Hinton, DE Field, NP Nickerson, A Bryant, RA Simon, N AF Hinton, Devon E. Field, Nigel P. Nickerson, Angela Bryant, Richard A. Simon, Naomi TI Dreams of the Dead Among Cambodian Refugees: Frequency, Phenomenology, and Relationship to Complicated Grief and Posttraumatic Stress Disorder SO DEATH STUDIES LA English DT Article ID DIAGNOSTIC-CRITERIA; BEREAVEMENT; SURVIVORS; DEPRESSION; EARTHQUAKE; SYMPTOMS; ISSUES AB The authors investigated the importance of dreams of the deceased in the experiencing of prolonged grief (PG) and posttraumatic stress disorder (PTSD) among Cambodian refugees who survived the Pol Pot genocide (1975-1979). Such dreams were frequent in the last month (52% of those surveyed), and most often involved a relative who died in the Pol Pot period. Past month frequency was correlated with PG severity (r=.59) and PTSD severity (r=.52). The dreams were almost always deeply upsetting because the dreams indicated the deceased to be in a difficult spiritual state. Dreams of the deceased as a central component of PG and PTSD among Cambodian refugees is discussed. C1 [Hinton, Devon E.; Simon, Naomi] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Field, Nigel P.] Palo Alto Univ, Program Clin Psychol, Palo Alto, CA USA. [Nickerson, Angela] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Bryant, Richard A.] Univ New S Wales, Sch Psychol, Kensington, NSW 2033, Australia. RP Hinton, DE (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, 1 Bowdoin Sq,6th Floor, Boston, MA 02114 USA. EM devon_hinton@hms.harvard.edu OI Bryant, Richard/0000-0002-9607-819X NR 29 TC 7 Z9 7 U1 4 U2 10 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0748-1187 J9 DEATH STUD JI Death Stud. PD SEP 1 PY 2013 VL 37 IS 8 BP 750 EP 767 DI 10.1080/07481187.2012.692457 PG 18 WC Psychology, Multidisciplinary; Social Issues; Social Sciences, Biomedical SC Psychology; Social Issues; Biomedical Social Sciences GA 160DZ UT WOS:000320098500004 PM 24521031 ER PT J AU Hinton, DE Nickerson, A Bryant, RA AF Hinton, Devon E. Nickerson, Angela Bryant, Richard A. TI Prolonged Grief in Cambodian Refugees Following Genocide: Rebirth Concerns and Avoidance of Reminders SO JOURNAL OF LOSS & TRAUMA LA English DT Article DE Cambodian refugees; culture; functional impairment; prolonged grief; PTSD; rebirth concerns ID POSTTRAUMATIC-STRESS-DISORDER; COMPLICATED GRIEF; PSYCHOMETRIC PROPERTIES; BEREAVED ADULTS; TRAUMATIC GRIEF; DEPRESSION; PREVALENCE; SURVIVORS; ANXIETY; SCALE AB This study investigated whether prolonged grief (PG) forms a coherent syndrome that is discrete from posttraumatic stress disorder (PTSD) in a Cambodian refugee population and examined the relative centrality to PG of avoidance of reminders of the deceased as compared to rebirth concerns in the group. The Prolonged Grief 13 (PG-13) scale significantly explained variance over and beyond PTSD in regression analyses of severity of bereavement, as assessed by a culturally sensitive measure of grief (CSM-G) and by the presence of grief-related functional impairment. Rebirth concerns were significantly more correlated than avoidance of reminders to the PG-13 and CSM-G. In an item analysis of the PG-13 and its addendum item (rebirth concerns) to determine predictive power in respect to presence of grief-related functional impairment, the avoidance item performed very poorly and the rebirth item very well (as did the bitterness item). These findings point to the applicability of the prolonged grief disorder construct to the Cambodian experience of loss, yet indicate the poor performance of the avoidance item and the centrality of rebirth issues in this group. C1 [Hinton, Devon E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hinton, Devon E.] Harvard Univ, Sch Med, Boston, MA USA. [Hinton, Devon E.] Arbour Counseling Serv, Lowell, MA USA. [Nickerson, Angela; Bryant, Richard A.] Univ New S Wales, Sch Psychol, Sydney, NSW, Australia. RP Hinton, DE (reprint author), Massachusetts Gen Hosp, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM devon_hinton@hms.harvard.edu OI Bryant, Richard/0000-0002-9607-819X NR 50 TC 1 Z9 1 U1 8 U2 30 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1532-5024 EI 1532-5032 J9 J LOSS TRAUMA JI J. Loss Trauma PD SEP 1 PY 2013 VL 18 IS 5 BP 444 EP 460 DI 10.1080/15325024.2012.714218 PG 17 WC Psychology, Social SC Psychology GA 108WY UT WOS:000316328200006 ER PT J AU Perera, MA Cavallari, LH Limdi, NA Gamazon, ER Konkashbaev, A Daneshjou, R Pluzhnikov, A Crawford, DC Wang, JL Liu, NJ Tatonetti, N Bourgeois, S Takahashi, H Bradford, Y Burkley, BM Desnick, RJ Halperin, JL Khalifa, SI Langaee, TY Lubitz, SA Nutescu, EA Oetjens, M Shahin, MH Patel, SR Sagreiya, H Tector, M Weck, KE Rieder, MJ Scott, SA Wu, AHB Burmester, JK Wadelius, M Deloukas, P Wagner, MJ Mushiroda, T Kubo, M Roden, DM Cox, NJ Altman, RB Klein, TE Nakamura, Y Johnson, JA AF Perera, Minoli A. Cavallari, Larisa H. Limdi, Nita A. Gamazon, Eric R. Konkashbaev, Anuar Daneshjou, Roxana Pluzhnikov, Anna Crawford, Dana C. Wang, Jelai Liu, Nianjun Tatonetti, Nicholas Bourgeois, Stephane Takahashi, Harumi Bradford, Yukiko Burkley, Benjamin M. Desnick, Robert J. Halperin, Jonathan L. Khalifa, Sherief I. Langaee, Taimour Y. Lubitz, Steven A. Nutescu, Edith A. Oetjens, Matthew Shahin, Mohamed H. Patel, Shitalben R. Sagreiya, Hersh Tector, Matthew Weck, Karen E. Rieder, Mark J. Scott, Stuart A. Wu, Alan H. B. Burmester, James K. Wadelius, Mia Deloukas, Panos Wagner, Michael J. Mushiroda, Taisei Kubo, Michiaki Roden, Dan M. Cox, Nancy J. Altman, Russ B. Klein, Teri E. Nakamura, Yusuke Johnson, Julie A. TI Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study SO LANCET LA English DT Article ID EUROPEAN-AMERICANS; ATRIAL-FIBRILLATION; VKORC1; POLYMORPHISM; CYP2C9; ANTICOAGULATION; REQUIREMENTS; MAINTENANCE; HAPLOTYPES; GENOTYPE AB Background VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. Methods We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged >= 18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G -> A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5x10(-8) in the discovery cohort and p<0.0038 in the replication cohort. Findings The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1.51x10(-8)). This association was confirmed in the replication cohort (p=5.04x10(-5)); analysis of the two cohorts together produced a p value of 4.5x10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6.92 mg/week and those homozygous 9.34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). Interpretation A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. C1 [Perera, Minoli A.; Gamazon, Eric R.; Konkashbaev, Anuar; Pluzhnikov, Anna; Cox, Nancy J.] Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. [Cavallari, Larisa H.; Nutescu, Edith A.; Patel, Shitalben R.] Univ Illinois, Dept Pharm Practice, Chicago, IL USA. [Limdi, Nita A.] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA. [Limdi, Nita A.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Wang, Jelai; Liu, Nianjun] Univ Alabama Birmingham, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. [Daneshjou, Roxana; Tatonetti, Nicholas; Sagreiya, Hersh; Altman, Russ B.] Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. [Klein, Teri E.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Crawford, Dana C.; Bradford, Yukiko; Oetjens, Matthew] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN 37235 USA. [Roden, Dan M.] Vanderbilt Univ, Dept Med, Nashville, TN USA. [Roden, Dan M.] Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA. [Bourgeois, Stephane; Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge, England. [Takahashi, Harumi] Meiji Pharmaceut Univ, Dept Biopharmaceut, Tokyo, Japan. [Burkley, Benjamin M.; Langaee, Taimour Y.; Shahin, Mohamed H.; Johnson, Julie A.] Univ Florida, Ctr Pharmacogen, Dept Pharmacotherapy & Translat Res, Gainesville, FL 32610 USA. [Desnick, Robert J.; Scott, Stuart A.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Halperin, Jonathan L.] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, New York, NY USA. [Khalifa, Sherief I.] Qatar Univ, Coll Pharm, Pharmaceut Sci Sect, Doha, Qatar. [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Lubitz, Steven A.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Tector, Matthew] Aurora St Lukes Med Ctr, Milwaukee, WI USA. [Weck, Karen E.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. [Weck, Karen E.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Wagner, Michael J.] Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. [Rieder, Mark J.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Wu, Alan H. B.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Burmester, James K.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [Wadelius, Mia] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Mushiroda, Taisei; Kubo, Michiaki; Nakamura, Yusuke] RIKEN Ctr Genom Med, Yokohama, Kanagawa, Japan. RP Johnson, JA (reprint author), Univ Florida, Ctr Pharmacogen, Dept Pharmacotherapy & Translat Res, Box 100486, Gainesville, FL 32610 USA. EM johnson@cop.ufl.edu RI Deloukas, Panos/B-2922-2013; Mushiroda, Taisei/E-3022-2010; Wadelius, Mia/C-7740-2016; Kubo, Michiaki/N-7947-2015; OI Deloukas, Panos/0000-0001-9251-070X; Wadelius, Mia/0000-0002-6368-2622; Weck, Karen/0000-0002-8516-333X; Tatonetti, Nicholas/0000-0002-2700-2597; Gamazon, Eric/0000-0003-4204-8734 FU National Institutes of Health; American Heart Association; Howard Hughes Medical Institute; Wisconsin Network for Health Research; Wellcome Trust FX National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust. NR 33 TC 69 Z9 76 U1 0 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 31 PY 2013 VL 382 IS 9894 BP 790 EP 796 DI 10.1016/S0140-6736(13)60681-9 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 215VP UT WOS:000324239200029 PM 23755828 ER PT J AU Andrawes, MB Xu, X Liu, H Ficarro, SB Marto, JA Aster, JC Blacklow, SC AF Andrawes, Marie Blanke Xu, Xiang Liu, Hong Ficarro, Scott B. Marto, Jarrod A. Aster, Jon C. Blacklow, Stephen C. TI Intrinsic Selectivity of Notch 1 for Delta-like 4 Over Delta-like 1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LINKED-N-ACETYLGLUCOSAMINE; CELL LINEAGE COMMITMENT; INHIBITS TUMOR-GROWTH; LIGAND-BINDING; INTRACELLULAR DOMAIN; DROSOPHILA NOTCH; MAMMALIAN NOTCH; ABRUPTEX DOMAIN; MODIFIES NOTCH; MOUSE NOTCH1 AB Notch signaling makes critical contributions to cell fate determination in all metazoan organisms, yet remarkably little is known about the binding affinity of the four mammalian Notch receptors for their three Delta-like and two Jagged family ligands. Here, we utilized signaling assays and biochemical studies of purified recombinant ligand and receptor molecules to investigate the differences in signaling behavior and intrinsic affinity between Notch1-Dll1 and Notch1-Dll4 complexes. Systematic deletion mutagenesis of the human Notch1 ectodomain revealed that epidermal growth factor (EGF) repeats 6-15 are sufficient to maintain signaling in a reporter assay at levels comparable with the full-length receptor, and identified important contributions from EGF repeats 8-10 in conveying an activating signal in response to either Dll1 or Dll4. Truncation studies of the Dll1 and Dll4 ectodomains showed that the MNNL-EGF3 region was both necessary and sufficient for full activation. Plate-based and cell binding assays revealed a specific, calcium-dependent interaction between cell-surface and recombinant Notch receptors and ligand molecules. Finally, direct measurement of the binding affinity of Notch1 EGF repeats 6-15 for Dll1 and Dll4 revealed that Dll4 binds with at least an order of magnitude higher affinity than Dll1. Together, these studies give new insights into the features of ligand recognition by Notch1, and highlight how intrinsic differences in the biochemical behavior of receptor-ligand complexes can influence receptor-mediated responses of developmental signaling pathways. C1 [Blacklow, Stephen C.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Andrawes, Marie Blanke; Xu, Xiang; Liu, Hong; Ficarro, Scott B.; Marto, Jarrod A.; Blacklow, Stephen C.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02114 USA. [Aster, Jon C.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Blacklow, SC (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. EM Stephen_blacklow@hms.harvard.edu FU National Institutes of Health [R01 CA092433, P01 CA119070] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 CA092433 (to S. C. B.) and P01 CA119070. NR 67 TC 27 Z9 28 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 30 PY 2013 VL 288 IS 35 BP 25477 EP 25489 DI 10.1074/jbc.M113.454850 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302QC UT WOS:000330619000043 PM 23839946 ER PT J AU Braunwald, E AF Braunwald, Eugene TI Research Advances in Heart Failure A Compendium SO CIRCULATION RESEARCH LA English DT Review ID CARDIAC RESYNCHRONIZATION THERAPY; PRESERVED EJECTION FRACTION; RYANODINE RECEPTOR PHOSPHORYLATION; HYPERTROPHIC SUBAORTIC STENOSIS; VENTRICULAR ASSIST DEVICE; DILATED CARDIOMYOPATHY; SARCOPLASMIC-RETICULUM; MAGNETIC-RESONANCE; MITOCHONDRIAL CA2+; SHATTUCK LECTURE C1 [Braunwald, Eugene] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Braunwald, E (reprint author), TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. EM ebraunwald@partners.org NR 104 TC 25 Z9 25 U1 1 U2 20 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG 30 PY 2013 VL 113 IS 6 BP 633 EP 645 DI 10.1161/CIRCRESAHA.113.302254 PG 13 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 286OX UT WOS:000329479700001 PM 23888056 ER PT J AU Ky, B Vejpongsa, P Yeh, ETH Force, T Moslehi, JJ AF Ky, Bonnie Vejpongsa, Pimprapa Yeh, Edward T. H. Force, Thomas Moslehi, Javid J. TI Emerging Paradigms in Cardiomyopathies Associated With Cancer Therapies SO CIRCULATION RESEARCH LA English DT Review DE angiogenesis inhibitors; anthracyclines; cancer; chemotherapies; cardiomyopathy; cardio-oncology; HER2-targeted therapies ID METASTATIC BREAST-CANCER; CHRONIC HEART-FAILURE; TYROSINE KINASE INHIBITOR; RECOMBINANT HUMAN NEUREGULIN-1; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACTIVATED PROTEIN-KINASE; TOPOISOMERASE-II; INDUCED CARDIOTOXICITY; GROWTH-FACTOR; OPEN-LABEL AB The cardiovascular care of cancer patients (cardio-oncology) has emerged as a new discipline in clinical medicine, given recent advances in cancer therapy, and is driven by the cardiovascular complications that occur as a direct result of cancer therapy. Traditional therapies such as anthracyclines and radiation have been recognized for years to have cardiovascular complications. Less expected were the cardiovascular effects of targeted cancer therapies, which were initially thought to be specific to cancer cells and would spare any adverse effects on the heart. Cancers are typically driven by mutations, translocations, or overexpression of protein kinases. The majority of these mutated kinases are tyrosine kinases, though serine/threonine kinases also play key roles in some malignancies. Several agents were developed to target these kinases, but many more are in development. Major successes have been largely restricted to agents targeting human epidermal growth factor receptor-2 (mutated or overexpressed in breast cancer), BCR-ABL (chronic myelogenous leukemia and some cases of acute lymphoblastic leukemia), and c-Kit (gastrointestinal stromal tumor). Other agents targeting more complex malignancies, such as advanced solid tumors, have had successes, but have not extended life to the degree seen with chronic myelogenous leukemia. Years before the first targeted therapy, Judah Folkman correctly proposed that to address solid tumors one had to target the inherent neoangiogenesis. Unfortunately, emerging evidence confirms that angiogenesis inhibitors cause cardiac complications, including hypertension, thrombosis, and heart failure. And therein lies the catch-22. Nevertheless, cardio-oncology has the potential to be transformative as the human cardiomyopathies that arise from targeted therapies can provide insights into the normal function of the heart. C1 [Ky, Bonnie] Univ Penn, Sch Med, Dept Med, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Vejpongsa, Pimprapa; Yeh, Edward T. H.] Univ Texas MD Anderson Canc Ctr, Texas Heart Inst, Dept Cardiol, Houston, TX 77030 USA. [Force, Thomas] Temple Univ, Sch Med, Div Cardiol, Ctr Translat Med, Philadelphia, PA 19140 USA. [Moslehi, Javid J.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Moslehi, Javid J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Cardiooncol Program, Boston, MA 02115 USA. RP Force, T (reprint author), Temple Univ, Sch Med, Ctr Translat Med, MERB, 3500 N Broad St,Room 943, Philadelphia, PA 19140 USA. EM Thomas.force@temple.edu; jmoslehi@partners.org OI Force, Thomas/0000-0002-0450-8659 FU National Institute of Health (NIH) [K23 HL095661]; Cancer Prevention Research Institute of Texas; National Heart, Lung, and Blood Institute (NHLBI) [HL061688, HL114124]; NIH Career Development Award; Watkins Discovery Award by Brigham and Women's Hospital; Cardiovascular Leadership Council Investigator Award by Brigham and Women's Hospital FX B. Ky is supported by National Institute of Health (NIH) K23 HL095661. E. T. H. Yeh is supported by the Cancer Prevention Research Institute of Texas. T. Force is supported by grants from the National Heart, Lung, and Blood Institute (NHLBI; HL061688 and HL114124). J. Moslehi is supported by an NIH Career Development Award, Watkins Discovery Award, and Cardiovascular Leadership Council Investigator Award (both by Brigham and Women's Hospital). NR 93 TC 42 Z9 42 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG 30 PY 2013 VL 113 IS 6 BP 754 EP 764 DI 10.1161/CIRCRESAHA.113.300218 PG 11 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 286OX UT WOS:000329479700009 PM 23989717 ER PT J AU DePasse, JW Lee, PT AF DePasse, Jacqueline W. Lee, Patrick T. TI A model for 'reverse innovation' in health care SO GLOBALIZATION AND HEALTH LA English DT Article AB 'Reverse innovation,' a principle well established in the business world, describes the flow of ideas from emerging to more developed economies. There is strong and growing interest in applying this concept to health care, yet there is currently no framework for describing the stages of reverse innovation or identifying opportunities to accelerate the development process. This paper combines the business concept of reverse innovation with diffusion of innovation theory to propose a model for reverse innovation as a way to innovate in health care. Our model includes the following steps: (1) identifying a problem common to lower-and higher-income countries; (2) innovation and spread in the low-income country (LIC); (3) crossover to the higher-income country (HIC); and (4) innovation and spread in the HIC. The crucial populations in this pathway, drawing from diffusion of innovation theory, are LIC innovators, LIC early adopters, and HIC innovators. We illustrate the model with three examples of current reverse innovations. We then propose four sets of specific actions that forward-looking policymakers, entrepreneurs, health system leaders, and researchers may take to accelerate the movement of promising solutions through the reverse innovation pipeline: (1) identify high-priority problems shared by HICs and LICs; (2) create slack for change, especially for LIC innovators, LIC early adopters, and HIC innovators; (3) create spannable social distances between LIC early adopters and HIC innovators; and (4) measure reverse innovation activity globally. C1 [DePasse, Jacqueline W.] Massachusetts Gen Hosp, Dept Internal Med, Boston, MA 02114 USA. [Lee, Patrick T.] Massachusetts Gen Hosp, Global Primary Care Program, Boston, MA 02114 USA. RP Lee, PT (reprint author), Massachusetts Gen Hosp, Global Primary Care Program, Boston, MA 02114 USA. EM ptlee@partners.org NR 13 TC 12 Z9 12 U1 1 U2 30 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8603 J9 GLOBALIZATION HEALTH JI Global. Health PD AUG 30 PY 2013 VL 9 AR UNSP 40 DI 10.1186/1744-8603-9-40 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 216EX UT WOS:000324265800001 PM 24001367 ER PT J AU Katz, IT Nkala, B Dietrich, J Wallace, M Bekker, LG Pollenz, K Bogart, LM Wright, AA Tsai, AC Bangsberg, DR Gray, GE AF Katz, Ingrid T. Nkala, Busisiwe Dietrich, Janan Wallace, Melissa Bekker, Linda-Gail Pollenz, Kathryn Bogart, Laura M. Wright, Alexi A. Tsai, Alexander C. Bangsberg, David R. Gray, Glenda E. TI A Qualitative Analysis of Factors Influencing HPV Vaccine Uptake in Soweto, South Africa among Adolescents and Their Caregivers SO PLOS ONE LA English DT Article ID HUMAN-PAPILLOMAVIRUS VACCINATION; RANDOMIZED CONTROLLED-TRIAL; CERVICAL-CANCER PREVENTION; LOW-RESOURCE SETTINGS; SUB-SAHARAN AFRICA; DECISION-MAKING; WOMEN; ACCEPTABILITY; ACCEPTANCE; ATTITUDES AB Background: In South Africa, the prevalence of oncogenic Human Papillomavirus (HPV) may be as high as 64%, and cervical cancer is the leading cause of cancer-related death among women. The development of efficacious prophylactic vaccines has provided an opportunity for primary prevention. Given the importance of psycho-social forces in vaccine uptake, we sought to elucidate factors influencing HPV vaccination among a sample of low-income South African adolescents receiving the vaccine for the first time in Soweto. Methods: The HPV vaccine was introduced to adolescents in low-income townships throughout South Africa as part of a nationwide trial to understand adolescent involvement in future vaccine research targeting human immunodeficiency virus (HIV). We performed in-depth semi-structured interviews with purposively-sampled adolescents and their care providers to understand what forces shaped HPV vaccine uptake. Interviews were recorded, transcribed, translated, and examined using thematic analysis. Results: Of 224 adolescents recruited, 201 initiated the vaccine; 192 (95.5%) received a second immunization; and 164 (81.6%) completed three doses. In our qualitative study of 39 adolescent-caregiver dyads, we found that factors driving vaccine uptake reflected a socio-cultural backdrop of high HIV endemnicity, sexual violence, poverty, and an abundance of female-headed households. Adolescents exercised a high level of autonomy and often initiated decision-making. Healthcare providers and peers provided support and guidance that was absent at home. The impact of the HIV epidemic on decision-making was substantial, leading participants to mistakenly conflate HPV and HIV. Conclusions: In a setting of perceived rampant sexual violence and epidemic levels of HIV, adolescents and caregivers sought to decrease harm by seeking a vaccine targeting a sexually transmitted infection (STI). Despite careful consenting, there was confusion regarding the vaccine's target. Future interventions promoting STI vaccines will need to provide substantial information for participants, particularly adolescents who may exercise a significant level of autonomy in decision-making. C1 [Katz, Ingrid T.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Katz, Ingrid T.; Pollenz, Kathryn; Bogart, Laura M.; Wright, Alexi A.; Tsai, Alexander C.; Bangsberg, David R.] Harvard Univ, Sch Med, Boston, MA USA. [Katz, Ingrid T.; Tsai, Alexander C.; Bangsberg, David R.] Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Nkala, Busisiwe; Dietrich, Janan; Gray, Glenda E.] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. [Wallace, Melissa; Bekker, Linda-Gail] Univ Cape Town, Inst Infect Dis & Mol Med, Desmond Tutu HIV Ctr, ZA-7925 Cape Town, South Africa. [Bogart, Laura M.] Childrens Hosp Boston, Boston, MA USA. [Wright, Alexi A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bangsberg, David R.] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA USA. [Bangsberg, David R.] Harvard Univ, Boston, MA 02115 USA. RP Katz, IT (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM ikatz2@partners.org OI Tsai, Alexander/0000-0001-6397-7917 FU KL2 MeRIT program of Harvard Catalyst \ The Harvard Clinical and Translational Science Center [UL1 RR 025758]; Harvard University; National Institute of Mental Health [1K23MH097667-01, K23 MH-096620, 5K24AA015287-06]; Harvard University Center for AIDS Research (HU CFAR HIV/NIAID) [5P30A1060354-08]; European & Developing Countries Clinical Trials Partnership; South African AIDS Vaccine Initiative (SAAVI) FX This qualitative study was funded by a grant to Dr. Katz, MD, MHS, from the KL2 MeRIT program of Harvard Catalyst vertical bar The Harvard Clinical and Translational Science Center (Award #UL1 RR 025758), and by financial contributions from Harvard University and its affiliated academic health care centers. Dr. Katz currently receives salary support through the National Institute of Mental Health (1K23MH097667-01) and the Harvard University Center for AIDS Research (HU CFAR HIV/NIAID, Fund 5P30A1060354-08. Ms. Nkala received support from The European & Developing Countries Clinical Trials Partnership. Ms. Dietrich receives partial salary support through The South African AIDS Vaccine Initiative (SAAVI). Dr. Tsai receives salary support through The National Institute of Mental Health (K23 MH-096620). Dr. Bangsberg receives salary support through The National Institute of Mental Health (5K24AA015287-06). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 11 Z9 11 U1 3 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 30 PY 2013 VL 8 IS 8 AR e72094 DI 10.1371/journal.pone.0072094 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 211BX UT WOS:000323880200008 PM 24023613 ER PT J AU Bui, E LeBlanc, NJ Morris, LK Marques, L Shear, MK Simon, NM AF Bui, Eric LeBlanc, Nicole J. Morris, Laura K. Marques, Luana Shear, M. Katherine Simon, Naomi M. TI Panic-agoraphobic spectrum symptoms in complicated grief SO PSYCHIATRY RESEARCH LA English DT Article DE Panic disorder; Bereavement; Quality of life ID QUALITY-OF-LIFE; TREATMENT RESPONSE; MAJOR DEPRESSION; ANXIETY; BEREAVEMENT; IMPAIRMENT AB Little is known about the presence and role of subclinical anxiety symptoms and traits in complicated grief (CG). Data from adults with CG (n=28) suggest that they experience more panic-spectrum symptoms (PSS) than bereaved controls (n=44), and that the presence of greater PSS is independently associated with poorer quality of life. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Bui, Eric; LeBlanc, Nicole J.; Morris, Laura K.; Marques, Luana; Simon, Naomi M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Bui, Eric; Marques, Luana; Simon, Naomi M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Bui, Eric] CHU Toulouse, Dept Psychiat, Toulouse, France. [Bui, Eric] Univ Toulouse 3, F-31062 Toulouse, France. [Shear, M. Katherine] Columbia Univ, Dept Psychiat, New York, NY USA. RP Bui, E (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, 1 Bowdoin Sq, Boston, MA 02114 USA. EM tebui@partners.org RI Bui, Eric/J-8347-2015 OI Bui, Eric/0000-0002-1413-6473 FU NIMH NIH HHS [R01 MH085308, R01 MH060783] NR 15 TC 1 Z9 1 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 30 PY 2013 VL 209 IS 1 BP 118 EP 120 DI 10.1016/j.psychres.2013.03.033 PG 3 WC Psychiatry SC Psychiatry GA 210XY UT WOS:000323869600019 PM 23623453 ER PT J AU Caruso, TJ Fuzaylov, G AF Caruso, Thomas J. Fuzaylov, Gennadiy TI Severe Vitamin D Deficiency Rickets SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material AB A 12-year-old girl from Ukraine was hospitalized for evaluation of a history of long-bone fractures and failure to thrive. On initial presentation, she had hypocalcemia (calcium level, 6.7 mg per deciliter [1.7 mmol per liter]), a low 25-hydroxyvitamin D level (5 ng per milliliter [12 nmol per liter]), an elevated parathyroid hormone level (435 pg per milliliter), an elevated alkaline phosphatase level (546 U per liter), and a normal phosphorus level (4.1 mg per deciliter [1.3 mmol per liter]). These findings were consistent with vitamin D-deficient rickets. She also showed multiple sequelae of long-standing rickets, including costochondral swelling (rachitic rosary), ... C1 [Caruso, Thomas J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Fuzaylov, Gennadiy] Shriners Hosp Children, Boston, MA USA. RP Caruso, TJ (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 4 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 AUG 29 PY 2013 VL 369 IS 9 BP E11 EP E11 DI 10.1056/NEJMicm1205540 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 208KB UT WOS:000323676100001 PM 23984751 ER PT J AU Pulido, T Adzerikho, I Channick, RN Delcroix, M Galie, N Ghofrani, HA Jansa, P Jing, ZC Le Brun, FO Mehta, S Mittelholzer, CM Perchenet, L Sastry, BKS Sitbon, O Souza, R Torbicki, A Zeng, XF Rubin, LJ Simonneau, G AF Pulido, Tomas Adzerikho, Igor Channick, Richard N. Delcroix, Marion Galie, Nazzareno Ghofrani, Hossein-Ardeschir Jansa, Pavel Jing, Zhi-Cheng Le Brun, Franck-Olivier Mehta, Sanjay Mittelholzer, Camilla M. Perchenet, Loic Sastry, B. K. S. Sitbon, Olivier Souza, Rogerio Torbicki, Adam Zeng, Xiaofeng Rubin, Lewis J. Simonneau, Gerald CA SERAPHIN Investigators TI Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ENDOTHELIN-RECEPTOR ANTAGONIST; 6-MINUTE WALK DISTANCE; DOUBLE-BLIND; AMBRISENTAN THERAPY; INHALED ILOPROST; CONTROLLED-TRIAL; CLINICAL-TRIAL; BOSENTAN; TREPROSTINIL; EPOPROSTENOL AB Background Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial. Methods We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. Results A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P=0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. Conclusions Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.) C1 [Pulido, Tomas] Ignacio Chavez Natl Heart Inst, Cardiopulm Dept, Mexico City, DF, Mexico. [Adzerikho, Igor] Republican Sci Pract Ctr Cardiol, Minsk, Byelarus. [Channick, Richard N.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Delcroix, Marion] Univ Hosp Gasthuisberg, Dept Pneumol, B-3000 Louvain, Belgium. [Galie, Nazzareno] Bologna Univ Hosp, Dept Expt Diagnost & Specialty Med, Bologna, Italy. [Ghofrani, Hossein-Ardeschir] Univ Giessen, D-35390 Giessen, Germany. [Ghofrani, Hossein-Ardeschir] Marburg Lung Ctr, Giessen, Germany. [Ghofrani, Hossein-Ardeschir] Univ London Imperial Coll Sci Technol & Med, Dept Med, London, England. [Jansa, Pavel] Charles Univ Prague, Dept Med 2, Fac Med 1, Clin Dept Cardiol & Angiol, Prague, Czech Republic. [Jing, Zhi-Cheng] Chinese Acad Med Sci, Fu Wai Hosp, State Key Lab Cardiovasc Dis, Thrombosis Med Ctr, Beijing 100730, Peoples R China. [Zeng, Xiaofeng] Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Rheumatol, Beijing 100730, Peoples R China. Peking Union Med Coll, Beijing 100021, Peoples R China. [Le Brun, Franck-Olivier; Mittelholzer, Camilla M.; Perchenet, Loic] Actelion Pharmaceut, Allschwil, Switzerland. [Mehta, Sanjay] Western Univ, Victoria Hosp, London Hlth Sci Ctr, Div Respirol,Dept Med, London, ON, Canada. [Sastry, B. K. S.] CARE Hosp, Dept Cardiol, Hyderabad, Andhra Pradesh, India. [Sitbon, Olivier; Simonneau, Gerald] Univ Paris 11, Hop Bicetre, AP HP,Serv Pneumol, Lab Excellence Rech Medicament & Innovat Therapeu, Le Kremlin Bicetre, France. [Sitbon, Olivier; Simonneau, Gerald] INSERM, U999, F-94275 Le Kremlin Bicetre, France. [Souza, Rogerio] Univ Sao Paulo, Sch Med, Inst Heart, Dept Pulm, Sao Paulo, Brazil. [Torbicki, Adam] European Hlth Ctr Otwock, Med Ctr Postgrad Educ, Dept Pulm Circulat & Thromboembol Dis, Otwock, Poland. [Rubin, Lewis J.] Univ Calif San Diego, Div Pulm & Crit Care Med, La Jolla, CA 92093 USA. RP Pulido, T (reprint author), Ignacio Chavez Natl Heart Inst, Cardiopulm Dept, Juan Badiano 1,4th Fl, Mexico City, DF, Mexico. EM tpulido@prodigy.net.mx RI Souza, Rogerio/I-3584-2013; Arkhipov, Mikhail/Q-2316-2015; Chazova, Irina/B-8688-2017; OI Chazova, Irina/0000-0002-9822-4357; Galie, Nazzareno/0000-0003-4271-8670; vizza, carmine dario/0000-0002-3540-4983 FU Actelion Pharmaceuticals FX Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179. NR 26 TC 306 Z9 322 U1 3 U2 35 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 AUG 29 PY 2013 VL 369 IS 9 BP 809 EP 818 DI 10.1056/NEJMoa1213917 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 208KB UT WOS:000323676100008 PM 23984728 ER PT J AU Iyengar, SR Ebb, DH Yuan, Q Shailam, R Bhan, AK AF Iyengar, Shuba R. Ebb, David H. Yuan, Qian Shailam, Randheer Bhan, Atul K. TI Case 27-2013: A 6.5-Month-Old Boy with Fever, Rash, and Cytopenias SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; IMMUNE THROMBOCYTOPENIC PURPURA; SYNDROME ALPS; T-CELLS; CHILDREN; EXPRESSION; MANAGEMENT; APOPTOSIS; ONSET C1 [Ebb, David H.; Yuan, Qian] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Shailam, Randheer] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Bhan, Atul K.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ebb, David H.; Yuan, Qian] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Shailam, Randheer] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Bhan, Atul K.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Iyengar, SR (reprint author), Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. NR 20 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 AUG 29 PY 2013 VL 369 IS 9 BP 853 EP 863 DI 10.1056/NEJMcpc1209277 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 208KB UT WOS:000323676100013 PM 23984733 ER PT J AU He, CC Wei, YJ Sun, K Li, BH Dong, XN Zou, ZJ Liu, Y Kinch, LN Khan, S Sinha, S Xavier, RJ Grishin, NV Xiao, GH Eskelinen, EL Scherer, PE Whistler, JL Levine, B AF He, Congcong Wei, Yongjie Sun, Kai Li, Binghua Dong, Xiaonan Zou, Zhongju Liu, Yang Kinch, Lisa N. Khan, Shaheen Sinha, Sangita Xavier, Ramnik J. Grishin, Nick V. Xiao, Guanghua Eskelinen, Eeva-Liisa Scherer, Philipp E. Whistler, Jennifer L. Levine, Beth TI Beclin 2 Functions in Autophagy, Degradation of G Protein-Coupled Receptors, and Metabolism SO CELL LA English DT Article ID MEMBRANE-TRAFFICKING; SORTING PROTEINS; LINKAGE; SYSTEM; CELLS; FAMILY; SCAN AB The molecular mechanism of autophagy and its relationship to other lysosomal degradation pathways remain incompletely understood. Here, we identified a previously uncharacterized mammalian-specific protein, Beclin 2, which, like Beclin 1, functions in autophagy and interacts with class III PI3K complex components and Bcl-2. However, Beclin 2, but not Beclin 1, functions in an additional lysosomal degradation pathway. Beclin 2 is required for ligand-induced endolysosomal degradation of several G protein-coupled receptors (GPCRs) through its interaction with GASP1. Beclin 2 homozygous knockout mice have decreased embryonic viability, and heterozygous knockout mice have defective autophagy, increased levels of brain cannabinoid 1 receptor, elevated food intake, and obesity and insulin resistance. Our findings identify Beclin 2 as a converging regulator of autophagy and GPCR turnover and highlight the functional and mechanistic diversity of Beclin family members in autophagy, endolysosomal trafficking, and metabolism. C1 [He, Congcong; Wei, Yongjie; Zou, Zhongju; Kinch, Lisa N.; Grishin, Nick V.; Levine, Beth] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [He, Congcong; Wei, Yongjie; Dong, Xiaonan; Zou, Zhongju; Liu, Yang; Levine, Beth] Univ Texas SW Med Ctr Dallas, Ctr Autophagy Res, Dallas, TX 75390 USA. [Sun, Kai; Scherer, Philipp E.] Univ Texas SW Med Ctr Dallas, Touchstone Diabet Ctr, Dallas, TX 75390 USA. [He, Congcong; Wei, Yongjie; Sun, Kai; Li, Binghua; Dong, Xiaonan; Zou, Zhongju; Liu, Yang; Khan, Shaheen; Scherer, Philipp E.; Levine, Beth] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Kinch, Lisa N.; Grishin, Nick V.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Kinch, Lisa N.; Grishin, Nick V.] Univ Texas SW Med Ctr Dallas, Dept Biophys, Dallas, TX 75390 USA. [Xiao, Guanghua] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Levine, Beth] Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. [Sinha, Sangita] N Dakota State Univ, Dept Chem & Biochem, Fargo, ND 58102 USA. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. [Xavier, Ramnik J.] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] MIT, Cambridge, MA 02142 USA. [Eskelinen, Eeva-Liisa] Univ Helsinki, Div Biochem & Biotechnol, Dept Biosci, FI-00014 Helsinki, Finland. [Whistler, Jennifer L.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. RP Levine, B (reprint author), Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. EM beth.levine@utsouthwestern.edu FU NIH [ROI CA109618, ROI GM094575, ROI DK55758, PO1 DK088761, ROI DA019958, ROI DK043351, K99 DK094980, R21 AI078198, P20 RR015566]; Welch Foundation [I-1505]; state of California for medical research on alcohol and substance abuse through the University of California, San Francisco; Academy of Finland FX We thank Haley Harrington for assistance with manuscript preparation and the Electron Microscopy Unit of the Institute of Biotechnology, University of Helsinki, Finland for providing laboratory facilities. This work was supported by NIH awards ROI CA109618 (B. L.), ROI GM094575 (N. V. G.), ROI DK55758 (P. E. S.), PO1 DK088761 (P. E. S.), ROI DA019958 (J. L. W.), ROI DK043351 (R. J. X.), K99 DK094980 (C. H.), R21 AI078198 (S. S.), and P20 RR015566 (S. S.); a Welch Foundation Award I-1505 (N. V. G.); and funds provided by the state of California for medical research on alcohol and substance abuse through the University of California, San Francisco to J. L. W. E.-L. E. was supported by the Academy of Finland. The authors Y. W., K. S., and B. Li all contributed equally to this manuscript. NR 31 TC 42 Z9 55 U1 1 U2 36 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 29 PY 2013 VL 154 IS 5 BP 1085 EP 1099 DI 10.1016/j.cell.2013.07.035 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 209OE UT WOS:000323767300021 PM 23954414 ER PT J AU Schroeder, FA Chonde, DB Riley, MM Moseley, CK Granda, ML Wilson, CM Wagner, FF Zhang, YL Gale, J Holson, EB Haggarty, SJ Hooker, JM AF Schroeder, Frederick A. Chonde, Daniel B. Riley, Misha M. Moseley, Christian K. Granda, Michael L. Wilson, Colin M. Wagner, Florence F. Zhang, Yan-Ling Gale, Jennifer Holson, Edward B. Haggarty, Stephen J. Hooker, Jacob M. TI FDG-PET imaging reveals local brain glucose utilization is altered by class I histone deacetylase inhibitors SO NEUROSCIENCE LETTERS LA English DT Article DE Metabolism; Epigenetic; Chromatin; Rat; Necuroimaging; Acetylation ID RAT; DEPRESSION; PLASTICITY; PROTOCOL; BEHAVIOR; NUCLEUS; PREDICT; TRIAL; HDAC AB The purpose of this work - the first of its kind - was to evaluate the impact of chronic selective histone deacetylase (HDAC) inhibitor treatment on brain activity using uptake of the radioligand F-18-fluorodeoxyglucose and positron emission tomography ((18)FDG-PET). HDAC dysfunction and other epigenetic mechanisms are implicated in diverse CNS disorders and animal research suggests HDAC inhibition may provide a lead toward developing improved treatment. To begin to better understand the role of the class I HDAC subtypes HDAC 1, 2 and 3 in modulating brain activity, we utilized two benzamide inhibitors from the literature, compound 60 (Cpd-60) and CI-994 which selectively inhibit HDAC 1 and 2 or HDACs 1, 2 and 3, respectively. One day after the seventh treatment with Cpd-60 (22.5 mg/kg) or CI-994 (5 mg/kg), (18)FDG-PET experiments (n = 11-12 rats per treatment group) revealed significant, local changes in brain glucose utilization. These 2-17% changes were represented by increases and decreases in glucose uptake. The pattern of changes was similar but distinct between Cpd-60 and CI-994, supporting that (18)FDG-PET is a useful tool to examine the relationship between HDAC subtype activity and brain activity. Further work using additional selective HDAC inhibitors will be needed to clarify these effects as well as to understand how brain activity changes influence behavioral response. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Schroeder, Frederick A.; Chonde, Daniel B.; Riley, Misha M.; Moseley, Christian K.; Granda, Michael L.; Wilson, Colin M.; Hooker, Jacob M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02129 USA. [Schroeder, Frederick A.; Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Neurol, Chem Neurobiol Lab, Boston, MA 02114 USA. [Schroeder, Frederick A.; Haggarty, Stephen J.] Massachusetts Gen Hosp, Ctr Human Genet Res, Dept Psychiat, Boston, MA 02114 USA. [Wagner, Florence F.; Zhang, Yan-Ling; Gale, Jennifer; Holson, Edward B.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA. RP Hooker, JM (reprint author), Athinoula A Martinos Ctr Biomed Imaging, Bldg 149,13th St,Suite 2301, Charlestown, MA 02129 USA. EM hooker@nmr.mgh.harvard.edu OI Hooker, Jacob/0000-0002-9394-7708; Haggarty, Stephen J./0000-0002-7872-168X FU National Institute of Drug Abuse (NIDA) of the National Institutes of Health [R01DA030321, R01DA028301]; Alzheimer's Association and Tau Consortium FX Research was supported by the National Institute of Drug Abuse (NIDA) of the National Institutes of Health under grant numbers R01DA030321 (J.M.H.; S.J.H); R01DA028301 (S.J.H.). Additional support was provided by the Alzheimer's Association and Tau Consortium (S.J.H.). We thank members of the Hooker and Haggarty labs for their critical feedback and Dr. Stephen Sawiak, University of Cambridge, for assistance with SPM software. NR 32 TC 5 Z9 7 U1 1 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD AUG 29 PY 2013 VL 550 BP 119 EP 124 DI 10.1016/j.neulet.2013.06.016 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 210RE UT WOS:000323851400023 PM 23810801 ER PT J AU Katz, SG Fisher, JK Correll, M Bronson, RT Ligon, KL Walensky, LD AF Katz, S. G. Fisher, J. K. Correll, M. Bronson, R. T. Ligon, K. L. Walensky, L. D. TI Brain and testicular tumors in mice with progenitor cells lacking BAX and BAK SO ONCOGENE LA English DT Article DE BAX; BAK; neural progenitor cell; apoptosis; tumorigenesis ID NEURAL STEM-CELLS; ABUNDANT NEUROPIL; MALIGNANT GLIOMA; TRANSGENIC MICE; NERVOUS-SYSTEM; EMBRYONIC STEM; TRUE ROSETTES; LEYDIG-CELLS; MOUSE MODEL; IN-VIVO AB The proapoptotic BCL-2 family proteins BAX and BAK serve as essential gatekeepers of the intrinsic apoptotic pathway and, when activated, transform into pore-forming homo-oligomers that permeabilize the mitochondrial outer membrane. Deletion of Bax and Bak causes marked resistance to death stimuli in a variety of cell types. Bax(-/-) Bak(-/-) mice are predominantly non-viable and survivors exhibit multiple developmental abnormalities characterized by cellular excess, including accumulation of neural progenitor cells in the periventricular, hippocampal, cerebellar and olfactory bulb regions of the brain. To explore the long-term pathophysiological consequences of BAX/BAK deficiency in a stem cell niche, we generated Bak(-/-) mice with conditional deletion of Bax in Nestin-positive cells. Aged Nestin(Cre)Bax(fl/fl)Bak(-/-) mice manifest progressive brain enlargement with a profound accumulation of NeuN- and Sox2-positive neural progenitor cells within the subventricular zone (SVZ). One-third of the mice develop frank masses comprised of neural progenitors, and in 20% of these cases, more aggressive, hypercellular tumors emerged. Unexpectedly, 60% of Nestin(Cre)Bax(fl/fl)Bak(-/-) mice harbored high-grade tumors within the testis, a peripheral site of Nestin expression. This in vivo model of severe apoptotic blockade highlights the constitutive role of BAX/BAK in long-term regulation of Nestin-positive progenitor cell pools, with loss of function predisposing to adult-onset tumorigenesis. C1 [Katz, S. G.; Fisher, J. K.; Walensky, L. D.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA. [Katz, S. G.; Fisher, J. K.; Walensky, L. D.] Dana Farber Canc Inst, Program Canc Chem Biol, Boston, MA 02215 USA. [Katz, S. G.; Ligon, K. L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Correll, M.] Dana Farber Canc Inst, Boston, MA 02215 USA. [Bronson, R. T.; Ligon, K. L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ligon, K. L.] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA USA. [Ligon, K. L.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. RP Walensky, LD (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 450 Brookline Ave,Mayer 664, Boston, MA 02215 USA. EM Loren_Walensky@dfci.harvard.edu FU NIH [5R01CA050239, 1P01CA142536, 5K08HL103847]; Todd J Schwartz Memorial Fund FX We thank E Smith for editorial and graphics assistance, R Segal, R Folkerth and C Stiles for helpful discussions, and S Rodig and the Harvard Medical School Rodent Histopathology and Brigham and Women's Hospital, Specialized Histopathology cores for technical support. This work was supported by NIH Grants 5R01CA050239 and 1P01CA142536 to LDW, NIH Grant 5K08HL103847 to SGK and the Todd J Schwartz Memorial Fund. NR 42 TC 0 Z9 0 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 29 PY 2013 VL 32 IS 35 BP 4078 EP 4085 DI 10.1038/onc.2012.421 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 209IG UT WOS:000323748500003 PM 22986529 ER PT J AU Jin, HY Oda, H Lai, MY Skalsky, RL Bethel, K Shepherd, J Kang, SG Liu, WH Sabouri-Ghomi, M Cullen, BR Rajewsky, K Xiao, CC AF Jin, Hyun Yong Oda, Hiroyo Lai, Maoyi Skalsky, Rebecca L. Bethel, Kelly Shepherd, Jovan Kang, Seung Goo Liu, Wen-Hsien Sabouri-Ghomi, Mohsen Cullen, Bryan R. Rajewsky, Klaus Xiao, Changchun TI MicroRNA-17 similar to 92 plays a causative role in lymphomagenesis by coordinating multiple oncogenic pathways SO EMBO JOURNAL LA English DT Article ID B-CELL LYMPHOMAS; MICRORNA TARGET PREDICTIONS; TGF-BETA PATHWAY; MIR-17-92 CLUSTER; BURKITT-LYMPHOMA; MESSENGER-RNAS; CANCER; MICE; MYC; PATHOGENESIS AB MicroRNAs (miRNAs) have been broadly implicated in cancer, but their exact function and mechanism in carcinogenesis remain poorly understood. Elevated miR-17 similar to 92 expression is frequently found in human cancers, mainly due to gene amplification and Myc-mediated transcriptional upregulation. Here we show that B cell-specific miR-17 similar to 92 transgenic mice developed lymphomas with high penetrance and that, conversely, Myc-driven lymphomagenesis stringently requires two intact alleles of miR-17 similar to 92. We experimentally identified miR-17 similar to 92 target genes by PAR-CLIP and validated select target genes in miR-17 similar to 92 transgenic mice. These analyses demonstrate that miR17 similar to 92 drives lymphomagenesis by suppressing the expression of multiple negative regulators of the PI3K and NF kappa B pathways and by inhibiting the mitochondrial apoptosis pathway. Accordingly, miR-17 similar to 92-driven lymphoma cells exhibited constitutive activation of the PI3K and NF kappa B pathways and chemical inhibition of either pathway reduced tumour size and prolonged the survival of lymphoma-bearing mice. These findings establish miR-17 similar to 92 as a powerful cancer driver that coordinates the activation of multiple oncogenic pathways, and demonstrate for the first time that chemical inhibition of miRNA downstream pathways has therapeutic value in treating cancers caused by miRNA dysregulation. C1 [Jin, Hyun Yong; Oda, Hiroyo; Lai, Maoyi; Shepherd, Jovan; Kang, Seung Goo; Liu, Wen-Hsien; Sabouri-Ghomi, Mohsen; Xiao, Changchun] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Jin, Hyun Yong] Scripps Res Inst, Kellogg Sch Sci & Technol, La Jolla, CA 92037 USA. [Skalsky, Rebecca L.; Cullen, Bryan R.] Duke Univ, Med Ctr, Ctr Virol, Dept Mol Genet & Microbiol, Durham, NC USA. [Bethel, Kelly] Scripps Clin, Dept Pathol, La Jolla, CA 92037 USA. [Rajewsky, Klaus] Harvard Univ, Sch Med, Childrens Hosp, Immune Dis Inst,Program Cellular & Mol Med, Boston, MA USA. RP Xiao, CC (reprint author), Scripps Res Inst, Dept Immunol & Microbial Sci, 10550 North Torrey Pines Rd, La Jolla, CA 92037 USA. EM cxiao@scripps.edu RI Jin, Hyun Yong/I-6464-2013; Lai, Maoyi/I-5946-2013 OI Lai, Maoyi/0000-0001-5648-7717 FU PEW Charitable Trusts; Cancer Research Institute; National Institute of Health [R01 AI067968, R01 AI087634, RC1 CA146299]; [T32-CA90111] FX We thank A Feeney, D Nemazee, A Gonzalez Martin, N Choi, A Baumgart, J Hart, Y Kang, L Liao, G Fu, Y Kuwano, A Ramirez-Borrero, Y Sasaki, M. Schmidt-Supprian, and I Song for advice and technical assistance; TSRI Flow Cytometry Core Facility for their expert support; A Gonzalez Martin, P Sun, D Calado, and J Kefauver for critical reading of the manuscript and discussion. RLS was supported by T32-CA90111. CX is a Pew Scholar in Biomedical Sciences. This study is supported by the PEW Charitable Trusts, Cancer Research Institute, and National Institute of Health (R01 AI067968 to B.R.C., R01 AI087634 and RC1 CA146299 to C.X.). NR 70 TC 60 Z9 62 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 28 PY 2013 VL 32 IS 17 BP 2377 EP 2391 DI 10.1038/emboj.2013.178 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 209LM UT WOS:000323758300008 PM 23921550 ER PT J AU Qi, L Qi, QB Prudente, S Mendonca, C Andreozzi, F di Pietro, N Sturma, M Novelli, V Mannino, GC Formoso, G Gervino, EV Hauser, TH Muehlschlegel, JD Niewczas, MA Krolewski, AS Biolo, G Pandolfi, A Rimm, E Sesti, G Trischitta, V Hu, F Doria, A AF Qi, Lu Qi, Qibin Prudente, Sabrina Mendonca, Christine Andreozzi, Francesco di Pietro, Natalia Sturma, Mariella Novelli, Valeria Mannino, Gaia Chiara Formoso, Gloria Gervino, Ernest V. Hauser, Thomas H. Muehlschlegel, Jochen D. Niewczas, Monika A. Krolewski, Andrzej S. Biolo, Gianni Pandolfi, Assunta Rimm, Eric Sesti, Giorgio Trischitta, Vincenzo Hu, Frank Doria, Alessandro TI Association Between a Genetic Variant Related to Glutamic Acid Metabolism and Coronary Heart Disease in Individuals With Type 2 Diabetes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID GENOME-WIDE ASSOCIATION; GLUCAGON-LIKE PEPTIDE-1; ARTERY-DISEASE; MYOCARDIAL-INFARCTION; RISK; SUSCEPTIBILITY; METAANALYSIS; GLUTATHIONE; PREVENTION; LOCUS AB IMPORTANCE Diabetes is associated with an elevated risk of coronary heart disease (CHD). Previous studies have suggested that the genetic factors predisposing to excess cardiovascular risk may be different in diabetic and nondiabetic individuals. OBJECTIVE To identify genetic determinants of CHD that are specific to patients with diabetes. DESIGN, SETTING, AND PARTICIPANTS We studied 5 independent sets of CHD cases and CHD-negative controls from the Nurses' Health Study (enrolled in 1976 and followed up through 2008), Health Professionals Follow-up Study (enrolled in 1986 and followed up through 2008), Joslin Heart Study (enrolled in 2001-2008), Gargano Heart Study (enrolled in 2001-2008), and Catanzaro Study (enrolled in 2004-2010). Included were a total of 1517 CHD cases and 2671 CHD-negative controls, all with type 2 diabetes. Results in diabetic patients were compared with those in 737 nondiabetic CHD cases and 1637 nondiabetic CHD-negative controls from the Nurses' Health Study and Health Professionals Follow-up Study cohorts. Exposures included 2 543 016 common genetic variants occurring throughout the genome. MAIN OUTCOMES AND MEASURES Coronary heart disease-defined as fatal or nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, or angiographic evidence of significant stenosis of the coronary arteries. RESULTS A variant on chromosome 1q25 (rs10911021) was consistently associated with CHD risk among diabetic participants, with risk allele frequencies of 0.733 in cases vs 0.679 in controls (odds ratio, 1.36 [95% CI, 1.22-1.51]; P = 2 x 10(-8)). No association between this variant and CHD was detected among nondiabetic participants, with risk allele frequencies of 0.697 in cases vs 0.696 in controls (odds ratio, 0.99 [95% CI, 0.87-1.13]; P = .89), consistent with a significant gene x diabetes interaction on CHD risk (P = 2 x 10(-4)). Compared with protective allele homozygotes, rs10911021 risk allele homozygotes were characterized by a 32% decrease in the expression of the neighboring glutamate-ammonia ligase (GLUL) gene in human endothelial cells (P = .0048). A decreased ratio between plasma levels of gamma-glutamyl cycle intermediates pyroglutamic and glutamic acid was also shown in risk allele homozygotes (P = .029). CONCLUSION AND RELEVANCE A single-nucleotide polymorphism (rs10911021) was identified that was significantly associated with CHD among persons with diabetes but not in those without diabetes and was functionally related to glutamic acid metabolism, suggesting a mechanistic link. C1 [Qi, Lu; Qi, Qibin; Rimm, Eric; Hu, Frank] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Qi, Lu; Rimm, Eric; Hu, Frank] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Qi, Lu; Rimm, Eric; Hu, Frank] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Prudente, Sabrina; Trischitta, Vincenzo] IRCSS Casa Sollievo Sofferenza Mendel Lab, San Giovanni Rotondo, Italy. [Mendonca, Christine; Novelli, Valeria; Mannino, Gaia Chiara; Niewczas, Monika A.; Krolewski, Andrzej S.; Doria, Alessandro] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Andreozzi, Francesco; Mannino, Gaia Chiara; Sesti, Giorgio] Magna Graecia Univ Catanzaro, Dept Med & Surg Sci, Catanzaro, Italy. [di Pietro, Natalia; Pandolfi, Assunta] Univ G DAnnunzio, Dept Expt & Clin Sci, Aging Res Ctr, G dAnnunzio Univ Fdn, Chieti, Italy. [Sturma, Mariella; Biolo, Gianni] Univ Trieste, Dept Med Surg & Hlth Sci, I-34127 Trieste, Italy. [Novelli, Valeria; Gervino, Ernest V.; Hauser, Thomas H.; Muehlschlegel, Jochen D.; Niewczas, Monika A.; Krolewski, Andrzej S.; Doria, Alessandro] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Formoso, Gloria] Univ G DAnnunzio, Dept Med & Aging Sci, Aging Res Ctr, G dAnnunzio Univ Fdn, Chieti, Italy. [Gervino, Ernest V.; Hauser, Thomas H.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Muehlschlegel, Jochen D.] Brigham & Womens Hosp, Dept Anesthesiol Perioperat & Pain Med, Boston, MA 02115 USA. [Trischitta, Vincenzo] IRCSS Casa Sollievo Sofferenza, Res Unit Diabet & Endocrine Dis, San Giovanni Rotondo, Italy. [Trischitta, Vincenzo] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy. RP Qi, L (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02115 USA. EM nhlqi@channing.harvard.edu; alessandro.doria@joslin.harvard.edu RI Sesti, Giorgio/B-1509-2012; Prudente, Sabrina/H-2886-2016; Trischitta, Vincenzo/K-1487-2016; Mannino, Gaia/K-1580-2016; Di Pietro, Natalia/K-1604-2016; pandolfi, assunta/K-4595-2016 OI Andreozzi, Francesco/0000-0001-9375-1513; BIOLO, GIANNI/0000-0002-6397-1598; Sesti, Giorgio/0000-0002-1618-7688; Prudente, Sabrina/0000-0001-9220-8981; Trischitta, Vincenzo/0000-0003-1174-127X; Mannino, Gaia/0000-0002-6341-4572; Di Pietro, Natalia/0000-0001-9720-2116; pandolfi, assunta/0000-0003-4135-7631 FU National Institutes of Health [HL071981, DK091718, HL073168, DK046200, DK36836]; American Heart Association Scientist Development Award [0730094N]; Italian Ministry of Health ("Ricerca Corrente"); Fondazione Roma ("Sostegno alla ricerca scientifica biomedica"); National Institutes of Health Research Facilities Improvement Program from the National Center for Research Resources [RR10600-01, CA62528-01, RR14514-01] FX This study was supported by grants HL071981, DK091718, HL073168, DK046200 (Boston Obesity Nutrition Research Center), and DK36836 (Genetics Core of the Diabetes Research Center at the Joslin Diabetes Center) from the National Institutes of Health, an American Heart Association Scientist Development Award (0730094N), a grant from the Italian Ministry of Health ("Ricerca Corrente 2011 e 2012"), and a grant from Fondazione Roma ("Sostegno alla ricerca scientifica biomedica 2008"). A portion of this work was conducted in a facility constructed with support from the National Institutes of Health Research Facilities Improvement Program (RR10600-01, CA62528-01, RR14514-01) from the National Center for Research Resources. NR 51 TC 33 Z9 35 U1 1 U2 13 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 AUG 28 PY 2013 VL 310 IS 8 BP 821 EP 828 DI 10.1001/jama.2013.276305 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 206YA UT WOS:000323561400022 PM 23982368 ER PT J AU Low, D Mizoguchi, A Mizoguchi, E AF Low, Daren Mizoguchi, Atsushi Mizoguchi, Emiko TI DNA methylation in inflammatory bowel disease and beyond SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Review DE Intestinal inflammation; Crohn's disease; Colitis; DNA methyltransferase; Epi-therapy ID INTESTINAL TREFOIL FACTOR; ULCERATIVE-COLITIS PATIENTS; CROHNS-DISEASE; BACTERIAL-DNA; EPIGENETIC REGULATION; COLONIC INFLAMMATION; COLORECTAL-CANCER; HYDROGEN-SULFIDE; CELL ACTIVATION; PROMOTER DNA AB Inflammatory bowel disease (IBD) is a consequence of the complex, dysregulated interplay between genetic predisposition, environmental factors, and microbial composition in the intestine. Despite a great advancement in identifying host-susceptibility genes using genome-wide association studies (GWAS), the majority of IBD cases are still underrepresented. The immediate challenge in post-GWAS era is to identify other causative genetic factors of IBD. DNA methylation has received increasing attention for its mechanistical role in IBD pathogenesis. This stable, yet dynamic DNA modification, can directly affect gene expression that have important implications in IBD development. The alterations in DNA methylation associated with IBD are likely to outset as early as embryogenesis all the way until old-age. In this review, we will discuss the recent advancement in understanding how DNA methylation alterations can contribute to the development of IBD. (c) 2013 Baishideng. All rights reserved. C1 [Low, Daren; Mizoguchi, Emiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Gastrointestinal Unit, Boston, MA 02114 USA. [Mizoguchi, Atsushi] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol,Mol Pathol Unit, Charlestown, MA 02129 USA. [Mizoguchi, Atsushi; Mizoguchi, Emiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. RP Mizoguchi, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Gastrointestinal Unit, GRJ 825D,55 Fruit St, Boston, MA 02114 USA. EM emizoguchi@partners.org FU National Institute of Health [DK80070, DK74454, DK64289]; Eli and Edythe L. Broad Medical Foundation; American Gastroenterological Association Foundation; Singapore A*STAR Graduate Academy [BM/AIF/13/001] FX Supported by National Institute of Health (DK80070, DK74454, and DK64289); the Eli and Edythe L. Broad Medical Foundation and American Gastroenterological Association Foundation to Mizoguchi E; and the Singapore A*STAR Graduate Academy (BM/AIF/13/001) to Low D NR 81 TC 6 Z9 6 U1 1 U2 20 PU BAISHIDENG PUBL GRP CO LTD PI WANCHAI PA ROOM 1701, 17-F, HENAN BUILDING, NO. 90, JAFFE RD, WANCHAI, HONG KONG 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD AUG 28 PY 2013 VL 19 IS 32 BP 5238 EP 5249 DI 10.3748/wjg.v19.i32.5238 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 211PC UT WOS:000323920200004 PM 23983426 ER PT J AU McGrath, ER Kapral, MK Fang, JM Eikelboom, JW O'Conghaile, A Canavan, M O'Donnell, MJ AF McGrath, Emer R. Kapral, Moira K. Fang, Jiming Eikelboom, John W. O'Conghaile, Aengus Canavan, Michelle O'Donnell, Martin J. CA Ontario Stroke Registry TI Association of atrial fibrillation with mortality and disability after ischemic stroke SO NEUROLOGY LA English DT Article ID CANADIAN NEUROLOGICAL SCALE; RISK-FACTORS; SEVERITY; RELIABILITY; VALIDATION; PREDICTORS; REGISTRY; TRIALS; DEATH; SCORE AB Objective: We determined whether patient characteristics (age, sex, comorbidities), stroke severity, and quality of care explained a proportion of the association between atrial fibrillation (AF) and increased disability and mortality in patients with acute ischemic stroke. Methods: The study included a prospective cohort of consecutive patients admitted with acute ischemic stroke included in the Registry of the Canadian Stroke Network (July 1, 2003 to March 31, 2008). Multivariable logistic regression analyses were used to determine the magnitude of association between AF and modified Rankin score 4-5 at discharge, 30-day mortality, and 1-year mortality. Results: There were 10,528 patients admitted with acute ischemic stroke. AF was associated with an increased risk of severe disability and mortality, but the magnitude of association was substantially attenuated in the full multivariable models: modified Rankin score 4-5 at discharge (univariate odds ratio [OR] 1.74, 95% confidence interval [CI] 1.57-1.93; multivariable OR 1.19, 95% CI 1.03-1.36), 30-day mortality (univariate OR 2.52, 95% CI 2.25-2.84; multivariable OR 1.36, 95% CI 1.17-1.58), and 1-year mortality (univariate OR 2.41, 95% CI 2.19-2.66; multivariable OR 1.25, 95% CI 1.10-1.42). Older age and increased stroke severity explained most of the association between AF and poor stroke outcomes. We found no association between AF and poor stroke outcomes in patients receiving therapeutic preadmission oral anticoagulant therapy. Conclusions: Older age and increased stroke severity explain most of the association between AF and poorer outcomes after acute ischemic stroke. Nonuse of oral anticoagulant therapy represents the most important modifiable care gap to mitigate the association between AF and poor outcomes after ischemic stroke. C1 [McGrath, Emer R.; O'Conghaile, Aengus; Canavan, Michelle; O'Donnell, Martin J.] Natl Univ Ireland Galway, HRB Clin Res Facil Galway, Galway, Ireland. [McGrath, Emer R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kapral, Moira K.] Univ Toronto, Toronto, ON, Canada. [Kapral, Moira K.; Fang, Jiming] Inst Clin Evaluat Sci, Toronto, ON, Canada. [Eikelboom, John W.] McMaster Univ, Hamilton, ON, Canada. RP McGrath, ER (reprint author), Natl Univ Ireland Galway, HRB Clin Res Facil Galway, Galway, Ireland. EM e.mcgrath7@nuigalway.ie OI O'Donnell, Martin/0000-0002-7347-7761; McGrath, Emer/0000-0002-3589-2964 FU Health Research Board Fellowship from the Health Research Board of Ireland; Boehringer Ingelheim Stroke Research Fellowship Award; Canadian Stroke Network; Ontario Ministry of Health and Long Term Care; Heart and Stroke Foundation of Canada FX Funding source: E.R.M. is the recipient of a Health Research Board Fellowship from the Health Research Board of Ireland and a Boehringer Ingelheim Stroke Research Fellowship Award. Neither the Health Research Board nor Boehringer Ingelheim had any role in the design or conduct of the study; collection, management, analysis, and interpretation of data; or preparation, review, or approval of this manuscript. Industry sponsorship: none. The Registry of the Canadian Stroke Network is funded by grants from the Canadian Stroke Network and the Ontario Ministry of Health and Long Term Care. The Institute for Clinical Evaluative Sciences is supported by an operating grant from the Ontario Ministry of Health and Long Term Care. Dr. Moira Kapral is supported by the Canadian Stroke Network and holds a Career Investigator Award from the Heart and Stroke Foundation of Canada. The results and conclusions are those of the authors and should not be attributed to any sponsoring organization. NR 25 TC 27 Z9 30 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 27 PY 2013 VL 81 IS 9 BP 825 EP 832 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 304JL UT WOS:000330742800016 PM 23902702 ER PT J AU Goenka, N Venna, N AF Goenka, Naila Venna, Nagagopal TI Teaching NeuroImages: Sarcoidosis presenting as longitudinally extensive myelitis Excellent response to infliximab SO NEUROLOGY LA English DT Editorial Material C1 [Goenka, Naila; Venna, Nagagopal] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Goenka, N (reprint author), Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. EM nailabharti@gmail.com NR 2 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 27 PY 2013 VL 81 IS 9 BP E61 EP E61 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 304JL UT WOS:000330742800004 PM 23978728 ER PT J AU Kotton, CN Kumar, D Caliendo, AM Asberg, A Chou, SW Danziger-Isakov, L Humar, A AF Kotton, Camille N. Kumar, Deepali Caliendo, Angela M. Asberg, Anders Chou, Sunwen Danziger-Isakov, Lara Humar, Atul CA Transplantation Soc Int CMV TI Updated International Consensus Guidelines on the Management of Cytomegalovirus in Solid-Organ Transplantation SO TRANSPLANTATION LA English DT Article DE Cytomegalovirus; CMV; Ganciclovir; Prevention; Prophylaxis; Resistance; Treatment; Valganciclovir ID T-CELL RESPONSES; BRONCHIOLITIS OBLITERANS SYNDROME; ORTHOTOPIC LIVER-TRANSPLANTATION; DRUG-RESISTANT CYTOMEGALOVIRUS; PEDIATRIC LUNG TRANSPLANTATION; EPSTEIN-BARR-VIRUS; RECEIVING VALGANCICLOVIR PROPHYLAXIS; ANTICYTOMEGALOVIRUS COMPOUND AIC246; BRONCHOALVEOLAR LAVAGE FLUID; HEPATIC-ARTERY THROMBOSIS AB Cytomegalovirus (CMV) continues to be one of the most common infections after solid-organ transplantation, resulting in significant morbidity, graft loss, and adverse outcomes. Management of CMV varies considerably among transplant centers but has been become more standardized by publication of consensus guidelines by the Infectious Diseases Section of The Transplantation Society. An international panel of experts was reconvened in October 2012 to revise and expand evidence and expert opinion-based consensus guidelines on CMV management, including diagnostics, immunology, prevention, treatment, drug resistance, and pediatric issues. The following report summarizes the recommendations. C1 [Kotton, Camille N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. [Kumar, Deepali] Univ Alberta, Edmonton, AB, Canada. [Caliendo, Angela M.] Brown Univ, Alpert Med Sch Brown, Providence, RI 02912 USA. [Asberg, Anders] Univ Oslo, Sch Pharm, Dept Pharmaceut Biosci, Oslo, Norway. [Chou, Sunwen] Oregon Hlth & Sci Univ, Div Infect Dis, Portland, OR 97201 USA. [Danziger-Isakov, Lara] Cincinnati Childrens Hosp Med Ctr, Div Infect Dis, Cincinnati, OH 45229 USA. [Humar, Atul] Univ Alberta, Dept Med, Alberta Transplant Inst, Edmonton, AB, Canada. RP Kotton, CN (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, 55 Fruit St,Cox 5, Boston, MA 02114 USA. EM ckotton@partners.org RI Snydman, David/O-3889-2014; Lilleri, Daniele/K-7776-2016; OI Snydman, David/0000-0003-0119-3978; Emery, Vincent/0000-0001-5893-9756; Munoz Garcia, Patricia Carmen/0000-0001-5706-5583 FU Roche FX The CMV Consensus Conference was organized by the Infectious Diseases Section of The Transplantation Society. An independent, nonrestricted grant from Roche made this conference possible. At no time did the funding source have input into the list of attendees, discussion, or content. NR 270 TC 201 Z9 210 U1 8 U2 37 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD AUG 27 PY 2013 VL 96 IS 4 BP 333 EP 360 DI 10.1097/TP.0b013e31829df29d PG 28 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 299FM UT WOS:000330381200010 PM 23896556 ER PT J AU Vallabhajosyula, P Hirakata, A Shimizu, A Okumi, M Tchipashvili, V Hong, HZ Yamada, K Sachs, DH AF Vallabhajosyula, Prashanth Hirakata, Atsushi Shimizu, Akira Okumi, Masayoshi Tchipashvili, Vaja Hong, Hanzhou Yamada, Kazuhiko Sachs, David H. TI Assessing the Effect of Immunosuppression on Engraftment of Pancreatic Islets SO TRANSPLANTATION LA English DT Article DE Islet; Transplant; Pig; Immunosuppression; Islet-kidney ID MINIATURE SWINE; CELL TRANSPLANTATION; DIABETES-MELLITUS; INSULIN-SECRETION; TYPE-1; CYCLOSPORINE; AUTOGRAFTS; ALLOGRAFTS; AUTOTRANSPLANTATION; TOXICITY AB Background. In addition to ischemia and immunologic factors, immunosuppressive drugs have been suggested as a possible contributing factor to the loss of functional islets after allogeneic islet cell transplantation. Using our previously described islet-kidney (IK) transplantation model in miniature swine, we studied whether an islet-toxic triple-drug immunosuppressive regimen (cyclosporine+azathioprine+prednisone) affects the islet engraftment process and thus long-term islet function. Methods. Donor animals underwent partial pancreatectomy, autologous islet preparation, and injection of these islets under the autologous kidney capsule to prepare an IK. Experimental animals received daily triple-drug immunosuppression during the islet engraftment period. Control animals did not receive any immunosuppression during this period. Four to 8 weeks later, these engrafted IK were transplanted across a minor histocompatibility mismatched barrier into pancreatectomized, nephrectomized recipient animals at an islet dose of approximately 4500 islet equivalents/kg recipient weight. Cyclosporine was administered for 12 days to the recipients to induce tolerance of the IK grafts and the animals were followed long-term. Results. Diabetes was corrected by IK transplantation in all pancreatectomized recipients on both the control arm (n=3) and the experimental arm (n=4) of the study and all animals showed normal glucose regulation over the follow-up period. Intravenous glucose tolerance tests performed at 1, 2, and 3 or more months after IK transplantation showed essentially equivalent glycemic control in both control and experimental animals. Conclusion. In this preclinical in vivo large animal model of islet transplantation, the effect of triple-drug immunosuppression on islet function does not negatively affect islet engraftment as assessed by the long-term function of engrafted islets. C1 [Vallabhajosyula, Prashanth; Hirakata, Atsushi; Shimizu, Akira; Okumi, Masayoshi; Hong, Hanzhou; Yamada, Kazuhiko; Sachs, David H.] Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. [Vallabhajosyula, Prashanth] Hosp Univ Penn, Div Cardiovasc Surg, Philadelphia, PA 19104 USA. [Tchipashvili, Vaja] Joslin Diabet Ctr, Dept Islet Transplantat & Cell Biol, Boston, MA 02215 USA. RP Sachs, DH (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Bldg 149,13th St, Boston, MA 02129 USA. EM tx@dhsachs.com FU American College of Surgeons fellowship; American Society of Transplant Surgeons Roche Scientific Research Fellowship; Ruth L. Kirschstein National Research Scholarship Award [5 F32 AI066699-02]; national Institute of Diabetes and Digestive and Kidney Diseases of the National Institute of Health [5U01DK080653] FX P.V. was supported by the American College of Surgeons fellowship, American Society of Transplant Surgeons Roche Scientific Research Fellowship, and Ruth L. Kirschstein National Research Scholarship Award (5 F32 AI066699-02). This work was also supported by the national Institute of Diabetes and Digestive and Kidney Diseases of the National Institute of Health grant 5U01DK080653. the authors also gratefully acknowledge CO6RR020135-01 for construction of the facility utilized for production and maintenance of miniature swine. NR 29 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD AUG 27 PY 2013 VL 96 IS 4 BP 372 EP 378 DI 10.1097/TP.0b013e31829f7515 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 299FM UT WOS:000330381200014 PM 23883972 ER PT J AU Desai, NR Kohli, P Giugliano, RP O'Donoghue, ML Somaratne, R Zhou, J Hoffman, EB Huang, FN Rogers, WJ Wasserman, SM Scott, R Sabatine, MS AF Desai, Nihar R. Kohli, Payal Giugliano, Robert P. O'Donoghue, Michelle L. Somaratne, Ransi Zhou, Jing Hoffman, Elaine B. Huang, Fannie Rogers, William J. Wasserman, Scott M. Scott, Robert Sabatine, Marc S. TI AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy: An Analysis From the LDL-C Assessment With Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 Trial SO CIRCULATION LA English DT Article DE biomarker; lipids; lipoproteins; PCSK9 protein; human ID CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; RISK-FACTOR; PLASMA-LEVELS; LP(A); APOLIPOPROTEIN; CHOLESTEROL; EFFICACY; RECEPTOR; SAFETY AB Background Lipoprotein(a) [Lp(a)] is an emerging risk factor for cardiovascular disease. Currently, there are few available therapies to lower Lp(a). We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a). Methods and Results As part of the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial, 631 patients with hypercholesterolemia receiving statin therapy were randomized to receive AMG145 at 1 of 3 different doses every 2 weeks or 1 of 3 different doses every 4 weeks versus placebo. Lp(a) and other lipid parameters were measured at baseline and at week 12. Compared with placebo, AMG14570 mg, 105 mg, and 140 mg every 2 weeks reduced Lp(a) at 12 weeks by 18%, 32%, and 32%, respectively (P<0.001 for each dose versus placebo). Likewise, AMG145280 mg, 350 mg, and 420 mg every 4 weeks reduced Lp(a) by 18%, 23%, and 23%, respectively (P<0.001 for each dose versus placebo). The reduction in Lp(a) correlated with the reduction in low-density lipoprotein cholesterol (=0.33, P<0.001). The effect of AMG145 on Lp(a) was consistent regardless of age, sex, race, history of diabetes mellitus, and background statin regimen. Patients with higher levels of Lp(a) at baseline had larger absolute reductions but comparatively smaller percent reductions in Lp(a) with AMG145 compared with those with lower baseline Lp(a) values. Conclusions AMG145 significantly reduces Lp(a), by up to 32%, among subjects with hypercholesterolemia receiving statin therapy, offering an additional, complementary benefit beyond robust low-density lipoprotein cholesterol reduction with regard to a patient's atherogenic lipid profile. Clinical Trial Registration URL: . Unique identifier: NCT01380730. C1 [Desai, Nihar R.; Kohli, Payal; Giugliano, Robert P.; O'Donoghue, Michelle L.; Zhou, Jing; Hoffman, Elaine B.; Sabatine, Marc S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, TIMI Study Grp,Div Cardiovasc Med, Boston, MA 02115 USA. [Somaratne, Ransi; Huang, Fannie; Wasserman, Scott M.; Scott, Robert] Amgen Inc, Thousand Oaks, CA 91320 USA. [Rogers, William J.] Univ Alabama Birmingham, Birmingham, AL USA. RP Sabatine, MS (reprint author), TIMI Study Grp, 350 Longwood Ave, Boston, MA 02115 USA. EM msabatine@partners.org FU Amgen, Inc FX The LAPLACE-TIMI 57 Trial was supported by a research grant from Amgen, Inc, to the TIMI Study Group, Brigham and Women's Hospital. NR 30 TC 79 Z9 82 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 27 PY 2013 VL 128 IS 9 BP 962 EP 969 DI 10.1161/CIRCULATIONAHA.113.001969 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 208BF UT WOS:000323649600012 PM 23884353 ER PT J AU Lee, J Wang, JB Bersani, F Parekkadan, B AF Lee, Jungwoo Wang, Jennifer B. Bersani, Francesca Parekkadan, Biju TI Capture and Printing of Fixed Stromal Cell Membranes for Bioactive Display on PDMS Surfaces SO LANGMUIR LA English DT Article ID EMBRYONIC STEM-CELLS; BONE-MARROW STROMA; TERM SELF-RENEWAL; IN-VITRO; MICROFLUIDIC DEVICES; POLY(DIMETHYLSILOXANE); DIFFERENTIATION; PROLIFERATION; ADHESION; MAINTENANCE AB Poly(dimethylsiloxane) (PDMS) has emerged as an extremely useful polymer for various biological applications. The conjugation of PDMS with bioactive molecules to create functional surfaces is feasible yet limited to a single-molecule display with imprecise localization of the molecules on PDMS. Here we report a robust technique that can transfer and print the membrane surface of glutaraldehyde-fixed stromal cells intact onto a PDMS substrate using an intermediate polyvinylalcohol (PVA) film as a transporter system. The cell-PVA film capturing the entirety of surface molecules can be peeled off and subsequently printed onto PDMS while maintaining the spatial display of the original cell surface molecules. Proof-of-concept studies are described using human bone marrow stromal cell membranes including a demonstration of the bioactivity of transferred membranes to capture and adhere hematopoietic cells. The presented process is applicable to virtually any adherent cell and can broaden the functional display of biomolecules on PDMS for biotechnology applications. C1 [Lee, Jungwoo; Wang, Jennifer B.; Parekkadan, Biju] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. [Lee, Jungwoo; Wang, Jennifer B.; Parekkadan, Biju] Shriners Hosp Children Boston, Boston, MA 02114 USA. [Bersani, Francesca] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. [Parekkadan, Biju] Harvard Stem Cell Inst, Boston, MA 02155 USA. RP Parekkadan, B (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. EM biju_parekkadan@hms.harvard.edu FU National Institutes of Health [R01EB012521, K01DK087770]; Shriners Hospitals for Children; National Cancer Institute [1K99CA163671-01A1] FX This work was supported by the National Institutes of Health (R01EB012521 and K01DK087770) and postdoctoral fellowships from the Shriners Hospitals for Children and the National Cancer Institute (1K99CA163671-01A1). NR 35 TC 3 Z9 3 U1 0 U2 44 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD AUG 27 PY 2013 VL 29 IS 34 BP 10611 EP 10616 DI 10.1021/la4012795 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 210EE UT WOS:000323811300001 PM 23927769 ER PT J AU de Timary, P Uva, MCD Denoel, C Hebborn, L Derely, M Desseilles, M Luminet, O AF de Timary, Philippe Uva, Mariana Cordovil de Sousa Denoel, Catherine Hebborn, Ludger Derely, Marc Desseilles, Martin Luminet, Olivier TI The Associations between Self-Consciousness, Depressive State and Craving to Drink among Alcohol Dependent Patients Undergoing Protracted Withdrawal SO PLOS ONE LA English DT Article ID AWARENESS MODEL; CONSUMPTION; STIGMA; ALEXITHYMIA; MOTIVATION; INPATIENTS; SCALE; MINDFULNESS; ABSTINENCE; NALTREXONE AB Context: In order to understand how certain personality traits influence the relation between depression symptoms and craving for alcohol, trait self-consciousness (trait SC) was examined during a withdrawal and detoxification program. Methods: Craving (Obsessive and Compulsive Drinking Scale), depressive state (Beck Depression Inventory) and trait SC (Revised Self-Consciousness Scale) were assessed in alcohol-dependent inpatients (DSM-IV, N = 30) both at the beginning (T1: day 1 or 2) and at the end (T2: day 14 to 18) of protracted withdrawal during rehabilitation. Results: A significant decrease in craving and depressive symptoms was observed from T1 to T2, while SC scores remained stable. At both times, strong positive correlations were observed between craving and depression. Moreover, regression analyses indicated that trait SC significantly moderated the impact of depression on cravings for alcohol. Limitations: This study was performed on a relatively small sample size. Administration of medications during detoxification treatment can also be a confounding factor. Finally, craving could have been evaluated through other types of measurements. Conclusions: During protracted withdrawal, alcohol craving decreased with the same magnitude as depressive mood. Depressive symptoms were related to alcohol craving but only among patients with high trait SC scores. Our results suggest that metacognitive approaches targeting SC could decrease craving and, in turn, prevent future relapses. C1 [de Timary, Philippe] Catholic Univ Louvain, Inst Neurosci, B-1348 Louvain, Belgium. [Uva, Mariana Cordovil de Sousa; Denoel, Catherine; Luminet, Olivier] Catholic Univ Louvain, Res Inst Psychol Sci, B-1348 Louvain, Belgium. [de Timary, Philippe; Desseilles, Martin; Luminet, Olivier] Belgian Natl Fund Sci Res FRS FNRS, Brussels, Belgium. [Desseilles, Martin] Harvard Univ, Sch Med, Dept Psychiat, Depress Clin & Res Program,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Desseilles, Martin] Univ Namur, Dept Psychol, Namur, Belgium. [de Timary, Philippe; Uva, Mariana Cordovil de Sousa] Catholic Univ Louvain, Unite Hepatol Integree, Dept Adult Psychiat, B-1348 Louvain, Belgium. [de Timary, Philippe; Uva, Mariana Cordovil de Sousa] Catholic Univ Louvain, Inst Neurosci, Acad Hosp St Luc, B-1348 Louvain, Belgium. [Hebborn, Ludger] Clin Europe St Michel, Psychiat Ward, Brussels, Belgium. [Derely, Marc] Clin La Ramee, Alcohol Dependence Unit, Brussels, Belgium. RP de Timary, P (reprint author), Catholic Univ Louvain, Inst Neurosci, B-1348 Louvain, Belgium. EM Philippe.detimary@uclouvain.be FU Belgian National Fund for Scientific Research (FNRS-FRS) [3.4585.07] FX This research was supported by the Belgian National Fund for Scientific Research (FNRS-FRS; grant 3.4585.07). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 7 Z9 7 U1 3 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 27 PY 2013 VL 8 IS 8 AR e71560 DI 10.1371/journal.pone.0071560 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 210FR UT WOS:000323815200016 PM 24013131 ER PT J AU Myers, CE Moustafa, AA Sheynin, J VanMeenen, KM Gilbertson, MW Orr, SP Beck, KD Pang, KCH Servatius, RJ AF Myers, Catherine E. Moustafa, Ahmed A. Sheynin, Jony VanMeenen, Kirsten M. Gilbertson, Mark W. Orr, Scott P. Beck, Kevin D. Pang, Kevin C. H. Servatius, Richard J. TI Learning to Obtain Reward, but Not Avoid Punishment, Is Affected by Presence of PTSD Symptoms in Male Veterans: Empirical Data and Computational Model SO PLOS ONE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; BEHAVIORALLY INHIBITED TEMPERAMENT; ANXIETY DISORDERS; WAR VETERANS; PREDICTION ERRORS; DECISION-MAKING; DORSAL STRIATUM; COMBAT VETERANS; MENTAL-HEALTH; HUMAN BRAIN AB Post-traumatic stress disorder (PTSD) symptoms include behavioral avoidance which is acquired and tends to increase with time. This avoidance may represent a general learning bias; indeed, individuals with PTSD are often faster than controls on acquiring conditioned responses based on physiologically-aversive feedback. However, it is not clear whether this learning bias extends to cognitive feedback, or to learning from both reward and punishment. Here, male veterans with self-reported current, severe PTSD symptoms (PTSS group) or with few or no PTSD symptoms (control group) completed a probabilistic classification task that included both reward-based and punishment-based trials, where feedback could take the form of reward, punishment, or an ambiguous "no-feedback" outcome that could signal either successful avoidance of punishment or failure to obtain reward. The PTSS group outperformed the control group in total points obtained; the PTSS group specifically performed better than the control group on reward-based trials, with no difference on punishment-based trials. To better understand possible mechanisms underlying observed performance, we used a reinforcement learning model of the task, and applied maximum likelihood estimation techniques to derive estimated parameters describing individual participants' behavior. Estimations of the reinforcement value of the no-feedback outcome were significantly greater in the control group than the PTSS group, suggesting that the control group was more likely to value this outcome as positively reinforcing (i.e., signaling successful avoidance of punishment). This is consistent with the control group's generally poorer performance on reward trials, where reward feedback was to be obtained in preference to the no-feedback outcome. Differences in the interpretation of ambiguous feedback may contribute to the facilitated reinforcement learning often observed in PTSD patients, and may in turn provide new insight into how pathological behaviors are acquired and maintained in PTSD. C1 [Myers, Catherine E.; Moustafa, Ahmed A.; Sheynin, Jony; VanMeenen, Kirsten M.; Beck, Kevin D.; Pang, Kevin C. H.; Servatius, Richard J.] VA New Jersey Hlth Care Syst, Dept Vet Affairs, E Orange, NJ USA. [Myers, Catherine E.; Sheynin, Jony; VanMeenen, Kirsten M.; Beck, Kevin D.; Pang, Kevin C. H.; Servatius, Richard J.] Rutgers State Univ, New Jersey Med Sch, Stress & Motivated Behav Inst, Dept Neurol & Neurosci, Newark, NJ 07102 USA. [Myers, Catherine E.] Rutgers State Univ, Dept Psychol, Newark, NJ 07102 USA. [Myers, Catherine E.; Sheynin, Jony; Beck, Kevin D.; Pang, Kevin C. H.; Servatius, Richard J.] Rutgers State Univ, Grad Sch Biomed Sci, Newark, NJ 07102 USA. [Moustafa, Ahmed A.] Univ Western Sydney, Marcs Inst Brain & Behav, Sydney, NSW, Australia. [Moustafa, Ahmed A.] Univ Western Sydney, Sch Social Sci & Psychol, Sydney, NSW, Australia. [Gilbertson, Mark W.] Dept Vet Affairs, Manchester, NH USA. [Orr, Scott P.] Harvard Univ, Sch Med, Boston, MA USA. [Orr, Scott P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Myers, CE (reprint author), VA New Jersey Hlth Care Syst, Dept Vet Affairs, E Orange, NJ USA. EM Catherine.Myers2@va.gov OI Myers, Catherine/0000-0002-2776-4823 FU NSF/NIH Collaborative Research in Computational Neuroscience (CRCNS) program; NIAAA [R01 AA018737]; Clinical Science Research and Development Service of the VA Office of Research and Development [I01CX000771]; SMBI FX This work was partially supported by the NSF/NIH Collaborative Research in Computational Neuroscience (CRCNS) program and NIAAA R01 AA018737, by Award Number I01CX000771 from the Clinical Science Research and Development Service of the VA Office of Research and Development, and by the SMBI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 10 Z9 10 U1 8 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 27 PY 2013 VL 8 IS 8 AR e72508 DI 10.1371/journal.pone.0072508 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 210FR UT WOS:000323815200045 PM 24015254 ER PT J AU Nikolaou, P Coffey, AM Walkup, LL Gust, BM Whiting, N Newton, H Barcus, S Muradyan, I Dabaghyan, M Moroz, GD Rosen, MS Patz, S Barlow, MJ Chekmenev, EY Goodson, BM AF Nikolaou, Panayiotis Coffey, Aaron M. Walkup, Laura L. Gust, Brogan M. Whiting, Nicholas Newton, Hayley Barcus, Scott Muradyan, Iga Dabaghyan, Mikayel Moroz, Gregory D. Rosen, Matthew S. Patz, Samuel Barlow, Michael J. Chekmenev, Eduard Y. Goodson, Boyd M. TI Near-unity nuclear polarization with an open-source Xe-129 hyperpolarizer for NMR and MRI SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hyperpolarization; laser-polarized xenon; lung imaging; optical pumping ID VOLUME HOLOGRAPHIC GRATINGS; LASER-DIODE ARRAYS; SPIN-EXCHANGE; MAGNETIC-RESONANCE; NOBLE-GASES; XENON; SURFACE; RB; SPECTROSCOPY; RELAXATION AB The exquisite NMR spectral sensitivity and negligible reactivity of hyperpolarized xenon-129 ((HPXe)-Xe-129) make it attractive for a number of magnetic resonance applications; moreover, (HPXe)-Xe-129 embodies an alternative to rare and nonrenewable He-3. However, the ability to reliably and inexpensively produce large quantities of (HPXe)-Xe-129 with sufficiently high Xe-129 nuclear spin polarization (P-Xe) remains a significant challenge-particularly at high Xe densities. We present results from our "open-source" large-scale (similar to 1 L/h) Xe-129 polarizer for clinical, preclinical, and materials NMR and MRI research. Automated and composed mostly of off-the-shelf components, this "hyperpolarizer" is designed to be readily implementable in other laboratories. The device runs with high resonant photon flux (up to 200 W at the Rb D-1 line) in the xenon-rich regime (up to 1,800 torr Xe in 500 cc) in either single-batch or stopped-flow mode, negating in part the usual requirement of Xe cryocollection. Excellent agreement is observed among four independent methods used to measure spin polarization. In-cell P-Xe values of similar to 90%, similar to 57%, similar to 50%, and similar to 30% have been measured for Xe loadings of similar to 300, similar to 500, similar to 760, and similar to 1,570 torr, respectively. P-Xe values of similar to 41% and similar to 28% (with similar to 760 and similar to 1,545 torr Xe loadings) have been measured after transfer to Tedlar bags and transport to a clinical 3 T scanner for MR imaging, including demonstration of lung MRI with a healthy human subject. Long "in-bag" Xe-129 polarization decay times have been measured (T-1 similar to 38 min and similar to 5.9 h at similar to 1.5 mT and 3 T, respectively)-more than sufficient for a variety of applications. C1 [Nikolaou, Panayiotis; Coffey, Aaron M.; Chekmenev, Eduard Y.] Vanderbilt Univ, Inst Imaging Sci, Dept Radiol, Nashville, TN 37232 USA. [Nikolaou, Panayiotis; Walkup, Laura L.; Gust, Brogan M.; Barcus, Scott; Goodson, Boyd M.] So Illinois Univ, Dept Chem & Biochem, Carbondale, IL 62901 USA. [Coffey, Aaron M.; Chekmenev, Eduard Y.] Vanderbilt Univ, Dept Biomed Engn, Nashville, TN 37235 USA. [Whiting, Nicholas; Newton, Hayley; Barlow, Michael J.] Univ Nottingham, Sir Peter Mansfield Magnet Resonance Ctr, Nottingham NG7 2RD, England. [Barcus, Scott] Drake Univ, Dept Phys, Des Moines, IA 50311 USA. [Muradyan, Iga; Dabaghyan, Mikayel; Patz, Samuel] Brigham & Womens Hosp, Boston, MA 02115 USA. [Dabaghyan, Mikayel; Patz, Samuel] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Moroz, Gregory D.] So Illinois Univ, Grad Sch Cent Res Shop, Carbondale, IL 62901 USA. [Rosen, Matthew S.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [Rosen, Matthew S.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. [Chekmenev, Eduard Y.] Vanderbilt Univ, Dept Biochem, Nashville, TN 37205 USA. RP Goodson, BM (reprint author), So Illinois Univ, Dept Chem & Biochem, Carbondale, IL 62901 USA. EM bgoodson@chem.siu.edu RI Barlow, Michael/L-2549-2013; Coffey, Aaron/Q-3921-2016 OI Barlow, Michael/0000-0003-3609-6043; FU National Science Foundation (NSF) [OISE-0966393]; NSF [DMR 0852004, 1157058]; National Institutes of Health (NIH) [1R01 HL096471]; Southern Illinois University Office of Sponsored Projects Administration; School of Clinical Sciences, University of Nottingham; NIH/National Cancer Institute [5R00 CA134749-03]; Department of Defense [W81XWH-12-1-0159/BC112431]; NIH [R25 CA136440] FX We thank B. Saam and G. Schrank for helpful conversations, K. Ranta for simulations, E. Koehnemann for glassblowing, and the reviewers for helpful suggestions. N.W. was supported by National Science Foundation (NSF) Postdoctoral Fellowship OISE-0966393; S.B., B. M. Gust, and B. M. Goodson were supported in part by NSF Grants DMR 0852004 and 1157058. This work was funded by National Institutes of Health (NIH) Grant 1R01 HL096471 and Southern Illinois University Office of Sponsored Projects Administration. M.J.B. is supported by the School of Clinical Sciences, University of Nottingham. E.Y.C. thanks the support from NIH/National Cancer Institute Grant 5R00 CA134749-03 and Department of Defense Congressionally Directed Medical Research Programs Era of Hope Award W81XWH-12-1-0159/BC112431. A.M.C. thanks the support from training NIH Grant R25 CA136440. NR 42 TC 77 Z9 78 U1 5 U2 67 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 AUG 27 PY 2013 VL 110 IS 35 BP 14150 EP 14155 DI 10.1073/pnas.1306586110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ZC UT WOS:000323564600024 PM 23946420 ER PT J AU Hanker, AB Pfefferle, AD Balko, JM Kuba, MG Young, CD Sanchez, V Sutton, CR Cheng, HL Perou, CM Zhao, JJ Cook, RS Arteaga, CL AF Hanker, Ariella B. Pfefferle, Adam D. Balko, Justin M. Kuba, Maria Gabriela Young, Christian D. Sanchez, Violeta Sutton, Cammie R. Cheng, Hailing Perou, Charles M. Zhao, Jean J. Cook, Rebecca S. Arteaga, Carlos L. TI Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TO-MESENCHYMAL TRANSITION; HUMAN BREAST-TUMORS; PI3K PATHWAY; STEM-CELL; TRASTUZUMAB RESISTANCE; TYROSINE KINASE; UP-REGULATION; OPEN-LABEL; CANCER; ACTIVATION AB Human epidermal growth factor receptor 2 (HER2; ERBB2) amplification and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations often co-occur in breast cancer. Aberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway has been shown to correlate with a diminished response to HER2-directed therapies. We generated a mouse model of HER2-overexpressing (HER2(+)), PIK3CA(H1047R)-mutant breast cancer. Mice expressing both human HER2 and mutant PIK3CA in the mammary epithelium developed tumors with shorter latencies compared with mice expressing either oncogene alone. HER2 and mutant PIK3CA also cooperated to promote lung metastases. By microarray analysis, HER2-driven tumors clustered with luminal breast cancers, whereas mutant PIK3CA tumors were associated with claudin-low breast cancers. PIK3CA and HER2(+)/PIK3CA tumors expressed elevated transcripts encoding markers of epithelial-tomesenchymal transition and stem cells. Cells from HER2(+)/PIK3CA tumors more efficiently formed mammospheres and lung metastases. Finally, HER2(+)/PIK3CA tumors were resistant to trastuzumab alone and in combination with lapatinib or pertuzumab. Both drug resistance and enhanced mammosphere formation were reversed by treatment with a PI3K inhibitor. In sum, PIK3CA(H1047R) accelerates HER2-mediated breast epithelial transformation and metastatic progression, alters the intrinsic phenotype of HER2-overexpressing cancers, and generates resistance to approved combinations of anti-HER2 therapies. C1 [Hanker, Ariella B.; Balko, Justin M.; Young, Christian D.; Sanchez, Violeta; Sutton, Cammie R.; Arteaga, Carlos L.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN 37232 USA. [Kuba, Maria Gabriela] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Pathol, Nashville, TN 37232 USA. [Cook, Rebecca S.; Arteaga, Carlos L.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Canc Biol, Nashville, TN 37232 USA. [Balko, Justin M.; Cook, Rebecca S.; Arteaga, Carlos L.] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Breast Canc Res Program, Nashville, TN 37232 USA. [Pfefferle, Adam D.; Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Perou, Charles M.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Genet, Chapel Hill, NC 27599 USA. [Cheng, Hailing; Zhao, Jean J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhao, Jean J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Zhao, JJ (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St, Boston, MA 02115 USA. EM jean_zhao@dfci.harvard.edu; carlos.arteaga@vanderbilt.edu OI Hanker, Ariella/0000-0002-8655-8341; Perou, Charles/0000-0001-9827-2247 FU Department of Defense Postdoctoral Fellowship Award [BC103785]; Breast Cancer Specialized Program of Research Excellence [P50CA98131, P50CA58223]; Vanderbilt-Ingram Cancer Center Support Grant [P30CA68485]; Breast Cancer Research Foundation; American Cancer Society Clinical Research Professorship Grant [CRP-07-234]; Lee Jeans Translational Breast Cancer Research Program; Stand Up to Cancer Dream Team Translational Research Grant, a program of the Entertainment Industry Foundation [SU2C-AACR-DT0209]; Susan G. Komen for the Cure Foundation [CCR12225834, PDF12229712, SAC100013, KG100677]; National Institutes of Health [R01s CA80195, CA143126, CA134502, CA172461-01, CA138255, CA148761] FX This work was supported by Department of Defense Postdoctoral Fellowship Award BC103785 (to A.B.H.); Breast Cancer Specialized Program of Research Excellence Grants P50CA98131 to Vanderbilt University and P50CA58223 to University of North Carolina; Vanderbilt-Ingram Cancer Center Support Grant P30CA68485; Breast Cancer Research Foundation grants (to C.L.A. and C.M.P.); American Cancer Society Clinical Research Professorship Grant CRP-07-234 (to C.L.A.); the Lee Jeans Translational Breast Cancer Research Program (C.L.A.); Stand Up to Cancer Dream Team Translational Research Grant, a program of the Entertainment Industry Foundation (SU2C-AACR-DT0209) (to C.L.A.); Susan G. Komen for the Cure Foundation Grants CCR12225834 (to H.C.), PDF12229712 (to J.M.B.), SAC100013 (to C.L.A.), and KG100677 (to R.S.C.); and National Institutes of Health R01s CA80195 (to C.L.A.), CA143126 (to R.S.C.), CA134502 and CA172461-01 (to J.J.Z.), and CA138255 and CA148761 (to C.M.P.). NR 39 TC 53 Z9 55 U1 1 U2 17 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 AUG 27 PY 2013 VL 110 IS 35 BP 14372 EP 14377 DI 10.1073/pnas.1303204110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ZC UT WOS:000323564600062 PM 23940356 ER PT J AU Papaioannou, G Inloes, JB Nakamura, Y Paltrinieri, E Kobayashi, T AF Papaioannou, Garyfallia Inloes, Jennifer B. Nakamura, Yukio Paltrinieri, Elena Kobayashi, Tatsuya TI let-7 and miR-140 microRNAs coordinately regulate skeletal development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chondrocyte differentiation; chondrocyte proliferation; mouse ID EMBRYONIC STEM-CELLS; DE-NOVO GERMLINE; CRE RECOMBINASE; TRANSGENIC MICE; LUNG-CANCER; SMALL RNAS; MOUSE; EXPRESSION; FAMILY; DIFFERENTIATION AB MicroRNAs (miRNAs) play critical roles in multiple processes of skeletal development. A global reduction of miRNAs in growth plate chondrocytes results in defects in both proliferation and differentiation; however, specific microRNAs responsible for these defects have not been identified. In this study, we provide evidence that let-7 miRNAs and microRNA-140 (miR-140), among other miRNAs expressed in chondrocytes, play major roles in endochondral bone development. We overexpressed lin-28 homolog A (Lin28a) to inhibit let-7 miRNA biogenesis in growth plate chondrocytes. Lin28a overexpression efficiently and specifically reduced let-7 miRNAs and up-regulated let-7 target genes. However, unlike the previous notion that let-7 miRNAs inhibit proliferation and growth, suppression of let-7 miRNAs via Lin28a overexpression decreased proliferation in growth plate chondrocytes, likely through up-regulation of the let-7 target cell cycle regulators cell division cycle 34 (Cdc34) and E2F transcription factor 5 (E2F5). Deficiency of the chondrocyte-specific miRNA, miR-140, causes a differentiation defect in growth plate chondrocytes. Although either Lin28a overexpression or miR-140 deficiency alone caused only mild growth impairment, mice with both miR-140 deficiency and Lin28a overexpression in chondrocytes showed a dramatic growth defect. Deregulation of distinct processes in the absence of these miRNAs synergistically decreased the proliferating chondrocyte mass; miR-140 deficiency reduced differentiation into proliferating chondrocytes, whereas Lin28a overexpression decreased proliferation per se. C1 [Papaioannou, Garyfallia; Inloes, Jennifer B.; Paltrinieri, Elena; Kobayashi, Tatsuya] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Papaioannou, Garyfallia; Inloes, Jennifer B.; Paltrinieri, Elena; Kobayashi, Tatsuya] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Nakamura, Yukio] Shinshu Univ, Sch Med, Dept Orthopaed Surg, Nagano 3908621, Japan. RP Kobayashi, T (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM kobayash@helix.mgh.harvard.edu FU National Institutes of Health [AR054500, AR056645]; American Society for Bone and Mineral Research [CEA0811] FX We thank Dr. Andy McMahon for the Cre-dependent expression construct pBGSApBpACAGftIGn. We thank Dr. Arthur Broadus for PTHrP-LacZ knock-in mice. We thank the Massachusetts General Hospital Transgenic Core Facility for pronuclear injection and the Beth Israel Deaconess Medical Center Genomics and Proteomics Center for microarray analysis. This work was supported by National Institutes of Health Grants AR054500 and AR056645 (to T.K.) and American Society for Bone and Mineral Research Grant CEA0811 (to T.K.). NR 48 TC 28 Z9 29 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 27 PY 2013 VL 110 IS 35 BP E3291 EP E3300 DI 10.1073/pnas.1302797110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ZC UT WOS:000323564600008 PM 23940373 ER PT J AU Carlson, AL Fujisaki, J Wu, J Runnels, JM Turcotte, R Lo Celso, C Scadden, DT Strom, TB Lin, CP AF Carlson, Alicia L. Fujisaki, Joji Wu, Juwell Runnels, Judith M. Turcotte, Raphael Lo Celso, Cristina Scadden, David T. Strom, Terry B. Lin, Charles P. TI Tracking Single Cells in Live Animals Using a Photoconvertible Near-Infrared Cell Membrane Label SO PLOS ONE LA English DT Article ID REGULATORY T-CELLS; RED FLUORESCENT PROTEINS; IN-VIVO; HEMATOPOIETIC STEM; OPTICAL HIGHLIGHTER; IMMUNE-SYSTEM; GENERATION; CONVERSION; EFFECTOR; LINEAGE AB We describe a novel photoconversion technique to track individual cells in vivo using a commercial lipophilic membrane dye, DiR. We show that DiR exhibits a permanent fluorescence emission shift ( photoconversion) after light exposure and does not reacquire the original color over time. Ratiometric imaging can be used to distinguish photoconverted from non-converted cells with high sensitivity. Combining the use of this photoconvertible dye with intravital microscopy, we tracked the division of individual hematopoietic stem/progenitor cells within the calvarium bone marrow of live mice. We also studied the peripheral differentiation of individual T cells by tracking the gain or loss of FoxP3-GFP expression, a marker of the immune suppressive function of CD4(+) T cells. With the near-infrared photoconvertible membrane dye, the entire visible spectral range is available for simultaneous use with other fluorescent proteins to monitor gene expression or to trace cell lineage commitment in vivo with high spatial and temporal resolution. C1 [Carlson, Alicia L.; Fujisaki, Joji; Wu, Juwell; Runnels, Judith M.; Turcotte, Raphael; Lin, Charles P.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Carlson, Alicia L.; Fujisaki, Joji; Wu, Juwell; Runnels, Judith M.; Turcotte, Raphael; Lin, Charles P.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Carlson, Alicia L.; Fujisaki, Joji; Wu, Juwell; Runnels, Judith M.; Turcotte, Raphael; Strom, Terry B.; Lin, Charles P.] Harvard Univ, Sch Med, Boston, MA USA. [Turcotte, Raphael] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. [Lo Celso, Cristina; Scadden, David T.] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Scadden, David T.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Scadden, David T.; Lin, Charles P.] Harvard Stem Cell Inst, Cambridge, MA USA. [Scadden, David T.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Strom, Terry B.] Beth Israel Deaconess Med Ctr, Transplant Inst, Boston, MA 02215 USA. RP Lin, CP (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. EM charles_lin@hms.harvard.edu OI Lo Celso, Cristina/0000-0002-1163-4207 FU National Institutes of Health (NIH) [HL097748, HL97794, CA086355, HL100402]; NIH [5 PO1 AI041521-12]; Juvenile Diabetes Research Foundation [7-2005-1329, 4-2007-1057]; JDRF Center in Immunologic Tolerance FX This work was supported by National Institutes of Health (NIH) grants HL097748, HL97794, CA086355, and HL100402. TBS was supported by NIH grant 5 PO1 AI041521-12, Juvenile Diabetes Research Foundation grants 7-2005-1329 and 4-2007-1057, and the JDRF Center in Immunologic Tolerance. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 13 Z9 13 U1 0 U2 19 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 26 PY 2013 VL 8 IS 8 AR e69257 DI 10.1371/journal.pone.0069257 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215RU UT WOS:000324228800005 PM 23990881 ER PT J AU Mekkaoui, C Porayette, P Jackowski, MP Kostis, WJ Dai, GP Sanders, S Sosnovik, DE AF Mekkaoui, Choukri Porayette, Prashob Jackowski, Marcel P. Kostis, William J. Dai, Guangping Sanders, Stephen Sosnovik, David E. TI Diffusion MRI Tractography of the Developing Human Fetal Heart SO PLOS ONE LA English DT Article ID MYOCARDIAL MICROSTRUCTURE; HISTOLOGICAL VALIDATION; LEFT-VENTRICLE; TENSOR MRI; ARCHITECTURE; ARRANGEMENT; INFARCTION; MYOFIBERS AB Objective: Human myocardium has a complex and anisotropic 3D fiber pattern. It remains unknown, however, when in fetal life this anisotropic pattern develops and whether the human heart is structurally fully mature at birth. We aimed here to use diffusion tensor MRI (DTI) tractography to characterize the evolution of fiber architecture in the developing human fetal heart. Methods: Human fetal hearts (n = 5) between 10-19 weeks of gestation were studied. The heart from a 6-day old neonate and an adult human heart served as controls. The degree of myocardial anisotropy was measured by calculating the fractional anisotropy (FA) index. In addition, fiber tracts were created by numerically integrating the primary eigenvector field in the heart into coherent streamlines. Results: At 10-14 weeks the fetal hearts were highly isotropic and few tracts could be resolved. Between 14-19 weeks the anisotropy seen in the adult heart began to develop. Coherent fiber tracts were well resolved by 19 weeks. The 19-week myocardium, however, remained weakly anisotropic with a low FA and no discernable sheet structure. Conclusions: The human fetal heart remains highly isotropic until 14-19 weeks, at which time cardiomyocytes self-align into coherent tracts. This process lags 2-3 months behind the onset of cardiac contraction, which may be a prerequisite for cardiomyocyte maturation and alignment. No evidence of a connective tissue scaffold guiding this process could be identified by DTI. Maturation of the heart's sheet structure occurs late in gestation and evolves further after birth. C1 [Mekkaoui, Choukri; Kostis, William J.; Dai, Guangping; Sosnovik, David E.] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Mekkaoui, Choukri; Kostis, William J.; Dai, Guangping; Sosnovik, David E.] Harvard Univ, Sch Med, Boston, MA USA. [Porayette, Prashob; Sanders, Stephen] Harvard Univ, Sch Med, Boston Childrens Hosp, Pathol Registry,Dept Cardiol, Boston, MA USA. [Porayette, Prashob; Sanders, Stephen] Harvard Univ, Sch Med, Dept Pathol, Boston Childrens Hosp,Pathol Registry, Boston, MA 02115 USA. [Porayette, Prashob; Sanders, Stephen] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Cardiac Surg,Pathol Registry, Boston, MA 02115 USA. [Jackowski, Marcel P.] Univ Sao Paulo, Inst Math & Stat, Dept Comp Sci, Sao Paulo, Brazil. [Kostis, William J.; Sosnovik, David E.] Massachusetts Gen Hosp, Div Cardiol, Cardiovasc Res Ctr, Boston, MA 02114 USA. RP Sosnovik, DE (reprint author), Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. EM sosnovik@nmr.mgh.harvard.edu RI Jackowski, Marcel/G-7602-2012; Cesar-Jr, Roberto/I-8222-2015; OI Sanders, Stephen/0000-0003-3521-4044 FU National Institutes of Health [R01 HL093038, P41RR14075] FX This work was funded in part by the following grants from the National Institutes of Health: R01 HL093038 and P41RR14075. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 20 TC 4 Z9 4 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 26 PY 2013 VL 8 IS 8 AR e72795 DI 10.1371/journal.pone.0072795 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215RU UT WOS:000324228800086 PM 23991152 ER PT J AU Tian, HJ Bi, XD Li, CS Zhao, KW Brochmann, EJ Montgomery, SR Aghdasi, B Chen, DY Daubs, MD Wang, JC Murray, SS AF Tian, Haijun Bi, Xiaoda Li, Chen-Shuang Zhao, Ke-Wei Brochmann, Elsa J. Montgomery, Scott R. Aghdasi, Bayan Chen, Deyu Daubs, Michael D. Wang, Jeffrey C. Murray, Samuel S. TI Secreted Phosphoprotein 24 kD (Spp24) and Spp14 Affect TGF-beta Induced Bone Formation Differently SO PLOS ONE LA English DT Article ID GROWTH-FACTOR-BETA; MORPHOGENETIC PROTEIN-2; LIGAND-BINDING; TRANSFORMING GROWTH-FACTOR-BETA-1; CRYSTAL-STRUCTURE; RECEPTOR; MATRIX; ANTAGONISTS; MUTAGENESIS; EXPRESSION AB Transforming growth factor-beta (TGF-beta) and bone morphogenetic proteins (BMPs) have opposing but complementary functions in directing bone growth, repair, and turnover. Both are found in the bone matrix. Proteins that bind to and affect the activity of these growth factors will determine the relative abundance of the growth factors and, therefore, regulate bone formation. Secreted phosphoprotein 24 kD (Spp24) is a bone matrix protein that has been demonstrated to bind to and affect the activity of BMPs. The arginine-rich carboxy terminus of Spp24 is proteolytically processed to produce three other predictable truncation products (Spp18.1, Spp16.0, and Spp14.5). In this work, we report that kinetic data obtained by surface plasmon resonance demonstrate that Spp24 and the three C-terminal truncation products all bind to TGF-beta 1 and TGF-beta 2 with a similar but somewhat less affinity than they bind BMP-2; that, as in the case of BMP-2, the full-length (FL) form of Spp24 binds TGF-beta with greater affinity than do the truncation products; that FL-Spp24 inhibits TGF-beta 2 induced bone formation in vivo, but Spp14.5 does not; and that co-administration of FL-Spp24 or Spp14.5 with TGF-beta 2 in vivo is associated with a reduction in the amount of cartilage, relative to new bone, present at the site of injection. This finding is consistent with the observation that low-dose TGF-beta administration in vivo is associated with greater bone formation than high-dose TGF-beta administration, and suggests that one function of Spp24 and its truncation products is to down-regulate local TGF-beta activity or availability during bone growth and development. The similarities and differences of the interactions between Spp24 proteins and TGF-beta compared to the interaction of the Spp24 proteins and BMPs have significant implications with respect to the regulation of bone metabolism and with respect to engineering therapeutic proteins for skeletal disorders. C1 [Tian, Haijun; Chen, Deyu] Second Mil Med Univ, Changzheng Hosp, Dept Orthopaed Surg, Shanghai, Peoples R China. [Bi, Xiaoda] 309th Hosp PLA, Dept Ophthalmol, Beijing, Peoples R China. [Li, Chen-Shuang] Peking Univ, Sch & Hosp Stomatol, Dept Orthodont, Beijing 100871, Peoples R China. [Zhao, Ke-Wei; Brochmann, Elsa J.; Murray, Samuel S.] VA Greater Los Angeles Healthcare Syst, Res Serv, Educ & Clin Ctr, North Hills, CA USA. [Brochmann, Elsa J.; Murray, Samuel S.] VA Greater Los Angeles Healthcare Syst, Educ & Clin Ctr, Geriatr Res, North Hills, CA USA. [Brochmann, Elsa J.; Murray, Samuel S.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. [Bi, Xiaoda] Univ Calif Los Angeles, Dept Physiol, Los Angeles, CA 90024 USA. [Montgomery, Scott R.; Daubs, Michael D.; Wang, Jeffrey C.] Univ Calif Los Angeles, Dept Orthopaed Surg, Los Angeles, CA USA. [Aghdasi, Bayan] Methodist Hosp Syst, Dept Orthopaed Surg, Houston, TX USA. RP Tian, HJ (reprint author), Second Mil Med Univ, Changzheng Hosp, Dept Orthopaed Surg, Shanghai, Peoples R China. EM haijuntianmd@gmail.com FU Department of Veterans Affairs Biomedical Laboratory Research; Development and Rehabilitation Research and Development Services [1I01BX000511, 1I0RX000383] FX This work was supported by the Department of Veterans Affairs Biomedical Laboratory Research (http://www.research.va.gov/services/blrd/#.UW8XKqV9FFg) and Development and Rehabilitation Research and Development Services (http://www.research.va.gov/services/rrd.cfm#.UW8XV6V9FFg) (1I01BX000511 and 1I0RX000383). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 9 Z9 9 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 26 PY 2013 VL 8 IS 8 AR e72645 DI 10.1371/journal.pone.0072645 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215RU UT WOS:000324228800081 PM 23991133 ER PT J AU Wang, MY Zhao, QS Yang, JH Jiang, BJ Wang, FZ Liu, KM Fang, X AF Wang, Mingyu Zhao, Qiushuang Yang, Jinghua Jiang, Baojie Wang, Fangzhong Liu, Kuimei Fang, Xu TI A Mitogen-Activated Protein Kinase Tmk3 Participates in High Osmolarity Resistance, Cell Wall Integrity Maintenance and Cellulase Production Regulation in Trichoderma reesei SO PLOS ONE LA English DT Article ID FUNGUS ASPERGILLUS-NIDULANS; HYPOCREA-JECORINA; SACCHAROMYCES-CEREVISIAE; OSMOTIC-STRESS; MAP KINASE; HYPHAL MORPHOGENESIS; HYPEROSMOTIC STRESS; SIGNAL-TRANSDUCTION; FILAMENTOUS FUNGUS; CHITIN SYNTHESIS AB The mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways conserved in essentially all eukaryotes, but haven't been subjected to functional studies in the most important cellulase-producing filamentous fungus Trichoderma reesei. Previous reports suggested the presence of three MAPKs in T. reesei: Tmk1, Tmk2, and Tmk3. By exploring the phenotypic features of T. reesei Delta tmk3, we first showed elevated NaCl sensitivity and repressed transcription of genes involved in glycerol/trehalose biosynthesis under higher osmolarity, suggesting Tmk3 participates in high osmolarity resistance via derepression of genes involved in osmotic stabilizer biosynthesis. We also showed significant downregulation of genes encoding chitin synthases and a beta-1,3-glucan synthase, decreased chitin content, 'budded' hyphal appearance typical to cell wall defective strains, and increased sensitivity to calcofluor white/Congo red in the tmk3 deficient strain, suggesting Tmk3 is involved in cell wall integrity maintenance in T. reesei. We further observed the decrease of cellulase transcription and production in T. reesei Delta tmk3 during submerged cultivation, as well as the presence of MAPK phosphorylation sites on known transcription factors involved in cellulase regulation, suggesting Tmk3 is also involved in the regulation of cellulase production. Finally, the expression of cell wall integrity related genes, the expression of cellulase coding genes, cellulase production and biomass accumulation were compared between T. reesei Delta tmk3 grown in solid state media and submerged media, showing a strong restoration effect in solid state media from defects resulted from tmk3 deletion. These results showed novel physiological processes that fungal Hog1-type MAPKs are involved in, and present the first experimental investigation of MAPK signaling pathways in T. reesei. Our observations on the restoration effect during solid state cultivation suggest that T. reesei is evolved to favor solid state growth, bringing up the proposal that the submerged condition normally used during investigations on fungal physiology might be misleading. C1 [Wang, Mingyu; Zhao, Qiushuang; Jiang, Baojie; Wang, Fangzhong; Liu, Kuimei; Fang, Xu] Shandong Univ, State Key Lab Microbial Technol, Jinan 250100, Peoples R China. [Wang, Mingyu; Fang, Xu] Shandong Univ, Natl Glycoengn Res Ctr, Jinan 250100, Peoples R China. [Yang, Jinghua] Boston Univ, Dept Surg, VA Boston Healthcare Syst, Boston, MA 02215 USA. [Yang, Jinghua] Shandong Univ, Sch Med, Canc Res Ctr, Jinan 250100, Peoples R China. RP Fang, X (reprint author), Shandong Univ, State Key Lab Microbial Technol, Jinan 250100, Peoples R China. EM fangxu@sdu.edu.cn RI Fang, Xu/B-8313-2015 OI Fang, Xu/0000-0002-9196-5697 FU National High-Tech R&D Program of China (863 program) [2011AA022302]; National Natural Science Foundation of China [31200051]; Shandong Province Natural Science Foundation [ZR2012CQ022]; Independent Innovation Foundation of Shandong University [2011HW008] FX This work was supported by National High-Tech R&D Program of China (863 program, number 2011AA022302), National Natural Science Foundation of China (number 31200051), Shandong Province Natural Science Foundation (number ZR2012CQ022), and Independent Innovation Foundation of Shandong University (number 2011HW008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 4 Z9 6 U1 0 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 26 PY 2013 VL 8 IS 8 AR e72189 DI 10.1371/journal.pone.0072189 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215RU UT WOS:000324228800049 PM 23991059 ER PT J AU Wu, F Guo, LL Jakubowski, A Su, LH Li, WC Bonner-Weir, S Burkly, LC AF Wu, Fei Guo, Lili Jakubowski, Aniela Su, Lihe Li, Wan-Chun Bonner-Weir, Susan Burkly, Linda C. TI TNF-Like Weak Inducer of Apoptosis (TWEAK) Promotes Beta Cell Neogenesis from Pancreatic Ductal Epithelium in Adult Mice SO PLOS ONE LA English DT Article ID HOMEODOMAIN PROTEIN IDX-1; GLUCAGON-LIKE PEPTIDE-1; ISLET NEOGENESIS; PROGENITOR CELLS; ENDOCRINE-CELLS; TRANSGENIC MICE; MOUSE PANCREAS; IN-VITRO; REGENERATION; GROWTH AB Aim/Hypothesis: The adult mammalian pancreas has limited ability to regenerate in order to restore adequate insulin production from multipotent progenitors, the identity and function of which remain poorly understood. Here we test whether the TNF family member TWEAK (TNF-like weak inducer of apoptosis) promotes beta-cell neogenesis from proliferating pancreatic ductal epithelium in adult mice. Methods: C57Bl/6J mice were treated with Fc-TWEAK and pancreas harvested at different time points for analysis by histology and immunohistochemistry. For lineage tracing, 4 week old double transgenic mice CAII-CreER (TM) : R26R-eYFP were implanted with tamoxifen pellet, injected with Fc-TWEAK or control Ig twice weekly and analyzed at day 18 for TWEAK-induced duct cell progeny by costaining for insulin and YFP. The effect of TWEAK on pancreatic regeneration was determined by pancytokeratin immunostaining of paraffin embedded sections from wildtype and TWEAK receptor (Fn14) deficient mice after Px. Results: TWEAK stimulates proliferation of ductal epithelial cells through its receptor Fn14, while it has no mitogenic effect on pancreatic alpha- or beta-cells or acinar cells. Importantly, TWEAK induces transient expression of endogenous Ngn3, a master regulator of endocrine cell development, and induces focal ductal structures with characteristics of regeneration foci. In addition, we identify by lineage tracing TWEAK-induced pancreatic beta-cells derived from pancreatic duct epithelial cells. Conversely, we show that Fn14 deficiency delays formation of regenerating foci after Px and limits their expansion. Conclusions/Interpretation: We conclude that TWEAK is a novel factor mediating pancreatic b-cell neogenesis from ductal epithelium in normal adult mice. C1 [Wu, Fei; Jakubowski, Aniela; Su, Lihe; Burkly, Linda C.] Biogen Idec Inc, Dept Immunobiol, Cambridge, MA USA. [Guo, Lili; Li, Wan-Chun; Bonner-Weir, Susan] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Islet Cell & Regenerat Biol,Dept Med, Boston, MA 02115 USA. RP Burkly, LC (reprint author), Biogen Idec Inc, Dept Immunobiol, Cambridge, MA USA. EM linda.burkly@biogenidec.com FU Juvenile Diabetes Research Foundation (JDRF) [15-2007-1060]; National Institutes of Health NIDDK [P30 DK36836] FX This study was supported by Juvenile Diabetes Research Foundation (JDRF) Grant 15-2007-1060 and National Institutes of Health NIDDK P30 DK36836. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 8 Z9 8 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 26 PY 2013 VL 8 IS 8 AR e72132 DI 10.1371/journal.pone.0072132 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 215RU UT WOS:000324228800047 PM 23991053 ER PT J AU Bassett, IV Giddy, J Chaisson, CE Ross, D Bogart, LM Coleman, SM Govender, T Robine, M Erlwanger, A Freedberg, KA Katz, JN Walensky, RP Losina, E AF Bassett, Ingrid V. Giddy, Janet Chaisson, Christine E. Ross, Douglas Bogart, Laura M. Coleman, Sharon M. Govender, Tessa Robine, Marion Erlwanger, Alison Freedberg, Kenneth A. Katz, Jeffrey N. Walensky, Rochelle P. Losina, Elena TI A randomized trial to optimize HIV/TB care in South Africa: design of the Sizanani trial SO BMC INFECTIOUS DISEASES LA English DT Article DE (3-10): HIV/AIDS; Tuberculosis; South Africa; Linkage to care; SMS reminders; Randomized controlled trial; Counseling/Support ID SUB-SAHARAN AFRICA; ANTIRETROVIRAL THERAPY; MEDICAL-CARE; PATIENT RETENTION; CASE-MANAGEMENT; DURBAN; ADHERENCE; INTERVENTIONS; MORTALITY; DETERMINANTS AB Background: Despite increases in HIV testing, only a fraction of people newly diagnosed with HIV infection enter the care system and initiate antiretroviral therapy (ART) in South Africa. We report on the design and initial enrollment of a randomized trial of a health system navigator intervention to improve linkage to HIV care and TB treatment completion in Durban, South Africa. Methods/Design: We employed a multi-site randomized controlled trial design. Patients at 4 outpatient sites were enrolled prior to HIV testing. For all HIV-infected participants, routine TB screening with sputum for mycobacterial smear and culture were collected. HIV-infected participants were randomized to receive the health system navigator intervention or usual care. Participants in the navigator arm underwent a baseline interview using a strengths-based case management approach to assist in identifying barriers to entering care and devising solutions to best cope with perceived barriers. Over 4 months, participants in the navigator arm received scheduled phone and text messages. The primary outcome of the study is linkage and retention in care, assessed 9 months after enrollment. For ART-eligible participants without TB, the primary outcome is 3 months on ART as documented in the medical record; participants co-infected with TB are also eligible to meet the primary outcome of completion of 6 months of TB treatment, as documented by the TB clinic. Secondary outcomes include mortality, receipt of CD4 count and TB test results, and repeat CD4 counts for those not ART-eligible at baseline. We hypothesize that a health system navigator can help identify and positively affect modifiable patient factors, including self-efficacy and social support, that in turn can improve linkage to and retention in HIV and TB care. Discussion: We are currently evaluating the clinical impact of a novel health system navigator intervention to promote entry to and retention in HIV and TB care for people newly diagnosed with HIV. The details of this study protocol will inform clinicians, investigators, and policy makers of strategies to best support HIV-infected patients in resource-limited settings. C1 [Bassett, Ingrid V.; Robine, Marion; Erlwanger, Alison; Freedberg, Kenneth A.; Walensky, Rochelle P.; Losina, Elena] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Bassett, Ingrid V.; Freedberg, Kenneth A.; Walensky, Rochelle P.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Bassett, Ingrid V.; Robine, Marion; Erlwanger, Alison; Freedberg, Kenneth A.; Walensky, Rochelle P.; Losina, Elena] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Bassett, Ingrid V.; Bogart, Laura M.; Freedberg, Kenneth A.; Walensky, Rochelle P.; Losina, Elena] Harvard Univ, Sch Med, Boston, MA USA. [Bassett, Ingrid V.; Bogart, Laura M.; Freedberg, Kenneth A.; Walensky, Rochelle P.; Losina, Elena] Harvard Univ, Ctr AIDS Res, Cambridge, MA 02138 USA. [Giddy, Janet; Govender, Tessa] McCord Hosp, Durban, South Africa. [Chaisson, Christine E.; Coleman, Sharon M.] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Ross, Douglas] St Marys Hosp, Durban, South Africa. [Bogart, Laura M.] Childrens Hosp, Dept Med, Div Gen Pediat, Boston, MA 02115 USA. [Freedberg, Kenneth A.] Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. [Freedberg, Kenneth A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Katz, Jeffrey N.; Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Katz, Jeffrey N.] Brigham & Womens Hosp, Div Rheumatol, Boston, MA 02115 USA. [Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Losina, Elena] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Bassett, IV (reprint author), Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. EM ibassett@partners.org OI Walensky, Rochelle P./0000-0002-8795-379X FU National Institute of Mental Health [R01 MH090326, R01 MH073445]; Harvard University Center for AIDS Research [P30 AI060354]; National Institute of Arthritis and Musculoskeletal and Skin Diseases [K24 AR057827]; National Center for Research Resources (the Harvard Catalyst) [UL1 RR 025758]; Burke Global Health Fellowship; Claflin Distinguished Scholar Award FX This protocol is supported by the National Institute of Mental Health R01 MH090326 (IVB) and R01 MH073445 (RPW); the Harvard University Center for AIDS Research P30 AI060354; the National Institute of Arthritis and Musculoskeletal and Skin Diseases K24 AR057827 (EL); the National Center for Research Resources (the Harvard Catalyst UL1 RR 025758); the Burke Global Health Fellowship (IVB); and the Claflin Distinguished Scholar Award (IVB). The funders had no role in the study design, the data collection and the analysis, the decision to publish, or in the preparation of the manuscript. NR 40 TC 7 Z9 7 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD AUG 26 PY 2013 VL 13 AR 390 DI 10.1186/1471-2334-13-390 PG 9 WC Infectious Diseases SC Infectious Diseases GA 211TJ UT WOS:000323933500001 PM 23972276 ER PT J AU Bulliard, Y Jolicoeur, R Windman, M Rue, SM Ettenberg, S Knee, DA Wilson, NS Dranoff, G Brogdon, JL AF Bulliard, Yannick Jolicoeur, Rose Windman, Maurice Rue, Sarah M. Ettenberg, Seth Knee, Deborah A. Wilson, Nicholas S. Dranoff, Glenn Brogdon, Jennifer L. TI Activating Fc gamma receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID REGULATORY T-CELLS; ANTI-GITR MAB; CANCER-IMMUNOTHERAPY; TUMOR-IMMUNITY; BINDING; RESPONSES; MELANOMA; COSTIMULATION; BLOCKADE; IGG1 AB Fc gamma receptor (Fc gamma R) coengagement can facilitate antibody-mediated receptor activation in target cells. In particular, agonistic antibodies that target tumor necrosis factor receptor (TNFR) family members have shown dependence on expression of the inhibitory Fc gamma R, Fc gamma RIIB. It remains unclear if engagement of Fc gamma RIIB also extends to the activities of antibodies targeting immunoregulatory TNFRs expressed by T cells. We have explored the requirement for activating and inhibitory Fc gamma Rs for the antitumor effects of antibodies targeting the TNFR glucocorticoid-induced TNFR-related protein (GITR; TNFRSF18; CD357) expressed on activated and regulatory T cells (T reg cells). We found that although Fc gamma RIIB was dispensable for the in vivo efficacy of anti-GITR antibodies, in contrast, activating Fc gamma Rs were essential. Surprisingly, the dependence on activating Fc gamma Rs extended to an antibody targeting the non-TNFR receptor CTLA-4 (CD152) that acts as a negative regulator of T cell immunity. We define a common mechanism that correlated with tumor efficacy, whereby antibodies that coengaged activating Fc gamma Rs expressed by tumor-associated leukocytes facilitated the selective elimination of intratumoral T cell populations, particularly T reg cells. These findings may have broad implications for antibody engineering efforts aimed at enhancing the therapeutic activity of immunomodulatory antibodies. C1 [Bulliard, Yannick; Ettenberg, Seth; Wilson, Nicholas S.; Brogdon, Jennifer L.] Novartis Inst Biomed Res, Dept Oncol, Cambridge, MA 02139 USA. [Jolicoeur, Rose; Windman, Maurice] Novartis Inst Biomed Res, Lab Anim Serv, Cambridge, MA 02139 USA. [Rue, Sarah M.; Knee, Deborah A.] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Dranoff, Glenn] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Dranoff, Glenn] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02215 USA. [Dranoff, Glenn] Harvard Univ, Sch Med, Dept Med, Brigham & Womens Hosp, Boston, MA 02215 USA. RP Brogdon, JL (reprint author), Novartis Inst Biomed Res, Dept Oncol, Cambridge, MA 02139 USA. EM jennifer.brogdon@novartis.com FU Novartis, Inc. FX Glenn Dranoff is a consultant and receives sponsored research support from Novartis, Inc. The authors have no additional financial interests. NR 33 TC 123 Z9 127 U1 0 U2 7 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 AUG 26 PY 2013 VL 210 IS 9 BP 1685 EP 1693 DI 10.1084/jem.20130573 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 207ZV UT WOS:000323644800006 PM 23897982 ER PT J AU Raccosta, L Fontana, R Maggioni, D Lanterna, C Villablanca, EJ Paniccia, A Musumeci, A Chiricozzi, E Trincavelli, ML Daniele, S Martini, C Gustafsson, JA Doglioni, C Feo, SG Leiva, A Ciampa, MG Mauri, L Sensi, C Prinetti, A Eberini, I Mora, JR Bordignon, C Steffensen, KR Sonnino, S Sozzani, S Traversari, C Russo, V AF Raccosta, Laura Fontana, Raffaella Maggioni, Daniela Lanterna, Claudia Villablanca, Eduardo J. Paniccia, Aida Musumeci, Andrea Chiricozzi, Elena Trincavelli, Maria Letizia Daniele, Simona Martini, Claudia Gustafsson, Jan-Ake Doglioni, Claudio Feo, Safiye Gonzalvo Leiva, Andrea Ciampa, Maria Grazia Mauri, Laura Sensi, Cristina Prinetti, Alessandro Eberini, Ivano Mora, J. Rodrigo Bordignon, Claudio Steffensen, Knut R. Sonnino, Sandro Sozzani, Silvano Traversari, Catia Russo, Vincenzo TI The oxysterol-CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MYELOID CELLS; CHOLESTEROL HOMEOSTASIS; MASS-SPECTROMETRY; NUCLEAR RECEPTORS; DENDRITIC CELLS; IMMUNE-SYSTEM; CANCER; ANGIOGENESIS; METASTASIS; MIGRATION AB Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses, thereby facilitating tumor growth. Among immune cells, neutrophils play an important protumorigenic role by favoring neoangiogenesis and/or by suppressing antitumor immune responses. Tumor-derived oxysterols have recently been shown to favor tumor growth by inhibiting dendritic cell migration toward lymphoid organs. We report that tumor-derived oxysterols recruit protumor neutrophils in a liver X receptor (LXR)-independent, CXCR2-dependent manner, thus favoring tumor growth by promoting neoangiogenesis and immunosuppression. We demonstrate that interfering with the oxysterol-CXCR2 axis delays tumor growth and prolongs the overall survival of tumor-bearing mice. These results identify an unanticipated protumor function of the oxysterol-CXCR2 axis and a possible target for cancer therapy. C1 [Raccosta, Laura; Fontana, Raffaella; Maggioni, Daniela; Lanterna, Claudia; Paniccia, Aida; Musumeci, Andrea; Leiva, Andrea; Russo, Vincenzo] Ist Sci San Raffaele, Canc Gene Therapy Unit, Program Immunol & Bio Immuno Gene Therapy Canc, Div Mol Oncol, I-20132 Milan, Italy. [Doglioni, Claudio] Ist Sci San Raffaele, Dept Pathol, I-20132 Milan, Italy. [Villablanca, Eduardo J.; Mora, J. Rodrigo] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Chiricozzi, Elena; Ciampa, Maria Grazia; Mauri, Laura; Prinetti, Alessandro; Sonnino, Sandro] Univ Milan, Dept Med Chem Biochem & Biotechnol, Ctr Excellence Neurodegenerat Dis, I-20090 Segrate, Italy. [Trincavelli, Maria Letizia; Daniele, Simona; Martini, Claudia] Univ Pisa, Dept Pharm, I-56126 Pisa, Italy. [Gustafsson, Jan-Ake; Steffensen, Knut R.] Karolinska Inst, Dept Biosci & Nutr, S-14183 Huddinge, Sweden. [Gustafsson, Jan-Ake] Univ Houston, Ctr Nucl Receptors & Cell Signaling, Houston, TX 77204 USA. [Doglioni, Claudio; Bordignon, Claudio] Univ Vita Salute San Raffaele, I-20132 Milan, Italy. [Feo, Safiye Gonzalvo; Sozzani, Silvano] Humanitas Clin & Res Ctr, I-20089 Rozzano, Italy. [Sensi, Cristina; Eberini, Ivano] Univ Milan, Prote & Prot Struct Study Grp, Dept Pharmacol Sci, I-20133 Milan, Italy. [Bordignon, Claudio; Traversari, Catia] MolMed SpA, I-20132 Milan, Italy. [Sozzani, Silvano] Univ Brescia, Dept Mol & Translat Med, I-25123 Brescia, Italy. RP Russo, V (reprint author), Ist Sci San Raffaele, Canc Gene Therapy Unit, Program Immunol & Bio Immuno Gene Therapy Canc, Div Mol Oncol, I-20132 Milan, Italy. EM v.russo@hsr.it RI Villablanca, Eduardo/E-1380-2016; raccosta, laura/K-3101-2016; Russo, Vincenzo/K-5650-2016; OI Villablanca, Eduardo/0000-0001-9522-9729; raccosta, laura/0000-0002-1625-9573; Russo, Vincenzo/0000-0003-1592-5041; Steffensen, Knut/0000-0001-6093-2801; Trincavelli, Maria Letizia/0000-0001-8124-977X; Sozzani, Silvano/0000-0002-3144-8743; DOGLIONI, Claudio/0000-0002-4969-5216; Musumeci, Andrea/0000-0002-2497-0699; Martini, Claudia/0000-0001-9379-3027 FU Association for International Cancer Research (AICR, UK); Italian Association for Cancer Research (AIRC); Italian Ministry of Health [RF-2009]; Crohn's & Colitis Foundation of America (CCFA); Cancer Research Institute (CRI); Howard H. Goodman (MGH); Massachusetts Life Science Center (MLSC); NIH [DP2 2009A054301]; Swedish Science Council [522-2008-3745]; Robert A. Welch Foundation; Special Program Molecular Clinical Oncology AIRC 5 per mille [9965] FX This work was supported by the Association for International Cancer Research (AICR, UK), Italian Association for Cancer Research (AIRC), and Italian Ministry of Health (RF-2009). E.J. Villablanca was supported by grants from Crohn's & Colitis Foundation of America (CCFA). J.R. Mora was supported by grants from Crohn's & Colitis Foundation of America (CCFA), Cancer Research Institute (CRI), Howard H. Goodman (MGH), Massachusetts Life Science Center (MLSC), and NIH DP2 2009A054301. K.R. Steffensen and J.-A. Gustafsson were supported by grants from the Swedish Science Council (522-2008-3745) and J.-A. Gustafsson from the Robert A. Welch Foundation. A. Paniccia conducted this study as partial fulfillment of the PhD in Biology and Biotherapy of Cancer, Universita Vita-Salute San Raffaele (Milan, Italy), and is supported by the Special Program Molecular Clinical Oncology AIRC 5 per mille (9965). C. Traversari and C. Bordignon are employees of MolMed S.p.A. NR 60 TC 39 Z9 39 U1 0 U2 13 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 AUG 26 PY 2013 VL 210 IS 9 BP 1711 EP 1728 DI 10.1084/jem.20130440 PG 18 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 207ZV UT WOS:000323644800008 PM 23897983 ER PT J AU Mikhak, Z Strassner, JP Luster, AD AF Mikhak, Zamaneh Strassner, James P. Luster, Andrew D. TI Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID LYMPHOCYTE TRAFFICKING; INFLUENZA INFECTION; VIRUS-INFECTION; CUTTING EDGE; IN-VIVO; TISSUE; EXPRESSION; MEMORY; SKIN; ANTIGEN AB T cell trafficking into the lung is critical for lung immunity, but the mechanisms that mediate T cell lung homing are not well understood. Here, we show that lung dendritic cells (DCs) imprint T cell lung homing, as lung DC-activated T cells traffic more efficiently into the lung in response to inhaled antigen and at homeostasis compared with T cells activated by DCs from other tissues. Consequently, lung DC-imprinted T cells protect against influenza more effectively than do gut and skin DC-imprinted T cells. Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting. Lung DC-activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect against influenza as effectively as lung DC-activated, CCR4-sufficient T cells. Thus, lung DCs imprint T cell lung homing and promote lung immunity in part through CCR4. C1 [Mikhak, Zamaneh; Strassner, James P.; Luster, Andrew D.] Harvard Univ, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Sch Med,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Mikhak, Z (reprint author), Harvard Univ, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Sch Med,Massachusetts Gen Hosp, Charlestown, MA 02129 USA. EM mikhak.zamaneh@mgh.harvard.edu; aluster@mgh.harvard.edu FU US National Institutes of Health [K08AI67519, R37AI040618]; American Academy of Allergy Asthma and Immunology R Award Bridge Grant FX This work is funded by the US National Institutes of Health (grant K08AI67519 to Z. Mikhak and R37AI040618 to A.D. Luster) and the 2012 American Academy of Allergy Asthma and Immunology R Award Bridge Grant to Z. Mikhak. NR 61 TC 43 Z9 45 U1 0 U2 9 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 AUG 26 PY 2013 VL 210 IS 9 BP 1855 EP 1869 DI 10.1084/jem.20130091 PG 15 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 207ZV UT WOS:000323644800017 PM 23960189 ER PT J AU Haberer, JE Kiwanuka, J Nansera, D Muzoora, C Hunt, PW So, J O'Donnell, M Siedner, M Martin, JN Bangsberg, DR AF Haberer, Jessica E. Kiwanuka, Julius Nansera, Denis Muzoora, Conrad Hunt, Peter W. So, Jacquelyn O'Donnell, Michael Siedner, Mark Martin, Jeffrey N. Bangsberg, David R. TI Realtime adherence monitoring of antiretroviral therapy among HIV-infected adults and children in rural Uganda SO AIDS LA English DT Article AB A real-time wireless electronic adherence monitor (EAM) and weekly self-report of missed doses via interactive voice response (IVR) and short message service (SMS) queries were used to measure anti-retroviral therapy adherence in 49 adults and 46 children in rural Uganda. Median adherence was 89.5% among adults and 92.8% among children by EAM, and 99-100% for both adults and children by IVR/SMS self-report. Loss of viral suppression was significantly associated with adherence by EAM (odds ratio 0.58 for each 10% increase), but not IVR/SMS. Wireless EAM creates an exciting opportunity to monitor and potentially intervene with adherence challenges as they are happening. C1 [Haberer, Jessica E.] MGH Ctr Global Hlth, Boston, MA 02114 USA. [Haberer, Jessica E.; O'Donnell, Michael; Siedner, Mark; Bangsberg, David R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Haberer, Jessica E.; Bangsberg, David R.] Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA 02114 USA. [Haberer, Jessica E.; Bangsberg, David R.] Ragon Inst MGH MIT & Harvard, Cambridge, MA USA. [Kiwanuka, Julius; Nansera, Denis; Muzoora, Conrad; Bangsberg, David R.] Mbarara Univ Sci & Technol, Mbarara, Uganda. [Hunt, Peter W.; So, Jacquelyn; Martin, Jeffrey N.] Univ Calif San Francisco, San Francisco, CA USA. RP Haberer, JE (reprint author), MGH Ctr Global Hlth, 100 Cambridge St,15th floor, Boston, MA 02114 USA. EM jhaberer@partners.org FU NIAID NIH HHS [P30 AI027763]; NIMH NIH HHS [K24 MH087227, K23 MH087228, R01 MH054907, R21 MH083306] NR 0 TC 21 Z9 21 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD AUG 24 PY 2013 VL 27 IS 13 BP 2166 EP 2168 DI 10.1097/QAD.0b013e328363b53f PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 248MG UT WOS:000326703500021 PM 23751260 ER PT J AU Belzil, C Neumayer, G Vassilev, AP Yap, KL Konishi, H Rivest, S Sanada, K Ikura, M Nakatani, Y Nguyen, MD AF Belzil, Camille Neumayer, Gernot Vassilev, Alex P. Yap, Kyoko L. Konishi, Hiroaki Rivest, Serge Sanada, Kamon Ikura, Mitsuhiko Nakatani, Yoshihiro Minh Dang Nguyen TI A Ca2+-dependent Mechanism of Neuronal Survival Mediated by the Microtubule-associated Protein p600 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; METHYL-D-ASPARTATE; KINASE-II CLUSTERS; ALZHEIMERS-DISEASE; NEURODEGENERATIVE DISEASES; CEREBRAL-ISCHEMIA; INDUCED APOPTOSIS; CNS NEURONS; CALCIUM; CALMODULIN AB In acute and chronic neurodegeneration, Ca2+ mishandling and disruption of the cytoskeleton compromise neuronal integrity, yet abnormalities in the signaling roles of cytoskeletal proteins remain largely unexplored. We now report that the microtubule-associated protein p600 (also known as UBR4) promotes neuronal survival. Following depletion of p600, glutamate-induced Ca2+ influx through NMDA receptors, but not AMPA receptors, initiates a degenerative process characterized by endoplasmic reticulum fragmentation and endoplasmic reticulum Ca2+ release via inositol 1,4,5-trisphosphate receptors. Downstream of NMDA receptors, p600 associates with the calmodulin-calmodulin-dependent protein kinase II alpha complex. A direct and atypical p600/calmodulin interaction is required for neuronal survival. Thus, p600 counteracts specific Ca2+-induced death pathways through regulation of Ca2+ homeostasis and signaling. C1 [Belzil, Camille; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB T2N 4N1, Canada. [Belzil, Camille; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Dept Clin Neurosci, Calgary, AB T2N 4N1, Canada. [Belzil, Camille; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Dept Cell Biol & Anat, Calgary, AB T2N 4N1, Canada. [Belzil, Camille; Neumayer, Gernot; Minh Dang Nguyen] Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. [Vassilev, Alex P.] NICHD, NIH, Bethesda, MD 20892 USA. [Yap, Kyoko L.; Ikura, Mitsuhiko] Univ Toronto, Ontario Canc Inst, Toronto, ON M5G 1L7, Canada. [Konishi, Hiroaki] Prefectural Univ Hiroshima, Fac Life & Environm Sci, Shobara, Hiroshima 7270023, Japan. [Rivest, Serge] Univ Laval, Ctr Hosp Univ Laval, Ctr Rech, Quebec City, PQ G1V 0A6, Canada. [Sanada, Kamon] Univ Tokyo, Grad Sch Sci, Mol Genet Res Lab, Bunkyo Ku, Tokyo 1130033, Japan. [Nakatani, Yoshihiro] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Nguyen, MD (reprint author), Univ Calgary, Hotchkiss Brain Inst, Dept Clin Neurosci, HMRB 151,3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. EM mdnguyen@ucalgary.ca RI SANADA, YOSHIKADO/G-5014-2014 FU Canadian Institutes of Health Research (CIHR); Human Frontier Science Program Organization (HFSPO); Brenda Strafford Chair Foundation in Alzheimer's disease; Alberta Innovates Health Solutions (AIHS); Ted Fong/Hotchkiss Brain Institute; Austrian Academy of Sciences at the University of Calgary; Achievers in Medical Sciences award; CIHR; Canadian Cancer Society; AIHS FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by an operating grant from the Canadian Institutes of Health Research (CIHR), the Human Frontier Science Program Organization (HFSPO), and the Brenda Strafford Chair Foundation in Alzheimer's disease (to M. D. N.).; Recipient of an Alberta Innovates Health Solutions (AIHS) studentship and a Ted Fong/Hotchkiss Brain Institute doctoral scholarship.; Recipient of a doctoral fellowship of the Austrian Academy of Sciences at the University of Calgary and an Achievers in Medical Sciences award.; Supported by CIHR and the Canadian Cancer Society and holder of a Canada Research Chair.; Recipient of a New Investigator Award from the CIHR and a Scholarship from AIHS. NR 53 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2013 VL 288 IS 34 BP 24452 EP 24464 DI 10.1074/jbc.M113.483107 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302NW UT WOS:000330612300015 PM 23861403 ER PT J AU Ghosh-Choudhury, N Mandal, CC Das, F Ganapathy, S Ahuja, S Choudhury, GG AF Ghosh-Choudhury, Nandini Mandal, Chandi C. Das, Falguni Ganapathy, Suthakar Ahuja, Seema Choudhury, Goutam Ghosh TI c-Abl-dependent Molecular Circuitry Involving Smad5 and Phosphatidylinositol 3-Kinase Regulates Bone Morphogenetic Protein-2-induced Osteogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-BETA; ACTIVATED PROTEIN-KINASE; BMP-2 GENE-TRANSCRIPTION; TGF-BETA; TYROSINE KINASE; OSTEOBLAST DIFFERENTIATION; SIGNAL-TRANSDUCTION; IMATINIB MESYLATE; CELL-DIFFERENTIATION; PRECURSOR CELLS AB Skeletal remodeling consists of timely formation and resorption of bone by osteoblasts and osteoclasts in a quantitative manner. Patients with chronic myeloid leukemia receiving inhibitors of c-Abl tyrosine kinase often show reduced bone remodeling due to impaired osteoblast and osteoclast function. BMP-2 plays a significant role in bone generation and resorption by contributing to the formation of mature osteoblasts and osteoclasts. The effects of c-Abl on BMP-2-induced bone remodeling and the underlying mechanisms are not well studied. Using a pharmacological inhibitor and expression of a dominant negative mutant of c-Abl, we show an essential role of this tyrosine kinase in the development of bone nodules containing mature osteoblasts and formation of multinucleated osteoclasts in response to BMP-2. Calvarial osteoblasts prepared from c-Abl null mice showed the absolute requirement of this tyrosine kinase in maturation of osteoblasts and osteoclasts. Activation of phosphatidylinositol 3-kinase (PI 3-kinase)/Akt signaling by BMP-2 leads to osteoblast differentiation. Remarkably, inhibition of c-Abl significantly suppressed BMP-2-stimulated PI 3-kinase activity and its downstream Akt phosphorylation. Interestingly, c-Abl regulated BMP-2-induced osteoclastogenic CSF-1 expression. More importantly, we identified the requirements of c-Abl in BMP-2 autoregulation and the expressions of alkaline phosphatase and osterix that are necessary for osteoblast differentiation. c-Abl contributed to BMP receptor-specific Smad-dependent transcription of CSF-1, osterix, and BMP-2. Finally, c-Abl associates with BMP receptor IA and regulates phosphorylation of Smad in response to BMP-2. We propose that activation of c-Abl is an important step, which induces into two signaling pathways involving noncanonical PI 3-kinase and canonical Smads to integrate BMP-2-induced osteogenesis. C1 [Ghosh-Choudhury, Nandini; Ahuja, Seema; Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Vet Affairs Res, San Antonio, TX 78229 USA. [Choudhury, Goutam Ghosh] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini; Mandal, Chandi C.; Ganapathy, Suthakar] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Das, Falguni; Ahuja, Seema; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. RP Ghosh-Choudhury, N (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. EM choudhury@uthscsa.edu FU National Institutes of Health [RO1 AR52425, RO1 DK50190]; Veterans Affairs Merit Review grant; CTRC P30 Cancer Center Support Grant [CA 054174]; Veterans Affairs Merit Review grants; Cancer Prevention Research Institute of Texas; Veterans Affairs Senior Research Career Scientist Award FX This work was supported, in whole or in part, by National Institutes of Health Grants RO1 AR52425 (to N. G. C.) and RO1 DK50190 (to G. G. C.). This work was also supported by Veterans Affairs Merit Review grant and CTRC P30 Cancer Center Support Grant CA 054174 (to N. G. C.) and in part by Veterans Affairs Merit Review grants (to G. G. C.).; Recipient of a fellowship from the Cancer Prevention Research Institute of Texas.; Recipient of Veterans Affairs Senior Research Career Scientist Award. NR 78 TC 10 Z9 10 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 23 PY 2013 VL 288 IS 34 BP 24503 EP 24517 DI 10.1074/jbc.M113.455733 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302NW UT WOS:000330612300019 PM 23821550 ER PT J AU Tan, A Farhatnia, Y Goh, D Natasha, G de Mel, A Lim, J Teoh, SH Malkovskiy, AV Chawla, R Rajadas, J Cousins, BG Hamblin, MR Alavijeh, MS Seifalian, AM AF Tan, Aaron Farhatnia, Yasmin Goh, Debbie Natasha, G. de Mel, Achala Lim, Jing Teoh, Swee-Hin Malkovskiy, Andrey V. Chawla, Reema Rajadas, Jayakumar Cousins, Brian G. Hamblin, Michael R. Alavijeh, Mohammad S. Seifalian, Alexander M. TI Surface modification of a polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) nanocomposite polymer as a stent coating for enhanced capture of endothelial progenitor cells SO BIOINTERPHASES LA English DT Article DE POSS-PCU; Stent coatings; Anti-CD34 antibody; Endothelialization; Endothelial progenitor cell capture; Nanotechnology; Regenerative medicine; Biomaterials ID CORONARY-ARTERY-DISEASE; IN-VITRO; RE-ENDOTHELIALIZATION; ELUTING STENT; ANTIBODY; GRAFT; HEMOCOMPATIBILITY; RESTENOSIS; MODEL; RISK AB An unmet need exists for the development of next-generation multifunctional nanocomposite materials for biomedical applications, particularly in the field of cardiovascular regenerative biology. Herein, we describe the preparation and characterization of a novel polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSS-PCU) nanocomposite polymer with covalently attached anti-CD34 antibodies to enhance capture of circulating endothelial progenitor cells (EPC). This material may be used as a new coating for bare metal stents used after balloon angioplasty to improve re-endothelialization. Biophysical characterization techniques were used to assess POSS-PCU and its subsequent functionalization with anti-CD34 antibodies. Results indicated successful covalent attachment of anti-CD34 antibodies on the surface of POSS-PCU leading to an increased propensity for EPC capture, whilst maintaining in vitro biocompatibility and hemocompatibility. POSS-PCU has already been used in 3 first-in-man studies, as a bypass graft, lacrimal duct and a bioartificial trachea. We therefore postulate that its superior biocompatibility and unique biophysical properties would render it an ideal candidate for coating medical devices, with stents as a prime example. Taken together, anti-CD34 functionalized POSS-PCU could form the basis of a nano-inspired polymer platform for the next generation stent coatings. C1 [Tan, Aaron; Farhatnia, Yasmin; Goh, Debbie; Natasha, G.; de Mel, Achala; Chawla, Reema; Cousins, Brian G.; Seifalian, Alexander M.] UCL, Ctr Nanotechnol & Regenerat Med, Div Surg & Intervent Sci, London, England. [Tan, Aaron; Goh, Debbie; Natasha, G.] UCL, Sch Med, London W1N 8AA, England. [Lim, Jing; Teoh, Swee-Hin] Nanyang Technol Univ, Sch Chem & Biomed Engn, Div Bioengn, Singapore 639798, Singapore. [Malkovskiy, Andrey V.; Rajadas, Jayakumar] Stanford Univ, Sch Med, Biomat & Adv Drug Delivery Lab, Stanford, CA 94305 USA. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 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. [Alavijeh, Mohammad S.] Pharmidex Pharmaceut Serv Ltd, London, England. [Seifalian, Alexander M.] Royal Free London NHS Fdn Trust, London, England. RP Seifalian, AM (reprint author), UCL, Ctr Nanotechnol & Regenerat Med, Div Surg & Intervent Sci, London, England. EM a.seifalian@ucl.ac.uk RI Seifalian, Alexander/I-6028-2013; OI Seifalian, Alexander/0000-0002-1180-3322; G, Natasha/0000-0002-9262-4595; Hamblin, Michael/0000-0001-6431-4605 FU Engineering and Physical Sciences Research Council (EPSRC) - Industrial CASE FX The authors would like to thank the Engineering and Physical Sciences Research Council (EPSRC) - Industrial CASE for funding this work. NR 46 TC 14 Z9 14 U1 3 U2 58 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1934-8630 J9 BIOINTERPHASES JI Biointerphases PD AUG 23 PY 2013 VL 8 AR UNSP 23 DI 10.1186/1559-4106-8-23 PG 18 WC Biophysics; Materials Science, Biomaterials SC Biophysics; Materials Science GA 227CE UT WOS:000325084800001 PM 24706135 ER PT J AU Lyoo, IK Yoon, S Renshaw, PF Hwang, J Bae, S Musen, G Kim, JE Bolo, N Jeong, HS Simonson, DC Lee, SH Weinger, K Jung, JJ Ryan, CM Choi, Y Jacobson, AM AF Lyoo, In Kyoon Yoon, Sujung Renshaw, Perry F. Hwang, Jaeuk Bae, Sujin Musen, Gail Kim, Jieun E. Bolo, Nicolas Jeong, Hyeonseok S. Simonson, Donald C. Lee, Sun Hea Weinger, Katie Jung, Jiyoung J. Ryan, Christopher M. Choi, Yera Jacobson, Alan M. TI Network-Level Structural Abnormalities of Cerebral Cortex in Type 1 Diabetes Mellitus SO PLOS ONE LA English DT Article ID TOP-DOWN CONTROL; CORTICAL THICKNESS; BRAIN NETWORKS; COGNITIVE PERFORMANCE; PREFRONTAL CORTEX; TOPOLOGICAL PATTERNS; SEVERE HYPOGLYCEMIA; MRI; VOLUME; DISEASE AB Type 1 diabetes mellitus (T1DM) usually begins in childhood and adolescence and causes lifelong damage to several major organs including the brain. Despite increasing evidence of T1DM-induced structural deficits in cortical regions implicated in higher cognitive and emotional functions, little is known whether and how the structural connectivity between these regions is altered in the T1DM brain. Using inter-regional covariance of cortical thickness measurements from high-resolution T1-weighted magnetic resonance data, we examined the topological organizations of cortical structural networks in 81 T1DM patients and 38 healthy subjects. We found a relative absence of hierarchically high-level hubs in the prefrontal lobe of T1DM patients, which suggests ineffective top-down control of the prefrontal cortex in T1DM. Furthermore, inter-network connections between the strategic/executive control system and systems subserving other cortical functions including language and mnemonic/emotional processing were also less integrated in T1DM patients than in healthy individuals. The current results provide structural evidence for T1DM-related dysfunctional cortical organization, which specifically underlie the top-down cognitive control of language, memory, and emotion. C1 [Lyoo, In Kyoon; Lee, Sun Hea] Ewha W Univ, Ewha Brain Inst, Seoul, South Korea. [Lyoo, In Kyoon; Lee, Sun Hea] Ewha W Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Seoul, South Korea. [Yoon, Sujung] Catholic Univ Korea, Coll Med, Dept Psychiat, Seoul, South Korea. [Renshaw, Perry F.; Bae, Sujin] Univ Utah, Inst Brain, Salt Lake City, UT USA. [Hwang, Jaeuk] Soonchunhyang Univ, Dept Psychiat, Coll Med, Seoul, South Korea. [Musen, Gail; Weinger, Katie; Jacobson, Alan M.] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Musen, Gail; Bolo, Nicolas; Weinger, Katie] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Kim, Jieun E.] Ewha W Univ, Grad Sch, Dept Brain & Cognit Sci, Seoul, South Korea. [Jeong, Hyeonseok S.; Jung, Jiyoung J.; Choi, Yera] Seoul Natl Univ, Coll Nat Sci, Interdisciplinary Program Brain Sci, Seoul 151742, South Korea. [Simonson, Donald C.] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. [Ryan, Christopher M.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA. [Jacobson, Alan M.] Winthrop Univ Hosp, Dept Psychiat, Mineola, NY 11501 USA. RP Lyoo, IK (reprint author), Ewha W Univ, Ewha Brain Inst, Seoul, South Korea. EM inkylyoo@ewha.ac.kr FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [DK-060754, DK-084202]; Global Research Network Program, The Korea Research Foundation [KRF-2008-220-E00021]; National Research Foundation of Korea [2012R1A2A2A01010739]; Joslin Diabetes and Endocrinology Research Center [P30-DK-36836]; Joslin Diabetes Center Herbert Graetz Fund; Winthrop University Hospital Research Institute FX This study was supported by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (DK-060754 and DK-084202); a grant from the Global Research Network Program, The Korea Research Foundation (KRF-2008-220-E00021); a grant from the National Research Foundation of Korea (2012R1A2A2A01010739); a grant from Joslin Diabetes and Endocrinology Research Center (P30-DK-36836); a grant from the Joslin Diabetes Center Herbert Graetz Fund; and a grant from the Winthrop University Hospital Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 76 TC 7 Z9 7 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 23 PY 2013 VL 8 IS 8 AR e71304 DI 10.1371/journal.pone.0071304 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 217ZW UT WOS:000324403200006 PM 24058401 ER PT J AU Wang, MP Viswanath, K Lam, TH Wang, X Chan, SS AF Wang, Man Ping Viswanath, Kasisomayajula Lam, Tai Hing Wang, Xin Chan, Sophia S. TI Social Determinants of Health Information Seeking among Chinese Adults in Hong Kong SO PLOS ONE LA English DT Article ID INTERNET; INEQUALITIES; MECHANISMS; ONLINE AB Background: Health communication inequalities were observed in Western population but less is known about them among the Chinese. We investigated health information seeking behaviours and its social determinants among Chinese adults in Hong Kong. Methods: Probability-based sample surveys over telephone were conducted in 2009, 2010/11 and 2012 to monitor family health and information use. Frequency of health information seeking from television, radio, newspapers/magazines and Internet were recorded and dichotomised as >= 1 time/month and <1 time/month (reference). Logistic regression was used to yield adjusted odds ratios (aOR) of health information seeking for different demographic characteristics, socioeconomic status (education, employment and income), chronic disease and behaviours (smoking, drinking and physical activity). Results: Among 4553 subjects in all surveys, most (85.1%) had sought health information monthly from newspapers/magazines (66.2%), television (61.4%), radio (35.6%) or Internet (33.2%). Overall, being male, lower education attainment, lower household income, ever-smoking and physical inactivity were associated with less frequent health information seeking (all P<0.05). Compared with younger people, older people were less likely to search health information from Internet but more like to obtain it from radio (both P for trend <0.001). Having chronic diseases was associated with frequent health information seeking from television (aOR = 1.25, 95% CI: 1.07-1.47) and Internet (aOR = 1.46, 95% CI: 1.24-1.73). Conclusions: This study has provided the first evidence on health information inequalities from a non-Western population with advanced mass media and Internet penetration. Socioeconomic inequalities and behavioural clustering of health information seeking suggested more resources are needed for improving health communication in disadvantage groups. C1 [Wang, Man Ping; Lam, Tai Hing; Wang, Xin] Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. [Viswanath, Kasisomayajula] Harvard Univ, Sch Publ Hlth, Dept Social & Behav Sci, Dana Farber Canc Inst,Ctr Community Based Res, Boston, MA 02115 USA. [Chan, Sophia S.] Univ Hong Kong, Sch Nursing, Hong Kong, Hong Kong, Peoples R China. RP Lam, TH (reprint author), Univ Hong Kong, Sch Publ Hlth, Hong Kong, Hong Kong, Peoples R China. EM hrmrlth@hku.hk FU Hong Kong Jockey Club Charities Trust FX This study was a part of the project "FAMILY: A Jockey Club Initiative for a Harmonious Society," which was funded by The Hong Kong Jockey Club Charities Trust. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 7 Z9 7 U1 4 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 23 PY 2013 VL 8 IS 8 AR e73049 DI 10.1371/journal.pone.0073049 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 217ZW UT WOS:000324403200040 PM 24009729 ER PT J AU Medvedovic, J Ebert, A Tagoh, H Tamir, IM Schwickert, TA Novatchkova, M Sun, Q Veld, PJHI Guo, CG Yoon, HS Denizot, Y Holwerda, SJB de Laat, W Cogne, M Shi, Y Alt, FW Busslinger, M AF Medvedovic, Jasna Ebert, Anja Tagoh, Hiromi Tamir, Ido M. Schwickert, Tanja A. Novatchkova, Maria Sun, Qiong in't Veld, Pim J. Huis Guo, Chunguang Yoon, Hye Suk Denizot, Yves Holwerda, Sjoerd J. B. de Laat, Wouter Cogne, Michel Shi, Yang Alt, Frederick W. Busslinger, Meinrad TI Flexible Long-Range Loops in the V-H Gene Region of the Igh Locus Facilitate the Generation of a Diverse Antibody Repertoire SO IMMUNITY LA English DT Article ID HEAVY-CHAIN LOCUS; PRO-B CELLS; INTRONIC ENHANCER; CHROMATIN ARCHITECTURE; SWITCH RECOMBINATION; GENOMIC INTERACTIONS; REGULATORY ELEMENTS; IMMUNOGLOBULIN LOCI; V(D)J RECOMBINATION; 3D STRUCTURE AB The immunoglobulin heavy-chain (Igh) locus undergoes large-scale contraction in pro-B cells, which facilitates V-H-DJ(H) recombination by juxtaposing distal V-H genes next to the DJ(H)-rearranged gene segment in the 3' proximal Igh domain. By using high-resolution mapping of long-range interactions, we demonstrate that local interaction domains established the three-dimensional structure of the extended Igh locus in lymphoid progenitors. In proB cells, these local domains engaged in long-range interactions across the Igh locus, which depend on the regulators Pax5, YY1, and CTCF. The large VH gene cluster underwent flexible long-range interactions with the more rigidly structured proximal domain, which probably ensures similar participation of all V-H genes in V-H-DJ(H) recombination to generate a diverse antibody repertoire. These long-range interactions appear to be an intrinsic feature of the V-H gene cluster, because they are still generated upon mutation of the E mu enhancer, IGCR1 insulator, or 30 regulatory region in the proximal Igh domain. C1 [Medvedovic, Jasna; Ebert, Anja; Tagoh, Hiromi; Tamir, Ido M.; Schwickert, Tanja A.; Novatchkova, Maria; Sun, Qiong; in't Veld, Pim J. Huis; Busslinger, Meinrad] Vienna Bioctr, Res Inst Mol Pathol, A-1030 Vienna, Austria. [Tamir, Ido M.] Campus Sci Support Facil, A-1030 Vienna, Austria. [Novatchkova, Maria] Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria. [Guo, Chunguang; Yoon, Hye Suk; Alt, Frederick W.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Childrens Hosp,Immune Dis Inst, Boston, MA 02115 USA. [Denizot, Yves; Cogne, Michel] Univ Limoges, CNRS, UMR CNRS 7276, F-87025 Limoges, France. [Holwerda, Sjoerd J. B.; de Laat, Wouter] Hubrecht Inst KNAW, NL-3584 CT Utrecht, Netherlands. [Holwerda, Sjoerd J. B.; de Laat, Wouter] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands. [Shi, Yang] Harvard Univ, Sch Med, Dept Cell Biol, Div Newborn Med,Childrens Hosp, Boston, MA 02115 USA. RP Busslinger, M (reprint author), Vienna Bioctr, Res Inst Mol Pathol, Dr Bohr Gasse 7, A-1030 Vienna, Austria. EM busslinger@imp.ac.at RI Denizot, Yves Pierre/H-9769-2016; Busslinger, Meinrad/J-1249-2016; cogne, michel/D-7370-2015; Tagoh, Hiromi/B-2954-2009 OI Busslinger, Meinrad/0000-0002-9111-9351; cogne, michel/0000-0002-8519-4427; Tagoh, Hiromi/0000-0001-9905-6992 FU Boehringer-Ingelheim; Vienna Science and Technology Fund (WWTF); ERC Advanced Grant from the European Community's Seventh Framework Program [291740-LymphoControl]; Austrian GEN-AU initiative; Bundesminsterium fur Bildung und Wissenschaft; EMBO fellowship FX We thank A. Sommer and P. Stolt-Berger at the Campus Science Support Facilities for deep sequencing and protein expression, E. Axelsson for RNA-seq analysis, W. van Ijcken and F. Grosveld for advice on 4C sequencing, J. Skok for help with DNA-FISH analysis, and J.-M. Peters for advice on CTCF purification. This research was supported by Boehringer-Ingelheim, the Vienna Science and Technology Fund (WWTF), an ERC Advanced Grant (291740-LymphoControl) from the European Community's Seventh Framework Program, the Austrian GEN-AU initiative (financed by the Bundesminsterium fur Bildung und Wissenschaft), and an EMBO fellowship (to T.S.). NR 35 TC 48 Z9 48 U1 2 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD AUG 22 PY 2013 VL 39 IS 2 BP 229 EP 244 DI 10.1016/j.immuni.2013.08.011 PG 16 WC Immunology SC Immunology GA AA2UE UT WOS:000330948800007 PM 23973221 ER PT J AU Rosenbaum, L Shrank, WH AF Rosenbaum, Lisa Shrank, William H. TI Taking Our Medicine - Improving Adherence in the Accountability Era SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID MEDICATION AB

Many U.S. patients do not adhere to prescribed medication regimens, ultimately costing the United States $100 billion to $290 billion annually. As physician payment is increasingly tied to patient outcomes, nonadherence poses new challenges and opportunities.

A new patient with an abnormal electrocardiogram comes to your office. He is 53, smokes, and has hypertension and hyperlipidemia. Though he comes for preoperative risk evaluation, he needs more than medical clearance he needs a primary doctor. Given his risk factors and hesitance to change his lifestyle, you recommend aspirin, a statin, and an antihypertensive. When he doesn't show up for his stress test, you call him, and he says he doesn't understand what the fuss is all about he feels fine. Why don't you wait until something is wrong with me to give me these medications? ... C1 [Rosenbaum, Lisa] Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. [Rosenbaum, Lisa] Univ Penn, Robert Wood Johnson Fdn Clin Scholars Program, Philadelphia, PA 19104 USA. [Shrank, William H.] Brigham & Womens Hosp, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02115 USA. [Shrank, William H.] Harvard Univ, Sch Med, Boston, MA USA. RP Rosenbaum, L (reprint author), Univ Penn, Philadelphia Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. NR 5 TC 13 Z9 13 U1 0 U2 9 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 AUG 22 PY 2013 VL 369 IS 8 BP 694 EP 695 DI 10.1056/NEJMp1307084 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 204FA UT WOS:000323349300004 PM 23964931 ER PT J AU Motzer, RJ Hutson, TE Cella, D Reeves, J Hawkins, R Guo, J Nathan, P Staehler, M de Souza, P Merchan, JR Boleti, E Fife, K Jin, J Jones, R Uemura, H De Giorgi, U Harmenberg, U Wang, JW Sternberg, CN Deen, K McCann, L Hackshaw, MD Crescenzo, R Pandite, LN Choueiri, TK AF Motzer, Robert J. Hutson, Thomas E. Cella, David Reeves, James Hawkins, Robert Guo, Jun Nathan, Paul Staehler, Michael de Souza, Paul Merchan, Jaime R. Boleti, Ekaterini Fife, Kate Jin, Jie Jones, Robert Uemura, Hirotsugu De Giorgi, Ugo Harmenberg, Ulrika Wang, Jinwan Sternberg, Cora N. Deen, Keith McCann, Lauren Hackshaw, Michelle D. Crescenzo, Rocco Pandite, Lini N. Choueiri, Toni K. TI Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FUNCTIONAL ASSESSMENT; CANCER; THERAPY; FATIGUE; TRIAL AB BACKGROUND Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy. METHODS We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life. RESULTS Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons). CONCLUSIONS Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. C1 [Motzer, Robert J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Hutson, Thomas E.] Baylor Sammons Canc Center Texas Oncol, Dallas, TX USA. [Cella, David] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Reeves, James] Florida Canc Specialists, Ft Myers, FL USA. [Hawkins, Robert] Univ Manchester, Manchester, Lancs, England. [Hawkins, Robert] Natl Hlth Serv Fdn Trust, Christie Hosp, Manchester, Lancs, England. [Nathan, Paul] Mt Vernon Hosp, Northwood HA6 2RN, Middx, England. [Boleti, Ekaterini] Royal Free Hosp, Dept Oncol, London NW3 2QG, England. [Fife, Kate] Addenbrookes Hosp, Ctr Oncol, Cambridge, England. [Jones, Robert] Univ Glasgow, Inst Canc Sci, Glasgow, Lanark, Scotland. [Guo, Jun] Peking Univ, Renal Canc & Melanoma Unit, Canc Hosp, Beijing 100871, Peoples R China. [Jin, Jie] Peking Univ, Hosp 1, Beijing 100871, Peoples R China. [Wang, Jinwan] Chinese Acad Med Sci, Canc Hosp, Beijing 100730, Peoples R China. [Wang, Jinwan] Peking Union Med Coll, Beijing 100021, Peoples R China. [Staehler, Michael] Univ Munich, Interdisciplinary Ctr Renal Tumors, Dept Urol, Munich, Germany. [de Souza, Paul] Univ Western Sydney, Canc Res Grp, Sch Med, Mol Med Res Grp, Sydney, NSW, Australia. [Merchan, Jaime R.] Univ Miami, Sylvester Canc Ctr, Miami, FL USA. [Uemura, Hirotsugu] Kinki Univ, Dept Urol, Fac Med, Osaka, Japan. [De Giorgi, Ugo] Ist Sci Romagnolo Studio & Cura Tumori, Ist Ricovero & Cura Carattere Sci, Meldola, Italy. [Sternberg, Cora N.] San Camillo Hosp, Dept Med Oncol, Rome, Italy. [Sternberg, Cora N.] Forlanini Hosp, Dept Med Oncol, Rome, Italy. [Harmenberg, Ulrika] Karolinska Univ Hosp, Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Deen, Keith; McCann, Lauren; Hackshaw, Michelle D.; Crescenzo, Rocco; Pandite, Lini N.] GlaxoSmithKline, Collegeville, PA USA. [Choueiri, Toni K.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dana Farber Harvard Canc Ctr, Kidney Canc Program, Boston, MA 02115 USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Boston, MA USA. RP Motzer, RJ (reprint author), Mem Sloan Kettering Canc Ctr, Genitourinary Oncol Serv, Dept Med, 1275 York Ave, New York, NY 10021 USA. EM motzerr@mskcc.org FU GlaxoSmithKline Pharmaceuticals FX Supported by GlaxoSmithKline Pharmaceuticals. NR 22 TC 420 Z9 429 U1 3 U2 40 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 AUG 22 PY 2013 VL 369 IS 8 BP 722 EP 731 DI 10.1056/NEJMoa1303989 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 204FA UT WOS:000323349300009 PM 23964934 ER PT J AU Seton, M Wu, CC Louissaint, A AF Seton, Margaret Wu, Carol C. Louissaint, Abner, Jr. TI Case 26-2013: A 46-Year-Old Woman with Muscle Pain and Swelling SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID AUTOIMMUNE REGULATOR AIRE; POPULATION-BASED COHORT; RED-CELL APLASIA; MYASTHENIA-GRAVIS; INFLAMMATORY MYOPATHY; THYMOMA; DERMATOMYOSITIS; POLYMYOSITIS; CANCER; RISK AB

A 46-year-old woman presented with pain and swelling in her arms and lower legs for 3 weeks. Examination showed swelling and tenderness of the left arm and tenderness in both calves. Chest imaging revealed a mediastinal mass. A diagnostic procedure was performed.

Presentation of Case

Dr. Luke A. Neilans (Medicine): A 46-year-old woman was seen in the emergency department at this hospital because of muscle pain and swelling in her arms and lower legs.

The patient had been well until approximately 3 weeks before admission, when a deep ache developed in her left triceps, in the absence of trauma. During the following weeks, the pain persisted, gradually spreading to both arms and both legs, and was exacerbated by movement; she began having difficulty rising from chairs and climbing stairs because of pain. Two weeks before admission, examination by her primary care physician ... C1 [Seton, Margaret] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wu, Carol C.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Louissaint, Abner, Jr.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Seton, Margaret] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Wu, Carol C.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Louissaint, Abner, Jr.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Seton, M (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. NR 27 TC 3 Z9 3 U1 0 U2 8 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 AUG 22 PY 2013 VL 369 IS 8 BP 764 EP 773 DI 10.1056/NEJMcpc1208152 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 204FA UT WOS:000323349300014 PM 23964939 ER PT J AU Parchman, ML Noel, PH Culler, SD Lanham, HJ Leykum, LK Romero, RL Palmer, RF AF Parchman, Michael L. Noel, Polly H. Culler, Steven D. Lanham, Holly J. Leykum, Luci K. Romero, Raquel L. Palmer, Raymond F. TI A randomized trial of practice facilitation to improve the delivery of chronic illness care in primary care: initial and sustained effects SO IMPLEMENTATION SCIENCE LA English DT Article ID HEALTH-CARE; INTERVENTIONS; QUALITY; MODEL; DESIGN AB Background: Practice facilitation (PF) is an implementation strategy now commonly used in primary care settings for improvement initiatives. PF occurs when a trained external facilitator engages and supports the practice in its change efforts. The purpose of this group-randomized trial is to assess PF as an intervention to improve the delivery of chronic illness care in primary care. Methods: A randomized trial of 40 small primary care practices who were randomized to an initial or a delayed intervention (control) group. Trained practice facilitators worked with each practice for one year to implement tailored changes to improve delivery of diabetes care within the Chronic Care Model framework. The Assessment of Chronic Illness Care (ACIC) survey was administered at baseline and at one-year intervals to clinicians and staff in both groups of practices. Repeated-measures analyses of variance were used to assess the main effects (mean differences between groups) and the within-group change over time. Results: There was significant improvement in ACIC scores (p < 0.05) within initial intervention practices, from 5.58 (SD 1.89) to 6.33 (SD 1.50), compared to the delayed intervention (control) practices where there was a small decline, from 5.56 (SD 1.54) to 5.27 (SD 1.62). The increase in ACIC scores was sustained one year after withdrawal of the PF intervention in the initial intervention group, from 6.33 (SD 1.50) to 6.60 (SD 1.94), and improved in the delayed intervention (control) practices during their one year of PF intervention, from 5.27 (SD 1.62) to 5.99 (SD 1.75). Conclusions: Practice facilitation resulted in a significant and sustained improvement in delivery of care consistent with the CCM as reported by those involved in direct patient care in small primary care practices. The impact of the observed change on clinical outcomes remains uncertain. Trial registration: This protocol followed the CONSORT guidelines and is registered per ICMJE guidelines: Clinical Trial Registration Number: NCT00482768. C1 [Parchman, Michael L.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, MacColl Ctr Healthcare Innovat, Seattle, WA USA. [Noel, Polly H.; Lanham, Holly J.; Leykum, Luci K.] South Texas Vet Hlth Care Syst, VERDICT Hlth Serv Res Program, San Antonio, TX USA. [Noel, Polly H.; Leykum, Luci K.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Culler, Steven D.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Lanham, Holly J.] Univ Texas Austin, McCombs Sch Business, Austin, TX 78712 USA. [Romero, Raquel L.; Palmer, Raymond F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Family & Community Med, San Antonio, TX 78229 USA. RP Parchman, ML (reprint author), Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, MacColl Ctr Healthcare Innovat, 1730 Minor Ave Suite 1600, Seattle, WA USA. EM parchman.m@ghc.org OI Parchman, Michael/0000-0001-7129-2889 FU National Institute of Diabetes, Digestive, and Kidney Disorders [R18 DK 075692] FX This study was funded by a grant from the National Institute of Diabetes, Digestive, and Kidney Disorders (R18 DK 075692), follows the Consolidated Standards of Reporting Trials guidelines, and is registered per International Committee of Medical Journal Editors guidelines (Clinical Trial Registration Number NCT00482768). This work was also supported with resources and the use of facilities at the Audie L. Murphy Veterans Hospital, Veterans Health Administration, Department of Veterans Affairs. This study received approval for human subjects research from the institutional review board of the University of Texas Health Science Center at San Antonio. The views expressed in this article are those of the author(s) and do not necessarily represent the views of the Department of Veterans Affairs. We would like to express our appreciation to the physicians and offices staff in the South Texas Ambulatory Research Network (STARNet) for their participation in this study. NR 27 TC 21 Z9 21 U1 1 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD AUG 22 PY 2013 VL 8 AR 93 DI 10.1186/1748-5908-8-93 PG 7 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 210QO UT WOS:000323849700001 PM 23965255 ER PT J AU Jeon, S Haley, J Flikkema, J Nalla, V Wang, M Sfeir, M Tan, LS Cooper, T Ji, W Hamblin, MR Chiang, LY AF Jeon, Seaho Haley, Joy Flikkema, Jonathan Nalla, Venkatram Wang, Min Sfeir, Matthew Tan, Loon-Seng Cooper, Thomas Ji, Wei Hamblin, Michael R. Chiang, Long Y. TI Linear and Nonlinear Optical Properties of Photoresponsive [60]Fullerene Hybrid Triads and Tetrads with Dual NIR Two-Photon Absorption Characteristics SO JOURNAL OF PHYSICAL CHEMISTRY C LA English DT Article ID C-60-DIPHENYLAMINOFLUORENE DYAD; LIMITING PROPERTIES; ENERGY-TRANSFER; C-60; ENHANCEMENT; DIPHENYLAMINOFLUORENE; FULLERENES; MECHANISM; DEVICES AB Two C-60-(antenna)(x) analogous compounds having branched hybrid triad C-60(>DPAF-C-18)(>CPAF-C-2M) and tetrad C-60(>DPAF-C-18) (>CPAF-C-2M)(2) nanostructures were synthesized and characterized. The structural design was intended to facilitate the ultrafast femtosecond intramolecular energy transfer from photoexcited C-60[>(1)(DPAF)*-C-18](>CPAF-C-2M)(1 or 2) or C-60(>DPAF-C-18)[>(1)(CPAF)*-C-2M](1 or 2) to the C-60> cage moiety upon two-photon pumping at either 780 or 980 nm, respectively. The latter nanostructure showed approximately equal extinction coefficients of optical absorption over 400-550 nm that corresponds to near-IR two-photon-based excitation wavelengths at 780-1100 nm for broadband nonlinear optical (NLO) applications. Aside from their enhanced two-photon absorption (2PA) activity at 780 nm, we also demonstrated ultrafast photoresponses at 980 nm showing 2PA cross-section (sigma(2)) values of 995-1100 GM for the hybrid tetrad. These sigma(2) values were correlated to the observed good efficiency in reducing femtosecond light-transmittance down to 3596 at the light intensity of 110 GW/cm(2). Accordingly, 2PA characteristics of these nanostructures at multiple NIR wavelengths provided support for their suitability in uses as broadband NLO nanomaterials at 600-1100 nm that includes the 2PA ability of two antenna, DPAF (700-850 nm) and CPAF (850-1100 nm), and the fullerene cage at shorter wavelengths (600-700 nm). C1 [Jeon, Seaho; Wang, Min; Chiang, Long Y.] Univ Massachusetts, Inst Nanosci & Engn Technol, Dept Chem, Lowell, MA 01854 USA. [Haley, Joy; Flikkema, Jonathan; Tan, Loon-Seng; Cooper, Thomas] Air Force Res Lab, Mat & Mfg Directorate, Wright Patterson AFB, OH 45433 USA. [Flikkema, Jonathan] Southwestern Ohio Council Higher Educ, Dayton, OH 45420 USA. [Nalla, Venkatram; Ji, Wei] Natl Univ Singapore, Dept Phys, Singapore 117542, Singapore. [Sfeir, Matthew] Brookhaven Natl Lab, Ctr Funct Nanomat, Upton, NY 11973 USA. [Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Wellman Ctr Photomed,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Chiang, LY (reprint author), Univ Massachusetts, Inst Nanosci & Engn Technol, Dept Chem, Lowell, MA 01854 USA. EM long_chiang@uml.edu RI Nalla, Venkatram/A-2139-2009; JI, WEI/H-5795-2015; Tan, Loon-Seng/F-6985-2012; OI Nalla, Venkatram/0000-0003-4535-290X; JI, WEI/0000-0003-0303-0830; Tan, Loon-Seng/0000-0002-2134-9290; Sfeir, Matthew/0000-0001-5619-5722; Hamblin, Michael/0000-0001-6431-4605 FU Air Force Office of Scientific Research (AFOSR) [FA9550-09-1-0380, FA9550-09-1-0183]; National Institutes of Health (NIH) [4R01CA137108, R01AI058075]; U.S. Department of Energy, Office of Basic Energy Sciences [DE-AC02-98CH10886] FX We at UML thank the Air Force Office of Scientific Research (AFOSR) under grant numbers FA9550-09-1-0380 and FA9550-09-1-0183 and National Institutes of Health (NIH) under grant number 4R01CA137108 for financial support. M.R.H. was supported by NIH R01AI058075.; Research carried out in part at the Center for Functional Nanomaterials, Brookhaven National Laboratory is supported by the U.S. Department of Energy, Office of Basic Energy Sciences, under Contract No. DE-AC02-98CH10886. NR 37 TC 5 Z9 6 U1 0 U2 38 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1932-7447 J9 J PHYS CHEM C JI J. Phys. Chem. C PD AUG 22 PY 2013 VL 117 IS 33 BP 17186 EP 17195 DI 10.1021/jp405424q PG 10 WC Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 207IW UT WOS:000323593100050 PM 24163713 ER PT J AU Toiber, D Erdel, F Bouazoune, K Silberman, DM Zhong, L Mulligan, P Sebastian, C Cosentino, C Martinez-Pastor, B Giacosa, S D'Urso, A Naar, AM Kingston, R Rippe, K Mostoslavsky, R AF Toiber, Debra Erdel, Fabian Bouazoune, Karim Silberman, Dafne M. Zhong, Lei Mulligan, Peter Sebastian, Carlos Cosentino, Claudia Martinez-Pastor, Barbara Giacosa, Sofia D'Urso, Agustina Naeaer, Anders M. Kingston, Robert Rippe, Karsten Mostoslavsky, Raul TI SIRT6 Recruits SNF2H to DNA Break Sites, Preventing Genomic Instability through Chromatin Remodeling SO MOLECULAR CELL LA English DT Article ID HISTONE DEACETYLASE SIRT6; DOUBLE-STRAND BREAKS; HOMOLOGOUS RECOMBINATION; DAMAGE RESPONSE; FACTOR CHD4; HUMAN-CELLS; REPAIR; ACETYLATION; RESECTION; H3 AB DNA damage is linked to multiple human diseases, such as cancer, neurodegeneration, and aging. Little is known about the role of chromatin accessibility in DNA repair. Here, we find that the deacetylase sirtuin 6 (SIRT6) is one of the earliest factors recruited to double-strand breaks (DSBs). SIRT6 recruits the chromatin remodeler SNF2H to DSBs and focally deacetylates histone H3K56. Lack of SIRT6 and SNF2H impairs chromatin remodeling, increasing sensitivity to genotoxic damage and recruitment of downstream factors such as 53BP1 and breast cancer 1 (BRCA1). Remarkably, SIRT6-deficient mice exhibit lower levels of chromatin-associated SNF2H in specific tissues, a phenotype accompanied by DNA damage. We demonstrate that SIRT6 is critical for recruitment of a chromatin remodeler as an early step in the DNA damage response, indicating that proper unfolding of chromatin plays a rate-limiting role. We present a unique crosstalk between a histone modifier and a chromatin remodeler, regulating a coordinated response to prevent DNA damage. C1 [Toiber, Debra; Silberman, Dafne M.; Zhong, Lei; Mulligan, Peter; Sebastian, Carlos; Cosentino, Claudia; Martinez-Pastor, Barbara; Giacosa, Sofia; D'Urso, Agustina; Naeaer, Anders M.; Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. [Erdel, Fabian; Rippe, Karsten] Deutsch Krebsforschungszentrum DKFZ, Res Grp Genome Org & Funct, D-69120 Heidelberg, Germany. [Erdel, Fabian; Rippe, Karsten] BioQuant, D-69120 Heidelberg, Germany. [Bouazoune, Karim; Kingston, Robert] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02115 USA. [Bouazoune, Karim; Kingston, Robert] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Silberman, Dafne M.] CEFyBO UBA CONICET, Sch Med, Dept Human Biochem, Buenos Aires, DF, Argentina. [Mulligan, Peter; Naeaer, Anders M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Mostoslavsky, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. EM rmostoslavsky@mgh.harvard.edu RI Rippe, Karsten/A-3562-2012 OI Rippe, Karsten/0000-0001-9951-9395 FU NIH [GM093072-01]; Brain Power for Israel Foundation; Ellison Medical Foundation/AFAR Postdoctoral Fellowship; Fondazione Umberto Veronesi; CDMRP/DoD Cancer Research Program Postdoctoral Fellowship; Spanish Ministry of Education FX This work was supported in part by NIH grant GM093072-01 (R.M.). R.M is a Howard Goodman Scholar Awardee and an MGH Research Scholar. D.T. is the recipient of the Brain Power for Israel Foundation grant and the Ellison Medical Foundation/AFAR Postdoctoral Fellowship. C.C. is supported by a Fellowship from the Fondazione Umberto Veronesi. C.S. is the recipient of a CDMRP/DoD Cancer Research Program Postdoctoral Fellowship. B.M.-P is the recipient of a postdoctoral fellowship from the Spanish Ministry of Education. We would like to thank Steve Jackson for the SIRT6-GFP and SIRT6-RFP plasmids and Laura Prickett-Rice and Kate Folz-Donahue for technical assistance with the FACS analysis. NR 43 TC 91 Z9 98 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 22 PY 2013 VL 51 IS 4 BP 454 EP 468 DI 10.1016/j.molcel.2013.06.018 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 208QJ UT WOS:000323693900006 PM 23911928 ER PT J AU Koreth, J AF Koreth, John TI Paneth cells in gut GVHD: a Panglossian perspective SO BLOOD LA English DT Editorial Material ID VERSUS-HOST-DISEASE C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Koreth, J (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 10 TC 0 Z9 0 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 22 PY 2013 VL 122 IS 8 BP 1336 EP 1337 DI 10.1182/blood-2013-06-509646 PG 2 WC Hematology SC Hematology GA 204UD UT WOS:000323394300006 PM 23970355 ER PT J AU Cutler, C Kim, HT Bindra, B Sarantopoulos, S Ho, VT Chen, YB Rosenblatt, J McDonough, S Watanaboonyongcharoen, P Armand, P Koreth, J Glotzbecker, B Alyea, E Blazar, BR Soiffer, RJ Ritz, J Antin, JH AF Cutler, Corey Kim, Haesook T. Bindra, Bhavjot Sarantopoulos, Stefanie Ho, Vincent T. Chen, Yi-Bin Rosenblatt, Jacalyn McDonough, Sean Watanaboonyongcharoen, Phandee Armand, Philippe Koreth, John Glotzbecker, Brett Alyea, Edwin Blazar, Bruce R. Soiffer, Robert J. Ritz, Jerome Antin, Joseph H. TI Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW-TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; REFRACTORY CHRONIC GVHD; WORKING GROUP-REPORT; TERM-FOLLOW-UP; B-CELLS; HEMATOLOGIC MALIGNANCIES; UNRELATED DONORS; CLINICAL-TRIALS AB B cells are implicated in the pathophysiology of chronic graft-vs-host disease (GVHD), and phase 2 trials suggest that B cell depletion can treat established chronic GVHD. We hypothesized that posttransplantation B cell depletion could prevent the occurrence of chronic GVHD. We performed a 65-patient phase 2 trial of rituximab (375 mg/m(2) IV), administered at 3, 6, 9, and 12 months after transplantation. Rituximab administration was safe without severe infusional adverse events. The cumulative incidences of chronic GVHD and systemic corticosteroid-requiring chronic GVHD at 2 years from transplantation were 48% and 31%, respectively, both lower than the corresponding rates in a concurrent control cohort (60%, P = .1, and 48.5%, P = .015). There was no difference in relapse incidence, but treatment-related mortality at 4 years from transplantation was significantly lower in treated subjects when compared with controls (5% vs 19%, P = .02), and overall survival was superior at 4 years (71% vs 56%, P = .05). At 2 years from transplantation, the B-cell activating factor/B-cell ratio was significantly higher in subjects who developed chronic GVHD in comparison with those without chronic GVHD (P = .039). Rituximab can prevent systemic corticosteroid-requiring chronic GVHD after peripheral blood stem cell transplantation and should be tested in a prospective randomized trial. This trial was registered at www.clinicaltrials.gov as NCT00379587. C1 [Cutler, Corey; Bindra, Bhavjot; Ho, Vincent T.; McDonough, Sean; Armand, Philippe; Koreth, John; Glotzbecker, Brett; Alyea, Edwin; Soiffer, Robert J.; Ritz, Jerome; Antin, Joseph H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02215 USA. [Sarantopoulos, Stefanie; Watanaboonyongcharoen, Phandee] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Chen, Yi-Bin] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [Rosenblatt, Jacalyn] Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. [Blazar, Bruce R.] Univ Minnesota, Minneapolis, MN USA. RP Cutler, C (reprint author), Dana Farber Canc Inst, 450 Brookline Ave, Boston, MA 02215 USA. EM corey_cutler@dfci.harvard.edu FU Gateway for Cancer Research [P-06-005, P-01 CA142106, P01 AI056299, K08-HL107756]; Jock and Bunny Adams Research and Education Endowment; Ted and Eileen Pasquarello Research Fund; King Chulalongkorn Memorial Hospital, Thailand; Stem Cell Cyclists of the Pan-Mass Challenge FX The study was funded in part by the Gateway for Cancer Research P-06-005 (to C.C.), P-01 CA142106 (to J.H.A.), P01 AI056299 (to B.B.), and K08-HL107756 (to S.S.); by the Jock and Bunny Adams Research and Education Endowment (to J.H.A.); and by the Ted and Eileen Pasquarello Research Fund (to J.R.). P.W. is supported by the King Chulalongkorn Memorial Hospital, Thailand. C.C. is supported by the Stem Cell Cyclists of the Pan-Mass Challenge. NR 49 TC 39 Z9 40 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 22 PY 2013 VL 122 IS 8 BP 1510 EP 1517 DI 10.1182/blood-2013-04-495895 PG 8 WC Hematology SC Hematology GA 204UD UT WOS:000323394300029 PM 23861248 ER PT J AU Saddi-Rosa, P Oliveira, CS Crispim, F Giuffrida, FMA de Lima, VC Vieira, JG Doria, A Velho, G Reis, AF AF Saddi-Rosa, Pedro Oliveira, Carolina Soares Crispim, Felipe Giuffrida, Fernando M. A. de Lima, Valter Correia Vieira, Jose Gilberto Doria, Alessandro Velho, Gilberto Reis, Andre Fernandes TI Association of circulating levels of nicotinamide phosphoribosyltransferase (NAMPT/Visfatin) and of a frequent polymorphism in the promoter of the NAMPT gene with coronary artery disease in diabetic and non-diabetic subjects SO CARDIOVASCULAR DIABETOLOGY LA English DT Article DE NAMPT; Visfatin; Coronary artery disease; Type 2 diabetes; rs9770242 ID MONOCYTE-DERIVED MACROPHAGES; PLASMA VISFATIN LEVELS; INSULIN-RESISTANCE; METABOLIC SYNDROME; CARDIOVASCULAR RISK; GLUCOSE-METABOLISM; INFLAMMATION; ADIPONECTIN; EXPRESSION; ATHEROSCLEROSIS AB Background: Nicotinamide phosphoribosyltransferase (NAMPT) is the limiting enzyme in one of pathways of synthesis of Nicotinamide Adenine Dinucleotide, a redox coenzyme. NAMPT is considered as an insulin-mimetic factor and a potential regulatory factor in inflammatory and immune processes. Associations of circulating NAMPT levels with cardiovascular disease (CVD) and insulin resistance have been reported. We investigated association of circulating NAMPT levels and the rs9770242 NAMPT gene polymorphism with coronary artery disease (CAD). Methods: We studied 594 Brazilian subjects undergoing a coronary angiography (49% of whom had type 2 diabetes). CAD, defined as stenosis greater than 50% in one major coronary vessel or branch, was observed in 68% of subjects. Genetic studies were also performed in 858 North-American Non-Hispanic White subjects with type 2 diabetes (49% with CAD). Results: We observed an interaction between glycemic and CAD status on the comparison of NAMPT levels by CAD status. NAMPT levels were higher in type 2 diabetic patients with CAD as compared to those without CAD: 5.27 +/- 2.93 ng/ml vs. 4.43 +/- 2.94 ng/ml, p = 0.006 (mean +/- SD). NAMPT levels were not significantly different in non-diabetic subjects with or without CAD. The T-allele of rs9770242 was associated with CAD in the Brazilian cohort (OR 1.46, 95% CI 1.06 - 2.01, p = 0.02) while no association was observed in the North-American cohort. Conclusions: Our data suggest that circulating NAMPT levels are associated with CAD in type 2 diabetic patients. NAMPT rs9770242 polymorphism may be associated with CAD in some populations. C1 [Saddi-Rosa, Pedro; Oliveira, Carolina Soares; Crispim, Felipe; Giuffrida, Fernando M. A.; Vieira, Jose Gilberto; Reis, Andre Fernandes] Fed Univ Sao Paulo UNIFESP, Ctr Diabet, BR-04039002 Sao Paulo, Brazil. [Giuffrida, Fernando M. A.] CEDEBA, BR-41820000 Salvador, BA, Brazil. [de Lima, Valter Correia] Univ Fed Sao Paulo, Cardiol Unit, BR-04039002 Sao Paulo, Brazil. [Doria, Alessandro] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Velho, Gilberto] Univ Paris 07, INSERM, Res Unit 695, F-75018 Paris, France. RP Reis, AF (reprint author), Fed Univ Sao Paulo UNIFESP, Ctr Diabet, Rua Pedro de Toledo 910, BR-04039002 Sao Paulo, Brazil. EM andrefreis@terra.com.br OI Giuffrida, Fernando/0000-0002-5566-8070 FU FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo), Sao Paulo, Brazil [2008/10209-6]; CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)-Brazil FX This study was supported by grant #2008/10209-6 from FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo), Sao Paulo, Brazil. This study was partialy supported by CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior)-Brazil. NR 41 TC 7 Z9 8 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2840 J9 CARDIOVASC DIABETOL JI Cardiovasc. Diabetol. PD AUG 22 PY 2013 VL 12 AR 119 DI 10.1186/1475-2840-12-119 PG 7 WC Cardiac & Cardiovascular Systems; Endocrinology & Metabolism SC Cardiovascular System & Cardiology; Endocrinology & Metabolism GA 207EU UT WOS:000323581000001 PM 23968400 ER PT J AU Alexandrov, LB Nik-Zainal, S Wedge, DC Aparicio, SAJR Behjati, S Biankin, AV Bignell, GR Bolli, N Borg, A Borresen-Dale, AL Boyault, S Burkhardt, B Butler, AP Caldas, C Davies, HR Desmedt, C Eils, R Eyfjord, JE Foekens, JA Greaves, M Hosoda, F Hutter, B Ilicic, T Imbeaud, S Imielinsk, M Jager, N Jones, DTW Jones, D Knappskog, S Kool, M Lakhani, SR Lopez-Otin, C Martin, S Munshi, NC Nakamura, H Northcott, PA Pajic, M Papaemmanuil, E Paradiso, A Pearson, JV Puente, XS Raine, K Ramakrishna, M Richardson, AL Richter, J Rosenstiel, P Schlesner, M Schumacher, TN Span, PN Teague, JW Totoki, Y Tutt, ANJ Valdes-Mas, R van Buuren, MM van 't Veer, L Vincent-Salomon, A Waddell, N Yates, LR Zucman-Rossi, J Futreal, PA McDermott, U Lichter, P Meyerson, M Grimmond, SM Siebert, R Campo, E Shibata, T Pfister, SM Campbell, PJ Stratton, MR AF Alexandrov, Ludmil B. Nik-Zainal, Serena Wedge, David C. Aparicio, Samuel A. J. R. Behjati, Sam Biankin, Andrew V. Bignell, Graham R. Bolli, Niccolo Borg, Ake Borresen-Dale, Anne-Lise Boyault, Sandrine Burkhardt, Birgit Butler, Adam P. Caldas, Carlos Davies, Helen R. Desmedt, Christine Eils, Roland Eyfjord, Jorunn Erla Foekens, John A. Greaves, Mel Hosoda, Fumie Hutter, Barbara Ilicic, Tomislav Imbeaud, Sandrine Imielinsk, Marcin Jaeger, Natalie Jones, David T. W. Jones, David Knappskog, Stian Kool, Marcel Lakhani, Sunil R. Lopez-Otin, Carlos Martin, Sancha Munshi, Nikhil C. Nakamura, Hiromi Northcott, Paul A. Pajic, Marina Papaemmanuil, Elli Paradiso, Angelo Pearson, John V. Puente, Xose S. Raine, Keiran Ramakrishna, Manasa Richardson, Andrea L. Richter, Julia Rosenstiel, Philip Schlesner, Matthias Schumacher, Ton N. Span, Paul N. Teague, Jon W. Totoki, Yasushi Tutt, Andrew N. J. Valdes-Mas, Rafael van Buuren, Marit M. van 't Veer, Laura Vincent-Salomon, Anne Waddell, Nicola Yates, Lucy R. Zucman-Rossi, Jessica Futreal, P. Andrew McDermott, Ultan Lichter, Peter Meyerson, Matthew Grimmond, Sean M. Siebert, Reiner Campo, Elias Shibata, Tatsuhiro Pfister, Stefan M. Campbell, Peter J. Stratton, Michael R. CA Australian Pancreatic Canc Genome ICGC Breast Canc Consortium ICGC MMML-Seq Consortium ICGC PedBrain TI Signatures of mutational processes in human cancer SO NATURE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; SQUAMOUS-CELL CARCINOMA; ACUTE MYELOID-LEUKEMIA; 21 BREAST CANCERS; LUNG ADENOCARCINOMA; PROSTATE-CANCER; RECURRENT MUTATIONS; SOMATIC MUTATIONS; GENETIC LANDSCAPE; FREQUENT MUTATION AB All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy. C1 [Alexandrov, Ludmil B.; Nik-Zainal, Serena; Wedge, David C.; Behjati, Sam; Bignell, Graham R.; Bolli, Niccolo; Butler, Adam P.; Davies, Helen R.; Ilicic, Tomislav; Jones, David; Martin, Sancha; Papaemmanuil, Elli; Raine, Keiran; Ramakrishna, Manasa; Teague, Jon W.; Yates, Lucy R.; Futreal, P. Andrew; McDermott, Ultan; Campbell, Peter J.; Stratton, Michael R.] Wellcome Trust Sanger Inst, Canc Genome Project, Hinxton CB10 1SA, Cambs, England. [Nik-Zainal, Serena] Addenbrookes Hosp NHS Trust, Dept Med Genet, Cambridge CB2 0QQ, England. [Aparicio, Samuel A. J. R.] BC Canc Agcy, Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada. [Aparicio, Samuel A. J. R.] BC Canc Agcy, Michael Smith Genome Sci Ctr, Ctr Translat & Appl Genom, Vancouver, BC V5Z 1L3, Canada. [Aparicio, Samuel A. J. R.] Univ British Columbia, Dept Pathol, Vancouver, BC V6T 2B5, Canada. [Behjati, Sam] Univ Cambridge, Dept Paediat, Cambridge CB2 2XY, England. [Biankin, Andrew V.; Pajic, Marina] Univ Glasgow, Wolfson Wohl Canc Res Ctr, Inst Canc Sci, Glasgow G61 1BD, Lanark, Scotland. [Biankin, Andrew V.] Glasgow Royal Infirm, West Scotland Pancreat Unit, Glasgow G4 0SF, Lanark, Scotland. [Biankin, Andrew V.] Kinghorn Canc Ctr, Darlinghurst, NSW, Australia. [Biankin, Andrew V.] Garvan Inst Med Res, Canc Res Program, Darlinghurst, NSW 2010, Australia. [Biankin, Andrew V.] Bankstown Hosp, Dept Surg, Sydney, NSW 2200, Australia. [Biankin, Andrew V.] Univ New S Wales, South Western Sydney Clin Sch, Fac Med, Liverpool, NSW 2170, Australia. [Bolli, Niccolo; Campbell, Peter J.] Addenbrookes Hosp, Dept Haematol, Cambridge CB2 0QQ, England. [Bolli, Niccolo; Campbell, Peter J.] Univ Cambridge, Dept Haematol, Cambridge CB2 2XY, England. [Borg, Ake] Lund Univ, Dept Oncol, SE-22185 Lund, Sweden. [Borresen-Dale, Anne-Lise] Norwegian Radium Hosp, Oslo Univ Hosp, Dept Genet, Inst Canc Res, N-0310 Oslo, Norway. [Borresen-Dale, Anne-Lise] Univ Oslo, Fac Med, Inst Clin Med, KG Jebsen Ctr Breast Canc Res, N-0310 Oslo, Norway. [Boyault, Sandrine] Ctr Leon Berard, Plateforme Bioinformat Synergie Lyon Canc, F-69373 Lyon 08, France. [Burkhardt, Birgit] Univ Childrens Hosp, NHL BFM Study Ctr, D-48149 Munster, Germany. [Burkhardt, Birgit] Univ Childrens Hosp, Dept Pediat Hematol & Oncol, D-48149 Munster, Germany. [Burkhardt, Birgit] Univ Childrens Hosp, NHL BFM Study Ctr, D-35392 Giessen, Germany. [Burkhardt, Birgit] Univ Childrens Hosp, Dept Pediat Hematol & Oncol, D-35392 Giessen, Germany. [Caldas, Carlos] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England. [Desmedt, Christine] Univ Libre Brussels, Inst Jules Bordet, Breast Canc Translat Res Lab BCTL, B-1000 Brussels, Belgium. [Eils, Roland; Hutter, Barbara; Jaeger, Natalie; Schlesner, Matthias] German Canc Res Ctr, Dept Theoret Bioinformat B080, D-69120 Heidelberg, Germany. [Eyfjord, Jorunn Erla] Univ Iceland, Canc Res Lab, Fac Med, Biomed Ctr, IS-101 Reykjavik, Iceland. [Foekens, John A.] Erasmus MC Canc Inst, Dept Med Oncol, NL-3015 CE Rotterdam, Netherlands. [Greaves, Mel] Inst Canc Res, Dept Haematooncol, Sutton SM2 5NG, Surrey, England. [Hosoda, Fumie; Nakamura, Hiromi; Totoki, Yasushi; Shibata, Tatsuhiro] Natl Canc Ctr, Res Inst, Div Canc Genom, Chuo Ku, Tokyo 1040045, Japan. [Imbeaud, Sandrine; Zucman-Rossi, Jessica] IUH, INSERM, UMR 674, F-75475 Paris, France. [Imbeaud, Sandrine; Zucman-Rossi, Jessica] Univ Paris 05, Sorbonne Paris Cite, Fac Med, F-75006 Paris, France. [Imielinsk, Marcin; Meyerson, Matthew] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA. [Jones, David T. W.; Kool, Marcel; Northcott, Paul A.; Pfister, Stefan M.] German Canc Res Ctr, Div Pediat Neurooncol, D-69120 Heidelberg, Germany. [Knappskog, Stian] Univ Bergen, Dept Clin Sci, Sect Oncol, N-5020 Bergen, Norway. [Knappskog, Stian] Haukeland Hosp, Dept Oncol, N-5021 Bergen, Norway. [Lakhani, Sunil R.] Univ Queensland, Royal Brisbane & Womens Hosp, Clin Res Ctr, Sch Med & Pathol Queensland, Brisbane, Qld 4029, Australia. [Lopez-Otin, Carlos; Puente, Xose S.; Valdes-Mas, Rafael] Univ Oviedo, IUOPA, Dept Bioquim & Biol Mol, E-33006 Oviedo, Spain. [Munshi, Nikhil C.] Harvard Univ, Sch Med, Jerome Lipper Multiple Myeloma Dis Ctr, Dana Farber Canc Inst, Boston, MA 02215 USA. [Munshi, Nikhil C.] Boston Vet Adm Healthcare Syst, West Roxbury, MA 02132 USA. [Paradiso, Angelo] Natl Canc Inst, Clin Expt Oncol Lab, I-70126 Bari, Italy. [Pearson, John V.; Waddell, Nicola; Grimmond, Sean M.] Univ Queensland, Queensland Ctr Med Genom, Inst Mol Biosci, Brisbane, Qld 4072, Australia. [Richardson, Andrea L.; Meyerson, Matthew] Dana Farber Canc Inst, Boston, MA 02215 USA. [Richardson, Andrea L.; Meyerson, Matthew] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Richardson, Andrea L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Richter, Julia; Siebert, Reiner] Univ Kiel, Inst Human Genet, D-24118 Kiel, Germany. [Rosenstiel, Philip] Univ Kiel, Inst Clin Mol Biol, D-24118 Kiel, Germany. [Schumacher, Ton N.; van Buuren, Marit M.] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. [Span, Paul N.] Radboud Univ Nijmegen, Med Ctr, Dept Radiat Oncol, NL-6500 HB Nijmegen, Netherlands. [Span, Paul N.] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, NL-6500 HB Nijmegen, Netherlands. [Tutt, Andrew N. J.] Kings Coll London, Sch Med, Breakthrough Breast Canc Res Unit, London SW3 6JB, England. [van 't Veer, Laura] Netherlands Canc Inst, NL-1066 CX Amsterdam, Netherlands. [Vincent-Salomon, Anne] INSERM, U830, Dept Pathol, Inst Curie, F-75248 Paris 05, France. [Lichter, Peter] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany. [Campo, Elias] Univ Barcelona, Unidad Hematopatol, Serv Anat Patol, Hosp Clin,IDIBAPS, E-08036 Barcelona, Spain. [Pfister, Stefan M.] Dept Pediat Hematol & Oncol, D-69120 Heidelberg, Germany. RP Alexandrov, LB (reprint author), Wellcome Trust Sanger Inst, Canc Genome Project, Wellcome Trust Genome Campus, Hinxton CB10 1SA, Cambs, England. EM mrs@sanger.ac.uk RI Grimmond, Sean/J-5304-2016; Lopez-Otin, Carlos/C-6657-2013; Pearson, John/F-2249-2011; Klapper, Wolfram/S-6314-2016; Bolli, Niccolo/D-4057-2011; Gill, Anthony/D-4215-2015; Kool, Marcel/H-2541-2013; Siebert, Reiner/A-8049-2010; Schreiber, Stefan/B-6748-2008; Sweep, C.G.J./H-8096-2014; Span, Paul/G-4710-2012; Schlesner, Matthias/I-4030-2013; Eils, Roland/B-6121-2009; Pfister, Stefan/F-6860-2013; Waddell, Nic/H-4929-2015; Ammerpohl, Ole/G-2691-2010; Stadler, Peter F./L-7857-2015; Hoell, Jessica/J-8136-2016 OI Campo, elias/0000-0001-9850-9793; Rosenstiel, Philip/0000-0002-9692-8828; Wedge, David/0000-0002-7572-3196; Alexandrov, Ludmil/0000-0003-3596-4515; Desmedt, Christine/0000-0002-5223-5579; Martin, Sancha/0000-0001-6213-5259; Claviez, Alexander/0000-0002-1561-5185; Biankin, Andrew/0000-0002-0362-5597; Kuppers, Ralf/0000-0002-6691-7191; Grimmond, Sean/0000-0002-8102-7998; Lopez-Otin, Carlos/0000-0001-6964-1904; Pearson, John/0000-0003-0904-4598; Bolli, Niccolo/0000-0002-1018-5139; Jaeger, Natalie/0000-0002-9589-7580; Radlwimmer, Bernhard/0000-0002-4553-7800; Suarez-Puente, Xose/0000-0001-9525-1483; Hutter, Barbara/0000-0002-9034-0329; zucman-rossi, Jessica/0000-0002-5687-0334; Knappskog, Stian/0000-0002-4153-1655; McDermott, Ultan/0000-0001-9032-4700; Gill, Anthony/0000-0002-9447-1967; Schreiber, Stefan/0000-0003-2254-7771; Span, Paul/0000-0002-1930-6638; Schlesner, Matthias/0000-0002-5896-4086; Eils, Roland/0000-0002-0034-4036; Pfister, Stefan/0000-0002-5447-5322; Stadler, Peter F./0000-0002-5016-5191; Hoell, Jessica/0000-0002-5532-9845 FU Wellcome Trust [098051] FX We would like to thank the Wellcome Trust for support (grant reference 098051) together with many other funding bodies and individuals (Supplementary Note 1). NR 64 TC 1211 Z9 1229 U1 54 U2 325 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 22 PY 2013 VL 500 IS 7463 BP 415 EP + DI 10.1038/nature12477 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 203TJ UT WOS:000323316100026 PM 23945592 ER PT J AU Ziller, MJ Gu, HC Muller, F Donaghey, J Tsai, LTY Kohlbacher, O De Jager, PL Rosen, ED Bennett, DA Bernstein, BE Gnirke, A Meissner, A AF Ziller, Michael J. Gu, Hongcang Mueller, Fabian Donaghey, Julie Tsai, Linus T. -Y. Kohlbacher, Oliver De Jager, Philip L. Rosen, Evan D. Bennett, David A. Bernstein, Bradley E. Gnirke, Andreas Meissner, Alexander TI Charting a dynamic DNA methylation landscape of the human genome SO NATURE LA English DT Article ID MAMMALIAN DEVELOPMENT; CELLS; WIDE; METHYLOME; DISEASE; MOUSE; PLURIPOTENT; SELECTION; TRAITS; LOCI AB DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development(1,2). Most cell types, except germ cells and pre-implantation embryos(3-5), display relatively stable DNA methylation patterns, with 70-80% of all CpGs being methylated(6). Despite recent advances, we still have a limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, most of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription-factor-binding sites, which allow identification of key lineage-specific regulators. In addition, differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell-type-related diseases as determined by genome-wide association studies. The results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70-80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation. To demonstrate further the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore, our selected DMRs can serve as a starting point to guide new, more effective reduced representation approaches to capture the most informative fraction of CpGs, as well as further pinpoint putative regulatory elements. C1 [Ziller, Michael J.; Gu, Hongcang; Donaghey, Julie; De Jager, Philip L.; Rosen, Evan D.; Bernstein, Bradley E.; Gnirke, Andreas; Meissner, Alexander] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Ziller, Michael J.; Donaghey, Julie; Meissner, Alexander] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Ziller, Michael J.; Mueller, Fabian; Donaghey, Julie; Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Tsai, Linus T. -Y.; Rosen, Evan D.] Beth Israel Deaconess Med Ctr, Div Endocrinol, Boston, MA 02215 USA. [Kohlbacher, Oliver] Univ Tubingen, Ctr Bioinformat, D-72074 Tubingen, Germany. [Kohlbacher, Oliver] Univ Tubingen, Quantitat Biol Ctr, D-72074 Tubingen, Germany. [De Jager, Philip L.] Brigham & Womens Hosp, Inst Neurosci, Program Translat NeuroPsychiat Genom, Dept Neurol, Boston, MA 02115 USA. [De Jager, Philip L.] Brigham & Womens Hosp, Inst Neurosci, Program Translat NeuroPsychiat Genom, Dept Psychiat, Boston, MA 02115 USA. [Bennett, David A.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Bernstein, Bradley E.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Meissner, A (reprint author), Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. EM alexander_meissner@harvard.edu RI Kohlbacher, Oliver/B-7310-2008; Waha, Andreas/J-2950-2014; OI Kohlbacher, Oliver/0000-0003-1739-4598; Tsai, Linus/0000-0002-0134-6949 FU National Institutes of Health (NIH) Roadmap Epigenomics Project [ES017690]; NIH [P30AG10161, R01AG17917, R01AG15819, R01AG36042, U01ES017155, P01GM099117]; Pew Charitable Trusts; New York Stem Cell Foundation FX We would like to thank K. Clement, P. Samavarchi-Tehrani, Z. Smith, M. Chan and R. Karnik for discussions and feedback. We would also like to thank F. Kelley, T. Durham, C. Epstein, N. Shoresh, G. Lauwers and the Massachusetts General Hospital tissue repository for assisting in sample and data management. E.D.R. is supported by the National Institutes of Health (NIH) Roadmap Epigenomics Project (ES017690). D.A.B. is supported by NIH grants P30AG10161, R01AG17917, R01AG15819 and R01AG36042. A.M. is supported by the Pew Charitable Trusts and is a New York Stem Cell Foundation, Robertson Investigator. This work was funded by NIH grants (U01ES017155 and P01GM099117) and The New York Stem Cell Foundation. NR 30 TC 403 Z9 413 U1 10 U2 110 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 22 PY 2013 VL 500 IS 7463 BP 477 EP 481 DI 10.1038/nature12433 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 203TJ UT WOS:000323316100039 PM 23925113 ER PT J AU Kong, J Spaeth, RB Wey, HY Cheetham, A Cook, AH Jensen, K Tan, Y Liu, HS Wang, DH Loggia, ML Napadow, V Smoller, JW Wasan, AD Gollub, RL AF Kong, Jian Spaeth, Rosa B. Wey, Hsiao-Ying Cheetham, Alexandra Cook, Amanda H. Jensen, Karin Tan, Ying Liu, Hesheng Wang, Danhong Loggia, Marco L. Napadow, Vitaly Smoller, Jordan W. Wasan, Ajay D. Gollub, Randy L. TI S1 is associated with chronic low back pain: a functional and structural MRI study SO MOLECULAR PAIN LA English DT Article DE Chronic low back pain; fMRI; Functional connectivity; Cortical thickness; Primary somatosensory cortex ID PRIMARY SOMATOSENSORY CORTEX; SURFACE-BASED ANALYSIS; HUMAN BRAIN; GRAY-MATTER; SPONTANEOUS FLUCTUATIONS; CEREBRAL-CORTEX; CLINICAL PAIN; CONNECTIVITY; NEUROPLASTICITY; INTENSITY AB A fundamental characteristic of neural circuits is the capacity for plasticity in response to experience. Neural plasticity is associated with the development of chronic pain disorders. In this study, we investigated 1) brain resting state functional connectivity (FC) differences between patients with chronic low back pain (cLBP) and matched healthy controls (HC); 2) FC differences within the cLBP patients as they experienced different levels of endogenous low back pain evoked by exercise maneuvers, and 3) morphometric differences between cLBP patients and matched HC. We found the dynamic character of FC in the primary somatosensory cortex (S1) in cLBP patients, i.e., S1 FC decreased when the patients experienced low intensity LBP as compared with matched healthy controls, and FC at S1 increased when cLBP patients experienced high intensity LBP as compared with the low intensity condition. In addition, we also found increased cortical thickness in the bilateral S1 somatotopically associated with the lower back in cLBP patients as compared to healthy controls. Our results provide evidence of structural plasticity co-localized with areas exhibiting FC changes in S1 in cLBP patients. C1 [Kong, Jian; Spaeth, Rosa B.; Wey, Hsiao-Ying; Cheetham, Alexandra; Cook, Amanda H.; Jensen, Karin; Tan, Ying; Liu, Hesheng; Wang, Danhong; Loggia, Marco L.; Smoller, Jordan W.; Gollub, Randy L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA 02129 USA. [Kong, Jian; Wey, Hsiao-Ying; Loggia, Marco L.; Napadow, Vitaly; Gollub, Randy L.] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Wasan, Ajay D.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Anesthesiol, Chestnut Hill, MA USA. [Wasan, Ajay D.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Psychiat, Chestnut Hill, MA USA. RP Kong, J (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, 120 2nd Ave,Room 101, Charlestown, MA 02129 USA. EM kongj@nmr.mgh.harvard.edu OI Gollub, Randy L./0000-0002-9434-4044; Jensen, Karin/0000-0003-2521-3160 FU NCCAM [KO1AT003883, R21AT004497, R01AT006364, R01AT005280, PO1-AT002048]; NIDA [R03AT218317, K23DA020681]; Arthritis Investigator Award; National Center for Research Resources (NCRR) [M01-RR-01066, UL1 RR025758-01]; NCRR [P41RR14075] FX This work was supported by KO1AT003883 (NCCAM), R21AT004497 (NCCAM), R03AT218317 (NIDA), R01AT006364 (NCCAM) to Jian Kong, R01AT005280 (NCCAM) to Randy Gollub, K23DA020681 (NIDA) and Arthritis Investigator Award to Ajay Wasan, PO1-AT002048 (NCCAM) to Bruce Rosen, M01-RR-01066 and UL1 RR025758-01 for Clinical Research Center Biomedical Imaging Core from National Center for Research Resources (NCRR), and P41RR14075 for Center for Functional Neuroimaging Technologies from NCRR. NR 73 TC 23 Z9 25 U1 1 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD AUG 21 PY 2013 VL 9 AR 43 DI 10.1186/1744-8069-9-43 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 209OU UT WOS:000323769200001 PM 23965184 ER PT J AU Xiong, XRR Liang, FX Li, HF Mesik, L Zhang, KK Polley, DB Tao, HZW Xiao, ZJ Zhang, LI AF Xiong, Xiaorui R. Liang, Feixue Li, Haifu Mesik, Lukas Zhang, Ke K. Polley, Daniel B. Tao, Huizhong W. Xiao, Zhongju Zhang, Li I. TI Interaural Level Difference-Dependent Gain Control and Synaptic Scaling Underlying Binaural Computation SO NEURON LA English DT Article ID PRIMARY VISUAL-CORTEX; BATS INFERIOR COLLICULUS; PRIMARY AUDITORY-CORTEX; SOUND PRESSURE LEVEL; INTRACELLULAR-RECORDINGS; CENTRAL NUCLEUS; IN-VIVO; FREQUENCY REPRESENTATION; ASCENDING PROJECTIONS; INTENSITY DISPARITIES AB Binaural integration in the central nucleus of inferior colliculus (ICC) plays a critical role in sound localization. However, its arithmetic nature and underlying synaptic mechanisms remain unclear. Here, we showed in mouse ICC neurons that the contralateral dominance is created by a "push-pull"-like mechanism, with contralaterally dominant excitation and more bilaterally balanced inhibition. Importantly, binaural spiking response is generated apparently from an ipsilaterally mediated scaling of contralateral response, leaving frequency tuning unchanged. This scaling effect is attributed to a divisive attenuation of contralaterally evoked synaptic excitation onto ICC neurons with their inhibition largely unaffected. Thus, a gain control mediates the linear transformation from monaural to binaural spike responses. The gain value is modulated by interaural level difference (ILD) primarily through scaling excitation to different levels. The ILD-dependent synaptic scaling and gain adjustment allow ICC neurons to dynamically encode interaural sound localization cues while maintaining an invariant representation of other independent sound attributes. C1 [Xiong, Xiaorui R.; Mesik, Lukas; Tao, Huizhong W.; Zhang, Li I.] Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Los Angeles, CA 90033 USA. [Xiong, Xiaorui R.; Mesik, Lukas] Univ So Calif, Keck Sch Med, Neurosci Grad Program, Los Angeles, CA 90033 USA. [Xiong, Xiaorui R.; Zhang, Li I.] Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. [Tao, Huizhong W.] Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, Los Angeles, CA 90033 USA. [Liang, Feixue; Li, Haifu; Xiao, Zhongju] Southern Med Univ, Sch Basic Med Sci, Dept Physiol, Guangzhou 510515, Guangdong, Peoples R China. [Polley, Daniel B.] Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Polley, Daniel B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. [Zhang, Ke K.] Univ N Dakota, Dept Pathol, Grand Forks, ND 58202 USA. RP Xiao, ZJ (reprint author), Southern Med Univ, Sch Basic Med Sci, Dept Physiol, Guangzhou 510515, Guangdong, Peoples R China. EM xiaozj@fimmu.com; liizhang@usc.edu OI Polley, Daniel/0000-0002-5120-2409 FU US National Institutes of Health (NIH) [R01DC008983]; David and Lucile Packard Foundation; NIH [R01EY019049, R01DC009836, P20RR016471, P20GM103442]; China NSF [31228013, 31171059, 31200831]; 973 program [2014CB943002] FX This work was supported by grants to L.I.Z. from the US National Institutes of Health (NIH; R01DC008983) and the David and Lucile Packard Foundation (Packard Fellowships for Science and Engineering). H.W.T. was supported by an NIH grant R01EY019049. D.B.P was supported by an NIH grant R01DC009836. K.K.Z was supported by NIH grants P20RR016471 and P20GM103442. Z.X., L.I.Z., and F.L. were supported by China NSF grants (31228013, 31171059, 31200831) and a 973 program (2014CB943002). NR 64 TC 20 Z9 20 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD AUG 21 PY 2013 VL 79 IS 4 BP 738 EP 753 DI 10.1016/j.neuron.2013.06.012 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 207GN UT WOS:000323587000013 PM 23972599 ER PT J AU Eappen, S Rosenberg, B Gawande, AA AF Eappen, Sunil Rosenberg, Barry Gawande, Atul A. TI Complications From Surgery and Hospital Finances Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Eappen, Sunil] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Rosenberg, Barry] Boston Consulting Grp Inc, Chicago, IL USA. [Gawande, Atul A.] Brigham & Womens Hosp, Div Gen & Gastrointestinal Surg, Boston, MA 02115 USA. RP Gawande, AA (reprint author), Brigham & Womens Hosp, 75 Francis St,ASBII 3rd Floor, Boston, MA 02115 USA. EM agawande@partners.org OI Gawande, Atul/0000-0002-1824-9176 NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 21 PY 2013 VL 310 IS 7 BP 747 EP 748 DI 10.1001/jama.2013.8409 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 202XP UT WOS:000323254500028 PM 23989285 ER PT J AU Sergeyenko, Y Lall, K Liberman, MC Kujawa, SG AF Sergeyenko, Yevgeniya Lall, Kumud Liberman, M. Charles Kujawa, Sharon G. TI Age-Related Cochlear Synaptopathy: An Early-Onset Contributor to Auditory Functional Decline SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SPIRAL GANGLION-CELL; TEMPORAL PROCESSING DEFICITS; INDUCED HEARING-LOSS; OUTER HAIR-CELLS; SPEECH RECOGNITION; NERVE FIBERS; BRAIN-STEM; QUANTITATIVE-ANALYSIS; WORD RECOGNITION; MOUSE COCHLEA AB Aging listeners experience greater difficulty understanding speech in adverse listening conditions and exhibit degraded temporal resolution, even when audiometric thresholds are normal. When threshold evidence for peripheral involvement is lacking, central and cognitive factors are often cited as underlying performance declines. However, previous work has uncovered widespread loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with recovered thresholds and no hair cell loss (Kujawa and Liberman 2009). Here, we characterize age-related cochlear synaptic and neural degeneration in CBA/CaJ mice never exposed to high-level noise. Cochlear hair cell and neuronal function was assessed via distortion product otoacoustic emissions and auditory brainstem responses, respectively. Immunostained cochlear whole mounts and plastic-embedded sections were studied by confocal and conventional light microscopy to quantify hair cells, cochlear neurons, and synaptic structures, i.e., presynaptic ribbons and postsynaptic glutamate receptors. Cochlear synaptic loss progresses from youth (4 weeks) to old age (144 weeks) and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts. Cochlear nerve loss parallels the synaptic loss, after a delay of several months. Key functional clues to the synaptopathy are available in the neural response; these can be accessed noninvasively, enhancing the possibilities for translation to human clinical characterization. C1 [Sergeyenko, Yevgeniya; Lall, Kumud; Liberman, M. Charles; Kujawa, Sharon G.] Massachusetts Eye & Ear Infirm, Eaton Peabody Labs, Boston, MA 02114 USA. [Kujawa, Sharon G.] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. [Lall, Kumud; Liberman, M. Charles; Kujawa, Sharon G.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Kujawa, SG (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. EM sharon_kujawa@meei.harvard.edu RI Lall, Kumud/A-4585-2010 OI Lall, Kumud/0000-0002-5576-955X FU National Institute on Deafness and other Communication Disorders [R01 DC08577, RO1 DC00188] FX This work was supported by National Institute on Deafness and other Communication Disorders Grants R01 DC08577 (S.G.K.) and RO1 DC00188 (M.C.L.). NR 71 TC 101 Z9 103 U1 6 U2 37 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 AUG 21 PY 2013 VL 33 IS 34 BP 13686 EP 13694 DI 10.1523/JNEUROSCI.1783-13.2013 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 205FC UT WOS:000323427000010 PM 23966690 ER PT J AU Tamaki, M Huang, TR Yotsumoto, Y Hamalainen, M Lin, FH Nanez, JE Watanabe, T Sasaki, Y AF Tamaki, Masako Huang, Tsung-Ren Yotsumoto, Yuko Haemaelaeinen, Matti Lin, Fa-Hsuan Nanez, Jose E., Sr. Watanabe, Takeo Sasaki, Yuka TI Enhanced Spontaneous Oscillations in the Supplementary Motor Area Are Associated with Sleep-Dependent Offline Learning of Finger-Tapping Motor-Sequence Task SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SURFACE-BASED ANALYSIS; MEDIAL FRONTAL-CORTEX; EYE-MOVEMENT SLEEP; MEMORY CONSOLIDATION; REM-SLEEP; FUNCTIONAL MRI; HUMAN BRAIN; SKILL; PLASTICITY; SPINDLES AB Sleep is beneficial for various types of learning and memory, including a finger-tapping motor-sequence task. However, methodological issues hinder clarification of the crucial cortical regions for sleep-dependent consolidation in motor-sequence learning. Here, to investigate the core cortical region for sleep-dependent consolidation of finger-tapping motor-sequence learning, while human subjects were asleep, we measured spontaneous cortical oscillations by magnetoencephalography together with polysomnography, and source-localized the origins of oscillations using individual anatomical brain information from MRI. First, we confirmed that performance of the task at a retest session after sleep significantly increased compared with performance at the training session before sleep. Second, spontaneous delta and fast-sigma oscillations significantly increased in the supplementary motor area (SMA) during post-training compared with pretraining sleep, showing significant and high correlation with the performance increase. Third, the increased spontaneous oscillations in the SMA correlated with performance improvement were specific to slow-wave sleep. We also found that correlations of delta oscillation between the SMA and the prefrontal and between the SMA and the parietal regions tended to decrease after training. These results suggest that a core brain region for sleep-dependent consolidation of the finger-tapping motor-sequence learning resides in the SMA contralateral to the trained hand and is mediated by spontaneous delta and fast-sigma oscillations, especially during slow-wave sleep. The consolidation may arise along with possible reorganization of a larger-scale cortical network that involves the SMA and cortical regions outside the motor regions, including prefrontal and parietal regions. C1 [Tamaki, Masako; Watanabe, Takeo; Sasaki, Yuka] Brown Univ, Dept Cognit Linguist & Psychol Sci, Providence, RI 02912 USA. [Huang, Tsung-Ren; Yotsumoto, Yuko] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Haemaelaeinen, Matti] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Lin, Fa-Hsuan] Natl Taiwan Univ, Inst Biomed Engn, Taipei 100, Taiwan. [Nanez, Jose E., Sr.] Arizona State Univ, Sch Social & Behav Sci, Phoenix, AZ 85004 USA. RP Sasaki, Y (reprint author), Brown Univ, Dept Cognit Linguist & Psychol Sci, Box 1821,190 Thayer St, Providence, RI 02912 USA. EM yuka_sasaki@brown.edu RI Lin, Fa-Hsuan/G-6988-2012; Hamalainen, Matti/C-8507-2013; OI Lin, Fa-Hsuan/0000-0002-9539-1731; Huang, Tsung-Ren/0000-0003-4396-7943 FU National Institutes of Health [R01AG031941, R01MH091801, R01EY015980, R01EY019466, R01EY018334]; NSF [BCS-0964776]; Japanese Society for the Promotion of Science; Sleep Research Society Foundation FX This work was supported by National Institutes of Health Grants R01AG031941, R01MH091801, R01EY015980, R01EY019466, and R01EY018334 and by NSF Grant BCS-0964776. M. T. was supported by the Research Fellowship for Young Scientists, from the Japanese Society for the Promotion of Science. Y. S. was supported in part by the Sleep Research Society Foundation. This work was performed in part at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies (NCRR P41RR14075, S10RR014978, S10RR021110, and S10RR023401). Part of this research was also conducted using computational resources and services at the Center for Computation and Visualization, Brown University. We thank Drs. Tadao Hori and Simon Durrant for their comments on earlier drafts. NR 58 TC 13 Z9 13 U1 0 U2 17 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 AUG 21 PY 2013 VL 33 IS 34 BP 13894 EP + DI 10.1523/JNEUROSCI.1198-13.2013 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 205FC UT WOS:000323427000029 PM 23966709 ER PT J AU Kassam, A Wolfe, J AF Kassam, Alisha Wolfe, Joanne TI Time to Define High-Quality Palliative Care in Oncology Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID CLINICAL ONCOLOGY; AMERICAN SOCIETY; CANCER CARE; MATTERS C1 [Kassam, Alisha] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Kassam, Alisha] Southlake Reg Hlth Ctr, Newmarket, ON, Canada. [Wolfe, Joanne] Childrens Hosp Boston, Dana Farber Canc Inst, Boston, MA USA. [Wolfe, Joanne] Harvard Univ, Sch Med, Boston, MA USA. RP Kassam, A (reprint author), Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. NR 10 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 EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2013 VL 31 IS 24 BP 3047 EP 3048 DI 10.1200/JCO.2013.50.7178 PG 3 WC Oncology SC Oncology GA 301NW UT WOS:000330540000021 PM 23943830 ER PT J AU Chhatwal, JP Schultz, AP Johnson, K Benzinger, TLS Jack, C Ances, BM Sullivan, CA Salloway, SP Ringman, JM Koeppe, RA Marcus, DS Thompson, P Saykin, AJ Correia, S Schofield, PR Rowe, CC Fox, NC Brickman, AM Mayeux, R McDade, E Bateman, R Fagan, AM Goate, AM Xiong, CJ Buckles, VD Morris, JC Sperling, RA AF Chhatwal, Jasmeer P. Schultz, Aaron P. Johnson, Keith Benzinger, Tammie L. S. Jack, Clifford, Jr. Ances, Beau M. Sullivan, Caroline A. Salloway, Stephen P. Ringman, John M. Koeppe, Robert A. Marcus, Daniel S. Thompson, Paul Saykin, Andrew J. Correia, Stephen Schofield, Peter R. Rowe, Christopher C. Fox, Nick C. Brickman, Adam M. Mayeux, Richard McDade, Eric Bateman, Randall Fagan, Anne M. Goate, Allison M. Xiong, Chengjie Buckles, Virginia D. Morris, John C. Sperling, Reisa A. TI Impaired default network functional connectivity in autosomal dominant Alzheimer disease SO NEUROLOGY LA English DT Article ID MILD COGNITIVE IMPAIRMENT; MODE NETWORK; RESTING BRAIN; OLDER-ADULTS; MEMORY; APOE; MRI; DISRUPTION; HYPOTHESIS; PREVENTION AB Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease. C1 [Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith; Sullivan, Caroline A.; Sperling, Reisa A.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Johnson, Keith] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith; Sullivan, Caroline A.; Sperling, Reisa A.] Harvard Univ, Sch Med, Martinos Ctr Biomed Imaging, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Benzinger, Tammie L. S.; Marcus, Daniel S.] Washington Univ, Sch Med, Dept Radiol, Neuroradiol Sect, St Louis, MO 63110 USA. [Benzinger, Tammie L. S.; Ances, Beau M.; Marcus, Daniel S.] Washington Univ, Sch Med, Mallinckrodt Inst Radiol, St Louis, MO USA. [Ances, Beau M.; Bateman, Randall; Fagan, Anne M.; Buckles, Virginia D.; Morris, John C.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Goate, Allison M.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Goate, Allison M.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Xiong, Chengjie] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Jack, Clifford, Jr.] Mayo Clin, Dept Radiol, Rochester, MN USA. [Salloway, Stephen P.] Brown Univ, Sch Med, Dept Neurol, Butler Hosp, Providence, RI 02912 USA. [Correia, Stephen] Brown Univ, Sch Med, Dept Psychiat, Providence, RI 02912 USA. [Ringman, John M.; Thompson, Paul] Univ Calif Los Angeles, Dept Neurol, Easton Ctr Alzheimers Dis Res, Los Angeles, CA 90024 USA. [Koeppe, Robert A.] Univ Michigan, Dept Radiol, Sch Med, Ann Arbor, MI 48109 USA. Indiana Univ Sch Med, Dept Radiol, IU Ctr Neuroimaging, Indianapolis, IN 46202 USA. [Schofield, Peter R.] Neurosci Res Australia, Sydney, NSW, Australia. [Schofield, Peter R.] Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia. [Rowe, Christopher C.] Univ Melbourne, Austin Hlth, Dept Nucl Med, Melbourne, Vic 3010, Australia. [Rowe, Christopher C.] Univ Melbourne, Austin Hlth, Ctr PET, Melbourne, Vic 3010, Australia. [Fox, Nick C.] UCL, Dept Neurol, London WC1E 6BT, England. [Brickman, Adam M.; Mayeux, Richard] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [McDade, Eric] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15260 USA. [Sullivan, Caroline A.; Sperling, Reisa A.] Harvard Univ, Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment,Med Sch, Boston, MA 02115 USA. RP Sperling, RA (reprint author), Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM reisa@rics.bwh.harvard.edu RI Saykin, Andrew/A-1318-2007; Fox, Nick/B-1319-2009; Jack, Clifford/F-2508-2010; OI Saykin, Andrew/0000-0002-1376-8532; Fox, Nick/0000-0002-6660-657X; Jack, Clifford/0000-0001-7916-622X; Ances, Beau/0000-0003-3862-7397 FU Dominantly Inherited Alzheimer Network (DIAN) [U19AG032438]; National Institute on Aging (NIA); K24 grant [AG035007] FX Data collection for this project was supported by the Dominantly Inherited Alzheimer Network (DIAN, U19AG032438 to J.C.M.) and data analyses by a K24 grant (AG035007 to R. A. S.), both funded by the National Institute on Aging (NIA). NR 40 TC 37 Z9 40 U1 3 U2 16 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 20 PY 2013 VL 81 IS 8 BP 736 EP 744 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 304JV UT WOS:000330743800011 PM 23884042 ER PT J AU Bouazoune, K Kingston, RE AF Bouazoune, Karim Kingston, Robert E. TI Assembly, remodelled SO ELIFE LA English DT Editorial Material ID CHROMATIN; IDENTIFICATION; ISWI; ACF C1 [Bouazoune, Karim; Kingston, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. [Bouazoune, Karim; Kingston, Robert E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Genet, Boston, MA USA. RP Bouazoune, K (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. EM bouazoune@molbio.mgh.harvard.edu; kingston@molbio.mgh.harvard.edu FU NIGMS NIH HHS [R37 GM048405] NR 9 TC 1 Z9 1 U1 1 U2 2 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD AUG 20 PY 2013 VL 2 AR e01270 DI 10.7554/eLife.01270 PG 4 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 274RY UT WOS:000328625100004 PM 23986864 ER PT J AU Erickson, CE Gul, R Blessing, CP Nguyen, J Liu, T Pulakat, L Bastepe, M Jackson, EK Andresen, BT AF Erickson, Catherine E. Gul, Rukhsana Blessing, Christopher P. Jenny Nguyen Liu, Tammy Pulakat, Lakshmi Bastepe, Murat Jackson, Edwin K. Andresen, Bradley T. TI The beta-blocker Nebivolol Is a GRK/beta-arrestin Biased Agonist SO PLOS ONE LA English DT Article ID PROTEIN-COUPLED RECEPTORS; EPIDERMAL GROWTH-FACTOR; NITRIC-OXIDE PRODUCTION; ADRENERGIC BLOCKERS; ENDOTHELIAL-CELLS; RAT AORTA; CARVEDILOL; BINDING; EGF; BETA(3)-ADRENOCEPTOR AB Nebivolol, a third generation beta-adrenoceptor (beta-AR) antagonist (beta-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another beta-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of G alpha(s) and involves G protein-coupled receptor kinase (GRK)/beta-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/beta-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express beta(2)-ARs, and HL-1 cardiac myocytes that express beta(1)- and beta(2)-ARs and no detectable beta(3)-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of beta-ARs indicating that nebivolol is also not a classical beta-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective beta-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from beta-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of beta-arrestin 1/2. Additionally, nebivolol induced redistribution of beta-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a beta(2)-AR, and likely beta(1)-AR, GRK/beta-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at beta(1)- and/or beta(2)-ARs. C1 [Erickson, Catherine E.; Gul, Rukhsana; Blessing, Christopher P.; Pulakat, Lakshmi] Univ Missouri, Dept Internal Med, Columbia, MO USA. [Pulakat, Lakshmi] Univ Missouri, Dept Nutr & Exercise Physiol, Columbia, MO USA. [Pulakat, Lakshmi; Andresen, Bradley T.] Univ Missouri, Dept Med Pharmacol & Physiol, Columbia, MO 65211 USA. [Erickson, Catherine E.; Gul, Rukhsana; Pulakat, Lakshmi] Harry S Truman Mem Vet Hosp, Columbia, MO 65201 USA. [Gul, Rukhsana] King Saud Univ, Coll Med, Obes Res Ctr, Riyadh 11461, Saudi Arabia. [Bastepe, Murat] Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. [Bastepe, Murat] Harvard Univ, Sch Med, Boston, MA USA. [Jackson, Edwin K.] Univ Pittsburgh, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA. [Jenny Nguyen; Liu, Tammy; Andresen, Bradley T.] Western Univ Hlth Sci, Dept Pharmaceut Sci, Pomona, CA USA. RP Andresen, BT (reprint author), Univ Missouri, Dept Med Pharmacol & Physiol, Columbia, MO 65211 USA. EM bandresen@westernu.edu FU Life Science Mission Enhancement Fund from UM-Columbia; National Institutes of Health [R01 DK073911, HL109002, DK091190, HL069846, DK068575, DK079307]; University of Missouri; Western University FX This work was supported, in part, by the Life Science Mission Enhancement Fund from UM-Columbia to LP, as well as research grants from the National Institutes of Health R01 DK073911 to MB; HL109002, DK091190, HL069846, DK068575, and DK079307 to EKJ. Internal funds from the University of Missouri and Western University to BTA were also used to conduct these studies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 18 Z9 19 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 20 PY 2013 VL 8 IS 8 AR e71980 DI 10.1371/journal.pone.0071980 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219RU UT WOS:000324527300057 PM 23977191 ER PT J AU Joynt, KE AF Joynt, Karen E. TI Rightsizing Invasive Cardiac Services in the United States SO CIRCULATION LA English DT Editorial Material DE Editorials; ethics ID ACUTE MYOCARDIAL-INFARCTION; PERCUTANEOUS CORONARY INTERVENTION; QUALITY-OF-CARE; MEDICARE BENEFICIARIES; CRITICAL ACCESS; HOSPITALS; OUTCOMES; REVASCULARIZATION; APPROPRIATENESS; OVERUSE C1 [Joynt, Karen E.] Brigham & Womens Hosp, Dept Internal Med, Div Cardiovasc Med, Boston, MA 02115 USA. [Joynt, Karen E.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Joynt, Karen E.] VA Boston Healthcare Syst, Div Cardiol, Boston, MA USA. RP Joynt, KE (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. EM kjoynt@partners.org NR 20 TC 2 Z9 2 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 AUG 20 PY 2013 VL 128 IS 8 BP 780 EP 782 DI 10.1161/CIRCULATIONAHA.113.004718 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 208BT UT WOS:000323651700009 PM 23877257 ER PT J AU Roussel, R Hadjadj, S Pasquet, B Wilson, PWF Smith, SC Goto, S Tubach, F Marre, M Porath, A Krempf, M Bhatt, DL Steg, PG AF Roussel, Ronan Hadjadj, Samy Pasquet, Blandine Wilson, Peter W. F. Smith, Sidney C., Jr. Goto, Shinya Tubach, Florence Marre, Michel Porath, Avi Krempf, Michel Bhatt, Deepak L. Steg, P. Gabriel CA REACH Investigators TI Thiazolidinedione use is not associated with worse cardiovascular outcomes: A study in 28,332 high risk patients with diabetes in routine clinical practice Brief title: Thiazolidinedione use and mortality SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Thiazolidinedione; Diabetes; Cardiovascular risk; Mortality; Registry ID ACUTE MYOCARDIAL-INFARCTION; CONGESTIVE-HEART-FAILURE; ALL-CAUSE MORTALITY; OLDER PATIENTS; ROSIGLITAZONE; PIOGLITAZONE; EVENTS; DEATH; ATHEROTHROMBOSIS; OUTPATIENTS AB Objective: Assess the cardiovascular safety of Thiazolidinediones (TZD) in routine clinical practice. Background: TZD are insulin-sensitizing antidiabetic drugs commonly used in type 2 diabetes, but their cardiovascular safety has been questioned. We examined the association between TZD use and major cardiovascular outcomes. Methods: We examined 2-year mortality, non-fatal myocardial infarction (MI), and congestive heart failure (CHF) rates among outpatients with high cardiovascular risk and diabetes according to TZD use in the REACH Registry. Multivariable adjustment and propensity scores were used in the analyses. Results: A total of 4997 out of 28,332 patients took TZDs at baseline. During follow-up, 1532 patients died. Themortality rates (95% confidence interval [CI]) were 6.5% (5.5-7.6) with TZD and 7.2% (6.33-8.06) without; adjusted hazard ratio (HR) was 1.06 (0.89-1.26, P=0.54). The lack of association with mortality was consistent across subgroups regardless of history of atherothrombosis or CHF. Rates of non-fatal MI (HR 1.10, 95% CI 0.83-1.45, P=0.50) and non-fatal CHF (HR 0.90, CI 0.75-1.09, P=0.27) were similar in users and non-users. TZD use was associated with an increased risk of CHF in patients aged >80 years (HR 1.59, CI 1.06-2.40, P=0.03). Conclusions: Use of TZD was not associated with increased incidence of major cardiovascular events in patients with diabetes from this large registry. Older patients experienced an increased risk of CHF over the study interval. Limitations of this study include its observational design, and thus unmeasured confounders cannot be excluded. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Roussel, Ronan; Marre, Michel] INSERM, U695, F-75006 Paris, France. [Roussel, Ronan; Marre, Michel; Steg, P. Gabriel] Univ Paris Diderot, Sorbonne Paris Cite, UMR 738, F-75018 Paris, France. [Roussel, Ronan; Marre, Michel; Steg, P. Gabriel] Hop Bichat Claude Bernard, AP HP, F-75018 Paris, France. [Hadjadj, Samy] CHU, F-86000 Poitiers, France. [Hadjadj, Samy] INSERM, CIC, F-86000 Poitiers, France. [Pasquet, Blandine; Tubach, Florence] Univ Paris 07, INSERM, CIE 801, F-75018 Paris, France. [Pasquet, Blandine; Tubach, Florence] Hop Bichat Claude Bernard, APHP, Dept Epidemiol & Rech Clin, F-75018 Paris, France. [Wilson, Peter W. F.] Atlanta VA Med Ctr, Atlanta, GA USA. [Wilson, Peter W. F.] Emory Univ, Sch Med, Atlanta, GA USA. [Smith, Sidney C., Jr.] UNC Sch Med, Ctr Cardiovasc Sci & Med, Chapel Hill, NC USA. [Goto, Shinya] Tokai Univ, Sch Med, Isehara, Kanagawa 25911, Japan. [Porath, Avi] Maccabi Healthcare Serv, Div Med, Beer Sheva, Israel. [Porath, Avi] Ben Gurion Univ Negev, Fac Hlth Sci, Beer Sheva, Israel. [Krempf, Michel] Univ Nantes, CHU, Inst Thorax, INSERM,UMR915, Nantes, France. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Steg, P. Gabriel] INSERM, U698, Paris, France. RP Roussel, R (reprint author), Hop Xavier Bichat, Dept Diabetol Endocrinol & Nutr, 46 Rue Henri Huchard, F-75018 Paris, France. EM ronan.roussel@bch.aphp.fr OI Marre, Michel/0000-0002-3071-1837 FU sanofi-aventis; Bristol-Myers Squibb; Waksman Foundation (Tokyo, Japan) FX This work was supported by sanofi-aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan). All analyses from the REACH Registry are prepared by independent authors who are not governed by the funding sponsors and are prioritized and reviewed by an academic publications committee before submission. The statistical analyses were conducted solely by an academic team (BP, PR). The funding sponsors have the opportunity to review manuscript submissions but do not have authority to change any aspect of a manuscript. NR 27 TC 2 Z9 3 U1 0 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD AUG 20 PY 2013 VL 167 IS 4 BP 1380 EP 1384 DI 10.1016/j.ijcard.2012.04.019 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 206ZV UT WOS:000323566800059 PM 22560911 ER PT J AU Siegel, E Thai, WE Techasith, T Major, G Szymonifka, J Tawakol, A Nagurney, JT Hoffmann, U Truong, QA AF Siegel, Emily Thai, Wai-Ee Techasith, Tust Major, Gyongyi Szymonifka, Jackie Tawakol, Ahmed Nagurney, John T. Hoffmann, Udo Truong, Quynh A. TI Aortic distensibility and its relationship to coronary and thoracic atherosclerosis plaque and morphology by MDCT: Insights from the ROMICAT Trial SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Article DE Aortic distensibility; Coronary atherosclerosis; Thoracic atherosclerosis; Peripheral vascular disease; Computed tomography; Cardiovascular aging ID MULTIDETECTOR COMPUTED-TOMOGRAPHY; INDEPENDENT PREDICTOR; HYPERTENSIVE PATIENTS; CARDIOVASCULAR RISK; ARTERIAL DISTENSIBILITY; DIAGNOSTIC PERFORMANCE; CALCIUM SCORES; ANGIOGRAPHY; STIFFNESS; EVENTS AB Background: Multi-detector cardiac computed tomography (CT) allows for simultaneous assessment of aortic distensibility (AD), coronary atherosclerosis, and thoracic aortic atherosclerosis. Objectives: We sought to determine the relationship of AD to the presence and morphological features in coronary and thoracic atherosclerosis. Methods: In 293 patients (53 +/- 12 years, 63% male), retrospectively-gated MDCT were performed. We measured intraluminal aortic areas across 10 phases of the cardiac cycle (multiphase reformation 10% increments) at pre-defined locations to calculate the ascending, descending, and local AD (at locations of thoracic plaque). AD was calculated as maximum change in area/(minimum area x pulse pressure). Coronary and thoracic plaques were categorized as calcified, mixed, or non-calcified. Results: Ascending and descending AD were lower in patients with any coronary plaque, calcified or mixed plaque than those without (all p<0.0001) but not with non-calcified coronary plaque (p >= 0.46). Per 1 mm Hg-1 10(-3) increase in ascending and descending AD, there was an 18-29% adjusted risk reduction for having any coronary, calcified plaque, or mixed coronary plaque (ascending AD only) (all p <= 0.04). AD was not associated with non-calcified coronary plaque or when age was added to the models (all p>0.39). Local AD was lower at locations of calcified and mixed thoracic plaque when compared to non-calcified thoracic atherosclerosis (p<0.04). Conclusions: A stiffer, less distensible aorta is associated with coronary and thoracic atherosclerosis, particularly in the presence of calcified and mixed plaques, suggesting that the mechanism of atherosclerosis in small and large vessels is similar and influenced by advancing age. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Siegel, Emily; Thai, Wai-Ee; Techasith, Tust; Major, Gyongyi; Tawakol, Ahmed; Hoffmann, Udo; Truong, Quynh A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR PET CT Program,Div Cardiol, Boston, MA USA. [Siegel, Emily; Techasith, Tust; Major, Gyongyi; Tawakol, Ahmed; Hoffmann, Udo; Truong, Quynh A.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Szymonifka, Jackie] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. [Nagurney, John T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Truong, QA (reprint author), Massachusetts Gen Hosp, Div Cardiol, Cardiac MR PET CT Program, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM qtruong@partners.org FU NIH [R01 HL080053, K23HL098370, L30HL093896]; Siemens Medical Solutions; General Electrics Healthcare FX This work was supported by the NIH R01 HL080053, and in part supported by Siemens Medical Solutions and General Electrics Healthcare. Dr. Truong received support from NIH grant K23HL098370 and L30HL093896. NR 33 TC 6 Z9 6 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD AUG 20 PY 2013 VL 167 IS 4 BP 1616 EP 1621 DI 10.1016/j.ijcard.2012.04.107 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 206ZV UT WOS:000323566800096 PM 22578738 ER PT J AU Shi, FX Hua, LX Edge, ASB AF Shi, Fuxin Hua, Lingxiang Edge, Albert S. B. TI Generation of hair cells in neonatal mice by beta-catenin overexpression in Lgr5-positive cochlear progenitors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID STEM-CELLS; INNER-EAR; IN-VIVO; RETINOBLASTOMA PROTEIN; STEM/PROGENITOR CELLS; SENSORY REGENERATION; MAMMALIAN COCHLEA; SUPPORTING CELLS; SMALL-INTESTINE; GENE-TRANSFER AB Mammalian hair cells do not regenerate, and their loss is a major cause of deafness. We recently identified leucine-rich repeat containing, G-protein-coupled receptor 5 (Lgr5)-expressing cochlear supporting cells with the capacity for self-renewal and hair cell differentiation in vitro. We found that these cells, a subset of cochlear supporting cells, were responsive to Wnt signaling. Here we asked whether these Lgr5-positive cells, despite their lack of contribution to hair cell replacement after degenerative loss, could be driven by forced expression of beta-catenin to act as hair cell progenitors in vivo. We showed that forced stabilization of beta-catenin in supporting cells in neonatal animals resulted in proliferation of supporting cells and generation of hair cells. Although beta-catenin expression was increased by genetic means in all supporting cells, entry to the cell cycle and differentiation to hair cells of the normally postmitotic cells was restricted to the Lgr5-positive population. Our finding suggests that Wnt/beta-catenin can drive Lgr5-positive cells to act as hair cell progenitors, even after their exit from the cell cycle and apparent establishment of cell fate. C1 [Shi, Fuxin; Hua, Lingxiang; Edge, Albert S. B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Shi, Fuxin; Hua, Lingxiang; Edge, Albert S. B.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Edge, Albert S. B.] MIT, Harvard Mit Div Hlth Sci & Technol, Program Speech & Hearing Biosci & Technol, Cambridge, MA 02139 USA. RP Edge, ASB (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. EM albert_edge@meei.harvard.edu FU National Institute on Deafness and Other Communication Disorders [R01 DC007174, P30 DC05209, R03 DC010270]; Shulsky Foundation FX This work was supported by grants from the National Institute on Deafness and Other Communication Disorders (R01 DC007174, P30 DC05209, and R03 DC010270), by the Shulsky Foundation and by Robert Boucai. NR 50 TC 52 Z9 53 U1 0 U2 17 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 AUG 20 PY 2013 VL 110 IS 34 BP 13851 EP 13856 DI 10.1073/pnas.1219952110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 203DU UT WOS:000323271400046 PM 23918377 ER PT J AU Shi, LZ Kalupahana, NS Turnis, ME Neale, G Hock, H Vignali, DAA Chi, HB AF Shi, Lewis Zhichang Kalupahana, Nishan S. Turnis, Meghan E. Neale, Geoffrey Hock, Hanno Vignali, Dario A. A. Chi, Hongbo TI Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HEMATOPOIETIC STEM-CELLS; TGF-BETA; LYMPHOCYTE DEVELOPMENT; IMMUNE SUPPRESSION; TUMOR-IMMUNITY; FACTOR FOXP3; EXPRESSION; DIFFERENTIATION; THYMOCYTES; INDUCTION AB Foxp3(+) regulatory T (T-reg) cells are essential for the maintenance of self-tolerance and immune homeostasis. The majority of T-reg cells is generated in the thymus as a specific subset of CD4(+) T cells, known as thymus-derived or natural T-reg (nT(reg)) cells, in response to signals from T-cell receptors, costimulatory molecules, and cytokines. Recent studies have identified intracellular signaling and transcriptional pathways that link these signals to Foxp3 induction, but how the production of these extrinsic factors is controlled remains poorly understood. Here, we report that the transcription repressor growth factor independent 1 (Gfi1) has a key inhibitory role in the generation of nT(reg) cells by a noncell-autonomous mechanism. T cell-specific deletion of Gfi1 results in aberrant expansion of thymic nT(reg) cells and increased production of cytokines. In particular, IL-2 overproduction plays an important role in driving the expansion of nT(reg) cells. In contrast, although Gfi1 deficiency elevated thymocyte apoptosis, Gfi1 repressed nT(reg) generation independently of its prosurvival effect. Consistent with an inhibitory role of Gfi1 in this process, loss of Gfi1 dampens antitumor immunity. These data point to a previously unrecognized extrinsic control mechanism that negatively shapes thymic generation of nT(reg) cells. C1 [Shi, Lewis Zhichang; Kalupahana, Nishan S.; Turnis, Meghan E.; Vignali, Dario A. A.; Chi, Hongbo] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Neale, Geoffrey] St Jude Childrens Res Hosp, Hartwell Ctr Bioinformat & Biotechnol, Memphis, TN 38105 USA. [Hock, Hanno] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Hock, Hanno] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med, Boston, MA 02114 USA. [Hock, Hanno] Harvard Stem Cell Inst, Boston, MA 02114 USA. RP Chi, HB (reprint author), St Jude Childrens Res Hosp, Dept Immunol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM hongbo.chi@stjude.org FU National Institutes of Health [AI 101407, AI 094089, NS 064599, CA 122726]; American Lebanese Syrian Associated Charities FX The authors thank Stuart H. Orkin for help with Gfi1-targeted mice; Alexander Rudensky for Foxp3YFP-Cre mice; Maureen McGargill for reading of the manuscript and critical scientific inputs; Caryn Cloer and Nicholas Brydon for animal colony management and other technical support; and Richard Cross, Greig Lennon, and Stephanie Morgan for cell sorting. This work was supported by National Institutes of Health Grants AI 101407, AI 094089, NS 064599 (to H. C.), and CA 122726 (to H. H.) and the American Lebanese Syrian Associated Charities (H. C.). NR 51 TC 6 Z9 7 U1 0 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 AUG 20 PY 2013 VL 110 IS 34 BP E3198 EP E3205 DI 10.1073/pnas.1300950110 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 203DU UT WOS:000323271400010 PM 23918371 ER PT J AU Warren, HS Tompkins, RG Mindrinos, MN Xiao, WZ Davis, RW AF Warren, H. Shaw Tompkins, Ronald G. Mindrinos, Michael N. Xiao, Wenzhong Davis, Ronald W. TI Reply to Cauwels et al.: Of men, not mice, and inflammation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter ID TUMOR-NECROSIS-FACTOR C1 [Warren, H. Shaw; Tompkins, Ronald G.; Xiao, Wenzhong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Warren, H. Shaw; Tompkins, Ronald G.; Xiao, Wenzhong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. [Warren, H. Shaw; Tompkins, Ronald G.; Xiao, Wenzhong] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat, Boston, MA 02114 USA. [Mindrinos, Michael N.; Davis, Ronald W.] Stanford Univ, Stanford Genome Technol Ctr, Stanford, CA 94305 USA. RP Davis, RW (reprint author), Stanford Univ, Stanford Genome Technol Ctr, Stanford, CA 94305 USA. EM dbowe@stanford.edu FU NIGMS NIH HHS [U54 GM062119, R24 GM102656] NR 4 TC 3 Z9 3 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 20 PY 2013 VL 110 IS 34 BP E3151 EP E3151 DI 10.1073/pnas.1308943110 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 203DU UT WOS:000323271400004 PM 24137663 ER PT J AU Guinan, JJ AF Guinan, John J., Jr. TI New Insights into Cochlear Amplification SO BIOPHYSICAL JOURNAL LA English DT News Item ID TECTORIAL MEMBRANE; TRAVELING-WAVES; MICROMECHANICS C1 [Guinan, John J., Jr.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Guinan, John J., Jr.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. RP Guinan, JJ (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. EM jjg@epl.meei.harvard.edu FU PHS HHS [R01 000235, R01 005977] NR 9 TC 0 Z9 0 U1 0 U2 2 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 AUG 20 PY 2013 VL 105 IS 4 BP 839 EP 840 DI 10.1016/j.bpj.2013.07.016 PG 2 WC Biophysics SC Biophysics GA 205SN UT WOS:000323465200007 PM 23972835 ER PT J AU Clark, KB AF Clark, Kevin B. TI Ciliates learn to diagnose and correct classical error syndromes in mating strategies SO FRONTIERS IN MICROBIOLOGY LA English DT Article DE courtship and dominance displays; evolutionary psychology; intracellular calcium; mate selection; mating pathways; pheromones; social decision making; soft-matter physics ID SPIROSTOMUM-AMBIGUUM; MATHEMATICAL-THEORY; EUPLOTES-RAIKOVI; SOCIAL-BEHAVIOR; SEX-PHEROMONE; IN-VIVO; COMMUNICATION; HABITUATION; EVOLUTION; CALCIUM AB Preconjugal ciliates learn classical repetition error-correction codes to safeguard mating messages and replies from corruption by "rivals" and local ambient noise. Because individual cells behave as memory channels with Szilard engine attributes, these coding schemes also might be used to limit, diagnose, and correct mating-signal errors due to noisy intracellular information processing. The present study, therefore, assessed whether heterotrich ciliates effect fault-tolerant signal planning and execution by modifying engine performance, and consequently entropy content of codes, during mock cell cell communication. Socially meaningful serial vibrations emitted from an ambiguous artificial source initiated ciliate behavioral signaling performances known to advertise mating fitness with varying courtship strategies. Microbes, employing calcium-dependent Hebbian-like decision making, learned to diagnose then correct error syndromes by recursively matching Boltzmann entropies between signal planning and execution stages via "power" or "refrigeration" cycles. All eight serial contraction and reversal strategies incurred errors in entropy magnitude by the execution stage of processing. Absolute errors, however, subtended expected threshold values for single bit-flip errors in three-bit replies, indicating coding schemes protected information content throughout signal production. Ciliate preparedness for vibrations selectively and significantly affected the magnitude and valence of Szilard engine performance during modal and non-modal strategy corrective cycles. But entropy fidelity for all replies mainly improved across learning trials as refinements in engine efficiency. Fidelity neared maximum levels for only modal signals coded in resilient three-bit repetition error-correction sequences. Together, these findings demonstrate microbes can elevate survival/reproductive success by learning to implement classical fault-tolerant information processing in social contexts. C1 [Clark, Kevin B.] Vet Affairs Greater Los Angeles Healthcare Syst, Res & Dev Serv, Los Angeles, CA USA. RP Clark, KB (reprint author), 4229 SE Harney St, Portland, OR 97206 USA. EM kbclarkphd@yahoo.com NR 97 TC 5 Z9 5 U1 1 U2 2 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1664-302X J9 FRONT MICROBIOL JI Front. Microbiol. PD AUG 19 PY 2013 VL 4 AR 229 DI 10.3389/fmicb.2013.00229 PG 22 WC Microbiology SC Microbiology GA AA9EQ UT WOS:000331397000001 PM 23966987 ER PT J AU Ekblad, S Mollica, RF Fors, U Pantziaras, I Lavelle, J AF Ekblad, Solvig Mollica, Richard F. Fors, Uno Pantziaras, Ioannis Lavelle, James TI Educational potential of a virtual patient system for caring for traumatized patients in primary care SO BMC MEDICAL EDUCATION LA English DT Article DE Primary health care; Virtual patients; Virtual encounters; Refugees; PTSD; Depression ID POSTTRAUMATIC-STRESS-DISORDER; HEALTH LITERACY; PHYSICIAN COMMUNICATION; LANGUAGE PROFICIENCY; CLINICAL SKILLS; MENTAL-HEALTH; DEPRESSION; PREVALENCE; SIMULATION; OUTCOMES AB Background: Virtual Patients (VPs) have been used in undergraduate healthcare education for many years. This project is focused on using VPs for training professionals to care for highly vulnerable patient populations. The aim of the study was to evaluate if Refugee Trauma VPs was perceived as an effective and engaging learning tool by primary care professionals (PCPs) in a Primary Health Care Centre (PHC). Methods: A VP system was designed to create realistic and engaging VP cases for Refugee Trauma for training refugee patient interview, use of established trauma and mental health instruments as well as to give feedback to the learners. The patient interview section was based on video clips with a Bosnian actor with a trauma story and mental health problems. The video clips were recorded in Bosnian language to further increase the realism, but also subtitled in English. The system was evaluated by 11 volunteering primary health clinicians at the Lynn Community Health Centre, Lynn, Massachusetts, USA. The participants were invited to provide insights/feedback about the system's usefulness and educational value. A mixed methodological approach was used, generating both quantitative and qualitative data. Results: Self-reported dimensions of clinical care, pre and post questionnaire questions on the PCPs clinical worldview, motivation to use the VP, and IT Proficiency. Construct items used in these questionnaires had previously demonstrated high face and construct validity. The participants ranked the mental status examination more positively after the simulation exercise compared to before the simulation. Follow up interviews supported the results. Conclusions: Even though virtual clinical encounters are quite a new paradigm in PHC, the participants in the present study considered our VP case to be a relevant and promising educational tool. Next phase of our project will be a RCT study including comparison with specially prepared paper-cases and determinative input on improving clinical diagnosis and treatment of the traumatized refugee patient. C1 [Ekblad, Solvig; Mollica, Richard F.; Pantziaras, Ioannis] Karolinska Inst, Cultural Med Unit, Dept Learning Informat Management & Eth LIME, SE-17177 Stockholm, Sweden. [Fors, Uno] Stockholm Univ, Dept Comp & Syst Sci, S-10691 Stockholm, Sweden. [Mollica, Richard F.; Lavelle, James] Massachusetts Gen Hosp, HPRT, Boston, MA 02114 USA. RP Ekblad, S (reprint author), Karolinska Inst, Cultural Med Unit, Dept Learning Informat Management & Eth LIME, Tomtebodavagen 18A,Plan 3, SE-17177 Stockholm, Sweden. EM Solvig.Ekblad@ki.se OI Pantziaras, Ioannis/0000-0003-4610-2611 FU NIH [PAR-08-269] FX This work was supported by the NIH PAR-08-269 Grant Exploratory and Developmental Grant to Improve health care Quality through Health Information Technology. NR 63 TC 4 Z9 4 U1 2 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6920 J9 BMC MED EDUC JI BMC Med. Educ. PD AUG 19 PY 2013 VL 13 AR 110 DI 10.1186/1472-6920-13-110 PG 12 WC Education & Educational Research; Education, Scientific Disciplines SC Education & Educational Research GA 207CX UT WOS:000323575800001 PM 23957962 ER PT J AU Thongsroy, J Matangkasombut, O Thongnak, A Rattanatanyong, P Jirawatnotai, S Mutirangura, A AF Thongsroy, Jirapan Matangkasombut, Oranart Thongnak, Araya Rattanatanyong, Prakasit Jirawatnotai, Siwanon Mutirangura, Apiwat TI Replication-Independent Endogenous DNA Double-Strand Breaks in Saccharomyces cerevisiae Model SO PLOS ONE LA English DT Article ID LINE-1 METHYLATION; YEAST; REPAIR; DAMAGE; PROTEINS; CANCER; CELLS AB Without exposure to any DNA-damaging agents, non-dividing eukaryotic cells carry endogenous DNA double-strand breaks (EDSBs), or Replication-Independent (RIND)-EDSBs. In human cells, RIND-EDSBs are enriched in the methylated heterochromatic areas of the genome and are repaired by an ATM-dependent non-homologous end-joining pathway (NHEJ). Here, we showed that Saccharomyces cerevisiae similarly possess RIND-EDSBs. Various levels of EDSBs were detected during different phases of the cell cycle, including G0. Using a collection of mutant yeast strains, we investigated various DNA metabolic and DNA repair pathways that might be involved in the maintenance of RIND-EDSB levels. We found that the RIND-EDSB levels increased significantly in yeast strains lacking proteins involved in NHEJ DNA repair and in suppression of heterochromatin formation. RIND-EDSB levels were also upregulated when genes encoding histone deacetylase, endonucleases, topoisomerase, and DNA repair regulators were deleted. In contrast, RIND-EDSB levels were downregulated in the mutants that lack chromatin-condensing proteins, such as the high-mobility group box proteins, and Sir2. Likewise, RIND-EDSB levels were also decreased in human cells lacking HMGB1. Therefore, we conclude that the genomic levels of RIND-EDSBs are evolutionally conserved, dynamically regulated, and may be influenced by genome topology, chromatin structure, and the efficiency of DNA repair systems. C1 [Thongsroy, Jirapan] Chulalongkorn Univ, Fac Grad Sch, Interdept Program BioMed Sci, Bangkok, Thailand. [Matangkasombut, Oranart] Chulalongkorn Univ, Fac Dent, Dept Microbiol, Bangkok, Thailand. [Matangkasombut, Oranart] Chulalongkorn Univ, Fac Dent, Developing Res Unit Oral Microbiol, Bangkok, Thailand. [Thongnak, Araya; Rattanatanyong, Prakasit; Mutirangura, Apiwat] Chulalongkorn Univ, Fac Med, Dept Anat, Bangkok 10330, Thailand. [Rattanatanyong, Prakasit; Mutirangura, Apiwat] Chulalongkorn Univ, Ctr Excellence Mol Genet Canc & Human Dis, Bangkok, Thailand. [Jirawatnotai, Siwanon] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Jirawatnotai, Siwanon] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Jirawatnotai, Siwanon] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Pharmacol, Bangkok 10700, Thailand. RP Matangkasombut, O (reprint author), Chulalongkorn Univ, Fac Dent, Dept Microbiol, Bangkok, Thailand. EM oranart@gmail.com; mapiwat@chula.ac.th FU National Science and Technology Development Agency (NSTDA), Thailand; Four Seasons Hotel Bangkok's 4th Cancer Care charity fun run; Chulalongkorn University under the office of the Higher Education Commission; Thai Red Cross Society; Chulalongkorn University FX This work was supported by the Discovery-Based Development Grant and the Research Chair Grant 2011 from the National Science and Technology Development Agency (NSTDA), Thailand; by the Four Seasons Hotel Bangkok's 4th Cancer Care charity fun run in coordination with the Thai Red Cross Society; and by Chulalongkorn University under the office of the Higher Education Commission. Funding for the open access charge was provided by Chulalongkorn University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 3 Z9 3 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 19 PY 2013 VL 8 IS 8 AR e72706 DI 10.1371/journal.pone.0072706 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 205ER UT WOS:000323425700186 PM 23977341 ER PT J AU Wang, PY Sun, YX Zhang, S Pang, M Zhang, HH Gao, SY Zhang, C Lv, CJ Xie, SY AF Wang, Ping-Yu Sun, Yun-Xiao Zhang, Shuai Pang, Min Zhang, Han-Han Gao, Shu-Yan Zhang, Can Lv, Chang-Jun Xie, Shu-Yang TI Let-7c inhibits A549 cell proliferation through oncogenic TRIB2 related factors SO FEBS LETTERS LA English DT Article DE Let-7c; TRIB2 gene; Lung adenocarcinoma; Cell proliferation; Gene expression ID UP-REGULATION; CANCER-CELLS; TUMOR-GROWTH; MICRORNA; TRIBBLES; SUPPRESSION; CARCINOMA; PROTEIN; FAMILY AB MicroRNAs have tumor suppressive or oncogenic roles in carcinogenesis. This study aimed to investigate the mechanism of let-7c in suppressing lung cancer cell proliferation. First, let-7c was revealed to be able to inhibit lung adenocarcinoma cell proliferation significantly. TRIB2 was further demonstrated to be a novel target and negatively regulated by let-7c. As downstream signals of TRIB2, the activities of C/EBP-alpha and phosphorylated p38MAPK were increased obviously in let-7c-treated cells compared with controls. Our results demonstrate that, through regulating the expression of TRIB2 and its downstream factors, let-7c can effectively inhibit A549 cell proliferation in vitro and in vivo. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 [Wang, Ping-Yu; Zhang, Shuai; Pang, Min; Zhang, Han-Han; Gao, Shu-Yan; Xie, Shu-Yang] Binzhou Med Univ, Key Lab Tumor Mol Biol, Dept Biochem & Mol Biol, Yantai 264003, Shandong, Peoples R China. [Sun, Yun-Xiao; Lv, Chang-Jun] Binzhou Med Univ, Affiliated Hosp, Binzhou 256603, Shandong, Peoples R China. [Zhang, Can] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA 02129 USA. [Zhang, Can] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Lv, CJ (reprint author), Binzhou Med Univ, Affiliated Hosp, Binzhou 256603, Shandong, Peoples R China. EM lucky_lcj@sina.com; shuyangxie@aliyun.com FU National Natural Science Foundation [30801324, 81141114, 81200601]; Foundation of ShanDong Educational Committee of China [J10LC60, J11LC01]; [NCET-10-0919] FX This study was supported by the NCET-10-0919, National Natural Science Foundation (No. 30801324, 81141114, 81200601), and the Foundation of ShanDong Educational Committee of China (No. J10LC60, J11LC01). NR 29 TC 14 Z9 16 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD AUG 19 PY 2013 VL 587 IS 16 BP 2675 EP 2681 DI 10.1016/j.febslet.2013.07.004 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 205QC UT WOS:000323458400030 PM 23850892 ER PT J AU Wiviott, SD White, HD Ohman, EM Fox, KAA Armstrong, PW Prabhakaran, D Hafley, G Lokhnygina, Y Boden, WE Hamm, C Clemmensen, P Nicolau, JC Menozzi, A Ruzyllo, W Widimsky, P Oto, A Leiva-Pons, J Pavlides, G Winters, KJ Roe, MT Bhatt, DL AF Wiviott, Stephen D. White, Harvey D. Ohman, E. Magnus Fox, Keith A. A. Armstrong, Paul W. Prabhakaran, Dorairaj Hafley, Gail Lokhnygina, Yuliya Boden, William E. Hamm, Christian Clemmensen, Peter Nicolau, Jose C. Menozzi, Alberto Ruzyllo, Witold Widimsky, Petr Oto, Ali Leiva-Pons, Jose Pavlides, Gregory Winters, Kenneth J. Roe, Matthew T. Bhatt, Deepak L. TI Prasugrel versus clopidogrel for patients with unstable angina or non-ST-segment elevation myocardial infarction with or without angiography: a secondary, prespecified analysis of the TRILOGY ACS trial SO LANCET LA English DT Article ID ACUTE CORONARY SYNDROMES; ACCF/AHA FOCUSED UPDATE; PLATELET INHIBITION; DOSE CLOPIDOGREL; 2007 GUIDELINE; MANAGEMENT; RISK; INTERVENTION; ASSOCIATION; STRATEGIES AB Background Treatment with prasugrel and aspirin improves outcomes compared with clopidogrel and aspirin for patients with acute coronary syndrome who have had angiography and percutaneous coronary intervention; however, no clear benefit has been shown for patients managed first with drugs only. We assessed outcomes from the TRILOGY ACS trial based on whether or not patients had coronary angiography before treatment was chosen. Methods TRILOGY ACS (ClinicalTrials.gov number NCT00699998) was a randomised controlled trial, done at more than 800 sites worldwide. Patients with non-ST-elevation acute coronary syndrome who were selected for management with revascularisation were randomly assigned to clopidogrel or prasugrel. The primary endpoint was cardiovascular death, myocardial infarction, or stroke at 30 months. In the present analysis we assessed differences in the primary endpoint by angiography status and whether the effects of treatment on the primary endpoint differed between patients who had angiography before enrolment and those who had not. Findings 7243 patients younger than 75 years were included in the TRILOGY ACS primary analysis. 3085 (43%) had angiography at baseline, 4158 (57%) had not. Fewer patients who had angiography reached the primary endpoint at 30 months compared with those who did not have angiography, according to Kaplan-Meier analysis (281/3085 [12.8%] vs 480/4158 [16.5%], adjusted hazard ratio [HR] 0.63, 95% CI 0.53-0.75; p<0.0001). The proportion of patients who reached the primary endpoint was lower in the prasugrel group than in the clopidogrel group for those who had angiography (122/1524 [10.7%] vs 159/1561 [14.9%], HR 0.77, 95% CI 0.61-0.98; p=0.032) but did not differ between groups in patients who did not have angiography (242/2096 [16.3%] vs 238/2062 [16.7%], HR 1.01, 0.84-1.20; p=0.94; p(interaction)=0.08). Overall, TIMI major bleeding and GUSTO severe bleeding were rare. Bleeding outcomes tended to be higher with prasugrel but did not differ significantly between treatment groups in either angiography cohort. Interpretation Among patients who had angiography who took prasugrel there were fewer cardiovascular deaths, myocardial infarctions, or strokes than in those who took clopidogrel. This result needs to be corroborated, but it is consistent with previous trials of more versus less intensive antiplatelet treatment. When angiography is done for acute coronary syndrome and anatomic coronary disease confirmed, the benefits and risks of intensive antiplatelet treatment exist whether the patient is treated with drugs or percutaneous coronary intervention. C1 [Wiviott, Stephen D.; Bhatt, Deepak L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Cardiovasc Div,TIMI Study Grp, Boston, MA 02115 USA. [White, Harvey D.] Auckland City Hosp, Green Lane Cardiovasc Serv, Auckland, New Zealand. [Ohman, E. Magnus; Hafley, Gail; Lokhnygina, Yuliya; Roe, Matthew T.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Ohman, E. Magnus; Roe, Matthew T.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Fox, Keith A. A.] Univ Edinburgh, Ctr Cardiovasc Sci, Edinburgh, Midlothian, Scotland. [Armstrong, Paul W.] Univ Alberta, Div Cardiol, Edmonton, AB, Canada. [Prabhakaran, Dorairaj] Ctr Chron Dis Control, New Delhi, India. [Boden, William E.] Albany Stratton VA Med Ctr, Albany, NY USA. [Boden, William E.] Albany Med Ctr, Albany, NY USA. [Hamm, Christian] Kerckhoff Heart & Thoraxctr, Bad Nauheim, Germany. [Clemmensen, Peter] Univ Copenhagen, Rigshosp, Ctr Heart, Dept Cardiol, DK-2100 Copenhagen, Denmark. [Nicolau, Jose C.] Univ Sao Paulo, Inst Heart, Sao Paulo, Brazil. [Menozzi, Alberto] Azienda Osped Univ Parma, Div Cardiol, Parma, Italy. [Ruzyllo, Witold] Inst Cardiol, Dept Coronary Artery Dis, Warsaw, Poland. [Widimsky, Petr] Charles Univ Prague, Cardioctr, Prague, Czech Republic. [Oto, Ali] Hacettepe Univ, Fac Med, Dept Cardiol, TR-06100 Ankara, Turkey. [Leiva-Pons, Jose] Hosp Cent Dr Morones Prieto, Dept Cardiol, San Luis Potosi, Mexico. [Pavlides, Gregory] Onassis Cardiac Surg Ctr, Div Cardiol, Kallithea, Greece. [Winters, Kenneth J.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. RP Wiviott, SD (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM swiviott@partners.org RI Nicolau, Jose/E-1487-2012; Widimsky, Petr/P-8088-2016 OI Widimsky, Petr/0000-0001-5686-7752 FU Daiichi Sankyo; Eli Lilly FX Funding Daiichi Sankyo, Eli Lilly. NR 26 TC 48 Z9 48 U1 2 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 17 PY 2013 VL 382 IS 9892 BP 605 EP 613 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 205DV UT WOS:000323422800024 PM 23953385 ER PT J AU Curzen, N Gurbel, PA Myat, A Bhatt, DL Redwood, SR AF Curzen, Nicholas Gurbel, Paul A. Myat, Aung Bhatt, Deepak L. Redwood, Simon R. TI What is the optimum adjunctive reperfusion strategy for primary percutaneous coronary intervention? SO LANCET LA English DT Article ID ELEVATION MYOCARDIAL-INFARCTION; ST-SEGMENT-ELEVATION; RANDOMIZED CONTROLLED-TRIAL; INTRAVENOUS BOLUS ABCIXIMAB; GLYCOPROTEIN IIB/IIIA INHIBITOR; ANGIOPLASTY REGISTRY SCAAR; DRUG-ELUTING STENTS; BARE-METAL STENTS; THROMBUS ASPIRATION; DOUBLE-BLIND AB Acute ST-segment elevation myocardial infarction (STEMI) is a dynamic, thrombus-driven event. As understanding of its pathophysiology has improved, the central role of platelets in initiation and orchestration of this process has become clear. Key components of STEMI include formation of occlusive thrombus, mediation and ultimately amplification of the local vascular inflammatory response resulting in increased vasoreactivity, oedema formation, and microvascular obstruction. Activation, degranulation, and aggregation of platelets are the platforms from which these components develop. Therefore, prompt, potent, and predictable antithrombotic therapy is needed to optimise clinical outcomes after primary percutaneous coronary intervention. We review present pharmacological and mechanical adjunctive therapies for reperfusion and ask what is the optimum combination when primary percutaneous coronary intervention is used as the mode of revascularisation in patients with STEMI. C1 [Curzen, Nicholas] Univ Hosp Southampton NHS Fdn Trust, Wessex Cardiothorac Unit, Southampton SO16 6YD, Hants, England. [Gurbel, Paul A.] Sinai Hosp, Sinai Ctr Thrombosis Res, Cardiac Catheterisat Lab, Baltimore, MD 21215 USA. [Myat, Aung; Redwood, Simon R.] Kings Coll London, London BHF Ctr Res Excellence, St Thomas Hosp, Rayne Inst,Cardiovasc Div, London, England. [Bhatt, Deepak L.] Harvard Univ, Brigham & Womens Hosp, Sch Med, VA Boston Healthcare Syst, Boston, MA 02115 USA. RP Curzen, N (reprint author), Univ Hosp Southampton NHS Fdn Trust, Southampton SO16 6YD, Hants, England. EM nick.curzen@uhs.nhs.uk FU Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre; King's College London; King's College Hospital NHS Foundation Trust; British Heart Foundation [FS/11/70/28917] FX AM is supported by the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust, in partnership with King's College London and King's College Hospital NHS Foundation Trust. AM acknowledges financial support from the British Heart Foundation via a Clinical Research Training Fellowship (grant number FS/11/70/28917). We thank Udaya Tantry (Sinai Center for Thrombosis Research, Baltimore, MD, USA) for providing us with the image for figure 1. NR 73 TC 9 Z9 10 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 17 PY 2013 VL 382 IS 9892 BP 633 EP 643 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 205DV UT WOS:000323422800027 PM 23953387 ER PT J AU Caballero-Franco, C Choo, MK Sano, Y Ritprajak, P Sakurai, H Otsu, K Mizoguchi, A Park, JM AF Caballero-Franco, Celia Choo, Min-Kyung Sano, Yasuyo Ritprajak, Patcharee Sakurai, Hiroaki Otsu, Kinya Mizoguchi, Atsushi Park, Jin Mo TI Tuning of Protein Kinase Circuitry by p38 alpha Is Vital for Epithelial Tissue Homeostasis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; GROWTH-FACTOR RECEPTOR; MAP KINASE; RHEUMATOID-ARTHRITIS; CELL PROLIFERATION; DOWN-REGULATION; JNK ACTIVATION; DOUBLE-BLIND; STEM-CELLS; P38 AB The epithelium of mucosal and skin surfaces serves as a permeability barrier and affords mechanisms for local immune defense. Crucial to the development and maintenance of a properly functioning epithelium is the balance of cell proliferation, differentiation, and death. Here we show that this balance depends on cross-regulatory interactions among multiple protein kinase-mediated signals and their coordinated transmission. From an investigation of conditional gene knock-out mice, we find that epithelial-specific loss of the protein kinase p38 alpha leads to aberrant activation of TAK1, JNK, EGF receptor, and ERK in distinct microanatomical areas of the intestines and skin. Consequently, the epithelial tissues display excessive proliferation, inadequate differentiation, and sensitivity to apoptosis. These anomalies leave the tissue prone to damage and collapse at the trigger of an environmental insult. The vulnerability of p38 alpha-deficient epithelium predicts adverse effects of long term pharmacological p38 alpha inhibition; yet such limitations could be overcome by concomitant blockade of one or more of the dysregulated protein kinase signaling pathways. C1 [Caballero-Franco, Celia; Choo, Min-Kyung; Sano, Yasuyo; Ritprajak, Patcharee; Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Caballero-Franco, Celia; Choo, Min-Kyung; Sano, Yasuyo; Ritprajak, Patcharee; Mizoguchi, Atsushi; Park, Jin Mo] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Ritprajak, Patcharee] Chulalongkorn Univ, Fac Dent, Dept Microbiol & Immunol, Bangkok 10330, Thailand. [Ritprajak, Patcharee] Chulalongkorn Univ, Fac Dent, Dent Res Unit Oral Microbiol, Bangkok 10330, Thailand. [Sakurai, Hiroaki] Toyama Univ, Grad Sch Med & Pharmaceut Sci, Dept Canc Cell Biol, Toyama 9300194, Japan. [Otsu, Kinya] Osaka Univ, Grad Sch Med, Dept Cardiovasc Med, Suita, Osaka 5650871, Japan. [Otsu, Kinya] Kings Coll London, Div Cardiovasc, London SE5 9NU, England. [Mizoguchi, Atsushi] Massachusetts Gen Hosp, Dept Pathol, Mol Pathol Unit, Charlestown, MA 02129 USA. RP Park, JM (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, 149 Thirteenth St, Charlestown, MA 02129 USA. EM jmpark@cbrc2.mgh.harvard.edu OI Sakurai, Hiroaki/0000-0003-0657-9570 FU National Institutes of Health [AI074957] FX This work was supported by National Institutes of Health Grant AI074957 (to J. M. P.). NR 49 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 16 PY 2013 VL 288 IS 33 BP 23788 EP 23797 DI 10.1074/jbc.M113.452029 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302NO UT WOS:000330611400018 PM 23836897 ER PT J AU Liu, YH Qi, WB Richardson, A Van Remmen, H Ikeno, Y Salmon, AB AF Liu, Yuhong Qi, Wenbo Richardson, Arlan Van Remmen, Holly Ikeno, Yuji Salmon, Adam B. TI Oxidative damage associated with obesity is prevented by overexpression of CuZn- or Mn-superoxide dismutase SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Diabetes; Mitochondria; F-2-isoprostane; Oxidative stress ID INSULIN-RESISTANCE; DIABETES-MELLITUS; STRESS; MITOCHONDRIA; DEFICIENCY; MICE; DNA AB The development of insulin resistance is the primary step in the etiology of type 2 diabetes mellitus. There are several risk factors associated with insulin resistance, yet the basic biological mechanisms that promote its development are still unclear. There is growing literature that suggests mitochondrial dysfunction and/or oxidative stress play prominent roles in defects in glucose metabolism. Here, we tested whether increased expression of CuZn-superoxide dismutase (Sod1) or Mn-superoxide dismutase (Sod2) prevented obesity-induced changes in oxidative stress and metabolism. Both Sod1 and Sod2 overexpressing mice were protected from high fat diet-induced glucose intolerance. Lipid oxidation (F-2-isoprostanes) was significantly increased in muscle and adipose with high fat feeding. Mice with increased expression of either Sod1 or Sod2 showed a significant reduction in this oxidative damage. Surprisingly, mitochondria from the muscle of high fat diet-fed mice showed no significant alteration in function. Together, our data suggest that targeting reduced oxidative damage in general may be a more applicable therapeutic target to prevent insulin resistance than is improving mitochondrial function. Published by Elsevier Inc. C1 [Richardson, Arlan; Van Remmen, Holly; Ikeno, Yuji; Salmon, Adam B.] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX 78229 USA. [Liu, Yuhong; Qi, Wenbo; Richardson, Arlan; Van Remmen, Holly; Ikeno, Yuji; Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Richardson, Arlan; Van Remmen, Holly] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Ikeno, Yuji] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Salmon, Adam B.] Univ Texas Hlth Sci Ctr San Antonio, Dept Mol Med, San Antonio, TX 78229 USA. RP Salmon, AB (reprint author), 15355 Lambda Dr, San Antonio, TX 78245 USA. EM salmona@uthscsa.edu FU Geriatric Research Education and Clinical Center of the South Texas Veterans Health Care System; Biomedical Laboratory Research & Development Service of the Veteran's Affairs Office of Research and Development by [VA Merit Review Grants] [1I01BX001023, 1I01BX000547]; American Federation for Aging Research; Glenn Foundation FX Mitochondria and F2-isoprostane measurements were performed by the Mitochondrial Function and Oxidative Damage Core Facility of the San Antonio Nathan Shock Center of Excellence in the Basic Biology of Aging. This work was supported by the Geriatric Research Education and Clinical Center of the South Texas Veterans Health Care System, and grants from the Biomedical Laboratory Research & Development Service of the Veteran's Affairs Office of Research and Development by [VA Merit Review Grants 1I01BX001023 (Y.I.) and 1I01BX000547 (A.R.)], the American Federation for Aging Research (Y.I.) and the Glenn Foundation (Y.I.). NR 23 TC 15 Z9 16 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 16 PY 2013 VL 438 IS 1 BP 78 EP 83 DI 10.1016/j.bbrc.2013.07.029 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 205TG UT WOS:000323467100014 PM 23872067 ER PT J AU Wei, R Bhattacharya, A Hamilton, RT Jernigan, AL Chaudhuri, AR AF Wei, Rochelle Bhattacharya, Arunabh Hamilton, Ryan T. Jernigan, Amanda L. Chaudhuri, Asish R. TI Differential effects of mutant SOD1 on protein structure of skeletal muscle and spinal cord of familial amyotrophic lateral sclerosis: Role of chaperone network SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Heat shock proteins; Familial ALS; BisANS; Protein conformation; Mutant SOD1; Surface hydrophobicity ID DELAYS DISEASE PROGRESSION; MOTOR-NEURON DEGENERATION; HEAT-SHOCK PROTEINS; MOUSE MODEL; RESTRICTED EXPRESSION; EXTENDING SURVIVAL; MOTONEURON DISEASE; CELL-DEATH; ALS; MICE AB Protein misfolding is considered to be a potential contributing factor for motor neuron and muscle loss in diseases like Amyotrophic lateral sclerosis (ALS). Several independent studies have demonstrated using over-expressed mutated Cu/Zn-superoxide dismutase (mSOD1) transgenic mouse models which mimic familial ALS (f-ALS), that both muscle and motor neurons undergo degeneration during disease progression. However, it is unknown whether protein conformation of skeletal muscle and spinal cord is equally or differentially affected by mSOD1-induced toxicity. It is also unclear whether heat shock proteins (Hsp's) differentially modulate skeletal muscle and spinal cord protein structure during ALS disease progression. We report three intriguing observations utilizing the f-ALS mouse model and cell-free in vitro system; (i) muscle proteins are equally sensitive to misfolding as spinal cord proteins despite the presence of low level of soluble and absence of insoluble G93A protein aggregate, unlike in spinal cord, (ii) Hsp's levels are lower in muscle compared to spinal cord at any stage of the disease, and (iii) G93ASOD1 enzyme-induced toxicity selectively affects muscle protein conformation over spinal cord proteins. Together, these findings strongly suggest that differential chaperone levels between skeletal muscle and spinal cord may be a critical determinant for G93A-induced protein misfolding in ALS. Published by Elsevier Inc. C1 [Wei, Rochelle; Bhattacharya, Arunabh; Hamilton, Ryan T.; Jernigan, Amanda L.; Chaudhuri, Asish R.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. [Chaudhuri, Asish R.] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem, San Antonio, TX 78229 USA. [Bhattacharya, Arunabh] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Chaudhuri, Asish R.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Chaudhuri, AR (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, Texas Res Pk Campus,15355 Lambda Dr, San Antonio, TX 78245 USA. EM chaudhuria@uthscsa.edu FU VA-Merit Grant FX This work was supported by VA-Merit Grant (to A.R.C.). We like to thank Dr. Holly Van Remmen for providing wild-type and G93A mouse tissues and to Dr. John Hart for providing purified recombinant G93ASOD1 enzyme. NR 27 TC 3 Z9 3 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 16 PY 2013 VL 438 IS 1 BP 218 EP 223 DI 10.1016/j.bbrc.2013.07.060 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 205TG UT WOS:000323467100037 PM 23886956 ER PT J AU Kim, S Beyer, BA Lewis, C Nadel, JA AF Kim, Suil Beyer, Brittney A. Lewis, Courtney Nadel, Jay A. TI Normal CFTR Inhibits Epidermal Growth Factor Receptor-Dependent Pro-Inflammatory Chemokine Production in Human Airway Epithelial Cells SO PLOS ONE LA English DT Article ID NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; TRANSMEMBRANE CONDUCTANCE REGULATOR; PSEUDOMONAS-AERUGINOSA INFECTION; CYSTIC-FIBROSIS AIRWAYS; INTERLEUKIN-8 PRODUCTION; TNF-ALPHA; CYTOKINE SECRETION; SIGNALING CASCADE; IL-8 EXPRESSION AB Mutations in cystic fibrosis transmembrane conductance regulator (CFTR) protein cause cystic fibrosis, a disease characterized by exaggerated airway epithelial production of the neutrophil chemokine interleukin (IL)-8, which results in exuberant neutrophilic inflammation. Because activation of an epidermal growth factor receptor (EGFR) signaling cascade induces airway epithelial IL-8 production, we hypothesized that normal CFTR suppresses EGFR-dependent IL-8 production and that loss of CFTR at the surface exaggerates IL-8 production via activation of a pro-inflammatory EGFR cascade. We examined this hypothesis in human airway epithelial (NCI-H292) cells and in normal human bronchial epithelial (NHBE) cells containing normal CFTR treated with a CFTR-selective inhibitor (CFTR-172), and in human airway epithelial (IB3) cells containing mutant CFTR versus isogenic (C38) cells containing wild-type CFTR. In NCI-H292 cells, CFTR-172 induced IL-8 production EGFR-dependently. Pretreatment with an EGFR neutralizing antibody or the metalloprotease TACE inhibitor TAPI-1, or TACE siRNA knockdown prevented CFTR-172-induced EGFR phosphorylation (EGFR-P) and IL-8 production, implicating TACE-dependent EGFR pro-ligand cleavage in these responses. Pretreatment with neutralizing antibodies to I-L1R or to IL-1alpha, but not to IL-1beta, markedly suppressed CFTR-172-induced EGFR-P and IL-8 production, suggesting that binding of IL-1alpha to IL-1R stimulates a TACE-EGFR-IL-8 cascade. Similarly, in NHBE cells, CFTR-172 increased IL-8 production EGFR-, TACE-, and IL-1alpha/IL-1R-dependently. In IB3 cells, constitutive IL-8 production was markedly increased compared to C38 cells. EGFR-P was increased in IB3 cells compared to C38 cells, and exaggerated IL-8 production in the IB3 cells was EGFR-dependent. Activation of TACE and binding of IL-1alpha to IL-1R contributed to EGFR-P and IL-8 production in IB3 cells but not in C38 cells. Thus, we conclude that normal CFTR suppresses airway epithelial IL-8 production that occurs via a stimulatory EGFR cascade, and that loss of normal CFTR activity exaggerates IL-8 production via activation of a pro-inflammatory EGFR cascade. C1 [Kim, Suil; Beyer, Brittney A.] Oregon Hlth & Sci Univ, Dept Med, Portland Vet Affairs Med Ctr, Div Pulm & Crit Care Med, Portland, OR 97201 USA. [Kim, Suil] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA. [Lewis, Courtney; Nadel, Jay A.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Lewis, Courtney; Nadel, Jay A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Nadel, Jay A.] Univ Calif San Francisco, Dept Physiol, San Francisco, CA USA. RP Kim, S (reprint author), Oregon Hlth & Sci Univ, Dept Med, Portland Vet Affairs Med Ctr, Div Pulm & Crit Care Med, Portland, OR 97201 USA. EM kimsui@ohsu.edu FU Cystic Fibrosis Foundation Pilot Research Award; Portland VA Research Foundation; Cardiovascular Research Institute FX This work was supported by a Cystic Fibrosis Foundation Pilot Research Award (www.cff.org) and Portland VA Research Foundation (www.pvarf.org) grant to SK, and by Cardiovascular Research Institute funding to JN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 12 Z9 12 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 16 PY 2013 VL 8 IS 8 AR e72981 DI 10.1371/journal.pone.0072981 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207BA UT WOS:000323570200094 PM 23977375 ER PT J AU Zhang, ZR Chu, WF Song, BL Gooz, M Zhang, JN Yu, CJ Jiang, S Baldys, A Gooz, P Steele, S Owsianik, G Nilius, B Komlosi, P Bell, PD AF Zhang, Zhi-Ren Chu, Wen-Feng Song, Binlin Gooz, Monika Zhang, Jia-Ning Yu, Chang-Jiang Jiang, Shuai Baldys, Aleksander Gooz, Pal Steele, Stacy Owsianik, Grzegorz Nilius, Bernd Komlosi, Peter Bell, P. Darwin TI TRPP2 and TRPV4 Form an EGF-Activated Calcium Permeable Channel at the Apical Membrane of Renal Collecting Duct Cells SO PLOS ONE LA English DT Article ID POLYCYSTIC KIDNEY-DISEASE; NONSELECTIVE CATION CHANNEL; GROWTH-FACTOR RECEPTOR; PORE PROPERTIES; MUTANT MICE; PROTEIN; PKD2; INHIBITION; PERMEATION; RESTORES AB Objective: Regulation of apical calcium entry is important for the function of principal cells of the collecting duct. However, the molecular identity and the regulators of the transporter/channel, which is responsible for apical calcium entry and what factors regulate the calcium conduction remain unclear. Methods and Results: We report that endogenous TRPP2 and TRPV4 assemble to form a 23-pS divalent cation-permeable non-selective ion channel at the apical membrane of renal principal cells of the collecting duct. TRPP2\TRPV4 channel complex was identified by patch-clamp, immunofluorescence and co-immunprecipitation studies in both principal cells that either possess normal cilia (cilia (+)) or in which cilia are absent (cilia (-)). This channel has distinct biophysical and pharmacological and regulatory profiles compared to either TRPP2 or TRPV4 channels. The rate of occurrence detected by patch clamp was higher in cilia (-) compared to cilia (+) cells. In addition, shRNA knockdown of TRPP2 increased the prevalence of TRPV4 channel activity while knockdown of TRPV4 resulted in TRPP2 activity and knockdown of both proteins vastly decreased the 23-pS channel activity. Epidermal growth factor (EGF) stimulated TRPP2\TRPV4 channel through the EGF receptor (EGFR) tyrosine kinase-dependent signaling. With loss of cilia, apical EGF treatment resulted in 64-fold increase in channel activity in cilia (-) but not cilia (+) cells. In addition EGF increased cell proliferation in cilia (-) cell that was dependent upon TRPP2\TRPV4 channel mediated increase in intracellular calcium. Conclusion: We conclude that in the absence of cilia, an EGF activated TRPP2\TRPV4 channel may play an important role in increased cell proliferation and cystogenesis. C1 [Bell, P. Darwin] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Zhang, Zhi-Ren; Chu, Wen-Feng; Song, Binlin; Gooz, Monika; Baldys, Aleksander; Gooz, Pal; Steele, Stacy; Komlosi, Peter; Bell, P. Darwin] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Zhang, Zhi-Ren; Chu, Wen-Feng; Song, Binlin; Zhang, Jia-Ning; Yu, Chang-Jiang; Jiang, Shuai] Harbin Med Univ, Educ Minist Myocardial Ischemia & Treatment, Affiliated Hosp 2, Dept Pharm,Key Labs,Dept Pharmacol, Harbin, Peoples R China. [Zhang, Zhi-Ren; Chu, Wen-Feng; Song, Binlin; Zhang, Jia-Ning; Yu, Chang-Jiang; Jiang, Shuai] Harbin Med Univ, Educ Minist Myocardial Ischemia & Treatment, Affiliated Hosp 2, Dept Cardiol,Key Labs,Dept Pharmacol, Harbin, Peoples R China. [Owsianik, Grzegorz; Nilius, Bernd] Katholieke Univ Leuven, Dept Cellular & Mol Med, Lab Ion Channel Res, Louvain, Belgium. RP Zhang, ZR (reprint author), Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. EM zhirenz@yahoo.com; Bellpd@musc.edu OI Komlosi, Peter/0000-0002-5284-8877 FU Key Project of Chinese National Program for Fundamental Research and Development (973 Program) [2012CB517803]; National Natural Science Foundation, China [81070217, 30871007]; Key Project National Science Foundation of Heilongjiang, China [ZD200807-01]; Heilongjiang Educational Committee, China [1154HZ11]; Veterans Affairs Merit Grant; National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD) [DK074038]; NIH/NIDDK [RO1 DK32032]; Dialysis Clinic, Inc. (DCI) [C-2618A] FX This work was supported by Key Project of Chinese National Program for Fundamental Research and Development (973 Program, 2012CB517803) National Natural Science Foundation, China (# 81070217 & # 30871007), Key Project National Science Foundation of Heilongjiang, China (# ZD200807-01) and Grant from Heilongjiang Educational Committee, China (# 1154HZ11) to ZRZ and by Veterans Affairs Merit Grant, National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD) DK074038, NIH/NIDDK RO1 DK32032 and a Grant from the Dialysis Clinic, Inc. (DCI) # C-2618A to PDB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 18 Z9 18 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 16 PY 2013 VL 8 IS 8 AR UNSP e73424 DI 10.1371/journal.pone.0073424 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 207BA UT WOS:000323570200095 PM 23977387 ER PT J AU Souda, S Gaseitsiwe, S Georgette, N Powis, K Moremedi, D Iketleng, T Leidner, J Moffat, C Ogwu, A Lockman, S Moyo, S Mmalane, M Musonda, R Makhema, J Essex, M Shapiro, R AF Souda, Sajini Gaseitsiwe, Simani Georgette, Nathan Powis, Kathleen Moremedi, Daisy Iketleng, Thato Leidner, Jean Moffat, Claire Ogwu, Anthony Lockman, Shahin Moyo, Sikhulile Mmalane, Mompati Musonda, Rosemary Makhema, Joseph Essex, Max Shapiro, Roger TI No Clinically Significant Drug-Resistance Mutations in HIV-1 Subtype C-Infected Women After Discontinuation of NRTI-Based or PI-Based HAART for PMTCT in Botswana SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE mother-to-child HIV transmission; highly active anti-retroviral therapy; minor drug-resistance mutations; Botswana ID MOTHER-TO-CHILD; COMBINATION ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; REVERSE-TRANSCRIPTASE; TREATMENT INTERRUPTIONS; INITIAL TREATMENT; DOSE NEVIRAPINE; TREATMENT-NAIVE; DOUBLE-BLIND; LAMIVUDINE AB Risk of developing drug resistance after stopping antiretroviral regimens to prevent mother-to-child HIV-1 transmission is unknown. The Mma Bana Study randomized treatment-naive pregnant women with CD4 >= 200 cells per cubic millimeter to receive either abacavir/zidovudine/lamivudine [triple nucleoside reverse transcriptase inhibitor (NRTI) arm] or lopinavir/ritonavir/zidovudine/lamivudine [protease inhibitor (PI) arm]. Drugs were discontinued after 6 months of breastfeeding. One month after discontinuation, 29 NRTI arm samples and 25 PI arm samples were successfully genotyped. No clinically significant antiretroviral resistance mutations were detected. Eight minor resistance mutations were found among 11 (20%) women (3 from NRTI arm and 8 from PI arm), occurring at similar frequencies to those reported in HIV-1 subtype C treatment-naive cohorts. C1 [Souda, Sajini; Gaseitsiwe, Simani; Powis, Kathleen; Moremedi, Daisy; Iketleng, Thato; Moffat, Claire; Ogwu, Anthony; Lockman, Shahin; Moyo, Sikhulile; Mmalane, Mompati; Musonda, Rosemary; Makhema, Joseph; Essex, Max; Shapiro, Roger] Botswana Harvard AIDS Inst Partnership HIV Res &, Gaborone, Botswana. [Souda, Sajini] Univ Botswana, Sch Med, Dept Pathol, Gaborone, Botswana. [Georgette, Nathan] Harvard Univ, Cambridge, MA 02138 USA. [Powis, Kathleen] Massachusetts Gen Hosp, Dept Med & Pediat, Boston, MA 02114 USA. [Powis, Kathleen; Leidner, Jean; Lockman, Shahin; Essex, Max; Shapiro, Roger] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Lockman, Shahin] Brigham & Womens Hosp, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Shapiro, Roger] Beth Israel Deaconess Med Ctr, Div Infect Dis, Boston, MA 02215 USA. RP Souda, S (reprint author), Univ Botswana, Dept Pathol, Sch Med, Fac Hlth Sci, Private Bag UB 00712, Gaborone, Botswana. EM sajini.souda@gmail.com OI Moyo, Sikhulile/0000-0003-3821-4592 FU National Institute of Allergy and Infectious Diseases [U01AI066454]; National Institutes of Health FX Supported by the National Institute of Allergy and Infectious Diseases (U01AI066454) and National Institutes of Health. NR 56 TC 2 Z9 2 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2013 VL 63 IS 5 BP 572 EP 577 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FN UT WOS:000330449900015 PM 23542639 ER PT J AU Hyle, EP Wood, BR Backman, ES Noubary, F Hwang, J Lu, ZG Losina, E Walensky, RP Gandhi, RT AF Hyle, Emily P. Wood, Brian R. Backman, Elke S. Noubary, Farzad Hwang, Janice Lu, Zhigang Losina, Elena Walensky, Rochelle P. Gandhi, Rajesh T. TI High Frequency of Hypothalamic-Pituitary-Adrenal Axis Dysfunction After Local Corticosteroid Injection in HIV-Infected Patients on Protease Inhibitor Therapy SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; adrenal insufficiency; Cushing syndrome; corticosteroid; protease inhibitor; CYP34A ID IATROGENIC CUSHINGS-SYNDROME; EPIDURAL TRIAMCINOLONE; RITONAVIR; INDIVIDUALS; EVENTS; COHORT; DRUGS; RISK AB Background: The frequency of hypothalamic-pituitary-adrenal axis dysfunction among HIV-infected patients receiving steroid injections has not been reported, and the risk factors for this adverse event are poorly characterized. Methods: We conducted a retrospective analysis of data from HIV-infected patients in the Partners HealthCare system (Boston, MA) who received corticosteroid injection(s) between 2002 and 2011. Chart review focused on HIV status, antiretroviral therapy [eg, protease inhibitors (PI)], steroid injection(s), and adrenal axis dysfunction (eg, adrenal insufficiency and/or Cushing syndrome). Because all cases occurred among patients on PIs, we performed additional detailed data extraction and conducted univariate and multivariate analyses to identify risk factors in this group. Results: One hundred seventy-one HIV-infected patients received >= 1 corticosteroid injection(s) in the study period. Nine cases (event frequency: 5.3%; 95% confidence interval: 2.4% to 9.8%) of secondary adrenal insufficiency were diagnosed; 5 (55%) of these 9 patients also had clinical evidence of Cushing syndrome. All cases occurred among the 81 patients on PIs (event frequency among those on PIs: 11.1%; 95% confidence interval: 5.2% to 20.0%). Among patients on PIs, the major risk factor for hypothalamic-pituitary-adrenal axis dysfunction was having >2 injections within 6 months. Conclusions: In this retrospective cohort study, 11% of HIV-infected patients on PIs at the time of steroid injection were later diagnosed with hypothalamic-pituitary-adrenal axis dysfunction. Corticosteroid injections in HIV-infected patients on PIs should only be used with great caution and close monitoring. C1 [Hyle, Emily P.; Noubary, Farzad; Lu, Zhigang; Losina, Elena; Walensky, Rochelle P.] Massachusetts Gen Hosp, Med Practice Evaluat Ctr, Boston, MA 02114 USA. [Hyle, Emily P.; Walensky, Rochelle P.; Gandhi, Rajesh T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Wood, Brian R.] Univ Washington, Div Allergy & Infect Dis, Seattle, WA 98195 USA. [Wood, Brian R.; Walensky, Rochelle P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Backman, Elke S.] Massachusetts Gen Hosp, Dept Pharm, Boston, MA 02114 USA. [Noubary, Farzad] Tufts Univ, Clin & Translat Sci Inst, Res Design Ctr, Biostat Res Ctr, Boston, MA 02111 USA. [Hwang, Janice] Yale Univ, Sch Med, Div Endocrinol, New Haven, CT USA. [Hwang, Janice] Massachusetts Gen Hosp, Div Endocrinol, Boston, MA 02114 USA. [Lu, Zhigang] Brigham & Womens Hosp, Dept Newborn Med, Boston, MA 02115 USA. [Losina, Elena; Walensky, Rochelle P.] Harvard Univ, Ctr AIDS Res, Boston, MA 02115 USA. [Losina, Elena] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Ragon Inst, MIT, Charlestown, MA USA. RP Hyle, EP (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM ehyle@partners.org FU National Institute of Allergy and Infectious Disease [T32 AI 007433]; National Institutes of Health (NIH) [R01 AI066992-04A1]; NIH [G08LM008830-01, P30 AI060354]; Harvard University Center for AIDS Research [NIH 2P30 AI060354-06]; NIAID; NCI; NICHD; NHLBI; NIDA; NIMH; NIA; FIC; OAR; [NIH U01 AI 694722] FX E. P. H. is supported by National Institute of Allergy and Infectious Disease [T32 AI 007433]. R. T. G. is supported by National Institutes of Health (NIH) [R01 AI066992-04A1] and NIH G08LM008830-01 and by grants to the AIDS Clinical Trials Group (NIH U01 AI 694722) and the Harvard University Center for AIDS Research (NIH 2P30 AI060354-06). This publication was made possible with help from the Harvard University Center for AIDS Research (CFAR), an NIH-funded program (P30 AI060354), which is supported by the following NIH co-funding and participating institutes and centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR. NR 18 TC 3 Z9 4 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2013 VL 63 IS 5 BP 602 EP 608 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FN UT WOS:000330449900019 PM 23714741 ER PT J AU Chiao, EY Hartman, CM El-Serag, HB Giordano, TP AF Chiao, Elizabeth Y. Hartman, Christine M. El-Serag, Hashem B. Giordano, Thomas P. TI The Impact of HIV Viral Control on the Incidence of HIV-Associated Anal Cancer SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE anal cancer; HIV; epidemiology; combined antiretroviral therapy ID SQUAMOUS INTRAEPITHELIAL LESIONS; ANTIRETROVIRAL THERAPY; HUMAN IMMUNODEFICIENCY; UNITED-STATES; POSITIVE MEN; INFECTION; HAART; EPIDEMIOLOGY; PROGRESSION; NEOPLASIA AB Background: Recent studies have shown that the incidence of squamous cell cancer of the anus (SCCA) has increased in the combined antiretroviral therapy (cART) era. The effect of undetectable HIV viral loads as a result of successful cART has not been evaluated. Methods: We performed a retrospective cohort study among male US veterans diagnosed with HIV and followed between 1985 and 2009 using the Veterans Affairs Immunologic Case Registry (VA-ICR). We calculated age-adjusted incidence rates and rate ratios for SCCA. We conducted Cox proportional hazards ratios of SCCA in a multivariable model including time-varying covariates of nadir CD4 count and overall percentage of time with an undetectable HIV viral load. Results: The age-adjusted SCCA incidence rate among the group who ever received cART was 146.8/100,000 person-years (95% confidence interval, 124.1 to 172.6) and was not significantly higher than the SCCA rate of those who never received cART (134.3/100,000 person-years; 95% confidence interval, 112.5 to 159.0). In a multivariable model limited to veterans who had ever received cART (adjusted for demographic variables, nadir, and most recent CD4 counts) individuals who had 61%-80% or 81%-100% of follow-up time with undetectable HIV viral loads had significantly decreased SCCA risk compared with those who had undetectable HIV viral loads <20% of the time (odds ratio, 0.56; P = 0.040 and odds ratio, 0.55; P = 0.0004, respectively). Conclusions: HIV control as measured by the percent of time with undetectable HIV viral load seems to decrease the risk of SCCA. Optimizing cART adherence and HIV viral load control may decrease the risk of subsequent SCCA. C1 [Chiao, Elizabeth Y.; Hartman, Christine M.; El-Serag, Hashem B.; Giordano, Thomas P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Chiao, Elizabeth Y.; Hartman, Christine M.; El-Serag, Hashem B.; Giordano, Thomas P.] Michael E DeBakey VA Med Ctr, Houston Hlth Serv Res & Dev Ctr Excellence, Houston, TX USA. [Chiao, Elizabeth Y.; Hartman, Christine M.; El-Serag, Hashem B.; Giordano, Thomas P.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. RP Chiao, EY (reprint author), Michael E DeBakey Vet Affairs Med Ctr 152, Houston Hlth Serv Res & Dev Ctr Excellence, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM echiao@bcm.edu FU Houston Health Services Research and Development Center of Excellence [FP90-020]; Michael E. DeBakey Veterans Affairs Medical Center; Baylor College of Medicine; National Cancer Institute [K23CA124318, R01CA163103, K24DK078154, P30DK58338] FX Supported with resources and the use of facilities at the Houston Health Services Research and Development Center of Excellence (FP90-020), Michael E. DeBakey Veterans Affairs Medical Center, and by a seed fund grant from the Baylor College of Medicine. E.Y.C. (K23CA124318 and R01CA163103) and H.B.E.-S. (K24DK078154 and P30DK58338) received support from the National Cancer Institute. NR 26 TC 17 Z9 17 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 EI 1077-9450 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2013 VL 63 IS 5 BP 631 EP 638 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 300FN UT WOS:000330449900023 PM 23614995 ER PT J AU Sanna-Cherchi, S Sampogna, RV Papeta, N Burgess, KE Nees, SN Perry, BJ Choi, M Bodria, M Liu, Y Weng, PL Lozanovski, VJ Verbitsky, M Lugani, F Sterken, R Paragas, N Caridi, G Carrea, A Dagnino, M Materna-Kiryluk, A Santamaria, G Murtas, C Ristoska-Bojkovska, N Izzi, C Kacak, N Bianco, B Giberti, S Gigante, M Piaggio, G Gesualdo, L Vukic, DK Vukojevic, K Saraga-Babic, M Saraga, M Gucev, Z Allegri, L Latos-Bielenska, A Casu, D State, M Scolari, F Ravazzolo, R Kiryluk, K Al-Awqati, Q D'Agati, VD Drummond, IA Tasic, V Lifton, RP Ghiggeri, GM Gharavi, AG AF Sanna-Cherchi, S. Sampogna, R. V. Papeta, N. Burgess, K. E. Nees, S. N. Perry, B. J. Choi, M. Bodria, M. Liu, Y. Weng, P. L. Lozanovski, V. J. Verbitsky, M. Lugani, F. Sterken, R. Paragas, N. Caridi, G. Carrea, A. Dagnino, M. Materna-Kiryluk, A. Santamaria, G. Murtas, C. Ristoska-Bojkovska, N. Izzi, C. Kacak, N. Bianco, B. Giberti, S. Gigante, M. Piaggio, G. Gesualdo, L. Vukic, D. Kosuljandic Vukojevic, K. Saraga-Babic, M. Saraga, M. Gucev, Z. Allegri, L. Latos-Bielenska, A. Casu, D. State, M. Scolari, F. Ravazzolo, R. Kiryluk, K. Al-Awqati, Q. D'Agati, V. D. Drummond, I. A. Tasic, V. Lifton, R. P. Ghiggeri, G. M. Gharavi, A. G. TI Mutations in DSTYK and Dominant Urinary Tract Malformations SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONGENITAL-ANOMALIES; RENAL HYPODYSPLASIA; ZEBRAFISH; KIDNEY; FGF; ABNORMALITIES; EMBRYOGENESIS; CHILDREN; GENES AB BackgroundCongenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. MethodsWe performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. ResultsLinkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases. ConclusionsWe detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.) Exome sequencing in a family with autosomal dominant congenital urinary tract malformations showed a mutation in dual serine-threonine and tyrosine protein kinase (DSTYK), confirmed in other, unrelated patients, identifying a major determinant of human urinary tract development. Congenital malformations of the kidney and urinary tract contribute to 23% of birth defects(1),(2) and account for 40 to 50% of pediatric cases and 7% of adult cases of end-stage renal disease (ESRD) worldwide.(3),(4) These disorders are genetically heterogeneous and encompass a wide range of anatomical defects, such as renal agenesis, renal hypodysplasia, ureteropelvic junction obstruction, or vesicoureteral reflux.(5) Mutations in genes that cause syndromic disorders, such as HNF1B and PAX2 mutations, are detected in only 5 to 10% of cases.(6),(7) Familial forms of nonsyndromic disease have been reported, further supporting genetic determination(8),(9); however, owing ... C1 [Sanna-Cherchi, S.; Sampogna, R. V.; Papeta, N.; Burgess, K. E.; Nees, S. N.; Perry, B. J.; Weng, P. L.; Verbitsky, M.; Lugani, F.; Sterken, R.; Paragas, N.; Kacak, N.; Kiryluk, K.; Al-Awqati, Q.; Gharavi, A. G.] Columbia Univ, Div Nephrol, New York, NY USA. [Weng, P. L.] Columbia Univ, Div Pediat Nephrol, New York, NY USA. [D'Agati, V. D.] Columbia Univ, Dept Pathol, New York, NY USA. [Sanna-Cherchi, S.] St Lukes Roosevelt Hosp, Dept Med, New York, NY USA. [Choi, M.; Saraga, M.; Lifton, R. P.] Yale Univ, Dept Genet, Howard & Hughes Med Inst, New Haven, CT USA. [Choi, M.; Saraga, M.; Lifton, R. P.] Yale Univ, Yale Ctr Mendelian Genom, New Haven, CT USA. [Choi, M.] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea. [Bodria, M.; Lugani, F.; Caridi, G.; Carrea, A.; Dagnino, M.; Murtas, C.; Piaggio, G.; Ghiggeri, G. M.] Univ Genoa, Div Nephrol Dialysis & Transplantat, Ist Giannina Gaslini, I-16126 Genoa, Italy. [Santamaria, G.; Ravazzolo, R.] Univ Genoa, Mol Genet Lab, Ist Giannina Gaslini, I-16126 Genoa, Italy. [Bodria, M.] Univ Genoa, Div Nephrol, Dept Internal Med, I-16126 Genoa, Italy. [Ravazzolo, R.] Univ Genoa, Dipartimento Neurosci Riabilitaz Oftalmol Genet &, I-16126 Genoa, Italy. [Bodria, M.] IRCCS San Martino IST, Genoa, Italy. [Izzi, C.; Scolari, F.] Univ Brescia, Cattedra Nefrol, Div Nefrol 2, Azienda Osped Spedali Civili Brescia Presidio Mon, Brescia, Italy. [Bianco, B.; Giberti, S.; Allegri, L.] Univ Parma, Dept Clin Med Nephrol & Hlth Sci, Nephrol Unit, I-43100 Parma, Italy. [Gigante, M.] Univ Foggia, Dept Med & Surg Sci, Foggia, Italy. [Gesualdo, L.] Univ Bari, Dept Emergency & Organ Transplantat, Bari, Italy. [Casu, D.] Hosp Alghero, Div Nephrol & Dialysis, Alghero, Italy. [Liu, Y.; Drummond, I. A.] Massachusetts Gen Hosp, Div Nephrol, Charlestown, MA USA. [Drummond, I. A.] Harvard Univ, Sch Med, Dept Genet, Charlestown, MA USA. [Lozanovski, V. J.; Ristoska-Bojkovska, N.; Gucev, Z.; Tasic, V.] Univ Childrens Hosp, Med Sch Skopje, Skopje, Macedonia. [Materna-Kiryluk, A.; Latos-Bielenska, A.] Poznan Univ Med Sci, Dept Med Genet, Poznan, Poland. [Vukic, D. Kosuljandic; Saraga, M.] Univ Split, Univ Hosp Split, Dept Pediat, Split, Croatia. [Vukojevic, K.; Saraga-Babic, M.] Univ Split, Dept Anat Histol & Embryol, Split, Croatia. [State, M.] Univ Split, Sch Med, Split, Croatia. RP Gharavi, AG (reprint author), Columbia Univ Coll Phys & Surg, Div Nephrol, 1150 St Nicholas Ave,Russ Berrie Pavil 413, New York, NY 10032 USA. EM ag2239@columbia.edu RI Ghiggeri, Gian Marco/N-4712-2015; Lugani, Francesca/J-7183-2016; Caridi, Gianluca/F-7052-2010; bodria, monica/K-2115-2016; Gigante, Maddalena/R-4369-2016; Vukojevic, Katarina/D-5246-2017; Saraga-Babic, Mirna/D-6362-2017; Saraga, Marijan/E-7647-2017; Gesualdo, Loreto/K-7751-2016; OI Paragas, Neal/0000-0001-6084-8220; Gigante, Maddalena/0000-0001-8228-7639; Ghiggeri, Gian Marco/0000-0003-3659-9062; Lugani, Francesca/0000-0002-4189-8561; Caridi, Gianluca/0000-0001-6700-3001; bodria, monica/0000-0001-9690-9945; Vukojevic, Katarina/0000-0003-2182-2890; Gesualdo, Loreto/0000-0002-4861-0911; Al-Awqati, Qais/0000-0001-7141-1040 FU National Institutes of Health [1R01DK080099, DK071041]; Italian Telethon Foundation [GGP08050]; National Human Genome Research Institute Centers for Mendelian Genomics [HG006504]; National Institute of Diabetes and Digestive and Kidney Diseases [K23-DK090207]; American Heart Association Scientist Development Grant [0930151N]; American Heart Association Grant-in-Aid [13GRNT14680075]; American Society of Nephrology Carl W. Gottschalk Research Scholar Grant; Fondazione Malattie Renali nel Bambino; American Society of Nephrology; Doris Duke Charitable Foundation; Polish Ministry of Health FX Supported by grants from the National Institutes of Health (1R01DK080099, to Dr. Gharavi; DK071041, to Dr. Drummond), the Italian Telethon Foundation (GGP08050, to Dr. Ghiggeri), the National Human Genome Research Institute Centers for Mendelian Genomics (HG006504, to Dr. Lifton), and the National Institute of Diabetes and Digestive and Kidney Diseases (K23-DK090207, to Dr. Kiryluk); an American Heart Association Scientist Development Grant (0930151N), an American Heart Association Grant-in-Aid (13GRNT14680075), and an American Society of Nephrology Carl W. Gottschalk Research Scholar Grant (all to Dr. Sanna-Cherchi); and funding from the Fondazione Malattie Renali nel Bambino (to Dr. Ghiggeri), the American Society of Nephrology and the Doris Duke Charitable Foundation (to Dr. Nees), and the Polish Ministry of Health (to Drs. Materna-Kiryluk and Latos-Bielenska). NR 25 TC 32 Z9 34 U1 1 U2 10 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 AUG 15 PY 2013 VL 369 IS 7 BP 621 EP 629 DI 10.1056/NEJMoa1214479 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 243YO UT WOS:000326354500008 PM 23862974 ER PT J AU Olumi, AF Kaufman, DS Zietman, A Harisinghani, MG Wu, CL AF Olumi, Aria F. Kaufman, Donald S. Zietman, Anthony Harisinghani, Mukesh G. Wu, Chin-Lee TI Case 25-2013: A 71-Year-Old Man with Hematuria and a Mass in the Bladder SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PROSTATIC DUCT ADENOCARCINOMA; RADICAL PROSTATECTOMY; ENDOMETRIOID FEATURES; CARCINOMA; UTRICLE C1 [Olumi, Aria F.] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [Kaufman, Donald S.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Zietman, Anthony] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Harisinghani, Mukesh G.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Wu, Chin-Lee] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Olumi, Aria F.] Harvard Univ, Sch Med, Dept Urol, Boston, MA USA. [Kaufman, Donald S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Zietman, Anthony] Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA USA. [Harisinghani, Mukesh G.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Wu, Chin-Lee] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Olumi, AF (reprint author), Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. NR 12 TC 0 Z9 0 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 15 PY 2013 VL 369 IS 7 BP 660 EP 667 DI 10.1056/NEJMcpc1209278 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 243YO UT WOS:000326354500013 PM 23944304 ER PT J AU Biederman, J Wozniak, J Martelon, MK Spencer, TJ Woodworth, Y Joshi, G Spencer, A Uchida, M Kotte, A Faraone, SV AF Biederman, Joseph Wozniak, Janet Martelon, Mary Kate Spencer, Thomas J. Woodworth, Yvonne Joshi, Gagan Spencer, Andrea Uchida, Mai Kotte, Amelia Faraone, Stephen V. TI Can pediatric bipolar-I disorder be diagnosed in the context of posttraumatic stress disorder? A familial risk analysis SO PSYCHIATRY RESEARCH LA English DT Article DE Comorbidity; Clinical correlates; Family risk analysis ID DEFICIT HYPERACTIVITY DISORDER; MAJOR DEPRESSION; TRAUMA EXPOSURE; SEXUAL-ABUSE; CHILDREN; SYMPTOMS; EVENTS; YOUTH; GIRLS; ADHD AB Despite ongoing concerns that traumatized children with severe symptoms of emotional dysregulation may be inappropriately receiving a diagnosis of pediatric bipolar-I (BP-I) disorder, this issue has not been adequately examined in the literature. Because both pediatric BP-I disorder and posttraumatic stress disorder (PTSD) are familial disorders, if children with both BP-I and PTSD were to be truly affected with BP-I disorder, their relatives would be at high risk for BP-I disorder. To this end, we compared patterns of familial aggregation of BP-I disorder in BP-I children with and without PTSD with age and sex matched controls. Participants were 236 youths with BP-I disorder and 136 controls of both sexes along with their siblings. Participants completed a large battery of measures designed to assess psychiatric disorders, psychosocial, educational, and cognitive parameters. Familial risk analysis revealed that relatives of BP-I probands with and without PTSD had similar elevated rates of BP-I disorder that significantly differed from those of relatives of controls. Pediatric BP-I disorder is similarly highly familial in probands with and without PTSD indicating that their co-occurrence is not due to diagnostic error. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Biederman, Joseph; Wozniak, Janet; Martelon, Mary Kate; Spencer, Thomas J.; Woodworth, Yvonne; Joshi, Gagan; Spencer, Andrea; Uchida, Mai; Kotte, Amelia] Massachusetts Gen Hosp, Clin & Res Programs Pediat Psychopharmacol & Adul, Boston, MA 02114 USA. [Biederman, Joseph; Wozniak, Janet; Spencer, Thomas J.; Joshi, Gagan; Spencer, Andrea; Uchida, Mai] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY 13210 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY 13210 USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Yawkey Ctr Outpatient Care, Clin & Res Programs Pediat Psychopharmacol & Adul, YAW-6A-6900,32 Fruit St, Boston, MA 02114 USA. EM jbiederman@partners.org OI Kotte, Amelia/0000-0002-0198-7914; Faraone, Stephen/0000-0002-9217-3982 FU NIH [K08MH001503, R01MH066237, R01MH050657, R01HD036317]; Heinz C. Prechter Bipolar Research Fund; Susan G. Berk Endowed Fund; MGH Pediatric Psychopharmacology Council FX This work was supported by NIH Grants K08MH001503 and R01MH066237 to Dr Wozniak and R01MH050657 and R01HD036317 to Dr. Biederman. This work was also supported by a grant from the Heinz C. Prechter Bipolar Research Fund, the support of members of the MGH Pediatric Psychopharmacology Council, and the Susan G. Berk Endowed Fund for juvenile Bipolar Disorder. NR 30 TC 1 Z9 1 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 15 PY 2013 VL 208 IS 3 BP 215 EP 224 DI 10.1016/j.psychres.2013.05.011 PG 10 WC Psychiatry SC Psychiatry GA 202AU UT WOS:000323186700003 PM 23790757 ER PT J AU Sowden, GL Mastromauro, CA Seabrook, RC Celano, CM Rollman, BL Huffman, JC AF Sowden, Gillian L. Mastromauro, Carol A. Seabrook, Rita C. Celano, Christopher M. Rollman, Bruce L. Huffman, Jeff C. TI Baseline physical health-related quality of life and subsequent depression outcomes in cardiac patients SO PSYCHIATRY RESEARCH LA English DT Article DE Health-related quality of life; Collaborative care; Cardiovascular disease ID COLLABORATIVE CARE; MANAGEMENT PROGRAM; MORTALITY AB Among 137 depressed cardiac patients, lower baseline physical health-related quality of life (HRQoL) was independently associated with greater depression persistence at 6 months among patients randomized to collaborative care, but not usual care. Low physical HRQoL may impact collaborative care effectiveness and indicate a need for alternate depression treatment. (C) 2013 Elsevier Ireland Ltd. All rights reserved. C1 [Sowden, Gillian L.; Celano, Christopher M.; Huffman, Jeff C.] Harvard Univ, Sch Med, Boston, MA USA. [Mastromauro, Carol A.; Celano, Christopher M.; Huffman, Jeff C.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Seabrook, Rita C.] Univ Michigan, Dept Psychol, Ann Arbor, MI USA. [Rollman, Bruce L.] Univ Pittsburgh, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. [Sowden, Gillian L.] Cambridge Hlth Alliance, Dept Psychiat, Cambridge, MA USA. RP Huffman, JC (reprint author), Massachusetts Gen Hosp, Blake 11,55 Fruit St, Boston, MA 02114 USA. EM jhuffman@partners.org FU American Heart Association Scientist Development [0735530T] FX Funding source: American Heart Association Scientist Development Grant 0735530T (Huffman) NR 11 TC 1 Z9 1 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 15 PY 2013 VL 208 IS 3 BP 288 EP 290 DI 10.1016/j.psychres.2013.05.019 PG 3 WC Psychiatry SC Psychiatry GA 202AU UT WOS:000323186700013 PM 23747159 ER PT J AU Ding, YN Li, J Wu, Q Yang, P Luo, B Xie, ST Druey, KM Zajac, AJ Hsu, HC Mountz, JD AF Ding, Yanna Li, Jun Wu, Qi Yang, Pingar Luo, Bao Xie, Shutao Druey, Kirk M. Zajac, Allan J. Hsu, Hui-Chen Mountz, John D. TI IL-17RA Is Essential for Optimal Localization of Follicular Th Cells in the Germinal Center Light Zone To Promote Autoantibody-Producing B Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; HELPER-CELLS; BXD2 MICE; CENTER SELECTION; AUTOIMMUNITY; DIFFERENTIATION; RECEPTOR; IL-21; INTERLEUKIN-21; PATHWAY AB Germinal centers (GCs) provide a microenvironment that promotes and regulates the interactions of B cells with follicular Th (T-FH) cells. In this study, we show that there are significantly higher frequencies of CXCR5(+)ICOS(+) T-FH cells in autoimmune BXD2 mice, and these cells express both IL-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of T-FH cells in BXD2 mice. The total numbers of T-FH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra(-/-) mice, the majority of CXCR5(+) T-FH cells from BXD2-Il17ra(-/-) mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra(-/-), disrupted T-FH-B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling 16 (RGS16) to promote the ability of T-FH to form conjugates with B cells, which was abolished in T-FH cells from BXD2-Rgs16(-/-) mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on postdifferentiated IL-17RA(+) T-FH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that T-FH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development. C1 [Ding, Yanna; Li, Jun; Wu, Qi; Yang, Pingar; Luo, Bao; Xie, Shutao; Hsu, Hui-Chen; Mountz, John D.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Ding, Yanna] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Druey, Kirk M.] NIAID, NIH, Bethesda, MD 20892 USA. [Zajac, Allan J.] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA. [Mountz, John D.] Birmingham VA Med Ctr, Birmingham, AL 35294 USA. RP Hsu, HC (reprint author), Univ Alabama Birmingham, Dept Med, Room 311 Shelby Bldg,1825 Univ Blvd, Birmingham, AL 35294 USA. EM rheu078@uab.edu; jdmountz@uab.edu FU Veterans Affairs Merit Review Grant [1I01BX000600-01]; National Institutes of Health/National Institute of Allergy and Infectious Diseases [1AI 071110, ARRA 3RO1AI71110-02S1, 1RO1 AI083705, U01 AI082966, P30 AI027767]; American College of Rheumatology-Within-Our-Reach, the Rheumatology Research Foundation; Alliance for Lupus Research; Arthritis Foundation; Lupus Research Institute; National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] [P30 AR048311]; University of Alabama at Birmingham Analytic Imaging and Immunoreagents Core (NIAMS) [P30 AR048311] FX This work was supported by Veterans Affairs Merit Review Grant 1I01BX000600-01; the National Institutes of Health/National Institute of Allergy and Infectious Diseases Grants 1AI 071110, ARRA 3RO1AI71110-02S1, 1RO1 AI083705, and U01 AI082966; American College of Rheumatology-Within-Our-Reach, the Rheumatology Research Foundation; the Alliance for Lupus Research; the Arthritis Foundation; the Lupus Research Institute; and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Flow cytometry and confocal imaging data acquisition were carried out at the University of Alabama at Birmingham Comprehensive Flow Cytometry Core (supported by National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] Grant P30 AR048311 and National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant P30 AI027767) and University of Alabama at Birmingham Analytic Imaging and Immunoreagents Core (NIAMS Grant P30 AR048311), respectively. NR 49 TC 24 Z9 25 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2013 VL 191 IS 4 BP 1614 EP 1624 DI 10.4049/jimmunol.1300479 PG 11 WC Immunology SC Immunology GA 194KT UT WOS:000322632900012 PM 23858031 ER PT J AU AlShwaimi, E Berggreen, E Furusho, H Rossall, JC Dobeck, J Yoganathan, S Stashenko, P Sasaki, H AF AlShwaimi, Emad Berggreen, Ellen Furusho, Hisako Rossall, Jonathan Caleb Dobeck, Justine Yoganathan, Subbiah Stashenko, Philip Sasaki, Hajime TI IL-17 Receptor A Signaling Is Protective in Infection-Stimulated Periapical Bone Destruction SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MACROPHAGE INFLAMMATORY PROTEIN-2; INTERLEUKIN-17 FAMILY-MEMBERS; RESORPTION IN-VIVO; RHEUMATOID-ARTHRITIS; PERIODONTAL-DISEASE; LESIONS; RAT; EXPRESSION; CYTOKINES; CELLS AB IL-17 is a pleiotropic cytokine produced by Th17 T cells that induces a myriad of proinflammatory mediators. However, different models of inflammation report opposite functional roles of IL-17 signal in terms of its effects on bone destruction. In this study we determined the role of IL-17RA signal in bone resorption stimulated by dentoalveolar infections. Infrabony resorptive lesions were induced by surgical pulp exposure and microbial infection of mouse molar teeth. IL-17 was strongly induced in periapical tissues in wild-type (WT) mice by 7 d after the infection but was not expressed in uninfected mice. Dentoalveolar infections of IL-17RA knockout (KO) mice demonstrated significantly increased bone destruction and more abscess formation in the apical area compared with WT mice. Infected IL-17RA KO mice exhibited significantly increased neutrophils and macrophages compared with the WT littermates at day 21, suggesting a failure of transition from acute to chronic inflammation in the IL-17RA KO mice. The expression of IL-1 (both alpha and beta isoforms) and MIP2 were significantly upregulated in the IL-17RA KO compared with WT mice at day 21 postinfection. The development of periapical lesions in IL-17RA KO mice was significantly attenuated by neutralization of IL-1 beta and MIP2. Taken together, these results demonstrate that IL-17RA signal seems to be protective against infection-induced periapical inflammation and bone destruction via suppression of neutrophil and mononuclear inflammation. C1 [AlShwaimi, Emad] Univ Dammam, Coll Dent, Dept Restorat Dent Sci, Dammam 1982, Saudi Arabia. [AlShwaimi, Emad; Rossall, Jonathan Caleb] Harvard Univ, Sch Dent Med, Dept Restorat Dent & Biomat Sci, Boston, MA 02115 USA. [Berggreen, Ellen] Univ Bergen, Dept Biomed, N-5020 Bergen, Norway. [Furusho, Hisako] Hiroshima Univ, Grad Sch Biomed Sci, Dept Oral & Maxillofacial Pathobiol, Hiroshima 7348553, Japan. [Furusho, Hisako; Rossall, Jonathan Caleb; Stashenko, Philip; Sasaki, Hajime] Forsyth Inst, Dept Immunol & Infect Dis, Cambridge, MA 02142 USA. [Dobeck, Justine] Forsyth Inst, Dept Biomineralizat, Cambridge, MA 02142 USA. [Yoganathan, Subbiah] Forsyth Inst, Anim Facil, Cambridge, MA 02142 USA. [Stashenko, Philip; Sasaki, Hajime] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. RP Sasaki, H (reprint author), Forsyth Inst, Dept Immunol & Infect Dis, 245 1st St, Cambridge, MA 02142 USA. EM hsasaki@forsyth.org FU Krakow Endodontic Research Fund; Norwegian Research Council; Japan Society for the Promotion of Science; National Institute of Dental and Craniofacial Research/National Institutes of Health [DE-09018]; National Center for Research Resources/National Institutes of Health [RR027553] FX This work was supported by grants from the Krakow Endodontic Research Fund (E. A., J.C.R.), the Norwegian Research Council (Leiv Eriksson Grant), the Japan Society for the Promotion of Science Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation (to H. F.), as well as by National Institute of Dental and Craniofacial Research/National Institutes of Health Grant DE-09018 (to P. S.) and National Center for Research Resources/National Institutes of Health Grant RR027553 (to H.S.). NR 38 TC 10 Z9 13 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2013 VL 191 IS 4 BP 1785 EP 1791 DI 10.4049/jimmunol.1202194 PG 7 WC Immunology SC Immunology GA 194KT UT WOS:000322632900029 PM 23863904 ER PT J AU Kant, CD Akiyama, Y Tanaka, K Shea, S Connolly, SE Germana, S Winn, HJ LeGuern, C Tocco, G Benichou, G AF Kant, Cavit D. Akiyama, Yoshinobu Tanaka, Katsunori Shea, Susan Connolly, Sarah E. Germana, Sharon Winn, Henry J. LeGuern, Christian Tocco, Georges Benichou, Gilles TI Primary Vascularization of Allografts Governs Their Immunogenicity and Susceptibility to Tolerogenesis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; MHC CLASS-II; DONOR-SPECIFIC TRANSFUSION; SKIN-GRAFT REJECTION; INDIRECT RECOGNITION; IN-VIVO; INTRAVENOUS-INJECTION; CARDIAC ALLOGRAFTS; LANGERHANS CELLS; SOLUBLE-ANTIGEN AB We investigated the influence of allograft primary vascularization on alloimmunity, rejection, and tolerance in mice. First, we showed that fully allogeneic primarily vascularized and conventional skin transplants were rejected at the same pace. Remarkably, however, short-term treatment of mice with anti-CD40L Abs achieved long-term survival of vascularized skin and cardiac transplants but not conventional skin grafts. Nonvascularized skin transplants triggered vigorous direct and indirect proinflammatory type 1 T cell responses (IL-2 and IFN-gamma), whereas primarily vascularized skin allografts failed to trigger a significant indirect alloresponse. A similar lack of indirect alloreactivity was also observed after placement of different vascularized organ transplants, including hearts and kidneys, whereas hearts placed under the skin (nonvascularized) triggered potent indirect alloresponses. Altogether, these results suggest that primary vascularization of allografts is associated with a lack of indirect T cell alloreactivity. Finally, we show that long-term survival of vascularized skin allografts induced by anti-CD40L Abs was associated with a combined lack of indirect alloresponse and a shift of the direct alloresponse toward a type 2 cytokine (IL-4, IL-10)-secretion pattern but no activation/expansion of Foxp3(+) regulatory T cells. Therefore, primary vascularization of allografts governs their immunogenicity and tolerogenicity. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr,Dept Surg, Boston, MA 02114 USA. RP Benichou, G (reprint author), Massachusetts Gen Hosp, Dept Surg, Thier 807,55 Fruit St, Boston, MA 02114 USA. EM gbenichou@partners.org FU National Institutes of Health, National Institute for Allergy and Infectious Diseases [R03AI094235, R21AI100278] FX This work was supported by grants from the National Institutes of Health, National Institute for Allergy and Infectious Diseases (R03AI094235 and R21AI100278 to G.B.). NR 56 TC 7 Z9 7 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2013 VL 191 IS 4 BP 1948 EP 1956 DI 10.4049/jimmunol.1202092 PG 9 WC Immunology SC Immunology GA 194KT UT WOS:000322632900046 PM 23833234 ER PT J AU Lee, JB Werbowetski-Ogilvie, TE Lee, JH McIntyre, BAS Schnerch, A Hong, SH Park, IH Daley, GQ Bernstein, ID Bhatia, M AF Lee, Jung Bok Werbowetski-Ogilvie, Tamra E. Lee, Jong-Hee McIntyre, Brendan A. S. Schnerch, Angelique Hong, Seok-Ho Park, In-Hyun Daley, George Q. Bernstein, Irwin D. Bhatia, Mickie TI Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embryonic and induced pluripotent stem cells SO BLOOD LA English DT Article ID HUMAN SOMATIC-CELLS; LIGAND JAGGED-1; NOTCH1; LETHALITY; GROWTH; DIFFERENTIATION; HEMATOPOIESIS; SEGMENTATION; MAINTENANCE; ACTIVATION AB Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and small interfering RNA to Notch receptors we have demonstrated that Notch1, but not Notch2, activation induced hairy and enhancer of split 1 (HES1) expression and generation of committed hematopoietic progenitors. Using gain- and loss-of-function approaches, this was shown to be attributed to Notch-signaling regulation through HES1, which dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs endothelial fate specification. C1 [Lee, Jung Bok; Werbowetski-Ogilvie, Tamra E.; Lee, Jong-Hee; McIntyre, Brendan A. S.; Schnerch, Angelique; Hong, Seok-Ho; Bhatia, Mickie] McMaster Univ, Michael G DeGroote Sch Med, McMaster Stem Cell & Canc Res Inst, Hamilton, ON L8N 3Z5, Canada. [Lee, Jung Bok; Werbowetski-Ogilvie, Tamra E.; Lee, Jong-Hee; McIntyre, Brendan A. S.; Schnerch, Angelique; Hong, Seok-Ho; Bhatia, Mickie] McMaster Univ, Dept Biochem, Hamilton, ON L8N 3Z5, Canada. [Park, In-Hyun; Daley, George Q.] Childrens Hosp Boston, Dept Med, Div Pediat Hematol Oncol, Boston, MA USA. [Park, In-Hyun; Daley, George Q.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Park, In-Hyun; Daley, George Q.] Harvard Stem Cell Inst, Boston, MA USA. [Bernstein, Irwin D.] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. RP Bhatia, M (reprint author), McMaster Univ, Michael G DeGroote Sch Med, SCC RI, MDCL 5029,1200 Main St West, Hamilton, ON L8N 3Z5, Canada. EM mbhatia@mcmaster.ca OI Werbowetski-Ogilvie, Tamra/0000-0002-5469-0559 FU Canadian Cancer Society Research Institute FX This work was supported by a grant from the Canadian Cancer Society Research Institute (M.B.). M.B. holds a Canada Research Chair in human stem cell biology. NR 40 TC 18 Z9 18 U1 1 U2 17 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2013 VL 122 IS 7 BP 1162 EP 1173 DI 10.1182/blood-2012-12-471649 PG 12 WC Hematology SC Hematology GA 204TQ UT WOS:000323392900016 PM 23733337 ER PT J AU Yang, G Zhou, YS Liu, X Xu, L Cao, Y Manning, RJ Patterson, CJ Buhrlage, SJ Gray, N Tai, YT Anderson, KC Hunter, ZR Treon, SP AF Yang, Guang Zhou, Yangsheng Liu, Xia Xu, Lian Cao, Yang Manning, Robert J. Patterson, Christopher J. Buhrlage, Sara J. Gray, Nathanael Tai, Yu-Tzu Anderson, Kenneth C. Hunter, Zachary R. Treon, Steven P. TI A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenstrom macroglobulinemia SO BLOOD LA English DT Article ID NF-KAPPA-B; SOMATIC MUTATION; MULTIPLE-MYELOMA; DRUG-COMBINATION; IGM MGUS; RECEPTOR; RESPONSES; LYMPHOMA; COMPLEX; GENOME AB Myeloid differentiation factor 88 (MYD88) L265P somatic mutation is highly prevalent in Waldenstrom macroglobulinemia (WM) and supports malignant growth through nuclear factor kappa B (NF-kappa B). The signaling cascade(s) by which MYD88 L265P promotes NF-kappa B activation in WM remain unclear. By lentiviral knockdown or use of a MYD88 inhibitor, decreased phosphorylation of the NF-kappa B gatekeeper I kappa B alpha and survival occurred in MYD88 L265P-expressing WM cells. Conversely, WM cells engineered to overexpress MYD88 L265P showed enhanced survival. Coimmunoprecipitation studies identified Bruton tyrosine kinase (BTK) complexed to MYD88 in L265P-expressing WM cells, with preferential binding of MYD88 to phosphorylated BTK (pBTK). Increased pBTK was also observed inWMcells transduced to overexpress L265P vs wild-type MYD88. Importantly, MYD88 binding to BTK was abrogated following treatment of MYD88 L265P-expressing cells with a BTK kinase inhibitor. Inhibition of BTK or interleukin-1 receptor-associated kinase 1 and 4 (IRAK-1 and -4) kinase activity induced apoptosis of WM cells, and their combination resulted in more robust inhibition of NF-kappa B signaling and synergistic WM cell killing. The results establish BTK as a downstream target of MYD88 L265P signaling, and provide a framework for the study of BTK inhibitors alone, and in combination with IRAK inhibitors for the treatment of WM. C1 [Yang, Guang; Zhou, Yangsheng; Liu, Xia; Xu, Lian; Cao, Yang; Manning, Robert J.; Patterson, Christopher J.; Hunter, Zachary R.; Treon, Steven P.] Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, Boston, MA 02215 USA. [Yang, Guang; Zhou, Yangsheng; Liu, Xia; Cao, Yang; Buhrlage, Sara J.; Gray, Nathanael; Tai, Yu-Tzu; Anderson, Kenneth C.; Hunter, Zachary R.; Treon, Steven P.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Buhrlage, Sara J.; Gray, Nathanael] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Tai, Yu-Tzu; Anderson, Kenneth C.] Dana Farber Canc Inst, Jerome Lipper Ctr Multiple Myeloma, Boston, MA 02215 USA. RP Treon, SP (reprint author), Dana Farber Canc Inst, Bing Ctr Waldenstroms Macroglobulinemia, 450 Brookline Ave,M548, Boston, MA 02215 USA. EM steven_treon@dfci.harvard.edu OI Hunter, Zachary/0000-0002-1689-1691 NR 32 TC 90 Z9 94 U1 2 U2 16 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2013 VL 122 IS 7 BP 1222 EP 1232 DI 10.1182/blood-2012-12-475111 PG 11 WC Hematology SC Hematology GA 204TQ UT WOS:000323392900022 PM 23836557 ER PT J AU Cagnetta, A Cea, M Calimeri, T Acharya, C Fulciniti, M Tai, YT Hideshima, T Chauhan, D Zhong, MY Patrone, F Nencioni, A Gobbi, M Richardson, P Munshi, N Anderson, KC AF Cagnetta, Antonia Cea, Michele Calimeri, Teresa Acharya, Chirag Fulciniti, Mariateresa Tai, Yu-Tzu Hideshima, Teru Chauhan, Dharminder Zhong, Mike Y. Patrone, Franco Nencioni, Alessio Gobbi, Marco Richardson, Paul Munshi, Nikhil Anderson, Kenneth C. TI Intracellular NAD(+) depletion enhances bortezomib-induced anti-myeloma activity SO BLOOD LA English DT Article ID HUMAN MULTIPLE-MYELOMA; NF-KAPPA-B; BIOSYNTHESIS INHIBITOR; NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; HEMATOLOGIC MALIGNANCIES; PROTEASOME INHIBITION; ANTITUMOR-ACTIVITY; BONE-MARROW; CELLS; APOPTOSIS AB We recently demonstrated that Nicotinamide phosphoribosyltransferase (Nampt) inhibition depletes intracellular NAD 1 content leading, to autophagic multiple myeloma (MM) cell death. Bortezomib has remarkably improved MM patient outcome, but doselimiting toxicities and development of resistance limit its long-term utility. Here we observed higher Nampt messenger RNA levels in bortezomib-resistant patient MM cells, which correlated with decreased overall survival. We demonstrated that combining the NAD 1 depleting agent FK866 with bortezomib induces synergistic anti-MM cell death and overcomes bortezomib resistance. This effect is associated with (1) activation of caspase8, caspase-9, caspase-3, poly (ADP-ribose) polymerase, and downregulation of Mcl-1; (2) enhanced intracellular NAD(+) depletion; (3) inhibition of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities; (4) inhibition of nuclear factor kappa B signaling; and (5) inhibition of angiogenesis. Furthermore, Nampt knockdown significantly enhances the anti-MM effect of bortezomib, which can be rescued by ectopically overexpressing Nampt. In a murine xenograft MM model, lowdose combination FK866 and Bortezomib iswell tolerated, significantly inhibits tumor growth, and prolongs host survival. Taken together, these findings indicate that intracellular NAD(+) level represents amajor determinant in the ability of bortezomib to induce apoptosis in MM cells and provide proof of concept for the combination with FK866 as a new strategy to enhance sensitivity or overcome resistance to bortezomib. C1 [Cagnetta, Antonia; Cea, Michele; Calimeri, Teresa; Acharya, Chirag; Fulciniti, Mariateresa; Tai, Yu-Tzu; Hideshima, Teru; Chauhan, Dharminder; Zhong, Mike Y.; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C.] Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Boston, MA USA. [Cagnetta, Antonia; Cea, Michele; Calimeri, Teresa; Acharya, Chirag; Fulciniti, Mariateresa; Tai, Yu-Tzu; Hideshima, Teru; Chauhan, Dharminder; Zhong, Mike Y.; Richardson, Paul; Munshi, Nikhil; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Cagnetta, Antonia; Cea, Michele; Gobbi, Marco] Univ San Martino IST, Azienda Osped, Ist Ricovero & Cura Carattere Sci, Dept Hematol & Oncol, Genoa, Italy. [Patrone, Franco; Nencioni, Alessio] Univ San Martino IST, Azienda Osped, Ist Ricovero & Cura Carattere Sci, Dept Internal Med, Genoa, Italy. RP Cea, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, M551,450 Brookline Ave, Boston, MA 02115 USA. EM michele_cea@dfci.harvard.edu; kenneth_anderson@dfci.harvard.edu FU National Institutes of Health [RO-1 50947, RO-1 73878]; DF/HCC SPORE in Multiple Myeloma [P-50100707]; International Multiple Myeloma Foundation; American Italian Cancer Foundation; American Cancer Society Clinical Research Professor FX This work was supported by the National Institutes of Health (grants RO-1 50947, RO-1 73878); The DF/HCC SPORE in Multiple Myeloma (P-50100707); International Multiple Myeloma Foundation (to A.C.); American Italian Cancer Foundation (to M.C.). K.C.A. is an American Cancer Society Clinical Research Professor. NR 47 TC 28 Z9 29 U1 1 U2 9 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2013 VL 122 IS 7 BP 1243 EP 1255 DI 10.1182/blood-2013-02-483511 PG 13 WC Hematology SC Hematology GA 204TQ UT WOS:000323392900024 PM 23823317 ER PT J AU Li, XH Redus, L Chen, C Martinez, PA Strong, R Li, SL O'Connor, JC AF Li, Xiuhua Redus, Laney Chen, Cang Martinez, Paul A. Strong, Randy Li, Senlin O'Connor, Jason C. TI Cognitive Dysfunction Precedes the Onset of Motor Symptoms in the MitoPark Mouse Model of Parkinson's Disease SO PLOS ONE LA English DT Article ID DEPRESSIVE-LIKE BEHAVIOR; NONMOTOR SYMPTOMS; TREATED PATIENTS; CALMETTE-GUERIN; MICE; IMPAIRMENT; INDUCTION; DOPAMINE; DEMENTIA; MEMORY AB Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by progressive loss of dopamine neurons, leading to loss of motor coordination. However, PD is associated with a high rate of non-motor neuropsychiatric comorbities that often develop before the onset of movement symptoms. The MitoPark transgenic mouse model is the first to recapitulate the cardinal clinical features, namely progressive neurodegeneration and death of neurons, loss of motor function and therapeutic response to L-DOPA. To investigate whether MitoPark mice exhibit early onset of cognitive impairment, a non-motor neuropsychiatric comorbidity, we measured performance on a spatial learning and memory task before (similar to 8 weeks) or after (similar to 20 weeks) the onset of locomotor decline in MitoPark mice or in littermate controls. Consistent with previous studies, we established that a progressive loss of spontaneous locomotor activity began at 12 weeks of age, which was followed by progressive loss of body weight beginning at 16-20 weeks. Spatial learning and memory was measured using the Barnes Maze. By 20 weeks of age, MitoPark mice displayed a substantial reduction in overall locomotor activity that impaired their ability to perform the task. However, in the 8-week-old mice, locomotor activity was no different between genotypes, yet MitoPark mice took longer, traveled further and committed more errors than same age control mice, while learning to successfully navigate the maze. The modest between-day learning deficit of MitoPark mice was characterized by impaired within-day learning during the first two days of testing. No difference was observed between genotypes during probe trials conducted one or twelve days after the final acquisition test. Additionally, 8-week-old MitoPark mice exhibited impaired novel object recognition when compared to control mice. Together, these data establish that mild cognitive impairment precedes the loss of motor function in a novel rodent model of PD, which may provide unique opportunities for therapeutic development. C1 [Li, Xiuhua; Redus, Laney; Chen, Cang; Martinez, Paul A.; Strong, Randy; Li, Senlin; O'Connor, Jason C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. [Li, Xiuhua; Chen, Cang; Li, Senlin] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Martinez, Paul A.; Strong, Randy; Li, Senlin; O'Connor, Jason C.] Univ Texas Hlth Sci Ctr San Antonio, Ctr Biomed Neurosci, San Antonio, TX 78229 USA. [O'Connor, Jason C.] Univ Texas Hlth Sci Ctr San Antonio, Mood Disorders Translat Res Core, San Antonio, TX 78229 USA. [Strong, Randy; Li, Senlin] South Texas Vet Hlth Care Syst, Geriatr Res Educ & Clin Ctr, San Antonio, TX USA. [Strong, Randy; Li, Senlin] Barshop Inst Longev & Aging Studies, San Antonio, TX USA. [Li, Xiuhua] Shandong Univ, Shandong Prov Qianfoshan Hosp, Dept Neurol, Jinan 250100, Peoples R China. RP Li, SL (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, San Antonio, TX 78229 USA. EM lis1@uthscsa.edu; oconnorj@uthscsa.edu FU Owen's Medical research Foundation; [R01-MH090127]; [P30-MH089868]; [NIA-1P30-AG13319]; [VA-BX001641]; [VA-BX000737]; [NIH-UL1-TR0000149] FX This research was supported by grants R01-MH090127 and P30-MH089868 (to JO); NIA-1P30-AG13319 and VA-BX001641 (to RS); and VA-BX000737, NIH-UL1-TR0000149 Pilot Project grant and an Owen's Medical research Foundation Award (to SL). The content is the sole the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health or the Department of Veterans Affairs. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 14 Z9 14 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 15 PY 2013 VL 8 IS 8 AR e71341 DI 10.1371/journal.pone.0071341 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 204OU UT WOS:000323378000043 PM 23977020 ER PT J AU Mega, JL Braunwald, E Wiviott, SD Murphy, SA Plotnikov, A Gotcheva, N Ruda, M Gibson, CM AF Mega, Jessica L. Braunwald, Eugene Wiviott, Stephen D. Murphy, Sabina A. Plotnikov, Alexei Gotcheva, Nina Ruda, Mikhail Gibson, C. Michael TI Comparison of the Efficacy and Safety of Two Rivaroxaban Doses in Acute Coronary Syndrome (from ATLAS ACS 2-TIMI 51) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ANTIPLATELET THERAPY; RANDOMIZED-TRIAL; DOUBLE-BLIND; DISCHARGE; PLACEBO; EVENTS AB The dosing of anticoagulants is critical when balancing efficacy and safety. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome 2 Thrombolysis In Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial was designed to evaluate 2 low doses of rivaroxaban compared with placebo in patients with recent acute coronary syndromes being treated with antiplatelet therapies. Because the 2 doses significantly reduced the primary efficacy end point, a further comparison of the 2 treatment strategies was deemed important. In total, 15,526 patients were randomized to twice-daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Comparing the 2 active doses, there were no significant differences between 2.5 and 5 mg for the primary efficacy end point of cardiovascular death, myocardial infarction, or stroke (9.1% vs 8.8%, p = 0.89), myocardial infarction (6.1% vs 4.9%, p = 0.23), or stent thrombosis (2.2% vs 2.3%, p = 0.59). However, there was a divergence in cardiovascular death, which included ischemic and hemorrhagic events, with the 2.5-mg dose resulting in lower rates than the 5-mg dose (2.7% vs 4.0%, p = 0.009). Notably, with 2.5 versus 5 mg, there were fewer study drug discontinuations (p = 0.004) and fewer non coronary artery bypass grafting TIMI major or minor bleeds (p = 0.021) and fatal bleeds (p = 0.044). Of the patients who died, 8 in the 2.5-mg group and 20 in the 5-mg group experienced non coronary artery bypass grafting TIMI major or minor bleeding events before death. In conclusion, the 2 doses of rivaroxaban reduced cardiovascular events in patients with recent acute coronary syndromes treated with antiplatelet therapies; however, the 2.5-mg dose was associated with lower mortality and fewer bleeding complications than the 5-mg dose. Thus, the addition of rivaroxaban 2.5 mg twice daily offers a more favorable balance of efficacy and safety in patients with recent acute coronary syndromes. (C) 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;112:472-478) C1 [Mega, Jessica L.; Braunwald, Eugene; Wiviott, Stephen D.; Murphy, Sabina A.; Gibson, C. Michael] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Cardiovasc Div,TIMI Study Grp, Boston, MA 02115 USA. [Plotnikov, Alexei] Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ USA. [Gotcheva, Nina] Natl Heart Ctr, Dept Cardiol, Sofia, Bulgaria. [Ruda, Mikhail] Cardiol Res Ctr, Dept Emergency Cardiol, Moscow 121552, Russia. [Gibson, C. Michael] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Cardiovasc Div, Boston, MA USA. RP Mega, JL (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Cardiovasc Div,TIMI Study Grp, Boston, MA 02115 USA. EM jmega@partners.org FU Johnson & Johnson, New Brunswick, New Jersey; Bayer Healthcare, Leverkusen, Germany; Bristol-Myers Squibb/Sanofi-Aventis, New York, New York; Daiichi Sankyo, Tokyo, Japan; Eli Lilly & Company, Indianapolis, Indiana; Bayer Healthcare; Johnson Johnson; Daiichi Sankyo; Eli Lilly Company; Merck/Schering-Plough, Kenilworth, New Jersey; AstraZeneca; Novartis, Basel, Switzerland; Merck/Schering-Plough; Bristol-Myers Squibb; Medicines Company FX Dr. Mega has received research grant support from Johnson & Johnson, New Brunswick, New Jersey; Bayer Healthcare, Leverkusen, Germany; Bristol-Myers Squibb/Sanofi-Aventis, New York, New York; Daiichi Sankyo, Tokyo, Japan; and Eli Lilly & Company, Indianapolis, Indiana. Dr. Mega has received research supplies from Accumetrics, San Diego, California, and Nanosphere, Northbrook, Illinois. Dr. Mega has received honoraria for consulting from Boehringer Ingelheim, Ingelheim, Germany and Janssen Pharmaceuticals, Titusville, New Jersey. Dr. Braunwald has received research grant support from Bayer Healthcare, Johnson & Johnson, and Daiichi Sankyo. Dr. Wiviott has received research grant support from Johnson & Johnson; Eli Lilly & Company; Daiichi Sankyo; Merck/Schering-Plough, Kenilworth, New Jersey. Dr. Wiviott has received honoraria for consulting from Arena Pharmaceuticals, San Diego, California; Bayer Healthcare; Ortho McNeil, Titusville, New Jersey; Bristol-Myers Squibb, New York, New York; and AstraZeneca, Wilmington, Delaware. Dr. Wiviott has received continuing medical education speaking fees from Eli Lilly & Company; Daiichi Sankyo; AstraZeneca; Novartis, Basel, Switzerland; and Merck/Schering-Plough. Ms. Murphy and Dr. Gotcheva have received research grant support from Bayer Healthcare and Johnson & Johnson. Dr. Ruda reports no disclosures. Dr. Plotnikov is employed by and owns stock in Johnson & Johnson. Dr. Gibson has received research grant support from Johnson & Johnson, Bayer Healthcare, and Bristol-Myers Squibb. Dr. Gibson has received honoraria for consulting from Porto la Pharmaceuticals, South San Francisco, California; Sanofi-Aventis, Paris, France; The Medicines Company, Parsippany, New Jersey; Daiichi Sankyo; Eli Lilly & Company; Biogen Idec, Weston, Massachusetts; Bristol-Myers Squibb; Ischemix, Inc., Maynard, Massachusetts; Johnson & Johnson; Bayer Healthcare; GlaxoSmithKline, London, United Kingdom; Merck/Schering-Plough; Ortho McNeil; Medicare, Inc., Winnipeg, Manitoba, Canada; Archemix, Inc., South San Francisco, California; Genentech, Inc., South San Francisco, California; and Boeringer Ingelheim. Dr. Gibson has received payments for lectures from Daiichi Sankyo, Eli Lilly & Company, and The Medicines Company. Dr. Gibson has received payments for the development of educational presentations from Daiichi Sankyo and Eli Lilly & Company. NR 11 TC 16 Z9 16 U1 1 U2 11 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 AUG 15 PY 2013 VL 112 IS 4 BP 472 EP 478 DI 10.1016/j.amjcard.2013.04.011 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 204YR UT WOS:000323407700002 PM 23711804 ER PT J AU Cruz-Gonzalez, I Semigram, MJ Inglessis-Azuaje, I Sanchez-Ledesma, M Martin-Moreiras, J Jneid, H Rengifo-Moreno, P Cubeddu, RJ Maree, AO Sanchez, PL Palacios, IF AF Cruz-Gonzalez, Ignacio Semigram, Marc J. Inglessis-Azuaje, Ignacio Sanchez-Ledesma, Maria Martin-Moreiras, Javier Jneid, Hani Rengifo-Moreno, Pablo Cubeddu, Roberto J. Maree, Andrew O. Sanchez, Pedro L. Palacios, Igor F. TI Effect of Elevated Pulmonary Vascular Resistance on Outcomes After Percutaneous Mitral Valvuloplasty SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID SIGNIFICANT TRICUSPID REGURGITATION; 30 YEARS EXPERIENCE; VALVE-REPLACEMENT; BALLOON VALVULOPLASTY; ARTERY HYPERTENSION; VALVOTOMY; STENOSIS; IMMEDIATE; SURGERY; RISK AB Patients with mitral stenosis with severe pulmonary hypertension constitute a high-risk subset for surgical commissurotomy or valve replacement. The aim of the present study was to examine the effect of elevated pulmonary vascular resistance (PVR) on percutaneous mitral valvuloplasty (PMV) procedural success, short- and long-term clinical outcomes (i.e., mortality, mitral valve surgery, and redo PMV) in 926 patients. Of the 926 patients, 263 (28.4%) had PVR >= 4 Woods units (WU) and 663 (71.6%) had PVR <4 WU. Patients with PVR >= 4 WU were older and more symptomatic and had worse valve morphology for PMV. The patients with PVR >= 4 WU also had lower PMV procedural success than those with PVR <4 WU (78.2% vs 85.6%, p = 0.006). However, after multivariate adjustment, PVR was no longer an independent predictor of PMV success nor an independent predictor of the combined end point at a median follow-up of 3.2 years. In conclusion, elevated PVR at PMV is not an independent predictor of procedural success or long-term outcomes. Therefore, appropriately selected patients with rheumatic mitral stenosis might benefit from PMV, even in the presence of elevated preprocedural PVR. (C) 2013 Elsevier Inc. All rights reserved. C1 [Cruz-Gonzalez, Ignacio; Semigram, Marc J.; Inglessis-Azuaje, Ignacio; Sanchez-Ledesma, Maria; Rengifo-Moreno, Pablo; Palacios, Igor F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. [Cruz-Gonzalez, Ignacio; Sanchez-Ledesma, Maria; Martin-Moreiras, Javier] Univ Hosp Salamanca, Div Cardiol, Salamanca, Spain. [Jneid, Hani] Baylor Coll Med, Div Cardiol, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Cubeddu, Roberto J.] Aventura Hosp & Med Ctr, Miami, FL USA. [Maree, Andrew O.] Waterford Reg Hosp, Div Cardiol, Waterford, Ireland. [Sanchez, Pedro L.] Gregorio Maranon Univ Hosp, Div Cardiol, Madrid, Spain. RP Cruz-Gonzalez, I (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. EM cruzgonzalez.ignacio@gmail.com OI Sanchez, Pedro L/0000-0002-4288-345X FU Spanish Society of Cardiology; Medtronic Iberia S.A. FX Dr. Cruz-Gonzalez acknowledges the support of the Spanish Society of Cardiology and Medtronic Iberia S.A. NR 29 TC 4 Z9 4 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2013 VL 112 IS 4 BP 580 EP 584 DI 10.1016/j.amjcard.2013.04.022 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 204YR UT WOS:000323407700020 PM 23683954 ER PT J AU Schwartz, CE Holt, DJ Rosenbaum, JF AF Schwartz, Carl E. Holt, Daphne J. Rosenbaum, Jerrold F. TI Methodological Challenges of Moving Beyond DSM Categories: Transdiagnostic Studies of Frontolimbic Connectivity Changes in Vulnerable Individuals SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID BEHAVIORAL-INHIBITION; PSYCHIATRIC-DISORDERS; REACTIVITY; CHILDREN; PARENTS C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rosenbaum, Jerrold F.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Rosenbaum, JF (reprint author), Massachusetts Gen Hosp, 55 Fruit St Bulfinch 351, Boston, MA 02114 USA. EM JRosenbaum@Partners.org NR 10 TC 1 Z9 1 U1 1 U2 4 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 AUG 15 PY 2013 VL 74 IS 4 BP 240 EP 241 DI 10.1016/j.biopsych.2013.05.030 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 201PY UT WOS:000323156100003 PM 23885753 ER PT J AU Vestman, NR Timby, N Holgerson, PL Kressirer, CA Claesson, R Domellof, M Ohman, C Tanner, ACR Hernell, O Johansson, I AF Vestman, Nelly Romani Timby, Niklas Holgerson, Pernilla Lif Kressirer, Christine A. Claesson, Rolf Domellof, Magnus Ohman, Carina Tanner, Anne C. R. Hernell, Olle Johansson, Ingegerd TI Characterization and in vitro properties of oral lactobacilli in breastfed infants SO BMC MICROBIOLOGY LA English DT Article DE Lactobacillus; L.gasseri; Growth; Adhesion; Gp340; Breastfed infants ID LACTIC-ACID BACTERIA; BLOOD-GROUP ANTIGENS; HUMAN-MILK; MUTANS STREPTOCOCCI; DENTAL-CARIES; HELICOBACTER-PYLORI; MEMBRANE-PROTEINS; ADHESION; PROBIOTICS; SALIVA AB Background: Lactobacillus species can contribute positively to general and oral health and are frequently acquired by breastfeeding in infancy. The present study aimed to identify oral lactobacilli in breast and formula-fed 4 month-old infants and to evaluate potential probiotic properties of the dominant Lactobacillus species detected. Saliva and oral swab samples were collected from 133 infants who were enrolled in a longitudinal study (n=240) examining the effect of a new infant formula on child growth and development. Saliva was cultured and Lactobacillus isolates were identified from 16S rRNA gene sequences. Five L. gasseri isolates that differed in 16S rRNA sequence were tested for their ability to inhibit growth of selected oral bacteria and for adhesion to oral tissues. Oral swab samples were analyzed by qPCR for Lactobacillus gasseri. Results: 43 (32.3%) infants were breastfed and 90 (67.7%) were formula-fed with either a standard formula (43 out of 90) or formula supplemented with a milk fat globule membrane (MFGM) fraction (47 out of 90). Lactobacilli were cultured from saliva of 34.1% breastfed infants, but only in 4.7% of the standard and 9.3% of the MFGM supplemented formula-fed infants. L. gasseri was the most prevalent (88% of Lactobacillus positive infants) of six Lactobacillus species detected. L. gasseri isolates inhibited Streptococcus mutans binding to saliva-coated hydroxyapatite, and inhibited growth of S. mutans, Streptococcus sobrinus, Actinomyces naeslundii, Actinomyces oris, Candida albicans and Fusobacterium nucleatum in a concentration dependent fashion. L. gasseri isolates bound to parotid and submandibular saliva, salivary gp340 and MUC7, and purified MFGM, and adhered to epithelial cells. L. gasseri was detected by qPCR in 29.7% of the oral swabs. Breastfed infants had significantly higher mean DNA levels of L. gasseri (2.14 pg/uL) than infants fed the standard (0.363 pg/uL) or MFGM (0.697 pg/uL) formula. Conclusions: Lactobacilli colonized the oral cavity of breastfed infants significantly more frequently than formulafed infants. The dominant Lactobacillus was L. gasseri, which was detected at higher levels in breastfed than formula-fed infants and displayed probiotic traits in vitro. C1 [Vestman, Nelly Romani; Holgerson, Pernilla Lif; Ohman, Carina; Johansson, Ingegerd] Umea Univ, Dept Odontol, Cardiol Sect, Umea, Sweden. [Timby, Niklas; Domellof, Magnus; Hernell, Olle] Umea Univ, Pediat Sect, Dept Clin Sci, Umea, Sweden. [Kressirer, Christine A.; Tanner, Anne C. R.] Forsyth Inst, Dept Microbiol, Cambridge, MA 02142 USA. [Kressirer, Christine A.; Tanner, Anne C. R.] Harvard Univ, Sch Dent Med, Dept Oral Med Infect & Immun, Boston, MA 02115 USA. [Claesson, Rolf] Umea Univ, Dept Odontol, Microbiol Sect, Umea, Sweden. RP Vestman, NR (reprint author), Umea Univ, Dept Odontol, Cardiol Sect, Umea, Sweden. EM nelly.romani.vestman@odont.umu.se RI Domellof, Magnus/E-5307-2011 OI Domellof, Magnus/0000-0002-0726-7029 FU Vinnova; Semper AB; Vasterbotten County Council (TUA); Swedish Research Council; School of Odontological Sciences; Public Health Service Grants from the National Institute of Dental and Craniofacial Research, USA [DE-021796, T32 DE-007327] FX The present study was supported by Vinnova, Semper AB, Vasterbotten County Council (TUA), The Swedish Research Council funded National School of Odontological Sciences, and by Public Health Service Grants DE-021796 and T32 DE-007327 from the National Institute of Dental and Craniofacial Research, USA. NR 59 TC 15 Z9 16 U1 2 U2 36 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD AUG 15 PY 2013 VL 13 AR 193 DI 10.1186/1471-2180-13-193 PG 12 WC Microbiology SC Microbiology GA 205FF UT WOS:000323427400001 PM 23945215 ER PT J AU Horning, SJ Haber, DA Selig, WKD Ivy, SP Roberts, SA Allen, JD Sigal, EV Sawyers, CL AF Horning, Sandra J. Haber, Daniel A. Selig, Wendy K. D. Ivy, S. Percy Roberts, Samantha A. Allen, Jeff D. Sigal, Ellen V. Sawyers, Charles L. TI Developing Standards for Breakthrough Therapy Designation in Oncology SO CLINICAL CANCER RESEARCH LA English DT Article AB In July 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). The Advancing Breakthrough Therapies for Patients Act was incorporated into a Title of FDASIA to expedite clinical development of new, potential "breakthrough" drugs or treatments that show dramatic responses in early-phase studies. Using this regulatory pathway, once a promising new drug candidate is designated as a "Breakthrough Therapy", the U. S. Food and Drug Administration (FDA) and sponsor would collaborate to determine the best path forward to abbreviate the traditional three-phase approach to drug development. The breakthrough legislation requires that an FDA guidance be drafted that details specific requirements of the bill to aid FDA in implementing requirements of the Act. In this article, we have proposed criteria to define a product as a Breakthrough Therapy, and discussed critical components of the development process that would require flexibility in order to enable expedited development of a Breakthrough Therapy. (C)2013 AACR. C1 [Horning, Sandra J.] Genentech Inc, San Francisco, CA 94080 USA. [Haber, Daniel A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Haber, Daniel A.; Sawyers, Charles L.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Selig, Wendy K. D.] Melanoma Res Alliance, Washington, DC USA. [Roberts, Samantha A.; Allen, Jeff D.; Sigal, Ellen V.] Friends Canc Res, Washington, DC 20036 USA. [Ivy, S. Percy] NCI, Invest Drug Branch, CTEP, Rockville, MD USA. [Sawyers, Charles L.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Roberts, SA (reprint author), Friends Canc Res, 1800 M St NW,Suite 1050 South, Washington, DC 20036 USA. EM sroberts@focr.org RI Sawyers, Charles/G-5327-2016 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [R01 CA129933] NR 9 TC 10 Z9 11 U1 0 U2 4 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 AUG 15 PY 2013 VL 19 IS 16 BP 4297 EP 4304 DI 10.1158/1078-0432.CCR-13-0523 PG 8 WC Oncology SC Oncology GA 201NG UT WOS:000323147700002 PM 23719260 ER PT J AU Salama, AKS Flaherty, KT AF Salama, April K. S. Flaherty, Keith T. TI BRAF in Melanoma: Current Strategies and Future Directions SO CLINICAL CANCER RESEARCH LA English DT Review AB Selective BRAF inhibitors have now been established as a standard of care option for patients diagnosed with metastatic melanoma whose tumors carry a BRAF mutation. Their successful development represents a milestone in the treatment of this disease, and has the potential to impact therapy for other malignancies as well. The use of these agents, however, has introduced a number of critical questions about the optimal use and selection of patients for BRAF inhibitor therapy. This review discusses the current status of BRAF inhibitor clinical development, the clinicopathologic features of BRAF-mutated melanoma, as well as strategies for overcoming resistance. (C)2013 AACR. C1 [Salama, April K. S.] Duke Univ, Med Ctr, Div Med Oncol, Durham, NC USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA 02114 USA. RP Flaherty, KT (reprint author), 55 Fruit St Yawkey 9E, Boston, MA 02114 USA. EM kflaherty@partners.org NR 69 TC 45 Z9 46 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2013 VL 19 IS 16 BP 4326 EP 4334 DI 10.1158/1078-0432.CCR-13-0779 PG 9 WC Oncology SC Oncology GA 201NG UT WOS:000323147700006 PM 23770823 ER PT J AU Moschetta, M Basile, A Ferrucci, A Frassanito, MA Rao, L Ria, R Solimando, AG Giuliani, N Boccarelli, A Fumarola, F Coluccia, M Rossini, B Ruggieri, S Nico, B Maiorano, E Ribatti, D Roccaro, AM Vacca, A AF Moschetta, Michele Basile, Antonio Ferrucci, Arianna Frassanito, Maria Antonia Rao, Luigia Ria, Roberto Solimando, Antonio Giovanni Giuliani, Nicola Boccarelli, Angelina Fumarola, Fabio Coluccia, Mauro Rossini, Bernardo Ruggieri, Simona Nico, Beatrice Maiorano, Eugenio Ribatti, Domenico Roccaro, Aldo M. Vacca, Angelo TI Novel Targeting of Phospho-cMET Overcomes Drug Resistance and Induces Antitumor Activity in Multiple Myeloma SO CLINICAL CANCER RESEARCH LA English DT Article AB Purpose: The aim of the study was to verify the hypothesis that the cMet oncogene is implicated in chemio- and novel drug resistance in multiple myeloma. Experimental Design: We have evaluated the expression levels of cMET/phospho-cMET (p-cMET) and the activity of the novel selective p-cMET inhibitor (SU11274) in multiple myeloma cells, either sensitive (RPMI-8226 and MM.1S) or resistant (R5 and MM.1R) to anti-multiple myeloma drugs, in primary plasma cells and in multiple myeloma xenograft models. Results: We found that resistant R5 and MM.1R cells presented with higher cMET phosphorylation, thus leading to constitutive activation of cMET-dependent signaling pathways. R5 cells exhibited a higher susceptibility to the SU11274 inhibitory effects on viability, proliferation, chemotaxis, adhesion, and to its apoptogenic effects. SU11274 was able to revert drug resistance in R5 cells. R5 but not RPMI-8226 cells displayed cMET-dependent activation of mitogen-activated protein kinase pathway. The cMET and p-cMET expression was higher on plasma cells from patients with multiple myeloma at relapse or on drug resistance than on those from patients at diagnosis, complete/partial remission, or from patients with monoclonal gammopathy of unknown significance. Viability, chemotaxis, adhesion to fibronectin or paired bone marrow stromal cells of plasma cells from relapsed or resistant patients was markedly inhibited by SU11274. Importantly, SU11274 showed higher therapeutic activity in R5-than in RPMI-8226-induced plasmocytomas. In R5 tumors, it caused apoptosis and necrosis and reverted bortezomib resistance. Conclusion: Our findings suggest that the cMET pathway is constitutively activated in relapsed and resistant multiple myeloma where it may also be responsible for induction of drug resistance, thus providing the preclinical rationale for targeting cMET in patients with relapsed/refractory multiple myeloma. (C)2013 AACR. C1 [Moschetta, Michele; Basile, Antonio; Ferrucci, Arianna; Frassanito, Maria Antonia; Rao, Luigia; Ria, Roberto; Solimando, Antonio Giovanni; Vacca, Angelo] Univ Bari, Sch Med, Dept Biomed Sci & Human Oncol, Internal Med Unit, Bari, Italy. [Boccarelli, Angelina; Fumarola, Fabio; Coluccia, Mauro] Univ Bari, Sch Med, Dept Biomed Sci & Human Oncol, Gen Pathol Unit, Bari, Italy. [Ruggieri, Simona; Nico, Beatrice; Ribatti, Domenico] Univ Bari, Sch Med, Dept Human Anat Histol & Embryol, Bari, Italy. [Maiorano, Eugenio] Univ Bari, Sch Med, Bari, Italy. [Giuliani, Nicola] Univ Parma, Sch Med, I-43100 Parma, Italy. [Giuliani, Nicola] Univ Parma, Sch Med, Bone Marrow Transplantat Ctr, I-43100 Parma, Italy. [Rossini, Bernardo] Fdn Osped Cardinale G Panico, Hematol Unit, Lecce, Italy. [Roccaro, Aldo M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Vacca, A (reprint author), Dept Biomed Sci & Human Oncol DIMO, Sect Internal Med & Clin Oncol, Policlin Piazza Giulio Cesare 11, I-70124 Bari, BA, Italy. EM angelo.vacca@uniba.it RI Maiorano, Eugenio/F-1382-2015; OI Ria, Roberto/0000-0002-1515-0090; Roccaro, Aldo/0000-0002-1872-5128; Giuliani, Nicola/0000-0003-3457-3774 FU Associazione Italiana per la Ricerca sul Cancro (AIRC) [10099]; Special Program Molecular Clinical Oncology 5 per thousand, Milan [9965]; European Commission's Seventh Framework programme (EU FPT7) OVER-MyR [278706]; OPTATIO [278570]; Ministry of Health (Progetto PRIN), Rome, Italy; Federazione Italiana per la Ricerca sul Cancro (FIRC), Milan, Italy FX This work was supported by Associazione Italiana per la Ricerca sul Cancro (AIRC), Investigator Grant (number 10099) and Special Program Molecular Clinical Oncology 5 per thousand (number 9965), Milan (to A. Vacca), the European Commission's Seventh Framework programme (EU FPT7) OVER-MyR (number 278706 to AV) and OPTATIO (number 278570 to D. Ribatti), and the Ministry of Health (Progetto PRIN 2009 to R. Ria and M. Coluccia and 2012 to A. Vacca), Rome, Italy. A. Boccarelli was supported by a studentship from Federazione Italiana per la Ricerca sul Cancro (FIRC), Milan, Italy. NR 42 TC 16 Z9 16 U1 0 U2 4 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 AUG 15 PY 2013 VL 19 IS 16 BP 4371 EP 4382 DI 10.1158/1078-0432.CCR-13-0039 PG 12 WC Oncology SC Oncology GA 201NG UT WOS:000323147700010 PM 23804425 ER PT J AU Ji, ZY Kumar, R Taylor, M Rajadurai, A Marzuka-Alcala, A Chen, YE Njauw, CNJ Flaherty, K Jonsson, G Tsao, H AF Ji, Zhenyu Kumar, Raj Taylor, Michael Rajadurai, Anpuchchelvi Marzuka-Alcala, Alexander Chen, Y. Erin Njauw, Ching-Ni Jenny Flaherty, Keith Jonsson, Goran Tsao, Hensin TI Vemurafenib Synergizes with Nutlin-3 to Deplete Survivin and Suppresses Melanoma Viability and Tumor Growth SO CLINICAL CANCER RESEARCH LA English DT Article AB Purpose: For patients with advanced melanoma, primary and secondary resistance to selective BRAF inhibition remains one of the most critically compelling challenges. One rationale argues that novel biologically informed strategies are needed to maximally cripple melanoma cells up front before compensatory mechanisms emerge. As p53 is uncommonly mutated in melanoma, restoration of its function represents an attractive adjunct to selective BRAF inhibition. Experimental Design: Thirty-seven BRAF(V600E)-mutated melanoma lines were subjected to synergy studies in vitro using a combination of vemurafenib and nutlin-3 (Nt-3). In addition, cellular responses and in vivo efficacy were also determined. We also analyzed changes in the levels of canonical apoptotic/survival factors in response to vemurafenib. Results: Dual targeting of BRAF(V600E) and Hdm2 with vemurafenib and Nt-3, respectively, synergistically induced apoptosis and suppressed melanoma viability in vitro and tumor growth in vivo. Suppression of p53 in melanoma cells abrogated Nt-3's effects fully and vemurafenib's effects partially. A survey of canonical survival factors revealed that both vemurafenib and Nt-3 independently attenuated levels of the antiapoptotic protein, survivin. Genetic depletion of survivin reproduces the cytotoxic effects of the combination strategy. Conclusion: These results show preclinical feasibility for overcoming primary vemurafenib resistance by restoring p53 function. Moreover, it identifies survivin as one downstream mediator of the observed synergism and a potential secondary target. (C)2013 AACR. C1 [Ji, Zhenyu; Kumar, Raj; Taylor, Michael; Rajadurai, Anpuchchelvi; Njauw, Ching-Ni Jenny; Tsao, Hensin] Wellman Ctr Photomed, Boston, MA USA. [Ji, Zhenyu; Kumar, Raj; Taylor, Michael; Rajadurai, Anpuchchelvi; Njauw, Ching-Ni Jenny; Tsao, Hensin] Dept Dermatol, Boston, MA USA. [Flaherty, Keith; Tsao, Hensin] Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02114 USA. [Chen, Y. Erin] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Marzuka-Alcala, Alexander] Yale Univ, Sch Med, New Haven, CT USA. [Jonsson, Goran] Lund Univ, Dept Oncol, S-22100 Lund, Sweden. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Edwards 211,55 Fruit St, Boston, MA 02114 USA. EM htsao@partners.org RI Jonsson, Goran/D-1212-2014; Kumar, Raj/M-3662-2014 FU American Skin Association; Melanoma Research Alliance; NIH [K24 CA149202] FX This work is supported in part by grants from the American Skin Association, Melanoma Research Alliance, and the gracious donors to the MGH Millennium Melanoma Fund. Postdoctoral supervision and mentorship during this project was supported in part by the NIH (K24 CA149202 to H. Tsao). NR 24 TC 13 Z9 13 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2013 VL 19 IS 16 BP 4383 EP 4391 DI 10.1158/1078-0432.CCR-13-0074 PG 9 WC Oncology SC Oncology GA 201NG UT WOS:000323147700011 PM 23812671 ER PT J AU Cardarella, S Ogino, A Nishino, M Butaney, M Shen, J Lydon, C Yeap, BY Sholl, LM Johnson, BE Janne, PA AF Cardarella, Stephanie Ogino, Atsuko Nishino, Mizuki Butaney, Mohit Shen, Jeanne Lydon, Christine Yeap, Beow Y. Sholl, Lynette M. Johnson, Bruce E. Jaenne, Pasi A. TI Clinical, Pathologic, and Biologic Features Associated with BRAF Mutations in Non-Small Cell Lung Cancer SO CLINICAL CANCER RESEARCH LA English DT Article AB Purpose: BRAF mutations are found in a subset of non-small cell lung cancers (NSCLC). We examined the clinical characteristics and treatment outcomes of patients with NSCLC harboring BRAF mutations. Experimental Design: Using DNA sequencing, we successfully screened 883 patients with NSCLC for BRAF mutations between July 1, 2009 and July 16, 2012. Baseline characteristics and treatment outcomes were compared between patients with and without BRAF mutations. Wild-type controls consisted of patients with NSCLC without a somatic alteration in BRAF, KRAS, EGFR, and ALK. In vitro studies assessed the biologic properties of selected non-V600E BRAF mutations identified from patients with NSCLC. Results: Of 883 tumors screened, 36 (4%) harbored BRAF mutations (V600E, 18; non-V600E, 18) and 257 were wild-type for BRAF, EGFR, KRAS, and ALK negative. Twenty-nine of 36 patients with BRAF mutations were smokers. There were no distinguishing clinical features between BRAF-mutant and wildtype patients. Patients with advanced NSCLC with BRAF mutations and wild-type tumors showed similar response rates and progression-free survival (PFS) to platinum-based combination chemotherapy and no difference in overall survival. Within the BRAF cohort, patients with V600E-mutated tumors had a shorter PFS to platinum-based chemotherapy compared with those with non-V600E mutations, although this did not reach statistical significance (4.1 vs. 8.9 months; P = 0.297). We identified five BRAF mutations not previously reported in NSCLC; two of five were associated with increased BRAF kinase activity. Conclusions: BRAF mutations occur in 4% of NSCLCs and half are non-V600E. Prospective trials are ongoing to validate BRAF as a therapeutic target in NSCLC. (C)2013 AACR. C1 [Cardarella, Stephanie; Ogino, Atsuko; Butaney, Mohit; Lydon, Christine; Johnson, Bruce E.; Jaenne, Pasi A.] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Med Oncol, Boston, MA 02215 USA. [Jaenne, Pasi A.] Dana Farber Canc Inst, Belfer Inst Appl Canc Sci, Boston, MA 02215 USA. [Nishino, Mizuki] Dana Farber Canc Inst, Dept Radiol, Boston, MA 02215 USA. [Cardarella, Stephanie; Johnson, Bruce E.; Jaenne, Pasi A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Nishino, Mizuki] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. [Shen, Jeanne; Sholl, Lynette M.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Cardarella, Stephanie; Yeap, Beow Y.; Johnson, Bruce E.; Jaenne, Pasi A.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Shen, Jeanne; Sholl, Lynette M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Yeap, Beow Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Cardarella, S (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, 450 Brookline Ave,Dana 1234C, Boston, MA 02215 USA. EM scardarella@partners.org FU Dana-Farber/Harvard Cancer Center Lung Cancer Specialized Program in Research Excellence (SPORE) [P50 CA090578]; American Society of Clinical Oncology (ASCO) Conquer Cancer Foundation Translational Research Professorship; National Cancer Institute (NCI) [1K23CA157631-01A1]; Nirenberg Fellowship; Alice and Stephen D. Cutler Investigator Fund in Thoracic Oncology at the Dana-Farber Cancer Institute FX This work was funded in part by the Dana-Farber/Harvard Cancer Center Lung Cancer Specialized Program in Research Excellence (SPORE) P50 CA090578; the American Society of Clinical Oncology (ASCO) Conquer Cancer Foundation Translational Research Professorship (to B. E. Johnson); National Cancer Institute (NCI) grant 1K23CA157631-01A1 (to M. Nishino); the Nirenberg Fellowship (to A. Ogino); and the Alice and Stephen D. Cutler Investigator Fund in Thoracic Oncology at the Dana-Farber Cancer Institute (to S. Cardarella). NR 41 TC 67 Z9 71 U1 2 U2 9 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 AUG 15 PY 2013 VL 19 IS 16 BP 4532 EP 4540 DI 10.1158/1078-0432.CCR-13-0657 PG 9 WC Oncology SC Oncology GA 201NG UT WOS:000323147700025 PM 23833300 ER PT J AU Agostoni, P Swenson, ER Fumagalli, R Salvioni, E Cattadori, G Farina, S Bussotti, M Tamplenizza, M Lombardi, C Bonacina, D Brioschi, M Caravita, S Modesti, P Revera, M Giuliano, A Meriggi, P Faini, A Bilo, G Banfi, C Parati, G AF Agostoni, Piergiuseppe Swenson, Erik R. Fumagalli, Roberto Salvioni, Elisabetta Cattadori, Gaia Farina, Stefania Bussotti, Maurizio Tamplenizza, Margherita Lombardi, Carolina Bonacina, Daniele Brioschi, Maura Caravita, Sergio Modesti, Pietro Revera, Miriam Giuliano, Andrea Meriggi, Paolo Faini, Andrea Bilo, Grzegorz Banfi, Cristina Parati, Gianfranco TI Acute high-altitude exposure reduces lung diffusion: Data from the HIGHCARE Alps project SO RESPIRATORY PHYSIOLOGY & NEUROBIOLOGY LA English DT Article DE Gas exchange; Surfactant derived proteins; Pulmonary edema; Hypoxia ID ACUTE MOUNTAIN-SICKNESS; INTERSTITIAL PULMONARY-EDEMA; CHRONIC HEART-FAILURE; SURFACTANT PROTEIN-B; RECREATIONAL CLIMBERS; CARBON-MONOXIDE; GAS-EXCHANGE; EXERCISE; CAPACITY; PLASMA AB The causes and development of lung fluid, as well as the integrity of the alveolar-capillary membrane at high altitude, are undefined. This study was conceived to see whether fluid accumulates within the lung with acute high altitude exposure, and whether this is associated with alveolar capillary membrane damage. We studied lung carbon monoxide diffusion (DLCO), its components membrane diffusion (D-M) and capillary volume (V-C) and alveolar volume (V-A) measured in 43 healthy subjects in Milan (122 m) and after 1 and 3 days at Capanna Regina Margherita (4559 m). DLCO measurement was adjusted for hemoglobin and inspired oxygen. We also measured plasma surfactant derived protein B (SPB) and Receptor of Advanced Glycation End-products (RAGE) as markers of alveolar-capillary membrane damage, and ultrasound lung comets as a marker of extravascular lung water. 21 subjects received acetazolamide and 22 placebo. DLCO was lower at Capanna Regina Margherita (day 1: 24.3 +/- 4.7 and day 3: 23.6 +/- 5.4 mL/mmHg/min), than in Milan (25.8 +/- 5.5; p < 0.001 vs. day 1 and 3) due to D-M reduction (Milan: 50.5 +/- 14.6 mL/mmHg/min, Capanna Regina Margherita day 1: 45.1 +/- 11.5 mL/mmHg/min, day 3: 43.2 +/- 13.9 mL/mmHg/min; p < 0.05 Milan vs. day 3) with a partially compensatory V-C increase (Milan: 96 +/- 37 mL, Capanna Regina Margherita day 1: 152 66 mL, day 3: 153 59 mL; p < 0.001 Milan vs. day 1 and day 3). Acetazolamide did not prevent the fall in DLCO albeit, between day 1 and 3, such a trend was observed. Regardless of treatment lung comets increased from 0 to 7.2 +/- 3.6 (p < 0.0001). SPB and RAGE were unchanged. Lung fluid increased at high altitude without evidence from plasma measurements, supporting alveolar-capillary damage. (C) 2013 Elsevier B.V. All rights reserved. C1 [Agostoni, Piergiuseppe; Salvioni, Elisabetta; Cattadori, Gaia; Farina, Stefania; Brioschi, Maura; Banfi, Cristina] IRCCS, Ctr Cardiol Monzino, I-20138 Milan, Italy. [Agostoni, Piergiuseppe] Univ Washington, Div Pulm Crit Care & Med, Dept Med, VA Med Ctr, Seattle, WA 98108 USA. [Agostoni, Piergiuseppe] Dept Clin Sci & Community Hlth, I-20138 Milan, Italy. [Swenson, Erik R.] Univ Washington, Div Pulm & Crit Care & Med, Dept Med, VA Puget Sound Hlth Care Syst,VA Med Ctr, Seattle, WA 98108 USA. [Fumagalli, Roberto; Bonacina, Daniele] Univ Milano Bicocca, Dipartimento Med Sperimentale, Osped S Gerardo Monza, Unita Operat Anestesia & Rianimaz 1, Milan, Italy. [Bussotti, Maurizio] IRCCS, Fdn S Maugeri, Milan, Italy. [Tamplenizza, Margherita] Univ Milan, CIMAINA, Milan, Italy. [Lombardi, Carolina; Caravita, Sergio; Revera, Miriam; Giuliano, Andrea; Faini, Andrea; Bilo, Grzegorz; Parati, Gianfranco] S Luca Hosp, Ist Auxol Italian, Dept Cardiol, I-20131 Milan, Italy. [Lombardi, Carolina; Revera, Miriam; Parati, Gianfranco] Univ Milano Bicocca, Dept Clin Med & Prevent, I-20149 Milan, Italy. [Modesti, Pietro] Univ Florence, Dipartimento Area Crit Med Chirurg, I-50134 Florence, Italy. [Meriggi, Paolo] Fdn Don Carlo Gnocchi, Biomed Technol Dept, I-20148 Milan, Italy. RP Agostoni, P (reprint author), Ctr Cardiol Monzino, Via Parea 4, I-20138 Milan, Italy. EM piergiuseppe.agostoni@unimi.it RI Modesti, Pietro Amedeo/B-2638-2012; Bilo, Grzegorz/J-8694-2016; OI Modesti, Pietro Amedeo/0000-0002-9511-2173; Bilo, Grzegorz/0000-0002-5104-9176; Revera, Miriam/0000-0002-3388-1858; caravita, sergio/0000-0002-3003-6499; Parati, Gianfranco/0000-0001-9402-7439; Faini, Andrea/0000-0002-8924-8234 NR 40 TC 13 Z9 14 U1 1 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9048 J9 RESP PHYSIOL NEUROBI JI Respir. Physiol. Neuro. PD AUG 15 PY 2013 VL 188 IS 2 BP 223 EP 228 DI 10.1016/j.resp.2013.04.005 PG 6 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 204YU UT WOS:000323408000018 PM 23619193 ER PT J AU Yeung, TL Leung, CS Wong, KK Samimi, G Thompson, MS Liu, JS Zaid, TM Ghosh, S Birrer, MJ Mok, SC AF Yeung, Tsz-Lun Leung, Cecilia S. Wong, Kwong-Kwok Samimi, Goli Thompson, Melissa S. Liu, Jinsong Zaid, Tarrik M. Ghosh, Sue Birrer, Michael J. Mok, Samuel C. TI TGF-beta Modulates Ovarian Cancer Invasion by Upregulating CAF-Derived Versican in the Tumor Microenvironment SO CANCER RESEARCH LA English DT Article ID STROMAL CELLS; STEM-CELLS; CROSS-TALK; EXPRESSION; MATRIX; TRANSCRIPTION; FIBROBLASTS; INHIBITION; CONTRIBUTE; MEMBRANE AB TGF-beta has limited effects on ovarian cancer cells, but its contributions to ovarian tumor growth might be mediated through elements of the tumor microenvironment. In the present study, we tested the hypothesis that TGF modulates ovarian cancer progression by modulating the contribution of cancer-associated fibroblasts (CAF) that are present in the microenvironment. Transcriptome profiling of microdissected stromal and epithelial components of high-grade serous ovarian tumors and TGF-beta-treated normal ovarian fibroblasts identified versican (VCAN) as a key upregulated target gene in CAFs. Functional evaluations in coculture experiments showed that TGF-beta enhanced the aggressiveness of ovarian cancer cells by upregulating VCAN in CAFs. VCAN expression was regulated in CAFs through TGF-beta receptor type II and SMAD signaling. Upregulated VCAN promoted the motility and invasion of ovarian cancer cells by activating the NF-kappa B signaling pathway and by upregulating expression of CD44, matrix metalloproteinase-9, and the hyaluronan-mediated motility receptor. Our work identified a TGF-beta-inducible gene signature specific to CAFs in advanced high-grade serous ovarian tumors, and showed how TGF-beta stimulates ovarian cancer cell motility and invasion by upregulating the CAF-specific gene VCAN. These findings suggest insights to develop or refine strategies for TGF-beta-targeted therapy of ovarian cancer. (C) 2013 AACR. C1 [Yeung, Tsz-Lun; Leung, Cecilia S.; Wong, Kwong-Kwok; Thompson, Melissa S.; Zaid, Tarrik M.; Mok, Samuel C.] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA. [Liu, Jinsong] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Leung, Cecilia S.; Wong, Kwong-Kwok; Mok, Samuel C.] Univ Texas Grad Sch Biomed Sci Houston, Houston, TX USA. [Samimi, Goli] Garvan Inst Med Res, Kinghorn Canc Ctr, Sydney, NSW, Australia. [Samimi, Goli] St Vincents Clin Sch, Sydney, NSW, Australia. [Ghosh, Sue] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Birrer, Michael J.] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA USA. RP Mok, SC (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Unit 1362, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM scmok@mdanderson.org FU NIH [R01CA133057, U54CA149196, RC4CA156551]; MD Anderson Ovarian Cancer SPORE grant from the NIH [P50CA083639]; MD Anderson Cancer Center [CA016672] FX This study was supported in part by grants R01CA133057, U54CA149196 and RC4CA156551 and MD Anderson Ovarian Cancer SPORE grant P50CA083639 from the NIH and by the MD Anderson Cancer Center Support Grant CA016672. NR 35 TC 57 Z9 58 U1 2 U2 17 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 AUG 15 PY 2013 VL 73 IS 16 BP 5016 EP 5028 DI 10.1158/0008-5472.CAN-13-0023 PG 13 WC Oncology SC Oncology GA 201RX UT WOS:000323161800007 PM 23824740 ER PT J AU Boichuk, S Parry, JA Makielski, KR Litovchick, L Baron, JL Zewe, JP Wozniak, A Mehalek, KR Korzeniewski, N Seneviratne, DS Scohoffski, P Debiec-Rychter, M DeCaprio, JA Duensing, A AF Boichuk, Sergei Parry, Joshua A. Makielski, Kathleen R. Litovchick, Larisa Baron, Julianne L. Zewe, James P. Wozniak, Agnieszka Mehalek, Keith R. Korzeniewski, Nina Seneviratne, Danushka S. Schoffski, Patrick Debiec-Rychter, Maria DeCaprio, James A. Duensing, Anette TI The DREAM Complex Mediates GIST Cell Quiescence and Is a Novel Therapeutic Target to Enhance Imatinib-Induced Apoptosis SO CANCER RESEARCH LA English DT Article ID GASTROINTESTINAL STROMAL TUMORS; RETINOBLASTOMA PROTEIN; KINASE INHIBITORS; UBIQUITIN LIGASE; S-PHASE; DYRK1A; MESYLATE; P130; ACCUMULATION; DEGRADATION AB Gastrointestinal stromal tumors (GIST) can be successfully treated with imatinib mesylate (Gleevec); however, complete remissions are rare and patients frequently achieve disease stabilization in the presence of residual tumor masses. The clinical observation that discontinuation of treatment can lead to tumor progression suggests that residual tumor cells are, in fact, quiescent and, therefore, able to re-enter the cell-division cycle. In line with this notion, we have previously shown that imatinib induces GIST cell quiescence in vitro through the APC(CDH1)-SKP2-p27(Kip1) signaling axis. Here, we provide evidence that imatinib induces GIST cell quiescence in vivo and that this process also involves the DREAM complex, a multisubunit complex that has recently been identified as an additional key regulator of quiescence. Importantly, inhibition of DREAM complex formation by depletion of the DREAM regulatory kinase DYRK1A or its target LIN52 was found to enhance imatinib-induced cell death. Our results show that imatinib induces apoptosis in a fraction of GIST cells while, at the same time, a subset of cells undergoes quiescence involving the DREAM complex. Inhibition of this process enhances imatinib-induced apoptosis, which opens the opportunity for future therapeutic interventions to target the DREAM complex for more efficient imatinib responses. (C) 2013 AACR. C1 [Boichuk, Sergei; Parry, Joshua A.; Makielski, Kathleen R.; Baron, Julianne L.; Zewe, James P.; Mehalek, Keith R.; Seneviratne, Danushka S.; Duensing, Anette] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Canc Virol Program, Pittsburgh, PA 15213 USA. [Duensing, Anette] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Litovchick, Larisa; DeCaprio, James A.] Brigham & Womens Hosp, Dept Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Litovchick, Larisa; DeCaprio, James A.] Harvard Univ, Sch Med, Boston, MA USA. [Litovchick, Larisa] Virginia Commonwealth Univ, Dept Med, Richmond, VA 23298 USA. [Wozniak, Agnieszka; Schoffski, Patrick] Katholieke Univ Leuven, Dept Oncol & Gen Med Oncol, Louvain, Belgium. [Debiec-Rychter, Maria] Katholieke Univ Leuven, Dept Human Genet, Louvain, Belgium. [Debiec-Rychter, Maria] Katholieke Univ Leuven Hosp, Louvain, Belgium. [Korzeniewski, Nina] Heidelberg Univ, Med Fac Heidelberg, Sch Med, Heidelberg, Germany. [Boichuk, Sergei] Kazan State Med Univ, Dept Pathol, Kazan, Russia. RP Duensing, A (reprint author), Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Res Pavil,Suite 1-8,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM aduensin@pitt.edu OI Duensing, Anette/0000-0002-0168-4067 FU American Cancer Society [RSG-08-092-01-CCG]; GIST Cancer Research Fund; Life Raft Group; UPCI; Pennsylvania Department of Health; [P30CA047904] FX This work was financially supported by a Research Scholar Grant from the American Cancer Society (RSG-08-092-01-CCG; A. Duensing), the GIST Cancer Research Fund (A. Duensing), The Life Raft Group (A. Duensing and M. Debiec-Rychter), and a number of private donations (A. Duensing). University of Pittsburgh Cancer Institute (UPCI) shared resources that are supported, in part, by award P30CA047904 and were used for this project. A. Duensing is supported by the UPCI and, in part, by a grant from the Pennsylvania Department of Health. NR 42 TC 14 Z9 15 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2013 VL 73 IS 16 BP 5120 EP 5129 DI 10.1158/0008-5472.CAN-13-0579 PG 10 WC Oncology SC Oncology GA 201RX UT WOS:000323161800016 PM 23786773 ER PT J AU Penney, KL Stampfer, MJ Jahn, JL Sinnott, JA Flavin, R Rider, JR Finn, S Giovannucci, E Sesso, HD Loda, M Mucci, LA Fiorentino, M AF Penney, Kathryn L. Stampfer, Meir J. Jahn, Jaquelyn L. Sinnott, Jennifer A. Flavin, Richard Rider, Jennifer R. Finn, Stephen Giovannucci, Edward Sesso, Howard D. Loda, Massimo Mucci, Lorelei A. Fiorentino, Michelangelo TI Gleason Grade Progression Is Uncommon SO CANCER RESEARCH LA English DT Article ID PROSTATE-CANCER GRADE; CONTINUED STAGE MIGRATION; RADICAL PROSTATECTOMY; LEAD-TIME; FOLLOW-UP; SCORE; MEN; DEDIFFERENTIATION; PATTERNS; DISEASE AB Gleason grade is universally used for pathologic scoring of the differentiation of prostate cancer. However, it is unknown whether prostate tumors arise well differentiated and then progress to less differentiated forms or if Gleason grade is an early and largely unchanging feature. Prostate-specific antigen (PSA) screening has reduced the proportion of tumors diagnosed at advanced stage, which allows assessment of this question on a population level. If Gleason grade progresses as stage does, one would expect a similar reduction in high-grade tumors. We studied 1,207 Physicians' Health Study and Health Professionals Follow-up Study participants diagnosed with prostate cancer from 1982 to 2004 and treated with prostatectomy. We compared the distribution of grade and clinical stage across the pre-PSA and PSA screening eras. We re-reviewed grade using the ISUP 2005 revised criteria. The proportion of advanced stage tumors dropped more than six-fold, from the earliest period (12/1982-1/1993), 19.9% stage >= T3, to the latest (5/2000-12/2004), 3% stage T3, none T4. The proportion of Gleason score >= 8 decreased substantially less, from 25.3% to 17.6%. A significant interaction between stage and diagnosis date predicting grade (P = 0.04) suggests that the relationship between grade and stage varies by time period. As the dramatic shift in stage since the introduction of PSA screening was accompanied by a more modest shift in Gleason grade, these findings suggest that grade may be established early in tumor pathogenesis. This has implications for the understanding of tumor progression and prognosis, and may help patients diagnosed with lower grade disease feel more comfortable choosing active surveillance. (C) 2013 AACR. C1 [Penney, Kathryn L.; Stampfer, Meir J.; Rider, Jennifer R.; Giovannucci, Edward; Sesso, Howard D.; Mucci, Lorelei A.; Fiorentino, Michelangelo] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Stampfer, Meir J.; Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Sinnott, Jennifer A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Penney, Kathryn L.; Stampfer, Meir J.; Jahn, Jaquelyn L.; Sinnott, Jennifer A.; Rider, Jennifer R.; Mucci, Lorelei A.] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA 02115 USA. [Sesso, Howard D.] Brigham & Womens Hosp, Dept Prevent Med, Boston, MA 02115 USA. [Loda, Massimo] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Loda, Massimo] Harvard Univ, Sch Med, Boston, MA USA. [Flavin, Richard; Finn, Stephen; Loda, Massimo; Fiorentino, Michelangelo] Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. [Loda, Massimo] Broad Inst, Cambridge, MA USA. [Flavin, Richard; Finn, Stephen] Trinity Coll Dublin, Dept Histopathol Res, Dublin, Ireland. [Fiorentino, Michelangelo] Univ Bologna, Addarii Inst Oncol, Pathol Unit, I-40126 Bologna, Italy. RP Penney, KL (reprint author), Brigham & Womens Hosp, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM kpenney@hsph.harvard.edu OI Rider, Jennifer/0000-0002-2637-6036; Finn, Stephen/0000-0002-8628-5814 FU Dana-Farber/Harvard Cancer Center Prostate SPORE [5P50CA090381-08]; National Cancer Institute [5R01CA141298, CA34944, CA40360, CA097193]; National Heart, Lung, and Blood Institute [HL26490, HL34595]; National Research Service Award [T32 CA009001-32]; Prostate Cancer Foundation; [CA55075] FX This work was supported by the Dana-Farber/Harvard Cancer Center Prostate SPORE (5P50CA090381-08) and the National Cancer Institute (5R01CA141298). The PHS was supported by grants CA34944, CA40360, and CA097193 from the National Cancer Institute and HL26490 and HL34595 from the National Heart, Lung, and Blood Institute. The HPFS was supported by CA55075. K. L. Penney was supported by a National Research Service Award (T32 CA009001-32); J.A. Sinnott is supported by T32 CA009001-32. K. L. Penney and L. A. Mucci are supported by the Prostate Cancer Foundation. NR 26 TC 28 Z9 28 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 AUG 15 PY 2013 VL 73 IS 16 BP 5163 EP 5168 DI 10.1158/0008-5472.CAN-13-0427 PG 6 WC Oncology SC Oncology GA 201RX UT WOS:000323161800020 PM 23946472 ER PT J AU Liao, RG Jung, J Tchaicha, J Wilkerson, MD Sivachenko, A Beauchamp, EM Liu, QS Pugh, TJ Pedamallu, CS Hayes, DN Gray, NS Getz, G Wong, KK Haddad, RI Meyerson, M Hammerman, PS AF Liao, Rachel G. Jung, Joonil Tchaicha, Jeremy Wilkerson, Matthew D. Sivachenko, Andrey Beauchamp, Ellen M. Liu, Qingsong Pugh, Trevor J. Pedamallu, Chandra Sekhar Hayes, D. Neil Gray, Nathanael S. Getz, Gad Wong, Kwok-Kin Haddad, Robert I. Meyerson, Matthew Hammerman, Peter S. TI Inhibitor-Sensitive FGFR2 and FGFR3 Mutations in Lung Squamous Cell Carcinoma SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR-2; TYROSINE KINASE; ACTIVATING MUTATIONS; SELECTIVE INHIBITOR; CANCER; GEFITINIB; FAMILY; POTENT; SPECIFICITY; DISCOVERY AB A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC. (C) 2013 AACR. C1 [Liao, Rachel G.; Tchaicha, Jeremy; Beauchamp, Ellen M.; Pugh, Trevor J.; Pedamallu, Chandra Sekhar; Wong, Kwok-Kin; Haddad, Robert I.; Meyerson, Matthew; Hammerman, Peter S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Liu, Qingsong; Gray, Nathanael S.] Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. [Liao, Rachel G.; Jung, Joonil; Sivachenko, Andrey; Pugh, Trevor J.; Pedamallu, Chandra Sekhar; Getz, Gad; Meyerson, Matthew; Hammerman, Peter S.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Wilkerson, Matthew D.; Hayes, D. Neil] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Hammerman, PS (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM Robert_Haddad@dfci.harvard.edu; Matthew_meyerson@dfci.harvard.edu; phammerman@partners.org OI Liao, Rachel/0000-0002-7830-1976; liu, qing song/0000-0002-7829-2547; wong, kwok kin/0000-0001-6323-235X FU Young Investigator Grant from the National Lung Cancer Partnership; National Cancer Institute (NCI) [1K08CA163677]; Stephen D. and Alice Cutler Investigator Fund; Uniting Against Lung Cancer; Lung Cancer Research Foundation; American Lung Association; Novartis Pharmaceuticals; NCI [P50CA090578]; Ruth L. Kirschstein National Research Service Award Individual Fellowship from the NCI [NIH F32CA142039]; Canadian Institutes of Health Research Fellowship FX P.S. Hammerman is a recipient of a Young Investigator Grant from the National Lung Cancer Partnership and is supported by National Cancer Institute (NCI) grants 1K08CA163677 and the Stephen D. and Alice Cutler Investigator Fund. M. Meyerson is supported by Uniting Against Lung Cancer, the Lung Cancer Research Foundation, the American Lung Association, Novartis Pharmaceuticals, and NCI grant P50CA090578. M. D. Wilkerson is supported by a Ruth L. Kirschstein National Research Service Award Individual Fellowship from the NCI (NIH F32CA142039). T.J. Pugh is supported by a Canadian Institutes of Health Research Fellowship. NR 42 TC 74 Z9 80 U1 1 U2 21 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 AUG 15 PY 2013 VL 73 IS 16 BP 5195 EP 5205 DI 10.1158/0008-5472.CAN-12-3950 PG 11 WC Oncology SC Oncology GA 201RX UT WOS:000323161800023 PM 23786770 ER PT J AU Barroilhet, L Yang, J Hasselblatt, K Paranal, RM Ng, SK Rauh-Hain, JA Welch, WR Bradner, JE Berkowitz, RS Ng, SW AF Barroilhet, L. Yang, J. Hasselblatt, K. Paranal, R. M. Ng, S-K Rauh-Hain, J. A. Welch, W. R. Bradner, J. E. Berkowitz, R. S. Ng, S-W TI C-terminal binding protein-2 regulates response of epithelial ovarian cancer cells to histone deacetylase inhibitors SO ONCOGENE LA English DT Article DE ovarian cancer; tumor antigens; HDAC inhibitors ID TRANSCRIPTIONAL COREPRESSOR; BETA-CATENIN; CTBP; REPRESSOR; BINDING-PROTEIN-1; ASSOCIATION; METASTASIS AB Ovarian cancer survival rates have stagnated in the last 20 years despite the development of novel chemotherapeutic agents. Modulators of gene expression, such as histone deacetylase (HDAC) inhibitors, are among the new agents being used in clinical trials. Predictors of sensitivity to chemotherapy have remained elusive. In this study, we show that the expression of the transcriptional corepressor C-terminal binding protein-2 (CtBP2) is elevated in human ovarian tumors. Downregulation of CtBP2 expression in ovarian cancer cell lines using short-hairpin RNA strategy suppressed the growth rate and migration of the resultant cancer cells. The knockdown cell lines also showed upregulation of HDAC activity and increased sensitivity to selected HDAC inhibitors. Conversely, forced expression of wild-type CtBP2 in the knockdown cell lines reversed HDAC activity and partially rescued cellular sensitivity to the HDAC inhibitors. We propose that CtBP2 is an ovarian cancer oncogene that regulates gene expression program by modulating HDAC activity. CtBP2 expression may be a surrogate indicator of cellular sensitivity to HDAC inhibitors. C1 [Barroilhet, L.; Yang, J.; Hasselblatt, K.; Rauh-Hain, J. A.; Berkowitz, R. S.; Ng, S-W] Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Paranal, R. M.; Bradner, J. E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Ng, S-K] Griffith Univ, Griffith Hlth Inst, Sch Med, Meadowbrook, Qld 4131, Australia. [Welch, W. R.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP Ng, SW (reprint author), Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, 221 Longwood Ave BLI-449A, Boston, MA 02115 USA. EM sng@partners.org FU Ruth N White Gynecologic Oncology Research Fellowship; Robert and Deborah First Fund; Sperling Family Fund Foundation; Women's Cancer Program; Gillette Center for Women's Cancer from Dana-Farber Cancer Institute; Ovarian Cancer Research Foundation; Adler Foundation, Inc.; Friends of Dana-Farber Cancer Institute FX We thank critical reading of the manuscript by Professor YF Wong. We acknowledge the provision of belinostat, vorinostat, MGCD0103 from Selleck Inc. LB was supported by Ruth N White Gynecologic Oncology Research Fellowship. The Laboratory of Gynecologic Oncology was partly supported by Robert and Deborah First Fund, the Sperling Family Fund Foundation, Women's Cancer Program and Gillette Center for Women's Cancer from Dana-Farber Cancer Institute, Ovarian Cancer Research Foundation, Adler Foundation, Inc., and Friends of Dana-Farber Cancer Institute. NR 29 TC 8 Z9 8 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 AUG 15 PY 2013 VL 32 IS 33 BP 3896 EP 3903 DI 10.1038/onc.2012.380 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 202JH UT WOS:000323210200012 PM 22945647 ER PT J AU Nakabayashi, M Hayes, J Taplin, ME Lefebvre, P Lafeuille, MH Pomerantz, M Sweeney, C Duh, MS Kantoff, PW AF Nakabayashi, Mari Hayes, Julia Taplin, Mary-Ellen Lefebvre, Patrick Lafeuille, Marie-Helene Pomerantz, Mark Sweeney, Christopher Duh, Mei Sheng Kantoff, Philip W. TI Clinical predictors of survival in men with castration-resistant prostate cancer: Evidence That Gleason Score 6 Cancer Can Evolve to Lethal Disease SO CANCER LA English DT Article DE castration-resistant prostate cancer; biopsy Gleason score; prostate-specific antigen; overall survival; clinical predictors ID CHEMOTHERAPY; MITOXANTRONE; PREDNISONE; SURROGACY; DOCETAXEL; PATTERNS; ANTIGEN; SYSTEM AB BACKGROUND: This study sought to characterize Modern patients with castration-resistant prostate cancer (CRPC) and identify pretreatment clinical predictors of survival. METHODS: A cohort of men with CRPC with and without metastases (M) treated with secondary hormonal therapy (2eHT) and/or chemotherapy (CT) was identified from the authors' institutional database. Associations of patient and disease characteristics at diagnosis, at androgen-deprivation therapy (ADT) initiation, at CRPC index date, and survival were evaluated. CRPC index date was defined as the start date of either 2eHT or CT, whichever came first. RESULTS: In the cohort of 622 men, 434 men (70%) had M-positive disease; 552 men (89%) received 2eHT and 70 men (11%) received CT as their initial CRPC treatment. There were 410 deaths (66%) at the time of analysis. Median overall survival (OS) was 35 months (quartile 1, quartile 3: 21 months, 61 months). In multivariate analyses, higher biopsy Gleason score, the presence of M at ADT initiation, shorter time from ADT start to CRPC, higher prostate-specific antigen and poorer Eastern Cooperative Oncology Group performance status at CRPC and M at CRPC were predictive of shorter OS. Interestingly, whereas some men with biopsy Gleason scores of 6 died of their disease (N542), they had a longer OS after CRPC compared with those with a Gleason score >= 7. CONCLUSIONS: This large retrospective study of patients with CRPC in a tertiary cancer center shows that biopsy Gleason score of 6 is associated with a less aggressive CRPC course, and the impact that M at ADT initiation and CRPC have on outcome is quantified. Cancer 2013; 119: 2990-8. (C) 2013 American Cancer Society. C1 [Nakabayashi, Mari; Hayes, Julia; Taplin, Mary-Ellen; Pomerantz, Mark; Sweeney, Christopher; Kantoff, Philip W.] Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02215 USA. [Nakabayashi, Mari; Hayes, Julia; Taplin, Mary-Ellen; Pomerantz, Mark; Sweeney, Christopher; Kantoff, Philip W.] Harvard Univ, Sch Med, Boston, MA USA. [Lefebvre, Patrick; Lafeuille, Marie-Helene; Duh, Mei Sheng] Anal Grp LLC, Boston, MA USA. RP Hayes, J (reprint author), Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 450 Brookline Ave, Boston, MA 02215 USA. EM julia_hayes@dfci.harvard.edu FU Janssen Scientific Affairs, LLC FX Mr. Lefebvre, Ms. Lafeuille, and Dr. Duh are employees of Analysis Group, Inc., a consulting company that has received research grants from Janssen Scientific Affairs, LLC. NR 16 TC 13 Z9 14 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2013 VL 119 IS 16 BP 2990 EP 2998 DI 10.1002/cncr.28102 PG 9 WC Oncology SC Oncology GA 194KQ UT WOS:000322632400010 PM 23719969 ER PT J AU Kroeger, N Xie, WL Lee, JL Bjarnason, GA Knox, JJ MacKenzie, MJ Wood, L Srinivas, S Vaishamayan, UN Rha, SY Pal, SK Yuasa, T Donskov, F Agarwal, N Kollmannsberger, CK Tan, MH North, SA Rini, BI Choueiri, TK Heng, DYC AF Kroeger, Nils Xie, Wanling Lee, Jae-Lyn Bjarnason, Georg A. Knox, Jennifer J. MacKenzie, Mary J. Wood, Lori Srinivas, Sandy Vaishamayan, Ulka N. Rha, Sun-Young Pal, Sumanta K. Yuasa, Takeshi Donskov, Frede Agarwal, Neeraj Kollmannsberger, Christian K. Tan, Min-Han North, Scott A. Rini, Brian I. Choueiri, Toni K. Heng, Daniel Y. C. TI Metastatic non-clear cell renal cell carcinoma treated with targeted therapy agents: Characterization of survival outcome and application of the International mRCC Database Consortium criteria SO CANCER LA English DT Article DE non-clear cell renal cell carcinoma; targeted therapies; overall survival; prognostication; Heng risk criteria; IMDC risk model ID INTERFERON-ALPHA; PROGNOSTIC MODEL; PHASE-3 TRIAL; SUNITINIB; TEMSIROLIMUS; EVEROLIMUS; SORAFENIB; TUMORS AB BACKGROUND: This study aimed to apply the International mRCC Database Consortium (IMDC) prognostic model in metastatic non-clear cell renal cell carcinoma (nccRCC). In addition, the survival outcome of metastatic nccRCC patients was characterized. METHODS: Data on 2215 patients (1963 with clear-cell RCC [ccRCC] and 252 with nccRCC) treated with first-line VEGF- and mTOR-targeted therapies were collected from the IMDC. Time to treatment failure (TTF) and overall survival (OS) were compared in groups with favorable, intermediate, and poor prognoses according to IMDC prognostic criteria RESULTS: The median OS of the entire cohort was 20.9 months. nccRCC patients were younger (P < .0001) and more often presented with low hemoglobin (P = .014) and elevated neutrophils (P = .0001), but otherwise had clinicopathological features similar to those of ccRCC patients. OS (12.8 vs 22.3 months; P < .0001) and TTF (4.2 vs 7.8 months; P < .0001) were worse in nccRCC patients compared with ccRCC patients. The hazard ratio for death and TTF when adjusted for the prognostic factors was 1.41 (95% CI, 1.19-1.67; P < .0001) and 1.54 (95% CI, 1.33-1.79; P < .0001), respectively. The IMDC prognostic model reliably discriminated 3 risk groups to predict OS and TTF in nccRCC; the median OS of the favorable, intermediate, and poor prognosis groups was 31.4, 16.1, and 5.1 months, respectively (P < .0001), and the median TTF was 9.6, 4.9, and 2.1 months, respectively (P < .0001). CONCLUSIONS: Although targeted agents have significantly improved the outcome of patients with nccRCC, for the majority survival is still inferior compared with patients with ccRCC. The IMDC prognostic model reliably predicts OS and TTF in nccRCC and ccRCC patients. Cancer 2013; 119: 2999-3006. (C) 2013 American Cancer Society. C1 [Kroeger, Nils; Heng, Daniel Y. C.] Tom Baker Canc Clin, Calgary, AB, Canada. [Kroeger, Nils] Univ Med Greifswald, Dept Urol, Greifswald, Germany. [Xie, Wanling; Choueiri, Toni K.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Lee, Jae-Lyn] Univ Ulsan, Coll Med, Asan, South Korea. [Bjarnason, Georg A.] Sunnybrook Odette Canc Ctr, Toronto, ON, Canada. [Knox, Jennifer J.] Univ Toronto, Princess Margaret Hosp, Toronto, ON, Canada. [MacKenzie, Mary J.] London Hlth Sci Ctr, London, ON, Canada. [Wood, Lori] Queen Elizabeth 2 Hlth Sci Ctr, Halifax, NS, Canada. [Srinivas, Sandy] Stanford Univ, Stanford Canc Inst, Sch Med, Stanford, CA 94305 USA. [Vaishamayan, Ulka N.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Rha, Sun-Young] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Seoul 120749, South Korea. [Pal, Sumanta K.] City Hope Comprehens Canc Ctr, Dept Med Oncol & Expt Therapeut, Duarte, CA USA. [Yuasa, Takeshi] Japanese Fdn Canc Res, Canc Inst Hosp, Dept Urol, Tokyo, Japan. [Donskov, Frede] Aarhus Univ Hosp, Dept Oncol, DK-8000 Aarhus, Denmark. [Agarwal, Neeraj] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Kollmannsberger, Christian K.] British Columbia Canc Agcy, Vancouver Canc Ctr, Vancouver, BC V5Z 4E6, Canada. [Tan, Min-Han] Natl Canc Ctr, Dept Med Oncol, Singapore, Singapore. [Tan, Min-Han] Inst Bioengn & Nanotechnol, Singapore, Singapore. [North, Scott A.] Univ Alberta, Cross Canc Ctr, Edmonton, AB, Canada. [Rini, Brian I.] Cleveland Clin Fdn, Taussig Canc Inst, Cleveland, OH 44195 USA. [Heng, Daniel Y. C.] Harvard Univ, Sch Med, Boston, MA USA. [Heng, Daniel Y. C.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Heng, DYC (reprint author), Univ Calgary, Tom Baker Canc Ctr, Staff Med Oncologist, 1331-29th St NW, Calgary, AB T2N 4N2, Canada. EM daniel.heng@albertahealthservices.ca OI Bjarnason, Georg Arnold/0000-0001-6903-5357; Donskov, Frede/0000-0002-8449-863X FU Bayer; Pfizer; Novartis; GlaxoSmithKline; Bayer Korea FX Nils Kroeger, Wanling Xie, Sandy Srinivas, Sumanta K. Pal, Takeshi Yuasa, Neeraj Agarwal, and Min-Han Tan made no disclosures. Jae-Lyn Lee has received honoraria from Novartis, Bayer, and Pfizer; has received research funding from Bayer. Georg A. Bjarnason has been a consultant and played an advisory role at Pfizer and received honoraria and research funding from Pfizer. Jennifer J. Knox has been a consultant and played an advisory role at Aveo and has received research funding from Pfizer. Mary J. MacKenzie has an advisory role at Novartis and Pfizer and has received research funding from both. Lori Wood has an advisory role at Pfizer and Novartis and has received research funding from Pfizer, Novartis, and GlaxoSmithKline. Ulka N. Vaishamayan has received honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Sun-Young Rha has an advisory role at Novartis, Pfizer, and GlaxoSmithKline and has received research funding from Novartis and Bayer Korea. Frede Donskov has received research funding from Novartis. Christian K. Kollmannsberger has an advisory role at Pfizer, Novartis, and GlaxoSmithKline and has received honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Scott A. North is a consultant and has an advisory role at Novartis, Bayer, GlaxoSmithKline, and Pfizer. Brian I. Rini has an advisory role at Pfizer, GlaxoSmithKline, Aveo, Bayer, and Onyx and has received research funding from GlaxoSmithKline and Pfizer. Toni K. Choueiri has received research funding from Pfizer and has an advisory role at Aveo, Pfizer, Novartis, GlaxoSmithKline, Genentech, Bayer, and Onyx. Daniel Y. C. Heng has an advisory role at Aveo, Pfizer, Novartis, and Bayer. NR 29 TC 44 Z9 45 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2013 VL 119 IS 16 BP 2999 EP 3006 DI 10.1002/cncr.28151 PG 8 WC Oncology SC Oncology GA 194KQ UT WOS:000322632400011 PM 23696129 ER PT J AU Mroz, EA Tward, AD Pickering, CR Myers, JN Ferris, RL Rocco, JW AF Mroz, Edmund A. Tward, Aaron D. Pickering, Curtis R. Myers, Jeffrey N. Ferris, Robert L. Rocco, James W. TI High intratumor genetic heterogeneity is related to worse outcome in patients with head and neck squamous cell carcinoma SO CANCER LA English DT Article DE head and neck cancer; intratumor genetic heterogeneity; tumor biomarkers; next-generation DNA sequencing; somatic mutations; overall survival ID NEXT-GENERATION; MUTATIONAL EVOLUTION; HUMAN-PAPILLOMAVIRUS; CLONAL EVOLUTION; BREAST-CANCER; TUMOR; METASTASIS; DIVERSITY; SURVIVAL; PROGRESSION AB BACKGROUND: Although the presence of genetic heterogeneity within the tumors of individual patients is established, it is unclear whether greater heterogeneity predicts a worse outcome. A quantitative measure of genetic heterogeneity based on next-generation sequencing (NGS) data, mutant-allele tumor heterogeneity (MATH), was previously developed and applied to a data set on head and neck squamous cell carcinoma (HNSCC). Whether this measure correlates with clinical outcome was not previously assessed. METHODS: The authors examined the association between MATH and clinical, pathologic, and overall survival data for 74 patients with HNSCC for whom exome sequencing was completed. RESULTS: High MATH (a MATH value above the median) was found to be significantly associated with shorter overall survival (hazards ratio, 2.5; 95% confidence interval, 1.3-4.8). MATH was similarly found to be associated with adverse outcomes in clinically high-risk patients with an advanced stage of disease, and in those with tumors classified as high risk on the basis of validated biomarkers including those that were negative for human papillomavirus or having disruptive tumor protein p53 mutations. In patients who received chemotherapy, the hazards ratio for high MATH was 4.1 (95% confidence interval, 1.6-10.2). CONCLUSIONS: This novel measure of tumor genetic heterogeneity is significantly associated with tumor progression and adverse treatment outcomes, thereby supporting the hypothesis that higher genetic heterogeneity portends a worse clinical outcome in patients with HNSCC. The prognostic value of some known biomarkers may be the result of their association with high genetic heterogeneity. MATH provides a useful measure of that heterogeneity to be prospectively validated as NGS data from homogeneously treated patient cohorts become available Cancer 2013; 119: 3034-42. (C) 2013 American Cancer Society. C1 [Mroz, Edmund A.; Rocco, James W.] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA. [Mroz, Edmund A.; Rocco, James W.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Tward, Aaron D.; Rocco, James W.] Harvard Univ, Sch Med, Dept Otolaryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. [Pickering, Curtis R.; Myers, Jeffrey N.] Univ Texas MD Anderson Canc Ctr, Dept Head & Neck Surg, Houston, TX 77030 USA. [Ferris, Robert L.] Univ Pittsburgh, Dept Otolaryngol, Inst Canc, Pittsburgh, PA 15260 USA. [Ferris, Robert L.] Univ Pittsburgh, Dept Radiat Oncol, Inst Canc, Pittsburgh, PA USA. [Ferris, Robert L.] Univ Pittsburgh, Dept Immunol, Inst Canc, Pittsburgh, PA USA. RP Rocco, JW (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Jackson 904G,55 Fruit St, Boston, MA 02114 USA. EM jrocco@partners.org OI Ferris, Robert/0000-0001-6605-2071 FU National Institute of Dental and Craniofacial Research [R01 DE022087, RC2DE020958]; National Cancer Institute [R21 CA119591]; Cancer Prevention Research Institute of Texas [RP100233]; Bacardi MEEI Biobank Fund FX Supported by The National Institute of Dental and Craniofacial Research (R01 DE022087 and RC2DE020958), the National Cancer Institute (R21 CA119591), the Cancer Prevention Research Institute of Texas (RP100233), and the Bacardi MEEI Biobank Fund. NR 33 TC 49 Z9 49 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2013 VL 119 IS 16 BP 3034 EP 3042 DI 10.1002/cncr.28150 PG 9 WC Oncology SC Oncology GA 194KQ UT WOS:000322632400016 PM 23696076 ER PT J AU Kwak, EL Shapiro, GI Cohen, SM Becerra, CR Lenz, HJ Cheng, WF Su, WC Robohn, M Le Maulf, F Lobmeyer, MT Chand, VK Iafrate, AJ AF Kwak, Eunice L. Shapiro, Geoffrey I. Cohen, Seth M. Becerra, Carlos R. Lenz, Heinz-Josef Cheng, Wen-Fang Su, Wu-Chou Robohn, Meghan Le Maulf, Florence Lobmeyer, Maximilian T. Chand, Vikram K. Iafrate, A. John TI Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation SO CANCER LA English DT Article DE afatinib; epidermal growth factor receptor; EGFR; EGFR-activating mutations; ErbB Family Blocker; gene amplification; human epidermal growth factor receptor 2; HER2; solid tumors ID GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; EGFR MUTATIONS; KINASE DOMAIN; BIBW 2992; INHIBITOR; HER2; ADENOCARCINOMA; GEFITINIB; THERAPY AB BACKGROUND: The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations. METHODS: Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. RESULTS: Of 385 pre-screened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. CONCLUSIONS: Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging. Cancer 2013; 119: 3043-51. (C) 2013 American Cancer Society. C1 [Kwak, Eunice L.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Shapiro, Geoffrey I.] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA. [Cohen, Seth M.] Continuum Canc Ctr New York, St Lukes Roosevelt Hosp Ctr, New York, NY USA. [Becerra, Carlos R.] USON Texas Oncol Baylor Charles A Sammons Canc Ct, Translat Oncol Program, Dallas, TX USA. [Lenz, Heinz-Josef] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Div Med Oncol, Los Angeles, CA 90033 USA. [Cheng, Wen-Fang] Natl Taiwan Univ Hosp, Dept Obstet & Gynecol, Taipei, Taiwan. [Su, Wu-Chou] Natl Cheng Kung Univ Hosp, Dept Internal Med, Tainan 70428, Taiwan. [Robohn, Meghan] Boehringer Ingelheim Pharmaceut Inc, Clin Trials Management, Ridgefield, CT 06877 USA. [Le Maulf, Florence] Boehringer Ingelheim Pharmaceut, Biostat & Data Management, Reims, France. [Lobmeyer, Maximilian T.] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. [Chand, Vikram K.] Boehringer Ingelheim Pharmaceut Inc, Clin Dev Med Affairs, Ridgefield, CT 06877 USA. [Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Kwak, EL (reprint author), Massachusetts Gen Hosp, 55 Fruit St Yawkey 7E, Boston, MA 02114 USA. EM ekwak@partners.org OI CHENG, WEN-FANG/0000-0002-3282-6304 FU Boehringer Ingelheim FX This study was supported by Boehringer Ingelheim. Medical writing assistance, supported financially by Boehringer Ingelheim, was provided by Aurora O'Brate of Ogilvy Healthworld. NR 32 TC 10 Z9 10 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2013 VL 119 IS 16 BP 3043 EP 3051 DI 10.1002/cncr.28120 PG 9 WC Oncology SC Oncology GA 194KQ UT WOS:000322632400017 PM 23775486 ER PT J AU Baldwin, LM Andrilla, CHA Porter, MP Rosenblatt, RA Patel, S Doescher, MP AF Baldwin, Laura-Mae Andrilla, C. Holly A. Porter, Michael P. Rosenblatt, Roger A. Patel, Shilpen Doescher, Mark P. TI Treatment of early-stage prostate cancer among rural and urban patients SO CANCER LA English DT Article DE prostatic neoplasms; rural population; health care quality; access; and evaluation; SEER Program ID BREAST-CANCER; RADIATION-THERAPY; TRAVEL DISTANCE; TREATMENT CHOICES; RADIOTHERAPY; MASTECTOMY; OUTCOMES; RECEIPT; CARCINOMA; SURVIVAL AB BACKGROUND: Geographic barriers and limited availability of cancer specialists may influence early prostate cancer treatment options for rural men. This study compares receipt of different early prostate cancer treatments between rural and urban patients. METHODS: Using 2004-2006 SEER Limited-Use Data, 51,982 early prostate cancer patients were identified (T1c, T2a, T2b, T2c, T2NOS; no metastases) who were most likely to benefit from definitive treatment (<75 years old, Gleason score<8, PSA <= 20). Definitive treatment included radical prostatectomy, daily external beam radiation for 5 to 8 weeks, brachytherapy, or combination external beam radiation/brachytherapy. Adjusted definitive treatment rates were calculated by rural-urban residence overall, and for different sociodemographic and cancer characteristics, and different states based on logistic regression analyses, using general estimating equation methods to account for clustering by county. RESULTS: Adjusted definitive treatment rates were lower for rural (83.7%) than urban (87.1%) patients with early-stage prostate cancer (P <= .01). Rural men were more likely than urban men to receive non-definitive surgical treatment and no initial treatment. The lowest definitive treatment rates were among rural subgroups: 70 to 74 years (73.9%), African Americans (75.6%), American Indians/Alaska Natives (77.8%), single/separated/divorced (76.8%), living in New Mexico (69.3%), and living in counties with persistent poverty (79.6%). CONCLUSIONS: Between 2004 and 2006, this adjusted analysis found that men who were living in rural areas were less likely to receive definitive treatment for their early-stage prostate cancer than those living in urban areas. Certain rural patient groups with prostate cancer need particular attention to ensure their access to appropriate treatment. Rural providerss, rural health care systems, and cancer advocacy and support organizations should ensure resources are in place so that the most vulnerable rural groups (men between 60 and 74 years of age; African American men; men who are single, separated, or divorced; and men living in rural New Mexico) can make informed prostate cancer treatment choices based on their preferences. Cancer 2013; 119: 3067-75. (C) 2013 American Cancer Society. C1 [Baldwin, Laura-Mae; Andrilla, C. Holly A.; Rosenblatt, Roger A.] Univ Washington, Dept Family Med, WWAMI Rural Hlth Res Ctr, Seattle, WA 98195 USA. [Porter, Michael P.] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Porter, Michael P.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Patel, Shilpen] Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. [Doescher, Mark P.] Univ Oklahoma, Hlth Serv Ctr, Peggy & Charles Stephenson Canc Ctr, Oklahoma City, OK USA. [Doescher, Mark P.] Univ Oklahoma, Hlth Serv Ctr, Dept Family Med, Oklahoma City, OK USA. RP Baldwin, LM (reprint author), Univ Washington, Dept Family Med, Box 354982, Seattle, WA 98195 USA. EM lmb@uw.edu FU federal Office of Rural Health Policy, Health Resources and Services Administration, Department of Health and Human Services FX This University of Washington Rural Health Research Center study was supported by the federal Office of Rural Health Policy, Health Resources and Services Administration, Department of Health and Human Services. This article is the result of work supported in part by resources from the VA Puget Sound Health Care System, Seattle, Washington. NR 31 TC 10 Z9 10 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X EI 1097-0142 J9 CANCER-AM CANCER SOC JI Cancer PD AUG 15 PY 2013 VL 119 IS 16 BP 3067 EP 3075 DI 10.1002/cncr.28037 PG 9 WC Oncology SC Oncology GA 194KQ UT WOS:000322632400020 PM 23765584 ER PT J AU Vick, A Estrada, CA Rodriguez, JM AF Vick, Amanda Estrada, Carlos A. Rodriguez, J. Martin TI Clinical Reasoning for the Infectious Disease Specialist: A Primer to Recognize Cognitive Biases SO CLINICAL INFECTIOUS DISEASES LA English DT Article DE cognitive biases; clinical reasoning; histoplasmosis; granulomatosis with polyangiitis ID DIAGNOSTIC ERROR; EDUCATIONAL-STRATEGIES; MEDICINE; MODEL AB Infectious disease specialists are frequently consulted for diagnostic and therapeutic advice on challenging cases. When evaluating patients, the infectious disease specialist is well positioned to offer an appropriate diagnostic approach but is also at risk of not recognizing the correct diagnosis for a variety of reasons. We believe it is important to provide infectious disease specialists and trainees with a fundamental understanding of diagnostic errors, clinical reasoning, and cognitive biases. We present 2 cases demonstrating common cognitive biases leading to diagnostic errors, and we reflect on strategies that may aid in their prevention. We hope to provide knowledge and tools that may help prevent diagnostic errors in the future. C1 [Vick, Amanda] Tinsley Harrison Internal Med Residency Program, Birmingham, AL USA. [Estrada, Carlos A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Estrada, Carlos A.] Univ Alabama Birmingham, Div Gen Internal Med, Birmingham, AL 35294 USA. [Rodriguez, J. Martin] Univ Alabama Birmingham, Div Infect Dis, Birmingham, AL 35294 USA. RP Rodriguez, JM (reprint author), Univ Alabama Birmingham, Div Infect Dis, THT 229 Tinsley Harrison Tower,1530 3rd Ave S, Birmingham, AL 35294 USA. EM mrodri2@uab.edu FU Merck Co, Inc. FX J. M. R. has received research support from Merck & Co, Inc. All other authors report no potential conflicts. NR 24 TC 3 Z9 3 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2013 VL 57 IS 4 BP 573 EP 578 DI 10.1093/cid/cit248 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 190LV UT WOS:000322342500022 PM 23595833 ER PT J AU Lee, JM Galkina, EI Levantovsky, RM Fossale, E Anderson, MA Gillis, T Mysore, JS Coser, KR Shioda, T Zhang, B Furia, MD Derry, J Kohane, IS Seong, IS Wheeler, VC Gusella, JF MacDonald, ME AF Lee, Jong-Min Galkina, Ekaterina I. Levantovsky, Rachel M. Fossale, Elisa Anderson, Mary Anne Gillis, Tammy Mysore, Jayalakshmi Srinidhi Coser, Kathryn R. Shioda, Toshi Zhang, Bin Furia, Matthew D. Derry, Jonathan Kohane, Isaac S. Seong, Ihn Sik Wheeler, Vanessa C. Gusella, James F. MacDonald, Marcy E. TI Dominant effects of the Huntingtons disease HTT CAG repeat length are captured in gene-expression data sets by a continuous analysis mathematical modeling strategy SO HUMAN MOLECULAR GENETICS LA English DT Article ID AGE-OF-ONSET; TRINUCLEOTIDE REPEAT; BRAIN; POLYGLUTAMINE; TRANSCRIPTION; CHROMOSOMES; PREDICTION; BIOMARKERS; EXPANSION; REVEAL AB In Huntingtons disease (HD), the size of the expanded HTT CAG repeat mutation is the primary driver of the processes that determine age at onset of motor symptoms. However, correlation of cellular biochemical parameters also extends across the normal repeat range, supporting the view that the CAG repeat represents a functional polymorphism with dominant effects determined by the longer allele. A central challenge to defining the functional consequences of this single polymorphism is the difficulty of distinguishing its subtle effects from the multitude of other sources of biological variation. We demonstrate that an analytical approach based upon continuous correlation with CAG size was able to capture the modest (21) contribution of the repeat to the variation in genome-wide gene expression in 107 lymphoblastoid cell lines, with alleles ranging from 15 to 92 CAGs. Furthermore, a mathematical model from an iterative strategy yielded predicted CAG repeat lengths that were significantly positively correlated with true CAG allele size and negatively correlated with age at onset of motor symptoms. Genes negatively correlated with repeat size were also enriched in a set of genes whose expression were CAG-correlated in human HD cerebellum. These findings both reveal the relatively small, but detectable impact of variation in the CAG allele in global data in these peripheral cells and provide a strategy for building multi-dimensional data-driven models of the biological network that drives the HD disease process by continuous analysis across allelic panels of neuronal cells vulnerable to the dominant effects of the HTT CAG repeat. C1 [Lee, Jong-Min; Galkina, Ekaterina I.; Levantovsky, Rachel M.; Fossale, Elisa; Anderson, Mary Anne; Gillis, Tammy; Mysore, Jayalakshmi Srinidhi; Seong, Ihn Sik; Wheeler, Vanessa C.; Gusella, James F.; MacDonald, Marcy E.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Coser, Kathryn R.; Shioda, Toshi] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Zhang, Bin; Furia, Matthew D.; Derry, Jonathan] Sage Bionetworks, Seattle, WA 98109 USA. [Kohane, Isaac S.] Childrens Hosp, Informat Program, Boston, MA 02115 USA. [Kohane, Isaac S.] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA 02114 USA. [Kohane, Isaac S.] I2b2 Natl Ctr Biomed Comp, Boston, MA 02115 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Simches Res Bldg,Room 5818,185 Cambridge St, Boston, MA 02114 USA. EM jlee51@partners.org FU CHDI Foundation, Inc.; National Institutes of Health; NINDS Massachusetts HD Center Without Walls [NS16367, NS32765]; NLM i2b2 [LM008748-01] FX This work was supported by grants from CHDI Foundation, Inc., the National Institutes of Health, NINDS Massachusetts HD Center Without Walls (grant number NS16367 to J.F.G. and M. E. M. and NS32765 to M. E. M.) and NLM i2b2 (grant number LM008748-01 to I. S. K.) and a gift from an Anonymous Donor. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 7 Z9 7 U1 2 U2 39 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 AUG 15 PY 2013 VL 22 IS 16 BP 3227 EP 3238 DI 10.1093/hmg/ddt176 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 190LK UT WOS:000322341300005 PM 23595883 ER PT J AU Korvatska, O Strand, NS Berndt, JD Strovas, T Chen, DH Leverenz, JB Kiianitsa, K Mata, IF Karakoc, E Greenup, JL Bonkowski, E Chuang, J Moon, RT Eichler, EE Nickerson, DA Zabetian, CP Kraemer, BC Bird, TD Raskind, WH AF Korvatska, Olena Strand, Nicholas S. Berndt, Jason D. Strovas, Tim Chen, Dong-Hui Leverenz, James B. Kiianitsa, Konstantin Mata, Ignacio F. Karakoc, Emre Greenup, J. Lynne Bonkowski, Emily Chuang, Joseph Moon, Randall T. Eichler, Evan E. Nickerson, Deborah A. Zabetian, Cyrus P. Kraemer, Brian C. Bird, Thomas D. Raskind, Wendy H. TI Altered splicing of ATP6AP2 causes X-linked parkinsonism with spasticity (XPDS) SO HUMAN MOLECULAR GENETICS LA English DT Article ID H+-ATPASE; (PRO)RENIN RECEPTOR; MENTAL-RETARDATION; PRORENIN RECEPTOR; MUTATIONS; REPEATS; PROTEIN; BAFILOMYCIN-A1; ACIDIFICATION; INHIBITOR AB We report a novel gene for a parkinsonian disorder. X-linked parkinsonism with spasticity (XPDS) presents either as typical adult onset Parkinsons disease or earlier onset spasticity followed by parkinsonism. We previously mapped the XPDS gene to a 28 Mb region on Xp11.2X13.3. Exome sequencing of one affected individual identified five rare variants in this region, of which none was missense, nonsense or frame shift. Using patient-derived cells, we tested the effect of these variants on expression/splicing of the relevant genes. A synonymous variant in ATP6AP2, c.345CT (p.S115S), markedly increased exon 4 skipping, resulting in the overexpression of a minor splice isoform that produces a protein with internal deletion of 32 amino acids in up to 50 of the total pool, with concomitant reduction of isoforms containing exon 4. ATP6AP2 is an essential accessory component of the vacuolar ATPase required for lysosomal degradative functions and autophagy, a pathway frequently affected in Parkinsons disease. Reduction of the full-size ATP6AP2 transcript in XPDS cells and decreased level of ATP6AP2 protein in XPDS brain may compromise V-ATPase function, as seen with siRNA knockdown in HEK293 cells, and may ultimately be responsible for the pathology. Another synonymous mutation in the same exon, c.321CT (p.D107D), has a similar molecular defect of exon inclusion and causes X-linked mental retardation Hedera type (MRXSH). Mutations in XPDS and MRXSH alter binding sites for different splicing factors, which may explain the marked differences in age of onset and manifestations. C1 [Korvatska, Olena; Raskind, Wendy H.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Strand, Nicholas S.; Berndt, Jason D.; Moon, Randall T.; Kraemer, Brian C.] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. [Chen, Dong-Hui; Leverenz, James B.; Mata, Ignacio F.; Bonkowski, Emily; Zabetian, Cyrus P.; Bird, Thomas D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Kiianitsa, Konstantin] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Karakoc, Emre; Eichler, Evan E.; Nickerson, Deborah A.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Chuang, Joseph; Bird, Thomas D.; Raskind, Wendy H.] Univ Washington, Dept Med Med Genet, Seattle, WA 98195 USA. [Kraemer, Brian C.] Univ Washington, Dept Med, Gerontol Div, Seattle, WA 98195 USA. [Strovas, Tim; Leverenz, James B.; Mata, Ignacio F.; Greenup, J. Lynne; Zabetian, Cyrus P.; Kraemer, Brian C.; Bird, Thomas D.] VA Puget Sound Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Leverenz, James B.; Zabetian, Cyrus P.] VA Puget Sound Hlth Care Syst, Parkinsons Dis Res Educ & Clin Ctr, Seattle, WA 98108 USA. [Leverenz, James B.; Raskind, Wendy H.] Dept Vet Affairs, Mental Illness Res Educ & Clin Ctr VISN 20, Seattle, WA 98108 USA. [Moon, Randall T.; Eichler, Evan E.] Howard Hughes Med Inst, Seattle, WA USA. RP Korvatska, O (reprint author), Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. EM ok5@u.washington.edu; wendyrun@uw.edu RI Berndt, Jason/M-3681-2013; Moon, Randall/B-1743-2014; OI Berndt, Jason/0000-0002-7388-6792; Moon, Randall/0000-0002-9352-1408; Fernandez Mata, Ignacio/0000-0003-1198-0633; Zabetian, Cyrus/0000-0002-7739-4306 FU Department of Veteran Affairs (VISN-20 MIRECC VA Puget Sound Health Care System); Department of Veteran Affairs (VA Merit Award) [1I01BX000531]; Department of Veteran Affairs (GRECC); Department of Veteran Affairs (PADRECC VA Puget Sound Health Care System, VA Merit Award) [I01BX000877]; American Recovery and Reinvestment Act funds, National Institutes of Health [RC2HG005608]; National Institutes of Health [T32 GM00727, P01 GM081619, R01NS069719, R01NS064131, R01 NS065070]; National Heart, Lung and Blood Institute [HL 1029230, HL 102924, HL-102925, HL 102926, HL-103010] FX This work was supported by the Department of Veteran Affairs (VISN-20 MIRECC VA Puget Sound Health Care System and VA Merit Award for T. D. B. and W. H. R., GRECC and PADRECC VA Puget Sound Health Care System, VA Merit Award I01BX000877 for B. C. K. and VA Merit Award 1I01BX000531 for C.P.Z.), the American Recovery and Reinvestment Act funds [through RC2HG005608 from the National Institutes of Health to D.A.N. and W. H. R.] and the National Institutes of Health (T32 GM00727 and P01 GM081619 to N.S.S., R01NS069719 to W. H. R., R01NS064131 to B. C. K. and R01 NS065070 to C.P.Z.). We would also like to recognize the following ongoing studies that produced and provided exome variant calls for comparison: the National Heart, Lung and Blood Institute [Lung GO Cohort Sequencing Project (HL 1029230) and the Women's Health Initiative Sequencing Project (HL 102924)], the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL 102926) and the Heart GO Sequencing Project (HL-103010). NR 34 TC 24 Z9 25 U1 3 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2013 VL 22 IS 16 BP 3259 EP 3268 DI 10.1093/hmg/ddt180 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 190LK UT WOS:000322341300008 PM 23595882 ER PT J AU Morrison, VA Oxman, MN Levin, MJ Schmader, KE Guatelli, JC Betts, RF Gelb, LD Pachucki, CT Keay, SK Menzies, B Griffin, MR Kauffman, CA Marques, AR Toney, JF Simberkoff, MS Serrao, R Arbeit, RD Gnann, JW Greenberg, RN Holodniy, M Keitel, WA Yeh, SS Davis, LE Crawford, GE Neuzil, KM Johnson, GR Zhang, JH Harbecke, R Chan, ISF Keller, PM Williams, HM Boardman, KD Silber, JL Annunziato, PW AF Morrison, Vicki A. Oxman, Michael N. Levin, Myron J. Schmader, Kenneth E. Guatelli, John C. Betts, Robert F. Gelb, Larry D. Pachucki, Constance T. Keay, Susan K. Menzies, Barbara Griffin, Marie R. Kauffman, Carol A. Marques, Adriana R. Toney, John F. Simberkoff, Michael S. Serrao, Richard Arbeit, Robert D. Gnann, John W. Greenberg, Richard N. Holodniy, Mark Keitel, Wendy A. Yeh, Shingshing S. Davis, Larry E. Crawford, George E. Neuzil, Kathy M. Johnson, Gary R. Zhang, Jane H. Harbecke, Rith Chan, Ivan S. F. Keller, Paul M. Williams, Heather M. Boardman, Kathy D. Silber, Jeffrey L. Annunziato, Paula W. CA Shingles Prevention Study Grp TI Safety of Zoster Vaccine in Elderly Adults Following Documented Herpes Zoster SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE zoster vaccine; herpes zoster; zoster vaccine safety; zoster vaccine in elderly persons; ACIP recommendations ID IMMUNE-RESPONSES; VIRUS; TRIAL AB After completion of the Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Studies Program Number 403), SPS participants who had initially received placebo were offered investigational zoster vaccine without charge. This provided an opportunity to determine the relative safety of zoster vaccine in older adults following documented herpes zoster (HZ). Methods. A total of 13 681 SPS placebo recipients who elected to receive zoster vaccine were followed for serious adverse events (SAE) for 28 days after vaccination. In contrast to the SPS, a prior episode of HZ was not a contraindication to receiving zoster vaccine. The SPS placebo recipients who received zoster vaccine included 420 who had developed documented HZ during the SPS. Results. The mean interval between the onset of HZ and the receipt of zoster vaccine in the 420 recipients with prior HZ was 3.61 years (median interval, 3.77 years [range, 3-85 months]); the interval was <5 years for approximately 80% of recipients. The proportion of vaccinated SPS placebo recipients with prior HZ who developed >= 1 SAE (0.95%) was not significantly different from that of vaccinated SPS placebo recipients with no prior history of HZ (0.66%), and the distribution of SAEs in the 2 groups was comparable. Conclusions. These results demonstrate that the general safety of zoster vaccine in older persons is not altered by a recent history of documented HZ, supporting the safety aspect of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommendation to administer zoster vaccine to all persons >= 60 years of age with no contraindications, regardless of a prior history of HZ. C1 [Morrison, Vicki A.] Vet Affairs Med Ctr, Minneapolis, MN USA. [Morrison, Vicki A.] Univ Minnesota, Minneapolis, MN USA. [Oxman, Michael N.; Guatelli, John C.; Harbecke, Rith; Williams, Heather M.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Oxman, Michael N.; Guatelli, John C.; Harbecke, Rith; Williams, Heather M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Levin, Myron J.] Univ Colorado Denver, Denver, CO USA. [Schmader, Kenneth E.] Durham Vet Affairs Med Ctr, GRECC, Durham, NC USA. [Schmader, Kenneth E.] Duke Univ, Med Ctr, Durham, NC USA. [Betts, Robert F.] Univ Rochester, New York, NY USA. [Gelb, Larry D.] Vet Affairs Med Ctr, St Louis, MO USA. [Pachucki, Constance T.] Hines Vet Affairs Med Ctr, Hines, IL USA. [Keay, Susan K.] Vet Affairs Maryland Hlth Care Syst, Baltimore, MD USA. [Keay, Susan K.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Menzies, Barbara; Neuzil, Kathy M.] Vet Affairs Med Ctr Puget Sound, Seattle, WA USA. [Griffin, Marie R.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Kauffman, Carol A.] Vet Affairs Ann Arbor Healthcare Syst, Ann Arbor, MI USA. [Kauffman, Carol A.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Marques, Adriana R.] NIAID, Bethesda, MD 20892 USA. [Toney, John F.] Vet Affairs Med Ctr, Tampa, FL USA. [Simberkoff, Michael S.] VA New York Harbor Healthcare Syst, New York, NY USA. [Simberkoff, Michael S.] NYU, Sch Med, New York, NY USA. [Serrao, Richard; Arbeit, Robert D.] Boston Univ, Boston, MA 02215 USA. [Gnann, John W.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Gnann, John W.] Univ Alabama Birmingham, Birmingham, AL USA. [Greenberg, Richard N.] Univ Kentucky, Sch Med, Lexington, KY 40506 USA. [Holodniy, Mark] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Keitel, Wendy A.] Baylor Coll Med, Houston, TX 77030 USA. [Yeh, Shingshing S.] Northport Vet Affairs Med Ctr, Northport, NY USA. [Davis, Larry E.] Vet Affairs Med Ctr, Albuquerque, NM USA. [Crawford, George E.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Johnson, Gary R.; Zhang, Jane H.] Dept Vet Affairs, Cooperat Studies Program, Coordinating Ctr, West Haven, CT USA. [Chan, Ivan S. F.; Keller, Paul M.; Silber, Jeffrey L.; Annunziato, Paula W.] Merck Sharp & Dohme Corp, Whitehouse Stn, NJ USA. [Boardman, Kathy D.] Dept Vet Affairs, Cooperat Studies Program, Clin Res Pharm Coordinating Ctr, Albuquerque, NM USA. RP Morrison, VA (reprint author), VAMC, Hematol Oncol Sect, 111E,1 Vet Dr, Minneapolis, MN 55417 USA. EM morri002@umn.edu RI Irwin, Michael/H-4870-2013; OI Irwin, Michael/0000-0002-1502-8431; Serrao, Richard/0000-0002-7440-8645 FU James R. and Jesse V. Scott Fund for Shingles Research FX The study was conducted by the Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development. Additional support was provided by Merck Sharp & Dohme, by the James R. and Jesse V. Scott Fund for Shingles Research, and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Data management and analysis support was provided at West Haven CSPCC by Karen Dellert and Kathy Newvine. NR 9 TC 18 Z9 18 U1 0 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2013 VL 208 IS 4 BP 559 EP 563 DI 10.1093/infdis/jit182 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 191KO UT WOS:000322412100005 PM 23633406 ER PT J AU French, AL Evans, CT Agniel, DM Cohen, MH Peters, M Landay, AL Desai, SN AF French, Audrey L. Evans, Charlesnika T. Agniel, Denis M. Cohen, Mardge H. Peters, Marion Landay, Alan L. Desai, Seema N. TI Microbial Translocation and Liver Disease Progression in Women Coinfected With HIV and Hepatitis C Virus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article DE HIV; hepatitis C; microbial translocation; fibrosis; liver disease progression; soluble CD14 ID HUMAN-IMMUNODEFICIENCY-VIRUS; PLATELET RATIO INDEX; GASTROINTESTINAL-TRACT; INFECTION; FIBROSIS; LIPOPOLYSACCHARIDE; THERAPY; FAILURE; PERFORMANCE; PREDICTION AB Background. Microbial translocation has been implicated in the pathogenesis of liver fibrosis and cirrhosis. We sought to determine whether markers of microbial translocation are associated with liver disease progression during coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Methods. We measured serial plasma lipopolysaccharide (LPS), endotoxin core antibody, intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), interleukin 6 (IL-6), interleukin 10, and tumor necrosis factor a (TNF-alpha) levels over a 5-year period in 44 HIV/HCV-coinfected women, 21 of whom experienced liver disease progression and 23 were nonprogressors. Results. While LPS levels did not differ significantly over time between progressors and nonprogressors (P = .60), progressors had significantly higher plasma levels of sCD14, a marker of monocyte activation by LPS, at the first time point measured (P = .03) and throughout the study period (P = .001); progressors also had higher IL-6 and I-FABP levels over the 5-year study period (P = .02 and .03, respectively). The associations between progression and sCD14, I-FABP, and IL-6 levels were unchanged in models controlling for HIV RNA and CD4(+) T-cell count. Conclusions. Although LPS levels did not differ between liver disease progressors and nonprogressors, the association of sCD14, I-FABP, and IL-6 levels with liver disease progression suggests that impairment of gut epithelial integrity and consequent microbial translocation may play a role in the complex interaction of HIV and HCV pathogenesis. C1 [French, Audrey L.; Agniel, Denis M.; Cohen, Mardge H.] John H Stroger Jr Hosp Cook Cty, CORE Ctr, Dept Med, Chicago, IL 60612 USA. [French, Audrey L.; Cohen, Mardge H.] Rush Univ, Med Ctr, Dept Med, Chicago, IL 60612 USA. [Landay, Alan L.; Desai, Seema N.] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. [Evans, Charlesnika T.] Northwestern Univ, Inst Healthcare Studies, Chicago, IL 60611 USA. [Evans, Charlesnika T.] US Dept Vet Affairs, Hines, IL USA. [Peters, Marion] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. RP French, AL (reprint author), John H Stroger Jr Hosp Cook Cty, Div Infect Dis, 1900 W Polk St,Rm 1243, Chicago, IL 60612 USA. EM audrey_French@rush.edu FU Chicago Consortium of the Women's Interagency HIV Study; National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; National Center for Research Resources [MO1-RR-00071, MO1-RR-00079, MO1-RR-00083]; Chicago Developmental Center for AIDS Research [P30 AI-082151] FX This work was supported by the Chicago Consortium of the Women's Interagency HIV Study, which is funded by the National Institute of Allergy and Infectious Diseases (grants UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and the National Institute of Child Health and Human Development (grant UO1-HD-32632); the National Cancer Institute; the National Institute on Drug Abuse; the National Institute on Deafness and Other Communication Disorders; the National Center for Research Resources (grants MO1-RR-00071, MO1-RR-00079, and MO1-RR-00083); and the Chicago Developmental Center for AIDS Research (grant P30 AI-082151 to A. L. F.). NR 43 TC 21 Z9 21 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2013 VL 208 IS 4 BP 679 EP 689 DI 10.1093/infdis/jit225 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 191KO UT WOS:000322412100018 PM 23687224 ER PT J AU Dhimolea, E Denes, V Lakk, M Al-Bazzaz, S Aziz-Zaman, S Pilichowska, M Geck, P AF Dhimolea, Eugen Denes, Viktoria Lakk, Monika Al-Bazzaz, Sana Aziz-Zaman, Sonya Pilichowska, Monika Geck, Peter TI High male chimerism in the female breast shows quantitative links with cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE fetal chimerism; allogeneic stem cells; Y-chromosome; breast cancer; HER2; pregnancy protection ID POLYMERASE-CHAIN-REACTION; EPITHELIAL STEM-CELLS; FETAL MICROCHIMERISM; PRENATAL-DIAGNOSIS; EMBEDDED TISSUES; PREGNANCY; DNA; TRAFFICKING; MARKER; WOMEN AB Clinical observations suggest that pregnancy provides protection against cancer. The mechanisms involved, however, remain unclear. Fetal cells are known to enter the mother's circulation during pregnancy and establish microchimerism. We investigated if pregnancy-related embryonic/fetal stem cell integration plays a role in breast cancer. A high-sensitivity Y-chromosome assay was developed to trace male allogeneic cells (from male fetus) in females. Fixed-embedded samples (n=206) from both normal and breast cancer patients were screened for microchimerism. The results were combined with matching clinicopathological and histological parameters and processed statistically. The results show that in our samples (182 informative) more than half of healthy women (56%) carried male cells in their breast tissue for decades (n=68), while only one out of five in the cancer sample pool (21%) (n=114) (odds ratio=4.75, CI at 95% 2.34-9.69; p=0.0001). The data support the notion that a biological link may exist between chimerism and tissue-integrity. The correlation, however, is non-linear, since male microchimerism in excess (hyperchimerism) is also involved in cancer. The data suggest a link between hyperchimerism and HER2-type cancers, while decreased chimerism (hypochimerism) associates with ER/PR-positive (luminal-type) breast cancers. Chimerism levels that correlate with protection appear to be non-random and share densities with the mammary progenitor components of the stem cell lineage in the breast. The results suggest that protection may involve stem/progenitor level interactions and implicate novel quantitative mechanisms in chimerism biology. C1 [Dhimolea, Eugen] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Denes, Viktoria; Lakk, Monika] Univ Pecs, Dept Expt Zool & Neurobiol, Pecs, Hungary. [Al-Bazzaz, Sana; Geck, Peter] Tufts Univ, Sch Med, Dept Anat & Cell Biol, Boston, MA 02111 USA. [Aziz-Zaman, Sonya] NYU Med Ctr, Inst Biomol Med, New York, NY 10016 USA. [Pilichowska, Monika] Tufts Med Ctr, Dept Pathol, Boston, MA USA. RP Geck, P (reprint author), Tufts Univ, Sch Med, Dept Anat & Cell Biol, Boston, MA 02111 USA. EM peter.geck@tufts.edu FU DOD [W81XWH08-1-0575, W81XWH09-1-00411] FX Grant sponsor: DOD Research Grants; Grant numbers: W81XWH08-1-0575 and W81XWH09-1-00411 NR 48 TC 7 Z9 9 U1 1 U2 43 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 15 PY 2013 VL 133 IS 4 BP 835 EP 842 DI 10.1002/ijc.28077 PG 8 WC Oncology SC Oncology GA 161LM UT WOS:000320194400007 PM 23390035 ER PT J AU London, MJ Schwartz, GG Henderson, WG AF London, Martin J. Schwartz, Gregory G. Henderson, William G. TI Mortality After Perioperative beta-Blocker Use in Noncardiac Surgery Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [London, Martin J.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Schwartz, Gregory G.] Vet Affairs Med Ctr, Cardiol Sect, Denver, CO USA. [Henderson, William G.] Colorado Sch Publ Hlth, Hlth Outcomes Program, Aurora, CO USA. RP London, MJ (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM londonm@anesthe-sia.ucsf.edu NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 14 PY 2013 VL 310 IS 6 BP 645 EP 645 DI 10.1001/jama.2013.8522 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 200HI UT WOS:000323058400026 PM 23942690 ER PT J AU Kostic, AD Chun, EY Robertson, L Glickman, JN Gallini, CA Michaud, M Clancy, TE Chung, DC Lochhead, P Hold, GL El-Omar, EM Brenner, D Fuchs, CS Meyerson, M Garrett, WS AF Kostic, Aleksandar D. Chun, Eunyoung Robertson, Lauren Glickman, Jonathan N. Gallini, Carey Ann Michaud, Monia Clancy, Thomas E. Chung, Daniel C. Lochhead, Paul Hold, Georgina L. El-Omar, Emad M. Brenner, Dean Fuchs, Charles S. Meyerson, Matthew Garrett, Wendy S. TI Fusobacterium nucleatum Potentiates Intestinal Tumorigenesis and Modulates the Tumor-Immune Microenvironment SO CELL HOST & MICROBE LA English DT Article ID REGULATORY T-CELLS; NF-KAPPA-B; COLORECTAL-CANCER; MICROBIAL PRODUCTS; BET DEFICIENCY; INFLAMMATION; ACTIVATION; DIVERSITY; INNATE; SYSTEM AB Increasing evidence links the gut microbiota with colorectal cancer. Metagenomic analyses indicate that symbiotic Fusobacterium spp. are associated with human colorectal carcinoma, but whether this is an indirect or causal link remains unclear. We find that Fusobacterium spp. are enriched in human colonic adenomas relative to surrounding tissues and in stool samples from colorectal adenoma and carcinoma patients compared to healthy subjects. Additionally, in the Apc(Min/+) mouse model of intestinal tumorigenesis, Fusobacterium nucleatum increases tumor multiplicity and selectively recruits tumor-infiltrating myeloid cells, which can promote tumor progression. Tumors from Apc(Min/+) mice exposed to F. nucleatum exhibit a proinflammatory expression signature that is shared with human fusobacteria-positive colorectal carcinomas. However, unlike other bacteria linked to colorectal carcinoma, F. nucleatum does not exacerbate colitis, enteritis, or inflammation-associated intestinal carcinogenesis. Collectively, these data suggest that, through recruitment of tumor-infiltrating immune cells, fusobacteria generate a proinflammatory microenvironment that is conducive for colorectal neoplasia progression. C1 [Kostic, Aleksandar D.; Glickman, Jonathan N.; Clancy, Thomas E.; Chung, Daniel C.; Fuchs, Charles S.; Meyerson, Matthew; Garrett, Wendy S.] Harvard Univ, Sch Med, Dept Med, Dept Pathol, Boston, MA 02115 USA. [Kostic, Aleksandar D.; Glickman, Jonathan N.; Clancy, Thomas E.; Chung, Daniel C.; Fuchs, Charles S.; Meyerson, Matthew; Garrett, Wendy S.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Kostic, Aleksandar D.; Clancy, Thomas E.; Fuchs, Charles S.; Meyerson, Matthew; Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Kostic, Aleksandar D.; Meyerson, Matthew; Garrett, Wendy S.] Broad Inst Harvard & MIT, Canc Program, Cambridge, MA 02142 USA. [Chun, Eunyoung; Robertson, Lauren; Gallini, Carey Ann; Michaud, Monia; Fuchs, Charles S.; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Chun, Eunyoung; Robertson, Lauren; Gallini, Carey Ann; Michaud, Monia; Fuchs, Charles S.; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Glickman, Jonathan N.] Miraca Life Sci Inc, Newton, MA 02464 USA. [Clancy, Thomas E.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Chung, Daniel C.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lochhead, Paul; Hold, Georgina L.; El-Omar, Emad M.] Univ Aberdeen, Sch Med & Dent, Aberdeen AB25 2ZD, Scotland. [Brenner, Dean] Univ Michigan, Med Ctr, Canc & Geriatr Ctr, Ann Arbor, MI 48109 USA. RP Meyerson, M (reprint author), Harvard Univ, Sch Med, Dept Med, Dept Pathol, Boston, MA 02115 USA. EM matthew_meyerson@dfci.harvard.edu; wgarrett@hsph.harvard.edu OI Kostic, Aleksandar/0000-0002-0837-4360 FU NCI; NCI [R01CA154426, P50CA127003, RC2CA148317]; NIAID [K08AI078942]; Burroughs Wellcome Career in Medical Sciences Award; Searle Scholars Award; Cancer Research Institute Investigator Award; National Genome Research Institute [U54HG003067]; Starr Cancer Consortium Award; SPORE [P50CA127003] FX We thank members of the Garrett and Meyerson labs for discussions and E. Allen-Vercoe for Fusobacterium strains and culturing advice. Adenomas and matched normal tissue samples were provided by the Cooperative Human Tissue Network, a NCI-supported resource. These studies were supported by R01CA154426 (NCI), K08AI078942 (NIAID), a Burroughs Wellcome Career in Medical Sciences Award, a Searle Scholars Award, and a Cancer Research Institute Investigator Award to W. S. G.; U54HG003067 (National Genome Research Institute), P50CA127003 (NCI), RC2CA148317 (NCI), R01CA154426 (NCI), and a Starr Cancer Consortium Award to M. Meyerson, and P50CA127003 (SPORE) to C.S.F. NR 39 TC 211 Z9 225 U1 16 U2 68 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 EI 1934-6069 J9 CELL HOST MICROBE JI Cell Host Microbe PD AUG 14 PY 2013 VL 14 IS 2 BP 207 EP 215 DI 10.1016/j.chom.2013.07.007 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA AA1JE UT WOS:000330851600011 PM 23954159 ER PT J AU Brack, AS AF Brack, Andrew S. TI Ageing of the heart reversed by youthful systemic factors! SO EMBO JOURNAL LA English DT Editorial Material ID REJUVENATION AB Age-associated changes in tissue maintenance and repair have severe consequences to human physiology. The signals and mechanisms that cause age-related tissue demise are unclear. A recently published study in Cell (Loffredo et al, 2013) proposes that blood-borne factors in the adult systemic environment are lost during ageing, which leads to cardiac hypertrophy. One such factor is GDF11. Exposure of aged mice to youthful systemic factors or GDF11 decreases cardiac hypertrophy of the heart. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med,Harvard Stem Cell Inst, Boston, MA 02114 USA. RP Brack, AS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Regenerat Med,Harvard Stem Cell Inst, Boston, MA 02114 USA. EM Brack.Andrew@mgh.harvard.edu FU NIAMS NIH HHS [R01 AR060868] NR 9 TC 1 Z9 1 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 14 PY 2013 VL 32 IS 16 BP 2189 EP 2190 DI 10.1038/emboj.2013.162 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 201YL UT WOS:000323178900002 PM 23860129 ER PT J AU Lefort, K Brooks, Y Ostano, P Cario-Andre, M Calpini, V Guinea-Viniegra, J Albinger-Hegyi, A Hoetzenecker, W Kolfschoten, I Wagner, EF Werner, S Dotto, GP AF Lefort, Karine Brooks, Yang Ostano, Paola Cario-Andre, Muriel Calpini, Valerie Guinea-Viniegra, Juan Albinger-Hegyi, Andrea Hoetzenecker, Wolfram Kolfschoten, Ingrid Wagner, Erwin F. Werner, Sabine Dotto, Gian Paolo TI A miR-34a-SIRT6 axis in the squamous cell differentiation network SO EMBO JOURNAL LA English DT Article DE actinic keratosis; miR-34a; p53; SIRT6; squamous cell carcinoma ID HISTONE DEACETYLASE SIRT6; SKIN DEVELOPMENT; FEEDBACK LOOP; PROMOTES DIFFERENTIATION; HUMAN KERATINOCYTES; TUMOR SUPPRESSION; EPITHELIAL-CELLS; GENE-EXPRESSION; GROWTH-CONTROL; MIR-34 FAMILY AB Squamous cell carcinomas (SCCs) are highly heterogeneous tumours, resulting from deranged expression of genes involved in squamous cell differentiation. Here we report that microRNA-34a (miR-34a) functions as a novel node in the squamous cell differentiation network, with SIRT6 as a critical target. miR-34a expression increases with keratinocyte differentiation, while it is suppressed in skin and oral SCCs, SCC cell lines, and aberrantly differentiating primary human keratinocytes (HKCs). Expression of this miRNA is restored in SCC cells, in parallel with differentiation, by reversion of genomic DNA methylation or wild-type p53 expression. In normal HKCs, the pro-differentiation effects of increased p53 activity or UVB exposure are miR-34a-dependent, and increased miR-34a levels are sufficient to induce differentiation of these cells both in vitro and in vivo. SIRT6, a sirtuin family member not previously connected with miR-34a function, is a direct target of this miRNA in HKCs, and SIRT6 down-modulation is sufficient to reproduce the miR-34a pro-differentiation effects. The findings are of likely biological significance, as SIRT6 is oppositely expressed to miR-34a in normal keratinocytes and keratinocyte-derived tumours. C1 [Lefort, Karine; Calpini, Valerie; Kolfschoten, Ingrid; Dotto, Gian Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Lefort, Karine] Univ Hosp CHUV, Dept Dermatol, Lausanne, Switzerland. [Brooks, Yang; Hoetzenecker, Wolfram; Dotto, Gian Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Ostano, Paola] Fdn Edo & Elvo Tempia Valenta, Lab Canc Genom, Biella, Italy. [Cario-Andre, Muriel] Bordeaux Univ Hosp, INSERM, U876, Bordeaux, France. [Cario-Andre, Muriel] Bordeaux Univ Hosp, Natl Reference Ctr Rare Skin Dis, Bordeaux, France. [Guinea-Viniegra, Juan; Wagner, Erwin F.] Ctr Nacl Invest Oncol, Fdn Banco Bilbao Vizcaya F BBVA, CNIO Canc Cell Biol Program, Madrid, Spain. [Albinger-Hegyi, Andrea] HNO Zuerich Fraumunster, HNO Praxis, Zurich, Switzerland. [Werner, Sabine] ETH, Inst Cell Biol, CH-8093 Zurich, Switzerland. RP Dotto, GP (reprint author), Univ Lausanne, Dept Biochem, Chemin Boveresses 155, CH-1066 Epalinges, Switzerland. EM karine.lefort@unil.ch; paolo.dotto@unil.ch RI Wagner, Erwin/G-9637-2012 OI Wagner, Erwin/0000-0001-7872-0196 FU Swiss National Foundation [CRSI33-130576/1, 3100A0-122281/1]; Oncosuisse [02361-02-2009]; NIH [AR39190]; Swiss L'Oreal 'ForWomen in Science' award; Lauretana S.P.A. FX We thank Drs J Rheinwald, J Rocco, A Rustgi, R Agami, KF Chua, X-F Wang, C Missero, SE Elledge and L Ellisen for their gifts of cells or plasmids. We are also grateful to Elena Menietti in our group for cloning the pINDUCER20-p53R248W and to N Allioli (University of Lyon, France) for her technical assistance for ISH in paraffin embedded tissues. We thank Donald Singer, Einar Castillo, as well as Florine Favre for their technical assistance. This work was supported by grants from the Swiss National Foundation (grants CRSI33-130576/1; 3100A0-122281/1), Oncosuisse (grant 02361-02-2009) and NIH (grant AR39190) to GPD. KL is a recipient of the Swiss L'Oreal 'ForWomen in Science' award. PO was supported by a grant from Lauretana S.P.A. NR 95 TC 39 Z9 45 U1 0 U2 17 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 14 PY 2013 VL 32 IS 16 BP 2248 EP 2263 DI 10.1038/emboj.2013.156 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 201YL UT WOS:000323178900007 PM 23860128 ER PT J AU Sawides, L Dorronsoro, C Haun, AM Peli, E Marcos, S AF Sawides, Lucie Dorronsoro, Carlos Haun, Andrew M. Peli, Eli Marcos, Susana TI Using Pattern Classification to Measure Adaptation to the Orientation of High Order Aberrations SO PLOS ONE LA English DT Article ID VISUAL PERFORMANCE; NEURAL COMPENSATION; SIGNAL-DETECTION; FEATURES; SURGERY; VISION; IMAGES; ACUITY; MYOPIA; TASKS AB Background: The image formed by the eye's optics is blurred by the ocular aberrations, specific to each eye. Recent studies demonstrated that the eye is adapted to the level of blur produced by the high order aberrations (HOA). We examined whether visual coding is also adapted to the orientation of the natural HOA of the eye. Methods and Findings: Judgments of perceived blur were measured in 5 subjects in a psychophysical procedure inspired by the "Classification Images" technique. Subjects were presented 500 pairs of images, artificially blurred with HOA from 100 real eyes (i.e. different orientations), with total blur level adjusted to match the subject's natural blur. Subjects selected the image that appeared best focused in each random pair, in a 6-choice ranked response. Images were presented through Adaptive Optics correction of the subject's aberrations. The images selected as best focused were identified as positive, the other as negative responses. The highest classified positive responses correlated more with the subject's Point Spread Function, PSF, (r = 0.47 on average) than the negative (r = 0.34) and the difference was significant for all subjects (p<0.02). Using the orientation of the best fitting ellipse of angularly averaged integrated PSF intensities (weighted by the subject's responses) we found that in 4 subjects the positive PSF response was close to the subject's natural PSF orientation (within 21 degrees on average) whereas the negative PSF response was almost perpendicularly oriented to the natural PSF (at 76 degrees on average). Conclusions: The Classification-Images inspired method is very powerful in identifying the internally coded blur of subjects. The consistent bias of the Positive PSFs towards the natural PSF in most subjects indicates that the internal code of blur appears rather specific to each subject's high order aberrations and reveals that the calibration mechanisms for normalizing blur also operate using orientation cues. C1 [Sawides, Lucie; Dorronsoro, Carlos; Marcos, Susana] CSIC, Inst Opt, E-28006 Madrid, Spain. [Haun, Andrew M.; Peli, Eli] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA USA. RP Sawides, L (reprint author), CSIC, Inst Opt, Serrano 121, E-28006 Madrid, Spain. EM lucie@io.cfmac.csic.es RI Dorronsoro, Carlos/A-2297-2011; Haun, Andrew/I-4956-2012; Sawides, Lucie/O-1431-2016 OI Haun, Andrew/0000-0001-9458-8957; Sawides, Lucie/0000-0002-8918-8753 FU Spanish Government [FIS2011-25637]; European Research Council [ERC-AdG-294099]; US National Institutes of Health [EY05957] FX The authors acknoweldge funding from Spanish Government grant FIS2011-25637 (to SM), European Research Council Advanced Grant ERC-AdG-294099 (to SM), and US National Institutes of Health EY05957 (to EP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 6 Z9 6 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2013 VL 8 IS 8 AR e70856 DI 10.1371/journal.pone.0070856 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202MQ UT WOS:000323221500041 PM 23967123 ER PT J AU Schroeder, FA Lewis, MC Fass, DM Wagner, FF Zhang, YL Hennig, KM Gale, J Zhao, WN Reis, S Barker, DD Berry-Scott, E Kim, SW Clore, EL Hooker, JM Holson, EB Haggarty, SJ Petryshen, TL AF Schroeder, Frederick A. Lewis, Michael C. Fass, Daniel M. Wagner, Florence F. Zhang, Yan-Ling Hennig, Krista M. Gale, Jennifer Zhao, Wen-Ning Reis, Surya Barker, Douglas D. Berry-Scott, Erin Kim, Sung Won Clore, Elizabeth L. Hooker, Jacob M. Holson, Edward B. Haggarty, Stephen J. Petryshen, Tracey L. TI A Selective HDAC 1/2 Inhibitor Modulates Chromatin and Gene Expression in Brain and Alters Mouse Behavior in Two Mood-Related Tests SO PLOS ONE LA English DT Article ID HISTONE DEACETYLASE INHIBITORS; VALPROIC ACID; STRAIN DIFFERENCES; NUCLEUS-ACCUMBENS; PROTEIN-KINASE; MESSENGER-RNA; LITHIUM; MICE; ACETYLATION; HIPPOCAMPUS AB Psychiatric diseases, including schizophrenia, bipolar disorder and major depression, are projected to lead global disease burden within the next decade. Pharmacotherapy, the primary - albeit often ineffective - treatment method, has remained largely unchanged over the past 50 years, highlighting the need for novel target discovery and improved mechanism-based treatments. Here, we examined in wild type mice the impact of chronic, systemic treatment with Compound 60 (Cpd-60), a slow-binding, benzamide-based inhibitor of the class I histone deacetylase (HDAC) family members, HDAC1 and HDAC2, in mood-related behavioral assays responsive to clinically effective drugs. Cpd-60 treatment for one week was associated with attenuated locomotor activity following acute amphetamine challenge. Further, treated mice demonstrated decreased immobility in the forced swim test. These changes are consistent with established effects of clinical mood stabilizers and antidepressants, respectively. Whole-genome expression profiling of specific brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from mice treated with Cpd-60 identified gene expression changes, including a small subset of transcripts that significantly overlapped those previously reported in lithium-treated mice. HDAC inhibition in brain was confirmed by increased histone acetylation both globally and, using chromatin immunoprecipitation, at the promoter regions of upregulated transcripts, a finding consistent with in vivo engagement of HDAC targets. In contrast, treatment with suberoylanilide hydroxamic acid (SAHA), a non-selective fast-binding, hydroxamic acid HDAC 1/2/3/ 6 inhibitor, was sufficient to increase histone acetylation in brain, but did not alter mood-related behaviors and had dissimilar transcriptional regulatory effects compared to Cpd-60. These results provide evidence that selective inhibition of HDAC1 and HDAC2 in brain may provide an epigenetic-based target for developing improved treatments for mood disorders and other brain disorders with altered chromatin-mediated neuroplasticity. C1 [Schroeder, Frederick A.; Fass, Daniel M.; Hennig, Krista M.; Zhao, Wen-Ning; Reis, Surya; Haggarty, Stephen J.; Petryshen, Tracey L.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Schroeder, Frederick A.; Haggarty, Stephen J.; Petryshen, Tracey L.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Schroeder, Frederick A.; Hooker, Jacob M.; Haggarty, Stephen J.; Petryshen, Tracey L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Haggarty, Stephen J.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Hooker, Jacob M.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Schroeder, Frederick A.; Hooker, Jacob M.] Harvard Univ, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Sch Med,Dept Radiol, Charlestown, MA USA. [Lewis, Michael C.; Fass, Daniel M.; Wagner, Florence F.; Zhang, Yan-Ling; Hennig, Krista M.; Gale, Jennifer; Barker, Douglas D.; Berry-Scott, Erin; Clore, Elizabeth L.; Hooker, Jacob M.; Holson, Edward B.; Haggarty, Stephen J.; Petryshen, Tracey L.] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA. [Kim, Sung Won] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. RP Haggarty, SJ (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM haggarty@chgr.mgh.harvard.edu; petryshen@chgr.mgh.harvard.edu OI Hooker, Jacob/0000-0002-9394-7708 FU Stanley Medical Research Institute; NIH [R01DA028301, R01DA030321] FX This work was supported by the Stanley Medical Research Institute (T. L. P. and S.J.H.) and the NIH (R01DA028301 to S.J.H. and R01DA030321 to S.J.H. and J.M.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 39 Z9 39 U1 0 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2013 VL 8 IS 8 AR e71323 DI 10.1371/journal.pone.0071323 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202MQ UT WOS:000323221500074 PM 23967191 ER PT J AU Yamaguchi, T Turhan, A Harris, DL Hu, K Pruss, H von Andrian, U Hamrah, P AF Yamaguchi, Takefumi Turhan, Aslihan Harris, Deshea L. Hu, Kai Pruess, Harald von Andrian, Ulrich Hamrah, Pedram TI Bilateral Nerve Alterations in a Unilateral Experimental Neurotrophic Keratopathy Model: A Lateral Conjunctival Approach for Trigeminal Axotomy SO PLOS ONE LA English DT Article ID VIVO-CONFOCAL-MICROSCOPY; STROMAL HERPETIC-KERATITIS; CORNEAL EPITHELIAL-CELLS; RAT SPINAL-CORD; SUBSTANCE-P; INTRAOCULAR-PRESSURE; DIABETIC-RETINOPATHY; ZOSTER OPHTHALMICUS; SENSORY DENERVATION; SJOGRENS-SYNDROME AB To study bilateral nerve changes in a newly developed novel mouse model for neurotrophic keratopathy by approaching the trigeminal nerve from the lateral fornix. Surgical axotomy of the ciliary nerve of the trigeminal nerve was performed in adult BALB/c mice at the posterior sclera. Axotomized, contralateral, and sham-treated corneas were excised on post-operative days 1, 3, 5, 7 and 14 and immunofluorescence histochemistry was performed with anti-beta-tubulin antibody to evaluate corneal nerve density. Blink reflex was evaluated using a nylon thread. The survival rate was 100% with minimal bleeding during axotomy and a surgical time of 8 +/- 0.5 minutes. The blink reflex was diminished at day 1 after axotomy, but remained intact in the contralateral eyes in all mice. The central and peripheral subbasal nerves were not detectable in the axotomized cornea at day 1 (p<0.001), compared to normal eyes (101.3 +/- 14.8 and 69.7 +/- 12.0 mm/mm(2) centrally and peripherally). Interestingly, the subbasal nerve density in the contralateral non-surgical eyes also decreased significantly to 62.4 +/- 2.8 mm/mm(2) in the center from day 1 (p<0.001), but did not change in the periphery (77.3 +/- 11.7 mm/mm(2), P = 0.819). Our novel trigeminal axotomy mouse model is highly effective, less invasive, rapid, and has a high survival rate, demonstrating immediate loss of subbasal nerves in axotomized eyes and decreased subbasal nerves in contralateral eyes after unilateral axotomy. This model will allow investigating the effects of corneal nerve damage and serves as a new model for neurotrophic keratopathy. C1 [Yamaguchi, Takefumi; Turhan, Aslihan; Harris, Deshea L.; Hu, Kai; Hamrah, Pedram] Harvard Univ, Sch Med, Dept Ophthalmol, Schepens Eye Res Inst, Boston, MA 02114 USA. [Yamaguchi, Takefumi; Turhan, Aslihan; Harris, Deshea L.; Hamrah, Pedram] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Cornea Serv,Dept Ophthalmol, Boston, MA USA. [Pruess, Harald] Charite, Dept Neurol, D-13353 Berlin, Germany. [von Andrian, Ulrich; Hamrah, Pedram] Harvard Univ, Sch Med, Immune Dis Inst, Program Cellular & Mol Med,Childrens Hosp Boston, Boston, MA USA. RP Hamrah, P (reprint author), Harvard Univ, Sch Med, Dept Ophthalmol, Schepens Eye Res Inst, Boston, MA 02114 USA. EM pedram_hamrah@meei.harvard.edu OI Harris, Deshea/0000-0002-8194-1827 FU National Institutes of Health (NIH) [K08-EY020575, K12-EY016335]; Research to Prevent Blindness Career Development Award; Bausch Lomb Ocular Surface Research Award FX This study was supported by the National Institutes of Health (NIH) K08-EY020575 (PH), NIH K12-EY016335 (PH), Research to Prevent Blindness Career Development Award (PH), and Bausch Lomb Ocular Surface Research Award (TY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 77 TC 6 Z9 7 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2013 VL 8 IS 8 AR e70908 DI 10.1371/journal.pone.0070908 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202MQ UT WOS:000323221500046 PM 23967133 ER PT J AU Ybarra, ML Bull, SS Prescott, TL Korchmaros, JD Bangsberg, DR Kiwanuka, JP AF Ybarra, Michele L. Bull, Sheana S. Prescott, Tonya L. Korchmaros, Josephine D. Bangsberg, David R. Kiwanuka, Julius P. TI Adolescent Abstinence and Unprotected Sex in CyberSenga, an Internet-Based HIV Prevention Program: Randomized Clinical Trial of Efficacy SO PLOS ONE LA English DT Article ID BEHAVIORAL SKILLS MODEL; SOUTH-AFRICAN YOUTH; INFORMATION; MOTIVATION; INTERVENTION; HEALTH; TRENDS; MEN AB Context: Cost-effective, scalable programs are urgently needed in countries deeply affected by HIV. Methods: This parallel-group RCT was conducted in four secondary schools in Mbarara, Uganda. Participants were 12 years and older, reported past-year computer or Internet use, and provided informed caregiver permission and youth assent. The intervention, CyberSenga, was a five-hour online healthy sexuality program. Half of the intervention group was further randomized to receive a booster at four-months post-intervention. The control arm received 'treatment as usual' (i.e., school-delivered sexuality programming). The main outcome measures were: 1) condom use and 2) abstinence in the past three months at six-months' post-intervention. Secondary outcomes were: 1) condom use and 2) abstinence at three-month's post-intervention; and 6-month outcomes by booster exposure. Analyses were intention to treat. Results: All 416 eligible youth were invited to participate, 88% (n = 366) of whom enrolled. Participants were randomized to the intervention (n = 183) or control (n = 183) arm; 91 intervention participants were further randomized to the booster. No statistically significant results were noted among the main outcomes. Among the secondary outcomes: At three-month follow-up, trends suggested that intervention participants (81%) were more likely to be abstinent than control participants (74%; p = 0.08), and this was particularly true among youth who were abstinent at baseline (88% vs. 77%; p = 0.02). At six-month follow-up, those in the booster group (80%) reported higher rates of abstinence than youth in the intervention, no booster (57%) and control (55%) groups (p = 0.15); they also reported lower rates of unprotected sex (5%) compared to youth in the intervention, no booster (24%) and control (21%) groups (p = 0.21) among youth sexually active at baseline. Conclusions: The CyberSenga program may affect HIV preventive behavior among abstinent youth in the short term and, with the booster, may also promote HIV preventive behavior among sexually active youth in the longer term. C1 [Ybarra, Michele L.; Prescott, Tonya L.; Korchmaros, Josephine D.] Ctr Innovat Publ Hlth Res, San Clemente, CA USA. [Bull, Sheana S.] Colorado Sch Publ Hlth, Dept Community & Behav Hlth, Aurora, CO USA. [Bangsberg, David R.] Mbarara Univ Sci & Technol, Ragon Inst Massachusetts Gen Hosp Massachusetts I, Massachusetts Gen Hosp, Ctr Global Hlth, Boston, MA 02114 USA. [Kiwanuka, Julius P.] Mbarara Univ Sci & Technol, Dept Pediat, Mbarara, Uganda. RP Ybarra, ML (reprint author), Ctr Innovat Publ Hlth Res, San Clemente, CA USA. EM Michele@InnovativePublicHealth.org FU National Institute of Mental Health [R01MH080662] FX The project described was supported by Award Number R01MH080662 from the National Institute of Mental Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 11 Z9 11 U1 2 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 14 PY 2013 VL 8 IS 8 AR e70083 DI 10.1371/journal.pone.0070083 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202MQ UT WOS:000323221500014 PM 23967069 ER PT J AU Dhaliwal, G Detsky, AS AF Dhaliwal, Gurpreet Detsky, Allan S. TI The Evolution of the Master Diagnostician SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PHYSICIANS C1 [Dhaliwal, Gurpreet] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, Med Serv, San Francisco, CA USA. [Detsky, Allan S.] Univ Toronto, Dept Med, Inst Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Detsky, Allan S.] Mt Sinai Hosp, Dept Med, Toronto, ON M5G 1X5, Canada. [Detsky, Allan S.] Univ Hlth Network, Toronto, ON, Canada. RP Detsky, AS (reprint author), Mt Sinai Hosp, 600 Univ Ave,Room 429, Toronto, ON M5G 1X5, Canada. EM adetsky@mtsinai.on.ca NR 9 TC 4 Z9 4 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 14 PY 2013 VL 310 IS 6 BP 579 EP 580 DI 10.1001/jama.2013.7572 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 200HI UT WOS:000323058400009 PM 23942674 ER PT J AU Murray, CJL Abraham, J Ali, MK Alvarado, M Atkinson, C Baddour, LM Bartels, DH Benjamin, EJ Bhalla, K Birbeck, G Bolliger, I Burstein, R Carnahan, E Chen, HL Chou, D Chugh, SS Cohen, A Colson, KE Cooper, LT Couser, W Criqui, MH Dabhadkar, KC Dahodwala, N Danaei, G Dellavalle, RP Des Jarlais, DC Dicker, D Ding, EL Dorsey, R Duber, H Ebel, BE Engell, RE Ezzati, M Felson, DT Finucane, MM Flaxman, S Flaxman, AD Fleming, T Forouzanfar, MH Freedman, G Freeman, MK Gabriel, SE Gakidou, E Gillum, RF Gonzalez-Medina, D Gosselin, R Grant, B Gutierrez, HR Hagan, H Havmoeller, R Hoffman, H Jacobsen, KH James, SL Jasrasaria, R Jayaraman, S Johns, N Kassebaum, N Khatibzadeh, S Knowlton, LM Lan, Q Leasher, JL Lim, S Lin, JK Lipshultz, SE London, S Lozano, R Lu, Y MacIntyre, MF Mallinger, L McDermott, MM Meltzer, M Mensah, GA Michaud, C Miller, TR Mock, C Moffitt, TE Mokdad, AA Mokdad, AH Moran, AE Mozaffarian, D Murphy, T Naghavi, M Narayan, KMV Nelson, RG Olives, C Omer, SB Ortblad, K Ostro, B Pelizzari, PM Phillips, D Pope, CA Raju, M Ranganathan, D Razavi, H Ritz, B Rivara, FP Roberts, T Sacco, RL Salomon, JA Sampson, U Sanman, E Sapkota, A Schwebel, DC Shahraz, S Shibuya, K Shivakoti, R Silberberg, D Singh, GM Singh, D Singh, JA Sleet, DA Steenland, K Tavakkoli, M Taylor, JA Thurston, GD Towbin, JA Vavilala, MS Vos, T Wagner, GR Weinstock, MA Weisskopf, MG Wilkinson, JD Wulf, S Zabetian, A Lopez, AD AF Murray, Christopher J. L. Abraham, Jerry Ali, Mohammed K. Alvarado, Miriam Atkinson, Charles Baddour, Larry M. Bartels, David H. Benjamin, Emelia J. Bhalla, Kavi Birbeck, Gretchen Bolliger, Ian Burstein, Roy Carnahan, Emily Chen, Honglei Chou, David Chugh, Sumeet S. Cohen, Aaron Colson, K. Ellicott Cooper, Leslie T. Couser, William Criqui, Michael H. Dabhadkar, Kaustubh C. Dahodwala, Nabila Danaei, Goodarz Dellavalle, Robert P. Des Jarlais, Don C. Dicker, Daniel Ding, Eric L. Dorsey, Ray Duber, Herbert Ebel, Beth E. Engell, Rebecca E. Ezzati, Majid Felson, David T. Finucane, Mariel M. Flaxman, Seth Flaxman, Abraham D. Fleming, Thomas Forouzanfar, Mohammad H. Freedman, Greg Freeman, Michael K. Gabriel, Sherine E. Gakidou, Emmanuela Gillum, Richard F. Gonzalez-Medina, Diego Gosselin, Richard Grant, Bridget Gutierrez, Hialy R. Hagan, Holly Havmoeller, Rasmus Hoffman, Howard Jacobsen, Kathryn H. James, Spencer L. Jasrasaria, Rashmi Jayaraman, Sudha Johns, Nicole Kassebaum, Nicholas Khatibzadeh, Shahab Knowlton, Lisa Marie Lan, Qing Leasher, Janet L. Lim, Stephen Lin, John Kent Lipshultz, Steven E. London, Stephanie Lozano, Rafael Lu, Yuan MacIntyre, Michael F. Mallinger, Leslie McDermott, Mary M. Meltzer, Michele Mensah, George A. Michaud, Catherine Miller, Ted R. Mock, Charles Moffitt, Terrie E. Mokdad, Ali A. Mokdad, Ali H. Moran, Andrew E. Mozaffarian, Dariush Murphy, Tasha Naghavi, Mohsen Narayan, K. M. Venkat Nelson, Robert G. Olives, Casey Omer, Saad B. Ortblad, Katrina Ostro, Bart Pelizzari, Pamela M. Phillips, David Pope, C. Arden, III Raju, Murugesan Ranganathan, Dharani Razavi, Homie Ritz, Beate Rivara, Frederick P. Roberts, Thomas Sacco, Ralph L. Salomon, Joshua A. Sampson, Uchechukwu Sanman, Ella Sapkota, Amir Schwebel, David C. Shahraz, Saeid Shibuya, Kenji Shivakoti, Rupak Silberberg, Donald Singh, Gitanjali M. Singh, David Singh, Jasvinder A. Sleet, David A. Steenland, Kyle Tavakkoli, Mohammad Taylor, Jennifer A. Thurston, George D. Towbin, Jeffrey A. Vavilala, Monica S. Vos, Theo Wagner, Gregory R. Weinstock, Martin A. Weisskopf, Marc G. Wilkinson, James D. Wulf, Sarah Zabetian, Azadeh Lopez, Alan D. CA Us Burden Dis Collaborators TI The State of US Health, 1990-2010 Burden of Diseases, Injuries, and Risk Factors SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID BODY-MASS INDEX; ADJUSTED LIFE YEARS; GLOBAL BURDEN; SYSTEMATIC ANALYSIS; UNITED-STATES; PUBLIC-HEALTH; CARDIOVASCULAR-DISEASE; BUILT ENVIRONMENT; PHYSICAL-ACTIVITY; BLOOD-PRESSURE AB IMPORTANCE Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy. OBJECTIVES To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries. DESIGN We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages. RESULTS US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th. CONCLUSIONS AND RELEVANCE From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations. C1 [Murray, Christopher J. L.; Alvarado, Miriam; Atkinson, Charles; Bolliger, Ian; Burstein, Roy; Carnahan, Emily; Chou, David; Colson, K. Ellicott; Dicker, Daniel; Duber, Herbert; Engell, Rebecca E.; Flaxman, Abraham D.; Gakidou, Emmanuela; Gonzalez-Medina, Diego; James, Spencer L.; Jasrasaria, Rashmi; Johns, Nicole; Lim, Stephen; MacIntyre, Michael F.; Mallinger, Leslie; Mokdad, Ali A.; Mokdad, Ali H.; Murphy, Tasha; Naghavi, Mohsen; Ortblad, Katrina; Phillips, David; Ranganathan, Dharani; Roberts, Thomas; Sanman, Ella; Vos, Theo; Wulf, Sarah] Inst Hlth Metr & Evaluat, Seattle, WA 98121 USA. [Couser, William; Ebel, Beth E.; Kassebaum, Nicholas; Mock, Charles; Olives, Casey; Rivara, Frederick P.; Vavilala, Monica S.] Univ Washington, Seattle, WA 98195 USA. [Abraham, Jerry] Univ Texas San Antonio, Sch Med, San Antonio, TX USA. [Omer, Saad B.; Steenland, Kyle] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Ali, Mohammed K.; Dabhadkar, Kaustubh C.; Narayan, K. M. Venkat; Zabetian, Azadeh] Emory Univ, Atlanta, GA 30322 USA. [Baddour, Larry M.; Gabriel, Sherine E.] Mayo Clin, Rochester, MN USA. [Danaei, Goodarz; Ding, Eric L.; Finucane, Mariel M.; Khatibzadeh, Shahab; Knowlton, Lisa Marie; Lin, John Kent; Lu, Yuan; Singh, Gitanjali M.; Tavakkoli, Mohammad; Weisskopf, Marc G.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bartels, David H.; Jayaraman, Sudha; Mozaffarian, Dariush] Harvard Univ, Sch Med, Boston, MA USA. [Bhalla, Kavi] Harvard Univ, Boston, MA 02115 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Felson, David T.] Boston Univ, Boston, MA 02215 USA. [Birbeck, Gretchen] Michigan State Univ, E Lansing, MI USA. [Chen, Honglei; London, Stephanie] NIEHS, Res Triangle Pk, NC 27709 USA. [Lan, Qing] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Grant, Bridget; Hoffman, Howard; Mensah, George A.] NIH, Bethesda, MD 20892 USA. [Nelson, Robert G.] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA. [Wagner, Gregory R.] NIOSH, Baltimore, MD USA. [Chugh, Sumeet S.; Havmoeller, Rasmus] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Havmoeller, Rasmus] Karolinska Inst, Stockholm, Sweden. [Cohen, Aaron] Hlth Effects Inst, Boston, MA USA. [Cooper, Leslie T.] Loyola Univ, Sch Med, Chicago, IL 60611 USA. [Criqui, Michael H.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Dahodwala, Nabila; Silberberg, Donald] Univ Penn, Philadelphia, PA 19104 USA. [Dellavalle, Robert P.] Denver VA Med Ctr, Denver, CO USA. [Des Jarlais, Don C.] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Dorsey, Ray; Shivakoti, Rupak] Johns Hopkins Univ, Baltimore, MD USA. [Ezzati, Majid] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostatist, MRC HPA Ctr Environm & Hlth, London, England. [Flaxman, Seth] Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. [Gillum, Richard F.] Howard Univ, Coll Med, Washington, DC USA. [Gosselin, Richard] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Gutierrez, Hialy R.] Mailman Sch Publ Hlth, New York, NY USA. [Moran, Andrew E.] Columbia Univ, New York, NY USA. [Hagan, Holly; Thurston, George D.] NYU, New York, NY USA. [Jacobsen, Kathryn H.] George Mason Univ, Fairfax, VA 22030 USA. [Leasher, Janet L.] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Lipshultz, Steven E.; Sacco, Ralph L.; Wilkinson, James D.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Lopez, Alan D.] Univ Melbourne, Sch Populat & Global Hlth, Melbourne, Vic, Australia. [Lozano, Rafael] Inst Nacl Salud Publ, Ctr Invest Sistemas Salud, Cuernavaca, Morelos, Mexico. [McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Evanston, IL USA. [Meltzer, Michele] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Michaud, Catherine] China Med Board, Boston, MA USA. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Moffitt, Terrie E.] Duke Univ, Durham, NC USA. [Mozaffarian, Dariush] Brigham & Womens Hosp, Boston, MA 02115 USA. [Ostro, Bart] Calif Environm Protect Agcy, Sacramento, CA USA. [Pelizzari, Pamela M.] Ctr Medicare & Medicaid Serv, Baltimore, MD USA. [Pope, C. Arden, III] Brigham Young Univ, Provo, UT 84602 USA. [Raju, Murugesan] Univ Missouri, Mason Eye Inst, Columbia, MO 65211 USA. [Razavi, Homie] Ctr Dis Anal, Louisville, CO USA. [Ritz, Beate] Univ Calif Los Angeles, Los Angeles, CA USA. [Sampson, Uchechukwu] Vanderbilt Univ, Nashville, TN 37235 USA. [Sapkota, Amir] Univ Maryland, Sch Publ Hlth, College Pk, MD 20742 USA. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Shahraz, Saeid] Brandeis Univ, Waltham, MA USA. [Shibuya, Kenji] Univ Tokyo, Dept Global Hlth Policy, Tokyo, Japan. [Singh, David] Queens Med Ctr, Honolulu, HI USA. [Sleet, David A.] Natl Ctr Injury Prevent & Control, Atlanta, GA USA. [Taylor, Jennifer A.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Towbin, Jeffrey A.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Weinstock, Martin A.] Brown Univ, Providence, RI 02912 USA. RP Murray, CJL (reprint author), Inst Hlth Metr & Evaluat, 2301 5th Ave,Ste 600, Seattle, WA 98121 USA. EM cjlm@uw.edu RI Lopez, Alan D/F-1487-2010; Dellavalle, Robert/L-2020-2013; Moffitt, Terrie/D-5295-2011; Narayan, K.M. Venkat /J-9819-2012; Ritz, Beate/E-3043-2015; Sapkota, Amir/A-5968-2011; Bolliger, Ian/C-4207-2016; Jacobsen, Kathryn/B-5857-2008; Salomon, Joshua/D-3898-2009; OI Lopez, Alan D/0000-0001-5818-6512; Mock, Charles/0000-0002-0564-568X; Ding, Eric/0000-0002-5881-8097; singh, jasvinder/0000-0003-3485-0006; Johns, Nicole/0000-0003-4513-4582; Mensah, George/0000-0002-0387-5326; Benjamin, Emelia/0000-0003-4076-2336; Miller, Ted/0000-0002-0958-2639; Ranganathan, Dharani/0000-0001-6506-2825; Dellavalle, Robert/0000-0001-8132-088X; Moffitt, Terrie/0000-0002-8589-6760; Narayan, K.M. Venkat /0000-0001-8621-5405; Bolliger, Ian/0000-0001-8055-297X; Jacobsen, Kathryn/0000-0002-4198-6246; Salomon, Joshua/0000-0003-3929-5515; Pelizzari, Pamela/0000-0002-6992-9462; Chen, Honglei/0000-0003-3446-7779; London, Stephanie/0000-0003-4911-5290 FU National Institutes of Health, the National Institute of Environmental Health Sciences; Bill and Melinda Gates Foundation FX This study is supported in part by the Intramural Program of the National Institutes of Health, the National Institute of Environmental Health Sciences, and in part by the Bill and Melinda Gates Foundation. NR 81 TC 551 Z9 556 U1 39 U2 251 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 AUG 14 PY 2013 VL 310 IS 6 BP 591 EP 608 DI 10.1001/jama.2013.13805 PG 18 WC Medicine, General & Internal SC General & Internal Medicine GA 200HI UT WOS:000323058400015 PM 23842577 ER PT J AU Saygin, ZM Norton, ES Osher, DE Beach, SD Cyr, AB Ozernov-Palchik, O Yendiki, A Fischl, B Gaab, N Gabrieli, JDE AF Saygin, Zeynep M. Norton, Elizabeth S. Osher, David E. Beach, Sara D. Cyr, Abigail B. Ozernov-Palchik, Ola Yendiki, Anastasia Fischl, Bruce Gaab, Nadine Gabrieli, John D. E. TI Tracking the Roots of Reading Ability: White Matter Volume and Integrity Correlate with Phonological Awareness in Prereading and Early-Reading Kindergarten Children SO JOURNAL OF NEUROSCIENCE LA English DT Article ID EVENT-RELATED POTENTIALS; HUMAN CEREBRAL-CORTEX; DEVELOPMENTAL DYSLEXIA; SPATIAL STATISTICS; BRAIN CONNECTIVITY; ARCUATE FASCICULUS; FAMILIAL RISK; SKILLS; CHILDHOOD; READERS AB Developmental dyslexia, an unexplained difficulty in learning to read, has been associated with alterations in white matter organization as measured by diffusion-weighted imaging. It is unknown, however, whether these differences in structural connectivity are related to the cause of dyslexia or if they are consequences of reading difficulty (e.g., less reading experience or compensatory brain organization). Here, in 40 kindergartners who had received little or no reading instruction, we examined the relation between behavioral predictors of dyslexia and white matter organization in left arcuate fasciculus, inferior longitudinal fasciculus, and the parietal portion of the superior longitudinal fasciculus using probabilistic tractography. Higher composite phonological awareness scores were significantly and positively correlated with the volume of the arcuate fasciculus, but not with other tracts. Two other behavioral predictors of dyslexia, rapid naming and letter knowledge, did not correlate with volumes or diffusion values in these tracts. The volume and fractional anisotropy of the left arcuate showed a particularly strong positive correlation with a phoneme blending test. Whole-brain regressions of behavioral scores with diffusion measures confirmed the unique relation between phonological awareness and the left arcuate. These findings indicate that the left arcuate fasciculus, which connects anterior and posterior language regions of the human brain and which has been previously associated with reading ability in older individuals, is already smaller and has less integrity in kindergartners who are at risk for dyslexia because of poor phonological awareness. These findings suggest a structural basis of behavioral risk for dyslexia that predates reading instruction. C1 [Saygin, Zeynep M.; Norton, Elizabeth S.; Osher, David E.; Beach, Sara D.; Cyr, Abigail B.; Gabrieli, John D. E.] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Saygin, Zeynep M.; Norton, Elizabeth S.; Osher, David E.; Beach, Sara D.; Cyr, Abigail B.; Gabrieli, John D. E.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Fischl, Bruce] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. [Ozernov-Palchik, Ola; Gaab, Nadine] Boston Childrens Hosp, Div Dev Med, Labs Cognit Neurosci, Boston, MA 02115 USA. [Yendiki, Anastasia; Fischl, Bruce] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Yendiki, Anastasia; Fischl, Bruce] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Saygin, ZM (reprint author), MIT, 43 Vassar St,46-4033, Cambridge, MA 02139 USA. EM zsaygin@mit.edu; esn@mit.edu OI Norton, Elizabeth/0000-0002-4023-8051 FU National Institutes of Health-National Institute of Child Health and Human Development [R01 HD067312]; National Institutes of Health-National Institute of Biomedical Imaging and Bioengineering [K99/R00 EB008129]; Halis Family Foundation; Ellison Medical Foundation FX This work was supported by grants from the National Institutes of Health-National Institute of Child Health and Human Development (Grant #R01 HD067312), the National Institutes of Health-National Institute of Biomedical Imaging and Bioengineering (Grant #K99/R00 EB008129), the Halis Family Foundation, and the Ellison Medical Foundation. We thank Christina Triantafyllou, Steven Shannon, Sheeba Arnold, and the Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research at MIT, Tyler Perrachione, Carlos Cardenas, Keri-Lee Garel, and Rebecca Winter for technical assistance, and our research testers, school coordinators and principals, and participating families. Participating schools are listed on our website: http://gablab.mit.edu/index.php/READstudy. NR 72 TC 46 Z9 47 U1 9 U2 36 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 AUG 14 PY 2013 VL 33 IS 33 BP 13251 EP 13258 DI 10.1523/JNEUROSCI.4383-12.2013 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 201PV UT WOS:000323155700001 PM 23946384 ER PT J AU Polydoro, M de Calignon, A Suarez-Calvet, M Sanchez, L Kay, KR Nicholls, SB Roe, AD Pitstick, R Carlson, GA Gomez-Isla, T Spires-Jones, TL Hyman, BT AF Polydoro, Manuela de Calignon, Alix Suarez-Calvet, Marc Sanchez, Laura Kay, Kevin R. Nicholls, Samantha B. Roe, Allyson D. Pitstick, Rose Carlson, George A. Gomez-Isla, Teresa Spires-Jones, Tara L. Hyman, Bradley T. TI Reversal of Neurofibrillary Tangles and Tau-Associated Phenotype in the rTgTauEC Model of Early Alzheimer's Disease SO JOURNAL OF NEUROSCIENCE LA English DT Article ID ENTORHINAL CORTEX LESIONS; DENTATE GYRUS; MOUSE MODEL; CASPASE ACTIVATION; LAYER II; NEURONS; PATHOLOGY; PLASTICITY; MEMORY; RAT AB Neurofibrillary tangles (NFTs), a marker of neuronal alterations in Alzheimer's disease (AD) and other tauopathies, are comprised of aggregates of hyperphosphorylated tau protein. We recently studied the formation of NFTs in the entorhinal cortex (EC) and their subsequent propagation through neural circuits in the rTgTauEC mouse model (de Calignon et al., 2012). We now examine the consequences of suppressing transgene expression with doxycycline on the NFT-associated pathological features of neuronal system deafferentation, NFT progression and propagation, and neuronal loss. At 21 months of age we observe that EC axonal lesions are associated with an abnormal sprouting response of acetylcholinesterase (AChE)-positive fibers, a phenotype reminiscent of human AD. At 24 months, NFTs progress, tau inclusions propagate to the dentate gyrus, and neuronal loss is evident. Suppression of the transgene expression from 18 to 24 months led to reversal of AChE sprouting, resolution of Gallyas-positive and Alz50-positive NFTs, and abrogation of progressive neuronal loss. These data suggest that propagation of NFTs, as well as some of the neural system consequences of NFTs, can be reversed in an animal model of NFT-associated toxicity, providing proof in principle that these lesions can be halted, even in established disease. C1 [Polydoro, Manuela; de Calignon, Alix; Suarez-Calvet, Marc; Sanchez, Laura; Kay, Kevin R.; Nicholls, Samantha B.; Roe, Allyson D.; Gomez-Isla, Teresa; Spires-Jones, Tara L.; Hyman, Bradley T.] Harvard Univ, MassGen Inst Neurodegenerat Dis, Alzheimers Dis Res Lab, Dept Neurol,Massachusetts Gen Hosp,Med Sch, Charlestown, MA 02129 USA. [Suarez-Calvet, Marc; Gomez-Isla, Teresa] Univ Autonoma Barcelona, Dept Neurol, Hosp Santa Creu & St Pau, Barcelona 08025, Spain. [Pitstick, Rose; Carlson, George A.] McLaughlin Res Inst, Great Falls, MT 59405 USA. RP Hyman, BT (reprint author), Massachusetts Gen Hosp, Dept Neurol, Alzheimers Dis Res Lab, 114 16th St,Room 2009, Charlestown, MA 02129 USA. EM bhyman@partners.org OI Suarez-Calvet, Marc/0000-0002-2993-569X FU NIH [R00AG033670, R01AG026249-07, T32AG00022222]; Alzheimer's Association [ZEN-09-132524] FX This work was supported by NIH Grants R00AG033670, R01AG026249-07, T32AG00022222, and the Alzheimer's Association Zenith Award ZEN-09-132524. We thank Mark Mayford for providing neuropsin-tTA mice, Peter Davies for providing tau antibodies, and Robert Koffie for his technical support. NR 51 TC 13 Z9 13 U1 0 U2 19 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 AUG 14 PY 2013 VL 33 IS 33 BP 13300 EP 13311 DI 10.1523/JNEUROSCI.0881-13.2013 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 201PV UT WOS:000323155700005 PM 23946388 ER PT J AU Nielsen, AS Kinkel, RP Madigan, N Tinelli, E Benner, T Mainero, C AF Nielsen, A. Scott Kinkel, Revere P. Madigan, Nancy Tinelli, Emanuele Benner, Thomas Mainero, Caterina TI Contribution of cortical lesion subtypes at 7T MRI to physical and cognitive performance in MS SO NEUROLOGY LA English DT Article ID MULTIPLE-SCLEROSIS LESIONS; SURFACE-BASED ANALYSIS; MATTER PATHOLOGY; IMPAIRMENT; DYSFUNCTION; DEMYELINATION AB Objectives: Evaluate cross-sectionally the contribution of focal cortical lesion (CL) subtypes at ultra-high-field MRI and traditional MRI metrics of brain damage to neurologic disability and cognitive performance in a heterogeneous multiple sclerosis (MS) cohort. Methods: Thirty-four patients with early or established disease including clinically isolated syndrome, relapsing-remitting MS, and secondary progressive MS were scanned on a human 7-tesla (7T) (Siemens) scanner to acquire fast low-angle shot (FLASH) T2*-weighted images for characterization of white matter and deep gray matter lesion volume, and CL types. Patients also underwent anatomical 3T MRI for cortical thickness estimation, and neuropsychological testing within 1 week of the 7T scan. Twenty-seven patient scans were acceptable for further analysis. Neurologic disability was measured using the Expanded Disability Status Scale. Results: Type III-IV CLs had the strongest relationship to physical disability (rho = 0.670, p < 0.0001). White matter lesion volume and type I CLs are each significantly associated with 6 of 11 neuropsychological test variables. Type III-IV CLs significantly correlate with 4 of 11 neuropsychological test variables whereas type II CLs, deep gray matter lesion volume, and cortical thickness metrics are less frequently associated with cognitive performance. Conclusions: Leukocortical (type I) and subpial (III-IV) CLs identified on 7T FLASH-T2* sequences are potential cortical biomarkers of cognitive and neurologic status in MS. C1 [Nielsen, A. Scott] Virginia Mason Med Ctr, Seattle, WA 98101 USA. [Nielsen, A. Scott] Univ Washington, Seattle, WA 98195 USA. [Kinkel, Revere P.; Madigan, Nancy] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Kinkel, Revere P.; Madigan, Nancy; Mainero, Caterina] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Tinelli, Emanuele] Univ Roma La Sapienza, Dept Neurol & Psychiat, Rome, Italy. [Benner, Thomas; Mainero, Caterina] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Mainero, C (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. EM caterina@nmr.mgh.harvard.edu FU National Multiple Sclerosis Society [NMSS 4281-RG-A1]; Harvard Medical School SCSP [NH 1 KL2 RR025757-0]; Sylvia Lawry Physician Fellowship Award through the National Multiple Sclerosis Society [NMSS FP 1770A1] FX C. Mainero and R. Kinkel were funded by a grant from the National Multiple Sclerosis Society (NMSS 4281-RG-A1). A. Nielsen is funded through participation in the Harvard Medical School SCSP (NH 1 KL2 RR025757-0), and a Sylvia Lawry Physician Fellowship Award through the National Multiple Sclerosis Society (NMSS FP 1770A1). NR 39 TC 35 Z9 36 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 13 PY 2013 VL 81 IS 7 BP 641 EP 649 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 304JS UT WOS:000330743500012 PM 23864311 ER PT J AU Hu, ZT Tong, XJ Kaplan, JM AF Hu, Zhitao Tong, Xia-Jing Kaplan, Joshua M. TI UNC-13L, UNC-13S, and Tomosyn form a protein code for fast and slow neurotransmitter release in Caenorhabditis elegans SO ELIFE LA English DT Article ID TERM SYNAPTIC PLASTICITY; NEUROMUSCULAR-JUNCTION; C. ELEGANS; VESICLE DOCKING; CA2+; TRANSMISSION; MEMBRANE; POOL; INHIBITION; EXOCYTOSIS AB Synaptic transmission consists of fast and slow components of neurotransmitter release. Here we show that these components are mediated by distinct exocytic proteins. The Caenorhabditis elegans unc-13 gene is required for SV exocytosis, and encodes long and short isoforms (UNC-13L and S). Fast release was mediated by UNC-13L, whereas slow release required both UNC-13 proteins and was inhibited by Tomosyn. The spatial location of each protein correlated with its effect. Proteins adjacent to the dense projection mediated fast release, while those controlling slow release were more distal or diffuse. Two UNC-13L domains accelerated release. C2A, which binds RIM (a protein associated with calcium channels), anchored UNC-13 at active zones and shortened the latency of release. A calmodulin binding site accelerated release but had little effect on UNC-13's spatial localization. These results suggest that UNC-13L, UNC-13S, and Tomosyn form a molecular code that dictates the timing of neurotransmitter release. C1 [Hu, Zhitao; Tong, Xia-Jing; Kaplan, Joshua M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Kaplan, Joshua M.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Kaplan, JM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM kaplan@molbio.mgh.harvard.edu FU National Institutes of Health [R01 GM54728] FX National Institutes of Health R01 GM54728 Joshua M Kaplan NR 38 TC 17 Z9 22 U1 0 U2 1 PU ELIFE SCIENCES PUBLICATIONS LTD PI CAMBRIDGE PA SHERATON HOUSE, CASTLE PARK, CAMBRIDGE, CB3 0AX, ENGLAND SN 2050-084X J9 ELIFE JI eLife PD AUG 13 PY 2013 VL 2 AR e00967 DI 10.7554/eLife.00967 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 274RH UT WOS:000328623300002 PM 23951547 ER PT J AU Chan, PS Berg, RA Spertus, JA Schwamm, LH Bhatt, DL Fonarow, GC Heidenreich, PA Nallamothu, BK Tang, FM Merchant, RM AF Chan, Paul S. Berg, Robert A. Spertus, John A. Schwamm, Lee H. Bhatt, Deepak L. Fonarow, Gregg C. Heidenreich, Paul A. Nallamothu, Brahmajee K. Tang, Fengming Merchant, Raina M. CA AHA GWTG-Resuscitation Investigato TI Risk-Standardizing Survival for In-Hospital Cardiac Arrest to Facilitate Hospital Comparisons SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiac arrest; risk adjustment; variation in care ID AMERICAN-HEART-ASSOCIATION; AUSTRALIAN-RESUSCITATION-COUNCIL; ACUTE MYOCARDIAL-INFARCTION; HEALTH-CARE-PROFESSIONALS; 30-DAY MORTALITY-RATES; CARDIOPULMONARY-RESUSCITATION; STROKE-FOUNDATION; SOUTHERN-AFRICA; STATEMENT; OUTCOMES AB Objectives The purpose of this study is to develop a method for risk-standardizing hospital survival after cardiac arrest. Background A foundation with which hospitals can improve quality is to be able to benchmark their risk-adjusted performance against other hospitals, something that cannot currently be done for survival after in-hospital cardiac arrest. Methods Within the Get With The Guidelines (GWTG)-Resuscitation registry, we identified 48,841 patients admitted between 2007 and 2010 with an in-hospital cardiac arrest. Using hierarchical logistic regression, we derived and validated a model for survival to hospital discharge and calculated risk-standardized survival rates (RSSRs) for 272 hospitals with at least 10 cardiac arrest cases. Results The survival rate was 21.0% and 21.2% for the derivation and validation cohorts, respectively. The model had good discrimination (C-statistic 0.74) and excellent calibration. Eighteen variables were associated with survival to discharge, and a parsimonious model contained 9 variables with minimal change in model discrimination. Before risk adjustment, the median hospital survival rate was 20% (interquartile range: 14% to 26%), with a wide range (0% to 85%). After adjustment, the distribution of RSSRs was substantially narrower: median of 21% (interquartile range: 19% to 23%; range 11% to 35%). More than half (143 [52.6%]) of hospitals had at least a 10% positive or negative absolute change in percentile rank after risk standardization, and 50 (23.2%) had a >= 20% absolute change in percentile rank. Conclusions We have derived and validated a model to risk-standardize hospital rates of survival for in-hospital cardiac arrest. Use of this model can support efforts to compare hospitals in resuscitation outcomes as a foundation for quality assessment and improvement. (C) 2013 by the American College of Cardiology Foundation C1 [Chan, Paul S.; Spertus, John A.] St Lukes Mid Amer Heart Inst, Kansas City, MO USA. [Chan, Paul S.; Spertus, John A.; Tang, Fengming] Univ Missouri, Kansas City, MO 64110 USA. [Berg, Robert A.; Merchant, Raina M.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Berg, Robert A.] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Bhatt, Deepak L.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Boston, MA 02115 USA. [Bhatt, Deepak L.] Harvard Univ, Sch Med, Boston, MA USA. [Fonarow, Gregg C.] Ronald Reagan UCLA Med Ctr, Los Angeles, CA USA. [Heidenreich, Paul A.] VA Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Nallamothu, Brahmajee K.] Univ Michigan, Dept Internal Med, VA Ann Arbor Healthcare Syst, VA Hlth Serv Res & Dev Ctr Excellence, Ann Arbor, MI 48109 USA. [Nallamothu, Brahmajee K.] Univ Michigan, Ctr Healthcare Outcomes & Policy, Ann Arbor, MI 48109 USA. RP Chan, PS (reprint author), St Lukes Hosp, Mid Amer Heart Inst, 5th Floor,4401 Wornall Rd, Kansas City, MO 64111 USA. EM pchan@cc-pc.com OI Heidenreich, Paul/0000-0001-7730-8490; Schwamm, Lee/0000-0003-0592-9145 FU U.S. National Institutes of Health; National Heart Lung and Blood Institute (NHBLI) [K23HL102224, K23109083]; AHA; Amarin; AstraZeneca; Bristol-Myers Squibb; Eisai; Ethicon; Medtronic; Sanofi Aventis; Medicines Company; FlowCo; PLx Pharma; Takeda; NHLBI; AHRQ; NIH [10714038]; Lilly; Amorcyte; Genentech; Physio-Control; Zoll Medical; Cardiac Science; Philips Medical FX The underlying research reported in the article was funded by the U.S. National Institutes of Health. Drs. Chan (K23HL102224) and Merchant (K23109083) are supported by Career Development Grant Awards from the National Heart Lung and Blood Institute (NHBLI). Dr. Chan is also supported by funding from the AHA. GWTG-Resuscitation is sponsored by the AHA. Dr. Schwamm is the Chair of the AHA's GWTGNational Steering Committee. Dr. Bhatt is on the advisory board of Medscape Cardiology; the Board of Directors of Boston VA Research Institute and the Society of Chest Pain Centers; is Chair of the AHA GWTG Science Subcommittee; has received honoraria from the American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees); is the Senior Associate Editor, Journal of Invasive Cardiology; has received research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, and The Medicines Company; and has received unfunded research from FlowCo, PLx Pharma, and Takeda. Dr. Fonarow has received grant funding from the NHLBI and AHRQ; and consulting for Novartis and Medtronic. Dr. Spertus has received grant funding from the NIH, AHA, Lilly, Amorcyte, and Genentech; serves on Scientific Advisory Boards for United Healthcare, St. Jude Medical, and Genentech; and serves as a paid editor for Circulation: Cardiovascular Quality and Outcomes; has intellectual property rights for the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, Peripheral Artery Questionnaire; and has equity interest in Health Outcomes Sciences. Dr. Merchant has received grant funding from NIH, K23 Grant 10714038, Physio-Control, Zoll Medical, Cardiac Science, and Philips Medical. All other authors have reported they have no relationships relevant to the contents of this paper to disclose. NR 22 TC 27 Z9 27 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 13 PY 2013 VL 62 IS 7 BP 601 EP 609 DI 10.1016/j.jacc.2013.05.051 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 207MQ UT WOS:000323605200007 PM 23770167 ER PT J AU Wu, Q Gardiner, GJ Berry, E Wagner, SR Lu, T Clay, BS Moore, TV Ferreira, CM Williams, JW Luster, AD Medoff, BD Cannon, JL Sperling, AI Shilling, RA AF Wu, Qiang Gardiner, Gail J. Berry, Elizabeth Wagner, Sarah R. Lu, Tiffany Clay, Bryan S. Moore, Tamson V. Ferreira, Caroline M. Williams, Jesse W. Luster, Andrew D. Medoff, Benjamin D. Cannon, Judy L. Sperling, Anne I. Shilling, Rebecca A. TI ICOS-Expressing Lymphocytes Promote Resolution of CD8-Mediated Lung Injury in a Mouse Model of Lung Rejection SO PLOS ONE LA English DT Article AB Acute rejection, a common complication of lung transplantation, may promote obliterative bronchiolitis leading to graft failure in lung transplant recipients. During acute rejection episodes, CD8(+) T cells can contribute to lung epithelial injury but the mechanisms promoting and controlling CD8-mediated injury in the lung are not well understood. To study the mechanisms regulating CD8(+) T cell-mediated lung rejection, we used a transgenic model in which adoptively transferred ovalbumin (OVA)-specific cytotoxic T lymphocytes (CTL) induce lung injury in mice expressing an ovalbumin transgene in the small airway epithelium of the lungs (CC10-OVA mice). The lung pathology is similar to findings in humans with acute lung transplant. In the presence of an intact immune response the inflammation resolves by day 30. Using CC10-OVA. RAG(-/-) mice, we found that CD4(+) T cells and ICOS+/+ T cells were required for protection against lethal lung injury, while neutrophil depletion was not protective. In addition, CD4(+) Foxp3 (+) ICOS+ T cells were enriched in the lungs of animals surviving lung injury and ICOS+/+ Tregs promoted survival in animals that received ICOS-/- T cells. Direct comparison of ICOS-/- Tregs to ICOS+/+ Tregs found defects in vitro but no differences in the ability of ICOS-/- Tregs to protect from lethal lung injury. These data suggest that ICOS affects Treg development but is not necessarily required for Treg effector function. C1 [Wu, Qiang; Gardiner, Gail J.; Wagner, Sarah R.; Shilling, Rebecca A.] Indiana Univ Sch Med, Dept Med, Div Pulm & Crit Care Med, Ctr Immunobiol, Indianapolis, IN 46202 USA. [Wu, Qiang; Gardiner, Gail J.; Wagner, Sarah R.; Shilling, Rebecca A.] Indiana Univ Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Berry, Elizabeth; Lu, Tiffany; Clay, Bryan S.; Moore, Tamson V.; Ferreira, Caroline M.; Williams, Jesse W.; Cannon, Judy L.; Sperling, Anne I.] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA. [Berry, Elizabeth; Lu, Tiffany; Clay, Bryan S.; Moore, Tamson V.; Ferreira, Caroline M.; Williams, Jesse W.; Cannon, Judy L.; Sperling, Anne I.] Univ Chicago, Dept Med, Pulm & Crit Care Med Sect, Chicago, IL 60637 USA. [Luster, Andrew D.] Massachusetts Gen Hosp, Div Rheumatol Allergy & Immunol, Ctr Immunol & Inflammatory Dis, Charlestown, MA USA. [Luster, Andrew D.] Harvard Univ, Sch Med, Charlestown, MA USA. [Medoff, Benjamin D.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Medoff, Benjamin D.] Harvard Univ, Sch Med, Boston, MA USA. RP Shilling, RA (reprint author), Indiana Univ Sch Med, Dept Med, Div Pulm & Crit Care Med, Ctr Immunobiol, Indianapolis, IN 46202 USA. EM shilling@uic.edu OI Cannon, Judy/0000-0003-0069-8106; Williams, Jesse/0000-0003-3815-0891 FU NIH/NIAID [K08AI059105, R01AI67697]; American Society of Transplantation/Wyeth; Blowitz-Ridgeway Foundation; American Cancer Society-Illinois Division; Irvington Institute Fellowship Program of the Cancer Research Institute; Scientist Development Grant, American Heart Association; Roche Organ Transplantation Research Foundation; NIH [R01CA069212] FX This work was supported by NIH/NIAID K08AI059105 (RAS), American Society of Transplantation/Wyeth (RAS), NIH/NIAID R01AI67697 (AIS), Blowitz-Ridgeway Foundation (AIS), American Cancer Society-Illinois Division (J.L.C.), Irvington Institute Fellowship Program of the Cancer Research Institute (J.L.C.), Scientist Development Grant, American Heart Association (J.L.C), Roche Organ Transplantation Research Foundation (BDM and ADL) and NIH R01CA069212 (ADL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 1 Z9 2 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 13 PY 2013 VL 8 IS 8 AR e72955 DI 10.1371/journal.pone.0072955 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201BN UT WOS:000323115800118 PM 23967339 ER PT J AU Steinberg, BA Kim, S Piccini, JP Fonarow, GC Lopes, RD Thomas, L Ezekowitz, MD Ansell, J Kowey, P Singer, DE Gersh, B Mahaffey, KW Hylek, E Go, AS Chang, P Peterson, ED AF Steinberg, Benjamin A. Kim, Sunghee Piccini, Jonathan P. Fonarow, Gregg C. Lopes, Renato D. Thomas, Laine Ezekowitz, Michael D. Ansell, Jack Kowey, Peter Singer, Daniel E. Gersh, Bernard Mahaffey, Kenneth W. Hylek, Elaine Go, Alan S. Chang, Paul Peterson, Eric D. CA ORBIT-AF Investigators Patients TI Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry SO CIRCULATION LA English DT Article DE anticoagulants; aspirin; atrial fibrillation; hemorrhage; outcome assessment (health care) ID ACUTE CORONARY SYNDROMES; SERVICES-TASK-FORCE; CARDIOVASCULAR EVENTS; PRIMARY PREVENTION; RANDOMIZED-TRIALS; PREDICTING STROKE; WARFARIN; METAANALYSIS; MANAGEMENT; ANTIPLATELET AB Background-The role of concomitant aspirin (ASA) therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant ASA use and its association with clinical outcomes among AF patients treated with OAC. Methods and Results-The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry enrolled 10 126 AF patients from 176 US practices from June 2010 through August 2011. The study population was limited to those on OAC (n=7347). Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant ASA therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% of AF patients (n=2543) on OAC also received ASA (OAC+ASA). Patients receiving OAC+ASA were more likely to be male (66% versus 53%; P<0.0001) and had more comorbid illness than those on OAC alone. More than one third of patients (39%) receiving OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding risk scores (5). Major bleeding (adjusted hazard ratio, 1.53; 95% confidence interval, 1.20-1.96) and bleeding hospitalizations (adjusted hazard ratio, 1.52; 95% confidence interval, 1.17-1.97) were significantly higher in those on OAC+ASA compared with those on OAC alone. Rates of ischemic events were low. Conclusions-Patients with AF receiving OAC are often treated with concomitant ASA, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant ASA outweigh the risks in AF patients already on OAC. C1 [Steinberg, Benjamin A.; Piccini, Jonathan P.; Lopes, Renato D.; Mahaffey, Kenneth W.; Peterson, Eric D.] Duke Univ, Med Ctr, Durham, NC 27705 USA. [Steinberg, Benjamin A.; Kim, Sunghee; Piccini, Jonathan P.; Lopes, Renato D.; Thomas, Laine; Mahaffey, Kenneth W.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Div Cardiol, Los Angeles, CA USA. [Ezekowitz, Michael D.] Thomas Jefferson Med Coll, Lankenau Med Ctr, Wynnewood, PA USA. [Ansell, Jack] NYU, Lenox Hill Hosp, Sch Med, New York, NY USA. [Kowey, Peter] Lankenau Inst Med Res, Wynnewood, PA USA. [Singer, Daniel E.] Harvard Univ, Sch Med, Boston, MA USA. [Singer, Daniel E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gersh, Bernard] Mayo Clin, Rochester, MN USA. [Hylek, Elaine] Boston Univ, Sch Med, Boston, MA 02118 USA. [Go, Alan S.] Kaiser Permanente, Oakland, CA USA. [Chang, Paul] Janssen Sci Affairs, Raritan, NJ USA. RP Peterson, ED (reprint author), Duke Univ, Med Ctr, 2400 Pratt St,Ste 7009, Durham, NC 27705 USA. EM eric.peterson@dm.duke.edu FU Janssen Scientific Affairs, LLC, Raritan, NJ; National Institutes of Health [5 T32 HL 7101-37] FX The ORBIT-AF registry is sponsored by Janssen Scientific Affairs, LLC, Raritan, NJ. Dr Steinberg was funded by National Institutes of Health T-32 training grant 5 T32 HL 7101-37. NR 27 TC 48 Z9 49 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 13 PY 2013 VL 128 IS 7 BP 721 EP 728 DI 10.1161/CIRCULATIONAHA.113.002927 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 200WR UT WOS:000323102400016 PM 23861512 ER PT J AU Dagnell, M Frijhoff, J Pader, I Augsten, M Boivin, B Xu, JQ Mandal, PK Tonks, NK Hellberg, C Conrad, M Arner, ESJ Ostman, A AF Dagnell, Markus Frijhoff, Jeroen Pader, Irina Augsten, Martin Boivin, Benoit Xu, Jianqiang Mandal, Pankaj K. Tonks, Nicholas K. Hellberg, Carina Conrad, Marcus Arner, Elias S. J. Ostman, Arne TI Selective activation of oxidized PTP1B by the thioredoxin system modulates PDGF-beta receptor tyrosine kinase signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE redox regulation; cell signaling ID ENDOPLASMIC-RETICULUM STRESS; EPIDERMAL-GROWTH-FACTOR; ACTIVE-SITE CYSTEINE; REDOX REGULATION; PHOSPHATASE 1B; CELL-ADHESION; REVERSIBLE INACTIVATION; PROTEIN; OXIDATION; REDUCTASE AB The inhibitory reversible oxidation of protein tyrosine phosphatases (PTPs) is an important regulatory mechanism in growth factor signaling. Studies on PTP oxidation have focused on pathways that increase or decrease reactive oxygen species levels and thereby affect PTP oxidation. The processes involved in reactivation of oxidized PTPs remain largely unknown. Here the role of the thioredoxin (Trx) system in reactivation of oxidized PTPs was analyzed using a combination of in vitro and cell-based assays. Cells lacking the major Trx reductase TrxR1 (Txnrd1(-/-)) displayed increased oxidation of PTP1B, whereas SHP2 oxidation was unchanged. Furthermore, in vivo-oxidized PTP1B was reduced by exogenously added Trx system components, whereas SHP2 oxidation remained unchanged. Trx1 reduced oxidized PTP1B in vitro but failed to reactivate oxidized SHP2. Interestingly, the alternative TrxR1 substrate TRP14 also reactivated oxidized PTP1B, but not SHP2. Txnrd1-depleted cells displayed increased phosphorylation of PDGF-beta receptor, and an enhanced mitogenic response, after PDGF-BB stimulation. The TrxR inhibitor auranofin also increased PDGF-beta receptor phosphorylation. This effect was not observed in cells specifically lacking PTP1B. Together these results demonstrate that the Trx system, including both Trx1 and TRP14, impacts differentially on the oxidation of individual PTPs, with a preference of PTP1B over SHP2 activation. The studies demonstrate a previously unrecognized pathway for selective redox-regulated control of receptor tyrosine kinase signaling. C1 [Dagnell, Markus; Frijhoff, Jeroen; Augsten, Martin; Ostman, Arne] Karolinska Inst, Canc Ctr Karolinska, Dept Oncol & Pathol, SE-17176 Stockholm, Sweden. [Pader, Irina; Xu, Jianqiang; Arner, Elias S. J.] Karolinska Inst, Dept Med Biochem & Biophys, Div Biochem, SE-17177 Stockholm, Sweden. [Boivin, Benoit] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada. [Boivin, Benoit] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Mandal, Pankaj K.] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02116 USA. [Mandal, Pankaj K.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Tonks, Nicholas K.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Hellberg, Carina] Univ Birmingham, Coll Life & Environm Sci, Sch Biosci, Birmingham B15 2TT, W Midlands, England. [Conrad, Marcus] Helmholtz Zentrum Munchen, Inst Dev Genet, D-85764 Neuherberg, Germany. RP Ostman, A (reprint author), Karolinska Inst, Canc Ctr Karolinska, Dept Oncol & Pathol, SE-17176 Stockholm, Sweden. EM Arne.Ostman@ki.se RI Arner, Elias/J-5832-2012; mandal, pankaj/B-4885-2016 OI Arner, Elias/0000-0002-4807-6114; FU Swedish Research Council; European Union; Swedish Cancer Society (Cancerfonden); Swedish Research Council (Medicine); Swedish Cancer Society; Karolinska Institutet FX We thank members of A.O. group for helpful discussions throughout the project. hPtpn1 and Ptpn1-/- cells were kindly provided by Benjamin G. Neel. A.O. was supported by the Swedish Research Council, the European Union-sponsored PTPNET, and the Swedish Cancer Society (Cancerfonden). E.S.J.A. acknowledges support for these studies from the Swedish Research Council (Medicine), the Swedish Cancer Society, and Karolinska Institutet. NR 64 TC 25 Z9 25 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP 13398 EP 13403 DI 10.1073/pnas.1302891110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200049 PM 23901112 ER PT J AU Gartner, JJ Parker, SCJ Prickett, TD Dutton-Regester, K Stitzel, ML Lin, JC Davis, S Simhadri, VL Jha, S Katagiri, N Gotea, V Teer, JK Wei, XM Morken, MA Bhanot, UK Chen, G Elnitski, LL Davies, MA Gershenwald, JE Carter, H Karchin, R Robinson, W Robinson, S Rosenberg, SA Collins, FS Parmigiani, G Komar, AA Kimchi-Sarfaty, C Hayward, NK Margulies, EH Samuels, Y AF Gartner, Jared J. Parker, Stephen C. J. Prickett, Todd D. Dutton-Regester, Ken Stitzel, Michael L. Lin, Jimmy C. Davis, Sean Simhadri, Vijaya L. Jha, Sujata Katagiri, Nobuko Gotea, Valer Teer, Jamie K. Wei, Xiaomu Morken, Mario A. Bhanot, Umesh K. Chen, Guo Elnitski, Laura L. Davies, Michael A. Gershenwald, Jeffrey E. Carter, Hannah Karchin, Rachel Robinson, William Robinson, Steven Rosenberg, Steven A. Collins, Francis S. Parmigiani, Giovanni Komar, Anton A. Kimchi-Sarfaty, Chava Hayward, Nicholas K. Margulies, Elliott H. Samuels, Yardena CA NISC Comparative Sequencing Progra TI Whole-genome sequencing identifies a recurrent functional synonymous mutation in melanoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TERT PROMOTER MUTATIONS; HUMAN CANCER; POSITIVE SELECTION; EVOLUTION; REVEALS; DISEASE; CONSTRAINT; SUBSTRATE; GENE; SITE AB Synonymous mutations, which do not alter the protein sequence, have been shown to affect protein function [Sauna ZE, Kimchi-Sarfaty C (2011) Nat Rev Genet 12(10):683-691]. However, synonymous mutations are rarely investigated in the cancer genomics field. We used whole-genome and -exome sequencing to identify somatic mutations in 29 melanoma samples. Validation of one synonymous somatic mutation in BCL2L12 in 285 samples identified 12 cases that harbored the recurrent F17F mutation. This mutation led to increased BCL2L12 mRNA and protein levels because of differential targeting of WT and mutant BCL2L12 by hsa-miR-671-5p. Protein made from mutant BCL2L12 transcript bound p53, inhibited UV-induced apoptosis more efficiently than WT BCL2L12, and reduced endogenous p53 target gene transcription. This report shows selection of a recurrent somatic synonymous mutation in cancer. Our data indicate that silent alterations have a role to play in human cancer, emphasizing the importance of their investigation in future cancer genome studies. C1 [Gartner, Jared J.; Parker, Stephen C. J.; Prickett, Todd D.; Stitzel, Michael L.; Gotea, Valer; Teer, Jamie K.; Wei, Xiaomu; Morken, Mario A.; Elnitski, Laura L.; Collins, Francis S.; Margulies, Elliott H.; Samuels, Yardena; NISC Comparative Sequencing Progra] NHGRI, Bethesda, MD 20892 USA. [Davis, Sean; Rosenberg, Steven A.] NCI, NIH, Bethesda, MD 20892 USA. [Dutton-Regester, Ken; Hayward, Nicholas K.] Queensland Inst Med Res, Div Genet & Computat Biol, Brisbane, Qld 4006, Australia. [Lin, Jimmy C.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Simhadri, Vijaya L.; Katagiri, Nobuko; Kimchi-Sarfaty, Chava] US FDA, Lab Hemostasis, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Jha, Sujata; Komar, Anton A.] Cleveland State Univ, Ctr Gene Regulat Hlth & Dis, Cleveland, OH 44115 USA. [Jha, Sujata; Komar, Anton A.] Cleveland State Univ, Dept Biol Geol & Environm Sci, Cleveland, OH 44115 USA. [Bhanot, Umesh K.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Chen, Guo; Davies, Michael A.; Gershenwald, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA. [Carter, Hannah; Karchin, Rachel] Johns Hopkins Univ, Inst Computat Med, Dept Biomed Engn, Baltimore, MD 21218 USA. [Robinson, William; Robinson, Steven] Univ Colorado, Sch Med, Div Med Oncol, Aurora, CO 80045 USA. [Parmigiani, Giovanni] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Parmigiani, Giovanni] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Margulies, Elliott H.] Illumina United Kingdom, Saffron Walden CB10 1XL, Essex, England. [Samuels, Yardena] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Samuels, Y (reprint author), NHGRI, Bethesda, MD 20892 USA. EM yardena.samuels@weizmann.ac.il RI Karchin, Rachel/A-3385-2010; hayward, nicholas/C-1367-2015; OI hayward, nicholas/0000-0003-4760-1033; Bhanot, Umeshkumar/0000-0001-6656-1239; Davis, Sean/0000-0002-8991-6458; Gotea, Valer/0000-0001-7857-3309 FU NIGMS Postdoctoral Research Associate (PRAT) Fellowship; Intramural Research Programs of the National Human Genome Research Institute; Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics; estate of Alice Schwarz-Gardos; estate of John Hunter; Knell Family; Peter and Patricia Gruber Award; National Cancer Institute [R21CA152432]; National Institutes of Health; University of Texas MD Anderson Cancer Center Melanoma Specialized Programs of Research Excellence [P50 CA093459]; Cancer Center Support Grant (CCSG) Core Grant [NCI 5P30 CA006516-46]; Human Frontier Science Program [RGP0024]; National Health and Medical Research Council of Australia [1026112, 613686]; National Cancer Institute; Eli Lilly and Company FX We thank Drs. Chris Schmidt and Peter Parsons for establishment of the majority of melanoma cell lines and V. Maduro, H. Ozel Abaan, and P. Cruz for generating the sequence data analyzed here. We thank Dr. V. G. Prieto for pathologic review of the biospecimens from the Melanoma Informatics, Tissue Resource, and Pathology Core (MelCore) at MD Anderson. We thank Dr. T. Wolfsberg for bioinformatics help, J. Jiang for sequencing help, and J. Fekecs and D. Leja for graphical assistance. We thank Drs. T. Barber and M. Willard for critical comments on the manuscript. S.C.J.P. is supported by an NIGMS Postdoctoral Research Associate (PRAT) Fellowship. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, by the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics, the estate of Alice Schwarz-Gardos, the estate of John Hunter, the Knell Family, the Peter and Patricia Gruber Award, National Cancer Institute Grant R21CA152432 (to R.K.), the National Institutes of Health, University of Texas MD Anderson Cancer Center Melanoma Specialized Programs of Research Excellence Grant P50 CA093459, Cancer Center Support Grant (CCSG) Core Grant NCI 5P30 CA006516-46 (to G.P.), the Human Frontier Science Program RGP0024 Grant (to A.A.K.), National Health and Medical Research Council of Australia Grants 1026112 and 613686, and a public-private partnership between the Intramural Research Programs of the National Human Genome Research Institute, the National Cancer Institute, and Eli Lilly and Company coordinated by the Foundation for the National Institutes of Health. NR 35 TC 63 Z9 64 U1 0 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 AUG 13 PY 2013 VL 110 IS 33 BP 13481 EP 13486 DI 10.1073/pnas.1304227110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200063 PM 23901115 ER PT J AU Wermeling, F Anthony, RM Brombacher, F Ravetch, JV AF Wermeling, Fredrik Anthony, Robert M. Brombacher, Frank Ravetch, Jeffrey V. TI Acute inflammation primes myeloid effector cells for anti-inflammatory STAT6 signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neutrophils; monocytes; macrophages ID COLLAGEN-INDUCED ARTHRITIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; RECEPTOR ALPHA-CHAIN; STIMULATORY FACTOR-I; T-CELL; AUTOIMMUNE-DISEASE; EXPRESSION; IL-4; INTERLEUKIN-4; MECHANISMS AB The anti-inflammatory drug high-dose intravenous immunoglobulin, widely used to suppress inflammation, depends on a specific alpha-2,6-sialylated glycoform of IgG Fc to induce Interleukin 4 (IL-4) and Signal Transducer and Activator of Transcription 6 (STAT6) signaling for its activity. Here we show that anti-inflammatory activities of IL-4 can be attributed to the direct action of this cytokine on myeloid effector cells, depending on their expression of the IL-4 receptor alpha chain (IL-4R alpha/CD124). However, in their basal state, these cells express low levels of IL-4R alpha and would not be expected to result in significant signaling compared with other cell populations. This apparent paradox can be explained by the observation that during inflammation, triggered by a variety of stimuli (including autoantibodies, adjuvants, and TLR ligands), IL-4R alpha is up-regulated specifically on these cells, priming them for STAT6 signaling. The regulation is mediated by a soluble, proteinase K-sensitive factor, released to the circulation by bone marrow-derived, non-B/non-T cells found in several organs, including the lungs, and fat. We propose that this regulation is part of a homeostatic mechanism to limit excessive inflammation and tissue damage. High-dose intravenous immunoglobulin thus exploits an endogenous feedback loop, general to inflammation, that could be further targeted for therapeutic purposes. C1 [Wermeling, Fredrik; Anthony, Robert M.; Ravetch, Jeffrey V.] Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10065 USA. [Anthony, Robert M.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02129 USA. [Brombacher, Frank] Int Ctr Genet Engn & Biotechnol, Cape Town, South Africa. [Brombacher, Frank] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Rondebosch, South Africa. RP Ravetch, JV (reprint author), Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10065 USA. EM ravetch@rockefeller.edu OI Wermeling, Fredrik/0000-0001-9633-677X FU Wenner-Gren Foundations; National Institutes of Health FX We thank Drs. Pete Stavropoulos, Pontus Bostrom, Ajay Chawla, Fred Finkelman, Manish Ponda, Brian T. Chait, Matam Vijay-Kumar, Philipp Scherer, Michelle Lepherd, Ruben Peraza, and Klara Velinzon, and members of the J.V.R. laboratory for providing reagents, technical help, and helpful discussions. F.W. is a Wenner-Gren Fellow supported by the Wenner-Gren Foundations. This work was supported by grants from the National Institutes of Health (to J.V.R.). NR 36 TC 11 Z9 11 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 13 PY 2013 VL 110 IS 33 BP 13487 EP 13491 DI 10.1073/pnas.1312525110 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200064 PM 23898202 ER PT J AU Panigrahy, D Kalish, BT Huang, S Bielenberg, DR Le, HD Yang, J Edin, ML Lee, CR Benny, O Mudge, DK Butterfield, CE Mammoto, A Mammoto, T Inceoglu, B Jenkins, RL Simpson, MA Akino, T Lih, FB Tomer, KB Ingber, DE Hammock, BD Falck, JR Manthati, VL Kaipainen, A D'Amore, PA Puder, M Zeldin, DC Kieran, MW AF Panigrahy, Dipak Kalish, Brian T. Huang, Sui Bielenberg, Diane R. Le, Hau D. Yang, Jun Edin, Matthew L. Lee, Craig R. Benny, Ofra Mudge, Dayna K. Butterfield, Catherine E. Mammoto, Akiko Mammoto, Tadanori Inceoglu, Bora Jenkins, Roger L. Simpson, Mary A. Akino, Tomoshige Lih, Fred B. Tomer, Kenneth B. Ingber, Donald E. Hammock, Bruce D. Falck, John R. Manthati, Vijaya L. Kaipainen, Arja D'Amore, Patricia A. Puder, Mark Zeldin, Darryl C. Kieran, Mark W. TI Epoxyeicosanoids promote organ and tissue regeneration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autacoid; organ regeneration; small molecule mediator; angiocrine; VEGF ID SOLUBLE EPOXIDE HYDROLASE; ENDOTHELIAL GROWTH-FACTOR; EPOXYEICOSATRIENOIC ACIDS; LIVER-REGENERATION; ANGIOCRINE SIGNALS; TUMOR-GROWTH; STEM-CELLS; IN-VIVO; ANGIOGENESIS; EXPRESSION AB Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis. C1 [Panigrahy, Dipak; Kalish, Brian T.; Bielenberg, Diane R.; Le, Hau D.; Benny, Ofra; Mudge, Dayna K.; Butterfield, Catherine E.; Mammoto, Akiko; Mammoto, Tadanori; Akino, Tomoshige; Ingber, Donald E.; Puder, Mark; Kieran, Mark W.] Harvard Univ, Sch Med, Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. [Kalish, Brian T.; Le, Hau D.; Puder, Mark] Harvard Univ, Sch Med, Boston Childrens Hosp, Dept Surg, Boston, MA 02115 USA. [Panigrahy, Dipak; Kieran, Mark W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. [Panigrahy, Dipak; Mudge, Dayna K.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Ctr Vasc Biol Res, Boston, MA 02115 USA. [Panigrahy, Dipak; Mudge, Dayna K.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02115 USA. [Le, Hau D.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02115 USA. [Huang, Sui] Inst Syst Biol, Seattle, WA 98109 USA. [Yang, Jun; Inceoglu, Bora; Hammock, Bruce D.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Yang, Jun] Univ Calif Davis, Ctr Canc, Davis, CA 95616 USA. [Edin, Matthew L.; Lih, Fred B.; Tomer, Kenneth B.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Lee, Craig R.] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. [Jenkins, Roger L.; Simpson, Mary A.] Lahey Clin Med Ctr, Dept Transplantat, Burlington, MA 01805 USA. [Ingber, Donald E.] Harvard Univ, Wyss Inst Biol Inspired Engn, Boston, MA 02115 USA. [Falck, John R.; Manthati, Vijaya L.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75235 USA. [Kaipainen, Arja] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA. [D'Amore, Patricia A.] Harvard Univ, Sch Med, Schepens Eye Res Inst, Dept Ophthalmol,Massachusetts Eye & Ear, Boston, MA 02114 USA. RP Panigrahy, D (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. EM dpanigra@bidmc.harvard.edu; bdhammock@ucdavis.edu; zeldin@niehs.nih.gov; mark_kieran@dfci.harvard.edu RI Yang, Jun/B-2262-2010; OI Yang, Jun/0000-0002-4630-3838; Kieran, Mark/0000-0003-2184-7692; Falck, John/0000-0002-9219-7845; Edin, Matthew/0000-0002-7042-500X; Lee, Craig/0000-0003-3595-5301; Inceoglu, Bora/0000-0002-8473-6036 FU National Cancer Institute Grant [RO1CA148633-01A4]; Stop and Shop Pediatric Brain Tumor Fund; C. J. Buckley Pediatric Brain Tumor Fund; Joshua Ryan Rappaport Fellowship; Children's Hospital Boston Surgical Foundation; Vascular Biology Program; Howard Hughes Medical Institute Research Fellowship; Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) [Z01 025034, Z01 050167]; NIH [R01 GM088199, GM31278, R01 ES002710, R01 ES013933, CA045548]; Robert A. Welch Foundation [GL625910]; NIEHS Superfund Basic Research Program NIH [P42 ES004699] FX We thank Kristin Johnson for photography and preparation of the figures; J. Alyce Bradbury, Joan P. Graves, Laura M. DeGraff, and Ricky Sanchez for excellent technical assistance; and Sung Hee Hwang for sEHi. This work was supported by National Cancer Institute Grant RO1CA148633-01A4 (to D.P.); the Stop and Shop Pediatric Brain Tumor Fund (M.W.K.); the C. J. Buckley Pediatric Brain Tumor Fund (M.W.K.); the Joshua Ryan Rappaport Fellowship (H.D.L.); the Children's Hospital Boston Surgical Foundation and the Vascular Biology Program (M.P. and H.D.L.); a Howard Hughes Medical Institute Research Fellowship (to B.T.K.); Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) (Z01 025034 to D.C.Z.; Z01 050167 to K.B.T.); NIH Grant R01 GM088199 (to C.R.L.); NIH Grant GM31278 and Robert A. Welch Foundation Grant GL625910 (to J.R.F.); NIEHS Superfund Basic Research Program NIH Grant P42 ES004699 and NIH Grants R01 ES002710 and R01 ES013933 (to B.D.H.); and NIH Grant CA045548 (to D.E.I.). B.D.H. is a George and Judy Marcus Senior Fellow of the American Asthma Foundation. NR 47 TC 42 Z9 45 U1 1 U2 39 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 AUG 13 PY 2013 VL 110 IS 33 BP 13528 EP 13533 DI 10.1073/pnas.1311565110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200LA UT WOS:000323069200071 PM 23898174 ER PT J AU Shafiee, H Jahangir, M Inci, F Wang, SQ Willenbrecht, RBM Giguel, FF Tsibris, AMN Kuritzkes, DR Demirci, U AF Shafiee, Hadi Jahangir, Muntasir Inci, Fatih Wang, ShuQi Willenbrecht, Remington B. M. Giguel, Francoise F. Tsibris, Athe M. N. Kuritzkes, Daniel R. Demirci, Utkan TI Acute On-Chip HIV Detection Through Label-Free Electrical Sensing of Viral Nano-Lysate SO SMALL LA English DT Article DE pathogen detection; impedance spectroscopy; point-of-care diagnosis; virus lysis; lab-on-chip ID VIRUS TYPE-1 INFECTION; IMPEDANCE SPECTROSCOPY; INTERDIGITATED ELECTRODES; REVERSE TRANSCRIPTION; CELLS; SEPARATION; DIELECTROPHORESIS; MICROFLUIDICS; DIAGNOSTICS; CYTOMETRY AB Development of portable biosensors has broad applications in environmental monitoring, clinical diagnosis, public health, and homeland security. There is an unmet need for pathogen detection at the point-of-care (POC) using a fast, sensitive, inexpensive, and easy-to-use method that does not require complex infrastructure and well-trained technicians. For instance, detection of Human Immunodeficiency Virus (HIV-1) at acute infection stage has been challenging, since current antibody-based POC technologies are not effective due to low concentration of antibodies. In this study, we demonstrated for the first time a label-free electrical sensing method that can detect lysed viruses, i.e. viral nano-lysate, through impedance analysis, offering an alternative technology to the antibody-based methods such as dipsticks and Enzyme-linked Immunosorbent Assay (ELISA). The presented method is a broadly applicable platform technology that can potentially be adapted to detect multiple pathogens utilizing impedance spectroscopy for other infectious diseases including herpes, influenza, hepatitis, pox, malaria, and tuberculosis. The presented method offers a rapid and portable tool that can be used as a detection technology at the POC in resource-constrained settings, as well as hospital and primary care settings. C1 [Shafiee, Hadi; Jahangir, Muntasir; Inci, Fatih; Wang, ShuQi; Willenbrecht, Remington B. M.; Demirci, Utkan] Harvard Univ, Brigham & Womens Hosp, Dept Med,Sch Med, Bioacoust MEMS Med BAMM Lab,Div Biomed Engn, Boston, MA 02115 USA. [Giguel, Francoise F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA USA. [Tsibris, Athe M. N.; Kuritzkes, Daniel R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Infect Dis, Boston, MA 02115 USA. [Demirci, Utkan] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Biomed Engn,Div Infect Dis,Dept Med, Cambridge, MA 02138 USA. RP Demirci, U (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Med,Sch Med, Bioacoust MEMS Med BAMM Lab,Div Biomed Engn, Boston, MA 02115 USA. EM udemirci@rics.bwh.harvard.edu RI Shafiee, Hadi/C-8646-2014; Arumugam, Thirumagal/C-3408-2014 FU National Institute of Health [RO1AI093282, RO1AI081534, R21AI087107, 1F32AI102590]; US Army Medical Research and Materiel Command; Telemedicine and Advanced Technology Research Center (TATRC), at Fort Detrick, MD; NIH [U54EB15408] FX The authors would like to thank Dr. Zixin Hu at the Division of Infectious Diseases, Brigham and Women's Hospital for his generous help on providing GFP tagged HIV-1 samples. The devices were fabricated using facilities at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Infrastructure Network (NNIN). This work was supported by the National Institute of Health under NIH award numbers RO1AI093282, RO1AI081534, R21AI087107, 1F32AI102590 and NIH U54EB15408. This work was also supported by a research grant that was awarded and administered by the US Army Medical Research and Materiel Command and the Telemedicine and Advanced Technology Research Center (TATRC), at Fort Detrick, MD. NR 42 TC 34 Z9 34 U1 2 U2 64 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1613-6810 EI 1613-6829 J9 SMALL JI Small PD AUG 12 PY 2013 VL 9 IS 15 BP 2553 EP 2563 DI 10.1002/smll.201202195 PG 11 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 263FO UT WOS:000327792600013 PM 23447456 ER PT J AU Gross, R Bellamy, SL Strom, BL AF Gross, Robert Bellamy, Scarlett L. Strom, Brian L. TI Does Managed Problem Solving Work and in What Setting? Reply SO JAMA INTERNAL MEDICINE LA English DT Letter C1 [Gross, Robert; Bellamy, Scarlett L.; Strom, Brian L.] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gross, Robert; Bellamy, Scarlett L.; Strom, Brian L.] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Gross, Robert] Univ Penn, Div Infect Dis, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Gross, Robert] Philadelphia Vet Affairs Med Ctr, Philadelphia, PA USA. RP Gross, R (reprint author), Univ Penn, Dept Med, Div Infect Dis, Ctr Clin Epidemiol & Biostat,Perelman Sch Med, 423 Guardian Dr,804 Blockley Hall, Philadelphia, PA 19104 USA. EM grossr@mail.med.upenn.edu FU NIMH NIH HHS [R01 MH067498] NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 2168-6106 J9 JAMA INTERN MED JI JAMA Intern. Med. PD AUG 12 PY 2013 VL 173 IS 15 BP 1475 EP 1476 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 218NY UT WOS:000324440400029 PM 23939524 ER PT J AU Otto, T Sicinski, P AF Otto, Tobias Sicinski, Piotr TI The Kinase-Independent, Second Life of CDK6 in Transcription SO CANCER CELL LA English DT Editorial Material ID CYCLIN; REQUIREMENT C1 [Otto, Tobias; Sicinski, Piotr] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. [Otto, Tobias; Sicinski, Piotr] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Sicinski, P (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. EM peter_sicinski@dfci.harvard.edu OI Otto, Tobias/0000-0001-5594-3055 FU NCI NIH HHS [R01 CA108420] NR 10 TC 5 Z9 6 U1 0 U2 4 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 AUG 12 PY 2013 VL 24 IS 2 BP 141 EP 143 DI 10.1016/j.ccr.2013.07.019 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 201KT UT WOS:000323141200002 PM 23948293 ER PT J AU Petrocca, F Altschuler, G Tan, SM Mendillo, ML Yan, HH Jerry, DJ Kung, AL Hide, W Ince, TA Lieberman, J AF Petrocca, Fabio Altschuler, Gabriel Tan, Shen Mynn Mendillo, Marc L. Yan, Haoheng Jerry, D. Joseph Kung, Andrew L. Hide, Winston Ince, Tan A. Lieberman, Judy TI A Genome-wide siRNA Screen Identifies Proteasome Addiction as a Vulnerability of Basal-like Triple-Negative Breast Cancer Cells SO CANCER CELL LA English DT Article ID IN-VIVO; GENE; BORTEZOMIB; SUBTYPES; METASTASIS; APOPTOSIS; THERAPY; SYSTEM; NOXA AB Basal-like triple-negative breast cancers (TNBCs) have poor prognosis. To identify basal-like TNBC dependencies, a genome-wide siRNA lethality screen compared two human breast epithelial cell lines transformed with the same genes: basal-like BPLER and myoepithelial HMLER. Expression of the screen's 154 BPLER dependency genes correlated with poor prognosis in breast, but not lung or colon, cancer. Proteasome genes were overrepresented hits. Basal-like TNBC lines were selectively sensitive to proteasome inhibitor drugs relative to normal epithelial, luminal, and mesenchymal TNBC lines. Proteasome inhibition reduced growth of established basal-like TNBC tumors in mice and blocked tumor-initiating cell function and macronnetastasis. Proteasome addiction in basal-like TNBCs was mediated by NOXA and linked to MCL-1 dependence. C1 [Petrocca, Fabio; Tan, Shen Mynn; Lieberman, Judy] Harvard Univ, Sch Med, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Petrocca, Fabio; Tan, Shen Mynn; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Altschuler, Gabriel; Hide, Winston] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Mendillo, Marc L.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Yan, Haoheng; Jerry, D. Joseph] Univ Massachusetts, Dept Vet & Anim Sci, Amherst, MA 01003 USA. [Kung, Andrew L.] Columbia Univ, Dept Pediat, Med Ctr, New York, NY 10032 USA. [Ince, Tan A.] Univ Miami, Miller Sch Med, Braman Family Breast Canc Inst, Miami, FL 33136 USA. [Ince, Tan A.] Univ Miami, Miller Sch Med, Interdisciplinary Stem Cell Inst, Dept Pathol, Miami, FL 33136 USA. RP Petrocca, F (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. EM fabio.petrocca@childrens.harvard.edu; judy.lieberman@childrens.harvard.edu RI Hide, Winston Hide/C-7217-2009; Lieberman, Judy/A-2717-2015 OI Hide, Winston Hide/0000-0002-8621-3271; FU Department of Defense Breast Cancer Research Program; National Cancer Institute [R01-CA146445]; Breast Cancer Research Foundation; Stemgent, Inc. FX This work was supported by the Department of Defense Breast Cancer Research Program (to J.L., F.P., and S.M.T.), the National Cancer Institute (R01-CA146445 to T.A.I.), and the Breast Cancer Research Foundation (to T.A.I.). We thank Robert Weinberg for useful discussions, Caroline Shamu, Sean Johnston, and Stewart Rudnicki of ICCB-Longwood for invaluable help performing the screen, Giorgia Zadra for critical advice on histopathology, Natasha Barteneva and Ken Ketman for flow cytometry assistance, and members of the Lieberman laboratory for helpful suggestions. T.A.I. receives royalty payments for WIT medium and was a consultant to Stemgent, Inc. from 2008-2010. NR 43 TC 37 Z9 37 U1 0 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 AUG 12 PY 2013 VL 24 IS 2 BP 182 EP 196 DI 10.1016/j.ccr.2013.07.008 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 201KT UT WOS:000323141200008 PM 23948298 ER PT J AU Forastiere, AA Adelstein, DJ Manola, J AF Forastiere, Arlene A. Adelstein, David J. Manola, Judi TI Induction Chemotherapy Meta-Analysis in Head and Neck Cancer: Right Answer, Wrong Question SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID LOCALLY ADVANCED HEAD; RANDOMIZED-TRIALS; CISPLATIN; CHEMORADIOTHERAPY; FLUOROURACIL; CARCINOMA; DOCETAXEL; QUALITY C1 [Forastiere, Arlene A.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Forastiere, Arlene A.] Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Adelstein, David J.] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA. [Manola, Judi] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Forastiere, AA (reprint author), Johns Hopkins Univ, Baltimore, MD 21218 USA. NR 19 TC 6 Z9 6 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2013 VL 31 IS 23 BP 2844 EP 2846 DI 10.1200/JCO.2013.50.3136 PG 3 WC Oncology SC Oncology GA 301NP UT WOS:000330539300006 PM 23835711 ER PT J AU Goswami, RS Atenafu, EG Xuan, YL Waldron, L Reis, PP Sun, T Datti, A Xu, W Kuruvilla, J Good, DJ Lai, R Church, AJ Lam, WS Baetz, T LeBrun, DP Sehn, LH Farinha, P Jurisica, I Bailey, DJ Gascoyne, RD Crump, M Kamel-Reid, S AF Goswami, Rashmi S. Atenafu, Eshetu G. Xuan, Yali Waldron, Levi Reis, Patricia P. Sun, Thomas Datti, Alessandro Xu, Wei Kuruvilla, John Good, David J. Lai, Raymond Church, Alanna J. Lam, Wilson S. Baetz, Tara LeBrun, David P. Sehn, Laurie H. Farinha, Pedro Jurisica, Igor Bailey, Denis J. Gascoyne, Randy D. Crump, Michael Kamel-Reid, Suzanne TI MicroRNA Signature Obtained From the Comparison of Aggressive With Indolent Non-Hodgkin Lymphomas: Potential Prognostic Value in Mantle-Cell Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; HEMATOLOGICAL MALIGNANCIES; MOLECULAR SUBTYPES; EXPRESSION PROFILE; CANCER-DIAGNOSIS; PROLIFERATION; RNA; SURVIVAL; MIR-29 AB Purpose Mantle-cell lymphoma (MCL) has a variable natural history but is incurable with current therapies. MicroRNAs (miRs) are useful in prognostic assessment of cancer. We determined an miR signature defining aggressiveness in B-cell non-Hodgkin lymphomas (NHL) and assessed whether this signature aids in MCL prognosis. Methods We assessed miR expression in a training set of 43 NHL cases. The miR signature was validated in 44 additional cases and examined on a training set of 119 MCL cases from four institutions in Canada. miRs significantly associated with overall survival were examined in an independent cohort of 114 MCL cases to determine association with patient outcome. miR expression was combined with current clinical prognostic factors to develop an enhanced prognostic model in patients with MCL. Results Fourteen miRs were differentially expressed between aggressive and indolent NHL; 11 of 14 were validated in an independent set of NHL (excluding MCL). miR-127-3p and miR-615-3p were significantly associated with overall survival in the MCL training set. Their expression was validated in an independent MCL patient set. In comparison with Ki-67, expression of these miRs was more significantly associated with overall survival among patients with MCL. miR-127-3p was combined with Ki-67 to create a new prognostic model for MCL. A similar model was created with miR-615-3p and Mantle Cell Lymphoma International Prognostic Index scores. Conclusion Eleven miRs are differentially expressed between aggressive and indolent NHL. Two novel miRs were associated with overall survival in MCL and were combined with clinical prognostic models to generate novel prognostic data for patients with MCL. (C) 2013 by American Society of Clinical Oncology C1 [Goswami, Rashmi S.; Xuan, Yali; Reis, Patricia P.; Kamel-Reid, Suzanne] Ontario Canc Inst, Univ Hlth Network, Toronto, ON M4X 1K9, Canada. [Goswami, Rashmi S.; Jurisica, Igor; Kamel-Reid, Suzanne] Univ Toronto, Toronto, ON, Canada. [Atenafu, Eshetu G.; Xu, Wei; Kuruvilla, John; Crump, Michael] Princess Margaret Hosp, Univ Hlth Network, Toronto, ON M4X 1K9, Canada. [Sun, Thomas; Datti, Alessandro] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Good, David J.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Jurisica, Igor] Ontario Canc Inst, Campbell Family Inst Canc Res, Toronto, ON M4X 1K9, Canada. [Jurisica, Igor] Univ Hlth Network, Techna Inst, Toronto, ON, Canada. [Bailey, Denis J.; Kamel-Reid, Suzanne] Toronto Gen Hosp, Univ Hlth Network, Toronto, ON, Canada. [Church, Alanna J.; Lam, Wilson S.; Baetz, Tara; LeBrun, David P.] Queens Univ, Kingston Gen Hosp, Kingston, ON, Canada. [Lai, Raymond] Univ Alberta, Cross Canc Inst, Edmonton, AB, Canada. [Sehn, Laurie H.; Farinha, Pedro; Gascoyne, Randy D.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Waldron, Levi] Dana Farber Canc Inst, Boston, MA 02115 USA. [Waldron, Levi] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Reis, Patricia P.] Univ Estadual Paulista, Sao Paulo, Brazil. [Datti, Alessandro] Univ Perugia, I-06100 Perugia, Italy. RP Kamel-Reid, S (reprint author), Princess Margaret Hosp, Ontario Canc Inst, 200 Elizabeth St,11 Eaton S,11-418, Toronto, ON M5G 2C4, Canada. EM suzanne.kamel-reid@uhn.ca OI Datti, Alessandro/0000-0001-6824-7382; Farinha, Pedro/0000-0001-9364-9391; Atenafu, Eshetu/0000-0002-4613-3680; Waldron, Levi/0000-0003-2725-0694 FU Canadian Institute of Health Research [STP-53912]; Frank Fletcher Memorial Fund; University of Toronto Fellowship; Wallace H. Coulter Foundation; Terry Fox Foundation [019001]; Biology of Cancer: Insights from Genomic Analysis of Lymphoid Neoplasms; Canada Foundation for Innovation [12301, 203383]; Irving and Mary Storfer Mantle Cell Lymphoma Research Fund; Princess Margaret Hospital Foundation; La Societe de Recherche sur le Cancer/Cancer Research Society; Galloway Fund; Ontario Ministry of Health and Long Term Care; Canada Research Chair Program FX R.S.G. is a Research Fellow of The Terry Fox Foundation through an award from the Canadian Cancer Society Research Institute and an Ontario Graduate Scholar; received funding through a grant from the Canadian Institute of Health Research (Reference No. STP-53912), the Frank Fletcher Memorial Fund, and through a University of Toronto Fellowship; and is an EHA-ASH TRTH trainee, a program funded with the help of the Wallace H. Coulter Foundation. R. D. G. is supported by a Terry Fox Foundation grant (Grant No. 019001), Biology of Cancer: Insights from Genomic Analysis of Lymphoid Neoplasms. Computational analysis was supported by the Canada Research Chair Program, Canada Foundation for Innovation (Grant Nos. 12301 and 203383) and IBM. This work also received generous support from the Irving and Mary Storfer Mantle Cell Lymphoma Research Fund, the Princess Margaret Hospital Foundation, La Societe de Recherche sur le Cancer/Cancer Research Society, the Galloway Fund, and the Ontario Ministry of Health and Long Term Care. NR 77 TC 13 Z9 14 U1 0 U2 9 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 AUG 10 PY 2013 VL 31 IS 23 BP 2903 EP + DI 10.1200/JCO.2012.45.3050 PG 10 WC Oncology SC Oncology GA 301NP UT WOS:000330539300015 PM 23835716 ER PT J AU Tarbell, NJ Friedman, H Polkinghorn, WR Yock, T Zhou, TN Chen, ZJ Burger, P Barnes, P Kun, L AF Tarbell, Nancy J. Friedman, Henry Polkinghorn, William R. Yock, Torunn Zhou, Tianni Chen, Zhengjia Burger, Peter Barnes, Patrick Kun, Larry TI High-Risk Medulloblastoma: A Pediatric Oncology Group Randomized Trial of Chemotherapy Before or After Radiation Therapy (POG 9031) SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NEWLY-DIAGNOSED MEDULLOBLASTOMA; HIGH-DOSE CHEMOTHERAPY; STEM-CELL RESCUE; ADJUVANT CHEMOTHERAPY; INTERNATIONAL-SOCIETY; CRANIOSPINAL RADIOTHERAPY; NEUROECTODERMAL TUMOR; PROGNOSTIC-FACTORS; PHASE-III; CHILDREN AB Purpose To compare event-free survival (EFS) in children with high-risk medulloblastoma randomly assigned to receive either chemotherapy before radiation or chemotherapy after radiation. Patients and Methods One hundred twelve patients were randomly assigned to each arm. Criteria used to categorize patients as high risk included M1-4 disease by modified Chang staging classification, T3b/T4 disease, or greater than 1.5 cm(3) of residual tumor after surgery. Postoperatively, children with high-risk medulloblastoma were randomly assigned to two arms, either chemotherapy entailing three cycles of cisplatin and etoposide before radiation (chemotherapy first [CT1]) or the same chemotherapy regimen after radiation (radiation therapy first [RT1]). Both groups received consolidation chemotherapy consisting of vincristine and cyclophosphamide. Results The median follow-up time was 6.4 years. Five-year EFS was 66.0% in the CT1 arm and 70.0% in the RT1 arm (P = .54), and 5-year overall survival in the two groups was 73.1% and 76.1%, respectively (P = .47). In the CT1 arm, 40 of the 62 patients with residual disease achieved either complete or partial remission. Conclusion Five-year EFS did not differ significantly whether, after surgery, patients received chemotherapy before or after radiotherapy. (C) 2013 by American Society of Clinical Oncology C1 [Tarbell, Nancy J.; Yock, Torunn] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Friedman, Henry] Duke Univ, Durham, NC USA. [Polkinghorn, William R.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Zhou, Tianni] Calif State Univ Long Beach, Long Beach, CA 90840 USA. [Barnes, Patrick] Stanford Univ, Stanford, CA 94305 USA. [Chen, Zhengjia] Emory Univ, Atlanta, GA 30322 USA. [Burger, Peter] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Kun, Larry] St Jude Childrens Res Hosp, Memphis, TN 38105 USA. RP Tarbell, NJ (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM nancy_tarbell@hms.harvard.edu NR 21 TC 25 Z9 28 U1 0 U2 1 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 AUG 10 PY 2013 VL 31 IS 23 BP 2936 EP + DI 10.1200/JCO.2012.43.9984 PG 7 WC Oncology SC Oncology GA 301NP UT WOS:000330539300019 PM 23857975 ER PT J AU Visvanathan, K Hurley, P Bantug, E Brown, P Col, NF Cuzick, J Davidson, NE DeCensi, A Fabian, C Ford, L Garber, J Katapodi, M Kramer, B Morrow, M Parker, B Runowicz, C Vogel, VG Wade, JL Lippman, SM AF Visvanathan, Kala Hurley, Patricia Bantug, Elissa Brown, Powel Col, Nananda F. Cuzick, Jack Davidson, Nancy E. DeCensi, Andrea Fabian, Carol Ford, Leslie Garber, Judy Katapodi, Maria Kramer, Barnett Morrow, Monica Parker, Barbara Runowicz, Carolyn Vogel, Victor G., III Wade, James L. Lippman, Scott M. TI Use of Pharmacologic Interventions for Breast Cancer Risk Reduction: American Society of Clinical Oncology Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SURGICAL ADJUVANT BREAST; BOWEL PROJECT P-1; POSTMENOPAUSAL OSTEOPOROTIC WOMEN; CONTINUING OUTCOMES RELEVANT; PRIMARY-CARE PHYSICIANS; PREVENTION TRIAL; RANDOMIZED-TRIAL; TAMOXIFEN PROPHYLAXIS; CARDIOVASCULAR EVENTS; TECHNOLOGY-ASSESSMENT AB Purpose To update the 2009 American Society of Clinical Oncology guideline on pharmacologic interventions for breast cancer (BC) risk reduction. Methods A systematic review of randomized controlled trials and meta-analyses published from June 2007 through June 2012 was completed using MEDLINE and Cochrane Collaboration Library. Primary outcome of interest was BC incidence (invasive and noninvasive). Secondary outcomes included BC mortality, adverse events, and net health benefits. Guideline recommendations were revised based on an Update Committee's review of the literature. Results Nineteen articles met the selection criteria. Six chemoprevention agents were identified: tamoxifen, raloxifene, arzoxifene, lasofoxifene, exemestane, and anastrozole. Recommendations In women at increased risk of BC age >= 35 years, tamoxifen (20 mg per day for 5 years) should be discussed as an option to reduce the risk of estrogen receptor (ER) -positive BC. In postmenopausal women, raloxifene (60 mg per day for 5 years) and exemestane (25 mg per day for 5 years) should also be discussed as options for BC risk reduction. Those at increased BC risk are defined as individuals with a 5-year projected absolute risk of BC >= 1.66% (based on the National Cancer Institute BC Risk Assessment Tool or an equivalent measure) or women diagnosed with lobular carcinoma in situ. Use of other selective ER modulators or other aromatase inhibitors to lower BC risk is not recommended outside of a clinical trial. Health care providers are encouraged to discuss the option of chemoprevention among women at increased BC risk. The discussion should include the specific risks and benefits associated with each chemopreventive agent. (C) 2013 by American Society of Clinical Oncology C1 [Visvanathan, Kala] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Bantug, Elissa] Johns Hopkins Med & Sidney Kimmel Comprehens Canc, Baltimore, MD USA. [Ford, Leslie; Kramer, Barnett] NCI, Bethesda, MD 20892 USA. [Brown, Powel] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Col, Nananda F.] Univ New England, Biddeford, ME USA. [Cuzick, Jack] Queen Mary Univ London, London, England. [Davidson, Nancy E.] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. [Davidson, Nancy E.] Med Ctr Canc Ctr, Pittsburgh, PA USA. [Vogel, Victor G., III] Geisinger Med Ctr Canc Inst, Danville, PA USA. [DeCensi, Andrea] Ente Osped Osped Galliera, Genoa, Italy. [Fabian, Carol] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Garber, Judy] Dana Farber Canc Inst, Boston, MA 02115 USA. [Katapodi, Maria] Univ Michigan, Sch Nursing, Ann Arbor, MI 48109 USA. [Morrow, Monica] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Parker, Barbara; Lippman, Scott M.] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. [Runowicz, Carolyn] Florida Int Univ, Herbert Wertheim Coll Med, Miami, FL 33199 USA. [Wade, James L.] Canc Care Specialists Cent Illinois, Decatur, IL USA. RP Visvanathan, K (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org FU AstraZeneca; Novartis; Pfizer FX Research Funding: Jack Cuzick, AstraZeneca; Judy Garber, AstraZeneca, Novartis, Pfizer NR 65 TC 104 Z9 105 U1 0 U2 13 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 AUG 10 PY 2013 VL 31 IS 23 BP 2942 EP + DI 10.1200/JCO.2013.49.3122 PG 22 WC Oncology SC Oncology GA 301NP UT WOS:000330539300020 PM 23835710 ER PT J AU Giobbie-Hurder, A Gelber, RD Regan, MM AF Giobbie-Hurder, Anita Gelber, Richard D. Regan, Meredith M. TI Challenges of Guarantee-Time Bias SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BREAST-CANCER; TUMOR RESPONSE; SURVIVAL; THERAPY; AMENORRHEA; OUTCOMES; MODELS; IMPACT; LONGER; EVENT AB The potential for guarantee-time bias (GTB), also known as immortal time bias, exists whenever an analysis that is timed from enrollment or random assignment, such as disease-free or overall survival, is compared across groups defined by a classifying event occurring sometime during follow-up. The types of events associated with GTB are varied and may include the occurrence of objective disease response, onset of toxicity, or seroconversion. However, comparative analyses using these types of events as predictors are different from analyses using baseline characteristics that are specified completely before the occurrence of any outcome event. Recognizing the potential for GTB is not always straightforward, and it can be challenging to know when GTB is influencing the results of an analysis. This article defines GTB, provides examples of GTB from several published articles, and discusses three analytic techniques that can be used to remove the bias: conditional landmark analysis, extended Cox model, and inverse probability weighting. The strengths and limitations of each technique are presented. As an example, we explore the effect of bisphosphonate use on disease-free survival (DFS) using data from the BIG (Breast International Group) 1-98 randomized clinical trial. An analysis using a naive approach showed substantial benefit for patients who received bisphosphonate therapy. In contrast, analyses using the three methods known to remove GTB showed no statistical evidence of a reduction in risk of a DFS event with bisphosphonate therapy. (C) 2013 by American Society of Clinical Oncology C1 [Giobbie-Hurder, Anita; Gelber, Richard D.; Regan, Meredith M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Gelber, Richard D.; Regan, Meredith M.] Harvard Univ, Sch Med, Boston, MA USA. [Gelber, Richard D.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Giobbie-Hurder, A (reprint author), Dept Biostat & Computat Biol, CLS11007,450 Brookline Ave, Boston, MA 02215 USA. EM agiohur@jimmy.harvard.edu FU National Cancer Institute [CA-75362]; International Breast Cancer Study Group FX International Breast Cancer Study Group Statistical Center is supported by National Cancer Institute Grant No. CA-75362 and by the International Breast Cancer Study Group. NR 26 TC 71 Z9 71 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2013 VL 31 IS 23 BP 2963 EP + DI 10.1200/JCO.2013.49.5283 PG 8 WC Oncology SC Oncology GA 301NP UT WOS:000330539300025 PM 23835712 ER PT J AU Spector, J AF Spector, Jonathan TI Practical criteria for maternal near miss needed for low-income settings SO LANCET LA English DT Letter C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Spector, J (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM spectorjm@gmail.com NR 2 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD AUG 10 PY 2013 VL 382 IS 9891 BP 504 EP 505 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 201SD UT WOS:000323162400022 PM 23931920 ER PT J AU Nallamshetty, S Wang, H Rhee, EJ Kiefer, FW Brown, JD Lotinun, S Le, P Baron, R Rosen, CJ Plutzky, J AF Nallamshetty, Shriram Wang, Hong Rhee, Eun-Jung Kiefer, Florian W. Brown, Jonathan D. Lotinun, Sutada Le, Phuong Baron, Roland Rosen, Clifford J. Plutzky, Jorge TI Deficiency of Retinaldehyde Dehydrogenase 1 Induces BMP2 and Increases Bone Mass In Vivo SO PLOS ONE LA English DT Article ID MESENCHYMAL STEM-CELLS; GROWTH-FACTOR-I; RETINOIC ACID; MINERAL DENSITY; ALDEHYDE DEHYDROGENASE; HYPERVITAMINOSIS-A; GENE-EXPRESSION; VITAMIN-A; MORPHOGENETIC PROTEINS; OSTEOBLASTIC CELLS AB The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (mu CT) demonstrated that Aldh1a1-deficient (Aldh1a1(-/-)) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demonstrated significantly higher bone marrow adiposity in Aldh1a1(-/-) mice. In serum assays, Aldh1a1(-/-) mice also had higher serum IGF-1 levels. In vitro, primary Aldh1a1(-/-) mesenchymal stem cells (MSCs) expressed significantly higher levels of bone morphogenetic protein 2 (BMP2) and demonstrated enhanced osteoblastogenesis and adipogenesis versus WT MSCs. BMP2 was also expressed at higher levels in the femurs and tibias of Aldh1a1(-/-) mice with accompanying induction of BMP2-regulated responses, including expression of Runx2 and alkaline phosphatase, and Smad phosphorylation. In vitro, Rald, which accumulates in Aldh1a1(-/-) mice, potently induced BMP2 in WT MSCs in a retinoic acid receptor (RAR)-dependent manner, suggesting that Rald is involved in the BMP2 increases seen in Aldh1a1 deficiency in vivo. Collectively, these data implicate Aldh1a1 as a novel determinant of cortical bone density and marrow adiposity in the skeleton in vivo through modulation of BMP signaling. C1 [Nallamshetty, Shriram; Wang, Hong; Rhee, Eun-Jung; Kiefer, Florian W.; Brown, Jonathan D.; Plutzky, Jorge] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Nallamshetty, Shriram] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Lotinun, Sutada; Baron, Roland] Harvard Univ, Dept Oral Med Infect & Immun, Sch Dent Med, Boston, MA 02115 USA. [Le, Phuong; Rosen, Clifford J.] Maine Med Ctr Res Inst, Ctr Clin & Translat Res, Scarborough, ME USA. RP Plutzky, J (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. EM jplutzky@rics.bwh.harvard.edu OI Rhee, Eun-Jung/0000-0002-6108-7758 FU NIH PPG [5P01HL048743-20]; NIH [5T32HL007208-34]; Austrian Science Fund (FWF) [J3107-B19] FX Research supported by NIH PPG Grant 5P01HL048743-20. SN supported by NIH Training Grant 5T32HL007208-34. FWK supported by Austrian Science Fund (FWF): J3107-B19. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 63 TC 6 Z9 6 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 9 PY 2013 VL 8 IS 8 AR e71307 DI 10.1371/journal.pone.0071307 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 245OM UT WOS:000326473200038 PM 23951127 ER PT J AU Makam, AN Lanham, HJ Batchelor, K Samal, L Moran, B Howell-Stampley, T Kirk, L Cherukuri, M Santini, N Leykum, LK Halm, EA AF Makam, Anil N. Lanham, Holly J. Batchelor, Kim Samal, Lipika Moran, Brett Howell-Stampley, Temple Kirk, Lynne Cherukuri, Manjula Santini, Noel Leykum, Luci K. Halm, Ethan A. TI Use and satisfaction with key functions of a common commercial electronic health record: a survey of primary care providers SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article DE Electronic health record (EHR); Attitude of health personnel; Attitude to computers; Primary care; Efficiency; Quality of care; Medical informatics/utilization ID DECISION-SUPPORT-SYSTEMS; INFORMATION-TECHNOLOGY; AMBULATORY-CARE; STATEWIDE-SURVEY; QUALITY; PHYSICIANS; IMPACT; DOCUMENTATION; EFFICIENCY AB Background: Despite considerable financial incentives for adoption, there is little evidence available about providers' use and satisfaction with key functions of electronic health records (EHRs) that meet "meaningful use" criteria. Methods: We surveyed primary care providers (PCPs) in 11 general internal medicine and family medicine practices affiliated with 3 health systems in Texas about their use and satisfaction with performing common tasks (documentation, medication prescribing, preventive services, problem list) in the Epic EHR, a common commercial system. Most practices had greater than 5 years of experience with the Epic EHR. We used multivariate logistic regression to model predictors of being a structured documenter, defined as using electronic templates or prepopulated dot phrases to document at least two of the three note sections (history, physical, assessment and plan). Results: 146 PCPs responded (70%). The majority used free text to document the history (51%) and assessment and plan (54%) and electronic templates to document the physical exam (57%). Half of PCPs were structured documenters (55%) with family medicine specialty (adjusted OR 3.3, 95% CI, 1.4-7.8) and years since graduation (nonlinear relationship with youngest and oldest having lowest probabilities) being significant predictors. Nearly half (43%) reported spending at least one extra hour beyond each scheduled half-day clinic completing EHR documentation. Three-quarters were satisfied with documenting completion of pneumococcal vaccinations and half were satisfied with documenting cancer screening (57% for breast, 45% for colorectal, and 46% for cervical). Fewer were satisfied with reminders for overdue pneumococcal vaccination (48%) and cancer screening (38% for breast, 37% for colorectal, and 31% for cervical). While most believed the problem list was helpful (70%) and kept an up-to-date list for their patients (68%), half thought they were unreliable and inaccurate (51%). Conclusions: Dissatisfaction with and suboptimal use of key functions of the EHR may mitigate the potential for EHR use to improve preventive health and chronic disease management. Future work should optimize use of key functions and improve providers' time efficiency. C1 [Makam, Anil N.; Batchelor, Kim; Moran, Brett; Howell-Stampley, Temple; Kirk, Lynne; Santini, Noel; Halm, Ethan A.] Univ Texas SW Med Ctr Dallas, Div Gen Internal Med, Dallas, TX 75390 USA. [Lanham, Holly J.; Leykum, Luci K.] Univ Texas Hlth Sci Ctr San Antonio, Div Hosp Med, San Antonio, TX 78229 USA. [Lanham, Holly J.; Leykum, Luci K.] South Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Samal, Lipika] Brigham & Womens Hosp, Div Gen Internal Med & Primary Care, Boston, MA 02120 USA. [Cherukuri, Manjula] Univ North Texas Hlth Sci Ctr, Dept Family & Community Med, Ft Worth, TX 76105 USA. [Santini, Noel] Parkland Hlth & Hosp Syst, Community Med Div, Dallas, TX 75235 USA. RP Makam, AN (reprint author), Univ Texas SW Med Ctr Dallas, Div Gen Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM anil.makam@utsouthwestern.edu OI Makam, Anil/0000-0001-7072-9946 FU University of Texas Chancellors Fellow for Health Information Technology program; NRSA training grant [T32HP19025-07-00] FX We would like to thank the primary care physicians who participated in this study. This study was supported by a grant from the University of Texas Chancellors Fellow for Health Information Technology program (PI, Halm). Much of Dr. Makam's work on this project was completed while he was a Primary Care Research Fellow at the University of California San Francisco, funded by an NRSA training grant (T32HP19025-07-00). Preliminary results of this study were presented at the Society of General Internal Medicine (SGIM) annual meeting in Orlando, Florida, in 2012. NR 26 TC 11 Z9 11 U1 7 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD AUG 9 PY 2013 VL 13 AR 86 DI 10.1186/1472-6947-13-86 PG 7 WC Medical Informatics SC Medical Informatics GA 200HH UT WOS:000323058300001 PM 24070335 ER PT J AU Sienko, KH Balkwill, MD Oddsson, LIE Wall, C AF Sienko, Kathleen H. Balkwill, M. David Oddsson, Lars I. E. Wall, Conrad, III TI The effect of vibrotactile feedback on postural sway during locomotor activities SO JOURNAL OF NEUROENGINEERING AND REHABILITATION LA English DT Article DE Balance; Gait; Locomotion; Vibrotactile; Biofeedback; Vestibular; Sensory augmentation; Balance aid ID UNILATERAL VESTIBULAR LOSS; SENSORY SUBSTITUTION; TANDEM GAIT; BIOFEEDBACK; BALANCE; PERTURBATIONS; INFORMATION; DEFICITS AB Background: Although significant progress has been achieved in developing sensory augmentation methods to improve standing balance, attempts to extend this research to locomotion have been quite limited in scope. The goal of this study was to characterize the effects of two real-time feedback displays on locomotor performance during four gait-based tasks ranging in difficulty. Methods: Seven subjects with vestibular deficits used a trunk-based vibrotactile feedback system that provided real-time feedback regarding their medial-lateral (M/L) trunk tilt when they exceeded a subject-specific predefined tilt threshold during slow and self-paced walking, walking along a narrow walkway, and walking on a foam surface. Two feedback display configurations were evaluated: the continuous display provided real-time continuous feedback of trunk tilt, and the gated display provided feedback for 200 ms during the period immediately following heel strike. The root-mean-square (RMS) trunk tilt and percentage of time below the tilt thresholds were calculated for all locomotor tasks. Results: Use of continuous feedback resulted in significant decreases in M/L trunk tilt and increases in percentage times below the tilt thresholds during narrow and foam trials. The gated display produced generally smaller changes. Conclusions: This preliminary study demonstrated that use of continuous vibrotactile feedback during challenging locomotor tasks allowed subjects with vestibular deficits to significantly decrease M/L RMS trunk tilt. Analysis of the results also showed that continuous feedback was superior. C1 [Sienko, Kathleen H.] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Sienko, Kathleen H.; Balkwill, M. David; Wall, Conrad, III] Massachusetts Eye & Ear Infirm, Jenks Vestibular Diagnost Lab, Boston, MA 02114 USA. [Sienko, Kathleen H.] Univ Michigan, Dept Mech Engn, Ann Arbor, MI 48109 USA. [Sienko, Kathleen H.] Univ Michigan, Dept Biomed Engn, Ann Arbor, MI 48109 USA. [Wall, Conrad, III] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Oddsson, Lars I. E.] Boston Univ, Neuromuscular Res Ctr, Boston, MA 02215 USA. [Oddsson, Lars I. E.] Courage Kenny Rehabil Inst Part Allina Hlth, Courage Kenny Res Ctr, Minneapolis, MN USA. RP Sienko, KH (reprint author), Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. EM sienko@umich.edu OI Mihailidis, Alex/0000-0003-2233-0919 FU NIH [R01 DC06201-01]; National Science Foundation [RAPD-0846471]; American Recovery and Reinvestment Act FX This work was supported in part by the NIH Research Grant R01 DC06201-01 and the National Science Foundation's CAREER program (RAPD-0846471, funded under the American Recovery and Reinvestment Act of 2009). We thank Dr. Kennyn Statler and Matthew Christensen for their help with testing subjects, Jimmy Robertsson for helping to develop the wireless balance aid, and Ann Stewart for technical writing assistance. NR 17 TC 8 Z9 8 U1 0 U2 13 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-0003 J9 J NEUROENG REHABIL JI J. NeuroEng. Rehabil. PD AUG 9 PY 2013 VL 10 AR 93 DI 10.1186/1743-0003-10-93 PG 6 WC Engineering, Biomedical; Neurosciences; Rehabilitation SC Engineering; Neurosciences & Neurology; Rehabilitation GA 201VJ UT WOS:000323170800001 PM 23938136 ER PT J AU Nathan, DG AF Nathan, David G. TI Hemoglobin disorders: a look to the future SO BLOOD LA English DT Editorial Material ID BONE-MARROW-TRANSPLANTATION; SICKLE-CELL-DISEASE; THALASSEMIA; ANEMIA C1 [Nathan, David G.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Nathan, David G.] Boston Childrens Hosp, Boston, MA USA. [Nathan, David G.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Nathan, DG (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 9 TC 1 Z9 1 U1 0 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 8 PY 2013 VL 122 IS 6 BP 859 EP 860 DI 10.1182/blood-2013-06-506154 PG 4 WC Hematology SC Hematology GA 197VE UT WOS:000322879100006 PM 23929837 ER PT J AU Della Beffa, C Slansky, E Pommerenke, C Klawonn, F Li, JL Dai, L Schumacher, HR Pessler, F AF Della Beffa, Cristina Slansky, Elisabeth Pommerenke, Claudia Klawonn, Frank Li, Jialiang Dai, Lie Schumacher, H. Ralph, Jr. Pessler, Frank TI The Relative Composition of the Inflammatory Infiltrate as an Additional Tool for Synovial Tissue Classification SO PLOS ONE LA English DT Article ID WAR-VETERANS-ILLNESS; JOINT PAIN; ARTHRITIS; ARTHROPATHIES; BIOMARKER; SCORE AB Objectives: Traditionally, differences in absolute numbers of cells expressing a certain marker (e. g., positive staining cells per mm(2)) have been used in immunohistological synovial tissue classification. We have begun to evaluate the relative composition of the inflammatory infiltrates, i.e. percentages of inflammatory cell types in inflammatory infiltrates, as an alternate classification tool that may potentially improve tissue diagnostics, subgrouping in clinical trials, and understanding of pathogenesis of inflammatory and noninflammatory arthropathies. Methods: Synovial tissue specimens (normal synovium, n=15; orthopedic arthropathies, n=6; osteoarthritis, n=26; early undifferentiated arthritis, n=10; rheumatoid arthritis, n=26; chronic septic arthritis, n=11) were stained for CD15, CD68, CD3, CD20, and CD38. Densities of cells expressing a given marker were determined in the superficial subintima. Binary and multicategory receiver operating characteristic (ROC) analysis and naive Bayes classifier were used to compare the abilities of (1) the absolute densities of cells expressing a given marker (absolute method) with (2) the percentages of these cells in the inflammatory cell population (relative method) to differentiate among the six tissue classes. Results: The inflammatory infiltrates in normal synovium and the orthopedic arthropathies consisted almost exclusively of CD68+ and CD3+ cells. Notable fractions of CD20+ and CD38+ cells appeared in a subset of osteoarthritis samples, and increased further in early, rheumatoid and chronic septic arthritis. ROC analyses and naive Bayes classifier ranked the absolute method above the relative method in terms of overall discriminatory ability. The relative method became slightly superior when the samples were also stratified according to the total number of inflammatory cells/mm(2). Conclusions: This exploratory investigation featuring a variety of joint disorders revealed that measuring the relative proportions of inflammatory cell types may aid in synovial tissue classification if the samples are also stratified according to the intensity of inflammation. C1 [Della Beffa, Cristina; Klawonn, Frank] Helmholtz Ctr Infect Res, Dept Cellular Prote, Braunschweig, Germany. [Pommerenke, Claudia] Helmholtz Ctr Infect Res, Dept Infect Genet, Braunschweig, Germany. [Klawonn, Frank] Ostfalia Univ Appl Sci, Dept Comp Sci, Wolfenbuttel, Germany. [Slansky, Elisabeth; Li, Jialiang] Natl Univ Singapore, Dept Stat & Appl Probabil, Singapore 117548, Singapore. [Dai, Lie] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Rheumatol, Guangzhou 510275, Guangdong, Peoples R China. [Schumacher, H. Ralph, Jr.] Philadelphia Vet Affairs Med Ctr, Div Rheumatol, Philadelphia, PA USA. [Pessler, Frank] TWINCORE Ctr Expt & Clin Infect Res, Res Grp Biomarkers Infect Dis, Hannover, Germany. RP Pessler, F (reprint author), TWINCORE Ctr Expt & Clin Infect Res, Res Grp Biomarkers Infect Dis, Hannover, Germany. EM frank.pessler@twincore.de RI Li, Jialiang/B-9132-2014 OI Li, Jialiang/0000-0002-9704-4135 FU International Collaboration Seed from the German Federal Ministry for Education and Science (International Office) [SGP 08/A01, SGP 09/1AP] FX Support is gratefully acknowledged from International Collaboration Seed Grant SGP 08/A01 and grant SGP 09/1AP "German-Singaporean Network for Rheumatology Research" from the German Federal Ministry for Education and Science (International Office). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 18 TC 2 Z9 2 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 8 PY 2013 VL 8 IS 8 AR e72494 DI 10.1371/journal.pone.0072494 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 201ER UT WOS:000323124000085 PM 23951325 ER PT J AU Zariwala, MA Gee, HY Kurkowiak, M Al-Mutairi, DA Leigh, MW Hurd, TW Hjeij, R Dell, SD Chaki, M Dougherty, GW Adan, M Spear, PC Esteve-Rudd, J Loges, NT Rosenfeld, M Diaz, KA Olbrich, H Wolf, WE Sheridan, E Batten, TFC Halbritter, J Porath, JD Kohl, S Lovric, S Hwang, DY Pittman, JE Burns, KA Ferkol, TW Sagel, SD Olivier, KN Morgan, LC Werner, C Raidt, J Pennekamp, P Sun, ZX Zhou, WB Airik, R Natarajan, S Allen, SJ Amirav, I Wieczorek, D Landwehr, K Nielsen, K Schwerk, N Sertic, J Kohler, G Washburn, J Levy, S Fan, SL Koerner-Rettberg, C Amselem, S Williams, DS Mitchell, BJ Drummond, LA Otto, EA Omran, H Knowles, MR Hildebrandt, F AF Zariwala, Maimoona A. Gee, Heon Yung Kurkowiak, Malgorzata Al-Mutairi, Dalal A. Leigh, Margaret W. Hurd, Toby W. Hjeij, Rim Dell, Sharon D. Chaki, Moumita Dougherty, Gerard W. Adan, Mohamed Spear, Philip C. Esteve-Rudd, Julian Loges, Niki T. Rosenfeld, Margaret Diaz, Katrina A. Olbrich, Heike Wolf, Whitney E. Sheridan, Eamonn Batten, Trevor F. C. Halbritter, Jan Porath, Jonathan D. Kohl, Stefan Lovric, Svjetlana Hwang, Daw-Yang Pittman, Jessica E. Burns, Kimberlie A. Ferkol, Thomas W. Sagel, Scott D. Olivier, Kenneth N. Morgan, Lucy C. Werner, Claudius Raidt, Johanna Pennekamp, Petra Sun, Zhaoxia Zhou, Weibin Airik, Rannar Natarajan, Sivakumar Allen, Susan J. Amirav, Israel Wieczorek, Dagmar Landwehr, Kerstin Nielsen, Kim Schwerk, Nicolaus Sertic, Jadranka Koehler, Gabriele Washburn, Joseph Levy, Shawn Fan, Shuling Koerner-Rettberg, Cordula Amselem, Serge Williams, David S. Mitchell, Brian J. Drummond, Lain A. Otto, Edgar A. Omran, Heymut Knowles, Michael R. Hildebrandt, Friedhelm TI ZMYND10 Is Mutated in Primary Ciliary Dyskinesia and Interacts with LRRC6 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID DYNEIN REGULATORY COMPLEX; CELL-CYCLE; MUTATIONS; CILIOGENESIS; DEFECTS; CILIOPATHY; MOTILITY; DISEASE; HUMANS; GENES AB Defects of motile cilia cause primary ciliary dyskinesia (PCD), characterized by recurrent respiratory infections and male infertility Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families. We show that ZMYND10 and LRRC6 interact and that certain ZMYND10 and LRRC6 mutations abrogate the interaction between the LRRC6 CS domain and the ZMYND10 C-terminal domain. Additionally ZMYND10 and LRRC6 colocalize with the centriole markers SAS6 and PCM1. Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia. Animal models support the association between ZMYND10 and human PCD, given that zmynd10 knockdown in zebrafish caused ciliary paralysis leading to cystic kidneys and otolith defects and that knockdown in Xenopus interfered with ciliogenesis. Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function. C1 [Zariwala, Maimoona A.] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. [Gee, Heon Yung; Halbritter, Jan; Porath, Jonathan D.; Kohl, Stefan; Lovric, Svjetlana; Hwang, Daw-Yang; Airik, Rannar; Hildebrandt, Friedhelm] Harvard Univ, Boston Childrens Hosp, Sch Med, Div Nephrol,Dept Med, Boston, MA 02115 USA. [Kurkowiak, Malgorzata; Hjeij, Rim; Dougherty, Gerard W.; Loges, Niki T.; Olbrich, Heike; Werner, Claudius; Raidt, Johanna; Pennekamp, Petra; Omran, Heymut] Univ Childrens Hosp Muenster, Dept Gen Pediat, D-48149 Munster, Germany. [Kurkowiak, Malgorzata] Polish Acad Sci, Inst Human Genet, Dept Mol & Clin Genet, PL-60479 Poznan, Poland. [Kurkowiak, Malgorzata] Int Inst Mol & Cell Biol, PL-02109 Warsaw, Poland. [Al-Mutairi, Dalal A.] Kuwait Univ, Fac Med, Hlth Sci Ctr, Dept Pathol, Safat 13110, Kuwait. [Batten, Trevor F. C.] Univ Leeds, Fac Med & Hlth, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England. [Leigh, Margaret W.; Pittman, Jessica E.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27599 USA. [Hurd, Toby W.] Univ Edinburgh, Inst Genet & Mol Med, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Dell, Sharon D.] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Chaki, Moumita; Diaz, Katrina A.; Zhou, Weibin; Natarajan, Sivakumar; Allen, Susan J.; Otto, Edgar A.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Adan, Mohamed; Drummond, Lain A.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Spear, Philip C.; Mitchell, Brian J.] Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Esteve-Rudd, Julian; Williams, David S.] Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Dept Ophthalmol & Neurobiol, Los Angeles, CA 90095 USA. [Rosenfeld, Margaret] Univ Washington, Sch Med, Seattle Childrens Hosp, Seattle, WA 98105 USA. [Wolf, Whitney E.; Burns, Kimberlie A.; Knowles, Michael R.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. [Sheridan, Eamonn] St James Univ Hosp, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. [Ferkol, Thomas W.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. [Sagel, Scott D.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO 80045 USA. [Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Morgan, Lucy C.] Concord Hosp, Dept Resp Med, Concord 2139, NSW, Australia. [Sun, Zhaoxia] Yale Univ, Dept Genet, New Haven, CT 06520 USA. [Amirav, Israel] Bar Ilan Univ, Fac Med, Ziv Med Ctr, Dept Pediat, IL-13100 Safed, Israel. [Wieczorek, Dagmar] Univ Duisburg Essen, Univ Klinikum Essen, Inst Human Genet, D-45122 Essen, Germany. [Landwehr, Kerstin] Evangel Krankenhaus Bielefeld, Klin Kinder & Jugendmed, D-33617 Bielefeld, Nordrhein Westf, Germany. [Nielsen, Kim] Copenhagen Univ Hosp, Rigshosp, Dept Paediat & Adolescent Med, Paediat Pulm Serv, DK-2100 Copenhagen, Denmark. [Schwerk, Nicolaus] Hannover Med Sch, Univ Childrens Hosp, Dept Pneumol Allergy & Neonatol, D-30625 Hannover, Germany. [Sertic, Jadranka] Univ Zagreb, Sch Med, Zagreb Clin Hosp, Clin Inst Lab Diag, Zagreb 10000, Croatia. [Koehler, Gabriele] Univ Hosp Muenster, Dept Pathol, D-48149 Munster, Germany. [Washburn, Joseph] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Levy, Shawn] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA. [Fan, Shuling] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Koerner-Rettberg, Cordula] Ruhr Univ Bochum, St Josef Hosp, Klin Kinder & Jugendmed, D-44791 Bochum, Germany. [Amselem, Serge] Univ Paris 06, INSERM, Unite Mixte Rech S933, F-75012 Paris, France. [Drummond, Lain A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Hildebrandt, Friedhelm] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Hildebrandt, F (reprint author), Harvard Univ, Boston Childrens Hosp, Sch Med, Div Nephrol,Dept Med, Boston, MA 02115 USA. EM knowles@med.unc.edu; friedhelm.hildebrandt@childrens.harvard.edu RI Spear, Philip/L-5446-2014; OI Spear, Philip/0000-0002-7657-3433; Otto, Edgar/0000-0002-2387-9973; Batten, Trevor/0000-0003-3988-5603; Mitchell, Brian/0000-0001-6281-1536 FU National Institutes of Health (NIH) [DK068306, DK090917, DK091405, DK053093, DK070263, EY013408, DK092808-01A1, 5 U54 HL096458-06]; NIH from the National Center for Advancing Translational Sciences [UL1 TR000083, UL1 TR000154]; project "Studies of nucleic acids and proteins from basic to applied research"; Foundation for Polish Science; European Union Regional Development Fund; Department of Pathology, Faculty of Medicine, Kuwait University; Office of the Director; Office of Rare Diseases Research; National Heart, Lung, and Blood Institute (NHLBI); NIH NHLBI [5 R01HL071798]; Deutsche Forschungsgemeinschaft [DFG Om 6/4, Om 6/5, GRK1104, SFB592]; IZKF Munster; Cell Dynamics and Disease graduate school; project SYSCILIA from the European Community FX We are grateful to all individuals with primary ciliary dyskinesia (PCD) and family members for their participation, as well as Michele Manion, who founded the United States PCD Foundation. We thank the German support group "Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V." This research was supported by grants from the National Institutes of Health (NIH) to F.H. (DK068306 and DK090917), to W.Z. (DK091405), to I.A.D. (DK053093 and DK070263), to D.S.W (EY013408), and to Z.S. (DK092808-01A1). This work was supported in part by NIH grants UL1 TR000083 and UL1 TR000154 from the National Center for Advancing Translational Sciences. M.K. is supported by the project "Studies of nucleic acids and proteins from basic to applied research," sponsored by the International PhD Projects Programme of Foundation for Polish Science. The project is cofinanced by the European Union Regional Development Fund. D.A.M. was supported by the Department of Pathology, Faculty of Medicine, Kuwait University. M.A.Z., M.W.L., S.D.D., M.R., T.W.F., S.D.S., J.E.P., K.N.O., and M.R.K. are supported by NIH research grant 5 U54 HL096458-06, funded by the Office of the Director, and supported by the Office of Rare Diseases Research and the National Heart, Lung, and Blood Institute (NHLBI). M.A.Z. and M.R.K. are supported by NIH NHLBI grant 5 R01HL071798. H.O. is supported by the Deutsche Forschungsgemeinschaft (DFG Om 6/4 and Om 6/5, GRK1104, and SFB592), IZKF Munster, the Cell Dynamics and Disease graduate school, and project SYSCILIA from the European Community. Additional acknowledgements are provided in the Supplemental Data. NR 33 TC 43 Z9 49 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG 8 PY 2013 VL 93 IS 2 BP 336 EP 345 DI 10.1016/j.ajhg.2013.06.007 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 202AP UT WOS:000323186200014 PM 23891469 ER PT J AU Morain, S Greene, MF Mello, MM AF Morain, Stephanie Greene, Michael F. Mello, Michelle M. TI A New Era in Noninvasive Prenatal Testing SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Morain, Stephanie] Harvard Univ, Edmond J Safra Ctr Eth, Cambridge, MA 02138 USA. [Greene, Michael F.] Massachusetts Gen Hosp, Vincent Dept Obstet & Gynecol, Boston, MA 02114 USA. [Greene, Michael F.] Harvard Univ, Sch Med, Boston, MA USA. [Mello, Michelle M.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Morain, S (reprint author), Harvard Univ, Edmond J Safra Ctr Eth, Cambridge, MA 02138 USA. NR 5 TC 44 Z9 47 U1 0 U2 14 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 AUG 8 PY 2013 VL 369 IS 6 BP 499 EP 501 DI 10.1056/NEJMp1304843 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 197HX UT WOS:000322842000003 PM 23862975 ER PT J AU Bhatt, AS Freeman, SS Herrera, AF Pedamallu, CS Gevers, D Duke, F Jung, J Michaud, M Walker, BJ Young, S Earl, AM Kostic, AD Ojesina, AI Hasserjian, R Ballen, KK Chen, YB Hobbs, G Antin, JH Soiffer, RJ Baden, LR Garrett, WS Hornick, JL Marty, FM Meyerson, M AF Bhatt, Ami S. Freeman, Samuel S. Herrera, Alex F. Pedamallu, Chandra Sekhar Gevers, Dirk Duke, Fujiko Jung, Joonil Michaud, Monia Walker, Bruce J. Young, Sarah Earl, Ashlee M. Kostic, Aleksander D. Ojesina, Akinyemi I. Hasserjian, Robert Ballen, Karen K. Chen, Yi-Bin Hobbs, Gabriela Antin, Joseph H. Soiffer, Robert J. Baden, Lindsey R. Garrett, Wendy S. Hornick, Jason L. Marty, Francisco M. Meyerson, Matthew TI Sequence-Based Discovery of Bradyrhizobium enterica in Cord Colitis Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE MARROW TRANSPLANTATION; IN-SITU HYBRIDIZATION; HEPATIC COMPLICATIONS; IDENTIFICATION; BLOOD; NITROIMIDAZOLES; METRONIDAZOLE; GENOMICS; SEARCH AB BACKGROUND Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin. METHODS We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls. RESULTS DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease. CONCLUSIONS We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen. C1 [Bhatt, Ami S.; Herrera, Alex F.; Pedamallu, Chandra Sekhar; Duke, Fujiko; Kostic, Aleksander D.; Ojesina, Akinyemi I.; Antin, Joseph H.; Soiffer, Robert J.; Baden, Lindsey R.; Garrett, Wendy S.; Marty, Francisco M.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Michaud, Monia; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Hasserjian, Robert; Ballen, Karen K.; Chen, Yi-Bin] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Baden, Lindsey R.; Marty, Francisco M.] Brigham & Womens Hosp, Dept Internal Med, Div Infect Dis, Boston, MA 02115 USA. [Hornick, Jason L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bhatt, Ami S.; Freeman, Samuel S.; Pedamallu, Chandra Sekhar; Gevers, Dirk; Duke, Fujiko; Jung, Joonil; Walker, Bruce J.; Young, Sarah; Earl, Ashlee M.; Kostic, Aleksander D.; Ojesina, Akinyemi I.; Garrett, Wendy S.; Meyerson, Matthew] Broad Inst, Cambridge, MA USA. [Hobbs, Gabriela] Mem Sloan Kettering Canc Ctr, Dept Med Oncol, New York, NY 10021 USA. RP Meyerson, M (reprint author), 450 Brookline Ave, Boston, MA 02215 USA. EM matthew_meyerson@dfci.harvard.edu OI Ojesina, Akinyemi/0000-0003-0755-3639; Earl, Ashlee/0000-0001-7857-9145; Hobbs, Gabriela/0000-0002-0199-9333; Kostic, Aleksandar/0000-0002-0837-4360 FU National Cancer Institute; American Association for Cancer Research; American Society for Blood and Marrow Transplantation; Bladder Cancer Advocacy Network; Starr Cancer Consortium; National Cancer Institute [RC2CA148317] FX Funded by the National Cancer Institute and others.; Supported by grants from the American Association for Cancer Research, the American Society for Blood and Marrow Transplantation, and the Bladder Cancer Advocacy Network (all to Dr. Bhatt); and by grants from the Starr Cancer Consortium and National Cancer Institute (RC2CA148317) (both to Dr. Meyerson). NR 39 TC 45 Z9 48 U1 0 U2 13 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 AUG 8 PY 2013 VL 369 IS 6 BP 517 EP 528 DI 10.1056/NEJMoa1211115 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 197HX UT WOS:000322842000008 PM 23924002 ER PT J AU Vander Lugt, MT Braun, TM Hanash, S Ritz, J Ho, VT Antin, JH Zhang, Q Wong, CH Wang, H Chin, A Gomez, A Harris, AC Levine, JE Choi, SW Couriel, D Reddy, P Ferrara, JLM Paczesny, S AF Vander Lugt, Mark T. Braun, Thomas M. Hanash, Samir Ritz, Jerome Ho, Vincent T. Antin, Joseph H. Zhang, Qing Wong, Chee-Hong Wang, Hong Chin, Alice Gomez, Aurelie Harris, Andrew C. Levine, John E. Choi, Sung W. Couriel, Daniel Reddy, Pavan Ferrara, James L. M. Paczesny, Sophie TI ST2 as a Marker for Risk of Therapy-Resistant Graft-versus-Host Disease and Death SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HEMATOPOIETIC-CELL TRANSPLANTATION; ALLERGIC AIRWAY INFLAMMATION; HELPER T-CELLS; ACUTE GVHD; CLINICAL-TRIALS; EXPRESSION; SURVIVAL; PROTEIN; IL-33; BIOMARKERS AB BACKGROUND No plasma biomarkers are associated with the response of acute graft-versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation. METHODS We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation. RESULTS Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen. CONCLUSIONS ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation. C1 [Vander Lugt, Mark T.; Gomez, Aurelie; Harris, Andrew C.; Levine, John E.; Choi, Sung W.; Ferrara, James L. M.; Paczesny, Sophie] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Braun, Thomas M.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Couriel, Daniel; Reddy, Pavan; Ferrara, James L. M.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Hanash, Samir; Zhang, Qing; Wong, Chee-Hong; Wang, Hong; Chin, Alice; Paczesny, Sophie] Fred Hutchinson Canc Res Ctr, Mol Diagnost Program, Seattle, WA 98104 USA. [Ritz, Jerome; Ho, Vincent T.; Antin, Joseph H.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Paczesny, S (reprint author), Indiana Univ, Bone Marrow & Stem Cell Transplantat Program, Melvin & Bren Simon Canc Ctr, 1044 W Walnut St,Rm 425, Indianapolis, IN 46202 USA. EM sophpacz@iu.edu OI Levine, John/0000-0002-9133-0800; Harris, Andrew/0000-0002-4538-8817; Ritz, Jerome/0000-0001-5526-4669 FU National Institutes of Health [RC1HL101102, R01CA168814, P01-CA039542, T32-HL007622]; M.J. Murdock Charitable Trust FX Funded by the National Institutes of Health.; Supported by grants (RC1HL101102, R01CA168814, P01-CA039542, and T32-HL007622) from the National Institutes of Health. The linear trap quadrupole-Fourier-transform mass spectrometer used in this work was funded in part by the M.J. Murdock Charitable Trust. NR 38 TC 53 Z9 53 U1 4 U2 14 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 AUG 8 PY 2013 VL 369 IS 6 BP 529 EP 539 DI 10.1056/NEJMoa1213299 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 197HX UT WOS:000322842000009 PM 23924003 ER PT J AU Crane, PK Walker, R Hubbard, RA Li, G Nathan, DM Zheng, H Haneuse, S Craft, S Montine, TJ Kahn, SE McCormick, W McCurry, SM Bowen, JD Larson, EB AF Crane, Paul K. Walker, Rod Hubbard, Rebecca A. Li, Ge Nathan, David M. Zheng, Hui Haneuse, Sebastien Craft, Suzanne Montine, Thomas J. Kahn, Steven E. McCormick, Wayne McCurry, Susan M. Bowen, James D. Larson, Eric B. TI Glucose Levels and Risk of Dementia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; APOLIPOPROTEIN-E; FOLLOW-UP; INSULIN; METABOLISM; EPIDEMIC; BRAIN AB BACKGROUND Diabetes is a risk factor for dementia. It is unknown whether higher glucose levels increase the risk of dementia in people without diabetes. METHODS We used 35,264 clinical measurements of glucose levels and 10,208 measurements of glycated hemoglobin levels from 2067 participants without dementia to examine the relationship between glucose levels and the risk of dementia. Participants were from the Adult Changes in Thought study and included 839 men and 1228 women whose mean age at baseline was 76 years; 232 participants had diabetes, and 1835 did not. We fit Cox regression models, stratified according to diabetes status and adjusted for age, sex, study cohort, educational level, level of exercise, blood pressure, and status with respect to coronary and cerebrovascular diseases, atrial fibrillation, smoking, and treatment for hypertension. RESULTS During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P=0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P=0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76). CONCLUSIONS Our results suggest that higher glucose levels may be a risk factor for dementia, even among persons without diabetes. C1 [Crane, Paul K.; McCormick, Wayne; Larson, Eric B.] Univ Washington, Dept Med, Seattle, WA USA. [Li, Ge] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [McCurry, Susan M.] Univ Washington, Dept Psychosocial & Community Hlth, Seattle, WA 98195 USA. [Walker, Rod; Hubbard, Rebecca A.; Larson, Eric B.] Grp Hlth Res Inst, Seattle, WA USA. [Kahn, Steven E.] VA Puget Sound Hlth Care Syst, Dept Med, Seattle, WA USA. [Kahn, Steven E.] Univ Washington, Seattle, WA 98195 USA. [Bowen, James D.] Swedish Neurosci Inst, Seattle, WA USA. [Nathan, David M.] Massachusetts Gen Hosp, Diabet Ctr, Boston, MA 02114 USA. [Nathan, David M.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Zheng, Hui] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Haneuse, Sebastien] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Craft, Suzanne] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. RP Crane, PK (reprint author), Univ Washington, Harborview Med Ctr, Box 359780,325 9th Ave, Seattle, WA 98104 USA. EM pcrane@uw.edu RI Crane, Paul/C-8623-2014; OI Hubbard, Rebecca/0000-0003-0879-0994; Crane, Paul/0000-0003-4278-7465; Kahn, Steven/0000-0001-7307-9002 FU National Institutes of Health [U01 AG 06781] FX Funded by the National Institutes of Health.; Supported by a grant (U01 AG 06781, to Dr. Larson) from the National Institutes of Health. NR 30 TC 158 Z9 162 U1 5 U2 57 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 AUG 8 PY 2013 VL 369 IS 6 BP 540 EP 548 DI 10.1056/NEJMoa1215740 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 197HX UT WOS:000322842000010 PM 23924004 ER PT J AU Carter, JB Barnes, JA Niell, BL Nardi, V AF Carter, Joi B. Barnes, Jeffrey A. Niell, Bethany L. Nardi, Valentina TI Case 24-2013: A 53-Year-Old Woman with Erythroderma, Pruritus, and Lymphadenopathy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID T-CELL LYMPHOMA C1 [Carter, Joi B.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Barnes, Jeffrey A.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Niell, Bethany L.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Nardi, Valentina] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Carter, Joi B.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Barnes, Jeffrey A.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Niell, Bethany L.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Nardi, Valentina] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Carter, JB (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. FU Harvard Medical School Department of Continuing Medical Education; Massachusetts General Hospital, Department of Pathology; Beth Israel Deaconess Medical Center, Department of Pathology; Brigham and Women's Hospital, Department of Pathology FX This case was discussed at the postgraduate course Dermatopathology Update, with course directors Drs. Lyn M. Duncan, Mai P. Hoang, Martin C. Mihm, Jr., George F. Murphy, and Steven R. Tahan, and was sponsored by the Harvard Medical School Department of Continuing Medical Education and Massachusetts General Hospital, Department of Pathology; Beth Israel Deaconess Medical Center, Department of Pathology; and Brigham and Women's Hospital, Department of Pathology. NR 9 TC 1 Z9 1 U1 1 U2 4 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 AUG 8 PY 2013 VL 369 IS 6 BP 559 EP 569 DI 10.1056/NEJMcpc1201415 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 197HX UT WOS:000322842000013 PM 23924007 ER PT J AU Cadenhead, KS Addington, J Cannon, TD Cornblatt, BA de la Fuente-Sandoval, C Mathalon, DH Perkins, DO Seidman, LJ Tsuang, M Walker, EF Woods, SW Bachman, P Belger, A Carrion, RE Donkers, FCL Duncan, E Johannesen, J Leon-Ortiz, P Light, G Mondragon, A Niznikiewicz, M Nunag, J Roach, BJ Solis-Vivanco, R AF Cadenhead, Kristin S. Addington, Jean Cannon, Tyrone D. Cornblatt, Barbara A. de la Fuente-Sandoval, Camilo Mathalon, Dan H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming Walker, Elaine F. Woods, Scott W. Bachman, Peter Belger, Ayse Carrion, Ricardo E. Donkers, Franc C. L. Duncan, Erica Johannesen, Jason Leon-Ortiz, Pablo Light, Gregory Mondragon, Alejandra Niznikiewicz, Margaret Nunag, Jason Roach, Brian J. Solis-Vivanco, Rodolfo CA North Amer Prodromal Longitudinal TI Between-site reliability of startle prepulse inhibition across two early psychosis consortia SO NEUROREPORT LA English DT Article DE endophenotype; prepulse inhibition; reliability; startle ID TEST-RETEST RELIABILITY; ACOUSTIC STARTLE; SCHIZOPHRENIA; REFLEX; HABITUATION; GENETICS; HERITABILITY; POPULATION; MULTISITE AB Prepulse inhibition (PPI) and reactivity of the acoustic startle response are widely used biobehavioral markers in psychopathology research. Previous studies have demonstrated that PPI and startle reactivity exhibit substantial within-site stability; however, between-site stability has not been established. In two separate consortia investigating biomarkers of early psychosis, traveling participants studies were carried out as a part of quality assurance procedures to assess the fidelity of data across sites. In the North American Prodromal Longitudinal Studies (NAPLS) consortium, eight normal participants traveled to each of the eight NAPLS sites and were tested twice at each site on the startle PPI paradigm. In preparation for a binational study, 10 healthy participants were assessed twice in both San Diego and Mexico City. Intraclass correlations between and within sites were significant for PPI and startle response parameters, confirming the reliability of startle measures across sites in both consortia. There were between-site differences in startle magnitude in the NAPLS study that did not appear to be related to methods or equipment. In planning multisite studies, it is essential to institute quality assurance procedures early and establish between-site reliability to assure comparable data across sites. NeuroReport 24:626-630 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Cadenhead, Kristin S.; Tsuang, Ming; Light, Gregory; Nunag, Jason] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Cadenhead, Kristin S.; Light, Gregory] Vet Affairs San Diego Healthcare Syst, La Jolla, CA USA. [Mathalon, Dan H.; Roach, Brian J.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Mathalon, Dan H.; Roach, Brian J.] San Francisco VA Med Ctr, San Francisco, CA USA. [Bachman, Peter] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Cannon, Tyrone D.; Johannesen, Jason] Yale Univ, Dept Psychol, New Haven, CT 06520 USA. [Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Cornblatt, Barbara A.; Carrion, Ricardo E.] Zucker Hillside Hosp, Dept Psychiat, New York, NY USA. [Cornblatt, Barbara A.; Carrion, Ricardo E.] Feinstein Inst Med Res, Ctr Psychiat Neurosci, Manhasset, NY USA. [Cornblatt, Barbara A.; Carrion, Ricardo E.] Hofstra North Shore LIJ Sch Med, Dept Psychiat & Mol Med, New York, NY USA. [Perkins, Diana O.; Belger, Ayse; Donkers, Franc C. L.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.; Niznikiewicz, Margaret] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Psychiat, Boston, MA 02215 USA. [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Duncan, Erica] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Duncan, Erica] Emory Univ, Dept Atlanta Vet Affairs, Atlanta, GA 30322 USA. [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [de la Fuente-Sandoval, Camilo; Leon-Ortiz, Pablo; Mondragon, Alejandra; Solis-Vivanco, Rodolfo] INNN, Dept Psychiat, Mexico City, DF, Mexico. RP Cadenhead, KS (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM kcadenhead@ucsd.edu RI Duncan, Erica/B-1671-2016; Donkers, Franc/H-2391-2013; OI Donkers, Franc/0000-0002-8252-0426; Roach, Brian/0000-0002-3264-1465; Belger, Aysenil/0000-0003-2687-1966; Mathalon, Daniel/0000-0001-6090-4974; Carrion, Ricardo/0000-0002-6393-392X; de la Fuente-Sandoval, Camilo/0000-0003-0773-1642 FU UCMEXUS-CONACYT; National Institutes of Health (NIH) [U01 MH081944, U01 MH082022, U01MH081984, U01 MH081902, UO1 MH081857, U01MH082004, U01 MH081928, U01MH081988] FX This research was supported by a collaborative grant from UCMEXUS-CONACYT (K. S. C. and C.d.l.F.-S., co-PIs), National Institutes of Health (NIH)-supported grants U01 MH081944 to K. S. C., U01 MH082022 to S. W. W., U01MH081984 to J.A., U01 MH081902 to T. D. C., UO1 MH081857 to B. A. C., U01MH082004 to D.O.P., U01 MH081928 to L. J. S., and U01MH081988 to E.F.W. NR 22 TC 0 Z9 0 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 EI 1473-558X J9 NEUROREPORT JI Neuroreport PD AUG 7 PY 2013 VL 24 IS 11 BP 626 EP 630 DI 10.1097/WNR.0b013e3283637845 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 299DJ UT WOS:000330375000009 PM 23799460 ER PT J AU LeardMann, CA Powell, TM Smith, TC Bell, MR Smith, B Boyko, EJ Hooper, TI Gackstetter, GD Ghamsary, M Hoge, CW AF LeardMann, Cynthia A. Powell, Teresa M. Smith, Tyler C. Bell, Michael R. Smith, Besa Boyko, Edward J. Hooper, Tomoko I. Gackstetter, Gary D. Ghamsary, Mark Hoge, Charles W. TI Risk Factors Associated With Suicide in Current and Former US Military Personnel SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NATIONAL-DEATH-INDEX; MILLENNIUM COHORT; SERVICE MEMBERS; PRIMARY-CARE; VITAL STATUS; FOLLOW-UP; PRIME-MD; HEALTH; POPULATION AB IMPORTANCE Beginning in 2005, the incidence of suicide deaths in the US military began to sharply increase. Unique stressors, such as combat deployments, have been assumed to underlie the increasing incidence. Previous military suicide studies, however, have relied on case series and cross-sectional investigations and have not linked data during service with postservice periods. OBJECTIVE To prospectively identify and quantify risk factors associated with suicide in current and former US military personnel including demographic, military, mental health, behavioral, and deployment characteristics. DESIGN, SETTING, AND PARTICIPANTS Prospective longitudinal study with accrual and assessment of participants in 2001, 2004, and 2007. Questionnaire data were linked with the National Death Index and the Department of Defense Medical Mortality Registry through December 31, 2008. Participants were current and former US military personnel from all service branches, including active and Reserve/National Guard, who were included in the Millennium Cohort Study (N = 151 560). MAIN OUTCOMES AND MEASURES Death by suicide captured by the National Death Index and the Department of Defense Medical Mortality Registry. RESULTS Through the end of 2008, findings were 83 suicides in 707 493 person-years of follow-up (11.73/100 000 person-years [95% CI, 9.21-14.26]). In Cox models adjusted for age and sex, factors significantly associated with increased risk of suicide included male sex, depression, manic-depressive disorder, heavy or binge drinking, and alcohol-related problems. None of the deployment-related factors (combat experience, cumulative days deployed, or number of deployments) were associated with increased suicide risk in any of the models. In multivariable Cox models, individuals with increased risk for suicide were men (hazard ratio [HR], 2.14; 95% CI, 1.17-3.92; P = .01; attributable risk [AR], 3.5 cases/10 000 persons), and those with depression (HR, 1.96; 95% CI, 1.05-3.64; P = .03; AR, 6.9/10 000 persons), manic-depressive disorder (HR, 4.35; 95% CI, 1.56-12.09; P = .005; AR, 35.6/10 000 persons), or alcohol-related problems (HR, 2.56; 95% CI, 1.56-4.18; P < .001; AR, 7.7/10 000 persons). A nested, matched case-control analysis using 20: 1 control participants per case confirmed these findings. CONCLUSIONS AND RELEVANCE In this sample of current and former military personnel observed July 1, 2001-December 31, 2008, suicide risk was independently associated with male sex and mental disorders but not with military-specific variables. These findings may inform approaches to mitigating suicide risk in this population. C1 [LeardMann, Cynthia A.; Powell, Teresa M.; Smith, Tyler C.; Smith, Besa] Naval Hlth Res Ctr, Dept Deployment Hlth Res, San Diego, CA 92106 USA. [Smith, Tyler C.] Natl Univ, Sch Hlth & Human Serv, San Diego, CA USA. [Smith, Besa] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Bell, Michael R.; Hooper, Tomoko I.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Boyko, Edward J.] Vet Affairs Puget Sound Hlth Care Syst, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [Gackstetter, Gary D.] Analyt Serv Inc, Arlington, VA USA. [Ghamsary, Mark] Loma Linda Univ, Sch Publ Hlth, Loma Linda, CA 92350 USA. [Hoge, Charles W.] Walter Reed Army Inst Res, Silver Spring, MD USA. RP LeardMann, CA (reprint author), Naval Hlth Res Ctr, Dept Deployment Hlth Res, 140 Sylvester Rd, San Diego, CA 92106 USA. EM cynthia.leardmann@med.navy.mil FU Department of Defense [12-53, 60002]; Military Operational Medicine Research Program of the US Army Medical Research and Materiel Command, Fort Detrick, Maryland; VA Puget Sound Health Care System FX This work represents report 12-53, supported by the Department of Defense, under work unit no. 60002. The Millennium Cohort Study is funded through the Military Operational Medicine Research Program of the US Army Medical Research and Materiel Command, Fort Detrick, Maryland. Dr Boyko's effort in this project was supported by VA Puget Sound Health Care System. NR 38 TC 108 Z9 108 U1 5 U2 34 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 7 PY 2013 VL 310 IS 5 BP 496 EP 506 DI 10.1001/jama.2013.65164 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 196OZ UT WOS:000322786400022 PM 23925620 ER PT J AU Kemmling, A Lev, MH Payabvash, S Betensky, RA Qian, J Masrur, S Schwamm, LH AF Kemmling, Andre Lev, Michael H. Payabvash, Seyedmehdi Betensky, Rebecca A. Qian, Jing Masrur, Shihab Schwamm, Lee H. TI Hospital Acquired Pneumonia Is Linked to Right Hemispheric Peri-Insular Stroke SO PLOS ONE LA English DT Article ID ACUTE ISCHEMIC-STROKE; LATERALIZATION; CORTEX; COMPLICATIONS; INFECTION; IMMUNODEPRESSION; CONSEQUENCES; LOCALIZATION; PREDICTORS; ACTIVATION AB Purpose: Hospital acquired pneumonia (HAP) is a major complication of stroke. We sought to determine associations between infarction of specific brain regions and HAP. Methods: 215 consecutive acute stroke patients with HAP (2003-2009) were carefully matched with 215 non-pneumonia controls by gender, then NIHSS, then age. Admission imaging and binary masks of infarction were registered to MNI-152 space. Regional atlas and voxel-based log-odds were calculated to assess the relationship between infarct location and the likelihood of HAP. An independently validated penalized conditional logistic regression model was used to identify HAP associated imaging regions. Results: The HAP and control patients were well matched by gender (100%), age (95% within 5-years), NIHSS (98% within 1-point), infarct size, dysphagia, and six other clinical variables. Right hemispheric infarcts were more frequent in patients with HAP versus controls (43.3% vs. 34.0%, p = 0.054), whereas left hemispheric infarcts were more frequent in controls (56.7% vs. 44.7%, p = 0.012); there was no significant difference between groups in the rate of brainstem strokes (p = 1.0). Of the 10 most infarcted regions, only right insular cortex volume was different in HAP versus controls (20 vs. 12 ml, p = 0.02). In univariate analyses, the highest log-odds regions for pneumonia were right hemisphere, cerebellum, and brainstem. The best performing multivariate model selected 7 brain regions of infarction and 2 infarct volume-based variables independently associated with HAP. Conclusions: HAP is associated with right hemispheric peri-insular stroke. These associations may be related to autonomic modulation of immune mechanisms, supporting recent hypotheses of stroke mediated immune suppression. C1 [Kemmling, Andre; Lev, Michael H.; Payabvash, Seyedmehdi] Harvard Univ, Sch Med, Dept Radiol, Div Neuroradiol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Betensky, Rebecca A.; Qian, Jing] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Kemmling, Andre] Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Neuroradiol, Hamburg, Germany. [Masrur, Shihab; Schwamm, Lee H.] Harvard Univ, Dept Neurol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Qian, Jing] Univ Massachusetts, Div Biostat & Epidemiol, Amherst, MA 01003 USA. RP Kemmling, A (reprint author), Harvard Univ, Sch Med, Dept Radiol, Div Neuroradiol,Massachusetts Gen Hosp, Boston, MA 02115 USA. EM a.kemmling@uke.de OI Schwamm, Lee/0000-0003-0592-9145 FU National Institutes of Health [NIH CA075971] FX The study was supported in part by the National Institutes of Health (NIH CA075971). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 11 Z9 13 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 7 PY 2013 VL 8 IS 8 AR e71141 DI 10.1371/journal.pone.0071141 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ZE UT WOS:000323109700081 PM 23951094 ER PT J AU Namjou, B Kim-Howard, X Sun, CL Adler, A Chung, SA Kaufman, KM Kelly, JA Glenn, SB Guthridge, JM Scofield, RH Kimberly, RP Brown, EE Alarcon, GS Edberg, JC Kim, JH Choi, J Ramsey-Goldman, R Petri, MA Reveille, JD Vila, LM Boackle, SA Freedman, BI Tsao, BP Langefeld, CD Vyse, TJ Jacob, CO Pons-Estel, B Niewold, TB Sivils, KLM Merrill, JT Anaya, JM Gilkeson, GS Gaffney, PM Bae, SC Alarcon-Riquelme, ME Harley, JB Criswell, LA James, JA Nath, SK AF Namjou, Bahram Kim-Howard, Xana Sun, Celi Adler, Adam Chung, Sharon A. Kaufman, Kenneth M. Kelly, Jennifer A. Glenn, Stuart B. Guthridge, Joel M. Scofield, Robert H. Kimberly, Robert P. Brown, Elizabeth E. Alarcon, Graciela S. Edberg, Jeffrey C. Kim, Jae-Hoon Choi, Jiyoung Ramsey-Goldman, Rosalind Petri, Michelle A. Reveille, John D. Vila, Luis M. Boackle, Susan A. Freedman, Barry I. Tsao, Betty P. Langefeld, Carl D. Vyse, Timothy J. Jacob, Chaim O. Pons-Estel, Bernardo Niewold, Timothy B. Sivils, Kathy L. Moser Merrill, Joan T. Anaya, Juan-Manuel Gilkeson, Gary S. Gaffney, Patrick M. Bae, Sang-Cheol Alarcon-Riquelme, Marta E. Harley, John B. Criswell, Lindsey A. James, Judith A. Nath, Swapan K. CA Argentine Collaborative Grp BIOLUPUS GENLES Networks TI PTPN22 Association in Systemic Lupus Erythematosus (SLE) with Respect to Individual Ancestry and Clinical Sub-Phenotypes SO PLOS ONE LA English DT Article ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISM; LYMPHOID TYROSINE PHOSPHATASE; OF-FUNCTION VARIANT; AUTOIMMUNE-DISEASE; RHEUMATOID-ARTHRITIS; R620W POLYMORPHISM; C1858T POLYMORPHISM; GENETIC ASSOCIATION; SUSCEPTIBILITY LOCI AB Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7 x 10(-9), OR = 1.40 (95% CI = 1.25-1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67-0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7 x 10(-5), OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG. C1 [Namjou, Bahram; Kim-Howard, Xana; Sun, Celi; Adler, Adam; Kelly, Jennifer A.; Glenn, Stuart B.; Guthridge, Joel M.; Scofield, Robert H.; Sivils, Kathy L. Moser; Gaffney, Patrick M.; Alarcon-Riquelme, Marta E.; James, Judith A.; Nath, Swapan K.] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, Oklahoma City, OK 73104 USA. [Namjou, Bahram; Kaufman, Kenneth M.; Harley, John B.] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA. [Chung, Sharon A.; Criswell, Lindsey A.] Univ Calif San Francisco, Rosalind Russell Med Res Ctr Arthrit, Dept Med, San Francisco, CA 94143 USA. [Kaufman, Kenneth M.; Harley, John B.] US Dept Vet Affairs, Med Ctr, Cincinnati, OH USA. [Scofield, Robert H.; James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. [Kimberly, Robert P.; Brown, Elizabeth E.; Alarcon, Graciela S.; Edberg, Jeffrey C.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Kim, Jae-Hoon; Choi, Jiyoung; Bae, Sang-Cheol] Hanyang Univ, Hosp Rheumat Dis, Dept Rheumatol, Seoul 133791, South Korea. [Ramsey-Goldman, Rosalind] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA. [Petri, Michelle A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Reveille, John D.] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Houston, TX 77030 USA. [Vila, Luis M.] Univ Puerto Rico Med Sci Campus, Dept Med, San Juan, PR USA. [Boackle, Susan A.] Univ Colorado, Sch Med, Div Rheumatol, Aurora, CO USA. [Freedman, Barry I.] Wake Forest Univ Hlth Sci, Ctr Publ Hlth Genom, Wake Forest, NC USA. [Freedman, Barry I.; Langefeld, Carl D.] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Wake Forest, NC USA. [Tsao, Betty P.] Univ Calif Los Angeles, Div Rheumatol, Los Angeles, CA USA. [Vyse, Timothy J.] Kings Coll London, Div Genet & Mol Med, London, England. [Vyse, Timothy J.] Kings Coll London, Div Immunol, London, England. [Jacob, Chaim O.] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA. [Pons-Estel, Bernardo] Sanatorio Parque, Dept Med, Rosario, Santa Fe, Argentina. [Niewold, Timothy B.] Mayo Clin, Div Rheumatol, Rochester, MN USA. [Niewold, Timothy B.] Mayo Clin, Dept Immunol, Rochester, MN USA. [Merrill, Joan T.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Anaya, Juan-Manuel] Univ Rosario, Ctr Autoimmune Dis Res, Bogota, Colombia. [Gilkeson, Gary S.] Med Univ S Carolina, Dept Med, Div Rheumatol, Charleston, SC 29425 USA. [Alarcon-Riquelme, Marta E.] Pfizer Univ Granada Junta Andalucia, Ctr Genom & Invest Oncol GENYO, Granada, Spain. RP Nath, SK (reprint author), Oklahoma Med Res Fdn, Arthrit & Clin Immunol Res Program, 825 NE 13th St, Oklahoma City, OK 73104 USA. EM Swapan-nath@omrf.org RI D'Alfonso, Sandra/K-7295-2014; Witte, Torsten/B-5783-2016; Anaya, Juan-Manuel/J-1960-2016; OI D'Alfonso, Sandra/0000-0002-3983-9925; Anaya, Juan-Manuel/0000-0002-6444-1249; Universidad del Rosario, Biblioteca/0000-0003-3491-9392; Silva, Berta/0000-0001-6579-5068; Frostegard, Johan/0000-0002-3569-3367; Kimberly, Robert/0000-0002-5330-3086; Alarcon Riquelme, Marta Eugenia/0000-0002-7632-4154; Niewold, Timothy/0000-0003-3532-6660 FU US National Institutes of Health [AR060366, AR053483, AR43814, AR049084, AR002138, AR030692, AR053308, AR057172, AI094377, AI101934, AI082714, AI070304, AI078004, AI063274, GM103510, GM103456, RR025741, RR020143]; National Center for Advancing Translational Research of the National Institutes of Health [UL1TR00165, UL1TR000004, UL1RR024131]; Alliance for Lupus Research; Kirkland Scholar Award; Korea Healthcare Technology RD Project; Ministry for Health and Welfare, Republic of Korea [A120404]; European Union; European Science Foundation FX This work was supported by grants from the US National Institutes of Health (AR060366, AR053483, AR43814, AR049084, AR002138, AR030692, AR053308, AR057172, AI094377, AI101934, AI082714, AI063274, AI070304, AI078004, AI063274, AI083194, AI078004, GM103510, GM103456, RR025741, and RR020143); National Center for Advancing Translational Research of the National Institutes of Health (UL1TR00165, UL1TR000004, and UL1RR024131); the Alliance for Lupus Research, Kirkland Scholar Award, the Korea Healthcare Technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A120404). Instituto de Salud Carlos III partly financed through FEDER funds from the European Union; the BIOLUPUS Research Network is supported by funding from the European Science Foundation. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 19 Z9 19 U1 1 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 7 PY 2013 VL 8 IS 8 AR e69404 DI 10.1371/journal.pone.0069404 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ZE UT WOS:000323109700017 PM 23950893 ER PT J AU Srinivasan, VJ Mandeville, ET Can, A Blasi, F Climov, M Daneshmand, A Lee, JH Yu, E Radhakrishnan, H Lo, EH Sakadzic, S Eikermann-Haerter, K Ayata, C AF Srinivasan, Vivek J. Mandeville, Emiri T. Can, Anil Blasi, Francesco Climov, Mihail Daneshmand, Ali Lee, Jeong Hyun Yu, Esther Radhakrishnan, Harsha Lo, Eng H. Sakadzic, Sava Eikermann-Haerter, Katharina Ayata, Cenk TI Multiparametric, Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke SO PLOS ONE LA English DT Article ID CEREBRAL-BLOOD-FLOW; PENETRATING ARTERIOLES; SPREADING DEPRESSION; ARTERY OCCLUSION; MICROSCOPY; NEOCORTEX; TISSUE; RAT; PERFUSION; BRAIN AB Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties. C1 [Srinivasan, Vivek J.; Radhakrishnan, Harsha] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Mandeville, Emiri T.; Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Neuroprotect Res Lab, Charlestown, MA USA. [Mandeville, Emiri T.; Lo, Eng H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Neuroprotect Res Lab, Charlestown, MA USA. [Can, Anil; Blasi, Francesco; Climov, Mihail; Daneshmand, Ali; Lee, Jeong Hyun; Yu, Esther; Eikermann-Haerter, Katharina; Ayata, Cenk] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurovasc Res Lab,Dept Radiol, Charlestown, MA USA. [Lee, Jeong Hyun] Korea Res Inst Chem Technol, Div Drug Discovery Res, Taejon 305606, South Korea. [Radhakrishnan, Harsha; Lo, Eng H.; Sakadzic, Sava] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Martinos Ctr Biomed Imaging, Boston, MA USA. [Ayata, Cenk] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Stroke Serv, Boston, MA USA. [Ayata, Cenk] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Neurosci Intens Care Unit, Boston, MA USA. RP Srinivasan, VJ (reprint author), Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. EM vjsriniv@ucdavis.edu RI Blasi, Francesco/G-1055-2015; OI Blasi, Francesco/0000-0002-6616-8418; Climov, Mihail/0000-0001-9150-8608; Lee, Jeong Hyun/0000-0003-0504-0119 FU National Institutes of Health [R00NS067050, NS055104, EB001954 R01]; American Heart Association [IRG5440002, SDG7600037, SDG2610275]; Glaucoma Research Foundation Catalyst for a Cure 2 FX The authors acknowledge support from the National Institutes of Health (R00NS067050, NS055104, EB001954 R01), the American Heart Association (IRG5440002, SDG7600037, SDG2610275), and the Glaucoma Research Foundation Catalyst for a Cure 2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 25 Z9 25 U1 2 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 7 PY 2013 VL 8 IS 8 AR e71478 DI 10.1371/journal.pone.0071478 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200ZE UT WOS:000323109700104 PM 23940761 ER PT J AU Liu, Q Izamis, ML Xu, HZ Berendsen, T Yarmush, M Uygun, K AF Liu, Qiang Izamis, Maria-Louisa Xu, Hongzhi Berendsen, Tim Yarmush, Martin Uygun, Korkut TI Strategies to rescue steatotic livers before transplantation in clinical and experimental studies SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Review DE Liver transplantation; Steatosis; Donor liver; Clinical; Experimental ID ISCHEMIA-REPERFUSION INJURY; UNIVERSITY-OF-WISCONSIN; POLYUNSATURATED FATTY-ACIDS; ACTIVATED PROTEIN-KINASE; TRYPTOPHAN-KETOGLUTARATE SOLUTION; CHOLINE-DEFICIENT DIET; NORMOTHERMIC EXTRACORPOREAL PERFUSION; SUBNORMOTHERMIC MACHINE PERFUSION; SINUSOIDAL ENDOTHELIAL-CELLS; MACROSTEATOTIC MOUSE-LIVER AB The shortage of donor livers has led to an increased use of organs from expanded criteria donors. Included are livers with steatosis, a metabolic abnormality that increases the likelihood of graft complications post-transplantation. After a brief introduction on the etiology, pathophysiology, categories and experimental models of hepatic steatosis, we herein review the methods to rescue steatotic donor livers before transplantation applied in clinical and experimental studies. The methods span the spectrum of encouraging donor weight loss, employing drug therapy, heat shock preconditioning, ischemia preconditioning and selective anesthesia on donors, and the treatment on isolated grafts during preservation. These methods work at different stages of transplantation process, although share similar molecular mechanisms including lipid metabolism stimulation through enzymes or nuclear receptor e.g., peroxisomal proliferator-activated receptor, or anti-inflammation through suppressing cytokines e.g., tumor necrosis factor-alpha, or antioxidant therapies to alleviate oxidative stress. This similarity of molecular mechanisms implies possible future attempts to reinforce each approach by repeating the same treatment approach at several stages of procurement and preservation, as well as utilizing these alternative approaches in tandem. (C) 2013 Baishideng. All rights reserved. C1 [Liu, Qiang; Izamis, Maria-Louisa; Xu, Hongzhi; Berendsen, Tim; Yarmush, Martin; Uygun, Korkut] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, Boston, MA 02114 USA. [Liu, Qiang; Izamis, Maria-Louisa; Xu, Hongzhi; Berendsen, Tim; Yarmush, Martin; Uygun, Korkut] Shriners Burns Hosp, Boston, MA 02114 USA. [Yarmush, Martin] Rutgers State Univ, Dept Biomed Engn, Piscataway, NJ 08854 USA. RP Yarmush, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org RI Liu, Qiang/M-5922-2013 FU Shriners Hospitals for Children FX We thank the support of the Shriners Hospitals for Children. NR 165 TC 2 Z9 2 U1 1 U2 9 PU BAISHIDENG PUBL GRP CO LTD PI WANCHAI PA ROOM 1701, 17-F, HENAN BUILDING, NO. 90, JAFFE RD, WANCHAI, HONG KONG 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD AUG 7 PY 2013 VL 19 IS 29 BP 4638 EP 4650 DI 10.3748/wjg.v19.i29.4638 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 194OE UT WOS:000322641800002 PM 23922462 ER PT J AU Hong, CH Falvey, C Harris, TB Simonsick, EM Satterfield, S Ferrucci, L Metti, AL Patel, KV Yaffe, K AF Hong, Chang Hyung Falvey, Cherie Harris, Tamara B. Simonsick, Eleanor M. Satterfield, Suzanne Ferrucci, Luigi Metti, Andrea L. Patel, Kushang V. Yaffe, Kristine TI Anemia and risk of dementia in older adults Findings from the Health ABC study SO NEUROLOGY LA English DT Article ID ALZHEIMER-DISEASE; HEMOGLOBIN CONCENTRATION; CARDIOVASCULAR HEALTH; COGNITIVE IMPAIRMENT; ERYTHROPOIETIN; MORTALITY; PREVALENCE; OUTCOMES; DECLINE; COHORT AB Objective: To determine whether anemia is associated with incident dementia in older adults. Methods: We studied 2,552 older adults (mean age 76.1 years; 38.9% black; 51.8% female) participating in the Health, Aging, and Body Composition study and free of dementia at baseline. We defined anemia using WHO criteria (hemoglobin concentration <13 g/dL for men and <12 g/dL for women). Dementia diagnosis was determined by dementia medication use, hospital records, or a change in Modified Mini-Mental State (3MS) score of more than 1.5 SD from mean. Discrete time Cox proportional hazard regression models were used to examine the hazard for developing dementia associated with anemia. Results: Of 2,552 participants, 392 (15.4%) older adults had anemia at baseline. Over 11 years of follow-up, 455 (17.8%) participants developed dementia. In the unadjusted model, those with baseline anemia had an increased risk of dementia (23% vs 17%, hazard ratio = 1.64; 95% confidence interval 1.30, 2.07) compared to those without anemia. The association remained significant after adjusting for demographics, APOE epsilon 4, baseline 3MS score, comorbidities, and renal function. Additional adjustment for other anemia measures (mean corpuscular volume, red cell distribution width), erythropoietin, and C-reactive protein did not appreciably change the results. There was no interaction by sex and race on risk of developing dementia. Conclusion: Among older adults, anemia is associated with an increased risk of developing dementia. Findings suggest that further study of anemia as a risk factor for dementia and a target for intervention for cognitive health is warranted. C1 [Hong, Chang Hyung] Ajou Univ Sch Med, Dept Psychiat, Suwon, South Korea. [Hong, Chang Hyung] Ajou Univ Sch Med, Inst Aging, Suwon, South Korea. [Falvey, Cherie; Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA USA. [Falvey, Cherie; Yaffe, Kristine] San Francisco VA Med Ctr, San Francisco, CA USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Satterfield, Suzanne] Univ Tennessee Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Metti, Andrea L.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Patel, Kushang V.] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Sch Med, Dept Psychiat, San Francisco, CA 94143 USA. EM kristine.yaffe@ucsf.edu FU NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]; NINR [R01-NR012459]; NIH; National Institute of Aging; National Institute of Aging [K24AG031155]; American Health Assistance Foundation [A201-0029] FX NIA contract numbers: N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106. NIA grant numbers: R01-AG028050, NINR grant R01-NR012459. This research was supported in part by the Intramural Research Program of the NIH and National Institute of Aging. Dr. Yaffe is supported in part by a National Institute of Aging Grant (K24AG031155) and a grant from the American Health Assistance Foundation (A201-0029). NR 34 TC 28 Z9 28 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD AUG 6 PY 2013 VL 81 IS 6 BP 528 EP 533 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 304JH UT WOS:000330742400007 PM 23902706 ER PT J AU Jilaveanu, LB Zhao, FM Zito, CR Kirkwood, JM Nathanson, KL D'Andrea, K Wilson, M Rimm, DL Flaherty, KT Lee, SJ Kluger, HM AF Jilaveanu, Lucia B. Zhao, Fengmin Zito, Christopher R. Kirkwood, John M. Nathanson, Katherine L. D'Andrea, Kurt Wilson, Melissa Rimm, David L. Flaherty, Keith T. Lee, Sandra J. Kluger, Harriet M. TI Expression of Drug Targets in Patients Treated with Sorafenib, Carboplatin and Paclitaxel SO PLOS ONE LA English DT Article ID METASTATIC MELANOMA; RAF/MEK/ERK PATHWAY; TISSUE MICROARRAYS; IMPROVED SURVIVAL; PHASE-III; APOPTOSIS; GROWTH; CELLS; INHIBITOR; TRIAL AB Introduction: Sorafenib, a multitarget kinase inhibitor, targets members of the mitogen-activated protein kinase (MAPK) pathway and VEGFR kinases. Here we assessed the association between expression of sorafenib targets and biomarkers of taxane sensitivity and response to therapy in pre-treatment tumors from patients enrolled in ECOG 2603, a phase III comparing sorafenib, carboplatin and paclitaxel (SCP) to carboplatin, paclitaxel and placebo (CP). Methods: Using a method of automated quantitative analysis (AQUA) of in situ protein expression, we quantified expression of VEGF-R2, VEGF-R1, VEGF-R3, FGF-R1, PDGF-Rb, c-Kit, B-Raf, C-Raf, MEK1, ERK1/2, STMN1, MAP2, EB1 and Bcl-2 in pretreatment specimens from 263 patients. Results: An association was found between high FGF-R1 and VEGF-R1 and increased progression-free survival (PFS) and overall survival (OS) in our combined cohort (SCP and CP arms). Expression of FGF-R1 and VEGF-R1 was higher in patients who responded to therapy ((CR+PR) vs. (SD+PD+ un-evaluable)). Conclusions: In light of the absence of treatment effect associated with sorafenib, the association found between FGF-R1 and VEGF-R1 expression and OS, PFS and response might reflect a predictive biomarker signature for carboplatin/paclitaxel-based therapy. Seeing that carboplatin and pacitaxel are now widely used for this disease, corroboration in another cohort might enable us to improve the therapeutic ratio of this regimen. C1 [Jilaveanu, Lucia B.; Zito, Christopher R.; Kluger, Harriet M.] Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA. [Zhao, Fengmin; Lee, Sandra J.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Zito, Christopher R.] Univ St Joseph, Dept Biol, Sch Hlth & Nat Sci, Hartford, CT USA. [Kirkwood, John M.] Univ Pittsburgh, Pittsburgh Hillman Canc Ctr, Pittsburgh, PA USA. [Nathanson, Katherine L.; D'Andrea, Kurt; Wilson, Melissa; Flaherty, Keith T.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Rimm, David L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Flaherty, Keith T.] Massachusetts Gen Hosp, Dept Med, Ctr Canc, Boston, MA 02114 USA. RP Kluger, HM (reprint author), Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA. EM Harriet.Kluger@yale.edu OI Nathanson, Katherine/0000-0002-6740-0901; Wilson, Melissa/0000-0002-5391-7838 FU National Institutes of Health [CA115756] FX This work was supported by National Institutes of Health grant CA115756 (to H. Kluger). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 0 Z9 0 U1 2 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 6 PY 2013 VL 8 IS 8 AR e69748 DI 10.1371/journal.pone.0069748 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 217ZG UT WOS:000324401500017 PM 23936348 ER PT J AU Shah, R Heydari, B Coelho, O Murthy, VL Abbasi, S Feng, JZH Pencina, M Neilan, TG Meadows, JL Francis, S Blankstein, R Steigner, M di Carli, M Jerosch-Herold, M Kwong, RY AF Shah, Ravi Heydari, Bobak Coelho-Filho, Otavio Murthy, Venkatesh L. Abbasi, Siddique Feng, Jiazhuo H. Pencina, Michael Neilan, Tomas G. Meadows, Judith L. Francis, Sanjeev Blankstein, Ron Steigner, Michael di Carli, Marcelo Jerosch-Herold, Michael Kwong, Raymond Y. TI Stress Cardiac Magnetic Resonance Imaging Provides Effective Cardiac Risk Reclassification in Patients With Known or Suspected Stable Coronary Artery Disease SO CIRCULATION LA English DT Article DE chronic ischemia; magnetic resonance imaging ID EMISSION COMPUTED-TOMOGRAPHY; INCREMENTAL PROGNOSTIC VALUE; MYOCARDIAL-PERFUSION SPECT; OPTIMAL MEDICAL THERAPY; ASSOCIATION TASK-FORCE; PRACTICE GUIDELINES; AMERICAN-COLLEGE; HEART-DISEASE; REVASCULARIZATION; STRATIFICATION AB Background A recent large-scale clinical trial found that an initial invasive strategy does not improve cardiac outcomes beyond optimized medical therapy in patients with stable coronary artery disease. Novel methods to stratify at-risk patients may refine therapeutic decisions to improve outcomes. Methods and Results In a cohort of 815 consecutive patients referred for evaluation of myocardial ischemia, we determined the net reclassification improvement of the risk of cardiac death or nonfatal myocardial infarction (major adverse cardiac events) incremental to clinical risk models, using guideline-based low (<1%), moderate (1% to 3%), and high (>3%) annual risk categories. In the whole cohort, inducible ischemia demonstrated a strong association with major adverse cardiac events (hazard ratio=14.66; P<0.0001) with low negative event rates of major adverse cardiac events and cardiac death (0.6% and 0.4%, respectively). This prognostic robustness was maintained in patients with previous coronary artery disease (hazard ratio=8.17; P<0.0001; 1.3% and 0.6%, respectively). Adding inducible ischemia to the multivariable clinical risk model (adjusted for age and previous coronary artery disease) improved discrimination of major adverse cardiac events (C statistic, 0.81-0.86; P=0.04; adjusted hazard ratio=7.37; P<0.0001) and reclassified 91.5% of patients at moderate pretest risk (65.7% to low risk; 25.8% to high risk) with corresponding changes in the observed event rates (0.3%/y and 4.9%/y for low and high risk posttest, respectively). Categorical net reclassification index was 0.229 (95% confidence interval, 0.063-0.391). Continuous net reclassification improvement was 1.11 (95% confidence interval, 0.81-1.39). Conclusions Stress cardiac magnetic resonance imaging effectively reclassifies patient risk beyond standard clinical variables, specifically in patients at moderate to high pretest clinical risk and in patients with previous coronary artery disease. C1 [Shah, Ravi; Heydari, Bobak; Abbasi, Siddique; Feng, Jiazhuo H.; Neilan, Tomas G.; Meadows, Judith L.; Blankstein, Ron; Steigner, Michael; di Carli, Marcelo; Jerosch-Herold, Michael; Kwong, Raymond Y.] Harvard Univ, Noninvas Cardiovasc Imaging Sect, Div Cardiovasc, Dept Med,Brigham & Womens Hosp,Med Sch, Boston, MA 02115 USA. [Shah, Ravi; Heydari, Bobak; Abbasi, Siddique; Feng, Jiazhuo H.; Neilan, Tomas G.; Meadows, Judith L.; Blankstein, Ron; Steigner, Michael; di Carli, Marcelo; Jerosch-Herold, Michael; Kwong, Raymond Y.] Harvard Univ, Noninvas Cardiovasc Imaging Sect, Div Cardiovasc, Dept Radiol,Brigham & Womens Hosp,Med Sch, Boston, MA 02115 USA. [Neilan, Tomas G.] Harvard Univ, Div Cardiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Coelho-Filho, Otavio] Univ Estadual Campinas, Div Cardiol, Sao Paulo, Brazil. [Murthy, Venkatesh L.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Murthy, Venkatesh L.] Univ Michigan, Dept Radiol, Ann Arbor, MI 48109 USA. [Pencina, Michael] Harvard Clin Res Inst, Boston, MA USA. RP Kwong, RY (reprint author), Harvard Univ, Noninvas Cardiovasc Imaging Sect, Div Cardiovasc, Dept Med,Brigham & Womens Hosp,Med Sch, 75 Francis St, Boston, MA 02115 USA. EM rykwong@partners.org RI Murthy, Venkatesh/B-3448-2013; OI Murthy, Venkatesh/0000-0002-7901-1321; Abbasi, Siddique/0000-0002-9601-7565 FU American Heart Association Postdoctoral Fellowship Award [11POST000002]; Heart Failure National Institutes of Health Clinical Research Network [U01-HL084877]; Alberta Heritage Foundation for Medical Research; National Institutes of Health [T32-HL094301] FX Dr Shah is supported by an American Heart Association Postdoctoral Fellowship Award (11POST000002) and a training grant from the Heart Failure National Institutes of Health Clinical Research Network (U01-HL084877). Dr Heydari is supported by a Clinical Fellowship Award from the Alberta Heritage Foundation for Medical Research. Drs Murthy and Neilan were supported by National Institutes of Health training grant T32-HL094301. NR 25 TC 17 Z9 17 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 AUG 6 PY 2013 VL 128 IS 6 BP 605 EP 614 DI 10.1161/CIRCULATIONAHA.113.001430 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 196FP UT WOS:000322759200012 PM 23804252 ER PT J AU Patti, ME AF Patti, Mary Elizabeth TI Reducing maternal weight improves offspring metabolism and alters (or modulates) methylation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID BILIOPANCREATIC DIVERSION; INTRAUTERINE EXPOSURE; INSULIN-RESISTANCE; IN-UTERO; OBESITY; SURGERY; GAIN; CHILDREN; GROWTH; BIRTH C1 [Patti, Mary Elizabeth] Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. [Patti, Mary Elizabeth] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Patti, ME (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. EM mary.elizabeth.patti@joslin.harvard.edu NR 24 TC 5 Z9 5 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 AUG 6 PY 2013 VL 110 IS 32 BP 12859 EP 12860 DI 10.1073/pnas.1309724110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 196JQ UT WOS:000322771100019 PM 23884649 ER PT J AU Vashishtha, M Ng, CW Yildirim, F Gipson, TA Kratter, IH Bodai, L Song, W Lau, A Labadorf, A Vogel-Ciernia, A Troncosco, J Ross, CA Bates, GP Krainc, D Sadri-Vakili, G Finkbeiner, S Marsh, JL Housman, DE Fraenkel, E Thompson, LM AF Vashishtha, Malini Ng, Christopher W. Yildirim, Ferah Gipson, Theresa A. Kratter, Ian H. Bodai, Laszlo Song, Wan Lau, Alice Labadorf, Adam Vogel-Ciernia, Annie Troncosco, Juan Ross, Christopher A. Bates, Gillian P. Krainc, Dimitri Sadri-Vakili, Ghazaleh Finkbeiner, Steven Marsh, J. Lawrence Housman, David E. Fraenkel, Ernest Thompson, Leslie M. TI Targeting H3K4 trimethylation in Huntington disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE polyglutamine; neurodegeneration ID MUTANT HUNTINGTIN; GENE-EXPRESSION; NEUROTROPHIC FACTOR; DNA METHYLATION; HISTONE H3; TRANSCRIPTIONAL DYSREGULATION; NERVOUS-SYSTEM; ACTIVE GENES; HUMAN GENOME; MOUSE MODEL AB Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD. C1 [Vashishtha, Malini; Lau, Alice; Thompson, Leslie M.] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92697 USA. [Vashishtha, Malini; Lau, Alice; Thompson, Leslie M.] Univ Calif Irvine, UCI Inst Memory Impairments & Neurol Disorders, Irvine, CA 92697 USA. [Bodai, Laszlo; Song, Wan; Marsh, J. Lawrence] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA. [Bodai, Laszlo; Song, Wan; Marsh, J. Lawrence] Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92697 USA. [Kratter, Ian H.] Univ Calif San Francisco, Gladstone Inst Neurol Dis, Biomed Sci Grad Program, San Francisco, CA 94158 USA. [Kratter, Ian H.] Univ Calif San Francisco, Med Scientist Training Program, San Francisco, CA 94158 USA. [Finkbeiner, Steven] Univ Calif San Francisco, Gladstone Inst Neurol Dis, Taube Koret Ctr Huntingtons Dis Res, Dept Neurol, San Francisco, CA 94158 USA. [Finkbeiner, Steven] Univ Calif San Francisco, Gladstone Inst Neurol Dis, Taube Koret Ctr Huntingtons Dis Res, Dept Physiol, San Francisco, CA 94158 USA. [Troncosco, Juan; Ross, Christopher A.] Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21287 USA. [Troncosco, Juan; Ross, Christopher A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Troncosco, Juan; Ross, Christopher A.] Johns Hopkins Univ, Dept Neurosci & Neuropathol, Baltimore, MD 21287 USA. [Bates, Gillian P.] Kings Coll London, Dept Med & Mol Genet, London SE1 9RT, England. [Krainc, Dimitri; Sadri-Vakili, Ghazaleh] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Housman, DE (reprint author), MIT, Ctr Canc Res, Cambridge, MA 02139 USA. EM dhousman@mit.edu; fraenkel-admin@mit.edu; lmthomps@uci.edu RI Bodai, Laszlo/A-9764-2012; Ross, Christopher/H-8395-2013; OI Bodai, Laszlo/0000-0001-8411-626X; Bates, Gillian/0000-0002-4041-6305; Fraenkel, Ernest/0000-0001-9249-8181 FU University of California at San Francisco Medical Scientist Training Program; National Institute of Health [2R01 NS45491, NS-45283, NS-52789, U01-NS063953, U54-CA112967, R01-GM089903, c NS072793, PN2EY016525]; National Research Service Award [1F31 NS077543]; CHDI Foundation; Huntington's Disease Society of America; Hereditary Disease Foundation; Hereditary Disease Foundation through the Leslie Gehry Brenner Award for Innovation in Science; Koch Institute Support (Core) from the National Cancer Institute [P30-CA14051]; National Science Foundation [DB1-0821391]; National Institutes of Health [P30-ES002109]; Optical Biology Shared Resource of Cancer Center at the University of California at Irvine [CA-62203] FX We thank Dr. Jack Reidling for helpful reading of the manuscript. We also acknowledge generation of lentivirus from the University of California at Los Angeles vector core and early studies in Drosophila by J. Pallos. This work was supported by the University of California at San Francisco Medical Scientist Training Program (I.H.K.), National Institute of Health Grants 2R01 NS45491 (to S.F.), NS-45283 (to J.L.M. and L.M.T.), NS-52789 (to J.L.M. and L.M.T.), U01-NS063953 Subaward (to J.L.M. and L.M.T.), U54-CA112967 (to E.F.), R01-GM089903 (to E.F.), c NS072793 (to L.M.T.), PN2EY016525 (subawards to L.M.T. and D.E.H.), National Research Service Award Grant 1F31 NS077543, CHDI Foundation (J.L.M.), Huntington's Disease Society of America (J.L.M. and L.M.T.), and the Hereditary Disease Foundation (L.M.T.). Work in the laboratory of D.E.H. was supported by funds from the Hereditary Disease Foundation through the Leslie Gehry Brenner Award for Innovation in Science (to D.E.H.) and Koch Institute Support (Core) Grant P30-CA14051 from the National Cancer Institute. Support also included computing resources from National Science Foundation Grant DB1-0821391 and sequencing support from National Institutes of Health Grant P30-ES002109. This work was made possible, in part, by the availability of the Optical Biology Shared Resource of Cancer Center Support Grant CA-62203 at the University of California at Irvine, the Johns Hopkins Center Without Walls for Huntington's Disease, and the sequencing for RNA-Seq and ChIP-Seq performed at the Massachusetts Institute of Technology BioMicro Center. NR 55 TC 45 Z9 45 U1 1 U2 23 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 AUG 6 PY 2013 VL 110 IS 32 BP E3027 EP E3036 DI 10.1073/pnas.1311323110 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 196JQ UT WOS:000322771100015 PM 23872847 ER PT J AU Cury, V Moretti, AIS Assis, L Bossini, P Crusca, JD Neto, CB Fangel, R de Souza, HP Hamblin, MR Parizotto, NA AF Cury, Vivian Soares Moretti, Ana Iochabel Assis, Livia Bossini, Paulo Crusca, Jaqueline de Souza Benatti Neto, Carlos Fangel, Renan de Souza, Heraldo Possolo Hamblin, Michael R. Parizotto, Nivaldo Antonio TI Low level laser therapy increases angiogenesis in a model of ischemic skin flap in rats mediated by VEGF, HIF-1 alpha and MMP-2 SO JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY LA English DT Article DE LLLT; Hypoxia; Angiogenesis; HIF1-alpha; VEGF; MMP-2 ID ENDOTHELIAL GROWTH-FACTOR; HELIUM-NEON LASER; ENHANCED ANGIOGENESIS; HYPOXIA; CELLS; MICE; TUMORIGENESIS; PATHWAY; PROTEIN; HEART AB It is known that low level laser therapy is able to improve skin flap viability by increasing angiogenesis. However, the mechanism for new blood vessel formation is not completely understood. Here, we investigated the effects of 660 nm and 780 nm lasers at fluences of 30 and 40 J/cm(2) on three important mediators activated during angiogenesis. Sixty male Wistar rats were used and randomly divided into five groups with twelve animals each. Groups were distributed as follows: skin flap surgery non-irradiated group as a control; skin flap surgery irradiated with 660 nm laser at a fluence of 30 or 40 J/cm(2) and skin flap surgery irradiated with 780 nm laser at a fluence of 30 or 40 J/cm(2). The random skin flap was performed measuring 10 x 4 cm, with a plastic sheet interposed between the flap and the donor site. Laser irradiation was performed on 24 points covering the flap and surrounding skin immediately after the surgery and for 7 consecutive days thereafter. Tissues were collected, and the number of vessels, angiogenesis markers (vascular endothelial growth factor, VEGF and hypoxia inducible factor, HIF-1 alpha) and a tissue remodeling marker (matrix metalloproteinase, MMP-2) were analyzed. LLLT increased an angiogenesis, HIF-1 alpha and VEGF expression and decrease MMP-2 activity. These phenomena were dependent on the fluences, and wavelengths used. In this study we showed that LLLT may improve the healing of skin flaps by enhancing the amount of new vessels formed in the tissue. Both 660 nm and 780 nm lasers were able to modulate VEGF secretion, MMP-2 activity and HIF-1 alpha expression in a dose dependent manner. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved. C1 [Cury, Vivian; Assis, Livia; Bossini, Paulo; Crusca, Jaqueline de Souza; Fangel, Renan; Parizotto, Nivaldo Antonio] Univ Fed Sao Carlos, Dept Physiotherapy, BR-13560 Sao Carlos, SP, Brazil. [Soares Moretti, Ana Iochabel; de Souza, Heraldo Possolo] Univ Sao Paulo, Fac Med, Emergency Med Div, BR-01246903 Sao Paulo, Brazil. [Soares Moretti, Ana Iochabel] Inst Assistancia Med Servidor Publ Estadual IAMSP, Postgrad Hlth Sci Program, Sao Paulo, Brazil. [Benatti Neto, Carlos] Univ Estadual Sao Paulo, Dept Physiol & Pathol, Sao Paulo, Brazil. [Hamblin, Michael R.] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. [Hamblin, Michael R.] Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Moretti, AIS (reprint author), Univ Sao Paulo, Fac Med, Lab Med Res, Div Emergency Med, Av Dr Arnaldo,455 Sala 3189, BR-01246903 Sao Paulo, Brazil. EM aismoretti@yahoo.com.br RI PARIZOTTO, Nivaldo/D-5347-2014; Bossini, Paulo/G-2333-2014; Assis, Livia/H-8299-2012; moretti, ana/J-9064-2012; Cury, Vivian/O-4405-2015 OI PARIZOTTO, Nivaldo/0000-0003-1774-9053; Assis, Livia/0000-0002-8343-3375; FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ); Coordenagao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES) FX The authors are grateful for financial support from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ), and Coordenagao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES). NR 29 TC 27 Z9 30 U1 1 U2 11 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 1011-1344 J9 J PHOTOCH PHOTOBIO B JI J. Photochem. Photobiol. B-Biol. PD AUG 5 PY 2013 VL 125 BP 164 EP 170 DI 10.1016/j.jphotobiol.2013.06.004 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 217MT UT WOS:000324364300022 PM 23831843 ER PT J AU Best, LG Saxena, R Anderson, CM Barnes, MR Hakonarson, H Falcon, G Martin, C Castillo, BA Karumanchi, A Keplin, K Pearson, N Lamb, F Bercier, S Keating, BJ AF Best, Lyle G. Saxena, Richa Anderson, Cindy M. Barnes, Michael R. Hakonarson, Hakon Falcon, Gilbert Martin, Candelaria Castillo, Berta Almoguera Karumanchi, Ananth Keplin, Kylie Pearson, Nichole Lamb, Felicia Bercier, Shellee Keating, Brendan J. TI Two Variants of the C-Reactive Protein Gene Are Associated with Risk of Pre-Eclampsia in an American Indian Population SO PLOS ONE LA English DT Article ID MATERNAL SUSCEPTIBILITY LOCUS; HYPERTENSIVE DISORDERS; HUMAN GENOME; PREGNANCY; CRP; MARKERS; FETAL; POLYMORPHISMS; MECHANISMS; EXPRESSION AB Background: The etiology of pre-eclampsia (PE) is unknown; but it is accepted that normal pregnancy represents a distinctive challenge to the maternal immune system. C-reactive protein is a prominent component of the innate immune system; and we previously reported an association between PE and the CRP polymorphism, rs1205. Our aim was to explore the effects of additional CRP variants. The IBC (Cardiochip) genotyping microarray focuses on candidate genes and pathways related to the pathophysiology of cardiovascular disease. Methods: This study recruited 140 cases of PE and 270 matched controls, of which 95 cases met criteria as severe PE, from an American Indian community. IBC array genotypes from 10 suitable CRP SNPs were analyzed. A replication sample of 178 cases and 427 controls of European ancestry was also genotyped. Results: A nominally significant difference (p value <0.05) was seen in the distribution of discordant matched pairs for rs3093068; and Bonferroni corrected differences (P<0.005) were seen for rs876538, rs2794521, and rs3091244. Univariate conditional logistic regression odds ratios (OR) were nominally significant for rs3093068 and rs876538 models only. Multivariate logistic models with adjustment for mother's age, nulliparity and BMI attenuated the effect (OR 1.58, P = 0.066, 95% CI 0.97-2.58) for rs876538 and (OR 2.59, P = 0.050, 95% CI 1.00-6.68) for rs3093068. An additive risk score of the above two risk genotypes shows a multivariate adjusted OR of 2.04 (P = 0.013, 95% CI 1.16-3.56). The replication sample also demonstrated significant association between PE and the rs876538 allele (OR = 1.55, P = 0.01, 95% CI 2.16-1.10). We also show putative functionality for the rs876538 and rs3093068 CRP variants. Conclusion: The CRP variants, rs876538 and rs3093068, previously associated with other cardiovascular disease phenotypes, show suggestive association with PE in this American Indian population, further supporting a possible role for CRP in PE. C1 [Best, Lyle G.; Falcon, Gilbert; Martin, Candelaria; Keplin, Kylie; Pearson, Nichole; Lamb, Felicia; Bercier, Shellee] Turtle Mt Community Coll, Dept Sci, Belcourt, ND USA. [Best, Lyle G.] Univ N Dakota, Sch Med & Hlth Sci, Grand Forks, ND 58201 USA. [Saxena, Richa] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Anderson, Cindy M.] Univ N Dakota, Coll Nursing, Grand Forks, ND 58201 USA. [Barnes, Michael R.] Barts & London Queen Marys Sch Med & Dent, William Harvey Res Inst, London, England. [Hakonarson, Hakon; Castillo, Berta Almoguera; Keating, Brendan J.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Karumanchi, Ananth] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Vasc Biol Res Ctr, Boston, MA 02215 USA. RP Best, LG (reprint author), Turtle Mt Community Coll, Dept Sci, Belcourt, ND USA. EM lbest@restel.com OI Barnes, Michael/0000-0001-9097-7381 FU National Institute of General Medical Sciences of the National Institutes of Health [P20GM12345]; Department of Defense [W911NF-09-1-0016] FX Research reported in this publication was supported by an Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM12345, and grant number W911NF-09-1-0016 from the Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 8 Z9 8 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR UNSP e71231 DI 10.1371/journal.pone.0071231 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000197 PM 23940726 ER PT J AU Nogiec, CD Kasif, S AF Nogiec, Christopher D. Kasif, Simon TI To Supplement or Not to Supplement: A Metabolic Network Framework for Human Nutritional Supplements SO PLOS ONE LA English DT Article ID AMINO-ACID LEVELS; FLUX ANALYSIS; RECONSTRUCTION; FOREARM; MUSCLE; EXERCISE; BALANCE AB Flux balance analysis and constraint based modeling have been successfully used in the past to elucidate the metabolism of single cellular organisms. However, limited work has been done with multicellular organisms and even less with humans. The focus of this paper is to present a novel use of this technique by investigating human nutrition, a challenging field of study. Specifically, we present a steady state constraint based model of skeletal muscle tissue to investigate amino acid supplementation's effect on protein synthesis. We implement several in silico supplementation strategies to study whether amino acid supplementation might be beneficial for increasing muscle contractile protein synthesis. Concurrent with published data on amino acid supplementation's effect on protein synthesis in a post resistance exercise state, our results suggest that increasing bioavailability of methionine, arginine, and the branched-chain amino acids can increase the flux of contractile protein synthesis. The study also suggests that a common commercial supplement, glutamine, is not an effective supplement in the context of increasing protein synthesis and thus, muscle mass. Similar to any study in a model organism, the computational modeling of this research has some limitations. Thus, this paper introduces the prospect of using systems biology as a framework to formally investigate how supplementation and nutrition can affect human metabolism and physiology. C1 [Nogiec, Christopher D.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Nogiec, Christopher D.] Joslin Diabet Ctr, Boston, MA 02215 USA. [Kasif, Simon] Boston Univ, Dept Bioengn, Boston, MA 02215 USA. [Kasif, Simon] Harvard MIT, Div Hlth Sci & Technol CHIP HST, Childrens Hosp Informat Program, Boston, MA USA. RP Nogiec, CD (reprint author), Boston Univ, Bioinformat Program, Boston, MA 02215 USA. EM nogiec@bu.edu NR 21 TC 8 Z9 8 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e68751 DI 10.1371/journal.pone.0068751 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000009 PM 23967053 ER PT J AU SanGiovanni, JP Lee, PH AF SanGiovanni, John Paul Lee, Phil H. TI AMD-Associated Genes Encoding Stress-Activated MAPK Pathway Constituents Are Identified by Interval-Based Enrichment Analysis SO PLOS ONE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MACULAR DEGENERATION; PROTEIN-KINASES; THERAPEUTIC TARGETS; INDUCED RETINOPATHY; UNITED-STATES; JNK; POLYMORPHISMS; PATHOGENESIS; INHIBITION AB Purpose: To determine whether common DNA sequence variants within groups of genes encoding elements of stress-activated mitogen-activated protein kinase (MAPK) signaling pathways are, in aggregate, associated with advanced AMD (AAMD). Methods: We used meta-regression and exact testing methods to identify AAMD-associated SNPs in 1177 people with AAMD and 1024 AMD-free elderly peers from 3 large-scale genotyping projects on the molecular genetics of AMD. SNPs spanning independent AAMD-associated genomic intervals were examined with a multi-locus-testing method (INRICH) for enrichment within five sets of genes encoding constituents of stress-activated MAPK signaling cascades. Results: Four-of-five pathway gene sets showed enrichment with AAMD-associated SNPs; findings persisted after adjustment for multiple testing in two. Strongest enrichment signals (P = 0.006) existed in a c-Jun N-terminal kinase (JNK)/MAPK cascade (Science Signaling, STKE CMP_10827). In this pathway, seven independent AAMD-associated regions were resident in 6 of 25 genes examined. These included sequence variants in: 1) three MAP kinase kinase kinases (MAP3K4, MAP3K5, MAP3K9) that phosphorylate and activate the MAP kinase kinases MAP2K4 and MAP2K7 (molecules that phosphorylate threonine and tyrosine residues within the activation loop of JNK); 2) a target of MAP2K7 (JNK3A1) that activates complexes involved in transcriptional regulation of stress related genes influencing cell proliferation, apoptosis, motility, metabolism and DNA repair; and 3) NR2C2, a transcription factor activated by JNK1A1 (a drugable molecule influencing retinal cell viability in model systems). We also observed AAMD-related sequence variants resident in genes encoding PPP3CA (a drugable molecule that inactivates MAP3K5), and two genes (TGFB2, TGFBR2) encoding factors involved in MAPK sensing of growth factors/cytokines. Conclusions: Linkage disequilibrium (LD)-independent genomic enrichment analysis yielded associations of AAMD with aggregates of functionally related genes encoding constituents of the JNK MAPK signaling pathway. FDA-approved drugs now exist to target constituents of stress-activated MAPK pathways and may offer reasonable approaches to preventing or treating AAMD. C1 [SanGiovanni, John Paul] NEI, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. [Lee, Phil H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Analyt & Translat Genet Unit,Ctr Human Genet Res, Boston, MA USA. RP SanGiovanni, JP (reprint author), NEI, Clin Trials Branch, NIH, Bethesda, MD 20892 USA. EM jpsangio@post.harvard.edu FU National Eye Institute FX Funding for NEI-AMD was provided by the National Eye Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 6 Z9 6 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e71239 DI 10.1371/journal.pone.0071239 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000199 PM 23940728 ER PT J AU Webster, CM Hokari, M McManus, A Tang, XN Ma, HL Kacimi, R Yenari, MA AF Webster, Corey M. Hokari, Masaaki McManus, April Tang, Xian Nan Ma, Hualong Kacimi, Rachid Yenari, Midori A. TI Microglial P2Y(12) Deficiency/Inhibition Protects against Brain Ischemia SO PLOS ONE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; PREVENTS ATP EXCITOTOXICITY; EXPERIMENTAL STROKE; ANTITHROMBOTIC DRUGS; THERAPEUTIC TARGETS; CEREBRAL-ISCHEMIA; MILD HYPOTHERMIA; NERVE INJURY; RAT-BRAIN; RECEPTOR AB Objective: Microglia are among the first immune cells to respond to ischemic insults. Triggering of this inflammatory response may involve the microglial purinergic GPCR, P2Y(12), activation via extracellular release of nucleotides from injured cells. It is also the inhibitory target of the widely used antiplatelet drug, clopidogrel. Thus, inhibiting this GPCR in microglia should inhibit microglial mediated neurotoxicity following ischemic brain injury. Methods: Experimental cerebral ischemia was induced, in vitro with oxygen-glucose deprivation (OGD), or in vivo via bilateral common carotid artery occlusion (BCCAO). Genetic knock-down in vitro via siRNA, or in vivo P2Y(12) transgenic mice (P2Y(12)-/- or P2Y(12)+/-), or in vivo treatment with clopidogrel, were used to manipulate the receptor. Neuron death, microglial activation, and microglial migration were assessed. Results: The addition of microglia to neuron-astrocyte cultures increases neurotoxicity following OGD, which is mitigated by microglial P2Y(12) deficiency (P < 0.05). Wildtype microglia form clusters around these neurons following injury, which is also prevented in P2Y(12) deficient microglia (P < 0.01). P2Y(12) knock-out microglia migrated less than WT controls in response to OGD-conditioned neuronal supernatant. P2Y(12) (+/-) or clopidogrel treated mice subjected to global cerebral ischemia suffered less neuronal injury (P < 0.01, P < 0.001) compared to wild-type littermates or placebo treated controls. There were also fewer microglia surrounding areas of injury, and less activation of the pro-inflammatory transcription factor, nuclear factor Kappa B (NFkB). Interpretation: P2Y(12) participates in ischemia related inflammation by mediating microglial migration and potentiation of neurotoxicity. These data also suggest an additional anti-inflammatory, neuroprotective benefit of clopidogrel. C1 [Yenari, Midori A.] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. San Francisco VA Med Ctr, San Francisco, CA USA. RP Yenari, MA (reprint author), Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. EM yenari@alum.mit.edu FU National Institutes of Health [NS40516]; Veteran's Merit Award FX This work was supported by grants from the National Institutes of Health (NS40516) and the Veteran's Merit Award to MAY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 28 Z9 28 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 5 PY 2013 VL 8 IS 8 AR e70927 DI 10.1371/journal.pone.0070927 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218XC UT WOS:000324465000158 PM 23940669 ER PT J AU Jia, T Barabasi, AL AF Jia, Tao Barabasi, Albert-Laszlo TI Control Capacity and A Random Sampling Method in Exploring Controllability of Complex Networks SO SCIENTIFIC REPORTS LA English DT Article ID SCALE-FREE NETWORKS; STRUCTURAL CONTROLLABILITY; METABOLIC NETWORKS; CELL-DIVISION; FOOD-WEB; DYNAMICS; ORGANIZATION; MODEL; SIZE AB Controlling complex systems is a fundamental challenge of network science. Recent advances indicate that control over the system can be achieved through a minimum driver node set (MDS). The existence of multiple MDS's suggests that nodes do not participate in control equally, prompting us to quantify their participations. Here we introduce control capacity quantifying the likelihood that a node is a driver node. To efficiently measure this quantity, we develop a random sampling algorithm. This algorithm not only provides a statistical estimate of the control capacity, but also bridges the gap between multiple microscopic control configurations and macroscopic properties of the network under control. We demonstrate that the possibility of being a driver node decreases with a node's in-degree and is independent of its out-degree. Given the inherent multiplicity of MDS's, our findings offer tools to explore control in various complex systems. C1 [Jia, Tao; Barabasi, Albert-Laszlo] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Jia, Tao; Barabasi, Albert-Laszlo] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Barabasi, Albert-Laszlo] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Network Med, Boston, MA 02115 USA. [Jia, Tao] Rensselaer Polytech Inst, Social Cognit Networks Acad Res Ctr, Troy, NY 12180 USA. [Jia, Tao] Rensselaer Polytech Inst, Dept Comp Sci, Troy, NY 12180 USA. RP Barabasi, AL (reprint author), Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. EM barabasi@gmail.com RI Jia, Tao/C-3215-2014 OI Jia, Tao/0000-0002-2337-2857 FU Network Science Collaborative Technology Alliance; US Army Research Laboratory [W911NF-09-2-0053]; Defense Advanced Research Projects Agency [11645021]; Defense Threat Reduction Agency [WMD BRBAA07-J-2-0035] FX We thank Y.-Y. Liu, M. Posfai, E. Csoka, J.-J. Slotine, C. Song and D. Wang for discussions. This work was supported by the Network Science Collaborative Technology Alliance sponsored by the US Army Research Laboratory under Agreement Number W911NF-09-2-0053; the Defense Advanced Research Projects Agency under Agreement Number 11645021; the Defense Threat Reduction Agency award WMD BRBAA07-J-2-0035; and though the generous support of Lockheed Martin. NR 60 TC 35 Z9 36 U1 1 U2 66 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD AUG 5 PY 2013 VL 3 AR 2354 DI 10.1038/srep02354 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 195JR UT WOS:000322698700004 PM 23912679 ER PT J AU Deschenes-Simard, X Mizukami, Y Bardeesy, N AF Deschenes-Simard, Xavier Mizukami, Yusuke Bardeesy, Nabeel TI Macrophages in pancreatic cancer: Starting things off on the wrong track SO JOURNAL OF CELL BIOLOGY LA English DT Editorial Material ID NF-KAPPA-B; TO-DUCTAL METAPLASIA; MICE; PROGRESSION; ACTIVATION; ADENOCARCINOMA; INFLAMMATION; EXPRESSION; STAT3 AB Chronic inflammation drives initiation and progression of many malignancies, including pancreatic cancer. In this issue, Liou et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201301001) report that inflammatory macrophages are major players in the earliest stages of pancreatic cancer. They show that paracrine signals from the macrophages activate the nuclear factor. B transcriptional program in normal pancreatic acinar cells, resulting in acinar-ductal metaplasia, a dedifferentiated state that is poised for oncogenic transformation. C1 [Deschenes-Simard, Xavier; Mizukami, Yusuke; Bardeesy, Nabeel] Harvard Univ, Sch Med, Massachusetts Gen Hosp Canc Ctr, Boston, MA 02114 USA. [Deschenes-Simard, Xavier] Univ Montreal, Dept Biochim & Med Mol, Montreal, PQ H3C 3J7, Canada. [Mizukami, Yusuke] Sapporo Higashi Tokushukai Hosp, Ctr Clin & Biomed Res, Sapporo, Hokkaido 0650033, Japan. RP Bardeesy, N (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp Canc Ctr, Boston, MA 02114 USA. EM bardeesy.nabeel@mgh.harvard.edu OI Deschenes-Simard, Xavier/0000-0002-4689-886X FU NCI NIH HHS [P01 CA117969-07, P01 CA117969, R01 CA133557-05, R01 CA133557] NR 20 TC 0 Z9 0 U1 0 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 5 PY 2013 VL 202 IS 3 BP 403 EP 405 DI 10.1083/jcb.201307066 PG 3 WC Cell Biology SC Cell Biology GA 196JB UT WOS:000322769400003 PM 23918935 ER PT J AU Lefkimmiatis, K Leronni, D Hofer, AM AF Lefkimmiatis, Konstantinos Leronni, Daniela Hofer, Aldebaran M. TI The inner and outer compartments of mitochondria are sites of distinct cAMP/PKA signaling dynamics SO JOURNAL OF CELL BIOLOGY LA English DT Article ID DEPENDENT PROTEIN-KINASE; CYTOCHROME-C-OXIDASE; REVERSIBLE PHOSPHORYLATION; FLUORESCENT INDICATORS; CALCIUM UNIPORTER; INHIBITION; METABOLISM; MODULATION; MECHANISMS; CONTACTS AB Cyclic AMP (cAMP)-dependent phosphorylation has been reported to exert biological effects in both the mitochondrial matrix and outer mitochondrial membrane (OMM). However, the kinetics, targets, and effectors of the cAMP cascade in these organellar domains remain largely undefined. Here we used sensitive FRET-based sensors to monitor cAMP and protein kinase A (PKA) activity in different mitochondrial compartments in real time. We found that cytosolic cAMP did not enter the matrix, except during mitochondrial permeability transition. Bicarbonate treatment (expected to activate matrix-bound soluble adenylyl cyclase) increased intramitochondrial cAMP, but along with membrane-permeant cAMP analogues, failed to induce measureable matrix PKA activity. In contrast, the OMM proved to be a domain of exceptionally persistent cAMP-dependent PKA activity. Although cAMP signaling events measured on the OMM mirrored those of the cytosol, PKA phosphorylation at the OMM endured longer as a consequence of diminished control by local phosphatases. Our findings demonstrate that mitochondria host segregated cAMP cascades with distinct functional and kinetic signatures. C1 [Lefkimmiatis, Konstantinos; Leronni, Daniela; Hofer, Aldebaran M.] VA Boston Healthcare Syst, West Roxbury, MA 02132 USA. [Lefkimmiatis, Konstantinos; Leronni, Daniela; Hofer, Aldebaran M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, West Roxbury, MA 02132 USA. RP Hofer, AM (reprint author), VA Boston Healthcare Syst, West Roxbury, MA 02132 USA. EM konstantinos.lefkimmiatis@dpag.ox.ac.uk; ahofer@rics.bwh.harvard.edu RI Lefkimmiatis, Konstantinos/I-1239-2016 OI Lefkimmiatis, Konstantinos/0000-0001-7137-7866 FU VA Office of Research and Development [1 I01 BX000968-01]; NIH/NIDDK [1R21DK088197-0] FX This paper was supported by grants to A.M. Hofer from the VA Office of Research and Development (1 I01 BX000968-01) and from the NIH/NIDDK (1R21DK088197-0). NR 44 TC 51 Z9 52 U1 3 U2 21 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 5 PY 2013 VL 202 IS 3 BP 453 EP 462 DI 10.1083/jcb.201303159 PG 10 WC Cell Biology SC Cell Biology GA 196JB UT WOS:000322769400008 PM 23897891 ER PT J AU Ross, JS Hu, W Rosen, B Snider, AJ Obeid, LM Cowart, LA AF Ross, Jessica S. Hu, Wei Rosen, Bess Snider, Ashley J. Obeid, Lina M. Cowart, L. Ashley TI Sphingosine Kinase 1 Is Regulated by Peroxisome Proliferator-activated Receptor alpha in Response to Free Fatty Acids and Is Essential for Skeletal Muscle Interleukin-6 Production and Signaling in Diet-induced Obesity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; INDUCED INSULIN-RESISTANCE; FACTOR-KAPPA-B; ADIPOSE-TISSUE; MYOGENIC DIFFERENTIATION; CERAMIDE BIOSYNTHESIS; METABOLIC SYNDROME; DEPENDENT ACTIVATION; GENE-EXPRESSION; DOWN-REGULATION AB We previously demonstrated that sphingosine kinase 1 (Sphk1) expression and activity are up-regulated by exogenous palmitate (PAL) in a skeletal muscle model system and in diet-induced obesity in mice; however, potential functions and in vivo relevance of this have not been addressed. Here, we aimed to determine the mechanism by which PAL regulates SphK1 in muscle, and to determine potential roles for its product, sphingosine-1-phosphate (S1P), in muscle biology in the context of obesity. Cloning and analysis of the mouse Sphk1 promoter revealed a peroxisome proliferator-activated receptor (PPAR) alpha cis-element that mediated activation of a reporter under control of the Sphk1 promoter; direct interaction of PPAR alpha was demonstrated by chromatin immunoprecipitation. PAL treatment induced the proinflammatory cytokine interleukin (IL)-6 in a manner dependent on SphK1, and this was attenuated by inhibition of the sphingosine-1-phosphate receptor 3 (S1PR3). Diet-induced obesity in mice demonstrated that IL-6 expression in muscle, but not adipose tissue, increased in obesity, but this was attenuated in Sphk1(-/-)mice. Moreover, plasma IL-6 levels were significantly decreased in obese Sphk1(-/-) mice relative to obese wild type mice, and muscle, but not adipose tissue IL-6 signaling was activated. These data indicate that PPAR alpha regulates Sphk1 expression in the context of fatty acid oversupply and links PAL to muscle IL-6 production. Moreover, this function of SphK1 in diet-induced obesity suggests a potential role for SphK1 in obesity-associated pathological outcomes. C1 [Ross, Jessica S.; Hu, Wei; Cowart, L. Ashley] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Ross, Jessica S.] Med Univ S Carolina, Dept Mol & Cellular Biol, Charleston, SC 29425 USA. [Ross, Jessica S.] Med Univ S Carolina, Pathobiol Program, Charleston, SC 29425 USA. [Snider, Ashley J.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Rosen, Bess] Boston Univ, Sch Med, Ctr Regenerat Med, Boston, MA 02118 USA. [Obeid, Lina M.] SUNY Stony Brook, Dept Med, Stony Brook, NY 11790 USA. [Obeid, Lina M.] Northport Vet Affairs Med Ctr, Northpoint, NY 11768 USA. [Snider, Ashley J.; Cowart, L. Ashley] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Cowart, LA (reprint author), Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Dept Biochem & Mol Biol, 173 Ashley Ave,MSC509, Charleston, SC 29425 USA. EM cowartl@musc.edu FU National Institutes of Health COBREaward [P20 RR017677]; Veterans Affairs Merit award; GAANN fellowship in Lipidomics and Systems Biology; Office of the Director of the National Institutes of Health [C06 RR018823]; National Center for Research Resources; Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina Grant [P30 CA138313]; Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE Grant [P20 RR017677] FX This work was supported, in whole or in part, by National Institutes of Health COBREaward P20 RR017677 (to L. A. C.), a Veterans Affairs Merit award, and a GAANN fellowship in Lipidomics and Systems Biology (to J. S. R.). Lipidomic analysis was performed by the Medical University of South Carolina Lipidomic Core supported by the National Center for Research Resources and the Office of the Director of the National Institutes of Health through Grant C06 RR018823. Research was supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina Grant P30 CA138313, and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE Grant P20 RR017677. NR 100 TC 10 Z9 10 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 2 PY 2013 VL 288 IS 31 BP 22193 EP 2206 DI 10.1074/jbc.M113.477786 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302HY UT WOS:000330596300002 PM 23766515 ER PT J AU Chavan, H Khan, MMT Tegos, G Krishnamurthy, P AF Chavan, Hemantkumar Khan, Mohiuddin Md Taimur Tegos, George Krishnamurthy, Partha TI Efficient Purification and Reconstitution of ATP Binding Cassette Transporter B6 (ABCB6) for Functional and Structural Studies SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLYCOPROTEIN MULTIDRUG TRANSPORTER; P-GLYCOPROTEIN; HEPATOCELLULAR-CARCINOMA; LIPID FLIPPASE; MECHANISM; EXPRESSION; PROTEOLIPOSOMES; RESISTANCE; LOCALIZES; MUTATIONS AB The mitochondrial ATP binding cassette transporter ABCB6 has been associated with a broad range of physiological functions, including growth and development, therapy-related drug resistance, and the new blood group system Langereis. ABCB6 has been proposed to regulate heme synthesis by shuttling coproporphyrinogen III from the cytoplasm into the mitochondria. However, direct functional information of the transport complex is not known. To understand the role of ABCB6 in mitochondrial transport, we developed an in vitro system with pure and active protein. ABCB6 overexpressed in HEK293 cells was solubilized from mitochondrial membranes and purified to homogeneity. Purified ABCB6 showed a high binding affinity for MgATP (K-d = 0.18 mu M) and an ATPase activity with a K-m of 0.99 mM. Reconstitution of ABCB6 into liposomes allowed biochemical characterization of the ATPase including (i) substrate-stimulated ATPase activity, (ii) transport kinetics of its proposed endogenous substrate coproporphyrinogen III, and (iii) transport kinetics of substrates identified using a high throughput screening assay. Mutagenesis of the conserved lysine to alanine (K629A) in the Walker A motif abolished ATP hydrolysis and substrate transport. These results suggest a direct interaction between mitochondrial ABCB6 and its transport substrates that is critical for the activity of the transporter. Furthermore, the simple immunoaffinity purification of ABCB6 to near homogeneity and efficient reconstitution of ABCB6 into liposomes might provide the basis for future studies on the structure/function of ABCB6. C1 [Chavan, Hemantkumar; Krishnamurthy, Partha] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. [Khan, Mohiuddin Md Taimur] Washington State Univ, Dept Chem Engn & Bioengn, Pullman, WA 99146 USA. [Khan, Mohiuddin Md Taimur] Pacific NW Natl Lab, Div Bioenergy & Biotechnol, Richland, WA 99352 USA. [Tegos, George] Univ New Mexico, Ctr Mol Discovery, Albuquerque, NM 87131 USA. [Tegos, George] Univ New Mexico, Sch Med, Albuquerque, NM 87131 USA. [Chavan, Hemantkumar; Krishnamurthy, Partha] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. [Tegos, George] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USA. RP Krishnamurthy, P (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM pkasturi@kumc.edu OI Chavan, Hemantkumar/0000-0002-9963-6230 FU National Institutes of Health [P20RR021940, R03MH093193] FX This work was supported, in whole or in part, by National Institutes of Health Grants P20RR021940 and R03MH093193. NR 50 TC 9 Z9 10 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 2 PY 2013 VL 288 IS 31 BP 22658 EP 22669 DI 10.1074/jbc.M113.485284 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 302HY UT WOS:000330596300045 PM 23792964 ER PT J AU Okemoto, K Wagner, B Meisen, H Haseley, A Kaur, B Chiocca, EA AF Okemoto, Kazuo Wagner, Benjamin Meisen, Hans Haseley, Amy Kaur, Balveen Chiocca, Ennio Antonio TI STAT3 Activation Promotes Oncolytic HSV1 Replication in Glioma Cells SO PLOS ONE LA English DT Article ID GLIOBLASTOMA-MULTIFORME; GENE-EXPRESSION; SMALL-MOLECULE; BRAIN-TUMORS; VIRUS; INHIBITION AB Recent studies report that STAT3 signaling is a master regulator of mesenchymal transformation of gliomas and that STAT3 modulated genes are highly expressed in the mesenchymal transcriptome of gliomas. A currently studied experimental treatment for gliomas consists of intratumoral injection of oncolytic viruses (OV), such as oncolytic herpes simplex virus type 1 (oHSV). We have described one particular oHSV (rQNestin34.5) that exhibits potent anti-glioma activity in animal models. Here, we hypothesized that alterations in STAT3 signaling in glioma cells may affect the replicative ability of rQNestin34.5. In fact, human U251 glioma cells engineered to either over-express STAT3 or with genetic down-regulation of STAT3 supported oHSV replication to a significantly higher or lesser degree, respectively, when compared to controls. Administration of pharmacologic agents that increase STAT3 phosphorylation/activation (Valproic Acid) or increase STAT3 levels (Interleukin 6) also significantly enhanced oHSV replication. Instead, administration of inhibitors of STAT3 phosphorylation/activation (LLL12) significantly reduced oHSV replication. STAT3 led to a reduction in interferon signaling in oHSV infected cells and inhibition of interferon signaling abolished the effect of STAT3 on oHSV replication. These data thus indicate that STAT3 signaling in malignant gliomas enhances oHSV replication, likely by inhibiting the interferon response in infected glioma cells, thus suggesting avenues for possible potentiation of oncolytic virotherapy. C1 [Okemoto, Kazuo; Wagner, Benjamin; Meisen, Hans; Haseley, Amy; Kaur, Balveen; Chiocca, Ennio Antonio] Ohio State Univ, James Canc Hosp, Ctr Comprehens Canc,Dept Neurol Surg, Dardinger Ctr Neurooncol & Neurosci,Solove Res In, Columbus, OH 43210 USA. [Okemoto, Kazuo; Wagner, Benjamin; Meisen, Hans; Haseley, Amy; Kaur, Balveen; Chiocca, Ennio Antonio] Ohio State Univ, Wexner Med Ctr, Columbus, OH 43210 USA. [Chiocca, Ennio Antonio] Brigham & Womens Faulkner Hosp, Inst Neurosci Brigham, Dept Neurosurg, Harvey Cushing Neurooncol Labs, Boston, MA USA. [Chiocca, Ennio Antonio] Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Chiocca, EA (reprint author), Ohio State Univ, James Canc Hosp, Ctr Comprehens Canc,Dept Neurol Surg, Dardinger Ctr Neurooncol & Neurosci,Solove Res In, Columbus, OH 43210 USA. EM Eachiocca@partners.org RI kaur, Balveen/E-3355-2011 FU NIH [1P01CA163205-01A1] FX This work was supported by NIH grant 1P01CA163205-01A1 to EAC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 19 TC 11 Z9 12 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 2 PY 2013 VL 8 IS 8 AR e71932 DI 10.1371/journal.pone.0071932 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219XU UT WOS:000324545800072 PM 23936533 ER PT J AU Takahashi, K Kurokawa, K Moyo, P Jung, DJ An, JH Chigweshe, L Paul, E Lee, BL AF Takahashi, Kazue Kurokawa, Kenji Moyo, Patience Jung, Dong-Jun An, Jang-Hyun Chigweshe, Lorencia Paul, Elahna Lee, Bok Luel TI Intradermal Immunization with Wall Teichoic Acid (WTA) Elicits and Augments an Anti-WTA IgG Response that Protects Mice from Methicillin-Resistant Staphylococcus aureus Infection Independent of Mannose-Binding Lectin Status SO PLOS ONE LA English DT Article ID GRAM-POSITIVE BACTERIA; IMMUNE-RESPONSE; DEFICIENT MICE; RECOGNITION; SUSCEPTIBILITY; LIPOPROTEINS; VACCINATION; MECHANISMS; INCREASES; VIRULENCE AB The objectives of this study were to investigate the immune response to intradermal immunization with wall teichoic acid (WTA) and the effect of MBL deficiency in a murine model of infection with methicillin-resistant Staphylococcus aureus (MRSA). WTA is a bacterial cell wall component that is implicated in invasive infection. We tested susceptibility to MRSA infection in wild type (WT) and MBL deficient mice using two strains of MRSA: MW2, a community-associated MRSA (CA-MRSA); and COL, a healthcare-associated MRSA (HA-MRSA). We also performed in vitro assays to investigate the effects of anti-WTA IgG containing murine serum on complement activation and bacterial growth in whole blood. We found that MBL knockout (KO) mice are relatively resistant to a specific MRSA strain, MW2 CA-MRSA, compared to WT mice, while both strains of mice had similar susceptibility to a different strain, COL HA-MRSA. Intradermal immunization with WTA elicited and augmented an anti-WTA IgG response in both WT and MBL KO mice. WTA immunization significantly reduced susceptibility to both MW2 CA-MRSA and COL HA-MRSA, independent of the presence of MBL. The protective mechanisms of anti-WTA IgG are mediated at least in part by complement activation and clearance of bacteria from blood. The significance of these findings is that 1) Intradermal immunization with WTA induces production of anti-WTA IgG; and 2) This anti-WTA IgG response protects from infection with both MW2 CA-MRSA and COL HA-MRSA even in the absence of MBL, the deficiency of which is common in humans. C1 [Takahashi, Kazue; Moyo, Patience; Chigweshe, Lorencia; Paul, Elahna] Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Paul, Elahna] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Pediat Nephrol, Boston, MA USA. [Kurokawa, Kenji; Jung, Dong-Jun; An, Jang-Hyun; Lee, Bok Luel] Pusan Natl Univ, Natl Res Lab Def Prot, Coll Pharm, Pusan, South Korea. RP Takahashi, K (reprint author), Harvard Univ, Sch Med, Dept Pediat, Massachusetts Gen Hosp, Boston, MA 02115 USA. EM ktakahashi1@partners.org FU National Institutes of Health [U01-074503] FX The work was supported in part by a National Institutes of Health grant U01-074503. No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 46 TC 5 Z9 5 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 2 PY 2013 VL 8 IS 8 AR e69739 DI 10.1371/journal.pone.0069739 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219XU UT WOS:000324545800022 PM 23936347 ER PT J AU Thunemann, M Wen, L Hillenbrand, M Vachaviolos, A Feil, S Ott, T Han, XX Fukumura, D Jain, RK Russwurm, M Wit, C Feil, R AF Thunemann, Martin Wen, Lai Hillenbrand, Matthias Vachaviolos, Angelos Feil, Susanne Ott, Thomas Han, Xiaoxing Fukumura, Dai Jain, Rakesh K. Russwurm, Michael de Wit, Cor Feil, Robert TI Transgenic Mice for cGMP Imaging SO CIRCULATION RESEARCH LA English DT Article DE biosensing techniques; cyclic GMP; fluorescence resonance energy transfer; microscopy; fluorescence; multiphoton; muscle; smooth; vasodilation ID SMOOTH-MUSCLE-CELLS; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; NITRIC-OXIDE; IN-VIVO; RELAXATION; MECHANISMS; INDICATORS; NO AB Rationale: Cyclic GMP (cGMP) is an important intracellular signaling molecule in the cardiovascular system, but its spatiotemporal dynamics in vivo is largely unknown. Objective: To generate and characterize transgenic mice expressing the fluorescence resonance energy transfer-based ratiometric cGMP sensor, cGMP indicator with an EC50 of 500 nmol/L (cGi500), in cardiovascular tissues. Methods and Results: Mouse lines with smooth muscle-specific or ubiquitous expression of cGi500 were generated by random transgenesis using an SM22 promoter fragment or by targeted integration of a Cre recombinase-activatable expression cassette driven by the cytomegalovirus early enhancer/chicken -actin/-globin promoter into the Rosa26 locus, respectively. Primary smooth muscle cells isolated from aorta, bladder, and colon of cGi500 mice showed strong sensor fluorescence. Basal cGMP concentrations were <100 nmol/L, whereas stimulation with cGMP-elevating agents such as 2-(N,N-diethylamino)-diazenolate-2-oxide diethylammonium salt (DEA/NO) or the natriuretic peptides, atrial natriuretic peptide, and C-type natriuretic peptide evoked fluorescence resonance energy transfer changes corresponding to cGMP peak concentrations of approximate to 3 mu mol/L. However, different types of smooth muscle cells had different sensitivities of their cGMP responses to DEA/NO, atrial natriuretic peptide, and C-type natriuretic peptide. Robust nitric oxide-induced cGMP transients with peak concentrations of approximate to 1 to >3 mu mol/L could also be monitored in blood vessels of the isolated retina and in the cremaster microcirculation of anesthetized mice. Moreover, with the use of a dorsal skinfold chamber model and multiphoton fluorescence resonance energy transfer microscopy, nitric oxide-stimulated vascular cGMP signals associated with vasodilation were detected in vivo in an acutely untouched preparation. Conclusions: These cGi500 transgenic mice permit the visualization of cardiovascular cGMP signals in live cells, tissues, and mice under normal and pathological conditions or during pharmacotherapy with cGMP-elevating drugs. C1 [Thunemann, Martin; Wen, Lai; Hillenbrand, Matthias; Vachaviolos, Angelos; Feil, Susanne; Feil, Robert] Univ Tubingen, Interfak Inst Biochem, D-72076 Tubingen, Germany. [Ott, Thomas] Univ Tubingen, IZKF Transgene Tiere, D-72076 Tubingen, Germany. [Han, Xiaoxing; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Han, Xiaoxing; Fukumura, Dai; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA USA. [Russwurm, Michael] Ruhr Univ Bochum, Inst Pharmakol & Toxikol, Bochum, Germany. [de Wit, Cor] Med Univ Lubeck, Inst Physiol, D-23538 Lubeck, Germany. RP Feil, R (reprint author), Univ Tubingen, Interfak Inst Biochem, Hoppe Seyler Str 4, D-72076 Tubingen, Germany. EM robert.feil@uni-tuebingen.de RI de Wit, Cor/A-5560-2009; Feil, Robert/B-8918-2014 OI de Wit, Cor/0000-0003-4621-0399; Feil, Robert/0000-0002-7335-4841 FU Deutsche Forschungsgemeinschaft FX This work was supported by grants from the Deutsche Forschungsgemeinschaft. NR 30 TC 21 Z9 21 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 2 PY 2013 VL 113 IS 4 BP 365 EP 371 DI 10.1161/CIRCRESAHA.113.301063 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 196ZV UT WOS:000322817100011 PM 23801067 ER PT J AU Li, Q Park, K Li, CZ Rask-Madsen, C Mima, A Qi, W Mizutani, K Huang, P King, GL AF Li, Qian Park, Kyoungmin Li, Chenzhong Rask-Madsen, Christian Mima, Akira Qi, Weier Mizutani, Koji Huang, Paul King, George L. TI Induction of Vascular Insulin Resistance and Endothelin-1 Expression and Acceleration of Atherosclerosis by the Overexpression of Protein Kinase C- Isoform in the Endothelium SO CIRCULATION RESEARCH LA English DT Article DE atherosclerosis; endothelium; insulin resistance; protein kinase C ID SMOOTH-MUSCLE-CELLS; E NULL MICE; NITRIC-OXIDE; DIABETIC-RATS; GROWTH-FACTOR; PKC-BETA; ACTIVATION; GLUCOSE; INHIBITION; OUTCOMES AB Rationale: Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C- isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions. Objective: To demonstrate that overexpressing protein kinase C-2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta. Methods and Results: Protein kinase C-2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell cadherin. These mice were cross-bred with apoE(-/-) mice [Tg (Prkcb)apoE(-/-)]. On a Western diet, Tg(Prkcb)apoE(-/-) and apoE(-/-) mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid, or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb)apoE(-/-) mice was impaired by approximate to 40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)apoE(-/-) mice compared with that from apoE(-/-) mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb)apoE(-/-) mice compared with apoE(-/-) mice. The severity of atherosclerosis in the aorta from Tg(Prkcb)apoE(-/-) mice increased by approximate to 70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages, and extracellular matrix. Conclusions: Specific protein kinase C-2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression. C1 [Li, Qian; Park, Kyoungmin; Li, Chenzhong; Rask-Madsen, Christian; Mima, Akira; Qi, Weier; Mizutani, Koji; King, George L.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dianne Nunnally Hoppes Lab Diabet Complicat,Sect, Boston, MA 02215 USA. [Huang, Paul] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02215 USA. [Huang, Paul] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02215 USA. RP King, GL (reprint author), Joslin Diabet Ctr, Dianne Nunnally Hoppes Lab Diabet Complicat, Sect Vasc Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM George.king@joslin.harvard.edu FU American Diabetes Association mental fellowship; Juvenile Diabetes Research Foundation fellowship; National Institutes of Health [DK053105] FX Q. Li was supported by an American Diabetes Association mental fellowship. W. Qi was supported by a Juvenile Diabetes Research Foundation fellowship. The study also was supported by National Institutes of Health R01 grants DK053105 (G.L. King). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. NR 35 TC 27 Z9 29 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 2 PY 2013 VL 113 IS 4 BP 418 EP 427 DI 10.1161/CIRCRESAHA.113.301074 PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 196ZV UT WOS:000322817100017 PM 23759514 ER PT J AU Smith, PM Howitt, MR Panikov, N Michaud, M Gallini, CA Bohlooly-Y, M Glickman, JN Garrett, WS AF Smith, Patrick M. Howitt, Michael R. Panikov, Nicolai Michaud, Monia Gallini, Carey Ann Bohlooly-Y, Mohammad Glickman, Jonathan N. Garrett, Wendy S. TI The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic T-reg Cell Homeostasis SO SCIENCE LA English DT Article ID GUT MICROBIOTA; INTESTINAL MICROBIOTA; IMMUNE-SYSTEM; DIVERSITY; MICE; INFLAMMATION; INHIBITION; RESPONSES; RECEPTOR; PROTECT AB Regulatory T cells (T-regs) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate T-reg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic T-regs. We determined that short-chain fatty acids, gut microbiota-derived bacterial fermentation products, regulate the size and function of the colonic T-reg pool and protect against colitis in a Ffar2-dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health. C1 [Smith, Patrick M.; Howitt, Michael R.; Panikov, Nicolai; Michaud, Monia; Gallini, Carey Ann; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Smith, Patrick M.; Howitt, Michael R.; Panikov, Nicolai; Michaud, Monia; Gallini, Carey Ann; Garrett, Wendy S.] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA. [Garrett, Wendy S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Garrett, Wendy S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Garrett, Wendy S.] Broad Inst Harvard & MIT, Cambridge, MA USA. [Bohlooly-Y, Mohammad] AstraZeneca, RAD Transgen, Molndal, Sweden. [Glickman, Jonathan N.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Glickman, Jonathan N.] Miraca Life Sci, Newton, MA USA. RP Garrett, WS (reprint author), Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, 665 Huntington Ave, Boston, MA 02115 USA. EM wgarrett@hsph.harvard.edu FU National Research Service Award (NRSA) [F32DK095506]; NRSA [F32DK098826]; Burroughs Wellcome Career in Medical Sciences Award; Searle Scholars Award; Cancer Research Institute; Harvard University; [R01CA154426]; [K08AI078942] FX We thank members of the Garrett Lab for discussion, K. Sigrist for embryo rederivation, C. Gallini for genotyping, J. Ramirez for animal husbandry, and A. Rudensky (Memorial Sloan-Kettering Cancer Center) for Foxp3YFP-Cre mice. A material transfer agreement was required for obtaining Ffar2+/- embryos from AstraZeneca. The data presented in this study are tabulated in the main paper and the supplementary materials. This study was supported by National Research Service Award (NRSA) F32DK095506 to P. M. S.; NRSA F32DK098826 to M. R. H.; and grants R01CA154426 and K08AI078942, a Burroughs Wellcome Career in Medical Sciences Award, a Searle Scholars Award, and a Cancer Research Institute Investigator Award to W. S. G. A patent (U.S. 61/800,299) was filed with the U.S. Patent and Trademark Office on 15 March 2013 on short chain fatty acids and their regulation of colonic regulatory T cell populations and function by Harvard University, with W. S. G. and P. M. S. as co-inventors. P. M. S., M. R. H., and W. S. G. designed and carried out the experiments and wrote the manuscript; M. M., C. A. G., and N.P. carried out experiments; J.N.G. performed all histological assessment; and M.B.-Y provided Ffar2+/- embryos. NR 25 TC 621 Z9 644 U1 24 U2 169 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 AUG 2 PY 2013 VL 341 IS 6145 BP 569 EP 573 DI 10.1126/science.1241165 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 193UJ UT WOS:000322586700059 PM 23828891 ER PT J AU Wu, Y Collier, L Qin, WP Creasey, G Bauman, WA Jarvis, J Cardozo, C AF Wu, Yong Collier, Lauren Qin, Weiping Creasey, Graham Bauman, William A. Jarvis, Jonathan Cardozo, Christopher TI Electrical stimulation modulates Wnt signaling and regulates genes for the motor endplate and calcium binding in muscle of rats with spinal cord transection SO BMC NEUROSCIENCE LA English DT Article DE Spinal cord injury; Paralysis; Electrical stimulation; Exercise; Gene expression ID ANKYRIN REPEAT PROTEIN; SKELETAL-MUSCLE; RESISTANCE EXERCISE; INJURED INDIVIDUALS; MOLECULAR RESPONSES; BETA-CATENIN; FIBER-TYPE; EXPRESSION; GROWTH; HYPERTROPHY AB Background: Spinal cord injury (SCI) results in muscle atrophy and a shift of slow oxidative to fast glycolytic fibers. Electrical stimulation (ES) at least partially restores muscle mass and fiber type distribution. The objective of this study was to was to characterize the early molecular adaptations that occur in rat soleus muscle after initiating isometric resistance exercise by ES for one hour per day for 1, 3 or 7 days when ES was begun 16 weeks after SCI. Additionally, changes in mRNA levels after ES were compared with those induced in soleus at the same time points after gastrocnemius tenotomy (GA). Results: ES increased expression of Hey1 and Pitx2 suggesting increased Notch and Wnt signaling, respectively, but did not normalize RCAN1.4, a measure of calcineurin/NFAT signaling, or PGC-1 beta mRNA levels. ES increased PGC-1 alpha expression but not that of slow myofibrillar genes. Microarray analysis showed that after ES, genes coding for calcium binding proteins and nicotinic acetylcholine receptors were increased, and the expression of genes involved in blood vessel formation and morphogenesis was altered. Of the 165 genes altered by ES only 16 were also differentially expressed after GA, of which 12 were altered in the same direction by ES and GA. In contrast to ES, GA induced expression of genes related to oxidative phosphorylation. Conclusions: Notch and Wnt signaling may be involved in ES-induced increases in the mass of paralyzed muscle. Molecular adaptations of paralyzed soleus to resistance exercise are delayed or defective compared to normally innervated muscle. C1 [Wu, Yong; Collier, Lauren; Qin, Weiping; Bauman, William A.; Cardozo, Christopher] James J Peters VA Med Ctr, Ctr Excellence Med Consequences SCI, Bronx, NY 10468 USA. [Qin, Weiping; Bauman, William A.; Cardozo, Christopher] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Cardozo, Christopher] Mt Sinai Sch Med, Dept Rehabil Med, New York, NY USA. [Creasey, Graham] Stanford Univ, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. [Jarvis, Jonathan] Univ Liverpool, Sch Biomed Sci, Liverpool L69 3BX, Merseyside, England. RP Cardozo, C (reprint author), James J Peters VA Med Ctr, Ctr Excellence Med Consequences SCI, 130 West Kingsbridge Rd, Bronx, NY 10468 USA. EM chris.cardozo@mssm.edu FU Veterans Health Administration, Rehabilitation Research and Development Service [B9212C, B4055X, B3347K]; European Commission Project [RISE QLG5-CT-2001-02191] FX This work was supported by the Veterans Health Administration, Rehabilitation Research and Development Service (grants B9212C to WAB and B4055X and B3347K to CC) and European Commission Project RISE QLG5-CT-2001-02191 to JCJ. NR 63 TC 6 Z9 6 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD AUG 2 PY 2013 VL 14 AR 81 DI 10.1186/1471-2202-14-81 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 196OP UT WOS:000322785300001 PM 23914941 ER PT J AU McQuaid, JW Tanrikut, C AF McQuaid, Joseph W. Tanrikut, Cigdem TI Ejaculatory Duct Obstruction: Current Diagnosis and Treatment SO CURRENT UROLOGY REPORTS LA English DT Article DE Azoospermia; Infertility; Ejaculatory duct obstruction; Transrectal ultrasound; Transurethral resection of the ejaculatory ducts ID TRANSURETHRAL SEMINAL VESICULOSCOPY; INFERTILE MEN; TRANSRECTAL ULTRASONOGRAPHY; RESECTION; VESICLE; US; RECANALIZATION; VESICULOGRAPHY; EXPERIENCE; DILATION AB Ejaculatory duct obstruction is an infrequent cause of obstructive azoospermia, occurring in up to 5 % of such patients. However, it is potentially correctable and warrants consideration in the differential diagnosis of the patient presenting for infertility evaluation. This review provides an overview of ejaculatory duct obstruction: its various etiologies, presentation, and associated clinical assessment. It includes a description of diagnostic imaging and interventional studies available to the practicing urologist and concludes with a discussion of current endoscopic management. C1 [McQuaid, Joseph W.; Tanrikut, Cigdem] Massachusetts Gen Hosp, MGH Fertil Ctr, Dept Urol, Boston, MA 02114 USA. RP Tanrikut, C (reprint author), Massachusetts Gen Hosp, MGH Fertil Ctr, Dept Urol, 55 Fruit St, Boston, MA 02114 USA. EM ctanrikut@partners.org NR 50 TC 0 Z9 3 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1527-2737 J9 CURR UROL REP JI Curr. Urol. Rep. PD AUG PY 2013 VL 14 IS 4 BP 291 EP 297 DI 10.1007/s11934-013-0340-y PG 7 WC Urology & Nephrology SC Urology & Nephrology GA AI1FU UT WOS:000336596500004 PM 23733548 ER PT J AU Culla, BS Behlau, I Sayegh, RR Stacy, RC Dohlman, CH Delori, F AF Culla, B. Salvador Behlau, I. Sayegh, R. R. Stacy, R. C. Dohlman, C. H. Delori, F. TI Very low risk of light-induced retinal damage during Boston Keratoprosthesis surgery SO ACTA OPHTHALMOLOGICA LA English DT Meeting Abstract C1 [Culla, B. Salvador; Behlau, I.; Sayegh, R. R.; Stacy, R. C.; Dohlman, C. H.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Culla, B. Salvador; Behlau, I.; Sayegh, R. R.; Stacy, R. C.; Dohlman, C. H.; Delori, F.] Harvard Univ, Sch Med, Boston, MA USA. [Delori, F.] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-375X EI 1755-3768 J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD AUG PY 2013 VL 91 SU 252 MA 3435 DI 10.1111/j.1755-3768.2013.3435.x PG 3 WC Ophthalmology SC Ophthalmology GA AI0QH UT WOS:000336552300538 ER PT J AU Fuchsluger, T Mueller, C Dana, R AF Fuchsluger, T. Mueller, C. Dana, R. TI Adeno-associated viral vector serotypes for gene transfer to corneal endothelial cells SO ACTA OPHTHALMOLOGICA LA English DT Meeting Abstract C1 [Fuchsluger, T.] Dept Ophthalmol, Dusseldorf, Germany. [Mueller, C.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Dana, R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Eye Res Inst 4Schepens,Dept Ophthalmol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-375X EI 1755-3768 J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD AUG PY 2013 VL 91 SU 252 MA 4767 DI 10.1111/j.1755-3768.2013.4767.x PG 3 WC Ophthalmology SC Ophthalmology GA AI0QH UT WOS:000336552300788 ER PT J AU Grzybowski, A Lessell, S AF Grzybowski, A. Lessell, S. TI Idiopathic optico-chiasmatic arachnoiditis (IOCA) - enigmatic or non existant disorder? SO ACTA OPHTHALMOLOGICA LA English DT Meeting Abstract C1 [Grzybowski, A.] Dept Ophthalmol, Poznan, Poland. [Grzybowski, A.] Univ Warmia & Mazury, Dept Ophthalmol, Olsztyn, Poland. [Lessell, S.] Massachusets Eye & Ear Infirm, Dept Neuroophthalmol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-375X EI 1755-3768 J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD AUG PY 2013 VL 91 SU 252 MA 3775 DI 10.1111/j.1755-3768.2013.3775.x PG 2 WC Ophthalmology SC Ophthalmology GA AI0QH UT WOS:000336552300639 ER PT J AU Pastak, M Singer, BB Schwartzkopff, J Saban, D Czugala, M Dana, R Steuhl, KP Ergun, S Fuchsluger, TA AF Pastak, M. Singer, B. B. Schwartzkopff, J. Saban, D. Czugala, M. Dana, R. Steuhl, K. P. Erguen, S. Fuchsluger, T. A. TI Immunomodulatory effects of gene therapy in composite corneal grafts SO ACTA OPHTHALMOLOGICA LA English DT Meeting Abstract C1 [Pastak, M.; Singer, B. B.; Czugala, M.] Essen Univ Hosp, Inst Anat, Essen, Germany. [Pastak, M.] Tartu Univ Hosp, Eye Clin, Tartu, Estonia. [Schwartzkopff, J.] Univ Freiburg, Hosp Eye, Freiburg, Germany. [Saban, D.] Duke Univ, Sch Med, Duke Eye Ctr, Durham, NC 27706 USA. [Czugala, M.; Fuchsluger, T. A.] Dusseldorf Univ Hosp, Dept Ophthalmol, Dusseldorf, Germany. [Dana, R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. [Steuhl, K. P.] Essen Univ Hosp, Dept Ophthalmol, Essen, Germany. [Erguen, S.] Univ Wurzburg, Inst Anat & Cellular Biol, D-97070 Wurzburg, Germany. NR 0 TC 0 Z9 0 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1755-375X EI 1755-3768 J9 ACTA OPHTHALMOL JI Acta Ophthalmol. PD AUG PY 2013 VL 91 SU 252 MA 4736 DI 10.1111/j.1755-3768.2013.4736.x PG 3 WC Ophthalmology SC Ophthalmology GA AI0QH UT WOS:000336552300776 ER PT J AU Misra, M Katzman, DK Estella, NM Eddy, KT Weigel, T Goldstein, MA Miller, KK Klibanski, A AF Misra, Madhusmita Katzman, Debra K. Estella, Nara Mendes Eddy, Kamryn T. Weigel, Thomas Goldstein, Mark A. Miller, Karen K. Klibanski, Anne TI Impact of Physiologic Estrogen Replacement on Anxiety Symptoms, Body Shape Perception, and Eating Attitudes in Adolescent Girls With Anorexia Nervosa: Data From a Randomized Controlled Trial SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID TURNER-SYNDROME; BONE-DENSITY; RATS; COMORBIDITY; DISORDERS; HORMONES; THERAPY; WOMEN; CYCLE AB Objective: Anorexia nervosa is characterized by low weight, aberrant eating attitudes, body image distortion, and hypogonadism. Anxiety is a common comorbid condition. Estrogen replacement reduces anxiety in animal models, and reported variations. in food intake across the menstrual cycle may be related to gonadal steroid levels. The impact of estrogen replacement on anxiety, eating attitudes, and body image has not been reported in anorexia nervosa. We hypothesized that physiologic estrogen replacement would ameliorate anxiety and improve eating attitudes without affecting body image in anorexia nervosa. Method: Girls 13-18 years old with anorexia nervosa (DSM-IV) were randomized to transdermal estradiol (100 pp twice weekly) with cyclic progesterone or placebo patches and pills for 18-months, between 2002 and 2010. The State:Trait Anxiety Inventory for Children (STAIC), the Eating Disorders Inventory-2 (EDI-2), and the Body Shape Questionnaire (BSQ-34) were administered. 72 girls completed these measures at baseline (n = 38 [girls receiving estrogen] and n = 34 [girls receiving placebo]) and 37 at IS months (n = 20 [girls receiving estrogen] and n = 17 [girls receiving placebo]). The primary outcome measure was the change in these scores over 18 months. Results: Estrogen replacement caused a decrease in STAIC-trait scores (-3.05 [1.22] vs 2.07 [1.73], P=.02), without impacting STAIC-state scores (-1.11 [2.17] vs 0.20 [1.42], P=.64). There was no effect of estrogen replacement on EDI-2 or BSQ-34 scores. Body mass index (BMI) changes did not differ between groups, and effects of estrogen replacement on STAIC-trait scores persisted after controlling for BMI changes (P=.03). Increases in serum estradiol were significantly associated with decreases in STAIC-trait scores (Spearman rho=-0.45, P=.03). Conclusions: Estrogen replacement improved trait anxiety (the tendency to experience anxiety) but did not impact eating attitudes or body shape perception. Trial Registration: ClinicalTrials.gov identifier: NCT00088153 (C) 2013 Physicians Postgraduate Press, Inc. C1 [Misra, Madhusmita; Estella, Nara Mendes; Miller, Karen K.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Misra, Madhusmita] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Goldstein, Mark A.] Massachusetts Gen Hosp, Div Adolescent & Young Adult Med, Boston, MA 02114 USA. [Eddy, Kamryn T.] Harvard Univ, Sch Med, Boston, MA USA. [Eddy, Kamryn T.] Massachusetts Gen Hosp, Harris Ctr, Boston, MA 02114 USA. [Weigel, Thomas] McLean Hosp, Klarman Ctr, Belmont, MA 02178 USA. [Katzman, Debra K.] Hosp Sick Children, Div Adolescent Med, Toronto, ON M5G 1X8, Canada. RP Misra, M (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL 457,55 Fruit St, Boston, MA 02114 USA. EM mmisra@partners.org RI Mendes Estella, Nara/A-1469-2015 FU National Institutes of Health [R01 DK 062249, M01-RR-01066, 1 UL1 RR025758-03] FX This work was supported by National Institutes of Health grants R01 DK 062249, M01-RR-01066, and 1 UL1 RR025758-03. NR 25 TC 14 Z9 15 U1 1 U2 10 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 752870, MEMPHIS, TN 38175-2870 USA SN 0160-6689 EI 1555-2101 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2013 VL 74 IS 8 BP E765 EP E771 DI 10.4088/JCP.13m08365 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 212NI UT WOS:000323989700020 PM 24021517 ER PT J AU Kasai, K Nakashima, H Liu, F Kerr, S Wang, J Phelps, M Potter, PM Goins, WB Fernandez, SA Chiocca, EA AF Kasai, Kazue Nakashima, Hiroshi Liu, Fang Kerr, Samantha Wang, Jiang Phelps, Mitch Potter, Philip M. Goins, William B. Fernandez, Soledad A. Chiocca, E. Antonio TI Toxicology and Biodistribution Studies for MGH2.1, an Oncolytic Virus that Expresses Two Prodrug-activating Genes, in Combination with Prodrugs SO MOLECULAR THERAPY-NUCLEIC ACIDS LA English DT Article DE carboxylesterase; CPT11; cyclophosphamide; cytochrome P450; herpes simplex virus; irinotecan ID HERPES-SIMPLEX-VIRUS; HUMAN-INTESTINAL-CARBOXYLESTERASE; MALIGNANT GLIOMA; PHOSPHORAMIDE MUSTARD; CANCER-TREATMENT; NERVOUS-SYSTEM; CYCLOPHOSPHAMIDE; THERAPY; BRAIN; GLIOBLASTOMA AB MGH2.1 is a herpes simplex virus type 1 (HSV1) oncolytic virus that expresses two prodrug-activating transgenes: the cyclophosphamide (CPA)-activating cytochrome P4502B1 (CYP2B1) and the CPT11-activating secreted human intestinal carboxylesterase (shiCE). Toxicology and biodistribution of MGH2.1 in the presence/absence of prodrugs was evaluated in mice. MGH2.1 +/- prodrugs was cytotoxic to human glioma cells, but not to normal cells. Pharmacokinetically, intracranial MGH2.1 did not significantly alter the metabolism of intraperitoneally (i.p.) administered prodrugs in mouse plasma, brain, or liver. MGH2.1 did not induce an acute inflammatory reaction. MGH2.1 DNA was detected in brains of mice inoculated with 10(8) pfus for up to 60 days. However, only one animal showed evidence of viral gene expression at this time. Expression of virally encoded genes was restricted to brain. Intracranial inoculation of MGH2.1 did not induce lethality at 10(8) pfus in the absence of prodrugs and at 10(6) pfus in the presence of prodrugs. This study provides safety and toxicology data justifying a possible clinical trial of intratumoral injection of MGH2.1 with peripheral administration of CPA and/or CPT11 prodrugs in humans with malignant gliomas. C1 [Kasai, Kazue; Nakashima, Hiroshi; Liu, Fang; Kerr, Samantha; Chiocca, E. Antonio] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Neurosurg, Neurooncol Labs, Boston, MA 02115 USA. [Kasai, Kazue; Nakashima, Hiroshi; Liu, Fang; Kerr, Samantha; Chiocca, E. Antonio] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Wang, Jiang; Phelps, Mitch] Ohio State Univ, James Comprehens Canc Ctr, Pharmacol Core, Columbus, OH 43210 USA. [Potter, Philip M.] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA. [Goins, William B.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. [Fernandez, Soledad A.] Ohio State Univ, Dept Biostat, Columbus, OH 43210 USA. RP Chiocca, EA (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Neurosurg, Neurooncol Labs, PBB3,75 Francis St, Boston, MA 02115 USA. EM eachiocca@partners.org RI Potter, Philip/J-4515-2013 FU Alliance for Cancer Gene Therapy (Greenwich, CT); NCI [1P01CA163205-01A1]; NIH [CA108775]; American Lebanese Syrian Associated Charities (ALSAC); St. Jude Children's Research Hospital (SJCRH); Cancer Center Core grant [CA21765] FX These studies were funded by the Alliance for Cancer Gene Therapy (Greenwich, CT) to E.A.C. and NCI 1P01CA163205-01A1 to E.A.C. and W.B.G. Work in the Potter lab is supported in part by NIH grant CA108775, a Cancer Center Core grant CA21765, and by the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children's Research Hospital (SJCRH). The authors declared no conflict of interest. NR 54 TC 3 Z9 4 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 2162-2531 J9 MOL THER-NUCL ACIDS JI Mol. Ther.-Nucl. Acids PD AUG PY 2013 VL 2 AR e113 DI 10.1038/mtna.2013.38 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA AC4CB UT WOS:000332467100001 PM 23922029 ER PT J AU Chaudhuri, D Sancak, Y Mootha, VK Clapham, DE AF Chaudhuri, Dipayan Sancak, Yasemin Mootha, Vamsi K. Clapham, David E. TI Mitochondrial Calcium Currents Are Conducted By A Pore Encoded By The MCU Gene SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Basic Cardiovascular Sciences CY JUL 22-25, 2013 CL Las Vegas, NV SP Amer Heart Assoc DE mitoplast electrophysiology; calcium channel; mitochondrial uniporter C1 [Chaudhuri, Dipayan; Sancak, Yasemin; Mootha, Vamsi K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Clapham, David E.] Boston Childrens Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG PY 2013 VL 113 IS 4 SU S MA 091 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AB8TP UT WOS:000332063200088 ER PT J AU Danielson, K Melman, Y Simonson, B Barth, A Chakir, K Kleber, A Singh, J Kass, D Das, S AF Danielson, Kirsty Melman, Yonathan Simonson, Bridget Barth, Andreas Chakir, Khalid Kleber, Andre Singh, Jagmeet Kass, David Das, Saumya TI A Novel Functional Role for Plasma miR-30d in Dyssynchronous Heart Failure SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Basic Cardiovascular Sciences CY JUL 22-25, 2013 CL Las Vegas, NV SP Amer Heart Assoc DE microRNA; cardiac resynchronisation therapy C1 [Danielson, Kirsty; Melman, Yonathan; Simonson, Bridget; Kleber, Andre; Das, Saumya] Beth Israel Deaconess Med Cntr, Boston, MA USA. [Barth, Andreas; Chakir, Khalid; Kass, David] Johns Hopkins Univ Med Insts, Baltimore, MD USA. [Singh, Jagmeet] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG PY 2013 VL 113 IS 4 SU S MA 271 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AB8TP UT WOS:000332063200265 ER PT J AU Gao, EH He, H Zhang, B Wheeler, DG Mahamud, SD Dwyer, KM Robson, SC Cowan, PJ Koch, WJ Gumina, RJ AF Gao, Erhe He, Heng Zhang, Bo Wheeler, Debra G. Mahamud, Shouvik D. Dwyer, Karen M. Robson, Simon C. Cowan, Peter J. Koch, Walter J. Gumina, Richard J. TI Nucleotide Triphosphate Diphosphohydrolase-1 (NTPDase1) Overexpression Improves Post-Myocardial Infarction Recovery SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Basic Cardiovascular Sciences CY JUL 22-25, 2013 CL Las Vegas, NV SP Amer Heart Assoc DE NTPDase; myocardial infarction; transgenic C1 [Gao, Erhe; Koch, Walter J.] Temple Univ, Dept Pharmacol, Cntr Translat Med, Philadelphia, PA 19122 USA. [He, Heng; Zhang, Bo; Wheeler, Debra G.; Mahamud, Shouvik D.] Ohio State Univ, Columbus, OH 43210 USA. [Dwyer, Karen M.; Cowan, Peter J.] Univ Melbourne, St Vincents Hosp, Immunol Rsch Cntr, Fitzroy, Vic 3065, Australia. [Robson, Simon C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Massachusetts Gen Hosp, Transplantat Biol Rsch Cntr,Med Sch, Boston, MA 02215 USA. [Gumina, Richard J.] Vanderbilt Univ, Vanderbilt Heart & Vasc Inst, Nashville, TN 37235 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 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG PY 2013 VL 113 IS 4 SU S MA 341 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AB8TP UT WOS:000332063200331 ER PT J AU Lauriol, J Keith, K Goonasekera, SA Ke, QG Kang, P Molkentin, JD Kontaridis, MI AF Lauriol, Jessica Keith, Kimberly Goonasekera, Sanjeewa A. Ke, Qingen Kang, Peter Molkentin, Jeffery D. Kontaridis, Maria I. TI Cardiomyocyte-specific Deletion Of Rhoa Accelerates Heart Failure But Prevents Cardiac Fibrosis In Response To Pressure-overload SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Basic Cardiovascular Sciences CY JUL 22-25, 2013 CL Las Vegas, NV SP Amer Heart Assoc DE Contractility; Fibrosis; Signaling C1 [Lauriol, Jessica; Keith, Kimberly; Ke, Qingen; Kang, Peter; Kontaridis, Maria I.] Harvard Univ, Sch Med, BIDMC, Boston, MA USA. [Goonasekera, Sanjeewa A.; Molkentin, Jeffery D.] Cincinattis Children Hosp, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG PY 2013 VL 113 IS 4 SU S MA 200 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AB8TP UT WOS:000332063200196 ER PT J AU Tucker, NR Mahida, S Mills, R Simonson, B Macri, V Lemoine, M Das, S Milan, DJ Ellinor, PT AF Tucker, Nathan R. Mahida, Saagar Mills, Robert Simonson, Bridget Macri, Vincenzo Lemoine, Marc Das, Saumya Milan, David J. Ellinor, Patrick T. TI Overexpression of SK3 in a Murine Model Results in Sudden Cardiac Death SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association on Basic Cardiovascular Sciences CY JUL 22-25, 2013 CL Las Vegas, NV SP Amer Heart Assoc C1 [Tucker, Nathan R.; Mahida, Saagar; Mills, Robert; Macri, Vincenzo; Milan, David J.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Simonson, Bridget; Das, Saumya] Beth Isreal Deaconess Med Inst, Boston, MA USA. [Lemoine, Marc] Univ Hosp Munster, Munster, Germany. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 EI 1524-4571 J9 CIRC RES JI Circ.Res. PD AUG PY 2013 VL 113 IS 4 SU S MA 285 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA AB8TP UT WOS:000332063200278 ER PT J AU Ginat, DT Schatz, CJ AF Ginat, D. T. Schatz, C. J. TI Imaging Features of Midface Injectable Fillers and Associated Complications SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Review ID SOFT-TISSUE AUGMENTATION; HYALURONIC-ACID INJECTION; L-LACTIC ACID; CALCIUM HYDROXYLAPATITE; NASOLABIAL FOLDS; LIQUID SILICONE; DERMAL FILLERS; HISTORY; GRANULOMAS; WRINKLES AB Injectable fillers are increasingly used for midface augmentation, which can be performed for facial rejuvenation and treatment of HIV facial lipoatrophy. A variety of temporary and permanent filler agents has been developed, including calcium hydroxylapatite, collagen, liquid silicone, polytetrafluoroethylene, hyaluronic acid, poly-L-lactic acid, and polyacrylamide gel. Facial fillers are sometimes encountered on radiologic imaging incidentally and should not be mistaken for pathology. Alternatively, patients with facial fillers may undergo imaging specifically to evaluate associated complications, such as infection, overfilling, migration, foreign-body reaction, and scarring. Therefore, it is important to be familiar with the imaging appearances of the various filler materials and their complications. C1 [Ginat, D. T.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Schatz, C. J.] Univ So Calif, Dept Radiol, Keck Sch Med, Los Angeles, CA USA. RP Ginat, DT (reprint author), 55 Fruit St, Boston, MA 02114 USA. EM ginatd01@gmail.com NR 40 TC 16 Z9 16 U1 1 U2 5 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD AUG PY 2013 VL 34 IS 8 BP 1488 EP 1495 DI 10.3174/ajnr.A3161 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301NI UT WOS:000330538600010 PM 22837310 ER PT J AU Romero, JM Kelly, HR Almandoz, JED Hernandez-Siman, J Passanese, JC Lev, MH Gonzalez, RG AF Romero, J. M. Kelly, H. R. Almandoz, J. E. Delgado Hernandez-Siman, J. Passanese, J. C. Lev, M. H. Gonzalez, R. G. TI Contrast Extravasation on CT Angiography Predicts Hematoma Expansion and Mortality in Acute Traumatic Subdural Hemorrhage SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID PRIMARY INTRACEREBRAL HEMORRHAGE; SEVERE HEAD-INJURY; SPOT SIGN SCORE; IDENTIFIES PATIENTS; COMATOSE PATIENTS; HIGHEST RISK; TOMOGRAPHY; LESION AB BACKGROUND AND PURPOSE: The presence of active contrast extravasation at CTA predicts hematoma expansion and in-hospital mortality in patients with nontraumatic intracerebral hemorrhage. This study aims to determine the frequency and predictive value of the contrast extravasation in patients with aSDH. MATERIALS AND METHODS: We retrospectively reviewed 157 consecutive patients who presented to our emergency department over a 9-year period with aSDH and underwent CTA at admission and a follow-up NCCT within 48 hours. Two experienced readers, blinded to clinical data, reviewed the CTAs to assess for the presence of contrast extravasation. Medical records were reviewed for baseline clinical characteristics and in-hospital mortality. aSDH maximum width in the axial plane was measured on both baseline and follow-up NCCTs, with hematoma expansion defined as >20% increase from baseline. RESULTS: Active contrast extravasation was identified in 30 of 199 discrete aSDHs (15.1%), with excellent interobserver agreement (kappa = 0.80; 95% CI, 0.7-0.9). The presence of contrast extravasation indicated a significantly increased risk of hematoma expansion (odds ratio, 4.5; 95% CI, 2.0-10.1; P = .0001) and in-hospital mortality (odds ratio, 7.6; 95% CI, 2.6-22.3; P = 0.0004). In a multivariate analysis controlled for standard risk factors, the presence of contrast extravasation was an independent predictor of aSDH expansion (P = .001) and in-hospital mortality (P = .0003). CONCLUSIONS: Contrast extravasation stratifies patients with aSDH into those at high risk and those at low risk of hematoma expansion and in-hospital mortality. This distinction could affect patient treatment, clinical trial selection, and possible surgical intervention. C1 [Romero, J. M.; Kelly, H. R.; Hernandez-Siman, J.; Lev, M. H.; Gonzalez, R. G.] Harvard Univ, Sch Med, Dept Radiol, Div Neuroradiol,Massachusetts Gen Hosp, Boston, MA 02115 USA. [Almandoz, J. E. Delgado] Abbott Northwestern Hosp Minneapolis, Minneapolis, MN USA. RP Kelly, HR (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Neuroradiol, Gray 2,Room 273A,55 Fruit St, Boston, MA 02114 USA. EM hkelly2@partners.org FU Doris Duke Charitable Foundation Clinical Research Program Scholarship FX This work was funded in part by the Doris Duke Charitable Foundation Clinical Research Program Scholarship. NR 22 TC 4 Z9 4 U1 1 U2 2 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD AUG PY 2013 VL 34 IS 8 BP 1528 EP 1534 DI 10.3174/ajnr.A3434 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301NI UT WOS:000330538600016 PM 23449655 ER PT J AU Johnson, JM Reed, MS Burbank, HN Filippi, CG AF Johnson, J. M. Reed, M. S. Burbank, H. N. Filippi, C. G. TI Quality of Extracranial Carotid Evaluation with 256-Section CT SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID SYMPTOM ONSET; IMAGE QUALITY; STROKE; ANGIOGRAPHY; ARTERIES; OCCLUSION; DISEASE; BOLUS AB BACKGROUND AND PURPOSE: To date, no systematic evaluation of image quality has been performed on the 256-section multidetector CT scanner for extracranial carotid evaluations. We evaluated image quality, patient dose, and examination time and compared these parameters with a 64-section multidetector CT. MATERIALS AND METHODS: We reviewed extracranial CTA scans obtained on a 256-detector CT scanner in 50 consecutive patients. Image quality was analyzed for artifacts and vessel contrast opacification from the aortic arch to the skull base, dose to patient, and scan time. Results were compared with a control group of 50 patients imaged on a 64-section CT scanner. A Fisher exact test was used to analyze both groups with respect to vessel contrast opacification and presence of artifacts, and a Student t test was used to assess differences in patient dose between the 2 groups. RESULTS: Quantitative and qualitative evaluations revealed >95% acceptable vessel opacification at all levels measured on the 256-section scanner. Scan time was improved (4 seconds on 256-channel). There were fewer artifacts related to metallic streak on the 256-channel CTA study, and DLP was lower on the 256-channel CTA (113.9 versus 159.8 mGy). CONCLUSIONS: The 256-channel CTA imaging protocol for carotid arteries yielded similar vessel contrast opacification compared with the 64-channel CTA but with fewer metallic artifacts, a modest decrease in scan time, similar image quality, and a statistically significant reduction in radiation dose of 10%. C1 [Johnson, J. M.; Reed, M. S.; Burbank, H. N.; Filippi, C. G.] Fletcher Allen Hlth Care, Dept Radiol, Neuroradiol Sect, Burlington, VT USA. [Johnson, J. M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Johnson, JM (reprint author), Massachusetts Gen Hosp, Dept Radiol, FND216, Boston, MA 02114 USA. EM JJohnson57@partners.org NR 30 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC NEURORADIOLOGY PI DENVILLE PA PO BOX 3000, DENVILLE, NJ 07834-9349 USA SN 0195-6108 EI 1936-959X J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD AUG PY 2013 VL 34 IS 8 BP 1626 EP 1631 DI 10.3174/ajnr.A3433 PG 6 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 301NI UT WOS:000330538600033 PM 23471025 ER PT J AU Mimiaga, MJ Reisner, SL Grasso, C Crane, HM Safren, SA Kitahata, MM Schumacher, JE Mathews, WC Mayer, KH AF Mimiaga, Matthew J. Reisner, Sari L. Grasso, Chris Crane, Heidi M. Safren, Steven A. Kitahata, Mari M. Schumacher, Joseph E. Mathews, W. Christopher Mayer, Kenneth H. TI Substance Use Among HIV-Infected Patients Engaged in Primary Care in the United States: Findings From the Centers for AIDS Research Network of Integrated Clinical Systems Cohort SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID INJECTION-DRUG-USERS; ANTIRETROVIRAL THERAPY ADHERENCE; SCREENING-TEST ASSIST; TRANSMISSION RISK; PSYCHIATRIC-DISORDERS; MEDICATION ADHERENCE; METHAMPHETAMINE USE; ALCOHOL-CONSUMPTION; LONGITUDINAL DATA; SEXUAL-BEHAVIOR AB Objectives. The purpose of this study was to better understand substance use behaviors and deleterious health consequences among individuals with HIV. Methods. We examined a multicenter cohort of HIV-infected patients (n = 3413) receiving care in 4 US cities (Seattle, Birmingham, San Diego, Boston) between December 2005 and April 2010 in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS). We used generalized estimating equations to model specific substance use outcomes. Results. Overall, 24% of patients reported recent use of marijuana; 9% reported amphetamine use, 9% reported crack-cocaine use, 2% reported opiate use, 3.8% reported injection drug use, and 10.3% reported polydrug use. In adjusted multivariable models, those who reported unprotected anal sex had higher odds of marijuana, amphetamine, injection drug, and polydrug use. An increased number of distinct vaginal sexual partners was associated with polydrug and crack-cocaine use. Nonadherence to antiretroviral therapy was associated with the use of all substances other than marijuana. Conclusions. The co-occurrence of substance use, unprotected intercourse, and medication nonadherence could attenuate the public health benefits of test, treat, and link to care strategies. Prevention programs are needed that address these coprevalent conditions. C1 [Mimiaga, Matthew J.; Reisner, Sari L.; Safren, Steven A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Grasso, Chris; Mayer, Kenneth H.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Crane, Heidi M.; Kitahata, Mari M.] Univ Washington, Sch Med, Div Infect Dis, Seattle, WA USA. [Schumacher, Joseph E.] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA. [Mathews, W. Christopher] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. RP Mimiaga, MJ (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, 1 Bowdoin Sq,7th Floor, Boston, MA 02114 USA. EM mmimiaga@partners.org RI Mathews, William/E-4451-2010 OI Mathews, William/0000-0002-2352-0725 FU National Institute on Drug Abuse [R34 DA031028]; Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) [R24 AI067039]; PROMIS [U01 AR057954] FX This work was supported in part by the National Institute on Drug Abuse (grant R34 DA031028) and the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS; grant R24 AI067039). Data collection in CNICS is also supported in part by PROMIS grant U01 AR057954. NR 66 TC 22 Z9 22 U1 2 U2 3 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2013 VL 103 IS 8 BP 1457 EP 1467 DI 10.2105/AJPH.2012.301162 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3MU UT WOS:000330997500036 PM 23763417 ER PT J AU Chi, DL Tucker-Seeley, R AF Chi, Donald L. Tucker-Seeley, Reginald TI Gender-Stratified Models to Examine the Relationship Between Financial Hardship and Self-Reported Oral Health for Older US Men and Women SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID FOOD INSECURITY; SOCIOECONOMIC-STATUS; PERIODONTAL-DISEASE; DENTAL-CARIES; SOCIAL GRADIENTS; UNITED-STATES; RISK-FACTORS; CARDIOVASCULAR EVENTS; ELDERLY POPULATION; CARE UTILIZATION AB Objectives. We evaluated the relationship between financial hardship and self-reported oral health for older men and women. Methods. We focused on adults in the 2008 Health and Retirement Study (n = 1359). The predictor variables were 4 financial hardship indicators. We used Poisson regression models to estimate the prevalence ratio of poor self-reported oral health. Results. In the non-gender-stratified model, number of financial hardships was not significantly associated with self-reported oral health. Food insecurity was associated with a 12% greater prevalence of poor self-reported oral health (95% confidence interval [CI] = 1.04, 1.21). In the gender-stratified models, women with 3 or more financial hardships had a 24% greater prevalence of poor self-reported oral health than women with zero (95% CI = 1.09, 1.40). Number of hardships was not associated with self-reported oral health for men. For men, skipping medications was associated with 50% lower prevalence of poor self-reported oral health (95% CI = 0.32, 0.76). Conclusions. Number of financial hardships was differentially associated with self-reported oral health for older men and women. Most financial hardship indicators affected both genders similarly. Future interventions to improve vulnerable older adults' oral health should account for gender-based heterogeneity in financial hardship experiences. C1 [Chi, Donald L.] Univ Washington, Dept Oral Hlth Sci, Seattle, WA 98195 USA. [Tucker-Seeley, Reginald] Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. [Tucker-Seeley, Reginald] Harvard Univ, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. RP Chi, DL (reprint author), Univ Washington, Sch Dent, Dept Oral Hlth Sci, Box 357475, Seattle, WA 98195 USA. EM dchi@uw.edu FU National Institute of Dental and Craniofacial Research [K08DE020856] FX This study was supported by the National Institute of Dental and Craniofacial Research (grant K08DE020856). NR 109 TC 4 Z9 4 U1 4 U2 13 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2013 VL 103 IS 8 BP 1507 EP 1515 DI 10.2105/AJPH.2012.301145 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3MU UT WOS:000330997500042 PM 23327271 ER PT J AU Bernstein, SL Yu, SY Post, LA Dziura, J Rigotti, NA AF Bernstein, Steven L. Yu, Sunkyung Post, Lori A. Dziura, James Rigotti, Nancy A. TI Undertreatment of Tobacco Use Relative to Other Chronic Conditions SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID SMOKING-CESSATION TREATMENT; VITAL SIGNS PREVALENCE; UNITED-STATES; DEPENDENCE TREATMENTS; MEDICAID COVERAGE; PRIMARY-CARE; SMOKERS; PHYSICIANS; VISITS AB Objectives. We compared the likelihood that a tobacco user would receive treatment with the likelihood that an adult with another common chronic condition would receive treatment for that condition at an office visit. Methods. We analyzed data from the 2005-2007 National Ambulatory Medical Care Survey to compare the proportion of US office visits at which tobacco users and individuals with hypertension, hyperlipidemia, diabetes, asthma, or depression received condition-specific treatment. We calculated the odds that a visit for a comparison condition would result in treatment relative to a visit for tobacco dependence. Results. From 2005 to 2007, 38 004 patient visits involved at least 1 study condition. Tobacco users received medication at fewer visits (4.4%) than individuals with hypertension (57.4%), diabetes (46.2%), hyperlipidemia (47.1%), asthma (42.6%), and depression (53.3%). In multivariate analyses, the odds for pharmacological treatment of these disorders relative to tobacco use were, for hypertension, 32.8; diabetes, 20.9; hyperlipidemia, 16.5; asthma, 22.1; and depression, 24.0 (all Ps < .001). Patients with hypertension, diabetes, or hyperlipidemia were also more likely to receive behavioral counseling. Conclusions. Alternate models of engagement may be needed to enhance use of effective treatments for tobacco use. C1 [Bernstein, Steven L.; Post, Lori A.; Dziura, James] Yale Univ, Sch Med, Dept Emergency Med, New Haven, CT USA. [Bernstein, Steven L.] Yale Canc Ctr, New Haven, CT USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. [Yu, Sunkyung] Yale Univ, Sch Publ Hlth, New Haven, CT USA. RP Bernstein, SL (reprint author), Yale Dept Emergency Med, 464 Congress Ave,Suite 260, New Haven, CT 06519 USA. EM steven.bernstein@yale.edu NR 31 TC 14 Z9 14 U1 2 U2 8 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2013 VL 103 IS 8 BP E59 EP E65 DI 10.2105/AJPH.2012.301112 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3MU UT WOS:000330997500016 PM 23763395 ER PT J AU Ma, YS Balasubramanian, R Pagoto, SL Schneider, KL Hebert, JR Phillips, LS Goveas, JS Culver, AL Olendzki, BC Beck, J Smoller, JW Sepavich, DM Ockene, JK Uebelacker, L Zorn, M Liu, SM AF Ma, Yunsheng Balasubramanian, Raji Pagoto, Sherry L. Schneider, Kristin L. Hebert, James R. Phillips, Lawrence S. Goveas, Joseph S. Culver, Annie L. Olendzki, Barbara C. Beck, James Smoller, Jordan W. Sepavich, Deidre M. Ockene, Judith K. Uebelacker, Lisa Zorn, Martha Liu, Simin TI Relations of Depressive Symptoms and Antidepressant Use to Body Mass Index and Selected Biomarkers for Diabetes and Cardiovascular Disease SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID C-REACTIVE PROTEIN; BASE-LINE CHARACTERISTICS; DIETARY MODIFICATION TRIAL; NECROSIS-FACTOR-ALPHA; WOMENS HEALTH; MAJOR DEPRESSION; POSTMENOPAUSAL WOMEN; INSULIN-RESISTANCE; SOLUBLE INTERLEUKIN-2; PLASMA-CONCENTRATIONS AB Objectives. We investigated whether depressive symptoms and antidepressant use are associated with biomarkers for glucose dysregulation and inflammation, body mass index (BMI), and waist circumference. Methods. Postmenopausal women were recruited into the Women's Health Initiative from 1993 to 1998, and data were collected at regular intervals through 2005. We used multiple linear regression models to examine whether depressive symptoms and antidepressant use are associated with BMI, waist circumference, and biomarkers. Results. Analysis of data from 71 809 women who completed all relevant baseline and year 3 assessments showed that both elevated depressive symptoms and antidepressant use were significantly associated with higher BMI and waist circumference. Among 1950 women, elevated depressive symptoms were significantly associated with increased insulin levels and measures of insulin resistance. Analyses of baseline data from 2242 women showed that both elevated depressive symptoms and antidepressant use were associated with higher C-reactive protein levels. Conclusions. Monitoring body habitus and other biomarkers among women with elevated depression symptoms or taking antidepressant medication may be prudent to prevent diabetes and cardiovascular disease. C1 [Ma, Yunsheng; Pagoto, Sherry L.; Schneider, Kristin L.; Culver, Annie L.; Olendzki, Barbara C.; Sepavich, Deidre M.; Ockene, Judith K.] Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Dept Med, Worcester, MA 01655 USA. [Balasubramanian, Raji; Zorn, Martha] Univ Massachusetts Amherst, Div Biostat & Epidemiol, Amherst, MA 01003 USA. [Hebert, James R.] Univ S Carolina, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Hebert, James R.] Univ S Carolina, Canc Prevent & Control Program, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Phillips, Lawrence S.] Emory Univ, Div Endocrinol, Atlanta, GA 30322 USA. [Goveas, Joseph S.] Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI 53226 USA. [Beck, James] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Smoller, Jordan W.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Uebelacker, Lisa] Brown Univ, Div Biol & Med, Psychosocial Res Program, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Epidemiol, Providence, RI 02912 USA. [Liu, Simin] Brown Univ, Dept Med, Div Endocrinol, Providence, RI 02912 USA. RP Ma, YS (reprint author), Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Dept Med, 55 Lake Ave North, Worcester, MA 01655 USA. EM Yunsheng.Ma@umassmed.edu RI Liu, Simin/I-3689-2014; Pagoto, Sherry/L-2014-2013; OI Liu, Simin/0000-0003-2098-3844; Pagoto, Sherry/0000-0002-2462-8797; Ma, Yunsheng/0000-0003-2317-3716 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [1 R21 DK083700-01A1]; National Heart, Lung, and Blood Institute (NHLBI) [1R01HL094575-01A1]; NIDDK [R01DK062290, 5 P30 DK32520]; NHLBI, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX This research was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; 1 R21 DK083700-01A1) and the National Heart, Lung, and Blood Institute (NHLBI; 1R01HL094575-01A1) to Y. Ma. Assessment of biomarkers was supported by a grant funded by the NIDDK (R01DK062290) to S. Liu. It was also supported in part by a Center Grant from NIDDK (5 P30 DK32520). Y. Ma and S. L. Pagoto are members of the UMass Diabetes and Endocrinology Research Center (DK32520). The Women's Health Initiative (WHI) program is funded by the NHLBI, National Institutes of Health, US Department of Health and Human Services (contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221). NR 64 TC 8 Z9 8 U1 0 U2 5 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 EI 1541-0048 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2013 VL 103 IS 8 BP E34 EP E43 DI 10.2105/AJPH.2013.301394 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA AA3MU UT WOS:000330997500013 PM 23763394 ER PT J AU Tirumani, H Jagannathan, JP Hornick, JL Ramaiya, NH AF Tirumani, H. Jagannathan, J. P. Hornick, J. L. Ramaiya, N. H. TI Resistance to treatment in gastrointestinal stromal tumours: What radiologists should know SO CLINICAL RADIOLOGY LA English DT Review ID IMATINIB MESYLATE; PHASE-II; RESPONSE ASSESSMENT; TARGETED THERAPY; KIT MUTATIONS; FDG-PET; GIST; RECURRENCE; CRITERIA; SARCOMAS AB Gastrointestinal stromal tumour resistance to treatment with imatinib occurs due to pre-existing or acquired mutations. Computed tomography and positron-emission tomography play an essential role in prompt recognition of resistance to treatment. Primary resistance to treatment, which is encountered in the first 6 months of treatment, is associated with specific mutations. Imaging of these tumours shows no anatomical or metabolic response to treatment. Secondary resistance to treatment, which develops after an initial response, is associated with a variety of mutations acquired after the start of treatment. Imaging findings of secondary resistance are of disease progression. (C) 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. C1 [Tirumani, H.; Jagannathan, J. P.; Ramaiya, N. H.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, Boston, MA 02215 USA. [Tirumani, H.; Jagannathan, J. P.; Ramaiya, N. H.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02215 USA. [Hornick, J. L.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. RP Tirumani, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Imaging, 450 Brookline Ave, Boston, MA 02215 USA. EM stirumani@partners.org NR 50 TC 2 Z9 2 U1 0 U2 2 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0009-9260 EI 1365-229X J9 CLIN RADIOL JI Clin. Radiol. PD AUG PY 2013 VL 68 IS 8 BP E429 EP E437 DI 10.1016/j.crad.2013.03.016 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA AA5PE UT WOS:000331151300001 ER PT J AU Cheng, CE Javorsky, E Kimball, AB AF Cheng, Carol E. Javorsky, Emilia Kimball, Alexa Boer TI Women in Leadership Positions Within Obstetrics and Gynecology: Does the Past Explain the Present? SO OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 [Cheng, Carol E.; Kimball, Alexa Boer] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cheng, Carol E.; Kimball, Alexa Boer] Harvard Univ, Sch Med, Boston, MA USA. [Javorsky, Emilia] Univ Massachusetts, Sch Med, Worcester, MA USA. RP Cheng, CE (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 EI 1873-233X J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2013 VL 122 IS 2 BP 396 EP 397 PN 1 PG 4 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 301GL UT WOS:000330520700038 PM 23969819 ER PT J AU Viana, LM Salviz, M Rauch, SD Nadol, JB AF Viana, Lucas M. Salviz, Mehti Rauch, Steven D. Nadol, Joseph B. TI Otopathology in Idiopathic Dandy's Syndrome SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Bilateral vestibulopathy; Oscillopsia; Vertigo; Vestibular diseases; Vestibular disorders AB Background: Dandy's syndrome, or bilateral vestibular hypofunction and oscillopsia, may cause chronic disequilibrium aggravated by head movement or in the presence of reduced light. It may be secondary to ototoxicity, central nervous system tumors, Meniere's syndrome, infections, or trauma or may be idiopathic. Objective: To describe the temporal bone histopathology in one individual with idiopathic Dandy's syndrome. Materials and Methods: Temporal bones from 1 individual were removed at autopsy and studied using light and Nomarski microscopy. Results: In this case, the otopathology demonstrated vestibular atelectasis of the membranous labyrinth of the superior, lateral, and posterior semicircular canals but not the utricle or saccule bilaterally. The findings also included mild hair cell loss in the cristae of all semicircular canals and of the utricular and saccular maculae and severely reduced neuronal count in Scarpa's ganglion bilaterally. There was also a scattered loss of inner and outer hair cells throughout the cochlea and moderate-to-severe loss of cochlear neurons bilaterally. Conclusion: We have reported the histopathologic findings in a case of idiopathic Dandy's syndrome. Both temporal bones showed vestibular atelectasis of all three semicircular canals, preservation of normal saccule and utricle, and severe reduction of the neuronal population in Scarpa's ganglion bilaterally. Both ears also showed substantial degeneration of the spiral ganglion of the cochleas. Severe Scarpa's ganglion degeneration was also noted in the only other case of idiopathic Dandy's Syndrome in the literature. However, that other case had no evidence of vestibular atelectasis and had normal hearing. C1 [Viana, Lucas M.; Salviz, Mehti; Rauch, Steven D.; Nadol, Joseph B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. RP Viana, LM (reprint author), Harvard Univ, Sch Med, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Boston, MA 02115 USA. EM lucasmvianaorl@gmail.com FU NIDCD NIH HHS [U24 DC011943] NR 10 TC 2 Z9 2 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD AUG PY 2013 VL 34 IS 6 BP 1099 EP 1103 PG 5 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 301GU UT WOS:000330521600028 PM 23542133 ER PT J AU Salviz, M Montoya, JG Nadol, JB Santos, F AF Salviz, Mehti Montoya, Jose G. Nadol, Joseph B. Santos, Felipe TI Otopathology in Congenital Toxoplasmosis SO OTOLOGY & NEUROTOLOGY LA English DT Article DE Hearing loss; Histopathology; Temporal bone; Toxoplasmosis ID INFECTION; CHILDREN AB Objective: To describe the temporal bone histopathology in children with congenital toxoplasmosis. Background: Toxoplasmosis is a parasitic infection caused by Toxoplasma gondii. If fetal infection occurs early in gestation, severe inflammation and necrosis can cause brain lesions, chorioretinitis, and hearing loss. Hearing loss in congenital toxoplasmosis may be preventable with early diagnosis and treatment. Materials and Methods: The temporal bones of 9 subjects with congenital toxoplasmosis were removed at autopsy and studied under light microscopy. Cytocochleograms were constructed for hair cells, the stria vascularis, and cochlear neuronal cells. Results: Three (33%) of 9 subjects were found to have parasites in the temporal bone. The organism was identified in the internal auditory canal, the spiral ligament, stria vascularis, and saccular macula. The cystic form of the parasite was not associated with the inflammatory response seen in the active tachyzoite form. Conclusion: We infer that the hearing loss of toxoplasmosis is likely the result of a postnatal inflammatory response to the tachyzoite form of T. gondii. Our findings have implications for the early identification and management of Toxoplasmosis. C1 [Salviz, Mehti; Nadol, Joseph B.; Santos, Felipe] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Salviz, Mehti; Nadol, Joseph B.; Santos, Felipe] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Montoya, Jose G.] Palo Alto Med Fdn, Toxoplasma Serol Lab, Palo Alto, CA USA. [Montoya, Jose G.] Stanford Sch Med, Dept Infect Dis, Palo Alto, CA USA. RP Santos, F (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM felipe_santos@meei.harvard.edu OI Santos, Felipe/0000-0002-3523-665X FU National Institutes of Health [1U24DC011943-01] FX This study was supported in part by National Institutes of Health Grant 1U24DC011943-01. NR 13 TC 9 Z9 9 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 EI 1537-4505 J9 OTOL NEUROTOL JI Otol. Neurotol. PD AUG PY 2013 VL 34 IS 6 BP 1165 EP 1169 PG 5 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 301GU UT WOS:000330521600037 PM 23598697 ER PT J AU Kidd, E Moore, D Varia, MA Gaffney, DK Elshaikh, MA Erickson, B Jhingran, A Lee, LJ Mayr, NA Puthawala, AA Rao, GG Small, W Wahl, AO Wolfson, AH Yashar, CM Yuh, W Cardenes, HR AF Kidd, Elizabeth Moore, David Varia, Mahesh A. Gaffney, David K. Elshaikh, Mohamed A. Erickson, Beth Jhingran, Anuja Lee, Larissa J. Mayr, Nina A. Puthawala, Ajmel A. Rao, Gautam G. Small, William, Jr. Wahl, Andrew O. Wolfson, Aaron H. Yashar, Catheryn M. Yuh, William Cardenes, Higinia Rosa CA Expert Panel Radiation TI ACR Appropriateness Criteria (R) Management of Locoregionally Advanced Squamous Cell Carcinoma of the Vulva SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Review DE vulvar cancer; Appropriateness Criteria; neoadjuvant chemoradiotherapy ID GYNECOLOGIC-ONCOLOGY-GROUP; POSITRON-EMISSION-TOMOGRAPHY; LOCALLY ADVANCED-CARCINOMA; LYMPH-NODE METASTASES; RADIATION-THERAPY; MITOMYCIN-C; PREOPERATIVE CHEMORADIATION; CERVICAL-CANCER; ANAL CANCER; FDG-PET/CT AB Objectives: Locoregionally advanced vulvar cancer (LRAVC) is a rare disease that presents many challenging medical decisions. An expert panel was convened to reach consensus on the most appropriate pretreatment assessment and therapeutic interventions in LRAVC patients. Methods: The American College of Radiology Appropriateness Criteria are evidenced-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journal and the application of a well-established consensus methodology (modified Delphi) to rate appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to formulate recommendations. Results: Three clinical variants were developed to address common scenarios in the management of LRAVC. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches, with numerical ratings and descriptive commentary. Conclusions: In combining available medical literature and expert opinion, this manuscript may serve as an aid for other practitioners in the appropriate management of patients with LRAVC. C1 [Kidd, Elizabeth] Stanford Canc Ctr, Stanford, CA USA. [Puthawala, Ajmel A.] Long Beach Mem Med Ctr, Long Beach, CA USA. [Yashar, Catheryn M.] Univ Calif San Diego, San Diego, CA 92103 USA. [Moore, David] Indiana Univ Sch Med, Amer Coll Obstetricians & Gynecologists, Indianapolis, IN 46202 USA. [Cardenes, Higinia Rosa] Indiana Univ, Med Ctr, Indianapolis, IN USA. [Varia, Mahesh A.] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Gaffney, David K.] Univ Utah, Med Ctr, Salt Lake City, UT USA. [Elshaikh, Mohamed A.] Henry Ford Hlth Syst, Detroit, MI USA. [Erickson, Beth] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Jhingran, Anuja] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lee, Larissa J.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mayr, Nina A.] James Canc Hosp, Ohio State Comprehens Canc Ctr, Columbus, OH USA. [Yuh, William] Ohio State Univ, Columbus, OH 43210 USA. [Rao, Gautam G.] Univ Maryland, Sch Med, Amer Soc Clin Oncol, Baltimore, MD 21201 USA. [Small, William, Jr.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Wahl, Andrew O.] Univ Nebraska Med Ctr, Omaha, NE USA. [Wolfson, Aaron H.] Univ Miami, Miami, FL USA. RP Kidd, E (reprint author), Amer Coll Radiol, 1891 Preston White Dr, Reston, VA 20191 USA. EM ekidd@stanford.edu NR 66 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 EI 1537-453X J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD AUG PY 2013 VL 36 IS 4 BP 415 EP 422 DI 10.1097/COC.0b013e318295af1d PG 8 WC Oncology SC Oncology GA 298VC UT WOS:000330351600018 ER PT J AU Turko, A Fuzaylov, G Savchyn, V Driscoll, D AF Turko, Arthur Fuzaylov, Gennadiy Savchyn, Vasyl Driscoll, Daniel TI Immediate and Early Tissue Expander Placement for Acute Closure of Scalp Wounds SO ANNALS OF PLASTIC SURGERY LA English DT Article DE tissue expander; tissue expansion; burn wound; scalp wound; scalp reconstruction; acute wound reconstruction ID NECK BURN RECONSTRUCTION; SKIN EXPANSION; DEFECTS; HEAD; COMPLICATIONS; ALOPECIA; CHILDREN; REPAIR AB Background: Scalp tissue expansion is a reliable technique for reconstruction of scalp alopecia and other deformities. However, the conventional practice involves establishing temporary wound coverage before expander placement, expansion, and definitive reconstruction. We propose that immediate (at the time of injury and initial wound debridement, leaving an open wound during expansion) tissue expander placement may be a reasonable approach to the management of full-thickness scalp wounds not amenable to primary closure. Methods: We performed a retrospective chart review identifying all patients who underwent immediate placement of scalp tissue expanders at the Lviv Burn Center (Lviv Medical University Burn Center, Ukraine). Results: A total of 15 patients were identified who received a total of 21 tissue expanders at the time of acute burn treatment. The indications included electrical burn (46.7%), trauma (20%), tumor resection (13.3%), flame burn (13.3%), and chemical burn (6.7%). Of the 21 expanders placed, 4 (19%) complications were reported. There was 1 (4.7%) implant exposure and 3 (14%) implant infections. All of the patients in this series had complete reconstructions after removal of their expanders because all complications occurred toward the end of expansion. Conclusions: Immediate placement of tissue expanders is a reasonable approach that greatly expedites scalp reconstruction. In this series, the complication rate was consistent with or slightly higher than published rates of complications in conventional techniques. Immediate expansion may be especially useful when other reconstructive options (such as free tissue transfer) are unavailable or not feasible. C1 [Turko, Arthur; Driscoll, Daniel] Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Boston, MA 02114 USA. [Turko, Arthur; Fuzaylov, Gennadiy; Driscoll, Daniel] Massachusetts Gen Hosp, Shriners Burns Inst, Boston, MA 02114 USA. [Fuzaylov, Gennadiy] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Savchyn, Vasyl] Lviv Med Univ, Burn Ctr, Lvov, Ukraine. RP Turko, A (reprint author), Massachusetts Gen Hosp, Div Plast & Reconstruct Surg, Wang Ambulatory Care Ctr 435,55 Fruit St, Boston, MA 02114 USA. EM aturko@partners.org NR 25 TC 2 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-7043 EI 1536-3708 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD AUG PY 2013 VL 71 IS 2 BP 160 EP 165 DI 10.1097/SAP.0b013e3182933e05 PG 6 WC Surgery SC Surgery GA 300FI UT WOS:000330449400010 PM 23838756 ER PT J AU Xie, ZC McAuliffe, S Swain, CA Ward, SAP Crosby, CA Zheng, H Sherman, J Dong, YL Zhang, YY Sunder, N Burke, D Washicosky, KJ Tanzi, RE Marcantonio, ER AF Xie, Zhongcong McAuliffe, Sayre Swain, Celeste A. Ward, Sarah A. P. Crosby, Catherine A. Zheng, Hui Sherman, Janet Dong, Yuanlin Zhang, Yiying Sunder, Neelakantan Burke, Dennis Washicosky, Kevin J. Tanzi, Rudolph E. Marcantonio, Edward R. TI Cerebrospinal Fluid A beta to Tau Ratio and Postoperative Cognitive Change SO ANNALS OF SURGERY LA English DT Article DE A beta/tau ratio; Biomarker; cognition; CSF; surgery ID ARTERY-BYPASS-SURGERY; ALZHEIMERS-DISEASE; NEUROCOGNITIVE FUNCTION; AMYLOID PROTEIN; CSF BIOMARKERS; DYSFUNCTION; A-BETA-40; DEMENTIA; BRAIN; IMPAIRMENT AB Objective: Determination of biomarker and neuropathogenesis of postoperative cognitive change (POCC) or postoperative cognitive dysfunction. Background: POCC is one of the most common postoperative complications in elderly patients. Whether preoperative cerebrospinal fluid (CSF) beta-amyloid protein (A beta) to tau ratio, an Alzheimer disease biomarker, is a biomarker for risk of POCC remains unknown. We therefore set out to assess the association between preoperative CSF A beta 42 or A beta 40 to tau ratio and POCC. Methods: Patients who had total hip/knee replacement were enrolled. The CSF was obtained during the administration of spinal anesthesia. Cognitive tests were performed with these participants at 1 week before and at 1 week and 3 to 6 months after the surgery. Z scores of the changes from preoperative to postoperative on several key domains of the cognitive battery were determined. We then examined the association between preoperative CSF A beta 42/tau or A beta 40/tau ratio and the outcome measures described earlier, adjusting for age and sex. Results: Among the 136 participants (mean age = 71 +/- 5 years; 55% men), preoperative CSF A beta 42/tau ratio was associated with postoperative Hopkins Verbal Learning Test Retention [Z score = 8.351; age, sex-adjusted (adj.) P = 0.003], and the Benton Judgment of Line Orientation (Z score = 1.242; adj. P = 0.007). A beta 40/tau ratio was associated with Brief Visuospatial Memory Test Total Recall (Z score = 1.045; adj. P = 0.044). Conclusions: Preoperative CSF A beta/tau ratio is associated with postoperative changes in specific cognitive domains. The presence of the Alzheimer's disease biomarker, specifically the A beta/tau ratio, may identify patients at higher risk for cognitive changes after surgery. C1 [Xie, Zhongcong; McAuliffe, Sayre; Swain, Celeste A.; Ward, Sarah A. P.; Crosby, Catherine A.; Dong, Yuanlin; Zhang, Yiying] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, Charlestown, MA 02129 USA. [Xie, Zhongcong; McAuliffe, Sayre; Swain, Celeste A.; Ward, Sarah A. P.; Crosby, Catherine A.; Dong, Yuanlin; Zhang, Yiying; Washicosky, Kevin J.; Tanzi, Rudolph E.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Zheng, Hui] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. [Sherman, Janet] Massachusetts Gen Hosp, Psychol Assessment Ctr, Boston, MA 02114 USA. [Sunder, Neelakantan] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Burke, Dennis] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Marcantonio, Edward R.] Harvard Univ, Sch Med, Boston, MA USA. [Washicosky, Kevin J.; Tanzi, Rudolph E.] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Marcantonio, Edward R.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Marcantonio, Edward R.] Beth Israel Deaconess Med Ctr, Dept Med, Div Gerontol, Boston, MA 02215 USA. RP Xie, ZC (reprint author), Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Geriatr Anesthesia Res Unit, 149 13th St,Room 4310, Charlestown, MA 02129 USA. EM zxie@partners.org FU National Institutes of Health (Bethesda, MD) [K08 NS048140, R21 AG029856, R01 GM088801, R21 AG038994, R01 AG041274]; Alzheimer's Association (Chicago, IL); Cure Alzheimer's Fund; National Institute on Aging [K24AG035075]; [R01AG030618]; [P01AG031720] FX This study was supported by National Institutes of Health grants (Bethesda, MD) (K08 NS048140, R21 AG029856, R01 GM088801, R21 AG038994, and R01 AG041274); Investigator-Initiated Research Grant from Alzheimer's Association (Chicago, IL); and Cure Alzheimer's Fund (to Z.X.). Dr Marcantonio was funded in part by grants R01AG030618, P01AG031720, and a Mid-Career Investigator Award (K24AG035075) from the National Institute on Aging. The authors declare no conflicts of interest. NR 44 TC 15 Z9 19 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 EI 1528-1140 J9 ANN SURG JI Ann. Surg. PD AUG PY 2013 VL 258 IS 2 BP 364 EP 369 DI 10.1097/SLA.0b013e318298b077 PG 6 WC Surgery SC Surgery GA 300JR UT WOS:000330460700028 PM 23732272 ER PT J AU Meyerhardt, JA AF Meyerhardt, Jeffrey A. TI We Are What We Eat, Or Are We? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID III COLON-CANCER; COLORECTAL-CANCER; DIETARY PATTERNS; METAANALYSIS; RECURRENCE; SURVIVAL C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [R01CA14922, P50 CA127003] NR 9 TC 2 Z9 2 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2013 VL 31 IS 22 BP 2763 EP + DI 10.1200/JCO.2013.50.7731 PG 3 WC Oncology SC Oncology GA 301NK UT WOS:000330538800004 PM 23816969 ER PT J AU Goff, DC McEvoy, JP Citrome, L Mech, AW Bustillo, JR Gil, R Buckley, P Manschreck, TC Achtyes, ED Macklin, EA AF Goff, Donald C. McEvoy, Joseph P. Citrome, Leslie Mech, Arnold W. Bustillo, Juan R. Gil, Roberto Buckley, Peter Manschreck, Theo C. Achtyes, Eric D. Macklin, Eric A. TI High-Dose Oral Ziprasidone Versus Conventional Dosing in Schizophrenia Patients With Residual Symptoms The ZEBRAS Study SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE high-dose ziprasidone; schizophrenia; residual symptoms ID PLACEBO-CONTROLLED TRIAL; SCHIZOAFFECTIVE DISORDER; ANTIPSYCHOTIC-DRUGS; ACUTE EXACERBATION; QTC INTERVAL; HALOPERIDOL; ABSORPTION; OCCUPANCY; MG/DAY AB Uncontrolled studies have suggested that increasing the dose of ziprasidone above the standard maximum daily dose of 160 mg may be more effective for some patients with schizophrenia. To test this hypothesis, we conducted an 8-week, placebo-controlled, fixed-dose escalation trial comparing ziprasidone 160 versus 320 mg/d in individuals with schizophrenia or schizoaffective disorder who remained symptomatic despite treatment with ziprasidone 160 mg/d for at least 3 weeks. Of 75 randomized patients, 42 completed the study. Serum ziprasidone concentrations increased significantly in the high-dose group compared with the standard-dose group at week 4 but did not differ between groups at week 8. Both treatment groups exhibited significant symptomatic improvement. Response did not differ between treatment groups; however, in the high-dose group, higher ziprasidone serum concentrations were associated with better response at a trend level. Higher ziprasidone concentrations were also associated with reductions in diastolic blood pressure and, at a trend level, with more prominent negative symptoms and greater QTc prolongation. In summary, increasing the ziprasidone dose to 320 mg/d did not produce a sustained elevation in serum concentrations or symptomatic improvement compared with a standard ziprasidone dose of 160 mg/d. C1 [Goff, Donald C.] Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. [Goff, Donald C.] NYU, Langone Med Ctr, New York, NY USA. [McEvoy, Joseph P.] John Umstead Hosp, Durham, NC USA. [McEvoy, Joseph P.] Duke Sch Med, Durham, NC USA. [Citrome, Leslie] New York Med Coll, Valhalla, NY 10595 USA. [Mech, Arnold W.] Mech Psychiat Associates, Plano, TX USA. [Bustillo, Juan R.] Univ New Mexico, Albuquerque, NM 87131 USA. [Gil, Roberto] Columbia Univ Coll Phys & Surg, New York Psychiat Inst, New York, NY 10032 USA. [Buckley, Peter] Med Coll Georgia, Augusta, GA 30912 USA. [Manschreck, Theo C.] Corrigan Mental Hlth Ctr, Fall River, MA USA. [Manschreck, Theo C.] Harvard Univ, Sch Med, Boston, MA USA. [Achtyes, Eric D.] Michigan State Univ, Coll Human Med, Cherry St Hlth Serv, Grand Rapids, MI USA. [Macklin, Eric A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Goff, DC (reprint author), Nathan S Kline Inst Psychiat Res, 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA. EM dgoff@nki.rfmh.org OI Citrome, Leslie/0000-0002-6098-9266; Macklin, Eric/0000-0003-1618-3502; Achtyes, Eric/0000-0001-8939-1535 FU Schering Plough; Bristol-Myers Squibb; Eli Lilly; Eli Lilly, GlaxoSmithKline; Janssen Pharmaceuticals; Pfizer Inc; Solvay; Otsuka Pharmaceuticals; Biovail Pharmaceuticals; Abbott Pharmaceuticals; Endo Pharmaceuticals; Genetech; Hoffman-La Roche Inc; Dainippon Sumitomo Consulting, Panlab; Novartis; Duke University; AstraZeneca; Azur; Forest; GlaxoSmithKline; Jazz; Merck; Sunovion; Valeant; Vanda; Alexza; Alkermes; Avanir; Janssen; Lundbeck; Noven; Otsuka; Shire; NYSPRI; RFMH; Sunovian; Shire Human Genetic Therapies; Takeda Pharmaceuticals FX Dr Goff is a consultant for, has received honoraria from, or has conducted clinical research supported within the past 3 years by the following: Schering Plough, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceuticals, Pfizer Inc, Solvay, Otsuka Pharmaceuticals Takeda Pharmaceuticals, Biovail Pharmaceuticals, Abbott Pharmaceuticals, Endo Pharmaceuticals, Genetech, Hoffman-La Roche Inc, Dainippon Sumitomo Consulting, Panlab, and Novartis. Over the past 3 years Dr McEvoy has received research funding from Duke University. Dr Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported within the past 3 years by the following: AstraZeneca, Azur, Eli Lilly, Forest, GlaxoSmithKline, Jazz, Merck, Pfizer Inc, Sunovion, Valeant, Vanda, Alexza, Alkermes, Avanir, Bristol-Myers Squibb, Janssen, Lundbeck, Merck, Novartis, Noven, Otsuka, and Shire. During the past 3 years, Dr Bustillo received remuneration for consultation to Novartis. During the past 3 years, Dr Gill received research funding and reimbursement for expenses from NYSPRI and RFMH. During the past 3 years, Dr Buckley consulted to or received research funding from Pfizer Inc and Sunovian. During the past 3 years, Dr Manschreck received research funding from Pfizer Inc. During the past 3 years, Dr Achtyes received reimbursement for travel expenses from Eli Lilly and research funding from Janssen and Otsuka. Over the past 3 years Dr Macklin received research funding from Pfizer Inc and serves on the Boards of Lantheus Medical Imaging and Shire Human Genetic Therapies. Dr Mech has no conflicts of interest to declare. NR 22 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 EI 1533-712X J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD AUG PY 2013 VL 33 IS 4 BP 485 EP 490 DI 10.1097/JCP.0b013e3182977308 PG 6 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 298SQ UT WOS:000330345100006 PM 23775057 ER PT J AU Januzzi, JL AF Januzzi, James L., Jr. TI Natriuretic Peptides as Biomarkers in Heart Failure SO JOURNAL OF INVESTIGATIVE MEDICINE LA English DT Article DE natriuretic peptides; biology; diagnosis; prognosis; therapy ID EMERGENCY-DEPARTMENT; GUIDED THERAPY; ACUTE DYSPNEA; HUMAN PLASMA; A-TYPE; BRAIN; BNP; MORTALITY; MANAGEMENT; ATRIAL AB Following the initial discovery of a natriuretic and diuretic peptide factor present in atrial myocardial tissue homogenates, subsequent elucidation of the natriuretic peptide (NP) family has led to substantial advances in the understanding of the autocrine, paracrine, and endocrine regulation of the cardiovascular system. Furthermore, with the development of assays for the measurement of the NPs, these important biomarkers have gone from being regarded as biological mediators of the cardiovascular system to now represent important clinical tools for the diagnostic and prognostic evaluation of patients with heart failure and may have potential as a therapeutic target in this setting as well. An historical perspective on the NPs from bench to bedside translation will be discussed. C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Januzzi, JL (reprint author), Massachusetts Gen Hosp, Div Cardiol, Yawkey 5984,55 Fruit St, Boston, MA 02114 USA. EM jjanuzzi@partners.org FU National Center for Research Resources [R13 RR023236]; Roman W. Desanctis Endowed Distinguished Clinical Scholar Fund; Roche Diagnostics; BG Medicine; Thermo Fisher; Critical Diagnostics; Siemens AG FX This symposium was supported in part by a grant from the National Center for Research Resources (R13 RR023236). Dr. Januzzi is supported in part by the Roman W. Desanctis Endowed Distinguished Clinical Scholar Fund. He also has received grant support from Roche Diagnostics, Siemens AG, BG Medicine, Thermo Fisher, and Critical Diagnostics. NR 56 TC 12 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1081-5589 EI 1708-8267 J9 J INVEST MED JI J. Invest. Med. PD AUG PY 2013 VL 61 IS 6 BP 950 EP 955 PG 6 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 299AH UT WOS:000330366100003 PM 23661103 ER PT J AU Kirkwood, CM Ciuchta, J Ikonomovic, MD Fish, KN Abrahamson, EE Murray, PS Klunk, WE Sweet, RA AF Kirkwood, Caitlin M. Ciuchta, Jennifer Ikonomovic, Milos D. Fish, Kenneth N. Abrahamson, Eric E. Murray, Patrick S. Klunk, William E. Sweet, Robert A. TI Dendritic Spine Density, Morphology, and Fibrillar Actin Content Surrounding Amyloid-beta Plaques in a Mouse Model of Amyloid-beta Deposition SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE Alzheimer disease; Amyloid-beta; Dendritic spine; Genetic mouse models; Phalloidin; X-34 ID LONG-TERM POTENTIATION; ALZHEIMERS-DISEASE; A-BETA; TRANSGENIC MICE; SYNAPSE LOSS; PRECURSOR-PROTEIN; OLIGOMERS; ABNORMALITIES; PRESENILIN-1; DEPRESSION AB Dendritic spines are the site of most excitatory synapses, the loss of which correlates with cognitive impairment in patients with Alzheimer disease. Substantial evidence indicates that amyloid-beta (A beta) peptide, either insoluble fibrillar A beta deposited into plaques or soluble nonfibrillar A beta species, can cause spine loss but the concurrent contributions of fibrillar A beta and nonfibrillar A beta to spine loss has not been previously assessed. We used multiple-label immunohistochemistry to measure spine density, size, and F-actin content surrounding plaques in the cerebral cortex in the PSAPP mouse model of A beta deposition. Our approach allowed us to measure fibrillar A beta plaque content and an index of nonfibrillar A beta species concurrently. We found that spine density was reduced within 6 Km of the plaque perimeter, remaining spines were more compact, and F-actin content per spine was increased. Measures of fibrillar A beta plaque content were associated with reduced spine density near plaques, whereas measures of nonfibrillar A beta species were associated with reduced spine density and size but not altered F-actin content. These findings suggest that strategies to preserve dendritic spines in AD patients may need to address both nonfibrillar and fibrillar forms of A beta and that nonfibrillar A beta may exert spine toxicity through pathways not mediated by depolymerization of F-actin. C1 [Kirkwood, Caitlin M.; Ciuchta, Jennifer; Ikonomovic, Milos D.; Fish, Kenneth N.; Murray, Patrick S.; Klunk, William E.; Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Psychiat, Translat Neurosci Program, Pittsburgh, PA USA. [Klunk, William E.; Sweet, Robert A.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA USA. [Ikonomovic, Milos D.; Murray, Patrick S.; Sweet, Robert A.] VA Pittsburgh Healthcare Syst, Educ & Clin Ctr, Pittsburgh, PA USA. RP Sweet, RA (reprint author), 3811 OHara St,BST W1645, Pittsburgh, PA 15213 USA. EM sweetra@upmc.edu OI Klunk, William/0000-0001-5512-0251 FU National Institutes of Health [AG027224, AG14449, AG044070] FX This work was supported by Grants AG027224, AG14449, and AG044070 from the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the Department of Veterans Affairs, or the United States Government. There are no actual or potential conflicts of interest. NR 49 TC 15 Z9 15 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3069 EI 1554-6578 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD AUG PY 2013 VL 72 IS 8 BP 791 EP 800 PG 10 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 299GI UT WOS:000330383600008 PM 23860033 ER PT J AU Le Moual, N Varraso, R Zock, JP Henneberger, P Speizer, FE Kauffmann, F Camargo, CA AF Le Moual, Nicole Varraso, Raphaelle Paul Zock, Jan Henneberger, Paul Speizer, Frank E. Kauffmann, Francine Camargo, Carlos A., Jr. TI Are Operating Room Nurses at Higher Risk of Severe Persistent Asthma? The Nurses' Health Study SO JOURNAL OF OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID IN-HOSPITAL WORKERS; OCCUPATIONAL EXPOSURES; GENERAL-POPULATION; CARE PROFESSIONALS; DISABILITY; COHORT; WOMEN; WORKFORCE; SYMPTOMS; OUTCOMES AB Objective: To assess the associations between operating room (OR) nursing, a category of health care workers at high risk of exposure to various inhaled agents, and asthma severity/control among women with asthma. Methods: The level of severity/control in nurses with prevalent doctor-diagnosed asthma in 1998/2000 was compared, using nominal logistic regression, in OR nursing (n = 69) and administrative nursing (n = 546) from the US Nurses' Health Study for whom detailed information on asthma and nursing employment status was available. Results: We observed a significant association between OR nursing, compared with administrative nursing, and severe persistent asthma (adjusted odds ratio, 2.48; 95% confidence interval, 1.06 to 5.77). Conclusions: Our findings suggest that nurses working in the OR are at a higher risk of severe persistent asthma. Further studies with detailed estimates of occupational exposures, especially to disinfectant/cleaning agents, are warranted. C1 [Le Moual, Nicole; Varraso, Raphaelle; Kauffmann, Francine] INSERM, Resp & Environm Epidemiol Team, Ctr Res Epidemiol & Populat Hlth, F-94807 Villejuif, France. [Le Moual, Nicole; Varraso, Raphaelle; Kauffmann, Francine] Univ Paris 11, Villejuif, France. [Paul Zock, Jan] Ctr Res Environm Epidemiol, Barcelona, Spain. [Paul Zock, Jan] Hosp del Mar, Res Inst, Barcelona, Spain. [Paul Zock, Jan] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Henneberger, Paul] NIOSH, Ctr Dis Control & Prevent, Morgantown, WV USA. [Speizer, Frank E.; Camargo, Carlos A., Jr.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Le Moual, N (reprint author), INSERM, U1018, Ctr Res Epidemiol & Populat Hlth, Resp & Environm Epidemiol Team, 16 Ave Paul Vaillant Couturier, F-94807 Villejuif, France. EM nicole.lemoual@inserm.fr RI Varraso, Raphaelle/R-8740-2016; LeMoual, Nicole/R-8976-2016 OI Varraso, Raphaelle/0000-0002-3338-7825; LeMoual, Nicole/0000-0002-2723-5569 FU National Institutes of Health (Bethesda, Maryland) [CA-87969, HL-63841, AI-52338] FX This study was funded by research grants CA-87969, HL-63841, and AI-52338 from the National Institutes of Health (Bethesda, Maryland). NR 32 TC 6 Z9 6 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-2752 EI 1536-5948 J9 J OCCUP ENVIRON MED JI J. Occup. Environ. Med. PD AUG PY 2013 VL 55 IS 8 BP 973 EP 977 DI 10.1097/JOM.0b013e318297325b PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 300EX UT WOS:000330448300019 PM 23887704 ER PT J AU Liu, WJ Zhou, DS Liu, F Weaver, MJ Vrahas, MS AF Liu, Wanjun Zhou, Dongsheng Liu, Fang Weaver, Michael J. Vrahas, Mark S. TI Mechanical complications of intertrochanteric hip fractures treated with trochanteric femoral nails SO JOURNAL OF TRAUMA AND ACUTE CARE SURGERY LA English DT Article DE Intertrochanteric hip fracture; trochanteric fixation nail; fracture fixation; cephalomedullary nail; complications ID GAMMA-NAIL; INTRAMEDULLARY NAIL; FIXATION NAIL; SCREW; FAILURE; PLATE; PFN AB BACKGROUND: The Trochanteric Fixation Nail System (TFN) was designed with a helical blade to improve resistance to cutout. We evaluated the incidence, modes, and predictors of failure for intertrochanteric hip fractures treated with this device. METHODS: A retrospective review of 341 intertrochanteric hip fractures treated with the TFN was conducted. Fractures were classified from the injury films using the Arbeitsgemeinschaft fur Osteosynthesefragen/Orthopedic Trauma Association (AO/OTA) classification, and quality of reduction and hardware placement was evaluated on the initial postoperative films. RESULTS: Two hundred twenty-three patients met inclusion criteria. The overall rate of mechanical complications was 20.5%. Twenty-one patients (9.4%) had excessive lateral migration of the helical blade (>= 10 mm). Fifteen patients (6.7%) had blade migration in the head, including 7 patients (3.1%) with typical cutout and 8 patients (3.6%) with medial perforation without loss of reduction. Three patients (1.3%) sustained a femoral shaft fracture at the tip of the nail. The quality of calcar reduction was significantly predictive of all modes of failure (p < 0.05), except femoral shaft fracture at the nail tip. CONCLUSION: The most common mechanical complication was lateral migration of the helical blade; however, this rarely led to a clinical problem. Medial migration of the blade in the head without loss of reduction was the second most frequent complication. We have identified a new complication associated with the TFN, that is, medial perforation without loss of reduction. Blade migration in the head was less frequent when blades were placed inferiorly with a tip-apex distance of at least 15 mm. (Copyright (C) 2013 by Lippincott Williams & Wilkins) C1 [Liu, Wanjun] Shanghai Sixth Peoples Hosp, Dept Orthopaed, Shanghai, Peoples R China. [Zhou, Dongsheng] Shandong Univ, Affiliated Shandong Prov Hosp, Dept Orthopaed, Jinan 250100, Peoples R China. [Liu, Fang] Massachusetts Gen Hosp, Dept Orthopaed Srug, Bioengn Lab, Boston, MA 02114 USA. [Weaver, Michael J.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Vrahas, MS (reprint author), Massachusetts Gen Hosp, 55 Fruit St,YAW3C, Boston, MA 02114 USA. EM mvrahas@partners.org NR 27 TC 8 Z9 11 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 2163-0755 EI 2163-0763 J9 J TRAUMA ACUTE CARE JI J. Trauma Acute Care Surg. PD AUG PY 2013 VL 75 IS 2 BP 304 EP 310 DI 10.1097/TA.0b013e31829a2c43 PG 7 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 300FL UT WOS:000330449700019 PM 23887564 ER PT J AU Pulliam, S AF Pulliam, Samantha TI The trouble with trabeculation SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Editorial Material ID BLADDER OUTLET OBSTRUCTION; PROSTATIC HYPERTROPHY; CYSTOSCOPIC-FINDINGS; SYMPTOMS C1 Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. RP Pulliam, S (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD AUG PY 2013 VL 20 IS 8 BP 800 EP 801 DI 10.1097/gme.0b013e31829ab42b PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 300KN UT WOS:000330462900002 PM 23860359 ER PT J AU Jessup, JA Wang, H MacNamara, LM Presley, TD Kim-Shapiro, DB Zhang, LL Chen, AF Groban, L AF Jessup, Jewell A. Wang, Hao MacNamara, Lindsay M. Presley, Tennille D. Kim-Shapiro, Daniel B. Zhang, Lili Chen, Alex F. Groban, Leanne TI Estrogen therapy, independent of timing, improves cardiac structure and function in oophorectomized mRen2.Lewis rats SO MENOPAUSE-THE JOURNAL OF THE NORTH AMERICAN MENOPAUSE SOCIETY LA English DT Article DE Cardiac biopterins; Diastolic dysfunction; Estrogen timing; Left ventricular remodeling; Menopause; Nitrite ID VENTRICULAR DIASTOLIC DYSFUNCTION; HYPERTENSIVE POSTMENOPAUSAL WOMEN; NITRIC-OXIDE SYNTHASE; HEART-FAILURE; CARDIOVASCULAR-DISEASE; EJECTION FRACTION; SYSTOLIC FUNCTION; HORMONE-THERAPY; 17-BETA-ESTRADIOL ANTAGONIZES; CARDIOMYOCYTE HYPERTROPHY AB Objective: mRen2.Lewis rats exhibit exacerbated increases in blood pressure, left ventricular (LV) remodeling, and diastolic impairment after the loss of estrogens. In this same model, depletion of estrogens has marked effects on the cardiac biopterin profile concomitant with suppressed nitric oxide release. With respect to the establishment of overt systolic hypertension after oophorectomy (OVX), we assessed the effects of timing long-term 17 beta-estradiol (E-2) therapy on myocardial function, myocardial structure, and the cardiac nitric oxide system. Methods: OVX (n = 24) or sham operation (Sham; n = 13) was performed in 4-week-old female mRen2.Lewis rats. After randomization, OVX rats received E-2 immediately (OVX + E-2-early; n = 7), E-2 at 11 weeks of age (OVX + E-2-late; n = 8), or no E-2 at all (OVX; n = 9). Results: E-2-early was associated with lower body weight, less hypertension-related cardiac remodeling, and decreased LV filling pressure compared with OVX rats without E-2 supplementation. E-2-late similarly attenuated the adverse effects of ovarian hormone loss on tissue Doppler-derived LV filling pressures and perivascular fibrosis, and significantly improved myocardial relaxation or mitral annular velocity (e'). Early and late exposures to E-2 decreased dihydrobiopterin, but only E-2-late yielded significant increases in cardiac nitrite concentrations. Conclusions: Although there are some similarities between E-2-early and E-2-late treatments in relation to preservation of diastolic function and cardiac structure after OVX, the lusitropic potential of E-2 is most consistent with late supplementation. The cardioprotective effects of E-2-late are independent of blood pressure and may have occurred through regulation of cardiac biopterins and nitric oxide production. C1 [Jessup, Jewell A.; Groban, Leanne] Wake Forest Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA. [Wang, Hao; MacNamara, Lindsay M.; Groban, Leanne] Wake Forest Sch Med, Dept Anesthesiol, Winston Salem, NC 27157 USA. [Presley, Tennille D.] Winston Salem State Univ, Dept Chem, Winston Salem, NC USA. [Presley, Tennille D.; Kim-Shapiro, Daniel B.; Groban, Leanne] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. [Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [Zhang, Lili; Chen, Alex F.] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. [Chen, Alex F.] Vet Affairs Pittsburgh Healthcare Syst, Vasc Surg Res, Pittsburgh, PA USA. [Groban, Leanne] Wake Forest Sch Med, Hypertens & Vasc Res Ctr, Winston Salem, NC 27157 USA. RP Groban, L (reprint author), Wake Forest Sch Med, Dept Anesthesiol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM lgroban@wakehealth.edu FU National Institutes of Health [R01-AG033727, HL058091, R01 GM077352]; American Heart Association [0855601GH] FX This work was supported, in part, by grants from the National Institutes of Health (R01-AG033727 to L. G., HL058091 to D.B.K.-S., and R01 GM077352 to A. F. C.) and the American Heart Association Grant-in-Aid (0855601GH to A.F.C.). NR 61 TC 10 Z9 10 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1072-3714 EI 1530-0374 J9 MENOPAUSE JI Menopause-J. N. Am. Menopause Soc. PD AUG PY 2013 VL 20 IS 8 BP 860 EP 868 DI 10.1097/gme.0b013e318280589a PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 300KN UT WOS:000330462900012 PM 23481117 ER PT J AU Joseph, J Loscalzo, J AF Joseph, Jacob Loscalzo, Joseph TI Methoxistasis: Integrating the Roles of Homocysteine and Folic Acid in Cardiovascular Pathobiology SO NUTRIENTS LA English DT Review DE methionine; homocysteine; folic acid; cardiovascular disease; heart failure; nutrition; pyridoxine; cobalamin; nutrition; redox; methylation ID RANDOMIZED CONTROLLED-TRIAL; CONGESTIVE-HEART-FAILURE; GLYCINE N-METHYLTRANSFERASE; CYSTATHIONINE BETA-SYNTHASE; ACUTE MYOCARDIAL-INFARCTION; LEFT-VENTRICULAR FUNCTION; GENOMIC DNA METHYLATION; ACUTE ISCHEMIC-STROKE; STAGE RENAL-DISEASE; PLASMA HOMOCYSTEINE AB Over the last four decades, abnormalities in the methionine-homocysteine cycle and associated folate metabolism have garnered great interest due to the reported link between hyperhomocysteinemia and human pathology, especially atherothrombotic cardiovascular disease. However, clinical trials of B-vitamin supplementation including high doses of folic acid have not demonstrated any benefit in preventing or treating cardiovascular disease. In addition to the fact that these clinical trials may have been shorter in duration than appropriate for modulating chronic disease states, it is likely that reduction of the blood homocysteine level may be an oversimplified approach to a complex biologic perturbation. The methionine-homocysteine cycle and folate metabolism regulate redox and methylation reactions and are, in turn, regulated by redox and methylation status. Under normal conditions, a normal redox-methylation balance, or "methoxistasis", exists, coordinated by the methionine-homocysteine cycle. An abnormal homocysteine level seen in pathologic states may reflect a disturbance of methoxistasis. We propose that future research should be targeted at estimating the deviation from methoxistasis and how best to restore it. This approach could lead to significant advances in preventing and treating cardiovascular diseases, including heart failure. C1 [Joseph, Jacob] VA Boston Healthcare Syst, Dept Med, Boston, MA 02132 USA. [Joseph, Jacob; Loscalzo, Joseph] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Joseph, J (reprint author), VA Boston Healthcare Syst, Dept Med, Boston, MA 02132 USA. EM jacob.joseph@va.gov; jloscalzo@partners.org FU National Institutes of Health [HL89734, HL 61795, HL 048743, HL 107192, HL 108630] FX This work presented in this article was supported by the National Institutes of Health grant number HL89734 (J.J.), and National Institutes of Health grant numbers HL 61795, HL 048743, HL 107192, and HL 108630. NR 105 TC 18 Z9 21 U1 0 U2 10 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 2072-6643 J9 NUTRIENTS JI Nutrients PD AUG PY 2013 VL 5 IS 8 BP 3235 EP 3256 DI 10.3390/nu5083235 PG 22 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 301GW UT WOS:000330521800021 PM 23955381 ER PT J AU Massof, RW Stelmack, JA AF Massof, Robert W. Stelmack, Joan A. TI Interpretation of Low-Vision Rehabilitation Outcome Measures SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE low-vision rehabilitation; patient-reported outcome measure; visual function questionnaire; differential item functioning; Rasch analysis; item response theory ID QUALITY-OF-LIFE; RATING-SCALE QUESTIONNAIRES; VISUAL FUNCTIONING QUESTIONNAIRE; RANDOMIZED CONTROLLED-TRIAL; MACULAR DEGENERATION; SYSTEMS-MODEL; SERVICE; RASCH; EFFICACY; IMPACT AB Purpose. This article presents a theoretical interpretation of patient-reported outcomes of low-vision rehabilitation (LVR) using rating scale questionnaires and uses previously published results of LVR outcome studies to illustrate theoretical points and validate assumptions. Theory. Patients' judgments of the difficulty they have performing tasks are interpreted as magnitude estimates of their functional reserve for each task, which is the difference between their visual ability and the visual ability demanded by the task. We assume that improvements in functional reserve can occur by increasing the patient's visual ability with medical, surgical, or refractive interventions or decreasing the visual ability demanded by the item with activity-specific vision assistive equipment, adaptations, and environmental modifications. Activity-specific interventions cause differential item functioning (intervention-related DIF). Intervention-related DIF makes the measured size of the treatment effect dependent on the item content and the mix of responsive and unresponsive items to intervention. Conclusions. Because intervention-related DIF depends on the choice of items, the outcome measure selected should be appropriate to the aims of the intervention and the impairment level of the sample to demonstrate the full effects of an intervention. Items that are given extreme positive ratings at preintervention baseline (e. g., "not difficult'') have no room for improvement. These items must also be filtered out because they will dilute the measured effect of the activity-specific interventions of LVR. C1 [Massof, Robert W.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Lions Vis Res & Rehabil Ctr, Baltimore, MD 21205 USA. [Stelmack, Joan A.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Blind Rehabil Ctr, Hines, IL 60141 USA. [Stelmack, Joan A.] Univ Illinois, Sch Med, UIC Dept Ophthalmol & Visual Sci, Illinois Eye & Ear Infirm, Chicago, IL USA. [Stelmack, Joan A.] Illinois Coll Optometry, Chicago, IL USA. RP Massof, RW (reprint author), Wilmer B43 Johns Hopkins Hosp, 600 N Wolfe St, Baltimore, MD 21287 USA. EM bmassof@jhmi.edu FU National Eye Institute [EY022322]; Department of Veterans Affairs Rehabilitation Research and Development Service [C3457] FX This study was supported by grants from the National Eye Institute (EY022322) and the Department of Veterans Affairs Rehabilitation Research and Development Service (C3457). NR 37 TC 8 Z9 8 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 EI 1538-9235 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD AUG PY 2013 VL 90 IS 8 BP 788 EP 798 PG 11 WC Ophthalmology SC Ophthalmology GA 298SP UT WOS:000330345000010 PM 23873035 ER PT J AU Jeon, S Wang, M Tan, LS Cooper, T Hamblin, MR Chiang, LY AF Jeon, Seaho Wang, Min Tan, Loon-Seng Cooper, Thomas Hamblin, Michael R. Chiang, Long Y. TI Synthesis of Photoresponsive Dual NIR Two-Photon Absorptive [60]Fullerene Triads and Tetrads SO MOLECULES LA English DT Article DE C-60-(antenna)(x) nanostructures; ultrafast intramolecular energy-transfer; NIR two-photon absorption; 2 gamma-photodynamic therapeutic agent; photosensitizer ID C-60-DIPHENYLAMINOFLUORENE DYAD; FULLERENE DERIVATIVES; ORGANIC MATERIALS; ENERGY-TRANSFER; DIPHENYLAMINOFLUORENE; C-60; ENHANCEMENT; MECHANISM AB Broadband nonlinear optical (NLO) organic nanostructures exhibiting both ultrafast photoresponse and a large cross-section of two-photon absorption throughout a wide NIR spectrum may make them suitable for use as nonlinear biophotonic materials. We report here the synthesis and characterization of two C-60-(antenna)(x) analogous compounds as branched triad C-60(>DPAF-C-18)(>CPAF-C-2M) and tetrad C-60(>DPAF-C-18)(>CPAF-C-2M)(2) nanostructures. These compounds showed approximately equal extinction coefficients of optical absorption over 400-550 nm that corresponds to near-IR two-photon based excitation wavelengths at 780-1,100 nm. Accordingly, they may be utilized as potential precursor candidates to the active-core structures of photosensitizing nanodrugs for 2 gamma-PDT in the biological optical window of 800-1,050 nm. C1 [Jeon, Seaho; Wang, Min; Chiang, Long Y.] Univ Massachusetts, Dept Chem, Inst Nanosci & Engn Technol, Lowell, MA 01854 USA. [Tan, Loon-Seng; Cooper, Thomas] US Air Force, AFRL RXAS, Funct Mat Div, Res Lab, Wright Patterson AFB, OH 45433 USA. [Hamblin, Michael R.] Harvard Univ, Sch Med, Dept Dermatol, Wellman Ctr Photomed,Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hamblin, Michael R.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Chiang, LY (reprint author), Univ Massachusetts, Dept Chem, Inst Nanosci & Engn Technol, Lowell, MA 01854 USA. EM Long_Chiang@uml.edu RI Tan, Loon-Seng/F-6985-2012; OI Tan, Loon-Seng/0000-0002-2134-9290; Hamblin, Michael/0000-0001-6431-4605 FU Air Force Office of Scientific Research (AFOSR) [FA9550-09-1-0380, FA9550-09-1-0183]; National Institute of Health (NIH) [4R01CA137108, R01AI058075] FX The authors at UML thank the financial support of Air Force Office of Scientific Research (AFOSR) under the grant number FA9550-09-1-0380 and FA9550-09-1-0183 and National Institute of Health (NIH) under the grant number 4R01CA137108. MR Hamblin was supported by NIH R01AI058075. NR 29 TC 2 Z9 2 U1 0 U2 14 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1420-3049 J9 MOLECULES JI Molecules PD AUG PY 2013 VL 18 IS 8 BP 9603 EP 9622 DI 10.3390/molecules18089603 PG 20 WC Chemistry, Organic SC Chemistry GA 298DL UT WOS:000330304100057 PM 23941881 ER PT J AU Wintermark, M Fiehler, J Kudo, K Liebeskind, DS Luby, M Michel, P Nogueira, R Parsons, M Sasaki, M Wardlaw, J Wu, O Zhang, WW Zhu, GM Warach, S AF Wintermark, Max Fiehler, Jens Kudo, Kohsuke Liebeskind, David S. Luby, Marie Michel, Patrik Nogueira, Raul Parsons, Mark Sasaki, Makoto Wardlaw, Joanna Wu, Ona Zhang, Weiwei Zhu, Guangming Warach, Steven CA Stroke Imaging Res STIR VISTA-Imaging Investigators TI International Survey of Acute Stroke Imaging Capabilities We Need You! SO STROKE LA English DT Editorial Material DE acute stroke; computed tomography; imaging; magnetic resonance imaging; perfusion imaging; thrombolysis C1 [Wintermark, Max] Univ Virginia, Dept Radiol, Charlottesville, VA USA. [Wintermark, Max] CHU Vaudois, Dept Radiol, Lausanne, Switzerland. [Fiehler, Jens] Univ Med Ctr Hamburg Eppendorf, Hamburg, Germany. [Kudo, Kohsuke] Hokkaido Univ Hosp, Dept Diagnost Radiol, Sapporo, Hokkaido 060, Japan. [Liebeskind, David S.] UCLA Stroke Ctr, Los Angeles, CA USA. [Luby, Marie] NINDS, NIH, Bethesda, MD 20892 USA. [Michel, Patrik] CHU Vaudois, Lausanne, Switzerland. [Michel, Patrik] Univ Lausanne, Lausanne, Switzerland. [Nogueira, Raul] Emory Univ, Sch Med, Grady Mem Hosp, Marcus Stroke & Neurosci Ctr, Atlanta, GA USA. [Parsons, Mark] Univ Newcastle, John Hunter Hosp, Hunter Med Res Inst, Dept Neurol, Callaghan, NSW 2308, Australia. [Sasaki, Makoto] Iwate Med Univ, Inst Biomed Sci, Yahaba, Iwate, Japan. [Wardlaw, Joanna] Univ Edinburgh, Div Neuroimaging Sci, Ctr Clin Brain Sci, Brain Res Imaging Ctr, Edinburgh, Midlothian, Scotland. [Wu, Ona] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wu, Ona] Harvard Univ, Sch Med, Boston, MA USA. [Warach, Steven] UT Southwestern Med Ctr, Seton UT Southwestern Clin Res Inst Austin, Dept Neurol & Neurotherapeut, Austin, TX USA. [Zhang, Weiwei; Zhu, Guangming] Mil Gen Hosp Beijing PLA, Dept Neurol, Beijing, Peoples R China. RP Wintermark, M (reprint author), UVA Dept Radiol, Neuroradiol Div, Box 800170, Charlottesville, VA 22908 USA. EM Max.Wintermark@gmail.com RI Parsons, Mark/G-3750-2014; Michel, Patrik/Q-2275-2016; OI Michel, Patrik/0000-0003-4954-7579; Wintermark, Max/0000-0002-6726-3951 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2013 VL 44 IS 8 BP 2091 EP 2091 DI 10.1161/STROKEAHA.113.001441 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 293OO UT WOS:000329982400015 ER PT J AU Moskowitz, MA Grotta, JC Koroshetz, WJ AF Moskowitz, Michael A. Grotta, James C. Koroshetz, Walter J. CA Stroke Progress Review Grp Natl Inst Neurological Disorders S TI The NINDS Stroke Progress Review Group Final Analysis and Recommendations SO STROKE LA English DT Article DE planning; priorities; recommendations C1 [Moskowitz, Michael A.] Massachusetts Gen Hosp, Ctr Neurosci, Boston, MA 02129 USA. [Grotta, James C.] Univ Texas Med Sch Houston, Dept Neurol, Houston, TX USA. [Koroshetz, Walter J.] NINDS, NIH, Bethesda, MD 20892 USA. RP Koroshetz, WJ (reprint author), NINDS, NIH, Bldg 31,Room 8A52,Ctr Dr MSC 2540, Bethesda, MD 20892 USA. EM koroshetzw@mail.nih.gov FU Haemonetics FX Dr Grotta receives grant support from Haemonetics and is a consultant for Lundbeck. The other authors have no conflicts to report. NR 1 TC 6 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2013 VL 44 IS 8 BP 2343 EP 2350 DI 10.1161/STROKEAHA.113.001192 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 293OO UT WOS:000329982400058 PM 23821230 ER PT J AU Hu, XM Li, PY Chen, J AF Hu, Xiaoming Li, Peiying Chen, Jun TI PRO: Regulatory T Cells Are Protective in Ischemic Stroke SO STROKE LA English DT Editorial Material DE regulatory T cells; stroke C1 [Hu, Xiaoming; Li, Peiying; Chen, Jun] Univ Pittsburgh, Sch Med, Dept Neurol, Ctr Cerebrovasc Dis Res, Pittsburgh, PA 15261 USA. [Hu, Xiaoming; Chen, Jun] Vet Affairs Pittsburgh Hlth Care Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Chen, J (reprint author), Univ Pittsburgh, Dept Neurol, Med Ctr, Pittsburgh, PA 15260 USA. EM chenj2@upmc.edu FU NINDS NIH HHS [NS45048, NS43802, NS36736] NR 8 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2013 VL 44 IS 8 BP E85 EP E86 DI 10.1161/STROKEAHA.113.001267 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 293OO UT WOS:000329982400002 PM 23821231 ER PT J AU James, SK Storey, RF Pieper, KS Cannon, CP Becker, RC Steg, PG Wallentin, L Harrington, RA AF James, Stefan K. Storey, Robert F. Pieper, Karen S. Cannon, Christopher P. Becker, Richard C. Steg, Philippe Gabriel Wallentin, Lars Harrington, Robert A. CA PLATO Study Grp TI Response to Letter Regarding Article, "Ticagrelor in Patients With Acute Coronary Syndromes and Stroke: Interpretation of Subgroups in Clinical Trials" SO STROKE LA English DT Letter ID CLOPIDOGREL C1 [James, Stefan K.; Wallentin, Lars] Uppsala Univ, Dept Med Sci, Uppsala Clin Res Ctr, Uppsala, Sweden. [Storey, Robert F.] Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. [Pieper, Karen S.; Becker, Richard C.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC USA. [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Steg, Philippe Gabriel] AP HP, INSERM, U698, Paris, France. [Steg, Philippe Gabriel] Univ Paris 07, Paris, France. [Harrington, Robert A.] Stanford Univ, Dept Med, Stanford, CA 94305 USA. RP James, SK (reprint author), Uppsala Univ, Dept Med Sci, Uppsala Clin Res Ctr, Uppsala, Sweden. NR 3 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD AUG PY 2013 VL 44 IS 8 BP E95 EP E96 DI 10.1161/STROKEAHA.113.002069 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 293OO UT WOS:000329982400009 PM 23800556 ER PT J AU Austad, KE Avorn, J Franklin, JM Kowal, MK Campbell, EG Kesselheim, AS AF Austad, Kirsten E. Avorn, Jerry Franklin, Jessica M. Kowal, Mary K. Campbell, Eric G. Kesselheim, Aaron S. TI Changing Interactions Between Physician Trainees and the Pharmaceutical Industry: A National Survey (vol 28, pg 1064, 2013) SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Correction C1 [Austad, Kirsten E.; Avorn, Jerry; Franklin, Jessica M.; Kowal, Mary K.; Kesselheim, Aaron S.] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, Boston, MA 02120 USA. [Austad, Kirsten E.; Avorn, Jerry; Franklin, Jessica M.; Kowal, Mary K.; Campbell, Eric G.; Kesselheim, Aaron S.] Harvard Univ, Sch Med, Boston, MA 02120 USA. [Austad, Kirsten E.; Kesselheim, Aaron S.] Harvard Univ, Edmond J Safra Ctr Eth, Cambridge, MA 02138 USA. [Campbell, Eric G.] Massachusetts Gen Hosp, Mongan Inst Hlth Policy, Boston, MA 02114 USA. RP Austad, KE (reprint author), Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 1620 Tremont St,Suite 3030, Boston, MA 02120 USA. NR 1 TC 1 Z9 1 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 EI 1525-1497 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2013 VL 28 IS 8 BP 1115 EP 1116 DI 10.1007/s11606-013-2524-Z PG 2 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 184DZ UT WOS:000321869000023 ER PT J AU Takeda, S Hashimoto, T Roe, AD Hori, Y Spires-Jones, TL Hyman, BT AF Takeda, Shuko Hashimoto, Tadafumi Roe, Allyson D. Hori, Yukiko Spires-Jones, Tara L. Hyman, Bradley T. TI Brain interstitial oligomeric amyloid beta increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease SO FASEB JOURNAL LA English DT Article DE in vivo microdialysis; apolipoprotein E ID A-BETA; APOLIPOPROTEIN-E; IN-VIVO; SYNAPTIC PLASTICITY; SECRETED OLIGOMERS; PRECURSOR PROTEIN; DEPOSITION; MEMORY; METABOLISM; PLASMA AB There is a growing body of evidence that soluble oligomeric forms of amyloid (A) play a critical role in Alzheimer's disease (AD). Despite the importance of soluble A oligomers as a therapeutic target for AD, the dynamic metabolism of these A species in vivo has not been elucidated because of the difficulty in monitoring brain A oligomers in living animals. Here, using a unique large pore-sized membrane microdialysis, we characterized soluble A oligomers in brain interstitial fluid (ISF) of awake, freely moving APP/PS1 transgenic and control WT mice. We could detect high-molecular-weight (HMW) and low-molecular-weight (LMW) A oligomers in the brain ISF of living animals, which increased dramatically in an age-dependent manner (5- to 8-fold increase, 4 vs. 17-18 mo). Notably, HMW A decreased more slowly than other forms of A after acute -secretase inhibition [% decrease from the baseline (HMW vs. LMW) was 36.9 vs. 74.1% (A(40), P<0.05) and 25.4 vs. 88.0% (A(42), P<0.01)], suggesting that HMW A oligomers clear more slowly than other forms from the brain. These data reveal the dynamic metabolism of neurotoxic A oligomers in AD brain and could provide new insights into A-targeted therapies for AD.Takeda, S., Hashimoto, T., Roe, A. D., Hori, Y., Spires-Jones, T. L., and Hyman, B. T. Brain interstitial oligomeric amyloid increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease. C1 [Takeda, Shuko; Hashimoto, Tadafumi; Roe, Allyson D.; Hori, Yukiko; Spires-Jones, Tara L.; Hyman, Bradley T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Alzheimers Dis Res Lab,Dept Neurol,MassGen Inst N, Charlestown, MA 02129 USA. RP Hyman, BT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Alzheimers Dis Res Lab,Dept Neurol,MassGen Inst N, Bldg 114,16th St, Charlestown, MA 02129 USA. EM bhyman@partners.org FU U.S. National Institutes of Health [P50AG05134]; Japan Society for the Promotion of Science (JSPS) FX This research is supported by U.S. National Institutes of Health grant P50AG05134 (B. T. H.). S. T. is supported by a fellowship from the Japan Society for the Promotion of Science (JSPS). The authors also thank Dr. Alberto Serrano-Pozo for valuable discussions. The authors declare no conflicts of interest. NR 32 TC 21 Z9 23 U1 3 U2 9 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2013 VL 27 IS 8 BP 3239 EP 3248 DI 10.1096/fj.13-229666 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 292BT UT WOS:000329877600029 PM 23640054 ER PT J AU Bagchi, M Kim, LA Boucher, J Walshe, TE Kahn, CR D'Amore, PA AF Bagchi, Mandrita Kim, Leo A. Boucher, Jeremie Walshe, Tony E. Kahn, C. Ronald D'Amore, Patricia A. TI Vascular endothelial growth factor is important for brown adipose tissue development and maintenance SO FASEB JOURNAL LA English DT Article DE sFlt1; apoptosis; mitochondria; proliferation ID MESSENGER-RNA EXPRESSION; VEGF-A; ADIPOCYTE DIFFERENTIATION; INSULIN-RESISTANCE; COLD-ACCLIMATION; ANGIOGENESIS; ADULT; APOPTOSIS; CELLS; GENE AB Vascular endothelial growth factor (VEGF) is critical for angiogenesis, but also has pleiotropic effects on several nonvascular cells. Our aim was to investigate the role of VEGF in brown adipose tissue (BAT). We show that VEGF expression increases 2.5-fold during differentiation of cultured murine brown adipocytes and that VEGF receptor-2 is phosphorylated, indicating VEGF signaling. VEGF increased proliferation in brown preadipocytes in vitro by 70%, and blockade of VEGF signaling using anti-VEGFR2 antibody DC101 increased brown adipocyte apoptosis, as determined by cell number and activation of caspase 3. Systemic VEGF neutralization in mice, accomplished by adenoviral expression of soluble Flt1, resulted in 7-fold increase in brown adipocyte apoptosis, mitochondrial degeneration, and increased mitophagy compared to control mice expressing a null adenovirus. Absence of the heparan sulfate-binding VEGF isoforms, VEGF164 and VEGF188, resulted in abnormal BAT development in mice at E15.5, with fewer brown adipocytes and lower mitochondrial protein compared to wild-type littermates. These results suggest a role for VEGF in brown adipocytes and preadipocytes to promote survival, proliferation, and normal mitochondria and development.Bagchi, M., Kim, L A., Boucher, J., Walshe, T. E., Kahn, C. R., D'Amore, P. A. Vascular endothelial growth factor is important for brown adipose tissue development and maintenance. C1 [Bagchi, Mandrita; D'Amore, Patricia A.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Pathol, Boston, MA 02115 USA. [Kim, Leo A.; D'Amore, Patricia A.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Ophthalmol, Boston, MA 02115 USA. [Boucher, Jeremie; Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 USA. [Bagchi, Mandrita; Kim, Leo A.; Walshe, Tony E.; D'Amore, Patricia A.] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. RP D'Amore, PA (reprint author), Massachusetts Eye & Ear, Schepens Eye Res Inst, 20 Staniford St, Boston, MA 02114 USA. EM patricia_damore@meei.harvard.edu FU U.S. National Institutes of Health [EY15435, K12-EY16335] FX This work was supported by U.S. National Institutes of Health grants EY15435 (to P. A. D.) and K12-EY16335 (to L. K.). The authors acknowledge Dhanesh Amarnani for his technical assistance in the sFlt1 experiments. NR 61 TC 18 Z9 18 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2013 VL 27 IS 8 BP 3257 EP 3271 DI 10.1096/fj.12-221812 PG 15 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 292BT UT WOS:000329877600031 PM 23682123 ER PT J AU Zhu, M Van Dyke, TE Gyurko, R AF Zhu, Min Van Dyke, Thomas E. Gyurko, Robert TI Resolvin E1 regulates osteoclast fusion via DC-STAMP and NFATc1 SO FASEB JOURNAL LA English DT Article DE osteoimmunology; inflammation resolution; lipid mediator ID BONE-RESORPTION; LIPID MEDIATORS; CELL-FUSION; IN-VIVO; INFLAMMATION; RESOLUTION; MECHANISMS; RECEPTOR; DIFFERENTIATION; ACTIVATION AB Interactions between the immune and skeletal systems in inflammatory bone diseases are well appreciated, but the underlying molecular mechanisms that coordinate the resolution phase of inflammation and bone turnover have not been unveiled. Here we investigated the direct actions of the proresolution mediator resolvin E1 (RvE1) on bone-marrow-cell-derived osteoclasts in an in vitro murine model of osteoclast maturation and inflammatory bone resorption. Investigation of the actions of RvE1 treatment on the specific stages of osteoclast maturation revealed that RvE1 targeted late stages of osteoclast maturation to decrease osteoclast formation by 32.8%. Time-lapse vital microscopy and migration assays confirmed that membrane fusion of osteoclast precursors was inhibited. The osteoclast fusion protein DC-STAMP was specifically targeted by RvE1 receptor binding and was down-regulated by 65.4%. RvE1 did not affect the induction of the essential osteoclast transcription factor nuclear factor of activated T cells c1 (NFATc1) or its nuclear translocation; however, NFATc1 binding to the DC-STAMP promoter was significantly inhibited by 60.9% with RvE1 treatment as shown in electrophoresis mobility shift assay. Our findings suggest that proresolution mediators act directly on osteoclasts, in addition to down-regulation of inflammation, providing a novel mechanism for modulating osteoclast signaling in osteolytic inflammatory disease.Zhu, M., Van Dyke, T. E., Gyurko, R. Resolvin E1 regulates osteoclast fusion via DC-STAMP and NFATc1. C1 [Zhu, Min; Gyurko, Robert] Boston Univ, Goldman Sch Dent Med, Dept Periodontol & Oral Biol, Boston, MA 02118 USA. [Van Dyke, Thomas E.] Forsyth Inst, Dept Periodontol, Cambridge, MA USA. RP Gyurko, R (reprint author), Boston Univ, 650 Albany St,Rm X-344A, Boston, MA 02118 USA. EM gyurko@bu.edu OI Gyurko, Robert/0000-0003-1457-6812 FU U.S. Public Health Service from the National Institutes of Dental and Craniofacial Research [DE19938] FX The authors thank Dr. B. S. Nikolajczyk and Dr. V. Trinkaus-Randall for technical support and discussion. RvE1 was kindly provided by Dr. C. N. Serhan, (Brigham and Women's Hospital, Boston, MA, USA). This work was supported by U.S. Public Health Service grant DE19938 from the National Institutes of Dental and Craniofacial Research. M.Z. designed and carried out experiments, analyzed data, and wrote the manuscript; T. E. V. D. was involved in experimental design and provided reagents, data analysis, and preparation of the manuscript; R. G was involved in experimental design, data analysis, and manuscript preparation. Conflicts of interest: T. E. V. D. is an inventor on patents (resolvins) assigned to Boston University and licensed to Resolvyx Pharmaceuticals. T. E. V. D. is a scientific founder of Resolvyx Pharmaceuticals and owns equity in the company. T.E.V.D.'s interests were reviewed and managed by Boston University and now the Forsyth Institute in accordance with their conflict of interest policies. NR 55 TC 10 Z9 11 U1 1 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD AUG PY 2013 VL 27 IS 8 BP 3344 EP 3353 DI 10.1096/fj.12-220228 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 292BT UT WOS:000329877600039 PM 23629863 ER PT J AU Liang, GY Zhang, Y AF Liang, Gaoyang Zhang, Yi TI Genetic and Epigenetic Variations in iPSCs: Potential Causes and Implications for Application SO CELL STEM CELL LA English DT Review ID PLURIPOTENT STEM-CELLS; X-CHROMOSOME INACTIVATION; HUMAN SOMATIC-CELLS; COPY NUMBER; DNA-DAMAGE; HOMOLOGOUS RECOMBINATION; GENOMIC INTEGRITY; CODING MUTATIONS; DIFFERENTIATION; EXPRESSION AB The ability to reprogram somatic cells to induced pluripotent stem cells (iPSCs) has revolutionized the field of regenerative medicine. However, recent studies on the genetic and epigenetic variations in iPSCs have raised concerns that these variations may compromise the utility of iPSCs. In this Perspective, we review the current understanding of genetic and epigenetic variations in iPSCs, trace their causes, discuss the implications of these variations for iPSC applications, and propose approaches to cope with these variations. C1 [Liang, Gaoyang; Zhang, Yi] Boston Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Liang, Gaoyang; Zhang, Yi] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Liang, Gaoyang; Zhang, Yi] Boston Childrens Hosp, Dept Pediat, Div Hematol Oncol, Boston, MA 02115 USA. [Zhang, Yi] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Zhang, Yi] Harvard Stem Cell Inst, Boston, MA 02115 USA. RP Zhang, Y (reprint author), Boston Childrens Hosp, Howard Hughes Med Inst, 300 Longwood Ave, Boston, MA 02115 USA. EM yzhang@genetics.med.harvard.edu RI Liang, Gaoyang/L-2087-2013 OI Liang, Gaoyang/0000-0002-2157-974X FU Howard Hughes Medical Institute; NIDDK NIH HHS [U01 DK089565, U01DK089565] NR 85 TC 85 Z9 89 U1 5 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 EI 1875-9777 J9 CELL STEM CELL JI Cell Stem Cell PD AUG 1 PY 2013 VL 13 IS 2 BP 149 EP 159 DI 10.1016/j.stem.2013.07.001 PG 11 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 287VO UT WOS:000329570600009 PM 23910082 ER PT J AU Walsh, CO Milliren, CE Feldman, HA Taveras, EM AF Walsh, Carolyn O. Milliren, Carly E. Feldman, Henry A. Taveras, Elsie M. TI Factors Affecting Subspecialty Referrals by Pediatric Primary Care Providers for Children With Obesity-Related Comorbidities SO CLINICAL PEDIATRICS LA English DT Article DE pediatric obesity; comorbidity; referral and consultation; health care surveys ID EXPERT COMMITTEE RECOMMENDATIONS; ADOLESCENT OVERWEIGHT; CARDIOVASCULAR RISK; GLAD-PC; DEPRESSION; MANAGEMENT; IDENTIFICATION; PREVENTION; PREVALENCE; GUIDELINES AB Objective. To determine referral patterns from pediatric primary care to subspecialists for overweight/obesity and related comorbidities. Methods. We used the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey to identify overweight/obesity and 5 related comorbidities in primary care visits between 2005 and 2009 by children 6 to 18 years. The primary outcome was whether the visit ended in referral. We used multivariable analysis to examine factors associated with referral. Results. We identified 34 225 database visits. A total of 17.1% were with overweight (body mass index = 85th to 94th percentile) or obese (body mass index 95th percentile) patients. A total of 7.1% of primary care visits with overweight/obese children ended in referral. Referral was more likely when obesity was the reason for visit (odds ratio = 2.83; 95% confidence interval = 1.61-4.97) but was not associated with presence of a comorbidity (odds ratio = 1.35; 95% confidence interval = 0.75-2.44). Conclusions. Most overweight or obese children are not referred, regardless of comorbidity status. One reason may be low levels of appropriate diagnosis. C1 [Walsh, Carolyn O.; Milliren, Carly E.; Feldman, Henry A.] Boston Childrens Hosp, Boston, MA USA. [Taveras, Elsie M.] Harvard Univ, Sch Med, Boston, MA 02214 USA. [Taveras, Elsie M.] Massachusetts Gen Hosp, Boston, MA 02214 USA. RP Taveras, EM (reprint author), Harvard Univ, Sch Med, Dept Pediat, Div Gen Pediat, 175 Cambridge St,5th Floor,CPZD 579B, Boston, MA 02214 USA. EM etaveras@partners.org FU Boston Combined Residency Program in Pediatrics Fred Lovejoy Research and Education Fund FX The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This project was funded by a grant from the Boston Combined Residency Program in Pediatrics Fred Lovejoy Research and Education Fund to Carolyn Walsh. NR 21 TC 3 Z9 3 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 EI 1938-2707 J9 CLIN PEDIATR JI Clin. Pediatr. PD AUG PY 2013 VL 52 IS 8 BP 777 EP 785 DI 10.1177/0009922813488647 PG 9 WC Pediatrics SC Pediatrics GA 287WR UT WOS:000329573500016 PM 23671268 ER PT J AU Han, SC Gallagher, MW Franz, MR Chen, MS Cabral, FM Marx, BP AF Han, Sohyun C. Gallagher, Matthew W. Franz, Molly R. Chen, May S. Cabral, Fabiana M. Marx, Brian P. TI Childhood Sexual Abuse, Alcohol Use, and PTSD Symptoms as Predictors of Adult Sexual Assault Among Lesbians and Gay Men SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE sexual minorities; posttraumatic stress disorder (PTSD); alcohol; sexual assault; childhood sexual abuse (CSA) ID POSTTRAUMATIC-STRESS-DISORDER; HETEROSEXUAL WOMEN; NATIONAL SAMPLE; REVICTIMIZATION; VICTIMIZATION; HEALTH; AGGRESSION; PREVALENCE; IMPACT; RAPE AB Prior research has indicated that childhood sexual abuse (CSA), alcohol use, and posttraumatic stress disorder (PTSD) symptoms are important risk factors for adult sexual assault (ASA). A notable limitation of this prior work, however, is that it has almost exclusively focused on heterosexual women. The present study sought to remedy this by examining the extent to which CSA, alcohol use, and PTSD symptoms related to ASA among lesbians (n = 122) and gay men (n = 117). Using structural equation modeling, we found that alcohol use was the best predictor of ASA among lesbians whereas CSA was the best predictor of ASA among gay men. These results suggest that certain risk factors may be differentially related to ASA among groups with different sexual orientations. Such findings deepen our current understanding of ASA and offer important directions for reducing the risk of ASA for lesbian and gay individuals. C1 [Han, Sohyun C.; Gallagher, Matthew W.; Franz, Molly R.; Chen, May S.; Cabral, Fabiana M.; Marx, Brian P.] VA Boston Healthcare Syst, VA Natl Ctr PTSD, Boston, MA 02130 USA. [Han, Sohyun C.; Gallagher, Matthew W.; Franz, Molly R.; Chen, May S.; Cabral, Fabiana M.; Marx, Brian P.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Marx, BP (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 116B-4,150 S Huntington Ave, Boston, MA 02130 USA. EM brian.marx@va.gov NR 37 TC 7 Z9 7 U1 3 U2 8 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 EI 1552-6518 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD AUG PY 2013 VL 28 IS 12 BP 2505 EP 2520 DI 10.1177/0886260513479030 PG 16 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA 287QS UT WOS:000329557900006 PM 23486851 ER PT J AU Alvarez, E Piccio, L Mikesell, RJ Klawiter, EC Parks, BJ Naismith, RT Cross, AH AF Alvarez, Enrique Piccio, Laura Mikesell, Robert J. Klawiter, Eric C. Parks, Becky J. Naismith, Robert T. Cross, Anne H. TI CXCL13 is a biomarker of inflammation in multiple sclerosis, neuromyelitis optica, and other neurological conditions SO MULTIPLE SCLEROSIS JOURNAL LA English DT Article DE Multiple sclerosis; neuromyelitis optica; CXCL13; neuroinflammation; neurofilament; myelin basic protein; biomarker ID RITUXIMAB; NMO AB CXCL13, a B-cell chemokine, has been proposed as a biomarker in a variety of conditions, some of which can mimic multiple sclerosis and can have very high levels. In this case-control study, cerebrospinal fluid (CSF) CXCL13 was elevated in multiple sclerosis, neuromyelitis optica and other inflammatory neurological controls compared with noninflammatory controls. Levels did not differentiate disease groups. For all subjects taken together, CSF CXCL13 correlated with CSF WBC, oligoclonal band numbers, CSF protein, EDSS, and neurofilament levels. In subgroup analyses, CSF CXCL13 correlated with CSF WBC in neuromyelitis optica and IgG index in multiple sclerosis. Additionally, serum CXCL13 was elevated in neuromyelitis optica. C1 [Alvarez, Enrique; Piccio, Laura; Mikesell, Robert J.; Klawiter, Eric C.; Parks, Becky J.; Naismith, Robert T.; Cross, Anne H.] Washington Univ, Dept Neurol, St Louis, MO 63110 USA. [Klawiter, Eric C.] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Alvarez, E (reprint author), Washington Univ, Dept Neurol, Neurol Campus Box 8111,660 S Euclid Ave, St Louis, MO 63110 USA. EM alvareze@neuro.wustl.edu RI Alvarez, Enrique/C-3743-2013 OI Alvarez, Enrique/0000-0001-5854-9643 FU Washington University Institute of Clinical and Translational Sciences from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) [UL1 TR000448, CO6 RR020092, K23NS052430-01A1]; Barnes-Jewish Hospital Foundation FX This research was supported by the Washington University Institute of Clinical and Translational Sciences from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH) (grant numbers UL1 TR000448, CO6 RR020092, and K23NS052430-01A1) and the Barnes-Jewish Hospital Foundation. NR 10 TC 24 Z9 24 U1 1 U2 5 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 EI 1477-0970 J9 MULT SCLER J JI Mult. Scler. J. PD AUG PY 2013 VL 19 IS 9 BP 1204 EP 1208 DI 10.1177/1352458512473362 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 287WT UT WOS:000329573700014 PM 23322500 ER PT J AU Hoffmann, U Grosse-Sundrup, M Eikermann-Haerter, K Zaremba, S Ayata, C Zhang, B Ma, D Isaacs, L Eikermann, M AF Hoffmann, Ulrike Grosse-Sundrup, Martina Eikermann-Haerter, Katharina Zaremba, Sebastina Ayata, Cenk Zhang, Ben Ma, Da Isaacs, Lyle Eikermann, Matthias TI A New Agent to Reverse the Effects of Benzylisoquinoline and Steroidal Neuromuscular-blocking Agents SO ANESTHESIOLOGY LA English DT Article ID PULMONARY-FUNCTION; MUSCLE-ACTIVITY; ION CHANNELS; BLOCKADE; SUGAMMADEX; NEOSTIGMINE; CHEMISTRY; RECOVERY; COMPLICATIONS; GENIOGLOSSUS AB Introduction: To evaluate whether calabadion 1, an acyclic member of the Cucurbit[n] uril family of molecular containers, reverses benzylisoquinoline and steroidal neuromuscular- blocking agent effects. Methods: A total of 60 rats were anesthetized, tracheotomized, and instrumented with IV and arterial catheters. Rocuronium (3.5 mg/kg) or cisatracurium (0.6 mg/kg) was administered and neuromuscular transmission quantified by acceleromyography. Calabadion 1 at 30, 60, and 90 mg/kg (for rocuronium) or 90, 120, and 150 mg/kg (for cisatracurium), or neostigmine/glycopyrrolate at 0.06/0.012 mg/ kg were administered at maximum twitch depression, and renal calabadion 1 elimination was determined by using a(1)H NMR assay. The authors also measured heart rate, arterial blood gas parameters, and arterial blood pressure. Results: After the administration of rocuronium, resumption of spontaneous breathing and recovery of train-of-four ratio to 0.9 were accelerated from 12.3 +/- 1.1 and 16.2 +/- 3.3 min with placebo to 4.6 +/- 1.8 min with neostigmine/glycopyrrolate to 15 +/- 8 and 84 +/- 33 s with calabadion 1 (90 mg/kg), respectively. After the administration of cisatracurium, recovery of breathing and train-of-four ratio of 0.9 were accelerated from 8.7 +/- 2.8 and 9.9 +/- 1.7 min with placebo to 2.8 +/- 0.8 and 7.6 +/- 2.1 min with neostigmine/glycopyrrolate to 47 +/- 13 and 87 +/- 16 s with calabadion 1 (150 mg/kg), respectively. Calabadion 1 did not affect heart rate, mean arterial blood pressure, pH, carbon dioxide pressure, and oxygen tension. More than 90% of the IV administered calabadion 1 appeared in the urine within 1 h. Conclusion: Calabadion 1 is a new drug for rapid and complete reversal of the effects of steroidal and benzylisoquinoline neuromuscular-blocking agents. C1 Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Eikermann, M (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Crit Care Div, 55 Fruit St, Boston, MA 02114 USA. EM meikermann@part-ners.org RI Isaacs, Lyle/B-4472-2009; Zhang, Ben/F-6580-2014 OI Isaacs, Lyle/0000-0002-4079-332X; FU National Science Foundation [CHE-1110911] FX Received from the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts. Submitted for publication November 23, 2012. Accepted for publication March 4, 2013. Support was provided solely from institutional and/or departmental sources. Support was received from the National Science Foundation (CHE-1110911). NR 46 TC 20 Z9 21 U1 2 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2013 VL 119 IS 2 BP 317 EP 325 DI 10.1097/ALN.0b013e3182910213 PG 9 WC Anesthesiology SC Anesthesiology GA 280WS UT WOS:000329062100011 PM 23549405 ER PT J AU Mirzakhani, H Williams, JN Mello, J Joseph, S Meyer, MJ Waak, K Schmidt, U Kelly, E Eikermann, M AF Mirzakhani, Hooman Williams, June-Noelle Mello, Jennifer Joseph, Sharma Meyer, Matthew J. Waak, Karen Schmidt, Ulrich Kelly, Emer Eikermann, Matthias TI Muscle Weakness Predicts Pharyngeal Dysfunction and Symptomatic Aspiration in Long-term Ventilated Patients SO ANESTHESIOLOGY LA English DT Article ID INTENSIVE-CARE-UNIT; FIBEROPTIC ENDOSCOPIC EVALUATION; CRITICALLY-ILL PATIENTS; PROLONGED ENDOTRACHEAL INTUBATION; CRITICAL ILLNESS POLYNEUROPATHY; HEALTHY OLDER-ADULTS; LENGTH-OF-STAY; MECHANICAL VENTILATION; HANDGRIP STRENGTH; INTEROBSERVER AGREEMENT AB Background: Prolonged mechanical ventilation is associated with muscle weakness, pharyngeal dysfunction, and symptomatic aspiration. The authors hypothesized that muscle strength measurements can be used to predict pharyngeal dysfunction (endoscopic evaluation-primary hypothesis), as well as symptomatic aspiration occurring during a 3-month follow-up period. Methods: Thirty long-term ventilated patients admitted in two intensive care units at Massachusetts General Hospital were included. The authors conducted a fiberoptic endoscopic evaluation of swallowing and measured muscle strength using medical research council score within 24 h of each fiberoptic endoscopic evaluation of swallowing. A medical research council score less than 48 was considered clinically meaningful muscle weakness. A retrospective chart review was conducted to identify symptomatic aspiration events. Results: Muscle weakness predicted pharyngeal dysfunction, defined as either valleculae and pyriform sinus residue scale of more than 1, or penetration aspiration scale of more than 1. Area under the curve of the receiver-operating curves for muscle strength (medical research council score) to predict pharyngeal, valleculae, and pyriform sinus residue scale of more than 1, penetration aspiration scale of more than 1, and symptomatic aspiration were 0.77 (95% CI, 0.63-0.97; P = 0.012), 0.79 (95% CI, 0.56-1; P = 0.02), and 0.74 (95% CI, 0.56-0.93; P = 0.02), respectively. Seventy percent of patients with muscle weakness showed symptomatic aspiration events. Muscle weakness was associated with an almost 10-fold increase in the symptomatic aspiration risk (odds ratio = 9.8; 95% CI, 1.6-60; P = 0.009). Conclusion: In critically ill patients, muscle weakness is an independent predictor of pharyngeal dysfunction and symptomatic aspiration. Manual muscle strength testing may help identify patients at risk of symptomatic aspiration. C1 [Mirzakhani, Hooman; Williams, June-Noelle; Mello, Jennifer; Joseph, Sharma; Meyer, Matthew J.; Waak, Karen; Schmidt, Ulrich; Kelly, Emer; Eikermann, Matthias] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Eikermann, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. EM meikermann@partners.org OI Mirzakhani, Hooman/0000-0002-2290-4436 NR 62 TC 18 Z9 19 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2013 VL 119 IS 2 BP 389 EP 397 DI 10.1097/ALN.0b013e31829373fe PG 9 WC Anesthesiology SC Anesthesiology GA 280WS UT WOS:000329062100018 PM 23584384 ER PT J AU Richtsfeld, M Yasuhara, S Fink, H Blobner, M Martyn, JAJ AF Richtsfeld, Martina Yasuhara, Shingo Fink, Heidrun Blobner, Manfred Martyn, J. A. Jeevendra TI Prolonged Administration of Pyridostigmine Impairs Neuromuscular Function with and without Downregulation of Acetylcholine Receptors SO ANESTHESIOLOGY LA English DT Article ID NERVE AGENT PRETREATMENT; GULF-WAR ILLNESSES; MULTISYMPTOM ILLNESS; REPEATED STRESS; MUSCLE-ACTIVITY; VETERANS; RAT; DISORDERS; EXPOSURE; BROMIDE AB Background: The acetylcholinesterase inhibitor, pyridostigmine, is prophylactically administered to mitigate the toxic effects of nerve gas poisoning. The authors tested the hypothesis that prolonged pyridostigmine administration can lead to neuromuscular dysfunction and even down-regulation of acetylcholine receptors. Methods: Pyridostigmine (5 or 25 mg.kg(-1).day-1) or saline was continuously administered via osmotic pumps to rats, and infused for either 14 or 28 days until the day of neuromuscular assessment (at day 14 or 28), or discontinued 24 h before neuromuscular assessment. Neurotransmission and muscle function were examined by single-twitch, train-of-four stimulation and 100-Hz tetanic stimulation. Sensitivity to atracurium and acetylcholine receptor number (quantitated by I-125-alpha-bungarotoxin) provided additional measures of neuromuscular integrity. Results: Specific tetanic tensions (Newton [N]/muscle weight [g]) were significantly (P < 0.05) decreased at 14 (10.3 N/g) and 28 (11.1 N/g) days of 25 mg.kg(-1).day-1 pyridostigmine compared with controls (13.1(-1)3.6 N/g). Decreased effective dose (0.81(-1).05 vs. 0.16-0.45 mg/kg; P < 0.05) and decreased plasma concentration (3.023.27 vs. 0.45(-1).37 mu g/ml; P < 0.05) of atracurium for 50% paralysis (controls vs. 25 mg.kg(-1).day-1 pyridostigmine, respectively), irrespective of discontinuation of pyridostigmine, confirmed the pyridostigmine-induced altered neuro-transmission. Pyridostigmine (25 mg.kg(-1).day-1) down-regulated acetylcholine receptors at 28 days. Conclusions: Prolonged administration of pyridostigmine (25 mg.kg(-1).day-1) leads to neuromuscular impairment, which can persist even when pyridostigmine is discontinued 24 h before assessment of neuromuscular function. Pyridostigmine has the potential to down-regulate acetylcholine receptors, but induces neuromuscular dysfunction even in the absence of receptor changes. C1 Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Tech Univ Munich, Klinikum Rechts Isar, Klin Anaesthesiol, D-80290 Munich, Germany. RP Richtsfeld, M (reprint author), Univ Minnesota, Dept Anesthesiol MMC 294, 420 Delaware St SE, Minneapolis, MN 55455 USA. EM richt298@umn.edu OI Lewald, Heidrun/0000-0002-5192-425X FU National Institutes of Health, Bethesda, Maryland [R01-GM05582-12, P50-GM21500-33-Project I]; Shriners Hospitals for Children Research Philanthropy, Tampa, Florida FX Received from the Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Shriners Hospital for Children, and Harvard Medical School, Boston, Massachusetts; and Klinik fur Anaesthesiologie der Technischen Universitat Munchen, Klinikum rechts der Isar, Munich, Germany. Submitted for publication August 16, 2011. Accepted for publication February 19, 2013. This work was supported by grants from the National Institutes of Health, Bethesda, Maryland (R01-GM05582-12, P50-GM21500-33-Project I) and from the Shriners Hospitals for Children Research Philanthropy, Tampa, Florida ( to Dr. J. A. J. Martyn). NR 51 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0003-3022 EI 1528-1175 J9 ANESTHESIOLOGY JI Anesthesiology PD AUG PY 2013 VL 119 IS 2 BP 412 EP 421 DI 10.1097/ALN.0b013e318291c02e PG 10 WC Anesthesiology SC Anesthesiology GA 280WS UT WOS:000329062100020 PM 23563362 ER PT J AU Wang, MH Fiocchi, C Ripke, S Zhu, XF Duerr, RH Achkar, JP AF Wang, Ming-Hsi Fiocchi, Claudio Ripke, Stephan Zhu, Xiaofeng Duerr, Richard H. Achkar, Jean-Paul TI A Novel Approach to Detect Cumulative Genetic Effects and Genetic Interactions in Crohn's Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE genetics; genetic interaction; cumulative genetic effect; Crohn's disease ID GENOME-WIDE ASSOCIATION; INFLAMMATORY-BOWEL-DISEASE; SUSCEPTIBILITY LOCI; LOGIC REGRESSION; GENOTYPE IMPUTATION; COMPLEX DISEASES; VARIANTS; RISK; PREDICTION; MUTATION AB Background:Genome-wide association studies have identified at least 71 Crohn's disease (CD) genetic risk loci, but the role of gene-gene interactions is unclear. The value of genetic variants in clinical practice is not defined because of limited explained heritability.Methods:We examined model predictability of combining the 71 CD risk alleles and genetic interactions in an ongoing inflammatory bowel disease genome-wide association study. The Wellcome Trust Case Control Consortium inflammatory bowel disease genome-wide association study was used as a replicate cohort. We used logic regression, an adaptive regression methodology, to search for high-order binary predictors (e.g., single-nucleotide polymorphism [SNP] interactions).Results:The combined 71 CD SNPs had good CD risk predictability (area under the curve of 0.75 and 0.73 in the 2 cohorts). Higher cumulative allele score predicted higher CD risk, but a relatively small difference in cumulative allele scores was observed between CD and controls (49 versus 47, P < 0.001). Through LR, we identified high-order genetic interactions and significantly improved the model predictability (area under the curve, from 0.75 to 0.77, P < 0.0001). A genetic interaction model, including NOD2, ATG16L1, IL10/IL19, C13orf31, and chr21q loci, was discovered and successfully replicated in the independent Wellcome Trust Case Control Consortium cohort. The explained heritability of the 71 CD SNPs alone was 24% and increased to 27% after adding the genetic interactions.Conclusions:A novel approach allowed the identification and replication of genetic interactions among NOD2, ATG16L1, IL10/IL19, C13orf31, and chr21q loci. CD risk can be predicted by a model of 71 CD loci and improved by adding genetic interactions. C1 [Wang, Ming-Hsi; Fiocchi, Claudio; Achkar, Jean-Paul] Cleveland Clin, Inst Digest Dis, Dept Gastroenterol & Hepatol, Cleveland, OH 44195 USA. [Wang, Ming-Hsi; Fiocchi, Claudio; Achkar, Jean-Paul] Cleveland Clin, Lerner Res Inst, Dept Pathobiol, Cleveland, OH 44195 USA. [Ripke, Stephan] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr, Pittsburgh, PA 15213 USA. [Zhu, Xiaofeng] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Duerr, Richard H.] Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. [Duerr, Richard H.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Achkar, JP (reprint author), Cleveland Clin, Inst Digest Dis, Dept Gastroenterol & Hepatol, Desk A31, Cleveland, OH 44195 USA. EM achkarj@ccf.org OI Duerr, Richard/0000-0001-6586-3905 FU Wellcome Trust [076113] FX The authors acknowledge Dr. M. Ilyas Kamboh from the University of Pittsburgh for the contribution of genotype data that was used in this study. The authors thank the patients and the controls for participating in this study. The authors acknowledge the Feinstein Institute for Medical Research of the North Shore-Long Island Jewish Health System for Illumina Genotyping BeadChip processing. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113. NR 41 TC 11 Z9 12 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD AUG PY 2013 VL 19 IS 9 BP 1799 EP 1808 DI 10.1097/MIB.0b013e31828706a0 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 284XH UT WOS:000329354900001 PM 23598818 ER PT J AU Ananthakrishnan, AN Cagan, A Gainer, VS Cai, TX Cheng, SC Savova, G Chen, P Szolovits, P Xia, ZQ De Jager, PL Shaw, SY Churchill, S Karlson, EW Kohane, I Plenge, RM Murphy, SN Liao, KP AF Ananthakrishnan, Ashwin N. Cagan, Andrew Gainer, Vivian S. Cai, Tianxi Cheng, Su-Chun Savova, Guergana Chen, Pei Szolovits, Peter Xia, Zongqi De Jager, Philip L. Shaw, Stanley Y. Churchill, Susanne Karlson, Elizabeth W. Kohane, Isaac Plenge, Robert M. Murphy, Shawn N. Liao, Katherine P. TI Normalization of Plasma 25-Hydroxy Vitamin D Is Associated with Reduced Risk of Surgery in Crohn's Disease SO INFLAMMATORY BOWEL DISEASES LA English DT Article DE Crohn's disease; ulcerative colitis; vitamin D; surgery; hospitalization ID INFLAMMATORY-BOWEL-DISEASE; ULCERATIVE-COLITIS; D DEFICIENCY; EPIDEMIOLOGY; PATHWAY; HEALTH; COHORT AB Background:Vitamin D may have an immunologic role in Crohn's disease (CD) and ulcerative colitis (UC). Retrospective studies suggested a weak association between vitamin D status and disease activity but have significant limitations.Methods:Using a multi-institution inflammatory bowel disease cohort, we identified all patients with CD and UC who had at least one measured plasma 25-hydroxy vitamin D (25(OH)D). Plasma 25(OH)D was considered sufficient at levels 30 ng/mL. Logistic regression models adjusting for potential confounders were used to identify impact of measured plasma 25(OH)D on subsequent risk of inflammatory bowel disease-related surgery or hospitalization. In a subset of patients where multiple measures of 25(OH)D were available, we examined impact of normalization of vitamin D status on study outcomes.Results:Our study included 3217 patients (55% CD; mean age, 49 yr). The median lowest plasma 25(OH)D was 26 ng/mL (interquartile range, 17-35 ng/mL). In CD, on multivariable analysis, plasma 25(OH)D <20 ng/mL was associated with an increased risk of surgery (odds ratio, 1.76; 95% confidence interval, 1.24-2.51) and inflammatory bowel disease-related hospitalization (odds ratio, 2.07; 95% confidence interval, 1.59-2.68) compared with those with 25(OH)D 30 ng/mL. Similar estimates were also seen for UC. Furthermore, patients with CD who had initial levels <30 ng/mL but subsequently normalized their 25(OH)D had a reduced likelihood of surgery (odds ratio, 0.56; 95% confidence interval, 0.32-0.98) compared with those who remained deficient.Conclusion:Low plasma 25(OH)D is associated with increased risk of surgery and hospitalizations in both CD and UC, and normalization of 25(OH)D status is associated with a reduction in the risk of CD-related surgery. C1 [Ananthakrishnan, Ashwin N.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.; Xia, Zongqi; De Jager, Philip L.; Shaw, Stanley Y.; Karlson, Elizabeth W.; Kohane, Isaac; Plenge, Robert M.; Murphy, Shawn N.; Liao, Katherine P.] Harvard Univ, Sch Med, Boston, MA USA. [Cagan, Andrew; Gainer, Vivian S.; Murphy, Shawn N.] Partners HealthCare, Res Comp, Charlestown, MA USA. [Cai, Tianxi; Cheng, Su-Chun] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Savova, Guergana; Chen, Pei; Kohane, Isaac] Childrens Hosp, Boston, MA 02115 USA. [Szolovits, Peter] MIT, Cambridge, MA 02139 USA. [Xia, Zongqi; De Jager, Philip L.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Shaw, Stanley Y.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Churchill, Susanne; Kohane, Isaac] Brigham & Womens Hosp, Natl Ctr Biomed Comp I2b2, Boston, MA 02115 USA. [Karlson, Elizabeth W.; Plenge, Robert M.; Liao, Katherine P.] Brigham & Womens Hosp, Div Rheumatol, Boston, MA 02115 USA. [Murphy, Shawn N.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org OI Szolovits, Peter/0000-0001-8411-6403 FU National Institutes of Health (NIH) [U54-LM008748]; US NIH [K23 DK097142, R01-AR056768, U01-GM092691, R01-AR059648]; NIH [K08 AR060257, K24 AR052403, P60 AR047782, R01 AR049880]; Katherine Swan Ginsburg Fund; Burroughs Wellcome Fund FX Supported by the National Institutes of Health (NIH, U54-LM008748). A. N. Ananthakrishnan is supported by funding from the US NIH (K23 DK097142). K. P. Liao is supported by the NIH (K08 AR060257) and the Katherine Swan Ginsburg Fund. R. M. Plenge is supported by grants from the US NIH (R01-AR056768, U01-GM092691, and R01-AR059648) and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund. E. W. Karlson is supported by grants from the NIH (K24 AR052403, P60 AR047782, and R01 AR049880). NR 35 TC 68 Z9 74 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD AUG PY 2013 VL 19 IS 9 BP 1921 EP 1927 DI 10.1097/MIB.0b013e3182902ad9 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 284XH UT WOS:000329354900018 PM 23751398 ER PT J AU Ananthakrishnan, AN Xavier, RJ AF Ananthakrishnan, Ashwin N. Xavier, Ramnik J. TI How Does Genotype Influence Disease Phenotype in Inflammatory Bowel Disease? SO INFLAMMATORY BOWEL DISEASES LA English DT Review DE Crohn's disease; ulcerative colitis; genetics; complications; surgery ID PRIMARY SCLEROSING CHOLANGITIS; ONSET CROHNS-DISEASE; WIDE ASSOCIATION ANALYSIS; ULCERATIVE-COLITIS; SUSCEPTIBILITY LOCI; INFLIXIMAB THERAPY; PREDICT RESPONSE; NATURAL-HISTORY; GENE VARIANTS; LUNG-CANCER AB Inflammatory bowel diseases (Crohn's disease and ulcerative colitis) are chronic immunologically mediated diseases of the gut. Advances in genetics have revolutionized our understanding of the pathogenesis of these conditions with 163 risk loci identified, encompassing a variety of immunologic functions. There is substantial heterogeneity in the natural history of these diseases with respect to disease onset, course, and progression to complications. There are also significant variations in response to therapies and susceptibility to therapy-related and disease-related complications. An important need in the field is to identify predictors of disease course, complications, and likelihood of response and adverse events to allow for targeted therapeutic decision making. The genotype of an individual in constant and non-modifiable, and thus could potentially fulfill the role of important predictors of these outcomes. In this review, we discuss the existing literature on the prediction of various disease phenotypes in Crohn's disease and ulcerative colitis using underlying genotype. We also identify gaps in the literature and suggest future directions for research. There is need for large, multi-institutional, and international collaborative consortia with efficient and detailed cohort accrual, phenotypic definition, genotyping, and dynamic assessments of external (e.g., diet) and internal (microbiome) environment to allow us to progress toward personalized and precision medicine in the management of these complex diseases. C1 [Ananthakrishnan, Ashwin N.; Xavier, Ramnik J.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Ananthakrishnan, Ashwin N.; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA USA. [Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Xavier, Ramnik J.] Harvard Univ, MIT, Broad Inst, Cambridge, MA 02139 USA. RP Ananthakrishnan, AN (reprint author), Massachusetts Gen Hosp, Crohns & Colitis Ctr, 165 Cambridge St,9th Floor, Boston, MA 02114 USA. EM aananthakrishnan@partners.org FU National Institutes of Health [P30 DK043351, K23 DK097142, U01 DK062432, R01 DK064869] FX Supported by the National Institutes of Health (P30 DK043351) to the Center for Study of Inflammatory Bowel Diseases. A. N. Ananthakrishnan is supported in part by a grant from the National Institutes of Health (K23 DK097142). R. J. Xavier is supported by grants U01 DK062432 & R01 DK064869 from the National Institutes of Health. NR 82 TC 8 Z9 8 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-0998 EI 1536-4844 J9 INFLAMM BOWEL DIS JI Inflamm. Bowel Dis. PD AUG PY 2013 VL 19 IS 9 BP 2021 EP 2030 DI 10.1097/MIB.0b013e318281f5c5 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 284XH UT WOS:000329354900029 PM 23644824 ER PT J AU Greiner, JV AF Greiner, Jack V. TI Long-term (12-month) improvement in meibomian gland function and reduced dry eye symptoms with a single thermal pulsation treatment SO CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article DE dry eye; LipiFlow thermal pulsation system; meibomian gland dysfunction ID LIPID LAYER THICKNESS; BREAK-UP TIME; THERMODYNAMIC TREATMENT; DYSFUNCTION; SYSTEM AB PurposeTo determine the 1-year post-treatment dry eye status of subjects with meibomian gland dysfunction and dry eye symptoms after receiving a single LipiFlow Thermal Pulsation System treatment. DesignSingle-centre, prospective, observational, open-label, 1-month-registered clinical trial with a 1-year follow-up examination. ParticipantsPatients with evaporative dry eye disease with meibomian gland dysfunction and dry eye symptoms who had participated in the registered 1-month clinical trial. MethodsEighteen of 30 subjects initially enrolled were able to return for a 1-year follow-up. Both eyes of all patients were treated with a single 12-min treatment using the LipiFlow Thermal Pulsation System. Meibomian gland function, tear break-up time and dry eye symptoms were measured. Data are presented for pretreatment (baseline), and 1-month and 1-year post-treatment. Main Outcome MeasuresMeibomian gland secretion scores, and tear break-up time and dry eye symptoms. ResultsSignificant improvement in meibomian gland secretion scores from baseline measurements (4.03.4) to 1-month post-treatment (11.3 +/- 4.7; P<0.0005) was maintained at 1-year (7.3 +/- 4.6; P<0.05). Baseline tear break-up time (4.9 +/- 3.0) was significantly increased at 1-month (9.5 +/- 6.9; P<0.05); however, this improvement was no longer evident at 1-year post-treatment (6.0 +/- 4.4). The significant improvement in symptom scores on Ocular Surface Disease Index and Standard Patient Evaluation of Eye Dryness questionnaires observed at 1-month (P<0.0005) was maintained at 1-year (Ocular Surface Disease Index [P<0.05]; Standard Patient Evaluation of Eye Dryness [P<0.0005]). ConclusionA single 12-min treatment with the Lipi Flow Thermal Pulsation System offers an effective treatment for evaporative dry eye and meibomian gland dysfunction resulting in significant and sustained improvement in signs and symptoms for up to 1 year. C1 [Greiner, Jack V.] Massachusetts Eye & Ear Infirm, Schepens Eye Res Inst, Boston, MA 02114 USA. [Greiner, Jack V.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Greiner, Jack V.] Boston Ocular Surface Ctr, Boston, MA USA. [Greiner, Jack V.] Boston Ocular Surface Ctr, Winchester, MA 01890 USA. RP Greiner, JV (reprint author), Boston Ocular Surface Ctr, 955 Main St,Suite 307, Winchester, MA 01890 USA. EM greiner@schepens.harvard.edu FU Valerie and Walter Winchester Grant; Boston Ocular Surface Center, Boston and Winchester, MA, USA; TearScience, Inc., Morrisville, NC, USA FX Funding sources: Valerie and Walter Winchester Grant, Boston Ocular Surface Center, Boston and Winchester, MA, USA, and TearScience, Inc., Morrisville, NC, USA. NR 20 TC 19 Z9 19 U1 0 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1442-6404 EI 1442-9071 J9 CLIN EXP OPHTHALMOL JI Clin. Exp. Ophthalmol. PD AUG PY 2013 VL 41 IS 6 BP 524 EP 530 DI 10.1111/ceo.12033 PG 7 WC Ophthalmology SC Ophthalmology GA 283XE UT WOS:000329279500003 PM 23145471 ER PT J AU Dwojak, SM Sequist, TD Emerick, K Deschler, DG AF Dwojak, Sunshine M. Sequist, Thomas D. Emerick, Kevin Deschler, Daniel G. TI Survival differences among American Indians/Alaska Natives with head and neck squamous cell carcinoma SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE squamous cell carcinoma; cancer; disparities; American Indians; outcomes ID ORAL-CAVITY; HUMAN-PAPILLOMAVIRUS; ALASKA-NATIVES; OROPHARYNGEAL CANCER; CARE; SURVEILLANCE; REGISTRY; PHARYNX AB BackgroundAmerican Indians/Alaska Natives experience poor overall survival. Data are limited on American Indians/Alaska Natives with head and neck squamous cell carcinoma (HNSCC). MethodsWe identified all cases of HNSCC among American Indians/Alaska Natives, and white patients from 1996 to 2007 using the Surveillance, Epidemiology, and End Results (SEER) database. Univariate, multivariate, and Cox models were fit to analyze racial differences in sex, age, stage, treatment, and survival. ResultsAmerican Indians/Alaska Natives experienced decreased survival for oropharyngeal cancer (hazard ratio [HR] = 1.4; p = .008). After adjusting for demographic factors, survival was decreased for oral cavity cancer (HR = 1.3; p = .05) and hypopharyngeal/laryngeal cancer (HR = 1.6; p = .04). These disparities were eliminated after adjusting for treatment for oral cavity cancer (HR = 1.2; p = .17) and stage for hypopharyngeal/laryngeal cancer (HR = 1.4; p = .12). American Indians/Alaska Natives received less surgery for oral cavity cancer (78% vs 85%; p = .02). ConclusionDisparities in survival exist among American Indians/Alaska Natives patients with HNSCC. They are related to stage and differential treatment patterns. (c) 2012 Wiley Periodicals, Inc. Head Neck, 2013 C1 [Dwojak, Sunshine M.; Emerick, Kevin; Deschler, Daniel G.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Dwojak, Sunshine M.; Sequist, Thomas D.; Emerick, Kevin; Deschler, Daniel G.] Harvard Univ, Sch Med, Boston, MA USA. [Sequist, Thomas D.] Brigham & Womens Hosp, Div Gen Med & Primary Care, Boston, MA 02115 USA. RP Dwojak, SM (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM sunshine_dwojak@meei.harvard.edu OI Dwojak, Sunshine/0000-0001-5094-9407 NR 21 TC 2 Z9 2 U1 1 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1043-3074 EI 1097-0347 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD AUG PY 2013 VL 35 IS 8 BP 1114 EP 1118 DI 10.1002/hed.23089 PG 5 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 283AO UT WOS:000329216700018 PM 22887354 ER PT J AU Kapa, S Epstein, AE Callans, DJ Garcia, FC Lin, D Bala, R Riley, MP Hutchinson, MD Gerstenfeld, EP Tzou, W Marchlinski, FE Frankel, DS Cooper, JM Supple, G Deo, R Verdino, RJ Patel, VV Dixit, S AF Kapa, Suraj Epstein, Andrew E. Callans, David J. Garcia, Fermin C. Lin, David Bala, Rupa Riley, Michael P. Hutchinson, Mathew D. Gerstenfeld, Edward P. Tzou, Wendy Marchlinski, Francis E. Frankel, David S. Cooper, Joshua M. Supple, Gregory Deo, Rajat Verdino, Ralph J. Patel, Vickas V. Dixit, Sanjay TI Assessing Arrhythmia Burden After Catheter Ablation of Atrial Fibrillation Using an Implantable Loop Recorder: The ABACUS Study SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE antiarrhythmic drugs; atrial fibrillation; catheter ablation; implantable loop recorder; monitoring; pulmonary vein isolation ID RADIOFREQUENCY ABLATION; FOLLOW-UP; MONITOR; RECURRENCES; PERFORMANCE; MANAGEMENT; SYNCOPE; TRIAL AB Assessing Arrhythmia Burden After Ablation IntroductionArrhythmia monitoring in patients undergoing atrial fibrillation (AF) ablation is challenging. Transtelephonic monitors (TTMs) are cumbersome to use and provide limited temporal assessment. Implantable loop recorders (ILRs) may overcome these limitations. We sought to evaluate the utility of ILRs versus conventional monitoring (CM) in patients undergoing AF ablation. Methods and ResultsForty-four patients undergoing AF ablation received ILRs and CM (30-day TTM at discharge and months 5 and 11 postablation). Over the initial 6 months, clinical decisions were made based on CM. Subjects were then randomized for the remaining 6 months to arrhythmia assessment and management by ILR versus CM. The primary endpoint was arrhythmia recurrence. The secondary endpoint was actionable clinical events (change of antiarrhythmic drugs [AADs], anticoagulation, non-AF arrhythmia events, etc.) due to either monitoring strategy. Over the study period, 6 patients withdrew. In the first 6 months, AF recurred in 18 patients (7 noted by CM, 18 by ILR; P = 0.002). Five patients in the CM (28%) and 5 in the ILR arm (25%; P = NS) had AF recurrence during the latter 6 months. AF was falsely diagnosed frequently by ILR (730 of 1,421 episodes; 51%). In more patients in the ILR compared with the CM arm, rate control agents (60% vs 39%, P = 0.02) and AADs (71% vs 44%, P = 0.04) were discontinued. ConclusionIn AF ablation patients, ILR can detect more arrhythmias than CM. However, false detection remains a challenge. With adequate oversight, ILRs may be useful in monitoring these patients after ablation. C1 [Kapa, Suraj; Epstein, Andrew E.; Callans, David J.; Garcia, Fermin C.; Lin, David; Bala, Rupa; Riley, Michael P.; Hutchinson, Mathew D.; Marchlinski, Francis E.; Frankel, David S.; Cooper, Joshua M.; Supple, Gregory; Deo, Rajat; Verdino, Ralph J.; Patel, Vickas V.; Dixit, Sanjay] Hosp Univ Penn, Dept Med, Div Cardiol, Philadelphia, PA 19104 USA. [Epstein, Andrew E.; Dixit, Sanjay] Philadelphia Vet Affairs Med Ctr, Dept Med, Philadelphia, PA USA. [Gerstenfeld, Edward P.] Univ Calif San Francisco, Dept Med, Div Cardiol, San Francisco, CA 94143 USA. [Tzou, Wendy] Univ Colorado, Dept Med, Div Cardiol, Aurora, CO USA. RP Dixit, S (reprint author), Hosp Univ Penn, 9 Founders Pavil,3400 Spruce St, Philadelphia, PA 19104 USA. EM sanjay.dixit@uphs.upenn.edu OI Marchlinski, Francis/0000-0001-7962-9423; Hutchinson, Mathew/0000-0002-8286-0113 FU Medtronic, Inc.; Medtronic FX The study was supported by an unrestricted grant from Medtronic, Inc., who had no role in the administration of the study, in the interpretation of data and writing of the manuscript.; A.E.E., D.J.C., R.B., M.D.H., E.P.G., F.E.M., D.F., J.M.C., R.J.C., and S.D. received honoraria from Medtronic. A.E.E., E.P.G., F.E.M., and S.D. received research support from Medtronic. M.D.H. and F.E.M. served on advisory boards for Medtronic and D.J.C. received consulting fees. Other authors: No disclosures. NR 23 TC 22 Z9 22 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1045-3873 EI 1540-8167 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD AUG PY 2013 VL 24 IS 8 BP 875 EP 881 DI 10.1111/jce.12141 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 283AW UT WOS:000329217500009 PM 23577826 ER PT J AU Hsieh, CL Kim, CC Ryba, BE Niemi, EC Bando, JK Locksley, RM Liu, JL Nakamura, MC Seaman, WE AF Hsieh, Christine L. Kim, Charles C. Ryba, Bryan E. Niemi, Erene C. Bando, Jennifer K. Locksley, Richard M. Liu, Jialing Nakamura, Mary C. Seaman, William E. TI Traumatic brain injury induces macrophage subsets in the brain SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Alternative activation; Inflammation; Macrophage; Traumatic brain injury ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; SPINAL-CORD-INJURY; ALTERNATIVE ACTIVATION; MICROGLIAL ACTIVATION; MICE; INFLAMMATION; RECRUITMENT; RECOVERY; HETEROGENEITY AB Traumatic brain injury (TBI) elicits innate inflammatory responses that can lead to secondary brain injury. To better understand the mechanisms involved in TBI-induced inflammation, we examined the nature of macrophages responding to TBI in mice. In this model, brain macrophages were increased >20-fold the day after injury and >77-fold 4 days after injury in the ipsilateral hemisphere compared with sham controls. TBI macrophage subsets were identified by using a reporter mouse strain (YARG) that expresses eYFP from an internal ribosome entry site (IRES) inserted at the 3 end of the gene for arginase-1 (Arg1), a hallmark of alternatively activated (M2) macrophages. One day after TBI, 21 +/- 1.5% of ipsilateral brain macrophages expressed relatively high levels of Arg1 as detected by yellow fluorescent protein, and this subpopulation declined thereafter. Arg1(+) cells localized with macrophages near the TBI lesion. Gene expression analysis of sorted Arg1(+) and Arg1(-) brain macrophages revealed that both populations had profiles that included features of conventional M2 macrophages and classically activated (M1) macrophages. The Arg1(+) cells differed from Arg1(-) cells in multiple aspects, most notably in their chemokine repertoires. Thus, the macrophage response to TBI initially involves heterogeneous polarization toward at least two major subsets. C1 [Hsieh, Christine L.; Ryba, Bryan E.; Liu, Jialing; Nakamura, Mary C.; Seaman, William E.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Hsieh, Christine L.; Kim, Charles C.; Niemi, Erene C.; Bando, Jennifer K.; Locksley, Richard M.; Nakamura, Mary C.; Seaman, William E.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Liu, Jialing] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA. [Hsieh, Christine L.; Liu, Jialing; Nakamura, Mary C.; Seaman, William E.] Northern Calif Inst Res & Educ, San Francisco, CA USA. RP Hsieh, CL (reprint author), San Francisco VA Med Ctr, 4150 Clement St 111R, San Francisco, CA 94121 USA. EM christine.hsieh@ucsf.edu RI Liu, Jialing/A-8627-2012; OI Liu, Jialing/0000-0003-4420-4382; Kim, Charles/0000-0001-6474-8227 FU NIH/NCRR UCSF-CTSI [UL1 RR024131]; Department of Veterans Affairs; Department of Defense FX The authors thank Ruby Gribi of the San Francisco VA Flow Cytometry core, Dr. David Erle, Andrea Barczak, Rebecca Barbeau, and Joshua Pollack at the Sandler Asthma Basic Research (SABRE) Center Functional Genomics Core Facility (NIH/NCRR UCSF-CTSI grant number UL1 RR024131), and Ivy Hsieh of the San Francisco VA Cell Imaging core for their contributions. This work was supported by the Department of Veterans Affairs and by grants from the Department of Defense to WES and CLH, which were administered by the Northern California Institute for Research and Education. NR 53 TC 33 Z9 34 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 EI 1521-4141 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD AUG PY 2013 VL 43 IS 8 BP 2010 EP 2022 DI 10.1002/eji.201243084 PG 13 WC Immunology SC Immunology GA 277SN UT WOS:000328839700006 PM 23630120 ER PT J AU Daubenmier, J Sze, J Kerr, CE Kemeny, ME Mehling, W AF Daubenmier, Jennifer Sze, Jocelyn Kerr, Catherine E. Kemeny, Margaret E. Mehling, Wolf TI Follow your breath: Respiratory interoceptive accuracy in experienced meditators SO PSYCHOPHYSIOLOGY LA English DT Article DE Meditation; Interoceptive awareness; Interoceptive accuracy; Respiration; Anxiety; Mindfulness ID INSPIRATORY RESISTIVE LOADS; PERCEPTUAL DECISION-MAKING; EVOKED-POTENTIALS; STRESS REDUCTION; EMOTIONAL EXPERIENCE; MINDFULNESS PRACTICE; RELAPSE PREVENTION; ANTERIOR INSULA; BODY AWARENESS; ELASTIC LOADS AB Attention to internal bodily sensations is a core feature of mindfulness meditation. Previous studies have not detected differences in interoceptive accuracy between meditators and nonmeditators on heartbeat detection and perception tasks. We compared differences in respiratory interoceptive accuracy between meditators and nonmeditators in the ability to detect and discriminate respiratory resistive loads and sustain accurate perception of respiratory tidal volume during nondistracted and distracted conditions. Groups did not differ in overall performance on the detection and discrimination tasks; however, meditators were more accurate in discriminating the resistive load with the lowest ceiling effect. Meditators were also more accurate during the nondistracted tracking task at a lag time of 1s following the breath. Results provide initial support for the notion that meditators have greater respiratory interoceptive accuracy compared to nonmeditators. C1 [Daubenmier, Jennifer] Univ Calif San Francisco, Dept Med, Osher Ctr Integrat Med, San Francisco, CA USA. [Sze, Jocelyn] San Francisco VA Med Ctr, Dept Vet Affairs, San Francisco, CA USA. [Kerr, Catherine E.] Brown Univ, Allpert Sch Med, Dept Family Med, Providence, RI 02912 USA. [Kemeny, Margaret E.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA. [Mehling, Wolf] Univ Calif San Francisco, Dept Family & Community Med, Osher Ctr Integrat Med, San Francisco, CA 94143 USA. RP Mehling, W (reprint author), Osher Ctr Integrat Med, 1545 Divisadero St,4th Floor, San Francisco, CA 94115 USA. EM jjdaubenmier@yahoo.com; MehlingW@ocim.ucsf.edu FU Mt. Zion Health Fund; National Institutes of Health (NIH) from the National Center for Complementary & Alternative Medicine (NCCAM) [K01AT004199, K01AT003459, K23-AT002298] FX We are grateful to David Goldman, Anthony Maes, Derek Ramsey, Kevin Chan, Viranjini Gopisetty, and Elizabeth Bartmess for their work on this project. We thank Cynthia Price, Paul Davenport, David Anderson, and two anonymous reviewers for valuable comments on earlier versions of this manuscript, and Paul Davenport and Paul Grossman for initial consultations on the task design. This research was supported by the Mt. Zion Health Fund; and National Institutes of Health (NIH) grants K01AT004199 awarded to JD, K01AT003459 awarded to CK, and K23-AT002298 awarded to WM from the National Center for Complementary & Alternative Medicine (NCCAM). The content is solely the responsibility of the authors and does not necessarily represent the official views of NCCAM or NIH. NR 74 TC 23 Z9 23 U1 8 U2 30 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0048-5772 EI 1469-8986 J9 PSYCHOPHYSIOLOGY JI Psychophysiology PD AUG PY 2013 VL 50 IS 8 BP 777 EP 789 DI 10.1111/psyp.12057 PG 13 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 279EL UT WOS:000328943100011 PM 23692525 ER PT J AU Swan, JS Kong, CY Lee, JM Itauma, O Halpern, EF Lee, PA Vavinskiy, S Williams, O Zoltick, ES Donelan, K AF Swan, J. Shannon Kong, Chung Yin Lee, Janie M. Itauma, Omosalewa Halpern, Elkan F. Lee, Pablo A. Vavinskiy, Sergey Williams, Olubunmi Zoltick, Emilie S. Donelan, Karen TI Patient and Societal Value Functions for the Testing Morbidities Index SO MEDICAL DECISION MAKING LA English DT Article DE outcomes research; preventive medicine; screening; public health ID QUALITY-OF-LIFE; HEALTH STATE UTILITIES; WILLINGNESS-TO-PAY; SHORT-TERM IMPACT; BREAST BIOPSY; RESPONSIVENESS; PREFERENCES; DISEASE; EQ-5D; TIME AB Background: We developed preference-based and summated scale scoring for the Testing Morbidities Index (TMI) classification, which addresses short-term effects on quality of life from diagnostic testing before, during, and after testing procedures. Methods: The two TMI preference functions use multiattribute value techniques; one is patient-based and the other has a societal perspective, informed by 206 breast biopsy patients and 466 (societal) subjects. Because of a lack of standard short-term methods for this application, we used the visual analog scale (VAS). Waiting tradeoff (WTO) tolls provided an additional option for linear transformation of the TMI. We randomized participants to 1 of 3 surveys: The first derived weights for generic testing morbidity attributes and levels of severity with the VAS; a second developed VAS values and WTO tolls for linear transformation of the TMI to a dead-healthy scale; the third addressed initial validation in a specific test (breast biopsy). The initial validation included 188 patients and 425 community subjects. Direct VAS and WTO values were compared with the TMI. Alternative TMI scoring as a nonpreference summated scale was included, given evidence of construct and content validity. Results: The patient model can use an additive function, whereas the societal model is multiplicative. Direct VAS and the VAS-scaled TMI were correlated across modeling groups (r = 0.45-0.62). Agreement was comparable to the value function validation of the Health Utilities Index 2. Mean absolute difference (MAD) calculations showed a range of 0.07-0.10 in patients and 0.11-0.17 in subjects. MAD for direct WTO tolls compared with the WTO-scaled TMI varied closely around 1 quality-adjusted life day. Conclusions: The TMI shows initial promise in measuring short-term testing-related health states. C1 [Swan, J. Shannon; Kong, Chung Yin; Lee, Janie M.; Halpern, Elkan F.; Lee, Pablo A.; Williams, Olubunmi; Zoltick, Emilie S.; Donelan, Karen] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. [Swan, J. Shannon; Kong, Chung Yin; Lee, Janie M.; Halpern, Elkan F.; Donelan, Karen] Harvard Univ, Sch Med, Boston, MA USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Vavinskiy, Sergey] Indiana Univ, Dept Radiol, Indianapolis, IN 46204 USA. [Vavinskiy, Sergey] Indiana State Govt, Indianapolis, IN USA. [Williams, Olubunmi] Emory Univ, Div Renal, Atlanta, GA 30322 USA. [Zoltick, Emilie S.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Donelan, Karen] Mongan Inst Hlth Policy, Boston, MA USA. [Donelan, Karen] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Swan, JS (reprint author), Massachusetts Gen Hosp, Inst Technol Assessment, 101 Merrimac St 10th Floor, Boston, MA 02114 USA. EM shannon@mgh-ita.org FU American Cancer Society [114130-RSGHP-07-266-01-CPHPS]; MGH ECOR Bridge Fund [1200-218421] FX Received 24 March 2012 from Massachusetts General Hospital Institute for Technology Assessment, Boston, MA (JSS, CYK, JML, OA, EFH, PL, OW, ESZ, KD); Harvard Medical School, Boston, MA (JSS, CYK, JML, EFH, KD); Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI (OA); Indiana University Department of Radiology, Indianapolis, IN (SV); Indiana State Government, Indianapolis, IN (SV); Renal Division, Emory University, Atlanta, GA (OW); Boston University School of Public Health, Boston, MA (ESZ); and Mongan Institute for Health Policy and Massachusetts General Hospital, Boston, MA (KD). Financial support for this study was provided in part by grants from the American Cancer Society (114130-RSGHP-07-266-01-CPHPS) and the MGH ECOR Bridge Fund (1200-218421). The funding agreement ensured the authors' independence in designing the study, interpreting the data, and writing and publishing the report. Revision accepted for publication 22 February 2013. NR 70 TC 6 Z9 6 U1 2 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD AUG PY 2013 VL 33 IS 6 BP 819 EP 838 DI 10.1177/0272989X13487605 PG 20 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 263MP UT WOS:000327813000008 PM 23689044 ER PT J AU Kim, DH Shin, N Kim, GH Song, GA Jeon, TY Kim, DH Lauwers, GY Park, DY AF Kim, Dae Hwan Shin, Nari Kim, Gwang Ha Song, Geum Am Jeon, Tae-Yong Kim, Dong-Heon Lauwers, Gregory Y. Park, Do Youn TI Mucin Expression in Gastric Cancer Reappraisal of Its Clinicopathologic and Prognostic Significance SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID RING CELL CARCINOMAS; ADENOCARCINOMA; PHENOTYPE; MUC5AC; HISTOGENESIS; INDICATORS; STOMACH AB Context.-The clinical validity of mucin expression in gastric cancer is debated. Whereas several reports demonstrate a correlation between mucin expression and prognosis, others deny such an association. Objective.-This survival analysis study aims to elucidate the prognostic significance of mucin expression in gastric cancer. Design.-A retrospective survival analysis was done with 412 cases of gastric cancer characterized on the basis of MUC immunohistochemistry using MUC2, MUC5AC, MUC6, and CD10 antibodies; the cases were divided into those with a gastric, an intestinal, or a null mucin phenotype based on the predominant mucin. Results.-There was no association between mucin expression and survival when considering overall gastric cancers or the advanced gastric cancer subtype. However, early gastric cancers with a gastric mucin phenotype showed longer survival than those with an intestinal mucin phenotype (P = .01) or a null phenotype (P = .01). In particular, MUC5AC-positive early gastric cancers resulted in longer survival than did those that did not express MUC5AC (P = .009). The loss of MUC5AC expression was identified as an independent, poor prognostic factor in early gastric cancers using the Cox regression proportional hazard model (hazard ratio, 3.50; P = .045). Conclusions.-MUC5AC expression is significantly associated with patient survival and can be used to predict outcomes in the gastric cancers, especially in the early gastric cancers. C1 [Kim, Dae Hwan; Jeon, Tae-Yong; Kim, Dong-Heon] Pusan Natl Univ Hosp, Dept Surg, Pusan 602739, South Korea. [Shin, Nari; Park, Do Youn] Pusan Natl Univ Hosp, Dept Pathol, Pusan 602739, South Korea. [Kim, Gwang Ha; Song, Geum Am] Pusan Natl Univ Hosp, Dept Internal Med, Pusan 602739, South Korea. [Park, Do Youn] Pusan Natl Univ, Sch Med, Pusan 602739, South Korea. Pusan Natl Univ Hosp, Biomed Res Inst, Pusan 602739, South Korea. [Lauwers, Gregory Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Lauwers, Gregory Y.] Harvard Univ, Sch Med, Boston, MA USA. RP Park, DY (reprint author), Pusan Natl Univ Hosp, Dept Pathol, 1-10 Ami Dong, Pusan 602739, South Korea. EM pdy220@pusan.ac.kr FU Ministry for Health, Welfare and Family Affairs, Republic of Korea [0920050]; Pusan National University Hospital FX This study was supported by grant 0920050 from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea, and a clinical research grant from Pusan National University Hospital 2011. NR 24 TC 11 Z9 11 U1 0 U2 2 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2013 VL 137 IS 8 BP 1047 EP 1053 DI 10.5858/arpa.2012-0193-OA PG 7 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 269RQ UT WOS:000328260000006 PM 23899060 ER PT J AU Corben, AD Abi-Raad, R Popa, I Teo, CHY Macklin, EA Koerner, FC Taghian, AG Brachtel, EF AF Corben, Adriana D. Abi-Raad, Rita Popa, Ion Teo, Clarence H. Y. Macklin, Eric A. Koerner, Frederick C. Taghian, Alphonse G. Brachtel, Elena F. TI Pathologic Response and Long-Term Follow-up in Breast Cancer Patients Treated With Neoadjuvant Chemotherapy A Comparison Between Classifications and Their Practical Application SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT 100th Annual Meeting United-States-and-Canadian-Academy-of-Pathology CY FEB 26-MAR 04, 2011 CL San Antonio, TX SP US & Canadian Acad Pathol ID NOTTINGHAM PROGNOSTIC INDEX; SURGICAL ADJUVANT BREAST; PREOPERATIVE CHEMOTHERAPY; INDUCTION CHEMOTHERAPY; LOBULAR CARCINOMA; RESIDUAL DISEASE; SURVIVAL; TRASTUZUMAB; EXPERIENCE; RECOMMENDATIONS AB Context.-Breast cancer is increasingly treated with neoadjuvant chemotherapy to improve surgical resectability and evaluate tumor response, which is assessed histopathologically. Several histopathologic classification systems have been previously described for assessment of treatment response. Objective.-To test performance in a side-by-side comparison of several histopathologic classification systems after neoadjuvant chemotherapy with clinical outcome. Design.-Sixty-two patients were enrolled in a randomized trial receiving sequential neoadjuvant chemotherapy with doxorubicin and paclitaxel. Histologic sections from the patients' tumors sampled before (core biopsy) and after treatment (excision or mastectomy) were reviewed. Histologic response was assessed following National Surgical Adjuvant Breast and Bowel Project protocol B18, Miller-Payne grading, Sataloff tumor and nodes, Residual Cancer Burden (RCB), and Residual Disease in Breast and Nodes (RDBN). Pathologic classification results were correlated with survival using Kaplan-Meier and Cox hazards regression with a median follow-up of 93 months. Results.-RDBN was associated with distant disease-free survival by univariate and multivariate analysis (P = .01 and .004, respectively), as were lymph node metastases (P = .02 and .01, respectively). Five patients (8%) had complete pathologic response after neoadjuvant chemotherapy, and none of them relapsed during the study period. Survival was shorter among patients with higher Residual Cancer Burden scores, but the associations were not significant. Miller-Payne grading and Sataloff tumor scores were not correlated with survival. Conclusions.-Evaluation of breast specimens after neoadjuvant chemotherapy by the composite index RDBN correlates with long-term outcome. The residual disease in breast and nodes system is suitable for routinely processed pathology cases. This study confirms the importance of lymph node status after neoadjuvant chemotherapy and favorable outcome in patients with pathologic complete response. C1 [Corben, Adriana D.; Popa, Ion; Teo, Clarence H. Y.; Koerner, Frederick C.; Brachtel, Elena F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Abi-Raad, Rita; Taghian, Alphonse G.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Macklin, Eric A.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Brachtel, EF (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN2, Boston, MA 02114 USA. EM ebrachtel@partners.org OI Macklin, Eric/0000-0003-1618-3502 NR 43 TC 16 Z9 17 U1 0 U2 2 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD AUG PY 2013 VL 137 IS 8 BP 1074 EP 1082 DI 10.5858/arpa.2012-0290-OA PG 9 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 269RQ UT WOS:000328260000009 PM 23899063 ER PT J AU Wen, SW Ager, EI Neo, J Christophi, C AF Wen, Shu Wen Ager, Eleanor I. Neo, Jaclyn Christophi, Christopher TI The renin angiotensin system regulates Kupffer cells in colorectal liver metastases SO CANCER BIOLOGY & THERAPY LA English DT Article DE macrophage; captopril; ACE inhibitor; Kupffer cell; colorectal cancer ID II TYPE-1 RECEPTOR; CONVERTING ENZYME-INHIBITION; KAPPA-B ACTIVATION; TUMOR-GROWTH; MACROPHAGE INFILTRATION; HEPATIC METASTASIS; CARCINOMA CELLS; RAT-LIVER; GADOLINIUM CHLORIDE; PLASMA-CHOLESTEROL AB Blockade of the renin angiotensin system (RAS) can inhibit tumor growth and this may be mediated via undefined immunomodulatory actions. This study investigated the effects of RAS blockade on liver macrophages (Kupffer cells; KCs) in an orthotopic murine model of colorectal cancer (CRC) liver metastases. Here we showed that pharmacological targeting of the RAS [ANG II (31.25 mu g/kg/h i.p.), ANG-(1-7) (24 mu g/kg/h i.p.) or the ACE inhibitor; captopril (750 mg/kg/d i.p.)] altered endogenous KC numbers in the tumor-bearing liver throughout metastatic growth. Captopril, and to a lesser extent ANG-(1-7), increased KC numbers in the liver but not tumor. KCs were found to express the key RAS components: ACE and AT1R. Treatment with captopril and ANG II increased the number of AT1R-expressing KCs, although total KC numbers were not affected by ANG II. Captopril (0.1 mu M) also increased macrophage invasion in vitro. Additionally, captopril was administered with KC depletion before tumor induction (day 0) or at established metastatic growth (day 18) using gadolinium chloride (GdCl3; 20 mg/kg). Livers were collected at day 21 and quantitative stereology used as a measure of tumor burden. Captopril reduced growth of CRC liver metastases. However, when captopril was combined with early KC depletion (day 0) tumor growth was significantly increased compared with captopril alone. In contrast, late KC depletion (day 18) failed to influence the anti-tumor effects of captopril. The result of these studies suggests that manipulation of the RAS can alter KC numbers and may subsequently influence progression of CRC liver metastases. C1 [Wen, Shu Wen; Christophi, Christopher] Univ Melbourne, Dept Surg, Austin Hlth, Heidelberg, Vic, Australia. [Wen, Shu Wen] Queensland Inst Med Res, Tumour Microenvironm Lab, Herston, Qld 4006, Australia. [Ager, Eleanor I.] Massachusetts Gen Hosp, Steele Lab Tumor Biol, Boston, MA 02114 USA. [Ager, Eleanor I.] Harvard Med Sch, Boston, MA USA. [Neo, Jaclyn] Mental Hlth Res Inst, Mol Psychiat Lab, Parkville, Vic, Australia. RP Wen, SW (reprint author), Univ Melbourne, Dept Surg, Austin Hlth, Heidelberg, Vic, Australia. EM ShuWen.Wen@qimr.edu.au OI Ager, Eleanor/0000-0002-7849-9206 FU Cancer Australia's Priority-driven Collaborative Cancer Research Scheme; Cancer Australia and Cure Cancer Australia Foundation; Cancer Council of Victoria; NHMRC Post-doctoral Training Award; Australian Rotary Health Research Fund PhD Scholarship FX This work was supported by Cancer Australia's Priority-driven Collaborative Cancer Research Scheme (co-funded by Cancer Australia and Cure Cancer Australia Foundation) and by the Cancer Council of Victoria. EIA was supported by an NHMRC Post-doctoral Training Award. SWW and JN were supported by an Australian Rotary Health Research Fund PhD Scholarship. TF aided in editing the manuscript. SWW performed experimental and statistical analysis and drafted the manuscript. EIA and SWW contributed equally to experimental design and protocol optimization. JN contributed to the RAS treatment and tissue collection. EIA and CC reviewed the manuscript and aided in the development of the concepts tested. NR 62 TC 5 Z9 5 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 EI 1555-8576 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG 1 PY 2013 VL 14 IS 8 BP 720 EP 727 DI 10.4161/cbt.25092 PG 8 WC Oncology SC Oncology GA 257XL UT WOS:000327421000006 PM 23792575 ER PT J AU Vantler, M Jesus, J Leppaenen, O Chen, X Vantler, M Ten Freyhaus, H Caglayan, E Blaschke, F Zhao, JJ Rosenkranz, S AF Vantler, M. Jesus, J. Leppaenen, O. Chen, X. Vantler, M. Ten Freyhaus, H. Caglayan, E. Blaschke, F. Zhao, J. J. Rosenkranz, S. TI Role of class IA PI 3-kinase isoforms in neointima formation following balloon angioplasty: only p110alpha is important SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Vantler, M.; Jesus, J.; Chen, X.; Vantler, M.; Ten Freyhaus, H.; Caglayan, E.; Rosenkranz, S.] Cologne Univ Hosp, Ctr Heart, Clin Internal Med 3, Cologne, Germany. [Leppaenen, O.] Uppsala Univ, UCR Uppsala Clin Res Ctr, Uppsala, Sweden. [Blaschke, F.] Charite Campus Virchow Klinikum, Dept Cardiol, Berlin, Germany. [Zhao, J. J.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 114 EP 115 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744600415 ER PT J AU Otermin, FC Raal, F Stein, EA Schou, MB Basart, DC Koren, MJ Ceska, R Somaratne, R Yang, J Sabatine, MS AF Civeira Otermin, F. Raal, F. Stein, E. A. Schou, M. B. Basart, D. C. Koren, M. J. Ceska, R. Somaratne, R. Yang, J. Sabatine, M. S. TI Statin therapy is a major determinant of PCSK9 plasma concentration: data from four clinical trials with AMG 145 SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Civeira Otermin, F.] Univ Hosp Miguel Servet, Zaragoza, Spain. [Raal, F.] Univ Witwatersrand, Johannesburg, South Africa. [Stein, E. A.] Metab & Atherosclerosis Res Ctr, Cincinnati, OH USA. [Schou, M. B.] CCBR Clin Res, Ballerup, Denmark. [Basart, D. C.] Cardioloog Vasc Onderzoek Ctr Hoorn BV, Holland, Netherlands. [Koren, M. J.] Jacksonville Ctr Clin Res, Jacksonville, FL USA. [Ceska, R.] Charles Univ Prague, Fac Med 1, Dept Internal Med 3, Prague, Czech Republic. [Somaratne, R.; Yang, J.] Amgen Inc, Thousand Oaks, CA USA. [Sabatine, M. S.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. RI Ceska, Richard/A-1840-2017 OI Ceska, Richard/0000-0002-2541-5179 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 135 EP 135 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744600491 ER PT J AU Giugliano, RP Raal, F Koren, MJ Sullivan, D Roth, EM Weiss, R Somaratne, R Yang, J Sabatine, MS Stein, EA AF Giugliano, R. P. Raal, F. Koren, M. J. Sullivan, D. Roth, E. M. Weiss, R. Somaratne, R. Yang, J. Sabatine, M. S. Stein, E. A. TI Safety of AMG 145, a fully human monoclonal antibody to PCSK9: Data from four phase 2 studies in 1314 patients SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Giugliano, R. P.; Sabatine, M. S.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Raal, F.] Univ Witwatersrand, Carbohydrate & Lipid Metab Res Unit, Johannesburg, South Africa. [Koren, M. J.] Jacksonville Ctr Clin Res, Jacksonville, FL USA. [Sullivan, D.] Royal Prince Alfred Hosp, Dept Clin Biochem, Camperdown, NSW 2050, Australia. [Roth, E. M.] Sterling Res Grp, Cincinnati, OH USA. [Weiss, R.] Maine Res Associates, Auburn, AL USA. [Somaratne, R.; Yang, J.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Stein, E. A.] Metab & Atherosclerosis Res Ctr, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 135 EP 136 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744600493 ER PT J AU Raal, F Giugliano, RP Koren, MJ Sullivan, D Roth, EM Weiss, R Kim, JB Yang, J Sabatine, MS Stein, EA AF Raal, F. Giugliano, R. P. Koren, M. J. Sullivan, D. Roth, E. M. Weiss, R. Kim, J. B. Yang, J. Sabatine, M. S. Stein, E. A. TI Efficacy of AMG 145, a fully human monoclonal antibody to PCSK9: data from 1252 patients in four phase 2 studies SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Raal, F.] Univ Witwatersrand, Johannesburg, South Africa. [Giugliano, R. P.; Sabatine, M. S.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Koren, M. J.] Jacksonville Ctr Clin Res, Jacksonville, FL USA. [Sullivan, D.] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia. [Roth, E. M.] Sterling Res Grp, Cincinnati, OH USA. [Weiss, R.] Maine Res Associates, Auburn, AL USA. [Kim, J. B.; Yang, J.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Stein, E. A.] Metab & Atherosclerosis Res Ctr, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 163 EP 163 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744601039 ER PT J AU Galie, N Channick, R Delcroix, M Ghofrani, HA Jansa, P Le Brun, FO Simonneau, G Rubin, LJ AF Galie, N. Channick, R. Delcroix, M. Ghofrani, H-A Jansa, P. Le Brun, F-O Simonneau, G. Rubin, L. J. CA SERAPHIN Steering Comm TI Sustained effect of macitentan, a novel oral endothelin receptor antagonist, on exercise capacity and the association of its measure with long-term outcomes in pulmonary arterial hypertension SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Galie, N.] Inst Cardiol, Bologna, Italy. [Channick, R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Delcroix, M.] Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. [Ghofrani, H-A] Univ Hosp Giessen, Giessen, Germany. [Jansa, P.] Charles Univ Prague, Prague, Czech Republic. [Le Brun, F-O] Actel Pharmaceut Ltd, Allschwil, Switzerland. [Simonneau, G.] Hop Univ Bicetre, Serv Pneumol, Paris, France. [Rubin, L. J.] Univ Calif San Diego, San Diego, CA 92103 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 186 EP 186 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744601120 ER PT J AU Wimmer, NJ Cohen, DJ Wasfy, JH Mauri, L Yeh, RW AF Wimmer, N. J. Cohen, D. J. Wasfy, J. H. Mauri, L. Yeh, R. W. TI Delay in reperfusion with transradial percutaneous coronary intervention for ST-elevation myocardial infarction: how much is acceptable? SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Wimmer, N. J.; Mauri, L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Cohen, D. J.] St Lukes Mid Amer Heart Inst, Kansas City, KS USA. [Wasfy, J. H.; Yeh, R. W.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 235 EP 235 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744601307 ER PT J AU Theroux, P Babin, J Ghitescu, MI Murphy, SA Morrow, DA Bonnefoy, A AF Theroux, P. Babin, J. Ghitescu, M. I. Murphy, S. A. Morrow, D. A. Bonnefoy, A. TI Is the inhibition of the PAR-1 receptor with vorapaxar associated with anti-inflammatory effects in patients with symptomatic atherosclerosis: observations from TRA 2P-TIMI 50 SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Theroux, P.; Babin, J.; Ghitescu, M. I.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Theroux, P.; Babin, J.; Ghitescu, M. I.] Univ Montreal, Montreal, PQ, Canada. [Murphy, S. A.; Morrow, D. A.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Bonnefoy, A.] Hosp St Justine, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 249 EP 250 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744601359 ER PT J AU Papafaklis, MI Bourantas, CV Yonetsu, T Kato, K Naka, KK Fotiadis, DI Feldman, CL Jang, IK Stone, PH Michalis, LK AF Papafaklis, M. I. Bourantas, C. V. Yonetsu, T. Kato, K. Naka, K. K. Fotiadis, D. I. Feldman, C. L. Jang, I. K. Stone, P. H. Michalis, L. K. TI Three-dimensional coronary reconstruction and endothelial shear stress assessment using frequency domain optical coherence tomography & angiography in humans: comparison with intravascular ultrasound SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Papafaklis, M. I.; Feldman, C. L.; Stone, P. H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. [Bourantas, C. V.] Univ Hull, Dept Acad Cardiol, Kingston Upon Hull HU6 7RX, N Humberside, England. [Yonetsu, T.; Kato, K.; Jang, I. K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Naka, K. K.; Michalis, L. K.] Univ Ioannina, Sch Med, Dept Cardiol, GR-45110 Ioannina, Greece. [Fotiadis, D. I.] Univ Ioannina, Dept Mat Sci & Engn, GR-45110 Ioannina, Greece. NR 0 TC 0 Z9 0 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 493 EP 493 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744603045 ER PT J AU Vegh, EM Kandala, J Orencole, M Upadhyay, G Parks, KA Mela, T Merkely, B Singh, JP AF Vegh, E. M. Kandala, J. Orencole, M. Upadhyay, G. Parks, K. A. Mela, T. Merkely, B. Singh, J. P. TI Device measured physical activity as a predictor of reverse remodeling and clinical outcome SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Vegh, E. M.; Kandala, J.; Orencole, M.; Upadhyay, G.; Parks, K. A.; Mela, T.; Singh, J. P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Resynchronizat Therapy Program, Boston, MA USA. [Merkely, B.] Semmelweis Univ, Ctr Heart, H-1085 Budapest, Hungary. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 582 EP 582 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744603379 ER PT J AU Freeman, C Kandala, J Orencole, M Vegh, EM Parks, KA Cowburn, PJ Dec, GW Singh, JP AF Freeman, C. Kandala, J. Orencole, M. Vegh, E. M. Parks, K. A. Cowburn, P. J. Dec, G. W. Singh, J. P. TI Anemia predicts clinical outcome in patients receiving cardiac resynchronization therapy SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Freeman, C.; Kandala, J.; Orencole, M.; Vegh, E. M.; Parks, K. A.; Dec, G. W.; Singh, J. P.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cowburn, P. J.] Univ Hosp Southampton NHS Fdn Trust, Southampton, Hants, England. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 584 EP 584 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744603387 ER PT J AU Koren, M Giugliano, RP Raal, F Sullivan, D Bolognese, M Langslet, G Civeira, F Nelson, P Xu, F Sabatine, M AF Koren, M. Giugliano, R. P. Raal, F. Sullivan, D. Bolognese, M. Langslet, G. Civeira, F. Nelson, P. Xu, F. Sabatine, M. TI Safety, tolerability, and efficacy of long-term administration of AMG 145: preliminary results from the OSLER study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Koren, M.] Jacksonville Ctr Clin Res, Jacksonville, FL USA. [Giugliano, R. P.; Sabatine, M.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Raal, F.] Univ Witwatersrand, Johannesburg, South Africa. [Sullivan, D.] Royal Prince Alfred Hosp, Camperdown, NSW 2050, Australia. [Bolognese, M.] Bethesda Hlth Res Ctr, Bethesda, MD USA. [Langslet, G.] Univ Oslo, Lipid Clin, Oslo, Norway. [Civeira, F.] Univ Hosp Miguel Servet, Zaragoza, Spain. [Nelson, P.; Xu, F.] Amgen Inc, Thousand Oaks, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 767 EP 767 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744604550 ER PT J AU Jones, WS Hellkamp, AS Halperin, J Piccini, JP Breithardt, G Singer, DE Fox, KAA Mahaffey, KW Califf, RM Patel, MR AF Jones, W. S. Hellkamp, A. S. Halperin, J. Piccini, J. P. Breithardt, G. Singer, D. E. Fox, K. A. A. Mahaffey, K. W. Califf, R. M. Patel, M. R. CA ROCKET AF TI Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Jones, W. S.; Hellkamp, A. S.; Piccini, J. P.; Mahaffey, K. W.; Califf, R. M.; Patel, M. R.] Duke Univ, Sch Med, Durham, NC USA. [Halperin, J.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Breithardt, G.] Univ Munster, Dept Cardiovasc Dis Adult, D-48149 Munster, Germany. [Singer, D. E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Fox, K. A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 809 EP 810 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744605025 ER PT J AU Tan, TC Flynn, AW Mehrotra, P Nunes, MP Shahian, DM Picard, MH Afilalo, J AF Tan, T. C. Flynn, A. W. Mehrotra, P. Nunes, M. P. Shahian, D. M. Picard, M. H. Afilalo, J. TI Incremental value of the echocardiogram to predict short- and long-term mortality and morbidity after surgical aortic valve replacement SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Tan, T. C.; Flynn, A. W.; Mehrotra, P.; Nunes, M. P.; Picard, M. H.] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. [Shahian, D. M.] Massachusetts Gen Hosp, Div Cardiac Surg, Boston, MA 02114 USA. [Afilalo, J.] McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 813 EP 813 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744605039 ER PT J AU Storey, RF Ardissino, D Vignali, L Cairns, R Becker, RC Cannon, CP Himmelmann, A Husted, S James, SK Wallentin, L AF Storey, R. F. Ardissino, D. Vignali, L. Cairns, R. Becker, R. C. Cannon, C. P. Himmelmann, A. Husted, S. James, S. K. Wallentin, L. TI Ischaemic events following planned discontinuation of study treatment with ticagrelor or clopidogrel in the PLATO study SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Storey, R. F.] Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. [Ardissino, D.; Vignali, L.] Univ Parma, Azienda Osped, I-43100 Parma, Italy. [Cairns, R.] Worldwide Clin Trials, Nottingham, England. [Becker, R. C.] Duke Univ, Sch Med, Durham, NC USA. Brigham & Womens Hosp, Cardiovascular Div, Dept Med, TIMI Study Grp, Boston, MA USA. [Cannon, C. P.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Himmelmann, A.] AstraZeneca, Wilmington, NC USA. [Husted, S.] Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. [James, S. K.] Uppsala Univ, Dept Med Sci, Uppsala Clin Res Ctr, Uppsala, Sweden. [Wallentin, L.] Uppsala Clin Res Ctr, Uppsala, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 826 EP 826 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744605086 ER PT J AU Varenhorst, C Alstrom, U Braun, OO Storey, RF Mahaffey, KW Cannon, C Himmelmann, A James, S Wallentin, L Held, C AF Varenhorst, C. Alstrom, U. Braun, O. O. Storey, R. F. Mahaffey, K. W. Cannon, C. Himmelmann, A. James, S. Wallentin, L. Held, C. TI Difference in causes of death between ticagrelor and clopidogrel in the PLATO trial SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Varenhorst, C.; James, S.; Wallentin, L.; Held, C.] Uppsala Univ, Uppsala Clin Res Ctr, Uppsala, Sweden. [Varenhorst, C.; James, S.; Wallentin, L.; Held, C.] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Alstrom, U.] Uppsala Univ, Dept Cardiac & Thorac Anaesthesia & Surg, Uppsala, Sweden. [Braun, O. O.] Lund Univ, Dept Cardiol, Lund, Sweden. [Storey, R. F.] Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. [Mahaffey, K. W.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27706 USA. [Cannon, C.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Himmelmann, A.] AstraZeneca R&D, Molndal, Sweden. NR 0 TC 0 Z9 0 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 827 EP 827 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744605087 ER PT J AU Azzalini, L Ghoshhajra, B Elmariah, S Passeri, JJ Inglessis, I Palacios, I Abbara, S AF Azzalini, L. Ghoshhajra, B. Elmariah, S. Passeri, J. J. Inglessis, I. Palacios, I. Abbara, S. TI The Aortic Valve Calcium Nodule Score (AVCNS) independently predicts paravalvular regurgitation after Transcatheter Aortic Valve Implantation (TAVI) SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [Azzalini, L.; Elmariah, S.; Passeri, J. J.; Inglessis, I.; Palacios, I.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Ghoshhajra, B.; Abbara, S.] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp,Cardiac MRI PET CT Prog, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 840 EP 840 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744605133 ER PT J AU James, S Storey, RF Cannon, C Janzon, M Nicolau, JC Parasuraman, B Mellstrom, K Wallentin, L Henriksson, M AF James, S. Storey, R. F. Cannon, C. Janzon, M. Nicolau, J. C. Parasuraman, B. Mellstrom, K. Wallentin, L. Henriksson, M. TI Health economic evaluation of ticagrelor compared to generic clopidogrel in patients with acute coronary syndromes intended for non-invasive management based on the PLATO trial SO EUROPEAN HEART JOURNAL LA English DT Meeting Abstract CT Congress of the European-Society-of-Cardiology (ESC) CY AUG 31-SEP 04, 2013 CL Amsterdam, NETHERLANDS SP European Soc Cardiol C1 [James, S.; Wallentin, L.] Uppsala Univ, UCR Uppsala Clin Res Ctr, Uppsala, Sweden. [Storey, R. F.] Univ Sheffield, Dept Cardiovasc Sci, Sheffield, S Yorkshire, England. [Cannon, C.] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Janzon, M.] Linkoping Univ, Dept Med & Hlth Sci, Div Cardiovasc Med, Linkoping, Sweden. [Nicolau, J. C.] Univ Sao Paulo Fac Med FMUSP, Heart Inst InCor, Sao Paulo, Brazil. [Parasuraman, B.] Astra Zeneca, Wilmington, DE USA. [Mellstrom, K.; Henriksson, M.] Astra Zeneca, Sodertalje, Sweden. RI Nicolau, Jose/E-1487-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X EI 1522-9645 J9 EUR HEART J JI Eur. Heart J. PD AUG PY 2013 VL 34 SU 1 BP 896 EP 896 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262OH UT WOS:000327744605342 ER EF