FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Reali, M Frangiskakis, JM Grimley, S Hanley-Yanez, K Gutmann, R Dudley, SC Ellinor, PT Weiss, R Shalaby, AA London, B McNamara, DM AF Reali, Manuela Frangiskakis, J. Michael Grimley, Sara Hanley-Yanez, Karen Gutmann, Rebecca Dudley, Samuel C. Ellinor, Patrick T. Weiss, Raul Shalaby, Alaaeldin A. London, Barry McNamara, Dennis M. TI NOS3 Asp298Glu polymorphism and the risk of ventricular arrhythmias in subjects with ICDs: Results front GRADE SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 12th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 21-24, 2008 CL Toronto, CANADA SP Heart Failure Soc Amer C1 [Reali, Manuela] Univ Roma La Sapienza, Dept Cardiovasc & Resp Dis, Rome, Italy. [Frangiskakis, J. Michael; Grimley, Sara; Hanley-Yanez, Karen; Gutmann, Rebecca; Shalaby, Alaaeldin A.; London, Barry; McNamara, Dennis M.] Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA USA. [Dudley, Samuel C.] Univ Illinois, Cardiol Sect, Chicago, IL USA. [Ellinor, Patrick T.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Weiss, Raul] Ohio State Univ, Div Cardiovasc Med, Columbus, OH 43210 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2008 VL 14 IS 6 SU 1 MA 133 BP S42 EP S42 DI 10.1016/j.cardfail.2008.06.293 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339GC UT WOS:000258565100134 ER PT J AU Shah, RV Lewis, GD Semigran, MJ AF Shah, Ravi V. Lewis, Gregory D. Semigran, Marc J. TI Determinants of ventilatory efficiency in heart failure: Right ventricular performance and pulmonary vascular tone SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 12th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 21-24, 2008 CL Toronto, CANADA SP Heart Failure Soc Amer C1 [Shah, Ravi V.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Lewis, Gregory D.; Semigran, Marc J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NR 0 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 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2008 VL 14 IS 6 SU 1 MA 079 BP S27 EP S27 DI 10.1016/j.cardfail.2008.06.091 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339GC UT WOS:000258565100080 ER PT J AU Shalaby', A Atwood, C Selzer, F Marwan, R Goiesan, J Strollo, P AF Shalaby', Alaa Atwood, Charles Selzer, Faith Marwan, Refaat Goiesan, John Strollo, Patrick TI Periodic breathing during wakefulness in cardiae resynchronization therapy: Can it predict outcome? SO JOURNAL OF CARDIAC FAILURE LA English DT Meeting Abstract CT 12th Annual Scientific Meeting of the Heart-Failure-Society-of-America CY SEP 21-24, 2008 CL Toronto, CANADA SP Heart Failure Soc Amer C1 [Shalaby', Alaa; Atwood, Charles; Marwan, Refaat] VA Pittsburgh Healthcare Syst, Div Cardiol, Pittsburgh, PA USA. [Selzer, Faith] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Shalaby', Alaa; Atwood, Charles; Marwan, Refaat; Goiesan, John; Strollo, Patrick] Univ Pittsburgh, Div Cardiol, Pittsburgh, PA USA. [Shalaby', Alaa; Atwood, Charles; Marwan, Refaat; Goiesan, John; Strollo, Patrick] Univ Pittsburgh, Div Pulmonol, Pittsburgh, PA USA. NR 0 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 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD AUG PY 2008 VL 14 IS 6 SU 1 MA 043 BP S15 EP S16 DI 10.1016/j.cardfail.2008.06.055 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 339GC UT WOS:000258565100044 ER PT J AU Aryana, A D'Avila, A Ruskin, JN Reddy, VY AF Aryana, Arash D'Avila, Andre Ruskin, Jeremy N. Reddy, Vivek Y. TI The proarrhythmic effect of incomplete pulmotricuspid isthmus ablation in a patient with sarcoid-related ventricular tachycardia ? SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Article DE ablation; proarrhythmia; myopathy; sarcoidosis; ventricular tachycardia ID CARDIAC SARCOIDOSIS AB Proarrhythmic Effect of VT Ablation. Proarrhythmia is relatively common after extensive atrial ablation for atrial fibrillation, but has not been frequently documented after catheter ablation of ventricular tachycardia (VT). In theory, this phenomenon could occur if an incomplete ablation line is created between two nonconducting structures, such as dense scar or valvular annuli. This report illustrates the possible proarrhythmic effect of ablation in a patient with sarcoid-related VT and extensive right ventricular (RV) myopathy who presented with slow incessant VT one month after an ablation procedure including ablation at the pulmotricuspid isthmus (PTI). The extensive preexisting RV myopathy appeared to be an important substrate in the pathogenesis of this patient's incessant VT. This case suggests that the PTI region may serve as a critical tachycardia isthmus if sufficiently modified with an incomplete ablation line in the setting of significant myocardial scarring. C1 [Reddy, Vivek Y.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Reddy, VY (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, 55 Fruit St,GRB 109, Boston, MA 02114 USA. EM vreddy@partners.org RI d'Avila, Andre Luiz/F-8009-2010; d'Avila, Andre/A-7693-2009 OI d'Avila, Andre Luiz/0000-0001-8769-1411; FU NHLBI NIH HHS [K23 HL68064] NR 4 TC 5 Z9 5 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-3873 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD AUG PY 2008 VL 19 IS 8 BP 869 EP 872 DI 10.1111/j.1540-8167.2008.01125.x PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 331BX UT WOS:000257988800020 PM 18363687 ER PT J AU Aryana, A Heist, EK Ruskin, JN Singh, JP AF Aryana, Arash Heist, E. Kevin Ruskin, Jeremy N. Singh, Jagmeet P. TI Masking of sinus rhythm by recipient atrial flutter in a patient with orthotopic heart transplant SO JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY LA English DT Editorial Material C1 [Aryana, Arash] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Aryana, A (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, GRB 109,55 Fruit St, Boston, MA 02114 USA. EM aaryana@partners.org NR 2 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-3873 J9 J CARDIOVASC ELECTR JI J. Cardiovasc. Electrophysiol. PD AUG PY 2008 VL 19 IS 8 BP 876 EP 877 DI 10.1111/j.1540-8167.2008.01112.x PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 331BX UT WOS:000257988800022 PM 18284492 ER PT J AU Xin, X Wang, Y Ma, XM Rompolas, P Keutmann, HT Mains, RE Eipper, BA AF Xin, Xiaonan Wang, Yanping Ma, Xin-ming Rompolas, Panteleimon Keutmann, Henry T. Mains, Richard E. Eipper, Betty A. TI Regulation of Kalirin by Cdk5 SO JOURNAL OF CELL SCIENCE LA English DT Article DE RhoGEF; PC12 cells; spectrin-like repeats; PP-1; phosphorylation; roscovitine; calyculin A ID NUCLEOTIDE EXCHANGE FACTOR; CYCLIN-DEPENDENT KINASE-5; NEURITE OUTGROWTH; PROTEIN PHOSPHATASE-1; DENDRITIC SPINES; RHO GTPASES; TRIO; PHOSPHORYLATION; ACTIVATOR; GROWTH AB Kalirin, one of the few Rho guanine nucleotide exchange factors ( GEFs) that contains spectrin-like repeats, plays a critical role in axon extension and maintenance of dendritic spines. PC12 cells were used to determine whether Cdk5, a critical participant in both processes, regulates the action of Kalirin. Expression of Kalirin-7 in nondifferentiated PC12 cells caused GEF-activity-dependent extension of broad cytoplasmic protrusions; coexpression of dominant-negative Cdk5 largely eliminated this response. The spectrin-like repeat region of Kalirin plays an essential role in this response, which is not mimicked by the GEF domain alone. Thr1590, which follows the first GEF domain of Kalirin, is the only Cdk5 phosphorylation site in Kalirin-7. Although mutant Kalirin-7 with Ala1590 retains GEF activity, it is unable to cause extension of protrusions. Kalirin-7 with an Asp1590 mutation has slightly increased GEF activity and dominant-negative Cdk5 fails to block its ability to cause extension of protrusions. Phosphorylation of Thr1590 causes a slight increase in GEF activity and Kalirin-7 solubility. Dendritic spines formed by cortical neurons in response to the expression of Kalirin-7 with Ala1590 differ in shape from those formed in response to wild-type Kalirin-7 or Kalirin-7 containing Asp1590. The presence of Thr1590 in each major Kalirin isoform would allow Cdk5 to regulate Kalirin function throughout development. C1 [Xin, Xiaonan; Wang, Yanping; Ma, Xin-ming; Rompolas, Panteleimon; Mains, Richard E.; Eipper, Betty A.] Univ Connecticut, Ctr Hlth, Dept Neurosci, Farmington, CT 06030 USA. [Keutmann, Henry T.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02115 USA. RP Eipper, BA (reprint author), Univ Connecticut, Ctr Hlth, Dept Neurosci, 263 Farmington Ave, Farmington, CT 06030 USA. EM eipper@uchc.edu FU NIDA NIH HHS [R01 DA015464, R01 DA015464-05, DA-015464] NR 57 TC 23 Z9 23 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 1 PY 2008 VL 121 IS 15 BP 2601 EP 2611 DI 10.1242/jcs.016089 PG 11 WC Cell Biology SC Cell Biology GA 329OU UT WOS:000257878400017 PM 18628310 ER PT J AU Geller, DA Wieland, N Carey, K Vivas, F Petty, CR Johnson, J Reichert, E Pauls, D Biederman, J AF Geller, Daniel A. Wieland, Natalie Carey, Kathleen Vivas, Fe Petty, Carter R. Johnson, Jessica Reichert, Elizabeth Pauls, David Biederman, Joseph TI Perinatal factors affecting expression of obsessive compulsive disorder in children and adolescents SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; MATERNAL SMOKING; RISK-FACTORS; GENERAL-POPULATION; OBSTETRIC COMPLICATIONS; TOURETTES-SYNDROME; BIRTH COHORT; ALCOHOL-USE; PREGNANCY AB Objective: To examine whether adverse perinatal experiences of children are associated with obsessive compulsive disorder (OCD) in youth. Methods: Subjects were 130 children and adolescents with OCD recruited from a family genetic study of pediatric OCD and 49 matched controls from a contemporaneous family case-control study of attention-deficit/hyperactivity disorder (ADHD). Subjects were comprehensively assessed in multiple domains of function. A systematic history of pregnancy, delivery, and infancy complications was obtained. Results: Compared to normal controls, children with OCD had mothers with significantly higher rates of illness during pregnancy requiring medical care (chi(2) = 8.61, p = 0.003) and more birth difficulties (induced labor, forceps delivery, nuchal cord, or prolonged labor) (chi(2) = 7.51, p = 0.006). Among the OCD-affected children, we found several significant associations between adverse perinatal experiences and earlier age at onset, increased OCD severity, and increased risk for comorbid ADHD, chronic tic disorder, anxiety disorder, and major depressive disorder. Conclusion: Although exploratory, our analyses found that children with OCD had higher rates of several adverse perinatal experiences compared with controls. Among OCD-affected children, comorbid psychopathology was predicted by specific perinatal risk factors. Prospective studies of perinatal adverse events that minimize potential recall bias and type I errors are needed. C1 [Geller, Daniel A.; Carey, Kathleen; Petty, Carter R.; Biederman, Joseph] Massachusetts Gen Hosp, Dept Psychiat, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. [Wieland, Natalie] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Vivas, Fe] Colgate Univ, Hamilton, NY 13346 USA. [Pauls, David] Harvard Univ, Sch Med, Lab Neurodev & Psychiat Genet, Boston, MA USA. [Reichert, Elizabeth] Univ Rhode Isl, Dept Psychol, Kingston, RI 02881 USA. [Johnson, Jessica] Univ S Carolina, Dept Psychol, Columbia, SC 29208 USA. RP Geller, DA (reprint author), Suite 2000,185 Alewife Brook Pkwy, Cambridge, MA 02318 USA. EM dageller@partners.org FU NIMH NIH HHS [K08 MH0148] NR 42 TC 22 Z9 22 U1 1 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD AUG PY 2008 VL 18 IS 4 BP 373 EP 379 DI 10.1089/cap.2007.0112 PG 7 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 348TJ UT WOS:000259232700008 PM 18759647 ER PT J AU Misra, M Katzman, DK Cord, J Manning, SJ Mendes, N Herzog, DB Miller, KK Klibanski, A AF Misra, Madhusmita Katzman, Debra K. Cord, Jennalee Manning, Stephanie J. Mendes, Nara Herzog, David B. Miller, Karen K. Klibanski, Anne TI Bone metabolism in adolescent boys with anorexia nervosa SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID LUTEINIZING-HORMONE; HEALTHY ADOLESCENTS; MINERAL DENSITY; HYPOTHALAMIC AMENORRHEA; ENERGY AVAILABILITY; SECRETORY DYNAMICS; FEMALE-PATIENTS; BODY FATNESS; YOUNG-WOMEN; WHOLE-BODY AB Background: Anorexia nervosa (AN) is a condition of severe undernutrition associated with low bone mineral density (BMD) in adolescent females with this disorder. Although primarily a disease in females, AN is increasingly being recognized in males. However, there are few or no data regarding BMD, bone turnover markers or their predictors in adolescent AN boys. Hypotheses: We hypothesized that BMD would be low in adolescent boys with AN compared with controls associated with a decrease in bone turnover markers, and that the gonadal steroids, testosterone and estradiol, and levels of IGF-I and the appetite regulatory hormones leptin, ghrelin, and peptide YY would predict BMD and bone turnover markers. Methods: We assessed BMD using dual-energy x-ray absorptiometry and measured fasting testosterone, estradiol, IGF-I, leptin, ghrelin, and peptide YY and a bone formation (aminoterminal propeptide of type 1 procollagen) and bone resorption (N-telopeptide of type 1 collagen) marker in 17 AN boys and 17 controls 12-19 yr old. Results: Boys with AN had lower BMD and corresponding Z-scores at the spine, hip, femoral neck, trochanter, intertrochanteric region, and whole body, compared with controls. Height-adjusted measures (lumbar bone mineral apparent density and whole body bone mineral content/height) were also lower. Bone formation and resorption markers were reduced in AN, indicating decreased bone turnover. Testosterone and lean mass predicted BMD. IGF-I was an important predictor of bone turnover markers. Conclusion: AN boys have low BMD at multiple sites associated with decreased bone turnover markers at a time when bone mass accrual is critical for attainment of peak bone mass. C1 [Misra, Madhusmita; Cord, Jennalee; Mendes, Nara; Miller, Karen K.; Klibanski, Anne] Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. [Herzog, David B.] Massachusetts Gen Hosp, Harris Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. [Misra, Madhusmita] Massachusetts Gen Hosp Children, Pediat Endocrine Unit, Boston, MA 02114 USA. [Katzman, Debra K.; Manning, Stephanie J.] 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/E-4682-2013; Mendes Estella, Nara/A-1469-2015 FU NCRR NIH HHS [K23 RR018851, M01 RR001066, M01-RR-01066]; NIDDK NIH HHS [R01 DK062249, P30 DK040561, P30 DK040561-13, R01 DK 062249] NR 59 TC 42 Z9 42 U1 0 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2008 VL 93 IS 8 BP 3029 EP 3036 DI 10.1210/jc.2008-0170 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 334SC UT WOS:000258240500015 PM 18544623 ER PT J AU Ingelsson, E Larson, MG Yin, X Wang, TJ Meigs, JB Lipinska, I Benjamin, EJ Keaney, JF Vasan, RS AF Ingelsson, Erik Larson, Martin G. Yin, Xiaoyan Wang, Thomas J. Meigs, James B. Lipinska, Izabella Benjamin, Emelia J. Keaney, John F., Jr. Vasan, Ramachandran S. TI Circulating ghrelin, leptin, and soluble leptin receptor concentrations and cardiometabolic risk factors in a community-based sample SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID LOW PLASMA GHRELIN; METABOLIC SYNDROME; INSULIN-RESISTANCE; BODY-COMPOSITION; CARDIOVASCULAR RISK; ENERGY HOMEOSTASIS; SERUM GHRELIN; OBESITY; BLOOD; INDEX AB Context: The conjoint effects and relative importance of ghrelin, leptin, and soluble leptin receptor (sOB-R), adipokines involved in appetite control and energy expenditure in mediating cardiometabolic risk, is unknown. Objective: The objective of the study was to study the cross-sectional relations of these adipokines to cardiometabolic risk factors in a community-based sample. Design, Setting, and Participants: We measured circulating ghrelin, leptin, and sOB-R in 362 participants (mean age 45 yr; 54% women) of the Framingham Third Generation Cohort. Main Outcome Measures: Body mass index, waist circumference (WC), blood pressure, lipid measures, fasting glucose, smoking, and metabolic syndrome (MetS) were measured. Results: Ghrelin and leptin concentrations were significantly higher in women (P < 0.0001). In multivariable models, ghrelin was inversely associated with age and systolic blood pressure, and leptin was positively related to body mass index and WC. sOB-R was positively associated with age, total cholesterol, and fasting glucose and inversely with WC and high-density lipoprotein cholesterol. Ghrelin and sOB-R concentrations were significantly lower with number of MetS components (P for trend = 0.022 and < 0.0001, respectively), whereas leptin concentrations were higher (P for trend = 0.0001). Relating all adipokines to MetS conjointly, higher ghrelin and leptin concentrations were associated with decreased and increased odds of MetS (odds ratio 0.55, P < 0.0001; odds ratio 4.44, P = 0.0002, per 1 SD increase of respective log adipokine). Conclusions: In our community-based sample, we observed a sexual dimorphism in circulating ghrelin and leptin concentrations. Ghrelin, leptin, and sOB-R were associated with number of MetS components cross-sectionally, consistent with the hypothesis that these adipokines may have a central role in cardiometabolic risk. C1 Boston Univ, Sch Med, Framingham Study, Framingham, MA 01702 USA. Karolinska Inst, Dept Med Epidemiol & Biostatist, SE-17177 Stockholm, Sweden. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. Boston Univ, Sch Med, Evans Mem Dept Med, Boston, MA 02215 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Univ Massachusetts, Sch Med, Div Cardiovasc Med, Worcester, MA 01655 USA. RP Vasan, RS (reprint author), Boston Univ, Sch Med, Framingham Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Benjamin, Emelia/0000-0003-4076-2336; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [N01HC25195, 2K24HL4334, K23 HL074077, K23-HL-074077, K24 HL004334, N01-HC-25195, R01 HL076784, R01-HL-076784]; NIA NIH HHS [1R01 AG028321, R01 AG028321]; NIDDK NIH HHS [1R01 DK 080739, K24 DK080140, K24 DK080140-01, R01 DK080739] NR 46 TC 38 Z9 43 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2008 VL 93 IS 8 BP 3149 EP 3157 DI 10.1210/jc.2008-0207 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 334SC UT WOS:000258240500031 PM 18492761 ER PT J AU Hivert, MF Sullivan, LM Fox, CS Nathan, DM Sr, RBD Wilson, PWF Meigs, JB AF Hivert, Marie-France Sullivan, Lisa M. Fox, Caroline S. Nathan, David M. Sr, Ralph B. D'Agostino Wilson, Peter W. F. Meigs, James B. TI Associations of adiponectin, resistin, and tumor necrosis factor-alpha with insulin resistance SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TYPE-2 DIABETES-MELLITUS; C-REACTIVE PROTEIN; ADIPOSE-TISSUE; SERUM RESISTIN; METABOLIC SYNDROME; PLASMA ADIPONECTIN; OBESITY; SENSITIVITY; POPULATION; MACROPHAGES AB Context: Adipose tissue-derived adipokines may contribute to insulin resistance. Objective: We tested the hypothesis that adipokines are associated with insulin resistance in a community-based cohort and that associations are maintained in people with and without the metabolic syndrome ( high vs. low risk of diabetes). Design, Setting, and Participants: We studied a cross-sectional sample of 2356 individuals attending the seventh examination (1998-2001) of the Framingham Offspring Study. We measured levels of glucose, insulin, adiponectin, resistin, and TNF alpha in fasting blood samples and defined metabolic syndrome by updated National Cholesterol Education Program criteria. We used ANOVA to test associations of adipokines with insulin resistance and multivariable logistic regression models to assess joint associations of adipokines and metabolic syndrome with insulin resistance. Main Outcome Measure: Homeostasis model (HOMA-IR), with insulin resistance defined by HOMA-IR greater than the 75th percentile, was measured. Results: Age- and sex-adjusted HOMA-IR levels were inversely related to adiponectin (r = -0.40, P < 0.0001) and positively related to resistin (r = 0.13, P < 0.0001) and TNF alpha (r = 0.12, P < 0.0001). The prevalence of insulin resistance increased with decreasing tertiles of adiponectin (from 10.9% in the third to 42.5% in the first tertile; P < 0.0001) and increasing tertiles of resistin ( from 19.3 to 30.9%; P < 0.0001) and TNF alpha (from 18.8 to 32.0%; P < 0.0001). Results were similar after adjustment for body mass index. These associations were present in individuals with or without the metabolic syndrome. In multivariable regression models, metabolic syndrome and adipokines individually and jointly were significantly associated with insulin resistance. Conclusion: Adverse levels of adipokines are associated with insulin resistance in individuals at low or high diabetes risk. C1 Massachusetts Gen Hosp, Div Gen Med, Dept Med, Ctr Diabet, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Div Gen Med, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Endocrinol & Metab, NHLBI,Framingham Heart Study, Cambridge, MA 02138 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. Boston Univ, Sch Publ Hlth, Dept Math & Stat, Consulting Unit, Boston, MA USA. Emory Univ, Sch Med, Div Cardiol, Dept Med, Atlanta, GA 30306 USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, Ctr Diabet, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM hjmeigs@partners.org OI Sullivan, Lisa/0000-0003-0726-7149 FU NCRR NIH HHS [M01 RR001066, M01-RR-01066]; NHLBI NIH HHS [N01-HC-25195, N01HC25195]; NIDDK NIH HHS [K24 DK080140, K24 DK080140-01]; PHS HHS [K24 DZK080140] NR 39 TC 134 Z9 148 U1 0 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2008 VL 93 IS 8 BP 3165 EP 3172 DI 10.1210/jc.2008-0425 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 334SC UT WOS:000258240500033 PM 18492747 ER PT J AU Ottowitz, WE Dougherty, DD Fischman, AJ Hall, JE AF Ottowitz, William E. Dougherty, Darin D. Fischman, Alan J. Hall, Janet E. TI [F-18]2-fluoro-2-deoxy-D-glucose positron emission tomography demonstration of estrogen negative and positive feedback on luteinizing hormone secretion in women SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; FOLLICLE-STIMULATING-HORMONE; PREOVULATORY GNRH SURGE; POSTMENOPAUSAL WOMEN; GENE-EXPRESSION; HUMAN HYPOTHALAMUS; OVARIAN-STEROIDS; GONADAL-STEROIDS; PITUITARY-CELLS; MIDCYCLE SURGE AB Context: Precise regulation of the neuroendocrine components of the female reproductive axis involves both negative and positive feedback of estrogen on gonadotropin secretion. Objective: Our objective was to determine the hypothalamic and/or pituitary sites of estrogen negative and positive feedback using neuroimaging techniques. Design and Setting: A graded estrogen infusion protocol was administered at a General Clinical Research Center in an academic medical center. Subjects: Healthy postmenopausal women (n = 11) were recruited for study. Interventions: Serum samples were measured every 4 h. A structural magnetic resonance imaging was performed at baseline, and [F-18]2-fluoro-2-deoxy-D-glucose ((18)FDG) positron emission tomography was performed at baseline and 24 and 72 h. FDG positron emission tomography was co-registered with magnetic resonance imaging scans, and region of interest analysis was performed. Main Outcome Measures: Serum LH and estradiol were assessed. Normalized values for glucose uptake were extracted from each region of interest for each subject at each time point. Results: A decrease in normalized (18)FDG uptake was apparent in the hypothalamus at 24 h (P < 0.02) associated with decreased LH (P < 0.0005). The increase in LH at 72 h (P < 0.0005) was associated with increased pituitary 18FDG uptake (P < 0.02) but no change in hypothalamic uptake. Conclusions: Changes in (18)FDG uptake as a measure of metabolic activity can be demonstrated in the hypothalamus and pituitary in association with discrete hormonal events. Results are consistent with mediation of estrogen negative feedback on LH at the hypothalamus, whereas estrogen positive feedback occurs at the pituitary with no evidence of increased hypothalamic activity in women. C1 [Ottowitz, William E.; Hall, Janet E.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. [Ottowitz, William E.; Dougherty, Darin D.] Massachusetts Gen Hosp, Psychiat Neurosci Program, Boston, MA 02114 USA. RP Hall, JE (reprint author), Massachusetts Gen Hosp, Reprod Endocrine Unit, BHX-5,55 Fruit St, Boston, MA 02114 USA. EM jehall@partners.org FU NCRR NIH HHS [M01 RR001066, M01 RR01066]; NIA NIH HHS [R01 AG013241, R01 AG13241]; NICHD NIH HHS [K24 HD01290, K24 HD001290] NR 49 TC 14 Z9 14 U1 0 U2 0 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD AUG PY 2008 VL 93 IS 8 BP 3208 EP 3214 DI 10.1210/jc.2008-0203 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 334SC UT WOS:000258240500039 PM 18522979 ER PT J AU Cheung, RC Currie, S Shen, H Bini, EJ Ho, SB Anand, BS Hu, KQ Wright, TL Morgan, TR AF Cheung, Ramsey C. Currie, Sue Shen, Hui Bini, Edmund J. Ho, Samuel B. Anand, Bhupinderjit S. Hu, Ke-Qin Wright, Teresa L. Morgan, Timothy R. CA VA HCV-001 Study Grp TI Can we predict the degree of fibrosis in chronic hepatitis C patients using routine blood tests in our daily practice? SO JOURNAL OF CLINICAL GASTROENTEROLOGY LA English DT Article DE noninvasive tests; liver biopsy; performance characteristics; veterans; fibrosis indexes; hepatitis C ID CHRONIC VIRAL-HEPATITIS; STANDARD LABORATORY TESTS; SIMPLE NONINVASIVE INDEX; LIVER-BIOPSY; VIRUS-INFECTION; CIRRHOSIS; INTRAOBSERVER; AMINOTRANSFERASE; VARIABILITY; MARKERS AB Goals: To determine the validity of fibrosis indexes based on simple laboratory tests in daily practice. Background: Fibrosis indexes were developed in referral centers using high-quality data. Methods: We compared the performance characteristics of several such indexes with liver biopsies in a cohort of 490 diverse veterans with chronic hepatitis C from 24 centers. All laboratory tests including interpretation of the liver biopsy were done locally. The following indexes were calculated and correlated with a 5-point fibrosis stage (F0-F4) on liver biopsies: platelet counts (< 100 or < 150 x 10(9)/L), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), Pohl score, AST-to-platelet ratio index (APRI) and "Lok's model." Results: Our cohort was predominantly male with 24% blacks, and fibrosis stages of 0, 1, 2, 3, and 4 in 11%, 24%, 28%, 24%, and 13%, respectively. All indexes performed better in predicting advanced (F3-4) than significant (F2-4) fibrosis. When patients with F3-4 were compared to those with F0-2, the area under the receiver operating characteristics curve were 0.534 and 0.641 for platelet count < 100 and < 150 x 10(9)/L, respectively, 0.524 for AAR, 0.534 for Pohl score, 0.693 for Lok's model, and 0.765 for APRI. The sensitivity, specificity, and predictive values of APRI and Lok's model were only slightly lower than those reported by the authors using the recommended cutoffs in clinical trial settings. Alcohol use within 12 months, normalization of AST, ALT, and race (blacks/non-blacks) had minimal impact on the performance. Conclusions: AAR, Pohl, and platelet counts < 100 x 10(9)/L have limited ability to predict significant/advanced fibrosis with area under the receiver operating characteristics curve similar to 0.5. However, platelet counts < 150 x 10(9)/L, Lok's model and APRI performed well for advanced fibrosis in our daily practice setting. C1 [Cheung, Ramsey C.] VA Palo Alto Healthcare Syst, Palo Alto, CA USA. [Cheung, Ramsey C.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Currie, Sue; Shen, Hui; Wright, Teresa L.] VA Med Ctr, San Francisco, CA USA. [Bini, Edmund J.] VA Med Ctr, New York, NY USA. [Ho, Samuel B.] VA Med Ctr, Minneapolis, MN USA. [Anand, Bhupinderjit S.] VA Med Ctr, Houston, TX USA. [Hu, Ke-Qin] VA Med Ctr, Loma Linda, CA USA. [Morgan, Timothy R.] VA Med Ctr, Long Beach, CA USA. RP Cheung, RC (reprint author), VA Palo Alto HCS, Div Gastroenterol & Hepatol, 154C,3801 Miranda Ave, Palo Alto, CA 94304 USA. EM rcheung@stanford.edu NR 31 TC 24 Z9 24 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0192-0790 J9 J CLIN GASTROENTEROL JI J. Clin. Gastroenterol. PD AUG PY 2008 VL 42 IS 7 BP 827 EP 834 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 336UJ UT WOS:000258389800012 PM 18285716 ER PT J AU Bloch, MJ Betancourt, J Green, A AF Bloch, Michael J. Betancourt, Joseph Green, Alex TI Overcoming Racial and Ethnic Disparities in Blood Pressure Control: A Patient-Centered Approach to Cross-Cultural Communication SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Editorial Material ID UNITED-STATES; HYPERTENSION; PREVALENCE; COMMITTEE; AWARENESS; CARE C1 [Bloch, Michael J.] Univ Nevada, Sch Med, St Marys Risk Ctr, Div Gen Internal Med,Dept Med, Reno, NV 89502 USA. [Bloch, Michael J.] Univ Nevada, Sch Med, Dept Med, Div Cardiol, Reno, NV 89502 USA. [Bloch, Michael J.] St Marys Reg Med Ctr, Risk Reduct Ctr, Reno, NV USA. [Betancourt, Joseph; Green, Alex] Massachusetts Gen Hosp, Inst Hlth Policy, Dispar Solut Ctr, Boston, MA 02114 USA. RP Bloch, MJ (reprint author), Univ Nevada, Sch Med, St Marys Risk Ctr, Div Gen Internal Med,Dept Med, 645 N Arlington,Suite 460, Reno, NV 89502 USA. EM mbloch@aol.com NR 14 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1524-6175 J9 J CLIN HYPERTENS JI J. Clin. Hypertens. PD AUG PY 2008 VL 10 IS 8 BP 589 EP 591 DI 10.1111/j.1751-7176.2008.08046.x PG 3 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 375FR UT WOS:000261100000001 PM 18772640 ER PT J AU Bloch, DB Wang, TJ Gerszten, RE AF Bloch, Donald B. Wang, Thomas J. Gerszten, Robert E. TI Novel antibody markers of unstable atherosclerotic lesions SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; CANCER; AUTOANTIBODIES; PREDICTION AB Detection of autoantibodies in human serum assists in the diagnosis of patients with autoimmune diseases. Diagnostic antibody signatures have also been proposed for colon, pancreatic, and breast cancers. In this issue of the JCI, Cleutjens et al. describe the application of a peptide array technique toward the development of antibody biomarkers of ruptured atherosclerotic lesions (see the related article beginning on page 2979). A phage-display library was prepared from mRNA derived from ruptured peripheral human atherosclerotic plaques, and the phages containing immunoreactive peptides were screened with serum from patients with ruptured atherosclerotic lesions. Antibodies reacting with 2 peptides, E1 and E12, were particularly sensitive for the early diagnosis of acute myocardial infarction. Further studies that include an adequate number of patients presenting very early after the onset of symptoms and additional control patient populations are warranted to compare the utility of these biomarkers to those in clinical use. C1 [Wang, Thomas J.; Gerszten, Robert E.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Bloch, Donald B.; Gerszten, Robert E.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Wang, Thomas J.; Gerszten, Robert E.] Harvard Univ, Sch Med, Boston, MA USA. RP Gerszten, RE (reprint author), Massachusetts Gen Hosp, Div Cardiol, E-8307,149 13th St, Charlestown, MA 02129 USA. EM rgerszten@partners.org NR 12 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2008 VL 118 IS 8 BP 2675 EP 2677 DI 10.1172/JCI36270 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 333IS UT WOS:000258146800002 PM 18654669 ER PT J AU Falardeau, J Chung, WCJ Beenken, A Raivio, T Plummer, L Sidis, Y Jacobson-Dickman, EE Eliseenkova, AV Ma, J Dvfyer, A Quinton, R Na, S Hall, JE Huot, C Alois, N Pearce, SHS Cole, LW Hughes, V Mohammadi, M Tsai, P Pitteloud, N AF Falardeau, John Chung, Wilson C. J. Beenken, Andrew Raivio, Taneli Plummer, Lacey Sidis, Yisrael Jacobson-Dickman, Elka E. Eliseenkova, Anna V. Ma, Jinghong Dvfyer, Andrew Quinton, Richard Na, Sandra Hall, Janet E. Huot, Celine Alois, Natalie Pearce, Simon H. S. Cole, Lindsay W. Hughes, Virginia Mohammadi, Moosa Tsai, Pei Pitteloud, Nelly TI Decreased FGF8 signaling causes deficiency of gonadotropin-releasing hormone in humans and mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; KALLMANN-SYNDROME; LUTEINIZING-HORMONE; STRUCTURAL BASIS; CELL-SURVIVAL; MUTATIONS; GROWTH; GENE; EXPRESSION; RECEPTOR AB Idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome; KS) or with a normal sense of smell (normosmic IHH; nIHH) are heterogeneous genetic disorders associated with deficiency of gonadotropin-releasing hormone (GnRH). While loss-of-function mutations in FGF receptor 1 (FGFR1) cause human GnRH deficiency, to date no specific ligand for FGFR1 has been identified in GnRH neuron ontogeny. Using a candidate gene approach, we identified 6 missense mutations in FGF8 in IHH probands with variable olfactory phenotypes. These patients exhibited varied degrees of GnRH deficiency, including the rare adult-onset form of hypogonadotropic hypogonadism. Four mutations affected all 4 FGF8 splice isoforms (FGF8a, FGF8b, FGF8e, and FGF8f), while 2 mutations affected FGF8e and FGF8f isoforms only. The mutant FGF8b and FGF8f ligands exhibited decreased biological activity in vitro. Furthermore, mice homozygous for a hypomorphic Fgf8 allele lacked GnRH neurons in the hypothalamus, while heterozygous mice showed substantial decreases in the number of GnRH neurons and hypothalamic GnRH peptide concentration. In conclusion, we identified FGF8 as a gene implicated in GnRH deficiency in both humans and mice and demonstrated an exquisite sensitivity of GnRH neuron development to reductions in FGF8 signaling. C1 [Falardeau, John; Raivio, Taneli; Plummer, Lacey; Sidis, Yisrael; Jacobson-Dickman, Elka E.; Dvfyer, Andrew; Na, Sandra; Hall, Janet E.; Cole, Lindsay W.; Hughes, Virginia; Pitteloud, Nelly] Massachusetts Gen Hosp, Harvard Ctr Reprod Endocrine Sci & Reprod Endocri, Dept Med, Boston, MA 02114 USA. [Chung, Wilson C. J.; Tsai, Pei] Univ Colorado, Dept Integrat Physiol, Boulder, CO 80309 USA. [Chung, Wilson C. J.; Tsai, Pei] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Beenken, Andrew; Eliseenkova, Anna V.; Ma, Jinghong; Mohammadi, Moosa] NYU, Sch Med, Dept Pharmacol, New York, NY USA. [Quinton, Richard; Pearce, Simon H. S.] Univ Newcastle, Inst Human Genet, Newcastle upon Tyne, Tyne & Wear, England. [Quinton, Richard; Pearce, Simon H. S.] Univ Newcastle, Sch Clin Med Sci, Newcastle upon Tyne, Tyne & Wear, England. [Quinton, Richard] Univ Newcastle, Newcastle Teaching Hosp, Newcastle upon Tyne, Tyne & Wear, England. [Huot, Celine; Alois, Natalie] CHU St Justine, Ctr Rech, Montreal, PQ, Canada. RP Pitteloud, N (reprint author), Massachusetts Gen Hosp, Harvard Ctr Reprod Endocrine Sci & Reprod Endocri, Dept Med, Bartlett Hall Extension 5, Boston, MA 02114 USA. EM npitteloud@partners.org RI Dwyer, Andrew/D-8099-2012; PITTELOUD, Nelly/K-2709-2014; OI Dwyer, Andrew/0000-0002-7023-6794; Chung, Wilson/0000-0003-0550-7567; Pearce, Simon/0000-0001-8384-8063; Mohammadi, Moosa/0000-0003-2434-9437 FU NCRR NIH HHS [M01 RR001066, M01-RR-01066]; NICHD NIH HHS [R01 HD015788, R01 HD015788-21, R01 HD042708, R01 HD42708, U54 HD028138, U54HD028138-16]; NIDCR NIH HHS [R01 DE013686, R01 DE13686-08] NR 54 TC 184 Z9 192 U1 1 U2 8 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD AUG PY 2008 VL 118 IS 8 BP 2822 EP 2831 DI 10.1172/JCI34538 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 333IS UT WOS:000258146800019 PM 18596921 ER PT J AU Mastali, M Babbitt, JT Li, Y Landaw, EM Gau, V Churchill, BM Haake, DA AF Mastali, Mitra Babbitt, Jane T. Li, Yang Landaw, Elliot M. Gau, Vincent Churchill, Bernard M. Haake, David A. TI Optimal probe length and target location for electrochemical detection of selected uropathogens at ambient temperature SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID 16S RIBOSOMAL-RNA; ESCHERICHIA-COLI; BIOSENSORS; DNA; HYBRIDIZATION; AMPLIFICATION; BACTERIA; FISH AB We have previously demonstrated the clinical validity of the rapid detection of uropathogens by use of a DNA biosensor. This assay involves the hybridization of capture and detector probe pairs with bacterial 16S rRNA target molecules to form a DNA-RNA sandwich on the sensor surface. Horseradish peroxidase-conjugated antibody binds to the detector probe to enzymatically amplify the hybridization signal. These previous studies involved the hybridization of bacterial 16S rRNA target sequences with 35-mer oligonucleotide probe pairs at 65 degrees C. Achievement of point-of-care technology will be greatly facilitated by ambient-temperature detection. The purpose of this study was to examine the effects of probe length and target location on signal intensity using hybridization temperatures of 20 to 25 degrees C. Signal intensity was found to vary dramatically with hybridization location in the species-specific bulge region of 16S rRNA helix 18. Probe pairs of as short as 10 nucleotides in length were able to produce a significant electrochemical signal, and signal intensity was correlated with probe length for probes of 10 to 20 nucleotides in length. The sensitivity of the Escherichia coli-specific 15-mer probe pairs was approximately 330 cells. These shorter probes allowed differentiation of Klebsiella pneumoniae from Proteus mirabilis 16S rRNA target sequences differing by a single nucleotide. A panel of oligonucleotide probe pairs ranging from 11 to 23 nucleotides in length was able to distinguish among seven groups of urinary tract pathogens. In conclusion, we have developed short oligonucleotide probe pairs for the species-specific identification of uropathogens at ambient temperature by use of an electrochemical sensor. C1 [Mastali, Mitra; Babbitt, Jane T.; Haake, David A.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Li, Yang; Churchill, Bernard M.] Univ Calif Los Angeles, Dept Urol, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Landaw, Elliot M.] Univ Calif Los Angeles, Dept Biomath, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Gau, Vincent] GeneFluidics, Monterey Pk, CA 91754 USA. [Haake, David A.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Haake, DA (reprint author), VA Greater LA Healthcare, Div Infect Dis, 111F, Los Angeles, CA 90073 USA. EM dhaake@ucla.edu FU National Institute of Biomedical Imaging and Bioengineering [EB00127]; National Institute of Allergy and Infectious Diseases [AI075565]; Wendy and Ken Ruby Fund for Excellence in Pediatric Urology Research FX This study was supported by Bioengineering Research Partnership Grant EB00127 (to B. M. C.) from the National Institute of Biomedical Imaging and Bioengineering, by Cooperative Agreement Award AI075565 (to D. A. H.) from the National Institute of Allergy and Infectious Diseases, and by the Wendy and Ken Ruby Fund for Excellence in Pediatric Urology Research. B. M. C. is the Judith and Robert Winston Chair in Pediatric Urology. NR 20 TC 11 Z9 11 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2008 VL 46 IS 8 BP 2707 EP 2716 DI 10.1128/JCM.00423-08 PG 10 WC Microbiology SC Microbiology GA 344EI UT WOS:000258908700032 PM 18562584 ER PT J AU Staropoli, JF Branda, JA AF Staropoli, John F. Branda, John A. TI Cord formation in a clinical isolate of Mycobacterium marinum SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID PRESUMPTIVE IDENTIFICATION; TUBERCULOSIS COMPLEX; CELL-WALL; PROBES AB Cord formation is a characteristic property of the cultured Mycobacterium tuberculosis complex species. We describe a case of Mycobacterium marinum demonstrating robust cord formation. Nontuberculous mycobacteria can form true cords in broth culture but do so rarely, despite the fact that many species contain the cell wall glycolipid that mediates cord formation. C1 Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Branda, JA (reprint author), 55 Fruit St,GRB-526, Boston, MA 02114 USA. EM jbranda@partners.org NR 13 TC 10 Z9 10 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD AUG PY 2008 VL 46 IS 8 BP 2814 EP 2816 DI 10.1128/JCM.00197-08 PG 3 WC Microbiology SC Microbiology GA 344EI UT WOS:000258908700052 PM 18579723 ER PT J AU Rini, BI Michaelson, MD Rosenberg, JE Bukowski, RM Sosman, JA Stadler, WM Hutson, TE Margolin, K Harmon, CS DePrimo, SE Kim, ST Chen, I George, DJ AF Rini, Brian I. Michaelson, M. Dror Rosenberg, Jonathan E. Bukowski, Ronald M. Sosman, Jeffrey A. Stadler, Walter M. Hutson, Thomas E. Margolin, Kim Harmon, Charles S. DePrimo, Samuel E. Kim, Sindy T. Chen, Isan George, Daniel J. TI Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 01-05, 2007 CL Chicago, IL SP Amer Soc Clin Oncol ID ENDOTHELIAL GROWTH-FACTOR; TARGETED THERAPY; VEGF; LYMPHANGIOGENESIS; CANCER; TRIAL AB Purpose To assess the safety and efficacy of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma (mRCC) and explore biomarkers for sunitinib response. Patients and Methods Patients with mRCC and disease progression after bevacizumab-based therapy received oral sunitinib 50 mg once daily in 6-week cycles on a 4/2 schedule (4 weeks with treatment followed by 2 weeks without treatment) in a phase II multicenter study. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), duration of response (DR), overall survival (OS), and safety. Plasma soluble proteins (vascular endothelial growth factor [VEGF]-A, VEGF-C, soluble VEGF receptor [sVEGFR]-3, and placental growth factor [PlGF]) levels were measured. Results Sixty-one patients were enrolled. The ORR was 23.0% (95% CI, 13.2% to 35.5%), median PFS was 30.4 weeks (95% CI, 18.3 to 36.7 weeks), median DR was 44.1 weeks (95% CI, 25.0 to 102.7 weeks), and median OS was 47.1 weeks (95% CI, 36.9 to 79.4 weeks). Mean plasma VEGF-A and PlGF levels significantly increased whereas VEGF-C and sVEGFR-3 levels decreased with sunitinib treatment. Lower baseline levels of sVEGFR-3 and VEGF-C were associated with longer PFS and ORR. Most treatment-related adverse events were of mild-to-moderate intensity and included fatigue, hypertension, and hand-foot syndrome. Conclusion Sunitinib has substantial antitumor activity in patients with bevacizumab-refractory mRCC and modulates circulating VEGF pathway biomarkers. These data support the hypothesis that sunitinib inhibits signaling pathways involved in bevacizumab resistance. Baseline levels of sVEGFR-3 and VEGF-C may have potential utility as biomarkers of clinical efficacy in this setting. C1 [Rini, Brian I.] Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol & Urol, Cleveland, OH 44195 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. City Hope Natl Med Ctr, Los Angeles, CA USA. Pfizer Global Res & Dev, La Jolla, CA USA. Vanderbilt Univ, Nashville, TN USA. Univ Chicago, Chicago, IL 60637 USA. Baylor Sammons Texas Oncol, Dallas, TX USA. Duke Univ, Med Ctr, Durham, NC USA. RP Rini, BI (reprint author), Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol & Urol, 9500 Euclid Ave,Desk R35, Cleveland, OH 44195 USA. EM rinib2@ccf.org OI Michaelson, Dror/0000-0001-9249-6338 NR 20 TC 292 Z9 299 U1 1 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2008 VL 26 IS 22 BP 3743 EP 3748 DI 10.1200/JCO.2007.15.5416 PG 6 WC Oncology SC Oncology GA 331ZV UT WOS:000258052100016 PM 18669461 ER PT J AU Kesari, S Akar, S Saad, A Drappatz, J Koralnik, IJ DeAngelo, DJ AF Kesari, Santosh Akar, Serra Saad, Ali Drappatz, Jan Koralnik, Igor J. DeAngelo, Daniel J. TI Progressive multifocal leukoencephalopathy in a patient with relapsed acute myelogenous leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; DISORDERS; CIDOFOVIR; DISEASE; AIDS C1 [Kesari, Santosh; Akar, Serra; Drappatz, Jan] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. [Kesari, Santosh; Drappatz, Jan] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [Kesari, Santosh; Drappatz, Jan; DeAngelo, Daniel J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Akar, Serra] Hacettepe Univ, Sch Med, Ankara, Turkey. [Saad, Ali] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol,Div Neuropathol, Boston, MA 02115 USA. [Koralnik, Igor J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Neurol,Div Viral Pathogenesis, Boston, MA 02215 USA. RP Kesari, S (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA 02115 USA. RI Kesari, Santosh/E-8461-2013 NR 18 TC 5 Z9 5 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 1 PY 2008 VL 26 IS 22 BP 3804 EP 3807 DI 10.1200/JCO.2008.17.3047 PG 5 WC Oncology SC Oncology GA 331ZV UT WOS:000258052100027 PM 18669471 ER PT J AU Gonzalez-Pinto, A Vega, P Ibanez, B Mosquera, F Barbeito, S Gutierrez, M De Azua, SR Ruiz, I Vieta, E AF Gonzalez-Pinto, Ana Vega, Patricia Ibanez, Berta Mosquera, Fernando Barbeito, Sara Gutierrez, Miguel De Azua, Sonia Ruiz Ruiz, Ivan Vieta, Eduard TI Impact of cannabis and other drugs on age at onset of psychosis SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID SUBSTANCE USE DISORDERS; 1ST-EPISODE PSYCHOSIS; BIPOLAR DISORDER; FOLLOW-UP; SCHIZOPHRENIA; MISUSE; ASSOCIATION; POPULATION; SMOKING; DEPENDENCE AB Objective: The aim of this study was to investigate the relationship between age and cannabis use in patients with a first psychotic episode, and to analyze the mediating effect of comorbid use of other drugs and sex on age at onset of psychosis. Method: All consenting patients (aged 15 to 65 years) with a first psychotic episode needing inpatient psychiatric treatment during a 2-year period between February 1997 and January 1999 were considered, confirming a total of 131 patients. Subjects were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders, and clinical and demographic data were collected. We used general linear models with age at onset as the response variable and survival Cox models to confirm the results. Both a multivariate linear model and the corresponding Cox model were fitted with a covariate that summarizes the most significant contributors that seemed to decrease age at onset. Results: Regarding the effect of cannabis use, a significant gradual reduction on age at onset was found as dependence on cannabis increased, consisting in a decrement of 7, 8.5, and 12 years for users, abusers, and dependents, respectively, with respect to nonusers (p = .004, p < .001, and p < .001, respectively). Multivariate analysis showed a clear effect of cannabis use on age at onset, which was not explained by the use of other drugs or by gender. The finding was similar in the youngest patients, suggesting that this effect was not due to chance. Conclusion: The major contribution of this investigation is the independent and strong link between cannabis use and early age at onset of psychosis, and the slight or nonexistent effect of sex and comorbid substance abuse in this variable. These results point to cannabis as a dangerous drug in young people at risk of developing psychosis. C1 [Gonzalez-Pinto, Ana; Vega, Patricia; Mosquera, Fernando; Barbeito, Sara; Gutierrez, Miguel; De Azua, Sonia Ruiz; Ruiz, Ivan] Santiago Apostol Hosp, Dept Psychiat, CIBER SAM, Vitoria 01004, Alava, Spain. [Ibanez, Berta] Basque Fdn Hlth Innovat & Res BIOEF, Sondika, Spain. Univ Barcelona, Hosp Clin, IDIBAPS, CIBER SAM, Barcelona, Spain. [Vieta, Eduard] Harvard Univ, Sch Med, Int Consortium Bipolar Disorders Res, Boston, MA 02115 USA. [Vieta, Eduard] Massachusetts Gen Hosp, McLean Div, Boston, MA 02114 USA. RP Gonzalez-Pinto, A (reprint author), Santiago Apostol Hosp, Dept Psychiat, CIBER SAM, Olaguibel 29,8th Floor,Sector B, Vitoria 01004, Alava, Spain. EM ANAMARIA.GONZALEZ-PINTOARRILLAGA@osakidetza.net RI Vieta, Eduard/I-6330-2013; Ibanez, Berta/A-6924-2017 OI Vieta, Eduard/0000-0002-0548-0053; Ibanez, Berta/0000-0002-7797-4845 NR 40 TC 57 Z9 57 U1 0 U2 7 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2008 VL 69 IS 8 BP 1210 EP 1216 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 339VF UT WOS:000258604700002 PM 18681755 ER PT J AU Biederman, J Petty, CR Fried, R Kaiser, R Dolan, CR Schoenfeld, S Doyle, AE Seidman, LJ Faraone, SV AF Biederman, Joseph Petty, Carter R. Fried, Ronna Kaiser, Roselinde Dolan, Chrystina R. Schoenfeld, Steven Doyle, Alysa E. Seidman, Larry J. Faraone, Stephen V. TI Educational and occupational underattainment in adults with attention-deficit/hyperactivity disorder: A controlled study SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; SUBTHRESHOLD DIAGNOSES; PSYCHIATRIC STATUS; LATE-ONSET; ADHD; BOYS; ACHIEVEMENT; COMORBIDITY; OUTCOMES; CHILDREN AB Objective: Attention-deficit/hyperactivity disorder (ADHD) has been consistently associated with intellectual, educational, and employment deficits. This study evaluated subjects to determine whether the educational and occupational deficits associated with ADHD are what would be expected given their intellectual abilities or lower than expected given their intellectual abilities. Method: Participants derived from a case-control study of adults with (N = 224) and without (N = 146) DSM-IV ADHD. Subjects were comprehensively assessed with structured diagnostic interviews and neuropsychological assessments. Educational and occupational attainments were based on Hollingshead socioeconomic status scale. The expected educational and occupational levels of participants with ADHD were computed using ordered logistic regression models as a function of age, sex, and full scale IQ of controls. The study was conducted from 1998 to 2003. Results: Based on their IQ, subjects with ADHD were predicted to have significantly more education than they actually attained. Additionally, based on their observed education, participants with ADHD were predicted to have significantly higher occupational levels than actually observed. Conclusion: These findings indicate that ADHD is associated with significant educational and occupational underattainments relative to what would have been expected on the basis of intellectual potential. C1 [Biederman, Joseph; Petty, Carter R.; Fried, Ronna; Kaiser, Roselinde; Dolan, Chrystina R.; Schoenfeld, Steven; Doyle, Alysa E.; Seidman, Larry J.] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. RP Biederman, J (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, 15 Parkman St,Warren 705, Boston, MA 02114 USA. EM jbiederman@partner.org OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [R01MH57934] NR 27 TC 68 Z9 68 U1 2 U2 10 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2008 VL 69 IS 8 BP 1217 EP 1222 PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 339VF UT WOS:000258604700003 PM 18681752 ER PT J AU Gilmer, WS Gollan, JK Wisniewski, SR Howland, RH Trivedi, MH Miyahara, S Fleck, J Thase, ME Alpert, JE Nierenberg, AA Warden, D Fava, M Rush, AJ AF Gilmer, William S. Gollan, Jackie K. Wisniewski, Stephen R. Howland, Robert H. Trivedi, Madhukar H. Miyahara, Sachiko Fleck, Jenelle Thase, Michael E. Alpert, Jonathan E. Nierenberg, Andrew A. Warden, Diane Fava, Maurizio Rush, A. John TI Does the duration of index episode affect the treatment outcome of major depressive disorder? A STAR*D report SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID SEQUENCED TREATMENT ALTERNATIVES; PROSPECTIVE FOLLOW-UP; REPORT QIDS-SR; RELIEVE DEPRESSION; PSYCHOMETRIC EVALUATION; SYMPTOMATOLOGY IDS; QUICK INVENTORY; HEALTH SURVEY; RATING SCALE; DOUBLE-BLIND AB Objective: This article aims to identify baseline sociodemographic and clinical characteristics associated with the duration of the index major depressive episode (MDE) and to assess the effect of the Current MDE duration oil response and remission rates with Lip to 14 weeks of citalopram. Method: Eligible participants met DSM-IV criteria for nonpsycholic major depressive disorder, scored >= 14 oil the 17-item Hamilton Rating Scale for Depression (HAM-D-17), and were not resistant to adequate antidepressant treatment in the current episode. The first patient was enrolled ill July 2001 and the last visit for the last patient in follow-up was in March 2006. The evaluable sample (N = 2851) was divided into 4 groups based on the index MDE duration at Study entry: acute (<= 6 months, N = 1324), subchronic (7-23 months, N = 807), chronic (24-41 months, N = 326), and ultrachronic (>= 42 months, N = 394). These 4 groups were compared in terms of baseline sociodemographic and clinical characteristics and treatment outcomes. Citalopram was generally begun at 20 mg/day and raised to 40 mg/day by weeks 2 through 4 and to 60 mg/day (final close) by weeks 4 through 6. Logistic regression models with adjusted post hoc analyses were used to control for associated baseline characteristics. Response was defined its >= 50% reduction in baseline 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16) scores at exit. Remission was defined as <= 7 on the HAM-D-17 or <= 5 on the QIDS-SR-16. Results: MDE duration was longer in primary care settings, blacks, Hispanics, single or widowed, unemployed, publicly insured or uninsured, older, and less educated participants and in those with lower income, less recurrence, or greater concurrent general medical or Axis I comorbidities. HAM-D-17 remission rates ranged from 31.0% (acute group) to 24.1% (ultrachronic group). HAM-D-17 remission rates were significantly related to MDE duration (p = .0010), but after adjustments for baseline differences among the 4 groups, remission rates were not different. QIDS-SR-16 response rates were lower for the subacute and chronic groups but not different for the acute and ultrachronic groups after adjustment. Conclusion: Longer MDE duration is associated with socioeconomic disadvantage and greater Axis I and medical comorbidity. Episode duration per se does not significantly affect the likelihood of remission. Trial Registration: clinicaltrials.gov Identifier: NCT00021528. C1 [Gilmer, William S.] Northwestern Univ, Feinberg Sch Med, Asher Ctr Study & Treatment Depress Disorders, Dept Psychiat & Behav Sci, Chicago, IL 60611 USA. [Wisniewski, Stephen R.; Miyahara, Sachiko] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA 15260 USA. [Howland, Robert H.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15260 USA. [Trivedi, Madhukar H.; Warden, Diane; Rush, A. John] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Rush, A. John] Univ Texas SW Med Ctr Dallas, Dept Clin Sci, Dallas, TX 75390 USA. [Thase, Michael E.] Univ Penn, Sch Med, Mood & Anxiety Disorders Treatment & Res Program, Philadelphia, PA 19104 USA. [Alpert, Jonathan E.; Nierenberg, Andrew A.; Fava, Maurizio] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. RP Gilmer, WS (reprint author), Northwestern Univ, Feinberg Sch Med, Asher Ctr Study & Treatment Depress Disorders, Dept Psychiat & Behav Sci, 446 E Ontario 7-100, Chicago, IL 60611 USA. EM w-gilmer@northwestern.edu RI Howland, Robert/K-6937-2015; OI Howland, Robert/0000-0002-6533-6010; Alpert, Jonathan/0000-0002-4332-908X; Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382 FU NIMH NIH HHS [N01MH90003] NR 53 TC 27 Z9 27 U1 4 U2 6 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2008 VL 69 IS 8 BP 1246 EP 1256 PG 13 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 339VF UT WOS:000258604700007 PM 18681756 ER PT J AU Papakostas, GI Stahl, SM Krishen, A Seifert, CA Tucker, VL Goodale, EP Fava, M AF Papakostas, George I. Stahl, Stephen M. Krishen, Alok Seifert, Cheryl A. Tucker, Vivian L. Goodale, Elizabeth P. Fava, Maurizio TI Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): A pooled analysis of 10 studies SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID DOUBLE-BLIND; SUSTAINED-RELEASE; ANTIDEPRESSANT EFFICACY; ATYPICAL DEPRESSION; PANIC ATTACKS; SERTRALINE; FLUOXETINE; OUTPATIENTS; PLACEBO; METAANALYSIS AB Objective: The goal of this work was to compare the efficacy of the norepinephrine and dopamine reuptake inhibitor bupropion with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder with high levels of anxiety (anxious depression). Method: Ten double-blind, randomized studies from 1991 through 2006 were combined (N = 2122). Anxious depression was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) anxiety-somatization factor score >= 7. Results: Among patients with anxious depression (N = 1275), response rates were greater following SSRI than bupropion treatment according to the HANI-D-17 (65.4% vs. 59.4%, p = .03) and the Hamilton Rating Scale for Anxiety (61.5% vs. 54.5%, p = .03). There was also a greater reduction in HAM-D-17 mean +/- SD scores (-14.1 +/- 7.6 vs. -13.2 +/- 7.9, p = .03) and a trend toward statistical significance for a greater reduction in HAM-A mean SD scores (-10.5 +/- 7.4 vs. -9.6 +/- 7.6, p = .05) in favor of SSRI treatment among patients with anxious depression. There was no statistically significant difference in efficacy between bupropion and the SSRIs among patients with moderate/low levels of anxiety. Conclusions: There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression (6% difference in response rates). Using the number-needed-to-treat (NNT) statistic as I indicator of clinical significance, nearly 17 patients would need to be treated with an SSRI than with bupropion in order to obtain I additional responder. This difference falls well above the limit of NNT = 10, which was suggested by the United Kingdom's National Institute of Clinical Excellence. Nevertheless, the present work is of theoretical interest because it provides preliminary evidence suggesting a central role for serotonin in the regulation of symptoms of negative affect Such as anxiety. C1 [Papakostas, George I.; Seifert, Cheryl A.; Fava, Maurizio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Stahl, Stephen M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Krishen, Alok; Tucker, Vivian L.; Goodale, Elizabeth P.] GlaxoSmithKline Inc, Durham, NC USA. RP Papakostas, GI (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 15 Parkman St,WACC 812, Boston, MA 02114 USA. EM gpapakostas@partners.org RI Papakostas, George/I-6905-2013 OI Papakostas, George/0000-0002-2465-5103 FU Akermes. AstraZeneca. Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly. GlaxoSmithKline, Janssen, Jazz Pharmaceuticals. Neutocrine Biosciences, Novartis, Organon. Pfizer. Sepracor, Shire. Somaxon, Takeda, and Wyeth FX Financial disclosure: Dr. Papakostas has served a, a consultant to Bristol-Myers Squibb. Eli Lilly, GlaxoSinithlKline, Evotec, Inflabloc Phamaceuticals, Jazz Pharmaceuticals. Pamlab, Pfizer, Pierre Fabre, Shire. and Wyeth has received honoraria front Bristol-Myers Squibb, Eli Lilly, Evotee, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Pamlab, Pfizer, Pierre Fabre, Shire, Titan Pharmaceuticals. and Wyeth: has received research support from Bristol-Myers Squibb, National Institute of Mental Health, Pamlab, Pfizer. and Precision Human Biolaboratories: and has served on the speakers bureau for Bristol-Myers Squibb and Pfizer. Dr. Stahl has received grant/research support from Akermes. AstraZeneca. Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly. GlaxoSmithKline, Janssen, Jazz Pharmaceuticals. Neutocrine Biosciences, Novartis, Organon. Pfizer. Sepracor, Shire. Somaxon, Takeda, and Wyeth; has served as a Consultant to Acadia. Amylin. AstraZeneca. Avera, Azur, Biovail, Boehringer Ingelheim, Bristol-Myers Squibb. Cephalon, CSC Pharmaceuticals. Cyberonics, Cypress Bioscience, Eli Lilly, EPIX Pharmaceuticals. Forest. GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, LaboPharm, Neurocrine Biosciences. Neuromolecular, Neuronetics, Novartis, Organon, Pamlab, Pfizer. Pierre Fabre, Sanofi-Aventis, Schering Plough, Sepracor, Shire. Solvay, SK Corporation, Somaxon. Tethys. Tetragenex, Vanda Pharmaceuticals, and Wyeth: has served on the speaker's bureau for Pfizer, AstraZeneca, Cephalon, CSC Pharmaceuticals, Eli Lilly, and Wyeth: and has served as a board member for Cypress Bioscience. Neuromolecular, Pierre Fabre, and Tetregenex. Drs. Tucker and Goodale are employees and stock shareholders of GlaxoSmithKline. Dr. Fava has received research support from Abbott, Alkermes, Aspect Medical Systems, AstraZeneca, Bristol-Myers Squibb. Cephalon. Eli Lilly, Forest, GlaxoSmithKline, Johnson & Johnson, Lichtwer Pharma GmbH, Lorex Pharmaceuticals, Novartis. Organon, Pamlab. Pfizer, Pharmavite, Roche, Sanofi-Synthelabo, Solvay, and Wyeth-Ayerst has served as an advisor/consultant for Aspect Medical Systems, AstraZeneca, Bayer. Best Practice Project Management, Biovail Pharmaceuticals, BrainCells. Bristol-Myers Squibb, Cephalon, Compellis, CNS Response, Cypress Pharmaceuticals, Dov Pharmaceuticals. Eli Lilly. EPIX Pharmaceuticals, Fabre-Kramer, Forest, GlaxoSmithKline, Grunenthal GmbH, Janssen, Jazz Pharmaceuticals, Johnson & Johnson, Knoll Pharmaceutical, Lundbeck, MedAvante. Merck, Neuronetics, Novartis, Nutrition 21. Organon, Pamlab. Pfizer. PharmaStar, Pharmavite, Precision Human Biolaboratory, Roche, Sanofi-Synthelabo, Sepracor, Solvay, Somaxon, Somerset Pharmaceuticals, Takeda, and Wyeth-Ayerst; has served as a speaker for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Novartis, Organon. Pfizer, PharmaStar. and Wyeth-Ayerst: and has equity holdings in Compellis and MedAvante. Mr. Krishen is an employee of GlaxoSmithKline. Ms. Seifert has no additional conflicts of interest to report. NR 43 TC 42 Z9 44 U1 1 U2 11 PU PHYSICIANS POSTGRADUATE PRESS PI MEMPHIS PA P O BOX 240008, MEMPHIS, TN 38124 USA SN 0160-6689 J9 J CLIN PSYCHIAT JI J. Clin. Psychiatry PD AUG PY 2008 VL 69 IS 8 BP 1287 EP 1292 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 339VF UT WOS:000258604700012 PM 18605812 ER PT J AU Monson, CM Fredman, SJ Adair, KC AF Monson, Candice M. Fredman, Steffany J. Adair, Kathryn C. TI Cognitive-behavioral conjoint therapy for Posttraumatic stress disorder: Application to operation enduring and Iraqi freedom veterans SO JOURNAL OF CLINICAL PSYCHOLOGY LA English DT Article DE posttraumatic stress disorder; couple therapy; cognitive-behavioral conjoint therapy ID SOLDIERS AB As the newest generation of veterans returns home from their duties abroad, many face the individual and interpersonal aftereffects of duty-related traumatic experiences. Despite the established association between posttraumatic stress disorder (PTSD) and relationship problems, there is a lack of evidence-based conjoint treatments that target both PTSD and relationship distress. Cognitive-behavioral conjoint therapy (CBCT) for PTSD was developed to address this need. The authors summarize knowledge on the association between PTSD and relationship functioning, as well as recent research on veterans and their partners. Following an overview of CBCT for PTSD, the authors present a case study to illustrate the application of CBCT to an Operation Enduring and Iraqi Freedom couple. (c) 2008 Wiley Periodicals, Inc. C1 [Monson, Candice M.; Fredman, Steffany J.; Adair, Kathryn C.] VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, Boston, MA 02130 USA. [Monson, Candice M.; Fredman, Steffany J.] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Monson, CM (reprint author), VA Boston Healthcare Syst, Womens Hlth Sci Div, Natl Ctr PTSD, 150 S Huntington Ave 116B-3, Boston, MA 02130 USA. EM Candice.Monson@va.gov; Steffany.Fredman@va.gov; Kathryn.Adair@va.gov FU NIMH NIH HHS [1 R34 MH076813-01A2] NR 15 TC 40 Z9 43 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9762 J9 J CLIN PSYCHOL JI J. Clin. Psychol. PD AUG PY 2008 VL 64 IS 8 BP 958 EP 971 DI 10.1002/jclp.20511 PG 14 WC Psychology, Clinical SC Psychology GA 330ES UT WOS:000257922900005 PM 18613094 ER PT J AU Rosenbaum, RS Moscovitch, M Foster, JK Schnyer, DM Ga, F Kovacevic, N Verfaellie, M Black, SE Levine, B AF Rosenbaum, R. Shayna Moscovitch, Morris Foster, Jonathan K. Schnyer, David M. Ga, Fuqiang Kovacevic, Natasha Verfaellie, Mieke Black, Sandra E. Levine, Brian TI Patterns of autobiographical memory loss in medial-temporal lobe amnesic patients SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID REMOTE SPATIAL MEMORY; BILATERAL HIPPOCAMPAL-LESIONS; AUTOMATED IMAGE REGISTRATION; RETROGRADE-AMNESIA; FUNCTIONAL NEUROANATOMY; COGNITIVE NEUROSCIENCE; ALZHEIMERS-DISEASE; EPISODIC MEMORIES; OLD MEMORIES; LIFE-SPAN AB The issue of whether the hippocampus and related structures in the medial-temporal lobe (MTL) play a temporary or permanent role in autobiographical episodic memory remains unresolved. One long-standing belief is that autobiographical memory (AIM), like semantic memory, is initially dependent on the MTL but ultimately can be retained and recovered independently of it. However, evidence that hippocampal amnesia results in severe loss of episodic memory for a lifetime of personally experienced events suggests otherwise. To test the opposing views, we conducted detailed investigations of autobiographical episodic memory in people with amnesia resulting from MTL lesions of varying extent. By combining precise quantification of MTL and neocortical volumes with sensitive measures of recollection of one's personal past, we show that the severity of episodic, but not semantic, AM loss is best accounted for by the degree of hippocampal damage and less likely related to additional neocortical compromise. C1 [Rosenbaum, R. Shayna] York Univ, Dept Psychol, Toronto, ON M3J 1P3, Canada. [Rosenbaum, R. Shayna; Moscovitch, Morris; Black, Sandra E.; Levine, Brian] Baycrest Ctr Geriatr Care, Toronto, ON, Canada. [Moscovitch, Morris; Black, Sandra E.; Levine, Brian] Univ Toronto, Toronto, ON, Canada. [Foster, Jonathan K.] Edith Cowan Univ, Perth, WA, Australia. [Foster, Jonathan K.] Hlth Dept Western Australia, Neurosci Unit, Perth, WA, Australia. [Schnyer, David M.] Univ Texas Austin, Austin, TX 78712 USA. [Ga, Fuqiang; Black, Sandra E.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Verfaellie, Mieke] Boston VA Healthcare Syst, Boston, MA USA. [Verfaellie, Mieke] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Rosenbaum, RS (reprint author), York Univ, Dept Psychol, 4700 Keele St, Toronto, ON M3J 1P3, Canada. EM shaynar@yorku.ca RI Levine, Brian/G-4328-2010; Hoang, Nick/N-5738-2015; OI Levine, Brian/0000-0003-4343-811X; Hoang, Nick/0000-0001-7097-7114; Black, Sandra/0000-0001-7093-8289 FU NICHD NIH HHS [HD 42385-01] NR 70 TC 66 Z9 66 U1 3 U2 24 PU M I T PRESS PI CAMBRIDGE PA 238 MAIN STREET, STE 500, CAMBRIDGE, MA 02142-1046 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD AUG PY 2008 VL 20 IS 8 BP 1490 EP 1506 DI 10.1162/jocn.2008.20105 PG 17 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 326OU UT WOS:000257669600013 PM 18303977 ER PT J AU Taft, CT Schumm, JA Panuzio, J Proctor, SP AF Taft, Casey T. Schumm, Jeremiah A. Panuzio, Jillian Proctor, Susan P. TI An examination of family adjustment among operation desert storm veterans SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE combat; posttraumatic stress disorder; family; veterans ID POSTTRAUMATIC-STRESS-DISORDER; MALE VIETNAM VETERANS; PSYCHOLOGICAL DISTRESS; COMBAT VETERANS; GULF-WAR; AMERICAN-LEGIONNAIRES; ARTICULATED THOUGHTS; POWER ANALYSIS; ANGER AROUSAL; RISK-FACTORS AB This study examined interrelationships among combat exposure, symptoms of posttraumatic stress disorder (PTSD), and family adjustment in a sample of male and female Operation Desert Storm veterans (N = 1,512). In structural equation models for both male and female veterans, higher combat exposure was associated with higher PTSD symptoms, which in turn were associated with poorer family adjustment, although these indirect effects did not reach statistical significance. The model for female veterans evidenced a significant direct negative association between combat exposure and family adjustment when it statistically accounted for PTSD symptoms. When the relative impacts of separate PTSD symptom groupings were examined, those reflecting withdrawal/numbing symptoms and arousal/lack of control symptoms significantly and indirectly accounted for the negative effects of combat exposure on family adjustment. Study findings indicate a number of possible pathways through which war-zone deployments negatively impact military families and suggest several avenues for future research. C1 [Taft, Casey T.; Panuzio, Jillian] Vet Affairs Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA USA. [Taft, Casey T.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Schumm, Jeremiah A.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Proctor, Susan P.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02215 USA. RP Taft, CT (reprint author), Vet Affairs Boston Healthcare Syst 116B 2, 150 S Huntington Ave, Boston, MA 02130 USA. EM casey.taft@va.gov NR 63 TC 43 Z9 43 U1 5 U2 11 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD AUG PY 2008 VL 76 IS 4 BP 648 EP 656 DI 10.1037/a0012576 PG 9 WC Psychology, Clinical SC Psychology GA 331JH UT WOS:000258008000010 PM 18665692 ER PT J AU Schaefer, JT Nuovo, GJ Yen, BTS Werner, B AF Schaefer, Jochen T. Nuovo, Gerard J. Yen, Benedict T. S. Werner, Betina TI Prominent eosinophilic intranuclear inclusions in melanocytes of a melanocytic nevus: the aftermath of an infection with molluscum contagiosum? A case report SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Article ID PARAMYXOVIRUS-LIKE INCLUSIONS; POLYMERASE-CHAIN-REACTION; MARINESCO BODIES; CORPUSCLES; ATAXIAS; PROTEIN; VIRUS; GENE AB A 65-year-old Latino man presented to his dermatologist for the removal of two melanocytic nevi from the back. The first nevus was removed from the right scapula and contained melanocytes with prominent eosinophilic nuclear inclusion bodies. The second nevus was removed from the paravertebral region, without evidence of inclusion bodies. Ultrastructurally, the inclusions in the first nevus contained dispersed finely granular, homogenous bodies without a limiting membrane. Immunohistochemistry characterized them as ubiquitin-positive material. Reverse transcriptase in situ polymerase chain reaction analysis was positive for molluscum-specific primers, suggesting that the inclusions encountered in the first nevus were secondary to a remote, local molluscum viral infection of melanocytes. C1 [Schaefer, Jochen T.] Cornell Univ, Weill Med Coll, Div Dermatopathol, Dept Pathol & Lab Med, New York, NY 10044 USA. [Nuovo, Gerard J.] Ohio State Univ, Dept Pathol, Columbus, OH 43210 USA. [Yen, Benedict T. S.] Univ Calif San Francisco, San Francisco VA Med Ctr, Pathol Serv, San Francisco, CA 94143 USA. [Yen, Benedict T. S.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Werner, Betina] Univ Curitiba, Dept Pathol, Curitiba, Parana, Brazil. RP Schaefer, JT (reprint author), Cornell Univ, Weill Med Coll, Div Dermatopathol, Dept Pathol & Lab Med, 1300 York Ave,F-309, New York, NY 10044 USA. EM jos9117@nyp.org NR 22 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6987 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD AUG PY 2008 VL 35 IS 8 BP 782 EP 788 DI 10.1111/j.1600-0560.2007.00902.x PG 7 WC Dermatology; Pathology SC Dermatology; Pathology GA 327GD UT WOS:000257716700014 PM 18430043 ER PT J AU Duailibi, SE Duailibi, MT Zhang, W Asrican, R Vacanti, JP Yelick, PC AF Duailibi, S. E. Duailibi, M. T. Zhang, W. Asrican, R. Vacanti, J. P. Yelick, P. C. TI Bioengineered dental tissues grown in the rat jaw SO JOURNAL OF DENTAL RESEARCH LA English DT Article DE tooth tissue engineering; dental stem cells; mandibular model ID MESENCHYMAL STEM-CELLS; PERIODONTAL-LIGAMENT; BONE-MARROW; IN-VITRO; TOOTH; PULP; TEETH; REGENERATION; NICHE; VIVO AB Our long-term objective is to develop methods to form, in the jaw, bioengineered replacement teeth that exhibit physical properties and functions similar to those of natural teeth. Our results show that cultured rat tooth bud cells, seeded onto biodegradable scaffolds, implanted into the jaws of adult rat hosts and grown for 12 weeks, formed small, organized, bioengineered tooth crowns, containing dentin, enamel, pulp, and periodontal ligament tissues, similar to identical cell-seeded scaffolds implanted and grown in the omentum. Radiographic, histological, and immunohisto chemical analyses showed that bioengineered teeth consisted of organized dentin, enamel, and pulp tissues. This study advances practical applications for dental tissue engineering by demonstrating that bioengineered tooth tissues can be regenerated at the site of previously lost teeth, and supports the use of tissue engineering strategies in humans, to regenerate previously lost and/or missing teeth. The results presented in this report support the feasibility of bioengineered replacement tooth formation in the jaw. C1 [Yelick, P. C.] Tufts Univ, Div Craniofacial & Mol Genet, Dept Oral & Maxillofacial Pathol, Boston, MA 02111 USA. [Duailibi, S. E.; Duailibi, M. T.] Univ Fed Sao Paulo, Interdisciplinary Ctr Gene Therapy, CINTERGEN, Dept Plast Surg, Sao Paulo, Brazil. [Asrican, R.] Harvard Univ, Sch Dent Med, Forsyth Inst, Dept Cytokine Biol, Boston, MA 02115 USA. [Asrican, R.] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Vacanti, J. P.] Massachusetts Gen Hosp, Lab Tissue Engn & Organ Fabricat, Boston, MA 02114 USA. [Vacanti, J. P.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Yelick, PC (reprint author), Tufts Univ, Div Craniofacial & Mol Genet, Dept Oral & Maxillofacial Pathol, 136 Harrison Ave,Room M824, Boston, MA 02111 USA. EM pamela.yelick@tufts.edu RI Zhang, Weibo/S-1546-2016 OI Zhang, Weibo/0000-0001-6246-2487 FU NIDCR NIH HHS [R01 DE016132, R01 DE016132-01A1] NR 36 TC 51 Z9 56 U1 2 U2 11 PU INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R PI ALEXANDRIA PA 1619 DUKE ST, ALEXANDRIA, VA 22314-3406 USA SN 0022-0345 J9 J DENT RES JI J. Dent. Res. PD AUG PY 2008 VL 87 IS 8 BP 745 EP 750 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 329PM UT WOS:000257880800008 PM 18650546 ER PT J AU Yiadom, MYMAB Platz, E Brown, DFM Nadel, ES AF Yiadom, Maarne Yaa Maya A. B. Platz, Elke Brown, David F. M. Nadel, Eric S. TI Pneumothorax in a blunt trauma patient SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID THORACIC ULTRASOUND; FOCUSED ASSESSMENT; SONOGRAPHY C1 [Yiadom, Maarne Yaa Maya A. B.; Nadel, Eric S.] Brigham & Womens Hosp, Harvard Affiliated Emergency Med Residency, Boston, MA 02114 USA. [Yiadom, Maarne Yaa Maya A. B.; Nadel, Eric S.] Massachusetts Gen Hosp, Harvard Affiliated Emergency Med Residency, Boston, MA 02114 USA. [Platz, Elke] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Brown, David F. M.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Nadel, ES (reprint author), Brigham & Womens Hosp, Harvard Affiliated Emergency Med Residency, 75 Francis St,Neville House,2nd Floor, Boston, MA 02114 USA. NR 13 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0736-4679 J9 J EMERG MED JI J. Emerg. Med. PD AUG PY 2008 VL 35 IS 2 BP 199 EP 203 DI 10.1016/j.jemermed.2008.05.014 PG 5 WC Emergency Medicine SC Emergency Medicine GA 337ZY UT WOS:000258475700015 PM 18599250 ER PT J AU Dumont, RH AF Dumont, Raymonde H. TI Drawing a family map: an experiential tool for engaging children in family therapy SO JOURNAL OF FAMILY THERAPY LA English DT Article ID SYSTEM-TEST; WORK; PARTICIPATION; PERCEPTION; INCLUSION; SPACE; PLAY AB Inclusion of children in the treatment process is a central aspect of the discipline of family therapy. Young children's verbal skill and level of abstraction may not be suited to 'talking therapy', but they have an intuitive grasp of family life which is invaluable, and their views and needs should be considered when effecting change in the family system. A method is offered to engage young children, adolescents and adults of divergent verbal skills into a shared process. It requires no special set-up or tools, only paper and markers. Distance and proximity are represented in a simple map of the family, adding symbols for affection and conflict. A spatial representation of the family system is created, and may be referred to in the course of the therapy. C1 [Dumont, Raymonde H.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Cambridge, MA 02138 USA. RP Dumont, RH (reprint author), Tamarack Pl,POB 470, Hancock, ME 04640 USA. EM raedumont@gmail.com NR 37 TC 0 Z9 0 U1 3 U2 11 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0163-4445 J9 J FAM THER JI J. Fam. Ther. PD AUG PY 2008 VL 30 IS 3 BP 247 EP 259 DI 10.1111/j.1467-6427.2008.00429.x PG 13 WC Psychology, Clinical; Family Studies SC Psychology; Family Studies GA 325CJ UT WOS:000257565500003 ER PT J AU Jaeger, JR Spielman, D Cronholm, PF Applebaum, S Holmes, WC AF Jaeger, Jeffrey R. Spielman, Darren Cronholm, Peter F. Applebaum, Sam Holmes, William C. TI Screening male primary care patients for intimate partner violence perpetration SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE male patients; intimate partner violence; primary care provider AB BACKGROUND: Primary prevention of intimate partner violence (IPV) at the level of the primary care provider is unexplored. OBJECTIVE: We sought to identify whether men disclose current IPV perpetration when asked by a primary care provider. DESIGN: Cross-sectional study. PARTICIPANTS: Consecutive male patients of 6 providers in public health, university, and VA hospital clinics. MEASUREMENTS: Men were screened for IPV perpetration during routine visits, then given a Conflict Tactics Scale questionnaire (CTS2) to complete and mail back anonymously. RESULTS: One hundred twenty-eight men were screened; 46 (36%) returned CTS2 questionnaires. Twenty-three and 2 men disclosed past and current perpetration to providers, respectively. Providers assessed lethality/safety issues in 58% of those reporting a perpetration history (including both with current perpetration), responded with direct counseling to 63% (including both with current perpetration), and referred 17% for services related to the screening (including 1 with current perpetration). Nine and 26 men reported current, CTS2-assessed physical and psychological aggression of a partner, respectively. CONCLUSIONS: Men appear to underreport current IPV perpetration in face-to-face primary care encounters when compared to other methods of reporting. Men may more readily report past IPV perpetration in face-to-face encounters. C1 [Jaeger, Jeffrey R.; Holmes, William C.] Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Jaeger, Jeffrey R.; Spielman, Darren; Cronholm, Peter F.] Inst Safe Families, Philadelphia, PA USA. [Cronholm, Peter F.] Univ Penn, Sch Med, Dept Family Med & Community Hlth, Philadelphia, PA 19104 USA. [Cronholm, Peter F.] Univ Penn, Sch Med, Firearm & Injury Ctr Penn, Philadelphia, PA 19104 USA. [Cronholm, Peter F.; Holmes, William C.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Holmes, William C.] Philadelphia VA Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. [Cronholm, Peter F.; Holmes, William C.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. RP Jaeger, JR (reprint author), 3701 Marker St,Suite 760, Philadelphia, PA 19104 USA. EM JaegerJ@uphs.upenn.edu NR 24 TC 7 Z9 7 U1 0 U2 1 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 AUG PY 2008 VL 23 IS 8 BP 1152 EP 1156 DI 10.1007/s11606-008-0634-9 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 337RX UT WOS:000258454300005 PM 18459009 ER PT J AU Nicolaidis, C Gregg, J Galian, H McFarland, B Curry, M Gerrity, M AF Nicolaidis, Christina Gregg, Jessica Galian, Hilary McFarland, Bentson Curry, MaryAnn Gerrity, Martha TI "You Always End up Feeling Like You're Some Hypochondriac": Intimate partner violence survivors' experiences addressing depression and pain SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE intimate partner violence; depression; pain; physical symptoms; qualitative research; physician-patient relationship ID PHYSICAL HEALTH CONSEQUENCES; SYMPTOM CHECKLIST HSCL; DOMESTIC VIOLENCE; SOMATIC SYMPTOMS; PRIMARY-CARE; WOMEN; FAMILY; DISORDERS; SEVERITY; VICTIMS AB OBJECTIVE: Little is known regarding how providers should use information about intimate partner violence (IPV) to care for depressed patients. Our objective was to explore what depressed IPV survivors believe about the relationship between abuse, mental health, and physical symptoms and to elicit their recommendations for addressing depression. DESIGN: Focus group study. PATIENTS/PARTICIPANTS: Adult, English-speaking, female, Internal Medicine clinic patients with depressive symptoms and a history of IPV. INTERVENTIONS: Thematic analysis using an inductive approach (consistent with grounded theory), at a semantic level, with an essentialist paradigm. MEASUREMENTS AND MAIN RESULTS: Twenty three women participated in 5 focus groups. Although selected because of their depression, participants often felt their greatest concerns were physical. They acknowledged that their abuse history, depression, and physical complaints compound each other. They appreciated the need for health care workers to know about their depression and IPV history to get a "full picture" of their health, but they were often hesitant to discuss such issues with providers because of their fear that such information would make providers think their symptoms were "all in their head" or would encourage providers to discount their pain. Participants discussed difficulties related to trust and control in relationships with providers and gave recommendations as to how providers can earn their trust. CONCLUSIONS: Understanding a patient's IPV history may allow providers to develop a better therapeutic relationship. To treat depression adequately, it is important for providers to reassure patients that they believe their physical symptoms; to communicate respect for patients' intelligence, experience, and complexity; and to share control. C1 [Nicolaidis, Christina; Gregg, Jessica; Galian, Hilary; Gerrity, Martha] Oregon Hlth & Sci Univ, Dept Med, Div Gen Internal Med, Portland, OR 97201 USA. [Nicolaidis, Christina; McFarland, Bentson] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. [McFarland, Bentson] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97201 USA. [Curry, MaryAnn] Oregon Hlth & Sci Univ, Sch Nursing, Portland, OR 97201 USA. [Gerrity, Martha] Portland VA Med Ctr, Portland, OR USA. RP Nicolaidis, C (reprint author), Oregon Hlth & Sci Univ, Dept Med, Div Gen Internal Med, Portland, OR 97201 USA. EM nicolaid@ohsu.edu OI McFarland, Bentson/0000-0001-9149-5616 FU NIMH NIH HHS [K23 MH073008-03, K23 MH073008] NR 34 TC 11 Z9 11 U1 2 U2 6 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 AUG PY 2008 VL 23 IS 8 BP 1157 EP 1163 DI 10.1007/s11606-008-0606-0 PG 7 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 337RX UT WOS:000258454300006 PM 18443884 ER PT J AU Goetz, MB Hoang, T Bowman, C Knapp, H Rossman, B Smith, R Anaya, H Osborn, T Gifford, AL Asch, SM AF Goetz, Matthew Bidwell Hoang, Tuyen Bowman, Candice Knapp, Herschel Rossman, Barbara Smith, Robert Anaya, Henry Osborn, Teresa Gifford, Allen L. Asch, Steven M. CA QUERI HIV Hepatitis Program TI A system-wide intervention to improve HIV testing in the Veterans Health Administration SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE diagnosis; HIV testing; quality improvement ID HUMAN-IMMUNODEFICIENCY-VIRUS; QUALITY-OF-CARE; CLINICAL REMINDERS; UNITED-STATES; COST-EFFECTIVENESS; CHRONIC ILLNESS; PERSONS AWARE; INFECTION; RECOMMENDATIONS; TRANSMISSION AB BACKGROUND: Although the benefits of identifying and treating asymptomatic HIV-infected individuals are firmly established, health care providers often miss opportunities to offer HIV-testing. OBJECTIVE: To evaluate whether a multi-component intervention increases the rate of HIV diagnostic testing. DESIGN: Pre- to post-quasi-experiment in 5 Veterans Health Administration facilities. Two facilities received the intervention; the other three facilities were controls. The intervention included a real-time electronic clinical reminder that encourages HIV testing, and feedback reports and a provider activation program. PATIENTS: Persons receiving health care between August 2004 and September 2006 who were at risk but had not been previously tested for HIV infection MEASUREMENTS: Pre- to post-changes in the rates of HIV testing at the intervention and control facilities RESULTS: At the two intervention sites, the adjusted rate of testing increased from 4.8% to 10.8% and from 5.5% to 12.8% (both comparisons, p <.001). In addition, there were 15 new diagnoses of HIV in the pre-intervention year (0.46% of all tests) versus 30 new diagnoses in the post-intervention year (0.45% of all tests). No changes were observed at the control facilities. CONCLUSIONS: Use of clinical reminders and provider feedback, activation, and social marketing increased the frequency of HIV testing and the number of new HIV diagnoses. These findings support a multimodal approach toward achieving the Centers for Disease Control and Prevention's goal of having every American know their HIV status as a matter of routine clinical practice. C1 [Goetz, Matthew Bidwell; Rossman, Barbara] VA Greater Los Angeles Healthcare Syst, Infect Dis Sect 111 F, Los Angeles, CA 90073 USA. [Goetz, Matthew Bidwell; Asch, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Bowman, Candice; Smith, Robert] VA San Diego Healthcare Syst, San Diego, CA USA. [Osborn, Teresa] VISN 22, Long Beach, CA USA. [Gifford, Allen L.] Edith Nourse Rogers Mem Vet Adm Hosp, VA Bedford Ctr Hlth Qual Qoutcomes & Econ Res, Bedford, MA 01730 USA. [Gifford, Allen L.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Gifford, Allen L.] Boston Univ, Sch Med, Boston, MA USA. RP Goetz, MB (reprint author), VA Greater Los Angeles Healthcare Syst, Infect Dis Sect 111 F, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM matthew.goetz@va.gov OI Goetz, Matthew/0000-0003-4542-992X NR 53 TC 37 Z9 37 U1 1 U2 3 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 AUG PY 2008 VL 23 IS 8 BP 1200 EP 1207 DI 10.1007/s11606-008-0637-6 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 337RX UT WOS:000258454300013 PM 18452045 ER PT J AU Koplan, KE Regan, S Goldszer, RC Schneider, LI Rigotti, NA AF Koplan, Kate E. Regan, Susan Goldszer, Robert C. Schneider, Louise I. Rigotti, Nancy A. TI A computerized aid to support smoking cessation treatment for hospital patients SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE hospital medicine; medical informatics; physician behavior; smoking cessation; quality improvement ID MORTALITY AB BACKGROUND: Hospital-based interventions promote smoking cessation after discharge. Strategies to deliver these interventions are needed, especially now that providing smoking cessation advice or treatment, or both, to inpatient smokers is a publicly reported quality-of-care measure for US hospitals. OBJECTIVE: To assess the effect of adding a tobacco order set to an existing computerized order-entry system used to admit Medicine patients to 1 hospital. DESIGN: Pre-post study. MEASUREMENTS AND MAIN RESULTS: Proportion of admitted patients who had smoking status identified, a smoking counselor consulted, or nicotine replacement therapy (NRT) ordered during 4 months before and after the change. In 4 months after implementation, the order set was used with 76% of Medicine admissions, and a known smoking status was recorded for 81% of these patients. The intervention increased the proportion of admitted patients who were referred for smoking counseling (0.8 to 2.1%) and had NRT ordered (1.6 to 2.5%) (p <.0001 for both). Concomitantly, the hospital's performance on the smoking cessation quality measure improved. CONCLUSIONS: Adding a brief tobacco order set to an existing computerized order-entry system increased a hospital's provision of evidence-based tobacco treatment and helped to improve its performance on a publicly reported quality measure. It provides a model for US hospitals seeking to improve their quality of care for inpatients. C1 [Koplan, Kate E.; Regan, Susan; Goldszer, Robert C.; Schneider, Louise I.; Rigotti, Nancy A.] Harvard Univ, Sch Med, Boston, MA USA. [Regan, Susan; Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. [Koplan, Kate E.; Schneider, Louise I.; Rigotti, Nancy A.] Partners Healthcare Inc, Tobacco Treatment Task Force, Boston, MA USA. [Koplan, Kate E.; Goldszer, Robert C.] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. RP Koplan, KE (reprint author), 275 Grove St,Suite 3-300, Auburndale, MA 02466 USA. EM kkoplan@partners.org OI Regan, Susan/0000-0003-0940-2017 FU NHLBI NIH HHS [K24 HL004440, K24 HL04440] NR 11 TC 16 Z9 16 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2008 VL 23 IS 8 BP 1214 EP 1217 DI 10.1007/s11606-008-0610-4 PG 4 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 337RX UT WOS:000258454300015 PM 18465176 ER PT J AU Balaban, RB Weissman, JS Samuel, PA Woolhandler, S AF Balaban, Richard B. Weissman, Joel S. Samuel, Peter A. Woolhandler, Stephanie TI Redefining and redesigning hospital discharge to enhance patient care: A randomized controlled study SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE hospital medicine; care management; quality improvement; continuity of care; patient-centered care ID PATIENTS AFTER-DISCHARGE; ADVERSE EVENTS; MEDICATION DISCREPANCIES; POSTHOSPITAL CARE; CONTINUITY; TRANSITIONS; QUALITY; SAFETY; PHYSICIANS; OUTCOMES AB BACKGROUND: Patients are routinely ill-prepared for the transition from hospital to home. Inadequate communication between Hospitalists and primary care providers can further compromise post-discharge care. Redesigning the discharge process may improve the continuity and the quality of patient care. OBJECTIVES: To evaluate a low-cost intervention designed to promptly reconnect patients to their "medical home" after hospital discharge. DESIGN: Randomized controlled study. Intervention patients received a "user-friendly" Patient Discharge Form, and upon arrival at home, a telephone outreach from a nurse at their primary care site. PARTICIPANTS: A culturally and linguistically diverse group of patients admitted to a small community teaching hospital. MEASUREMENTS: Four undesirable outcomes were measured after hospital discharge: (1) no outpatient follow-up within 21 days; (2) readmission within 31 days; (3) emergency department visit within 31 days; and (4) failure by the primary care provider to complete an outpatient workup recommended by the hospital doctors. Outcomes of the intervention group were compared to concurrent and historical controls. RESULTS: Only 25.5% of intervention patients had 1 or more undesirable outcomes compared to 55.1% of the concurrent and 55.0% of the historical controls. Notably, only 14.9% of the intervention patients failed to follow-up within 21 days compared to 40.8% of the concurrent and 35.0% of the historical controls. Only 11.5% of recommended outpatient workups in the intervention group were incomplete versus 31.3% in the concurrent and 31.0% in the historical controls. CONCLUSIONS: A low-cost discharge-transfer intervention may improve the rates of outpatient follow-up and of completed workups after hospital discharge. C1 [Balaban, Richard B.; Woolhandler, Stephanie] Cambridge Hlth Alliance, Dept Med, Cambridge, MA USA. [Weissman, Joel S.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA USA. [Weissman, Joel S.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Weissman, Joel S.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Cambridge, MA 02138 USA. RP Balaban, RB (reprint author), Cambridge Hlth Alliance, Dept Med, Cambridge, MA USA. EM rbalaban@massmed.org NR 33 TC 72 Z9 73 U1 0 U2 9 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 2008 VL 23 IS 8 BP 1228 EP 1233 DI 10.1007/s11606-008-0618-9 PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 337RX UT WOS:000258454300018 PM 18452048 ER PT J AU McDermott, KA Helfrich, CD Sales, AE Rumsfeld, JS Ho, PM Fihn, SD AF McDermott, Kelly A. Helfrich, Christian D. Sales, Anne E. Rumsfeld, John S. Ho, P. Michael Fihn, Stephan D. TI A review of interventions and system changes to improve time to reperfusion for ST-segment elevation myocardial infarction SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Review DE cardiac reperfusion; myocardial infarction; systematic review; quality improvement ID NURSE INITIATED THROMBOLYSIS; TO-BALLOON TIME; PERCUTANEOUS CORONARY INTERVENTION; EMERGENCY-DEPARTMENT; PRIMARY ANGIOPLASTY; NEEDLE TIMES; CARE-UNIT; NATIONAL-REGISTRY; CRITICAL PATHWAY; REDUCES DOOR AB OBJECTIVE: Identify and describe interventions to reduce time to reperfusion for patients with ST-segment elevation myocardial infarction (STEMI). DATA SOURCE: Key word searches of five research databases: MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), EMBASE, Web of Science, and Cochrane Clinical Trials Registry. INTERVENTIONS: We included controlled and uncontrolled studies of interventions to reduce time to reperfusion. One researcher reviewed abstracts and 2 reviewed full text articles. Articles were subsequently abstracted into structured data tables, which included study design, setting, intervention, and outcome variables. We inductively developed intervention categories from the articles. A second researcher reviewed data abstraction for accuracy. MEASUREMENTS AND MAIN RESULTS: We identified 666 articles, 42 of which met inclusion criteria. We identified 11 intervention categories and classified them as either process specific (e.g., emergency department administration of thrombolytic therapy, activation of the catheterization laboratory by emergency department personnel) or system level (e.g., continuous quality improvement, critical pathways). A majority of studies (59%) were single-site pre/post design, and nearly half (47%) had sample sizes less than 100 patients. Thirty-two studies (76%) reported significantly lower door to reperfusion times associated with an intervention, 12 (29%) of which met or exceeded guideline recommended times. Relative decreases in times to reperfusion ranged from 15 to 82% for door to needle and 13-64% for door to balloon. CONCLUSIONS: We identified an array of process and system-based quality improvement interventions associated with significant improvements in door to reperfusion time. However, weak study designs and inadequate information about implementation limit the usefulness of this literature. C1 [McDermott, Kelly A.; Helfrich, Christian D.; Sales, Anne E.; Fihn, Stephan D.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Sales, Anne E.] Univ Alberta, Edmonton, AB, Canada. [Rumsfeld, John S.; Ho, P. Michael] VA Eastern Colorado Hlth Care Syst, Denver, CO USA. RP Sales, AE (reprint author), 3-114 Clin Sci Bldg, Edmonton, AB T6G 2G3, Canada. EM anne.sales@ualberta.ca RI Sales, Anne/D-9678-2012; Helfrich, Christian/D-2382-2016; OI Helfrich, Christian/0000-0002-9827-4768; Sales, Anne/0000-0001-9360-3334 NR 64 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD AUG PY 2008 VL 23 IS 8 BP 1246 EP 1256 DI 10.1007/s11606-008-0563-7 PG 11 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 337RX UT WOS:000258454300021 PM 18459014 ER PT J AU May, FJ Li, L Zhang, SL Guzman, H Beasley, DWC Tesh, RB Higgs, S Raj, P Bueno, R Randle, Y Chandler, L Barrett, ADT AF May, Fiona J. Li, Li Zhang, Shuliu Guzman, Hilda Beasley, David W. C. Tesh, Robert B. Higgs, Stephen Raj, Pushker Bueno, Rudy, Jr. Randle, Yvonne Chandler, Laura Barrett, Alan D. T. TI Genetic variation of St. Louis encephalitis virus SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID WEST-NILE-VIRUS; TRANS-OVARIAL TRANSMISSION; MURRAY VALLEY ENCEPHALITIS; PARTIAL NUCLEOTIDE-SEQUENCE; STRONG PURIFYING SELECTION; YELLOW-FEVER VIRUS; PAPUA-NEW-GUINEA; JAPANESE ENCEPHALITIS; PHYLOGENETIC ANALYSIS; ENVELOPE PROTEIN AB St. Louis encephalitis virus (SLEV) has been regularly isolated throughout the Americas since 1933. Previous phylogenetic studies involving 62 isolates have defined seven major lineages (IVII), further divided into 14 clades. In this study, 28 strains isolated in Texas in 1991 and 2001 2003, and three older, previously unsequenced strains from Jamaica and California were sequenced over the envelope protein gene. The inclusion of these new sequences, and others published since 2001, has allowed better delineation of the previously published SLEV lineages, in particular the clades of lineage 11. Phylogenetic analysis of 106 isolates identified 13 clades. All 1991 and 2001 -2003 isolates from NUeces, Jefferson and Harris Counties (Texas Gulf Coast) group in clacle 1113 with other isolates from these counties isolated during the 1 980s and 1 990s. This lack of evidence for introduction of novel strains into the Texas Gulf Coast over a long period of time is consistent with overwintering of SLEV in this region. Two El Paso isolates, both from 2002, group in clade VA with recent Californian isolates from 1998-2001 and some South American strains with a broad temporal range. Overall, these data are consistent with multiple introductions of SLEV from South America into North America, and provide support for the hypothesis that in most situations, SLEV circulates within a locality, with occasional incursions from other areas. Finally, SLEV has much lower nucleotice (10.1 %) and amino acid variation (2.8 %) than other members of the Japanese encephalitis virus complex (maximum variation 24.6% nucleotide and 11.8% amino acid). C1 [May, Fiona J.; Li, Li; Zhang, Shuliu; Guzman, Hilda; Beasley, David W. C.; Tesh, Robert B.; Higgs, Stephen; Barrett, Alan D. T.] Univ Texas Galveston, Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. [May, Fiona J.; Li, Li; Zhang, Shuliu; Guzman, Hilda; Beasley, David W. C.; Tesh, Robert B.; Higgs, Stephen; Barrett, Alan D. T.] Univ Texas Galveston, Med Branch, Sealy Ctr Vaccine Dev, Galveston, TX 77555 USA. [May, Fiona J.; Li, Li; Zhang, Shuliu; Guzman, Hilda; Beasley, David W. C.; Tesh, Robert B.; Higgs, Stephen; Barrett, Alan D. T.] Univ Texas Galveston, Med Branch, Inst Human Infect & Immun, Galveston, TX 77555 USA. [May, Fiona J.; Li, Li; Guzman, Hilda; Tesh, Robert B.; Higgs, Stephen; Barrett, Alan D. T.] Univ Texas Galveston, Med Branch, Dept Pathol, Galveston, TX 77555 USA. [Zhang, Shuliu; Beasley, David W. C.] Univ Texas Galveston, Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. [Raj, Pushker] Texas Dept State Hlth Serv, Austin, TX USA. [Bueno, Rudy, Jr.; Randle, Yvonne] Harris Cty Publ Hlth & Environm Serv, Mosquito Control Div, Houston, TX 77021 USA. [Chandler, Laura] Philadelphia VA Med Ctr, Lab Med, Philadelphia, PA 19104 USA. RP Barrett, ADT (reprint author), Univ Texas Galveston, Med Branch, Ctr Biodef & Emerging Infect Dis, Galveston, TX 77555 USA. EM abarrett@UTMB.EDU FU NIAID NIH HHS [R01 AI067847, N01AI25489, N01AI30027, R01 AI 45559, N01-AI 25489, R01 AI067847-03, R01 AI 67847] NR 58 TC 17 Z9 17 U1 0 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD AUG PY 2008 VL 89 BP 1901 EP 1910 DI 10.1099/vir.0.2008/000190-0 PN 8 PG 10 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 335PF UT WOS:000258301800013 PM 18632961 ER PT J AU Rutgers, M Mudgal, CS Shin, R AF Rutgers, M. Mudgal, C. S. Shin, R. TI Combined fractures of the distal radius and scaphoid SO JOURNAL OF HAND SURGERY-EUROPEAN VOLUME LA English DT Article DE fracture; distal radius; scaphoid; combined; ipsilateral ID IPSILATERAL FRACTURES; FIXATION AB Combined fractures of the distal radius and scaphoid are uncommon, are usually the result of a high-energy trauma and there is no consensus regarding their optimal management. We present a retrospective study of ten patients, out of whom nine underwent internal fixation of their fractures. Open reduction and internal fixation were performed in six of the eight intraarticular fractures of the distal radius. After a mean follow-up of 40 months, eight patients reported no pain and the mean range of wrist motion was 55 degrees flexion and 71 degrees extension. Our current management protocol is outlined. Emphasis on treatment of this combined fracture should be placed on the management of the distal radius fracture. Internal fixation of both fractures, followed by early rehabilitation, optimises outcomes. Cast treatment is indicated only in patients with completely undisplaced fractures of both the radius and the scaphoid. C1 [Rutgers, M.; Mudgal, C. S.; Shin, R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, Boston, MA 02114 USA. RP Mudgal, CS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, 55 Fruit St,Suite 2100, Boston, MA 02114 USA. EM emudgal@parmers.org NR 15 TC 7 Z9 8 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1753-1934 J9 J HAND SURG-EUR VOL JI J. Hand Surg.-Eur. Vol. PD AUG PY 2008 VL 33E IS 4 BP 478 EP 483 DI 10.1177/1753193408090099 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 345RK UT WOS:000259013900014 PM 18687836 ER PT J AU Horwitz, RH Roberts, LW Warner, TD AF Horwitz, Russell H. Roberts, Laura Weiss Warner, Teddy D. TI Mexican immigrant women's perceptions of health care access for stigmatizing illnesses: A focus group study in Albuquerque, New Mexico SO JOURNAL OF HEALTH CARE FOR THE POOR AND UNDERSERVED LA English DT Article DE health care access; minority; stigma; social support; Hispanic ID QUALITY-OF-LIFE; SOCIAL SUPPORT; ETHNIC DISPARITIES; HIV-INFECTION; UNITED-STATES; BARRIERS; LANGUAGE; GENDER; RACE; CONSEQUENCES AB This study examines attitudes of Mexican female immigrants to Albuquerque, New Mexico, regarding barriers to health care access in the United States and Mexico for stigmatizing and non-stigmatizing illnesses and moderating effects of social support. Native Spanish speakers conducted three focus groups (in Spanish) lasting two hours with seven to eight participants. Focus groups were transcribed, translated, and coded. Frequency data were calculated by number of times concepts or themes were raised. Comparisons of barriers to health care access were made between US. and Mexican cultures. The majority (86%) of comments on barriers for non-stigmatizing illnesses implicated US. culture; the majority (90%) for stigmatizing illnesses implicated Mexican culture. Social support for stigmatizing illnesses was discussed. Participants discussed important issues of health care access for stigmatizing illnesses that may have implications for this population's health status. Greater attention should be paid to stigma and social support in future empirical studies. C1 [Horwitz, Russell H.] Massachusetts Gen Hosp, McLean Hosp, Adult Psychiat Residency Program, Boston, MA 02114 USA. [Horwitz, Russell H.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Roberts, Laura Weiss] Med Coll Wisconsin, Dept Psychiat & Behav Med, Madison, WI USA. [Roberts, Laura Weiss] Med Coll Wisconsin, Empir Eth Grp, Madison, WI USA. [Warner, Teddy D.] Univ New Mexico, Sch Med, Dept Family & Community Med, Albuquerque, NM 87131 USA. [Warner, Teddy D.] Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. RP Horwitz, RH (reprint author), Massachusetts Gen Hosp, McLean Hosp, Adult Psychiat Residency Program, Boston, MA 02114 USA. FU NIDA NIH HHS [1R01DA13139, 1F30DA14458]; NIMH NIH HHS [1K02MH 01918] NR 56 TC 7 Z9 7 U1 5 U2 8 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1049-2089 J9 J HEALTH CARE POOR U JI J. Health Care Poor Underserved PD AUG PY 2008 VL 19 IS 3 BP 857 EP 873 PG 17 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 336FW UT WOS:000258350700016 PM 18677075 ER PT J AU Bennett, GG Wolin, KY Okechukwu, CA Arthur, CM Askew, S Sorensen, G Emmons, KM AF Bennett, Gary G. Wolin, Kathleen Y. Okechukwu, Cassandra A. Arthur, Carlotta M. Askew, Sandy Sorensen, Glorian Emmons, Karen M. TI Nativity and Cigarette Smoking among Lower Income Blacks: Results from the Healthy Directions Study SO JOURNAL OF IMMIGRANT AND MINORITY HEALTH LA English DT Article DE Nativity; Acculturation; Smoking; Blacks AB Blacks in the United States bear the greatest disease burden associated with cigarette smoking. Previous studies have shown that the rapidly increasing population of foreign-born Blacks has lower smoking rates compared to their native-born counterparts. However, less is known about whether cigarette smoking among Blacks varies by region of birth (US, Africa, or the Caribbean), generational status, or acculturation. We examined the association between nativity and cigarette smoking among 667 Black adult men and women enrolled in the Harvard Cancer Prevention Program project. In multi-variable analyses, US-born Blacks were more likely to be smokers compared to those born in the Caribbean (OR = 0.16, 95% CI 0.08, and 0.34) or in Africa (OR = 0.24, 95% CI 0.08, and 0.74). Language acculturation was positively associated with cigarette smoking (OR = 2.62, 95% CI 1.17, and 5.85). We found that US-born Blacks were more likely to be current cigarette smokers than those born in either Caribbean or African countries. Our findings highlight the importance of intervening early new Black immigrants to stem the uptake of cigarette smoking behaviors as individuals become acculturated. C1 [Bennett, Gary G.; Okechukwu, Cassandra A.; Askew, Sandy; Sorensen, Glorian; Emmons, Karen M.] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Bennett, Gary G.; Okechukwu, Cassandra A.; Askew, Sandy; Sorensen, Glorian; Emmons, Karen M.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Wolin, Kathleen Y.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Arthur, Carlotta M.] Smith Coll, Dept Psychol, Northampton, MA 01063 USA. RP Bennett, GG (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 44 Binney St,SM256, Boston, MA 02115 USA. EM gbennett@hsph.harvard.edu RI Wolin, Kathleen/I-2154-2014 OI Wolin, Kathleen/0000-0001-7950-9042 FU NCI NIH HHS [R01 CA098864, 1 R25 CA100600-01A1, P01 CA075308, P01 CA075308-030002, R01 CA098864-04S1, P01 CA075308-020002, 5 P01 CA75308, P01 CA075308-01A20002, 5 R25 CA057711-12, R01 CA098864-03S1, R25 CA100600, R25 CA057711, R01 CA098864-02S1, P01 CA075308-040002] NR 48 TC 13 Z9 13 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1912 J9 J IMMIGR MINOR HEALT JI J. Immigr. Minor. Health PD AUG PY 2008 VL 10 IS 4 BP 305 EP 311 DI 10.1007/s10903-007-9088-0 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA V13DV UT WOS:000207648400002 PM 17924192 ER PT J AU Zhang, XK Moussa, O Larue, A Bradshaw, S Molano, I Spyropoulos, DD Gilkeson, GS Watson, DK AF Zhang, Xian K. Moussa, Omar LaRue, Amanda Bradshaw, Sarah Molano, Ivan Spyropoulos, Demetri D. Gilkeson, Gary S. Watson, Dennis K. TI The transcription factor Fli-1 modulates marginal zone and follicular B cell development in mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DNA-BINDING SPECIFICITIES; ETS FAMILY; IMMUNE-RESPONSE; RENAL-DISEASE; HUMAN CANCER; PRE-B; GENE; EXPRESSION; DIFFERENTIATION; PROTEINS AB Fli-1 belongs to the Ets transcription factor family and is expressed primarily in hematopoietic cells, including most cells active in immunity. To assess the role of Fli-1 in lymphocyte development in vivo, we generated mice that express a truncated Fli-1 protein, lacking the C-terminal transcriptional activation domain (Fli-1(Delta CTA)). Fli-1(Delta CTA)/Fli-1(Delta CTA) mice had significantly fewer splenic follicular B cells, and an increased number of transitional and marginal zone B cells, compared with wild-type controls. Bone marrow reconstitution studies demonstrated that this phenotype is the result of lymphocyte intrinsic effects. Expression of Ig alpha and other genes implicated in B cell development, including Pax-5, E2A, and Egr-1, are reduced, while Id1 and Id2 are increased in Fli-1(Delta CTA)/Fli-1(Delta CTA) mice. Proliferation of B cells from Fli-1(Delta CTA)/Fli-1(Delta CTA) mice was diminished, although intracellular Ca2+ flux in B cells from Fli-1(Delta CTA)/Fli-1(Delta CTA) mice was similar to that of wild-type controls after anti-IgM stimulation. Immune responses and in vitro class switch recombination were also altered in Fli-1(Delta CTA)/Fli-1(Delta CTA) mice. Thus, Fli-1 modulates B cell development both centrally and peripherally, resulting in a significant impact on the in vivo immune response. C1 [Zhang, Xian K.; Bradshaw, Sarah; Molano, Ivan; Gilkeson, Gary S.] Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Zhang, Xian K.; LaRue, Amanda; Gilkeson, Gary S.] Ralph H Johnson Vet Affairs Med Ctr, Med Res Serv, Charleston, SC 29403 USA. [Moussa, Omar; LaRue, Amanda; Spyropoulos, Demetri D.; Watson, Dennis K.] Med Univ S Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA. RP Zhang, XK (reprint author), Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, 96 Jonathan Lucas St,MSC637,Suite 912, Charleston, SC 29425 USA. EM zhangjo@muse.edu FU NCI NIH HHS [P01-CA78582, P01 CA078582]; NIAMS NIH HHS [AR051385, AR054546, K01 AR051385, K01 AR051385-01A1, R03 AR054546-01, R03 AR054546] NR 64 TC 33 Z9 33 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2008 VL 181 IS 3 BP 1644 EP 1654 PG 11 WC Immunology SC Immunology GA 329VG UT WOS:000257898100009 PM 18641300 ER PT J AU Haining, WN Ebert, BL Subrmanian, A Wherry, EJ Eichbaum, Q Evans, JW Mak, R Rivoli, S Pretz, J Angelosanto, J Smutko, JS Walker, BD Kaech, SM Ahmed, R Nadler, LM Golub, TR AF Haining, W. Nicholas Ebert, Benjamin L. Subrmanian, Aravind Wherry, E. John Eichbaum, Quentin Evans, John W. Mak, Raymond Rivoli, Stephen Pretz, Jennifer Angelosanto, Jill Smutko, John S. Walker, Bruce D. Kaech, Susan M. Ahmed, Rafi Nadler, Lee M. Golub, Todd R. TI Identification of an evolutionarily conserved transcriptional signature of CD8 memory differentiation that is shared by T and B cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC VIRAL-INFECTION; GENE-EXPRESSION; IN-VIVO; EFFECTOR; SUBSETS; PROGRAM; LYMPHOCYTES; PERSISTENCE; GENERATION; QUIESCENCE AB After Ag encounter, naive lymphocytes differentiate into populations of memory cells that share a common set of functions including faster response to Ag re-exposure and the ability to self-renew. However, memory lymphocytes in different lymphocyte lineages are functionally and phenotypically diverse. It is not known whether discrete populations of T and B cells use similar transcriptional programs during differentiation into the memory state. We used cross-species genomic analysis to examine the pattern of genes up-regulated during the differentiation of naive lymphocytes into memory cells in multiple populations of human CD4, CD8, and B cell lymphocytes as well as two mouse models of memory development. We identified and validated a signature of genes that was up-regulated in memory cells compared with naive cells in both human and mouse CD8 memory differentiation, suggesting marked evolutionary conservation of this transcriptional program. Surprisingly, this conserved CD8 differentiation signature was also up-regulated during memory differentiation in CD4 and B cell lineages. To validate the biologic significance of this signature, we showed that alterations in this signature of genes could distinguish between functional and exhausted CD8 T cells from a mouse model of chronic viral infection. Finally, we generated genome-wide microarray data from tetramer-sorted human T cells and showed profound differences in this differentiation signature between T cells specific for HIV and those specific for influenza. Thus, our data suggest that in addition to lineage-specific differentiation programs, T and B lymphocytes use a common transcriptional program during memory development that is disrupted in chronic viral infection. C1 [Ebert, Benjamin L.; Subrmanian, Aravind; Mak, Raymond; Pretz, Jennifer; Golub, Todd R.] Broad Inst Harvard, Canc Program, Cambridge, MA 02142 USA. [Ebert, Benjamin L.; Subrmanian, Aravind; Mak, Raymond; Pretz, Jennifer; Golub, Todd R.] MIT, Cambridge, MA 02142 USA. [Haining, W. Nicholas; Kaech, Susan M.; Golub, Todd R.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Ebert, Benjamin L.; Evans, John W.; Rivoli, Stephen; Angelosanto, Jill; Nadler, Lee M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Haining, W. Nicholas; Golub, Todd R.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Ebert, Benjamin L.] Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. [Wherry, E. John] Wistar Inst Anat & Biol, Program Immunol, Philadelphia, PA 19104 USA. [Smutko, John S.] Nugen Technol, San Carlos, CA 94070 USA. [Kaech, Susan M.] Yale Univ, Dept Immunobiol, New Haven, CT 06520 USA. [Ahmed, Rafi] Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Eichbaum, Quentin; Walker, Bruce D.] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. [Eichbaum, Quentin; Walker, Bruce D.] Div AIDS, Boston, MA 02114 USA. RP Golub, TR (reprint author), Broad Inst Harvard, Canc Program, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM golub@broad.mit.edu FU Howard Hughes Medical Institute; NCI NIH HHS [U19 CA100265]; NHLBI NIH HHS [K08 HL072750, K08 HL72750, R01 HL082945, R01HL82945]; NIAID NIH HHS [P30 AI060354, R01 AI030914] NR 48 TC 44 Z9 44 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 1 PY 2008 VL 181 IS 3 BP 1859 EP 1868 PG 10 WC Immunology SC Immunology GA 329VG UT WOS:000257898100032 PM 18641323 ER PT J AU Zhang, Y Bai, XT Zhu, KY Jin, Y Deng, M Le, HY Fu, YF Chen, Y Zhu, J Look, AT Kanki, J Chen, Z Chen, SJ Liu, TX AF Zhang, Yong Bai, Xue-Tao Zhu, Kang-Yong Jin, Yi Deng, Min Le, Huang-Ying Fu, Yan-Fang Chen, Yi Zhu, Jiang Look, A. Thomas Kanki, John Chen, Zhu Chen, Sai-Juan Liu, Ting Xi TI In vivo interstitial migration of primitive macrophages mediated by JNK-matrix metalloproteinase 13 signaling in response to acute injury SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; GENE-EXPRESSION; MAP KINASE; THERAPEUTIC TARGETS; CHEMOKINE RECEPTORS; CELL RECRUITMENT; IMMUNE-RESPONSES; ZEBRAFISH; INFLAMMATION; CHEMOTAXIS AB Interstitial cell migration through extracellular matrix is a hallmark of the inflammation response, tumor invasion, and metastasis. We have established a stable zebrafish transgenic line expressing enhanced GFP under the lysozyme C promoter for visualizing and measuring primitive macrophage migration in vivo. We show that tissue-resident primitive macrophages migrate rapidly through extracellular matrix to the site of acute injury induced by tail transection. Mechanistically, the specific inhibition of JNK, but not p38 and ERK, dramatically abolished the chemotactic migration in a dose-dependent manner, suppressing the trauma-induced recruitment of phosphorylated C-Jun transcription factor to proximal AP-1 sites in the promoter of matrix metalloproteinase 13 (mmp13), a gene specifically expressed in primitive macrophages during embryogenesis and required for the interstitial migration. Furthermore, dexamethasone suppressed the trauma-induced JNK phosphorylation and macrophage migration accompanied by simultaneous up-regulation of mkp-1, a well-known phosphatase capable of inactivating phosphorylated JNK. The results indicate that the JNK-Mmp13 signaling pathway plays an essential role in regulating the innate immune cell migration in response to severe injury in vivo. C1 [Zhang, Yong; Bai, Xue-Tao; Jin, Yi; Le, Huang-Ying; Fu, Yan-Fang; Chen, Yi; Zhu, Jiang; Look, A. Thomas; Chen, Zhu; Chen, Sai-Juan; Liu, Ting Xi] Shanghai Jiao Tong Univ, Sch Med, Lab Dev & Dis, Shanghai 200030, Peoples R China. [Zhang, Yong; Bai, Xue-Tao; Jin, Yi; Le, Huang-Ying; Fu, Yan-Fang; Chen, Yi; Zhu, Jiang; Chen, Zhu; Chen, Sai-Juan; Liu, Ting Xi] Shanghai Jiao Tong Univ, Sch Med, State Key Lab Med Genom, Shanghai 200030, Peoples R China. [Zhang, Yong; Bai, Xue-Tao; Jin, Yi; Le, Huang-Ying; Fu, Yan-Fang; Chen, Yi; Zhu, Jiang; Chen, Zhu; Chen, Sai-Juan; Liu, Ting Xi] Shanghai Jiao Tong Univ, Sch Med, Shanghai Inst Hematol, Shanghai 200030, Peoples R China. [Zhang, Yong; Zhu, Kang-Yong; Jin, Yi; Deng, Min; Le, Huang-Ying; Fu, Yan-Fang; Chen, Yi; Liu, Ting Xi] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Shanghai, Peoples R China. [Liu, Ting Xi] Shanghai Univ, E Inst, Model Organism Div, Shanghai, Peoples R China. [Look, A. Thomas; Kanki, John] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Look, A. Thomas; Kanki, John] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Chen, Zhu; Chen, Sai-Juan] Shanghai Jiao Tong Univ, Shanghai Ctr Syst Biomed, Shanghai 200030, Peoples R China. RP Liu, TX (reprint author), Inst Hlth Sci, Lab Dev & Dis, Room 408,Bldg 1,225 S Chong Qing Rd, Shanghai 200025, Peoples R China. EM sjchen@stn.sh.cn; txliu@sibs.ac.cn NR 57 TC 48 Z9 50 U1 2 U2 9 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 1 PY 2008 VL 181 IS 3 BP 2155 EP 2164 PG 10 WC Immunology SC Immunology GA 329VG UT WOS:000257898100063 PM 18641354 ER PT J AU Livorsi, DJ Daver, NG Atmar, RL Shelburne, SA White, AC Musher, DM AF Livorsi, Daniel J. Daver, Naval G. Atmar, Robert L. Shelburne, Samuel A. White, A. Clinton Musher, Daniel M. TI Outcomes of treatment for hematogenous Staphylococcus aureus vertebral osteomyelitis in the MRSA ERA SO JOURNAL OF INFECTION LA English DT Article DE vertebral osteomyelitis; abscess; Stophylococcus aureus ID SURGICAL-MANAGEMENT; US HOSPITALS; EPIDEMIOLOGY; INFECTIONS; BACTEREMIA; SURVEILLANCE; DENMARK AB Objectives: Hematogenous vertebral osteomyelitis is caused predominantly by Staphylococcus aureus. The rise in incidence of methicillin-resistant S. aureus (MRSA) has complicated the treatment of this infection. Our objective was to evaluate therapeutic outcomes for S. aureus vertebral. osteomyelitis in a setting of high MRSA prevalence. Methods: We conducted a retrospective chart review of all patients who presented with S. aureus vertebral osteomyelitis over a 7-year period at 2 tertiary care hospitals in Houston, TX, USA. Results: Thirty-five patients were identified who received >= 2-week course of parenteral antibiotics and had a follow-up period of at least 12 months post-therapy. MRSA was responsible for 20 (57%) cases. Mean duration of total antibiotic therapy was 61.4 days. The overall relapse rate was 14%. At 12 months post-therapy, 86% patients were cured. The one factor significantly associated with relapse was presence of undrained abscesses (p = 0.04). Conclusions: When the mean duration of effective antibiotic therapy was 60 days, cure rates for S. aureus vertebral, osteomyelitis exceeded 80%. Drainage of all associated abscesses correlated with a significantly higher rate of cure. (c) 2008 The British Infection Society. Published by Elsevier Ltd. All rights reserved. C1 [Livorsi, Daniel J.; Daver, Naval G.; Atmar, Robert L.; Shelburne, Samuel A.; Musher, Daniel M.] Baylor Coll Med, Infect Dis Sect, Houston, TX 77030 USA. [White, A. Clinton] Univ Texas Galveston, Med Branch, Div Infect Dis, Galveston, TX 77555 USA. [Atmar, Robert L.; Shelburne, Samuel A.; White, A. Clinton] Ben Taub Gen Hosp, Houston, TX 77030 USA. [Musher, Daniel M.] Michael E DeBakey Vet Affairs Med Ctr, Infect Dis Sect, Houston, TX 77030 USA. RP Livorsi, DJ (reprint author), 108 Ponce Leon Court, Decatur, GA 30030 USA. EM dlivorsi@alumni.rice.edu OI White, A Clinton/0000-0002-9668-4632 FU NCI NIH HHS [P30 CA016672] NR 15 TC 27 Z9 27 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0163-4453 J9 J INFECTION JI J. Infect. PD AUG PY 2008 VL 57 IS 2 BP 128 EP 131 DI 10.1016/j.jinf.2008.04.012 PG 4 WC Infectious Diseases SC Infectious Diseases GA 345VQ UT WOS:000259026000007 PM 18562009 ER PT J AU Eichler, FS Ratai, E Kok, T Wiggins, C Wiggins, G Grant, E Gagoski, B O'Neill, G Adalsteinsson, E AF Eichler, F. S. Ratai, E. Kok, T. Wiggins, C. Wiggins, G. Grant, E. Gagoski, B. O'Neill, G. Adalsteinsson, E. TI 7 Tesla proton magnetic resonance spectroscopic imaging in adult X-linked adrenoleukodystrophy SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Meeting Abstract C1 [Eichler, F. S.; Ratai, E.; Wiggins, C.; Wiggins, G.; Grant, E.; O'Neill, G.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Kok, T.; Gagoski, B.; Adalsteinsson, E.] MIT, Cambridge, MA 02139 USA. RI Adalsteinsson, Elfar/F-2477-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD AUG PY 2008 VL 31 SU 1 MA 265P BP 67 EP 67 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 340PB UT WOS:000258656400265 ER PT J AU Cismondi, IA Kohan, R Guelbert, N Anzolini, TV Ghio, A Mole, SE Xin, W Santorelli, F de Kremer, DR Ramirez, OAM de Halac, NI AF Cismondi, I. A. Kohan, R. Guelbert, N. Anzolini, Tapia, V Ghio, A. Mole, S. E. Xin, W. Santorelli, F. de Kremer, Dodelson R. Ramirez, Oller A. M. de Halac, Noher, I TI Morphologically targeted DNA screening of neuronal ceroid lipofuscinoses CLN5 and CLN6 in Argentina SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Meeting Abstract C1 [Cismondi, I. A.; Kohan, R.] Univ Nac Cordoba, Fac Odont, Cordoba, Argentina. [Guelbert, N.; Anzolini, Tapia, V; Ghio, A.; de Kremer, Dodelson R.; Ramirez, Oller A. M.] CEMECO, Hosp Ninos, Fac Med Cs, Cordoba, Argentina. [Mole, S. E.] UCL, Inst Child Hlth, London, England. [Mole, S. E.] UCL, MRC LMCB, London, England. [Xin, W.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Santorelli, F.] IRCCS, Bambino Gesu Hosp, Rome, Italy. [de Halac, Noher, I] CONICET RA, Cordoba, Argentina. RI Mole, Sara/C-2024-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD AUG PY 2008 VL 31 SU 1 MA 511P BP 129 EP 129 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 340PB UT WOS:000258656400511 ER PT J AU Cheng, CF Fan, JH Bandyopahdhay, B Mock, D Guan, SX Chen, M Woodley, DT Li, W AF Cheng, Chleh-Fang Fan, Jianhua Bandyopahdhay, Balaji Mock, Dennis Guan, Shengxi Chen, Mei Woodley, David T. Li, Wei TI Profiling motility signal-specific genes in primary human keratinocytes SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID DERMAL FIBROBLAST MIGRATION; EPIDERMAL-GROWTH-FACTOR; CELL MOTILITY; HUMAN SKIN; IN-VITRO; REEPITHILIALIZATION; LOCOMOTION; BETA; INHIBITION; MECHANISMS AB Regulation of human keratinocyte (HK) migration is critical for skin wound healing. Profiling HK migration-specific genes could help us gain a comprehensive understanding of the process. The main challenge is to separate genes that are unrelated to migration, but simultaneously induced by the same growth factor. In this study, we took advantage of a unique response of HKs to transforming growth factor-beta (TGF-beta), which inhibits proliferation but not migration of HKs, to suppress selectively the proliferation-related genes. Furthermore we stimulated HKs independently with TGF-alpha or insulin and identified the common genes and eliminated TGF-alpha- or insulin-specific genes. Under these conditions, we obtained profiles of the immediate-early genes (IEGs, at 30 minutes), early genes (EGs, at 60 minutes), and delayed-early genes (DEGs, at 120 minutes) by microarray analyses, followed by quantitative real-time reverse transcription-PCR (QRT-PCR) validation and functional characterization by RNA interference (RNAi). Our results revealed the following: (1) 25 upregulated and 1 downregulated IEGs; (2) 58 upregulated and 15 downregulated EGs, and (3) 13 upregulated and 3 downregulated DEGs in both TGF-alpha- and insulin-stimulated HKs. Three genes, all encoding secreted molecules, were investigated in HK migration. These cell motility-specific gene profiles may prove useful to skin wound healing. C1 [Cheng, Chleh-Fang; Fan, Jianhua; Bandyopahdhay, Balaji; Guan, Shengxi; Chen, Mei; Woodley, David T.; Li, Wei] Univ So Calif, Keck Sch Med, Dept Dermatol, Los Angeles, CA 90089 USA. [Cheng, Chleh-Fang; Fan, Jianhua; Bandyopahdhay, Balaji; Guan, Shengxi; Chen, Mei; Woodley, David T.; Li, Wei] Univ So Calif, Keck Sch Med, Norris Canc Ctr, Los Angeles, CA 90089 USA. [Mock, Dennis] Univ So Calif, CHLA, Genome Core Lab, Los Angeles, CA 90089 USA. [Woodley, David T.; Li, Wei] VA Greater Los Angles Healthcare Syst, Los Angeles, CA USA. RP Li, W (reprint author), Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90089 USA. EM wli@usc.edu FU NIAMS NIH HHS [GM/AR67100-01, AR46538] NR 41 TC 7 Z9 7 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD AUG PY 2008 VL 128 IS 8 BP 1981 EP 1990 DI 10.1038/jid.2008.34 PG 10 WC Dermatology SC Dermatology GA 331SA UT WOS:000258031700018 PM 18323786 ER PT J AU Andersson, C Al-Turkmani, MR Savaille, JE Alturkmani, R Katrangi, W Cluette-Brown, JE Zaman, MM Laposata, M Freedman, SD AF Andersson, Charlotte Al-Turkmani, M. Rabie Savaille, Juanito E. Alturkmani, Ragheed Katrangi, Waddah Cluette-Brown, Joanne E. Zaman, Munir M. Laposata, Michael Freedman, Steven D. TI Cell culture models demonstrate that CFTR dysfunction leads to defective fatty acid composition and metabolism SO JOURNAL OF LIPID RESEARCH LA English DT Article DE cystic fibrosis transmembrane conductance regulator; essential fatty acid deficiency; fetal bovine serum; horse serum; arachidonic acid; docosahexaenoic acid; confluence; Delta 6-desaturase ID TRANSMEMBRANE CONDUCTANCE REGULATOR; CYSTIC-FIBROSIS; ARACHIDONIC-ACID; EPITHELIAL-CELLS; CFTR(-/-) MICE; EXPRESSION; PHOSPHOLIPIDS; INFLAMMATION; CONFLUENCE; INFECTION AB Cystic fibrosis (CF) is associated with fatty acid alterations characterized by low linoleic and docosahexaenoic acid. It is not clear whether these fatty acid alterations are directly linked to cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction or result from nutrient malabsorption. We hypothesized that if fatty acid alterations are a result of CFTR dysfunction, those alterations should be demonstrable in CF cell culture models. Two CF airway epithelial cell lines were used: 16HBE, sense and antisense CFTR cells, and C38/IB3-1 cells. Wild-type (WT) and CF cells were cultured in 10% fetal bovine serum (FBS) or 10% horse serum. Fatty acid levels were analyzed by GC-MS. Culture of both WT and CF cells in FBS resulted in very low linoleic acid levels. When cells were cultured in horse serum containing concentrations of linoleic acid matching those found in human plasma, physiological levels of linoleic acid were obtained and fatty acid alterations characteristic of CF tissues were then evident in CF compared with WT cells. Kinetic studies with radiolabeled linoleic acid demonstrated in CF cells increased conversion to longer and more-desaturated fatty acids such as arachidonic acid. In conclusion, these data demonstrate that CFTR dysfunction is associated with altered fatty acid metabolism in cultured airway epithelial cells. C1 [Andersson, Charlotte; Zaman, Munir M.; Freedman, Steven D.] Beth Israel Deaconess Med Ctr, Div Gastroenterol, Boston, MA 02215 USA. [Al-Turkmani, M. Rabie; Savaille, Juanito E.; Alturkmani, Ragheed; Katrangi, Waddah; Cluette-Brown, Joanne E.; Laposata, Michael] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Freedman, SD (reprint author), Beth Israel Deaconess Med Ctr, Div Gastroenterol, Boston, MA 02215 USA. EM sfreedma@bidmc.harvard.edu FU NIDDK NIH HHS [R01 DK 52765, R01 DK052765] NR 30 TC 29 Z9 31 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD AUG PY 2008 VL 49 IS 8 BP 1692 EP 1700 DI 10.1194/jlr.M700388-JLR200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CS UT WOS:000257566400010 PM 18441018 ER PT J AU Andronesi, OC Mintzopoulos, D Struppe, J Black, PM Tzika, AA AF Andronesi, Ovidiu C. Mintzopoulos, Dionyssios Struppe, Jochem Black, Peter M. Tzika, A. Aria TI Solid-state NMR adiabatic TOBSY sequences provide enhanced sensitivity for multidimensional high-resolution magic-angle-spinning H-1 MR spectroscopy SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE Total through bond correlation spectroscopy (TOBSY); Total correlation spescroscopy (TOCSY); high-resolution magic-angle-spinning (HRMAS); adiabatic inversion pulses (AIP); glioblastoma multiforme (GBM) ID NUCLEAR-MAGNETIC-RESONANCE; BOND CORRELATION SPECTROSCOPY; MODEL-FREE APPROACH; SECONDARY STRUCTURE; BAND INVERSION; LIQUID-STATE; EX-VIVO; IN-VIVO; PULSES; MAS AB We propose a solid-state NMR method that maximizes the advantages of high-resolution magic-angle-spinning (HRMAS) applied to intact biopsies when compared to more conventional liquid-state NMR approaches. Theoretical treatment, numerical Simulations and experimental results oil intact human brain biopsies are presented. Experimentally, it is proven that an optimized adiabatic TOBSY (TOtal through Bond correlation SpectroscopY) solid-state NMR pulse sequence for two-dimensional H-1-H-1 homonuclear scalar-coupling longitudinal isotropic mixing provides a 20%-50% improvement in signal-to-noise ratio relative to its liquid-state analogue TOCSY (TOtal Correlation SpectroscopY). For this purpose we have refined the C9(15)(1), symmetry-based C-13 TOBSY Pulse sequence for H-1 MRS use and compared it to MLEV-16 TOCSY sequence. Both sequences were rotor-synchronized and implemented using WURST-8 adiabatic inversion pulses. As discussed theoretically and shown in Simulations, the improved magnetization-transfer comes from actively removing residual dipolar Couplings from the average Hamiltonian. Importantly, the solid-state NMR techniques are tailored to perform measurements at low temperatures where sample degradation is reduced. This is the first demonstration of such a concept for HRMAS metabolic profiling of disease processes, including cancer, from biopsies requiring reduced sample degradation for further genomic analysis. (c) 2008 Elsevier Inc. All rights reserved. C1 [Andronesi, Ovidiu C.; Mintzopoulos, Dionyssios; Tzika, A. Aria] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,NMR Surg Lab, Boston, MA 02114 USA. [Andronesi, Ovidiu C.; Mintzopoulos, Dionyssios; Tzika, A. Aria] Harvard Univ, Sch Med, Shriners Burn Inst, Boston, MA 02114 USA. [Andronesi, Ovidiu C.; Mintzopoulos, Dionyssios; Tzika, A. Aria] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Struppe, Jochem] Bruker BioSpin Corp, Billerica, MA 01821 USA. [Black, Peter M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. RP Andronesi, OC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg,NMR Surg Lab, 51 Blossom Str,Room 261, Boston, MA 02114 USA. EM ovidiu@nmr.mgh.harvard.edu; aaria_tzika@hms.harvard.edu NR 42 TC 11 Z9 11 U1 2 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD AUG PY 2008 VL 193 IS 2 BP 251 EP 258 DI 10.1016/j.jmr.2008.05.017 PG 8 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 336IN UT WOS:000258357600012 PM 18556227 ER PT J AU Kuntzen, T Berical, A Ndjomou, J Bennett, P Schneidewind, A Lennon, N Birren, BW Kuiken, C Henn, MR Simmonds, P Allen, TM AF Kuntzen, Thomas Berical, Andrew Ndjomou, Jean Bennett, Phil Schneidewind, Arne Lennon, Niall Birren, Bruce W. Kuiken, Carla Henn, Matthew R. Simmonds, Peter Allen, Todd M. TI A set of reference sequences for the hepatitis C genotypes 4d, 4f, and 4k covering the full open reading frame SO JOURNAL OF MEDICAL VIROLOGY LA English DT Article DE hepatitis C virus; subtype; long template PCR ID ALPHA-2B PLUS RIBAVIRIN; SENSITIVITY-DETERMINING REGION; IMMUNODEFICIENCY-VIRUS TYPE-1; COMPLETE NUCLEOTIDE-SEQUENCE; INTERFERON THERAPY; VIROLOGICAL RESPONSE; COMBINATION THERAPY; INITIAL TREATMENT; ST-PETERSBURG; 1B INFECTION AB Infection with genotype 4 of the Hepatitis C virus is common in Africa and the Mediterranean area, but has also been found at increasing frequencies in injection drug users in Europe and North America. Full length viral sequences to characterize viral diversity and structure have recently become available mostly for subtype 4a, and studies in Egypt and Saudi Arabia, where high proportions of subtype 4a infected patients exist, have begun to establish optimized treatment regimens. However knowledge about other subtype variants of genotype 4 present in less developed African states is lacking. In this study the full coding region from so far poorly characterized variants of HCV genotype 4 was amplified and sequenced using a long range PCR technique. Sequences were analyzed with respect to phylogenetic relationship, possible recombination and prominent sequence characteristics compared to other known HCV strains. We present for the first time two full-length sequences from the HCV genotype 4k, in addition to five strains from HCV genotypes 4d and 4f. Reference sequences for accurate HCV genotyping are required for optimized treatment, and a better knowledge of the global viral sequence diversity is needed to guide vaccines or new drugs effective in the world wide epidemic. C1 [Kuntzen, Thomas; Berical, Andrew; Schneidewind, Arne; Allen, Todd M.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners AIDS Res Ctr, Boston, MA 02115 USA. [Ndjomou, Jean] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN USA. [Bennett, Phil] Univ Warwick Sci Pk, Micropathol Ltd, Coventry, W Midlands, England. [Lennon, Niall; Birren, Bruce W.; Henn, Matthew R.] Massachusetts Inst Technol & Harvard, Broad Inst, Cambridge, MA USA. [Kuiken, Carla] Los Alamos Natl Lab, HCV Database, Los Alamos, NM USA. [Simmonds, Peter] Univ Edinburgh, Ctr Infect Dis, Edinburgh, Midlothian, Scotland. RP Kuntzen, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners AIDS Res Ctr, Boston, MA 02115 USA. EM t.kuntzen@gmx.de RI Allen, Todd/F-5473-2011 FU NIAID NIH HHS [R01 AI067926, HHSN266200400001C, R01 AI067926-01, R01-AI067926-01]; PHS HHS [HHSN266200400001C] NR 41 TC 7 Z9 7 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0146-6615 J9 J MED VIROL JI J. Med. Virol. PD AUG PY 2008 VL 80 IS 8 BP 1370 EP 1378 DI 10.1002/jmv.21240 PG 9 WC Virology SC Virology GA 319NN UT WOS:000257170800009 PM 18551618 ER PT J AU Marx, BP Humphreys, KL Weathers, FW Martin, EK Sloan, DM Grove, WM Kaloupek, DG Keane, TM AF Marx, Brian P. Humphreys, Kathryn L. Weathers, Frank W. Martin, Elaine K. Sloan, Denise M. Grove, William M. Kaloupek, Danny G. Keane, Terence M. TI Development and initial validation of a statistical prediction instrument for assessing combat-related posttraumatic stress disorder SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE posttraumatic stress disorder; statistical prediction; assessment; diagnosis; veterans ID RISK-FACTORS; VETERANS; VIETNAM; SCALE; GUILT; PTSD; METAANALYSIS; CONTROVERSY; ATROCITIES; SEVERITY AB Statistical analyses were used to derive and validate a statistical prediction instrument to determine combat-related posttraumatic stress disorder (PTSD) status. Participants were 1081 Vietnam veterans with and without combat-related PTSD. The statistical prediction instrument, which consisted of 12 well-known risk and resilience variables associated with PTSD, proved to be an accurate and efficient means of detecting PTSD among participants and compared well against other existing self-report measures of PTSD. The instrument's practical applications and its use in clinical appraisals of PTSD are discussed. C1 [Marx, Brian P.] VA Boston Healthcare Syst, Behav Sci Div, Natl Ctr PTSD, Dept Psychiat, Boston, MA 02130 USA. [Marx, Brian P.; Sloan, Denise M.; Kaloupek, Danny G.; Keane, Terence M.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Weathers, Frank W.] Auburn Univ, Dept Psychol, Auburn, AL 36849 USA. [Grove, William M.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. RP Marx, BP (reprint author), VA Boston Healthcare Syst, Behav Sci Div, Natl Ctr PTSD, Dept Psychiat, 150 S Huntington Ave,116B-2, Boston, MA 02130 USA. EM brian.marx@va.gov OI Sloan, Denise/0000-0002-0962-478X; Kaloupek, Danny/0000-0002-0795-593X NR 34 TC 6 Z9 6 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 2008 VL 196 IS 8 BP 605 EP 611 DI 10.1097/NMD.0b013e318181326d PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 345EN UT WOS:000258979000003 PM 18974672 ER PT J AU Tsuang, MT Simpson, JC AF Tsuang, Ming T. Simpson, John C. TI Commentary on Koenig (2008) - "Concerns About Measuring 'Spirituality' in Research" SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Editorial Material ID HEALTH C1 [Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Genom, La Jolla, CA 92037 USA. [Tsuang, Ming T.] Vet Affairs San Diego Healthcare Syst, Psychiat Serv, San Diego, CA USA. [Tsuang, Ming T.; Simpson, John C.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Harvard Inst Psychiat Epidemiol & Genet, Boston, MA 02115 USA. [Tsuang, Ming T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Tsuang, Ming T.] Beth Israel Deaconess Med Ctr, Dept Psychiat, Massachusetts Mental Hlth Ctr, Boston, MA 02215 USA. [Simpson, John C.] Vet Affairs Boston Healthcare Syst, Boston, MA USA. [Simpson, John C.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Tsuang, MT (reprint author), Univ Calif San Diego, Dept Psychiat, Ctr Behav Genom, Mail Code 0603,9500 Gilman Dr, La Jolla, CA 92037 USA. EM mtsuang@ucsd.edu NR 8 TC 7 Z9 7 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD AUG PY 2008 VL 196 IS 8 BP 647 EP 649 DI 10.1097/NMD.0b013e3181813570 PG 3 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 345EN UT WOS:000258979000010 PM 18974679 ER PT J AU Gilheeney, SW Saad, A Chi, S Turner, C Ullrich, NJ Goumnerova, L Scott, RM Marcus, K Lehman, L De Girolami, U Kieran, MW AF Gilheeney, Stephen W. Saad, Ali Chi, Susan Turner, Christopher Ullrich, Nicole J. Goumnerova, Liliana Scott, R. Michael Marcus, Karen Lehman, Leslie De Girolami, Umberto Kieran, Mark W. TI Outcome of pediatric pineoblastoma after surgery, radiation and chemotherapy SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE pineoblastoma; supratentorial PNET; chemotherapy; radiation therapy; outcomes ID PRIMITIVE NEUROECTODERMAL TUMORS; HIGH-DOSE CHEMOTHERAPY; CHILDRENS CANCER GROUP; STEM-CELL RESCUE; BRAIN-TUMORS; RISK STRATIFICATION; PROGNOSTIC FACTORS; YOUNG-CHILDREN; MEDULLOBLASTOMA; RECURRENT AB Introduction Pineoblastomas are a category of supratentorial primitive neuroectodermal tumors (sPNETs) occurring in the pineal gland; some studies support the impression that patients with pineoblastomas have a worse prognosis than those with other sPNETs. Methods We reviewed the medical records and tissue sections of all patients with the diagnosis of pineoblastoma that were treated at the Dana-Farber Cancer Institute/Children's Hospital Boston Pediatric Brain Tumor Program between 1986 and 2005. Results Thirteen patients with the pathologic diagnosis of pineoblastoma were treated at our Hospital; 11 of these cases had complete records suitable for study. The median age was 8 years 8 months (5 F, 6 M). Surgical, radiation and chemotherapeutic regimens varied from case to case. Three patients had gross total resection and are alive and free of disease, versus four of eight with subtotal resection or biopsy only. Patients who received CSI and multi-agent chemotherapy had improved overall survival. Conclusions Seven of eleven patients with pineoblastoma are currently alive and free of disease, reflecting an improved outcome and longer survival than previously appreciated. Gross total surgical resection appeared to correlate with improved survival, as did treatment with craniospinal irradiation and multi-agent chemotherapy. Further study of this group of patients as a distinct diagnostic entity will be necessary to determine optimal therapy. C1 [Gilheeney, Stephen W.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Gilheeney, Stephen W.; Chi, Susan; Turner, Christopher; Lehman, Leslie; Kieran, Mark W.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Saad, Ali; De Girolami, Umberto] Childrens Hosp, Dept Pathol Neuropathol, Boston, MA 02115 USA. [Chi, Susan; Turner, Christopher; Lehman, Leslie; Kieran, Mark W.] Childrens Hosp, Dept Oncol, Boston, MA 02115 USA. [Ullrich, Nicole J.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Goumnerova, Liliana; Scott, R. Michael] Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Marcus, Karen] Childrens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. RP Gilheeney, SW (reprint author), Mem Sloan Kettering Canc Ctr, Howard 1104,1275 York Ave, New York, NY 10021 USA. EM gilheens@mskcc.org OI Kieran, Mark/0000-0003-2184-7692 NR 25 TC 23 Z9 24 U1 0 U2 2 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 AUG PY 2008 VL 89 IS 1 BP 89 EP 95 DI 10.1007/s11060-008-9589-2 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 320BK UT WOS:000257208500014 PM 18415046 ER PT J AU Lugo, JN Barnwell, LF Ren, Y Lee, WL Johnston, LD Kim, R Hrachovy, RA Sweatt, JD Anderson, AE AF Lugo, Joaquin N. Barnwell, Lyndon Forbes Ren, Yajun Lee, Wai Ling Johnston, Lisa Danielle Kim, Rebecca Hrachovy, Richard A. Sweatt, John David Anderson, Anne E. TI Altered phosphorylation and localization of the A-type channel, Kv4.2 in status epilepticus SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE epilepsy; extracellular signal-regulated kinase; ion channels; mitogen-activated protein kinase; protein phosphorylation; seizures ID ACTIVATED PROTEIN-KINASE; HIPPOCAMPAL PYRAMIDAL NEURONS; TEMPORAL-LOBE EPILEPSY; LONG-TERM POTENTIATION; DENDRITIC K+ CHANNELS; MAP KINASE; SYNAPTIC PLASTICITY; POTASSIUM CHANNELS; RAT HIPPOCAMPUS; RECEPTOR TRAFFICKING AB Extracelluar signal-regulated kinase (ERK) pathway activation has been demonstrated following convulsant stimulation; however, little is known about the molecular targets of ERK in seizure models. Recently, it has been shown that ERK phosphorylates Kv4.2 channels leading to down-regulation of channel function, and substantially alters dendritic excitability. In the kainate model of status epilepticus (SE), we investigated whether ERK phosphorylates Kv4.2 and whether the changes in Kv4.2 were evident at a synaptosomal level during SE. Western blotting was performed on rat hippocampal whole cell, membrane, synaptosomal, and surface biotinylated extracts following systemic kainate using an antibody generated against the Kv4.2 ERK sites and for Kv4.2, ERK, and phospho-ERK. ERK activation was associated with an increase in Kv4.2 phosphorylation during behavioral SE. During SE, ERK activation and Kv4.2 phosphorylation were evident at the whole cell and synaptosomal levels. In addition, while whole-cell preparations revealed no alterations in total Kv4.2 levels, a decrease in synaptosomal and surface expression of Kv4.2 was evident after prolonged SE. These results demonstrate ERK pathway coupling to Kv4.2 phosphorylation. The finding of decreased Kv4.2 levels in hippocampal synaptosomes and surface membranes suggest additional mechanisms for decreasing the dendritic A-current, which could lead to altered intrinsic membrane excitability during SE. C1 [Anderson, Anne E.] Cain Fdn Labs, Feigin Ctr, Dept Pediat, Houston, TX 77030 USA. [Barnwell, Lyndon Forbes; Hrachovy, Richard A.; Anderson, Anne E.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Hrachovy, Richard A.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Sweatt, John David] Univ Alabama, Dept Neurobiol, Birmingham, AL USA. [Anderson, Anne E.] Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA. RP Anderson, AE (reprint author), Cain Fdn Labs, Feigin Ctr, Dept Pediat, MC 3-6365, Houston, TX 77030 USA. EM annea@bcm.edu OI Sweatt, J. David/0000-0003-3567-485X FU NINDS NIH HHS [F32 NS056664, F32 NS056664-01A2, R01 NS049427, R01 NS049427-03] NR 50 TC 42 Z9 42 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD AUG PY 2008 VL 106 IS 4 BP 1929 EP 1940 DI 10.1111/j.1471-4159.2008.05508.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 333RQ UT WOS:000258170400040 PM 18513371 ER PT J AU Paulsen, JS Langbehn, DR Stout, JC Aylward, E Ross, CA Nance, M Guttman, M Johnson, S MacDonald, M Beglinger, LJ Duff, K Kayson, E Biglan, K Shoulson, I Oakes, D Hayden, M AF Paulsen, J. S. Langbehn, D. R. Stout, J. C. Aylward, E. Ross, C. A. Nance, M. Guttman, M. Johnson, S. MacDonald, M. Beglinger, L. J. Duff, K. Kayson, E. Biglan, K. Shoulson, I. Oakes, D. Hayden, M. CA Predict HD Investigators & Coordin TI Detection of Huntington's disease decades before diagnosis: the Predict-HD study SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID AT-RISK; GENE CARRIERS; MOTOR CHANGES; ONSET; MANIFESTATIONS; INDIVIDUALS; ATROPHY; MEMORY; VOLUME AB Objective: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington's disease ( HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. Methods: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled nonlinearly using estimated time until diagnosis ( based on CAG repeat length and current age) as the predictor. Results: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. Conclusions: These findings from the Predict- HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials. C1 [Paulsen, J. S.; Langbehn, D. R.; Beglinger, L. J.; Duff, K.] Univ Iowa, Roy J & Lucille A Carver Coll Med Res, Iowa City, IA 52242 USA. [Stout, J. C.; Johnson, S.] Indiana Univ, Dept Psychol, Bloomington, IN USA. [Aylward, E.] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Ross, C. A.] Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Nance, M.] Pk Nicollet Clin, Dept Neurosci, St Louis Pk, MN USA. [Guttman, M.] Ctr Movement Disorders, Markham, ON, Canada. [MacDonald, M.] Massachusetts Gen Hosp, Ctr Neurosci, Boston, MA 02114 USA. [Kayson, E.; Biglan, K.; Shoulson, I.] Univ Rochester, Clin Trials Coordinat Ctr, Rochester, NY USA. [Oakes, D.] Univ Rochester, Med Ctr, Dept Biostat, Rochester, NY 14642 USA. [Hayden, M.] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Predict HD Investigators & Coordin] Huntington Study Grp, Rochester, NY USA. RP Paulsen, JS (reprint author), Univ Iowa, Roy J & Lucille A Carver Coll Med Res, 1-305 Med Educ Bldg, Iowa City, IA 52242 USA. EM jane-paulsen@uiowa.edu RI Johnson, Shannon/A-9870-2011; Raymond, Lynn/A-6664-2010; Ross, Christopher/H-8395-2013; Hayden, Michael/D-8581-2011 OI Raymond, Lynn/0000-0002-8610-1042; Hayden, Michael/0000-0001-5159-1419 FU Howard Hughes Medical Institute; NINDS NIH HHS [R01 NS040068]; PHS HHS [16375] NR 33 TC 307 Z9 310 U1 4 U2 30 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD AUG PY 2008 VL 79 IS 8 BP 874 EP 880 DI 10.1136/jnnp.2007.128728 PG 7 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 328KF UT WOS:000257796600008 PM 18096682 ER PT J AU Miller, LA Collins, RL Kent, TA AF Miller, Lisa A. Collins, Robert L. Kent, Thomas A. TI Language and the modulation of impulsive aggression SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; BORDERLINE PERSONALITY-DISORDER; TEMPORAL-LOBE EPILEPSY; ORBITAL FRONTAL-CORTEX; PREFRONTAL CORTEX; WORKING-MEMORY; EMOTION REGULATION; LIMBIC SYSTEM; BEHAVIOR; BRAIN AB The current conceptualization of the functional anatomy of impulsive aggression relies on data largely derived from studies of animal models of defensive rage. However, animal models cannot account for the replicable findings of verbal pairments and abnormalities ties in the language processing regions of the brain, described in more recent studies of impulsive aggression in humans. The authors present an updated model of impulsive aggression that preserves the core defensive rage functional anatomy while implicating the brain regions associated directly and indirectly with language processing and their relationship to executive function as integral to the etiology, modulation, and treatment of impulsive aggression. C1 [Miller, Lisa A.; Collins, Robert L.; Kent, Thomas A.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Miller, Lisa A.] Baylor Coll Med, Dept Psychiat, Houston, TX 77030 USA. [Collins, Robert L.; Kent, Thomas A.] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. RP Kent, TA (reprint author), 2B223 Neurol,2002 Holcombe Blvd, Houston, TX 77030 USA. EM tkent@bcm.tmc.edu OI Kent, Thomas/0000-0002-9877-7584 FU VA (South Central MI-RECC) FX This work was supported by the VA (South Central MI-RECC). The authors thank Lynn Maher, Ph.D., and Andrew Papanicoloau, Ph.D., for their critical review of the manuscript This work is dedicated to the memory of Ernest Barratt, Ph.D. NR 79 TC 11 Z9 11 U1 4 U2 8 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD AUG PY 2008 VL 20 IS 3 BP 261 EP 273 DI 10.1176/appi.neuropsych.20.3.261 PG 13 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 353WK UT WOS:000259599500002 PM 18806230 ER PT J AU Nha, KW Papannagari, R Gill, TJ Van de Velde, SK Freiberg, AA Rubash, HE Li, G AF Nha, Kyung W. Papannagari, Ramprasad Gill, Thomas J. Van de Velde, Samuel K. Freiberg, Andrew A. Rubash, Harry E. Li, Guoan TI In vivo patellar tracking: Clinical motions and patellofemoral indices SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article ID ANTERIOR CRUCIATE LIGAMENT; JOINT KINEMATICS; KNEE-JOINT; 3-DIMENSIONAL TRACKING; CONTACT AREAS; FLEXION; EXTENSION; WALKING; MODELS; SYSTEM AB Patellar tracking during in vivo weightbearing knee function is not well understood. This study investigated patellar tracking of eight subjects during a full range of weightbearing flexion using magnetic resonance imaging and dual orthogonal fluoroscopy. The data were reported using a clinical description based on patellar and femoral joint coordinate systems and using patellar indices based on geometrical features of the femur and patella. The mean patellar shift was within 3 mm over the entire range of flexion. The patella tilted laterally from 0 degrees to 75 degrees, and then tilted medially beyond 75 degrees of flexion. The mean tilt was within 6 degrees. Similarly, the mean patellar rotation was small at early flexion, and the mean total excursion of patellar rotation was about 8 degrees. The patellofemoral indices showed that the mean sulcus angle and congruence angle varied within 8 degrees over the entire flexion range. The mean lateral patellar displacement was within 6 mm. A consistent decrease in lateral patellar tilt and an increase in lateral patellofemoral angle were observed with knee flexion. In conclusion, patellar motion is relatively small with respect to the femur during in vivo weightbearing knee flexion. These data may provide baseline knowledge for understanding normal patellar tracking. (c) 2008 Orthopaedic Research Society. C1 [Nha, Kyung W.; Papannagari, Ramprasad; Gill, Thomas J.; Van de Velde, Samuel K.; Freiberg, Andrew A.; Rubash, Harry E.; Li, Guoan] Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, Boston, MA 02114 USA. [Nha, Kyung W.; Papannagari, Ramprasad; Gill, Thomas J.; Van de Velde, Samuel K.; Freiberg, Andrew A.; Rubash, Harry E.; Li, Guoan] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Nha, Kyung W.] Inje Univ, Dept Orthopaed Surg, Ilsan, South Korea. [Nha, Kyung W.] Ilsanpaik Hosp, Ilsan, South Korea. RP Li, G (reprint author), Massachusetts Gen Hosp, Dept Orthopaed Surg, Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM glil@partners.org FU NIAMS NIH HHS [R01 AR052408] NR 34 TC 52 Z9 53 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD AUG PY 2008 VL 26 IS 8 BP 1067 EP 1074 DI 10.1002/jor.20554 PG 8 WC Orthopedics SC Orthopedics GA 327FD UT WOS:000257714100005 PM 18327809 ER PT J AU Wan, L de Asia, RJ Rubash, HE Li, G AF Wan, Lu de Asia, Richard J. Rubash, Harry E. Li, Guoan TI In vivo cartilage contact deformation of human ankle joints under full body weight SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE cartilage; in vivo cartilage deformation; ankle joint; fluoroscopic image; in vivo biomechanies ID CRUCIATE LIGAMENT DEFICIENCY; HUMAN ARTICULAR-CARTILAGE; HUMAN HIP-JOINT; THICKNESS DISTRIBUTION; PRESSURE DISTRIBUTION; GENDER-DIFFERENCES; TIBIOTALAR JOINT; LOWER-LIMB; KNEE; KINEMATICS AB Quantitative data on in vivo deformation of articular cartilage is important for understanding the articular joint function and the etiology of degenerative joint diseases such as osteoarthritis. This study experimentally determined the in vivo cartilage thickness distribution and articular cartilage contact strain distribution in human ankle joints under full body weight loading conditions using a combined dual fluoroscopic and magnetic resonance imaging technique. The average cartilage thickness with the joint non-weight bearing was found to be 1.43 mm +/- 0.15 mm and 1.42 mm +/- 0.18 mm in the distal tibial and proximal talar cartilage layers, respectively. During weight bearing on a single leg, the strain distribution data revealed that 42.4% +/- 15.7% of the contact area had contact strain higher than 15% in the ankle joint. Peak cartilage contact strain reached 34.5% +/- 7.3%. This quantitative data on in vivo human cartilage morphology and deformation demonstrated that the cartilage may undergo large deformations under the loading conditions experienced in human ankle joints during daily activities. The in vivo cartilage contact deformation can be used as displacement boundary conditions in three-dimensional (3D) finite element models of the joint to calculate in vivo 3D articular cartilage contact stress/strain distributions. (c) 2008 Orthopaedic Research Society. C1 [Wan, Lu; de Asia, Richard J.; Rubash, Harry E.; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, Boston, MA 02114 USA. [Wan, Lu] MIT, Dept Phys, Cambridge, MA 02139 USA. RP Li, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Bioengn Lab, 55 Fruit St,GRJ 1215, Boston, MA 02114 USA. EM gli1@partners.org NR 57 TC 32 Z9 32 U1 3 U2 12 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD AUG PY 2008 VL 26 IS 8 BP 1081 EP 1089 DI 10.1002/jor.20593 PG 9 WC Orthopedics SC Orthopedics GA 327FD UT WOS:000257714100007 PM 18327792 ER PT J AU Poissant, SF Beaudoin, F Huang, JY Brodsky, J Lee, DJ AF Poissant, Sarah F. Beaudoin, Francesca Huang, Jiayi Brodsky, Jacob Lee, Daniel J. TI Impact of Cochlear Implantation on Speech Understanding, Depression, and Loneliness in the Elderly SO JOURNAL OF OTOLARYNGOLOGY-HEAD & NECK SURGERY LA English DT Article DE cochlear implant; depression; elderly; loneliness; speech perception AB Objective: To compare speech understanding ability, the level of depression, and the degree of loneliness experienced by elderly cochlear implant (CI) users (>= 70 years), adult CI users (<= 60 years), and elderly hearing aid (HA) users (>= 70 years). Design: Clinical study. Setting: Tertiary academic neuro-otologic and audiologic centre. Methods: Three groups of patients were enrolled: (1) nine unilateral CI users 70 years or older at the time of implantation (mean 77.7 years), (2) eight unilateral CI users 60 years or younger at the time of implantation (mean 51.1 years), and (3) nine bilateral HA users 70 years or older (mean 77.5 years). Subjects underwent speech perception testing and completed two scales regarding their perceived levels of depression (pre-/post-CI) and feelings of loneliness (pre-/post-CI). Main Outcome Measure: Speech understanding scores in quiet and in noise and quality of life indicators (UCLA Loneliness Questionnaire, Geriatric Depression Screening Scale). Results: There were no perioperative complications. No significant differences in speech understanding ability in quiet or in noise between elderly and younger CI patients were observed (p < .05). Cochlear implantation decreased perceived depression in elderly recipients and loneliness in both elderly and younger recipients. Finally, elderly CI users were no more depressed or lonely than their age-matched peers with mild-to-moderate hearing loss who use HAs. Conclusions: Cochlear implantation in elderly patients results in speech perception abilities comparable to those of younger CI recipients, as well as measurable improvements in depression and loneliness. C1 [Poissant, Sarah F.] Univ Massachusetts, Dept Commun Disorders, Amherst, MA 01003 USA. [Beaudoin, Francesca; Huang, Jiayi; Brodsky, Jacob; Lee, Daniel J.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Lee, Daniel J.] UMass Mem Med Ctr, Dept Otolaryngol, Worcester, MA USA. [Lee, Daniel J.] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. RP Poissant, SF (reprint author), Univ Massachusetts, Dept Commun Disorders, 358 N Pleasant St, Amherst, MA 01003 USA. EM spoissant@comdis.umass.edu FU Medical Student Summer Research Fellowship Program; Department of Otolaryngology, University of Massachusetts Medical School; Sounds of Life Research and Education Fund FX Supported by the Medical Student Summer Research Fellowship Program and the Department of Otolaryngology, University of Massachusetts Medical School, and the Sounds of Life Research and Education Fund. NR 19 TC 21 Z9 23 U1 1 U2 14 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1916-0216 J9 J OTOLARYNGOL-HEAD N JI J. Otolaryngol-Head Neck Surg. PD AUG PY 2008 VL 37 IS 4 BP 488 EP 494 DI 10.2310/7070.2008.0093 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA V10KN UT WOS:000207463000008 PM 19128581 ER PT J AU Gilger, MA El-Serag, HB Gold, BD Dietrich, CL Tsou, VM McDuffie, A Shub, MD AF Gilger, Mark A. El-Serag, Hashem B. Gold, Benjamin D. Dietrich, Craig L. Tsou, V. M. McDuffie, Addie Shub, Mitchell D. TI Prevalence of endoscopic findings of erosive esophagitis in children: A population-based study SO JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION LA English DT Article DE erosive esophagitis; outcomes research; pediatric endoscopy ID GASTROESOPHAGEAL-REFLUX DISEASE; ATRESIA AB Purpose: Symptoms of gastroesophageal reflux. disease (GERD) occur in 2% to 7% of children. The manifestations of GERD can be limited to symptoms (eg, heartburn, regurgitation) or can be more complicated, such as erosive esophagitis, esophageal strictures, or Barrett esophagus. The prevalence of such GERD complications in children is unknown. The purpose of this study was to determine the prevalence of endoscopic findings of erosive esophagitis in children. Patients and Methods: All children ages 0 to 17 years, 11 months who underwent upper endoscopy that was recorded in the Pediatric Endoscopic Database System-Clinical Outcomes Research Initiative between 1999 and 2002 were included. Endoscopic reports that were incomplete or that did not include demographic features, indications for endoscopy, or endoscopic findings were excluded. Erosive esophagitis was defined either descriptively or by the Los Angeles classification. Esophageal biopsy was not evaluated. Results: A total of 7188 children who underwent upper endoscopy fulfilled the inclusion and exclusion criteria. Of those, 888 (12.4%) had erosive esophagitis. The median age of children with erosive esophagitis was 12.7 +/- 4.9 years versus 10.0 +/- 5.1 years in those without erosive esophagitis (P <= 0.0001). Of those with erosive esophagitis, 55.2% (490/888) were male, compared with 48.2% (3040/6300) in those without erosive esophagitis (P <= 0.0001). Erosive esophagitis was found in 29 of 531 (5.5%) children ages 0 to 1 years and progressively increased to 106 in 542 individuals (19.6%) by age 17. Hiatal hernia was found in 68 (7.7%) of children with erosive esophagitis, compared with 157 (2.5%) without erosive esophagitis (P <= 0.0001. The prevalence of Barrett esophagus, esophageal stricture, ulcer, previous surgery, nodules, foreign body or retained food, and anatomic abnormalities was not significantly different between children with erosive esophagitis and those without. Conclusions: The frequency of erosive esophagitis is slightly higher in male children and increases with age. In contrast to erosive esophagitis in adults, there were no significant variations according to race or ethnicity. Hiatal hernia is the only endoscopic observation that predicts erosive esophagitis. C1 [Gilger, Mark A.; Dietrich, Craig L.] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. [El-Serag, Hashem B.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Vet Adm Hosp, Houston Ctr Qual Care & Utilizat Studies, Houston, TX USA. [Gold, Benjamin D.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Tsou, V. M.; McDuffie, Addie] Eastern Virginia Med Sch, Norfolk, VA 23501 USA. [Shub, Mitchell D.] Phoenix Childrens Hosp, Phoenix, AZ USA. RP Gilger, MA (reprint author), Texas Childrens Hosp, CCC 1010, Houston, TX 77030 USA. EM mgilger@bcm.edu FU NIDDK NIH HHS [R01-DK30144-21/23] NR 18 TC 28 Z9 33 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-2116 J9 J PEDIATR GASTR NUTR JI J. Pediatr. Gastroenterol. Nutr. PD AUG PY 2008 VL 47 IS 2 BP 141 EP 146 PG 6 WC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics SC Gastroenterology & Hepatology; Nutrition & Dietetics; Pediatrics GA 331JY UT WOS:000258009700005 PM 18664864 ER PT J AU King, GL AF King, George L. TI The Role of Inflammatory Cytokines in Diabetes and Its Complications SO JOURNAL OF PERIODONTOLOGY LA English DT Article; Proceedings Paper CT Conference on Inflammation and Periodontal Diseases CY JAN 29-30, 2008 CL Boston, MA SP Amer Acad Periodontol DE Complications; diabetes; hyperglycemia; inflammation; insulin resistance; periodontal disease ID PROTEIN-KINASE-C; REACTIVE PROTEIN; PERIODONTAL-DISEASE; INSULIN-RESISTANCE; VASCULAR COMPLICATIONS; OXIDATIVE STRESS; GLYCEMIC CONTROL; BETA; OBESITY; RUBOXISTAURIN AB The prevalence of diabetes worldwide is increasing rapidly in association with the increase in obesity. Complications are a major fear of patients with diabetes. Complications of diabetes affect many tissues and organs, causing retinopathy, nephropathy, neuropathy, cardiovascular diseases, peripheral vascular diseases, stroke, and periodontal pathologies. Immunologic abnormalities are associated with type 1 and type 2 diabetes and diabetic complications. T cell abnormalities are believed to be the major cause of autoimmune disease in type 1 diabetes, leading to the destruction of pancreatic islets. In type 2 diabetes, inflammation and activation of monocytes are postulated to be important for enhancing insulin resistance and may contribute to the loss of insulin secretory function by islet cells. Many factors can enhance insulin resistance, including genetics, a sedentary lifestyle, obesity, and other conditions, such as chronic inflammation or infection. Increases in inflammation, such as activation of monocytes and increased levels of inflammatory markers, e.g., C-reactive protein, plasminogen activator inhibitor-1, and other cytokines, were reported in insulin-resistant states without diabetes. One possible mechanism is that abnormal levels of metabolites, such as lipids, fatty acids, and various cytokines from the adipose tissue, activate monocytes and increase the secretion of inflammatory cytokines, enhancing insulin resistance. According to this model, obesity activates monocytes and enhances insulin resistance, increasing the risk for type 2 diabetes. Abnormalities in innate immunity might also participate in the development of diabetic complications. In general, hyperglycemia is the main initiator of diabetic retinopathy, nephropathy, and neuropathy, and it participates in the development of diabetic cardiovascular diseases. Although the precise role of inflammation in the development of diabetic microvascular diseases is still unclear, it is likely that inflammation induced by diabetes and insulin resistance can accelerate atherosclerosis in patients with diabetes. Also, it was shown that conditions with an inflammatory basis, such as obesity and type 2 diabetes, can contribute to periodontal disease, suggesting that periodontal abnormalities may be partly influenced by inflammatory changes. Further research is required to confirm the role of inflammation and the onset of diabetes, microvascular diseases, and periodontal pathologies. J Periodontoi 2008;79:7527-1534. C1 [King, George L.] Joslin Diabet Ctr, Sect Vasc Cell Biology, Boston, MA 02215 USA. [King, George L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP King, GL (reprint author), Joslin Diabet Ctr, Sect Vasc Cell Biology, 1 Joslin Pl, Boston, MA 02215 USA. EM george.king@joslin.harvard.edu FU NEI NIH HHS [R01 EY 16150]; NIDDK NIH HHS [P30 DK 36836, R01 DK 53105] NR 39 TC 209 Z9 228 U1 5 U2 32 PU AMER ACAD PERIODONTOLOGY PI CHICAGO PA 737 NORTH MICHIGAN AVENUE, SUITE 800, CHICAGO, IL 60611-2690 USA SN 0022-3492 J9 J PERIODONTOL JI J. Periodont. PD AUG PY 2008 VL 79 IS 8 BP 1527 EP 1534 DI 10.1902/jop.2008.080246 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 394IS UT WOS:000262441000006 PM 18673007 ER PT J AU Petyuk, VA Qian, WJ Hinault, C Gritsenko, MA Singhal, M Monroe, ME Camp, DG Kulkarni, RN Smith, RD AF Petyuk, Vladislav A. Qian, Wei-Jun Hinault, Charlotte Gritsenko, Marina A. Singhal, Mudita Monroe, Matthew E. Camp, David G., II Kulkarni, Rohit N. Smith, Richard D. TI Characterization of the mouse pancreatic islet proteome and comparative analysis with other mouse tissues SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE LC-MS/MS; pancreatic islets; proteomics; diabetes; mouse model; mass spectrometry; interaction network ID TANDEM MASS-SPECTROMETRY; BETA-CELL; INSULIN-RESISTANCE; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; INTERACTION NETWORKS; MESSENGER-RNA; SHOTGUN PROTEOMICS; OXIDATIVE STRESS; EXPRESSION; PEPTIDE AB The pancreatic islets of Langerhans, and especially the insulin-producing beta cells, play a central role in the maintenance of glucose homeostasis. Alterations in the expression of multiple proteins in the islets that contribute to the maintenance of islet function are likely to underlie the pathogenesis of types 1 and 2 diabetes. To identify proteins that constitute the islet proteome, we provide the first comprehensive proteomic characterization of pancreatic islets for mouse, the most commonly used animal model in diabetes research. Using strong cation exchange fractionation coupled with reversed phase LC-MS/MS we report the confident identification of 17 350 different tryptic peptides covering 2612 proteins having at least two unique peptides per protein. The data set also identified similar to 60 post-translationally modified peptides including oxidative modifications and phosphorylation. While many of the identified phosphorylation sites corroborate those previously known, the oxidative modifications observed on cysteinyl residues reveal potentially novel information suggesting a role for oxidative stress in islet function. Comparative analysis with 15 available proteomic data sets from other mouse tissues and cells revealed a set of 133 proteins predominantly expressed in pancreatic islets. This unique set of proteins, in addition to those with known functions such as peptide hormones secreted from the islets, contains several proteins with as yet unknown functions. The mouse islet protein and peptide database accessible at http://ncrr.pnl.gov, provides an important reference resource for the research community to facilitate research in the diabetes and metabolism fields. C1 [Hinault, Charlotte; Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Cell & Mol Physiol,Dept Med, Boston, MA 02215 USA. [Petyuk, Vladislav A.; Qian, Wei-Jun; Gritsenko, Marina A.; Monroe, Matthew E.; Camp, David G., II; Smith, Richard D.] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Petyuk, Vladislav A.; Qian, Wei-Jun; Gritsenko, Marina A.; Monroe, Matthew E.; Camp, David G., II; Smith, Richard D.] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Singhal, Mudita] Pacific NW Natl Lab, Computat Biol & Bioinformat Grp, Richland, WA 99352 USA. RP Kulkarni, RN (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Cell & Mol Physiol,Dept Med, Boston, MA 02215 USA. EM Rohit.Kulkarni@joslin.harvard.edu; rds@pnl.gov RI Qian, Weijun/C-6167-2011; Smith, Richard/J-3664-2012; OI Smith, Richard/0000-0002-2381-2349; Petyuk, Vladislav/0000-0003-4076-151X; hinault, charlotte/0000-0002-3588-039X FU NCRR NIH HHS [RR 018522, P41 RR018522-06, P41 RR018522]; NIDDK NIH HHS [R01 DK 67536, R01 DK067536, R01 DK074795] NR 56 TC 27 Z9 28 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD AUG PY 2008 VL 7 IS 8 BP 3114 EP 3126 DI 10.1021/pr800205b PG 13 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 334CR UT WOS:000258200400006 PM 18570455 ER PT J AU Hooper, JW Pitman, RK Su, Z Heyman, GM Lasko, NB Macklin, ML Orr, SP Lukas, SE Elman, I AF Hooper, James W. Pitman, Roger K. Su, Zhaohui Heyman, Gene M. Lasko, Natasha B. Macklin, Michael L. Orr, Scott P. Lukas, Scott E. Elman, Igor TI Probing reward function in posttraumatic stress disorder: Expectancy and satisfaction with monetary gains and losses SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE PTSD; reward; emotion; numbing; expectancy; satisfaction ID MEDIAL PREFRONTAL CORTEX; EVENT-RELATED FMRI; BEHAVIORAL ACTIVATION; MAJOR DEPRESSION; DOPAMINE; PTSD; NEUROBIOLOGY; RESPONSES; DECISION; AMYGDALA AB Background: Posttraumatic stress disorder (PTSD) may be associated with dysfunctional reward processing. The present study assessed for such dysfunction in both the expectancy and outcome phases of reward processing. Methods: Male Vietnam veterans with (n = 15) and without (n = 11) combat-related PTSD were administered a wheel of fortune-type gambling task. Self-reported ratings of expectancy and satisfaction were collected respectively before and after each experience of monetary gain or loss. Results: PTSD participants reported both lower expectancy of reward and lower satisfaction with reward when it was received. The latter result was manifest in a failure of PTSD participants to show the greater satisfaction that normally accompanies rewards received under conditions of low expectancy. Conclusion: These results suggest reward function impairment in PTSD related to expectancy, satisfaction, and the expectancy-satisfaction relationship. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Pitman, Roger K.; Lasko, Natasha B.; Orr, Scott P.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02129 USA. [Pitman, Roger K.; Lasko, Natasha B.; Orr, Scott P.] Harvard Univ, Sch Med, Boston, MA 02129 USA. [Hooper, James W.; Heyman, Gene M.; Lukas, Scott E.; Elman, Igor] Harvard Univ, Sch Med, Behnow, MA 02478 USA. [Hooper, James W.; Heyman, Gene M.; Lukas, Scott E.; Elman, Igor] McLean Hosp, Dept Psychiat, Behav Psychopharmacol Res Lab, Behnow, MA 02478 USA. [Su, Zhaohui] Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. [Lasko, Natasha B.; Macklin, Michael L.; Orr, Scott P.] Vet Affairs Med Ctr, Res Serv, Manchester, NH 03104 USA. RP Pitman, RK (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Room 2616,Bldg 149,l3th St, Boston, MA 02129 USA. EM roger_pitman@hms.harvard.edu NR 49 TC 2 Z9 2 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3956 EI 1879-1379 J9 J PSYCHIATR RES JI J. Psychiatr. Res. PD AUG PY 2008 VL 42 IS 10 BP 802 EP 807 DI 10.1016/j.jpsychires.2007.10.008 PG 6 WC Psychiatry SC Psychiatry GA 325QQ UT WOS:000257603800003 ER PT J AU Elhai, JD Grubaugh, AL Richardson, JD Egede, LE Creamer, M AF Elhai, Jon D. Grubaugh, Anouk L. Richardson, J. Don Egede, Leonard E. Creamer, Mark TI Outpatient medical and mental healthcare utilization models among military veterans: Results from the 2001 National Survey of Veterans SO JOURNAL OF PSYCHIATRIC RESEARCH LA English DT Article DE mental health services; military veterans; United States Department of Veterans Affairs; health services ID POSTTRAUMATIC-STRESS-DISORDER; VIETNAM VETERANS; SERVICE USE; HELP-SEEKING; PREDICTORS; AFFAIRS; ERA AB Using Andersen's (1995) [Andersen R.M. Revisiting the behavioral model and access to medical care: does it matter? Journal of Health and Social Behavior 1995;36: 1-10] behavioral model of healthcare use as our theoretical framework, we examined predisposing (i.e., sociodemographic), enabling (i.e., access resources), and need (i.e., illness) models of outpatient medical and mental healthcare utilization among a national sample of US veterans. Participants were 20,048 nationally representative participants completing the 2001 National Survey of Veterans. Outcomes were healthcare use variables for the past year, including the number of Veterans Affairs (VA) and non-VA outpatient healthcare visits, and whether VA and non-VA mental health treatment was used. Univariate results demonstrated that numerous predisposing, enabling and need variables predicted both VA and non-VA healthcare use intensity and mental healthcare use. In multivariate analyses, predisposing, enabling and need variables demonstrated significant associations with both types of healthcare use, but accounted for more variance in mental healthcare use. Need variables provided an additive effect over predisposing and enabling variables in accounting for medical and mental healthcare use, and accounted for some of the strongest effects. The results demonstrate that need remains an important factor that drives healthcare use among veterans and does not seem to be overshadowed by socioeconomic factors that may create unfair disparities in treatment access. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Elhai, Jon D.] Univ S Dakota, Disaster Mental Hlth Inst, Vermillion, SD 57069 USA. [Grubaugh, Anouk L.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. [Grubaugh, Anouk L.] Med Univ S Carolina, Dept Psychiat & Behav Sci, Charleston, SC 29425 USA. [Richardson, J. Don] Vet Affairs Canada, Med Serv, Hamilton, ON L8N 3J9, Canada. [Richardson, J. Don] St Josephs Hlth Care London Parkwood Hosp, Operat Stress Injury Clin, London, ON, Canada. [Egede, Leonard E.] Med Univ S Carolina, Dept Gen Internal Med & Geriatr, Charleston, SC 29425 USA. [Creamer, Mark] Univ Melbourne, Australian Ctr Posttraumat Mental Hlth, Heidelberg West, Vic 3081, Australia. RP Elhai, JD (reprint author), Univ S Dakota, Disaster Mental Hlth Inst, 414 E Clark St, Vermillion, SD 57069 USA. EM jonelhai@fastmail.fm; grubaugh@musc.edu; jdrichardson@sympatico.ca; egedel@musc.edu; markcc@unimelb.edu.au NR 25 TC 27 Z9 27 U1 2 U2 4 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 AUG PY 2008 VL 42 IS 10 BP 858 EP 867 DI 10.1016/j.jpsychires.2007.09.006 PG 10 WC Psychiatry SC Psychiatry GA 325QQ UT WOS:000257603800010 PM 18005993 ER PT J AU Nagymanyoki, Z Growdon, WB Sarno, J Callahan, MJ Parast, MM Fulop, V Mok, SC Horowitz, N Berkowitz, RS AF Nagymanyoki, Zoltan Growdon, Whitfield B. Sarno, Jennifer Callahan, Michael J. Parast, Marta M. Fulop, Vilmos Mok, Samuel C. Horowitz, Neil Berkowitz, Ross S. TI Vascularization and Expression of Angiogenic Factors in Partial and Complete Molar Pregnancies SO JOURNAL OF REPRODUCTIVE MEDICINE LA English DT Article DE angiogenesis; gestational trophoblastic disease; microvessel density; molar pregnancy; vascular endothelial growth factor ID ENDOTHELIAL GROWTH-FACTOR; MICROVESSEL DENSITY; ANGIOPOIETIN-2; CANCER; TUMORS; CELLS; TIE2; HCG AB OBJECTIVE: To determine the microvessel density (MVD) at the implantation site of normal placenta (NP) and molar pregnancies and to correlate MVD with clinical data and underlying angiogenic factors. STUDY DESIGN: Immunolocalization of CD31, vascular endothelial growth factor and angiopoietin 1 and 2 were performed on NPs, nonpersistent partial moles, persistent partial moles (PPM), nonpersistent complete moles and persistent complete moles (PCM). RESULTS: Significant differences were identified in the MVD between NP and complete mole (CM), and PM and CM (p < 0.001 and p < 0.035, respectively). M VD in PPM and PCM was significantly higher (p = 0.036 and p < 0.001, respectively) when compared to NP. MVD > 100 per high-power field was associated with an increased risk of persistence (p < 0.04). MVD showed a strong correlation with immediate postevacuation hCG levels (p < 0.03). Angiopoietin 2 staining was more heterogeneous, with lower overall expression in molar pregnancies as compared to more homogeneous expression in NP (p < 0.05). CONCLUSION: MVD is highly correlated with hCG levels, suggesting that hCG may act as an angiogenic factor during implantation of molar pregnancy. MVD at the implantation site may be associated with excessive trophoblastic proliferation or reflect high hCG levels, which places patients at increased risk of persistent neoplasia. (J Reprod Med 2008;53:589-594) C1 [Berkowitz, Ross S.] Harvard Univ, Dept Obstet & Gynecol,Brigham & Womens Hosp,Sch M, Div Gynecol Oncol,Trophoblast Tumor Registry,Dana, Lab Gynecol Oncol,New England TRophoblast Dis Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol,Div Womens & Perinatal Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Obstet & Gynecol,Div Gynecol Oncol, Boston, MA 02115 USA. State Hlth Ctr, Dept Obstet & Gynecol, Budapest, Hungary. Semmelweis Univ, H-1085 Budapest, Hungary. RP Berkowitz, RS (reprint author), Harvard Univ, Dept Obstet & Gynecol,Brigham & Womens Hosp,Sch M, Div Gynecol Oncol,Trophoblast Tumor Registry,Dana, Lab Gynecol Oncol,New England TRophoblast Dis Ctr, 75 Francis St, Boston, MA 02115 USA. EM rberkowitz@partners.org FU Choriocarcinoma Research FX Supported by the Choriocarcinoma Research Fund. NR 20 TC 9 Z9 11 U1 0 U2 1 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0024-7758 J9 J REPROD MED JI J. Reprod. Med. PD AUG PY 2008 VL 53 IS 8 BP 589 EP 594 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 339MY UT WOS:000258582900008 PM 18773623 ER PT J AU Emmons, KM Geller, AC Viswanath, V Rutsch, L Zwirn, J Gorham, S Puleo, E AF Emmons, Karen M. Geller, Alan C. Viswanath, Vish Rutsch, Linda Zwirn, Jodie Gorham, Sue Puleo, Elaine TI The SunWise Policy Intervention for School-Based Sun Protection: A Pilot Study SO JOURNAL OF SCHOOL NURSING LA English DT Article DE skin cancer prevention; schools; policy ID SKIN-CANCER PREVENTION; ELEMENTARY-SCHOOLS; EDUCATION; EXPOSURE AB Skin cancer is highly preventable, but clearly there is a critical need to focus on better ways to disseminate information about known skin cancer prevention. The U. S. Environmental Protection Agency's (EPA) SunWise Program is one channel for reaching children, teachers, and school nurses. In a pilot study designed to increase adoption of school-based sun protection policies, 28 schools were randomly assigned to one of three groups: Control, which included the EPA's original SunWise curriculum toolkit; SunWise Policy, which included a revised toolkit emphasizing policy; and SunWise Policy plus Technical Assistance, which included the policy toolkit and 3 technical assistance phone calls. The enhanced SunWise Policy plus Technical Assistance intervention led to more new sun protection policies. Use of study interventions for improving sun protection practices such as policy toolkits or brief counseling can be easily interwoven into school hours by school nurses and other health educators. C1 [Emmons, Karen M.; Viswanath, Vish] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Zwirn, Jodie] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Geller, Alan C.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Rutsch, Linda] US EPA, SunWise Program, Washington, DC 20460 USA. [Gorham, Sue] Fdn Amer, SHADE, Scottsdale, AZ USA. [Puleo, Elaine] Univ Massachusetts, Dept Publ Hlth Biostat & Epidemiol Concentrat, Amherst, MA 01003 USA. RP Emmons, KM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, 665 Huntington Ave, Boston, MA 02115 USA. NR 16 TC 12 Z9 12 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1059-8405 J9 J SCH NURS JI J. Sch. Nurs. PD AUG PY 2008 VL 24 IS 4 BP 215 EP 221 DI 10.1177/1059840508319627 PG 7 WC Nursing SC Nursing GA 483SV UT WOS:000268989300006 PM 18757354 ER PT J AU Guinan, JJ Cooper, NP AF Guinan, John J., Jr. Cooper, Nigel P. TI Medial olivocochlear efferent inhibition of basilar-membrane responses to clicks: Evidence for two modes of cochlear mechanical excitation SO JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA LA English DT Article ID OUTER HAIR-CELLS; AUDITORY-NERVE FIBERS; GUINEA-PIG COCHLEA; BROAD-BAND STIMULI; ACOUSTIC STIMULATION; CHINCHILLA COCHLEA; BUNDLE MOTION; WAVE-FORM; ORGAN; CORTI AB Conceptualizations of mammalian cochlear mechanics are based on basilar-membrane (BM) traveling waves that scale with frequency along the length of the cochlea, are amplified by outer hair cells (OHCs), and excite inner hair cells and auditory-nerve (AN) fibers in a simple way. However, recent experimental work has shown medial-olivocochlear (MOC) inhibition of AN responses to clicks that do not fit with this picture. To test whether this AN-initial-peak (ANIP) inhibition might result from hitherto unrecognized aspects of the traveling-wave or MOC-evoked inhibition, MOC effects on BM responses to clicks in the basal turns of guinea pig and chinchilla cochleae were measured. MOC stimulation inhibited BM click responses in a time and level dependent manner. Inhibition was not seen during the first half-cycle of the responses, but built up gradually, and ultimately increased the responses' decay rates. MOC stimulation also produced small phase leads in the response wave forms, but had little effect on the instantaneous frequency or the waxing and waning of the responses. These data, plus recent AN data, support the hypothesis that the MOC-evoked inhibitions of the traveling wave and of the ANIP response are separate phenomena, and indicate that the OHCs can affect at least two separate modes of excitation in the mammalian cochlea. (c) 2008 Acoustical Society of America. C1 [Guinan, John J., Jr.] Harvard Univ, Sch Med, Eaton Peabody Lab, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Guinan, John J., Jr.] Harvard MIT HST Speech & Hearing Biosci & Te, Cambridge, MA 02139 USA. [Cooper, Nigel P.] Univ Keele, Sch Life Sci ISTM Neurosci, Keele ST5 5BG, Staffs, England. RP Guinan, JJ (reprint author), Harvard Univ, Sch Med, Eaton Peabody Lab, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM jjg@epl.meei.harvard.edu FU NIDCD NIH HHS [R01 DC000235, R01DC00235] NR 59 TC 26 Z9 27 U1 1 U2 2 PU ACOUSTICAL SOC AMER AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0001-4966 EI 1520-8524 J9 J ACOUST SOC AM JI J. Acoust. Soc. Am. PD AUG PY 2008 VL 124 IS 2 BP 1080 EP 1092 DI 10.1121/1.2949435 PG 13 WC Acoustics; Audiology & Speech-Language Pathology SC Acoustics; Audiology & Speech-Language Pathology GA 334OG UT WOS:000258230500047 PM 18681598 ER PT J AU Rhoads, KF Ackerson, LK Jha, AK Dudley, RA AF Rhoads, Kim F. Ackerson, Leland K. Jha, Ashish K. Dudley, R. Adams TI Quality of colon cancer outcomes in hospitals with a high percentage of Medicaid patients SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID RACIAL DISPARITIES; ACUTE APPENDICITIS; COMORBIDITY INDEX; INSURANCE STATUS; OF-CARE; SURGERY AB BACKGROUND: There is evidence that patients with Medicaid insurance suffer worse outcomes from surgical conditions; but there is little research about whether this reflects clustering of such patients at hospitals with worse outcomes. We assess the outcomes of patients with colon and rectal cancers at hospitals with a high proportion of Medicaid patients. STUDY DESIGN: California Cancer Registry patient-level records were linked to discharge abstracts from California's Office of Statewide Health Planning and Development. All operative California Cancer Registry patients from 1998 and 1999 were included. Hospitals with > 40% Medicaid patients were labeled high Medicaid hospitals (HMH). We analyzed the odds of mortality at 30 days, 1, and 5 years for colon cancer and rectal cancer separately. Multilevel logistic regression models were constructed, using MLwiN 2.0, to include patient and hospital-level characteristics. RESULTS: Thirty-day mortality after colon operation was worse in HMH (1% versus 0.6%; p = 0.04); as was I-year mortality (3.4% versus 2.4%; p = 0.001). There was no substantial difference in rates of 5-year mortality. Individuals who were insured by Medicaid had worse outcomes at 5 years. Adjustment for surgical volume eliminated the effect of HMH at 30 days (1% versus 0.7%; p = 0.45) but not at I year (3.4% versus 2.5%; p = 0.01). Adjustment for academic affiliation did not alter these results. There were an insufficient number of rectal cancer patients to detect any differences by hospital type. CONCLUSIONS: HMH have higher postoperative colon cancer mortality rates at 30 days and 1 year but not at 5 years. The early effect can be explained by surgical volume, but additional research is needed to determine which factors contribute to differences in intermediate outcomes after operations in HMH settings. C1 [Rhoads, Kim F.] Stanford Univ, Colorectal Sect, Dept Surg, Stanford, CA 94305 USA. [Dudley, R. Adams] Philip R Lee Inst Hlth Policy Studies, San Francisco, CA USA. [Ackerson, Leland K.; Jha, Ashish K.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Ackerson, Leland K.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Rhoads, KF (reprint author), Stanford Univ, Colorectal Sect, Dept Surg, 300 Pasteur Dr,Ste H3680F, Stanford, CA 94305 USA. FU Robert Wood Johnson Foundation FX We acknowledge the support of the California Endowment and Joan Reede, Dean of Diversity and Community Partnership at Harvard Medical School. Dr Dudley's work on this project was supported by an Investigator Award in Health Policy from the Robert Wood Johnson Foundation. NR 16 TC 33 Z9 33 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1072-7515 J9 J AM COLL SURGEONS JI J. Am. Coll. Surg. PD AUG PY 2008 VL 207 IS 2 BP 197 EP 204 DI 10.1016/j.jamcollsurg.2008.02.014 PG 8 WC Surgery SC Surgery GA 338OP UT WOS:000258517600007 PM 18656047 ER PT J AU Niederman, R Gould, E Soncini, J Tavares, M Osborn, V Goodson, JM AF Niederman, Richard Gould, Ellen Soncini, Jennifer Tavares, Mary Osborn, Valarie Goodson, J. Max TI A model for extending the reach of the traditional dental practice - The ForsythKids program SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article DE caries prevention; evidence-based; community-based ID GLASS-IONOMER SEALANTS; FISSURE SEALANTS; CARIES; RESIN; ADOLESCENTS; MANAGEMENT; LESIONS; SYSTEM; TEETH; TIME AB Background. The authors describe and evaluate the short-term effectiveness of a community-based program for dental caries prevention in children. Methods. The authors enrolled pupils in the ForsythKids program after receiving informed consent. They targeted children at six Massachusetts elementary schools, grades 1 through 3, with pupil populations at high risk of developing caries. The children underwent examination by dentists using calibrated technique and received comprehensive preventive care from dental hygienists. The authors determined effectiveness by means of comparing results of the initial examination with those of a second examination performed six months later. Results. At baseline, 70 percent of the 1,196 participating children had decayed or filled teeth. More troublingly, 42.1 percent of the primary teeth and 31.1 percent of the permanent teeth had untreated decay. Six months after preventive intervention, the proportion of teeth with new decay was reduced 52 percent in primary teeth and 39 percent in permanent teeth. Furthermore, the percentage of children with newly decayed or restored primary and permanent teeth was reduced by 25.4 percent and 53.2 percent, respectively. Conclusions. These results indicate that this care model relatively quickly can overcome multiple barriers to care and improve children's oral health. Clinical Implications. If widely implemented, comprehensive caries prevention programs such as ForsythKids could accomplish national health goals and reduce the need for new care providers and clinics. C1 [Niederman, Richard] Forsyth Inst, Ctr Evidence Based Dent, Boston, MA 02115 USA. [Niederman, Richard; Soncini, Jennifer; Tavares, Mary] Boston Univ, Goldman Sch Dent Med, Boston, MA 02215 USA. [Tavares, Mary; Goodson, J. Max] Forsyth Inst, Clin Res Collaborat, Boston, MA USA. [Tavares, Mary; Goodson, J. Max] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. RP Niederman, R (reprint author), Forsyth Inst, Ctr Evidence Based Dent, 140 Fenway, Boston, MA 02115 USA. EM rniederman@forsyth.org FU Delta Dental Services of Massachusetts, Charlestown; Bingham Trust, Hadlyme, Conn; Massachusetts Department of Public Health; Bilezikian Family Foundation, Hyannis, Mass; Yawkey Foundation II, Dedham, Mass; Deborah Munroe Noonan Memorial Fund; Redwoods Group, Morrisville, N.C; American Dental Association Foundation; Samuel Harris Fund, Chicago; Kelley Foundation, Hyannis, Mass; Cape Cod Foundation, Yarmouthport, Mass; National Society of Dental Practitioners, Coral Springs, Fla; Foundation of the Pierre Fauchard Academy, Mesquite, Nev; MassHealth Access Program; University of Massachusetts Medical School, Worcester; Natural Dentist, Medford, Mass. FX The authors thank Delta Dental Services of Massachusetts, Charlestown, a prime contributor of seed funding needed to initiate this program;Bingham Trust, Hadlyme, Conn., the which provided continuous ongoing support; and the General Court of the Commonwealth of Massachusetts, which, through the Massachusetts Department of Public Health, provided funding for program expansion. The authors also thank the following for providing ongoing support, targeted funding, supplies or equipment for individual aspects of this program: the Bilezikian Family Foundation, Hyannis, Mass.; Yawkey Foundation II, Dedham, Mass.; Deborah Munroe Noonan Memorial Fund u/w/o Walter Noonan, Bank of America, Trustee, Boston; Redwoods Group, Morrisville, N.C.; American Dental Association Foundation, Samuel Harris Fund, Chicago; GC America, Alsip, III.; Kelley Foundation, Hyannis, Mass.; Cape Cod Foundation, Yarmouthport, Mass.; National Society of Dental Practitioners, Coral Springs, Fla.; Foundation of the Pierre Fauchard Academy, Mesquite, Nev.; MassHealth Access Program, a program of Commonwealth Medicine, University of Massachusetts Medical School, Worcester; and Natural Dentist, Medford, Mass.; The authors gratefully acknowledge the help of all of the pupils, teachers, nurses and administrators who facilitated this study in the following schools: Hyannis East Elementary School, Hyannis, Mass.; Hyannis West Elementary School, Hyannis, Mass.; E.J. Harrington Elementary School, Lynn, Mass.; Cobbett Elementary School, Lynn, Mass.; Maurice J. Tobin Elementary School, Boston; and David G. Farragut Elementary School, Boston. Without their help and support, none of this work would have been possible. The authors also thank Dr. Dominick DePaola for suggesting the ForsythKids program and then convincing them to take it on; Kathleen Zichy, MGA, for securing ongoing funding, without which the program would not exist; Dr. Philip Stashenko, for his unwavering trust and support; Jennifer Kelly, for ensuring that appropriate communication occurred among everyone involved; and Ralph Kent, DMSc, for his unending patience in guiding the authors through the intricacies of data analysis. NR 47 TC 5 Z9 6 U1 0 U2 2 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD AUG PY 2008 VL 139 IS 8 BP 1040 EP 1050 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 337IT UT WOS:000258430500014 PM 18682618 ER PT J AU Hersh, EV Moore, PA Papas, AS Goodson, JM Navalta, LA Rogy, S Rutherford, B Yagiela, JA AF Hersh, Elliot V. Moore, Paul A. Papas, Athena S. Goodson, J. Max Navalta, Laura A. Rogy, Siegfried Rutherford, Bruce Yagiela, John A. CA Soft Tissue Anesthesia Recovery Gr TI Reversal of soft-tissue local anesthesia with phentolamine mesylate in adolescents and adults SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article; Proceedings Paper CT 85th Annual Meeting of the International-Association-of-Dental-Research/Canadian-Association-for-De ntal-Research/American-Association-for-Dental-Research CY MAR 21-24, 2007 CL New Orleans, LA SP Int Assoc Dent Res, Canadian Assoc Dent Res, Amer Assoc Dent Res DE local anesthesia; lidocaine; articaine; mepivacame; prilocaine; phentolamine mesylate; epinephrine; levonordefrin ID PAIN AB Background. The authors conducted two multicenter, randomized, double-blinded, controlled Phase III clinical trials to study the efficacy and safety of phentolamine mesylate (PM) in shortening the duration and burden of soft-tissue anesthesia. The study involved 484 subjects who received one of four commercially available local anesthetic solutions containing vasoconstrictors for restorative or scaling procedures. Methods. On completion of the dental procedure, subjects randomly received a PM or a sham injection (an injection in which a needle does not penetrate the soft tissue) in the same site as the local anesthetic injection. The investigators measured the duration of soft-tissue anesthesia by using standardized lip- and tongue-tapping procedures every five minutes for five hours. They also evaluated functional measures and subject-perceived altered function, sensation, appearance and safety. Results. Median recovery times in the lower lip and tongue for subjects in the PM group were 70 minutes and 60 minutes, respectively. Median recovery times in the lower lip and tongue for subjects in the sham group were 155 minutes and 125 minutes, respectively. Upper lip median recovery times were 50 minutes for subjects in the PM group and 133 minutes for subjects in the sham group. These differences were significant (P <.0001). Recovery from actual functional deficits and subject-perceived altered function, sensation and appearance also showed significant differences between the PM and the sham groups. Conclusions. PM was efficacious and safe in reducing the duration of local anesthetic-induced soft-tissue numbness and its associated functional deficits. Clinical implications. Clinicians can use PM to accelerate reversal of soft-tissue anesthesia and the associated functional deficits. C1 [Hersh, Elliot V.] Univ Penn, Sch Dent Med, Philadelphia, PA 19104 USA. [Moore, Paul A.] Univ Pittsburgh, Sch Dent Med, Dept Anesthesiol, Pittsburgh, PA 15260 USA. [Papas, Athena S.] Tufts Univ, Sch Dent Med, Dept Oral Med, Boston, MA USA. [Goodson, J. Max] Forsyth Inst, Clin Research Collaborat, Boston, MA USA. [Navalta, Laura A.] Nova Pharmaceut Corp, Clin and Regulatory Affairs, San Diego, CA USA. [Rogy, Siegfried] Nova Pharmaceut Corp, Clin Operat & Clin Dev, San Diego, CA USA. [Rutherford, Bruce] Nova Pharmaceut Corp, Clin Dev, San Diego, CA USA. [Yagiela, John A.] Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. [Yagiela, John A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Hersh, EV (reprint author), Univ Penn, Sch Dent Med, 240 S 40th St, Philadelphia, PA 19104 USA. EM evhersh@pobox.upenn.edu RI freer, giulia/H-4609-2012; OI Giannobile, William/0000-0002-7102-9746 NR 19 TC 18 Z9 21 U1 0 U2 5 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD AUG PY 2008 VL 139 IS 8 BP 1080 EP 1093 PG 14 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 337IT UT WOS:000258430500019 PM 18682623 ER PT J AU Tavares, M Goodson, JM Studen-Pavlovich, D Yagiela, JA Navalta, LA Rogy, S Rutherford, B Gordon, S Papas, AS AF Tavares, Mary Goodson, J. Max Studen-Pavlovich, Deborah Yagiela, John A. Navalta, Laura A. Rogy, Siegfried Rutherford, Bruce Gordon, Sharon Papas, Athena S. CA Soft Tissue Anesthesia Reversal Gr TI Reversal of soft-tissue local anesthesia with phentolamine mesylate in pediatric patients SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article; Proceedings Paper CT 85th Annual Meeting of the International-Association-of-Dental-Research/Canadian-Association-for-De ntal-Research/American-Association-for-Dental-Research CY MAR 21-24, 2007 CL New Orleans, LA SP Int Assoc Dent Res, Canadian Assoc Dent Res, Amer Assoc Dent Res DE local anesthetics; dental care for children; drugs; injections; pain measurement; pediatric dentistry; randomized controlled clinical trials AB Background. The authors evaluated the safety and efficacy of a formulation of phentolamine mesylate (PM) as a local anesthesia reversal agent for pediatric patients. Methods. A total of 152 pediatric subjects received injections of local anesthetic with 2 percent lidocaine and 1:100,000 epinephrine before undergoing dental procedures. The authors then randomized subjects to receive a PM injection or a control injection (sham injection in which a needle does not penetrate the tissue) in the same sites as the local anesthetic was administered in a 1:1 cartridge ratio after the procedure was completed. Over a two-to-four-hour period, they measured the duration of soft-tissue anesthesia and evaluated vital signs, pain and adverse events. Results. The median recovery time to normal hp sensation was 60 minutes for the subjects in the PM group versus 135 minutes for subjects in the control group. The authors noted no differences in adverse events, pain, analgesic use or vital signs, and no subjects failed to complete the study. Conclusions. PM was well-tolerated and safe in children 4 to 11 years of age, and it accelerated the reversal of soft-tissue local anesthesia after a dental procedure in children 6 to 11 years of age. Clinical Implications., PM can help dental clinicians shorten the posttreatment duration of soft-tissue anesthesia and can reduce the number of posttreatment lip and tongue injuries in children. C1 [Tavares, Mary; Goodson, J. Max] Forsyth Inst, Clin Res Collaborat, Boston, MA 02115 USA. [Studen-Pavlovich, Deborah] Univ Pittsburgh, Sch Dent Med, Dept Pediat Dent, Pittsburgh, PA 15260 USA. [Yagiela, John A.] Univ Calif Los Angeles, Sch Dent, Los Angeles, CA 90024 USA. [Yagiela, John A.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Navalta, Laura A.] Nova Pharmaceut Corp, Clin & Regulatory Affairs, San Diego, CA USA. [Rogy, Siegfried] Nova Pharmaceut Corp, Clin Operat & Clin Dev, San Diego, CA USA. [Rutherford, Bruce] Nova Pharmaceut Corp, Clin Dev, San Diego, CA USA. [Gordon, Sharon] Univ Maryland, Sch Dent, Dept Biomed Sci, Baltimore, MD 21201 USA. [Papas, Athena S.] Tufts Univ, Sch Dent Med, Dept Oral Med, Boston, MA 02111 USA. RP Tavares, M (reprint author), Forsyth Inst, Clin Res Collaborat, 140 Fenway, Boston, MA 02115 USA. EM mtavares@forsyth.org NR 13 TC 14 Z9 15 U1 0 U2 2 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD AUG PY 2008 VL 139 IS 8 BP 1095 EP 1104 PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 337IT UT WOS:000258430500020 PM 18682624 ER PT J AU Kren, K Michael, P Johnson, EQ Thiessen, C Busey, JC AF Kren, Kari Michael, Pam Johnson, Eluira Q. Thiessen, Charlotte Busey, J. Craig TI Referral systems in ambulatory care - Providing access to the nutrition care process SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID MANAGEMENT C1 [Michael, Pam] Amer Dietet Assoc, Nutr Serv Coverage Team, Chicago, IL USA. [Johnson, Eluira Q.] Med Nutr Therapy Diabet & Dis Management Serv, EQJ Associates, Omaha, NE USA. [Thiessen, Charlotte] US Dept Vet Affairs, Nebraska Western Iowa Healthcare Syst, Omaha, NE USA. RP Kren, K (reprint author), 120 S Riverside Plaza,Suite 2000, Chicago, IL 60606 USA. EM kkren@eatright.org NR 15 TC 3 Z9 4 U1 0 U2 1 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD AUG PY 2008 VL 108 IS 8 BP 1375 EP 1379 DI 10.1016/j.jada.2008.05.001 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 335KZ UT WOS:000258290800020 PM 18656580 ER PT J AU Zhu, CW Leibman, C McLaughlin, T Scarmeas, N Albert, M Brandt, J Blacker, D Sano, M Stern, Y AF Zhu, Carolyn W. Leibman, Christopher McLaughlin, Trent Scarmeas, Nikolaos Albert, Marilyn Brandt, Jason Blacker, Deborah Sano, Mary Stern, Yaakov TI The effects of patient function and dependence on costs of care in Alzheimer's disease SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE Alzheimer's disease; cost; function; dependence ID INFORMAL CARE; HOME HEALTH; PREDICTORS; DEMENTIAS; MULTICENTER; SEVERITY; TIME AB OBJECTIVES: To estimate incremental effects of patients' dependence and function on costs of care during the early stages of Alzheimer's disease (AD) and to compare strengths of their relationships with different cost components. DESIGN: Multicenter, cross-sectional, observational study. SETTING: Three university hospitals in the United States. PARTICIPANTS: One hundred seventy-nine community-living patients with probable AD, with modified Mini-Mental State Examination scores of 30 or higher. MEASUREMENTS: Patients' dependence was measured using the Dependence Scale (DS). Functional capacity was measured using the Blessed Dementia Rating Scale (BDRS). Total cost was measured by summing direct medical costs and informal costs. Direct medical costs included costs of hospitalization, outpatient treatment and procedures, assistive devices, and medications. Informal costs were estimated from time spent helping with basic and instrumental activities of dally living for up to three caregivers per patient using national average hourly earnings as wage rate. RESULTS: DS and BDRS were associated with higher total cost, a 1-point increase in DS was associated with a $1,832 increase in total cost, and a I-point increase in BDRS was associated with a $3,333 increase. Examining component costs separately identified potential differences between DS and BDRS. A I.-point increase in BDRS was associated with a $1,406 increase in direct medical cost. A 1-point increase in DS was associated with a $1,690 increase in informal cost. CONCLUSION: Patients' dependence and function related differently to direct medical and informal Cost, Suggesting that measures of function and dependence provided unique information for explaining variations in cost of care for patients with AD, highlighting the value in measuring both constructs. C1 [Zhu, Carolyn W.; Sano, Mary] James J Peters VA Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY 10468 USA. [Zhu, Carolyn W.; Sano, Mary] James J Peters VA Med Ctr, Targeted Res Enhancement Program, Program Res Serious Phys & Mental Illness, Bronx, NY 10468 USA. [Zhu, Carolyn W.] Mt Sinai Sch Med, Brookdale Dept Geriatr, New York, NY USA. [Sano, Mary] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Leibman, Christopher; McLaughlin, Trent] Elan Pharmaceut Inc, San Francisco, CA USA. [Scarmeas, Nikolaos; Stern, Yaakov] Taub Inst Res Alzheimers Dis & Aging Brain, Cognit Neurosci Div, New York, NY USA. [Scarmeas, Nikolaos; Stern, Yaakov] Columbia Univ, Gertrude H Sergievsky Ctr, Med Ctr, New York, NY 10027 USA. [Scarmeas, Nikolaos; Stern, Yaakov] Columbia Univ, Dept Neurol, Med Ctr, New York, NY 10027 USA. [Albert, Marilyn; Brandt, Jason] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Blacker, Deborah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. RP Zhu, CW (reprint author), James J Peters VA Med Ctr, Ctr Geriatr Res Educ & Clin, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM carolyn.zhu@mssm.edu OI Brandt, Jason/0000-0001-7381-6244 FU NCRR NIH HHS [RR00645, M01 RR000645]; NIA NIH HHS [R01 AG007370, R01 AG007370-18, U01 AG010483, U01AG010483, U19 AG010483, Z01 AG007370] NR 35 TC 33 Z9 36 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD AUG PY 2008 VL 56 IS 8 BP 1497 EP 1503 DI 10.1111/j.1532-5415.2008.01798.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 340AD UT WOS:000258617500016 PM 18662215 ER PT J AU Wolf, M AF Wolf, Myles TI Active Vitamin D and Survival SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID CHRONIC KIDNEY-DISEASE; MAINTENANCE HEMODIALYSIS; D DEFICIENCY; MORTALITY; RISK C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. RP Wolf, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Bartlett 917,55 Fruit St, Boston, MA 02114 USA. EM mswolf@partners.org NR 15 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD AUG PY 2008 VL 19 IS 8 BP 1442 EP 1443 DI 10.1681/ASN.2008060595 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 367DW UT WOS:000260533700003 PM 18614769 ER PT J AU Ratcliffe, MB Howard, C Mann, M del Nido, P AF Ratcliffe, Mark B. Howard, Cheryl Mann, Michael del Nido, Pedro TI National Institutes of Health funding for cardiothoracic surgical research SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID SURGERY AB Objective: Our objective was determine the status of National Institutes of Health (NIH) funding for cardiothoracic surgery research. Summary Background Data: (1) Funding from the NIH is critical if new procedures and devices are to be developed. (2) The success rate for NIH applications coming from cardiothoracic surgery faculty is thought to be inferior. (3) Per capita numbers of surgical NIH application and awards and application success fate have recently been found to be below the average for the NIH. Methods: Application and award data for full-time academic cardiothoracic surgeons were obtained by matching records in the NIH IMPAC 11 database with membership rosters of The Society of Thoracic Surgeons and The American Association for Thoracic Surgery. Manpower data were obtained from 1999, 2003, and 2005 reports of the STS/AATS Workforce committee. Society membership was used as a surrogate for investigator experience. Results: The number of NIH applications has increased steeply in the past 7 years; however, the number of awards has remained constant. This pattern was observed for surgery and cardiothoracic surgery as well. Until 2003, the cardiothoracic surgery application success rate was actually higher than that of surgery and the NIH as a whole (between 25% and 40%). Since then, however, the cardiothoracic surgery application success rate has declined steeply and is now only 14%. NIH applications and awards per 100 cardiothoracic surgeons, although similar to those of surgery, are very much less than the NIH as a whole. Conclusion: Per capita NIH funding of cardiothoracic surgeons is very much less than that of the NIH as a whole. The primary cause is the low per capita number of applications submitted by cardiothoracic surgeons. Junior cardiothoracic faculty should be encouraged to apply for career development awards. However, since the ability to shift cost from clinical to academic faculty is declining, affirmative action from the NIH may be necessary. C1 [Ratcliffe, Mark B.] San Francisco VA Med Ctr, Surg Serv 112, San Francisco, CA 94121 USA. [Ratcliffe, Mark B.; Mann, Michael] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Howard, Cheryl] NHLBI, Div Sci Program Operat, Bethesda, MD 20892 USA. [del Nido, Pedro] Childrens Hosp, Boston, MA 02115 USA. RP Ratcliffe, MB (reprint author), San Francisco VA Med Ctr, Surg Serv 112, 4150 Clement St, San Francisco, CA 94121 USA. EM mark.ratcliffe@rned.va.gov NR 14 TC 16 Z9 16 U1 0 U2 1 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 AUG PY 2008 VL 136 IS 2 BP 392 EP 397 DI 10.1016/j.jtcvs.2008.04.009 PG 6 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 338UQ UT WOS:000258535300021 PM 18692647 ER PT J AU Chen, HJJ Brown, K Barack, BM AF Chen, Hui Jenny Jie Brown, Kathleen Barack, Bruce M. TI Absence of the left brachiocephalic vein with venous return through the left superior intercostal vein - CT findings SO JOURNAL OF THORACIC IMAGING LA English DT Editorial Material DE asymptomatic congenital thoracic venous anomalies; congenital absence of the left brachiocephalic vein; left superior intercostal vein; embryogenesis ID LEFT INNOMINATE VEIN; EMBRYOLOGY AB Asymptomatic congenital thoracic venous anomalies are becoming clinically more relevant with the increasing utilization of minimally invasive surgical vascular procedures, such as left-sided implantable cardioverter defibrillator implantation. The purpose of this report is to describe the computed tomography findings of the congenital absence of the left. brachiocephalic vein in a patient with no evidence of congenital cardiovascular disease and no prior history of central venous instrumentation. In this patient, the left internal jugular and the left subclavian veins drain via the left superior intercostal vein, the accessory hemiazygous, the hemiazygous, and the azygous vein into the right brachiocephalic vein to form the superior vena cava. The clinical significance and possible embryogenesis of this anomaly are discussed. C1 [Chen, Hui Jenny Jie; Brown, Kathleen] Univ Calif Los Angeles, Med Ctr, Dept Radiol Sci, Los Angeles, CA 90024 USA. [Barack, Bruce M.] VA Greater Los Angeles Healthcare Syst, Dept Imaging, Los Angeles, CA USA. RP Chen, HJJ (reprint author), Univ Calif Los Angeles, Med Ctr, Dept Radiol Sci, Los Angeles, CA 90024 USA. EM jenzhao@ucla.edu NR 14 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0883-5993 J9 J THORAC IMAG JI J. Thorac. Imaging PD AUG PY 2008 VL 23 IS 3 BP 202 EP 205 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 344DF UT WOS:000258905300010 PM 18728550 ER PT J AU Creaney, J Yeoman, D Demelker, Y Segal, A Musk, AW Skates, SJ Robinson, BWS AF Creaney, Jenette Yeoman, Deborah Demelker, Yvonne Segal, Amanda Musk, A. W. Skates, Steven J. Robinson, Bruce W. S. TI Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE mesothelioma; tumor markers; mesothelin; SMRP; MPF; osteopontin; diagnosis ID PLEURAL MESOTHELIOMA; OVARIAN-CANCER; MOLECULAR-CLONING; TUMOR-MARKER; DIAGNOSIS; ANTIGEN; CA125; CELLS AB Introduction: There is increasing interest in identifying a blood-based marker for the asbestos-related tumor, malignant mesothelioma. Three potential markers for mesothelioma are mesothelin, megakaryocyte potentiating factor (MPF) and osteopontin. The purpose of the current Study was to directly compare these biomarkers ill the same sample population, determining their sensitivity and specificity in establishing a diagnosis, and to determine if diagnostic accuracy for mesothelioma is improved by combining the data from all three markers. Methods: Serum levels of mesothelin, MPF and osteopontin were determined by commercially available assays ill 66 samples from patients with pleural malignant mesothelioma, 20 healthy individuals, 21 patients with asbestos-related lung or pleural disease, 30 patients presenting with benign Pleural effusions and 30 patients with other malignancies. Results: Serum levels of the three markers were elevated in mesothelioma patients. At a level of specificity of 95% relative to healthy controls and patients with benign asbestos relaled disease, the sensitivity for mesothelioma was 34% for MPF, 47% for osteopontin and 73% for mesothelin. Osteopontin and MPF were unable to differentiate patients with mesothelioma from patients with other malignancies or those presenting with transudative pleural effusions. Combining the data from the three biomarkers using a logistic regression model did not improve sensitivity for detecting mesothelioma above that of the mesothelin marker alone. Conclusion: Serum mesothelin remains the most specific marker for the diagnosis of mesothelioma. C1 [Creaney, Jenette; Yeoman, Deborah; Demelker, Yvonne; Musk, A. W.; Robinson, Bruce W. S.] Univ Western Australia, Sir Charles Gairdiner Hosp, Natl Res Ctr Asbestos Related Dis, Western Australian Inst Med Res,Sch Med & Pharmac, Nedlands, WA 6009, Australia. [Creaney, Jenette; Robinson, Bruce W. S.] Sir Charles Gairdner Hosp, Australian Mesothelioma Tissue Bank, Nedlands, WA 6009, Australia. [Segal, Amanda] Queen Elizabeth II Med Ctr, PathWest Lab Med WA, Nedlands, WA, Australia. [Musk, A. W.] Sir Charles Gairdner Hosp, Dept Resp Med, Nedlands, WA 6009, Australia. [Skates, Steven J.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Creaney, J (reprint author), Univ Western Australia, Sir Charles Gairdiner Hosp, Natl Res Ctr Asbestos Related Dis, Western Australian Inst Med Res,Sch Med & Pharmac, Verdun St, Nedlands, WA 6009, Australia. EM crcaneyj@cyllene.uwa.edu.au RI Robinson, Bruce/N-1900-2014 FU National Health and Medical Council of Australia; Insurance Commission of Western Australia; FDI FX Supported in part by research grants from the National Health and Medical Council of Australia and the Insurance Commission of Western Australia, and in part by FDI. The study sponsors had no role in study design, in the collection, analysis, and interpretation of data, in the writing of the manuscript, and in the decision to submit the mannuscript for publication.; We thank the staff of PathWest Laboratory Medicine, Sir Charles Gairdner Hospital, Hollywood Hospital and St. John of God Pathology for their assisstance with this study. NR 30 TC 65 Z9 67 U1 0 U2 2 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 AUG PY 2008 VL 3 IS 8 BP 851 EP 857 PG 7 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 337PF UT WOS:000258447300007 PM 18670302 ER PT J AU de Moya, MA Dunham, M Inaba, K Bahouth, H Alam, HB Sultan, B Namias, N AF de Moya, Marc A. Dunham, Michael Inaba, Kenji Bahouth, Hany Alam, Hasan B. Sultan, Babar Namias, Nicholas TI Long-term outcome of acellular dermal matrix when used for large traumatic open abdomen SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article; Proceedings Paper CT 37th Annual Meeting of the Western-Trauma-Association CY FEB 25-MAR 02, 2007 CL Steamboat Springs, CO SP Western Trauma Assoc DE open abdomen; alloderm; acellular cadaveric dermis ID ABDOMINAL-WALL DEFECTS; COMPONENTS SEPARATION METHOD; COMPARTMENT SYNDROME; HERNIA REPAIR; CLOSURE; RECONSTRUCTION; ALLODERM; ALLOGRAFT AB Background: The purpose of this study is to prospectively examine the use of Human Acellular Dermal Matrix (HADM) in trauma patients with large open abdominal wounds and assess the long-term outcome. Previous studies have not examined the long-term outcomes in trauma patients with abdominal wall reconstructions. Methods: An institutional review board approved prospective case series of consecutive patients admitted to a level I university trauma center, who were unable to have their abdomen closed primarily after trauma laparotomy. These patients had HADM placed to attain closure of the abdomen with skin advancement flaps to cover the HADM when possible. Our primary outcome measure was hernia formation and our secondary outcomes were laxity, fistulae, and infections associated with HADM. Results: Ten patients were enrolled during a t-year period. Mean time to HADM placement was 17.2 days +/- 3.6 days. Mean initial defect size was 425.1 cm(2) +/- 75.9 cm(2) with the largest 770 cm(2). Thirty day follow-up showed no recurrence in 100% patients. Six patients remained for long-term follow-up. Follow-up at 60 days demonstrated significant laxity or recurrent hernia or both in 67% of patients, and this increased to 100% by the end of I year follow-up. There were no bowel fistulae in these patients closed with HADM but 20% with infection. Conclusions: HADM is an alternative available to reconstruct the unclosable open abdomen with no fistulae formation, however, it is associated with a high rate of laxity in large abdominal wounds. C1 [de Moya, Marc A.; Alam, Hasan B.; Sultan, Babar] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Dept Surg, Boston, MA 02114 USA. [de Moya, Marc A.; Dunham, Michael; Inaba, Kenji; Bahouth, Hany; Namias, Nicholas] Univ Miami, Ryder Trauma Ctr, Div Trauma, Miami, FL USA. [Inaba, Kenji] USC Med Ctr, Dept Surg, Div Trauma, Los Angeles, CA USA. RP de Moya, MA (reprint author), 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM mdemoya@partners.org NR 23 TC 49 Z9 50 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD AUG PY 2008 VL 65 IS 2 BP 349 EP 353 DI 10.1097/TA.0b013e31817fb782 PG 5 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 337US UT WOS:000258461600022 PM 18695470 ER PT J AU Alam, HB AF Alam, Hasan B. TI The influence of the type of resuscitation fluid on gut injury and distant organ injury in a rat model of trauma/hemorrhagic shock - Comment SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Trauma Emergency Surg & Surg Crit C, Boston, MA 02115 USA. RP Alam, HB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Trauma Emergency Surg & Surg Crit C, Boston, MA 02115 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5282 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD AUG PY 2008 VL 65 IS 2 BP 414 EP 415 PG 2 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 337US UT WOS:000258461600036 ER PT J AU Bovin, MJ Jager-Hyman, S Gold, SD Marx, BP Sloan, DM AF Bovin, Michelle J. Jager-Hyman, Shari Gold, Sari D. Marx, Brian P. Sloan, Denise M. TI Tonic immobility mediates the influence of peritraumatic fear and perceived inescapability on posttraumatic stress symptom severity among sexual assault survivors SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID GALLUS-GALLUS; DISORDER; DISSOCIATION; RAPE; METAANALYSIS; ADULTS; SCALE; PTSD AB This study evaluated whether tonic immobility mediates the relations between perceived inescapability, peritraumatic fear, and posttraumatic stress disorder (PTSD) symptom severity among sexual assault survivors. Female undergraduates (N = 176) completed questionnaires assessing assault history, perceived inescapability, peritraumatic fear, tonic immobility, and PTSD symptoms. Results indicated that tonic immobility fully mediated relations between perceived inescapability and overall PTSD symptom severity, as well as reexperiencing and avoidance/numbing symptom clusters. Tonic immobility also fully mediated the relation between fear and reexperiencing symptoms, and partially mediated relations between fear and overall PTSD symptom severity, and avoidance/numbing symptoms. Results suggest that tonic immobility could be one path through which trauma survivors develop PTSD symptoms. Further study of tonic immobility may inform our ability to treat trauma victims. C1 [Gold, Sari D.; Marx, Brian P.] VA Boston Healthcare Syst, Natl Ctr PTSD 116B 2, Boston, MA 02130 USA. [Bovin, Michelle J.; Jager-Hyman, Shari] Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. [Marx, Brian P.; Sloan, Denise M.] Boston Univ, Sch Med, Boston, MA 02215 USA. RP Marx, BP (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B 2, 1550 S Huntington Ave, Boston, MA 02130 USA. EM brain.marx@va.gov OI Sloan, Denise/0000-0002-0962-478X NR 46 TC 34 Z9 34 U1 2 U2 12 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD AUG PY 2008 VL 21 IS 4 BP 402 EP 409 DI 10.1002/jts.20354 PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 344BI UT WOS:000258899800006 PM 18720396 ER PT J AU Meffert, SM Metzler, TJ Henn-Haase, C McCaslin, S Inslicht, S Chemtob, C Neylan, T Marmar, CR AF Meffert, Susan M. Metzler, Thomas J. Henn-Haase, Clare McCaslin, Shannon Inslicht, Sabra Chemtob, Claude Neylan, Thomas Marmar, Charles R. TI A prospective study of trait anger and PTSD symptoms in police SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; EMERGENCY SERVICES PERSONNEL; VIETNAM VETERANS; TRAUMATIC EVENTS; PREDICTORS; DISTRESS; EXPOSURE; VICTIMS; PREVALENCE; HOSTILITY AB It is unknown whether anger is a risk factor for the development of posttraumatic stress disorder (PTSD) symptoms, arises as a consequence of PTSD, or both. Two hypotheses were tested in 180 police recruits: Greater trait anger during training will predict greater PTSD symptoms at one year; greater PTSD symptoms at one year will predict greater state anger at one year. Both hypotheses were confirmed, suggesting that trait anger is a risk factor for PTSD symptoms, but that PTSD symptoms are also associated with an increase of state anger. Increased anger is important not only because of the impact it has on individual distress and physical health, but also because of its potential public health impact. C1 [Meffert, Susan M.; McCaslin, Shannon] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Meffert, Susan M.; Metzler, Thomas J.; Henn-Haase, Clare; McCaslin, Shannon; Inslicht, Sabra] San Francisco Vet Adm Med Ctr, San Francisco, CA USA. [Chemtob, Claude] Mt Sinai Sch Med, New York, NY USA. RP Meffert, SM (reprint author), Univ Calif San Francisco, Dept Psychiat, VAMC Bldg 8,Box 116P, San Francisco, CA 94143 USA. EM smeffert@lppi.ucsf.edu FU NIMH NIH HHS [R25 MH060482, R01 MH056350] NR 33 TC 30 Z9 31 U1 2 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD AUG PY 2008 VL 21 IS 4 BP 410 EP 416 DI 10.1002/jts.20350 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 344BI UT WOS:000258899800007 PM 18720397 ER PT J AU Thompson, CE Taylor, FB McFall, ME Barnes, RF Raskind, MA AF Thompson, Charles E. Taylor, Fletcher B. McFall, Miles E. Barnes, Robert F. Raskind, Murray A. TI Nonnightmare distressed awakenings in veterans with posttraumatic stress disorder: Response to prazosin SO JOURNAL OF TRAUMATIC STRESS LA English DT Article ID SLEEP DISTURBANCES; TRAUMA NIGHTMARES; COMBAT VETERANS; PTSD; SYMPTOMS AB Twenty-two veterans with posttraumatic stress disorder (PTSD) were assessed for trauma-related nightmares and nonnightmare distressed awakenings (NNDA) before and after treatment with the alpha-1 adrenoreceptor antagonist prazosin at an average bedtime dose of 9.6 mg/day. Ratings combining frequency and intensity dimensions of trauma-related nightmares decreased from 3.6 to 2.2, NNDA from 5.2 to 2. 1, and sleep difficulty from 7.2 to 4. 1 per week. These results suggest that increased brain adrenergic activity may contribute to the pathophysiology of both trauma-related nightmares and NNDA in PTSD. C1 [Thompson, Charles E.; McFall, Miles E.; Barnes, Robert F.; Raskind, Murray A.] VA Northwest Network, Mental Illness Res Educ & Clin Ctr, Seattle, WA USA. [Taylor, Fletcher B.] Rainier Associates, Tacoma, WA USA. RP Raskind, MA (reprint author), VA Puget Sound Hlth Care Syst, 1600 S Columbian Way,S116, Seattle, WA 98108 USA. EM murray.raskind@va.gov FU NIMH NIH HHS [R01 MH069867, R01 MH069867-04] NR 19 TC 34 Z9 36 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD AUG PY 2008 VL 21 IS 4 BP 417 EP 420 DI 10.1002/jts.20351 PG 4 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 344BI UT WOS:000258899800008 PM 18720392 ER PT J AU McDougal, WS AF McDougal, W. Scott TI Long-term oncological and overall outcomes of percutaneous radio frequency ablation in high risk surgical patients with a solitary small renal mass - Comment SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP McDougal, WS (reprint author), Massachusetts Gen Hosp, Dept Urol, 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 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2008 VL 180 IS 2 BP 504 EP 504 DI 10.1016/j.juro.2008.04.148 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 325LE UT WOS:000257589600022 ER PT J AU Hall, SA Link, CL Pulliam, SJ Hanno, PM Eggers, PW Kusek, JW McKinlay, JB AF Hall, Susan A. Link, Carol L. Pulliam, Samantha J. Hanno, Philip M. Eggers, Paul W. Kusek, John W. McKinlay, John B. TI The relationship of common medical conditions and medication use with symptoms of painful bladder syndrome: Results from the Boston Area Community Health Survey SO JOURNAL OF UROLOGY LA English DT Article DE cystitis; interstitial; epidemiology; comorbidity ID URINARY-TRACT SYMPTOMS; INTERSTITIAL CYSTITIS; LIFE; MEN AB Purpose: The etiology of painful bladder syndrome is currently unknown. We investigated the relationship between medical factors and symptoms suggestive of painful bladder syndrome in a population based random sample. Materials and Methods: Data were collected from the Boston Area Community Health Survey, an epidemiological study conducted from 2002 to 2005 in a racially and ethnically diverse population (30 to 79 years old) from Boston, Massachusetts. The operational definition of painful bladder syndrome was symptom based. Those reporting pain increasing as the bladder fills and/or pain relieved by urination (fairly often/usually/almost always) for 3+ months were considered to have symptoms suggestive of painful bladder syndrome. We used multivariate logistic regression to estimate odds ratios and 95% confidence intervals (adjusted for demographics, anthropometric and other factors) for the association of comorbidities, surgery and medication use with painful bladder syndrome symptoms. Results: The prevalence of painful bladder syndrome symptoms was 1.3% in men and 2.6% in women. In men only depression was associated in a multivariate model (OR 4.96; 95% CI 1.65, 14.92). In women associations were observed for depression (OR 3.35; 95% CI 1.93, 5.81), history of urinary tract infections (OR 2.17; 95% CI 1.49, 4.96), chronic yeast infections (OR 3.11; 95% CI -1.29, 7.51), hysterectomy (OR 2.82; 95% CI 1.20, 6.62), calcium channel blockers (OR 4.59; 95% CI 2.71, 9.72) and cardiac glycosides (OR 10.28; 95% CI 1.46, 72.35), while thyroid medications and statins were inversely associated (OR 0.13; 95% CI 0.03, 0.47 and OR 0.24; 95% CI 0.08, 0.76; respectively). Conclusions: Gynecologic factors and certain medications may be associated with the painful bladder syndrome in women. Our results for medications suggest potentially modifiable risk factors. C1 [Hall, Susan A.; Link, Carol L.; McKinlay, John B.] New England Res Inst, Watertown, MA 02472 USA. [Pulliam, Samantha J.] Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. [Hanno, Philip M.] Univ Penn, Dept Urol, Philadelphia, PA 19104 USA. [Eggers, Paul W.; Kusek, John W.] NIDDK, Bethesda, MD USA. RP Hall, SA (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02472 USA. EM shall@nerisicience.com FU NIDDK NIH HHS [U01 DK056842, DK 56842] NR 20 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2008 VL 180 IS 2 BP 593 EP 598 DI 10.1016/j.juro.2008.04.002 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 325LE UT WOS:000257589600056 PM 18554659 ER PT J AU Link, CL Pulliam, SJ Hanno, PM Hall, SA Eggers, PW Kusek, JW McKinlay, JB AF Link, Carol L. Pulliam, Samantha J. Hanno, Philip M. Hall, Susan A. Eggers, Paul W. Kusek, John W. McKinlay, John B. TI Prevalence and psychosocial correlates of symptoms suggestive of painful bladder syndrome: Results from the Boston Area Community Health Survey SO JOURNAL OF UROLOGY LA English DT Article DE cystitis; interstitial; anxiety; social class; urology ID INTERSTITIAL CYSTITIS SYMPTOMS; LOWER URINARY-TRACT; CONTINENCE SOCIETY; BACH SURVEY; WOMEN; POPULATION; DISORDERS; MEN AB Purpose: We estimated the prevalence of symptoms suggestive of painful bladder syndrome defined as pain increasing as the bladder fills and/or pain relieved by urination for at least 3 months, and its association with sociodemographics (gender, age, race/ethnicity and socioeconomic status), lifestyle (smoking, alcohol consumption, physical activity) and psychosocial variables (sexual, physical, emotional abuse experienced as a child or as an adult, worry, trouble paying for basics, depression). Materials and Methods: The data used come from the Boston Area Community Health Survey, an epidemiological study of 5,506 randomly selected adults 30 to 79 years old of 3 race/ethnic groups (black, Hispanic, white). Results: The overall prevalence of symptoms suggestive of painful bladder syndrome was 2% (1.3% in men and 2.6% in women) with increased prevalence in middle-aged adults and those of lower socioeconomic status. Symptoms suggestive of painful bladder syndrome were more common in those who experienced abuse, in those who were worried about someone close to them and in those who were having trouble paying for basics. This pattern held even after adjusting for depression. Conclusions: Painful bladder syndrome is associated with a number of lifestyle and psychosocial correlates. This suggests that the treatment of patients with painful bladder syndrome (physical symptoms) may benefit from a multifaceted approach of combining medical, psychological and cognitive treatment. C1 [Link, Carol L.; Hall, Susan A.; McKinlay, John B.] New England Res Inst, Watertown, MA 02472 USA. [Pulliam, Samantha J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hanno, Philip M.] Univ Penn Hlth Syst, Philadelphia, PA USA. [Eggers, Paul W.; Kusek, John W.] NIDDK, Bethesda, MD USA. RP Link, CL (reprint author), New England Res Inst, 9 Galen St, Watertown, MA 02472 USA. EM clink@neriscience.com FU NIDDK NIH HHS [U01 DK056842-05, U01 DK056842, U01 DK56842] NR 24 TC 24 Z9 24 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD AUG PY 2008 VL 180 IS 2 BP 599 EP 606 DI 10.1016/j.juro.2008.04.009 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 325LE UT WOS:000257589600057 PM 18554658 ER PT J AU Bansal, A Binkert, CA Robinson, MK Shulman, LN Pellerin, L Davison, B AF Bansal, Anu Binkert, Christoph A. Robinson, Malcolm K. Shulman, Lawrence N. Pellerin, Linda Davison, Brian TI Impact of quality management monitoring and intervention on central venous catheter dysfunction in the outpatient chemotherapy infusion setting SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID TIP POSITION; ACCESS; PLACEMENT; ALTEPLASE AB PURPOSE: To assess the utility of maintaining and analyzing a quality-management database while investigating a subjectively perceived increase in the incidence of tunneled catheter and port dysfunction in a cohort of oncology outpatients. MATERIALS AND METHODS: All 152 patients undergoing lytic therapy (2-4 mg alteplase) of a malfunctioning indwelling central venous catheter (CVC) from January through June 2004 at a single cancer center in the United States were included in a quality-management database. Patients were categorized by time to device failure and the initial method of catheter placement (surgery vs interventional radiology). Data were analyzed after 3 months, and areas of possible improvement were identified and acted upon. Three months of follow-up data were then collected and similarly analyzed. RESULTS: In a 6-month period, 152 patients treated for catheter malfunction received a total of 276 doses of lytic therapy. A 3-month interim analysis revealed a disproportionately high rate (34%) of early catheter malfunction (ECM; < 30 days from placement). Postplacement radiographs demonstrated suboptimal catheter positioning in 67% of these patients, all of whom had surgical catheter placement. There was a 50% absolute decrease in the number of patients presenting with catheter malfunction in the period from April through June (P < .001). Evaluation of postplacement radiographs in these patients demonstrated a 50% decrease in the incidence of suboptimal positioning (P < .05). CONCLUSIONS: Suboptimal positioning was likely responsible for some, but not all, cases of ECM. Maintenance of a quality-management database is a relatively simple intervention that can have a clear and important impact on the quality and cost of patient care. C1 [Bansal, Anu; Binkert, Christoph A.; Davison, Brian] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Robinson, Malcolm K.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg, Boston, MA 02115 USA. [Shulman, Lawrence N.; Pellerin, Linda] Dana Farber Canc Inst, Div Gen Oncol, Boston, MA 02115 USA. RP Bansal, A (reprint author), Barnes Jewish Hosp, Mallinckrodt Inst Radiol, 510 S Kingshighway Blvd, St Louis, MO 63110 USA. NR 17 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD AUG PY 2008 VL 19 IS 8 BP 1171 EP 1175 DI 10.1016/j.jvir.2008.04.026 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 333QT UT WOS:000258168100007 PM 18656009 ER PT J AU Tsibris, AMN Sagar, M Gulick, RM Su, ZH Hughes, M Greaves, W Subramanian, M Flexner, C Giguel, F Leopold, KE Coakley, E Kuritzkes, DR AF Tsibris, Athe M. N. Sagar, Manish Gulick, Roy M. Su, Zhaohui Hughes, Michael Greaves, Wayne Subramanian, Mani Flexner, Charles Giguel, Francoise Leopold, Kay E. Coakley, Eoin Kuritzkes, Daniel R. TI In vivo emergence of vicriviroc resistance in a human immunodeficiency virus type 1 subtype C-infected subject SO JOURNAL OF VIROLOGY LA English DT Article ID MOLECULE CCR5 INHIBITOR; HIV-1-INFECTED PATIENTS; CELL-LINE; HIV-1; VARIANTS; GP120; GENE; ANTAGONIST; REGIONS; TROPISM AB Little is known about the in vivo development of resistance to human immunodeficiency virus type 1 (HIV-1) CCR5 antagonists. We studied 29 subjects with virologic failure from a phase IIb study of the CCR5 antagonist vicriviroc (VCV) and identified one individual with HIV-1 subtype C who developed VCV resistance. Studies with chimeric envelopes demonstrated that changes within the V3 loop were sufficient to confer VCV resistance. Resistant virus showed VCV-enhanced replication, cross-resistance to another CCR5 antagonist, TAK779, and increased sensitivity to aminooxypentane-RANTES and the CCR5 monoclonal antibody HGS004. Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness costs. C1 [Tsibris, Athe M. N.; Giguel, Francoise] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Tsibris, Athe M. N.; Sagar, Manish; Kuritzkes, Daniel R.] Harvard Univ, Sch Med, Boston, MA USA. [Sagar, Manish; Kuritzkes, Daniel R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gulick, Roy M.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Su, Zhaohui; Hughes, Michael] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Greaves, Wayne] Schering Plough Res Inst, Kenilworth, NJ USA. [Flexner, Charles] Johns Hopkins Univ, Baltimore, MD USA. [Leopold, Kay E.] Harvard Univ, Cambridge, MA 02138 USA. [Coakley, Eoin] Monogram Biosci, San Francisco, CA USA. RP Kuritzkes, DR (reprint author), Brigham & Womens Hosp, Sect Retroviral Therapeut, 65 Landsdowne St,Room 435, Cambridge, MA 02139 USA. EM dkuritzkes@partners.org OI Sagar, Manish/0000-0001-9803-6594 FU NCRR NIH HHS [K24 RR016482]; NIAID NIH HHS [T32 AI007387, K24 AI051966, U01 AI068636, P30 AI060354, K24 AI-51966, R37 AI553537] NR 23 TC 90 Z9 92 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD AUG PY 2008 VL 82 IS 16 BP 8210 EP 8214 DI 10.1128/JVI.00444-08 PG 5 WC Virology SC Virology GA 333QF UT WOS:000258166500044 PM 18495779 ER PT J AU Penrod, JD Litke, A Hawkes, WG Magaziner, J Doucette, JT Koval, KJ Silberzweig, SB Egol, KA Siu, AL AF Penrod, Joan D. Litke, Ann Hawkes, William G. Magaziner, Jay Doucette, John T. Koval, Kenneth J. Silberzweig, Stacey B. Egol, Kenneth A. Siu, Albert L. TI The association of race, gender, and comorbidity with mortality and function after hip fracture SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE hip fracture; mobility; activities of daily living; mortality ID RECOVERY SCORE; FOLLOW-UP; REHABILITATION; PREDICTORS; OUTCOMES; PERFORMANCE; SURVIVAL; SURGERY; ILLNESS; COHORT AB Background. Few studies of hip fracture have large enough samples of men, minorities, and persons with specific comorbidities to examine differences in their mortality and functional outcomes. To address this problem, we combined three cohorts of hip fracture patients to produce a sample of 2692 patients followed for 6 months. Method. Data on mortality, mobility, and other activities of daily living (ADLs) were available from all three cohorts. We used multiple regression to examine the association of race, gender, and comorbidity with 6-month survival and function, controlling for prefracture mobility and ADLs, age, fracture type, cohort, and admission year. Results. The mortality rate at 6 months was 12%: 9% for women and 19% for men. Whites and women were more likely than were nonwhites and men to survive to 6 months, after adjusting for age, comorbidities, and prefracture mobility and function. Whites were more likely than were nonwhites to walk independently or with help at 6 months compared to not walking, after adjusting for age, comorbidities, and prefracture mobility and function. Dementia had a negative impact on survival, mobility, and ADLs at 6 months. The odds of survival to 6 months were significantly lower for people with chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and/or cancer. Parkinson's disease and stroke had negative impacts on mobility and ADLs, respectively, among survivors at 6 months. Conclusions. The finding of higher mortality and worse mobility for nonwhite patients with hip fractures highlights the need for more research on race/ethnicity disparities in hip fracture care. C1 [Egol, Kenneth A.] NYU, Hosp Joint Dis, Trauma Serv, New York, NY USA. [Koval, Kenneth J.] Dartmouth Hitchcock Med Ctr, Dept Orthopaed, Lebanon, NH 03766 USA. [Doucette, John T.] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. [Hawkes, William G.; Magaziner, Jay] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Penrod, Joan D.; Litke, Ann; Silberzweig, Stacey B.; Siu, Albert L.] Mt Sinai Sch Med, Dept Geriatr & Adult Dev, New York, NY USA. [Penrod, Joan D.; Siu, Albert L.] James J Peters VA Med Ctr, Program Res Serious Phys & Mental Illness & Geria, Bronx, NY 10468 USA. [Penrod, Joan D.; Siu, Albert L.] James J Peters VA Med Ctr, Ctr Clin, Bronx, NY 10468 USA. RP Penrod, JD (reprint author), James J Peters VA Med Ctr, Ctr Clin, 130 Kingsbridge Rd, Bronx, NY 10468 USA. EM joan.penrod@mssm.edu FU Department of Veterans Affairs; Veterans Health Administration; Health Services Research and Development Service [TRP 02-149]; National Institute on Aging (NIA) [RO1AG21992, R01 AG06322, R01 HD0073, R37 AG09901, P30 AG028747]; Mid-career Investigator Award [K24 AG00918] FX Drs. Penrod and Sin were Supported by the Department of Veterans Affairs. Veterans Health Administration, Health Services Research and Development Service (project no. TRP 02-149). Additional support was provided the National Institute on Aging (NIA; Research Grant RO1AG21992 and Mid-career Investigator Award K24 AG00918 to Dr. Sin). Drs. Hawkes and Magaziner were also supported by NIA grants R01 AG06322, R01 HD0073, R37 AG09901, and P30 AG028747. NR 33 TC 70 Z9 73 U1 0 U2 2 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD AUG PY 2008 VL 63 IS 8 BP 867 EP 872 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 352RT UT WOS:000259515800013 PM 18772476 ER PT J AU Johansen, KL AF Johansen, Kirsten L. TI Women in nephrology: one mother's strategies for success in academic medicine SO KIDNEY INTERNATIONAL LA English DT Editorial Material C1 San Francisco VA Med Ctr, Nephrol Sect, San Francisco, CA 94121 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Dept Med, Div Nephrol, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Johansen, KL (reprint author), San Francisco VA Med Ctr, Nephrol Sect, 4150 Clement St, San Francisco, CA 94121 USA. EM kirsten.johansen@ucsf.edu NR 5 TC 2 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2008 VL 74 IS 4 BP 401 EP 402 DI 10.1038/ki.2008.338 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 332ED UT WOS:000258064100001 PM 18670400 ER PT J AU Ng, DPK Nurbaya, S Ye, SHJ Krolewski, AS AF Ng, Daniel P. K. Nurbaya, Siti Ye, Sandra H. J. Krolewski, Andrzej S. TI An IL-6 haplotype on human chromosome 7p21 confers risk for impaired renal function in type 2 diabetic patients SO KIDNEY INTERNATIONAL LA English DT Article DE Bonferroni correction; chronic inflammation; proteinuria; chronic renal failure; end-stage renal disease; genetic susceptibility ID LOW-GRADE INFLAMMATION; GENE POLYMORPHISM; MESANGIAL CELLS; INTERLEUKIN-6; NEPHROPATHY; ASSOCIATION; DISEASE; URINARY; GENOME; SUSCEPTIBILITY AB The human chromosome 7p21 locus harbors a major gene that influences variation of glomerular filtration rate and development of end-stage renal disease. The pro-inflammatory IL-6 cytokine is a candidate gene since chronic inflammation has been implicated in diabetic nephropathy and this gene is located under the peak of linkage. To test this, single nucleotide polymorphism (SNP) and haplotype analyses were performed using a case-control study of 295 patients consisting of 138 with proteinuria, 157 with chronic renal failure and these were compared to174 control patients with normal albumin excretion. Five tagging SNPs were selected for analysis based on linkage disequilibrium patterns and proximity to the functionally important -634G > C SNP in the IL-6 promoter. Initial analysis suggested that a -174G > C polymorphism may be associated with risk of chronic renal failure but this was not significant after Bonferroni correction. While haplotype analyses showed no association with proteinuria; a significant association with chronic renal failure was found. There was significantly more of the GGGAGC haplotype among patients with chronic renal failure compared to controls and this association remained significant even after correction for multiple testing. Our study has found a specific IL-6 haplotype conferring risk for impaired renal function in patients with type 2 diabetes. C1 [Ng, Daniel P. K.; Nurbaya, Siti; Ye, Sandra H. J.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Community Occupat & Family Med, Singapore 117597, Singapore. [Krolewski, Andrzej S.] Joslin Diabet Ctr, Sect Genet & Epidemiol, Boston, MA 02215 USA. [Krolewski, Andrzej S.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Ng, DPK (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Community Occupat & Family Med, 16 Med Dr MD3, Singapore 117597, Singapore. EM confnpkd@nus.edu.sg FU NIDDK NIH HHS [R01 DK058549-06A1, DK-058549, R01 DK058549] NR 29 TC 15 Z9 19 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD AUG PY 2008 VL 74 IS 4 BP 521 EP 527 DI 10.1038/ki.2008.202 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 332ED UT WOS:000258064100019 PM 18496509 ER PT J AU Edd, JF Di Carlo, D Humphry, KJ Koster, S Irimia, D Weitz, DA Toner, M AF Edd, Jon F. Di Carlo, Dino Humphry, Katherine J. Koster, Sarah Irimia, Daniel Weitz, David A. Toner, Mehmet TI Controlled encapsulation of single-cells into monodisperse picolitre drops SO LAB ON A CHIP LA English DT Article ID DROPLETS; MICROFLUIDICS; MICROCHANNELS AB Encapsulation of cells within picolitre-size monodisperse drops provides new means to perform quantitative biological studies on a single-cell basis for large cell populations. Variability in the number of cells per drop due to stochastic cell loading is a major barrier to these techniques. We overcome this limitation by evenly spacing cells as they travel within a high aspect-ratio microchannel; cells enter the drop generator with the frequency of drop formation. C1 [Edd, Jon F.; Di Carlo, Dino; Irimia, Daniel; Toner, Mehmet] Massachusetts Gen Hosp, BioMEMS Resource Ctr, Charlestown, MA USA. [Humphry, Katherine J.; Koster, Sarah; Weitz, David A.] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. [Humphry, Katherine J.; Koster, Sarah; Weitz, David A.] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. RP Toner, M (reprint author), Massachusetts Gen Hosp, BioMEMS Resource Ctr, Charlestown, MA USA. EM mtoner@hms.harvard.edu RI Humphry, Katherine/C-1948-2008; Koester, Sarah/M-1983-2014; OI Koester, Sarah/0000-0002-0009-1024; Humphry, Katherine/0000-0002-9098-6402; Irimia, Daniel/0000-0001-7347-2082 FU NIBIB [P41 EB002503]; HFSP [RGPOO04/2005-CI02]; NSF [DMR-0602684, DBI-0649865]; Harvard MRSEC [DMR-0213805]; NIH [1F32EB007901]; American Cancer Society [PF-07-237-01-CCE]; Deutsche Forschungsgemeinschaft [KO 3572/1] FX This work was supported by the NIBIB (P41 EB002503), the HFSP (RGPOO04/2005-CI02), the NSF (DMR-0602684 and DBI-0649865) and by the Harvard MRSEC (DMR-0213805). JFE was supported by an NIH Postdoctoral Fellowship (1F32EB00790 ), DDC was supported by an American Cancer Society Postdoctoral Fellowship (PF-07-237-01-CCE), and SK was supported by the Deutsche Forschungsgemeinschaft (DFG, KO 3572/1). NR 17 TC 219 Z9 225 U1 16 U2 138 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1473-0197 J9 LAB CHIP JI Lab Chip PD AUG PY 2008 VL 8 IS 8 BP 1262 EP 1264 DI 10.1039/b805456h PG 3 WC Biochemical Research Methods; Chemistry, Multidisciplinary; Nanoscience & Nanotechnology SC Biochemistry & Molecular Biology; Chemistry; Science & Technology - Other Topics GA 339IX UT WOS:000258572400004 PM 18651066 ER PT J AU Kawada, M Chen, CC Arihiro, A Nagatani, K Watanabe, T Mizoguchi, E AF Kawada, Mayumi Chen, Chun-Chuan Arihiro, Atsuko Nagatani, Katsuya Watanabe, Takeshi Mizoguchi, Emiko TI Chitinase 3-like-1 enhances bacterial adhesion to colonic epithelial cells through the interaction with bacterial chitin-binding protein SO LABORATORY INVESTIGATION LA English DT Article DE inflammatory bowel disease; chitinase 3-like-1; chitin binding protein; bacterial adhesion; colonic epithelial cells; Serratia marcescens ID INFLAMMATORY-BOWEL-DISEASE; HUMAN CARTILAGE GP-39; SERRATIA-MARCESCENS; CRYSTAL-STRUCTURE; MAMMALIAN MEMBER; SYNOVIAL-CELLS; BLOOD-GROUP; FAMILY; IDENTIFICATION; CBP21 AB Dysregulated host/microbial interactions play a pivotal role in the pathogenesis of inflammatory bowel disease. We previously reported that chitinase 3-like-1 (CHI3L1) enhances bacterial adhesion and invasion on/into colonic epithelial cells (CECs). In this study, we designed to identify the exact mechanism of how CHI3L1 enhances the bacterial adhesion on CECs in vitro. As compared with wild type (WT) of Serratia marcescens, chitin binding protein (CBP) 21 knockout strain of S. marcescens significantly decreased the adhesion to SW480 cells that express CHI3L1 endogenously. A CBP21 fusion protein was produced with CBP21-expressing vector, which was transformed into BL21 strain of Escherichia coli. CBP21 overexpression significantly increased the adhesion, but not invasion, of nonpathogenic E. coli. The adhesion of S. marcescens and CBP21-overexpressing E. coli was inhibited by coculture with chitin, but not with other carbohydrates. After overexpressing CHI3L1 on SW480 cells, the adhesion rate of CBP21-overexpressing E. coli was further increased by approximately twofold. Genetically engineered E. coli with a single mutation of either Thy-54 or Glu-55 position of CBP21 exhibited a decreased binding ability, and the binding was 74% diminished by the combined mutations of three amino acids (Thy-54, Glu-55 and Glu-60) as compared with WT. Inhibition of CHI3L1 by anti-CHI3L1 antibody or CHI3L1-specific short interfering RNA reduced the adhesion of CBP21-overexpressing E. coli to CECs. In conclusion, CHI3L1 is involved in the enhancement of CBP-expressing bacterial adhesion to CECs. CBP21 and its homologs may be required for the CHI3L1-mediated enhancement of bacterial adhesion to CECs through the conserved amino-acid residues. C1 [Kawada, Mayumi; Chen, Chun-Chuan; Arihiro, Atsuko; Nagatani, Katsuya; Mizoguchi, Emiko] Dept Med, Gastrointestinal Unit, Boston, MA USA. [Kawada, Mayumi; Mizoguchi, Emiko] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Study Inflammatory Bowel Dis, Boston, MA USA. [Watanabe, Takeshi] Niigata Univ, Fac Agr, Dept Appl Biol Chem, Niigata 95021, Japan. RP Mizoguchi, E (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, GRJ 702,55 Fruit St, Boston, MA 02114 USA. EM emizoguchi@partners.org FU NIDDK NIH HHS [DK43351, DK74454, DK64289] NR 34 TC 42 Z9 42 U1 2 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD AUG PY 2008 VL 88 IS 8 BP 883 EP 895 DI 10.1038/labinvest.2008.47 PG 13 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 329TA UT WOS:000257892300009 PM 18490894 ER PT J AU Westerhaus, M Panjabi, R Mukherjee, J AF Westerhaus, Michael Panjabi, Rajesh Mukherjee, Joia TI Violence and the role of illness narratives SO LANCET LA English DT Editorial Material ID MEDICINE C1 [Westerhaus, Michael; Mukherjee, Joia] Brigham & Womens Hosp, Div Social Med & Hlth Inequal, Boston, MA 02115 USA. [Panjabi, Rajesh] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Westerhaus, M (reprint author), Brigham & Womens Hosp, Div Social Med & Hlth Inequal, 75 Francis St, Boston, MA 02115 USA. EM mwesterhaus@partners.org NR 13 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 0140-6736 J9 LANCET JI Lancet PD AUG-SEP PY 2008 VL 372 IS 9640 BP 699 EP 701 DI 10.1016/S0140-6736(08)61286-6 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 344YZ UT WOS:000258964500009 PM 18761209 ER PT J AU Zald, PB Hamilton, BE Larsen, ML Cohen, JI AF Zald, Philip B. Hamilton, Bronwyn E. Larsen, Michael L. Cohen, James I. TI The Role of Computed Tomography for Localization of Parathyroid Adenomas SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT Annual Meeting of the Western Section of the Triological-Society CY JAN 31-FEB 02, 2008 CL Rancho Mirage, CA SP Triol Soc Western Sect DE Hyperparathyroidism; parathyroid adenoma; computed tomography; endocrine surgery; otolaryngology; hypercalcemia; sestamibi; ultrasound ID PRIMARY HYPERPARATHYROIDISM; DIRECTED PARATHYROIDECTOMY; PREOPERATIVE LOCALIZATION; SURGERY; ULTRASOUND; CT; SESTAMIBI AB Objective/Hypothesis: The purpose of this study was to evaluate the use of computed tomography (CT) for localization of parathyroid adenomas (PA) when first-line imaging is indeterminate. Study Design: Retrospective case series. Methods: A search of operating room and radiology records identified 223 surgical explorations for primary hyperparathyroidism. Adenoma locations on CT, ultrasound, and nuclear scintigraphy were correlated with an independent review of operative records. Results: The presence of adenoma in the correct side and quadrant of the neck was predicted by CT in 89% and 77% of studies, respectively. When first-line studies were indeterminate, the positive predictive value of CT for localization of PA to the correct side and quadrant of the neck was 87% and 69%, respectively. Conclusions: When first-line localization studies are indeterminate in patients with primary hyperparathyroidism, CT is a valuable, rapid, and widely available imaging modality that can be used to localize PA. C1 [Zald, Philip B.; Cohen, James I.] Oregon Hlth & Sci Univ, Dept Otolaryngol, Portland, OR 97239 USA. [Hamilton, Bronwyn E.] Oregon Hlth & Sci Univ, Dept Radiol, Div Neuroradiol, Portland, OR 97239 USA. [Larsen, Michael L.] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97239 USA. [Cohen, James I.] Portland VA Med Ctr, Dept Otolaryngol, Portland, OR USA. RP Cohen, JI (reprint author), Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland VAMC P3-OC,3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM cohenj@ohsu.edu NR 16 TC 21 Z9 23 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2008 VL 118 IS 8 BP 1405 EP 1410 DI 10.1097/MLG.0b013e318177098c PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 368ZP UT WOS:000260662600013 PM 18528308 ER PT J AU Park, H Williams, R Goldman, N Choe, H Kobler, J Lopez-Guerra, G Heaton, JT Langer, R Zeitels, SM AF Park, Hyoungshin Williams, Rachel Goldman, Nathan Choe, Hannah Kobler, James Lopez-Guerra, Gerardo Heaton, James T. Langer, Robert Zeitels, Steven M. TI Comparison of Effects of 2 Harvesting Methods on Fat Autograft SO LARYNGOSCOPE LA English DT Article DE Soft tissue engineering; autologous fat graft; adipocytes; viability; laryngology; phonosurgery; voice surgery; vocal fold ID SOFT-TISSUE AUGMENTATION; ASPIRATED ADIPOSE-TISSUE; FIBROBLAST-GROWTH-FACTOR; VOCAL FOLD AUGMENTATION; CELL-BASED THERAPIES; AUTOLOGOUS FAT; AUTOGENOUS FAT; STROMAL CELLS; NUDE-MICE; FOLLOW-UP AB Objectives/Hypothesis: Fat preparation for vocal-fold injection medialization is typically done by scraping of excised fat or by lipo-aspiration; however, hpoaspiration is substantially more efficient. Considering this, we compared viability of fat tissues obtained by these two techniques. We also examined whether basic fibroblast growth factor (bFGF) would increase cell proliferation in samples harvested by these methods. Study Design: Harvesting techniques (scraping and lipo-aspiration) were compared using both human and ferret fat. In vitro assays were used to assess tissue viability and cell proliferation. Methods: Human (n = 5) and ferret (n = 15) abdominal fat specimens were harvested by scraping and lipo-aspiration, for a total of 40 specimens. Alamar Blue and glycerol-3-phosphate dehydrogenase assays were used to quantitatively assess metabolic activity and cellular damage immediately after harvest. PicoGreen assays assessed cell proliferation by quantifying total DNA in harvested specimens after 0, 14, or 21 days in culture. The effects of bFGF (10 ng/mL) on proliferation were measured for the same timepoints. Results: The glycerol-3-phosphate dehydrogenase assay indicated that lipo-aspiration caused more initial tissue damage (12 +/- 5 mU/mL) than scraping (5 +/- 3 mU/mL), but cell metabolic activity was similar in both groups based on the Alamar Blue assay. Cell proliferation at 14 and 21 days was significantly higher for lipo-aspirated fat than for scraped fat (92.5 +/- 8.8 vs. 55.1 +/- 1.3 ng DNA at 14 days and 111.1 +/- 10.5 vs. 44.6 +/- 4.1 ng DNA at 21 days). bFGF increased fibroblast-like cell proliferation significantly for both harvesting methods at day 21. Conclusions: Lipo-aspiration caused more initial damage than scraping, but may yield better long-term viability based on increased proliferation. bFGF may enhance cellularity of the stromal component grafted adipose tissue. C1 [Park, Hyoungshin; Kobler, James; Lopez-Guerra, Gerardo; Heaton, James T.; Zeitels, Steven M.] Massachusetts Gen Hosp, Dept Surg, Ctr Laryngeal Surg & Voice Rehabil, Boston, MA 02114 USA. [Park, Hyoungshin; Kobler, James; Heaton, James T.; Zeitels, Steven M.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [Williams, Rachel; Goldman, Nathan; Choe, Hannah; Langer, Robert] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Zeitels, SM (reprint author), Massachusetts Gen Hosp, Dept Surg, Ctr Laryngeal Surg & Voice Rehabil, 1 Bowdoin Sq,11 Floor, Boston, MA 02114 USA. EM zeitels.steven@mgh.harvard.edu OI Lopez-Guerra, Gerardo/0000-0003-0305-4680 FU Institute of Laryngology and Voice Restoration; Eugene B. Casey Foundation FX This research was supported in part by the Institute of Laryngology and Voice Restoration and the Eugene B. Casey Foundation. NR 30 TC 8 Z9 8 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD AUG PY 2008 VL 118 IS 8 BP 1493 EP 1499 DI 10.1097/MLG.0b013e3181735634 PG 7 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 368ZP UT WOS:000260662600030 PM 18496155 ER PT J AU Izikson, L Anderson, RR AF Izikson, Leonid Anderson, R. Rox TI Resolution of blue minocycline pigmentation of the face after fractional photothermolysis SO LASERS IN SURGERY AND MEDICINE LA English DT Article ID SWITCHED RUBY-LASER; INDUCED HYPERPIGMENTATION; ALEXANDRITE LASER; SKIN; ASIANS C1 [Izikson, Leonid] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Laser & Cosmet Dermatol Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Izikson, L (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Laser & Cosmet Dermatol Ctr, BHX 630 Bartlett Hall, Boston, MA 02114 USA. EM lizikson@partners.org NR 15 TC 20 Z9 21 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0196-8092 EI 1096-9101 J9 LASER SURG MED JI Lasers Surg. Med. PD AUG PY 2008 VL 40 IS 6 BP 399 EP 401 DI 10.1002/lsm.20648 PG 3 WC Dermatology; Surgery SC Dermatology; Surgery GA 335HP UT WOS:000258281700004 PM 18649380 ER PT J AU Hussein, MA Vrionis, FD Allison, R Berenson, J Berven, S Erdem, E Giralt, S Jagannath, S Kyle, RA LeGrand, S Pflugmacher, R Raje, N Rajkumar, SV Randall, RL Roodman, D Siegel, D Vescio, R Zonder, J Durie, BGM AF Hussein, M. A. Vrionis, F. D. Allison, R. Berenson, J. Berven, S. Erdem, E. Giralt, S. Jagannath, S. Kyle, R. A. LeGrand, S. Pflugmacher, R. Raje, N. Rajkumar, S. V. Randall, R. L. Roodman, D. Siegel, D. Vescio, R. Zonder, J. Durie, B. G. M. CA Int Myeloma Working Grp TI The role of vertebral augmentation in multiple myeloma: International Myeloma Working Group consensus statement SO LEUKEMIA LA English DT Editorial Material ID COMPRESSION FRACTURES; BALLOON KYPHOPLASTY; FOLLOW-UP; MORTALITY; OUTCOMES C1 [Durie, B. G. M.] Cedars Sinai Outpatient Canc Ctr, Aptium Oncol Inc, Dept Hematol Oncol, Los Angeles, CA 90048 USA. [Hussein, M. A.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Hematol Malignancies, Tampa, FL 33682 USA. [Vrionis, F. D.] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Neurooncol, Tampa, FL 33682 USA. [Allison, R.] Brody Sch Med ECU, Dept Radiat Oncol, Greenville, NC USA. [Berenson, J.] Inst Myeloma & Bone Canc Res, Dept Med Hematol Oncol, Los Angeles, CA USA. [Berven, S.] Univ Calif San Francisco, Dept Orthopaed Surg, San Francisco, CA 94143 USA. [Erdem, E.] Univ Arkansas Med Sci, Sect Intervent Neuroradiol, Div Radiol, Little Rock, AR 72205 USA. [Giralt, S.] Univ Texas MD Anderson Canc Ctr, Stem Cell Transplantat & Cellular Therapy Dept, Houston, TX 77030 USA. [Jagannath, S.] St Vincents Comprehens Canc Ctr, Dept Med Oncol Internal Med, New York, NY USA. [Kyle, R. A.; Rajkumar, S. V.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [LeGrand, S.] Cleveland Clin Fdn, Dept Med Oncol Internal Med, Cleveland, OH 44195 USA. [Pflugmacher, R.] Humboldt Univ, Charite, Dept Musculature, Berlin, Germany. [Raje, N.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med Oncol, Boston, MA USA. [Randall, R. L.] Huntsman Canc Inst, Dept Orthopaed, Salt Lake City, UT USA. [Roodman, D.] Univ Pittsburgh, Sch Med, Dept Hematol Oncol, Pittsburgh, PA USA. [Siegel, D.] Hackensack Canc Ctr, Dept Med Oncol, Hackensack, NJ USA. [Zonder, J.] Wayne State Univ, Karmanos Canc Ctr, Sch Med, Dept Med,Div Hematol Oncol, Detroit, MI USA. RP Durie, BGM (reprint author), Cedars Sinai Outpatient Canc Ctr, Aptium Oncol Inc, Dept Hematol Oncol, 8201 Beverly Blvd, Los Angeles, CA 90048 USA. EM mohamad.hussein@moffitt.org; bdurie@aptiumoncology.com RI Waage, Anders/D-7705-2013; Sangue, Inct/I-1919-2013; FACON, THIERRY/M-9736-2014; OI FACON, THIERRY/0000-0001-7705-8460; Rajkumar, S. Vincent/0000-0002-5862-1833; SAN MIGUEL, JESUS/0000-0002-9183-4857 NR 23 TC 34 Z9 35 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD AUG PY 2008 VL 22 IS 8 BP 1479 EP 1484 DI 10.1038/leu.2008.127 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 337CP UT WOS:000258413400002 PM 18509352 ER PT J AU Sun, PZ Sorensen, AG AF Sun, Phillip Zhe Sorensen, A. Gregory TI Imaging pH using the chemical exchange saturation transfer (CEST) MRI: Correction of concomitant RF irradiation effects to quantify CEST MRI for chemical exchange rate and pH SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE amide proton transfer; APT; chemical exchange saturation transfer; CEST; pH ID ACUTE CEREBRAL-ISCHEMIA; MAGNETIZATION-TRANSFER; PROTON-EXCHANGE; QUANTITATIVE DESCRIPTION; CONTRAST AGENTS; PARACEST AGENTS; HUMAN BRAIN; IN-VIVO; RESONANCE; PENUMBRA AB Chemical exchange saturation transfer (CEST) MRI has been shown capable of detecting dilute labile protons and abnormal tissue glucose/oxygen metabolism, and thus, may serve as a complementary imaging technique to the conventional MRI methods. CEST imaging, however, is also dependent on experimental parameters such as the power, duration, and waveform of the irradiation RF pulse. As a result, its sensitivity and specificity for microenvironment properties such as pH is not optimal. In this study, the dependence of CEST contrast on experimental parameters was solved and an iterative compensation algorithm was proposed that corrects the experimentally measured CEST contrast from the concomitant RF irradiation effects. The proposed algorithm was verified with both numerical simulation and experimental measurements from a tissue-like pH phantom, and showed that pH derived from the compensated CEST imaging agrees reasonably well with pH-electrode measurements within 0.1 pH unit. In sum, our study validates the use of a correction algorithm to compensate CEST imaging from concomitant RF irradiation effects for accurate calibration of the chemical exchange rate, and demonstrates the feasibility of pH imaging with CEST MRI. C1 [Sun, Phillip Zhe; Sorensen, A. Gregory] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Charlestown, MA 02129 USA. RP Sun, PZ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Athinoula A Martinos Ctr Biomed Imaging,Dept Radi, Rm 2301,149 13th St, Charlestown, MA 02129 USA. EM pzhesun@nmr.mgh.harvard.edu FU NCRR NIH HHS [P41RR14075] NR 39 TC 59 Z9 61 U1 5 U2 17 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD AUG PY 2008 VL 60 IS 2 BP 390 EP 397 DI 10.1002/mrm.21653 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 332TK UT WOS:000258105800019 PM 18666128 ER PT J AU Hassett, MJ Hughes, ME Niland, JC Ottesen, R Edge, SB Bookman, MA Carlson, RW Theriault, RL Weeks, JC AF Hassett, Michael J. Hughes, Melissa E. Niland, Joyce C. Ottesen, Rebecca Edge, Stephen B. Bookman, Michael A. Carlson, Robert W. Theriault, Richard L. Weeks, Jane C. TI Selecting high priority quality measures for breast cancer quality improvement SO MEDICAL CARE LA English DT Article; Proceedings Paper CT Annual Research Meeting of the Academy-Health CY JUN 27, 2006 CL Seattle, WA SP Acad Hlth DE quality measurement; quality improvement; clinical practice guidelines; breast cancer and medical intervention ID PAY-FOR-PERFORMANCE; UNITED-STATES; CARE QUALITY; HEALTH-CARE; OF-CARE; INDICATORS; GUIDELINES; THERAPY; NCCN; ORGANIZATIONS AB Background: Although many quality measures have been created, there is no consensus regarding which are the most important. We sought to develop a simple, explicit strategy for prioritizing breast cancer quality measures based on their potential to highlight areas where quality improvement efforts could most impact a population. Methods: Using performance data for 9019 breast cancer patients treated at 10 National Comprehensive Cancer Network institutions, we assessed concordance relative to 30 reliable, valid breast cancer process-based treatment measures. We identified 4 attributes that indicated there was room for improvement and characterized the extent of burden imposed by failing to follow each measure: number of nonconcordant patients, concordance across all institutions, highest concordance at any I institution, and magnitude of benefit associated with concordant care. For each measure, we used data from the concordance analyses to derive the first 3 attributes and surveyed expert breast cancer physicians to estimate the fourth. A simple algorithm incorporated these attributes and produced a final score for each measure; these scores were used to rank the measures. Results: We successfully prioritized quality measures using explicit, objective methods and actual performance data. The number of nonconcordant patients had the greatest influence on the rankings. The highest-ranking measures recommended chemotherapy and hormone therapy for hormone-receptor positive tumors and radiation therapy after breast-conserving surgery. Conclusions: This simple, explicit approach is a significant departure from methods used previously, and effectively identifies breast cancer quality measures that have broad clinical relevance. System-atically prioritizing quality measures could increase the efficiency and efficacy of quality improvement efforts and substantially improve outcomes. C1 [Hassett, Michael J.; Hughes, Melissa E.; Weeks, Jane C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Niland, Joyce C.; Ottesen, Rebecca] City Hope Natl Med Ctr, Div Informat Sci, Duarte, CA 91010 USA. [Edge, Stephen B.] Roswell Pk Canc Inst, Dept Breast & Soft Tissue Surg, Buffalo, NY 14263 USA. [Bookman, Michael A.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Carlson, Robert W.] Stanford Hosp & Clin, Stanford Canc Ctr, Stanford, CA USA. [Theriault, Richard L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Hassett, MJ (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM mhassett@partners.org; jane_weeks@dfci.harvard.edu FU NCI NIH HHS [P50 CA89393, P50 CA089393, R25 CA092203] NR 51 TC 28 Z9 28 U1 2 U2 8 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 AUG PY 2008 VL 46 IS 8 BP 762 EP 770 PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 331LT UT WOS:000258014400002 PM 18665055 ER PT J AU Shwartz, M Ren, J Pekoz, EA Wang, X Cohen, AB Restuccia, JD AF Shwartz, Michael Ren, Justin Pekoz, Erol A. Wang, Xin Cohen, Alan B. Restuccia, Joseph D. TI Estimating a composite measure of hospital quality from the hospital compare database - Differences when using a Bayesian hierarchical latent variable model versus denominator-based weights SO MEDICAL CARE LA English DT Article DE quality performance; quality measurement; Bayesian inference ID PAY-FOR-PERFORMANCE; US HOSPITALS; HEALTH-CARE; PLAN PERFORMANCE; MORTALITY-RATES; OF-CARE; INDICATORS; IMPROVEMENT; PRINCIPLES; SURGERY AB Background: A single composite measure calculated from individual quality indicators (QIs) is a useful measure of hospital performance and can be justified conceptually even when the indicators are not highly correlated with one another. Objective: To compare 2 basic approaches for calculating a composite measure: an extension of the most widely-used approach, which weights individual indicators based on the number of people eligible for the indicator (referred to as denominator-based weights, DBWs), and a Bayesian hierarchical latent variable model (BLVM). Methods: Using data for 15 QIs from 3275 hospitals in the Hospital Compare database, we calculated hospital ranks using several versions of DBWs and 2 BLVMs. Estimates in 1 BLVM were driven by differences in variances of the QIs (BLVM 1) and estimates in the other by differences in the signal-to-noise ratios of the QIs (BLVM2). Results: There was a high correlation in ranks among all of the DBW approaches and between those approaches and BLVM1. However, a high correlation does not necessarily mean that the same hospitals were ranked in the top or bottom quality deciles. In general, large hospitals were ranked in higher quality deciles by all of the approaches, though the effect was most apparent using BLVM2. Conclusions: Both conceptually and practically, hospital-specific DBWs are a reasonable approach for calculating a composite measure. However, this approach fails to take into account differences in the reliability of estimates from hospitals of different sizes, a big advantage of the Bayesian models. C1 [Shwartz, Michael; Ren, Justin; Pekoz, Erol A.; Cohen, Alan B.; Restuccia, Joseph D.] Boston Univ, Sch Management, Boston, MA 02215 USA. [Shwartz, Michael; Pekoz, Erol A.; Cohen, Alan B.; Restuccia, Joseph D.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Boston, MA USA. [Wang, Xin] Brandeis Univ, Int Business Sch, Waltham, MA USA. [Cohen, Alan B.] Boston Univ, Hlth Policy Inst, Boston, MA 02215 USA. RP Shwartz, M (reprint author), Boston Univ, Sch Management, 595 Commonwealth Ave, Boston, MA 02215 USA. EM mshwartz@bu.edu NR 51 TC 21 Z9 22 U1 2 U2 10 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 AUG PY 2008 VL 46 IS 8 BP 778 EP 785 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 331LT UT WOS:000258014400004 PM 18665057 ER PT J AU Ranji, SR Steinman, MA Shojania, KG Gonzales, R AF Ranji, Sumant R. Steinman, Michael A. Shojania, Kaveh G. Gonzales, Ralph TI Interventions to reduce unnecessary antibiotic prescribing - A systematic review and quantitative analysis SO MEDICAL CARE LA English DT Review DE quality improvement; systematic review; antibiotic; prescribing ID RANDOMIZED CONTROLLED-TRIAL; ACUTE OTITIS-MEDIA; RESPIRATORY-TRACT INFECTIONS; RESISTANT STREPTOCOCCUS-PNEUMONIAE; QUALITY IMPROVEMENT STRATEGIES; DELAYED PRESCRIPTIONS REDUCE; GENERAL-PRACTICE; PRIMARY-CARE; ANTIMICROBIAL RESISTANCE; ACUTE BRONCHITIS AB Background: Overuse of antibiotics in ambulatory care persists despite many efforts to address this problem. We performed a systematic review and quantitative analysis to assess the effectiveness of quality improvement (QI) strategies to reduce antibiotic prescribing for acute outpatient illnesses for which antibiotics are often inappropriately prescribed. Research Design and Methods: We searched the Cochrane Collaboration's Effective Practice and Organisation of Care database, supplemented by MEDLINE and manual review of article bibliographies. We included randomized trials, controlled before-after studies, and interrupted time series. Two independent reviewers abstracted all data, and disagreements were resolved by consensus and discussion with a third reviewer. The primary outcome was the absolute reduction in the proportion of patients receiving antibiotics. Results: Forty-three studies reporting 55 separate trials met inclusion criteria. Most studies (N = 38) addressed prescribing for acute respiratory infections (ARIs). Among the 30 trials eligible for quantitative analysis, the median reduction in the proportion of subjects receiving antibiotics was 9.7% [interquartile range (IQR), 6.6-13.7%] over 6 months median follow-up. No single QI strategy or combination of strategies was clearly superior. However, active clinician education strategies trended toward greater effectiveness than passive strategies (P = 0.096). Compared with studies targeting specific conditions or patient populations, broad-based interventions extrapolated to larger community-level impacts on total antibiotic use, with savings of 17-117 prescriptions per 1000 person-years. Study methodologic quality was fair. Conclusions: QI efforts are effective at reducing antibiotic use in ambulatory settings, although much room for improvement remains. Strategies using active clinician education and targeting management of all ARIs (rather than single conditions in single age groups) may yield larger reductions in community-level antibiotic use. C1 [Ranji, Sumant R.; Steinman, Michael A.; Gonzales, Ralph] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Steinman, Michael A.] San Francisco VA Med Ctr, Div Geriatr, San Francisco, CA USA. [Shojania, Kaveh G.] Univ Toronto, Dept Med, Toronto, ON, Canada. [Gonzales, Ralph] Univ Calif San Francisco, Dept Epidemiol & Biostat, Div Gen Internal Med, San Francisco, CA 94143 USA. RP Ranji, SR (reprint author), Univ Calif San Francisco, Dept Med, 533 Parnassus Ave,Box 0131 San Francisco, San Francisco, CA 94143 USA. EM sumantr@medicine.ucsf.edu NR 94 TC 91 Z9 92 U1 1 U2 14 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 AUG PY 2008 VL 46 IS 8 BP 847 EP 862 PG 16 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 331LT UT WOS:000258014400012 PM 18665065 ER PT J AU Nappi, J Yoshida, H AF Naeppi, Janne Yoshida, Hiroyuki TI Adaptive correction of the pseudo-enhancement of CT attenuation for fecal-tagging CT colonography SO MEDICAL IMAGE ANALYSIS LA English DT Article DE virtual colonoscopy; pseudo-enhancement; contrast agent; image processing; computer-aided detection ID COMPUTED TOMOGRAPHIC COLONOGRAPHY; NEURAL NETWORKS; POLYPS; COLONOSCOPY; CAD; RECONSTRUCTION; REDUCTION; NEOPLASIA; DIAGNOSIS; NUMBERS AB In fecal-tagging CT colonography (ftCTC), positive-contrast tagging agents are used for opacifying residual bowel materials to facilitate reliable detection of colorectal lesions. However, tagging agents that have high radiodensity tend to artificially elevate the observed CT attenuation of nearby materials toward that of tagged materials on Hounsfield unit (HU) scale. We developed an image-based adaptive density-correction (ADC) method for minimizing such pseudo-enhancement effect in fiCTC data. After the correction, we can confidently assume that soft-tissue materials and air are represented by their standard CT attenuations, whereas higher CT attenuations indicate tagged materials. The ADC method was optimized by use of an anthropomorphic phantom filled partially with three concentrations of a tagging agent. The effect of ADC on ftCTC was assessed visually and quantitatively by comparison of the accuracy of computer-aided detection (CAD) without and with the use of the ADC method in two different types of clinical/ftCTC databases: 20 laxative ftCTC cases with 24 polyps, and 23 reduced-preparation ftCTC cases with 28 polyps. Visual evaluation indicated that ADC minimizes the observed pseudo-enhancement effect. With ADC, the free-response receiver operating characteristic curves indicating CAD performance in polyp detection yielded normalized partial area-under-curve values of 0.91 and 0.80 for the two databases, respectively, with statistically significant improvement over conventional thresholding-based approaches (p < 0.05). The results indicate that ADC is a useful method for reducing the pseudo-enhancement effect and for improving CAD performance in CTC. (C) 2008 Elsevier B.V. All rights reserved. C1 [Naeppi, Janne] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Nappi, J (reprint author), Massachusetts Gen Hosp, Dept Radiol, 25 New Chardon St,Suite 400C, Boston, MA 02114 USA. EM jnappi@partners.org RI Nappi, Janne/B-9424-2008 OI Nappi, Janne/0000-0002-0108-0992 FU NCI NIH HHS [R01 CA095279-04, R01 CA131718, R01 CA095279-06, R01 CA095279, CA095279, R56 CA095279, R01 CA095279-05] NR 32 TC 30 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1361-8415 J9 MED IMAGE ANAL JI Med. Image Anal. PD AUG PY 2008 VL 12 IS 4 BP 413 EP 426 DI 10.1016/j.media.2008.01.001 PG 14 WC Computer Science, Artificial Intelligence; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 336CX UT WOS:000258343000003 PM 18313349 ER PT J AU Holschneider, DP Maarek, JMI AF Holschneider, D. P. Maarek, J. -M. I. TI Brain maps on the go: Functional imaging during motor challenge in animals SO METHODS LA English DT Article DE brain mapping; neuroplasticity; neurorehabilitation; motor activity; sport sciences ID CEREBRAL BLOOD-FLOW; EXTERNALLY TRIGGERED MOVEMENTS; PARKINSONS-DISEASE; BASAL GANGLIA; INDICATOR FRACTIONATION; STATISTICAL-ANALYSIS; ENERGY-METABOLISM; PHYSICAL-EXERCISE; TREADMILL WALKING; NONTETHERED RATS AB Brain mapping in the freely moving animal is useful for studying motor circuits, not only because it avoids the potential confound of sedation or restraints, but because activated brain states may serve to accentuate differences that only manifest partially while a subject is in the resting state. Perfusion or metabolic mapping using autoradiography allows one to examine changes in brain function at the circuit level across the entire brain with a spatial resolution (similar to 100 mu) appropriate for the rat or mouse brain, and a temporal resolution (seconds-miinutes) sufficient for capturing acute brain changes. Here we summarize the application of these methods to the functional brain mapping of behaviors involving locomotion of small animals, methods for the three-dimensional reconstruction of the brain from autoradiographic sections, voxel based analysis of the whole brain, and generation of maps of the flattened rat cortex. Application of these methods in animal models promises utility in improving our understanding of motor function in the normal brain, and of the effects of neuropathology and treatment interventions such as exercise have on the reorganization of motor circuits. (C) 2008 Elsevier Inc. All rights reserved. C1 [Holschneider, D. P.] Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, Los Angeles, CA 90033 USA. [Holschneider, D. P.] Univ So Calif, Keck Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Holschneider, D. P.] Univ So Calif, Keck Sch Med, Dept Neurol, Los Angeles, CA 90033 USA. [Holschneider, D. P.; Maarek, J. -M. I.] Univ So Calif, Viterbi Sch Engn, Dept Biomed Engn, Los Angeles, CA 90033 USA. [Holschneider, D. P.] Greater Los Angeles VA Healthcare Syst, Los Angeles, CA USA. RP Holschneider, DP (reprint author), Univ So Calif, Keck Sch Med, Dept Cell & Neurobiol, 1333 San Pablo St,BMT 403,MC 9112, Los Angeles, CA 90033 USA. EM holschne@usc.edu FU NIBIB [1R01 NS050171] FX Supported by the NIBIB 1R01 NS050171. NR 75 TC 18 Z9 18 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 J9 METHODS JI Methods PD AUG PY 2008 VL 45 IS 4 BP 255 EP 261 DI 10.1016/j.ymeth.2008.04.006 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 348MO UT WOS:000259214800002 PM 18554522 ER PT J AU Turbiner, J Moreno-Bueno, G Dahiya, S Sanchez-Estevez, C Hardisson, D Prat, J Oliva, E Palacios, J AF Turbiner, Julia Moreno-Bueno, Gema Dahiya, Sonika Sanchez-Estevez, Carolina Hardisson, David Prat, Jaime Oliva, Esther Palacios, Jose TI Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen SO MODERN PATHOLOGY LA English DT Article DE endometrial carcinoma; pathogenesis; estrogen; tamoxifen; beta-catenin ID NIH3T3 CELL-TRANSFORMATION; ESTROGEN-RECEPTOR-ALPHA; K-RAS MUTATIONS; BREAST-CANCER; DNA-ADDUCTS; MICROSATELLITE INSTABILITY; BETA-CATENIN; PTEN EXPRESSION; GENETIC-PATHWAYS; CARCINOGENESIS AB Use of tamoxifen for treatment and prevention of breast cancer is becoming increasingly common. Tamoxifen has been associated with increased risk of endometrial carcinoma, although the exact mechanism of action is unknown. The aim of our study was to seek a possible correlation between endometrial carcinoma, tamoxifen exposure and MSI, PTEN, beta-catenin and K-ras abnormalities. A group of 18 patients with endometrial carcinoma following treatment with tamoxifen were selected. A control group included 15 patients with endometrial carcinoma and associated ovarian hyperthecosis and one patient with endometrial carcinoma and adult granulosa cell tumor of the ovary, chosen because both conditions are associated with increased production of estrogen and increased risk of endometrial carcinoma development. The second control group included 27 randomly selected consecutive patients with endometrial carcinoma without identifiable associated conditions. Immunostaining for beta-catenin was performed on all cases; DNA was extracted and amplified by PCR with primers for beta-catenin, K-ras and PTEN genes. BAT-25 and BAT-26 were analyzed to assess for MSI. There were 16 endometrioid endometrial carcinomas, one mixed carcinoma and one clear cell carcinoma among patients in the tamoxifen group. All patients with ovarian hyperthecosis and adult granulosa cell tumor had endometrioid endometrial carcinoma. In the random control group, there were 26 endometrioid endometrial carcinomas and one carcinosarcoma. Immunohistochemical and mutational analysis for beta-catenin showed abnormalities in 4/11 (36%) and 3/ 10 (30%) informative cases in the tamoxifen group; 7/16 (44%) and 4/15 (27%) informative cases, respectively in the ovarian hyperthecosis group and 1/27 random control cases (4%) (P<0.05). Patients with tamoxifen exposure had more K-ras mutations and fewer PTEN mutations and MSI as opposed to controls, but the results were not statistically significant. In conclusion, there was a direct relationship between tamoxifen exposure and overexpression of beta-catenin oncoprotein, which is known to play a major role in the pathogenesis of estrogen-driven, type I endometrial adenocarcinoma. C1 [Moreno-Bueno, Gema] Inst Invest Biomed Alberto Sols, Madrid, Spain. [Sanchez-Estevez, Carolina] Ctr Nacl Invest Oncol, Madrid, Spain. [Hardisson, David] Hosp Univ La Paz, Madrid, Spain. [Prat, Jaime] Hosp Santa Creu & Sant Pau, Barcelona, Spain. [Palacios, Jose] Hosp Univ Virgen Rocio, Seville, Spain. [Turbiner, Julia; Dahiya, Sonika] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Turbiner, J (reprint author), Massachusetts Gen Hosp, Dept Pathol Warren 2, 55 Fruit St, Boston, MA 02114 USA. EM jturbiner@partners.org RI Prat, Jaime/G-4679-2011; Moreno-Bueno, Gema/K-9354-2016; Hardisson, David/E-2832-2010 OI Moreno-Bueno, Gema/0000-0002-5030-6687; Hardisson, David/0000-0002-2183-3699 NR 56 TC 10 Z9 11 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD AUG PY 2008 VL 21 IS 8 BP 925 EP 936 DI 10.1038/modpathol.2008.49 PG 12 WC Pathology SC Pathology GA 329SX UT WOS:000257892000001 PM 18500270 ER PT J AU Crane, JM Van Hoek, AN Skach, WR Verkman, AS AF Crane, Jonathan M. Van Hoek, Alfred N. Skach, William R. Verkman, A. S. TI Aquaporin-4 dynamics in orthogonal Arrays in live cells visualized by quantum dot single particle tracking SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID INSENSITIVE WATER CHANNEL; ENDOPLASMIC-RETICULUM; PLASMA-MEMBRANES; EPITHELIAL-CELLS; KNOCKOUT MICE; M23 ISOFORMS; BRAIN; DIFFUSION; LOCALIZATION; PERMEABILITY AB Freeze-fracture electron microscopy (FFEM) indicates that aquaporin-4 (AQP4) water channels can assemble in cell plasma membranes in orthogonal arrays of particles (OAPs). We investigated the determinants and dynamics of AQP4 assembly in OAPs by tracking single AQP4 molecules labeled with quantum dots at an engineered external epitope. In several transfected cell types, including primary astrocyte cultures, the long N-terminal "M1" form of AQP4 diffused freely, with diffusion coefficient similar to 5 x 10(-10) cm(2)/s, covering similar to 5 mu m in 5 min. The short N-terminal "M23" form of AQP4, which by FFEM was found to form OAPs, was relatively immobile, moving only similar to 0.4 mu m in 5 min. Actin modulation by latrunculin or jasplakinolide did not affect AQP4-M23 diffusion, but deletion of its C-terminal postsynaptic density 95/disc-large/zona occludens (PDZ) binding domain increased its range by approximately twofold over minutes. Biophysical analysis of short-range AQP4-M23 diffusion within OAPs indicated a spring-like potential, with a restoring force of similar to 6.5 pN/mu m. These and additional experiments indicated that 1) AQP4-M1 and AQP4-M23 isoforms do not coassociate in OAPs; 2) OAPs can be imaged directly by total internal reflection fluorescence microscopy; and 3) OAPs are relatively fixed, noninterconvertible assemblies that do not require cytoskeletal or PDZ-mediated interactions for formation. Our measurements are the first to visualize OAPs in live cells. C1 [Crane, Jonathan M.; Verkman, A. S.] Univ Calif San Francisco, Cardiovasc Res Inst, Dept Physiol & Med, San Francisco, CA 94143 USA. [Van Hoek, Alfred N.] Massachusetts Gen Hosp, Ctr Syst Biol, Program Membrane Biol, Boston, MA 02114 USA. [Van Hoek, Alfred N.] Massachusetts Gen Hosp, Div Nephrol, Boston, MA 02114 USA. [Skach, William R.] Oregon Hlth & Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA. RP Verkman, AS (reprint author), Univ Calif San Francisco, Cardiovasc Res Inst, Dept Physiol & Med, San Francisco, CA 94143 USA. EM alan.verkman@ucsf.edu FU National Institutes of Health [DK-35124, EB-00415, HL-73856, HL-59198, EY-13574, DK-72517]; Cystic Fibrosis Foundation; National Institutes of Health National Research Service Award [GM-808512] FX We thank Dr. Hua Zhang for providing primary astrocyte cell cultures and Dr. Andrew Bullen of the University of California San Francisco/Nikon Biological Imaging Development Center for confocal microscopy. This work was supported by National Institutes of Health grants DK-35124, EB-00415, HL-73856, HL-59198, EY-13574, and DK-72517, and Research Development Program and Drug Discovery grants from the Cystic Fibrosis Foundation. Dr. Crane was supported in part by National Institutes of Health National Research Service Award GM-808512. NR 38 TC 52 Z9 55 U1 1 U2 7 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2008 VL 19 IS 8 BP 3369 EP 3378 DI 10.1091/mbc.E08-03-0322 PG 10 WC Cell Biology SC Cell Biology GA 347SD UT WOS:000259160400019 PM 18495865 ER PT J AU Sharma, C Yang, XH Hemler, ME AF Sharma, Chandan Yang, Xiuwei H. Hemler, Martin E. TI DHHC2 affects palmitoylation, stability, and functions of tetraspanins CD9 and CD151 SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID EPITHELIAL-CELL PLASTICITY; PROTEIN PALMITOYLATION; ENRICHED MICRODOMAINS; PLASMA-MEMBRANE; TM4SF PROTEIN; CROSS-LINKING; METASTASIS; INTEGRIN; EXPRESSION; COMPLEXES AB Although palmitoylation markedly affects tetraspanin protein biochemistry and functions, relevant palmitoylating enzymes were not known. There are 23 mammalian "DHHC" (Asp-His-His-Cys) proteins, which presumably palmitoylate different sets of protein substrates. Among DHHC proteins tested, DHHC2 best stimulated palmitoylation of tetraspanins CD9 and CD151, whereas inactive DHHC2 (containing DH -> AA or C -> S mutations within the DHHC motif) failed to promote palmitoylation. Furthermore, DHHC2 associated with CD9 and CD151, but not other cell surface proteins, and DHHC2 knockdown diminished CD9 and CD151 palmitoylation. Knockdown of six other Golgi-resident DHHC proteins (DHHC3, -4, -8, -17, -18, and -21) had no effect on CD9 or CD151. DHHC2 selectively affected tetraspanin palmitoylation, but not the palmitoylations of integrin beta 4 subunit and bulk proteins visible in [H-3] palmitate-labeled whole cell lysates. DHHC2-dependent palmitoylation also had multiple functional effects. First, it promoted physical associations between CD9 and CD151, and between alpha 3 integrin and other proteins. Second, it protected CD151 and CD9 from lysosomal degradation. Third, the presence of DHHC2, but not other DHHC proteins, shifted cells away from a dispersed state and toward increased cell-cell contacts. C1 [Sharma, Chandan; Yang, Xiuwei H.; Hemler, Martin E.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Hemler, ME (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM martin_hemler@dfci.harvard.edu FU National Institutes of Health [GM-38903, CA-42368] FX This work was supported by National Institutes of Health grants GM-38903 and CA-42368. NR 50 TC 50 Z9 51 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD AUG PY 2008 VL 19 IS 8 BP 3415 EP 3425 DI 10.1091/mbc.E07-11-1164 PG 11 WC Cell Biology SC Cell Biology GA 347SD UT WOS:000259160400023 PM 18508921 ER PT J AU Padera, TP Kuo, AH Hoshida, T Liao, S Lobo, J Kozak, KR Fukumura, D Jain, RK AF Padera, Timothy P. Kuo, Angera H. Hoshida, Tohru Liao, Shan Lobo, Jennifer Kozak, Kevin R. Fukumura, Dai Jain, Rakesh K. TI Differential response of primary tumor versus lymphatic metastasis to VEGFR-2 and VEGFR-3 kinase inhibitors cediranib and vandetanib SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; CANCER-CELLS; FACTOR-C; LYMPHANGIOGENESIS; ANGIOGENESIS; VESSELS; MACROPHAGES; PROMOTES; THERAPY; SPREAD AB Blood vessels are required for a tumor to grow and functional lymphatic vessels are required for it to disseminate to lymph nodes. In an attempt to eradicate both the primary tumor and its lymphatic metastasis, we targeted both blood and lymphatic vessels using two different tyrosine kinase inhibitors (TKIs): cediranib and vandetanib, which block vascular endothelial growth factor receptor (VEGFR)-2 and -3 in enzymatic assays. We found that although both cediranib and vandetanib slowed the growth rate of primary tumors and reduced blood vessel density, neither agent was able to prevent lymphatic metastasis when given after tumor cells had seeded the lymph node. However, when given during tumor growth, cediranib reduced the diameters of the draining lymphatic vessels, the number of tumor cells arriving in the draining lymph node, and the incidence of lymphatic metastasis. On the other hand, vandetanib had minimal effect on any of these variables, suggesting that vandetanib did not effectively block VEGFR-3 on lymphatic endothelial cells in our animal model. Collectively, these data indicate that the response of lymphatic vessels to a TKI can determine the incidence of lymphatic metastasis, independent of the effect of the TKI on blood vessels. C1 [Padera, Timothy P.; Kuo, Angera H.; Hoshida, Tohru; Liao, Shan; Lobo, Jennifer; Kozak, Kevin R.; Fukumura, Dai; Jain, Rakesh K.] Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. [Padera, Timothy P.; Kuo, Angera H.; Hoshida, Tohru; Liao, Shan; Lobo, Jennifer; Kozak, Kevin R.; Fukumura, Dai; Jain, Rakesh K.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Hoshida, Tohru] Tohoku Univ, Sch Med, Dept Adv Surg Sci & Technol, Sendai, Miyagi 980, Japan. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Edwin L Steele Lab Tumor Biol, 100 Blossom St,Cox 7, Boston, MA 02114 USA. EM jain@steele.mgh.harvard.edu OI Padera, Timothy/0000-0002-3453-9384 FU National Cancer Institute [R01CA85140, P01CA80124] FX National Cancer Institute grants R01CA85140 (R.K. Jain) and P01CA80124 (R.K. Jain) and an unrestricted gift from AstraZeneca.; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 23 TC 61 Z9 65 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD AUG PY 2008 VL 7 IS 8 BP 2272 EP 2279 DI 10.1158/1535-7163.MCT-08-0182 PG 8 WC Oncology SC Oncology GA 343NE UT WOS:000258860000002 PM 18687659 ER PT J AU Duan, ZF Weinstein, EJ Ji, D Ames, RY Choy, E Mankin, H Hornicek, FJ AF Duan, Zhenfeng Weinstein, Edward J. Ji, Diana Ames, Rachel Y. Choy, Edwin Mankin, Henry Hornicek, Francis J. TI Lentiviral short hairpin RNA screen of genes associated with multidrug resistance identifies PRP-4 as a new regulator of chemoresistance in human ovarian cancer SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID PACLITAXEL RESISTANCE; CELL-LINES; SURVIVIN EXPRESSION; MDM2; PROTEIN; OVEREXPRESSION; PHENOTYPE; CARCINOMA; MDR1; OSTEOSARCOMA AB Published reports implicate a variety of mechanisms that may contribute to drug resistance in ovarian cancer. The chief aim of this study is to understand the relationship between overexpression of drug resistance associated genes and multidrug resistance in ovarian cancer. Using lentiviral short hairpin RNA collections targeting 132 genes identified from transcriptional profiling of drug-resistant cancer cell lines, individual knockdown experiments were done in the presence of sublethal doses of paclitaxel. Specific genes whose knockdown was found to be associated with cellular toxicity included MDR1 (ABCB1), survivin, and pre-mRNA processing factor-4 (PRP-4). These genes, when repressed, can reverse paclitaxel resistance in the multidrug-resistant cell line SKOV-3(TR) and OVCAR8(TR). Both MDR1 and survivin have been reported previously to play a role in multidrug resistance and chemotherapy-induced apoptosis; however, the effect of PRP-4 expression on drug sensitivity is currently unrecognized. PRP-4 belongs to the serine/threonine protein kinase family, plays a role in pre-mRNA splicing and cell mitosis, and interacts with CLK1. Northern analysis shows that PRP-4 is overexpressed in several paclitaxel-resistant cell lines and confirms that PRP-4 expression could be significantly repressed by PRP-4 lentiviral short hairpin RNA. Both clonogenic and MTT assays confirm that transcriptional repression of PRP-4 could reverse paclitaxel resistance 5-10-fold in SKOV-3(TR). Finally, overexpression of PRP-4 in drug-sensitive cells could induce a modest level of drug resistance to paclitaxel, doxorubicin, and vincristine. C1 [Duan, Zhenfeng; Mankin, Henry; Hornicek, Francis J.] Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, Boston, MA 02114 USA. [Choy, Edwin] Massachusetts Gen Hosp, Div Hematol & Oncol, Boston, MA 02114 USA. [Weinstein, Edward J.; Ji, Diana] Sigma Aldrich Corp, Res Biotechnol, St Louis, MO USA. [Ames, Rachel Y.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Sarcoma Biol Lab, Ctr Sarcoma & Connect Tissue Oncol, 100 Blossom St Jackson 1115, Boston, MA 02114 USA. EM zduan@partners.org OI Ames, Rachel/0000-0002-1550-2148; Choy, Edwin/0000-0001-9896-8084 FU Ovarian Cancer Research Foundation and Ovarian Cancer SPORE at Dana-Farber/Harvard Cancer Center; Gaetagno and Wechsler funds; National Cancer Institute, NIH (Nanotechnology Platform Partnership) [R01-CA119617] FX Ovarian Cancer Research Foundation and Ovarian Cancer SPORE at Dana-Farber/Harvard Cancer Center; Gaetagno and Wechsler funds; and National Cancer Institute, NIH (Nanotechnology Platform Partnership) grant R01-CA119617 (Z. Duan).; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 44 TC 18 Z9 19 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD AUG PY 2008 VL 7 IS 8 BP 2377 EP 2385 DI 10.1158/1535-7163.MCT-08-0316 PG 9 WC Oncology SC Oncology GA 343NE UT WOS:000258860000013 PM 18687998 ER PT J AU Butte, MJ Pena-Cruz, V Kim, MJ Freeman, GJ Sharpe, AH AF Butte, Manish J. Pena-Cruz, Victor Kim, Mi-Jung Freeman, Gordon J. Sharpe, Arlene H. TI Interaction of human PD-L1 and B7-1 SO MOLECULAR IMMUNOLOGY LA English DT Article DE CD80; CD274; surface plasmon resonance; adhesion; antibody ID T-CELL RESPONSES; PROGRAMMED DEATH-1; ACTIVATION; EXPRESSION; THYMOCYTES; INFECTION; LIGANDS; COMPLEX; ANTIGEN; CD28 AB Numerous studies have pointed to the role of programmed death-1 ligand 1 (PD-L1) in regulating tolerance, chronic infection, and tumor immunity. Recently, we have identified murine B7-1 as a new binding partner for murine PD-L1. Human and mouse B7-1 share only 46% identity, leading us to question whether human B7-1 and PD-L1 can participate in a similar interaction. Here we show that human B7-1 can interact with human PD-L1 with affinity greater than that of B7-1 with CD28, but less than that of B7-1 with CTLA-4 or of PD-L1 with PD-1. We characterize a series of anti-human PD-L1 monoclonal antibodies and identify antibodies that can block interactions of PD-L1 with B7-1, PD-1, or both. Since PD-L1 and CD28 on T cells may compete for B7-1 as a binding partner and CD8 T cells may express high or low levels of CD28, we examined when PD-L1 and CD28 are co-expressed on CD8 T cells. We compared the time-course and extent of PD-L1 induction on CD8 CD28(high) versus CD28(low) T cells following stimulation with anti-CD3. We show that PD-L1 is induced to a higher level on CD28high T cells than on CD28(low) T cells upon activation. These results suggest that PD-L1 may play an important and undervalued role on human T cells. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Sharpe, Arlene H.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Butte, Manish J.; Kim, Mi-Jung] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Butte, Manish J.] Harvard Univ, Dept Chem & Chem Biol, Cambridge, MA 02138 USA. [Pena-Cruz, Victor; Freeman, Gordon J.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Pena-Cruz, Victor; Freeman, Gordon J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Sharpe, AH (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM arlene_sharpe@hms.harvard.edu OI Butte, Manish/0000-0002-4490-5595 FU NIH/NIAID [R01 38310, R01 46414, P01 AI56299 BAA 05-11, P01 AI39671]; Foundation for the National Institutes of Health FX We are grateful to the Dana Farber Cancer Institute Blood Bank for blood samples. GJF draws royalties from patents regarding PD-L1. The other authors disclose no conflicts of interest. Funding for this project came from the NIH/NIAID (R01 38310, R01 46414, P01 AI56299 BAA 05-11 and P01 AI39671) and the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative. NR 20 TC 75 Z9 80 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2008 VL 45 IS 13 BP 3567 EP 3572 DI 10.1016/j.molimm.2008.05.014 PG 6 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 352CT UT WOS:000259473500008 PM 18585785 ER PT J AU Romero, V Zuniga, J Azocar, J Clavijo, OP Terreros, D Kidwai, H Pandey, JP Yunis, EJ AF Romero, Viviana Zuniga, Joaquin Azocar, Jose Clavijo, Olga P. Terreros, Daniel Kidwai, Hassan Pandey, Janardan P. Yunis, Edmond J. TI Genetic interactions of KIR and G1M immunoglobulin allotypes differ in obese from non-obese individuals with type 2 diabetes SO MOLECULAR IMMUNOLOGY LA English DT Article DE type 2 diabetes; natural killer cell immunoglobulin-like receptors; G1M immunoglobulin allotype; obesity; genetic interactions ID IMPAIRED GLUCOSE-TOLERANCE; LEPTIN RECEPTOR; INSULIN-RESISTANCE; ADIPOSE-TISSUE; TNF-ALPHA; POLYMORPHISMS; INFLAMMATION; HLA; INTERLEUKIN-6; COMBINATIONS AB We analyzed the natural killer cell immunoglobulin-like receptor (KIR) genes and immunoglobulin allotypes in the development of type 2 diabetes (T-2D) based on body mass index (BMI) measurements (obese vs. non-obese) in Puerto Rican Americans. Genetic interactions between the KIR haplotype A homozygotes (HAH) and its fraction containing two inhibitory receptors 2DL3 and 2DL1 and the activating receptor 2DS4 with immunoglobulin allotypes were studied. We found a significant association between the HAH and T2D (p = 0.002; OR = 7.97) and its interaction with the immunoglobulin allotype z: GM f/f (-) (p = <0.0001; OR, not determined) only in non-obese individuals. This association were due to the interactions between the 2DL3/2DL3, 2DL1/2DL1, and 2DS4 fragment with GM f/f (-) in T2D patients (p = 0.0017; OR = 3.45). Analysis based on BMI demonstrated associations in both obese (p = 0.037; OR = 2.43; 95% CI = 0.97-6.31) and non-obese individuals (p = <0.0001: OR = 8.38; 95% CI = 2.49-29.31). By contrast, the interaction of the GM allotype f/f (-) with the HAH fragment was associated with T2D only in non-obese individuals (p = <0.0001; OR= 18.2; 95% CI = 3.71-113.4). As expected, interaction of both HAH and its fragment with HLA-C group's ligands were significant. We used informative short tandem repeats (STRs) that distinguish major populations to determine genetic admixture and found that there was no genetic stratification in our cohort. Our findings are consistent with the possibility of an autoimmune and/or innateimmune component in the pathogenesis of T2D: NK receptors with chronic inflammation in obese and genetic interactions with G1M allotype in T2D non-obese possibly mediating autoimmunity. Published by Elsevier Ltd. C1 [Pandey, Janardan P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Zuniga, Joaquin; Yunis, Edmond J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zuniga, Joaquin] Inst Nacl Enfermedades Resp, Mexico City, DF, Mexico. [Azocar, Jose] Northgate Med Ctr, Springfield, MA 01103 USA. [Terreros, Daniel] Texas Tech Hlth Sci Ctr, El Paso, TX 79905 USA. [Pandey, Janardan P.] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. RP Pandey, JP (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. EM pandeyj@musc.edu; edmond_yunis@dfci.harvard.edu FU NIH [AI49213, HL29583, HL59838, AI69939]; Instituto Nacional de Enfermedades Respiratorias, Mexico City; Fundacion Mexico at Harvard, Boston, MA; Northgate Medical Center, Springfield, MA FX This work was supported by NIH grants AI49213, HL29583 and HL59838 (EJY, VR), and AI69939 (RTC). J.Z. was supported by grants from the Instituto Nacional de Enfermedades Respiratorias, Mexico City and Fundacion Mexico at Harvard, Boston, MA. J.A. was supported by Northgate Medical Center, Springfield, MA. NR 29 TC 5 Z9 6 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0161-5890 J9 MOL IMMUNOL JI Mol. Immunol. PD AUG PY 2008 VL 45 IS 14 BP 3857 EP 3862 DI 10.1016/j.molimm.2008.06.004 PG 6 WC Biochemistry & Molecular Biology; Immunology SC Biochemistry & Molecular Biology; Immunology GA 352CX UT WOS:000259473900021 PM 18632158 ER PT J AU Garti-Levi, S Hazan, R Kain, J Fujita, M Ben-Yehuda, S AF Garti-Levi, Sharon. Hazan, Ronen. Kain, James. Fujita, Masaya. Ben-Yehuda, Sigal. TI The FtsEX ABC transporter directs cellular differentiation in Bacillus subtilis SO MOLECULAR MICROBIOLOGY LA English DT Article ID ASPARTYL-PHOSPHATE PHOSPHATASES; ESCHERICHIA-COLI; TRANSCRIPTION FACTOR; SPO0A REGULON; PROTEIN FTSZ; SPORULATION; DIVISION; COMMITMENT; MUTANTS; GENE AB A fundamental challenge in developmental biology is to elucidate the regulatory events that trigger cellular differentiation. Sporulation in the Gram-positive bacterium Bacillus subtilis serves as a simple experimental model system to address this challenge. The hallmark of sporulation is the formation of an asymmetrically positioned septum that divides the cell into unequally sized progeny. Here we describe the role of an ABC transporter, comprising the FtsE and FtsX proteins, in the initiation of spore formation. We discovered that in the absence of this transporter, entry into sporulation is delayed and an atypical symmetric septum is formed instead of a polar one. We show that this phenotype can be suppressed by artificially activating the master regulator of sporulation, Spo0A, or by activating the histidine kinases that function upstream of Spo0A. Our data indicate that the FtsEX transporter is one of the top components in the hierarchy of factors required to initiate sporulation, and thus it is essential for establishing proper temporal activation of the process. C1 [Garti-Levi, Sharon.; Hazan, Ronen.; Ben-Yehuda, Sigal.] Hebrew Univ Jerusalem, Fac Med, Dept Mol Biol, IL-9112 Jerusalem, Israel. [Hazan, Ronen.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Kain, James.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Fujita, Masaya.] Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. RP Ben-Yehuda, S (reprint author), Hebrew Univ Jerusalem, Fac Med, Dept Mol Biol, POB 12272, IL-9112 Jerusalem, Israel. EM sigalb@ekmd.huji.ac.il FU Focal Initiatives in Science and Technology, the Israel Science Foundation (FIRST, ISF) [203/06]; Bruno-Goldberg Endowment Foundation; Robert A. Welch Foundation [E-1627] FX We thank R. Losick (Harvard University, USA) in whose laboratory the preliminary experiments for this study were performed and V. Molle (IBCP, France) for constructing the original Delta ftsE strain. We thank D. Rudner (Harvard University, USA), Alex Rouvinski (Hebrew University, IL), and members of the Ben-Yehuda laboratory for valuable comments on the manuscript. This work was supported by the Focal Initiatives in Science and Technology, the Israel Science Foundation (FIRST, ISF) (Grant No. 203/06) to S.B.-Y., by the Bruno-Goldberg Endowment Foundation to S.B.-Y., and by the Robert A. Welch Foundation (E-1627) to M.F. NR 46 TC 30 Z9 32 U1 2 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD AUG PY 2008 VL 69 IS 4 BP 1018 EP 1028 DI 10.1111/j.1365-2958.2008.06340.x PG 11 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 339RM UT WOS:000258595000019 PM 18573177 ER PT J AU Liu, Y Buck, DC Neve, KA AF Liu, Yong Buck, David C. Neve, Kim A. TI Novel interaction of the dopamine D-2 receptor and the Ca2+ binding protein S100B: Role in D-2 receptor function SO MOLECULAR PHARMACOLOGY LA English DT Article ID MEDIATED ERK ACTIVATION; TARGET PROTEINS; S-100 PROTEIN; CALMODULIN; IDENTIFICATION; SYSTEM; KINASE; FAMILY; TRANSACTIVATION; MODULATION AB S100B is a calcium-binding protein with both extracellular and intracellular regulatory activities in the mammalian brain. We have identified a novel interaction between S100B and the dopamine D-2 receptor. Our results also suggest that the binding of S100B to the dopamine D-2 receptor enhances receptor signaling. This conclusion is based on the following observations: 1) S100B and the third cytoplasmic loop of the dopamine D-2 receptor interact in a bacterial two-hybrid system and in a poly-histidine pull-down assay; 2) immunoprecipitation of the D-2 receptor also precipitates FLAG-S100B from human embryonic kidney 293 cell homogenates and endogenous S100B from rat neostriatal homogenates; 3) S100B immunoreactivity was detected in cultured neostriatal neurons expressing the D-2 receptor; 4) a putative S100B binding motif is located at residues 233 to 240 of the D-2 receptor, toward the amino terminus of the third cytoplasmic loop. D-3-IC3, which does not bind S100B, does not contain this motif; and 5) coexpression of S100B in D-2 receptor-expressing 293 cells selectively increased D-2 receptor stimulation of extracellular signal-regulated kinases and inhibition of adenylate cyclase. C1 [Liu, Yong; Buck, David C.; Neve, Kim A.] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. [Buck, David C.; Neve, Kim A.] Portland VA Med Ctr, Portland, OR USA. RP Neve, KA (reprint author), 3710 SW US Vet Hosp Rd, Portland, OR 97239 USA. EM nevek@ohsu.edu FU NIMH NIH HHS [R01 MH045372, R01 MH045372-17, MH045372] NR 39 TC 25 Z9 28 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD AUG PY 2008 VL 74 IS 2 BP 371 EP 378 DI 10.1124/mol.108.044925 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 329GH UT WOS:000257854400009 PM 18445708 ER PT J AU Shaham, O Wei, R Wang, TJ Ricciardi, C Lewis, GD Vasan, RS Carr, SA Thadhani, R Gerszten, RE Mootha, VK AF Shaham, Oded Wei, Ru Wang, Thomas J. Ricciardi, Catherine Lewis, Gregory D. Vasan, Ramachandran S. Carr, Steven A. Thadhani, Ravi Gerszten, Robert E. Mootha, Vamsi K. TI Metabolic profiling of the human response to a glucose challenge reveals distinct axes of insulin sensitivity SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE glucose homeostasis; insulin sensitivity; metabolic profiling ID BILE-ACIDS; LEUCINE TURNOVER; OBESITY; STARVATION; RESISTANCE; OXIDATION; SALVAGE; SERUM AB Glucose ingestion after an overnight fast triggers an insulin-dependent, homeostatic program that is altered in diabetes. The full spectrum of biochemical changes associated with this transition is currently unknown. We have developed a mass spectrometry-based strategy to simultaneously measure 191 metabolites following glucose ingestion. In two groups of healthy individuals (n = 22 and 25), 18 plasma metabolites changed reproducibly, including bile acids, urea cycle intermediates, and purine degradation products, none of which were previously linked to glucose homeostasis. The metabolite dynamics also revealed insulin's known actions along four key axes proteolysis, lipolysis, ketogenesis, and glycolysis-reflecting a switch from catabolism to anabolism. In pre-diabetics (n = 25), we observed a blunted response in all four axes that correlated with insulin resistance. Multivariate analysis revealed that declines in glycerol and leucine/isoleucine (markers of lipolysis and proteolysis, respectively) jointly provide the strongest predictor of insulin sensitivity. This observation indicates that some humans are selectively resistant to insulin's suppression of proteolysis, whereas others, to insulin's suppression of lipolysis. Our findings lay the groundwork for using metabolic profiling to define an individual's 'insulin response profile', which could have value in predicting diabetes, its complications, and in guiding therapy. C1 [Shaham, Oded; Wei, Ru; Lewis, Gregory D.; Carr, Steven A.; Gerszten, Robert E.; Mootha, Vamsi K.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Shaham, Oded] Harvard MIT Div Hlth Sci Technol, Cambridge, MA USA. [Shaham, Oded; Mootha, Vamsi K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Wang, Thomas J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Wang, Thomas J.; Vasan, Ramachandran S.] Boston Univ, Framingham, MA USA. [Wang, Thomas J.; Lewis, Gregory D.; Gerszten, Robert E.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Ricciardi, Catherine; Thadhani, Ravi] MIT, Gen Clin Res Ctr, Cambridge, MA 02139 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Sect Cardiol & Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Thadhani, Ravi] Massachusetts Gen Hosp, Dept Med, Renal Unit, Boston, MA 02114 USA. [Gerszten, Robert E.] Massachusetts Gen Hosp, Dept Med, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Mootha, VK (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, 185 Cambridge St,CPZN 5-806, Boston, MA 02114 USA. EM vamsi@hms.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU Bioinformatics and Integrative Genomics from the National Human Genome Research Institute; National Institutes of Health (NIH) [R01-HL-086875, R01-HL083197]; Heart Failure Society of America and the Harvard/ MIT Clinical Investigator Training Program; NIH [U01HL083141, MO1-RR01066]; Donald W Reynolds Foundation; e Broad Institute Scientific Planning and Allocation of Resources Committee; Framingham Heart Study [N01-HC-25195] FX We thank Joseph Avruch, Ronald Kahn, Barbara Kahn, Sudha Biddinger, and Mark Herman for helpful comments on the paper; Toshimori Kitami for glucose uptake measurements; and Alice M McKenney for assistance in preparing figures. OS was supported by a training grant for Bioinformatics and Integrative Genomics from the National Human Genome Research Institute. TJW was supported by the National Institutes of Health (NIH) (R01-HL-086875 and R01-HL083197). GDL was supported by the Heart Failure Society of America and the Harvard/ MIT Clinical Investigator Training Program. REG was supported by the NIH (U01HL083141), the Donald W Reynolds Foundation, and Fondation Leducq. VKM was supported by a Burroughs Wellcome Career Award in the Biomedical Sciences and a Howard Hughes Medical Institute Early Career Physician Scientist Award. This study was supported by a generous grant from the Broad Institute Scientific Planning and Allocation of Resources Committee, a General Clinical Research Center grant awarded by the NIH to the Massachusetts Institute of Technology General Clinical Research Center (MO1-RR01066), and a NIH/ National Heart Lung and Blood Institute contract supporting the Framingham Heart Study (N01-HC-25195). NR 26 TC 184 Z9 188 U1 2 U2 25 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1744-4292 J9 MOL SYST BIOL JI Mol. Syst. Biol. PD AUG PY 2008 VL 4 AR 214 DI 10.1038/msb.2008.50 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 344NS UT WOS:000258935100003 PM 18682704 ER PT J AU Taylor, CF Field, D Sansone, SA Aerts, J Apweiler, R Ashburner, M Ball, CA Binz, PA Bogue, M Booth, T Brazma, A Brinkman, RR Clark, AM Deutsch, EW Fiehn, O Fostel, J Ghazal, P Gibson, F Gray, T Grimes, G Hancock, JM Hardy, NW Hermjakob, H Julian, RK Kane, M Kettner, C Kinsinger, C Kolker, E Kuiper, M Le Novere, N Leebens-Mack, J Lewis, SE Lord, P Mallon, AM Marthandan, N Masuya, H McNally, R Mehrle, A Morrison, N Orchard, S Quackenbush, J Reecy, JM Robertson, DG Rocca-Serra, P Rodriguez, H Rosenfelder, H Santoyo-Lopez, J Scheuermann, RH Schober, D Smith, B Snape, J Stoeckert, CJ Tipton, K Sterk, P Untergasser, A Vandesompele, J Wiemann, S AF Taylor, Chris F. Field, Dawn Sansone, Susanna-Assunta Aerts, Jan Apweiler, Rolf Ashburner, Michael Ball, Catherine A. Binz, Pierre-Alain Bogue, Molly Booth, Tim Brazma, Alvis Brinkman, Ryan R. Clark, Adam Michael Deutsch, Eric W. Fiehn, Oliver Fostel, Jennifer Ghazal, Peter Gibson, Frank Gray, Tanya Grimes, Graeme Hancock, John M. Hardy, Nigel W. Hermjakob, Henning Julian, Randall K., Jr. Kane, Matthew Kettner, Carsten Kinsinger, Christopher Kolker, Eugene Kuiper, Martin Le Novere, Nicolas Leebens-Mack, Jim Lewis, Suzanna E. Lord, Phillip Mallon, Ann-Marie Marthandan, Nishanth Masuya, Hiroshi McNally, Ruth Mehrle, Alexander Morrison, Norman Orchard, Sandra Quackenbush, John Reecy, James M. Robertson, Donald G. Rocca-Serra, Philippe Rodriguez, Henry Rosenfelder, Heiko Santoyo-Lopez, Javier Scheuermann, Richard H. Schober, Daniel Smith, Barry Snape, Jason Stoeckert, Christian J., Jr. Tipton, Keith Sterk, Peter Untergasser, Andreas Vandesompele, Jo Wiemann, Stefan TI Promoting coherent minimum reporting guidelines for biological and biomedical investigations: the MIBBI project SO NATURE BIOTECHNOLOGY LA English DT Article ID SCIENTIFIC JOURNALS; MICROARRAY DATA; STANDARDS; INFORMATION; SPECIFICATION; ANNOTATION C1 [Taylor, Chris F.; Sansone, Susanna-Assunta; Apweiler, Rolf; Brazma, Alvis; Hermjakob, Henning; Le Novere, Nicolas; Orchard, Sandra; Rocca-Serra, Philippe; Schober, Daniel; Sterk, Peter] European Bioinformat Inst, Hinxton CB10 1SD, Cambs, England. [Taylor, Chris F.; Field, Dawn; Sansone, Susanna-Assunta; Booth, Tim; Gray, Tanya; Morrison, Norman] NERC, Environm Bioinformat Ctr, Oxford OX1 3SR, England. [Field, Dawn; Gray, Tanya] Oxford Ctr Ecol & Hydrol, Mol Evolut & Bioinformat Grp, Oxford OX1 3SR, England. [Aerts, Jan] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, Cambs, England. [Ashburner, Michael] Univ Cambridge, Dept Genet, Cambridge CB2 3EH, England. [Ball, Catherine A.] Stanford Univ, Dept Biochem, Stanford Microarray Database, Stanford, CA 94305 USA. [Binz, Pierre-Alain] Swiss Inst Bioinformat, CH-1211 Geneva, Switzerland. [Binz, Pierre-Alain] Geneva Bioinformat GeneBio SA, CH-1206 Geneva, Switzerland. [Bogue, Molly] Jackson Lab, Jax Mouse Phenome Project, Bar Harbor, ME 04609 USA. [Brinkman, Ryan R.] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. [Clark, Adam Michael] Lance Armstrong Fdn, Austin, TX 78716 USA. [Deutsch, Eric W.] Inst Syst Biol, Seattle, WA 98103 USA. [Fiehn, Oliver] Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. [Fostel, Jennifer] NIEHS, Res Triangle Pk, NC 27709 USA. [Fostel, Jennifer] Lockheed Martin Informat Technol, Res Triangle Pk, NC 27709 USA. [Ghazal, Peter; Grimes, Graeme; Santoyo-Lopez, Javier] Univ Edinburgh, Sch Med, Div Pathway Med, Edinburgh EH16 4SB, Midlothian, Scotland. [Gibson, Frank; Lord, Phillip] Newcastle Univ, Sch Comp Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Hancock, John M.; Mallon, Ann-Marie] MRC, Bioinformat Grp, Mammalian Genet Unit, Harwell OX11 0RD, Oxon, England. [Hardy, Nigel W.] Aberystwyth Univ, Dept Comp Sci, Aberystwyth SY23 3DB, Dyfed, Wales. [Julian, Randall K., Jr.] Indigo BioSyst Inc, Carmel, IN 46032 USA. [Kane, Matthew] Natl Sci Fdn, Div Mol & Cellular Biosci, Arlington, VA 22230 USA. [Kettner, Carsten] Beilstein Inst Forderung Chem Wissensch, D-60487 Frankfurt, Germany. [Kinsinger, Christopher; Rodriguez, Henry] NCI, Off Technol & Ind Relat, Off Director, Bethesda, MD 20892 USA. [Kolker, Eugene] Seattle Childrens Hosp Res Inst, Seattle, WA 98101 USA. [Kolker, Eugene] Seattle Childrens Hosp & Reg Med Ctr, Seattle, WA 98105 USA. [Kuiper, Martin] Univ Ghent VIB, Dept Plant Syst Biol, B-9052 Ghent, Belgium. [Kuiper, Martin] Univ Ghent, B-9052 Ghent, Belgium. [Kuiper, Martin] Norwegian Univ Sci & Technol, Dept Biol, N-7491 Trondheim, Norway. [Leebens-Mack, Jim] Univ Georgia, Dept Plant Biol, Athens, GA 30602 USA. [Lewis, Suzanna E.] Univ Calif Berkeley, Dept Mol & Cellular Biol, Berkeley, CA 94729 USA. [Marthandan, Nishanth; Scheuermann, Richard H.] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA. [Masuya, Hiroshi] RIKEN, Genom Sci Ctr, Tsukuba, Ibaraki 3050074, Japan. [McNally, Ruth] Univ Lancaster, Inst Adv Studies, ESRC CESAGen, Lancaster LA1 4YD, England. [Mehrle, Alexander; Rosenfelder, Heiko; Wiemann, Stefan] German Canc Res Ctr, Div Mol Genome Anal, D-69120 Heidelberg, Germany. [Morrison, Norman] Univ Manchester, Sch Comp Sci, Manchester M13 9PL, Lancs, England. [Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dept Biostat, Dana Farber Canc Inst,Dept Canc Biol, Boston, MA 02115 USA. [Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat,Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Reecy, James M.] Iowa State Univ, Dept Anim Sci, Ctr Integrated Anim Genom, Ames, IA 50011 USA. [Robertson, Donald G.] Bristol Myers Squibb Co, Princeton, NJ 08543 USA. [Smith, Barry] SUNY Buffalo, Dept Philosophy, Buffalo, NY 14260 USA. [Smith, Barry] SUNY Buffalo, Ctr Excellence Bioinformat & Life Sci, Buffalo, NY 14260 USA. [Snape, Jason] AstraZeneca UK Ltd, Brixham TQ5 8BA, Devon, England. [Stoeckert, Christian J., Jr.] Ctr Bioinformat, Dept Genet, Philadelphia, PA 19104 USA. [Tipton, Keith] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Dublin 2, Ireland. [Untergasser, Andreas] Wageningen Univ, Dept Plant Sci, Mol Biol Lab, Wageningen, Netherlands. [Vandesompele, Jo] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. RP Taylor, CF (reprint author), European Bioinformat Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SD, Cambs, England. EM chris.taylor@ebi.ac.uk; dfield@ceh.ac.uk; sansone@ebi.ac.uk RI Aerts, Jan/C-4374-2008; Field, Dawn/C-1653-2010; Booth, Tim/C-6751-2011; Hancock, John/A-2442-2009; Le Novere, Nicolas/F-9973-2010; Vandesompele, Jo/G-3086-2010; Kolker, Eugene/C-6711-2008; Santoyo-Lopez, Javier/C-9714-2012; Wiemann, Stefan/E-4424-2013; Brinkman, Ryan/B-1108-2008; Masuya, Hiroshi/A-6442-2016; Smith, Barry/A-9525-2011 OI Hermjakob, Henning/0000-0001-8479-0262; Kettner, Carsten/0000-0002-8697-6842; Scheuermann, Richard/0000-0003-1355-892X; Kuiper, Martin/0000-0002-1171-9876; Vandesompele, Jo/0000-0001-6274-0184; Brazma, Alvis/0000-0001-5988-7409; Sterk, Peter/0000-0003-1668-7778; Sansone, Susanna-Assunta/0000-0001-5306-5690; Taylor, Christopher/0000-0002-9666-798X; Binz, Pierre-Alain/0000-0002-0045-7698; Lewis, Suzanna/0000-0002-8343-612X; Gibson, Frank/0000-0003-3382-1748; Orchard, Sandra/0000-0002-8878-3972; Gray, Tanya/0000-0003-1561-7364; Apweiler, Rolf/0000-0001-7078-200X; Hancock, John/0000-0003-2991-2217; Le Novere, Nicolas/0000-0002-6309-7327; Santoyo-Lopez, Javier/0000-0003-1988-5059; Wiemann, Stefan/0000-0003-4683-3174; Brinkman, Ryan/0000-0002-9765-2990; Masuya, Hiroshi/0000-0002-3392-466X; Smith, Barry/0000-0003-1384-116X FU Biotechnology and Biological Sciences Research Council [E025080/1, BB/E025080/1, BB/E006248/1]; Medical Research Council [MC_U142684171]; NHGRI NIH HHS [U54 HG004028]; NIBIB NIH HHS [EB005034-01, R01 EB005034, R01 EB005034-04] NR 21 TC 251 Z9 254 U1 4 U2 31 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2008 VL 26 IS 8 BP 889 EP 896 DI 10.1038/nbt.1411 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 335WX UT WOS:000258325500022 PM 18688244 ER PT J AU Kolev, V Mandinova, A Guinea-Viniegra, J Hu, B Lefort, K Lambertini, C Neel, V Dummer, R Wagner, EF Dotto, GP AF Kolev, Vihren Mandinova, Anna Guinea-Viniegra, Juan Hu, Bing Lefort, Karine Lambertini, Chiara Neel, Victor Dummer, Reinhard Wagner, Erwin F. Dotto, G. Paolo TI EGFR signalling as a negative regulator of Notch1 gene transcription and function in proliferating keratinocytes and cancer SO NATURE CELL BIOLOGY LA English DT Article ID SKIN TUMOR-DEVELOPMENT; EPIDERMAL-GROWTH; C-JUN; P53 EXPRESSION; RECEPTOR; PATHWAY; CELLS; DIFFERENTIATION; SUPPRESSION; INHIBITORS AB The Notch1 gene has an important role in mammalian cell-fate decision and tumorigenesis. Upstream control mechanisms for transcription of this gene are still poorly understood. In a chemical genetics screen for small molecule activators of Notch signalling, we identified epidermal growth factor receptor ( EGFR) as a key negative regulator of Notch1 gene expression in primary human keratinocytes, intact epidermis and skin squamous cell carcinomas ( SCCs). The underlying mechanism for negative control of the Notch1 gene in human cells, as well as in a mouse model of EGFR-dependent skin carcinogenesis, involves transcriptional suppression of p53 by the EGFR effector c-Jun. Suppression of Notch signalling in cancer cells counteracts the differentiation-inducing effects of EGFR inhibitors while, at the same time, synergizing with these compounds in induction of apoptosis. Thus, our data reveal a key role of EGFR signalling in the negative regulation of Notch1 gene transcription, of potential relevance for combinatory approaches for cancer therapy. C1 [Kolev, Vihren; Mandinova, Anna; Dotto, G. Paolo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Guinea-Viniegra, Juan; Wagner, Erwin F.] Res Inst Mol Pathol IMP, A-1030 Vienna, Austria. [Hu, Bing; Lefort, Karine; Lambertini, Chiara; Dotto, G. Paolo] Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. [Neel, Victor; Dotto, G. Paolo] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Dummer, Reinhard] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. RP Dotto, GP (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. EM Gian-Paolo.Dotto@unil.ch RI Wagner, Erwin/G-9637-2012 OI Wagner, Erwin/0000-0001-7872-0196 NR 44 TC 10 Z9 10 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2008 VL 10 IS 8 DI 10.1038/ncb1750 PG 21 WC Cell Biology SC Cell Biology GA 333IV UT WOS:000258147100008 ER PT J AU Samaha, FF McKenney, J Bloedon, LT Sasiela, WJ Rader, DJ AF Samaha, Frederick F. McKenney, James Bloedon, LeAnne T. Sasiela, William J. Rader, Daniel J. TI Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia SO NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE LA English DT Article DE ezetimibe; hypercholesterolemia; microsomal triglyceride transfer protein inhibitor ID TREATMENT PANEL-III; APO-B-SECRETION; MTP-INHIBITOR; RATING-SCALE; VITAMIN-E; CHOLESTEROL; DISEASE; ABETALIPOPROTEINEMIA; ATHEROSCLEROSIS; IMPLITAPIDE AB Background Many patients with coronary heart disease do not achieve recommended LDL-cholesterol levels, due to either intolerance or inadequate response to available lipid- lowering therapy. Microsomal triglyceride transfer protein (MTP) inhibitors might provide an alternative way to lower LDL- cholesterol levels. We tested the safety and LDL- cholesterol- lowering efficacy of an MTP inhibitor, AEGR- 733 ( Aegerion Pharmaceuticals Inc., Bridgewater, NJ), alone and in combination with ezetimibe. Methods We performed a multicenter, double- blind, 12- week trial, which included 84 patients with hypercholesterolemia. Patients were randomly assigned ezetimibe 10 mg daily ( n = 29); AEGR- 733 5.0 mg daily for the first 4 weeks, 7.5 mg daily for the second 4 weeks and 10 mg daily for the last 4 weeks ( n = 28); or ezetimibe 10 mg daily and AEGR- 733 administered with the dose titration described above ( n = 28). Results Ezetimibe monotherapy led to a 20 - 22% decrease in LDLcholesterol concentrations. AEGR- 733 monotherapy led to a dosedependent decrease in LDL- cholesterol concentration: 19% at 5.0 mg, 26% at 7.5 mg and 30% at 10 mg. Combined therapy produced similar but larger dose- dependent decreases ( 35%, 38% and 46%, respectively). The number of patients who discontinued study drugs owing to adverse events was five with ezetimibe alone, nine with AEGR- 733 alone, and four with combined ezetimibe and AEGR- 733. Discontinuations from AEGR- 733 were due primarily to mild transaminase elevations. Conclusions Inhibition of LDL production with low- dose AEGR- 733, either alone or in combination with ezetimibe, could be an effective therapeutic option for patients unable to reach target LDL- cholesterol levels. C1 [Samaha, Frederick F.] Univ Penn, Med Ctr, Philadelphia VA Med Ctr, Philadelphia, PA 19104 USA. [Samaha, Frederick F.] Univ Penn, Div Cardiovasc Med, Dept Med, Sch Med, Philadelphia, PA 19104 USA. [McKenney, James] Virginia Commonwealth Univ, Sch Pharm, Richmond, VA USA. [Bloedon, LeAnne T.; Rader, Daniel J.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Sasiela, William J.] Aeger Pharmaceut, Bridgewater, NJ USA. RP Samaha, FF (reprint author), Univ Penn, Med Ctr, Philadelphia VA Med Ctr, 8th Floor Cardiol,MC 111C,3900 Woodland Ave, Philadelphia, PA 19104 USA. EM rick.samaha@va.gov NR 28 TC 128 Z9 133 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1743-4297 J9 NAT CLIN PRACT CARD JI Nat. Clin. Pract. Cardiovasc. Med. PD AUG PY 2008 VL 5 IS 8 BP 497 EP 505 DI 10.1038/ncpcardio1250 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 329KZ UT WOS:000257867800016 PM 18506154 ER PT J AU Sosnovik, DE Nahrendorf, M Weissleder, R AF Sosnovik, David E. Nahrendorf, Matthias Weissleder, Ralph TI Targeted imaging of myocardial damage SO NATURE CLINICAL PRACTICE CARDIOVASCULAR MEDICINE LA English DT Article DE fluorescence imaging; molecular imaging; MRI; myocardium; SPECT ID ULTRASMALL SUPERPARAMAGNETIC PARTICLES; CARDIAC ALLOGRAFT-REJECTION; IRON-OXIDE; IN-VIVO; ANNEXIN-V; NONINVASIVE DETECTION; ENHANCED MRI; CELL-DEATH; INFARCTION; TOMOGRAPHY AB Molecular imaging agents can be targeted to a specific receptor or protein on the cardiomyocyte surface, or to enzymes released into the interstitial space, such as cathepsins, matrix metalloproteinases and myeloperoxidase. Molecular imaging of the myocardium, however, requires the imaging agent to be small, sensitive (nanomolar levels or better), and able to gain access to the interstitial space. Several novel agents that fulfill these criteria have been used for targeted molecular imaging applications in the myocardium. Magnetic resonance, fluorescence, and single-photon emission CT have been used to image the molecular signals generated by these agents. The use of targeted imaging agents in the myocardium has the potential to provide valuable insights into the pathophysiology of myocardial injury and to facilitate the development of novel therapeutic strategies. C1 Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. [Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA 02115 USA. RP Sosnovik, DE (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, 149 13th St, Charlestown, MA 02129 USA. EM dsosnovik@mgh.harvard.edu FU NHLBI NIH HHS [K08 HL079984, K08 HL079984-03] NR 36 TC 13 Z9 13 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1743-4297 J9 NAT CLIN PRACT CARD JI Nat. Clin. Pract. Cardiovasc. Med. PD AUG PY 2008 VL 5 SU 2 BP S63 EP S70 DI 10.1038/ncpcardio1115 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 329LB UT WOS:000257868000010 PM 18641609 ER PT J AU Kaplan, LM Ahmad, NN AF Kaplan, Lee M. Ahmad, Nadia N. TI The cutting edge in diabetes treatment - is weight-loss surgery an effective therapeutic strategy? SO NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM LA English DT Editorial Material DE bariatric surgery; gastric banding; glycemic control; type 2 diabetes mellitus; weight loss ID BARIATRIC SURGERY; MELLITUS C1 [Kaplan, Lee M.] Massachusetts Gen Hosp, Weight Ctr, Boston, MA 02114 USA. RP Kaplan, LM (reprint author), Massachusetts Gen Hosp, Weight Ctr, 50 Staniford St,4th Floor, Boston, MA 02114 USA. EM lmkaplan@partners.org NR 6 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8366 J9 NAT CLIN PRACT ENDOC JI Nat. Clin. Pract. Endocrinol. Metab. PD AUG PY 2008 VL 4 IS 8 BP 438 EP 439 DI 10.1038/ncpendmet0893 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 328GI UT WOS:000257786000007 PM 18594488 ER PT J AU Yassa, L Sadow, P Marqusee, E AF Yassa, Leila Sadow, Peter Marqusee, Ellen TI Malignant struma ovarii SO NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM LA English DT Article DE malignant struma ovarii; ovarian teratoma; radioactive iodine; struma ovarii; thyroid carcinoma ID PAPILLARY THYROID-CARCINOMA; OF-THE-LITERATURE; FOLLICULAR VARIANT; FOCUS AB Background A 25-year-old woman presented to her gynecologist with pelvic pain. Pelvic ultrasonography showed a 9 cm left ovarian mass. The patient underwent left oophorectomy, omental biopsy, and lymph no e sampling. The ovarian mass proved to be a struma ovarii with numerous microscopic foci of papillary thyroid carcinoma. The patient had no symptoms of hyperthyroidism, and her thyroid function and serum thyroglobulin levels were normal. Investigations Investigations included a pelvic ultrasound scan, histological examination of the ovarian mass and omental nodules, and lymph node sampling. Diagnosis Malignant struma ovarii. Management The patient was referred to an endocrinology clinic for further investigations. Serum levels of TSH, thyroglobulin and thyroglobulin antibodies were measured. In addition, the patient underwent thyroid ultrasonography, which showed a I cm nodule that proved benign on biopsy. She was treated with thyroxine to reduce TSH secretion. Follow-up pelvic ultrasonography I year later showed no evidence of recurrent disease, and her serum thyroglobulin levels remained normal. C1 [Marqusee, Ellen] Brigham & Womens Hosp, Div Thyroid, Boston, MA 02115 USA. [Yassa, Leila] Newton Wellesley Hosp, Wellesley, MA USA. [Yassa, Leila; Sadow, Peter] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Marqusee, E (reprint author), Brigham & Womens Hosp, Div Thyroid, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM emarqusee@partners.org FU NIDDK NIH HHS [T32 DK007529] NR 16 TC 24 Z9 24 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8366 J9 NAT CLIN PRACT ENDOC JI Nat. Clin. Pract. Endocrinol. Metab. PD AUG PY 2008 VL 4 IS 8 BP 469 EP 472 DI 10.1038/ncpendmet0887 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 328GI UT WOS:000257786000013 PM 18560398 ER PT J AU Choueiri, TK Raghavan, D AF Choueiri, Toni K. Raghavan, Derek TI Chemotherapy for muscle-invasive bladder cancer treated with definitive radiotherapy: persisting uncertainties SO NATURE CLINICAL PRACTICE ONCOLOGY LA English DT Review DE bladder preservation; chemoradiation; muscle-invasive bladder cancer; neoadjuvant chemotherapy; radiotherapy ID TRANSITIONAL-CELL-CARCINOMA; SELECTIVE ORGAN PRESERVATION; EXTERNAL-BEAM RADIOTHERAPY; COMBINED-MODALITY PROGRAM; NEOADJUVANT CHEMOTHERAPY; RADIATION-THERAPY; RADICAL RADIOTHERAPY; PROGNOSTIC-FACTORS; PREOPERATIVE RADIOTHERAPY; ONCOLOGY GROUP AB Radical cystectomy for invasive bladder cancer remains the standard of care in many parts of the world, including North America and many parts of Europe; however, a large body of international experience from single institutions and cooperative groups indicates satisfactory results with bladder-sparing approaches in appropriately selected patients. Overall, selective bladder preservation with trimodality therapy, consisting of transurethral resection of the bladder tumor, radiation, and chemotherapy, can achieve complete response rates of 70%, long-term survival rates of 40-50%, and survival rates with an intact bladder of 30-45%. Neoadjuvant chemotherapy followed by radiotherapy might provide up to 5% additional long-term absolute survival benefit compared with radiotherapy alone, although the studies to support this are not appropriately powered. Concomitant chemoradiation provides high response rates and disease control, although the level of evidence for this approach and the follow-up data are even less robust than those for neoadjuvant chemotherapy. Although direct comparison of surgically based and radiotherapy-based approaches would be very useful, it is highly unlikely that such a trial could ever be completed among the patients treated by the clinicians who routinely deal with invasive bladder cancer. C1 [Raghavan, Derek] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44195 USA. [Raghavan, Derek] Lerner Coll Med, Cleveland, OH USA. Canc Div, Cleveland, OH USA. [Choueiri, Toni K.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. RP Raghavan, D (reprint author), Cleveland Clin, Taussig Canc Ctr, 9500 Euclid Ave,R35, Cleveland, OH 44195 USA. EM raghavd@ccf.org NR 65 TC 23 Z9 23 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1743-4254 J9 NAT CLIN PRACT ONCOL JI Nat. Clin. Pract. Oncol. PD AUG PY 2008 VL 5 IS 8 BP 444 EP 454 DI 10.1038/ncponc1159 PG 11 WC Oncology SC Oncology GA 332IQ UT WOS:000258077100007 PM 18577983 ER PT J AU Plotkin, SR Singh, MA O'Donnell, CC Harris, GJ McClatchey, AI Halpin, C AF Plotkin, Scott R. Singh, Marybeth A. O'Donnell, Caroline C. Harris, Gordon J. McClatchey, Andrea I. Halpin, Chris TI Audiologic and radiographic response of NF2-related vestibular schwannoma to erlotinib therapy SO NATURE CLINICAL PRACTICE ONCOLOGY LA English DT Article DE erlotinib; neurofibromatosis; schwannoma; vestibular ID STEREOTACTIC RADIOSURGERY; NEUROFIBROMATOSIS-2; MANAGEMENT; DISEASE; UPDATE; TUMORS; TYPE-2 AB Background A 48-year-old man presented to a neurologist with complaints of bilateral hearing loss and tinnitus. The patient was a member of a large family affected by neurofibromatosis type 2 and first noted hearing loss 10 years before presentation. Investigations Medical and neurological examination, MRI scan of the brain and spinal cord, pure-tone audiometry, NU-6 monosyllabic word test with phoneme scoring, City University of New York topic-related sentences test, noise/voice test of minimal auditory capability battery. Diagnosis Progressive neurofibromatosis-type-2-related vestibular schwannomas. Management Annual cranial MRI and audiology, surgical resection of right vestibular schwannoma, high-power behind-the-ear hearing aid, erlotinib therapy for progressive left vestibular schwannoma. C1 [Plotkin, Scott R.] Massachusetts Gen Hosp, Dept Neurol, Neurofibromatosis Clin, Boston, MA 02114 USA. [Harris, Gordon J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Harris, Gordon J.] Massachusetts Gen Hosp, Imaging Serv 3D, Boston, MA 02114 USA. [McClatchey, Andrea I.] Massachusetts Eye & Ear Infirm, Dept Audiol, Boston, MA 02114 USA. RP Plotkin, SR (reprint author), Massachusetts Gen Hosp, Dept Neurol, Neurofibromatosis Clin, 55 Fruit St,yawkey 9E, Boston, MA 02114 USA. EM splotkin@partners.org NR 18 TC 33 Z9 33 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1743-4254 J9 NAT CLIN PRACT ONCOL JI Nat. Clin. Pract. Oncol. PD AUG PY 2008 VL 5 IS 8 BP 487 EP 491 DI 10.1038/ncponc1157 PG 5 WC Oncology SC Oncology GA 332IQ UT WOS:000258077100011 PM 18560388 ER PT J AU Barrett, JC Hansoul, S Nicolae, DL Cho, JH Duerr, RH Rioux, JD Brant, SR Silverberg, MS Taylor, KD Barmada, MM Bitton, A Dassopoulos, T Datta, LW Green, T Griffiths, AM Kistner, EO Murtha, MT Regueiro, MD Rotter, JI Schumm, LP Steinhart, AH Targan, SR Xavier, RJ Libioulle, C Sandor, C Lathrop, M Belaiche, J Dewit, O Gut, I Heath, S Laukens, D Mni, M Rutgeerts, P Van Gossum, A Zelenika, D Franchimont, D Hugot, JP de Vos, M Vermeire, S Louis, E Cardon, LR Anderson, CA Drummond, H Nimmo, E Ahmad, T Prescott, NJ Onnie, CM Fisher, SA Marchini, J Ghori, J Bumpstead, S Gwilliam, R Tremelling, M Deloukas, P Mansfield, J Jewell, D Satsangi, J Mathew, CG Parkes, M Georges, M Daly, MJ AF Barrett, Jeffrey C. Hansoul, Sarah Nicolae, Dan L. Cho, Judy H. Duerr, Richard H. Rioux, John D. Brant, Steven R. Silverberg, Mark S. Taylor, Kent D. Barmada, M. Michael Bitton, Alain Dassopoulos, Themistocles Datta, Lisa Wu Green, Todd Griffiths, Anne M. Kistner, Emily O. Murtha, Michael T. Regueiro, Miguel D. Rotter, Jerome I. Schumm, L. Philip Steinhart, A. Hillary Targan, Stephan R. Xavier, Ramnik J. Libioulle, Cecile Sandor, Cynthia Lathrop, Mark Belaiche, Jacques Dewit, Olivier Gut, Ivo Heath, Simon Laukens, Debby Mni, Myriam Rutgeerts, Paul Van Gossum, Andre Zelenika, Diana Franchimont, Denis Hugot, Jean-Pierre de Vos, Martine Vermeire, Severine Louis, Edouard Cardon, Lon R. Anderson, Carl A. Drummond, Hazel Nimmo, Elaine Ahmad, Tariq Prescott, Natalie J. Onnie, Clive M. Fisher, Sheila A. Marchini, Jonathan Ghori, Jilur Bumpstead, Suzannah Gwilliam, Rhian Tremelling, Mark Deloukas, Panos Mansfield, John Jewell, Derek Satsangi, Jack Mathew, Christopher G. Parkes, Miles Georges, Michel Daly, Mark J. CA NIDDK IBD Genetics Consortium Belgian-French IBD Consortium Wellcome Trust Case Control TI Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease SO NATURE GENETICS LA English DT Article ID LARGE-SCALE; NONSYNONYMOUS SNPS; GENETIC-VARIATION; VARIANTS; CELLS; EXPRESSION; IL-23; MULTIPLE; COLITIS; RISK AB Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease ( a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development. C1 [Rioux, John D.; Green, Todd] MIT, Broad Inst, Cambridge, MA 02142 USA. [Barrett, Jeffrey C.; Cardon, Lon R.; Anderson, Carl A.] Univ Oxford, Wellcome Trust Ctr Human Genet, Bioinformat & Stat Genet, Oxford OX3 7BN, England. [Hansoul, Sarah; Libioulle, Cecile; Sandor, Cynthia] Univ Liege, Unit Anim Genom, GIGA R, B-4000 Liege, Belgium. Univ Liege, Fac Vet Med, B-4000 Liege, Belgium. [Nicolae, Dan L.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Cho, Judy H.; Murtha, Michael T.] Yale Univ, Dept Med, Div Gastroenterol, Inflammatory Bowel Dis Ctr, New Haven, CT 06519 USA. Yale Univ, Dept Genet, Div Gastroenterol, Inflammatory Bowel Dis Ctr, New Haven, CT 06519 USA. [Duerr, Richard H.] Univ Pittsburgh, Sch Med, Dept Med, Div Gastroenterol Hepatol & Nutr,Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Duerr, Richard H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. [Rioux, John D.] Univ Montreal, Montreal, PQ H1T 1C8, Canada. Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Brant, Steven R.; Dassopoulos, Themistocles] Johns Hopkins Univ, Dept Med, Harvey M & Lyn P Meyerhoff Inflammatory Bowel Dis, Baltimore, MD 21231 USA. [Brant, Steven R.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Silverberg, Mark S.; Steinhart, A. Hillary] Univ Toronto, Mt Sinai Hosp, IBD Ctr, Toronto, ON M5G 1X5, Canada. [Taylor, Kent D.; Rotter, Jerome I.; Targan, Stephan R.] Cedars Sinai Med Ctr, Med Genet Inst Inflammatory Bowel Dis Ctr, Los Angeles, CA 90048 USA. [Bitton, Alain] McGill Univ, Royal Victoria Hosp, Dept Med, Montreal, PQ H3A 1A1, Canada. [Griffiths, Anne M.] Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Kistner, Emily O.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [Xavier, Ramnik J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Lathrop, Mark; Gut, Ivo; Heath, Simon; Zelenika, Diana] Ctr Natl Genotypage, Evry, France. Univ Liege, CHU Liege, B-4000 Liege, Belgium. [Dewit, Olivier] Clin Univ St Luc, Dept Gastroenterol, UCL, B-1200 Brussels, Belgium. [Laukens, Debby; de Vos, Martine] Ghent Univ Hosp, Dept Gastroenterol & Hepatol, Ghent, Belgium. [Rutgeerts, Paul; Vermeire, Severine] Katholieke Univ Leuven Hosp, Dept Gastroenterol, Louvain, Belgium. [Van Gossum, Andre; Franchimont, Denis] Free Univ Brussels, Erasmus Hosp, Dept Gastroenterol, B-1050 Brussels, Belgium. [Hugot, Jean-Pierre] INSERM, F-75654 Paris 13, France. Univ Paris Diderot, Paris, France. Hosp Robert Debre, Paris, France. [Drummond, Hazel; Nimmo, Elaine; Satsangi, Jack] Univ Edinburgh, Western Gen Hosp, Sch Mol & Clin Med, Div Med Sci,Gastrointestinal Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Ahmad, Tariq] Peninsula Med Sch, Exeter EX2 5DW, Devon, England. [Prescott, Natalie J.; Onnie, Clive M.; Fisher, Sheila A.; Mathew, Christopher G.] Kings Coll London, Sch Med, Dept Med & Mol Genet, London SE1 9RT, England. [Marchini, Jonathan] Univ Oxford, Dept Stat, Oxford OX1 3TG, England. [Bumpstead, Suzannah; Gwilliam, Rhian; Deloukas, Panos] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Tremelling, Mark; Parkes, Miles] Univ Cambridge, Addenbrookes Hosp, IBD Res Grp, Cambridge CB2 2QQ, England. [Mansfield, John] Univ Newcastle Upon Tyne, Dept Gastroenterol & Hepatol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. [Jewell, Derek] Univ Oxford, Dept Infirm, Gastroenterol Unit, Oxford OX2 6HE, England. [Daly, Mark J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA 02114 USA. RP Daly, MJ (reprint author), MIT, Broad Inst, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM mjdaly@chgr.mgh.harvard.edu RI Prescott, Natalie/F-6490-2011; Hugot, Jean-Pierre/F-6594-2012; Heath, Simon/J-4138-2012; Deloukas, Panos/B-2922-2013; Anderson, Carl/B-8327-2013; Silverberg, Mark/B-4183-2008; Rioux, John/A-9599-2015; Mathew, Christopher/G-3434-2015; OI Prescott, Natalie/0000-0002-5901-7371; Deloukas, Panos/0000-0001-9251-070X; Anderson, Carl/0000-0003-1719-7009; Rioux, John/0000-0001-7560-8326; Mathew, Christopher/0000-0003-4178-1838; Laukens, Debby/0000-0002-1984-5850; Duerr, Richard/0000-0001-6586-3905; Vermeire, Severine/0000-0001-9942-3019; Barmada, M Michael/0000-0002-3604-6460; Barrett, Jeffrey/0000-0002-1152-370X FU Chief Scientist Office [CZB/4/540]; Medical Research Council [G0000934, G0600329, G0800759]; NIAID NIH HHS [AI06277, R01 AI062773, R01 AI062773-02]; NIDDK NIH HHS [U01 DK062413, DK064869, DK62413, DK62420, DK62422, DK62423, DK62429, DK62431, DK62432, P30 DK040561, P30 DK040561-13, P30 DK063491, P30 DK063491-019004, P30 DK063491-029004, P30 DK063491-039004, P30 DK063491-049004, P30 DK063491-05, R01 DK064869, R01 DK064869-04, U01 DK062413-06, U01 DK062420, U01 DK062420-01, U01 DK062420-02, U01 DK062420-03, U01 DK062420-04, U01 DK062420-05, U01 DK062420-06, U01 DK062422, U01 DK062422-07, U01 DK062423, U01 DK062423-06, U01 DK062429, U01 DK062429-07, U01 DK062431, U01 DK062431-06, U01 DK062432]; Wellcome Trust [068545/Z/02] NR 50 TC 1500 Z9 1523 U1 12 U2 101 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 AUG PY 2008 VL 40 IS 8 BP 955 EP 962 DI 10.1038/ng.175 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 331QF UT WOS:000258026900011 PM 18587394 ER PT J AU Pielberg, GR Golovko, A Sundstrom, E Curik, I Lennartsson, J Seltenhammer, MH Druml, T Binns, M Fitzsimmons, C Lindgren, G Sandberg, K Baumung, R Vetterlein, M Stromberg, S Grabherr, M Wade, C Lindblad-Toh, K Ponten, F Heldin, CH Solkner, J Andersson, L AF Pielberg, Gerli Rosengren Golovko, Anna Sundstrom, Elisabeth Curik, Ino Lennartsson, Johan Seltenhammer, Monika H. Druml, Thomas Binns, Matthew Fitzsimmons, Carolyn Lindgren, Gabriella Sandberg, Kaj Baumung, Roswitha Vetterlein, Monika Stromberg, Sara Grabherr, Manfred Wade, Claire Lindblad-Toh, Kerstin Ponten, Fredrik Heldin, Carl-Henrik Soelkner, Johann Andersson, Leif TI A cis-acting regulatory mutation causes premature hair graying and susceptibility to melanoma in the horse SO NATURE GENETICS LA English DT Article ID STIMULATING-HORMONE-RECEPTOR; STEM-CELL MAINTENANCE; COAT COLOR GENE; EQUUS-CABALLUS; MC1R; MECHANISMS; LINKAGE; GENOME AB In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Here we show that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (syntaxin-17) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in ASIP ( agouti signaling protein) had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses. The Gray horse provides a notable example of how humans have cherry-picked mutations with favorable phenotypic effects in domestic animals. C1 [Pielberg, Gerli Rosengren; Golovko, Anna; Fitzsimmons, Carolyn; Lindblad-Toh, Kerstin; Andersson, Leif] Uppsala Univ, Dept Med Biochem & Microbiol, SE-75124 Uppsala, Sweden. [Sundstrom, Elisabeth; Lindgren, Gabriella; Sandberg, Kaj; Andersson, Leif] Swedish Univ Agr Sci, Dept Anim Breeding & Genet, SE-75124 Uppsala, Sweden. [Curik, Ino] Univ Zagreb, Dept Anim Sci, Fac Agr, HR-10000 Zagreb, Croatia. [Lennartsson, Johan; Heldin, Carl-Henrik] Uppsala Univ, Ludwig Inst Canc Res, SE-75124 Uppsala, Sweden. [Seltenhammer, Monika H.] Univ Vet Med, Dept Clin Surg & Ophthalmol, A-1200 Vienna, Austria. [Druml, Thomas; Baumung, Roswitha; Soelkner, Johann] Univ Nat Resources & Appl Life Sci, Dept Sustainable Agr Syst, A-1180 Vienna, Austria. [Binns, Matthew] Univ London Royal Vet Coll, London NW1 0TU, England. [Vetterlein, Monika] Med Univ Vienna, Dept Cell Biol & Ultrastruct Res, Ctr Anat & Cell Biol, A-1080 Vienna, Austria. [Stromberg, Sara; Ponten, Fredrik] Uppsala Univ, Rudbeck Lab, Dept Genet & Pathol, SE-75185 Uppsala, Sweden. [Grabherr, Manfred; Wade, Claire; Lindblad-Toh, Kerstin] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA. [Wade, Claire] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Andersson, L (reprint author), Uppsala Univ, Dept Med Biochem & Microbiol, Box 597, SE-75124 Uppsala, Sweden. EM leif.andersson@imbim.uu.se OI Wade, Claire/0000-0003-3413-4771 NR 28 TC 98 Z9 105 U1 2 U2 25 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 AUG PY 2008 VL 40 IS 8 BP 1004 EP 1009 DI 10.1038/ng.185 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 331QF UT WOS:000258026900018 PM 18641652 ER PT J AU Halle, A Hornung, V Petzold, GC Stewart, CR Monks, BG Reinheckel, T Fitzgerald, KA Latz, E Moore, KJ Golenbock, DT AF Halle, Annett Hornung, Veit Petzold, Gabor C. Stewart, Cameron R. Monks, Brian G. Reinheckel, Thomas Fitzgerald, Katherine A. Latz, Eicke Moore, Kathryn J. Golenbock, Douglas T. TI The NALP3 inflammasome is involved in the innate immune response to amyloid-beta SO NATURE IMMUNOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; ALZHEIMERS-DISEASE; CATHEPSIN-B; MOUSE MODEL; MICROGLIA; RECEPTOR; ACTIVATION; EXPRESSION; INTERLEUKIN-1-BETA; CASPASE-1 AB The fibrillar peptide amyloid-beta (A beta) has a chief function in the pathogenesis of Alzheimer's disease. Interleukin 1 beta (IL-1 beta) is a key cytokine in the inflammatory response to A beta. Insoluble materials such as crystals activate the inflammasome formed by the cytoplasmic receptor NALP3, which results in the release of IL-1 beta. Here we identify the NALP3 inflammasome as a sensor of A beta in a process involving the phagocytosis of A beta and subsequent lysosomal damage and release of cathepsin B. Furthermore, the IL-1 beta pathway was essential for the microglial synthesis of proinflammatory and neurotoxic factors, and the inflammasome, caspase-1 and IL-1 beta were critical for the recruitment of microglia to exogenous A beta in the brain. Our findings suggest that activation of the NALP3 inflammasome is important for inflammation and tissue damage in Alzheimer's disease. C1 [Halle, Annett; Hornung, Veit; Monks, Brian G.; Fitzgerald, Katherine A.; Latz, Eicke; Golenbock, Douglas T.] Univ Massachusetts, Sch Med, Dept Immunol & Infect Dis, Worcester, MA 01605 USA. [Petzold, Gabor C.] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Petzold, Gabor C.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Stewart, Cameron R.; Moore, Kathryn J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Lipid Metab Unit, Boston, MA 02114 USA. [Reinheckel, Thomas] Univ Freiburg, Inst Mol Med & Cell Res, D-79104 Freiburg, Germany. RP Golenbock, DT (reprint author), Univ Massachusetts, Sch Med, Dept Immunol & Infect Dis, Worcester, MA 01605 USA. EM douglas.golenbock@umassmed.edu RI Stewart, Cameron/E-6823-2011; Monks, Brian/B-8362-2015; Latz, Eicke/H-3951-2014; Hornung, Veit/C-3565-2012; OI Monks, Brian/0000-0003-4008-3093; Latz, Eicke/0000-0003-1488-5666; Hornung, Veit/0000-0002-4150-194X; Moore, kathryn/0000-0003-2505-2547 FU NIA NIH HHS [AG20255, R01 AG020255, R01 AG020255-06A1]; NIAID NIH HHS [R01 AI065483, AI065483]; NIGMS NIH HHS [GM54060, R01 GM054060, R37 GM054060] NR 47 TC 790 Z9 836 U1 15 U2 100 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 AUG PY 2008 VL 9 IS 8 BP 857 EP 865 DI 10.1038/ni.1636 PG 9 WC Immunology SC Immunology GA 328EN UT WOS:000257780700008 PM 18604209 ER PT J AU Shedden, K Taylor, JMG Enkemann, SA Tsao, MS Yeatman, TJ Gerald, WL Eschrich, S Jurisica, I Giordano, TJ Misek, DE Chang, AC Zhu, CQ Strumpf, D Hanash, S Shepherd, FA Ding, K Seymour, L Naoki, K Pennell, N Weir, B Verhaak, R Ladd-Acosta, C Golub, T Gruidl, M Sharma, A Szoke, J Zakowski, M Rusch, V Kris, M Viale, A Motoi, N Travis, W Conley, B Seshan, VE Meyerson, M Kuick, R Dobbin, KK Lively, T Jacobson, JW Beer, DG AF Shedden, Kerby Taylor, Jeremy M. G. Enkemann, Steven A. Tsao, Ming-Sound Yeatman, Timothy J. Gerald, William L. Eschrich, Steven Jurisica, Igor Giordano, Thomas J. Misek, David E. Chang, Andrew C. Zhu, Chang Qi Strumpf, Daniel Hanash, Samir Shepherd, Frances A. Ding, Keyue Seymour, Lesley Naoki, Katsuhiko Pennell, Nathan Weir, Barbara Verhaak, Roel Ladd-Acosta, Christine Golub, Todd Gruidl, Michael Sharma, Anupama Szoke, Janos Zakowski, Maureen Rusch, Valerie Kris, Mark Viale, Agnes Motoi, Noriko Travis, William Conley, Barbara Seshan, Venkatraman E. Meyerson, Matthew Kuick, Rork Dobbin, Kevin K. Lively, Tracy Jacobson, James W. Beer, David G. CA Director's Challenge Consortium Mo TI Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study SO NATURE MEDICINE LA English DT Article ID CANCER AB Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas. C1 [Lively, Tracy; Jacobson, James W.] NCI, Cancer Diag Program, Rockville, MD 20852 USA. [Shedden, Kerby] Univ Michigan, S Univ 1085, Dept Stat, Ann Arbor, MI 48109 USA. [Shedden, Kerby; Taylor, Jeremy M. G.; Misek, David E.; Chang, Andrew C.; Hanash, Samir; Kuick, Rork; Beer, David G.] Univ Michigan, Ctr Canc, Ann Arbor, MI 48109 USA. [Taylor, Jeremy M. G.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Enkemann, Steven A.; Yeatman, Timothy J.; Gruidl, Michael; Sharma, Anupama] Univ S Florida, Dept Surg, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Tsao, Ming-Sound; Jurisica, Igor; Zhu, Chang Qi; Strumpf, Daniel; Shepherd, Frances A.] Ontario Canc Inst, Univ Hlth Network, Toronto, ON M5G 2M9, Canada. [Tsao, Ming-Sound; Jurisica, Igor; Zhu, Chang Qi; Strumpf, Daniel; Shepherd, Frances A.] Princess Margaret Hosp, Toronto, ON M5G 2M9, Canada. [Gerald, William L.; Szoke, Janos; Zakowski, Maureen; Rusch, Valerie; Kris, Mark; Viale, Agnes; Motoi, Noriko; Travis, William] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Giordano, Thomas J.] Univ Michigan, Dept Pathol, Univ Hosp 2G3320054, Ann Arbor, MI 48109 USA. [Misek, David E.; Chang, Andrew C.; Beer, David G.] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. [Ding, Keyue; Seymour, Lesley] Queens Univ, Kingston, ON K7L 3N6, Canada. [Ding, Keyue; Seymour, Lesley] Inst Canc Res, Canada Clin Trials Grp, Kingston, ON K7L 3N6, Canada. [Naoki, Katsuhiko; Pennell, Nathan; Weir, Barbara; Verhaak, Roel; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Dept Med Oncol, Boston, MA 02115 USA. [Ladd-Acosta, Christine; Golub, Todd; Meyerson, Matthew] 7 Cambridge Ctr, Broad Inst, Cambridge, MA 02142 USA. [Conley, Barbara] Michigan State Univ, Dept Med, Clin Ctr B414, E Lansing, MI 48824 USA. [Seshan, Venkatraman E.] Columbia Univ, New York, NY 10032 USA. [Dobbin, Kevin K.] Natl Canc Inst, Biometr Res Branch, Rockville, MD 20852 USA. RP Jacobson, JW (reprint author), NCI, Cancer Diag Program, EPN 6035A,6130 Execut Blvd, Rockville, MD 20852 USA. EM jacobsonj@ctep.nci.nih.gov; dgbeer@umich.edu RI Meyerson, Matthew/E-7123-2012; Eschrich, Steven/K-6848-2013; Motoi, Noriko/A-9718-2009; OI Motoi, Noriko/0000-0001-7098-3311; Kris, Mark/0000-0002-7317-5341; Chang, Andrew/0000-0001-9506-0425; Giordano, Thomas/0000-0003-0641-8873 NR 18 TC 498 Z9 505 U1 3 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2008 VL 14 IS 8 BP 822 EP 827 DI 10.1038/nm.1790 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 334QY UT WOS:000258237500028 ER PT J AU Ehninger, D Han, S Shilyansky, C Zhou, Y Li, WD Kwiatkowski, DJ Ramesh, V Silva, AJ AF Ehninger, Dan Han, Sangyeul Shilyansky, Carrie Zhou, Yu Li, Weidong Kwiatkowski, David J. Ramesh, Vijaya Silva, Alcino J. TI Reversal of learning deficits in a Tsc2(+/-) mouse model of tuberous sclerosis SO NATURE MEDICINE LA English DT Article ID SYNAPTIC PLASTICITY; COGNITIVE DEFICITS; RAT MODEL; FRAGILE-X; COMPLEX; MEMORY; HIPPOCAMPUS; TSC1; TRANSLATION; IDENTIFICATION AB Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene(1,2) and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%)(3-5) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits(6,7). Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice)(8) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved(5,9-11). We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder. C1 [Ehninger, Dan; Shilyansky, Carrie; Zhou, Yu; Li, Weidong; Silva, Alcino J.] Univ Calif Los Angeles, Dept Neurobiol, Los Angeles, CA 90095 USA. [Ehninger, Dan; Shilyansky, Carrie; Zhou, Yu; Li, Weidong; Silva, Alcino J.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Ehninger, Dan; Shilyansky, Carrie; Zhou, Yu; Li, Weidong; Silva, Alcino J.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90095 USA. [Ehninger, Dan; Shilyansky, Carrie; Zhou, Yu; Li, Weidong; Silva, Alcino J.] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90095 USA. [Han, Sangyeul; Ramesh, Vijaya] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res,Richard B Simches Res Ctr, Boston, MA 02114 USA. [Kwiatkowski, David J.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Genet Lab,Div Translat Med, Boston, MA 02115 USA. RP Silva, AJ (reprint author), Univ Calif Los Angeles, Dept Neurobiol, 695 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM silvaa@mednet.ucla.edu OI Silva, Alcino/0000-0001-5525-0494 FU Autism Speaks [AS1862]; NINDS NIH HHS [NS24279, P01 NS024279, P01 NS024279-160011, R01 NS038480, R01 NS038480-06, R01 NS038480-08, R01-NS38480] NR 30 TC 415 Z9 427 U1 3 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2008 VL 14 IS 8 BP 843 EP 848 DI 10.1038/nm1788 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 334QY UT WOS:000258237500031 PM 18568033 ER PT J AU Lee, H Sun, E Ham, D Weissleder, R AF Lee, Hakho Sun, Eric Ham, Donhee Weissleder, Ralph TI Chip-NMR biosensor for detection and molecular analysis of cells SO NATURE MEDICINE LA English DT Article ID CANCER; SPECTROSCOPY; MICROCOILS; MEDICINE; BIOLOGY; MARKERS; SYSTEMS; DESIGN AB Rapid and accurate measurement of biomarkers in tissue and fluid samples is a major challenge in medicine. Here we report the development of a new, miniaturized diagnostic magnetic resonance (DMR) system for multiplexed, quantitative and rapid analysis. By using magnetic particles as a proximity sensor to amplify molecular interactions, the handheld DMR system can perform measurements on unprocessed biological samples. We show the capability of the DMR system by using it to detect bacteria with high sensitivity, identify small numbers of cells and analyze them on a molecular level in real time, and measure a series of protein biomarkers in parallel. The DMR technology shows promise as a robust and portable diagnostic device. C1 [Lee, Hakho; Sun, Eric; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, Boston, MA 02114 USA. [Ham, Donhee] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. RP Weissleder, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol, 185 Cambridge St, Boston, MA 02114 USA. EM rweissleder@mgh.harvard.edu FU NCI NIH HHS [U54 CA119349, U54 CA119349-040003]; NHLBI NIH HHS [U01 HL080731, U01 HL080731-04] NR 30 TC 295 Z9 303 U1 15 U2 108 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2008 VL 14 IS 8 BP 869 EP 874 DI 10.1038/nm.1711 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 334QY UT WOS:000258237500035 PM 18607350 ER PT J AU Vyas, JM Van der Veen, AG Ploegh, HL AF Vyas, Jatin M. Van der Veen, Annemarthe G. Ploegh, Hidde L. TI The known unknowns of antigen processing and presentation SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID MHC CLASS-II; DENDRITIC CELL MATURATION; TOLL-LIKE RECEPTORS; ENDOPLASMIC-RETICULUM STRESS; PATHOGEN-CONTAINING VACUOLES; GENOME-WIDE ASSOCIATION; MINOR H-ANTIGENS; CROSS-PRESENTATION; TOXOPLASMA-GONDII; MYCOBACTERIUM-TUBERCULOSIS AB The principal components of both MHC class I and class II antigen processing and presentation pathways are well known. In dendritic cells, these pathways are tightly regulated by Toll-like-receptor signalling and include features, such as cross-presentation, that are not seen in other cell types. However, the exact mechanisms involved in the subcellular trafficking of antigens remain poorly understood and in some cases are controversial. Recent data suggest that diverse cellular machineries, including autophagy, participate in antigen processing and presentation, although their relative contributions remain to be fully elucidated. Here, we highlight some emerging themes of antigen processing and presentation that we think merit further attention. C1 [Vyas, Jatin M.; Van der Veen, Annemarthe G.; Ploegh, Hidde L.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Vyas, Jatin M.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Vyas, Jatin M.] Massachusetts Gen Hosp, Dept Med, Div Infect Dis, Boston, MA 02114 USA. [Ploegh, Hidde L.] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Ploegh, HL (reprint author), Whitehead Inst Biomed Res, 9 Cambridge Ctr, Cambridge, MA 02142 USA. EM ploegh@wi.mit.edu RI Vyas, Jatin/Q-1627-2016 OI Vyas, Jatin/0000-0002-9985-9565 FU NIAID NIH HHS [R37 AI033456, K08 AI057999, K08 AI57999, R01 AI033456, R01 AI033456-18, R01 AI034893, R01 AI034893-16, R01 AI057182, R01 AI057182-06, R01 AI34893, R37 AI033456-16, R37 AI33456]; NIGMS NIH HHS [R01 GM062502] NR 141 TC 246 Z9 254 U1 3 U2 64 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD AUG PY 2008 VL 8 IS 8 BP 607 EP 618 DI 10.1038/nri2368 PG 12 WC Immunology SC Immunology GA 329SW UT WOS:000257891900015 PM 18641646 ER PT J AU Goulder, PJR Watkins, DI AF Goulder, Philip J. R. Watkins, David I. TI Impact of MHC class I diversity on immune control of immunodeficiency virus replication SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID CYTOTOXIC T-LYMPHOCYTES; SIMIAN-IMMUNODEFICIENCY; DISEASE PROGRESSION; CELL RESPONSES; VIRAL ESCAPE; TYPE-1 INFECTION; RHESUS MACAQUES; HIV-1 INFECTION; MOLECULE MAMU-A-ASTERISK-01; SIVMAC239 REPLICATION AB The recent failure of the T-cell-based HIV vaccine trial led by Merck & Co., Inc. prompts the urgent need to refocus on the question of which T-cell responses are required to control HIV replication. The well-described association between the expression of particular MHC class I molecules and successful containment of HIV or, in the macaque model, SIV replication provide a valuable starting point from which to evaluate more precisely what might constitute effective CD8(+) T-cell responses. Here, we review recent studies of T-cell mediated control of HIV and SIV infection, and offer insight for the design of a successful T-cell-based HIV vaccine in the future. C1 [Goulder, Philip J. R.] Nuffield Dept Med, Dept Paediat, Oxford OX1 3SY, England. [Goulder, Philip J. R.] Massachusetts Gen Hosp East, Partners AIDS Res Ctr, Boston, MA 02129 USA. [Goulder, Philip J. R.] Univ KwaZulu Natal, Doris Duke Med Res Inst, HIV Pathogenesis Programme, Durban, South Africa. [Watkins, David I.] Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Madison, WI 53706 USA. RP Goulder, PJR (reprint author), Nuffield Dept Med, Dept Paediat, Peter Medawar Bldg Pathogens Res,S Parks Rd, Oxford OX1 3SY, England. EM philip.goulder@ndm.ox.ac.uk FU NCRR NIH HHS [R24 RR016038, R24 RR015371, R24 RR015371-12, R24 RR016038-11]; NIAID NIH HHS [R01 AI046995, R01 AI049120, R01 AI049120-09, R01 AI052056, R01 AI052056-05, R01 AI076114, R01 AI076114-05, R01 AI076117, R01 AI46995, R21 AI077472, R21 AI077472-02]; PHS HHS [HHSN266200400088C] NR 117 TC 274 Z9 283 U1 2 U2 26 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD AUG PY 2008 VL 8 IS 8 BP 619 EP 630 DI 10.1038/nri2357 PG 12 WC Immunology SC Immunology GA 329SW UT WOS:000257891900016 PM 18617886 ER PT J AU Xavier, RJ Rioux, JD AF Xavier, Ramnik J. Rioux, John D. TI Genome-wide association studies: a new window into immune-mediated diseases SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INFLAMMATORY-BOWEL-DISEASE; SINGLE-NUCLEOTIDE POLYMORPHISMS; TYPE-1 DIABETES LOCUS; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; MULTIPLE-SCLEROSIS; AUTOIMMUNE-DISEASE; CROHNS-DISEASE; GENE-EXPRESSION AB Given the recent explosion of genetic discoveries, 2007 is becoming known to human geneticists as the year of genome-wide association studies. In fact, more genetic risk factors for common diseases were identified in this one year than had been collectively reported before 2007. In particular, 2007 witnessed the discovery of many genes that influence susceptibility to individual immune-mediated diseases, as well as other genes that are associated with susceptibility to more than one disease. Although much work remains to be done, in this Review we discuss what effect these studies are having on our understanding of disease pathogenesis and their potential impact on future immunology studies. C1 [Rioux, John D.] Univ Montreal, Montreal, PQ H1T 1C8, Canada. [Rioux, John D.] Montreal Heart Inst, Res Ctr, Montreal, PQ H1T 1C8, Canada. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA USA. [Xavier, Ramnik J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA USA. RP Rioux, JD (reprint author), Univ Montreal, 5000 Belanger St, Montreal, PQ H1T 1C8, Canada. EM john.david.rioux@umontreal.ca RI Rioux, John/A-9599-2015 OI Rioux, John/0000-0001-7560-8326 FU NIAID NIH HHS [P01 AI065687, AI062773, AI065687, AI067152, P01 AI065687-030001, R01 AI062773, U19 AI067152, U19 AI067152-050006]; NIDDK NIH HHS [DK062432, DK064869, DK43351, P30 DK043351, R01 DK064869, R01 DK064869-06A1, U01 DK062432, U01 DK062432-08] NR 97 TC 77 Z9 78 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD AUG PY 2008 VL 8 IS 8 BP 631 EP 643 DI 10.1038/nri2361 PG 13 WC Immunology SC Immunology GA 329SW UT WOS:000257891900017 PM 18654571 ER PT J AU Lonn, S Rothman, N Shapiro, WR Fine, HA Selker, RG Black, PM Loeffler, JS Hutchinson, AA Inskip, PD AF Lonn, Stefan Rothman, Nathaniel Shapiro, William R. Fine, Howard A. Selker, Robert G. Black, Peter M. Loeffler, Jay S. Hutchinson, Amy A. Inskip, Peter D. TI Genetic variation in insulin-like growth factors and brain tumor risk SO NEURO-ONCOLOGY LA English DT Article DE central nervous system; glioma; insulin-like growth factor; meningioma; single nucleotide polymorphism ID FACTOR-I RECEPTOR; HARDY-WEINBERG EQUILIBRIUM; PROSTATE-CANCER RISK; BINDING PROTEIN-3; TUMORIGENESIS; POLYMORPHISMS; ASSOCIATIONS; ETIOLOGY; ADULTS; IGF1 AB Many studies support a role for insulin-like growth factors (IGFs) in the regulation of tumor cell biology. We hypothesized that single-nucleotide polymorphisms (SNPs) in IGF genes are risk factors for glioma and meningioma. To test the hypothesis, we examined associations of brain tumor risk with nine variants in five IGF genes in a hospital-based case-control study. The study was conducted at hospitals in Boston, Phoenix, and Pittsburgh between 1994 and 1998. Eligible cases were individuals (18 years or older) newly diagnosed with glioma or meningioma. Controls were selected among patients who were admitted to the same hospitals for a variety of nonmalignant conditions and frequency matched to cases by hospital, age, sex, race, and distance from residence. The present analysis was restricted to non-Hispanic whites. DNA was extracted from blood samples collected from 354 glioma cases, 133 meningioma cases, and 495 control individuals. We evaluated nine SNPs in five IGF genes (IGF1, IGF1R, IGF2, IGF2R, and IGFBP3). The majority of the analyzed IGF SNPs did not display statistically significant associations with glioma or meningioma. For glioma, one IGF1R SNP (rs2272037) indicated a possible association. No indications of asso-ciation were seen for glioblastoma, but for low-grade gliomas, the odds ratio under a dominant model was 0.56 (95% confidence interval [CI], 0.35-0.90) for IGF1 rs6220, 2.98 (95% CI, 1.65-5.38) for IGF1R rs2272037, and 1.60 (95% CI, 0.90-2.83) for IGF1R rs2016347. Overall, our results do not provide strong evidence of associations of brain tumor risk with IGF polymorphic variants but identify several associations for glioma that warrant further examination in other, larger studies. C1 [Lonn, Stefan; Rothman, Nathaniel; Inskip, Peter D.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fine, Howard A.] NCI, Neurooncol Branch, Bethesda, MD 20892 USA. [Shapiro, William R.] St Josephs Hosp, Barrow Neurol Inst, Phoenix, AZ USA. [Selker, Robert G.] Western Penn Hosp, Pittsburgh, PA 15224 USA. [Black, Peter M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Loeffler, Jay S.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Hutchinson, Amy A.] NCI, Div Canc Epidemiol & Genet, Core Genotyping Facil, Adv Technol Ctr,SAIC Frederick Inc, Frederick, MD 21701 USA. RP Lonn, S (reprint author), NCI, Div Canc Epidemiol & Genet, Room 7053,6120 Execut Blvd, Bethesda, MD 20892 USA. EM Stefan.Lonn@ki.se FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. government. NR 20 TC 17 Z9 17 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD AUG PY 2008 VL 10 IS 4 BP 553 EP 559 DI 10.1215/15228517-2008-026 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 340XS UT WOS:000258678900004 PM 18562769 ER PT J AU Grossman, SA Carson, KA Phuphanich, S Batchelor, T Peereboom, D Nabors, LB Lesser, G Hausheer, F Supko, JG AF Grossman, Stuart A. Carson, Kathryn A. Phuphanich, Surasak Batchelor, Tracy Peereboom, David Nabors, L. Burt Lesser, Glenn Hausheer, Fredrick Supko, Jeffrey G. CA New Approaches Brain Tumor Therapy TI Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas SO NEURO-ONCOLOGY LA English DT Article DE brain cancer; cancer therapy; drug interactions; glioblastoma multiforme; karenitecin ID CEREBROSPINAL-FLUID PHARMACOKINETICS; IRINOTECAN CPT-11; NONHUMAN-PRIMATES; TOPOTECAN; PLASMA; TRIAL; CAMPTOTHECIN; GLIOBLASTOMA; CANCER; ADULTS AB Karenitecin is a highly lipophilic camptothecin analogue with a lactone ring that is relatively resistant to inactivating hydrolysis under physiologic conditions. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of karenitecin in adults with recurrent malignant glioma (MG), to describe the effects of enzyme-inducing antiseizure drugs (EIASDs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Karenitecin was administered intravenously over 60 min daily for 5 consecutive days every 3 weeks to adults with recurrent MG who had no more than one prior chemotherapy regimen. The continual reassessment method was used to escalate doses, beginning at 1.0 mg/m(2)/day, in patients stratified by EIASD use. Treatment was continued until disease progression or treatment-related dose-limiting toxicity (DLT). Plasma pharmacokinetics was determined for the first daily dose of karenitecin. Thirty-two patients (median age, 52 years; median KPS score, 90) were accrued. Seventy-eight percent had glioblastoma, and 22% had anaplastic glioma. DLT was reversible neutropenia or thrombocytopenia. The MTD was 2.0 mg/m(2) in +EIASD patients and 1.5 mg/m(2) in - EIASD patients. The mean (+/- SD) total body clearance of karenitecin was 15.9 +/- 9.6 liters/h/m(2) in +EIASD patients and 10.2 +/- 3.5 liters/h/m(2) in - EIASD patients (p = 0.02). No objective responses were observed in 11 patients treated at or above the MTD. The total body clearance of karenitecin is significantly enhanced by the concurrent administration of EIASDs. This schedule of karenitecin, a novel lipophilic camptothecin analogue, has little activity in recurrent MG. C1 [Grossman, Stuart A.] Johns Hopkins Univ, NABTT Cent Off, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Phuphanich, Surasak] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Batchelor, Tracy; Supko, Jeffrey G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Peereboom, David] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Nabors, L. Burt] Univ Alabama, Birmingham, AL USA. [Lesser, Glenn] Wake Forest Univ, Sch Med, Hematol & Oncol Med Ctr, Winston Salem, NC 27109 USA. [Hausheer, Fredrick] BioNumerik Pharmaceut Inc, San Antonio, TX USA. RP Grossman, SA (reprint author), Johns Hopkins Univ, NABTT Cent Off, Sidney Kimmel Comprehens Canc Ctr, 1550 Orleans St,CRB2-IM-16, Baltimore, MD 21231 USA. EM grossman@jhmi.edu FU National Cancer Institute [U01-CA62475, U01-CA105689, P30-CA0516]; National Institutes of Health; U.S. Department of Health and Human Services (Bethesda, MD, USA); BioNumerik Pharmaceuticals, Inc. (San Antonio, TX, USA) FX This study was supported by grants U01-CA62475, U01-CA105689, and P30-CA0516 from the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (Bethesda, MD, USA), and by BioNumerik Pharmaceuticals, Inc. (San Antonio, TX, USA). NR 32 TC 16 Z9 17 U1 0 U2 3 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD AUG PY 2008 VL 10 IS 4 BP 608 EP 616 DI 10.1215/15228517-2008-030 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 340XS UT WOS:000258678900011 PM 18577560 ER PT J AU Chang, SM Lamborn, KR Kuhn, JG Yung, WKA Gilbert, MR Wen, PY Fine, HA Mehta, MP DeAngelis, LM Lieberman, FS Cloughesy, TF Robins, HI Abrey, LE Prados, MD AF Chang, Susan M. Lamborn, Kathleen R. Kuhn, John G. Yung, W. K. Alfred Gilbert, Mark R. Wen, Patrick Y. Fine, Howard A. Mehta, Minesh P. DeAngelis, Lisa M. Lieberman, Frank S. Cloughesy, Timothy F. Robins, H. Ian Abrey, Lauren E. Prados, Michael D. CA N Amer Brain Tumor Consortium TI Neurooncology clinical trial design for targeted therapies: Lessons learned from the North American Brain Tumor Consortium SO NEURO-ONCOLOGY LA English DT Review DE brain tumor; clinical trials; North American Brain Tumor Consortium; targeted therapies ID RECURRENT MALIGNANT GLIOMA; PHASE-II TRIAL; GROWTH-FACTOR RECEPTOR; GLIOBLASTOMA-MULTIFORME; DRUG DEVELOPMENT; ANTIEPILEPTIC DRUGS; ANTICANCER THERAPY; IRINOTECAN CPT-11; TASK-FORCE; CANCER AB The North American Brain Tumor Consortium (NABTC) is a multi-institutional consortium with the primary objective of evaluating novel therapeutic strategies through early phase clinical trials. The NABTC has made substantial changes to the design and methodology of its trials since its inception in 1994. These changes reflect developments in technology, new types of therapies, and advances in our understanding of tumor biology and biological markers. We identify the challenges of early clinical assessment of therapeutic agents by reviewing the clinical trial effort of the NABTC and the evolution of the protocol template used to design trials. To better prioritize effort and allocation of patient resources and funding, we propose an integrated clinical trial design for the early assessment of efficacy of targeted therapies in neurooncology. This design would mandate tissue acquisition prior to therapeutic intervention with the drug, allowing prospective evaluation of its effects. It would also include a combined phase 0/I pharmacokinetic study to determine the safety and biologically optimal dose of the agent and to verify successful modulation of the target prior to initiating a larger, phase II efficacy study. C1 [Chang, Susan M.; Lamborn, Kathleen R.; Prados, Michael D.] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Kuhn, John G.] Univ Texas Hlth Sci Ctr San Antonio, Pharmacotherapy Educ & Res Ctr, San Antonio, TX 78229 USA. [Yung, W. K. Alfred; Gilbert, Mark R.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA. [Wen, Patrick Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Fine, Howard A.] NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. [Mehta, Minesh P.; Robins, H. Ian] Univ Wisconsin Hosp, Madison, WI USA. [DeAngelis, Lisa M.; Abrey, Lauren E.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Lieberman, Frank S.] Univ Pittsburgh, Med Ctr Canc Pavil, Div Neurooncol, Pittsburgh, PA USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, David Geffen Sch Med, Neurooncol Program, Los Angeles, CA 90095 USA. [Cloughesy, Timothy F.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. RP Chang, SM (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 400 Parnassus Ave,A-808, San Francisco, CA 94143 USA. EM changs@neurosurg.ucsf.edu RI Gilbert, Mark/J-7494-2016; OI Gilbert, Mark/0000-0003-2556-9722; mehta, minesh/0000-0002-4812-5713 FU NCATS NIH HHS [UL1 TR000005]; NCI NIH HHS [CA 105663-03, CA 16672, CA 62399, CA 62405, CA 62407-13, CA 62412, CA 62421, CA 62422, CA 62426, U01 CA062399]; NCRR NIH HHS [1U11RR025011, M01-RR00056, M01-RR00079, M01-RR0865] NR 45 TC 20 Z9 20 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD AUG PY 2008 VL 10 IS 4 BP 631 EP 642 DI 10.1215/15228517-2008-021 PG 12 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 340XS UT WOS:000258678900014 PM 18559968 ER PT J AU Moran, EK Becker, JA Satlin, A Lyoo, IK Fischman, AJ Johnson, KA AF Moran, E. K. Becker, J. A. Satlin, A. Lyoo, In Kyoon Fischman, A. J. Johnson, K. A. TI Psychosis of Alzheimer's disease: Gender differences in regional perfusion SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer's disease; psychosis; SPECT; PET ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; NEUROPSYCHIATRIC SYMPTOMS; AGGRESSIVE-BEHAVIOR; GLUCOSE-METABOLISM; SPECT; DELUSIONS; DEMENTIA; BURDEN; APATHY AB We sought to determine whether the presence of psychotic symptoms in patients with Alzheimer's disease is associated with abnormal regional cerebral function. Perfusion single photon emission computed tomography images from 51 AD patients with psychotic symptoms were compared to images of 52 AD patients without such symptoms. Group comparisons were made with a voxel-based method, Statistical Parametric Mapping. We found that perfusion was lower in female patients with psychotic symptoms in right infero-lateral prefrontal cortex and in inferior temporal regions compared to female patients without such symptoms. In contrast, perfusion was higher in male patients with psychotic symptoms in the right striatum compared to male patients without such symptoms. Comparison groups did not differ in age or in dementia severity, as estimated by the Mini-Mental State Examination (MMSE). These results support the role of right hemisphere prefrontal and lateral temporal cortex in the psychosis of AD in women but not in men, and raise the possibility that these dysfunctional processes have a gender-specific regional pathophysiology in AD. (c) 2007 Elsevier Inc. All rights reserved. C1 [Moran, E. K.; Becker, J. A.; Fischman, A. J.; Johnson, K. A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Satlin, A.; Lyoo, In Kyoon] Harvard Univ, McLean Hosp, Dept Psychiat, Belmont, MA 02178 USA. [Satlin, A.] Novartis Pharmaceut, E Hanover, NJ USA. [Satlin, A.; Fischman, A. J.; Johnson, K. A.] Harvard Univ, Sch Med, Boston, MA USA. [Johnson, K. A.] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Johnson, KA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 55 Fruit St,Tilton 201, Boston, MA 02114 USA. EM kajohnson@partners.org NR 46 TC 16 Z9 17 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD AUG PY 2008 VL 29 IS 8 BP 1218 EP 1225 DI 10.1016/j.neurobiolaging.2007.02.024 PG 8 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 321KF UT WOS:000257302900012 PM 17408808 ER PT J AU Ottowitz, WE Derro, D Dougherty, DD Lindquist, MA Fischman, AJ Hall, JE AF Ottowitz, William E. Derro, David Dougherty, Darin D. Lindquist, Martin A. Fischman, Alan J. Hall, Janet E. TI FDG-PET analysis of amygdalar-cortical network covariance during pre- versus post-menopausal estrogen levels: Potential relevance to resting state networks, mood, and cognition SO NEUROENDOCRINOLOGY LETTERS LA English DT Article DE estradiol; functional connectivity; temporal cortex; prefrontal cortex; amygdala; neurophysiology; functional neuroimaging; depression; working memory ID POSITRON-EMISSION-TOMOGRAPHY; SHORT-TERM-MEMORY; MEDIAL AMYGDALA; WORKING-MEMORY; PREFRONTAL CORTEX; MENSTRUAL-CYCLE; RECEPTOR-ALPHA; MESSENGER-RNA; BRAIN; WOMEN AB OBJECTIVES: 1.) Expand the scope of neuroendocrine applications of functional neuroimaging techniques. 2.) Compare the covariance of amygdalar activity with that of the rest of the brain during pre- and post-menopausal levels of estrogen (E2). Based on the distribution of cortical E2 receptors and the neocortical regions where E2 has been shown to preferentially accumulate, we predict that E2 infusion will increase covariance of amygdalar activity with that of the temporal and frontal cortices. DESIGN: This basic physiology study employed a within-subject design. All participants were post-menopausal women (n = 7). Analysis of covariance between whole brain and amygdalar regional cerebral glucose consumption (CMRglc) was conducted in a voxel-wise manner by means of the basic regression option in SPM2 and was applied to FDG-PET scans acquired at baseline and after a 24 hour graded E2 infusion. SETTING: an academic medical center; Massachusetts General Hospital, Boston, Massachusetts. RESULTS: E2 levels (mean +/- sem) were significantly greater at 24 hours (257.9 pg/mL +/- 29.7) than at 0 hours (28.1 pg/mL +/- 3.4). Right amygdalar CMRglc showed a significant covariance with activity of three different regions of the temporal cortex during E2 infusion, but none at baseline. In addition, right amygdalar CMRglc covaried with that of the right medial and superior frontal gyri only during E2 infusion. CONCLUSIONS: In addition to suggesting changes in amygdalar-cortical network connectivity as a result of short-term E2 exposure, these analyses provide evidence that basic neuroendocrine research may benefit from further use of FDG-PET and other functional neuroimaging modalities for network level analyses. C1 [Ottowitz, William E.] Columbia Univ, Grad Sch Arts & Sci, Dept Stat, New York, NY 10027 USA. [Derro, David; Dougherty, Darin D.] Massachusetts Gen Hosp, Psychiat Neurosci Program, Charlestown, MA USA. [Lindquist, Martin A.] Columbia Univ, Dept Stat, New York, NY USA. [Fischman, Alan J.] Massachusetts Gen Hosp, Div Nucl Med, Boston, MA 02114 USA. [Hall, Janet E.] Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. RP Ottowitz, WE (reprint author), Columbia Univ, Grad Sch Arts & Sci, Dept Stat, Room 1005,MC 4690,1255 Amsterdam Ave, New York, NY 10027 USA. EM weo2101@columbia.edu FU NIH [R01 AG13241, K24HD01290, M01 RR01066] FX The authors gratefully acknowledge support from NIH Grants R01 AG13241, K24HD01290 and M01 RR01066. The authors also thank Mariko Jameson for her technical assistance. NR 51 TC 6 Z9 7 U1 1 U2 3 PU MAGHIRA & MAAS PUBLICATIONS PI STOCKHOLM PA PO BOX 26132, S-100 41 STOCKHOLM, SWEDEN SN 0172-780X J9 NEUROENDOCRINOL LETT JI Neuroendocrinol. Lett. PD AUG PY 2008 VL 29 IS 4 BP 467 EP 474 PG 8 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 356JJ UT WOS:000259774200015 PM 18766152 ER PT J AU Napadow, V Dhond, R Conti, G Makris, N Brown, EN Barbieri, R AF Napadow, Vitaly Dhond, Rupali Conti, Giulia Makris, Nikos Brown, Emery N. Barbieri, Riccardo TI Brain correlates of autonomic modulation: Combining heart rate variability with fMRI SO NEUROIMAGE LA English DT Article DE HF; HRV; cardiovagal; exercise; handgrip ID PREFRONTAL CORTICAL PROJECTIONS; FUNCTIONAL-ORGANIZATION; PERIAQUEDUCTAL GRAY; CINGULATE CORTEX; MACAQUE MONKEYS; CENTRAL COMMAND; NERVOUS-SYSTEM; INSULAR CORTEX; HUMANS; STIMULATION AB The central autonomic network (CAN) has been described in animal models but has been difficult to elucidate in humans. Potential confounds include physiological noise artifacts affecting brainstem neuroirnaging data, and difficulty in deriving non-invasive continuous assessments of autonomic modulation. We have developed and implemented a new method which relates cardiac-gated fMRI timeseries with continuous-time heart rate variability (HRV) to estimate central autonomic processing. As many autonomic structures of interest are in brain regions strongly affected by cardiogenic pulsatility, we chose to cardiac-gate our fMRI acquisition to increase sensitivity. Cardiac-gating introduces T1-variability, which was corrected by transforming fMRI data to a fixed TR using a previously published method [Guimaraes, A.R., Melcher, J.R., et al., 1998. Imaging subcortical auditory activity in humans. Hum. Brain Mapp. 6(l), 33-41]. The electrocardiogram was analyzed with a novel point process adaptive-filter algorithm for computation of the high-frequency (HF) index, reflecting the time-varying dynamics of efferent cardiovagal modulation. Central command of cardiovagal outflow was inferred by using the resample HF timeseries as a regressor to the tMRI data. A grip task was used to perturb the autonomic nervous system. Our combined HRV-fMRI approach demonstrated HF correlation with fMRI activity in the hypothalamus, cerebellum, parabrachial nucleus/locus ceruleus, peri-aqueductal gray, amygdala, hippocampus, thalamus, and dorsomedial/dorsolateral prefrontal, posterior insular, and middle temporal cortices. While some regions consistent with central cardiovagal control in animal models gave corroborative evidence for our methodology, other mostly higher cortical or limbic-related brain regions may be unique to humans. Our approach should be optimized and applied to study the human brain correlates of autonomic modulation for various stimuli in both physiological and pathological states. (C) 2008 Elsevier Inc. All rights reserved. C1 [Napadow, Vitaly; Dhond, Rupali] Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, MGH MIT HMS, Charlestown, MA 02119 USA. [Napadow, Vitaly; Dhond, Rupali] Logan Coll Chiropract, Dept Radiol, Chesterfield, MO USA. [Conti, Giulia; Brown, Emery N.; Barbieri, Riccardo] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Conti, Giulia; Brown, Emery N.; Barbieri, Riccardo] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Makris, Nikos] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02119 USA. [Conti, Giulia] Politecn Milan, Dept Biomed Engn, I-20133 Milan, Italy. RP Napadow, V (reprint author), Massachusetts Gen Hosp, Dept Radiol, Martinos Ctr Biomed Imaging, MGH MIT HMS, 149 13th St,Rm 2301, Charlestown, MA 02119 USA. EM vitaly@nmr.mgh.harvard.edu RI Frank, David/E-8213-2012; OI Barbieri, Riccardo/0000-0001-9381-3833 FU NCCIH NIH HHS [K01 AT002166, K01 AT002166-02, K01 AT002166-03, K01 AT002166-04, K01 AT002166-05, K01 AT004481, P01 AT002048, P01-AT002048]; NCRR NIH HHS [P41 RR014075, P41 RR014075-08, P41RR14075]; NHLBI NIH HHS [R01-HL084502, R01 HL084502, R01 HL084502-01A1, R01 HL084502-02]; NIBIB NIH HHS [R01 EB000522, R01 EB000522-03, R01 EB006385, R01 EB006385-01A1]; NIDA NIH HHS [R01 DA015644, R01-DA015644]; NIH HHS [DP1 OD003646, DP1 OD003646-01] NR 70 TC 130 Z9 131 U1 4 U2 25 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 AUG 1 PY 2008 VL 42 IS 1 BP 169 EP 177 DI 10.1016/j.neuroimage.2008.04.238 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 332TC UT WOS:000258105000018 PM 18524629 ER PT J AU Lin, FH Witzel, T Mandeville, JB Polimeni, JR Zeffiro, TA Greve, DN Wiggins, G Wald, LL Belliveau, JW AF Lin, Fa-Hsuan Witzel, Thomas Mandeville, Joseph B. Polimeni, Jonathan R. Zeffiro, Thomas A. Greve, Douglas N. Wiggins, Graham Wald, Lawrence L. Belliveau, John W. TI Event-related single-shot volumetric functional magnetic resonance inverse imaging of visual processing SO NEUROIMAGE LA English DT Article DE event-related; fMRI; inverse imaging; InI; visual; MRI; neuroiniaging ID SURFACE-BASED ANALYSIS; HUMAN BRAIN ACTIVITY; TO-NOISE RATIO; DISTORTION CORRECTION; BLOOD OXYGENATION; STEADY-STATE; IN-VIVO; MRI; SENSE; ACQUISITION AB Developments in multi-channel radio-frequency (RF) coil array technology have enabled functional magnetic resonance imaging (fMRI) with higher degrees of spatial and temporal resolution. While modest improvement in temporal acceleration has been achieved by increasing the number of RF coils, the maximum attainable acceleration in parallel MRI acqisition is intrinsically limited only by the amount of independent spatial information in the combined array channels. Since the geometric configuration of a large-n MRI head coil array is similar to that used in EEG electrode or MEG SQUID sensor arrays, the source localization algorithms used in MEG or EEG source imaging can be extended to also process MRI coil array data, resulting in greatly improved temporal resolution by minimizing k-space traversal during signal acquisition. Using a novel approach, we acquire multi-channel MRI head coil array data and then apply inverse reconstruction methods to obtain volumetric fMRI estimates of blood oxygenation level dependent (BOLD) contrast at unprecedented whole-brain acquisition rates of 100 ms. We call this combination of techniques magnetic resonance Inverse Imaging (10), a method that provides estimates of dynamic spatially-resolved signal change that can be used to construct statistical maps of task-related brain activity. We demonstrate the sensitivity and inter-subject reliability of volumetric InI using an event-related design to probe the hemodynamic signal modulations in primary visual cortex. Robust results from both single subject and group analyses demonstrate the sensitivity and feasibility of using volumetric InI in high temporal resolution investigations of human brain function. (C) 2008 Elsevier Inc. All rights reserved. C1 [Lin, Fa-Hsuan] Natl Taiwan Univ, Inst Biomed Engn, Taipei 10764, Taiwan. [Witzel, Thomas] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Zeffiro, Thomas A.] Massachusetts Gen Hosp, Neural Syst Grp, Charlestown, MA USA. [Lin, Fa-Hsuan; Mandeville, Joseph B.; Polimeni, Jonathan R.; Greve, Douglas N.; Wiggins, Graham; Wald, Lawrence L.; Belliveau, John W.] MGH HST Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. RP Lin, FH (reprint author), MGH HST Athinoula A Martinos Ctr, Room 2301,Bldg 149,13th St, Charlestown, MA 02129 USA. EM fhlin@nmr.mgh.harvard.edu RI Lin, Fa-Hsuan/G-6988-2012; Witzel, Thomas/P-1402-2014; Polimeni, Jonathan/P-1395-2014; Wald, Lawrence/D-4151-2009 OI Lin, Fa-Hsuan/0000-0002-9539-1731; Polimeni, Jonathan/0000-0002-1348-1179; FU NCRR NIH HHS [P41 RR014075, P41 RR014075-04, P41 RR14075]; NIBIB NIH HHS [R01 EB006847, R01 EB006847-01A2, R01 EB006847-02, R01 EB006847-02S1, T32 EB001680]; NICHD NIH HHS [R01 HD040712]; NINDS NIH HHS [R01 NS037462] NR 70 TC 34 Z9 34 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2008 VL 42 IS 1 BP 230 EP 247 DI 10.1016/j.neuroimage.2008.04.179 PG 18 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 332TC UT WOS:000258105000023 PM 18538587 ER PT J AU Sanchez-Pernaute, R Wang, JQ Kuruppu, D Cao, L Tueckmantel, W Kozikowski, A Isacson, O Brownell, AL AF Sanchez-Pernaute, R. Wang, J. -Q. Kuruppu, D. Cao, L. Tueckmantel, W. Kozikowski, A. Isacson, O. Brownell, A. -L. TI Enhanced binding of metabotropic glutamate receptor type 5 (mGluR5) PET tracers in the brain of parkinsonian primates SO NEUROIMAGE LA English DT Article ID DOPA-INDUCED DYSKINESIA; RAT MODEL; DISEASE; ANTAGONISM; MODULATION; BLOCKADE; LOOP AB The interplay between dopamine and glutamate in the basal ganglia regulates critical aspects of motor learning and behavior. Metabotropic glutamate receptors (mGluR) are increasingly regarded as key modulators of neuroadaptation in these circuits, in normal and disease conditions. Using PET, we demonstrate a significant upregulation of mGluR type 5 in the striatum of MPTP-lesioned, parkinsonian primates' providing the basis for therapeutic exploration of mGluR5 antagonists in Parkinson disease. (C) 2008 Elsevier Inc. All rights reserved. C1 [Wang, J. -Q.; Kuruppu, D.; Cao, L.; Brownell, A. -L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Sanchez-Pernaute, R.; Isacson, O.; Brownell, A. -L.] Harvard Univ, McLean Hosp, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02178 USA. [Sanchez-Pernaute, R.; Isacson, O.] McLean Hosp, Neuroregenerat Labs, Belmont, MA 02178 USA. [Tueckmantel, W.; Kozikowski, A.] Acenta Discovery Inc, Tucson, AZ USA. RP Brownell, AL (reprint author), Massachusetts Gen Hosp, Bartlett Hall 504R, Boston, MA 02114 USA. EM abrownell@partners.org RI Cao, Lei/B-3254-2012 OI Cao, Lei/0000-0003-4018-9496 FU NIBIB NIH HHS [1R01 EB001850, R01 EB001850, R01 EB001850-04, R01 EB012864]; NIMH NIH HHS [R01 MH091684]; NINDS NIH HHS [1P50 NS39793, P50 NS039793, P50 NS039793-059001, P50 NS039793-08] NR 20 TC 26 Z9 26 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2008 VL 42 IS 1 BP 248 EP 251 DI 10.1016/j.neuroimage.2008.04.170 PG 4 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 332TC UT WOS:000258105000024 PM 18501638 ER PT J AU Loevner, LA Kaplan, SL Cunnane, ME Moonis, G AF Loevner, Laurie A. Kaplan, Summer L. Cunnane, Mary Elizabeth Moonis, Gul TI Cross-sectional imaging of the thyroid gland SO NEUROIMAGING CLINICS OF NORTH AMERICA LA English DT Article DE thyroid gland; ultrasound; CT; MRI; radioablation; thyroid surgery; parathyroid localization; parathyroid surgery; sestamibi; radionuclides ID SOMATOSTATIN RECEPTOR SCINTIGRAPHY; POSITRON-EMISSION-TOMOGRAPHY; NEEDLE-ASPIRATION BIOPSY; SOLITARY COLD NODULES; PAPILLARY CARCINOMA; MEDULLARY CARCINOMA; MAGNETIC-RESONANCE; FOLLOW-UP; RADIOACTIVE IODINE; FOLLICULAR VARIANT AB Directed imaging is useful in assessing the thyroid gland. Nuclear scintigraphy reveals functional information about the thyroid gland, while cross-sectional imaging, including ultrasound, CT, and MR imaging provide important adjunctive anatomic information about the thyroid as well as about related structures in the neck, including the presence or absence of cervical and mediastinal lymphadenopathy, or extension of thyroid disease into adjacent soft tissues or the mediastinum. This article reviews the anatomy and physiology of the thyroid gland and addresses issues related to diseases affecting the thyroid gland, with an emphasis on neoplasms and the role of cross-sectional MR and CT imaging in the assessment of thyroid neoplasia. C1 [Loevner, Laurie A.] Hosp Univ Penn, Dept Radiol, Neuroradiol Div, Med Ctr, Philadelphia, PA 19104 USA. [Loevner, Laurie A.; Kaplan, Summer L.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Cunnane, Mary Elizabeth] Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Moonis, Gul] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. RP Loevner, LA (reprint author), Hosp Univ Penn, Dept Radiol, Neuroradiol Div, Med Ctr, 3400 Spruce St,2nd Floor Dulles,Suite 219, Philadelphia, PA 19104 USA. EM laurie.loevner@uphs.upenn.edu NR 89 TC 22 Z9 22 U1 2 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1052-5149 EI 1557-9867 J9 NEUROIMAG CLIN N AM JI Neuroimaging Clin. N. Am. PD AUG PY 2008 VL 18 IS 3 BP 445 EP 461 DI 10.1016/j.nic.2008.05.001 PG 17 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 340UP UT WOS:000258670800003 PM 18656027 ER PT J AU Davis, LE Beckham, JD Tyler, KL AF Davis, Larry E. Beckham, J. David Tyler, Kenneth L. TI North American encephalitic arboviruses SO NEUROLOGIC CLINICS LA English DT Review ID WEST-NILE-VIRUS; ST-LOUIS ENCEPHALITIS; EASTERN EQUINE ENCEPHALITIS; COLORADO TICK FEVER; CD8(+) T-CELLS; CULEX-PIPIENS-QUINQUEFASCIATUS; LINKED-IMMUNOSORBENT-ASSAY; IMMUNOGLOBULIN-M ANTIBODY; MR-IMAGING FINDINGS; NEW-YORK-CITY AB Arboviruses continue to be a major cause of encephalitis in North America, and West Nile virus neuroinvasive disease is now the dominant cause of encephalitis. Transmission to humans of North American arboviruses occurs by infected mosquitoes or ticks. Most infections are asymptomatic or produce a flulike illness. Rapid serum or cerebrospinal fluid IgM antibody capture ELISA assays are available to diagnosis the acute infection for all North American arboviruses. Unfortunately, no antiviral drugs are approved for the treatment of arbovirus infection and current therapy is supportive. C1 [Davis, Larry E.] New Mexico Vet Affairs Hlth Care Syst, Albuquerque, NM 87108 USA. [Davis, Larry E.] Univ New Mexico, Sch Med, Dept Neurol, Albuquerque, NM 87131 USA. [Beckham, J. David] Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA. [Beckham, J. David; Tyler, Kenneth L.] Denver Vet Affairs Med Ctr, Denver, CO USA. [Tyler, Kenneth L.] Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA. RP Davis, LE (reprint author), New Mexico Vet Affairs Hlth Care Syst, 1500 San Pedro Dr SE, Albuquerque, NM 87108 USA. EM ledavis@unm.edu OI Tyler, Kenneth/0000-0003-3294-5888 FU NIAID NIH HHS [T32 AI007537, T32AI07537]; NINDS NIH HHS [R01 NS051403-04, R01 NS050138, R01 NS050138-04, R01 NS050138-05, R01 NS050138-05S1, R01 NS051403] NR 115 TC 14 Z9 14 U1 1 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 0733-8619 J9 NEUROL CLIN JI Neurol. Clin. PD AUG PY 2008 VL 26 IS 3 BP 727 EP + DI 10.1016/j.ncl.2008.03.012 PG 32 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 344EX UT WOS:000258910500008 PM 18657724 ER PT J AU Zhang, XY Zhou, DF Wu, GY Cao, LY Tan, YL Haile, CN Li, J Lu, L Kosten, TA Kosten, TR AF Zhang, Xiang Yang Zhou, Dong Feng Wu, Gui Ying Cao, Lian Yuan Tan, Yun Long Haile, Colin N. Li, Jun Lu, Lin Kosten, Therese A. Kosten, Thomas R. TI BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE schizophrenia; antipsychotic; weight gain; BDNF; genotype; association ID NEUROTROPHIC FACTOR; ATYPICAL ANTIPSYCHOTICS; MELANOCORTIN-4 RECEPTOR; GENE POLYMORPHISM; ENERGY-BALANCE; DIABETIC MICE; RAT-BRAIN; OBESITY; PHARMACOGENETICS; MANAGEMENT AB Recent evidence suggests that centrally released brain-derived neurotrophic factor ( BDNF) modulates eating behavior and metabolism that is responsible for body weight fluctuation. BDNF also may play an important role in the therapeutic action of antipsychotic medications. We investigated whether the Val66Met polymorphism of the BDNF gene affected weight gain after long-term antipsychotic treatment in schizophrenia. The polymorphism was genotyped in 196 Chinese patients with schizophrenia on long-term antipsychotic medication. Serum BDNF was measured in all patients and 50 normal controls. Mean body mass index (BMI) change was evaluated retrospectively by means of clinical records. The results showed that there was a significant relationship between the three BDNF Val/Met genotypes and mean BMI gain, with genotype having a strong effect on BMI gain in male but not female patients. BDNF levels were significantly lower in patients than normal controls, and negatively correlated with BMI gain in female but not male patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment, and decreased BDNF levels may be associated with weight gain in females. C1 [Zhang, Xiang Yang] Baylor Coll Med, VA Med Ctr, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Zhang, Xiang Yang; Zhou, Dong Feng] Peking Univ, Inst Mental Hlth, Beijing 100083, Peoples R China. [Zhang, Xiang Yang; Wu, Gui Ying; Cao, Lian Yuan; Tan, Yun Long] Beijing HuiLongGuan Hosp, Ctr Biol Psychiat, Beijing, Peoples R China. [Li, Jun] Anhui Med Univ, Coll Pharmacol, Hefei, Anhui, Peoples R China. [Lu, Lin] Natl Inst Drug Dependence, Beijing, Peoples R China. RP Zhang, XY (reprint author), Baylor Coll Med, VA Med Ctr, Menninger Dept Psychiat & Behav Sci, Res Bldg 109,Room 130,2002 Holcombe Blvd, Houston, TX 77030 USA. EM xyzhang@bcm.edu; zhoudf@bjmu.edu.cn OI Haile, Colin/0000-0001-8293-7291 FU NIDA NIH HHS [P50-DA18827, K05-DA0454] NR 33 TC 49 Z9 53 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2008 VL 33 IS 9 BP 2200 EP 2205 DI 10.1038/sj.npp.1301619 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 325XN UT WOS:000257622200015 PM 17987059 ER PT J AU de Nigris, F Mancini, FP Balestrieri, ML Byrns, R Fiorito, C Williams-Ignarro, S Palagiano, A Crimi, E Ignarro, LJ Napoli, C AF de Nigris, Filomena Mancini, Francesco Paolo Balestrieri, Maria Luisa Byrns, Russell Fiorito, Carmela Williams-Ignarro, Sharon Palagiano, Antonio Crimi, Ettore Ignarro, Louis J. Napoli, Claudio TI Therapeutic dose of nebivolol, a nitric oxide-releasing beta-blocker, reduces atherosclerosis in cholesterol-fed rabbits SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article; Proceedings Paper CT 76th Congress of the European-Atherosclerosis-Society/15th Paavo Nurmi Symposium CY JUN 10-13, 2007 CL Univ Helsinki, Helsinki, FINLAND SP European Atheroscleros Soc HO Univ Helsinki DE nitric oxide; carvedilol; nebivolol; atherosclerosis; rabbit ID LOW-DENSITY-LIPOPROTEIN; RECEPTOR-DEFICIENT RABBITS; VASCULAR SMOOTH-MUSCLE; FREE-RADICAL SCAVENGER; CORONARY FLOW RESERVE; HEART-FAILURE SENIORS; ENDOTHELIAL-CELLS; MATERNAL HYPERCHOLESTEROLEMIA; OXIDATIVE INACTIVATION; ANTIHYPERTENSIVE AGENT AB Nitric oxide (NO) exerts a plethora of vascular beneficial effects. The NO-releasing beta-blocker nebivolol is a racemic mixture Of D/L-enantiomers that displays negative inotropic as well as direct vasodilating activity. The in vivo antiatherogenic activity of therapeutic doses of the beta-blocker with antioxidant properties carvedilol (12.5 mg/day) or nebivolol (5 mg/day) was tested in cholesterol-fed rabbits. Animals received a 1% cholesterol-rich diet alone (controls) or mixed with drugs (treated animals) for 8 weeks. While it did not affect hyperlipidemia, nebivolol inhibited the development of atherosclerosis, expressed as computer-assisted imaging analysis of aortic area covered by lesions (23.3 +/- 4.1 % in treated vs 38.2 +/- 6.4% in control animals, p < 0.01). Differently, in our experimental condition of therapeutic drug doses, this antiatherogenic effect did not reach statistical significance in rabbits treated with carvedilol (32.5 +/- 5.1% aortic area covered by lesions, p = NS vs controls). Plasma nitrates increased in rabbits treated with nebivolol while both beta-blockers reduced LDL oxidation. Moreover, nebivolol induced a consistent increase of endothelial reactivity and aortic eNOS expression compared with control animals (p < 0.05) and those receiving carvedilol (p < 0.05). Since NO may exert beneficial effects in atherosclerosis, a NO-dependent mechanism could explain this data. These observations suggest that the NO-releasing beta-blocker, nebivolol, might represent an effective pharmacological approach for preventing atherosclerotic lesion progression. (c) 2008 Elsevier Inc. All rights reserved. C1 [de Nigris, Filomena; Fiorito, Carmela; Napoli, Claudio] Univ Naples 2, Sch Med 1, Excellence Res Ctr Cardiovasc Dis, Dept Gen Pathol, I-80138 Naples, Italy. [Balestrieri, Maria Luisa] Univ Naples 2, Sch Med 1, Dept Biochem & Biophys, I-80138 Naples, Italy. [Palagiano, Antonio] Univ Naples 2, Sch Med 1, Dept Obstet & Gynecol, I-80138 Naples, Italy. [Mancini, Francesco Paolo] Univ Sannio, Dept Biol & Environm Sci, Benevento, Italy. [Byrns, Russell; Ignarro, Louis J.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Fiorito, Carmela] IRCCS Multimed, I-20138 Milan, Italy. [Williams-Ignarro, Sharon] Univ Calif Los Angeles, Div Anesthesiol, Los Angeles, CA 90095 USA. [Williams-Ignarro, Sharon] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Crimi, Ettore] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02138 USA. RP Napoli, C (reprint author), Univ Naples 2, Sch Med 1, Excellence Res Ctr Cardiovasc Dis, Dept Gen Pathol, Complesso S Andrea Dame,Via Crecchio 7, I-80138 Naples, Italy. EM claunap@tin.it OI de nigris, filomena/0000-0002-2322-1557; Napoli, Claudio/0000-0002-5455-555X NR 52 TC 28 Z9 29 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD AUG PY 2008 VL 19 IS 1 BP 57 EP 63 DI 10.1016/j.niox.2008.03.004 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 322HI UT WOS:000257365400008 PM 18435936 ER PT J AU Li, D Ambrogio, L Shimamura, T Kubo, S Takahashi, M Chirieac, LR Padera, RF Shapiro, GI Baum, A Himmelsbach, F Rettig, WJ Meyerson, M Solca, F Greulich, H Wong, KK AF Li, D. Ambrogio, L. Shimamura, T. Kubo, S. Takahashi, M. Chirieac, L. R. Padera, R. F. Shapiro, G. I. Baum, A. Himmelsbach, F. Rettig, W. J. Meyerson, M. Solca, F. Greulich, H. Wong, K-K TI BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models SO ONCOGENE LA English DT Article DE EGFR; HER2; lung cancer; BIBW2992; therapeutics ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITORS; EGF RECEPTOR; ACQUIRED-RESISTANCE; GEFITINIB; MUTATIONS; SENSITIVITY; ERLOTINIB; DOMAIN; ADENOCARCINOMAS AB Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to first generation EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes. C1 [Solca, F.] Boehringer Ingelheim Austria, Dept Pharmacol, Vienna, Austria. [Li, D.; Ambrogio, L.; Shimamura, T.; Shapiro, G. I.; Meyerson, M.; Greulich, H.; Wong, K-K] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Li, D.] Harvard Univ, Ctr Canc, Ludwig Ctr, Boston, MA 02115 USA. [Ambrogio, L.; Meyerson, M.; Greulich, H.] Broad Inst Harvard, Cambridge, MA USA. [Ambrogio, L.; Meyerson, M.; Greulich, H.] MIT, Cambridge, MA 02139 USA. [Shimamura, T.; Shapiro, G. I.; Meyerson, M.; Greulich, H.; Wong, K-K] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Shimamura, T.; Shapiro, G. I.; Meyerson, M.; Greulich, H.; Wong, K-K] Harvard Univ, Sch Med, Boston, MA USA. [Kubo, S.; Takahashi, M.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Chirieac, L. R.; Padera, R. F.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Himmelsbach, F.] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. RP Solca, F (reprint author), Boehringer Ingelheim Austria, Dept Pharmacol, Dr Boehringer Gasse 5-11, Vienna, Austria. EM flavio.solca@vie.boehringer-ingelheim.com RI Meyerson, Matthew/E-7123-2012 FU NCI NIH HHS [P20 CA090578, P20 CA90578, P50 CA090578, P50 CA090578-06, R01 CA090687, R01 CA122794, R01 CA122794-04, R01 CA90687]; NIA NIH HHS [K08 AG024004, R01 AG027757, R01 AG027757-03, R01 AG2400401] NR 37 TC 571 Z9 593 U1 8 U2 60 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 PY 2008 VL 27 IS 34 BP 4702 EP 4711 DI 10.1038/onc.2008.109 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 334QM UT WOS:000258236300008 PM 18408761 ER PT J AU Nguyen, PL D'Amico, AV AF Nguyen, Paul L. D'Amico, Anthony V. TI Possible selection bias and lack of mortality endpoints prevent conclusions about new standards of care - The Bittner/Merrick/Wallner et al article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID CANCER-SPECIFIC MORTALITY; CONFORMAL RADIATION-THERAPY; RANDOMIZED CONTROLLED-TRIAL; ADVANCED PROSTATE-CANCER; RADICAL PROSTATECTOMY; ANDROGEN SUPPRESSION; DOSE-ESCALATION; RADIOTHERAPY; DEPRIVATION; RISK C1 [D'Amico, Anthony V.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD AUG PY 2008 VL 22 IS 9 BP 1012 EP + PG 2 WC Oncology SC Oncology GA 342WX UT WOS:000258815400005 ER PT J AU Haddad, R Crum, C Chen, ZG Krane, J Posner, M Li, Y Burk, R AF Haddad, Robert Crum, Christopher Chen, Zigui Krane, Jeffrey Posner, Marshall Li, Yi Burk, Robert TI HPV16 transmission between a couple with HPV-related head and neck cancer SO ORAL ONCOLOGY LA English DT Article DE human papillomavirus 16; head and neck cancer ID HUMAN-PAPILLOMAVIRUS TYPES; SQUAMOUS-CELL CARCINOMA; CERVICAL-CANCER; TONSILLAR; TYPE-16; RISK; CLASSIFICATION; INFECTION; LINEAGES; SUBSET AB Although squamous cell carcinoma of the head and neck (SCCHN) is closely linked to tobacco and alcohol. use, there is an increasing incidence HPV16-related SCCHN arising in the oropharynx. The mechanisms of viral transmission, carcinogenesis and natural history are not welt understood. Here, we report a couple-husband and wife diagnosed synchronously with squamous cell carcinoma of the head and neck wherein the tumors were positive for HPV16 by PCR diagnosis. Both viral genomes were genetically identical and closely related to the revised European prototype, HPV16R. An uncommon signal variant nucleotide was identified in both genomes that is not present in the HPV16R. These tumors likely represent transmission between the couple. (c) 2007 Elsevier Ltd. All rights reserved. C1 [Haddad, Robert; Posner, Marshall] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Crum, Christopher; Krane, Jeffrey] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Chen, Zigui; Burk, Robert] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. [Li, Yi] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Haddad, R (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM Robert_haddad@dfci.harvard.edu RI Chen, Zigui/E-8490-2017 NR 21 TC 23 Z9 23 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD AUG PY 2008 VL 44 IS 8 BP 812 EP 815 DI 10.1016/j.oraloncology.2007.09.004 PG 4 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 340MK UT WOS:000258649500013 PM 18061523 ER PT J AU Bahmad, F O'Malley, J Tranebjaerg, L Merchant, SN AF Bahmad, Fayez O'Malley, Jennifer Tranebjaerg, Lisbeth Merchant, Saumil N. TI Histopathology of nonsyndromic autosomal dominant midfrequency sensorineural hearing loss SO OTOLOGY & NEUROTOLOGY LA English DT Article DE sensorineural hearing loss; temporal bone histopathology; genetic deafness ID MID-FREQUENCY; IMPAIRMENT; MUTATIONS; DEAFNESS; PHENOTYPE; DFNA13; LOCUS AB Background: Autosomal dominant, nonsyndromic, midfrequency sensorineural hearing loss (SNHL) is a well-known clinical entity. There are no reported histopathologic studies of temporal bones from individuals with such a hearing loss. Objectives: To describe the otopathology in 2 affected individuals from 2 different kindreds with nonsyndromic, dominant, midfrequency SNHL. Material and Methods: Both subjects belonged to multigenerational families with nonsyndromic, autosomal dominant SNHL showing a cookie-bite pattern. Temporal bones were removed at autopsy and studied by light microscopy. Cytocochleograms were constructed for hair cells, stria vascularis, and cochlear neuronal cells. Results: Subject 1 (a 77-yr-old man) from Kindred A was diagnosed in early childhood with an SNHL that was progressive, reaching profound levels by adulthood. Both cochleae showed complete loss of inner and outer hair cells, moderate to severe diffuse atrophy of the stria vascularis, and severe loss of cochlear neurons, including the peripheral dendrites. The hearing loss in Subject 2 (an 82-yr-old man from Kindred B) began in late childhood, was slowly progressive, and involved the higher frequencies later in life. Histopathology showed loss of outer and inner hair cells in the basal turn of the cochlea, moderate to severe loss of stria vascularis, but relative preservation of peripheral dendrites and cochlear neurons. Conclusion: The main histopathologic abnormalities were loss of hair cells, stria vascularis, and cochlear neurons in I case and loss of hair cells and stria vascularis in the second case. Our results are consistent with the hypothesis that dysfunction and loss of hair cells may have been the primary histopathologic correlate for the midfrequency hearing losses in these 2 subjects. C1 [Bahmad, Fayez; O'Malley, Jennifer; Merchant, Saumil N.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. [Bahmad, Fayez; Merchant, Saumil N.] Harvard Univ, Dept Otol & Laryngol, Sch Med, Boston, MA 02114 USA. [Tranebjaerg, Lisbeth] Univ Copenhagen, Panum Inst, Dept Audiol Bispebjerg Hosp, Copenhagen, Denmark. [Tranebjaerg, Lisbeth] Univ Copenhagen, Panum Inst, Wilhelm Johannsen Ctr Funct Gen, Inst Mol & Cell Med, Copenhagen, Denmark. RP Merchant, SN (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, 243 Charles St, Boston, MA 02114 USA. EM saumil_merchant@meei.harvard.edu FU NIDCD NIH HHS [U24 DC008559, U24 DC008559-02, U24DC0008559] NR 17 TC 3 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD AUG PY 2008 VL 29 IS 5 BP 601 EP 606 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 333ZZ UT WOS:000258193400005 PM 18665028 ER PT J AU Allen, JD Shelton, RC Harden, E Goldman, RE AF Allen, Jennifer D. Shelton, Rachel C. Harden, Elizabeth Goldman, Roberta E. TI Follow-up of abnormal screening mammograms among low-income ethnically diverse women: Findings from a qualitative study SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE mammography; health disparities; qualitative research ID AFRICAN-AMERICAN WOMEN; BREAST-CANCER SYMPTOMS; PATIENT NAVIGATION; RACIAL DISPARITIES; URBAN-POPULATION; HISPANIC WOMEN; UNITED-STATES; SELF-REPORT; DELAY; CARE AB Objective: To understand factors that women feel facilitate or hinder their receipt of diagnostic services following an abnormal screening mammogram. Methods: This qualitative study used a purposive sampling strategy to identify low-income, ethnically diverse women aged 40 or over who had a recent abnormal mammogram. Working with a community health center, breast evaluation center, and mobile mammography van, 64 women were interviewed to identify salient themes that differentiated women who received timely follow-Lip from those who did not. Results: prominent themes among women who delayed follow-up included dissatisfaction with communication of results; perceived disrespect on the part of providers and clinic staff; logistical barriers to access of diagnostic services; anxiety and fear about a possible cancer diagnosis; and a lack of information about breast cancer screening and symptoms. Women who received timely care more often reported an appreciation of efforts by providers and clinic staff to support their prompt follow-up; availability of social support that facilitated appointment-keeping; confidence in their ability to advocate for their health; and a high priority placed on self-care. Conclusion: A comprehensive approach to improving timely diagnostic follow-up among underserved groups must address patient beliefs and attitudes, provider practices and communication, and practices at the health care systems level. Practice implications: Implications and strategies for improving patient education, patient-provider communication, and organizational practices are discussed. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Allen, Jennifer D.] Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. [Allen, Jennifer D.] Boston Coll, Chestnut Hill, MA 02167 USA. [Allen, Jennifer D.; Shelton, Rachel C.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Goldman, Roberta E.] Brown Univ, Providence, RI 02912 USA. RP Allen, JD (reprint author), Dana Farber Canc Inst, Ctr Community Based Res, 44 Binney St, Boston, MA 02115 USA. EM Jennifer_allen@dfci.harvard.edu RI Allen, Jennifer/M-2113-2015 NR 60 TC 42 Z9 42 U1 2 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD AUG PY 2008 VL 72 IS 2 BP 283 EP 292 DI 10.1016/j.pec.2008.03.024 PG 10 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 332CL UT WOS:000258059300016 PM 18490127 ER PT J AU Ginde, AA Clark, S Goldstein, JN Camargo, CA AF Ginde, Adit A. Clark, Sunday Goldstein, Joshua N. Camargo, Carlos A., Jr. TI Demographic disparities in numeracy among emergency department patients: Evidence from two multicenter studies SO PATIENT EDUCATION AND COUNSELING LA English DT Article DE health literacy; numeracy; emergency medicine; risk; communication; disparities ID FUNCTIONAL HEALTH LITERACY; MANAGED CARE ENROLLEES; HOSPITAL ADMISSION; CONTROLLED-TRIAL; DECISION-MAKING; SELF-MANAGEMENT; CHRONIC DISEASE; REGULAR SOURCE; KNOWLEDGE; OUTCOMES AB Objective: To estimate the prevalence and demographic disparities in limited numeracy among emergency department (ED) patients. Methods: We performed two cross-sectional studies of ED patients with sub-critical illness in 2000-2001 and 2006. We enrolled 959 adult patients from 28 EDs in 17 US states and measured numeracy based on four validated questions. Results: Rates of correct responses for individual numeracy questions ranged from 15% to 68%; only 11 % of participants answered all questions correctly. Several demographic characteristics were independently associated with frequency of correct answers, including age (OR 0.92 [95% confidence interval (0), 0.87-0.97] per up arrow 5 years), race/ethnicity (compared to whites: OR 0.35 for blacks [95%CI, 0.20-0.63]; and OR 0.36 for Hispanics [95%CI, 0.19-0.69]), education (OR 4.74 [95%CI, 2.01-11.14] for high school graduates vs. not), health insurance (OR 1.70 [95%CI, 1.06-2.71] for those with private insurance vs. not), and income (OR 1.13 [95%CI, 1.05-1.22] per up arrow$10,000). Conclusion: We found a higher prevalence of limited numeracy among ED patients compared to the general population. Significant demographic disparities are consistent with previous observations for general health literacy. Practice implications: Greater understanding of the high prevalence of limited numeracy may guide healthcare providers to simplify messages and communicate health information more effectively. (c) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Ginde, Adit A.] Univ Colorado, Denver Sch Med, Div Emergency Med, Aurora, CO 80045 USA. [Clark, Sunday] New York Presbyterian Hosp, Dept Emergency Med, New York, NY USA. [Goldstein, Joshua N.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Goldstein, Joshua N.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Ginde, AA (reprint author), Univ Colorado, Denver Sch Med, Div Emergency Med, Leprino Bldg,7th Floor,12401 E 17th Ave,B-215, Aurora, CO 80045 USA. EM adit.ginde@uchse.edu RI Goldstein, Joshua/H-8953-2016; Siry, Bonnie/D-7189-2017 NR 46 TC 22 Z9 22 U1 2 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD AUG PY 2008 VL 72 IS 2 BP 350 EP 356 DI 10.1016/j.pec.2008.03.012 PG 7 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 332CL UT WOS:000258059300025 PM 18462915 ER PT J AU Meyer, JS Nadel, HR Marina, N Womer, RB Brown, KLB Eary, JF Gorlick, R Grier, HE Randall, RL Lawlor, ER Lessnick, SL Schomberg, PJ Kailo, MD AF Meyer, James S. Nadel, Helen R. Marina, Neyssa Womer, Richard B. Brown, Kenneth L. B. Eary, J. F. Gorlick, Richard Grier, Holcombe E. Randall, R. Lor Lawlor, Elizabeth R. Lessnick, Stephen L. Schomberg, Paula J. Kailo, Mark D. TI Imaging guidelines for children with Ewing sarcoma and osteosarcoma: A report from the Children's Oncology Group Bone Tumor Committee SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material DE osteosarcoma; ewing sarcoma; imaging ID POSITRON-EMISSION-TOMOGRAPHY; DIAGNOSTIC X-RAYS; PULMONARY METASTASES; COMPUTED-TOMOGRAPHY; NEOADJUVANT CHEMOTHERAPY; PEDIATRIC SARCOMA; FDG-PET; CT; CANCER; TISSUE AB The Children's Oncology Group (COG) is a multi-institutional cooperative group dedicated to childhood cancer research that has helped to increase the survival of children with cancer through clinical trials. These clinical trials include a standardized regimen of imaging examinations performed prior to, during, and following therapy. This article presents imaging guidelines developed by a multidisciplinary group from the COG Bone Tumor Committee. These guidelines provide both required and recommended studies. Recommended examinations may become required in the future. These guidelines should be considered a work in progress that will evolve with advances in imaging and childhood cancer research. C1 [Meyer, James S.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. [Nadel, Helen R.] Univ British Columbia, Dept Radiol, BC Childrens Hosp, Vancouver, BC V5Z 1M9, Canada. [Marina, Neyssa] Stanford Univ, Med Ctr, Dept Pediat, Div Hematol Oncol, Palo Alto, CA 94304 USA. [Marina, Neyssa] Stanford Univ, Sch Med, Lucile Packard Childrens Hosp, Palo Alto, CA 94304 USA. [Womer, Richard B.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Pediat,Div Oncol, Philadelphia, PA 19104 USA. [Brown, Kenneth L. B.] Univ British Columbia, BC Childrens Hosp, Dept Orthopaed, Vancouver, BC V5Z 1M9, Canada. [Eary, J. F.] Univ Washington, Med Ctr, Dept Radiol, Seattle, WA 98195 USA. [Eary, J. F.] Univ Washington, Med Ctr, Dept Orthoped, Seattle, WA 98195 USA. [Gorlick, Richard] Albert Einstein Coll Med, Childrens Hosp Montefiore, Dept Pediat, Div Hematol Oncol, Bronx, NY 10467 USA. [Grier, Holcombe E.] Harvard Univ, Sch Med, Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Randall, R. Lor] Univ Utah, Med Ctr, Sch Med, Huntsman Canc Inst & Primary Childrens,Dept Ortho, Salt Lake City, UT 84132 USA. [Lawlor, Elizabeth R.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Pediat,Div Hematol Oncol, Los Angeles, CA 90033 USA. [Lawlor, Elizabeth R.] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Dept Pathol, Los Angeles, CA 90033 USA. [Lessnick, Stephen L.] Univ Utah, Sch Med, Div Pediat Hematol Oncol, Dept Oncol Sci,Huntsman Canc Inst,Ctr Children, Salt Lake City, UT 84132 USA. [Schomberg, Paula J.] Mayo Clin, Dept Radiat Oncol, Rochester, MN USA. [Kailo, Mark D.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Meyer, JS (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Radiol, 34th St & Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM meyer@email.chop.edu FU NCI NIH HHS [U10 CA098543] NR 35 TC 62 Z9 64 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2008 VL 51 IS 2 BP 163 EP 170 DI 10.1002/pbc.21596 PG 8 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 315IK UT WOS:000256871800004 PM 18454470 ER PT J AU Butler, DA Zuehlke, JB Tovar, A Volkening, LK Anderson, BJ Laffel, LMB AF Butler, Deborah A. Zuehlke, Jessica B. Tovar, Alison Volkening, Lisa K. Anderson, Barbara J. Laffel, Lori M. B. TI The impact of modifiable family factors on glycemic control among youth with type 1 diabetes SO PEDIATRIC DIABETES LA English DT Article DE family; knowledge; psychosocial factors; T1DM; youth ID INSULIN PUMP THERAPY; CHILDREN; ADOLESCENTS; TRIAL; MELLITUS; OUTCOMES; COMPLICATIONS; INVOLVEMENT; CONFLICT; CARE AB Objective: To identify modifiable family factors impacting glycemic control in youth with type 1 diabetes (T1DM) beyond the anticipated physical, developmental, and behavioral issues associated with adolescence. Study design: In 153 youth (aged 8-16 yr) with T1DM duration of 6.3 +/- 3.5 yr and average hemoglobin A1c (HbA1c) of 8.4 +/- 1.4%, we examined modifiable family factors that might impact adherence to diabetes management and, in turn, influence glycemic control. Youth and parents completed surveys that assessed diabetes-specific knowledge, negative affect related to blood glucose monitoring (BGM), and parental-perceived burden of diabetes care. Clinician report and chart review provided data on growth, pubertal development, and diabetes management tasks. Glycemic control was measured as HbA1c. Results: In bivariate analyses, higher parental diabetes-specific knowledge (p < 0.0001), less youth negative affect related to BGM (p = 0.0005), and less parental-perceived burden (p = 0.0008) were associated with lower HbA1c. In a multivariate model controlling for demographic and diabetes-specific variables, these three factors remained independent and significant predictors of HbA1c (R(2) = 0.31 and p < 0.0001). Higher parental knowledge, less youth negative affect, and less parental burden predicted lower HbA1c, while youth knowledge and parental negative affect did not. Conclusion: To attain optimal glycemic control, treatment programs for youth with T1DM should include ongoing efforts to reinforce parental knowledge of diabetes tasks, promote positive youth affect related to diabetes management, and acknowledge and reduce parental-perceived burden of diabetes management. C1 [Zuehlke, Jessica B.; Tovar, Alison; Volkening, Lisa K.; Laffel, Lori M. B.] Joslin Diabet Ctr, Genet & Epidemiol Sect, Boston, MA 02215 USA. [Butler, Deborah A.; Zuehlke, Jessica B.; Tovar, Alison; Volkening, Lisa K.; Laffel, Lori M. B.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02115 USA. [Butler, Deborah A.] Joslin Diabet Ctr, Behav & Mental Hlth Sect, Boston, MA 02215 USA. [Anderson, Barbara J.] Baylor Coll Med, Dept Pediat, Endocrinol & Metab Sect, Houston, TX 77030 USA. RP Laffel, LMB (reprint author), Joslin Diabet Ctr, Genet & Epidemiol Sect, 1 Joslin Pl, Boston, MA 02215 USA. EM lori.laffel@joslin.harvard.edu FU NIDDK NIH HHS [DK-46887, R01 DK046887] NR 39 TC 28 Z9 28 U1 5 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1399-543X J9 PEDIATR DIABETES JI Pediatr. Diabetes PD AUG PY 2008 VL 9 IS 4 BP 373 EP 381 DI 10.1111/j.1399-5448.2008.00370.x PN 2 PG 9 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 332JE UT WOS:000258078500006 PM 18774997 ER PT J AU Swartz, LM Laffel, LM AF Swartz, Lisa M. Laffel, Lori M. TI A teenage girl with cystic fibrosis-related diabetes, diabetic ketoacidosis, and cerebral edema SO PEDIATRIC DIABETES LA English DT Article DE CF; diabetes; DKA ID GLUCOSE-TOLERANCE; CHILDREN; MELLITUS; ADOLESCENTS AB Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes, most commonly associated with type 1 diabetes. Here, we report the case of a 17-yr-old girl with cystic fibrosis and a prior diagnosis of cystic fibrosis -related diabetes (CFRD) who presented with DKA in the setting of insulin omission and glucocorticoid use. During the course of treatment for DKA, her neurologic status declined and head computerized tomography confirmed cerebral edema. Recognition of DKA and cerebral edema allowed for timely treatment, and the patient recovered without sequelae. This is the first report of DKA complicated by cerebral edema that is attributable to CFRD. C1 [Swartz, Lisa M.; Laffel, Lori M.] Childrens Hosp, Dept Med, Div Endocrinol, Boston, MA 02115 USA. [Swartz, Lisa M.; Laffel, Lori M.] Joslin Diabet Ctr, Pediat Adolescent & Young Adult Sect, Boston, MA 02215 USA. [Laffel, Lori M.] Joslin Diabet Ctr, Genet & Epidemiol Sect, Boston, MA 02215 USA. RP Swartz, LM (reprint author), Childrens Hosp, Dept Med, Div Endocrinol, 333 Longwood Ave, Boston, MA 02115 USA. EM lisa.swartz@childrens.harvard.edu NR 19 TC 10 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1399-543X J9 PEDIATR DIABETES JI Pediatr. Diabetes PD AUG PY 2008 VL 9 IS 4 BP 426 EP 430 DI 10.1111/j.1399-5448.2007.00359.x PN 2 PG 5 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 332JE UT WOS:000258078500015 PM 18775002 ER PT J AU Gonzalez, GE Caruso, PA Small, JE Jyung, RW Troulis, MJ Curtin, HD AF Gonzalez, Guido E. Caruso, Paul A. Small, Juan E. Jyung, Robert W. Troulis, Maria J. Curtin, Hugh D. TI Craniofacial and temporal bone CT findings in cleidocranial dysplasia SO PEDIATRIC RADIOLOGY LA English DT Article DE cleidocranial dysplasia; child ID MANIFESTATIONS AB Cleidocranial dysplasia (CCD) is a multistructural polyostotic genetic disorder that results from mutation of the CBFA1 gene. Hearing loss is a frequent finding in CCD. We describe the CT craniofacial findings in CCD and provide a comprehensive discussion of the CT temporal bone findings in these patients. C1 [Gonzalez, Guido E.; Caruso, Paul A.; Small, Juan E.; Curtin, Hugh D.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Radiol, Boston, MA 02114 USA. [Gonzalez, Guido E.; Caruso, Paul A.; Small, Juan E.; Jyung, Robert W.; Troulis, Maria J.; Curtin, Hugh D.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Jyung, Robert W.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Otol, Boston, MA 02114 USA. [Troulis, Maria J.] Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Caruso, PA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Dept Radiol, 243 Charles St, Boston, MA 02114 USA. EM paul_caruso@meei.harvard.edu NR 8 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0301-0449 J9 PEDIATR RADIOL JI Pediatr. Radiol. PD AUG PY 2008 VL 38 IS 8 BP 892 EP 897 DI 10.1007/s00247-008-0866-1 PG 6 WC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging SC Pediatrics; Radiology, Nuclear Medicine & Medical Imaging GA 325ND UT WOS:000257594700012 PM 18446333 ER PT J AU Misra, M Pacaud, D Petryk, A Collett-Solberg, PF Kappy, M AF Misra, Madhusmita Pacaud, Daniele Petryk, Anna Collett-Solberg, Paulo Ferrez Kappy, Michael CA Lawson Wilkins Pediat Endocrine So TI Vitamin D deficiency in children and its management: Review of current knowledge and recommendations SO PEDIATRICS LA English DT Review DE food fortification; breastfeeding; calcium; supplements; vitamin D ID BREAST-FED INFANTS; BONE-MINERAL DENSITY; SERUM 25-HYDROXYVITAMIN-D CONCENTRATIONS; ULTRAVIOLET-B RADIATION; NUTRITIONAL RICKETS; UNITED-STATES; HYPOVITAMINOSIS-D; PARATHYROID-HORMONE; D SUPPLEMENTATION; MULTIPLE-SCLEROSIS AB Given the recent spate of reports of vitamin D deficiency, there is a need to reexamine our understanding of natural and other sources of vitamin D, as well as mechanisms whereby vitamin D synthesis and intake can be optimized. This state-of-the-art report from the Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society was aimed to perform this task and also reviews recommendations for sun exposure and vitamin D intake and possible caveats associated with these recommendations. C1 [Misra, Madhusmita] Massachusetts Gen Hosp, Pediat Endocrine & Neuroendocrine Units, Boston, MA 02114 USA. [Pacaud, Daniele] Univ Calgary, Dept Pediat, Div Pediat Endocrinol, Alberta Childrens Prov Gen Hosp, Calgary, AB T2N 1N4, Canada. [Petryk, Anna] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. [Collett-Solberg, Paulo Ferrez] Inst Estadual Diabet & Endocrinol, Rio De Janeiro, Brazil. [Kappy, Michael] Univ Colorado, Hlth Sci Ctr, Childrens Hosp Assoc, Denver, CO USA. RP Misra, M (reprint author), Massachusetts Gen Hosp, Pediat Endocrine & Neuroendocrine Units, Boston, MA 02114 USA. EM mmisra@partners.org FU NCRR NIH HHS [K23 RR018851] NR 179 TC 439 Z9 469 U1 4 U2 43 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2008 VL 122 IS 2 BP 398 EP 417 DI 10.1542/peds.2007-1894 PG 20 WC Pediatrics SC Pediatrics GA 333HB UT WOS:000258142500023 PM 18676559 ER PT J AU Winickoff, JP Park, ER Hipple, BJ Berkowitz, A Vieira, C Friebely, J Healey, EA Rigotti, NA AF Winickoff, Jonathan P. Park, Elyse R. Hipple, Bethany J. Berkowitz, Anna Vieira, Cecilia Friebely, Joan Healey, Erica A. Rigotti, Nancy A. TI Clinical effort against secondhand smoke exposure: Development of framework and intervention SO PEDIATRICS LA English DT Article DE smoking; tobacco; pediatrics; family practice; parent; smoking cessation; secondhand smoke; environmental tobacco smoke; tobacco control; quitline; telephone counseling ID ENVIRONMENTAL TOBACCO-SMOKE; RANDOMIZED CONTROLLED-TRIAL; ADDRESSING PARENTAL SMOKING; HEALTH BEHAVIOR-CHANGE; CROSS-SECTIONAL SURVEY; PREVENTIVE SERVICES; ASTHMATIC-CHILDREN; ADOLESCENT SMOKING; ADVISING PARENTS; MATERNAL SMOKING AB OBJECTIVE. The purpose of this work was to describe a novel process and present results of formative research to develop a pediatric office intervention that uses available systems of care for addressing parental smoking. METHODS. The scientific development of the intervention occurred in 3 stages. In stage 1, we designed an office system for parental tobacco control in the pediatric outpatient setting on the basis of complementary conceptual frameworks of preventive services delivery, conceptualized for the child health care setting through a process of key interviews with leaders in the field of implementing practice change; existing Public Health Service guidelines that had been shown effective in adult practices; and adaptation of an evidence-based adult office system for tobacco control. This was an iterative process that yielded a theoretically framed intervention prototype. In stage 2, we performed focus-group testing in pediatric practices with pediatricians, nurses, clinical assistants, and key office staff. Using qualitative methods, we adapted the intervention prototype on the basis of this feedback to include 5 key implementation steps for the child health care setting. In stage 3, we presented the intervention to breakout groups at 2 national meetings of pediatric practitioners for additional refinements. RESULTS. The main result was a theoretically grounded intervention that was responsive to the barriers and suggestions raised in the focus groups and at the national meetings. The Clinical Effort Against Secondhand Smoke Exposure intervention was designed to be flexible and adaptable to the particular practices' staffing, resources, and physical configuration. Practice staff can choose materials relevant to their own particular systems of care (www.ceasetobacco.org). CONCLUSIONS. Conceptually grounded and focus-group-tested strategies for parental tobacco control are now available for implementation in the pediatric outpatient setting. The tobacco-control intervention-development process might have particular relevance for other chronic pediatric conditions that have a strong evidence base and have available treatments or resources that are underused. C1 [Winickoff, Jonathan P.; Hipple, Bethany J.; Berkowitz, Anna; Vieira, Cecilia; Friebely, Joan; Healey, Erica A.] Ctr Child & Adolescent Hlth Policy, Boston, MA 02114 USA. [Winickoff, Jonathan P.; Park, Elyse R.; Hipple, Bethany J.; Vieira, Cecilia; Friebely, Joan; Healey, Erica A.; Rigotti, Nancy A.] Massachusetts Gen Hosp, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. RP Winickoff, JP (reprint author), Ctr Child & Adolescent Hlth Policy, 50 Staniford St,Suite 901, Boston, MA 02114 USA. EM jwinickoff@partners.org FU NCI NIH HHS [K07 CA100213 A 01, K07 CA100213]; NHLBI NIH HHS [K24 HL004440-09, K24 HL004440, K24 HL0440] NR 96 TC 33 Z9 34 U1 1 U2 4 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD AUG PY 2008 VL 122 IS 2 BP E363 EP E375 DI 10.1542/peds.2008-0478 PG 13 WC Pediatrics SC Pediatrics GA 333HB UT WOS:000258142500055 PM 18676523 ER PT J AU Cobitz, A Zambanini, A Sowell, M Heise, M Louridas, B McMorn, S Semigran, M Koch, G AF Cobitz, Alexander Zambanini, Andrew Sowell, Margaret Heise, Mark Louridas, Bonnie McMorn, Stephen Semigran, Marc Koch, Gary TI A retrospective evaluation of congestive heart failure and myocardial ischemia events in 14 237 patients with type 2 diabetes mellitus enrolled in 42 short-term, double-blind, randomized clinical studies with rosiglitazone SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE rosiglitazone; heart failure; myocardial ischemia ID IMPROVES GLYCEMIC CONTROL; LOW-DOSE ROSIGLITAZONE; COMBINATION THERAPY; METABOLIC-CONTROL; CONTROLLED-TRIAL; SULFONYLUREA THERAPY; PLUS METFORMIN; INSULIN; MONOTHERAPY; GLUCOSE AB Purpose Retrospectively investigate potential associations between rosiglitazone and congestive heart failure (CHF) and, separately, events of myocardial ischemia. Methods Data from 14 237 individuals in 42 short-term, double-blind, randomized studies of rosiglitazone versus placebo or active diabetes medications were analyzed across seven treatment comparisons using an exact logistic regression model, adjusted for number of major cardiovascular risk factors and duration of exposure. Results CHF incidence ranged 0-1.27% (SAEs) and 0.12-2.42% (all AEs) with rosiglitazone versus 0.07-0.75% (SAEs) and 0.25-1.36% (all AEs) with control. Higher odds ratios (95%CI) were observed for CHF SAEs with sulfonylurea- and insulin-containing combinations: rosiglitazone monotherapy versus placebo, 0.25 (<0.01-4.75); rosiglitazone monotherapy versus sulfonylurea/metformin monotherapy, 0.23 (<0.01-2.14); sulfonylurea + rosiglitazone versus sulfonylurea monotherapy, 0.95 (0.01-75.20); metformin+rosiglitazone versus metformin monotherapy, 0.60 (0.00-8.28); metformin + rosiglitazone versus metformin + sulfonylurea, 1.04 (0.39-2.86); sulfonylurea + metformin + rosiglitazone versus sulfonylurea+metformin, 3.15 (0.35-150.52); insulin + rosiglitazone versus insulin monotherapy, 1.63 (0.52-6.01). Myocardial ischemia incidence ranged 0.75-1.40% (SAEs) and 1.49-2.77% (all AEs) with rosiglitazone versus 0.21-2.04% (SAEs) and 0.56-2.38% (all AEs) with control. Each comparison had an OR >1, with wide confidence intervals generally including unity. With data pooling, more events of myocardial ischemia were observed with rosiglitazone (2.00%) versus control (1.53%) (HR 1.30, 95%CI 1.004-1.69). Conclusions CHF incidence maybe greater when rosiglitazone is combined with sulfonylureas or insulin. When data were pooled, more events of myocardial ischemia were observed with rosiglitazone versus control. Final results from RECORD will allow a more rigorous evaluation of the cardiovascular safety profile. Copyright (C) 2008 John Wiley & Sons, Ltd. C1 [Cobitz, Alexander; Sowell, Margaret; Heise, Mark; Louridas, Bonnie; McMorn, Stephen] GlaxoSmithKline Inc, King Of Prussia, PA 19406 USA. [Zambanini, Andrew] GlaxoSmithKline Inc, Harlow, Essex, England. [Semigran, Marc] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Koch, Gary] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. RP Cobitz, A (reprint author), GlaxoSmithKline Inc, 2301 Renaissance Blvd, King Of Prussia, PA 19406 USA. EM alexander.r.cobitz@gsk.com NR 49 TC 22 Z9 22 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 IS 8 BP 769 EP 781 DI 10.1002/pds.1615 PG 13 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FD UT WOS:000258420000003 PM 18613278 ER PT J AU Hermos, JA Lawler, EV Young, MM Holmberg, EF Gagnon, DR Scranton, RE AF Hermos, John A. Lawler, Elizabeth V. Young, Melissa M. Holmberg, Erika F. Gagnon, David R. Scranton, Richard E. TI Patterns of Crohn's disease medications among US veteran patients: Associations with fistulas and cancers SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Hermos, John A.; Lawler, Elizabeth V.; Young, Melissa M.; Holmberg, Erika F.; Gagnon, David R.; Scranton, Richard E.] VA Boston Healthcare Syst, VA Cooperat Studies Program, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Hermos, John A.; Lawler, Elizabeth V.; Gagnon, David R.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Hermos, John A.; Lawler, Elizabeth V.; Gagnon, David R.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Scranton, Richard E.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 341 BP S150 EP S150 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100341 ER PT J AU Meropol, SB Chen, Z Metlay, JP AF Meropol, Sharon B. Chen, Zhen Metlay, Joshua P. TI Adverse events associated with pediatric antibiotic use SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Meropol, Sharon B.; Chen, Zhen; Metlay, Joshua P.] Univ PA, Cntr Clin Epidemiol & Biostat, Philadelphia, PA USA. [Meropol, Sharon B.; Metlay, Joshua P.] Univ PA, Penn Cntr Educ & Res Therapeut, Philadelphia, PA USA. [Metlay, Joshua P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 623 BP S273 EP S273 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100623 ER PT J AU Meropol, SB Chen, Z Metlay, JP AF Meropol, Sharon B. Chen, Zhen Metlay, Joshua P. TI Antibiotics for upper respiratory infections SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [Meropol, Sharon B.; Chen, Zhen; Metlay, Joshua P.] UPenn, Cntr Clin Epidem & Biostat, Philadelphia, PA USA. [Meropol, Sharon B.; Metlay, Joshua P.] UPenn, Penn Cntr Educ & Res Therapeut, Philadelphia, PA USA. [Metlay, Joshua P.] Philadelphia VA Med Ctr, Philadelphia, PA USA. [Metlay, Joshua P.] Univ PA, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 477 BP S209 EP S210 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100477 ER PT J AU Strom, BL Faich, G Eng, S Reynolds, R D'Agostino, R Ruskin, J Kane, J AF Strom, Brian L. Faich, Gerald Eng, Sybil Reynolds, Robert D'Agostino, Ralph Ruskin, Jeremy Kane, John TI Comparative mortality associated with ziprasidone vs. olanzapine in real-world use: The ziprasidone observational study of cardiac outcomes (ZODIAC) SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 [D'Agostino, Ralph] Boston U, Boston, MA USA. [Ruskin, Jeremy] Mass Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2008 VL 17 SU 1 MA 466 BP S205 EP S205 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 337FE UT WOS:000258420100466 ER PT J AU Reddy, KK Lefkove, B Chen, LB Govindarajan, B Carracedo, A Velasco, G Carrillo, CO Bhandarkar, SS Owens, MJ Mechta-Grigoriou, F Arbiser, JL AF Reddy, Kalpana K. Lefkove, Benjamin Chen, Lan Bo Govindarajan, Baskaran Carracedo, Arkaitz Velasco, Guillermo Carrillo, Carol O. Bhandarkar, Sulochana S. Owens, Michael J. Mechta-Grigoriou, Fatima Arbiser, Jack L. TI The antidepressant sertraline downregulates Akt and has activity against melanoma cells SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE sertraline; melanoma; AKT; SSRI; signal transduction; reactive oxygen ID TRANSPORTER BINDING PROFILE; MALIGNANT-MELANOMA; METASTATIC MELANOMA; NORMAL MELANOCYTES; OXIDATIVE STRESS; MAP KINASE; KAPPA-B; ACTIVATION; TRANSFORMATION; EXPRESSION AB Melanoma is a common malignancy which is poorly responsive to chemotherapy and radiation. One of the major reasons melanoma responds poorly to these modalities is constitutive expression of Akt, which protects against apoptosis. The antidepressant sertraline was found to be a potent cytotoxic agent against A375 human melanoma. To determine the mechanism by which sertraline kills melanoma cells, Western blot analysis of signaling molecules, including phosphorylated Akt, caspase 9 and phospho-p70 S6 kinase was performed. Finally, the effects of sertraline on A375 xenografts in mice were assessed. Sertaline potently inhibited the phosphorylation of Akt, and caused cell death through induction of endoplasmic reticulum in vitro. Sertraline monotherapy demonstrated activity against A375 xenografts in vivo. Akt is a major cause of resistance of melanoma to current therapy. Antidepressants are commonly used to prevent interferon-induced depression. Use of antidepressants that decrease Akt may improve the efficacy of interferon and other therapies against melanoma. Further studies are needed to elucidate whether sertraline acts as an Akt inhibitor in melanoma. C1 [Reddy, Kalpana K.; Lefkove, Benjamin; Govindarajan, Baskaran; Carrillo, Carol O.; Bhandarkar, Sulochana S.; Arbiser, Jack L.] Emory Univ, Sch Med, Dept Dermatol, Atlanta, GA 30322 USA. [Chen, Lan Bo] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Carracedo, Arkaitz; Velasco, Guillermo] Univ Complutense, Sch Biol, Dept Biochem & Mol Biol 1, E-28040 Madrid, Spain. [Owens, Michael J.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA USA. [Mechta-Grigoriou, Fatima] Inst Pasteur, CNRS, URA 1644, Unit Gene Express & Dis, Paris, France. RP Arbiser, JL (reprint author), Emory Univ, Sch Med, Dept Dermatol, Atlanta, GA 30322 USA. EM jarbise@emory.edu RI Carracedo, Arkaitz/F-7029-2011; Owens, Michael/G-5191-2012; Velasco, Guillermo/H-5260-2012; MECHTA-GRIGORIOU, Fatima/C-5253-2017 OI Carracedo, Arkaitz/0000-0001-5957-1260; Velasco, Guillermo/0000-0002-1994-2386; MECHTA-GRIGORIOU, Fatima/0000-0002-3751-6989 FU NIAMS NIH HHS [P30 AR42687, R01 AR47901] NR 33 TC 28 Z9 29 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD AUG PY 2008 VL 21 IS 4 BP 451 EP 456 DI 10.1111/j.1755-148X.2008.00481.x PG 6 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 325EM UT WOS:000257571300007 PM 18710373 ER PT J AU Yokoyama, S Feige, E Poling, LL Levy, C Widlund, HR Khaled, M Kung, AL Fisher, DE AF Yokoyama, Satoru Feige, Erez Poling, Laura L. Levy, Carmit Widlund, Hans R. Khaled, Mehdi Kung, Andrew L. Fisher, David E. TI Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE HDAC inhibitor; MITF; melanoma; clear cell sarcoma; pigmentation ID SUBEROYLANILIDE HYDROXAMIC ACID; HISTONE DEACETYLASE INHIBITOR; TRANSCRIPTION FACTOR GENE; MALIGNANT-MELANOMA; MICROPHTHALMIA LOCUS; PHASE-I; ONCOGENE; BINDING; CELLS; IDENTIFICATION AB Melanoma incidence continues to rise at an alarming rate while effective systemic therapies remain very limited. Microphthalmia-associated transcription factor (MITF) is required for development of melanocytes and is an amplified oncogene in a fraction of human melanomas. Microphthalmia-associated transcription factor also plays an oncogenic role in human clear cell sarcomas, which typically exhibit melanoma-like features. Although pharmacologic suppression of MITF is of potential interest in a variety of clinical settings, it is not known to contain intrinsic catalytic activity capable of direct small molecule inhibition. An alternative drug-targeting strategy is to identify and interfere with lineage-restricted mechanisms required for its expression. Here, we report that multiple histone deacetylase (HDAC)-inhibitor drugs potently suppress MITF expression in melanocytes, melanoma and clear cell sarcoma cells. Although HDAC inhibitors may affect numerous cellular targets, we observed suppression of skin pigmentation by topical drug application as well as evidence of anti-melanoma efficacy in vitro and in mouse xenografts. Consequently, HDAC inhibitor drugs are candidates to play therapeutic roles in targeting conditions affecting the melanocyte lineage. C1 [Fisher, David E.] Harvard Univ, Sch Med, Boston Childrens Hosp,Melanoma Program Med Oncol, Dana Farber Canc Inst,Dept Pediat Hematol Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Dermatol,Cutaneous Biol Res Ctr, Boston, MA 02114 USA. RP Fisher, DE (reprint author), Harvard Univ, Sch Med, Boston Childrens Hosp,Melanoma Program Med Oncol, Dana Farber Canc Inst,Dept Pediat Hematol Oncol, Boston, MA 02114 USA. EM dfisher3@partners.org RI khaled, mehdi/C-4854-2012; OI Kung, Andrew/0000-0002-9091-488X FU NIAMS NIH HHS [R01 AR043369-12, R01 AR043369] NR 30 TC 46 Z9 48 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD AUG PY 2008 VL 21 IS 4 BP 457 EP 463 DI 10.1111/j.1755-148X.2008.00480.x PG 7 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 325EM UT WOS:000257571300008 PM 18627530 ER PT J AU Gundogan, F Bianchi, DW Scherjon, SA Roberts, DJ AF Gundogan, F. Bianchi, D. W. Scherjon, S. A. Roberts, D. J. TI Placental findings in egg donor pregnancies SO PLACENTA LA English DT Meeting Abstract CT 14th Meeting of the International-Federation-of-Placental-Associations/12th Meeting of the European-Placenta-Group (IFPA/EPG) CY SEP 10-13, 2008 CL Seggau Castle, AUSTRIA SP Int Federat Placenta Assoc, European Placenta Grp C1 [Gundogan, F.] Women & Infants Hosp Rhode Isl, Dept Pathol, Providence, RI 02905 USA. [Bianchi, D. W.] Tufts Med Ctr, Dept Pediat, Boston, MA 02111 USA. [Scherjon, S. A.] Leiden Univ, Med Ctr, Dept Obstet, NL-2300 RA Leiden, Netherlands. [Roberts, D. J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD AUG PY 2008 VL 29 IS 8 BP A50 EP A50 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 345XM UT WOS:000259031100194 ER PT J AU Karve, A Rauh, BL Xia, XX Kandasamy, M Meagher, RB Sheen, J Moore, BD AF Karve, Abhijit Rauh, Bradley L. Xia, Xiaoxia Kandasamy, Muthugapatti Meagher, Richard B. Sheen, Jen Moore, Brandon d. TI Expression and evolutionary features of the hexokinase gene family in Arabidopsis SO PLANTA LA English DT Article DE glucose phosphorylation; hexokinase; hexokinase-like; molecular evolution; sliding windows ID SUGAR SIGNAL-TRANSDUCTION; HIGHER-PLANTS; SACCHAROMYCES-CEREVISIAE; GLUCOSE; THALIANA; GROWTH; MECHANISMS; PROTEINS; MITOCHONDRIA; SEPARATION AB Arabidopsis hexokinase1 (HXK1) is a moonlighting protein that has separable functions in glucose signaling and in glucose metabolism. In this study, we have characterized expression features and glucose phosphorylation activities of the six HXK gene family members in Arabidopsis thaliana. Three of the genes encode catalytically active proteins, including a stromal-localized HXK3 protein that is expressed mostly in sink organs. We also show that three of the genes encode hexokinase-like (HKL) proteins, which are about 50% identical to AtHXK1, but do not phosphorylate glucose or fructose. Expression studies indicate that both HKL1 and HKL2 transcripts occur in most, if not all, plant tissues and that both proteins are targeted within cells to mitochondria. The HKL1 and HKL2 proteins have 6-10 amino acid insertions/deletions (indels) at the adenosine binding domain. In contrast, HKL3 transcript was detected only in flowers, the protein lacks the noted indels, and the protein has many other amino acid changes that might compromise its ability even to bind glucose or ATP. Activity measurements of HXKs modified by site-directed mutagenesis suggest that the lack of catalytic activities in the HKL proteins might be attributed to any of numerous existing changes. Sliding windows analyses of coding sequences in A. thaliana and A. lyrata ssp. lyrata revealed a differential accumulation of nonsynonymous changes within exon 8 of both HKL1 and HXK3 orthologs. We further discuss the possibility that the non-catalytic HKL proteins have regulatory functions instead of catalytic functions. C1 [Karve, Abhijit; Rauh, Bradley L.; Xia, Xiaoxia; Moore, Brandon d.] Clemson Univ, Dept Biochem & Genet, Clemson, SC 29634 USA. [Kandasamy, Muthugapatti; Meagher, Richard B.] Univ Georgia, Dept Genet, Athens, GA 30602 USA. [Sheen, Jen] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Moore, BD (reprint author), Clemson Univ, Dept Biochem & Genet, Clemson, SC 29634 USA. EM moore8@clemson.edu FU NIGMS NIH HHS [R01 GM036397-21, R01 GM036397, R01 GM036397-23, R01 GM036397-19, R01 GM036397-20, R01 GM036397-20S1, R01 GM036397-22] NR 51 TC 40 Z9 43 U1 0 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0032-0935 J9 PLANTA JI Planta PD AUG PY 2008 VL 228 IS 3 BP 411 EP 425 DI 10.1007/s00425-008-0746-9 PG 15 WC Plant Sciences SC Plant Sciences GA 325NE UT WOS:000257594800005 PM 18481082 ER PT J AU May, JW AF May, James W., Jr. TI Gain without pain: The dawn of elective surgery SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP May, JW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, 15 Parkman St,Wang 435, Boston, MA 02114 USA. EM jwmay@partners.org NR 4 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD AUG PY 2008 VL 122 IS 2 BP 631 EP 638 DI 10.1097/PRS.0b013e31817d6119 PG 8 WC Surgery SC Surgery GA 333EX UT WOS:000258136900042 PM 18626386 ER PT J AU Yotsumoto, Y Watanabe, T AF Yotsumoto, Yuko Watanabe, Takeo TI Defining a link between perceptual learning and attention SO PLOS BIOLOGY LA English DT Editorial Material ID SUSTAINED ATTENTION; TEXTURE-DISCRIMINATION; FRONTAL LESIONS; VISUAL-CORTEX; PLASTICITY; ACTIVATION; PERFORMANCE; ORIENTATION; NETWORKS; DEFICITS C1 [Yotsumoto, Yuko; Watanabe, Takeo] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Yotsumoto, Yuko] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Yotsumoto, Yuko] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Watanabe, T (reprint author), Boston Univ, Dept Psychol, 64 Cummington St, Boston, MA 02215 USA. EM takeo@bu.edu NR 36 TC 18 Z9 18 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD AUG PY 2008 VL 6 IS 8 BP 1623 EP 1626 AR e221 DI 10.1371/journal.pbio.0060221 PG 4 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 341UA UT WOS:000258739400004 PM 18752357 ER PT J AU Komatsu, H Chao, MY Larkins-Ford, J Corkins, ME Somers, GA Tucey, T Dionne, HM White, JQ Wani, K Boxem, M Hart, AC AF Komatsu, Hidetoshi Chao, Michael Y. Larkins-Ford, Jonah Corkins, Mark E. Somers, Gerard A. Tucey, Tim Dionne, Heather M. White, Jamie Q. Wani, Khursheed Boxem, Mike Hart, Anne C. TI OSM-11 facilitates LIN-12 Notch signaling during Caenorhabditis elegans vulval development SO PLOS BIOLOGY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; GLR-1 GLUTAMATE-RECEPTOR; GENE SERRATE ENCODES; CELL FATE DECISION; C-ELEGANS; ALAGILLE-SYNDROME; EXTRACELLULAR DOMAIN; DSL PROTEINS; DROSOPHILA-MELANOGASTER; TRANSMEMBRANE PROTEIN AB Notch signaling is critical for cell fate decisions during development. Caenorhabditis elegans and vertebrate Notch ligands are more diverse than classical Drosophila Notch ligands, suggesting possible functional complexities. Here, we describe a developmental role in Notch signaling for OSM-11, which has been previously implicated in defecation and osmotic resistance in C. elegans. We find that complete loss of OSM-11 causes defects in vulval precursor cell (VPC) fate specification during vulval development consistent with decreased Notch signaling. OSM-11 is a secreted, diffusible protein that, like previously described C. elegans Delta, Serrate, and LAG-2 (DSL) ligands, can interact with the lineage defective-12 (LIN-12) Notch receptor extracellular domain. Additionally, OSM-11 and similar C. elegans proteins share a common motif with Notch ligands from other species in a sequence defined here as the Delta and OSM-11 (DOS) motif. osm-11 loss-of-function defects in vulval development are exacerbated by loss of other DOS-motif genes or by loss of the Notch ligand DSL-1, suggesting that DOS-motif and DSL proteins act together to activate Notch signaling in vivo. The mammalian DOS-motif protein Deltalike1 (DLK1) can substitute for OSM-11 in C. elegans development, suggesting that DOS-motif function is conserved across species. We hypothesize that C. elegans OSM-11 and homologous proteins act as coactivators for Notch receptors, allowing precise regulation of Notch receptor signaling in developmental programs in both vertebrates and invertebrates. C1 [Komatsu, Hidetoshi; Larkins-Ford, Jonah; Corkins, Mark E.; Somers, Gerard A.; Tucey, Tim; Dionne, Heather M.; White, Jamie Q.; Wani, Khursheed; Hart, Anne C.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. [Komatsu, Hidetoshi; White, Jamie Q.; Hart, Anne C.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Chao, Michael Y.] Calif State Univ San Bernardino, Dept Biol, San Bernardino, CA 92407 USA. [Boxem, Mike] CCSB, Boston, MA USA. [Boxem, Mike] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Boxem, Mike] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Hart, AC (reprint author), Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. EM hart@helix.mgh.harvard.edu RI Boxem, Mike/B-8857-2011 OI Boxem, Mike/0000-0003-3966-4173 FU National Institutes of Health (NIH); National Center for Research Resources (NCRR); Ministry of Education; National Institute of General Medical Sciences (NIGMS; Ellison Medical Foundation (ACH); Massachusetts Biomedical Research Foundation (MYC); Japan Society for the Promotion of Science FX Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health (NIH) National Center for Research Resources (NCRR), by the C. elegans Gene Knockout Project at the Oklahoma Medical Research Foundation funded by the NIH, and by the National Bioresource Project at the Tokyo Women's Medical University School of Medicine funded by the Ministry of Education. This work was supported by funding from NIH National Institute of General Medical Sciences (NIGMS), the Ellison Medical Foundation (ACH), the Massachusetts Biomedical Research Foundation (MYC), Japan Society for the Promotion of Science (HK), and an NIH postdoctoral fellowship (JQW). NR 96 TC 44 Z9 52 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD AUG PY 2008 VL 6 IS 8 BP 1730 EP 1745 AR e196 DI 10.1371/journal.pbio.0060196 PG 16 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 341UA UT WOS:000258739400016 PM 18700817 ER PT J AU Gupta, S Dennis, J Thurman, RE Kingston, R Stamatoyannopoulos, JA Noble, WS AF Gupta, Shobhit Dennis, Jonathan Thurman, Robert E. Kingston, Robert Stamatoyannopoulos, John A. Noble, William Stafford TI Predicting Human Nucleosome Occupancy from Primary Sequence SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; HYPERSENSITIVE SITES; NUCLEOTIDE-SEQUENCE; DNA INTERACTIONS; TRIPLET REPEATS; CHROMATIN DNA; HISTONE; CURVATURE; REGIONS; GENOME AB Nucleosomes are the fundamental repeating unit of chromatin and comprise the structural building blocks of the living eukaryotic genome. Micrococcal nuclease (MNase) has long been used to delineate nucleosomal organization. Microarray-based nucleosome mapping experiments in yeast chromatin have revealed regularly-spaced translational phasing of nucleosomes. These data have been used to train computational models of sequence-directed nuclesosome positioning, which have identified ubiquitous strong intrinsic nucleosome positioning signals. Here, we successfully apply this approach to nucleosome positioning experiments from human chromatin. The predictions made by the human-trained and yeast-trained models are strongly correlated, suggesting a shared mechanism for sequence-based determination of nucleosome occupancy. In addition, we observed striking complementarity between classifiers trained on experimental data from weakly versus heavily digested MNase samples. In the former case, the resulting model accurately identifies nucleosome-forming sequences; in the latter, the classifier excels at identifying nucleosome-free regions. Using this model we are able to identify several characteristics of nucleosome-forming and nucleosome-disfavoring sequences. First, by combining results from each classifier applied de novo across the human ENCODE regions, the classifier reveals distinct sequence composition and periodicity features of nucleosome-forming and nucleosome-disfavoring sequences. Short runs of dinucleotide repeat appear as a hallmark of nucleosome-disfavoring sequences, while nucleosome-forming sequences contain short periodic runs of GC base pairs. Second, we show that nucleosome phasing is most frequently predicted flanking nucleosome-free regions. The results suggest that the major mechanism of nucleosome positioning in vivo is boundary-event-driven and affirm the classical statistical positioning theory of nucleosome organization. C1 [Gupta, Shobhit; Stamatoyannopoulos, John A.; Noble, William Stafford] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Dennis, Jonathan; Kingston, Robert] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Thurman, Robert E.] Univ Washington, Dept Med Genet, Seattle, WA 98195 USA. [Noble, William Stafford] Univ Washington, Dept Comp Sci & Engn, Seattle, WA 98195 USA. RP Gupta, S (reprint author), Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. EM jstam@u.washington.edu; noble@gs.washington.edu FU National Institutes of Health [R01 GM071923] FX This work was supported by the National Institutes of Health award R01 GM071923. NR 61 TC 68 Z9 68 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2008 VL 4 IS 8 AR e1000134 DI 10.1371/journal.pcbi.1000134 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 360EX UT WOS:000260041300014 PM 18725940 ER PT J AU Hao, JH Serohijos, AWR Newton, G Tassone, G Wang, ZC Sgroi, DC Dokholyan, NV Basilion, JP AF Hao, Jihua Serohijos, Adrian W. R. Newton, Gail Tassone, Gina Wang, Zuncai Sgroi, Dennis C. Dokholyan, Nikolay V. Basilion, James P. TI Identification and Rational Redesign of Peptide Ligands to CRIP1, A Novel Biomarker for Cancers SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID GENE-EXPRESSION PROFILES; RICH INTESTINAL PROTEIN; PHAGE DISPLAY LIBRARY; MOLECULAR-DYNAMICS; SH3 DOMAIN; BINDING; DESIGN; SPECIFICITY; PREDICTION; STABILITY AB Cysteine-rich intestinal protein 1 (CRIP1) has been identified as a novel marker for early detection of cancers. Here we report on the use of phage display in combination with molecular modeling to identify a high-affinity ligand for CRIP1. Panning experiments using a circularized C7C phage library yielded several consensus sequences with modest binding affinities to purified CRIP1. Two sequence motifs, A1 and B5, having the highest affinities for CRIP1, were chosen for further study. With peptide structure information and the NMR structure of CRIP1, the higher-affinity A1 peptide was computationally redesigned, yielding a novel peptide, A1M, whose affinity was predicted to be much improved. Synthesis of the peptide and saturation and competitive binding studies demonstrated approximately a 10-28-fold improvement in the affinity of A1M compared to that of either A1 or B5 peptide. These techniques have broad application to the design of novel ligand peptides. C1 [Hao, Jihua; Basilion, James P.] Case Western Reserve Univ, Dept Radiol, Cleveland, OH 44106 USA. [Serohijos, Adrian W. R.; Dokholyan, Nikolay V.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC USA. [Serohijos, Adrian W. R.] Univ N Carolina, Dept Phys & Astron, Chapel Hill, NC USA. [Newton, Gail; Tassone, Gina; Wang, Zuncai; Sgroi, Dennis C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Dokholyan, Nikolay V.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Basilion, James P.] Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA. [Basilion, James P.] Case Western Reserve Univ, Natl Fdn Canc Res Ctr Mol Imaging, Cleveland, OH 44106 USA. RP Hao, JH (reprint author), Case Western Reserve Univ, Dept Radiol, Cleveland, OH 44106 USA. EM dokh@med.unc.edu; James.basilion@case.edu RI Dokholyan, Nikolay/B-2238-2009; Serohijos, Adrian /G-4607-2011; OI Dokholyan, Nikolay/0000-0002-8225-4025; Serohijos, Adrian/0000-0001-8369-982X FU Komen Foundation [IMG-0403019]; National Foundation for Cancer Research; National Institutes of Health [R01GM080742-01]; American Heart Association FX This work has been supported by the Komen Foundation grant IMG-0403019 (to JPB), an ongoing center grant from the National Foundation for Cancer Research (to JPB), and by the National Institutes of Health grant R01GM080742-01 (to NVD). AWRS is a predoctoral fellow of the American Heart Association. NR 56 TC 34 Z9 35 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-734X EI 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2008 VL 4 IS 8 AR e1000138 DI 10.1371/journal.pcbi.1000138 PG 10 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 360EX UT WOS:000260041300034 PM 18670594 ER PT J AU Kishi, S Bayliss, PE Uchiyama, J Koshimizu, E Qi, J Nanjappa, P Imamura, S Islam, A Neuberg, D Amsterdam, A Roberts, TM AF Kishi, Shuji Bayliss, Peter E. Uchiyama, Junzo Koshimizu, Eriko Qi, Jie Nanjappa, Purushothama Imamura, Shintaro Islam, Asiful Neuberg, Donna Amsterdam, Adam Roberts, Thomas M. TI The Identification of Zebrafish Mutants Showing Alterations in Senescence-Associated Biomarkers SO PLOS GENETICS LA English DT Article ID PHOTORECEPTOR CELL DEGENERATION; OXIDATIVE STRESS; DANIO-RERIO; ATAXIA-TELANGIECTASIA; GRADUAL SENESCENCE; NEURODEGENERATIVE DISEASES; INSERTIONAL MUTAGENESIS; MAMMALIAN TELOMERES; BETA-GALACTOSIDASE; AGING RESEARCH AB There is an interesting overlap of function in a wide range of organisms between genes that modulate the stress responses and those that regulate aging phenotypes and, in some cases, lifespan. We have therefore screened mutagenized zebrafish embryos for the altered expression of a stress biomarker, senescence-associated b-galactosidase (SA-b-gal) in our current study. We validated the use of embryonic SA-b-gal production as a screening tool by analyzing a collection of retrovirus-insertional mutants. From a pool of 306 such mutants, we identified 11 candidates that showed higher embryonic SA-b-gal activity, two of which were selected for further study. One of these mutants is null for a homologue of Drosophila spinster, a gene known to regulate lifespan in flies, whereas the other harbors a mutation in a homologue of the human telomeric repeat binding factor 2 (terf2) gene, which plays roles in telomere protection and telomere-length regulation. Although the homozygous spinster and terf2 mutants are embryonic lethal, heterozygous adult fish are viable and show an accelerated appearance of aging symptoms including lipofuscin accumulation, which is another biomarker, and shorter lifespan. We next used the same SA-b-gal assay to screen chemically mutagenized zebrafish, each of which was heterozygous for lesions in multiple genes, under the sensitizing conditions of oxidative stress. We obtained eight additional mutants from this screen that, when bred to homozygosity, showed enhanced SA-b-gal activity even in the absence of stress, and further displayed embryonic neural and muscular degenerative phenotypes. Adult fish that are heterozygous for these mutations also showed the premature expression of aging biomarkers and the accelerated onset of aging phenotypes. Our current strategy of mutant screening for a senescence-associated biomarker in zebrafish embryos may thus prove to be a useful new tool for the genetic dissection of vertebrate stress response and senescence mechanisms. C1 [Kishi, Shuji; Koshimizu, Eriko; Qi, Jie; Nanjappa, Purushothama; Imamura, Shintaro; Islam, Asiful] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02115 USA. [Kishi, Shuji; Uchiyama, Junzo; Koshimizu, Eriko; Qi, Jie; Nanjappa, Purushothama; Imamura, Shintaro] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Bayliss, Peter E.; Uchiyama, Junzo; Roberts, Thomas M.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Bayliss, Peter E.; Uchiyama, Junzo; Roberts, Thomas M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Koshimizu, Eriko] Tokyo Univ Marine Sci & Technol, Tokyo, Japan. [Qi, Jie] Ocean Univ China, Coll Marine Life Sci, Qingdao, Peoples R China. [Neuberg, Donna] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. [Neuberg, Donna] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Amsterdam, Adam] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA. RP Kishi, S (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02115 USA. EM shuji.kishi@schepens.harvard.edu; thomas_roberts@dfci.harvard.edu FU A-T Children's Project; Ellison Medical Foundation; NIA/NIH; NIH; NCI/NIH FX This work is funded by research grants from the A-T Children's Project, the Ellison Medical Foundation and NIA/NIH to SK, NIH to AA, and NCI/NIH to TMR. NR 68 TC 59 Z9 61 U1 0 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2008 VL 4 IS 8 AR e1000152 DI 10.1371/journal.pgen.1000152 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 365MN UT WOS:000260410800018 PM 18704191 ER PT J AU Lindroth, AM Park, YJ McLean, CM Dokshin, GA Persson, JM Herman, H Pasini, D Miro, X Donohoe, ME Lee, JT Helin, K Soloway, PD AF Lindroth, Anders M. Park, Yoon Jung McLean, Chelsea M. Dokshin, Gregoriy A. Persson, Jenna M. Herman, Herry Pasini, Diego Miro, Xavier Donohoe, Mary E. Lee, Jeannie T. Helin, Kristian Soloway, Paul D. TI Antagonism between DNA and H3K27 Methylation at the Imprinted Rasgrf1 Locus SO PLOS GENETICS LA English DT Article ID H3 LYSINE-9 METHYLATION; PSEUDOHYPOPARATHYROIDISM TYPE IB; INSULATOR PROTEIN CTCF; HISTONE H3; CPG METHYLATION; CONTROL ELEMENT; CHROMATIN INSULATOR; NEUROSPORA-CRASSA; MOUSE DEVELOPMENT; CONTROL REGIONS AB At the imprinted Rasgrf1 locus in mouse, a cis-acting sequence controls DNA methylation at a differentially methylated domain (DMD). While characterizing epigenetic marks over the DMD, we observed that DNA and H3K27 trimethylation are mutually exclusive, with DNA and H3K27 methylation limited to the paternal and maternal sequences, respectively. The mutual exclusion arises because one mark prevents placement of the other. We demonstrated this in five ways: using 5-azacytidine treatments and mutations at the endogenous locus that disrupt DNA methylation; using a transgenic model in which the maternal DMD inappropriately acquired DNA methylation; and by analyzing materials from cells and embryos lacking SUZ12 and YY1. SUZ12 is part of the PRC2 complex, which is needed for placing H3K27me3, and YY1 recruits PRC2 to sites of action. Results from each experimental system consistently demonstrated antagonism between H3K27me3 and DNA methylation. When DNA methylation was lost, H3K27me3 encroached into sites where it had not been before; inappropriate acquisition of DNA methylation excluded normal placement of H3K27me3, and loss of factors needed for H3K27 methylation enabled DNA methylation to appear where it had been excluded. These data reveal the previously unknown antagonism between H3K27 and DNA methylation and identify a means by which epigenetic states may change during disease and development. C1 [Lindroth, Anders M.; Park, Yoon Jung; McLean, Chelsea M.; Dokshin, Gregoriy A.; Persson, Jenna M.; Herman, Herry; Soloway, Paul D.] Cornell Univ, Coll Agr & Life Sci, Div Nutr Sci, Ithaca, NY 14853 USA. [Herman, Herry] Padjadjaran State Univ, Hasan Sadikin Gen Hosp, Sch Med, Dept Orthopaed Surg, Bandung, West Java, Indonesia. [Pasini, Diego; Helin, Kristian] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark. [Pasini, Diego; Helin, Kristian] Univ Copenhagen, Ctr Epigenet, Copenhagen, Denmark. [Miro, Xavier] Max Planck Inst Biophys Chem, Dept Mol Cell Biol, D-37077 Gottingen, Germany. [Donohoe, Mary E.; Lee, Jeannie T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lindroth, AM (reprint author), Cornell Univ, Coll Agr & Life Sci, Div Nutr Sci, Ithaca, NY 14853 USA. EM pds28@cornell.edu RI Pasini, Diego/J-9674-2012; OI Pasini, Diego/0000-0002-9879-6486; Dokshin, Gregoriy/0000-0002-8780-7143; Persson, Jenna/0000-0002-0208-8080; Lindroth, Anders/0000-0002-8291-2745; Helin, Kristian/0000-0003-1975-6097 FU NIH [CA98596, CA120870]; US Army [DAMD17-02-1-0652] FX Funding was provided to PDS by grants from the NIH (CA98596 and CA120870) and US Army (DAMD17-02-1-0652). NR 62 TC 59 Z9 60 U1 1 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2008 VL 4 IS 8 AR e1000145 DI 10.1371/journal.pgen.1000145 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 365MN UT WOS:000260410800036 PM 18670629 ER PT J AU Moon, NS Di Stefano, L Morris, EJ Patel, R White, K Dyson, NJ AF Moon, Nam-Sung Di Stefano, Luisa Morris, Erick J. Patel, Reena White, Kristin Dyson, Nicholas J. TI E2F and p53 Induce Apoptosis Independently during Drosophila Development but Intersect in the Context of DNA Damage SO PLOS GENETICS LA English DT Article ID TUMOR-SUPPRESSOR P53; S-PHASE; P53-INDUCED APOPTOSIS; PROAPOPTOTIC GENE; RETINOBLASTOMA; RB; EXPRESSION; PATHWAYS; CELLS; P73 AB In mammalian cells, RB/E2F and p53 are intimately connected, and crosstalk between these pathways is critical for the induction of cell cycle arrest or cell death in response to cellular stresses. Here we have investigated the genetic interactions between RBF/E2F and p53 pathways during Drosophila development. Unexpectedly, we find that the pro-apoptotic activities of E2F and p53 are independent of one another when examined in the context of Drosophila development: apoptosis induced by the deregulation of dE2F1, or by the overexpression of dE2F1, is unaffected by the elimination of dp53; conversely, dp53-induced phenotypes are unaffected by the elimination of dE2F activity. However, dE2F and dp53 converge in the context of a DNA damage response. Both dE2F1/dDP and dp53 are required for DNA damage-induced cell death, and the analysis of rbf1 mutant eye discs indicates that dE2F1/dDP and dp53 cooperatively promote cell death in irradiated discs. In this context, the further deregulation in the expression of pro-apoptotic genes generates an additional sensitivity to apoptosis that requires both dE2F/dDP and dp53 activity. This sensitivity differs from DNA damage-induced apoptosis in wild-type discs (and from dE2F/dDP-induced apoptosis in un-irradiated rbf1 mutant eye discs) by being dependent on both hid and reaper. These results show that pro-apoptotic activities of dE2F1 and dp53 are surprisingly separable: dp53 is required for dE2F-dependent apoptosis in the response to DNA damage, but it is not required for dE2F-dependent apoptosis caused simply by the inactivation of rbf1. C1 [Moon, Nam-Sung; Di Stefano, Luisa; Morris, Erick J.; Dyson, Nicholas J.] Massachusetts Gen Hosp, Canc Res Ctr, Charlestown, MA USA. [Moon, Nam-Sung; Di Stefano, Luisa; Morris, Erick J.; Dyson, Nicholas J.] Harvard Univ, Sch Med, Boston, MA USA. [Patel, Reena; White, Kristin] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Moon, NS (reprint author), McGill Univ, Dept Biol, 1205 Doctor Penfield Ave, Montreal, PQ H3A 1B1, Canada. EM Dyson@helix.mgh.harvard.edu RI White, Kristin/D-7936-2013 FU NIH [GM81607, GM53203]; Leukemia and Lymphoma Society; MGH ECOR Fund for Medical Discovery; [GM55568] FX This study was supported by NIH grants GM81607 and GM53203. KW and RP were supported by GM55568. NSM was supported by a fellowship from Leukemia and Lymphoma Society. LDS was supported by a fellowship from MGH ECOR Fund for Medical Discovery. NR 40 TC 34 Z9 34 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2008 VL 4 IS 8 AR e1000153 DI 10.1371/journal.pgen.1000153 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 365MN UT WOS:000260410800030 PM 18688282 ER PT J AU Sitara, D Kim, S Razzaque, MS Bergwitz, C Taguchi, T Schuler, C Erben, RG Lanske, B AF Sitara, Despina Kim, Somi Razzaque, Mohammed S. Bergwitz, Clemens Taguchi, Takashi Schueler, Christiane Erben, Reinhold G. Lanske, Beate TI Genetic Evidence of Serum Phosphate-Independent Functions of FGF-23 on Bone SO PLOS GENETICS LA English DT Article ID VITAMIN-D METABOLISM; HYP MOUSE PHENOTYPE; PARATHYROID-HORMONE; INORGANIC-PHOSPHATE; MINERAL METABOLISM; I COTRANSPORTER; DEFICIENT MICE; HOMEOSTASIS; ABLATION; PHEX AB Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23(-/-)) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23(-/-) mice and to examine serum phosphate-independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf23(-/-) mice on phosphate homeostasis and skeletal mineralization. Fgf-23(-/-)/NaPi2a(-/-) double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23(-/-) animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23(-/-) mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23(-/-)/NaPi2a(-/-), their skeletal phenotype still resembles the one of Fgf-23(-/-) animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23(-/-) mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis. C1 [Sitara, Despina; Kim, Somi; Razzaque, Mohammed S.; Lanske, Beate] Harvard Univ, Sch Dent Med, Dept Dev Biol, Boston, MA 02115 USA. [Bergwitz, Clemens] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Bergwitz, Clemens] Harvard Univ, Sch Med, Boston, MA USA. [Taguchi, Takashi] Nagasaki Univ, Sch Biomed Sci, Dept Pathol, Nagasaki 852, Japan. [Schueler, Christiane; Erben, Reinhold G.] Univ Vet Med, Dept Nat Sci, Vienna, Austria. RP Sitara, D (reprint author), Harvard Univ, Sch Dent Med, Dept Dev Biol, 188 Longwood Ave, Boston, MA 02115 USA. EM beate_lanske@hsdm.harvard.edu OI SITARA, DESPINA/0000-0002-4836-5039 FU Harvard School of Dental Medicine; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01-073944] FX This work was supported by funds from the Harvard School of Dental Medicine given to DS and by a grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) R01-073944 to BL. NR 38 TC 88 Z9 88 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2008 VL 4 IS 8 AR e1000154 DI 10.1371/journal.pgen.1000154 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 365MN UT WOS:000260410800031 PM 18688277 ER PT J AU Khan, AM Miotto, O Nascimento, EJM Srinivasan, KN Heiny, AT Zhang, GL Marques, ET Tan, TW Brusic, V Salmon, J August, JT AF Khan, Asif M. Miotto, Olivo Nascimento, Eduardo J. M. Srinivasan, K. N. Heiny, A. T. Zhang, Guang Lan Marques, E. T. Tan, Tin Wee Brusic, Vladimir Salmon, Jerome August, J. Thomas TI Conservation and Variability of Dengue Virus Proteins: Implications for Vaccine Design SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID T-CELL RESPONSES; HEMORRHAGIC-FEVER; CRYSTAL-STRUCTURE; ENVELOPE PROTEIN; MATHEMATICAL-THEORY; MUTUAL INFORMATION; GENUS FLAVIVIRUS; CATALYTIC DOMAIN; TRANSGENIC MICE; IMMUNE-RESPONSE AB Background: Genetic variation and rapid evolution are hallmarks of RNA viruses, the result of high mutation rates in RNA replication and selection of mutants that enhance viral adaptation, including the escape from host immune responses. Variability is uneven across the genome because mutations resulting in a deleterious effect on viral fitness are restricted. RNA viruses are thus marked by protein sites permissive to multiple mutations and sites critical to viral structure-function that are evolutionarily robust and highly conserved. Identification and characterization of the historical dynamics of the conserved sites have relevance to multiple applications, including potential targets for diagnosis, and prophylactic and therapeutic purposes. Methodology/Principal Findings: We describe a large-scale identification and analysis of evolutionarily highly conserved amino acid sequences of the entire dengue virus (DENV) proteome, with a focus on sequences of 9 amino acids or more, and thus immune-relevant as potential T-cell determinants. DENV protein sequence data were collected from the NCBI Entrez protein database in 2005 (9,512 sequences) and again in 2007 (12,404 sequences). Forty-four (44) sequences (pan-DENV sequences), mainly those of nonstructural proteins and representing similar to 15% of the DENV polyprotein length, were identical in 80% or more of all recorded DENV sequences. Of these 44 sequences, 34 (similar to 77%) were present in >= 95% of sequences of each DENV type, and 27 (similar to 61%) were conserved in other Flaviviruses. The frequencies of variants of the pan-DENV sequences were low (0 to similar to 5%), as compared to variant frequencies of similar to 60 to similar to 85% in the non pan-DENV sequence regions. We further showed that the majority of the conserved sequences were immunologically relevant: 34 contained numerous predicted human leukocyte antigen (HLA) supertype-restricted peptide sequences, and 26 contained T-cell determinants identified by studies with HLA-transgenic mice and/or reported to be immunogenic in humans. Conclusions/Significance: Forty-four (44) pan-DENV sequences of at least 9 amino acids were highly conserved and identical in 80% or more of all recorded DENV sequences, and the majority were found to be immune-relevant by their correspondence to known or putative HLA-restricted T-cell determinants. The conservation of these sequences through the entire recorded DENV genetic history supports their possible value for diagnosis, prophylactic and/or therapeutic applications. The combination of bioinformatics and experimental approaches applied herein provides a framework for large-scale and systematic analysis of conserved and variable sequences of other pathogens, in particular, for rapidly mutating viruses, such as influenza A virus and HIV. C1 [Khan, Asif M.; Miotto, Olivo; Heiny, A. T.; Tan, Tin Wee] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117595, Singapore. [Miotto, Olivo] Natl Univ Singapore, Inst Syst Sci, Singapore 117595, Singapore. [Nascimento, Eduardo J. M.; Marques, E. T.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Srinivasan, K. N.; Marques, E. T.; Salmon, Jerome; August, J. Thomas] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Srinivasan, K. N.] Hlth Sci Author, Ctr Drug Adm, Product Evaluat & Registrat Div, Singapore, Singapore. [Zhang, Guang Lan; Brusic, Vladimir] Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. RP Khan, AM (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117595, Singapore. EM taugust@jhmi.edu RI Tan, Tin Wee/B-8963-2009; Marques, Ernesto/L-4967-2013; Khan, Mohammad Asif/F-4663-2010; Saude Publica, Inct/J-9544-2013; Marques, Ernesto/L-4514-2013; Nascimento, Eduardo/J-4590-2014 OI Tan, Tin Wee/0000-0002-4062-2854; Marques, Ernesto/0000-0003-3826-9358; Miotto, Olivo/0000-0001-8060-6771; Khan, Mohammad Asif/0000-0001-9202-279X; Marques, Ernesto/0000-0003-3826-9358; Nascimento, Eduardo/0000-0002-9851-2332 FU National Institutes of Health; Department of Health and Human Services, USA [U19 AI56541] FX This project has been funded in part with the Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, USA, under Grant No. 5 U19 AI56541. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 81 TC 33 Z9 34 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD AUG PY 2008 VL 2 IS 8 AR e272 DI 10.1371/journal.pntd.0000272 PG 15 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 385IG UT WOS:000261807300009 PM 18698358 ER PT J AU Pugh, MJV Zeber, JE Copeland, LA Tabares, JV Cramer, JA AF Pugh, Mary Jo V. Zeber, John E. Copeland, Laurel A. Tabares, Jeff V. Cramer, Joyce A. TI Psychiatric disease burden profiles among veterans with epilepsy: The association with health services utilization SO PSYCHIATRIC SERVICES LA English DT Article ID QUALITY-OF-LIFE; COMORBID DEPRESSION; MENTAL-ILLNESS; IMPACT; CARE; PEOPLE AB Objective: This brief report describes patterns of psychiatric comorbidities among patients with epilepsy and their relationship with health care utilization. Methods: The study identified psychiatric comorbid conditions in a cohort of veterans identified as having epilepsy in fiscal year 1999. From these diagnoses, nine psychiatric disease burden profiles were created. Logistic regression examined variation in emergency, neurology, and primary care for groups having different profiles and compared them with those with only epilepsy. Results: Of the 23,752 individuals identified, 48% had comorbid psychiatric conditions; most had multiple psychiatric diagnoses. Compared with patients with epilepsy only, those with comorbid psychiatric conditions were more likely to have emergency care and high primary care utilization; those with serious mental illness (psychotic disorders) were less likely to receive neurology care. Conclusions: Multiple co-occurring psychiatric diseases are common among patients with epilepsy. Addressing the mental health and medical needs of these patients, particularly those with serious mental illness, represents a challenge for health organizations. C1 [Pugh, Mary Jo V.; Zeber, John E.; Copeland, Laurel A.; Tabares, Jeff V.] Vet Evidence Based Res Disseminat Implementat Ctr, Hlth Serv Res & Dev Serv, Dept Vet Affairs, San Antonio, TX 78229 USA. [Pugh, Mary Jo V.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Zeber, John E.; Copeland, Laurel A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Cramer, Joyce A.] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Pugh, MJV (reprint author), Vet Evidence Based Res Disseminat Implementat Ctr, Hlth Serv Res & Dev Serv, Dept Vet Affairs, 7400 Merton Minter Blvd 11C6, San Antonio, TX 78229 USA. EM pughm@uthscsa.edu OI Pugh, Mary Jo/0000-0003-4196-7763; Copeland, Laurel/0000-0002-9478-0209 FU HSRD VA [I01 HX000329] NR 15 TC 9 Z9 9 U1 1 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD AUG PY 2008 VL 59 IS 8 BP 925 EP 928 DI 10.1176/appi.ps.59.8.925 PG 4 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 333YZ UT WOS:000258190800017 PM 18678692 ER PT J AU Patenaude, AF Julian-Reynier, C AF Patenaude, Andrea Farkas Julian-Reynier, Claire TI Cancer genetic testing: current and emerging issues SO PSYCHO-ONCOLOGY LA English DT Editorial Material C1 [Patenaude, Andrea Farkas] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Patenaude, Andrea Farkas] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Julian-Reynier, Claire] INSERM, U912, F-13258 Marseille, France. [Julian-Reynier, Claire] Univ Aix Marseille, Inst J Paoli I Calmettes, IRD, UMR S912, Marseille, France. RP Patenaude, AF (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM andrea_patenaude@dfci.harvard.edu NR 16 TC 5 Z9 5 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD AUG PY 2008 VL 17 IS 8 BP 733 EP 736 DI 10.1002/pon.1419 PG 4 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 346GF UT WOS:000259056100001 PM 18688786 ER PT J AU Patenaude, AF Orozco, S Li, X Kaelin, CM Gadd, M Matory, Y Mayzel, K Roche, CA Smith, BL Farkas, W Garber, JF AF Patenaude, Andrea F. Orozco, Sara Li, Xiaochun Kaelin, Carolyn M. Gadd, Michelle Matory, Yvedt Mayzel, Kathleen Roche, Constance A. Smith, Barbara L. Farkas, Walden Garber, Judy F. TI Support needs and acceptability of psychological and peer consultation: attitudes of 108 women who had undergone or were considering prophylactic mastectomy SO PSYCHO-ONCOLOGY LA English DT Article DE cancer; oncology; prophylactic mastectomy; psychological service delivery; outcomes ID HEREDITARY BREAST-CANCER; QUALITY-OF-LIFE; OVARIAN-CANCER; FOLLOW-UP; BILATERAL MASTECTOMY; RISK-ASSESSMENT; BRCA1; SURGERY; MUTATION; SUSCEPTIBILITY AB Objective: Prophylactic mastectomy (PM) offers 90%. or greater reduction in risk of breast cancer to women at increased hereditary risk. Nonetheless, acceptance in North America is low (0-27%) and 25-50% of women electing surgery report psychological distress and/or difficulty adapting following PM. Most women also report reduced cancer worry postoperatively. Psychological consultation to aid decision-making and post-surgical coping is not routinely offered. This retrospective, cross-sectional study explored interest in and acceptability of psychological consultation for issues related to PM among 108 women who had undergone or were considering surgery. Method: Qualitative interviews were conducted with 26 healthy women who had undergone prophylactic mastectomy of both (bilateral) breasts (BPM), 45 women who had undergone prophylactic mastectomy of one breast (unilateral contralateral) (UPM) after diagnosis of invasive breast cancer in the other breast or ductal carcinoma in situ (DCIS), and 37 women who were considering having PM surgery. Results: Of the women who had undergone PM, more than half felt pre-surgical psychological consultation was advisable; nearly 2/3 thought post-surgical psychological consultation would be helpful. All women currently considering PM believed psychological consultation would aid decision-making and preparation for surgery. Strong support was reported in all groups for the emotional and informational value of speaking with a woman who had previously undergone PM. Conclusions: Narratives illustrate the nature and intensity of the need for psychological support and describe preferences for the role of the psychologist. Suggestions are offered for integration of psychological services for women deciding about or adapting to PM. Copyright (C) 2008 John Wiley & Sons, Ltd. C1 [Patenaude, Andrea F.; Orozco, Sara] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Li, Xiaochun] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. [Kaelin, Carolyn M.; Matory, Yvedt] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Gadd, Michelle; Smith, Barbara L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mayzel, Kathleen] Faulkner Hosp, Dept Surg, Boston, MA USA. [Roche, Constance A.] Massachusetts Gen Hosp, Avon Comprehens Breast Evaluat Ctr, Boston, MA 02114 USA. [Garber, Judy F.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Patenaude, AF (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. EM andrea-patenaude@dfci.harvard.edu FU U.S. Army Research Materiel Command [DAMD 17-99-1-9162, 1 RO3 HG003051] FX This paper is dedicated to the Subjects in this research who shared their stories for the benefit of others and to all who face challenging decisions related to hereditary cancer risk. Funding, Cor this project was provided by the U.S. Army Research Materiel Command under grant DAMD 17-99-1-9162 and under grant 1 RO3 HG003051 from the Ethical. Legal and Social Implications Program of the National Human Genome Research Institute. The authors report no financial or personal conflicts of interest in the presentation of this manuscript. NR 33 TC 15 Z9 15 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD AUG PY 2008 VL 17 IS 8 BP 831 EP 843 DI 10.1002/pon.1279 PG 13 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 346GF UT WOS:000259056100013 PM 18636423 ER PT J AU Ditman, T Holcomb, PI Kuperberg, GF AF Ditman, Tali Holcomb, Phillip I. Kuperberg, Gina F. TI Time travel through language: Temporal shifts rapidly decrease information accessibility during reading SO PSYCHONOMIC BULLETIN & REVIEW LA English DT Article ID EVENT-RELATED POTENTIALS; NARRATIVE COMPREHENSION; BRAIN POTENTIALS; SITUATION MODELS; MEMORY; BOUNDARIES; TEXT AB The present study dissociated the immediate neural costs from the subsequent neural consequences of integrating time shifts into our mental representations of events. Event-related potentials were recorded as participants read scenarios that included words referring to short temporal shifts (e.g., after one second), moderate temporal shifts (e.g., after one hour), or long temporal shifts (e.g., after one year). These words were followed by repeated noun-phrase anaphors, which are preferred as referents for information no longer in attentional focus. The N400 was measured as an index of online conceptual integration. As the discourse unfolded, the N400 was larger for long- (e.g., year) than for short- (e.g., second) shift words. For the anaphor, the N400 was modulated in the opposite direction. Thus, the introduction of a temporal discontinuity leads to immediate neural integration costs, as well as to decreased accessibility of earlier information. C1 [Ditman, Tali; Holcomb, Phillip I.; Kuperberg, Gina F.] Tufts Univ, Medford, MA 02155 USA. [Kuperberg, Gina F.] Massachusetts Gen Hosp, Charlestown, MA USA. RP Ditman, T (reprint author), Tufts Univ, Psychology Bldg,490 Boston Ave, Medford, MA 02155 USA. EM tali.ditman@tufts.edu FU NICHD NIH HHS [HD25889, R01 HD025889-15, R01 HD025889-17, R01 HD043251, R37 HD025889, R01 HD025889, HD043251, R01 HD025889-16, R01 HD025889-18]; NIMH NIH HHS [R01 MH071635] NR 24 TC 16 Z9 23 U1 1 U2 4 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 1069-9384 J9 PSYCHON B REV JI Psychon. Bull. Rev. PD AUG PY 2008 VL 15 IS 4 BP 750 EP 756 DI 10.3758/PBR.15.4.750 PG 7 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA 341XI UT WOS:000258748500005 PM 18792500 ER PT J AU Wright, R Thompson, WL Ganis, G Newcombe, NS Kosslyn, SM AF Wright, Rebecca Thompson, William L. Ganis, Giorgio Newcombe, Nora S. Kosslyn, Stephen M. TI Training generalized spatial skills SO PSYCHONOMIC BULLETIN & REVIEW LA English DT Article ID MENTAL ROTATION; PERFORMANCE; OBJECTS; EXPERIENCE; MEMORY AB Spatial transformation skills are an essential aspect of cognitive ability. These skills can be improved by practice, but such improvement has usually been specific to tasks and stimuli. The present study investigated whether intensive long-term practice leads to change that transcends stimulus and task parameters. Thirty-one participants (14 male, 17 female) were tested on three cognitive tasks: a computerized version of the Shepard-Metzler (197 1) mental rotation task (MRT), a mental paper-folding task (MPFT), and a verbal analogies task (VAT). Each individual then participated in daily practice sessions with the MRT or the MPFT over 21 days. Postpractice comparisons revealed transfer of practice gains to novel stimuli for the practiced task, as well as transfer to the other, nonpracticed spatial task. Thus, practice effects were process based, not instance based. Improvement in the nonpracticed spatial task was greater than that in the VAT; thus, improvement was not merely due to greater ease with computerized testing. C1 [Kosslyn, Stephen M.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Kosslyn, Stephen M.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wright, Rebecca] Univ Oxford, Oxford, England. [Ganis, Giorgio] Harvard Univ, Sch Med, Boston, MA USA. [Ganis, Giorgio] Massachusetts Gen Hosp, Charlestown, MA USA. [Newcombe, Nora S.] Temple Univ, Philadelphia, PA 19122 USA. RP Kosslyn, SM (reprint author), Harvard Univ, Dept Psychol, 830 William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. EM smkosslyn@wjh.harvard.edu OI Ganis, Giorgio/0000-0001-6175-2618 NR 19 TC 71 Z9 71 U1 1 U2 11 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 1069-9384 J9 PSYCHON B REV JI Psychon. Bull. Rev. PD AUG PY 2008 VL 15 IS 4 BP 763 EP 771 DI 10.3758/PBR.15.4.763 PG 9 WC Psychology, Mathematical; Psychology, Experimental SC Psychology GA 341XI UT WOS:000258748500007 PM 18792502 ER PT J AU Li, YQ Wang, XY Zhai, HF Zheng, YQ Zhang, XY Kosten, T Lu, L AF Li, Yan-Qin Wang, Xiao-Yi Zhai, Hai-feng Zheng, Yong-Qiu Zhang, Xiang Yang Kosten, Therese Lu, Lin TI Effects of early postnatal sibling deprivation on anxiety and vulnerability to cocaine in offspring rats SO PSYCHOPHARMACOLOGY LA English DT Article DE early postnatal sibling deprivation; anxiety behavior; natural reward; conditioned place preference; cocaine ID NEONATAL MATERNAL SEPARATION; CONDITIONED PLACE PREFERENCE; ADULT MALE RATS; FEMALE RATS; NEUROENDOCRINE RESPONSES; BEHAVIORAL SENSITIZATION; COGNITIVE-DEVELOPMENT; STRESS EXPERIENCE; MENTAL-HEALTH; CARE AB Rationale Early-life experience has long-term consequences on affective behavior and drug abuse in adults. While many manipulations used to study these consequences alter mother-infant interactions, the effects of sibling interactions are less well characterized. Objectives To examine the long-term effects of early postnatal sibling deprivation (EPSD) on anxiety-like behavior, sucrose preference and behavioral responses to cocaine in adult rats. Materials and methods After EPSD manipulation, in which litters were culled to one pup on postnatal day 1 (PN1) or 7 (PN7), the dams' maternal behavior was observed. After the pups reached adulthood, we tested their behavioral responses in the elevated plus maze and sucrose consumption, and to cocaine conditioned place preference and cocaine sensitization. Results The pups with EPSD on PN1 received more maternal licking/grooming during the first postnatal week. EPSD on PN1 but not PN7 enhanced locomotor activity in the open field test and exploration of open arms in the elevated plus maze in both female and male offspring. While EPSD had no effect on sucrose intake in adult rats, it decreased vulnerability to cocaine sensitization and cocaine conditioned place preference in male but not female rats. Conclusion Our findings that early postnatal sibling deprivation influences maternal licking/grooming behavior, as well as anxiety-like behavior and vulnerability to drugs in pups that have grown to adulthood, suggests that both sibling interaction and maternal behavior, play critical roles in individual development. C1 [Li, Yan-Qin; Wang, Xiao-Yi; Zhai, Hai-feng; Zheng, Yong-Qiu; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100083, Peoples R China. [Zhang, Xiang Yang; Kosten, Therese] Baylor Coll Med, VA Med Ctr, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. RP Lu, L (reprint author), Peking Univ, Natl Inst Drug Dependence, 38 Xue Yuan Rd,Haidian Dist, Beijing 100083, Peoples R China. EM linlu@bjmu.edu.cn NR 53 TC 6 Z9 6 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2008 VL 199 IS 2 BP 245 EP 253 DI 10.1007/s00213-008-1169-9 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 322NR UT WOS:000257383100011 PM 18452033 ER PT J AU Glasgow, JL McLennan, SR High, KJ Celi, LAG AF Glasgow, J. L. McLennan, S. R. High, K. J. Celi, L. A. G. TI Quality of dying in a New Zealand teaching hospital SO QUALITY & SAFETY IN HEALTH CARE LA English DT Article ID UNITED-STATES; INTENSIVE-CARE; LIFE; END AB Objective: Studies suggest that there is a need to improve the way we deliver care at the end of life. Based on recommendations from end-of-life experts, metrics were identified to measure the quality of dying in Dunedin Hospital. Design: A retrospective observational study was performed to assess the care provided to patients who died in the hospital in 2003. Setting: Dunedin Hospital is a 350-bed tertiary care teaching hospital located in the South Island of New Zealand. Subjects and method: Medical records of 200 consecutive decedents were reviewed to evaluate communication, interventions, and symptom control during their terminal hospitalisation. Results: Mean hospital length-of-stay was 8 days; 38 patients (19%) died following an ICU admission. There was documentation of end-of-life discussion with either the patient or the family in 164 patients (82%). 74% had a DNR order. Pain status was documented in 140 patients (70%); 134 of these patients were pain-free. Conclusion: Overall, the results suggest that the ideals in end-of-life care pertaining to pain control, communication and avoidance of unnecessary interventions were achieved in a majority of the decedents during the study period. The socialised healthcare system, the availability of resources, societal expectations and a lack of a litigious environment are theorised to positively influence end-of life care delivery in New Zealand. C1 [Glasgow, J. L.; High, K. J.; Celi, L. A. G.] Dunedin Publ Hosp, Dept Anaesthesia Intens Care & Pain Med, Dunedin, New Zealand. [McLennan, S. R.] Univ Otago, Ctr Bioeth, Dunedin Sch Med, Dunedin, New Zealand. RP Celi, LAG (reprint author), Massachusetts Gen Hosp, Comp Sci Lab, 50 Staniford St, Boston, MA 02114 USA. EM leo_celi@hms.harvard.edu RI McLennan, Stuart/C-1048-2015 OI McLennan, Stuart/0000-0002-2019-6253 NR 17 TC 9 Z9 9 U1 1 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1475-3898 J9 QUAL SAF HEALTH CARE JI Qual. Saf. Health Care PD AUG PY 2008 VL 17 IS 4 BP 244 EP 248 DI 10.1136/qshc.2007.024745 PG 5 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 333XI UT WOS:000258186500005 PM 18678719 ER PT J AU Kozin, SV Niemierko, A Huang, P Silva, J Doppke, KP Suit, HD AF Kozin, Sergey V. Niemierko, Andrzej Huang, Peigen Silva, Jose Doppke, Karen P. Suit, Herman D. TI Inter- and intramouse heterogeneity of radiation response for a growing paired organ SO RADIATION RESEARCH LA English DT Article ID SKIN TELANGIECTASIA; PREDICTIVE ASSAYS; RADIOTHERAPY; THERAPY; RADIOSENSITIVITY; MODELS AB An intensive search for predictive markers of individual radiation response of apparently normal tissues in cancer patients is in progress at the genetic and epigenetic levels. However, the relative impact of variability at these levels is not clear. Experimental results obtained in inbred rodents, which have significantly reduced genetic heterogeneity relative to a population of human patients, may help to clarify this issue. We investigated a paired-organ mouse system in a strain of inbred mice to evaluate the intermouse variability of normal tissue radiation response, singled out from measurement errors and stochastic effects. The legs of 5-day-old C3H mice were homogeneously gamma-irradiated with a range of single doses. The lengths of the right and left tibiae were measured in 30 kVp X-ray images taken at the time of irradiation and at 84 days postirradiation. The dose-effect curves were smooth and well defined, with bone growth retardation evident at similar to 14 Gy and higher, and were marginally gender-dependent. The intramouse (left compared to right) variability of the tibia length on day 89, which characterized stochastic effects, was not distinguishable from the measurement error for doses less than 16-18 Gy and slightly exceeded measurement errors only at the largest doses of 20-22 Gy. The corresponding intermouse variability was greater than the measurement error and stochastic effects at all doses used. Interestingly, the total variability, judged by the gamma(50) values of similar to 7 we obtained, was similar to that reported for severe late reactions in human normal tissue. If the variations of response determined by epigenetic events in human patients free of known factors associated with altered radiation sensitivity are comparable to those observed in this mouse model, our results imply a relatively low power of genetic approaches alone to predict individual side effects in radiotherapy. (C) 2008 by Radiation Research Society. C1 [Kozin, Sergey V.; Niemierko, Andrzej; Huang, Peigen; Silva, Jose; Doppke, Karen P.; Suit, Herman D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Radiat Dept,Edwin L Steele Lab Tumor Biol, Boston, MA 02114 USA. RP Kozin, SV (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Radiat Dept,Edwin L Steele Lab Tumor Biol, 100 Blossom St, Boston, MA 02114 USA. EM kozin@steele.mgh.harvard.edu FU NCI NIH HHS [CA 13311, CA 21239, CA 50628] NR 17 TC 5 Z9 5 U1 0 U2 0 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD AUG PY 2008 VL 170 IS 2 BP 264 EP 267 DI 10.1667/RR1262.1 PG 4 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 331IY UT WOS:000258007100015 PM 18666813 ER PT J AU Lee, JM Georgian-Smith, D Gazelle, GS Halpern, EF Rafferty, EA Moore, RH Yeh, ED D'Alessandro, HA Hitt, RA Kopans, DB AF Lee, Janie M. Georgian-Smith, Dianne Gazelle, G. Scott Halpern, Elkan F. Rafferty, Elizabeth A. Moore, Richard H. Yeh, Eren D. D'Alessandro, Helen A. Hitt, Rachel A. Kopans, Daniel B. TI Detecting nonpalpable recurrent breast cancer: The role of routine mammographic screening of transverse rectus Abdominis myocutaneous flap reconstructions SO RADIOLOGY LA English DT Article ID SKIN-SPARING MASTECTOMY; LOCAL RECURRENCE; IMMEDIATE RECONSTRUCTION; GUIDELINES; AGE AB Purpose: To perform a retrospective cohort study to determine the rates of recall and cancer detection and then to develop a decision analytic model to evaluate the effectiveness of routine screening of transverse rectus abdominis myocutaneous (TRAM) flap reconstructions. Materials and Methods: This study was approved by the institutional review board, and the methods comply with HIPAA regulations. A retrospective search of the institutional mammographic results database was done to identify bilateral screening mammographic examinations obtained from January 1, 1999, through July 15, 2005. The search included the term TRAM; the recall and cancer detetion rates were then detected. Subsequently, a decision analytic model was constructed to evaluate a hypothetical cohort of women with TRAM flap reconstructions. Results: Of 554 mammograms (265 TRAM flap reconstructions), 546 (98.6%) had negative results (Breast Imaging Reporting and Data System category 1 or 2). Eight (1.4%) had positive test results (Breast Imaging Reporting and Data System category 0, 3, 4, or 5). All suspicious lesions underwent biopsy and had benign pathologic results. No interval breast cancers were identified. The detection rate for nonpalpable recurrent breast cancer was 0% (exact 95% confidence interval: 0.0%, 1.4%). According to decision analysis, screening would help detect an estimated 12 additional recurrent cancers per 1000 women screened, providing an additional 1.6 days of life expectancy for the screened cohort. Under base-case conditions, screening of TRAM flap reconstructions is less effective than screening asymptomatic women in their 40s. Sensitivity analysis revealed that a benefit equivalent to that of screening asymptomatic women in their 40s was achievable under conditions related to estimates of screening effectiveness and cancer detection rate. Conclusion: Routine screening mammography of TRAM flap reconstructions has a very low detection rate for nonpalpable recurrent breast cancer. Decision analysis indicates that screening such women is less effective than screening asymptomatic women in their 40s for primary breast cancer. (C) RSNA, 2008. C1 [Lee, Janie M.; Gazelle, G. Scott; Halpern, Elkan F.; Rafferty, Elizabeth A.; Moore, Richard H.; D'Alessandro, Helen A.; Hitt, Rachel A.; Kopans, Daniel B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Georgian-Smith, Dianne; Yeh, Eren D.] Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Lee, JM (reprint author), Massachusetts Gen Hosp, Dept Radiol, 101 Merrimac St,10th Floor, Boston, MA 02114 USA. EM jlee45@partners.org NR 27 TC 14 Z9 14 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 AUG PY 2008 VL 248 IS 2 BP 398 EP 405 DI 10.1148/radiol.2482071635 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329KL UT WOS:000257866400011 PM 18539887 ER PT J AU Cury, RC Nieman, K Shapiro, MD Butler, J Nomura, CH Ferencik, M Hoffmann, U Abbara, S Jassal, DS Yasuda, T Gold, HK Jang, IK Brady, TJ AF Cury, Ricardo C. Nieman, Koen Shapiro, Michael D. Butler, Javed Nomura, Cesar H. Ferencik, Maros Hoffmann, Udo Abbara, Suhny Jassal, Davinder S. Yasuda, Tsunehiro Gold, Herman K. Jang, Ik-Kyung Brady, Thomas J. TI Comprehensive assessment of myocardial perfusion defects, regional wall motion, and left ventricular function by using 64-section multidetector CT SO RADIOLOGY LA English DT Article ID SPIRAL COMPUTED-TOMOGRAPHY; CARDIAC MAGNETIC-RESONANCE; CORONARY-ANGIOGRAPHY; ROW CT; INFARCTION; SPECT; EXPERIENCE; VIABILITY; HEART; SIZE AB Purpose: To evaluate the accuracy of 64-section multidetector computed tomography (CT) for the assessment of perfusion defects (PDs), regional wall motion (RWM), and global left ventricular (LV) function. Materials and Methods: All myocardial infarction (MI) patients signed informed consent. The IRB approved the study and it was HIPAA-compliant. Cardiac multidetector CT was performed in 102 patients (34 with recent acute MI and 68 without). Multidetector CT images were analyzed for myocardial PD, RWM abnormalities, and LV function. Global LV function and RWM were compared with transthoracic echocardiography (TTE) by using multidetector CT. PD was detected by using multidetector CT and was correlated with cardiac biomarkers and single photon emission CT (SPECT) myocardial perfusion imaging. Multidetector CT diagnosis of acute MI was made on the basis of matching the presence of PD with RWM abnormalities compared with clinical evaluation. Results: Correlation between multidetector CT and TTE for global function (r = 0.68) and RWM (kappa = 0.79) was good. The size of PD on multidetector CT had a moderate correlation against SPECT (r = 0.48, -7% +/- 9). There was good to excellent correlation between cardiac biomarkers and the percentage infarct size by using multidetector CT (r = 0.82 for creatinine phosphokinase, r = 0.76 for creatinine phosphokinase of the muscle band, and r = 0.75 for troponin). For detection of acute MI in patients, multidetector CT sensitivity was 94% (32 of 34) and specificity was 97% (66 of 68). Multidetector CT had an excellent interobserver reliability for ejection fraction quantification (r = 0.83), as compared with TTE (r = 0.68). Conclusion: Patients with acute MI can be identified by using multidetector CT on the basis of RWM abnormalities and PD. (C) RSNA, 2008. C1 [Cury, Ricardo C.; Nieman, Koen; Shapiro, Michael D.; Butler, Javed; Nomura, Cesar H.; Ferencik, Maros; Hoffmann, Udo; Abbara, Suhny; Brady, Thomas J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Jassal, Davinder S.; Yasuda, Tsunehiro; Gold, Herman K.; Jang, Ik-Kyung] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Cury, Ricardo C.; Nieman, Koen; Shapiro, Michael D.; Butler, Javed; Nomura, Cesar H.; Ferencik, Maros; Hoffmann, Udo; Abbara, Suhny; Brady, Thomas J.] Massachusetts Gen Hosp, Cardiac MR PT CT Program, Boston, MA 02114 USA. [Cury, Ricardo C.; Nieman, Koen; Shapiro, Michael D.; Butler, Javed; Nomura, Cesar H.; Ferencik, Maros; Hoffmann, Udo; Abbara, Suhny; Brady, Thomas J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Cury, RC (reprint author), Massachusetts Gen Hosp, Dept Radiol, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM rcury@partners.org RI Nomura, Cesar/H-1636-2012 FU NHLBI NIH HHS [1 T32 HL076136-02, T32 HL076136] NR 30 TC 96 Z9 101 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 AUG PY 2008 VL 248 IS 2 BP 466 EP 475 DI 10.1148/radiol.2482071478 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 329KL UT WOS:000257866400019 PM 18641250 ER PT J AU Dickey, CC Morocz, IA Niznikiewicz, MA Voglmaier, M Toner, S Khan, U Dreusicke, M Yoo, SS Shenton, ME McCarley, RW AF Dickey, Chandlee C. Morocz, Istvan A. Niznikiewicz, Margaret A. Voglmaier, Martina Toner, Sarah Khan, Usman Dreusicke, Mark Yoo, Seung-Schik Shenton, Martha E. McCarley, Robert W. TI Auditory processing abnormalities in schizotypal personality disorder: An fMRI experiment using tones of deviant pitch and duration SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizotypal personality disorder; auditory; schizophrenia; fMRI; MRI; imaging; tone processing; evoked potential; ERP; mismatch; negativity; pitch; frequency; duration; MMN ID MISMATCH NEGATIVITY GENERATION; EVENT-RELATED POTENTIALS; SUPERIOR TEMPORAL GYRUS; EMOTIONAL PROSODY; HESCHLS GYRUS; PLANUM TEMPORALE; THOUGHT-DISORDER; PROFILE ANALYSIS; WORKING-MEMORY; SCHIZOPHRENIA AB Background: One of the cardinal features of schizotypal personality disorder (SPD) is language abnormalities. The focus of this study was to determine whether or not there are also processing abnormalities of pure tones differing in pitch and duration in SPD. Methods: Thirteen neuroleptic-naive male subjects met full criteria for SPD and were group-matched on age and parental socioeconomic status to 13 comparison subjects. Verbal learning was measured with the California Verbal Learning Test. Heschl's gyros volumes were measured using structural MRI. Whole-brain fMRI activation patterns in an auditory task of listening to tones including pitch and duration deviants were compared between SPD and control subjects. In a second and separate ROI analysis we found that peak activation in superior temporal gyrus (STG), Brodmann Areas 41 and 42, was correlated with verbal learning and clinical measures derived from the SCID-II interview. Results: In the region of the STG, SPD subjects demonstrated more activation to pitch deviants bilaterally (p<0.001); and to duration deviants in the left hemisphere (p = 0.005) (two-sample t). SPD subjects also showed more bilateral parietal cortex activation to duration deviants. In no region did comparison subjects activate more than SPD subjects in either experiment. Exploratory correlations for SPD subjects suggest a relationship between peak activation on the right for deviant tones in the pitch experiment with odd speech and impaired verbal learning. There was no difference between groups on Heschl's gyrus volume. Conclusions: These data suggest that SPD subjects have inefficient or hyper-responsive processing Of pure tones both in terms of pitch and duration deviance that is not attributable to smaller Heschl's gyrus volumes. Finally, these auditory processing abnormalities may have significance for the odd speech heard in some SPD subjects and downstream language and verbal learning deficits. Published by Elsevier B.V. C1 [Dickey, Chandlee C.] VA Boston Healthcare Syst, Serious Mental Illness Program, Brockton, MA 02401 USA. [Dickey, Chandlee C.; Niznikiewicz, Margaret A.; Voglmaier, Martina; Toner, Sarah; Dreusicke, Mark; Shenton, Martha E.; McCarley, Robert W.] VA Boston Healthcare Syst, Neurosci Lab, Brockton, MA 02401 USA. [Dickey, Chandlee C.; Niznikiewicz, Margaret A.; Khan, Usman; Shenton, Martha E.] Brigham & Womens Hosp, Psychiat Neuroimaging Lab, Boston, MA 02115 USA. [Dickey, Chandlee C.; Morocz, Istvan A.; Yoo, Seung-Schik; Shenton, Martha E.] Brigham & Womens Hosp, Surg Planning Lab, Boston, MA 02115 USA. [Voglmaier, Martina] Cambridge Hlth Alliance, Cambridge, MA USA. RP Dickey, CC (reprint author), VA Boston Healthcare Syst, Serious Mental Illness Program, Psychiat 116A-RC,940 Belmont St, Brockton, MA 02401 USA. EM chandlee_dickey@hms.harvard.edu; pisti@bwh.harvard.edu; Margaret_niznikiewicz@hms.harvard.edu; mvoglmaier@challiance.org; sktoner@u.washington.edu; usman@bwh.harvard.edu; markdreusicke@gmail.com; yoo@bwh.harvard.edu; Shenton@bwh.harvard.edu; Robert_mccarley@hms.harvard.edu RI McCarley, Robert/N-5562-2014 OI McCarley, Robert/0000-0001-5705-7495 FU VA Advanced Career Development Award; Brigham & Women's Hospital; NIMH [RO1 MH52807] FX This study was funded by awards to CCD (VA Advanced Career Development Award and Brigham & Women's Hospital Translational Neuroscience Award), and to RWM (NIMH RO1 MH52807). The VA, BWH, and NIMH had no involvement in the study design, data collection or interpretation, nor in the writing or submitting of the report. NR 78 TC 17 Z9 17 U1 4 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2008 VL 103 IS 1-3 BP 26 EP 39 DI 10.1016/j.schres.2008.04.041 PG 14 WC Psychiatry SC Psychiatry GA 338CC UT WOS:000258481500004 PM 18555666 ER PT J AU Meyer, JM Davis, VG McEvoy, JP Goff, DC Nasrallah, HA Davis, SM Daumit, GL Hsiao, J Swartz, MS Stroup, TS Lieberman, JA AF Meyer, Jonathan M. Davis, Vicki G. McEvoy, Joseph P. Goff, Donald C. Nasrallah, Henry A. Davis, Sonia M. Daumit, Gail L. Hsiao, John Swartz, Marvin S. Stroup, T. Scott Lieberman, Jeffrey A. TI Impact of antipsychotic treatment on nonfasting triglycerides in the CATIE Schizophrenia Trial phase 1 SO SCHIZOPHRENIA RESEARCH LA English DT Article DE antipsychotic; schizophrenia; cardiovascular risk; lipids; triglycerides; nonfasting ID ISCHEMIC-HEART-DISEASE; METABOLIC SYNDROME; RISK; EFFICACY; WOMEN AB Background: Recent literature documents a stronger association between nonfasting triglycerides (TG) and cardiovascular risk compared to fasting TG. Given concerns over antipsychotic effects on serum TG, this analysis explored changes in nonfasting TG in phase I of the CATIE Schizophrenia Trial. Methods: Change in nonfasting TG, adjusted for baseline value, was compared between antipsychotic treatment groups using subjects with nonfasting laboratory assessments at baseline and 3 months. Results: Among the 246 subjects there were significant treatment differences in 3-month change from baseline (p = 0.009). The greatest increases in Median and adjusted Mean nonfasting TG levels were seen among those randomized to quetiapine (Mean+54.7 Mg/dl, median+26 mg/dl) and olarizapine (mean+23.4 mg/dl, median+26.5 mg/dl), while ziprasidone was neutral (mean+0.0 mg/dl, median+8mg/dl), and decreases were seen with risperidone(mean-18.4 mg/dl, median-6.5 mg/dl) and prephenazine (mean-1.3 mg/dl, median-22 mg/dl). Pairwise comparisons indicated a significant between-group difference for perphenazine vs. olanzapine (p=0.002) and a trend for perplienazine vs. quetiapine (p=0.006). Conclusions: This analysis provides further evidence for differential antipsychotic metabolic liabilities, and confirms signals for the effects of olanzapine and quetiapine on serum TG seen in earlier CATIE analyses. Future consensus recommendations will clarify the role of nonfasting TG monitoring in routine clinical practice. (C) 2008 Elsevier B.V. All rights reserved. C1 [Meyer, Jonathan M.] VA San Diego Healthcare Syst, San Diego, CA 92161 USA. [Meyer, Jonathan M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Davis, Vicki G.] Univ N Carolina, Collaborat Studies Coordinating Ctr, Bank Amer Ctr, Dept Biostat, Chapel Hill, NC 27514 USA. [McEvoy, Joseph P.] Duke Univ, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [McEvoy, Joseph P.] John Umstead Hosp, Butner, NC 27509 USA. [Goff, Donald C.] Harvard Univ, Dept Psychiat, Cambridge, MA 02138 USA. [Goff, Donald C.] Massachusetts Gen Hosp, Lindemann Mental Hlth Ctr, Freedom Trail Clin, Schizophrenia Program, Boston, MA 02114 USA. [Nasrallah, Henry A.] Univ Cincinnati, Cincinnati, OH 45267 USA. [Davis, Sonia M.] Quintiles Inc, Biostatistics, Morrisville, NC 27560 USA. [Daumit, Gail L.] Johns Hopkins Med Inst, Baltimore, MD 21287 USA. [Hsiao, John] NIMH, Adult Psychopharmacol Intervent Program, Bethesda, MD 20892 USA. [Swartz, Marvin S.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Stroup, T. Scott] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Lieberman, Jeffrey A.] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. RP Meyer, JM (reprint author), VA San Diego Healthcare Syst, 3350 La Jolla Village Dr,116A, San Diego, CA 92161 USA. EM jmmeyer@ucsd.edu; Vicki.Davis@mail.cscc.unc.edu; jpmcevoy@duke.edu; goff@psych.mgh.harvard.edu; NASRALHA@ucmail.uc.edu; sonia.davis@quintiles.com; gdaumit@jhmi.edu; jh23f@nih.gov; swart001@mc.duke.edu; scott_stroup@med.unc.edu; JL2616@columbia.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU National Institute of Mental health (NIMH) [N01MH90001] FX The CATIE Trials were supported by National Institute of Mental health (NIMH) grant #N01MH90001. We wish to acknowledge the contributions of all investigators, study personnel and subjects from all of the CATIE Schizophrenia Trial sites. NR 15 TC 47 Z9 49 U1 3 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2008 VL 103 IS 1-3 BP 104 EP 109 DI 10.1016/j.schres.2008.04.023 PG 6 WC Psychiatry SC Psychiatry GA 338CC UT WOS:000258481500011 PM 18534821 ER PT J AU Horan, WP Braff, DL Nuechterlein, KH Sugar, CA Cadenhead, KS Calkins, ME Dobie, DJ Freedman, R Greenwood, TA Gur, RE Gur, RC Light, GA Mintz, J Olincy, A Radant, AD Schork, NJ Seidman, LJ Siever, LJ Silverman, JM Stone, WS Swerdlow, NR Tsuang, DW Tsuang, MT Turetsky, BI Green, MF AF Horan, William P. Braff, David L. Nuechterlein, Keith H. Sugar, Catherine A. Cadenhead, Kristin S. Calkins, Monica E. Dobie, Dorcas J. Freedman, Robert Greenwood, Tiffany A. Gur, Raquel E. Gur, Ruben C. Light, Gregory A. Mintz, James Olincy, Ann Radant, Allan D. Schork, Nicholas J. Seidman, Larry J. Siever, Larry J. Silverman, Jeremy M. Stone, William S. Swerdlow, Neal R. Tsuang, Debbie W. Tsuang, Ming T. Turetsky, Bruce I. Green, Michael F. TI Verbal working memory impairments in individuals with schizophrenia and their first-degree relatives: Findings from the Consortium on the Genetics of Schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; endophenotype; working memory; genetics ID NAIVE PATIENTS; NEUROPSYCHOLOGICAL DEFICITS; ENDOPHENOTYPE CONCEPT; COGNITIVE DEFICITS; FOLLOW-UP; METAANALYSIS; GENES; HERITABILITY; SYMPTOMS; SPAN AB Working memory (WM) impairment is a promising candidate endophenotype for schizophrenia that could facilitate the identification of susceptibility genes for this disorder. The validity of this putative endophenotype was assessed by determining whether 149 probands with schizophrenia and 337 of their first-degree relatives demonstrated WM impairment as compared to 190 unaffected community comparison subjects. Subjects were participants in the Consortium on the Genetics of Schizophrenia (COGS) project, a seven-site research network that was established to investigate the genetic architecture of endophenotypes for schizophrenia. Participants received comprehensive clinical assessments and completed two verbal WM tasks, one requiring transient on-line storage and another requiring maintenance plus complex manipulation of information by reordering the stimuli. Schizophrenia probands performed worse than the other groups on both tasks, with larger deficits found for the more challenging reordering WM task. The probands' relatives performed more poorly than community comparison subjects Oil both tasks, but the difference was significant only for the more challenging maintenance plus complex manipulation WM task. This WM impairment was not attributable to diagnoses of schizophrenia spectrum disorder, mood disorders, or substance use disorders in the relatives. In conjunction with evidence that WM abilities are substantially heritable, the Current results support the validity and usefulness of verbal WM impairments in manipulation of information as endophenotypes for schizophrenia in large-scale genetic linkage and association studies. (C) 2008 Elsevier B.V. All rights reserved. C1 [Horan, William P.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Aftercare Res Program, Los Angeles, CA 90095 USA. [Braff, David L.; Cadenhead, Kristin S.; Greenwood, Tiffany A.; Light, Gregory A.; Schork, Nicholas J.; Swerdlow, Neal R.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Calkins, Monica E.; Gur, Raquel E.; Gur, Ruben C.; Turetsky, Bruce I.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Dobie, Dorcas J.; Radant, Allan D.; Tsuang, Debbie W.] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Dobie, Dorcas J.; Radant, Allan D.; Tsuang, Debbie W.] VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Freedman, Robert; Olincy, Ann] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Denver, CO 80262 USA. [Seidman, Larry J.; Stone, William S.; Tsuang, Ming T.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med,Publ Psychiat Div, Massachusetts Mental Hlth Ctr,Dept Psychiat, Boston, MA 02215 USA. [Seidman, Larry J.; Stone, William S.; Tsuang, Ming T.] Harvard Univ, Inst Psychiat Epidemiol & Genet, Boston, MA 02115 USA. [Siever, Larry J.; Silverman, Jeremy M.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Horan, WP (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Aftercare Res Program, 300 UCLA Med Plaza,Suite 2255, Los Angeles, CA 90095 USA. EM horan@ucla.edu; DBraff@ucsd.edu RI Greenwood, Tiffany/F-6356-2012; Tsuang, Debby/L-7234-2016 OI Greenwood, Tiffany/0000-0002-6080-6503; Tsuang, Debby/0000-0002-4716-1894 FU NIMH NIH HHS [R01 MH065554-05, R01 MH065554, R01 MH065558, R01 MH065558-05, R01 MH065562, R01 MH065562-05, R01 MH065571, R01 MH065571-05, R01 MH065578, R01 MH065578-05, R01 MH065588-05, R01 MH065707, R01 MH065707-05, R01 MH084071] NR 55 TC 61 Z9 62 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2008 VL 103 IS 1-3 BP 218 EP 228 DI 10.1016/j.schres.2008.02.014 PG 11 WC Psychiatry SC Psychiatry GA 338CC UT WOS:000258481500027 PM 18406578 ER PT J AU Bowie, CR Harvey, PD AF Bowie, Christopher R. Harvey, Philip D. TI Communication abnormalities predict functional outcomes in chronic schizophrenia: Differential associations with social and adaptive functions SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; thought disorder; communication; social; functional; cognition; outcome ID FORMAL THOUGHT-DISORDER; COGNITIVE DEFICITS; NEUROCOGNITIVE DEFICITS; EMPIRICAL-ASSESSMENT; FACTORIAL STRUCTURE; CLINICAL SYMPTOMS; OLDER PATIENTS; FOLLOW-UP; CAPACITY; IMPAIRMENTS AB Communication abnormalities are hallmark features of schizophrenia. Despite the prevalence and persistence of these symptoms, little is known about their functional implications. In this study, we examined, in a sample of chronically institutionalized schizophrenia patients (N=317), whether two types of communication abnormalities (i.e., verbal under-productivity and disconnected speech) had differential relationships with social and adaptive outcomes. Baseline ratings of verbal underproductivity, disconnected speech, global cognitive performance, and clinical symptoms, were entered into stepwise regression analyses to examine their relationship with 2.5 year social and adaptive outcomes. At baseline, disconnected speech was significantly associated with socially impolite behavior, while verbal underproductivity was associated with social disengagement and impaired friendships. Both types of communication abnormalities were significantly associated with other types of social skills. Verbal underproductivity predicted follow-up social skills, social engagement, and friendships, accounting for more variance than. cognition or symptoms. In contrast to social outcomes, adaptive outcomes were predicted by baseline neurocognition and clinical symptoms, but not communication abnormalities. These findings provide evidence for specific relationships of communication disorder subtypes with diverse impairments in social functions. In this chronically institutionalized sample, communication disorder was a stronger predictor of social, but not adaptive, outcomes than neurocognition or clinical symptoms. Published by Elsevier B.V. C1 [Bowie, Christopher R.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Bowie, Christopher R.] James J Peters Bronx VA Med Ctr, Bronx, NY 10468 USA. [Harvey, Philip D.] Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30032 USA. RP Bowie, CR (reprint author), Mt Sinai Sch Med, Dept Psychiat, 1425 Madison Ave,4th Floor,Box 1230, New York, NY 10029 USA. EM christopher.bowie@mssm.edu FU NIMH [MH 63116]; Mount. Sinai Silvio Conte Neuroscience Center [NIMH MH 36692, KL Davis PI]; VAVISN 3 MIRECC FX This research was supported by NIMH Grant Number MH 63116 to Dr. Harvey, the Mount. Sinai Silvio Conte Neuroscience Center (NIMH MH 36692; KL Davis PI) and the VAVISN 3 MIRECC. These sponsors had no role in study design, collection of data, data analysis., interpretation of results, or writing of the manuscript. NR 48 TC 43 Z9 46 U1 4 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2008 VL 103 IS 1-3 BP 240 EP 247 DI 10.1016/j.schres.2008.05.006 PG 8 WC Psychiatry SC Psychiatry GA 338CC UT WOS:000258481500029 PM 18571378 ER PT J AU Lee, J Nuechterlein, KH Subotnik, KL Sugar, CA Ventura, J Gretchen-Doorly, D Kelly, K Green, MF AF Lee, Junghee Nuechterlein, Keith H. Subotnik, Kenneth L. Sugar, Catherine A. Ventura, Joseph Gretchen-Doorly, Denise Kelly, Kimberly Green, Michael F. TI Stability of visual masking performance in recent-onset schizophrenia: An 18-month longitudinal study SO SCHIZOPHRENIA RESEARCH LA English DT Article DE visual masking; stability; vulnerability; recent-onset schizophrenia; longitudinal study ID INFORMATION-PROCESSING DEFICITS; AFFECTIVELY DISTURBED PATIENTS; BACKWARD-MASKING; UNAFFECTED SIBLINGS; VULNERABILITY; CHANNELS; TRANSIENT; DISORDER; STRESS; SYSTEM AB Visual masking deficit in schizophrenia has been suggested to be a potential vulnerability marker for schizophrenia. An important characteristic of a vulnerability marker is stability over time, but relatively little is known about the longitudinal course of masking performance of schizophrenia patients. In this study, we examined the stability of visual masking performance in recent onset schizophrenia patients over an 18-month period. We administered both forward and backward masking trials with multiple stimulus onset asynchronies for four masking conditions at three time points (baseline, 6-month, and 18-month). Recent-onset schizophrenia patients showed stable masking performance for both forward and backward conditions over a period of 18 months. Furthermore, the stable performance was observed across all four masking conditions. The findings of this study provide further support for the view that visual masking deficits reflect a possible Vulnerability marker for schizophrenia. (C) 2008 Published by Elsevier B.V. C1 [Lee, Junghee] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, MIRECC, Los Angeles, CA 90073 USA. [Lee, Junghee; Nuechterlein, Keith H.; Subotnik, Kenneth L.; Sugar, Catherine A.; Ventura, Joseph; Gretchen-Doorly, Denise; Kelly, Kimberly; Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90073 USA. [Nuechterlein, Keith H.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90073 USA. [Sugar, Catherine A.] Univ Calif Los Angeles, Dept Biostat, Los Angeles, CA 90073 USA. RP Lee, J (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, MIRECC, 11301 Wilshire Blvd,Bldg 210,MC 210A, Los Angeles, CA 90073 USA. EM JungheeLee@ucla.edu RI Lee, Junghee/C-5226-2014 OI Lee, Junghee/0000-0001-9567-8700 FU [MH43292]; [MH66286]; [MH37705] FX This work is supported by grants MH43292 to Dr. Green arid MH66286 and MH37705 to Dr. Nuechterlein. NR 39 TC 7 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2008 VL 103 IS 1-3 BP 266 EP 274 DI 10.1016/j.schres.2008.03.005 PG 9 WC Psychiatry SC Psychiatry GA 338CC UT WOS:000258481500032 PM 18450427 ER PT J AU Oberdoerffer, S Moita, LF Neems, D Freitas, RP Hacohen, N Rao, A AF Oberdoerffer, Shalini Moita, Luis Ferreira Neems, Daniel Freitas, Rui P. Hacohen, Nir Rao, Anjana TI Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL SO SCIENCE LA English DT Article ID PRE-MESSENGER-RNA; CELLS; ACTIVATION; BINDING; SYSTEM; EXPORT AB The transition from naive to activated T cells is marked by alternative splicing of pre- mRNA encoding the transmembrane phosphatase CD45. Using a short hairpin RNA interference screen, we identified heterogeneous ribonucleoprotein L- like ( hnRNPLL) as a critical inducible regulator of CD45 alternative splicing. HnRNPLL was up- regulated in stimulated T cells, bound CD45 transcripts, and was both necessary and sufficient for CD45 alternative splicing. Depletion or overexpression of hnRNPLL in B and T cell lines and primary T cells resulted in reciprocal alteration of CD45RA and RO expression. Exon array analysis suggested that hnRNPLL acts as a global regulator of alternative splicing in activated T cells. Induction of hnRNPLL during hematopoietic cell activation and differentiation may allow cells to rapidly shift their transcriptomes to favor proliferation and inhibit cell death. C1 [Oberdoerffer, Shalini; Neems, Daniel; Rao, Anjana] Harvard Univ, Sch Med, Dept Pathol, Immune Dis Inst, Boston, MA 02115 USA. [Moita, Luis Ferreira; Freitas, Rui P.; Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA. [Hacohen, Nir] Harvard & Massachusetts Inst Technol, Broad Inst, Cambridge, MA 02142 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Dept Pathol, Immune Dis Inst, Boston, MA 02115 USA. EM arao@idi.harvard.edu RI Moita, Luis/L-1296-2013 OI Moita, Luis/0000-0003-0707-315X FU NCI NIH HHS [CA42471, R01 CA042471, R01 CA042471-23]; NHLBI NIH HHS [T32 HL066987]; NIAID NIH HHS [R21 AI071060-02, AI40127, AI44432, R01 AI040127, R01 AI040127-18, R01 AI040127-19, R01 AI044432, R01 AI044432-09, R01 AI044432-10, R01 AI080875, R01 AI080875-01, R21 AI071060, R21 AI071060-01, U19 AI070352] NR 19 TC 89 Z9 91 U1 1 U2 3 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 1 PY 2008 VL 321 IS 5889 BP 686 EP 691 DI 10.1126/science.1157610 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 332IW UT WOS:000258077700043 PM 18669861 ER PT J AU Lehmann, S Jackson, AD Lautrup, BE AF Lehmann, Sune Jackson, Andrew D. Lautrup, Benny E. TI A quantitative analysis of indicators of scientific performance SO SCIENTOMETRICS LA English DT Article ID COMPLEX NETWORKS; SCIENCE AB Condensing the work of any academic scientist into a one-dimensional indicator of scientific performance is a difficult problem. Here, we employ Bayesian statistics to analyze several different indicators of scientific performance. Specifically, we determine each indicator's ability to discriminate between scientific authors. Using scaling arguments, we demonstrate that the best of these indicators require approximately 50 papers to draw conclusions regarding long term scientific performance with usefully small statistical uncertainties. Further, the approach described here permits statistical comparison of scientists working in distinct areas of science. C1 [Lehmann, Sune] Northeastern Univ, Dept Phys, Ctr Complex Network Res, Boston, MA 02115 USA. [Lehmann, Sune] Harvard Univ, Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Jackson, Andrew D.; Lautrup, Benny E.] Niels Bohr Inst, DK-2100 Copenhagen, Denmark. RP Lehmann, S (reprint author), Northeastern Univ, Dept Phys, Ctr Complex Network Res, 360 Huntington Ave, Boston, MA 02115 USA. EM lehmann@nbi.dk OI Lehmann, Sune/0000-0001-6099-2345 NR 23 TC 47 Z9 47 U1 4 U2 33 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0138-9130 J9 SCIENTOMETRICS JI Scientometrics PD AUG PY 2008 VL 76 IS 2 BP 369 EP 390 DI 10.1007/s11192-007-1868-8 PG 22 WC Computer Science, Interdisciplinary Applications; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 322UG UT WOS:000257400200010 ER PT J AU Scully, RE Young, RH AF Scully, Robert E. Young, Robert H. TI William B. Ober, MD (1920-1993): humanist, humorist, historian, and histo pathologist: recollections of his life and evaluation of his work SO SEMINARS IN DIAGNOSTIC PATHOLOGY LA English DT Review ID EXPERIMENTAL TOXEMIA; ENDOMETRIAL MORPHOLOGY; TROPHOBLASTIC PSEUDOTUMOR; SARCOMA BOTRYOIDES; ESTROGEN COMPOUNDS; CERVIX UTERI; LEPER CHANGE; CELL TUMOR; FINE-ARTS; PREGNANCY C1 [Scully, Robert E.; Young, Robert H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol,James Homer Wright Pathol Labs, Boston, MA 02114 USA. RP Scully, RE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol,James Homer Wright Pathol Labs, 55 Fruit St,Warren 215, Boston, MA 02114 USA. NR 256 TC 2 Z9 2 U1 1 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0740-2570 J9 SEMIN DIAGN PATHOL JI Semin. Diagn. Pathol. PD AUG PY 2008 VL 25 IS 3 BP 202 EP 229 DI 10.1053/j.semdp.2008.07.009 PG 28 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 363LL UT WOS:000260268700011 PM 19007106 ER PT J AU Kapur, VK Resnick, HE Gottlieb, DJ AF Kapur, Vishesh K. Resnick, Helaine E. Gottlieb, Daniel J. CA Sleep Heart Hlth Study Grp TI Sleep disordered breathing and hypertension: Does self-reported sleepiness modify the association? SO SLEEP LA English DT Article DE sleepiness; hypertension; Epworth; epidemiology; apnea; interaction; effect; modification; cardiovascular ID POSITIVE AIRWAY PRESSURE; MIDDLE-AGED ADULTS; DAYTIME SLEEPINESS; BLOOD-PRESSURE; HEART HEALTH; CARDIOVASCULAR-DISEASE; INTERMITTENT HYPOXIA; OLDER-ADULTS; APNEA; RECOMMENDATIONS AB Study Objectives: Epidemiologic studies that demonstrate increased risk of hypertension in persons with sleep disordered breathing indicate that only a minority of these persons report significant subjective sleepiness. Studies also suggest that presence of self-reported sleepiness may identify a subset of persons with sleep disordered breathing who are at greatest risk of cardiovascular sequelae, including hypertension. We explore whether self-reported sleepiness modifies the relationship between sleep disordered breathing and prevalent hypertension. Design: Cross-sectional Setting: Multicenter study Participants: 6046 subjects from the Sleep Heart Health Study Measurements: Polysomnography, systolic and diastolic blood pressure, antihypertensive medication use, questionnaire determined excessive sleepiness and Epworth Sleepiness Scale, and covariates. Results: The odds of hypertension at higher apnea hypopnea index categories were larger in participants identified as sleepy based on responses to a frequency of sleepiness question or the Epworth score. For example, for those with AHI >= 30 compared to AHI < 1.5, the adjusted odds ratio for hypertension was 2.83 (1.33-6.04) among those reporting sleepiness >= 5 days per month, but only 1.22 (0.89-1.68) among those reporting less frequent daytime sleepiness. In adjusted logistic regression models, there was statistical evidence for effect modification by frequency of sleepiness (P = 0.033) of the association between apnea hypopnea index and hypertension. In adjusted models that included the Epworth score as a continuous variable, the interaction term fell slightly short of statistical significance (beta = 0.010, P = 0.07). Conclusion: This study finds that the association of sleep disordered breathing with hypertension is stronger in individuals who report daytime sleepiness than in those who do not. C1 [Kapur, Vishesh K.] Univ Washington, Sleep Disorders Ctr, Dept Med, Seattle, WA 98104 USA. [Resnick, Helaine E.] Georgetown Univ, Div Endocrinol, Amer Assoc Homes & Serv Aging, Washington, DC USA. [Resnick, Helaine E.] Georgetown Univ, Div Endocrinol, Dept Med, Washington, DC USA. [Gottlieb, Daniel J.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Gottlieb, Daniel J.] VA Boston Healthcare Syst, Boston, MA USA. RP Kapur, VK (reprint author), Univ Washington, Sleep Disorders Ctr, Dept Med, Box 359803,325 9th Ave, Seattle, WA 98104 USA. EM vkapur@u.washington.edu RI Kapur, Vishesh/K-1054-2014 OI Kapur, Vishesh/0000-0002-5417-1097 FU NHLBI NIH HHS [U01 HL053941, U01 HL053916, U01 HL053931, U01 HL053934, U01 HL053937, U01 HL053938, U01 HL063429, U01 HL063463, U01 HL064360, U01HL53916, U01HL53931, U01HL53934, U01HL53937, U01HL53938, U01HL53940, U01HL53941, U01HL63429, U01HL63463, U01HL64360] NR 30 TC 54 Z9 56 U1 0 U2 0 PU AMER ACAD SLEEP MEDICINE PI WESTCHESTER PA ONE WESTBROOK CORPORATE CTR, STE 920, WESTCHESTER, IL 60154 USA SN 0161-8105 J9 SLEEP JI Sleep PD AUG 1 PY 2008 VL 31 IS 8 BP 1127 EP 1132 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 332VK UT WOS:000258111000010 PM 18714785 ER PT J AU Weintraub, HS Basile, J AF Weintraub, Howard S. Basile, Jan TI The pleiotropic effects of antihypertensive agents: Do they account for additional cardiovascular benefit beyond BP reduction? SO SOUTHERN MEDICAL JOURNAL LA English DT Review DE angiotensin-converting enzyme inhibitors; angiotensin II receptor blockers; calcium antagonists; cardiovascular disease; hypertension; pleiotropic effects ID ANGIOTENSIN-CONVERTING-ENZYME; CORONARY-ARTERY-DISEASE; RANDOMIZED CONTROLLED-TRIAL; BLOOD-PRESSURE REDUCTION; SMOOTH-MUSCLE-CELLS; END-POINT REDUCTION; LOSARTAN INTERVENTION; HYPERTENSIVE PATIENTS; ATRIAL-FIBRILLATION; ALDOSTERONE SYSTEM AB Hypertension commonly Clusters with other cardiovascular risk factors, giving rise to the concept that hypertension is a multifaceted disease that potentially shares common pathogenic pathways with other risk factors. The renin-angiotensin-aldosterone system has a central role in the shared mechanisms of hypertension and cardiovascular disease, primarily through angiotensin II. Increased levels of angiotensin II disrupt the balance of vasoactive substances and growth factors that regulate endothelial structure and function, and inhibition of the renin-angiotensin-aldosterone system with an angiotensin-converting enzyme inhibitor or angiotensin II type I receptor blocker helps restore this equilibrium. Some pathogenic mechanisms may also be favorably affected by calcium channel blockade. While the relative contribution of pleiotropic effects to clinical benefit is difficult to quantity, based on recent data it is reasonable to consider using newer antihypertensive agents in selected high-risk patients to realize the benefits that may derive front interfering with pathogenic mechanisms of disease. C1 [Weintraub, Howard S.] NYU Med Ctr, Ctr Prevent Cardiovasc Dis, New York, NY 10016 USA. [Weintraub, Howard S.; Basile, Jan] Med Univ S Carolina, Ralph H Johnson VA Med Ctr, Primary Care Serv Line, Charleston, SC 29425 USA. RP Weintraub, HS (reprint author), NYU Med Ctr, Ctr Prevent Cardiovasc Dis, 530 1st Ave, New York, NY 10016 USA. EM howard.weintraub@nyumc.org OI Weintraub, Howard/0000-0002-8159-0465 NR 48 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0038-4348 J9 SOUTH MED J JI South.Med.J. PD AUG PY 2008 VL 101 IS 8 BP 818 EP 823 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 339NV UT WOS:000258585200012 PM 18622353 ER PT J AU Rost, NS Smith, EE Chang, Y Snider, RW Chanderraj, R Schwab, K FitzMaurice, E Wendell, L Goldstein, JN Greenberg, SM Rosand, J AF Rost, Natalia S. Smith, Eric E. Chang, Yuchiao Snider, Ryan W. Chanderraj, Rishi Schwab, Kristin FitzMaurice, Emily Wendell, Lauren Goldstein, Joshua N. Greenberg, Steven M. Rosand, Jonathan TI Prediction of functional outcome in patients with primary intracerebral hemorrhage the FUNC score SO STROKE LA English DT Article DE intracerebral hemorrhage; outcome; models; statistical ID LONG-TERM SURVIVAL; PERTH COMMUNITY STROKE; 1ST-EVER STROKE; ICH SCORE; GRADING SCALE; MORTALITY; VALIDATION; WARFARIN; MODEL; CARE AB Background and Purpose - Intracerebral hemorrhage (ICH) is the most fatal and disabling stroke subtype. Widely used tools for prediction of mortality are fundamentally limited in that they do not account for effects of withdrawal of care and are not designed to predict functional recovery. We developed an acute clinical score to predict likelihood of functional independence. Methods - We prospectively characterized 629 consecutive patients with ICH at hospital presentation. Predictors of functional independence (Glasgow Outcome Score >= 4) at 90 days were used to develop a logistic regression-based risk stratification scale in a random subset of two thirds and validated in the remaining one third of the cohort. Results - At 90 days, 162 (26%) patients achieved independence. Age, Glasgow Coma Scale, ICH location, volume (all P < 0.0001), and pre-ICH cognitive impairment (P=0.005) were independently associated with Glasgow Outcome Score >= 4. The FUNC score was developed as a sum of individual points (0-11) based on strength of association with outcome. In both the development and validation cohorts, the proportion of patients who achieved Glasgow Outcome Score >= 4 increased steadily with FUNC score. No patient assigned a FUNC score <= 4 achieved functional independence, whereas > 80% with a score of 11 did. The predictive accuracy of the FUNC score remained unchanged when restricted to ICH survivors only, consistent with absence of confounding by early withdrawal of care. Conclusions - FUNC score is a valid clinical assessment tool that identifies patients with ICH who will attain functional independence and thus, can provide guidance in clinical decision-making and patient selection for clinical trials. C1 [Rost, Natalia S.; Smith, Eric E.; Snider, Ryan W.; Chanderraj, Rishi; Schwab, Kristin; FitzMaurice, Emily; Wendell, Lauren; Greenberg, Steven M.; Rosand, Jonathan] Massachusetts Gen Hosp, Hemorrhag Stroke Res Program, Boston, MA 02114 USA. [Rost, Natalia S.; Chanderraj, Rishi; Rosand, Jonathan] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Chang, Yuchiao] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Goldstein, Joshua N.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. RP Rost, NS (reprint author), Massachusetts Gen Hosp, J Philip Kistler Stroke Res Ctr, 175 Cambridge St,Suite 300, Boston, MA 02114 USA. EM nrost@partners.org RI Goldstein, Joshua/H-8953-2016; OI Smith, Eric/0000-0003-3956-1668 NR 40 TC 134 Z9 140 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD AUG PY 2008 VL 39 IS 8 BP 2304 EP 2309 DI 10.1161/STROKEAHA.107.512202 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 331DR UT WOS:000257993400018 PM 18556582 ER PT J AU Balakrishnan, A Stearns, AT Rhoads, DB Ashley, SW Tavakkolizadeh, A AF Balakrishnan, Anita Stearns, Adam T. Rhoads, David B. Ashley, Stanley W. Tavakkolizadeh, Ali TI Defining the transcriptional regulation of the intestinal sodium-glucose cotransporter using RNA-interference mediated gene silencing SO SURGERY LA English DT Article ID HEPATOCYTE NUCLEAR FACTOR-1-ALPHA; NA+/GLUCOSE COTRANSPORTER; ISOMALTASE GENE; MESSENGER-RNA; ACTIVATION; EXPRESSION; PROMOTER; HNF-1-ALPHA; SGLT1; HNF-1 AB Background. The sodium glucose cotransporter (SGLT1) is responsible for all active intestinal glucose uptake. Hepatocyte nuclear factors 1 alpha and beta (HNF1 alpha and HNF1 beta) activate the SGLT1 promoter, whereas GATA-binding protein 5 (GATA-5) and caudal-type homeobox protein 2 (CDX2) regulate transcription of other intestinal genes. We investigated SGLT1 regulation by these transcription factors using promoter studies and RNA interference. Methods. Chinese hamster ovary (CHO) cells were transiently cotransfected with an SGLT1-luciferase promoter construct and combinations of expression vectors for HNF1 alpha HNF1 beta, CDX2, and GATA-5. Caco-2 cells were stably transfected with knockdown vectors for either HNF1 alpha or HNF1 beta. mRNA levels of HNF1 alpha, HNF1 beta; and SGLT1 were determined using quantitative polymerise chain reaction (qPCR). Results. HNF1 alpha, GATA-5, and HNF1 beta significantly activated the SGLT1 promoter (P < .05). Co-transfection of GATA-5 with HNF1 alpha had an additive effect, whereas HNF1 beta and CDX2 antagonized HNF1 alpha and GATA-5. SGLT1 expression was significantly reduced in HNF1 alpha or HNF1 beta knockdowns (P < .001). HNF1 alpha knockdown significantly reduced HNF1 beta expression and vice versa (P < .005). Conclusions. HNF1 alpha and HNF1 beta are important transcription factors for endogenous SGLT1 expression by cultured enterocytes. GATA-5 and CDX2 also regulate SGLT1 promoter activity and show cooperativity with the HNF1s. We, therefore, propose a multifactorial model for SGLT1 regulation, with interactions between HNF1, GATA-5, and CDX2 modulating intestinal glucose absorption. C1 [Balakrishnan, Anita; Stearns, Adam T.; Ashley, Stanley W.; Tavakkolizadeh, Ali] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Balakrishnan, Anita; Stearns, Adam T.; Rhoads, David B.; Ashley, Stanley W.; Tavakkolizadeh, Ali] Harvard Univ, Sch Med, Boston, MA USA. [Stearns, Adam T.] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Rhoads, David B.] MassGen Hosp Children, Pediat Endocrine Unit, Boston, MA USA. RP Tavakkolizadeh, A (reprint author), Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA. EM atavakkolizadeh@partners.org OI Stearns, Adam/0000-0003-4327-7360 FU NIDDK NIH HHS [5 R01 DK047326, P30 DK040561, P30-DK040561, R01 DK047326, R01 DK047326-10S1] NR 24 TC 8 Z9 8 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD AUG PY 2008 VL 144 IS 2 BP 168 EP 173 DI 10.1016/j.surg.2008.03.010 PG 6 WC Surgery SC Surgery GA 335RS UT WOS:000258308400008 PM 18656622 ER PT J AU Sailhamer, EA Li, YQ Smith, EJ Shuja, F Shults, C Liu, BL Soupir, C Demoya, M Velmahos, G Alam, HB AF Sailhamer, Elizabeth A. Li, Yongqing Smith, Eleanor J. Shuja, Fahad Shults, Christian Liu, Baoling Soupir, Chad deMoya, Marc Velmahos, George Alam, Hasan B. TI Acetylation: a novel method for modulation of the immune response following trauma/hemorrhage and inflammatory second hit in animals and humans SO SURGERY LA English DT Article ID HISTONE DEACETYLASE; HEMORRHAGIC-SHOCK; CARDIAC HISTONES; RESUSCITATION STRATEGIES; SYSTEMIC INFLAMMATION; FLUID RESUSCITATION; MODEL; INHIBITOR; TRANSCRIPTION; CYTOKINES AB Background. Hemorrhage induces an imbalance in histone acetyl transferase/histone deacetylase (HAT/HDAC) ratio. Correction of this,imbalance with histone deacetylase inhibitors (HDACI) improves survival. We aimed to identify whether this was due to modulation of the post-shock immune response. Methods. We established a "two-hit" model in which rats (n=11; 5-6/group) and humans (n=10; 5/group) sustained trauma/hemorrhage, followed by exposure of splenic leukocytes to lipopolysaccharide (LPS, 10ng/mL) for 8 or 24 hours. The leukocytes were treated with: No treatment, SAHA (suberoylanilide hydroxamic acid, HDACI, 400nM), or Garcinol (HAT inhibitor, 20 mu M). Results. Hemorrhage in the animals produced severe shock and a pro-inflammatory state. SARA reduced TNFa secretion in the hemorrhaged leukocytes after LPS "second-hit" (34.0%, P = .003), whereas it increased transcript levels of TNFa and. IL-1b (2.1 +/- 0.3 and 5.1 +/- 2.2 fold respectively, P < .05). Leukocytes from trauma patients displayed 2 distinct responses to SAHA after LPS "second-hit," with markedly increased or decreased cytokine levels. Conclusions. SAHA normalizes TNFa levels following hemorrhage and LPS "second hit" in the rats, whereas trauma patients respond to SAHA in 2 distinct patterns, with either marked attenuation or exaggeration of inflammatory cytokines. Cytokine levels were independent of gene expression, implicating acetylation of non-nuclear proteins as the. dominant regulatory mechanism. C1 [Sailhamer, Elizabeth A.; Li, Yongqing; Smith, Eleanor J.; Shuja, Fahad; Shults, Christian; Liu, Baoling; deMoya, Marc; Velmahos, George; Alam, Hasan B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Soupir, Chad] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,Div Hematopathol, Boston, MA 02114 USA. [Shults, Christian] Washington Hosp Ctr, Dept Surg, Washington, DC 20010 USA. RP Alam, HB (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 hbalam@partners.org FU NIGMS NIH HHS [F32 GM79880] NR 24 TC 42 Z9 48 U1 1 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD AUG PY 2008 VL 144 IS 2 BP 204 EP 216 DI 10.1016/j.surg.2008.03.034 PG 13 WC Surgery SC Surgery GA 335RS UT WOS:000258308400013 PM 18656627 ER PT J AU Li, YQ Liu, BL Sailhamer, EA Yuan, ZQ Shults, C Velmahos, GC DeMoya, M Shuja, F Butt, MU Alam, HB AF Li, Yongqing Liu, Baoling Sailhamer, Elizabeth A. Yuan, Zengqiang Shults, Christian Velmahos, George C. DeMoya, Marc Shuja, Fahad Butt, Muhammad U. Alam, Hasan B. TI Cell protective mechanism of valproic acid in lethal hemorrhagic shock SO SURGERY LA English DT Article ID BETA-CATENIN; HISTONE DEACETYLASE; RESUSCITATION STRATEGIES; CARDIAC HISTONES; ACETYLATION; PROTEIN; INHIBITORS; NEURONS; MODEL; LUNG AB Background. We have demonstrated that valproic acid (VPA), a histone deacetylase inhibitor, can improve animal survival after hemorrhagic shock and protect neurons from hypoxia-induced apoptosis. This study investigated whether VPA treatment works through the beta-catenin survival pathways. Methods. Wistar-Kyoto rats underwent hemorrhagic shock (60% blood loss) followed by treatment with or without VPA (300 mg/kg). Brains were harvested after 1, 6, and 24 hours and analyzed for acetylated histone-H3 at lysine-9 (Ac-H3K9), acetylated and total,Q-catenin, and Bcl-2 by Western blot. In addition, primary neurons dissociated from E18 rat embryos were exposed to hypoxia (0.5 % 02) for 16 hours with or without VPA (1 mmol/L) and analyzed using confocal microscopy. Results. After treatment of hemorrhaged animals with VPA, acetylated beta-catenin was found in both the cytosol and nucleus, along with Ac-H3K9. Bcl-2 transcript increased after 1 hour followed by an increase in Bcl-2 protein cat 6 hours. Confocal imaging demonstrated that after VPA treatment, beta-catenin translocated into the nucleus and colocalized with Ac-H3K9. Conclusion. VPA treatment acetylates H3K9 and beta-catenin and enhances translocation of beta-catenin into the nucleus, where it colocalizes with Ac-H3K9 and stimulates the transcription of survival gene bcl-2. This finding suggests that VPA protects cells after severe insult through the beta-catenin survival pathway. C1 [Li, Yongqing; Liu, Baoling; Sailhamer, Elizabeth A.; Shults, Christian; Velmahos, George C.; DeMoya, Marc; Shuja, Fahad; Butt, Muhammad U.; Alam, Hasan B.] Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Surg, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Yuan, Zengqiang] Harvard Univ, Dept Pathol, Sch Med, Boston, MA 02114 USA. [Shults, Christian] Washington Hosp Ctr, Dept Surg, Washington, DC 20010 USA. RP Alam, HB (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 hbalam@partners.org FU NIGMS NIH HHS [F32 GM79880] NR 25 TC 39 Z9 46 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6060 J9 SURGERY JI Surgery PD AUG PY 2008 VL 144 IS 2 BP 217 EP 224 DI 10.1016/j.surg.2008.03.037 PG 8 WC Surgery SC Surgery GA 335RS UT WOS:000258308400014 PM 18656628 ER PT J AU Dixon, RF Stahl, JE AF Dixon, Ronald F. Stahl, James E. TI Virtual visits in a general medicine practice: A pilot study SO TELEMEDICINE JOURNAL AND E-HEALTH LA English DT Article DE virtual visits; general medicine practice; pilot study AB The purpose of this pilot study is to investigate the feasibility, effectiveness, and acceptability of a patient-physician real-time encounter using videoconferencing technology (a virtual visit) compared to a face-to-face office visit in the general medical setting. The three broad aims of the study are (1) to compare the physician's ability to make diagnoses in both settings, (2) to compare the physician's ability to provide therapy in both settings, and (3) to examine both patient and physician satisfaction with both modalities. Thirty patients were recruited from a single practice to participate in the study. Patients were first interviewed and examined in the virtual setting, and then in the face-to-face setting. Both patients and physician were surveyed after each visit type with regard to quality of the history, quality of the examination, and satisfaction with the experience. The data were analyzed using two-tailed t-tests and analysis of variance. Patients significantly preferred the in-person visit (4.7 of 5), but were very satisfied with the virtual visit as well (4.1 of 5) (p < 0.0001) (scale: 1= poor, 2 = fair, 3 = good, 4 = very good, 5 = excellent). Physical examination effectiveness was significantly worse in the virtual visit modality (2.3 versus 4.9 for the face-to-face visit, p < 0.0001), but history and therapeutic effectiveness were not significantly different. Both patients and the physician felt comfortable with the technology: patients 4.1, physician 4.3. Results suggest that both patients and the physician found the virtual visit a potentially useful alternative to the traditional visit for many medical conditions. This may have significant implications for the general medical care environment. Patients may benefit from reduced opportunity costs associated with physician visits and clinicians may benefit from decrease overhead costs. Further research is ongoing to investigate the generalizability of these findings. C1 [Dixon, Ronald F.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Integrat Med & Innovat Technol,Dept Med, Boston, MA 02115 USA. [Stahl, James E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Inst Technol Assessment,Dept Med, Boston, MA 02115 USA. RP Dixon, RF (reprint author), MGH Beacon Hill Associates, 165 Cambridge St, Boston, MA 02114 USA. EM rdixon@partners.org NR 9 TC 14 Z9 14 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-5627 J9 TELEMED J E-HEALTH JI Telemed. J. e-Health PD AUG PY 2008 VL 14 IS 6 BP 525 EP 530 DI 10.1089/tmj.2007.0101 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 347GN UT WOS:000259128700040 PM 18729750 ER PT J AU Dzik, W AF Dzik, W. TI Fresh blood for everyone? Balancing availability and quality of stored RBCs SO TRANSFUSION MEDICINE LA English DT Article DE cardiac surgery; preservation; red blood cells ID RED-CELL STORAGE; CARDIAC-SURGERY; TRANSFUSED BLOOD; MORBIDITY; MORTALITY; ASSOCIATION; DURATION; DISEASE; TIME; AGE AB Effective, prolonged ex vivo storage of red blood cells is an essential requirement for inventory management of each nation's blood supply. Current blood storage techniques are the development of a century of research. Blood undergoes metabolic and structural deterioration during prolonged ex vivo storage. Current regulatory requirements for the limit of blood storage do not consider oxygen delivery or clinical outcomes. Recently, concern that stored blood may produce adverse outcomes in recipients has sparked renewed interest in studies that can evaluate the clinical impact of fresh vs. stored blood. In 2008, a retrospective study of outcomes among transfused patients undergoing cardiac surgery suggested that blood stored for more than 14 days prior to transfusion led to higher perioperative mortality compared with blood stored for less than 14 days. Here, we critically examine the details of the above-mentioned study. Numerous substantial flaws in data analysis and presentation may have led to an erroneous conclusion about the effect of blood storage age and perioperative mortality. Given the fundamental importance of a safe and adequate blood supply to national healthcare, the question of the proper storage age for blood should be studied using a prospective study design. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. RP Dzik, W (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. EM sdzik@partners.org NR 14 TC 52 Z9 52 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0958-7578 J9 TRANSFUSION MED JI Transfus. Med. PD AUG PY 2008 VL 18 IS 4 BP 260 EP 265 DI 10.1111/j.1365-3148.2008.00870.x PG 6 WC Hematology SC Hematology GA 337ZA UT WOS:000258472800008 PM 18783585 ER PT J AU Brinton, EA Hodis, HN Merriam, GR Harman, SM Naftolin, F AF Brinton, Eliot A. Hodis, Howard N. Merriam, George R. Harman, S. Mitchell Naftolin, Frederick TI Can menopausal hormone therapy prevent coronary heart disease? SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID CONJUGATED EQUINE ESTROGENS; HEALTHY POSTMENOPAUSAL WOMEN; RANDOMIZED CONTROLLED-TRIAL; REPLACEMENT THERAPY; CARDIOVASCULAR-DISEASE; PLUS PROGESTIN; MEDROXYPROGESTERONE ACETATE; VENOUS THROMBOEMBOLISM; VASCULAR FUNCTION; BREAST-CANCER AB observational studies show that women who take menopausal hormone therapy (MHT) have a greatly reduced risk of coronary heart disease (CHD). But in some large randomized controlled trials, MHT failed to decrease CHD and so has been deemed inappropriate for long-term prophylaxis against atherosclerosis or other chronic diseases associated with the menopause. Despite the apparent strength of this conclusion, several recent reports suggest that MHT could be atheroprotective when started close to the menopause, and effects of early discontinuation of MHT have never been studied in randomized trials. Here, we examine these reports and highlight existing uncertainty regarding the effects of long-term continuation versus early discontinuation of early-start MHT on atherosclerosis and CHD risk. We call for new research on this question, and an evidence-based review of existing recommendations for MHT. C1 [Brinton, Eliot A.] Univ Utah, Sch Med, Salt Lake City, UT 84108 USA. [Hodis, Howard N.] Univ So Calif, Atherosclerosis Res Unit, Dept Med, Los Angeles, CA 90089 USA. [Hodis, Howard N.] Univ So Calif, Atherosclerosis Res Unit, Dept Prevent Med, Los Angeles, CA 90089 USA. [Merriam, George R.] VA Puget Sound Hlth Care Syst, Seattle, WA 98493 USA. [Merriam, George R.] Univ Washington, Sch Med, Seattle, WA 98493 USA. [Harman, S. Mitchell] Kronos Longev Res Inst, Phoenix, AZ 85016 USA. [Harman, S. Mitchell] Univ Arizona, Coll Med, Phoenix, AZ 85016 USA. [Naftolin, Frederick] NYU, Sch Med, Dept Obstet & Gynecol, New York, NY 10016 USA. RP Brinton, EA (reprint author), Univ Utah, Sch Med, Salt Lake City, UT 84108 USA. EM eliot.brinton@utah.edu FU Aurora Foundation FX The authors acknowledge a grant from the Aurora Foundation in support of this work, and are grateful to Dr. JoArnn Manson for valuable discussions. NR 60 TC 8 Z9 10 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD AUG PY 2008 VL 19 IS 6 BP 206 EP 212 DI 10.1016/j.tem.2008.03.002 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 338BS UT WOS:000258480500003 PM 18450469 ER PT J AU Theoharides, TC Doyle, R Francis, K Conti, P Kalogeromitros, D AF Theoharides, Theoharis C. Doyle, Robert Francis, Konstantinos Conti, Pio Kalogeromitros, Dimitris TI Novel therapeutic targets for autism SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID HUMAN MAST-CELLS; CORTICOTROPIN-RELEASING-HORMONE; BLOOD-BRAIN-BARRIER; INFLAMMATORY-BOWEL-DISEASE; ENDOTHELIAL GROWTH-FACTOR; SPECTRUM DISORDERS; OXIDATIVE STRESS; GASTROINTESTINAL SYMPTOMS; AUTOIMMUNE-DISEASES; FOOD ALLERGY AB Autism spectrum disorders (ASDs) are pervasive neuro-developmental disorders, diagnosed in early childhood when acquired skills are lost or the acquisition of new skills becomes delayed. ASDs are associated with varying degrees of dysfunctional communication and social skills, in addition to repetitive and stereotypic behaviors. The diagnosis has increased considerably to approximately one in 180 people, but it is not clear whether this is because of a higher prevalence of the disorder, improved awareness by clinicians or a combination of both. There are no defined mechanisms of pathogenesis or curative therapy presently available. Oxidative stress, overactivation of the hypothalamic-pituitary-adrenal axis and increased gut-blood-brain-barrier permeability might be involved. The scope of this article is to integrate these findings and present the opinion that non-allergic activation of gastrointestinal and brain mast cells could contribute to many of the pathologic findings and provide unique targets for ASD therapy. We make suggestions for new research directives and possible novel therapies from readily available molecules. C1 [Theoharides, Theoharis C.] Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut,Tufts Med Ctr, Lab Mol Immunopharmacol & Drug Discovery, Boston, MA 02111 USA. [Theoharides, Theoharis C.] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Internal Med, Boston, MA 02111 USA. [Theoharides, Theoharis C.] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Biochem, Boston, MA 02111 USA. [Theoharides, Theoharis C.] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Psychiat, Boston, MA 02111 USA. [Theoharides, Theoharis C.; Kalogeromitros, Dimitris] Attikon Gen Hosp, Athens Med Sch, Allergy Unit, Allergy Clin Res Ctr, Athens 12462, Greece. [Doyle, Robert] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pediat Psychopharmacol, Boston, MA 02114 USA. [Francis, Konstantinos] Attikon Gen Hosp, Athens Med Sch, Dept Psychiat 2, Athens 12462, Greece. [Conti, Pio] Univ G dAnnunzio, Sch Med, Dept Canc & Neurosci, Div Immunol, I-66013 Chieti, Italy. RP Theoharides, TC (reprint author), Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut,Tufts Med Ctr, Lab Mol Immunopharmacol & Drug Discovery, 136 Harrison Ave, Boston, MA 02111 USA. EM theoharis.theoharides@tufts.edu FU NIH [NS38326, AR47652]; Mastocytosis Society (USA); Theta Biomedical Consulting and Development (Brookline, MA) FX Aspects of this work were funded in part by NIH grants NS38326 and AR47652, the Mastocytosis Society (USA) and Theta Biomedical Consulting and Development (Brookline, MA) to T.C.T. Many thanks to Jessica Christian for her word-processing skills. NR 69 TC 34 Z9 36 U1 0 U2 7 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD AUG PY 2008 VL 29 IS 8 BP 375 EP 382 DI 10.1016/j.tips.2008.06.002 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 341WQ UT WOS:000258746600001 PM 18606459 ER PT J AU Raffetto, JD Gram, CH Overman, KC Menzoian, JO AF Raffetto, Joseph D. Gram, Christopher H. Overman, Kristen C. Menzoian, James O. TI Mitogen-Activated Protein Kinase p38 Pathway in Venous Ulcer Fibroblasts SO VASCULAR AND ENDOVASCULAR SURGERY LA English DT Article DE fibroblasts; venous ulcer; growth factors; senescence; cell proliferation; mitogen-activated protein kinase; MAPK p38; kinase inhibitor; SB203580 ID CHRONIC LEG ULCERS; WOUND FLUID; PERICAPILLARY FIBRIN; DERMAL FIBROBLASTS; GROWTH-FACTORS; INSUFFICIENCY; SENESCENCE; EXPRESSION; DISEASE; CELLS AB Objective: Venous ulcer fibroblasts (w-fb) have attenuated growth compared to normal fibroblasts (n-fb). The MAPKp38 pathway mediates stress-responses in various diseases. We hypothesize that p38 pathway is altered in w-fb. Methods: W-fb were isolated from venous ulcers and n-fb from the ipsilateral thigh. Fibroblasts were analyzed. for phosphorylated p38 using immunoblot. The relation between p38 and w-fb proliferation was assessed with SB203580 (p38 inhibitor). Fibroblasts were treated with bFGF, TNF-a, and IL-1 and p38 expression analyzed. Results: Phosphorylated p38 expression was increased in w-fb (AU%=233.5 +/- 59.7, P=0.039) compared to n-fb (AU%=99.9 +/- 14.6). W-fb treated with SB203580 demonstrated increased growth compared to untreated w-fb. W-fb treated with bFGF demonstrated decreased p38. TNF-alpha and IL-1 beta significantly increase p38 expression. Conclusions: MAM p38 is up-regulated in w-fb. Regulation of w-fb proliferation is influenced by p38. Altering the p38 pathway in vivo with growth factors or cytokine inhibition may improve fibroblast proliferation and venous ulcer healing. C1 [Raffetto, Joseph D.; Overman, Kristen C.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Raffetto, Joseph D.] Boston VA Healthcare Syst, Boston, MA USA. [Gram, Christopher H.] Surg Specialists, Decatur, IL USA. [Overman, Kristen C.] Boston Med Ctr, Boston, MA USA. [Menzoian, James O.] Univ Connecticut, Farmington, CT USA. RP Raffetto, JD (reprint author), VA Boston Healthcare Syst, Dept Surg 112, Vasc Surg Sect, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM joseph.raffetto@med.va.gov NR 40 TC 11 Z9 11 U1 2 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1538-5744 EI 1938-9116 J9 VASC ENDOVASC SURG JI Vasc. Endovasc. Surg. PD AUG-SEP PY 2008 VL 42 IS 4 BP 367 EP 374 DI 10.1177/1538574408316140 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 373HR UT WOS:000260963200009 PM 18583302 ER PT J AU Bernstein, J Esterhai, JL Staska, M Reinhardt, S Mitchell, ME AF Bernstein, Joseph Esterhai, John L. Staska, Mitchell Reinhardt, Sally Mitchell, Marc E. TI The prevalence of occult peripheral arterial disease among patients referred for orthopedic evaluation of leg pain SO VASCULAR MEDICINE LA English DT Article DE claudication; degenerative joint disease; peripheral artery disease ID TOTAL KNEE REPLACEMENT; PRIMARY-CARE/; MORTALITY AB Lower extremity peripheral arterial disease (PAD) and musculoskeletal conditions both produce symptoms of leg pain, and may coexist. This study assesses the prevalence of PAD among patients referred to orthopedic surgery for evaluation of lower extremity pain. Fifty consecutive patients aged 50 years or more who had a chief complaint of leg pain, no history of trauma, and no previous history of PAD were studied prospectively. The presence of known risk factors for PAD and classic claudication symptoms was assessed by telephone interview and medical record review. Individuals were then evaluated by measurement of the ankle-brachial index (ABI) using Doppler and pulse volume recordings (PVR). A patient was deemed to have PAD if the ABI was below 0.9 or if the PVR demonstrated significant abnormalities. Occult PAD was detected in 10 of the 50 patients (20%) on the basis of the non-invasive vascular studies. There were no differences between patients with PAD and those without PAD regarding the presence of risk factors for PAD. None of the patients without PAD had claudication, while only one of the 10 patients with PAD had symptoms of classic claudication. In conclusion, 20% of patients referred by primary care providers to the orthopedic surgery clinic for lower extremity pain were discovered to have occult PAD. The majority of these patients did not have claudication. Orthopedic surgeons and primary care providers must maintain an appropriately high index of suspicion for PAD when evaluating patients with non-traumatic lower extremity pain. C1 [Mitchell, Marc E.] Univ Mississippi, Dept Surg, Jackson, MS 39216 USA. [Bernstein, Joseph; Esterhai, John L.] Univ Penn, Dept Orthopaed Surg, Philadelphia, PA 19104 USA. [Bernstein, Joseph; Esterhai, John L.; Staska, Mitchell; Reinhardt, Sally] Vet Affairs Med Ctr, Philadelphia, PA USA. RP Mitchell, ME (reprint author), Univ Mississippi, Dept Surg, 2500 N State St, Jackson, MS 39216 USA. EM memitchell@surgery.umsmed.edu NR 14 TC 4 Z9 4 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1358-863X J9 VASC MED JI Vasc. Med. PD AUG PY 2008 VL 13 IS 3 BP 235 EP 238 DI 10.1177/1358863X08091970 PG 4 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 346PS UT WOS:000259081900004 PM 18687760 ER PT J AU Tsoulfas, G Hertl, M Ko, DSC Elias, N Delmonico, FL Romano, L Fernandes, I Schoenfeld, D Kawai, T AF Tsoulfas, George Hertl, Martin Ko, Dicken S. C. Elias, Nahel Delmonico, Francis L. Romano, Linda Fernandes, Isabel Schoenfeld, David Kawai, Tatsuo TI Long-term outcome of a cuffed expanded PTFE graft for hemodialysis vascular access SO WORLD JOURNAL OF SURGERY LA English DT Article ID DIALYSIS GRAFTS; ANASTOMOSIS AB Background Development of venous outflow stenosis has been a major obstacle in maintaining the patency of dialysis vascular grafts. In the present study, we retrospectively analyzed the long-term results of cuffed expanded polytetrafluoroethylene (ePTFE) and non-cuffed (standard) ePTFE grafts placed for hemodialysis access. Materials and methods A total of 67 patients who underwent placement of either cuffed (n = 41) or standard (n = 26) ePTFE grafts were retrospectively analyzed. There were no significant differences between the two groups with regard to age, gender, cause of end-stage renal disease, and anatomic placement of the graft. Endpoints consisted of primary (without any intervention) and secondary (with radiological or surgical intervention) graft patency rates at 1-3 years. Results There was a trend toward better primary graft patency rates in the cuffed versus the standard ePTFE: 37.7% vs. 25.7% at 1 year, 35% vs. 10.3% at 2 years, 28% vs. 5.1% at 3 years, respectively (p = 0.086, Kaplan-Meier). Secondary patency rates in the cuffed group were significantly superior (p = 0.047) to those in the standard group (81.8% vs. 56.1% at 1 year, 61.8% vs. 46.3% at 2 years, 51.5% vs. 33.1% at 3 years, respectively). Thrombosis as a cause of complete graft failure was significantly higher (34%) in the standard group than in the cuffed group (9%) (p = 0.0125). Conclusions Compared to the standard ePTFE, the cuffed ePTFE graft provided better long-term outcome, especially in terms of secondary patency rates after radiological intervention. C1 [Tsoulfas, George; Hertl, Martin; Ko, Dicken S. C.; Elias, Nahel; Delmonico, Francis L.; Kawai, Tatsuo] Massachusetts Gen Hosp, Dept Surg, Transplant Ctr, Boston, MA 02114 USA. [Romano, Linda; Fernandes, Isabel] Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. [Schoenfeld, David] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. RP Kawai, T (reprint author), Massachusetts Gen Hosp, Dept Surg, Transplant Ctr, White 510,55 Fruit St, Boston, MA 02114 USA. EM tkawai@partners.org RI Tsoulfas, Georgios/K-4801-2012 OI Tsoulfas, Georgios/0000-0001-5043-7962 NR 17 TC 9 Z9 9 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 AUG PY 2008 VL 32 IS 8 BP 1827 EP 1831 DI 10.1007/s00268-008-9514-z PG 5 WC Surgery SC Surgery GA 332PC UT WOS:000258093900037 PM 18343971 ER PT J AU Connolly, SS Yoo, JJ Abouheba, M Soker, S McDougal, WS Atala, A AF Connolly, Stephen S. Yoo, James J. Abouheba, Mohamed Soker, Shay McDougal, W. Scott Atala, Anthony TI Cavernous nerve regeneration using acellular nerve grafts SO WORLD JOURNAL OF UROLOGY LA English DT Article DE nerve regeneration; cavernous nerve; erectile dysfunction; radical prostatectomy; acellular tissue scaffold ID RADICAL RETROPUBIC PROSTATECTOMY; PERIPHERAL-NERVE; GROWTH-FACTOR; COLLAGEN MATRICES; PENILE ERECTION; SENSORY NEURONS; STEM-CELLS; FOLLOW-UP; IN-VIVO; RAT AB Introduction The restoration of erectile function following complete transection of nerve tissue during surgery remains challenging. Recently, graft procedures using sural nerve grafts during radical prostatectomy have had favorable outcomes, and this has rekindled interest in the applications of neural repair in a urologic setting. Although nerve repair using autologous donor graft is the gold standard of treatment currently, donor nerve availability and the associated donor site morbidity remain a problem. In this study, we investigated whether an "off-the-shelf" acellular nerve graft would serve as a viable substitute. We examined the capacity of acellular nerve scaffolds to facilitate the regeneration of cavernous nerve in a rodent model. Materials and methods Acellular nerve matrices, processed from donor rat corporal nerves, were interposed across nerve gaps. A total of 80 adult male Sprague-Dawley rats were divided into four groups. A 0.5-cm segment of cavernosal nerve was excised bilaterally in three of the four groups. In the first group, acellular nerve segments were inserted bilaterally at the defect site. The second group underwent autologous genitofemoral nerve grafts at the same site, and the third group had no repair. The fourth group underwent a sham procedure. Serial cavernosal nerve function assessment was performed using electromyography (EMG) at 1 and 3 months following initial surgery. Histological and immunocytochemical analyses were performed to identify the extent of nerve regeneration. Results Animals implanted with acellular nerve grafts demonstrated a significant recovery in erectile function when compared with the group that received no repair, both at 1 and 3 months. EMG of the acellular nerve grafts demonstrated adequate intracavernosal pressures by 3 months (87.6% of the normal non-injured nerves). Histologically, the retrieved regenerated nerve grafts demonstrated the presence of host cell infiltration within the nerve sheaths. Immunohistochemically, antibodies specific to axons and Schwann cells demonstrated an increase in nerve regeneration across the grafts over time. No organized nerve regeneration was observed when the cavernous nerve was not repaired. Conclusion These findings show that the use of nerve guidance channel systems allow for accelerated and precise cavernosal nerve regeneration. Acellular nerve grafts represent a viable alternative to fresh autologous grafts in a rodent model of erectile dysfunction. C1 [Connolly, Stephen S.; Yoo, James J.; Abouheba, Mohamed; Soker, Shay; Atala, Anthony] Wake Forest Inst Regenerat Med, Dept Urol, Winston Salem, NC 27157 USA. [McDougal, W. Scott] Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. [McDougal, W. Scott] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Yoo, JJ (reprint author), Wake Forest Inst Regenerat Med, Dept Urol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jyoo@wfubmc.edu OI Abouheba, Mohamed/0000-0001-7228-1313; Atala, Anthony/0000-0001-8186-2160 NR 44 TC 22 Z9 32 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-4983 J9 WORLD J UROL JI World J. Urol. PD AUG PY 2008 VL 26 IS 4 BP 333 EP 339 DI 10.1007/s00345-008-0283-y PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 339LB UT WOS:000258578000008 PM 18594832 ER PT J AU Xu, GG Intano, GW McCarrey, JR Walter, RB McMahan, CA Walter, CA AF Xu, Guogang Intano, Gabriel W. McCarrey, John R. Walter, Ronald B. McMahan, C. Alex Walter, Christi A. TI Recovery of a low mutant frequency after ionizing radiation-induced mutagenesis during spermatogenesis SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE ionizing radiation; mutagenesis; spermatogenic cells; Lac I mouse ID SEMINIFEROUS EPITHELIAL FUNCTION; SPERMATOGONIAL STEM-CELLS; ATOMIC-BOMB SURVIVORS; LACI TRANSGENIC MICE; MALE GERM-CELLS; TESTICULAR CELLS; INDUCED MUTATION; DOSE-RESPONSE; GENETIC RISKS; X-RAYS AB Humans are exposed to ionizing radiation (IR) under various circumstances, e.g. cosmic radiation, diagnostic X-rays and radiotherapy for cancer. It has been shown that IR can impair spermatogenesis and can cause mutations in germ cells. However, the mutagenic responses of germ cells exposed to IR at different stages of testicular maturation have not been examined by directly assessing the mutant frequency in defined spermatogenic cell types. This study was performed to address whether preadult exposure to IR can increase mutations in adult germ cells that could in turn have a major impact on adult reproductive function and the health of ensuing offspring. Male Lac I transgenic mice were irradiated with a single dose of 2.5 Gy of gamma-ray at different ages before adulthood, reflecting different stages of testicular maturation, and then mutant frequency (MF) was determined directly in spermatogenic cell types emanating from the irradiated precursor cells. The results showed that (I) preadult exposure to IR did not significantly increase MF in adult epididymal spermatozoa; (2) spermatogenic stages immediately following the irradiated stage(s) displayed an elevated mutant frequency; but (3) the mutant frequency was restored to unirradiated levels in later stages of spermatogenesis. These findings provide evidence that there is a mechanism(s) to prevent spermatogenic cells with elevated mutant frequencies from progressing through spermatogenesis. Published by Elsevier B.V. C1 [Xu, Guogang; Intano, Gabriel W.; Walter, Christi A.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [McCarrey, John R.] Univ Texas San Antonio, Dept Biol, San Antonio, TX 78249 USA. [Walter, Ronald B.] SW Texas State Univ, Dept Chem & Biochem, San Marcos, TX 78666 USA. [McMahan, C. Alex] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Walter, Christi A.] Univ Texas Hlth Sci Ctr San Antonio, Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. [Walter, Christi A.] Audie Murphy Hosp, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Walter, CA (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM walter@uthscsa.edu FU NIH [AG24364, AG21163] FX This work was supported by NIH grants AG24364 and AG21163 to Dr. C.A. Walter. The contents are solely the responsibility of the authors, and do not necessarily represent the official views of the NIH. NR 53 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD JUL 31 PY 2008 VL 654 IS 2 BP 150 EP 157 DI 10.1016/j.mrgentox.2008.05.012 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 342UN UT WOS:000258809200007 PM 18582597 ER PT J AU Kuchibhotla, KV Goldman, ST Lattarulo, CR Wu, HY Hyman, BT Bacskai, BJ AF Kuchibhotla, Kishore V. Goldman, Samuel T. Lattarulo, Carli R. Wu, Hai-Yan Hyman, Bradley T. Bacskai, Brian J. TI A beta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks SO NEURON LA English DT Article ID ALZHEIMERS-DISEASE; AMYLOID-BETA; CORTICAL-NEURONS; TRANSGENIC MICE; BILAYER-MEMBRANES; MOUSE MODEL; MULTIPHOTON MICROSCOPY; MUTANT PRESENILIN-1; HIPPOCAMPAL-NEURONS; SYNAPTIC DEPRESSION AB Alzheimer's disease is characterized by the deposition of senile plaques and progressive dementia. The molecular mechanisms that couple plaque deposition to neural system failure, however, are unknown. Using transgenic mouse models of AD together with multiphoton imaging, we measured neuronal calcium in individual neurites and spines in vivo using the genetically encoded calcium indicator Yellow Cameleon 3.6. Quantitative imaging revealed elevated [Ca(2+)]i (calcium overload) in similar to 20% of neurites in APP mice with cortical plaques, compared to less than 5% in wild-type mice, PS1 mutant mice, or young APP mice (animals without cortical plaques). Calcium overload depended on the existence and proximity to plaques. The downstream consequences included the loss of spinodendritic calcium compartmentalization (critical for synaptic integration) and a distortion of neuritic morphologies mediated, in part, by the phosphatase calcineurin. Together, these data demonstrate that senile plaques impair neuritic calcium homeostasis in vivo and result in the structural and functional disruption of neuronal networks. C1 [Kuchibhotla, Kishore V.; Goldman, Samuel T.; Lattarulo, Carli R.; Wu, Hai-Yan; Hyman, Bradley T.; Bacskai, Brian J.] Massachusetts Gen Hosp, Alzheimers Dis Res Lab, Dept Neurol, Charlestown, MA 02129 USA. [Kuchibhotla, Kishore V.] Harvard Univ, Program Biophys, Cambridge, MA 02138 USA. RP Bacskai, BJ (reprint author), Massachusetts Gen Hosp, Alzheimers Dis Res Lab, Dept Neurol, 114 16th St, Charlestown, MA 02129 USA. EM bbacskai@partners.org FU NCRR NIH HHS [S10 RR025645]; NIA NIH HHS [AG08487, P50 AG005134, R01 AG008487, R01 AG008487-18]; NIBIB NIH HHS [EB000768, R01 EB000768, R01 EB000768-07]; NINDS NIH HHS [F31 NS058075, F31 NS058075-02, NS580752] NR 54 TC 262 Z9 270 U1 2 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 31 PY 2008 VL 59 IS 2 BP 214 EP 225 DI 10.1016/j.neuron.2008.06.008 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 334WR UT WOS:000258252700007 PM 18667150 ER PT J AU Wen, PY Kesari, S AF Wen, Patrick Y. Kesari, Santosh TI Malignant gliomas in adults SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID PHASE-II TRIAL; HIGH-GRADE GLIOMA; TUMOR STEM-CELLS; RECURRENT GLIOBLASTOMA-MULTIFORME; ENDOTHELIAL GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; BRAIN-TUMORS; RADIATION-THERAPY; ANAPLASTIC OLIGODENDROGLIOMAS; VENOUS THROMBOEMBOLISM C1 Brigham & Womens Hosp, Div Neurooncol, Dept Neurol, Boston, MA 02115 USA. Dana Farber Canc Inst, Ctr Neurooncol, Boston, MA 02115 USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, SW430D,44 Binney St, Boston, MA 02115 USA. EM pwen@partners.org RI leng, xianwei/F-9073-2011; Kesari, Santosh/E-8461-2013 FU NCI NIH HHS [K08 CA1240804, U01 CA062407] NR 113 TC 1617 Z9 1685 U1 28 U2 181 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 31 PY 2008 VL 359 IS 5 BP 492 EP 507 DI 10.1056/NEJMra0708126 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 331VC UT WOS:000258039700007 PM 18669428 ER PT J AU Viguera, AC Emmerich, AD Cohen, LS Koukopoulos, AE Harris, NL Rosenbaum, JF Rosenberg, ES AF Viguera, Adele C. Emmerich, Anne D. Cohen, Lee S. Koukopoulos, Alexia E. Harris, Nancy Lee Rosenbaum, Jerrold F. Rosenberg, Eric S. TI A woman with postpartum confusion, agitation, and delusions - Postpartum psychosis in a patient with bipolar disorder SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SEROTONIN-REUPTAKE INHIBITORS; AFFECTIVE PUERPERAL PSYCHOSIS; ANTIDEPRESSANT TREATMENT; PROPHYLACTIC LITHIUM; SUICIDAL-BEHAVIOR; MENTAL-ILLNESS; MOOD DISORDERS; FAMILY-HISTORY; BIRTH-DEFECTS; UNITED-STATES C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Dept Psychiat, Cambridge, MA 02138 USA. RP Viguera, AC (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. NR 67 TC 6 Z9 6 U1 1 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 31 PY 2008 VL 359 IS 5 BP 509 EP 515 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 331VC UT WOS:000258039700010 PM 18669430 ER PT J AU Hafler, BP Choi, MY Shivdasani, RA Rowitch, DH AF Hafler, Brian P. Choi, Michael Y. Shivdasani, Ramesh A. Rowitch, David H. TI Expression and function of Nkx6.3 in vertebrate hindbrain SO BRAIN RESEARCH LA English DT Article DE homeobox transcription factor; CNS development; V2 interneuron; Nkx6.3; Nkx6.1; rhombomere; medullary reticular formation ID HOMEODOMAIN TRANSCRIPTION FACTOR; PANCREATIC BETA-CELLS; VENTRAL NEURAL-TUBE; TARGETED DISRUPTION; GENE-EXPRESSION; HOMEOBOX GENES; NEURONAL FATE; MOTOR-NEURON; MOUSE; CNS AB Homeodomain transcription factors serve important functions in organogenesis and tissue differentiation, particularly with respect to the positional identity of individual cells. The Nkx6 subfamily controls tissue differentiation in the developing central nervous system where they function as transcriptional repressor proteins. Recent work indicates that Nkx6.3 is expressed in hindbrain V2 interneurons that co-express Nkx6.1, suggesting the possibility of functional redundancy. Here, we report that Nkx6.3 expression is specific to Chx10(+) V2a interneurons but not to Cata3(+) V2b interneurons of the hindbrain, and that Nkx6.3 expression appears to mark cells of the prospective medullary reticular formation. Molecular analysis of Nkx6.3 null embryonic mouse hindbrain did not reveal detectable defects in progenitor markers, motor neuron or V2 interneuron sub-types. Forced expression of Nkx6.3 and Nkx6.1 promote V2 interneuron differentiation in the developing chick hindbrain. These findings indicate Nkx6.3 function is dispensable for CNS development and lead to the proposal that absence of overt defects is due to functional compensation from a related homeodomain transcription factor. (C) 2008 Elsevier B.V. All rights reserved. C1 [Hafler, Brian P.; Rowitch, David H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA. [Choi, Michael Y.; Shivdasani, Ramesh A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Hafler, Brian P.] Harvard Univ, Sch Med, Dept Neurobiol, Cambridge, MA 02138 USA. [Choi, Michael Y.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Choi, Michael Y.; Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. RP Rowitch, DH (reprint author), Univ Calif San Francisco, 533 Parnassus Ave,U-503, San Francisco, CA 94143 USA. EM rowitchd@peds.ucsf.edu FU NINDS; Harvard Center for Neurodegeneration and Repair; NIH; NIDDK; Carcinoid Foundation FX We would like to thank Sovann Kaing, Dong-in Yuk, and Anthony Romer for expert technical assistance. BPH is supported by an F30 training grant from the NINDS and the Harvard Center for Neurodegeneration and Repair. MYC is supported by the F32 training grant from the NIH. We are grateful to the Beta Cell Biology Consortium and C. Cepko. Lhx3 and Hb9 antibodies were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by the University of Iowa. This work was supported by grants from the NINDS (to DHR) and NIDDK (to RAS) and through the generosity of the Caring for Carcinoid Foundation (to RAS). NR 30 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 30 PY 2008 VL 1222 BP 42 EP 50 DI 10.1016/j.brainres.2008.04.072 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 338XB UT WOS:000258541600004 PM 18586225 ER PT J AU Parienti, JJ Das-Douglas, M Massari, V Guzman, D Deeks, SG Verdon, R Bangsberg, DR AF Parienti, Jean-Jacques Das-Douglas, Moupali Massari, Veronique Guzman, David Deeks, Steven G. Verdon, Renaud Bangsberg, David R. TI Not All Missed Doses Are the Same: Sustained NNRTI Treatment Interruptions Predict HIV Rebound at Low-to-Moderate Adherence Levels SO PLOS ONE LA English DT Article AB Background: While the relationship between average adherence to HIV potent antiretroviral therapy is well defined, the relationship between patterns of adherence within adherence strata has not been investigated. We examined medication event monitoring system (MEMS) defined adherence patterns and their relation to subsequent virologic rebound. Methods and Results: We selected subjects with at least 3-months of previous virologic suppression on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen from two prospective cohorts in France and North America. We assessed the risk of virologic rebound, defined as HIV RNA of >400 copies/mL according to several MEMS adherence measurements. Seventy two subjects were studied, five of them experienced virologic rebound. Subjects with and without virologic rebound had similar baseline characteristics including treatment durations, regimen (efavirenz vs nevirapine), and dosing schedule. Each 10% increase in average adherence decreased the risk of virologic rebound (OR = 0.56; 95% confidence interval (CI) [0.37, 0.81], P < 0.002). Each additional consecutive day off therapy for the longest treatment interruption (OR = 1.34; 95% CI [1.15, 1.68], P < 0.0001) and each additional treatment interruption for more than 2 days (OR = 1.38; 95% CI [1.13, 1.77], P < 0.002) increased the risk of virologic rebound. In those with low-to-moderate adherence (i.e.,80%), treatment interruption duration (16.2 days versus 6.1 days in the control group, P < 0.02), but not average adherence (53.1% vs 55.9%, respectively, P = 0.65) was significantly associated with virologic rebound. Conclusions: Sustained treatment interruption may pose a greater risk of virologic rebound on NNRTI therapy than the same number of interspersed missed doses at low-to-moderate adherence. C1 [Parienti, Jean-Jacques; Verdon, Renaud] Cote Nacre Univ Hosp, Clin Res & Biostat Dept, Caen, France. [Parienti, Jean-Jacques; Massari, Veronique] Pierre Marie Curie Univ Paris 6, INSERM U707, UMR S707, Paris, France. [Das-Douglas, Moupali; Deeks, Steven G.] Univ Calif San Francisco, San Francisco Gen Hosp, Epidemiol & Prevent Intervent Ctr, Div Infect Dis, San Francisco, CA USA. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA USA. [Guzman, David] Univ Calif San Francisco, Epidemiol & Prevent Intervent Ctr, Div Infect Dis, San Francisco, CA USA. RP Parienti, JJ (reprint author), Cote Nacre Univ Hosp, Clin Res & Biostat Dept, Caen, France. EM parienti-jj@chu-caen.fr RI Massari, Veronique/E-6151-2017 FU Cote de Nacre University Hospital; NIMH [RO-54907]; NIAAA [K-24 015287] FX This study was funded by Cote de Nacre University Hospital and NIMH RO-54907. Dr. Bangsberg received additional support from NIAAA K-24 015287. NR 21 TC 102 Z9 102 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 30 PY 2008 VL 3 IS 7 AR e2783 DI 10.1371/journal.pone.0002783 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 420QM UT WOS:000264304300002 PM 18665246 ER PT J AU Truong, QA Gupta, V Bezerra, HG Okada, DR Rogers, IS Holmvang, G Palacios, IF AF Truong, Quynh A. Gupta, Vishal Bezerra, Hiram G. Okada, David R. Rogers, Ian S. Holmvang, Godtfred Palacios, Igor F. TI The traveling Amplatzer rare complication of percutaneous atrial septal occluder device embolism SO CIRCULATION LA English DT Editorial Material ID TRANSCATHETER CLOSURE C1 [Gupta, Vishal; Rogers, Ian S.; Holmvang, Godtfred; Palacios, Igor F.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Truong, Quynh A.; Bezerra, Hiram G.; Okada, David R.; Rogers, Ian S.; Holmvang, Godtfred] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. RP Gupta, V (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. EM vishalgupta@yahoo.com NR 4 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 29 PY 2008 VL 118 IS 5 BP E93 EP E96 DI 10.1161/CIRCULATIONAHA.108.765586 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 331EC UT WOS:000257994500021 PM 18663093 ER PT J AU Joner, M Nakazawa, G Finn, AV Quee, SC Coleman, L Acampado, E Wilson, PS Skorija, K Cheng, Q Xu, X Gold, HK Kolodgie, FD Virmani, R AF Joner, Michael Nakazawa, Gaku Finn, Aloke V. Quee, Shawn Chin Coleman, Leslie Acampado, Eduardo Wilson, Patricia S. Skorija, Kristi Cheng, Qi Xu, Xin Gold, Herman K. Kolodgie, Frank D. Virmani, Renu TI Endothelial cell recovery between comparator polymer-based drug-eluting stents SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE drug-eluting stents; endothelium; platelet-endothelial adhesion molecule-1; vascular endothelial growth factor ID TISSUE FACTOR EXPRESSION; GROWTH-FACTOR; STRUT THICKNESS; THROMBOMODULIN EXPRESSION; ARTERIAL INJURY; SIROLIMUS; DELIVERY; THROMBOSIS; IMPLANTATION; PACLITAXEL AB Objectives The purpose of this study was to assess trends in endothelial coverage and recovery among leading polymer-based drug-eluting stents ( DES). Background Autopsy studies of human U. S. Food and Drug Administration (FDA)-approved DES implanted coronary arteries suggest that complications of late stent thrombosis are associated with incomplete endothelial coverage of struts. Methods Rabbits received sirolimus-eluting stents (SES), paclitaxel-eluting stents ( PES), zotarolimus-eluting stents ( ZES), and everolimus-eluting stents ( EES) for 14 or 28 days along with MULTI-LINK ( ML) Vision control stents. Endothelial coverage above and between struts was measured by morphometric analysis of images acquired through en face scanning electron microscopy. Dual fluorescent immunolabeling was performed for platelet-endothelial cell adhesion molecule ( PECAM)-1 and thrombomodulin ( TM), factors involved in cell-to-cell contact and thrombogenicity, respectively. In a separate analysis, the endothelial mitogen, vascular endothelial growth factor ( VEGF), was also assessed. Results Varying rates of endothelialization among comparator DES were most notable at 14 days, where coverage above struts remained poor in SES, PES, and ZES ( <= 30%) relative to EES and ML Vision controls (>= 70%), whereas no significant differences were observed at 28 days. Select DES with poor endothelialization showed a further reduced expression of PECAM-1. All DES showed an absence or weak expression of the antithrombotic cofactor TM. Incomplete endothelialization in select DES was further associated with increased VEGF secretion and messenger ribonucleic acid levels at 14 days, providing evidence of a transitional healing surface. Conclusions The present study marks the first comparator analysis of endothelial coverage in leading polymeric DES, supporting disparities in arterial healing based on endothelial regrowth and recovery, favoring newer designs over the current generation of FDA-approved stents. C1 [Nakazawa, Gaku; Acampado, Eduardo; Wilson, Patricia S.; Skorija, Kristi; Cheng, Qi; Xu, Xin; Kolodgie, Frank D.; Virmani, Renu] CVPath Inst Inc, Gaithersburg, MD 20878 USA. [Joner, Michael] German Heart Ctr, D-8000 Munich, Germany. [Finn, Aloke V.] Emory Univ, Div Cardiol, Atlanta, GA 30322 USA. [Quee, Shawn Chin; Coleman, Leslie] Abbott Vasc, Santa Clara, CA USA. [Gold, Herman K.] Massachusetts Gen Hosp, Dept Internal Med, Cardiac Unit, Boston, MA 02114 USA. [Virmani, Renu] Jack H Skirball Ctr Cardiovasc Res, Orangeburg, NY USA. RP Virmani, R (reprint author), CVPath Inst Inc, 19 Firstfeld Rd, Gaithersburg, MD 20878 USA. EM rvirmani@cvpath.org NR 47 TC 362 Z9 370 U1 1 U2 31 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 29 PY 2008 VL 52 IS 5 BP 333 EP 342 DI 10.1016/j.jacc.2008.04.030 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 329CP UT WOS:000257844800004 PM 18652940 ER PT J AU Choi, EK Il Choi, S Rivera, JJ Nasir, K Chang, SA Chun, EJ Kim, HK Choi, DJ Blumenthal, RS Chang, HJ AF Choi, Eue-Keun Il Choi, Sang Rivera, Juan J. Nasir, Khurram Chang, Sung-A Chun, Eun Ju Kim, Hyung-Kwan Choi, Dong-Joo Blumenthal, Roger S. Chang, Hyuk-Jae TI Coronary computed tomography angiography as a screening tool for the detection of occult coronary artery disease in asymptomatic individuals SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE arteriosclerosis; coronary angiography; coronary tomography; mass screening; X-ray computed ID TUBE CURRENT MODULATION; PANEL III GUIDELINES; MYOCARDIAL-INFARCTION; RADIATION-EXPOSURE; HEART-ASSOCIATION; RISK-FACTORS; CHEST-PAIN; CALCIUM; PLAQUE; PREVALENCE AB Objectives The purpose of this study was to evaluate the prevalence of occult coronary artery disease ( CAD) with coronary computed tomography angiography (CTA) to characterize plaque composition and to evaluate the potential of this new technology to impact risk stratification in asymptomatic middle-aged subjects. Background There is a paucity of information regarding the role of CTA for the detection of occult CAD in asymptomatic individuals. Methods We consecutively enrolled 1,000 middle-aged asymptomatic subjects ( age 50 +/- 9 years, 63% men) who underwent CTA ( 64-slice multidetector row computed tomography) as part of a general health evaluation. Results Atherosclerotic plaques were identified in 215 ( 22%, 2 +/- 1 segments/subject) individuals; 40 individuals (4%) had only noncalcified plaques. Fifty-two (5%) subjects had significant ( >= 50%) diameter stenosis and 21 (2%) had severe (>= 75%) stenosis. Thirteen (25%) and 30 (58%) subjects with significant stenosis were classified into National Cholesterol Education Program low-risk and mild coronary calcification ( coronary artery calcium scores <100), respectively. Midterm follow-up ( 17 +/- 2 months) revealed 15 cardiac events only in those with CAD on CTA: 1 unstable angina requiring hospital stay and 14 revascularization procedures. Most (87%) events occurred within 90 days of index CTA. Conclusions The prevalence of occult CAD in apparently healthy individuals was not negligible, although their midterm prognosis was good. CTA has a potential to provide a better insight about the occult CAD in this population. However, on the basis of our results and considering present radiation exposure data, we cannot recommend that CTA be used as a screening tool for this population at this point. C1 [Choi, Eue-Keun; Chang, Sung-A; Kim, Hyung-Kwan; Choi, Dong-Joo; Chang, Hyuk-Jae] Seoul Natl Univ, Bundang Hosp, Ctr Cardiovasc, Div Cardiol, Songnam 463802, Gyeonggi Do, South Korea. [Il Choi, Sang; Chun, Eun Ju] Seoul Natl Univ, Bundang Hosp, Ctr Cardiovasc, Div Radiol, Songnam 463802, Gyeonggi Do, South Korea. [Rivera, Juan J.; Blumenthal, Roger S.] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Nasir, Khurram] Massachusetts Gen Hosp, Cardiac MRI PET CT Program, Boston, MA 02114 USA. RP Chang, HJ (reprint author), Seoul Natl Univ, Bundang Hosp, Ctr Cardiovasc, Div Cardiol, 300 Gumi Dong, Songnam 463802, Gyeonggi Do, South Korea. EM hjchang@snu.ac.kr NR 32 TC 180 Z9 189 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 29 PY 2008 VL 52 IS 5 BP 357 EP 365 DI 10.1016/j.jacc.2008.02.086 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 329CP UT WOS:000257844800007 PM 18652943 ER PT J AU Freeman, GJ AF Freeman, Gordon J. TI Structures of PD-1 with its ligands: Sideways and dancing cheek to cheek SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID T-CELL-ACTIVATION; PROGRAMMED DEATH-1; COMPLEX; IMMUNITY; STIMULATION; RESPONSES; B7-H1 C1 Harvard Univ, Sch Med, Dept Med, Dana Farber Canc Inst,Dept Med Oncol, Boston, MA 02115 USA. RP Freeman, GJ (reprint author), Harvard Univ, Sch Med, Dept Med, Dana Farber Canc Inst,Dept Med Oncol, Boston, MA 02115 USA. EM gordon_freeman@dfci.harvard.edu FU NIAID NIH HHS [P01 AI056299, AI56299]; PHS HHS [BAA-05-11] NR 16 TC 21 Z9 21 U1 4 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 29 PY 2008 VL 105 IS 30 BP 10275 EP 10276 DI 10.1073/pnas.0805459105 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 334GZ UT WOS:000258211600002 PM 18650389 ER PT J AU Breault, DT Min, IM Carlone, DL Farilla, LG Ambruzs, DM Henderson, DE Algra, S Montgomery, RK Wagers, AJ Hole, N AF Breault, David T. Min, Irene M. Carlone, Diana L. Farilla, Loredana G. Ambruzs, Dana M. Henderson, Daniel E. Algra, Selma Montgomery, Robert K. Wagers, Amy J. Hole, Nicholas TI Generation of mTert-GFP mice as a model to identify and study tissue progenitor cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE intestinal stem cell; telomerase; tissue stem cells ID HEMATOPOIETIC STEM-CELLS; TELOMERASE ACTIVITY; MOUSE TELOMERASE; GERM-CELLS; DIFFERENTIATION; PROLIFERATION; EXPRESSION; RENEWAL; BIOLOGY; RISE AB Stem cells hold great promise for regenerative medicine, but remain elusive in many tissues in part because universal markers of "stemness" have not been identified. The ribonucleoprotein complex telomerase catalyzes the extension of chromosome ends, and its expression is associated with failure of cells to undergo cellular senescence. Because such resistance to senescence is a common characteristic of many stem cells, we hypothesized that telomerase expression may provide a selective biomarker for stem cells in multiple tissues. In fact, telomerase expression has been demonstrated within hematopoietic stem cells. We therefore generated mouse telomerase reverse transcriptase (mTert)-GFP-transgenic mice and assayed the ability of mTert-driven GFP to mark tissue stem cells in testis, bone marrow (BM), and intestine. mTert-GFP mice were generated by using a two-step embryonic stem cell-based strategy, which enabled primary and secondary screening of stably transfected clones before blastocyst injection, greatly increasing the probability of obtaining mTert reporter mice with physiologically appropriate regulation of GFP expression. Analysis of adult mice showed that GFP is expressed in differentiating male germ cells, is enriched among BM-derived hematopoietic stem cells, and specifically marks long-term BrdU-retaining intestinal crypt cells. In addition, telomerase-expressing GFP(+) BM cells showed long-term, serial, multilineage BM reconstitution, fulfilling the functional definition of hematopoietic stem cells. Together, these data provide direct evidence that mTert-GFP expression marks progenitor cells in blood and small intestine, validating these mice as a useful tool for the prospective identification, isolation, and functional characterization of progenitor/stem cells from multiple tissues. C1 [Breault, David T.; Carlone, Diana L.; Farilla, Loredana G.; Ambruzs, Dana M.; Henderson, Daniel E.] Harvard Univ, Sch Med, Div Endocrinol, Childrens Hosp, Boston, MA 02115 USA. [Algra, Selma; Montgomery, Robert K.] Harvard Univ, Sch Med, Div Gastroenterol, Childrens Hosp, Boston, MA 02115 USA. [Min, Irene M.; Wagers, Amy J.] Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, Boston, MA 02215 USA. [Min, Irene M.; Wagers, Amy J.] Harvard Stem Cell Inst, Boston, MA 02215 USA. [Hole, Nicholas] Univ Durham, Sch Biol & Biomed Sci, Durham DH1 3LE, England. RP Breault, DT (reprint author), Harvard Univ, Sch Med, Div Endocrinol, Childrens Hosp, Boston, MA 02115 USA. EM david.breault@childrens.harvard.edu FU NICHD NIH HHS [P30 HD018655, P30 HD18655]; NIDDK NIH HHS [5T32 DK007699, K08 DK066305, T32 DK007699, T32 DK007260, R37 DK32658, R37 DK032658, R01 DK084056, 2T32 DK07260] NR 33 TC 62 Z9 63 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 JUL 29 PY 2008 VL 105 IS 30 BP 10420 EP 10425 DI 10.1073/pnas.0804800105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 334GZ UT WOS:000258211600028 PM 18650388 ER PT J AU Dhaese, I Vanneste, G Sips, P Buys, E Brouckaert, P Lefebvre, RA AF Dhaese, Ingeborg Vanneste, Gwen Sips, Patrick Buys, Emmanuel Brouckaert, Peter Lefebvre, Romain A. TI Involvement of soluble guanylate cyclase alpha(1) and alpha(2), and SK(Ca) channels in NANC relaxation of mouse distal colon SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE soluble guanylate cyclase; nitric oxide; SK(Ca) channels (Ca(2+)-dependent K(+) channels); distal colon; sGC alpha(1) knockout (soluble guanylate cyclase alpha(1) knockout) ID CA2+-ACTIVATED K+ CHANNELS; NITRIC-OXIDE; CYCLIC-GMP; INDEPENDENT MECHANISMS; GASTROINTESTINAL-TRACT; INTERSTITIAL-CELLS; CIRCULAR MUSCLE; SMOOTH-MUSCLE; NO; EXPRESSION AB In distal colon, both nitric oxide (NO) and ATP are involved in non-adrenergic non-cholinergic (NANC) inhibitory neurotransmission. The role of the soluble guanylate cyclase (sGC) isoforms alpha(1)beta(1) and alpha(2)beta(1), and of the small conductance Ca(2+)-dependent K(+) channels (SK(Ca) channels) in the relaxation of distal colon by exogenous NO and by NANC nerve stimulation was investigated, comparing wild type (WT) and sGC alpha(1) knockout (KO) mice. In WT strips, the relaxation induced by electrical field stimulation (EFS) at 1 Hz but not at 2-8 Hz was significantly reduced by the NO-synthase inhibitor L-NAME or the sGC inhibitor ODQ. The SK(Ca) channel blocker apamin alone had no inhibitory effect on EFS-induced relaxation, but combined with ODQ or L-NAME, apamininhibited the relaxation induced by EFS at 2-8 Hz in WT strips and at 8Hz in sGC alpha(1) KO strips. Relaxation by exogenous NO was significantly attenuated in sGC alpha(1) KO strips, but could still be reduced further by ODQ. Basal cGMP levels were lower in sGC alpha(1) KO strips but NO still significantly increased cGMP levels versus basal. In conclusion, in the absence of sGC alpha(1)beta(1), exogenous NO is able to partially act through sGC alpha(2)beta(1). NO acting cia sGC alpha(1) is the principal neurotransmitter in EFS-evoked responses at 1 Hz. At higher stimulation frequencies, NO, acting at sGC alpha(1)beta(1) and/or sGC alpha(2)beta(1), functions together with another transmitter, probably ATP acting via SK(Ca) channels, with some degree of redundancy. (c) 2008 Elsevier B.V. All rights reserved. C1 [Dhaese, Ingeborg; Vanneste, Gwen; Lefebvre, Romain A.] Univ Ghent, Heymans Inst Pharmacol, B-9000 Ghent, Belgium. [Sips, Patrick; Buys, Emmanuel; Brouckaert, Peter] Univ Ghent VIB, Dept Mol Biomed Res, B-9052 Ghent, Belgium. [Sips, Patrick; Buys, Emmanuel; Brouckaert, Peter] Univ Ghent, Dept Mol Biol, B-9000 Ghent, Belgium. [Buys, Emmanuel] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care,Anesthesia Ctr Crit C, Boston, MA 02114 USA. RP Lefebvre, RA (reprint author), Univ Ghent, Heymans Inst Pharmacol, Pintelaan 185, B-9000 Ghent, Belgium. EM Romain.Lefebvre@UGent.be OI Sips, Patrick/0000-0001-9241-5980 FU Special Investigation Fund of Ghent University [GOA 1251004]; Northeast Affiliate Research Committee of the American Heart Association [G.0053.02] FX This study was financially supported by the Special Investigation Fund of Ghent University (GOA 1251004) and the fund for Scientific Research Flanders (G.0053.02). E.B. was supported by an award from the Northeast Affiliate Research Committee of the American Heart Association.; The authors thank Mr. V. Geers and Ms. E. Elinck for their technical assistance. NR 40 TC 17 Z9 17 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD JUL 28 PY 2008 VL 589 IS 1-3 BP 251 EP 259 DI 10.1016/j.ejphar.2008.05.021 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 340EH UT WOS:000258628400044 PM 18572161 ER PT J AU Martin, NM Abu Dayyeh, BK Chung, RT AF Martin, Nicole M. Abu Dayyeh, Barham K. Chung, Raymond T. TI Anabolic steroid abuse causing recurrent hepatic adenomas and hemorrhage SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE anabolic steroids; adenoma; liver; hemorrhage ID ANDROGENIC STEROIDS; PELIOSIS HEPATIS; PREVALENCE; THERAPY AB Anabolic steroid abuse is common among athletes and is associated with a number of medical complications. We describe a case of a 27-year-old male bodybuilder with multiple hepatic adenomas induced by anabolic steroids. He initially presented with tumor hemorrhage and was treated with left lateral hepatic segmentectomy. Regression of the remaining tumors was observed with cessation of steroid use. However, 3 years and a half after his initial hepatic segmentectomy, he presented with recurrent tumor enlargement and intraperitoneal hemorrhage in the setting of steroid abuse relapse. Given his limited hepatic reserve, he was conservatively managed with embolization of the right accessory hepatic artery. This is the first reported case of hepatic adenoma re-growth with recidivistic steroid abuse, complicated by life-threatening hemorrhage. While athletes and bodybuilders are often aware of the legal and social ramifications of steroid abuse, they should continue to be counseled about its serious medical risks. (C) 2008 The WJG Press. All rights reserved. C1 [Martin, Nicole M.; Abu Dayyeh, Barham K.; Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Chung, RT (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, WRN 1007,55 Fruit St, Boston, MA 02114 USA. EM rtchung@partners.org NR 14 TC 22 Z9 24 U1 0 U2 1 PU W J G PRESS PI BEIJING PA APT 1066, YISHOU GARDEN, NO 58, NORTH LANGXINZHUANG RD, PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUL 28 PY 2008 VL 14 IS 28 BP 4573 EP 4575 DI 10.3748/wjg.14.4573 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 335AP UT WOS:000258263500024 PM 18680242 ER PT J AU Asher, G Gatfield, D Stratmann, M Reinke, H Dibner, C Kreppel, F Mostoslavsky, R Alt, FW Schibler, U AF Asher, Gad Gatfield, David Stratmann, Markus Reinke, Hans Dibner, Charna Kreppel, Florian Mostoslavsky, Raul Alt, Frederick W. Schibler, Ueli TI SIRT1 regulates circadian clock gene expression through PER2 deacetylation SO CELL LA English DT Article ID HISTONE ACETYLTRANSFERASE; SUPRACHIASMATIC NUCLEUS; TRANSCRIPTION FACTORS; PROTEIN; LIVER; CELLS; BMAL1; ACETYLATION; DEGRADATION; OSCILLATOR AB The mammalian circadian timing system is composed of a central pacemaker in the suprachiasmatic nucleus of the brain that synchronizes countless subsidiary oscillators in peripheral tissues. The rhythm-generating mechanism is thought to rely on a feedback loop involving positively and negatively acting transcription factors. BMAL1 and CLOCK activate the expression of Period (Per) and Cryptochrome (Cry) genes, and once PER and CRY proteins accumulate to a critical level they form complexes with BMAL1-CLOCK heterodimers and thereby repress the transcription of their own genes. Here, we show that SIRT1, an NAD(+)- dependent protein deacetylase, is required for high-magnitude circadian transcription of several core clock genes, including Bmal1, Ror gamma, Per2, and Cry1. SIRT1 binds CLOCK-BMAL1 in a circadian manner and promotes the deacetylation and degradation of PER2. Given the NAD(+) dependence of SIRT1 deacetylase activity, it is likely that SIRT1 connects cellular metabolism to the circadian core clockwork circuitry. C1 [Asher, Gad; Gatfield, David; Stratmann, Markus; Reinke, Hans; Dibner, Charna; Schibler, Ueli] Univ Geneva, Dept Mol Biol Sci 3, CH-1211 Geneva 4, Switzerland. [Kreppel, Florian] Univ Ulm, Div Gene Therapy, D-89081 Ulm, Germany. [Mostoslavsky, Raul] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02114 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Childrens Hosp, Howard Hughes Med Inst,Ctr Blood Res, Boston, MA 02115 USA. [Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Schibler, U (reprint author), Univ Geneva, Dept Mol Biol Sci 3, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland. EM ueli.schibler@molbio.unige.ch RI Gatfield, David/C-2354-2011; ASHER, GAD/K-1333-2012 OI Gatfield, David/0000-0001-5114-2824; FU Howard Hughes Medical Institute NR 65 TC 533 Z9 553 U1 6 U2 46 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 25 PY 2008 VL 134 IS 2 BP 317 EP 328 DI 10.1016/j.cell.2008.06.050 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 329SU UT WOS:000257891700020 PM 18662546 ER PT J AU Jiang, W Betson, M Mulloy, R Foster, R Levay, M Ligeti, E Settleman, J AF Jiang, Wei Betson, Martha Mulloy, Roseann Foster, Rosemary Levay, Magdolna Ligeti, Erzsebet Settleman, Jeffrey TI p190A RhoGAP is a glycogen synthase kinase-3-beta substrate required for polarized cell migration SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID REGULATES CELL; DIRECTIONAL MIGRATION; MEMBRANE PROTRUSION; FAMILY GTPASES; RHOA ACTIVITY; BETA-CATENIN; LIPID RAFTS; C-SRC; P190RHOGAP; ADHESION AB The Rho GTPases are critical regulators of the actin cytoskeleton and are required for cell adhesion, migration, and polarity. Among the key Rho regulatory proteins in the context of cell migration are the p190 RhoGAPs (p190A and p190B), which function to modulate Rho signaling in response to integrin engagement. The p190 RhoGAPs undergo complex regulation, including phosphorylation by several identified kinases, interactions with phospholipids, and association with a variety of cellular proteins. Here, we have identified an additional regulatory mechanism unique to p190A RhoGAP that involves priming-dependent phosphorylation by glycogen synthase-3-beta (GSK-3 beta), a kinase previously implicated in establishing cell polarity. We found that p190A-deficient fibroblasts exhibit a defect in directional cell migration reflecting a requirement for GSK-3 beta-mediated phosphorylation of amino acids in the C-terminal "tail" of p190A. This phosphorylation leads to inhibition of p190A RhoGAP activity in vitro and in vivo. These studies identify p190A as a novel GSK-3 beta substrate and reveal a mechanism by which GSK-3 beta contributes to cellular polarization in directionally migrating cells via effects on Rho GTPase activity. C1 [Jiang, Wei; Betson, Martha; Mulloy, Roseann; Settleman, Jeffrey] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Jiang, Wei; Betson, Martha; Mulloy, Roseann; Foster, Rosemary; Settleman, Jeffrey] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Levay, Magdolna] Semmelweis Univ, Dept Physiol, H-1444 Budapest, Hungary. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA. EM settleman@helix.mgh.harvard.edu RI Betson, Martha/D-3818-2014 OI Betson, Martha/0000-0002-4220-3290 FU NCI NIH HHS [R01 CA 62142] NR 36 TC 25 Z9 25 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 25 PY 2008 VL 283 IS 30 BP 20978 EP 20988 DI 10.1074/jbc.M802588200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327RL UT WOS:000257746100040 PM 18502760 ER PT J AU Shimada, M Greer, PA McMahon, AP Bouxsein, ML Schipani, E AF Shimada, Masako Greer, Peter A. McMahon, Andrew P. Bouxsein, Mary L. Schipani, Ernestina TI In vivo targeted deletion of calpain small subunit, Capn4, in cells of the osteoblast lineage impairs cell proliferation, differentiation, and bone formation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HORMONE-RELATED PEPTIDE; C-FOS EXPRESSION; PARATHYROID-HORMONE; BINDING PROTEIN; TRABECULAR BONE; GROWTH; MOUSE; MICE; RECEPTOR; SYSTEM AB Calpains are intracellular cysteine proteases, which include widely expressed mu- and m-calpains (1). Both mu-calpains and m-calpains are heterodimers consisting of a large catalytic subunit and a small regulatory subunit. The calpain small subunit encoded by the gene Capn4 directly binds to the intracellular C-terminal tail (C-tail) of the receptor for parathyroid hormone and parathyroid hormone-related peptide and modulates its cellular functions in osteoblasts in vitro (2). To investigate a potential role of the calpain small subunit in osteoblasts in vivo, we generated osteoblast-specific Capn4 knock-out mice using the Cre-LoxP system (3). Mutant mice had smaller bodies with shorter limbs, reduced trabecular bone with thinner cortices, and decreased osteoblast number. In vitro analysis confirmed that deletion of Capn4 in osteoblasts severely affected multiple osteoblast functions including proliferation, differentiation, and matrix mineralization. Collectively, our findings provide the first in vivo demonstration that the calpain small subunit is essential for proper osteoblast activity and bone remodeling. C1 [Shimada, Masako; Schipani, Ernestina] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Shimada, Masako; Schipani, Ernestina] Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. [Greer, Peter A.] Queens Univ, Canc Res Inst, Kingston, ON K7L 3N6, Canada. [McMahon, Andrew P.] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. [Bouxsein, Mary L.] Beth Israel Deaconess Med Ctr, Orthopaed Biomech Lab, Boston, MA 02215 USA. RP Shimada, M (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. EM shimada@helix.mgh.harvard.edu FU NCRR NIH HHS [S10 RR017868]; NIDDK NIH HHS [R01 DK072102, R01 DK 72102] NR 39 TC 23 Z9 26 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 25 PY 2008 VL 283 IS 30 BP 21002 EP 21010 DI 10.1074/jbc.M710354200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327RL UT WOS:000257746100042 PM 18515801 ER PT J AU Maeder, ML Thibodeau-Beganny, S Osiak, A Wright, DA Anthony, RM Eichtinger, M Jiang, T Foley, JE Winfrey, RJ Townsend, JA Unger-Wallace, E Sander, JD Muller-Lerch, F Fu, FL Pearlberg, J Gobel, C Dassie, JP Pruett-Miller, SM Porteus, MH Sgroi, DC Iafrate, AJ Dobbs, D McCray, PB Cathomen, T Voytas, DF Joung, JK AF Maeder, Morgan L. Thibodeau-Beganny, Stacey Osiak, Anna Wright, David A. Anthony, Reshma M. Eichtinger, Magdalena Jiang, Tao Foley, Jonathan E. Winfrey, Ronnie J. Townsend, Jeffrey A. Unger-Wallace, Erica Sander, Jeffry D. Mueller-Lerch, Felix Fu, Fengli Pearlberg, Joseph Goebel, Carl Dassie, Justin P. Pruett-Miller, Shondra M. Porteus, Matthew H. Sgroi, Dennis C. Iafrate, A. John Dobbs, Drena McCray, Paul B., Jr. Cathomen, Toni Voytas, Daniel F. Joung, J. Keith TI Rapid "Open-Source" engineering of customized zinc-finger nucleases for highly efficient gene modification SO MOLECULAR CELL LA English DT Article ID 2-HYBRID SELECTION SYSTEM; TRANSCRIPTION FACTORS; HOMOLOGOUS RECOMBINATION; CHIMERIC NUCLEASES; RECOGNITION CODE; MAMMALIAN-CELLS; PROTEIN-DNA; CONSTRUCTION; MUTAGENESIS; DROSOPHILA AB Custom-made zinc-finger nucleases (ZFNs) can induce targeted genome modifications with high efficiency in cell types including Drosophila, C. elegans, plants, and humans. A bottleneck in the application of ZFN technology has been the generation of highly specific engineered zinc-finger arrays. Here we describe OPEN (Oligomerized Pool ENgineering), a rapid, publicly available strategy for constructing multifinger arrays, which we show is more effective than the previously published modular assembly method. We used OPEN to construct 37 highly active ZFN pairs which induced targeted alterations with high efficiencies (1%-50%) at 11 different target sites located within three endogenous human genes (VEGF-A, HoxB13, and CFTR), an endogenous plant gene (tobacco SuRA), and a chromosomally integrated EGFP reporter gene. In summary, OPEN provides an "open-source" method for rapidly engineering highly active zinc-finger arrays, thereby enabling broader practice, development, and application of ZFN technology for biological research and gene therapy. C1 [Maeder, Morgan L.; Thibodeau-Beganny, Stacey; Eichtinger, Magdalena; Jiang, Tao; Foley, Jonathan E.; Goebel, Carl; Sgroi, Dennis C.; Joung, J. Keith] Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02129 USA. [Maeder, Morgan L.; Thibodeau-Beganny, Stacey; Eichtinger, Magdalena; Jiang, Tao; Foley, Jonathan E.; Goebel, Carl; Sgroi, Dennis C.; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02129 USA. [Maeder, Morgan L.; Thibodeau-Beganny, Stacey; Eichtinger, Magdalena; Jiang, Tao; Foley, Jonathan E.; Goebel, Carl; Joung, J. Keith] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Iafrate, A. John] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Osiak, Anna; Mueller-Lerch, Felix] Charite Univ Sch, Inst Virol CBF, D-12203 Berlin, Germany. [Wright, David A.; Winfrey, Ronnie J.; Townsend, Jeffrey A.; Unger-Wallace, Erica; Sander, Jeffry D.; Fu, Fengli; Dobbs, Drena; Voytas, Daniel F.] Iowa State Univ, Dept Genet Dev & Cell Biol, Ames, IA 50011 USA. [Sander, Jeffry D.; Fu, Fengli] Iowa State Univ, Interdept Grad Program Bioinformat & Computat Bio, Ames, IA 50011 USA. [Anthony, Reshma M.; Dassie, Justin P.; McCray, Paul B., Jr.] Univ Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USA. [Eichtinger, Magdalena; Jiang, Tao; Sgroi, Dennis C.; Iafrate, A. John; Joung, J. Keith] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Pearlberg, Joseph] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Pruett-Miller, Shondra M.; Porteus, Matthew H.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. RP Joung, JK (reprint author), Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02129 USA. EM jjoung@partners.org OI Cathomen, Toni/0000-0002-7757-4630 FU NCI NIH HHS [R01 CA112021, R01CA112021]; NCRR NIH HHS [R21 RR024189, R21 RR024189-01, R21RR024189]; NHLBI NIH HHS [R01 HL079295]; NIGMS NIH HHS [R24 GM078369, R01 GM069906, R01 GM069906-03, R01 GM069906-04, R01 GM069906-05, R01GM069906, R24 GM078369-01A1, R24 GM078369-02, R24GM078369]; NIH HHS [DP1 OD006862] NR 38 TC 390 Z9 421 U1 7 U2 60 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 JUL 25 PY 2008 VL 31 IS 2 BP 294 EP 301 DI 10.1016/j.molcel.2008.06.016 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 332LB UT WOS:000258083400014 PM 18657511 ER PT J AU Sun, SL Wang, F Wei, J Cao, LY Wu, GY Lu, L Kosten, TA Kosten, TR Zhang, XY AF Sun, Shilong Wang, Fan Wei, Jun Cao, Lian Yuan Wu, Gui Ying Lu, Lin Kosten, Therese A. Kosten, Thomas R. Zhang, Xiang Yang TI Association between interleukin-3 receptor alpha polymorphism and schizophrenia in the Chinese population SO NEUROSCIENCE LETTERS LA English DT Article DE schizophrenia; interleukin-3 receptor; polymorphism; association; cytokine ID INTERLEUKIN-3 AB Schizophrenia has been observed to be associated with various abnormalities in cytokines and cytokine receptors. Three very recent reports showed the evidence that the IL3 gene, colony stimulating factor 2 receptor alpha (CSF2RA), beta (CSF2RB) and IL-3 receptor alpha (IL3RA), the IL-specific receptor sub-units for CSF2 and IL3, respectively, are associated with schizophrenia. To examine the association of the IBRA polymorphism (rs6603272) with schizophrenia in a Chinese population, 310 physically healthy patients with schizophrenia were compared with 330 age-, sex-matched normal controls. Statistically significant differences were observed in both allelic and genotypic frequencies of the rs6603272 polymorphism (Allele, chi(2) = 6.24, d.f. = 1, p =0.013, odds ratio (OR)= 1.35, 95% Cl 1.07-1.71; Genotype, chi(2) = 6.85, d.f. = 2, p = 0.033). Our results indicate a small but significant contribution of the IBRA polymorphism to susceptibility to schizophrenia, suggesting that the IL3 pathway may be involved in schizophrenia. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Wu, Gui Ying; Kosten, Therese A.; Kosten, Thomas R.; Zhang, Xiang Yang] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, VA Med Ctr, Houston, TX 77030 USA. Jilin Univ, Neurosci Res Ctr, Changchun 130023, Peoples R China. Jilin Univ, MH Radiobiol Res Unit, Changchun 130023, Peoples R China. [Wang, Fan; Cao, Lian Yuan; Zhang, Xiang Yang] Beijing HuiLongGuan Hosp, Ctr Biol Psychiat, Beijing 100096, Peoples R China. [Wei, Jun] Univ Highlands and Islands, Ness Fdn, Inverness IV3 8GY, Scotland. [Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100871, Peoples R China. RP Zhang, XY (reprint author), Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, VA Med Ctr, Res Bldg 109,Room 130,2002 Holcombe Blvd, Houston, TX 77030 USA. EM jun.wei@ness.uhi.ac.uk; kosten@bcm.edu; xyzhang@bcm.edu FU NIDA NIH HHS [P50-DA18827, K05-DA0454] NR 12 TC 16 Z9 17 U1 0 U2 0 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 JUL 25 PY 2008 VL 440 IS 1 BP 35 EP 37 DI 10.1016/j.neulet.2008.05.029 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 326EE UT WOS:000257640200009 PM 18547720 ER PT J AU Grant, RM Hamer, D Hope, T Johnston, R Lange, J Lederman, MM Lieberman, J Miller, CJ Moore, JP Mosier, DE Richman, DD Schooley, RT Springer, MS Veazey, RS Wainberg, MA AF Grant, Robert M. Hamer, Dean Hope, Thomas Johnston, Rowena Lange, Joep Lederman, Michael M. Lieberman, Judy Miller, Christopher J. Moore, John P. Mosier, Donald E. Richman, Douglas D. Schooley, Robert T. Springer, Marty S. Veazey, Ronald S. Wainberg, Mark A. TI Perspective - Whither or wither microbicides? SO SCIENCE LA English DT Editorial Material ID IMMUNODEFICIENCY-VIRUS TYPE-1; VAGINAL MICROBICIDE; DRUG-RESISTANCE; NONOXYNOL-9; HIV; STRATEGIES C1 [Grant, Robert M.] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94518 USA. [Grant, Robert M.] Univ Calif San Francisco, Gladstone Inst Virol & Immunol, San Francisco, CA 94518 USA. [Hamer, Dean] NCI, NIH, Bethesda, MD 20817 USA. [Hope, Thomas] Northwestern Univ, Chicago, IL 60611 USA. [Johnston, Rowena] Fdn AIDS Res amfAR, New York, NY 10005 USA. [Lange, Joep] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Lederman, Michael M.] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA. [Lieberman, Judy] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Lieberman, Judy] Harvard Univ, Sch Med, Div Aids, Boston, MA 02115 USA. [Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Davis, CA 95616 USA. [Moore, John P.] Cornell Univ, Weill Med Coll, New York, NY 10065 USA. [Mosier, Donald E.] Scripps Res Inst, La Jolla, CA 92037 USA. [Richman, Douglas D.] San Diego Healthcare Syst, La Jolla, CA 92093 USA. [Richman, Douglas D.; Schooley, Robert T.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Springer, Marty S.] Merck & Co Inc, Rahway, NJ 07090 USA. [Veazey, Ronald S.] Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. [Wainberg, Mark A.] McGill Univ, Jewish Gen Hosp, AIDS Ctr, Montreal, PQ H3T 1E2, Canada. RP Grant, RM (reprint author), Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94518 USA. RI Lieberman, Judy/A-2717-2015 FU NIAID NIH HHS [U19 AI076981, U19 AI076981-01] NR 19 TC 97 Z9 102 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 25 PY 2008 VL 321 IS 5888 BP 532 EP 534 DI 10.1126/science.1160355 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 329RS UT WOS:000257888900038 PM 18653884 ER PT J AU Handschin, C Spiegelman, BM AF Handschin, Christoph Spiegelman, Bruce M. TI The role of exercise and PGC1 alpha in inflammation and chronic disease SO NATURE LA English DT Article ID NECROSIS-FACTOR-ALPHA; TRANSCRIPTIONAL COACTIVATOR PGC-1-ALPHA; MUSCLE FIBER-TYPE; SKELETAL-MUSCLE; PHYSICAL-ACTIVITY; METABOLIC SYNDROME; OXIDATIVE-PHOSPHORYLATION; ANTIOXIDANT DEFENSE; PARKINSONS-DISEASE; INSULIN-RESISTANCE AB Inadequate physical activity is linked to many chronic diseases. But the mechanisms that tie muscle activity to health are unclear. The transcriptional coactivator PGC1 alpha has recently been shown to regulate several exercise-associated aspects of muscle function. We propose that this protein controls muscle plasticity, suppresses a broad inflammatory response and mediates the beneficial effects of exercise. C1 [Handschin, Christoph] Univ Zurich, Inst Physiol, CH-8057 Zurich, Switzerland. [Handschin, Christoph] Univ Zurich, Zurich Ctr Integrat Human Physiol ZIHP, CH-8057 Zurich, Switzerland. [Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Spiegelman, Bruce M.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Handschin, C (reprint author), Univ Zurich, Inst Physiol, CH-8057 Zurich, Switzerland. EM christoph.handschin@access.uzh.ch; bruce_spiegelman@dfci.harvard.edu RI Handschin, Christoph/E-6886-2015 OI Handschin, Christoph/0000-0003-0603-1097 FU NIDDK NIH HHS [R01 DK054477, R01 DK054477-09A1] NR 75 TC 388 Z9 400 U1 6 U2 52 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 24 PY 2008 VL 454 IS 7203 BP 463 EP 469 DI 10.1038/nature07206 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 329IC UT WOS:000257860300041 PM 18650917 ER PT J AU Maheswaran, S Sequist, LV Nagrath, S Ulkus, L Brannigan, B Collura, CV Inserra, E Diederichs, S Iafrate, AJ Bell, DW Digumarthy, S Muzikansky, A Irimia, D Settleman, J Tompkins, RG Lynch, TJ Toner, M Haber, DA AF Maheswaran, Shyamala Sequist, Lecia V. Nagrath, Sunitha Ulkus, Lindsey Brannigan, Brian Collura, Chey V. Inserra, Elizabeth Diederichs, Sven Iafrate, A. John Bell, Daphne W. Digumarthy, Subba Muzikansky, Alona Irimia, Daniel Settleman, Jeffrey Tompkins, Ronald G. Lynch, Thomas J. Toner, Mehmet Haber, Daniel A. TI Detection of mutations in EGFR in circulating lung-cancer cells SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID FACTOR-RECEPTOR MUTATIONS; METASTATIC BREAST-CANCER; DRUG-RESISTANCE MUTATION; TUMOR-CELLS; ACQUIRED-RESISTANCE; PERIPHERAL-BLOOD; GENE-MUTATIONS; KINASE DOMAIN; PHASE-II; GEFITINIB AB Background The use of tyrosine kinase inhibitors to target the epidermal growth factor receptor gene (EGFR) in patients with non-small-cell lung cancer is effective but limited by the emergence of drug-resistance mutations. Molecular characterization of circulating tumor cells may provide a strategy for noninvasive serial monitoring of tumor genotypes during treatment. Methods We captured highly purified circulating tumor cells from the blood of patients with non-small-cell lung cancer using a microfluidic device containing microposts coated with antibodies against epithelial cells. We performed EGFR mutational analysis on DNA recovered from circulating tumor cells using allele-specific polymerase-chain-reaction amplification and compared the results with those from concurrently isolated free plasma DNA and from the original tumor-biopsy specimens. Results We isolated circulating tumor cells from 27 patients with metastatic non-small-cell lung cancer (median number, 74 cells per milliliter). We identified the expected EGFR activating mutation in circulating tumor cells from 11 of 12 patients (92%) and in matched free plasma DNA from 4 of 12 patients (33%) (P=0.009). We detected the T790M mutation, which confers drug resistance, in circulating tumor cells collected from patients with EGFR mutations who had received tyrosine kinase inhibitors. When T790M was detectable in pretreatment tumor-biopsy specimens, the presence of the mutation correlated with reduced progression-free survival (7.7 months vs. 16.5 months, P<0.001). Serial analysis of circulating tumor cells showed that a reduction in the number of captured cells was associated with a radiographic tumor response; an increase in the number of cells was associated with tumor progression, with the emergence of additional EGFR mutations in some cases. Conclusions Molecular analysis of circulating tumor cells from the blood of patients with lung cancer offers the possibility of monitoring changes in epithelial tumor genotypes during the course of treatment. C1 [Maheswaran, Shyamala; Sequist, Lecia V.; Ulkus, Lindsey; Brannigan, Brian; Inserra, Elizabeth; Diederichs, Sven; Bell, Daphne W.; Digumarthy, Subba; Muzikansky, Alona; Settleman, Jeffrey; Lynch, Thomas J.; Haber, Daniel A.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Nagrath, Sunitha; Collura, Chey V.; Irimia, Daniel; Tompkins, Ronald G.; Toner, Mehmet] Massachusetts Gen Hosp, Biomicroelectromech Syst Resource Ctr, Boston, MA 02114 USA. [Maheswaran, Shyamala; Nagrath, Sunitha; Irimia, Daniel; Tompkins, Ronald G.; Toner, Mehmet] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Sequist, Lecia V.; Lynch, Thomas J.; Haber, Daniel A.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Digumarthy, Subba] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Muzikansky, Alona] Massachusetts Gen Hosp, Biostat Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Tompkins, Ronald G.; Toner, Mehmet] Shriners Hosp Children, Boston, MA USA. [Haber, Daniel A.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Haber, DA (reprint author), Massachusetts Gen Hosp, Ctr Canc, CNY-7,Bldg 149,13th St, Charlestown, MA 02129 USA. EM haber@helix.mgh.harvard.edu RI Diederichs, Sven/J-6237-2012; OI Diederichs, Sven/0000-0001-7901-4752; Irimia, Daniel/0000-0001-7347-2082 FU Howard Hughes Medical Institute; NCI NIH HHS [R01 CA129933-01A1, R01 CA129933]; NIBIB NIH HHS [P41 EB002503] NR 37 TC 894 Z9 960 U1 33 U2 206 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 24 PY 2008 VL 359 IS 4 BP 366 EP 377 DI 10.1056/NEJMoa0800668 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 329FK UT WOS:000257852100005 PM 18596266 ER PT J AU Sequist, LV Settleman, JE Ackman, JB Iafrate, AJ AF Sequist, Lecia V. Settleman, Jeffrey E. Ackman, Jeanne B. Iafrate, A. John TI A man with back pain and a mass in the lung - Poorly differentiated adenocarcinoma of the lung, with an activating mutation in the EGFR gene SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GROWTH-FACTOR-RECEPTOR; PHASE-II TRIAL; ACQUIRED-RESISTANCE; INITIAL GEFITINIB; T790M MUTATIONS; CANCER; ERLOTINIB; RETREATMENT; THERAPY; KINASE C1 [Sequist, Lecia V.; Settleman, Jeffrey E.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Ackman, Jeanne B.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Sequist, Lecia V.; Settleman, Jeffrey E.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Ackman, Jeanne B.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Iafrate, A. John] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Sequist, LV (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. NR 35 TC 1 Z9 1 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 24 PY 2008 VL 359 IS 4 BP 405 EP 414 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 329FK UT WOS:000257852100010 PM 18650517 ER PT J AU Kahyo, T Mostoslavsky, R Goto, M Setou, M AF Kahyo, Tomoaki Mostoslavsky, Raul Goto, Makoto Setou, Mitsutoshi TI Sirtuin-mediated deacetylation pathway stabilizes Werner syndrome protein SO FEBS LETTERS LA English DT Article DE SIRT; Werner syndrome; longevity; caloric restriction ID HISTONE DEACETYLASE; CALORIC RESTRICTION; CELL-SURVIVAL; DNA-REPAIR; SIR2; NAD; P53; ACTIVATORS; RELEASE; RODENTS AB Caloric restriction ( CR) is known to promote longevity in various species. Sirtuin- mediated deacetylation has been shown to be related to the promotion of longevity in some species. Here, we show that CR of rats led to an increase in the level of Werner syndrome protein ( WRN), a recognized DNA repair protein. In addition, CR simultaneously increased the level of SIRT1, a mammalian sirtuin. In HEK293T cells, sirtuin inhibitors decreased the WRN level, and this e. ect was suppressed by proteasomal inhibitors. Furthermore, we found a decrease in the WRN level in Sirt1- de. cient mice. These results indicate that sirtuin- mediated deacetylation stabilizes WRN. C1 [Kahyo, Tomoaki; Setou, Mitsutoshi] Mitsubishi Kagaku Inst Life Sci MITILS, Mol Gerontol Res Grp, Tokyo 1948511, Japan. [Mostoslavsky, Raul] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp,Canc Ctr, Boston, MA 02114 USA. [Goto, Makoto] Toin Univ Yokohama, Fac Med Engn, Dept Clin Engn, Div Antiageing & Longev Sci,Aoba Ku, Kanagawa 2258502, Japan. [Setou, Mitsutoshi] Hamamatsu Univ Sch Med, Dept Mol Anat, Hamamatsu, Shizuoka 4313192, Japan. RP Setou, M (reprint author), Hamamatsu Univ Sch Med, Dept Mol Anat, 1-20-1 Handayama, Hamamatsu, Shizuoka 4313192, Japan. EM setou@hama-med.ac.jp NR 29 TC 24 Z9 27 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD JUL 23 PY 2008 VL 582 IS 17 BP 2479 EP 2483 DI 10.1016/j.febslet.2008.06.031 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 332VU UT WOS:000258112000002 PM 18588880 ER PT J AU Baratelli, F Takedatsu, H Hazra, S Peebles, K Luo, J Kurimoto, PS Zeng, G Batra, RK Sharma, S Dubinett, SM Lee, JM AF Baratelli, Felicita Takedatsu, Hiroko Hazra, Saswati Peebles, Katherine Luo, Jie Kurimoto, Pam S. Zeng, Gang Batra, Raj K. Sharma, Sherven Dubinett, Steven M. Lee, Jay M. TI Pre-clinical characterization of GMP grade CCL21-gene modified dendritic cells for application in a phase I trial in Non-Small Cell Lung Cancer SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID CD4(+) T-CELLS; ADENOVIRAL VECTOR; IMMUNE-RESPONSES; ANTITUMOR IMMUNITY; TUMOR-IMMUNITY; VACCINATION; ANTIGEN; CHEMOKINE; VACCINES; IMMUNOTHERAPY AB Background: Our previous studies have demonstrated that transduction of human dendritic cells (DC) with adenovirus encoding secondary lymphoid chemokine, CCL21, led to secretion of biologically active CCL21 without altering DC phenotype or viability. In addition, intratumoral injections of CCL21-transduced DC into established murine lung tumors resulted in complete regression and protective anti-tumor immunity. These results have provided the rationale to generate a clinical grade adenoviral vector encoding CCL-21 for ex vivo transduction of human DC in order to assess intratumoral administration in late stage human lung cancer. Methods: In the current study, human monocyte-derived DC were differentiated by exposure to GM-CSF and IL-4 from cryopreserved mononuclear cells obtained from healthy volunteers. Transduction with clinical grade adenoviral vector encoding CCL21 (1167 viral particles per cell) resulted in secretion of CCL21 protein. Results: CCL21 protein production from transduced DC was detected in supernatants (24-72 hours, 3.5-6.7 ng/4-5 x 10(6) cells). DC transduced with the clinical grade adenoviral vector were > 88% viable (n = 16), conserved their phenotype and maintained integral biological activities including dextran uptake, production of immunostimulatory cytokines/chemokines and antigen presentation. Furthermore, supernatant from CCL21-DC induced the chemotaxis of T2 cells in vitro. Conclusion: Viable and biologically active clinical grade CCL21 gene-modified DC can be generated from cryopreserved PBMC. C1 [Baratelli, Felicita; Takedatsu, Hiroko; Hazra, Saswati; Peebles, Katherine; Luo, Jie; Kurimoto, Pam S.; Batra, Raj K.; Sharma, Sherven; Dubinett, Steven M.; Lee, Jay M.] Univ Calif Los Angeles, Lung Canc Res Program, Jonsson Comprehens Canc Ctr, Div Pulm & Crit Care Med,Dept Med, Los Angeles, CA 90095 USA. [Dubinett, Steven M.] Univ Calif Los Angeles, Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. [Batra, Raj K.; Sharma, Sherven; Dubinett, Steven M.] Vet Affairs Greater Los Angeles Healthcare Syst, Mol Med Lab, Los Angeles, CA 90073 USA. [Zeng, Gang] Univ Calif Los Angeles, Geffen Sch Med, Dept Urol, Los Angeles, CA 90095 USA. [Lee, Jay M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Div Cardiothorac Surg, Los Angeles, CA 90095 USA. RP Lee, JM (reprint author), Univ Calif Los Angeles, Lung Canc Res Program, Jonsson Comprehens Canc Ctr, Div Pulm & Crit Care Med,Dept Med, Los Angeles, CA 90095 USA. EM fbaratelli@mednet.ucla.edu; htakedatsu@mednet.ucla.edu; shazra@mednet.ucla.edu; katherine.peebles@gmail.com; jluo@mednet.ucla.edu; pkurimoto@mednet.ucla.edu; gzeng@mednet.ucla.edu; rbatra@ucla.edu; ssharma@mednet.ucla.edu; sdubinett@mednet.ucla.edu; jaymoonlee@mednet.ucla.edu OI Batra, Raj K./0000-0002-1126-543X FU UCLA Lung Cancer [SPORE NCI P50 CA90388]; UC Tobacco Related Research Program; Department of Veteran Affairs; UCLA Cancer Gene Medicine Training Program [NCI 5 K12 CA076095]; Ronald Binder Memorial Fund for Lung Cancer Research; NCI Rapid Access to Intervention Development ( RAID) Program [476]; National Institutes of Health [CA-16042, AI-28697]; Jonsson Comprehensive Cancer Center; UCLA AIDS Institute; David Geffen School of Medicine at UCLA FX Supported by the UCLA Lung Cancer SPORE NCI P50 CA90388, Grants from the UC Tobacco Related Research Program, Merit Review research funds from the Department of Veteran Affairs, UCLA Cancer Gene Medicine Training Program NCI 5 K12 CA076095, and the Ronald Binder Memorial Fund for Lung Cancer Research. Resources for the manufacture and testing of clinical-grade AdCCL21 were provided by the NCI Rapid Access to Intervention Development ( RAID) Program, Project # 476.; Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer for AIDS Research Flow Cytometry Core Facility supported by National Institutes of Health awards CA-16042 and AI-28697, by the Jonsson Comprehensive Cancer Center, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA. NR 47 TC 25 Z9 26 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUL 22 PY 2008 VL 6 AR 38 DI 10.1186/1479-5876-6-38 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 337JZ UT WOS:000258433700002 PM 18644162 ER PT J AU Braun, P Rietman, E Vidal, M AF Braun, Pascal Rietman, Edward Vidal, Marc TI Networking metabolites and diseases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID RECONSTRUCTIONS C1 [Braun, Pascal; Rietman, Edward; Vidal, Marc] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Braun, Pascal; Rietman, Edward; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Braun, Pascal; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Rietman, Edward] Phys Sci Inc, New England Business Ctr 20, Andover, MA 01810 USA. RP Braun, P (reprint author), Dana Farber Canc Inst, Ctr Canc Syst Biol, 44 Binney St, Boston, MA 02115 USA. EM pascal_braun@dfci.harvard.edu RI Braun, Pascal/B-9669-2013 OI Braun, Pascal/0000-0003-2012-6746 NR 6 TC 19 Z9 19 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 JUL 22 PY 2008 VL 105 IS 29 BP 9849 EP 9850 DI 10.1073/pnas.0805644105 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 330BB UT WOS:000257913200001 PM 18632571 ER PT J AU Lee, DS Park, J Kay, KA Christakis, NA Oltvai, ZN Barabasi, AL AF Lee, D. -S. Park, J. Kay, K. A. Christakis, N. A. Oltvai, Z. N. Barabasi, A. -L. TI The implications of human metabolic network topology for disease comorbidity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID INTEGRATIVE GENOMICS; GENETIC-DISORDERS; SYSTEMS BIOLOGY; EXPRESSION; RECONSTRUCTIONS; ORGANIZATION; INTERACTOME; OBESITY; CELLS; ERA AB Most diseases are the consequence of the breakdown of cellular processes, but the relationships among genetic/epigenetic defects, the molecular interaction networks underlying them, and the disease phenotypes remain poorly understood. To gain insights into such relationships, here we constructed a bipartite human disease association network in which nodes are diseases and two diseases are linked if mutated enzymes associated with them catalyze adjacent metabolic reactions. We find that connected disease pairs display higher correlated reaction flux rate, corresponding enzyme-encoding gene coexpression, and higher comorbidity than those that have no metabolic link between them. Furthermore, the more connected a disease is to other diseases, the higher is its prevalence and associated mortality rate. The network topology-based approach also helps to uncover potential mechanisms that contribute to their shared pathophysiology. Thus, the structure and modeled function of the human metabolic network can provide insights into disease comorbidity, with potentially important consequences for disease diagnosis and prevention. C1 [Lee, D. -S.; Park, J.; Barabasi, A. -L.] Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. [Lee, D. -S.; Park, J.; Barabasi, A. -L.] Northeastern Univ, Dept Phys Biol & Comp Sci, Boston, MA 02115 USA. [Kay, K. A.; Oltvai, Z. N.] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15261 USA. [Lee, D. -S.; Park, J.; Barabasi, A. -L.] Dana Farber Canc Inst, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Christakis, N. A.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Barabasi, AL (reprint author), Northeastern Univ, Ctr Complex Network Res, Boston, MA 02115 USA. EM alb@neu.edu RI Christakis, Nicholas/C-3205-2009; Lee, Deok-Sun/D-1335-2011; Park, Juyong/I-2290-2012 FU NCI NIH HHS [CA113004, U56 CA113004]; NHGRI NIH HHS [HG4233, P50 HG004233]; NIA NIH HHS [R01 AG017548, AG17548-01]; PHS HHS [A1070499-01] NR 41 TC 202 Z9 211 U1 2 U2 28 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 22 PY 2008 VL 105 IS 29 BP 9880 EP 9885 DI 10.1073/pnas.0802208105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 330BB UT WOS:000257913200008 PM 18599447 ER PT J AU Neimark, MA Konstas, AA Choi, JH Laine, AF Pile-Spellman, J AF Neimark, Matthew A. Konstas, Angelos-Aristeidis Choi, Jae H. Laine, Andrew F. Pile-Spellman, John TI Brain cooling maintenance with cooling cap following induction with intracarotid cold saline infusion: A quantitative model SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE intracarotid saline infusion; selective brain cooling; cooling cap; hemodilution; intravascular volume loading ID CEREBRAL-BLOOD-FLOW; ACUTE ISCHEMIC-STROKE; INDUCED HYPOTHERMIA; THERAPEUTIC HYPOTHERMIA; MODERATE HYPOTHERMIA; CARDIAC-ARREST; TEMPERATURE; FEASIBILITY; METABOLISM; HEAD AB Intracarotid cold saline infusion (ICSI) is potentially much faster than whole-body cooling and more effective than cooling caps in inducing therapeutic brain cooling. One drawback of ICSI is hemodilution and volume loading. We hypothesized that cooling caps could enhance brain cooling with ICSI and minimize hemodilution and volume loading. Six-hour-long simulations were performed in a 3D mathematical brain model. The Pennes bioheat equation was used to propagate brain temperature. Convective heat transfer through jugular venous return and the circle of Willis was simulated. Hemodilution and volume loading were modeled using a two-compartment saline infusion model. A feedback method of local brain temperature control was developed where ICSI flow rate was varied based on the rate of temperature change and the deviation of temperature to a target (32 degrees C) within a voxel in the treated region of brain. The simulations confirmed the inability of cooling caps alone to induce hypothermia. In the ICSI and the combination models (ICSI and cap), the control algorithm guided ICSI to quickly achieve and maintain the target temperature. The combination model had lower ICSI flow rates than the ICSI model resulting in a 55% reduction of infusion volume over a 6 h period and higher hematocrit values compared to the ICSI model. Moreover, in the combination model, the ICSI flow rate decreased to zero after 4h, and hypothermia was subsequently maintained solely by the cooling cap. This is the first study supporting a role of cooling caps in therapeutic hypothermia in adults. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Neimark, Matthew A.; Laine, Andrew F.] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. [Konstas, Angelos-Aristeidis] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Neimark, Matthew A.; Konstas, Angelos-Aristeidis; Choi, Jae H.; Laine, Andrew F.; Pile-Spellman, John] Columbia Univ, Dept Radiol, New York, NY 10032 USA. RP Neimark, MA (reprint author), Columbia Univ, Dept Biomed Engn, 1210 Amsterdam Ave, New York, NY 10027 USA. EM man2003@columbia.edu NR 43 TC 10 Z9 12 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD JUL 21 PY 2008 VL 253 IS 2 BP 333 EP 344 DI 10.1016/j.jtbi.2008.03.025 PG 12 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 324TM UT WOS:000257542300013 PM 18479713 ER PT J AU Sud, A Del Bono, EA Haines, JL Wiggs, JL AF Sud, A. Del Bono, E. A. Haines, J. L. Wiggs, J. L. TI Fine mapping of the GLC1K juvenile primary open-angle glaucoma locus and exclusion of candidate genes SO MOLECULAR VISION LA English DT Article ID GENOME-WIDE SCAN; BTB/POZ DOMAIN; PREVALENCE; ADULT; EXPRESSION; MUTATIONS; EYE; OPTINEURIN; DATABASE; CELLS AB Purpose: Primary open-angle glaucoma is a leading cause of blindness worldwide. We previously identified a region on chromosome 20p12 associated with Juvenile-onset primary open-angle glaucoma (JOAG) that was designated GLC1K. The aim of this study is to refine the boundaries of the GLC1K region and to screen selected candidate genes located within the refined region for biologically significant mutations. Methods: Four JOAG families (44 individuals) with linkage to GLC1K were used for this study. Informative single nucleotide polymorphism (SNP) markers located throughout the previously defined region were used for haplotype analysis. Four candidate genes within the refined region were screened for biologically significant mutations using direct genomic sequencing: bone morphogenetic protein 2 (BMP2); phospholipase C beta 1 (PLCB1); phospholipase C beta 4 (PLCB4); and BTB POZ domain containing 3 (BTBD3). Results: Haplotype analysis identified a new critical interval of 12.7 Mb using a combination of SNPs and microsatellite markers. This analysis extended the region of GLC1K from D20S846 to rs6081603 in affected individuals, and the region was further reduced to 9 Mb if unaffected recombinant individuals were included in the analysis. Biologically significant DNA sequence variants were not identified in the BMP2, PLCB1, PLCB4, or BTBD3 genes in these families. Conclusions: Using recombinant breakpoint mapping and haplotypes based on a combination of SNP and microsatellite markers, the GLC1K region has been reduced to a maximum of 12.7 Mb and a minimum of 9 Mb. Four genes that are located within the refined region with attractive ocular expression and function have been excluded as causative genes for JOAG. C1 [Sud, A.; Del Bono, E. A.; Wiggs, J. L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. [Haines, J. L.] Ctr Human Genet Res, Vanderbilt Sch Med, Nashville, TN USA. RP Wiggs, JL (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, 243 Charles St, Boston, MA 02114 USA. EM janey_wiggs@meei.harvard.edu RI Haines, Jonathan/C-3374-2012 FU Howard Hughes Medical Institute; NEI NIH HHS [P30 EY014104, P30EY014104, R01 EY009847, R01EY009847] NR 49 TC 7 Z9 7 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD JUL 21 PY 2008 VL 14 IS 159 BP 1319 EP 1326 PG 8 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 336DR UT WOS:000258345000001 PM 18648523 ER PT J AU Yamaoka, Y AF Yamaoka, Yoshio TI Roles of Helicobacter pylori BabA in gastroduodenal pathogenesis SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Helicobacter pylori; BabA; pathogenesis; Lewis antigens ID ANTIGEN-BINDING ADHESIN; HUMAN GASTRIC EPITHELIUM; BLOOD-GROUP ANTIGENS; COMPLETE GENOME SEQUENCE; OUTER-MEMBRANE PROTEINS; DUODENAL-ULCER; CLINICAL-RELEVANCE; VIRULENCE FACTORS; HUMAN STOMACH; MUCOUS LAYER AB Interactions between BabA and Lewis b (Le(b)) related antigens are the best characterized adhesin-receptor interactions in Helicobacter pylori (H pylori). Several mechanisms for the regulation of BabA expression are predicted, including at both transcriptional and translational levels. The formation of chimeric proteins (babA/B or babB/A chimeras) seems to play an especially important role in translational regulation. Chimeric BabB/A protein had the potential to bind Le(b); however, protein production was subject to phase variation through slipped strand mispairing. The babA gene was cloned initially from strain CCUG17875, which contains a silent babA1 gene and an expressed babA2 gene. The sequence of these two genes differs only by the presence of a 10 bp deletion in the signal peptide sequence of babA1 that eliminates its translational initiation codon. However, the babA1 type deletion was found only in strain CCUG17875. A few studies evaluated BabA status by immunoblot and confirmed that BabA-positive status in Western strains was closely associated with severe clinical outcomes. BabA-positive status also was associated with the presence of other virulence factors (e.g. cagA-positive status and vacA s1 genotype). A small class of strains produced low levels of the BabA protein and lacked Le(b) binding activity. These were more likely to be associated with increased mucosal inflammation and severe clinical outcomes than BabA-positive strains that exhibited Le(b) binding activity. The underlying mechanism is unclear, and further studies will be necessary to investigate how the complex BabA-receptor network is functionally coordinated during the interaction of H pylori with the gastric mucosa. (c) 2008 The WJG Press. All rights reserved. C1 [Yamaoka, Yoshio] Michael E DeBakey Vet Affairs Med Ctr, Dept Med Gastroenterol, Houston, TX 77030 USA. [Yamaoka, Yoshio] Baylor Coll Med, Houston, TX 77030 USA. RP Yamaoka, Y (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Dept Med Gastroenterol, 2002 Holcombe Blvd,111D,Rm 3A-320, Houston, TX 77030 USA. EM yyamaoka@bcm.tmc.edu FU NIDDK NIH HHS [R01 DK62813, R01 DK062813, R01 DK062813-04] NR 55 TC 42 Z9 47 U1 0 U2 2 PU W J G PRESS PI BEIJING PA APT 1066, YISHOU GARDEN, NO 58, NORTH LANGXINZHUANG RD, PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD JUL 21 PY 2008 VL 14 IS 27 BP 4265 EP 4272 DI 10.3748/wjg.14.4265 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 333JG UT WOS:000258148200001 PM 18666312 ER PT J AU Simon, GR Verschraegen, CF Janne, PA Langer, CJ Dowlati, A Gadgeel, SM Kelly, K Kalemkerian, GP Traynor, AM Peng, G Gill, J Obasaju, CK Kindler, HL AF Simon, George R. Verschraegen, Claire F. Jaenne, Pasi A. Langer, Corey J. Dowlati, Afshin Gadgeel, Shirish M. Kelly, Karen Kalemkerian, Gregory P. Traynor, Anne M. Peng, Guangbin Gill, John Obasaju, Coleman K. Kindler, Hedy L. TI Pemetrexed plus gemcitabine as first-line chemotherapy for patients with peritoneal mesothelioma: Final report of a phase II trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 02-06, 2006 CL Atlanta, GA SP Amer Soc Clin Oncol ID MALIGNANT PLEURAL MESOTHELIOMA; INTRAPERITONEAL CHEMOTHERAPY; PANCREATIC-CANCER; UNITED-STATES; CISPLATIN; COMBINATION; EXPERIENCE; EPIDEMIOLOGY; EFFICACY; PROGRAM AB Purpose Pemetrexed in combination with cisplatin is approved for the treatment of pleural mesothelioma and is active in malignant peritoneal mesothelioma (MPeM). Pemetrexed and gemcitabine are synergistic in preclinical models, but the activity of this combination in MPeM is unknown. This clinical study assessed safety and efficacy of pemetrexed plus gemcitabine in chemotherapy-naive patients with MPeM. Patients and Methods Treatment consisted of gemcitabine 1,250 mg/m(2) on days 1 and 8, and pemetrexed 500 mg/m2 on day 8, administered immediately before gemcitabine. Treatment was repeated every 21 days for six cycles or until disease progression. All patients received folic acid, vitamin B-12, and dexamethasone supplementation. End points included tumor response, toxicity, time to disease progression (TTPD), and overall survival (OS). Disease control rate (DCR) was also calculated. Results Twenty patients were enrolled between December 2002 and May 2004. The confirmed response rate was 15% (95% CI, 3.2% to 37.9%), with three patients experiencing a partial response. The DCR was 50% (95% CI, 27.2% to 72.8%). The most common grade 3 to 4 nonhematologic toxicities included fatigue (20%), constipation (10%), vomiting (10%), and dehydration (10%). Hematologic toxicities included grade 3 to 4 neutropenia (60%) and febrile neutropenia (10%). One patient death was attributed to treatment. Median TTPD and OS times were 10.4 months and 26.8 months, respectively. Conclusion The combination of pemetrexed plus gemcitabine was active in patients with MPeM with a notably high incidence of neutropenia. Median TTPD and OS seem promising. This regimen may provide an alternative to standard therapies, especially for patients who cannot tolerate a platinum-based regimen. C1 H Lee Moffitt Canc Ctr & Res Inst, Thorac Oncol Program, Tampa, FL 33612 USA. H Lee Moffitt Canc Ctr & Res Inst, Expt Therapeut Program, Tampa, FL 33612 USA. Univ New Mexico, Albuquerque, NM 87131 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Wayne State Univ, Detroit, MI USA. Univ Kansas, Ctr Canc, Kansas City, KS USA. Univ Michigan Hlth Syst, Ann Arbor, MI USA. Univ Wisconsin, Paul P Carbone Comprehens Canc Ctr, Madison, WI USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Univ Chicago, Chicago, IL 60637 USA. RP Simon, GR (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Thorac Oncol Program, MRC 4W,12902 Magnolia Dr, Tampa, FL 33612 USA. EM george.simon@moffitt.org NR 38 TC 45 Z9 45 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2008 VL 26 IS 21 BP 3567 EP 3572 DI 10.1200/JCO.2007.15.2868 PG 6 WC Oncology SC Oncology GA 331ZF UT WOS:000258050500018 PM 18640937 ER PT J AU Desch, CE McNiff, KK Schneider, EC Schrag, D McClure, J Lepisto, E Donaldson, MS Kahn, KL Weeks, JC Ko, CY Stewart, AK Edge, SB AF Desch, Christopher E. McNiff, Kristen K. Schneider, Eric C. Schrag, Deborah McClure, Joan Lepisto, Eva Donaldson, Molla S. Kahn, Katherine L. Weeks, Jane C. Ko, Clifford Y. Stewart, Andrew K. Edge, Stephen B. TI American society of clinical oncology/national comprehensive cancer network quality measures SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID EARLY BREAST-CANCER; COLON-CANCER; RECTAL-CANCER; LYMPH-NODES; ADJUVANT CHEMOTHERAPY; MESORECTAL EXCISION; CARE QUALITY; SURVIVAL; THERAPY; TRIAL AB Purpose The National Cancer Policy Board recommended the creation of quality measures and a national reporting system in 1999. Representatives from the American Society of Clinical Oncology ( ASCO) and the National Comprehensive Cancer Network ( NCCN) collaborated to create metrics suitable for national performance measurement. Methods Content and methodology experts nominated by ASCO and NCCN met to select and refine metrics for breast, colon, and rectal cancer based on National Initiative for Cancer Care Quality and NCCN measures and NCCN and ASCO guidelines. Measures were selected based on their impact on disease free and overall survival, the degree to which opportunities for improvement exist, and the feasibility of data collection. Results Three breast cancer measures and four colorectal cancer measures were chosen. Measures for breast cancer included adjuvant hormone therapy for hormone receptor - positive tumors, chemotherapy for hormone receptor - negative cancer, and radiation after lumpectomy. Colorectal measures included adjuvant radiation and chemotherapy for rectal cancer, and adjuvant chemotherapy for colon cancer. All but one were recommended as accountability measures and one for quality improvement ( removal and examination of 12 or more lymph nodes in colon cancer). Specifications were developed for each measure using tumor registries as the data source. Conclusion ASCO/ NCCN measures can be implemented by health systems, provider groups or payors for improvement or accountability using local tumor registries to furnish data on staging and treatment. C1 [Edge, Stephen B.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Natl Comprehens Canc Network, Ft Washington, PA USA. Amer Soc Clin Oncol, Alexandria, VA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RAND Corp, Santa Monica, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Amer Coll Surg, Chicago, IL USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. SUNY Buffalo, Buffalo, NY USA. RP Edge, SB (reprint author), Roswell Pk Canc Inst, Elm & Carlton St, Buffalo, NY 14263 USA. EM stephen.edge@roswellpark.org OI Schneider, Eric/0000-0002-1132-5084 NR 42 TC 115 Z9 117 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2008 VL 26 IS 21 BP 3631 EP 3637 DI 10.1200/JCO.2008.16.5068 PG 7 WC Oncology SC Oncology GA 331ZF UT WOS:000258050500026 PM 18640941 ER PT J AU Varadarajan, KM Moynihan, AL D'Lima, D Colwell, CW Li, G AF Varadarajan, Kartik M. Moynihan, Angela L. D'Lima, Darryl Colwell, Clifford W. Li, Guoan TI In vivo contact kinematics and contact forces of the knee after total knee arthroplasty during dynamic weight-bearing activities SO JOURNAL OF BIOMECHANICS LA English DT Article DE total knee arthroplasty; in vivo forces; in vivo kinematics; articular contact; fluoroscopy ID WEAR; COMPONENT; REPLACEMENTS; PROSTHESIS; PREDICTION; IMPLANT; DESIGNS; SYSTEM; VITRO AB Analysis of polyethylene component wear and implant loosening in total knee arthroplasty (TKA) requires precise knowledge of in vivo articular motion and loading conditions. This study presents a simultaneous in vivo measurement of tibiofemoral articular contact forces and contact kinematics in three TKA patients. These measurements were accomplished via a dual fluoroscopic imaging system and instrumented tibial implants, during dynamic single leg lunge and chair rising-sitting. The measured forces and contact locations were also used to determine mediolateral distribution of axial contact forces. Contact kinematics data showed a medial pivot during flexion of the knee, for all patients in the study. Average axial forces were higher for lunge compared to chair rising-sitting (224% vs. 187% body weight). In this study, we measured peak anteroposterior and mediolateral forces averaging 13.3% BW during lunge and 18.5% BW during chair rising-sitting. Mediolateral distributions of axial contact force were both patient and activity specific. All patients showed equitable medial-lateral loading during lunge but greater loads at the lateral compartment during chair rising-sitting. The results of this study may enable more accurate reproduction of in vivo loads and articular motion patterns in wear simulators and finite element models. This in turn may help advance Our understanding of factors limiting longevity of TKA implants, such as aseptic loosening and polyethylene component wear, and enable improved TKA designs. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Varadarajan, Kartik M.; Moynihan, Angela L.; Li, Guoan] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab, Boston, MA 02114 USA. [Varadarajan, Kartik M.] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [D'Lima, Darryl; Colwell, Clifford W.] Scripps Clin Ctr Orthopaed Res & Educ, La Jolla, CA USA. RP Li, G (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bioengn Lab, Boston, MA 02114 USA. EM gli1@partners.org OI D'Lima, Darryl/0000-0002-8707-1455 FU NIAMS NIH HHS [R21 AR051078-02, R21 AR051078, R21 AR051078-01A2]; NIBIB NIH HHS [R21 EB00458, R15 EB000458] NR 31 TC 36 Z9 37 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD JUL 19 PY 2008 VL 41 IS 10 BP 2159 EP 2168 DI 10.1016/j.jbiomech.2008.04.021 PG 10 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 336HF UT WOS:000258354200012 PM 18538328 ER PT J AU Shinohara, ML Kim, JH Garcia, VA Cantor, H AF Shinohara, Mari L. Kim, June-Ho Garcia, Virgilio A. Cantor, Harvey TI Engagement of the type I interferon receptor on dendritic cells inhibits T helper 17 cell development: Role of intracellular osteopontin SO IMMUNITY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; T-HELPER-CELLS; TH1 IMMUNE-RESPONSE; MULTIPLE-SCLEROSIS; IMMUNOLOGICAL-SYNAPSE; MEDIATED-IMMUNITY; CUTTING EDGE; INFLAMMATION; DISTINCT AB Mechanisms that prevent inappropriate or excessive interleukin-17-producing T helper (Th17) cell responses after microbial infection may be necessary to avoid autoimmunity. Here, we define a pathway initiated by engagement of type I IFN receptor (IFNAR) expressed by dendritic cells (DC) that culminated in suppression of Th17 cell differentiation. IFNAR-dependent inhibition of an intracellular translational isoform of Osteopontin, termed Opn-i, dere-pressed interleukin-27 (IL-27) secretion and prevented efficient Th17 responses. Moreover, Opn-i expression in DC and microglia. regulated the type and intensity of experimental autoimmune encephalomyelitis (EAE). Mice containing DC deficient in Opn-i produced excessive amounts of IL-27 and developed a delayed disease characterized by an enhanced Th1 response compared with the dominant Th17 response of Opn-sufficient mice. Definition of the IFNAR-Opn-i axis that controls Th17 development provides insight into regulation of Th cell sub-lineage development and the molecular basis of type I interferon therapy for MS and other autoimmune diseases. C1 [Shinohara, Mari L.; Cantor, Harvey] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Shinohara, Mari L.; Kim, June-Ho; Garcia, Virgilio A.; Cantor, Harvey] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Cantor, H (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. EM harvey_cantor@dfci.harvard.edu FU NCI NIH HHS [T32 CA070083, T32 CA70083]; NIAID NIH HHS [AI 12184, AI 48125, R01 AI048125, R01 AI048125-05, R37 AI012184, R37 AI012184-31] NR 48 TC 141 Z9 149 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL 18 PY 2008 VL 29 IS 1 BP 68 EP 78 DI 10.1016/j.immuni.2008.05.008 PG 11 WC Immunology SC Immunology GA 329YB UT WOS:000257905400011 PM 18619869 ER PT J AU Shrimali, RK Irons, RD Carlson, BA Sano, Y Gladyshev, VN Park, JM Hatfield, DL AF Shrimali, Rajeev K. Irons, Robert D. Carlson, Bradley A. Sano, Yasuyo Gladyshev, Vadim N. Park, Jin Mo Hatfield, Dolph L. TI Selenoproteins mediate T cell immunity through an antioxidant mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR STIMULATION; HYDROGEN-PEROXIDE; SELENIUM; MICE; ACTIVATION; GENERATION; RESPONSES; HEALTH AB Selenium is an essential dietary element with antioxidant roles in immune regulation, but there is little understanding of how this element acts at the molecular level in host defense and inflammatory disease. Selenium is incorporated into the amino acid selenocysteine (Sec), which in turn is inserted into selenoproteins in a manner dependent on Sec tRNA([Ser]Sec). To investigate the molecular mechanism that links selenium to T cell immunity, we generated mice with selenoprotein-less T cells by cell type-specific ablation of the Sec tRNA([Ser]Sec) gene (trsp). Herein, we show that these mutant mice exhibit decreased pools of mature T cells and a defect in T cell- dependent antibody responses. We also demonstrate that selenoprotein deficiency leads to oxidant hyperproduction in T cells and thereby suppresses T cell proliferation in response to T cell receptor stimulation. These findings offer novel insights into immune function of selenium and physiological antioxidants. C1 [Sano, Yasuyo; Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02129 USA. [Shrimali, Rajeev K.; Irons, Robert D.; Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Park, JM (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Boston, MA 02129 USA. EM jmpark@cbrc2.mgh.harvard.edu; hatfield@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU Intramural NIH HHS [Z01 BC005317-24]; NCI NIH HHS [CA 080946]; NIGMS NIH HHS [GM 065204] NR 23 TC 66 Z9 70 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 18 PY 2008 VL 283 IS 29 BP 20181 EP 20185 DI 10.1074/jbc.M802559200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CH UT WOS:000257565300034 PM 18487203 ER PT J AU Takeuchi, K Yang, H Ng, E Park, SY Sun, ZYJ Sun, ZYJ Reinherz, EL Wagner, G AF Takeuchi, Koh Yang, Hailin Ng, Elise Park, Sungh-youk Sun, Zhen-Yu J. Sun, Zhen-Yu J. Reinherz, Ellis L. Wagner, Gerhard TI Structural and functional evidence that Nck interaction with CD3 epsilon regulates T-cell receptor activity SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE CD3 epsilon; Nck; nuclear magnetic resonance; phosphorylation; receptor internalization ID PROLINE-RICH SEQUENCE; SIGNAL-TRANSDUCTION; CONFORMATIONAL-CHANGE; PROTEIN; COMPLEX; DOMAIN; NMR; RECOGNITION; ACTIVATION; THYMOCYTES AB Recruitment of signaling molecules to the cytoplasmic domains of the CD3 subunits of the T-cell receptor (TCR) is crucial for early T-cell activation. These transient associations either do or do not require tyrosine phosphorylation of CD3 immune tyrosine activation motifs (ITAMs). Here we show that the non-ITAM-requiring adaptor protein Nck forms a complex with an atypical PxxDY motif of the CD3 epsilon tail, which encompasses Tyr166 within the ITAM and a TCR endocytosis signal. As suggested by the structure of the complex, we find that Nck binding inhibits phosphorylation of the CD3e ITAM by Fyn and Lck kinases in vitro. Moreover, the CD3 epsilon-Nck interaction downregulates TCR surface expression upon physiological stimulation in mouse primary lymph node cells. This indicates that Nck performs an important regulatory function in T lymphocytes by inhibiting ITAM phosphorylation and/or removing cell surface TCR via CD3 epsilon interaction. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Takeuchi, Koh; Ng, Elise; Park, Sungh-youk; Sun, Zhen-Yu J.; Wagner, Gerhard] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Yang, Hailin; Reinherz, Ellis L.] Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. [Yang, Hailin; Reinherz, Ellis L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yang, Hailin; Park, Sungh-youk] Inha Univ, Coll Med, Biochem Lab, Inchon 400712, South Korea. RP Wagner, G (reprint author), Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, 240 Longwood Ave, Boston, MA 02115 USA. EM gerhard_wagner@hms.harvard.edu RI Takeuchi, Koh/B-4971-2010 FU NIAID NIH HHS [R37 AI019807, AI19807, AI37581, R01 AI019807, R01 AI037581, R01 AI037581-12, R01 AI037581-13, R37 AI019807-25, R56 AI019807]; NIBIB NIH HHS [EB002026, P41 EB002026, P41 EB002026-33]; NIGMS NIH HHS [GM47467, P01 GM047467, P01 GM047467-170011] NR 51 TC 27 Z9 30 U1 1 U2 4 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 18 PY 2008 VL 380 IS 4 BP 704 EP 716 DI 10.1016/j.jmb.2008.05.037 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 331XW UT WOS:000258046900011 PM 18555270 ER PT J AU Ekstrom, LB Roelfsema, PR Arsenault, JT Bonmassar, G Vanduffel, W AF Ekstrom, Leeland B. Roelfsema, Pieter R. Arsenault, John T. Bonmassar, Giorgio Vanduffel, Wim TI Bottom-up dependent gating of frontal signals in early visual cortex SO SCIENCE LA English DT Article ID EYE FIELD; INTRACORTICAL MICROSTIMULATION; ATTENTION INCREASES; SPATIAL ATTENTION; SQUIRREL-MONKEYS; MACAQUE MONKEYS; SINGLE NEURONS; OWL MONKEYS; AREA V4; CONNECTIONS AB The frontal eye field (FEF) is one of several cortical regions thought to modulate sensory inputs. Moreover, several hypotheses suggest that the FEF can only modulate early visual areas in the presence of a visual stimulus. To test for bottom-up gating of frontal signals, we microstimulated subregions in the FEF of two monkeys and measured the effects throughout the brain with functional magnetic resonance imaging. The activity of higher-order visual areas was strongly modulated by FEF stimulation, independent of visual stimulation. In contrast, FEF stimulation induced a topographically specific pattern of enhancement and suppression in early visual areas, but only in the presence of a visual stimulus. Modulation strength depended on stimulus contrast and on the presence of distractors. We conclude that bottom-up activation is needed to enable top-down modulation of early visual cortex and that stimulus saliency determines the strength of this modulation. C1 [Ekstrom, Leeland B.; Arsenault, John T.; Bonmassar, Giorgio; Vanduffel, Wim] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Ekstrom, Leeland B.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Ekstrom, Leeland B.] MIT, Dept Nucl Sci & Engn, Cambridge, MA 02139 USA. [Roelfsema, Pieter R.] Royal Netherlands Acad Arts & Sci, Dept Vis & Cognit, Netherlands Inst Neurosci, NL-1105 BA Amsterdam, Netherlands. [Roelfsema, Pieter R.] Vrije Univ Amsterdam, Dept Expt Neurophysiol, Ctr Neurogenom & cognit Res, NL-1081 HV Amsterdam, Netherlands. [Arsenault, John T.; Vanduffel, Wim] Katholieke Univ Leuven, Sch Med, Neuro & Psychofysiol Lab, B-3000 Louvain, Belgium. [Vanduffel, Wim] Harvard Univ, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. RP Vanduffel, W (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. EM wim@nmr.mgh.harvard.edu RI Roelfsema, Pieter/J-6903-2013 OI Roelfsema, Pieter/0000-0002-1625-0034 FU NCRR NIH HHS [P41 RR014075, P41 RR014075-13, P41RR14075]; NIBIB NIH HHS [R01 EB000790, R01 EB000790-05] NR 29 TC 158 Z9 158 U1 0 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 18 PY 2008 VL 321 IS 5887 BP 414 EP 417 DI 10.1126/science.1153276 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327FB UT WOS:000257713900053 PM 18635806 ER PT J AU Siggers, KA Lesser, CF AF Siggers, Keri A. Lesser, Cammie F. TI The yeast Saccharomyces cerevisiae: A versatile model system for the identification and characterization of bacterial virulence proteins SO CELL HOST & MICROBE LA English DT Review ID ENTEROPATHOGENIC ESCHERICHIA-COLI; MAPK SIGNALING PATHWAYS; III SECRETION SYSTEM; EFFECTOR PROTEIN; GENE-EXPRESSION; GLOBAL ANALYSIS; BUDDING YEAST; HOST-CELLS; YERSINIA; ACTIN AB Microbial pathogens utilize complex secretion systems to deliver proteins into host cells. These effector proteins target and usurp host cell processes to promote infection and cause disease. While secretion systems are conserved, each pathogen delivers its own unique set of effectors. The identification and characterization of these effector proteins has been difficult, often limited by the lack of detectable signal sequences and functional redundancy. Model systems including yeast, worms, flies, and fish are being used to circumvent these issues. This technical review details the versatility and utility of yeast Saccharomyces cerevisiae as a system to identify and characterize bacterial effectors. C1 [Siggers, Keri A.; Lesser, Cammie F.] Harvard Univ, Massachusetts Gen Hosp, Dept Med Microbiol & Mol Genet, Div Infect Dis,Med Sch, Cambridge, MA 02139 USA. RP Lesser, CF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Med Microbiol & Mol Genet, Div Infect Dis,Med Sch, Cambridge, MA 02139 USA. EM clesser@rics.bwh.harvard.edu FU NIAID NIH HHS [AI068924, R01 AI064285, T32 AI007061] NR 57 TC 46 Z9 48 U1 1 U2 12 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 JUL 17 PY 2008 VL 4 IS 1 BP 8 EP 15 DI 10.1016/j.chom.2008.06.004 PG 8 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 329ZF UT WOS:000257908400004 PM 18621006 ER PT J AU Shan, LB He, P Li, JM Heese, A Peck, SC Nurnberger, T Martin, GB Sheen, J AF Shan, Libo He, Ping Li, Jianming Heese, Antje Peck, Scott C. Nuernberger, Thorsten Martin, Gregory B. Sheen, Jen TI Bacterial effectors target the common signaling partner BAK1 to disrupt multiple MAMP receptor-signaling complexes and impede plant immunity SO CELL HOST & MICROBE LA English DT Article ID PSEUDOMONAS-SYRINGAE; INNATE IMMUNITY; MICROBE INTERACTIONS; PROTEIN-KINASE; ARABIDOPSIS; DEFENSE; PERCEPTION; FLAGELLIN; SYSTEM; ANIMALS AB Successful pathogens have evolved strategies to interfere with host immune systems. For example, the ubiquitous plant pathogen Pseudomonas syringae injects two sequence-distinct effectors, AvrPto and AvrPtoB, to intercept convergent innate immune responses stimulated by multiple microbe-associated molecular patterns (MAMPs). However, the direct host targets and precise molecular mechanisms of bacterial effectors remain largely obscure. We show that AvrPto and AvrPtoB bind the Arabidopsis receptor-like kinase BAK1, a shared signaling partner of both the flagellin receptor FLS2 and the brassinosteroid receptor BRI1. This targeting interferes with ligand-dependent association of FLS2 with BAK1 during infection. It also impedes BAKI1 dependent host immune responses to diverse other MAMPs and brassinosteroid signaling. Significantly, the structural basis of AvrPto-BAK1 interaction appears to be distinct from AvrPto-Pto association required for effector-triggered immunity. These findings uncover a unique strategy of bacterial pathogenesis where virulence effectors block signal transmission through a key common component of multiple MAMP-receptor complexes. C1 [Shan, Libo; He, Ping; Sheen, Jen] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Li, Jianming] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Heese, Antje; Peck, Scott C.] Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. [Nuernberger, Thorsten] Univ Tubingen, ZMBP, D-72076 Tubingen, Germany. [Martin, Gregory B.] Cornell Univ, Boyce Thompson Inst Plant Res, Ithaca, NY 14853 USA. [Martin, Gregory B.] Cornell Univ, Dept Plant Pathol & Plant Microbe Biol, Ithaca, NY 14853 USA. RP Shan, LB (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM shan@molbio.mgh.harvard.edu; phe@molbio.mgh.harvard.edu; sheen@molbio.mgh.harvard.edu RI Martin, Gregory/F-6262-2011 OI Martin, Gregory/0000-0003-0044-6830 FU NIGMS NIH HHS [R01 GM070567, R01 GM078021, R01 GM078021-01A1, R01 GM078021-02, R01 GM078021-03, R01 GM078021-04, R01 GM70567, R01GM078021] NR 46 TC 257 Z9 271 U1 8 U2 67 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUL 17 PY 2008 VL 4 IS 1 BP 17 EP 27 DI 10.1016/j.chom.2008.05.017 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 329ZF UT WOS:000257908400005 PM 18621007 ER PT J AU Hirsch, MS DeMaria, A Schaefer, PW Branda, JA Addo, MM Rosenberg, ES Ning, MM Buonanno, FS Spitzer, TR AF Hirsch, Martin S. DeMaria, Alfred, Jr. Schaefer, Pamela W. Branda, John A. Addo, Marylyn M. Rosenberg, Eric S. Ning, Ming-Ming Buonanno, Ferdinando S. Spitzer, Thomas R. TI A woman with fever and confusion - Eastern equine encephalitis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WEST-NILE-VIRUS; LYME-DISEASE; MANIFESTATIONS; MASSACHUSETTS; MOSQUITOS C1 [Hirsch, Martin S.] Massachusetts Gen Hosp, Dept Med, Infect Dis Serv, Boston, MA 02114 USA. [Schaefer, Pamela W.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Branda, John A.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [DeMaria, Alfred, Jr.] Massachusetts Dept Publ Hlth, Boston, MA USA. [Hirsch, Martin S.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [DeMaria, Alfred, Jr.] Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. [Schaefer, Pamela W.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA USA. [Branda, John A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. RP Hirsch, MS (reprint author), Massachusetts Gen Hosp, Dept Med, Infect Dis Serv, Boston, MA 02114 USA. NR 17 TC 5 Z9 5 U1 0 U2 5 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 17 PY 2008 VL 359 IS 3 BP 294 EP 303 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 326KD UT WOS:000257656600011 PM 18635435 ER PT J AU Vacharaksa, A Asrani, AC Gebhard, KH Fasching, CE Giacaman, RA Janoff, EN Ross, KF Herzberg, MC AF Vacharaksa, Anjalee Asrani, Anil C. Gebhard, Kristin H. Fasching, Claudine E. Giacaman, Rodrigo A. Janoff, Edward N. Ross, Karen F. Herzberg, Mark C. TI Oral keratinocytes support non-replicative infection and transfer of harbored HIV-1 to permissive cells SO RETROVIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; UTERINE EPITHELIAL-CELLS; SURFACE HEPARAN-SULFATE; SERUM-FREE MEDIUM; TYPE-1 INFECTION; LANGERHANS CELLS; GENE-EXPRESSION; HUMAN SALIVA; TRANSMISSION; ENTRY AB Background: Oral keratinocytes on the mucosal surface are frequently exposed to HIV-1 through contact with infected sexual partners or nursing mothers. To determine the plausibility that oral keratinocytes are primary targets of HIV-1, we tested the hypothesis that HIV-1 infects oral keratinocytes in a restricted manner. Results: To study the fate of HIV-1, immortalized oral keratinocytes (OKF6/TERT-2; TERT-2 cells) were characterized for the fate of HIV-specific RNA and DNA. At 6 h post inoculation with X4 or R5-tropic HIV-1, HIV-1gag RNA was detected maximally within TERT-2 cells. Reverse transcriptase activity in TERT-2 cells was confirmed by VSV-G-mediated infection with HIV-NL43.env-EGFP. AZT inhibited EGFP expression in a dose-dependent manner, suggesting that viral replication can be supported if receptors are bypassed. Within 3 h post inoculation, integrated HIV-1 DNA was detected in TERT-2 cell nuclei and persisted after subculture. Multiply spliced and unspliced HIV-1 mRNAs were not detectable up to 72 h post inoculation, suggesting that HIV replication may abort and that infection is non-productive. Within 48 h post inoculation, however, virus harbored by CD4 negative TERT-2 cells trans infected co-cultured peripheral blood mononuclear cells (PBMCs) or MOLT4 cells (CD4+ CCR5+) by direct cell-to-cell transfer or by releasing low levels of infectious virions. Primary tonsil epithelial cells also trans infected HIV-1 to permissive cells in a donor-specific manner. Conclusion: Oral keratinocytes appear, therefore, to support stable non-replicative integration, while harboring and transmitting infectious X4- or R5-tropic HIV-1 to permissive cells for up to 48 h. C1 [Vacharaksa, Anjalee; Asrani, Anil C.; Gebhard, Kristin H.; Giacaman, Rodrigo A.; Ross, Karen F.; Herzberg, Mark C.] Univ Minnesota, Sch Dent, Dept Diagnost & Biol Sci, Minneapolis, MN 55455 USA. [Vacharaksa, Anjalee; Asrani, Anil C.; Gebhard, Kristin H.; Fasching, Claudine E.; Giacaman, Rodrigo A.; Janoff, Edward N.; Ross, Karen F.; Herzberg, Mark C.] Minneapolis VA Med Ctr, Mucosal & Vaccine Res Ctr, Minneapolis, MN 55417 USA. [Janoff, Edward N.] Univ Colorado, Div Infect Dis, Colorado Ctr AIDS Res, Denver, CO 80220 USA. [Janoff, Edward N.] Univ Colorado, Mucosal & Vaccine Res Program Colorado, Denver, CO 80220 USA. [Janoff, Edward N.] Denver Vet Affairs Med Ctr, Denver, CO 80220 USA. RP Herzberg, MC (reprint author), Univ Minnesota, Sch Dent, Dept Diagnost & Biol Sci, Minneapolis, MN 55455 USA. EM tang0160@umn.edu; asran003@umn.edu; kristingebhard@mac.com; Claudine.Fasching@va.gov; giac0015@umn.edu; Edward.Janoff@ucdenver.edu; rossx007@umn.edu; mcherzb@umn.edu RI Giacaman, Rodrigo/A-9811-2010 OI Giacaman, Rodrigo/0000-0003-3362-5173 FU NIH [DE015503, DE15506, HD4136, DE72621] FX These studies were supported by NIH grants-in-aid DE015503 (to MCH), DE15506 (KFR), HD41361 (ENJ), DE72621 (ENJ), the Veterans Affairs Research Service, and the Mucosal and Vaccine Research Center. This manuscript has been submitted in partial fulfillment of the requirements for the PhD degree in oral biology by AV. NR 74 TC 19 Z9 19 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JUL 17 PY 2008 VL 5 AR 66 DI 10.1186/1742-4690-5-66 PG 14 WC Virology SC Virology GA 337XV UT WOS:000258469700002 PM 18637194 ER PT J AU Wang, SB Yang, Q Fung, KM Lin, HK AF Wang, Shaobin Yang, Qing Fung, Kar-Ming Lin, Hsueh-Kung TI AKR1C2 and AKR1C3 mediated prostaglandin D-2 metabolism augments the P13K/Akt proliferative signaling pathway in human prostate cancer cells SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE aldo-keto reductase; prostaglandin; prostate cancer ID ACTIVATED PROTEIN-KINASE; KETO REDUCTASE AKR1C3; ANDROGEN RECEPTOR; DEHYDROGENASE ISOFORMS; INCREASED EXPRESSION; F SYNTHASE; ADENOCARCINOMA; PROGRESSION; APOPTOSIS; TARGET AB Members of the aldo-keto reductase (AKR) superfamily have been implicated in prostaglandin (PG) metabolism and prostate cancer. AKR1C3 possesses 11-ketoprostaglandin reductase activity and is capable of converting PGD(2) to 9 alpha. 11 beta-PGF(2 alpha)., whereas AKR1C2-mediated PG metabolism remains unclear. The accumulation of PGF(2 alpha). may generate proliferative signals to promote prostate cell growth. Levels of AKR1C2 and AKR1C3 expression are elevated in localized and advanced prostate cancer. To study the significance of AKR1C2-and AKR1C3-mediated PGD(2) conversion in human prostatecell proliferation, we stably transfected androgen insensitive human prostate cancer PC-3 cells with AKR1C2 or AKR1C3 cDNA. PC-3 cells overexpressing AKR1C2 and AKR1C3 had elevated cell proliferation in response to PGD2 Stimulation as compared to mock transfectants. Overexpression of AKR1C2 or AKR1C3 did not alter levels of PGF receptor (FP) expression. Inclusion of an FP antagonist (AL8810) significantly suppressed PGD(2)-stimulated PC-3 cell proliferation in these stable transfectants. In addition, PGD2 significantly elevated levels of total Akt protein expression and Akt Ser(473) phosphorylation in AKR1C2 and AKR1C3 stable transfectants; and inclusion of a phosphatidylinositol 3-kinase (PI3K) chemical inhibitor (LY294002) attenuated PGD(2)-stimulated cell proliferation in these transfectants. Our results suggested that both AKR1C2 and AKR1C3 mediate similar PGD2 conversion toward the accumulation of proliferative signals through FP and PI3K/Akt signaling pathways to promote prostate cell proliferation. Published by Elsevier Ireland Ltd. C1 [Wang, Shaobin; Yang, Qing; Lin, Hsueh-Kung] Univ Oklahoma, Hlth Sci Ctr, Dept Urol, Oklahoma City, OK 73104 USA. [Wang, Shaobin; Lin, Hsueh-Kung] Univ Oklahoma, Hlth Sci Ctr, Dept Physiol, Oklahoma City, OK 73104 USA. [Fung, Kar-Ming] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK 73104 USA. [Fung, Kar-Ming; Lin, Hsueh-Kung] US Dept Vet Affairs, Med Ctr, Oklahoma City, OK 73104 USA. RP Lin, HK (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Urol, 920 Stanton L Young Blvd,WP 3150, Oklahoma City, OK 73104 USA. EM hk-in@ouhsc.edu RI wang, shaobin/D-7168-2011; wang, shaobin/A-2415-2015; wang, shaobin/L-8539-2015 OI wang, shaobin/0000-0002-0931-7210; NR 46 TC 26 Z9 28 U1 1 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUL 16 PY 2008 VL 289 IS 1-2 BP 60 EP 66 DI 10.1016/j.mce.2008.04.004 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 329BK UT WOS:000257841700008 PM 18508192 ER PT J AU Farr, MJ Lang, CC LaManca, JJ Zile, MR Francis, G Tavazzi, L Gaasch, WH Sutton, MSJ Itoh, H Mancini, D AF Farr, Mary Jane Lang, Chim C. LaManca, John J. Zile, Michael R. Francis, Gary Tavazzi, Luigi Gaasch, William H. Sutton, Martin St. John Itoh, Haruki Mancini, Donna CA MCC-135 GO1 Invest TI Cardiopulmonary exercise variables in diastolic versus systolic heart failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TRANSPLANTATION; DYSFUNCTION AB The response to cardiopulmonary exercise (CPX) in patients with heart failure (HF) with normal left ventricular (LV) ejection fractions (EFs) is not well characterized. To determine if CPX testing could distinguish between patients with HF with normal EFs (> 50%; i.e., diastolic HF) and those with decreased EFs ( >= 50%; i.e., systolic HF), CPX responses were compared between 185 patients with systolic HF (79% men, mean age 62.6 +/- 10.9 years) and 43 with diastolic HF (54% men, mean age 67.4 +/- 9.8 years) enrolled in a phase 11 multicenter clinical trial. All patients were evaluated with echocardiography and a standardized CPX test as part of the trial. CPX variables, including oxygen uptake at peak exercise (peak VO2) and the slope of the ventilation/carbon dioxide production ratio (VE/VCO2), were determined and analyzed by core laboratory personnel. Echocardiographic measurements included the LV EF, the E/A ratio, filling time, cavity volumes, right ventricular function, and mitral regurgitation. Patients in the diastolic HF group tended to be older (p < 0.08), with more women (p < 0.006) and with greater body mass indexes (p < 0.02), than those in the systolic HF group. There was no significant difference in the use of P blockers or the incidence of coronary artery disease. Patients with diastolic HF had decreased E/A ratios (0.9 +/- 0.4 vs 1.4 +/- 1.1, p < 0.02, diastolic HF vs systolic HF) and increased filling times (30.4 +/- 3.2 vs 26.5 +/- 4.7 ms, p < 0.01, diastolic HF vs systolic HF). No significant differences in peak VO2 (14.4 +/- 1.9 vs 15.6 3.2 ml/kg/min, p = 0.06, diastolic HF vs systolic HF) were observed. The VE/VCO2 ratios for the 2 groups were abnormal and comparable (32 2 +/- 7.5 vs 34.0 +/- 8.3, p = 0.3, diastolic HF vs systolic HF). In conclusion, the CPX response in patients with diastolic HF and systolic HF is markedly abnormal and indistinguishable with regard to peak VO2 and ventilation despite marked differences in the LV EF. (C) 2008 Elsevier Inc. All rights reserved. C1 [Farr, Mary Jane; LaManca, John J.; Mancini, Donna] Columbia Univ, Div Cardiol, New York, NY 10027 USA. [Lang, Chim C.] Univ Dundee, Ninewells Hosp & Med Sch, Div Med & Therapeut, Dundee DD1 9SY, Scotland. [Zile, Michael R.] Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, Div Cardiol, Charleston, SC 29425 USA. [Zile, Michael R.] Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. [Francis, Gary] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Tavazzi, Luigi] Osped Gen, Div Cardiol, Pavia, Italy. [Gaasch, William H.] Lahey Clin Fdn, Dept Cardiovasc Med, Burlington, MA USA. [Sutton, Martin St. John] Univ Penn, Philadelphia, PA 19104 USA. [Itoh, Haruki] Sakakibara Heart Inst, Tokyo, Japan. RP Lang, CC (reprint author), Columbia Univ, Div Cardiol, New York, NY 10027 USA. EM c.c.lang@dundee.ac.uk NR 9 TC 20 Z9 20 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 15 PY 2008 VL 102 IS 2 BP 203 EP 206 DI 10.1016/j.amjcard.2008.03.041 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 327MZ UT WOS:000257734500018 PM 18602522 ER PT J AU Kantarci, S Ragge, NK Thomas, NS Robinson, DO Noonan, KM Russell, MK Donnai, D Raymond, FL Walsh, CA Donahoe, PK Pober, BR AF Kantarci, Sibel Ragge, Nicola K. Thomas, N. Simon Robinson, David O. Noonan, Kristin M. Russell, Meaghan K. Donnai, Dian Raymond, F. Lucy Walsh, Christopher A. Donahoe, Patricia K. Pober, Barbara R. TI Donnai-Barrow syndrome (DBS/FOAR) in a child with a homozygous LRP2 mutation due to complete chromosome 2 paternal isodisomy SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Donnai-Barrow (DBS/FOAR) syndrome; uniparental isodisomy (UPD); paternal chromosome 2; reduction to homoallelism ID MATERNAL UNIPARENTAL DISOMY; CONFINED PLACENTAL MOSAICISM; TRISOMY-2; DEFICIENCY; PHENOTYPES; DEAFNESS; MEGALIN; UPD AB Donnai-Barrow syndrome [Faciooculoacousticorenal (FOAR) syndrome; DBS/FOARI is a rare autosomal recessive disorder resulting from mutations in the LRP2 gene located on chromosome 2q3I.I. We report a unique DBS/FOAR patient homozygous for a 4-bp LRP2 deletion secondary to paternal uniparental isodisomy for chromosome 2. The propositus inherited the mutation frorn his heterozygous carrier father, whereas the mother carried only wild-type LRP2 alleles. This is the first case of DBS/FOAR resulting from uniparental disomy (UPD) and the fourth published case of any paternal UPD 2 ascertained through unmasking of an autosomal recessive disorder. The absence of clinical symptoms above and beyond the classical phenotype in this and the other disorders suggests that paternal chromosome 2 is unlikely to contain imprinted genes notably affecting either growth or development. This report highlights the importance of parental genotyping in order to give accurate genetic counseling for autosomal recessive disorders. (c) 2008 Wiley-Liss, Inc. C1 [Kantarci, Sibel; Noonan, Kristin M.; Russell, Meaghan K.; Donahoe, Patricia K.] Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. [Kantarci, Sibel; Noonan, Kristin M.; Walsh, Christopher A.; Donahoe, Patricia K.; Pober, Barbara R.] Harvard Univ, Sch Med, Boston, MA USA. [Ragge, Nicola K.] Dept Physiol Anat & Genet, Oxford, England. [Ragge, Nicola K.] Moorfields Eye Hosp, London, England. [Thomas, N. Simon; Robinson, David O.] Wesses Reg Genet Lab, Salisbury, Wilts, England. [Donnai, Dian] St Marys Hosp, Manchester M13 0JH, Lancs, England. [Raymond, F. Lucy] Univ Cambridge, Addenbrookes Hosp, Cambridge CB2 2QQ, England. [Walsh, Christopher A.; Pober, Barbara R.] Childrens Hosp, Boston, MA 02115 USA. [Kantarci, Sibel] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. RP Kantarci, S (reprint author), Beth Israel Deaconess Med Ctr, Dept Pathol, 330 Brookline Ave,Yamins 309, Boston, MA 02215 USA. EM skantarc@bidmc.harvard.edu FU Howard Hughes Medical Institute; NICHD NIH HHS [R01 HD055150, R01 HD055150-02, R01 HD55150-01, T32 HD007396, T32 HD07396] NR 18 TC 25 Z9 26 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD JUL 15 PY 2008 VL 146A IS 14 BP 1842 EP 1847 DI 10.1002/ajmg.a.32381 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 328GF UT WOS:000257785700012 PM 18553518 ER PT J AU Schuster, MG Edwards, JE Sobel, JD Darouiche, RO Karchmer, AW Hadley, S Slotman, G Panzer, H Biswas, P Rex, JH AF Schuster, Mindy G. Edwards, John E., Jr. Sobel, Jack D. Darouiche, Rabih O. Karchmer, Adolf W. Hadley, Susan Slotman, Gus Panzer, Helene Biswas, Pinaki Rex, John H. TI Empirical fluconazole versus placebo for intensive care unit patients - A randomized trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CRITICALLY-ILL PATIENTS; SURGICAL-PATIENTS; DOUBLE-BLIND; PROSPECTIVE MULTICENTER; NEUTROPENIC PATIENTS; CANDIDAL INFECTIONS; AMPHOTERICIN-B; RISK-FACTORS; EPIDEMIOLOGY; PROPHYLAXIS AB Background: Invasive infection with Candida species is an important cause of morbidity and mortality in intensive care unit (ICU) patients. Optimal preventive strategies have not been clearly defined. Objective: To see whether empirical fluconazole improves clinical outcomes more than placebo in adult ICU patients at high risk for invasive candidiasis. Design: Double-blind, placebo-controlled, randomized trial conducted from 1995 to 2000. Setting: 26 ICUs in the United States. Patients: 270 adult ICU patients with fever despite administration of broad-spectrum antibiotics. All had central venous catheters and an Acute Physiology and Chronic Health Evaluation II score greater than 16. Intervention: Patients were randomly assigned to either intravenous fluconazole, 800 mg daily, or placebo for 2 weeks and were followed for 4 weeks thereafter. Two hundred forty-nine participants were available for outcome assessment. Measurements: A composite primary outcome that defined success as all 4 of the following: resolution of fever; absence of invasive fungal infection; no discontinuation because of toxicity; and no need for a nonstudy, systemic antifungal medication (as assessed by a blinded oversight committee). Results: Only 44 of 122 (36%) fluconazole recipients and 48 of 127 (38%) placebo recipients had a successful outcome (relative risk, 0.95 [95% CI, 0.69 to 1.32; P = 0.781). The main reason for failure was lack of resolution of fever (51 % for fluconazole and 57% for placebo). Documented invasive candidiasis occurred in 5% of fluconazole recipients and 9% of placebo recipients (relative risk, 0.57 [CI, 0.22 to 1.491). Seven (5%) fluconazole recipients and 10 (7%) placebo recipients had adverse events resulting in discontinuation of the study drug. Discontinuation because of abnormal liver test results occurred in 3 (2%) fluconazole recipients and 5 (4%) placebo recipients. Limitations: Twenty-one randomly assigned patients were not included in the analysis because they either did not meet entry criteria or did not have postbaseline assessments. Fewer fungal infections than anticipated occurred in the control group. Confidence bounds were wide and did not exclude potentially important differences in outcomes between groups. Conclusion: In critically ill adults with risk factors for invasive candidiasis, empirical fluconazole did not clearly improve a composite outcome more than placebo. C1 [Schuster, Mindy G.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Univ Calif Los Angeles, Harbor Med Ctr, Torrance, CA 90509 USA. Wayne State Univ, Sch Med, Detroit Med Ctr, Detroit, MI USA. Baylor Coll Med, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. Univ Texas Houston, Sch Med, Houston, TX USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Tufts Univ New England Med Ctr, Boston, MA USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Pfizer, New York, NY USA. RP Schuster, MG (reprint author), Univ Penn, Sch Med, 3 Silverstein,Suite E,3400 Spruce St, Philadelphia, PA 19104 USA. EM schustem@mail.med.upenn.edu NR 27 TC 102 Z9 110 U1 1 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 15 PY 2008 VL 149 IS 2 BP 83 EP 90 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 329GA UT WOS:000257853700002 PM 18626047 ER PT J AU Weissman, JS Schneider, EC Weingart, SN Epstein, AM David-Kasdan, J Feibelmann, S Annas, CL Ridley, N Kirle, L Gatsonis, C AF Weissman, Joel S. Schneider, Eric C. Weingart, Saul N. Epstein, Arnold M. David-Kasdan, JoAnn Feibelmann, Sandra Annas, Catherine L. Ridley, Nancy Kirle, Leslie Gatsonis, Constantine TI Comparing patient-reported hospital adverse events with medical record review: Do patients know something that hospitals do not? SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID HEALTH-CARE UTILIZATION; QUALITY-OF-CARE; SELF-REPORT; PROVIDER RECORDS; AMBULATORY-CARE; DRUG EVENTS; CONCORDANCE; DISCHARGE; VALIDITY AB Background: Hospitals routinely survey patients about the quality of care they receive, but little is known about whether patient interviews can detect adverse events that medical record reviews do not. Objective: To compare adverse events reported in postdischarge patient interviews with adverse events detected by medical record review. Design: Random sample survey. Setting: Massachusetts, 2003. Patients: Recently hospitalized adults. Measurements: By using parallel methods, physicians reviewed postdischarge interviews and medical records to classify hospital adverse events. Results: Among 998 study patients, 23% had at least 1 adverse event detected by an interview and 11 % had at least 1 adverse event identified by record review. The K statistic showed relatively poor agreement between interviews and medical records for occurrence of any type of adverse event (K = 0.20 [95% CI, 0.03 to 0.27]) and somewhat better agreement between interviews and medical records for life-threatening or serious events (K = 0.33 [CI, 0.20 to 0.451). Record review identified 11 serious, preventable events (1.1 % of patients). Interviews identified an additional 21 serious and preventable events that were not documented in the medical record, including 12 predischarge events and 9 postdischarge events, in which symptoms occurred after the patient left the hospital. Limitations: Patients had to be healthy enough to be interviewed. Delay in reaching patients (6 to 12 months after discharge) may have resulted in poor recall of events during the hospital stay. Conclusion: Patients report many events that are not documented in the medical record; some are serious and preventable. Hospitals should consider monitoring patient safety by adding questions about adverse events to postdischarge interviews. C1 Harvard Univ, Sch Publ Hlth, Massachusetts Gen Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Dept Publ Hlth, Boston, MA USA. Massachusetts Hosp Assoc, Burlington, MA USA. Brown Univ, Providence, RI 02912 USA. RP Weissman, JS (reprint author), Massachusetts Execut Off, Hlth & Human Serv, 1 Asburton Pl,Room 1109, Boston, MA 02108 USA. EM joel.weissman@state.ma.us OI Schneider, Eric/0000-0002-1132-5084 FU AHRQ HHS [U18 HS11928] NR 35 TC 94 Z9 95 U1 1 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUL 15 PY 2008 VL 149 IS 2 BP 100 EP 108 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 329GA UT WOS:000257853700004 PM 18626049 ER PT J AU Suryaprasad, A Stone, JH AF Suryaprasad, Anil Stone, John H. TI When is it safe to stop Pneumocystis jiroveci pneumonia prophylaxis? Insights from three cases complicating autoimmune diseases SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; CARINII-PNEUMONIA; WEGENERS-GRANULOMATOSIS; PULSE CYCLOPHOSPHAMIDE; THERAPY; RISK; DERMATOMYOSITIS; INFECTION; COUNTS C1 [Stone, John H.] Massachusetts Gen Hosp, Div Rheumatol Yawkey 2, Boston, MA 02114 USA. [Suryaprasad, Anil] Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. RP Stone, JH (reprint author), Massachusetts Gen Hosp, Div Rheumatol Yawkey 2, 55 Fruit St, Boston, MA 02114 USA. EM jhstone@partners.org NR 35 TC 18 Z9 18 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 EI 1529-0131 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD JUL 15 PY 2008 VL 59 IS 7 BP 1034 EP 1039 DI 10.1002/art.23822 PG 6 WC Rheumatology SC Rheumatology GA 325PY UT WOS:000257602000018 PM 18576286 ER PT J AU Pizzagalli, DA Goetz, E Ostacher, M Iosifescu, DV Perlis, RH AF Pizzagalli, Diego A. Goetz, Elena Ostacher, Michael Iosifescu, Dan V. Perlis, Roy H. TI Euthymic patients with bipolar disorder show decreased reward learning in a probabilistic reward task SO BIOLOGICAL PSYCHIATRY LA English DT Article DE anhedonia; bipolar disorder; dopamine; reinforcement learning; reward; depression ID TREATMENT ENHANCEMENT PROGRAM; DECISION-MAKING; DOPAMINE HYPOTHESIS; PREFRONTAL CORTEX; TRIPARTITE MODEL; SIGNAL-DETECTION; RATING-SCALE; ACUTE MANIA; STEP-BD; DEPRESSION AB Background: Bipolar disorder (BPD) features cycling mood states ranging from depression to mania with intermittent phases of euthymia. Bipolar disorder subjects often show excessive goal-directed and pleasure-seeking behavior during manic episodes and reduced hedonic capacity during depressive episodes, indicating that BPD might involve altered reward processing. Our goal was to test the hypothesis that BPD is characterized by impairments in adjusting behavior as a function of prior reinforcement history, particularly in the presence of residual anhedonic symptoms. Methods: Eighteen medicated BPD subjects and 25 demographically matched comparison subjects performed a probabilistic reward task. To identify putative dysfunctions in reward processing irrespective of mood state, primary analyses focused on euthymic BPD subjects (n = 13). With signal-detection methodologies, response bias toward a more frequently rewarded stimulus was used to objectively assess the participants' propensity to modulate behavior as a function of reinforcement history. Results: Relative to comparison subjects, euthymic BPD subjects showed a reduced and delayed acquisition of response bias toward the more frequently rewarded stimulus, which was partially due to increased sensitivity to single rewards of the disadvantageous stimulus. Analyses considering the entire BPD sample revealed that reduced reward learning correlated with self-reported anhedonic symptoms, even after adjusting for residual manic and anxious symptoms and general distress. Conclusions: The present study provides preliminary evidence indicating that BPD, even during euthymic states, is characterized by dysfunctional reward learning in situations requiring integration of reinforcement information over time and thus offers initial insights about the potential source of dysfunctional reward processing in this disorder. C1 [Pizzagalli, Diego A.; Goetz, Elena] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Ostacher, Michael; Iosifescu, Dan V.; Perlis, Roy H.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. RP Pizzagalli, DA (reprint author), Harvard Univ, Dept Psychol, 1220 William James Hall,33 Kirkland St, Cambridge, MA 02138 USA. EM dap@wjh.harvard.edu OI Ostacher, Michael/0000-0003-0353-7535 FU NIMH NIH HHS [R01 MH068376, R01 MH068376-01A1, R01 MH068376-02, R01 MH068376-03, R01 MH068376-04, R01 MH068376-05, R01MH68376] NR 48 TC 54 Z9 54 U1 2 U2 9 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 JUL 15 PY 2008 VL 64 IS 2 BP 162 EP 168 DI 10.1016/j.biopsych.2007.12.001 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 319TT UT WOS:000257187700011 PM 18242583 ER PT J AU Koivunen, JP Kim, J Lee, J Rogers, AM Park, JO Zhao, X Naoki, K Okamoto, I Nakagawa, K Yeap, BY Meyerson, M Wong, KK Richards, WG Sugarbaker, DJ Johnson, BE Janne, PA AF Koivunen, J. P. Kim, J. Lee, J. Rogers, A. M. Park, J. O. Zhao, X. Naoki, K. Okamoto, I. Nakagawa, K. Yeap, B. Y. Meyerson, M. Wong, K-K Richards, W. G. Sugarbaker, D. J. Johnson, B. E. Jaenne, P. A. TI Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients SO BRITISH JOURNAL OF CANCER LA English DT Article DE carcinoma; non-small cell lung; mutation; LKB1; EGFR; KRAS ID PEUTZ-JEGHERS-SYNDROME; FACTOR-RECEPTOR GENE; SOMATIC MUTATIONS; CIGARETTE-SMOKING; CELL-LINES; ADENOCARCINOMA; EXPRESSION; LKB1/STK11; CARCINOMAS AB Somatic mutations of LKB1 tumour suppressor gene have been detected in human cancers including non-small cell lung cancer (NSCLC). The relationship between LKB1 mutations and clinicopathological characteristics and other common oncogene mutations in NSCLC is inadequately described. In this study we evaluated tumour specimens from 310 patients with NSCLC including those with adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma histologies. Tumours were obtained from patients of US (n = 143) and Korean (n = 167) origin and screened for LKB1, KRAS, BRAF, and EGFR mutations using RT-PCR-based SURVEYOR-WAVE method followed by Sanger sequencing. We detected mutations in the LKB1 gene in 34 tumours (11%). LKB1 mutation frequency was higher in NSCLC tumours of US origin (17%) compared with 5% in NSCLCs of Korean origin (P = 0.001). They tended to occur more commonly in adenocarcinomas (13%) than in squamous cell carcinomas (5%) (P = 0.066). LKB1 mutations associated with smoking history (P = 0.007) and KRAS mutations (P = 0.042) were almost mutually exclusive with EGFR mutations (P = 0.002). The outcome of stages I and II NSCLC patients treated with surgery alone did not significantly differ based on LKB1 mutation status. Our study provides clinical and molecular characteristics of NSCLC, which harbour LKB1 mutations. C1 [Koivunen, J. P.; Rogers, A. M.; Park, J. O.; Zhao, X.; Naoki, K.; Meyerson, M.; Wong, K-K; Johnson, B. E.; Jaenne, P. A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lowe Ctr Thorac Oncol,Dept Med Oncol, Boston, MA 02115 USA. [Kim, J.; Lee, J.] Samsung Med Ctr, Dept Thorac Surg, Seoul, South Korea. [Kim, J.; Lee, J.] Sungkyunkwan Univ, Sch Med, Seoul, South Korea. [Okamoto, I.; Nakagawa, K.] Kinki Univ, Sch Med, Dept Med Oncol, Osaka 589, Japan. [Yeap, B. Y.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Meyerson, M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Meyerson, M.] MIT, Broad Inst, Cambridge, MA 02139 USA. [Meyerson, M.] Harvard Univ, Cambridge, MA 02138 USA. [Meyerson, M.; Wong, K-K; Johnson, B. E.; Jaenne, P. A.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Richards, W. G.; Sugarbaker, D. J.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Janne, PA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Lowe Ctr Thorac Oncol,Dept Med Oncol, D820A,44 Binney St, Boston, MA 02115 USA. EM pjanne@partners.org RI Kim, Jhingook/C-9663-2011; Meyerson, Matthew/E-7123-2012 FU NCI NIH HHS [1R01CA114465-01, P20 CA090578, P20CA90578-02, R01 CA114465] NR 31 TC 81 Z9 85 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 15 PY 2008 VL 99 IS 2 BP 245 EP 252 DI 10.1038/sj.bjc.6604469 PG 8 WC Oncology SC Oncology GA 326GX UT WOS:000257647700004 PM 18594528 ER PT J AU Safdar, A Rodriguez, GH Rueda, AM Wierda, WG Ferrajoli, A Musher, DM O'Brien, S Koller, CA Bodey, GR Keating, MJ AF Safdar, Amar Rodriguez, Gilhen H. Rueda, Adriana M. Wierda, William G. Ferrajoli, Alessandra Musher, Daniel M. O'Brien, Susan Koller, Charles A. Bodey, Gerald R. Keating, Michael J. TI Multiple-dose granulocyte-macrophage-colony-stimulating factor plus 23-valent polysaccharide pneumococcal vaccine in patients with chronic lymphocytic leukemia - A prospective, randomized trial of safety and immunogenicity SO CANCER LA English DT Article DE Streptococcus pneumonia; pneumococcal vaccine; chronic lymphocytic leukemia; granulocyte-macrophage-colony-stimulating factor; immunogenicity; reactogenicity ID ANTIBODY-RESPONSES; INFLUENZA VACCINE; DENDRITIC CELLS; RECEPTOR; DISEASE; CANCER AB BACKGROUND. For the current study, the authors sought to determine whether administration of multiple-dose granulocyte-macrophage-colony-stimulating factor (GM-CSF) could improve response to standard 23-valent polysaccharide pneumococcal vaccine (PPV) in patients with chronic lymphocytic leukemia (CLL). METHODS. Patients were allocated randomly to receive PPV either alone or with 3 doses of GM-CSF (250 mu g) given before or after vaccination. Serum was obtained before, 4 weeks after, and 12 weeks after vaccination for antibody determination. Thirty-two patients with CLL were given PPV They were randomized to receive 3 doses of GM-CSF either before or after vaccination or to receive no GM-CSE. RESULTS. A 4-fold rise in immunoglobulin G (IgG) to capsular polysaccharides from Streptococcus pneumoniae types 4, 613, 9V, 14, 19F, and 23F occurred in <10% of patients in each of the 3 groups. There were no differences in geometric mean IgG levels in any of the 3 groups 4 weeks or 12 weeks after vaccination. CONCLUSIONS. In patients with CLL, the response to pure polysaccharide pneumococcal vaccine was low despite immune enhancement with multiple doses of GM-CSF In all patients, reactogenicity was minor. C1 [Safdar, Amar; Rodriguez, Gilhen H.; Bodey, Gerald R.] Univ Texas MD Anderson Canc Ctr, Dept Infect Dis Infect Control & Employee Hlth, Unit 402, Houston, TX 77030 USA. [Rueda, Adriana M.; Musher, Daniel M.] Michael E DeBakey Vet Affairs Med Ctr, Infect Dis Sect, Med Serv, Houston, TX USA. [Rueda, Adriana M.; Musher, Daniel M.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Wierda, William G.; Ferrajoli, Alessandra; O'Brien, Susan; Koller, Charles A.; Keating, Michael J.] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. [Musher, Daniel M.] Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. RP Safdar, A (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Infect Dis Infect Control & Employee Hlth, Unit 402, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM asafdar@mdanderson.org FU NCI NIH HHS [CA16672, P30 CA016672] NR 15 TC 16 Z9 18 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD JUL 15 PY 2008 VL 113 IS 2 BP 383 EP 387 DI 10.1002/cncr.23561 PG 5 WC Oncology SC Oncology GA 322WM UT WOS:000257406000018 PM 18470901 ER PT J AU Inoue-Narita, T Hamada, K Sasaki, T Hatakeyama, S Fujita, S Kawahara, K Sasaki, M Kishimoto, H Eguchi, S Kojima, I Beermann, F Kimura, T Osawa, M Itami, S Mak, TW Nakano, T Manabe, M Suzuki, A AF Inoue-Narita, Tae Hamada, Koichi Sasaki, Takehiko Hatakeyama, Sachiko Fujita, Sachiko Kawahara, Kohichi Sasaki, Masato Kishimoto, Hiroyuki Eguchi, Satoshi Kojima, Itaru Beermann, Friedrich Kimura, Tetsunori Osawa, Masatake Itami, Satoshi Mak, Tak Wah Nakano, Toru Manabe, Motomu Suzuki, Akira TI Pten deficiency in melanocytes results in resistance to hair graying and susceptibility to carcinogen-induced melanomagenesis SO CANCER RESEARCH LA English DT Article ID HEMATOPOIETIC STEM-CELLS; LABEL-RETAINING CELLS; TUMOR-SUPPRESSOR GENE; MALIGNANT-MELANOMA; SELF-RENEWAL; IN-VIVO; EXPRESSION; MICE; NICHE; CYCLE AB Phosphate and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor gene inactivated in numerous sporadic cancers, including melanomas. To analyze Pten functions in melanocytes, we used the Cre-loxP system to delete Pten specifically in murine pigment-producing cells and generated DctCrePten(flox/flox) mice. Half of DctCrePten(flox/flox) mice died shortly after birth with enlargements of the cerebral cortex and hippocampus. Melanocytes were increased in the dermis of perinatal DetCrePten(flox/flox) mice. When the mutants were subjected to repeated depilations, melanocyte stem cells in the bulge of the hair follicle resisted exhaustion and the mice were protected against hair graying. Although spontaneous melanomas did not form in DctCrePten(flox/flox) mice, large nevi and melanomas developed after carcinogen exposure. DetCrePten(flox/flox) melanocytes were increased in size and exhibited heightened activation of Akt and extracellular signal-regulated kinases, increased expression of Bcl-2, and decreased expression of p27(KIP1). Our results show that Pten is important for the maintenance of melanocyte stem cells and the suppression of melanomagenesis. C1 [Hamada, Koichi; Kawahara, Kohichi; Suzuki, Akira] Kyushu Univ, Med Inst Bioregulat, Div Embryon & Genet Engn, Higashi Ku, Fukuoka 8128582, Japan. [Inoue-Narita, Tae; Hatakeyama, Sachiko; Fujita, Sachiko; Manabe, Motomu] Akita Univ, Sch Med, Dept Dermatol, Akita 010, Japan. [Hamada, Koichi; Kawahara, Kohichi; Sasaki, Masato; Kishimoto, Hiroyuki; Suzuki, Akira] Akita Univ, Sch Med, Dept Biol Mol, Akita 010, Japan. [Sasaki, Takehiko; Eguchi, Satoshi] Akita Univ, Sch Med, Dept Microbiol, Akita 010, Japan. [Kojima, Itaru] Gunma Univ, Inst Mol & Cellular Regulat, Lab Cell Physiol, Maebashi, Gumma 371, Japan. [Beermann, Friedrich] Ecole Polytech Fed Lausanne, Sch Life Sci, Swiss Inst Expt Canc Res, Epalinges, Switzerland. [Kimura, Tetsunori] Sapporo Inst Dermatopathol, Sapporo, Hokkaido, Japan. [Osawa, Masatake] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA USA. [Itami, Satoshi] Osaka Univ, Grad Sch Med, Dept Regenerat Dermatol, Suita, Osaka, Japan. [Nakano, Toru] Osaka Univ, Grad Sch Med, Dept Pathol, Suita, Osaka, Japan. [Mak, Tak Wah] Univ Toronto, Campbell Family Inst Breast Canc Res, Toronto, ON, Canada. [Mak, Tak Wah] Univ Toronto, Dept Immunol, Toronto, ON, Canada. [Mak, Tak Wah] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. RP Suzuki, A (reprint author), Kyushu Univ, Med Inst Bioregulat, Div Embryon & Genet Engn, Higashi Ku, Maidashi 3-1-1, Fukuoka 8128582, Japan. EM suzuki@bioreg.kyushu-u.ac.jp NR 50 TC 28 Z9 32 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2008 VL 68 IS 14 BP 5760 EP 5768 DI 10.1158/0008-5472.CAN-08-0889 PG 9 WC Oncology SC Oncology GA 327ZZ UT WOS:000257768300033 PM 18632629 ER PT J AU Chaiswing, L Zhong, WX Cullen, JJ Oberley, LW Oberley, TD AF Chaiswing, Luksana Zhong, Weixiong Cullen, Joseph J. Oberley, Larry W. Oberley, Terry D. TI Extracellular redox state regulates features associated with prostate cancer cell invasion SO CANCER RESEARCH LA English DT Article ID SUPEROXIDE-DISMUTASE; THIOL/DISULFIDE REDOX; OXIDATIVE STRESS; TUMOR-CELLS; THIOREDOXIN; CARCINOMA; METASTASIS; EXPRESSION; LINES AB We have examined the possible role of extracellular reduction-oxidation (redox) state in regulation of biological/biochemical features associated with prostate cancer cell invasion. DU145, PC-3, and RWPE1-derived human prostate cancer (WPE1-NB26) cell lines were used for the present in vitro analysis. Increasing levels of nitric oxide using S-nitroso-N-acetylpenicillamine resulted in a decrease in cell invasion ability, whereas increasing levels of extracellular superoxide radical (O-2(center dot-)) using xanthine/xanthine oxidase resulted in an increase in cell invasion ability in these three cell lines. WPE1-NB26 cells exhibited an increased glutathione/glutathione disulfide ratio in the medium in comparison with RWPE1 cells (immortalized but nonmalignant prostate epithelial cells), suggesting an alteration of extracellular redox state of WPE1-NB26 cells. We hypothesized that O-2(center dot-) production at or near the plasma membrane or in the adjacent extracellular matrix at least partially regulated prostate cancer cell invasion. Using adenovirus-mediated extracellular superoxide dismutase (EC- SOD) gene transduction to enzymatically decrease O-2(center dot-) levels, we showed that in the presence of heparin, adenovirus EC- SOD gene transduction resulted in an increase in the expression of EC-SOD outside the cells with resultant inhibition of cell invasion ability. This inhibition correlated with reduced metalloproteinase [matrix metalloproteinase (MMP) 2/membrane type 1-MMP] activities and increased levels of extracellular nitrite. Our results suggest a prominent role of extracellular redox status in regulation of cell invasion, which may provide opportunities for therapeutic interventions. C1 [Chaiswing, Luksana; Zhong, Weixiong; Oberley, Terry D.] William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, Madison, WI 53705 USA. [Chaiswing, Luksana; Zhong, Weixiong; Oberley, Terry D.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Pathol & Lab Med, Madison, WI USA. [Cullen, Joseph J.] Univ Iowa, Dept Surg, Iowa City, IA 52242 USA. [Cullen, Joseph J.] Vet Affairs Med Ctr, Iowa City, IA 52242 USA. [Oberley, Larry W.] Univ Iowa, Dept Radiat Oncol, Iowa City, IA USA. RP Oberley, TD (reprint author), William S Middleton Mem Vet Adm Med Ctr, Pathol & Lab Med Serv, A-35,2500 Overlook Terrace, Madison, WI 53705 USA. EM toberley@wisc.edu NR 27 TC 35 Z9 36 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2008 VL 68 IS 14 BP 5820 EP 5826 DI 10.1158/0008-5472.CAN-08-0162 PG 7 WC Oncology SC Oncology GA 327ZZ UT WOS:000257768300040 PM 18632636 ER PT J AU Shimamura, T Li, D Ji, H Haringsma, HJ Liniker, E Borgman, CL Lowell, AM Minami, Y McNamara, K Perera, SA Zaghlul, S Thomas, RK Greulich, H Kobayashi, S Chirieac, LR Padera, RF Kubo, S Takahashi, M Tenen, DG Meyerson, M Wong, KK Shapiro, GI AF Shimamura, Takeshi Li, Danan Ji, Hongbin Haringsma, Henry J. Liniker, Elizabeth Borgman, Christa L. Lowell, April M. Minami, Yuko McNamara, Kate Perera, Samanthi A. Zaghlul, Sara Thomas, Roman K. Greulich, Heidi Kobayashi, Susumu Chirieac, Lucian R. Padera, Robert F. Kubo, Shigeto Takahashi, Masaya Tenen, Daniel G. Meyerson, Matthew Wong, Kwok-Kin Shapiro, Geoffrey I. TI Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; TYROSINE KINASE; IRREVERSIBLE INHIBITORS; ACQUIRED-RESISTANCE; DOMAIN MUTATIONS; EGFR MUTATIONS; B-RAF; GEFITINIB; SENSITIVITY AB The epidermal growth factor receptor (EGFR) secondary kinase domain T790M non-small cell lung cancer (NSCLC) mutation enhances receptor catalytic activity and confers resistance to the reversible tyrosine kinase inhibitors gefitinib and erlotinib. Currently, irreversible inhibitors represent the primary approach in clinical use to circumvent resistance. We show that higher concentrations of the irreversible EGFR inhibitor CL-387,785 are required to inhibit EGFR phosphorylation in T790M-expressing cells compared with EGFR mutant NSCLC cells without T790M. Additionally, CL-387,785 does not fully suppress phosphorylation of other activated receptor tyrosine kinases (RTK) in T790M-expressing cells. These deficiencies result in residual Akt and mammalian target of rapamycin (mTOR) activities. Full suppression of EGFR-mediated signaling in T790M-expressing cells requires the combination of CL-387,785 and rapamycin. In contrast, Hsp90 inhibition overcomes these limitations in vitro and depletes cells of EGFR, other RTKs, and phospho-Akt and inhibits mTOR signaling whether or not T790M is present. EGFR-T790M-expressing cells rendered resistant to CL-387,785 by a kinase switch mechanism retain sensitivity to Hsp90 inhibition. Finally, Hsp90 inhibition causes regression in murine lung adenocarcinomas driven by mutant EGFR (L858R) with or without T790M. However, efficacy in the L858R-T790M model requires a more intense treatment schedule and responses were transient. Nonetheless, these findings suggest that Hsp90 inhibitors may be effective in T790M-expressing cells and offer an alternative therapeutic strategy for this subset of lung cancers. C1 [Shimamura, Takeshi; Li, Danan; Ji, Hongbin; Haringsma, Henry J.; Liniker, Elizabeth; Borgman, Christa L.; Lowell, April M.; Minami, Yuko; McNamara, Kate; Perera, Samanthi A.; Zaghlul, Sara; Greulich, Heidi; Meyerson, Matthew; Wong, Kwok-Kin; Shapiro, Geoffrey I.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA. [Minami, Yuko; Greulich, Heidi; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02215 USA. [Li, Danan; Ji, Hongbin; Perera, Samanthi A.; Wong, Kwok-Kin] Harvard Univ, Ctr Canc, Ludwig Ctr Dana Farber, Boston, MA 02115 USA. [Shimamura, Takeshi; Minami, Yuko; Wong, Kwok-Kin; Shapiro, Geoffrey I.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Chirieac, Lucian R.; Padera, Robert F.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kobayashi, Susumu; Tenen, Daniel G.] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Kubo, Shigeto; Takahashi, Masaya] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Thomas, Roman K.] Univ Cologne, Ctr Integrated Oncol, Cologne, Germany. [Greulich, Heidi; Meyerson, Matthew] Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. [Greulich, Heidi; Meyerson, Matthew] MIT, Cambridge, MA 02139 USA. RP Wong, KK (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Dana 810B,44 Binney St, Boston, MA 02215 USA. EM kwong1@partners.org; geoffrey_shapiro@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; OI wong, kwok kin/0000-0001-6323-235X; Tenen, Daniel/0000-0002-6423-3888 FU NCI NIH HHS [R01 CA116010, K99 CA126026-01A1, P20 CA090578, P20 CA090578-01A10004, P50 CA090578, P50 CA090578-06, R01 CA090687, R01 CA090687-08, R01 CA122794, R01 CA122794-01, R01 CA122794-03, K99 CA126026]; NIA NIH HHS [K08 AG024004, R01 AG027757, R01 AG027757-03, R01 AG2400401] NR 45 TC 102 Z9 105 U1 3 U2 12 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2008 VL 68 IS 14 BP 5827 EP 5838 DI 10.1158/0008-5472.CAN-07-5428 PG 12 WC Oncology SC Oncology GA 327ZZ UT WOS:000257768300041 PM 18632637 ER PT J AU Aponte, M Jiang, W Lakkis, M Li, MJ Edwards, D Albitar, L Vitonis, A Mok, SC Cramer, DW Ye, B AF Aponte, Margarita Jiang, Wei Lakkis, Montaha Li, Ming-Jiang Edwards, Dale Albitar, Lina Vitonis, Allison Mok, Samuel C. Cramer, Daniel W. Ye, Bin TI Activation of platelet-activating factor receptor and pleiotropic effects on tyrosine phospho-EGFR/Src/FAK/paxillin in ovarian cancer SO CANCER RESEARCH LA English DT Article ID PROTEIN-COUPLED RECEPTORS; FOCAL-ADHESION KINASE; FACTOR PAF; LYSOPHOSPHATIDIC ACID; BREAST-CANCER; SIGNALING PATHWAYS; ENDOTHELIAL-CELLS; LIPID MEDIATORS; CARCINOMA CELLS; UP-REGULATION AB Among the proinflammatory mediators, platelet-activating factor (PAF, 1-o-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine) is a major primary and secondary messenger involved in intracellular and extracellular communication. Evidence suggests that PAF plays a significant role in oncogenic transformation, tumor growth, angiogenesis, and metastasis. However, PAF, with its receptor (PAFR) and their downstream signaling targets, has not been thoroughly studied in cancer. Here, we characterized the PAFR expression pattern in 4 normal human ovarian surface epithelial (HOSE) cell lines, 13 ovarian cancer cell lines, paraffin blocks (n = 84), and tissue microarrays (n = 230) from patients with ovarian cancer. Overexpression of PAFR was found in most nonmucinous types of ovarian cancer but not in HOSE and mucinous cancer cells. Correspondingly, PAF significantly induced cell proliferation and invasion only in PAFR-positive cells (i.e., OVCA429 and OVCA432), but not in PAFR-negative ovarian cells (HOSE and mucinous RMUG-L). The dependency of cell proliferation and invasion on PAFR was further confirmed using PAFR-specific small interfering RNA gene silencing probes, antibodies against PAFR and PAFR antagonist, ginkgolide B. Using quantitative multiplex phospho-antibody array technology, we found that tyrosine phosphorylation of EGFR/Src/FAK/paxilin was coordinately activated by PAF treatment, which was correlated with the activation of phosphatidylinositol 3-kinase and cyclin D1 as markers for cell proliferation, as well as matrix metalloproteinase 2 and 9 for invasion. Specific tyrosine Src inhibitor (PP2) reversibly blocked PAF-activated cancer cell proliferation and invasion. We suggest that PAFR is an essential upstream target of Src and other signal pathways to control the PAT-mediated cancer progression. C1 [Aponte, Margarita; Jiang, Wei; Li, Ming-Jiang; Edwards, Dale; Albitar, Lina; Vitonis, Allison; Mok, Samuel C.; Cramer, Daniel W.; Ye, Bin] Harvard Univ, Sch Med, Dana Farber Canc Ctr,Lab Gynecol Oncol & Epidemio, Brigham & Womens Hosp,Dept Obstet & Gynecol & Rep, Boston, MA 02115 USA. [Lakkis, Montaha] Invitrogen Inc, BioSource, Carlsbad, CA USA. RP Ye, B (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Ctr,Lab Gynecol Oncol & Epidemio, Brigham & Womens Hosp,Dept Obstet & Gynecol & Rep, 221 Longwood Ave,LMRC 610, Boston, MA 02115 USA. EM bye@partners.org FU NCI NIH HHS [P50 CA105009-01, 1P50-CA105009-01, P50 CA105009, R01 CA054419, R01 CA054419-13, R01 CA54419-13, R21 CA111949, R21 CA111949-01, R21 CA111949-01A1, R21 CA111949-02] NR 45 TC 38 Z9 43 U1 0 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2008 VL 68 IS 14 BP 5839 EP 5848 DI 10.1158/0008-5472.CAN-07-5771 PG 10 WC Oncology SC Oncology GA 327ZZ UT WOS:000257768300042 PM 18632638 ER PT J AU Di Vizio, D Adam, RM Kim, J Kim, R Sotgia, F Williams, T Demichelis, F Solomon, KR Loda, M Rubin, MA Lisanti, MP Freeman, MR AF Di Vizio, Dolores Adam, Rosalyn M. Kim, Jayoung Kim, Robert Sotgia, Federica Williams, Terence Demichelis, Francesca Solomon, Keith R. Loda, Massimo Rubin, Mark A. Lisanti, Michael P. Freeman, Michael R. TI Caveolin-1 interacts with a lipid raft-associated population of fatty acid synthase SO CELL CYCLE LA English DT Article ID PROSTATE-CANCER CELLS; GROWTH-FACTOR; SCAFFOLDING DOMAIN; ANTITUMOR-ACTIVITY; SERUM CAVEOLIN-1; TYROSINE KINASE; EXPRESSION; CHOLESTEROL; PROTEINS; BINDING AB Fatty Acid Synthase (FASN), a cytoplasmic biosynthetic enzyme, is the major source of long-chain fatty acids, particularly palmitate. Caveolin-1 (Cav-1) is a palmitoylated lipid raft protein that plays a key role in signal transduction and cholesterol transport. Both proteins have been implicated in prostate cancer (PCa) progression, and Cav-1 regulates FASN expression in a mouse model of aggressive PCa. We demonstrate that FASN and Cav-1 are coordinately upregulated in human prostate tumors in a hormone-insensitive manner. Levels of FASN and Cav-1 protein expression discriminated between localized and metastatic cancers, and the two proteins exhibited analogous subcellular locations in a tumor subset. Endogenous FASN and Cav-1 were reciprocally co-immunoprecipitated from human and murine PCa cells, indicating that FASN forms a complex with Cav-1. FASN, a cytoplasmic enzyme, was induced to associate transiently with lipid raft membranes following alterations in signal transduction within the Src, Akt and EGFR pathways, suggesting that co-localization of FASN and Cav-1 is dependent on activation of upstream signaling mediators. A Cav-1 palmitoylation mutant, Cav-1(C133/143/156S), that prevents phosphorylation by Src, did not interact with FASN. When overexpressed in Cav-1-negative PCa cells, Cav-1(C133/143/156S) caused a reduction of both Src and Akt levels, as well as of their active, phosphorylated forms, in comparison with wild type Cav-1. These findings suggest that FASN and Cav-1 physically and functionally interact in PCa cells. They also imply that palmitoylation within this complex is involved in tumor growth and survival. C1 [Di Vizio, Dolores; Adam, Rosalyn M.; Kim, Jayoung; Freeman, Michael R.] Harvard Univ, Enders Res Labs, Urol Dis Res Ctr, Childrens Hosp Boston,Sch Med, Boston, MA 02115 USA. [Di Vizio, Dolores; Adam, Rosalyn M.; Kim, Jayoung; Freeman, Michael R.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Surg, Boston, MA 02115 USA. [Freeman, Michael R.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Kim, Robert; Demichelis, Francesca; Rubin, Mark A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Brigham & Womens Hosp,Dept Pathol, Boston, MA 02115 USA. [Sotgia, Federica; Williams, Terence; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Canc Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Sotgia, Federica; Williams, Terence; Lisanti, Michael P.] Thomas Jefferson Univ, Dept Biochem & Mol Biol, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Solomon, Keith R.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Orthopaed Surg,Program Mol Biol & Genet, Boston, MA 02115 USA. RP Di Vizio, D (reprint author), Harvard Univ, Enders Res Labs, Urol Dis Res Ctr, Childrens Hosp Boston,Sch Med, Rm 1149,300 Longwood Ave, Boston, MA 02115 USA. EM dolores.divizio@childrens.harvard.edu RI Lisanti, Michael/C-6866-2013; Williams, Terence/I-9614-2014; OI Rubin, Mark/0000-0002-8321-9950 FU American Italian Cancer Foundation [NIDDK R3747556, P50 DK65298, NCI R01 CA112303, DAMD17-03-2-0033, NCI R01 CA101046]; Pennsylvania Department of Health FX This study is supported by the American Italian Cancer Foundation (D.D.V.& M.L.), NIDDK R3747556, P50 DK65298, NCI R01 CA112303 and DAMD17-03-2-0033 (to M.R.F), and NCI R01 CA101046 (to K.R.S.). This project is also funded, in part, under a grant with the Pennsylvania Department of Health, to M.P.L. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. The authors wish to thank Drs. P. de Candia and J. Suh for helpful suggestions on co-IP experiments, and Mr. Paul Guthrie and Mr. Raj Jhaveri for technical assistance. NR 58 TC 45 Z9 45 U1 1 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUL 15 PY 2008 VL 7 IS 14 BP 2257 EP 2267 PG 11 WC Cell Biology SC Cell Biology GA 343CH UT WOS:000258829700025 PM 18635971 ER PT J AU Erkko, H Dowty, JG Nikkila, J Syrjaekoski, K Mannermaa, A Pylkas, K Southey, MC Holli, K Kallioniemi, A Jukkola-Vuorinen, A Kataja, V Kosma, VM Xia, B Livingston, DM Winqvist, R Hopper, JL AF Erkko, Hannele Dowty, James G. Nikkila, Jenni Syrjaekoski, Kirsi Mannermaa, Arto Pylkas, Katri Southey, Melissa C. Holli, Kaija Kallioniemi, Anne Jukkola-Vuorinen, Arja Kataja, Vesa Kosma, Veli-Matti Xia, Bing Livingston, David M. Winqvist, Robert Hopper, John L. TI Penetrance analysis of the PALB2 c.1592delT founder mutation SO CLINICAL CANCER RESEARCH LA English DT Article ID ONSET BREAST-CANCER; GENETIC EPIDEMIOLOGY; FANCONI-ANEMIA; PARTNER; RISKS; BRCA1 AB Purpose: PALB2 is a recently identified breast cancer susceptibility gene. We have previously identified in the Finnish population a PALB2 c.1592delT founder truncation mutation that is associated with an increased risk of breast cancer. In the present study, we wanted to assess in more detail the increased risk (hazard ratio, HR) and the age-specific cumulative risk (penetrance) of c.1592delT with regard to susceptibility to breast and other forms of cancer. Experimental Design: Modified segregation analyses fitted under maximum likelihood theory were used to estimate age-specific cumulative risks and HRs using the families of mutation carriers identified from a consecutive series of breast cancer cases unselected for age at onset or family history. Results: We found a substantially increased risk of breast cancer [HR, 6.1; 95% confidence interval (95% CI), 2.2-17.2; P = 0.01] equivalent to a 40% (95% CI, 17-77) breast cancer risk by age 70 years, comparable to that for carriers of mutations in BRCA2. We found marginal evidence (P = 0.06) that the HR for breast cancer decreased with age by 4.2% per year (95% CI, 0.2-8.1), from 7.5-fold at age 30 years to 2.0-fold at age 60 years. Conclusions: Our results suggest that it may be appropriate to offer PALB2 c.1592delT mutation testing to Finnish women with breast cancer, especially those with an early age at onset or a family history of breast or related cancers, and to offer carriers the option of participation in extended disease surveillance programs. C1 Univ Oulu, Dept Clin Genet, Canc Genet Lab, FIN-90014 Oulu, Finland. Oulu Univ Hosp, Canc Genet Lab, Oulu, Finland. Univ Oulu, Bioctr, FIN-90014 Oulu, Finland. Oulu Univ Hosp, Dept Oncol, Oulu, Finland. Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. Univ Tampere, Inst Med Technol, Canc Genet Lab, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Tampere, Finland. Univ Tampere, Sch Med, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Palliat Unit, Tampere, Finland. Univ Kuopio, Inst Clin Med, Dept Oncol, FIN-70211 Kuopio, Finland. Kuopio Univ Hosp, Dept Pathol, SF-70210 Kuopio, Finland. Vaasa Cent Hosp, Dept Oncol, Vaasa, Finland. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Winqvist, R (reprint author), Univ Oulu, Dept Clin Genet, Canc Genet Lab, POB 500, FIN-90014 Oulu, Finland. EM robert.winqvist@oulu.fi NR 17 TC 61 Z9 61 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 JUL 15 PY 2008 VL 14 IS 14 BP 4667 EP 4671 DI 10.1158/1078-0432.CCR-08-0210 PG 5 WC Oncology SC Oncology GA 328GD UT WOS:000257785500038 PM 18628482 ER PT J AU De Nicolo, A Tancredi, M Lombardi, G Flemma, CC Barbuti, S Di Cristofano, C Sobhian, B Bevilacqua, G Drapkin, R Caligo, MA AF De Nicolo, Arcangela Tancredi, Mariella Lombardi, Grazia Flemma, Cristina Chantal Barbuti, Serena Di Cristofano, Claudio Sobhian, Bijan Bevilacqua, Generoso Drapkin, Ronny Caligo, Maria Adelaide TI A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function SO CLINICAL CANCER RESEARCH LA English DT Article ID FANCONI-ANEMIA; BRCA2 MUTATIONS; SUSCEPTIBILITY GENES; GENOMIC INSTABILITY; RNA ABUNDANCE; DNA HELICASES; BACH1; RISK; PENETRANCE; FAMILIES AB Purpose: BRCA1-interacting protein 1 (BRIP1; FANCJ/BACH1), which encodes a DNA helicase that interacts with BRCA1, has been suggested to be a low-penetrance breast cancer predisposing gene. We aimed to assess whether BRIP1 mutations contribute to breast cancer susceptibility in our population and, if so, to investigate the effect of such mutation (s) on BRIP1 function. Experimental Design: A series of 49 breast/ovarian cancer families, devoid of a BRCA1/BRCA2 mutation, were screened for BRIP1 mutations. Functional analyses, including coimmunoprecipitation and stability assays, were employed to further characterize a previously unreported variant. Results: Five sequence alterations were identified, of which four had been already described. Herein, we report a novel BRIP1 germ-line mutation identified in a woman with early-onset breast cancer. The mutation consists of a 4-nucleotide deletion (c.2992-2995delAAGA) in BRIP1 exon 20 that causes a shift in the reading frame, disrupts the BRCA1-binding domain of BRIP1, and creates a premature stop codon. Functional analysis of the recombinant mutant protein in transfected cells showed that the truncation interferes with the stability of the protein and with its ability to interact with BRCA1. Loss of the wild-type BRIP1 allele with retention of the mutated one was observed in the patient's breast tumor tissue. Conclusions: These results, by showing that the newly identified BRIP1 c.2992-2995delAAGA mutation is associated with instability and functional impairment of the encoded protein, provide further evidence of a breast cancer - related role for BRIP1. C1 [Drapkin, Ronny] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [De Nicolo, Arcangela; Sobhian, Bijan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Drapkin, Ronny] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Univ Pisa, Div Surg Mol & Ultrastruct Pathol, Dept Oncol Transplants & New Technol Med, Sect Oncogenet, Pisa, Italy. Univ Hosp Pisa, Pisa, Italy. RP Drapkin, R (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM ronny_drapkin@dfci.harvard.edu RI Drapkin, Ronny/E-9944-2016; OI Drapkin, Ronny/0000-0002-6912-6977; Di Cristofano, Claudio/0000-0003-2891-5598 FU NCI NIH HHS [K08 CA108748, K08 CA108748-04, P50 CA105009, P50CA105009] NR 53 TC 28 Z9 28 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 JUL 15 PY 2008 VL 14 IS 14 BP 4672 EP 4680 DI 10.1158/1078-0432.CCR-08-0087 PG 9 WC Oncology SC Oncology GA 328GD UT WOS:000257785500039 PM 18628483 ER PT J AU Steere, AC McHugh, G Damle, N Sikand, VK AF Steere, Allen C. McHugh, Gail Damle, Nitin Sikand, Vijay K. TI Prospective study of serologic tests for Lyme disease SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; POLYMERASE CHAIN-REACTION; BORRELIA-BURGDORFERI DNA; ANTIBIOTIC-TREATMENT; ANTIBODY-RESPONSE; ARTHRITIS; SERODIAGNOSIS; PERSISTENCE; PEPTIDE; REGION AB Background. Tests to determine serum antibody levels-the 2-tier sonicate immunoglobulin M (IgM) and immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and Western blot method or the IgG of the variable major protein-like sequence-expressed (VlsE) sixth invariant region (C6) peptide ELISA method-are the major tests available for support of the diagnosis of Lyme disease. However, these tests have not been assessed prospectively. Methods. We used these tests prospectively to determine serologic responses in 134 patients with various manifestations of Lyme disease, 89 patients with other illnesses (with or without a history of Lyme disease), and 136 healthy subjects from areas of endemicity and areas in which the infection was not endemic. Results. With 2-tier tests and the C6 peptide ELISA, only approximately one-third of 76 patients with erythema migrans had results that were positive for IgM or IgG seroreactivity with Borrelia burgdorferi in acute-phase samples. During convalescence, 3-4 weeks later, almost two-thirds of patients had seroreactivity with the spirochete B. burgdorferi. The frequencies of seroreactivity were significantly greater among patients with spirochetal dissemination than they were among those who lacked evidence of disseminated disease. Of the 44 patients with Lyme disease who had neurologic, heart, or joint involvement, all had positive C6 peptide ELISA results, 42 had IgG responses with 2-tier tests, and 2 patients with facial palsy had only IgM responses. However, among the control groups, the IgG Western blot was slightly more specific than the C6 peptide ELISA. The differences between the 2 test systems (2-tier testing and C6 peptide ELISA) with respect to sensitivity and specificity were not statistically significant. Conclusions. Except in patients with erythema migrans, both test systems were sensitive for support of the diagnosis of Lyme disease. However, with current methods, 2-tier testing was associated with slightly better specificity. C1 [Steere, Allen C.; McHugh, Gail; Damle, Nitin; Sikand, Vijay K.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Boston, MA 02114 USA. RP Steere, AC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, 55 Fruit St,CNY 149-8301, Boston, MA 02114 USA. EM asteere@partners.org FU PHS HHS [CCU110291] NR 31 TC 100 Z9 104 U1 0 U2 5 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 JUL 15 PY 2008 VL 47 IS 2 BP 188 EP 195 DI 10.1086/589242 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 315UF UT WOS:000256905000007 PM 18532885 ER PT J AU Hirsch, MS Gunthard, HF Schapiro, JM Brun-Vezinet, F Clotet, B Hammer, SM Johnson, VA Kuritzkes, DR Mellors, JW Pillay, D Yeni, PG Jacobsen, DM Richman, DD AF Hirsch, Martin S. Guenthard, Huldrych F. Schapiro, Jonathan M. Brun-Vezinet, Francoise Clotet, Bonaventura Hammer, Scott M. Johnson, Victoria A. Kuritzkes, Daniel R. Mellors, John W. Pillay, Deenan Yeni, Patrick G. Jacobsen, Donna M. Richman, Douglas D. TI Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; INHIBITOR-EXPERIENCED PATIENTS; REVERSE-TRANSCRIPTASE INHIBITORS; CLEAVAGE SITE MUTATIONS; COST-EFFECTIVENESS ANALYSIS; PLACEBO-CONTROLLED TRIAL; FIXED-DOSE COMBINATION; SUBTYPE-C PROTEASE; VIROLOGICAL RESPONSE; TYPE-1 PROTEASE AB Resistance to antiretroviral drugs remains an important limitation to successful human immunodeficiency virus type 1 (HIV-1) therapy. Resistance testing can improve treatment outcomes for infected individuals. The availability of new drugs from various classes, standardization of resistance assays, and the development of viral tropism tests necessitate new guidelines for resistance testing. The International AIDS Society-USA convened a panel of physicians and scientists with expertise in drug-resistant HIV-1, drug management, and patient care to review recently published data and presentations at scientific conferences and to provide updated recommendations. Whenever possible, resistance testing is recommended at the time of HIV infection diagnosis as part of the initial comprehensive patient assessment, as well as in all cases of virologic failure. Tropism testing is recommended whenever the use of chemokine receptor 5 antagonists is contemplated. As the roll out of antiretroviral therapy continues in developing countries, drug resistance monitoring for both subtype B and non-subtype B strains of HIV will become increasingly important. C1 [Hirsch, Martin S.; Kuritzkes, Daniel R.] Harvard Univ, Sch Med, Boston, MA USA. [Hammer, Scott M.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Johnson, Victoria A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. [Johnson, Victoria A.] Univ Alabama, Sch Med, Birmingham, AL USA. [Mellors, John W.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Jacobsen, Donna M.] Int AIDS Soc USA, San Francisco, CA USA. [Richman, Douglas D.] Univ Calif San Diego, San Diego, CA 92103 USA. [Richman, Douglas D.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Guenthard, Huldrych F.] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Schapiro, Jonathan M.] Chaim Sheba Med Ctr, Tel Aviv, Israel. [Brun-Vezinet, Francoise] Hop Bichat Claude Bernard, F-75877 Paris 18, France. [Clotet, Bonaventura] Hosp Univ Germans Trias & Pujol, Irsi Caixa Fdn, Barcelona, Catalonia, Spain. [Pillay, Deenan] UCL Royal Free & Univ Coll Med Sch, London WC1E 6BT, England. RP Hirsch, MS (reprint author), Massachusetts Gen Hosp, 65 Landsdowne St,Rm 419, Cambridge, MA 02139 USA. EM mshirsch@partners.org RI gunthard, huldrych/F-1724-2011; Infektiologie, USZ/A-6921-2011 OI gunthard, huldrych/0000-0002-1142-6723; NR 226 TC 284 Z9 299 U1 2 U2 10 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 JUL 15 PY 2008 VL 47 IS 2 BP 266 EP 285 DI 10.1086/589297 PG 20 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 315UF UT WOS:000256905000020 PM 18549313 ER PT J AU Huang, XL Gao, XL Diaz-Trelles, R Ruiz-Lozano, P Wang, Z AF Huang, Xuling Gao, Xiaolin Diaz-Trelles, Ramon Ruiz-Lozano, Pilar Wang, Zhong TI Coronary development is regulated by ATP-dependent SWI/SNF chromatin remodeling component BAF180 SO DEVELOPMENTAL BIOLOGY LA English DT Article DE BAF180; SWI/SNF; PBAF; chromatin remodeling; epicardium; coronary development; EMT; angiogenesis; vasculogenesis; surface nodule ID SMOOTH-MUSCLE; MESENCHYMAL TRANSFORMATION; PERICARDIAL MESODERM; HEART DEVELOPMENT; ARTERY FORMATION; RETINOIC ACID; CELL-CYCLE; COMPLEXES; DIFFERENTIATION; TRANSCRIPTION AB Dissecting the molecular mechanisms that guide the proper development of epicardial cell lineages is critical for understanding the etiology of both congenital and adult forms of human cardiovascular disease. In this study, we describe the function of BAF180, a polybromo protein in ATP-dependent SWI/SNF chromatin remodeling complexes, in coronary development. Ablation of BAF180 leads to impaired epithelial-to-mesenchymal-transition (EMT) and arrested maturation of epicardium around E11.5. Three-dimensional collagen gel assays revealed that the BAF180 mutant epicardial cells indeed possess significantly compromised migrating and EMT potentials. Consequently, the mutant hearts form abnormal surface nodules and fail to develop the fine and continuous plexus of coronary vessels that cover the entire ventricle around E14. PECAM and alpha-SMA staining assays indicate that these nodules are defective structures resulting from the failure of endothelial and smooth muscle cells within them to form coronary vessels. PECAM staining also reveal that there are very few coronary vessels inside the myocardium of mutant hearts. Consistent with this, quantitative RT-PCR analysis indicate that the expression of genes involved in FGF, TGF, and VEGF pathways essential for coronary development are down-regulated in mutant hearts. Together, these data reveal for the first time that BAF180 is critical for coronary vessel formation. (c) 2008 Elsevier Inc. All rights reserved. C1 [Huang, Xuling; Gao, Xiaolin; Wang, Zhong] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Richard Simches Res Ctr,Cardiovasc Res Ctr, Boston, MA 02114 USA. [Diaz-Trelles, Ramon; Ruiz-Lozano, Pilar] Burnham Inst Med Res, Dev & Aging Program, La Jolla, CA 92037 USA. RP Wang, Z (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Richard Simches Res Ctr,Cardiovasc Res Ctr, 185 Cambridge St, Boston, MA 02114 USA. EM zhwang@partners.org OI Diaz Trelles, Ramon/0000-0002-2666-9728 NR 50 TC 42 Z9 45 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2008 VL 319 IS 2 BP 258 EP 266 DI 10.1016/j.ydbio.2008.04.020 PG 9 WC Developmental Biology SC Developmental Biology GA 327NA UT WOS:000257734600009 PM 18508041 ER PT J AU Tsai, CL Rowntree, RK Cohen, DE Lee, JT AF Tsai, Chia-Lun Rowntree, Rebecca K. Cohen, Dena E. Lee, Jeannie T. TI Higher order chromatin structure at the X-inactivation center via looping DNA SO DEVELOPMENTAL BIOLOGY LA English DT Article DE X-chromosome inactivation; Xist; Tsix; Xite; chromosome conformation capture; higher order structure; non-coding RNA ID RANGE INTRACHROMOSOMAL INTERACTIONS; MOUSE XIST GENE; CHROMOSOME INACTIVATION; CONTROL REGION; SPATIAL-ORGANIZATION; TSIX TRANSCRIPTION; COUNTING PROCESS; CTCF BINDING; GLOBIN LOCUS; CHOICE AB In mammals, the silencing step of the X-chromosome inactivation (XCI) process is initiated by the non-coding Xist RNA. Xist is known to be controlled by the non-coding Xite and Tsix loci, but the mechanisms by which Tsix and Xite regulate Xist are yet to be fully elucidated. Here, we examine the role of higher order chromatin structure across the 100-kb region of the mouse X-inactivation center (Xic) and map domains of specialized chromatin in vivo. By hypersensitive site mapping and chromosome conformation capture (K), we identify two domains of higher order chromatin structure. Xite makes looping interactions with Tsix, while Xist makes contacts with Jpx/Enox, another non-coding gene not previously implicated in XCI. These regions interact in a developmentally-specific and sex-specific manner that is consistent with a regulatory role in XCL We propose that dynamic changes in three-dimensional architecture leads to formation of separate chromatin hubs in Tsix and Xist that together regulate the initiation of X-chromosome inactivation. (c) 2008 Elsevier Inc. All rights reserved. C1 [Lee, Jeannie T.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Genet,Dept Mol Biol,Howard Hughes Med Inst, Boston, MA 02114 USA. RP Lee, JT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Genet,Dept Mol Biol,Howard Hughes Med Inst, Boston, MA 02114 USA. EM lee@molbio.mgh.harvard.edu FU Howard Hughes Medical Institute; NIGMS NIH HHS [R01 GM058839-10, R01 GM38895, R01 GM058839] NR 52 TC 56 Z9 56 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2008 VL 319 IS 2 BP 416 EP 425 DI 10.1016/j.ydbio.2008.04.010 PG 10 WC Developmental Biology SC Developmental Biology GA 327NA UT WOS:000257734600023 PM 18501343 ER PT J AU Wood, AW Sang, XP Curran, MS AF Wood, Antony W. Sang, Xianpeng Curran, Matthew S. TI A cell-intrinsic role for IGF signaling in zebrafish primordial germ cell migration SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 67th Annual Meeting of the Society-for-Developmental-Biology CY JUL 25-30, 2008 CL Univ Penn, Philadelphia, PA SP Soc Dev Biol HO Univ Penn C1 Massachusetts Gen Hosp, Vincent Ctr Reprod Biol, Boston, MA 02114 USA. Harvard Stem Cell Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2008 VL 319 IS 2 MA 275 BP 548 EP 549 DI 10.1016/j.ydbio.2008.05.293 PG 2 WC Developmental Biology SC Developmental Biology GA 327NA UT WOS:000257734600298 ER PT J AU Morgan, BA Enshell-Seijffers, D AF Morgan, Bruce A. Enshell-Seijffers, David TI The dermal papilla regulates the activity of pluri-potent follicular stem cells and the differentiation of their progeny to direct morphogenesis and regeneration of the hair SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 67th Annual Meeting of the Society-for-Developmental-Biology CY JUL 25-30, 2008 CL Univ Penn, Philadelphia, PA SP Soc Dev Biol HO Univ Penn C1 Harvard Univ, Sch Med, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Charlestown, MA 02129 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2008 VL 319 IS 2 MA 298 BP 556 EP 557 DI 10.1016/j.ydbio.2008.05.318 PG 2 WC Developmental Biology SC Developmental Biology GA 327NA UT WOS:000257734600319 ER PT J AU Wingert, RA Davidson, AJ AF Wingert, Rebecca A. Davidson, Alan J. TI Retinoic acid signaling plays key roles in the establishment of proximo-distal nephron segments in the zebrafish kidney SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract CT 67th Annual Meeting of the Society-for-Developmental-Biology CY JUL 25-30, 2008 CL Univ Penn, Philadelphia, PA SP Soc Dev Biol HO Univ Penn C1 [Wingert, Rebecca A.; Davidson, Alan J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2008 VL 319 IS 2 MA 415 BP 591 EP 591 DI 10.1016/j.ydbio.2008.05.492 PG 1 WC Developmental Biology SC Developmental Biology GA 327NA UT WOS:000257734600434 ER PT J AU Gilbertson, J Yagi, Y AF Gilbertson, John Yagi, Yukako TI Histology, imaging and new diagnostic work-flows in pathology SO DIAGNOSTIC PATHOLOGY LA English DT Article; Proceedings Paper CT 9th European Congress on Telepathology/3rd International Congress on Virtural Microscopy CY MAY 15-17, 2008 CL Toledo, SPAIN AB Introduction: Since their introduction in 1999, fully automated, high speed, high-resolution whole slide imaging devices have become increasing more reliable, fast and capable. While by no means perfect, these devices have evolved to a point where one can consider placing them in a pre-diagnostic role in a clinical histology lab. Methods: At the Massachusetts General Hospital, we are running a pilot study placing high end WSI devices in our main clinical histology lab (after the cover slipper and before slides are sent to the pathologist) to examine the requirement for both the machine and the laboratory. Results: Placing WSI systems in the clinical lab stresses the system in terms of reliability and throughput. Significantly however, success requires significant modification to the lab workflow. It is likely laboratories need to move from manual, large batch processes to increasingly automated, continuous flow (or mini-batch) processes orchestrated by the LIS using bar coding to track and direct slides, and incorporating the decision to image into the specimen type and the histology orders. Furthermore, image quality, capture speed and reliability are functions of the quality of the histology presented to the WSI devices. Conclusion: Imaging in pathology does not begin in a WSI robot but in the grossing room and in the histology lab. As more and more imaging devices are placed in histology lab, the interrelationships histology and pathology imaging will become increasing understood. C1 [Gilbertson, John; Yagi, Yukako] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. RP Gilbertson, J (reprint author), Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. EM GilbertsonJR@gmail.com NR 6 TC 14 Z9 14 U1 2 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1746-1596 J9 DIAGN PATHOL JI Diagn. Pathol. PD JUL 15 PY 2008 VL 3 SU 1 AR S14 DI 10.1186/1746-1596-3-S1-S14 PG 3 WC Pathology SC Pathology GA 605KI UT WOS:000278346100014 PM 18673502 ER PT J AU Napierala, D Sam, K Morello, R Zheng, Q Munivez, E Shivdasani, RA Lee, B AF Napierala, Dobrawa Sam, Kathy Morello, Roy Zheng, Qiping Munivez, Elda Shivdasani, Ramesh A. Lee, Brendan TI Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome SO HUMAN MOLECULAR GENETICS LA English DT Article ID SYNDROME TYPE-I; OSTEOBLAST DIFFERENTIATION; CLEIDOCRANIAL DYSPLASIA; BONE-FORMATION; REGULATES PROLIFERATION; INDIAN-HEDGEHOG; COLLAGEN GENE; CBFA1; EXPRESSION; RUNX2 AB Tricho-rhino-phalangeal syndrome (TRPS) is an autosomal dominant craniofacial and skeletal dysplasia that is caused by mutations involving the TRPS1 gene. Patients with TRPS have short stature, hip abnormalities, cone-shaped epiphyses and premature closure of growth plates reflecting defects in endochondral ossification. The TRPS1 gene encodes for the transcription factor TRPS1 that has been demonstrated to repress transcription in vitro. To elucidate the molecular mechanisms underlying skeletal abnormalities in TRPS, we analyzed Trps1 mutant mice (Trps1 Delta GT mice). Analyses of growth plates demonstrated delayed chondrocyte differentiation and accelerated mineralization of perichondrium in Trps1 mutant mice. These abnormalities were accompanied by increased Runx2 and Ihh expression and increased Indian hedgehog signaling. We demonstrated that Trps1 physically interacts with Runx2 and represses Runx2-mediated trans-activation. Importantly, generation of Trps1(Delta GT/+);Runx2(+/-) double heterozygous mice rescued the opposite growth plate phenotypes of single mutants, demonstrating the genetic interaction between Trps1 and Runx2 transcription factors. Collectively, these data suggest that skeletal dysplasia in TRPS is caused by dysregulation of chondrocyte and perichondrium development partially due to loss of Trps1 repression of Runx2. C1 [Lee, Brendan] Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA. [Napierala, Dobrawa; Sam, Kathy; Morello, Roy; Zheng, Qiping; Munivez, Elda; Lee, Brendan] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. [Shivdasani, Ramesh A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Lee, B (reprint author), Baylor Coll Med, Howard Hughes Med Inst, 1 Baylor Plaza, Houston, TX 77030 USA. EM blee@bcm.edu FU Howard Hughes Medical Institute; NICHD NIH HHS [HD22657, P01 HD022657-22]; NIDCR NIH HHS [DE16990, R01 DE016990, R01 DE016990-04] NR 29 TC 44 Z9 45 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 15 PY 2008 VL 17 IS 14 BP 2244 EP 2254 DI 10.1093/hmg/ddn125 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 319RK UT WOS:000257181300018 PM 18424451 ER PT J AU MacDonald, SM Safai, S Trofimov, A Wolfgang, J Fullerton, B Yeap, BY Bortfeld, T Tarbell, NJ Yock, T AF MacDonald, Shannon M. Safai, Sairos Trofimov, Alexei Wolfgang, John Fullerton, Barbara Yeap, Beow Y. Bortfeld, Thomas Tarbell, Nancy J. Yock, Torunn TI Proton radiotherapy for childhood ependymoma: Initial clinical outcomes and dose comparisons SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 49th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology CY OCT 28-NOV 01, 2007 CL Los Angeles, CA SP Amer Soc Therapeut & Oncol DE ependymoma; pediatric brain tumors; proton beam radiation ID CONFORMAL RADIATION-THERAPY; INTRACRANIAL EPENDYMOMAS; PROGNOSTIC FACTORS; BRAIN-TUMORS; LOCALIZED EPENDYMOMA; CRANIAL IRRADIATION; CURRENT MANAGEMENT; PEDIATRIC-PATIENTS; POSTERIOR-FOSSA; CHILDREN AB Purpose: To report preliminary clinical outcomes for pediatric patients treated with proton beam radiation for intracranial ependymoma and compare the dose distributions of intensity-modulated radiation therapy with photons (IMRT), three-dimensional conformal proton radiation, and intensity-modulated proton radiation therapy (IMPT) for representative patients. Methods and Materials: All children with intracranial ependymoma confined to the supratentorial or infratentorial brain treated at the Francis H. Burr Proton Facility and Harvard Cyclotron between November 2000 and March 2006 were included in this study. Seventeen patients were treated with protons. Proton, IMRT, and IMPT plans were generated with similar clinical constraints for representative infratentorial and supratentorial ependymoma cases. Tumor and normal tissue dose-volume histograms were calculated and compared. Results: At a median follow-up of 26 months from the start date of radiation therapy, local control, progression-free survival, and overall survival rates were 86%, 80%, and 89%, respectively. Subtotal resection was significantly associated with decreased local control (p = 0.016). Similar tumor volume coverage was achieved with IMPT, proton therapy, and IMRT. Substantial normal tissue sparing was seen with proton therapy compared with IMRT. Use of IMPT will allow for additional sparing of some critical structures. Conclusions: Preliminary disease control with proton therapy compares favorably with the literature. Dosimetric comparisons show the advantage of proton radiation compared with IMRT in the treatment of ependymoma. Further sparing of normal structures appears possible with IMPT. Superior dose distributions were accomplished with fewer beam angles with the use of protons and IMPT. (C) 2008 Elsevier Inc. C1 [MacDonald, Shannon M.; Safai, Sairos; Trofimov, Alexei; Wolfgang, John; Bortfeld, Thomas; Tarbell, Nancy J.; Yock, Torunn] Harvard Univ, Dept Radiat Oncol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Yeap, Beow Y.] Harvard Univ, Dept Internal Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Fullerton, Barbara] Harvard Univ, Dept Otol & Laryngol, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02114 USA. RP MacDonald, SM (reprint author), Harvard Univ, Dept Radiat Oncol, Massachusetts Gen Hosp, Sch Med, Cox 340,100 Blossom St, Boston, MA 02114 USA. EM smacdonald@partners.org NR 44 TC 87 Z9 88 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2008 VL 71 IS 4 BP 979 EP 986 DI 10.1016/j.ijrobp.2007.11.065 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 321IX UT WOS:000257299200003 PM 18325681 ER PT J AU Lyatskaya, Y James, S Killoran, JH Soto, R Mamon, HJ Chin, L Allen, AM AF Lyatskaya, Yulia James, Steven Killoran, Joseph H. Soto, Ricardo Mamon, Harvey J. Chin, Lee Allen, Aaron M. TI Infrared-guided patient setup for lung cancer patients SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology CY NOV 05-09, 2006 CL Philadelphia, PA SP Amer Soc Therapeut Radiol & Oncol DE lung cancer; radiotherapy; planning target volume; PTV; infrared markers ID INTENSITY-MODULATED RADIOTHERAPY; RADIATION-THERAPY; CONFORMAL RADIOTHERAPY; DOSE-ESCALATION; TARGET VOLUME; TUMOR MOTION; UP ERRORS; IMRT; UNCERTAINTIES; ACCURACY AB Purpose: To evaluate the utility of an infrared-guided patient setup (iGPS) system to reduce the uncertainties in the setup of lung cancer patients. Methods and Materials: A total of 15 patients were setup for lung irradiation using skin tattoos and lateral leveling marks. Daily electronic portal device images and iGPS marker locations were acquired and retrospectively reviewed. The iGPS-based shifts were compared with the daily electronic portal device image shifts using both the central axis iGPS marker and all five iGPS markers. For shift calculation using the five markers, rotational misalignment was included. The level of agreement between the iGPS and portal imaging to evaluate the setup was evaluated as the frequency of the shift difference in the range of 0-5 mm, 5-10 mm, and >10 mm. Results: Data were obtained for 450 treatment sessions for 15 patients. The difference in the isocenter shifts between the weekly vs. daily images was 0-5 min in 42%, 5-10 mm in 30%, and >10 mm in 10% of the images. The shifts seen using the iGPS data were 0-5 mm in 81%, 5-10 mm in 14%, and >10 mm in 5%. Using only the central axis iGPS marker, the difference between the iGPS and portal images was <5 mm in 77%, 5-10 nun in 16%, and >10 mm in 7% in the left-right direction and 73%, 18%, and 9% in the superoinferior direction, respectively. When all five iGPS markers were used, the disagreements between the iGPS and portal image shifts >10 mm were reduced from 7% to 2% in the left-right direction and 9% to 3% in the superoinferior direction. Larger reductions were also seen (e.g., a reduction from 50% to 0% in 1 patient). Conclusion: The daily iGPS-based shifts correlated well with the daily electronic portal device-based shifts. When patient movement has nonlinear rotational components, a combination of surface markers and portal images might be particularly beneficial to improve the setup for lung cancer patients. (C) 2008 Elsevier Inc. C1 [Lyatskaya, Yulia; James, Steven; Killoran, Joseph H.; Soto, Ricardo; Mamon, Harvey J.; Chin, Lee; Allen, Aaron M.] Brigham & Womens Hosp, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Allen, AM (reprint author), Dana Farber Canc Inst, 44 Binney St,Dana L2, Boston, MA 02115 USA. EM aallen@lroc.harvard.edu NR 26 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 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2008 VL 71 IS 4 BP 1124 EP 1133 DI 10.1016/j.ijrobp.2007.11.050 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 321IX UT WOS:000257299200022 PM 18249503 ER PT J AU Rietzel, E Liu, AK Chen, GTY Choi, NC AF Rietzel, Eike Liu, Arthur K. Chen, George T. Y. Choi, Noah C. TI Maximum-intensity volumes for fast contouring of lung tumors including respiratory motion in 4DCT planning SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology CY OCT 17-20, 2004 CL Atlanta, GA SP Amer Soc Therapeut Radiol & Oncol DE maximum-intensity volume; four-dimensional computed tomography; four-dimensional treatment planning; treatment planning; target volumes; organ motion ID 4-DIMENSIONAL COMPUTED-TOMOGRAPHY; CT SCANS; CORRELATED CT; RADIOTHERAPY; CANCER; DELINEATION; ARTIFACTS; MOVEMENT; LOCATION; IMPACT AB Purpose: To assess the accuracy of maximum-intensity volumes (MIV) for fast contouring of lung tumors including respiratory motion. Methods and Materials: Four-dimensional computed tomography (4DCT) data of 10 patients were acquired. Maximum-intensity volumes were constructed by assigning the maximum Hounsfield unit in all CT volumes per geometric voxel to a new, synthetic volume. Gross tumor volumes (GTVs) were contoured on all CT volumes, and their union was constructed. The GTV with all its respiratory motion was contoured on the MIV as well. Union GTVs and GTVs including motion were compared visually. Furthermore, planning target volumes (PTVs) were constructed for the union of GTVs and the GTV on MIV. These PTVs were compared by centroid position, volume, geometric extent, and surface distance. Results: Visual comparison of GTVs demonstrated failure of the MIV technique for 5 of 10 patients. For adequate GTV(MIV)S, differences between PTVs were <1.0 mm in centroid position, 5% in volume, 5 mm in geometric extent, and +/- 0.5 +/- 2.0 mm in surface distance. These values represent the uncertainties for successful MIV contouring. Conclusion: Maximum-intensity volumes are a good first estimate for target volume definition including respiratory motion. However, it seems mandatory to validate each individual MIV by overlaying it on a movie loop displaying the 4DCT data and editing it for possible inadequate coverage of GTVs on additional 4DCT motion states. (C) 2008 Elsevier Inc. C1 [Rietzel, Eike; Liu, Arthur K.; Chen, George T. Y.; Choi, Noah C.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. [Rietzel, Eike] Gesell Schwerionenforsch mbH, Biophys Abt, Darmstadt, Germany. RP Rietzel, E (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, 55 Fruit St, Boston, MA 02114 USA. EM eike@rietzel.net FU PHS HHS [NCI-P01-21239] NR 26 TC 23 Z9 30 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2008 VL 71 IS 4 BP 1245 EP 1252 DI 10.1016/j.ijrobp.2008.03.030 PG 8 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 321IX UT WOS:000257299200038 PM 18472367 ER PT J AU Daily, JP Wylie, BJ AF Daily, Johanna P. Wylie, Blair J. TI Iron deficiency during pregnancy: Blessing or curse? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID ANEMIA C1 [Daily, Johanna P.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Wylie, Blair J.] Massachusetts Gen Hosp, Div Maternal Fetal Med, Boston, MA USA. RP Daily, JP (reprint author), Harvard Univ, Sch Publ Hlth, 665 Huntington Ave,Bldg 1,Rm 103, Boston, MA 02115 USA. EM jdaily@partners.org NR 17 TC 2 Z9 2 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD JUL 15 PY 2008 VL 198 IS 2 BP 157 EP 158 DI 10.1086/589513 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 321QA UT WOS:000257320400001 PM 18500931 ER PT J AU Souayah, N Cros, D Stein, TD Chong, PST AF Souayah, Nizar Cros, Didler Stein, T. D. Chong, Peter Siao Tick TI Relapsing Guillain Barre Syndrome and nephrotic syndrome secondary to focal segmental glomerulosclerosis SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE Guillain Barrex syndrome; nephrotic syndrome; focal segmental glomerulosclerosis; relapse; IVIg ID INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY; MEMBRANOUS GLOMERULONEPHRITIS; ALBUMIN PERMEABILITY; PROTEIN EXCRETION; PLASMAPHERESIS; TRANSPLANTATION; POLYNEURITIS AB A 49-year-old man developed simultaneously a Guillain Barre Syndrome (GBS) and a nephrotic syndrome (NS). The patient relapsed twice, despite treatment with intravenous immunoglobulins (IVIg) after a full or partial recovery, and became resistant to IVIg. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS). He responded to plasmapheresis and corticosteroids with simultaneous recovery of his GBS and NS, suggesting a common pathogenesis of the two conditions. (C) 2008 Elsevier B.V. All rights reserved. C1 [Souayah, Nizar] Univ Med & Dent New Jersey, Dept Neurol & Neurosci, Newark, NJ 07103 USA. [Cros, Didler; Chong, Peter Siao Tick] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Stein, T. D.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Souayah, N (reprint author), 90 Bergen St,DOC 8128, Newark, NJ 07101 USA. EM souayani@umdnj.edu OI Stein, Thor/0000-0001-6954-4477 FU CSRD VA [I01 CX001038] NR 30 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD JUL 15 PY 2008 VL 270 IS 1-2 BP 184 EP 188 DI 10.1016/j.jns.2008.01.007 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 323ZE UT WOS:000257486500028 PM 18325535 ER PT J AU Taktak, S Weissleder, R Josephson, L AF Taktak, Sonia Weissleder, Ralph Josephson, Lee TI Electrode chemistry yields a nanoparticle-based NMR sensor for calcium SO LANGMUIR LA English DT Article ID IRON-OXIDE NANOPARTICLES; MAGNETIC-RELAXATION; IONOPHORES; NANOSENSORS; AGENTS; OPTODES; CARRIER; MR AB Magnetic nanoparticles (NPs) have been used to obtain NMR-based sensors for analytes ranging from small molecules to viruses by the conjugation of biomolecules (antibodies, proteins, oligonucleotides) to the surface of NPs. In the presence of an analyte, the NPs form clusters that alter the relaxation time of the surrounding water protons. Here, we show that an organic molecule that binds calcium ions of nombiological origin, rather than a biomolecule, can be employed to modify the surface of a magnetic NP. When calcium ions are added, they induce NP clustering, providing an NMR-based sensor for these ions. Our work suggests that the many chemistries of nonbiological origin, such as those employed for ion-selective electrodes, can be adapted to obtain NMR-based sensors for ions. C1 [Taktak, Sonia; Weissleder, Ralph; Josephson, Lee] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. [Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Josephson, L (reprint author), Massachusetts Gen Hosp, Ctr Mol Imaging Res, 149 l3th St, Charlestown, MA 02129 USA. EM josephso@helix.mgh.harvard.edu FU NIBIB NIH HHS [R01 EB004626-03, R01 EB004626, R01-EB004626] NR 22 TC 23 Z9 23 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD JUL 15 PY 2008 VL 24 IS 14 BP 7596 EP 7598 DI 10.1021/la8006298 PG 3 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 323SI UT WOS:000257468300077 PM 18558729 ER PT J AU Wedeen, VJ Wang, RP Schmahmann, JD Benner, T Tseng, WYI Dai, G Pandya, DN Hagmann, P D'Arceuil, H de Crespignya, AJ AF Wedeen, V. J. Wang, R. P. Schmahmann, J. D. Benner, T. Tseng, W. Y. I. Dai, G. Pandya, D. N. Hagmann, P. D'Arceuil, H. de Crespignya, A. J. TI Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers SO NEUROIMAGE LA English DT Article DE magnetic resonance imaging; diffusion spectrum imaging; diffusion tensor imaging; fiber crossing; neuroanatomy ID PERSISTENT ANGULAR STRUCTURE; HUMAN BRAIN CONNECTIVITY; MRI DATA; TRACKING; ARCHITECTURE; SIMULATIONS; ORIENTATION; PATHWAYS; INSIGHTS; STROKE AB MRI tractography is the mapping of neural fiber pathways based on diffusion MRI of tissue diffusion anisotropy. Tractography based on diffusion tensor imaging (DTI) cannot directly image multiple fiber orientations within a single voxel. To address this limitation, diffusion spectrum MRI (DSI) and related methods were developed to image complex distributions of intravoxel fiber orientation. Here we demonstrate that tractography based on DSI has the capacity to image crossing fibers in neural tissue. DSI was performed in formalin- fixed brains of adult macaque and in the brains of healthy human subjects. Fiber tract solutions were constructed by a streamline procedure, following directions of maximum diffusion at every point, and analyzed in an interactive visualization environment (TrackVis). We report that DSI tractography accurately shows the known anatomic fiber crossings in optic chiasm, centrum semiovale, and brainstem; fiber intersections in gray matter, including cerebellar folia and the caudate nucleus; and radial fiber architecture in cerebral cortex. In contrast, none of these examples of fiber crossing and complex structure was identified by DTI analysis of the same data sets. These findings indicate that DSI tractography is able to image crossing fibers in neural tissue, an essential step toward non-invasive imaging of connectional neuroanatomy. (c) 2008 Published by Elsevier Inc. C1 [Wedeen, V. J.; Wang, R. P.; Benner, T.; Dai, G.; D'Arceuil, H.; de Crespignya, A. J.] Harvard Univ, Sch Med, Dept Radiol, MGH Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Schmahmann, J. D.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Tseng, W. Y. I.] Natl Taiwan Univ, Coll Med, Ctr Optelect Biomed, Taipei 10764, Taiwan. [Pandya, D. N.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02215 USA. [Hagmann, P.] Univ Lausanne Hosp, CHUV, Dept Radiol, Lausanne, Switzerland. [Hagmann, P.] Ecole Polytech Fed Lausanne, Signal Proc Inst, CH-1015 Lausanne, Switzerland. RP Schmahmann, JD (reprint author), Massachusetts Gen Hosp, Dept Neurol, CPZS 340, 55 Fruit St, Boston, MA 02114 USA. EM van@nmr.mgh.harvard.edu; jschmahmann@partners.org OI Tseng, Wen-Yih Isaac/0000-0002-2314-6868 FU NCRR NIH HHS [1S10RR016811-01, P41RR14075]; NIBIB NIH HHS [1R01EB00790]; NIMH NIH HHS [1R01 MH 64044, 1R01 MH67980]; NINDS NIH HHS [1R01NS401285] NR 30 TC 388 Z9 398 U1 3 U2 65 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2008 VL 41 IS 4 BP 1267 EP 1277 DI 10.1016/j.neuroimage.2008.03.036 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 311SR UT WOS:000256620400010 PM 18495497 ER PT J AU Choi, W Yu, CC Fang-Yen, C Badizadegan, K Dasari, RR Feld, MS AF Choi, Wonshik Yu, Chung-Chieh Fang-Yen, Christopher Badizadegan, Kamran Dasari, Ramachandra R. Feld, Michael S. TI Field-based angle-resolved light-scattering study of single live cells SO OPTICS LETTERS LA English DT Article ID TOMOGRAPHIC PHASE MICROSCOPY; BIOLOGICAL CELLS; SPECTROSCOPY AB We perform field-based angle-resolved light-scattering measurements from single live cells. We use a laser interferometer to acquire phase and amplitude images of cells at the image plane. The angular scattering spectrum is calculated from the Fourier transform of the field transmitted through the cells. A concurrent 3D refractive index distribution of the same cells is measured using tomographic phase microscopy. By measuring transient increases in light scattering by single cells during exposure to acetic acid, we correlate the scattering properties of single cells with their refractive index distributions and show that results are in good agreement with a model based on the Born approximation. (C)2008 Optical Society of America. C1 [Choi, Wonshik; Yu, Chung-Chieh; Fang-Yen, Christopher; Badizadegan, Kamran; Dasari, Ramachandra R.; Feld, Michael S.] MIT, GR Harrison Spect Lab, Cambridge, MA 02139 USA. [Badizadegan, Kamran] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. [Badizadegan, Kamran] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Choi, W (reprint author), MIT, GR Harrison Spect Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM wonshik@mit.edu OI Fang-Yen, Christopher/0000-0002-4568-3218 FU NCRR NIH HHS [P41-RR02594-18, P41 RR002594, P41 RR002594-23] NR 12 TC 26 Z9 26 U1 0 U2 6 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD JUL 15 PY 2008 VL 33 IS 14 BP 1596 EP 1598 DI 10.1364/OL.33.001596 PG 3 WC Optics SC Optics GA 335SF UT WOS:000258309900016 PM 18628809 ER PT J AU Yuan, TL Choi, HS Matsui, A Benes, C Lifshits, E Luo, J Frangioni, JV Cantley, LC AF Yuan, Tina L. Choi, Hak Soo Matsui, Aya Benes, Cyril Lifshits, Eugene Luo, Ji Frangioni, John V. Cantley, Lewis C. TI Class 1A PI3K regulates vessel integrity during development and tumorigenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE angiogenesis; neovasculature; endothelium ID PHOSPHOINOSITIDE 3-KINASE; CATALYTIC SUBUNIT; DRUG DISCOVERY; LUNG-CANCER; ANGIOGENESIS; MUTATIONS; PIK3CA; PATHWAY; CELLS; INHIBITION AB PI3K is important in the regulation of growth, proliferation, and survival of tumor cells. We show that class 1A PI3K is also critical in the tumor microenvironment by regulating the integrity of the tumor vasculature. Using Tie2Cre-mediated deletion of the PI3K regulatory subunits (p85 alpha, p55 alpha, p50 alpha, and p85 beta), we generated mice with endothelial cell-specific loss of class 1A PI3K. Complete loss of all subunits caused acute embryonic lethality at E11.5 due to hemorrhaging, whereas retention of a single p85 alpha allele yielded viable mice that survived to adulthood. These heterozygous mice exhibited no vascular defects until challenged with a pathological insult, such as tumor cells or high levels of VEGF. Under these pathological conditions, heterozygous mice exhibited localized vascular abnormalities, including vessel leakage and the inability to maintain large vessels, which caused a deceleration of tumorigenesis. Furthermore, we show that a PI3K inhibitor can mimic the effects of class 1A PI3K loss, which suggests that targeting class 1A PI3K may be a promising therapy for blocking tumor angiogenesis. C1 [Yuan, Tina L.; Cantley, Lewis C.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. [Luo, Ji] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Yuan, Tina L.; Benes, Cyril; Cantley, Lewis C.] Beth Israel Deaconess Med Ctr, Dept Signal Transduct, Boston, MA 02115 USA. [Choi, Hak Soo; Matsui, Aya; Frangioni, John V.] Beth Israel Deaconess Med Ctr, Dept Hematol Oncol, Boston, MA 02115 USA. [Lifshits, Eugene] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Cantley, LC (reprint author), 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM lewis_cantley@hms.harvard.edu RI Choi, Hak Soo/C-9954-2011; Cantley, Lewis/D-1800-2014 OI Cantley, Lewis/0000-0002-1298-7653 FU NCI NIH HHS [1P50CA127003-01, P50 CA127003, R01 CA115296, R01-CA-115296]; NIGMS NIH HHS [R01 GM041890, R37 GM041890, R37GM41890] NR 37 TC 66 Z9 67 U1 0 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 JUL 15 PY 2008 VL 105 IS 28 BP 9739 EP 9744 DI 10.1073/pnas.0804123105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 328FV UT WOS:000257784700052 PM 18621722 ER PT J AU Hahn, CK Ross, KN Warrington, IM Mazitschek, R Kanegai, CM Wright, RD Kung, AL Golub, TR Stegmaier, K AF Hahn, Cynthia K. Ross, Kenneth N. Warrington, Ian M. Mazitschek, Ralph Kanegai, Cindy M. Wright, Renee D. Kung, Andrew L. Golub, Todd R. Stegmaier, Kimberly TI Expression-based screening identifies the combination of histone deacetylase inhibitors and retinoids for neuroblastoma differentiation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemical genomics; small molecule screening ID ACUTE PROMYELOCYTIC LEUKEMIA; HIGH-RISK NEUROBLASTOMA; NEURO-BLASTOMA CELLS; IN-VIVO; GROWTH-INHIBITION; ACID; TRANSPLANTATION; APOPTOSIS; VALPROATE; COMPLEX AB The discovery of new small molecules and their testing in rational combination poses an ongoing problem for rare diseases, in particular, for pediatric cancers such as neuroblastoma. Despite maximal cytotoxic therapy with double autologous stem cell transplantation, outcome remains poor for children with high-stage disease. Because differentiation is aberrant in this malignancy, compounds that modulate transcription, such as histone deacetylase (HDAC) inhibitors, are of particular interest. However, as single agents, HDAC inhibitors have had limited efficacy. In the present study, we use an HDAC inhibitor as an enhancer to screen a small-molecule library for compounds inducing neuroblastoma maturation. To quantify differentiation, we use an enabling gene expression-based screening strategy. The top hit identified in the screen was all-trans-retinoic acid. Secondary assays confirmed greater neuroblastoma differentiation with the combination of an HDAC inhibitor and a retinoid versus either alone. Furthermore, effects of combination therapy were synergistic with respect to inhibition of cellular viability and induction of apoptosis. In a xenograft model of neuroblastoma, animals treated with combination therapy had the longest survival. This work suggests that testing of an HDAC inhibitor and retinoid in combination is warranted for children with neuroblastoma and demonstrates the success of a signature-based screening approach to prioritize compound combinations for testing in rare diseases. C1 [Hahn, Cynthia K.; Warrington, Ian M.; Kanegai, Cindy M.; Wright, Renee D.; Kung, Andrew L.; Golub, Todd R.; Stegmaier, Kimberly] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hahn, Cynthia K.; Warrington, Ian M.; Kanegai, Cindy M.; Wright, Renee D.; Kung, Andrew L.; Golub, Todd R.; Stegmaier, Kimberly] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA. [Ross, Kenneth N.; Mazitschek, Ralph; Golub, Todd R.; Stegmaier, Kimberly] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Ross, Kenneth N.; Mazitschek, Ralph; Golub, Todd R.; Stegmaier, Kimberly] MIT, Cambridge, MA 02142 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Mazitschek, Ralph] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Stegmaier, K (reprint author), Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. EM Kimberly_stegmaier@dfci.harvard.edu RI Mazitschek, Ralph/E-3741-2013; OI Mazitschek, Ralph/0000-0002-1105-689X; Kung, Andrew/0000-0002-9091-488X NR 35 TC 51 Z9 53 U1 0 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 JUL 15 PY 2008 VL 105 IS 28 BP 9751 EP 9756 DI 10.1073/pnas.0710413105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 328FV UT WOS:000257784700054 PM 18607002 ER PT J AU Pinto, A Greenberg, BD Grados, MA Bienvenu, OJ Samuels, JF Murphy, DL Hasler, G Stout, RL Rauch, SL Shugart, YY Pauls, DL Knowles, JA Fyer, AJ McCracken, JT Piacentini, J Wang, Y Willour, VL Cullen, B Liang, KY Hoehn-Saric, R Riddle, MA Rasmussen, SA Nestadt, G AF Pinto, Anthony Greenberg, Benjamin D. Grados, Marco A. Bienvenu, O. Joseph Samuels, Jack F. Murphy, Dennis L. Hasler, Gregor Stout, Robert L. Rauch, Scott L. Shugart, Yin Y. Pauls, David L. Knowles, James A. Fyer, Abby J. McCracken, James T. Piacentini, John Wang, Ying Willour, Virginia L. Cullen, Bernadette Liang, Kung-Yee Hoehn-Saric, Rudolf Riddle, Mark A. Rasmussen, Steven A. Nestadt, Gerald TI Further development of YBOCS dimensions in the OCD Collaborative Genetics Study: Symptoms vs. categories SO PSYCHIATRY RESEARCH LA English DT Article DE obsessive compulsive disorder; symptoms; factors; familial; genetics ID OBSESSIVE-COMPULSIVE DISORDER; SEROTONIN REUPTAKE INHIBITORS; AFFECTED SIBLING PAIRS; LA-TOURETTE-SYNDROME; SCHIZOPHRENIA; SCALE; SUBTYPES; FAMILY; SAMPLE; FAMILIALITY AB Despite progress in identifying homogeneous subphenotypes of obsessive-compulsive disorder (OCD) through factor analysis of the Yale Brown Obsessive-Compulsive Scale Symptom Checklist (YBOCS-SC), prior solutions have been limited by a reliance on presupposed symptom categories rather than discrete symptoms. Furthermore, there have been few attempts to evaluate the familiality of OCD symptom dimensions. The purpose of this study was to extend prior work by this collaborative group in category-based dimensions by conducting the first-ever exploratory dichotomous factor analysis using individual OCD symptoms, comparing these results to a refined category-level solution, and testing the familiality of derived factors. Participants were 485 adults in the six-site OCD Collaborative Genetics Study, diagnosed with lifetime OCD using semi-structured interviews. YBOCS-SC data were factor analyzed at both the individual item and symptom category levels. Factor score intraclass correlations were calculated using a subsample of 145 independent affected sib pairs. The item- and category-level factor analyses yielded nearly identical 5-factor solutions. While significant sib-sib associations were found for four of the five factors, Hoarding and Taboo Thoughts were the most robustly familial (r(ICC) >= 0.2). This report presents considerable converging evidence for a five-factor structural model of OCD symptoms, including separate factor analyses employing individual symptoms and symptom categories, as well as sibling concordance. The results support investigation of this multidimensional model in OCD genetic linkage studies. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 [Pinto, Anthony; Greenberg, Benjamin D.; Rasmussen, Steven A.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Grados, Marco A.; Bienvenu, O. Joseph; Samuels, Jack F.; Shugart, Yin Y.; Wang, Ying; Willour, Virginia L.; Cullen, Bernadette; Liang, Kung-Yee; Hoehn-Saric, Rudolf; Riddle, Mark A.; Nestadt, Gerald] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Murphy, Dennis L.; Hasler, Gregor] NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Stout, Robert L.] Decis Sci Inst, Providence, RI USA. [Rauch, Scott L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Psychiat Neuroimaging Res Program, Charlestown, MA USA. [Rauch, Scott L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Obsess Compuls Disorders Program, Charlestown, MA USA. [Pauls, David L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Charlestown, MA USA. [McCracken, James T.] Univ So Calif, Keck Sch Med, Dept Psychiat, Los Angeles, CA 90033 USA. [Fyer, Abby J.] Columbia Univ, Dept Psychiat, Coll Phys & Surg, New York, NY USA. [Fyer, Abby J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [McCracken, James T.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Piacentini, John] Univ Calif Los Angeles, Sch Med, Div Child & Adolescent Psychiat, Los Angeles, CA USA. RP Pinto, A (reprint author), Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, 345 Blackstone Blvd, Providence, RI 02906 USA. EM Anthony_Pinto@brown.edu RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Hasler, Gregor/E-4845-2012; Pinto, Anthony/D-2718-2017; OI Hasler, Gregor/0000-0002-8311-0138; Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 FU NIMH NIH HHS [K23 MH064543, K23 MH064543-05, K23 MH066284, K23 MH066284-05, R01 MH050214, R01 MH050214-09, R01 MH50214] NR 55 TC 69 Z9 69 U1 1 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 JUL 15 PY 2008 VL 160 IS 1 BP 83 EP 93 DI 10.1016/j.psychres.2007.07.010 PG 11 WC Psychiatry SC Psychiatry GA 326GE UT WOS:000257645800011 PM 18514325 ER PT J AU Greenberg, DL Payne, ME MacFall, JR Steffens, DC Krishnan, RR AF Greenberg, Daniel L. Payne, Martha E. MacFall, James R. Steffens, David C. Krishnan, Ranga R. TI Hippocampal volumes and depression subtypes SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE depression; hippocampus; morphometry ID ALZHEIMERS-DISEASE CERAD; ATYPICAL DEPRESSION; BRAIN; DISORDER; METAANALYSIS; CONSORTIUM; ESTABLISH; REGISTRY; MRI AB Studies of depression and hippocampal volume have yielded inconsistent results. This inconsistency could stem from the heterogeneity of depressive disorders. We conducted cross-sectional and longitudinal analyses of hippocampal volumes in atypical depressive, melancholic depressive, and control subjects. We found no effect of depression subtype on hippocampal volume or memory performance. (c) 2007 Elsevier Ireland Ltd. All rights reserved. C1 [Greenberg, Daniel L.] VA Boston Healthcare Syst, Psychol Res, Boston, MA USA. [Payne, Martha E.; Steffens, David C.; Krishnan, Ranga R.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [MacFall, James R.] Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. [Payne, Martha E.; MacFall, James R.] Duke Univ, Med Ctr, Neuropsychiat Imaging Res Lab, Durham, NC USA. RP Greenberg, DL (reprint author), Psychol Res 151A, 150 S Huntington Ave, Boston, MA 02130 USA. EM dlg@bu.edu FU NIMH NIH HHS [K24-MH70027, K24 MH070027, K24 MH070027-05, P30 MH040159-149003, P30-MH40159, P50 MH060451, P50 MH060451-07, P50-MH60451, R01 MH054846, R01 MH054846-12, R01-MH54846] NR 25 TC 15 Z9 15 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD JUL 15 PY 2008 VL 163 IS 2 BP 126 EP 132 DI 10.1016/j.pscychresns.2007.12.009 PG 7 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 325HY UT WOS:000257581200004 PM 18508244 ER PT J AU Alanay, A Chen, CH Lee, S Murray, SS Brochmann, EJ Miyazaki, M Napoli, A Wang, JC AF Alanay, Ahmet Chen, ChiHui Lee, Sang Murray, Samuel S. Brochmann, Elsa J. Miyazaki, Masashi Napoli, Antonia Wang, Jeffrey C. TI The adjunctive effect of a binding peptide on bone morphogenetic protein enhanced bone healing in a rodent model of spinal fusion SO SPINE LA English DT Article DE rhBMP-2; bone morphogenetic binding peptide; spinal fusion; adjuvant ID ANTERIOR CERVICAL DISKECTOMY; LUMBAR FUSION; LIGAMENTUM-FLAVUM; INTERBODY FUSION; MARROW-CELLS; RHBMP-2; GRAFT; COMPLICATIONS; COMPRESSION; EFFICACY AB Study Design. A prospective 8-week interventional trial employing a rat model of spinal fusion to test the effect on bone morphogenetic protein binding peptide (BBP) on rhBMP-2 induced bone healing. Objectives. To determine if the addition of BBP to the collagen sponges used as a carrier for rhBMP-2 reduces the amount of rhBMP-2 required to achieve a satisfactory clinical outcome. Summary of Background Data. Bone morphogenetic proteins (BMPs) although effective in promoting osseous growth and spinal fusion have limitations in their extensive use because of higher costs and possible adverse effects including ectopic bone formation and local inflammatory reaction, particularly in the cervical spine. Methods. Posterolateral intertransverse process spinal fusion at L4-L5 was performed in Lewis rats. Two doses of BBP (500 mu g, and 1000 mu g) were tested with or without "low dose" (1 mu g) rhBMP-2 and the results were compared with the low dose (1 mu g) rhBMP-2. Fusion was evaluated by radiology, histology, and manual palpation tests. Results. Radiology revealed significant earlier fusion with 1000 mu g BBP + 1 mu g BMP-2 combination when compared with low dose BMP-2 (1 mu g) only (P < 0.05). Manual palpation and histology at eighth week revealed higher rate of fusion with the same combination with a nearly significant difference (P = 0.057). Conclusion. Specific growth factor binding agents, such as BBP, can be compounded into carriers used in fusion procedures to decrease the dosage of BMP and possibly decrease the side effects which are most likely dose-related. This may also decrease costs and improve clinical outcomes. C1 [Alanay, Ahmet] Hacettepe Univ, Fac Med, Dept Orthopaed & Traumatol, TR-06100 Ankara, Turkey. [Chen, ChiHui; Lee, Sang; Miyazaki, Masashi; Napoli, Antonia; Wang, Jeffrey C.] Univ Calif Los Angeles, Sch Med, Dept Orthopaed & Traumatol, Los Angeles, CA 90095 USA. [Murray, Samuel S.; Brochmann, Elsa J.] Ctr Geriatr Res Educ & Clin, Sepulveda, CA USA. [Murray, Samuel S.; Brochmann, Elsa J.] VA Greater Los Angeles Hlth Care System, Sepulveda, CA USA. [Murray, Samuel S.; Brochmann, Elsa J.] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. RP Wang, JC (reprint author), Univ Calif Los Angeles, Comprehens Spine Ctr, 1250 16th St,7th floor Tower 745, Los Angeles, CA 90095 USA. EM jwang@mednet.ucla.edu RI Alanay, Ahmet/D-7634-2015 FU NIAMS NIH HHS [5R21AR53259] NR 26 TC 29 Z9 30 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD JUL 15 PY 2008 VL 33 IS 16 BP 1709 EP 1713 DI 10.1097/BRS.0b013e31817e9dfd PG 5 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 327PF UT WOS:000257740300001 PM 18580546 ER PT J AU Smith, RN Kent, SC Nagle, J Selig, M Iafrate, AJ Najafian, N Hafler, DA Auchincloss, H Orban, T Cagliero, E AF Smith, R. Neal Kent, Sally C. Nagle, Julie Selig, Martin Iafrate, A. John Najafian, Nader Hafler, David A. Auchincloss, Hugh Orban, Tihamer Cagliero, Enrico TI Pathology of an islet transplant 2 years after transplantation: Evidence for a nonimmunological loss SO TRANSPLANTATION LA English DT Article DE islet; transplant; rejection; autoimmunity ID DEPENDENT DIABETES-MELLITUS; PANCREATIC BETA-CELL; LONG-TERM; ALLOGRAFT REJECTION; INSULIN-SECRETION; EDMONTON PROTOCOL; HLA ANTIBODIES; GRAFT; AUTOTRANSPLANTATION; HYPERGLYCEMIA AB Background. We report the immunological and pathological findings of a 52-year-old woman, who died two years after the second of two islet transplants performed using the Edmonton protocol. After each islet transplant, she gradually lost insulin independence while maintaining low levels of C-peptide secretion. Methods. A complete autopsy was performed including pathological and immunohistochemical analysis of hepatic allogeneic islets and native pancreatic islets to identify rejection or autoimmunity. Elispots assays for allogeneic sensitization and autoantibody assays for autoimmunity were performed antemortem after her islet transplantations to test in vitro for evidence of allogeneic sensitization or autoimmunity. Results. The cause of death was a hypertensive stroke. Small numbers of islets without inflammation were identified within portal venules and stained with insulin. The atrophic pancreas contained small numbers of islets, which stained for insulin, and lacked any inflammation within or adjacent to the islets. In vitro assays for alloantibodies were negative, and Elispots assays failed to identify allogeneic sensitization. In vitro assays for diabetic associated autoantibodies did not identify autoimmune resensitization. The allografted kidney showed only early changes of recurrent diabetic nephropathy, and no evidence of rejection. Conclusions. In summary, no evidence was found to support an immunological basis (either allo or autoimmunity) for the slow loss of intrahepatic islets, which may, therefore, be related to nonimmunological anatomic and physiological abnormalities of islets infused into the portal veins or to drug toxicity. C1 [Smith, R. Neal; Nagle, Julie; Selig, Martin; Iafrate, A. John] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kent, Sally C.; Hafler, David A.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Najafian, Nader] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Auchincloss, Hugh] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Orban, Tihamer] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Cagliero, Enrico] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Smith, RN (reprint author), Massachusetts Gen Hosp, Dept Pathol, 501D Warren Bldg,Fruit St, Boston, MA 02114 USA. EM rnsmith@partners.org NR 59 TC 20 Z9 22 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2008 VL 86 IS 1 BP 54 EP 62 DI 10.1097/TP.0b013e318173a5da PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 328IA UT WOS:000257790400011 PM 18622278 ER PT J AU Ross, JS Mulvey, GK Stauffer, B Patlolla, V Bernheim, SM Keenan, PS Krumholz, HM AF Ross, Joseph S. Mulvey, Gregory K. Stauffer, Brett Patlolla, Vishnu Bernheim, Susannah M. Keenan, Patricia S. Krumholz, Harlan M. TI Statistical models and patient predictors of readmission for heart failure - A systematic review SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 8th Scientific Forum of the American-Heart-Association on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke CY MAY 11, 2007 CL Washinton, DC SP Amer Heart Assoc ID BRAIN NATRIURETIC PEPTIDE; CARDIAC TROPONIN-T; VENTRICULAR EJECTION FRACTION; PRESERVED SYSTOLIC FUNCTION; QUALITY-OF-CARE; DISEASE MANAGEMENT PROGRAMS; OPTIMIZE-HF REGISTRY; ACID-BINDING PROTEIN; SHORT-TERM OUTCOMES; HOSPITAL READMISSION AB Background: Readmission after heart failure (HF) hospitalization is an increasing focus for physicians and policy makers, but statistical models are needed to assess patient risk and to compare hospital performance. We performed a systematic review to describe models designed to compare hospital rates of readmission or to predict patients' risk of readmission, as well as to identify studies evaluating patient characteristics associated with hospital readmission, all among patients admitted for HF. Methods: We identified relevant studies published between January 1, 1950, and November 19, 2007, by searching MEDLINE, Scopus, PsycINFO, and all 4 Ovid Evidence-Based Medicine Reviews. Eligible English-language publications reported on readmission after HF hospitalization among adult patients. We excluded experimental studies and publications without original data or quantitative outcomes. Results: From 941 potentially relevant articles, 117 met inclusion criteria: none contained models to compare readmission rates among hospitals, 5 (4.3%) presented models to predict patients' risk of readmission, and 112 (95.7%) examined patient characteristics associated with readmission. Studies varied in case identification, used multiple types of data sources, found few patient characteristics consistently associated with readmission, and examined differing outcomes, often either readmission alone or a combined outcome of readmission or death, measured across varying periods (from 14 days to 4 years). Two articles reported model discriminations of patient readmission risk, both of which were modest (C statistic, 0.60 for both). Conclusions: Our systematic review identified no model designed to compare hospital rates of readmission, while models designed to predict patients' readmission risk used heterogeneous approaches and found substantial inconsistencies regarding which patient characteristics were predictive. Clinically, patient risk stratification is challenging. From a policy perspective, a validated risk-standardized statistical model to accurately profile hospitals using readmission rates is unavailable in the published English-language literature to date. C1 [Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr & Adult Dev, New York, NY 10027 USA. [Ross, Joseph S.] Mt Sinai Sch Med, Dept Med, New York, NY 10027 USA. [Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Hlth Serv Res & Dev Targeted Res Enhancement Prog, Bronx, NY USA. [Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. [Mulvey, Gregory K.; Stauffer, Brett; Krumholz, Harlan M.] Yale Univ, Sch Med, Robert Wood Johnson Clin Scholars Program, New Haven, CT 06520 USA. [Mulvey, Gregory K.; Stauffer, Brett; Krumholz, Harlan M.] Yale Univ, Sch Med, Dept Med, New Haven, CT 06520 USA. [Patlolla, Vishnu; Krumholz, Harlan M.] Yale Univ, Sch Med, Sect Cardiovasc Med, Dept Med, New Haven, CT 06520 USA. [Bernheim, Susannah M.] Yale Univ, Sch Med, Sect Geriatr, Dept Med, New Haven, CT 06520 USA. [Keenan, Patricia S.; Krumholz, Harlan M.] Yale Univ, Sch Med, Sect Hlth Policy & Adm, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Krumholz, Harlan M.] Yale New Haven Med Ctr, Ctr Outcomes Res & Evaluat, New Haven, CT 06504 USA. RP Ross, JS (reprint author), Mt Sinai Sch Med, Dept Geriatr & Adult Dev, 1 Gustave L Levy Pl,Box 1070, New York, NY 10027 USA. EM joseph.ross@mssm.edu FU NIA NIH HHS [T32AG1934] NR 141 TC 161 Z9 162 U1 2 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUL 14 PY 2008 VL 168 IS 13 BP 1371 EP 1386 DI 10.1001/archinte.168.13.1371 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 325NH UT WOS:000257595100003 PM 18625917 ER PT J AU Zhou, XH Li, CM Yang, Z AF Zhou, X. H. Li, C. M. Yang, Z. TI Improving interval estimation of binomial proportions SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY A-MATHEMATICAL PHYSICAL AND ENGINEERING SCIENCES LA English DT Article DE binomial; diagnostic accuracy; skewness; confidence interval; Edgeworth expansion ID CONFIDENCE-INTERVALS AB In this paper, we propose one new confidence interval for the binomial proportion; our interval is based on the Edgeworth expansion of a logit transformation of the sample proportion. We provide theoretical justification for the proposed interval and also compare the finite-sample performance of the proposed interval with the three best existing intervals the Wilson interval, the Agresti Coull interval and the Jeffreys interval in terms of their coverage probabilities and expected lengths. We illustrate the proposed method in two real clinical studies. C1 [Zhou, X. H.] VA Puget Sound Hlth Care Syst, Seattle, WA 98101 USA. [Zhou, X. H.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Li, C. M.] Pfizer Inc, New York, NY 10017 USA. [Yang, Z.] Shandong Univ, Jinan 250100, Shandong, Peoples R China. RP Zhou, XH (reprint author), VA Puget Sound Hlth Care Syst, Met Pk W,1100 Olive Way,Suite 1400, Seattle, WA 98101 USA. EM azhou@u.washington.edu NR 21 TC 13 Z9 14 U1 0 U2 2 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1364-503X J9 PHILOS T R SOC A JI Philos. Trans. R. Soc. A-Math. Phys. Eng. Sci. PD JUL 13 PY 2008 VL 366 IS 1874 BP 2405 EP 2418 DI 10.1098/rsta.2008.0037 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 303US UT WOS:000256067000013 PM 18407898 ER PT J AU Weiser, TG Regenbogen, SE Thompson, KD Haynes, AB Lipsitz, SR Berry, WR Gawande, AA AF Weiser, Thomas G. Regenbogen, Scott E. Thompson, Katherine D. Haynes, Alex B. Lipsitz, Stuart R. Berry, William R. Gawande, Atul A. TI An estimation of the global volume of surgery: a modelling strategy based on available data SO LANCET LA English DT Article ID ADVERSE EVENTS; MORTALITY; EPIDEMIOLOGY; DISEASE; BURDEN AB Background Little is known about the amount and availability of surgical care globally. We estimated the number of major operations undertaken worldwide, described their distribution, and assessed the importance of surgical care in global public-health policy. Methods We gathered demographic, health, and economic data for 192 member states of WHO. Data for the rate of surgery were sought from several sources including governmental agencies, statistical and epidemiological organisations, published studies, and individuals involved in surgical policy initiatives. We also obtained per-head total expenditure on health from analyses done in 2004. Major surgery was defined as any intervention occurring in a hospital operating theatre involving the incision, excision, manipulation, or suturing of tissue, usually requiring regional or general anaesthesia or sedation. We created a model to estimate rates of major surgery for countries for which such data were unavailable, then used demographic information to calculate the total worldwide volume of surgery. Findings We obtained surgical data for 56 (29%) of 192 WHO member states. We estimated that 234.2 (95% Cl 187.2-281.2) million major surgical procedures are undertaken every year worldwide. Countries spending US$100 or less per head on health care have an estimated mean rate of major surgery of 295 (SE 53) procedures per 100 000 population per year, whereas those spending more than $1000 have a mean rate of 11110 (SE 1300; p<0 . 0001). Middle-expenditure ($401-1000) and high-expenditure (>$1000) countries, accounting for 30.2% of the world's population, provided 73.6% (172.3 million) of operations worldwide in 2004, whereas poor-expenditure (<=$100) countries account for 34.8% of the global population yet undertook only 3.5% (8 . 1 million) of all surgical procedures in 2004. Interpretation Worldwide volume of surgery is large. In view of the high death and complication rates of major surgical procedures, surgical safety should now be a substantial global public-health concern. The disproportionate scarcity of surgical access in low-income settings suggests a large unaddressed disease burden worldwide. Public-health efforts and surveillance in surgery should be established. C1 [Weiser, Thomas G.; Regenbogen, Scott E.; Thompson, Katherine D.; Haynes, Alex B.; Berry, William R.; Gawande, Atul A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Weiser, Thomas G.] Univ Calif Davis, Dept Surg, Sacramento, CA 95817 USA. [Regenbogen, Scott E.; Haynes, Alex B.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Lipsitz, Stuart R.; Gawande, Atul A.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. RP Weiser, TG (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. EM tweiser@hsph.harvard.edu NR 22 TC 793 Z9 813 U1 7 U2 37 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD JUL 12 PY 2008 VL 372 IS 9633 BP 139 EP 144 DI 10.1016/S0140-6736(08)60878-8 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 324XJ UT WOS:000257552400028 PM 18582931 ER PT J AU Brumme, ZL Tao, I Szeto, S Brumme, CJ Carlson, JA Chan, D Kadie, C Frahm, N Brander, C Walker, B Heckerman, D Harrigan, PR AF Brumme, Zabrina L. Tao, Iris Szeto, Sharon Brumme, Chanson J. Carlson, Jonathan A. Chan, Dennison Kadie, Carl Frahm, Nicole Brander, Christian Walker, Bruce Heckerman, David Harrigan, P. Richard TI Human leukocyte antigen-specific polymorphisms in HIV-1 Gag and their association with viral load in chronic untreated infection SO AIDS LA English DT Article DE cytotoxic T-lymphocyte escape; HIV-1; human leukocyte antigen class I; plasma viral load; viral evolution ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RESPONSES; LYMPHOCYTE ESCAPE MUTATION; TYPE-1 INFECTION; VACCINE DESIGN; DISEASE PROGRESSION; IMMUNE-RESPONSES; P24 GAG; HLA; SELECTION AB Objective: Selection of specific human leukocyte antigen (HLA)-restricted cytotoxic T-lymphocyte (CTL) escape mutations in key Gag epitopes has been associated with loss of HIV immune control on an individual basis. Here we undertake a population-based identification of HLA-associated polymorphisms in Gag and investigate their relationship with plasma viral load. Design: Cross-sectional analysis of 567 chronically HIV subtype B-infected, treatment-naive individuals. Methods: HLA class I-associated Gag substitutions were identified using phylogenetically corrected analysis methods featuring a multivariate adjustment for HLA linkage disequilibrium and a q-value correction for multiple tests. Presence of HLA-associated substitutions and markers of HIV disease status were correlated using Spearman's rank test. Results: We have created a gene-wide map of HLA class I-associated substitutions in HIV-1 subtype B Gag. This features 111 HLA-associated substitutions occurring at 51 of 500 Gag codons, more than 50% of which occur within published and/or putative HLA-restricted CTL epitopes. A modest inverse correlation was observed between the total number of HLA-associated Gag polymorphic sites within each individual and plasma viral load in chronic untreated infection (R=-0.17, P < 0.0001), supporting the hypothesis that a broad ability to target Gag in vivo contributes to viral control. A modest positive correlation was observed between the proportion of these sites exhibiting HLA-associated substitutions and plasma viral load (R=0.09, P=0.03), consistent with a loss of viremia control with the accumulation of CTL escape mutations. Conclusion: Results contribute to our understanding of immune-driven viral adaptation and suggest that the accumulation of CTL escape mutations in Gag results in clinically detectable consequences at the population level. These data have implications for HIV vaccines. (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Brumme, Zabrina L.; Brumme, Chanson J.; Frahm, Nicole; Brander, Christian; Walker, Bruce] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. [Tao, Iris; Szeto, Sharon; Chan, Dennison; Harrigan, P. Richard] BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. [Carlson, Jonathan A.; Kadie, Carl; Heckerman, David] Microsoft Res, Redmond, WA USA. [Carlson, Jonathan A.] Univ Washington, Dept Comp Sci, Seattle, WA 98195 USA. [Walker, Bruce] Howard Hughes Med Inst, Chevy Chase, MD USA. [Harrigan, P. Richard] Univ British Columbia, Div AIDS, Vancouver, BC V5Z 1M9, Canada. RP Brumme, ZL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr, 149 13th St, Charlestown, MA 02129 USA. FU PHS HHS [N01-AL-15422] NR 61 TC 51 Z9 52 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 11 PY 2008 VL 22 IS 11 BP 1277 EP 1286 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 326WM UT WOS:000257689800004 PM 18580606 ER PT J AU Prendergast, A Mphatswe, W Tudor-Williams, G Rakgotho, M Pillay, V Thobakgale, C McCarthy, N Morris, L Walker, BD Goulder, P AF Prendergast, Andrew Mphatswe, Wendy Tudor-Williams, Gareth Rakgotho, Mpho Pillay, Visva Thobakgale, Christina McCarthy, Noel Morris, Lynn Walker, Bruce D. Goulder, Philip TI Early virological suppression with three-class antiretroviral therapy in HIV-infected African infants SO AIDS LA English DT Article DE antiretroviral therapy; HIV; infant; paediatric ID SINGLE-DOSE NEVIRAPINE; IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1-INFECTED CHILDREN; EARLY MORTALITY; RESISTANCE; OUTCOMES; TRANSMISSION; PERSPECTIVES; PROPHYLAXIS; INTRAPARTUM AB Objectives: Infants infected with HIV-1 perinatally despite single-dose nevirapine progress rapidly. Data on treatment outcome in sub-Saharan African infants exposed to single-dose nevirapine are urgently required. This feasibility study addresses efficacy of infant antiretroviral therapy in this setting. Methods: HIV-infected infants in Durban, South Africa, received randomized immediate or deferred (when CD4 cell count reached < 20%) four-drug antiretroviral therapy (zidovudine/lamivudine/nelfinavir/nevirapine). Genotyping for non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance was undertaken pre-antiretroviral therapy. Monthly follow-up to 1-year post-antiretroviral therapy included viral load, CD4 cell count and verbal/measured adherence monitoring. Results: All 63 infants were exposed to single-dose nevirapine. Twenty-one out of 51 (39%) infants with baseline genotyping results had NNRTI resistance (most frequently Y181C; 20%). Forty-three infants were randomized to immediate antiretroviral therapy (ART): three withdrew pre-antiretroviral therapy; 36 out of 40 completed 1-year of ART. Twenty infants received deferred ART: 17 reached CD4 cell counts less than 20% (median d99) and 13 out of 17 started antiretroviral therapy in year 1. Verbal and measured adherence was 99% and 95%, respectively. One-year post-ART, 49 out of 49 (100%) infants had a viral load less than 400 copies/ml; 46 out of 49 (94%) had viral load less than 50 copies/ml. Ten infants (20%) required second-line ART due to virological failure or tuberculosis treatment, therefore 39 out of 49 (80%) achieved viral load less than 400 copies/ml by intention-to-treat. Time to viral load less than 50 copies/ml correlated with maternal CD4 cell count (r = -0.42; P = 0.005) and infant pre-ART viral load (r=0.64; P < 0.001). NNRTI mutations had no significant effect on virological suppression. Infants starting immediate compared with deferred ART had fewer illness episodes (P=0.003), but no significant difference in virological suppression. Conclusion: Excellent adherence and virological suppression are achievable in infants, despite high-frequency NNRTI mutations and rapid disease progression. Infants remain relatively neglected in roll-out programmes and ART provision must be expanded. (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Prendergast, Andrew; McCarthy, Noel; Goulder, Philip] Univ Oxford, Dept Paediat, Oxford, England. [Mphatswe, Wendy; Thobakgale, Christina; Walker, Bruce D.; Goulder, Philip] Univ KwaZulu Natal, Doris Duke Med Res Inst, Durban, South Africa. [Tudor-Williams, Gareth] Univ London Imperial Coll Sci Technol & Med, Dept Paediat, London, England. [Rakgotho, Mpho; Pillay, Visva; Morris, Lynn] Natl Inst Communicable Dis, Johannesburg, South Africa. [Walker, Bruce D.; Goulder, Philip] Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA USA. [Walker, Bruce D.] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Prendergast, A (reprint author), Peter Medawar Bldg Pathogen Res,S Parks Rd, Oxford OX1 3SY, England. EM andy.prendergast@gmail.com RI McCarthy, Noel/K-3314-2012; OI , Lynn/0000-0003-3961-7828 FU Medical Research Council [G0500384]; NIAID NIH HHS [2R01-AI-46995, R37 AI067073]; PHS HHS [U62/CCU022901-1]; Wellcome Trust NR 43 TC 43 Z9 43 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 11 PY 2008 VL 22 IS 11 BP 1333 EP 1343 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 326WM UT WOS:000257689800011 PM 18580613 ER PT J AU Cerletti, M Jurga, S Witczak, CA Hirshman, MF Shadrach, JL Goodyear, LJ Wagers, AJ AF Cerletti, Massimiliano Jurga, Sara Witczak, Carol A. Hirshman, Michael F. Shadrach, Jennifer L. Goodyear, Laurie J. Wagers, Amy J. TI Highly efficient, functional engraftment of skeletal muscle stem cells in dystrophic muscles SO CELL LA English DT Article ID DUCHENNE MUSCULAR-DYSTROPHY; MYOGENIC PROGENITOR CELLS; SATELLITE CELLS; HEMATOPOIETIC STEM; POSTNATAL MYOGENESIS; GENE-EXPRESSION; SELF-RENEWAL; MOUSE MUSCLE; MDX MICE; IN-VIVO AB Satellite cells reside beneath the basal lamina of skeletal muscle fibers and include cells that act as precursors for muscle growth and repair. Although they share a common anatomical localization and typically are considered a homogeneous population, satellite cells actually exhibit substantial heterogeneity. We used cell-surface marker expression to purify from the satellite cell pool a distinct population of skeletal muscle precursors (SMPs) that function as muscle stem cells. When engrafted into muscle of dystrophin-deficient mdx mice, purified SMPs contributed to up to 94% of myofibers, restoring dystrophin expression and significantly improving muscle histology and contractile function. Transplanted SMPs also entered the satellite cell compartment, renewing the endogenous stem cell pool and participating in subsequent rounds of injury repair. Together, these studies indicate the presence in adult skeletal muscle of prospectively isolatable muscle-forming stem cells and directly demonstrate the efficacy of myogenic stem cell transplant for treating muscle degenerative disease. C1 [Cerletti, Massimiliano; Jurga, Sara; Shadrach, Jennifer L.; Wagers, Amy J.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, Boston, MA 02115 USA. [Witczak, Carol A.; Hirshman, Michael F.; Goodyear, Laurie J.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Metab Sect, Boston, MA 02115 USA. [Cerletti, Massimiliano; Jurga, Sara; Shadrach, Jennifer L.; Wagers, Amy J.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Cerletti, Massimiliano; Jurga, Sara; Shadrach, Jennifer L.; Wagers, Amy J.] Harvard Univ, Stem Cell Inst, Cambridge, MA 02138 USA. RP Wagers, AJ (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Dev & Stem Cell Biol, 1 Joslin Pl, Boston, MA 02115 USA. EM amy.wagers@joslin.harvard.edu FU NIAMS NIH HHS [F32 AR051663, F32AR051663]; NIDDK NIH HHS [R01 DK068626, R01DK068626] NR 48 TC 234 Z9 237 U1 2 U2 34 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 11 PY 2008 VL 134 IS 1 BP 37 EP 47 DI 10.1016/j.cell.2008.05.049 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 324IU UT WOS:000257513100012 PM 18614009 ER PT J AU Pagliarini, DJ Calvo, SE Chang, B Sheth, SA Vafai, SB Ong, SE Walford, GA Sugiana, C Boneh, A Chen, WK Hill, DE Vidal, M Evans, JG Thorburn, DR Carr, SA Mootha, VK AF Pagliarini, David J. Calvo, Sarah E. Chang, Betty Sheth, Sunil A. Vafai, Scott B. Ong, Shao-En Walford, Geoffrey A. Sugiana, Canny Boneh, Avihu Chen, William K. Hill, David E. Vidal, Marc Evans, James G. Thorburn, David R. Carr, Steven A. Mootha, Vamsi K. TI A mitochondrial protein compendium elucidates complex I disease biology SO CELL LA English DT Article ID SUBCELLULAR-LOCALIZATION; GENOME; MOUSE; YEAST; SEQUENCE; DYSFUNCTION; EXPRESSION; EVOLUTION; SUBUNITS; MUSCLE AB Mitochondria are complex organelles whose dysfunction underlies a broad spectrum of human diseases. Identifying all of the proteins resident in this organelle and understanding how they integrate into pathways represent major challenges in cell biology. Toward this goal, we performed mass spectrometry, GFP tagging, and machine learning to create a mitochondrial compendium of 1098 genes and their protein expression across 14 mouse tissues. We link poorly characterized proteins in this inventory to known mitochondrial pathways by virtue of shared evolutionary history. Using this approach, we predict 19 proteins to be important for the function of complex I (CI) of the electron transport chain. Wevalidate a subset of these predictions using RNAi, including C8orf38, which we further show harbors an inherited mutation in a lethal, infantile CI deficiency. Our results have important implications for understanding CI function and pathogenesis and, more generally, illustrate how our compendium can serve as a foundation for systematic investigations of mitochondria. C1 [Pagliarini, David J.; Calvo, Sarah E.; Chang, Betty; Sheth, Sunil A.; Ong, Shao-En; Carr, Steven A.; Mootha, Vamsi K.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Pagliarini, David J.; Calvo, Sarah E.; Chang, Betty; Sheth, Sunil A.; Ong, Shao-En; Carr, Steven A.; Mootha, Vamsi K.] Harvard Univ, Cambridge, MA 02142 USA. [Pagliarini, David J.; Calvo, Sarah E.; Sheth, Sunil A.; Vafai, Scott B.; Walford, Geoffrey A.; Chen, William K.; Mootha, Vamsi K.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Pagliarini, David J.; Calvo, Sarah E.; Sheth, Sunil A.; Vafai, Scott B.; Walford, Geoffrey A.; Chen, William K.; Mootha, Vamsi K.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02446 USA. [Calvo, Sarah E.; Sheth, Sunil A.] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Sugiana, Canny; Boneh, Avihu; Thorburn, David R.] Univ Melbourne, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia. [Sugiana, Canny; Boneh, Avihu; Thorburn, David R.] Univ Melbourne, Dept Paediat, Parkville, Vic 3052, Australia. [Boneh, Avihu; Thorburn, David R.] Royal Childrens Hosp, Genet Hlth Serv Victoria, Parkville, Vic 3052, Australia. [Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA. [Hill, David E.; Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Evans, James G.] Whitehead MIT Bioimaging Ctr, Cambridge, MA 02139 USA. RP Carr, SA (reprint author), MIT, Broad Inst, Cambridge, MA 02142 USA. EM scarr@broad.mit.edu; vamsi@hms.harvard.edu RI Hill, David/B-6617-2011; Thorburn, David/G-6266-2013; OI thorburn, david/0000-0002-7725-9470; Pagliarini, Dave/0000-0002-0001-0087 FU Howard Hughes Medical Institute; NIDDK NIH HHS [DK43351, DK57521, P30 DK043351, P30 DK057521]; NIGMS NIH HHS [GM077465, R01 GM077465, R01 GM077465-04] NR 43 TC 886 Z9 907 U1 8 U2 85 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD JUL 11 PY 2008 VL 134 IS 1 BP 112 EP 123 DI 10.1016/j.cell.2008.06.016 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 324IU UT WOS:000257513100018 PM 18614015 ER PT J AU Ono, N Nakashima, K Rittling, SR Schipani, E Hayata, T Soma, K Denhardt, DT Kronenberg, HM Ezura, Y Noda, M AF Ono, Noriaki Nakashima, Kazuhisa Rittling, Susan R. Schipani, Ernestina Hayata, Tadayoshi Soma, Kunimichi Denhardt, David T. Kronenberg, Henry M. Ezura, Yoichi Noda, Masaki TI Osteopontin negatively regulates parathyroid hormone receptor signaling in osteoblasts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STEM-CELL NICHE; SYMPATHETIC-NERVOUS-SYSTEM; BONE-MINERAL DENSITY; OSTEOPOROSIS; COMPONENT; RESORPTION; TERIPARATIDE; ENHANCEMENT; COMBINATION; SUPPRESSION AB Systemic hormonal control exerts its effect through the regulation of local target tissues, which in turn regulate upstream signals in a feedback loop. The parathyroid hormone (PTH) axis is a well defined hormonal signaling system that regulates calcium levels and bone metabolism. To understand the interplay between systemic and local signaling in bone, we examined the effects of deficiency of the bone matrix protein osteopontin (OPN) on the systemic effects of PTH specifically within osteoblastic cell lineages. Parathyroid hormone receptor (PPR) transgenic mice expressing a constitutively active form of the receptor (caPPR) specifically in cells of the osteoblast lineage have a high bone mass phenotype. In these mice, OPN deficiency further increased bone mass. This increase was associated with conversion of the major intertrabecular cell population from hematopoietic cells to stromal/osteoblastic cells and parallel elevations in histomorphometric and biochemical parameters of bone formation and resorption. Treatment with small interfering RNA (siRNA) for osteopontin enhanced H223R mutant caPPR-induced cAMP-response element (CRE) activity levels by about 10-fold. Thus, in addition to the well known calcemic feedback system for PTH, local feedback regulation by the bone matrix protein OPN also plays a significant role in the regulation of PTH actions. C1 [Ono, Noriaki; Nakashima, Kazuhisa; Noda, Masaki] 21st Century Ctr Excellence Program Frontier Res, Chiyoda Ku, Tokyo 1010062, Japan. [Ono, Noriaki; Nakashima, Kazuhisa; Hayata, Tadayoshi; Ezura, Yoichi; Noda, Masaki] Tokyo Med & Dent Univ, Med Res Inst, Dept Mol Pharmacol, Chiyoda Ku, Tokyo 1010062, Japan. [Ono, Noriaki; Soma, Kunimichi] Tokyo Med & Dent Univ, Grad Sch, Bunkyo Ku, Tokyo 1138510, Japan. [Rittling, Susan R.] Forsyth Inst, Boston, MA 02115 USA. [Schipani, Ernestina; Kronenberg, Henry M.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Schipani, Ernestina; Kronenberg, Henry M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Denhardt, David T.] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08701 USA. [Noda, Masaki] Tokyo Med & Dent Univ, Adv Bone & Joint Sci ABJS Integrated Act Initiat, Tokyo 1010062, Japan. [Noda, Masaki] Tokyo Med & Dent Univ, Hard Tissue Genome Res Ctr, Tokyo 1010062, Japan. RP Noda, M (reprint author), Tokyo Med & Dent Univ, Med Res Inst, Dept Mol Pharmacol, Chiyoda Ku, 2-3-10 Kanda Surugadai, Tokyo 1010062, Japan. EM noda.mph@mri.tmd.ac.jp RI Ezura, Yoichi/L-9485-2016 FU NIDCR NIH HHS [K99 DE022564] NR 37 TC 20 Z9 21 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2008 VL 283 IS 28 BP 19400 EP 19409 DI 10.1074/jbc.M800005200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 322PK UT WOS:000257387600026 PM 18417476 ER PT J AU Rajala, A Tanito, M Le, YZ Kahn, CR Rajala, RVS AF Rajala, Ammaji Tanito, Masaki Le, Yun Z. Kahn, C. Ronald Rajala, Raju V. S. TI Loss of neuroprotective survival signal in mice lacking insulin receptor gene in rod photoreceptor cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETINAL LIGHT DAMAGE; PROTEIN-KINASE B; PHOSPHOINOSITIDE 3-KINASE; IN-VIVO; GLUCOSE-TOLERANCE; ADIPOSE-TISSUE; BETA-SUBUNIT; PHOSPHORYLATION; KNOCKOUT; DEATH AB Insulin receptor (IR) signaling provides a trophic signal for transformed retinal neurons in culture, but the role of IR activity in vivo is unknown. We previously reported that light causes increased tyrosine phosphorylation of the IR in vivo, which leads to the downstream activation of the phosphoinositide 3-kinase and Akt pathway in rod photoreceptor cells. The functional role of IR in rod photoreceptor cells is not known. We observed that light stress induced tyrosine phosphorylation of the IR in rod photoreceptor cells, and we hypothesized that IR activation is neuroprotective. To determine whether IR has a neuroprotective role on rod photoreceptor cells, we used the Cre/ lox system to specifically inactivate the IR gene in rod photoreceptors. Rod-specific IR knock-out mice have reduced the phosphoinositide 3-kinase and Akt survival signal in rod photoreceptors. The resultant mice exhibited no detectable phenotype when they were raised in dim cyclic light. However, reduced IR expression in rod photoreceptors significantly decreased retinal function and caused the loss of photoreceptors in mice exposed to bright light stress. These results indicate that reduced expression of IR in rod photoreceptor cells increases their susceptibility to light-induced photoreceptor degeneration. These data suggest that the IR pathway is important for photoreceptor survival and that activation of the IR may be an essential element of photoreceptor neuroprotection. C1 [Rajala, Ammaji; Tanito, Masaki; Rajala, Raju V. S.] Univ Oklahoma, Hlth Sci Ctr, Dept Ophthalmol, Oklahoma City, OK 73104 USA. [Le, Yun Z.; Rajala, Raju V. S.] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK 73104 USA. [Rajala, Ammaji; Tanito, Masaki; Rajala, Raju V. S.] Univ Oklahoma, Hlth Sci Ctr, Dean A McGee Eye Inst, Oklahoma City, OK 73104 USA. [Tanito, Masaki] Shimane Univ, Fac Med, Dept Ophthalmol, Izumo, Shimane 6938501, Japan. [Le, Yun Z.] Univ Oklahoma, Hlth Sci Ctr, Dept Med & Endocrinol, Oklahoma City, OK 73104 USA. [Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. [Kahn, C. Ronald] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Rajala, RVS (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Ophthalmol, 608 Stanton L Young Blvd, Oklahoma City, OK 73104 USA. EM raju-rajala@ouhsc.edu FU NCRR NIH HHS [P20-RR17703]; NEI NIH HHS [EY00871, EY016507] NR 58 TC 51 Z9 51 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 11 PY 2008 VL 283 IS 28 BP 19781 EP 19792 DI 10.1074/jbc.M802374200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 322PK UT WOS:000257387600062 PM 18480052 ER PT J AU Chowdhury, D Xu, XZ Zhong, XY Ahmed, F Zhong, JN Liao, J Dykxhoorn, DM Weinstock, DM Pfeifer, GP Lieberman, J AF Chowdhury, Dipanjan Xu, Xingzhi Zhong, Xueyan Ahmed, Fariyal Zhong, Jianing Liao, Ji Dykxhoorn, Derek M. Weinstock, David M. Pfeifer, Gerd P. Lieberman, Judy TI A PP4-phosphatase complex dephosphorylates gamma-H2AX generated during DNA replication SO MOLECULAR CELL LA English DT Article ID PROTEIN PHOSPHATASE 2A; HISTONE H2AX PHOSPHORYLATION; DOUBLE-STRAND BREAKS; DAMAGE CHECKPOINT; RADIOSENSITIZING AGENT; SIGNALING PATHWAYS; REGULATORY SUBUNIT; MAMMALIAN-CELLS; S-PHASE; ACTIVATION AB The histone H2A variant H2AX is rapidly phosphorylated in response to DNA double-stranded breaks to produce gamma-H2AX. gamma-H2AX stabilizes cell-cycle check-point proteins and DNA repair factors at the break site. We previously found that the protein phosphatase PP2A is required to resolve gamma-H2AX foci and complete DNA repair after exogenous DNA damage. Here we describe a three-protein PP4 phosphatase complex in mammalian cells, containing PP4C, PP4R2, and PP4R3 beta, that specifically dephosphorylates ATR-mediated gamma-H2AX generated during DNA replication. PP4 efficiently dephosphorylates gamma-H2AX within mononucleosomes in vitro and does not directly alter ATR or checkpoint kinase activity, suggesting that PP4 acts directly on gamma-H2AX in cells. When the PP4 complex is silenced, repair of DNA replication-mediated breaks is inefficient, and cells are hypersensitive to DNA replication inhibitors, but not radiomimetic drugs. Therefore, gamma-H2AX elimination at DNA damage foci is required for DNA damage repair, but accomplishing this task involves distinct phosphatases with potentially overlapping roles. C1 [Chowdhury, Dipanjan; Ahmed, Fariyal; Dykxhoorn, Derek M.; Lieberman, Judy] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Chowdhury, Dipanjan; Ahmed, Fariyal; Dykxhoorn, Derek M.; Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Xu, Xingzhi; Zhong, Jianing; Liao, Ji] Capital Normal Univ, Coll Life Sci, Canc Biol Lab, Beijing 100037, Peoples R China. [Chowdhury, Dipanjan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. [Weinstock, David M.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Zhong, Xueyan; Pfeifer, Gerd P.] City Hope Natl Med Ctr, Dept Biol, Duarte, CA 91010 USA. RP Chowdhury, D (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. EM dipanian_chowdhury@dfci.harvard.edii; xingzhi_xu@mail.cnu.edu.cn; lieberman@idi.harvard.edu RI xu, xingzhi/E-8158-2012; Lieberman, Judy/A-2717-2015; Dykxhoorn, Derek/D-1357-2015 OI xu, xingzhi/0000-0002-4459-2082; FU NCI NIH HHS [CA88873, R01 CA088873]; NIAID NIH HHS [AI45587, R01 AI045587, R01 AI045587-10, R56 AI045587] NR 48 TC 122 Z9 133 U1 1 U2 7 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 JUL 11 PY 2008 VL 31 IS 1 BP 33 EP 46 DI 10.1016/j.molcel.2008.05.016 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327KI UT WOS:000257727600007 PM 18614045 ER PT J AU Morrow, EM Yoo, SY Flavell, SW Kim, TK Lin, YX Hill, RS Mukaddes, NM Balkhy, S Gascon, G Hashmi, A Al-Saad, S Ware, J Joseph, RM Greenblatt, R Gleason, D Ertelt, JA Apse, KA Bodell, A Partlow, JN Barry, B Yao, H Markianos, K Ferland, RJ Greenberg, ME Walsh, CA AF Morrow, Eric M. Yoo, Seung-Yun Flavell, Steven W. Kim, Tae-Kyung Lin, Yingxi Hill, Robert Sean Mukaddes, Nahit M. Balkhy, Soher Gascon, Generoso Hashmi, Asif Al-Saad, Samira Ware, Janice Joseph, Robert M. Greenblatt, Rachel Gleason, Danielle Ertelt, Julia A. Apse, Kira A. Bodell, Adria Partlow, Jennifer N. Barry, Brenda Yao, Hui Markianos, Kyriacos Ferland, Russell J. Greenberg, Michael E. Walsh, Christopher A. TI Identifying autism loci and genes by tracing recent shared ancestry SO SCIENCE LA English DT Article ID SPECTRUM DISORDERS; CHROMOSOMAL REARRANGEMENTS; TRANSCRIPTION FACTORS; MUTATIONS; LINKAGE; PROTEIN; MEMBER; ASSOCIATION; SUPERFAMILY; INHERITANCE AB To find inherited causes of autism- spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 ( protocadherin 10) and DIA1 ( deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na(+)/H(+) exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations. C1 [Morrow, Eric M.; Yoo, Seung-Yun; Hill, Robert Sean; Greenblatt, Rachel; Gleason, Danielle; Ertelt, Julia A.; Apse, Kira A.; Bodell, Adria; Partlow, Jennifer N.; Barry, Brenda; Yao, Hui; Markianos, Kyriacos; Walsh, Christopher A.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Morrow, Eric M.; Yoo, Seung-Yun; Hill, Robert Sean; Greenblatt, Rachel; Gleason, Danielle; Ertelt, Julia A.; Apse, Kira A.; Bodell, Adria; Partlow, Jennifer N.; Barry, Brenda; Yao, Hui; Markianos, Kyriacos; Walsh, Christopher A.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Morrow, Eric M.; Yoo, Seung-Yun; Hill, Robert Sean; Greenblatt, Rachel; Gleason, Danielle; Ertelt, Julia A.; Apse, Kira A.; Bodell, Adria; Partlow, Jennifer N.; Barry, Brenda; Walsh, Christopher A.] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02115 USA. [Morrow, Eric M.; Yoo, Seung-Yun; Hill, Robert Sean; Greenblatt, Rachel; Gleason, Danielle; Ertelt, Julia A.; Apse, Kira A.; Bodell, Adria; Partlow, Jennifer N.; Barry, Brenda; Walsh, Christopher A.] Beth Israel Deaconess Med Ctr, Howard Hughes Med Inst, Boston, MA 02115 USA. [Morrow, Eric M.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Morrow, Eric M.; Yoo, Seung-Yun; Hill, Robert Sean; Walsh, Christopher A.] MIT, Program Med & Populat Genet, Broad Inst, Cambridge, MA 02142 USA. [Morrow, Eric M.; Yoo, Seung-Yun; Hill, Robert Sean; Walsh, Christopher A.] Harvard Univ, Cambridge, MA 02142 USA. [Morrow, Eric M.; Yoo, Seung-Yun; Flavell, Steven W.; Kim, Tae-Kyung; Lin, Yingxi; Hill, Robert Sean; Ware, Janice; Joseph, Robert M.; Apse, Kira A.; Greenberg, Michael E.; Walsh, Christopher A.] Autism Consortium, Boston, MA 02115 USA. [Flavell, Steven W.; Kim, Tae-Kyung; Lin, Yingxi; Greenberg, Michael E.] Childrens Hosp, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA. [Flavell, Steven W.; Kim, Tae-Kyung; Lin, Yingxi; Greenberg, Michael E.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Flavell, Steven W.; Kim, Tae-Kyung; Lin, Yingxi; Greenberg, Michael E.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. [Mukaddes, Nahit M.] Istanbul Univ, Istanbul Fac Med, Dept Child Psychiat, Istanbul, Turkey. [Balkhy, Soher; Gascon, Generoso] King Faisal Specialist Hosp & Res Ctr, Dept Neurosci & Pediat, Jeddah, Saudi Arabia. [Gascon, Generoso] Brown Univ, Sch Med, Providence, RI 02912 USA. [Hashmi, Asif] Combined Mil Hosp, Dept Neurol, Lahore, Pakistan. [Al-Saad, Samira] Kuwait Ctr Autism, Kuwait, Kuwait. [Ware, Janice] Childrens Hosp, Dev Med Ctr, Boston, MA 02115 USA. [Joseph, Robert M.] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 USA. [Ferland, Russell J.] Rensselaer Polytech Inst, Dept Biol, Troy, NY 12180 USA. RP Walsh, CA (reprint author), Childrens Hosp, Div Genet, 300 Longwood Ave, Boston, MA 02115 USA. EM christopher.walsh@childrens.harvard.edu RI Ferland, Russell/E-3500-2010; Morrow, Eric/J-2767-2013; OI Ferland, Russell/0000-0002-8044-2479; Flavell, Steven/0000-0001-9464-1877 FU Howard Hughes Medical Institute; NHGRI NIH HHS [N01-HG-65403]; NICHD NIH HHS [5P30HD018655-26]; NIMH NIH HHS [1K01MH71801, 1K23MH080954-01, 1R01 MH083565, K01 MH071801, K01 MH071801-04, K01 MH071801-05, K23 MH080954, K23 MH080954-01, MH64547, R01 MH083565]; NINDS NIH HHS [5R01NS048276-05, R01 NS048276, R01 NS048276-01, R01 NS048276-02, R01 NS048276-03, R01 NS048276-04, R01 NS048276-05] NR 43 TC 383 Z9 397 U1 1 U2 24 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUL 11 PY 2008 VL 321 IS 5886 BP 218 EP 223 DI 10.1126/science.1157657 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 324IS UT WOS:000257512900031 PM 18621663 ER PT J AU Kerber, RA Amos, CI Yeap, BY Finkelstein, DM Thomas, DC AF Kerber, Richard A. Amos, Christopher I. Yeap, Beow Y. Finkelstein, Dianne M. Thomas, Duncan C. TI Design considerations in a sib-pair study of linkage for susceptibility loci in cancer SO BMC MEDICAL GENETICS LA English DT Article ID NONPOLYPOSIS COLORECTAL-CANCER; UTAH POPULATION DATABASE; GENOME-WIDE ASSOCIATION; AFFECTED RELATIVE PAIRS; FAMILY-HISTORY; COLON-CANCER; QUANTITATIVE TRAITS; GERMLINE MUTATIONS; NUCLEAR FAMILIES; GENETIC-LINKAGE AB Background: Modern approaches to identifying new genes associated with disease allow very fine analysis of associaton and can be performed in population based case-control studies. However, the sibpair design is still valuable because it requires few assumptions other than acceptably high penetrance to identify genetic loci. Methods: We conducted simulation studies to assess the impact of design factors on relative efficiency for a linkage study of colorectal cancer. We considered two test statistics, one comparing the mean IBD probability in affected pairs to its null value of 0.5, and one comparing the mean IBD probabilities between affected and discordant pairs. We varied numbers of parents available, numbers of affected and unaffected siblings, reconstructing the genotype of an unavailable affected sibling by a spouse and offspring, and elimination of sibships where the proband carries a mutation at another locus. Results: Power and efficiency were most affected by the number of affected sibs, the number of sib pairs genotyped, and the risk attributable to linked and unlinked loci. Genotyping unaffected siblings added little power for low penetrance models, but improved validity of tests when there was genetic heterogeneity and for multipoint testing. The efficiency of the concordant-only test was nearly always better than the concordant-discordant test. Replacement of an unavailable affected sibling by a spouse and offspring recovered some linkage information, particularly if several offspring were available. In multipoint analysis, the concordant-only test was showed a small anticonservative bias at 5 cM, while the multipoint concordant-discordant test was generally the most powerful test, and was not biased away from the null at 5 cM. Conclusion: Genotyping parents and unaffected siblings is useful for detecting genotyping errors and if allele frequencies are uncertain. If adequate allele frequency data are available, we suggest a single-point affecteds-only analysis for an initial scan, followed by a multipoint analysis of affected and unaffected members of all available sibships with additional markers around initial hits. C1 [Yeap, Beow Y.; Finkelstein, Dianne M.] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Kerber, Richard A.] Hunstman Canc Inst, Populat Sci Program, Salt Lake City, UT USA. [Amos, Christopher I.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Thomas, Duncan C.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. RP Finkelstein, DM (reprint author), Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. EM richard.kerber@hci.utah.edu; camos@mdanderson.org; byeap@partners.org; dfinkelstein@partners.org; dthomas@usc.edu RI Kerber, Richard/B-8038-2009 FU NCI NIH HHS [U24 CA078142, U01 CA78296, R01 CA074302, U01 CA078296, 5 U42 CA78142, R01 CA052862, U24 CA078174, U01 CA078284, P01 CA073992, U01 CA78284, P01 CA73992, U24 CA78174, R01 CA74302, R01 CA040641, CA52862]; NHGRI NIH HHS [HG02275, R01 HG002275]; NIGMS NIH HHS [GM58897] NR 82 TC 5 Z9 5 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUL 10 PY 2008 VL 9 AR 64 DI 10.1186/1471-2350-9-64 PG 17 WC Genetics & Heredity SC Genetics & Heredity GA 335CT UT WOS:000258269100001 PM 18616822 ER PT J AU Peppercorn, J Partridge, AH AF Peppercorn, Jeffrey Partridge, Ann H. TI Breast cancer in young women: A new color or a different shade of pink? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ADJUVANT CHEMOTHERAPY; RECEPTOR STATUS; EXPRESSION; SURVIVAL; RECURRENCE; PATTERNS; SUBTYPES; TRASTUZUMAB; DISPARITIES; PACLITAXEL C1 [Peppercorn, Jeffrey] Duke Univ, Durham, NC 27706 USA. [Partridge, Ann H.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Peppercorn, J (reprint author), Duke Univ, Durham, NC 27706 USA. NR 30 TC 6 Z9 8 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2008 VL 26 IS 20 BP 3303 EP 3305 DI 10.1200/JCO.2008.16.5621 PG 3 WC Oncology SC Oncology GA 331XU UT WOS:000258046700004 PM 18612146 ER PT J AU Kulke, MH Lenz, HJ Meropol, NJ Posey, J Ryan, DP Picus, J Bergsland, E Stuart, K Tye, L Huang, X Li, JZ Baum, CM Fuchs, CS AF Kulke, Matthew H. Lenz, Heinz-Josef Meropol, Neal J. Posey, James Ryan, David P. Picus, Joel Bergsland, Emily Stuart, Keith Tye, Lesley Huang, Xin Li, Jim Z. Baum, Charles M. Fuchs, Charles S. TI Activity of sunitinib in patients with advanced neuroendocrine tumors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; RENAL-CELL CARCINOMA; PHASE-II TRIAL; FACTOR RECEPTOR; DIGESTIVE-SYSTEM; ANTITUMOR-ACTIVITY; ENDOCRINE TUMORS; ONCOLOGY-GROUP; SOLID TUMORS AB Purpose Standard cytotoxic chemotherapy has limited efficacy in metastatic neuroendocrine tumor patients. Neuroendocrine tumors express vascular endothelial growth factor (VEGF) and its receptor (VEGFR). Sunitinib malate, an oral tyrosine kinase inhibitor, has activity against VEGFRs as well as platelet-derived growth factor receptors, stem-cell factor receptor, glial cell line-derived neurotrophic factor, and FMS-like tyrosine kinase-3. We evaluated the efficacy of sunitinib in a two-cohort, phase II study of advanced carcinoid and pancreatic neuroendocrine tumor patients. Patients and Methods Patients were treated with repeated 6-week cycles of oral sunitinib (50 mg/d for 4 weeks, followed by 2 weeks off treatment). Patients were observed for response, survival, and adverse events. Patient-reported outcomes were assessed. Results Among 109 enrolled patients, 107 received sunitinib (carcinoid, n = 41; pancreatic endocrine tumor, n = 66). Overall objective response rate (ORR) in pancreatic endocrine tumor patients was 16.7% (11 of 66 patients), and 68% (45 of 66 patients) had stable disease (SD). Among carcinoid patients, ORR was 2.4% (one of 41 patients), and 83% (34 of 41 patients) had SD. Median time to tumor progression was 7.7 months in pancreatic neuroendocrine tumor patients and 10.2 months in carcinoid patients. One-year survival rate was 81.1% in pancreatic neuroendocrine tumor patients and 83.4% in carcinoid patients. No significant differences from baseline in patient-reported quality of life or fatigue were observed during treatment. Conclusion Sunitinib has antitumor activity in pancreatic neuroendocrine tumors; its activity against carcinoid tumors could not be definitively determined in this nonrandomized study. Randomized trials of sunitinib in patients with neuroendocrine tumors are warranted. C1 [Kulke, Matthew H.] Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Univ So Calif, San Francisco Comprehens Canc Ctr, Los Angeles, CA 90033 USA. Pfizer Global Res & Dev, La Jolla, CA USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Alabama, Birmingham, AL USA. Washington Univ, St Louis, MO USA. RP Kulke, MH (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM Matthew_Kulke@dfci.harvard.edu NR 49 TC 335 Z9 347 U1 1 U2 10 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 10 PY 2008 VL 26 IS 20 BP 3403 EP 3410 DI 10.1200/JCO.2007.15.9020 PG 8 WC Oncology SC Oncology GA 331XU UT WOS:000258046700020 PM 18612155 ER PT J AU Kumar, M Reeve, JR Hu, W Miller, LJ Keire, DA AF Kumar, Mohanraja Reeve, Joseph R., Jr. Hu, Weidong Miller, Laurence J. Keire, David A. TI The micelle-associated 3D structures of Boc-Y(SO(3))-Nle-G-W-Nle-D-2-phenylethylester (JMV-180) and CCK-8(s) share conformational elements of a calculated CCK(1) receptor-bound model SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; NUCLEAR-MAGNETIC-RESONANCE; AFFINITY CHOLECYSTOKININ RECEPTORS; FLUORESCENCE-TRANSFER MEASUREMENTS; HORMONE MEMBRANE INTERACTIONS; 3RD EXTRACELLULAR LOOP; COMMON AMINO-ACIDS; NMR-SPECTROSCOPY; INTERMOLECULAR INTERACTIONS; SEROTONIN(1A) RECEPTOR AB JMV-180 (1) and CCK-8(s) are high affinity ligands at the CCK(1) receptor that have similar and different actions via this receptor. Here we calculate the tertiary structure of 1 or CCK-8(s) in the presence of dodecylphosphocholine micelles at pH 5.0 and 35 degrees C from 2D (1)H NMR data recorded at 600 MHz. The NMR derived 3D structures of 1 and CCK-8(s) share a common type I beta-turn around residues Nle3/M3 and G4 and diverge from each other structurally at the N- and C-termini. The fluorescence and circular dichroism spectral properties of these peptides are consistent with their NMR derived structures. The structures determined in the presence of DPC micelles are compared to available models of 1 or CCK-8(s) bound to the CCK(1) receptor. For CCK and 1, these comparisons show that DPC micelle associated structures duplicate some important aspects of the models calculated from cross-linking derived constraints at the CCK(1) receptor. C1 [Kumar, Mohanraja; Reeve, Joseph R., Jr.; Keire, David A.] VA Greater Los Angeles Healthcare Syst, Digest Dis Res Ctr, CURE, Los Angeles, CA 90073 USA. [Kumar, Mohanraja; Reeve, Joseph R., Jr.; Keire, David A.] Univ Calif Los Angeles, Sch Med, Div Digest Dis, Los Angeles, CA 90095 USA. [Hu, Weidong] Beckman Res Inst, City Hope, Duarte, CA 90010 USA. [Miller, Laurence J.] Mayo Clin, Dept Mol Pharmacol & Expt Therapeut, Scottsdale, AZ 85259 USA. RP Reeve, JR (reprint author), VA Greater Los Angeles Healthcare Syst, Digest Dis Res Ctr, CURE, Los Angeles, CA 90073 USA. EM jreeve@ucla.edu FU NIDDK NIH HHS [DK33850, DK 41301, DK32878, P30 DK041301, R01 DK032878, R01 DK033850, R37 DK032878] NR 81 TC 4 Z9 4 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 10 PY 2008 VL 51 IS 13 BP 3742 EP 3754 DI 10.1021/jm701401j PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 322QS UT WOS:000257391000011 PM 18540665 ER PT J AU Adlard, PA Cherny, RA Finkelstein, DI Gautier, E Robb, E Cortes, M Volitakis, I Liu, X Smith, JP Perez, K Laughton, K Li, QX Charman, SA Nicolazzo, JA Wilkins, S Deleva, K Lynch, T Kok, G Ritchie, CW Tanzi, RE Cappai, R Masters, CL Barnham, KJ Bush, AI AF Adlard, Paul A. Cherny, Robert A. Finkelstein, David I. Gautier, Elisabeth Robb, Elysia Cortes, Mikhalina Volitakis, Irene Liu, Xiang Smith, Jeffrey P. Perez, Keyla Laughton, Katrina Li, Qiao-Xin Charman, Susan A. Nicolazzo, Joseph A. Wilkins, Simon Deleva, Karolina Lynch, Toni Kok, Gaik Ritchie, Craig W. Tanzi, Rudolph E. Cappai, Roberto Masters, Colin L. Barnham, Kevin J. Bush, Ashley I. TI Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial A beta SO NEURON LA English DT Article ID AMYLOID-BETA; IN-VIVO; DISEASE; PROTEIN; ZINC; TAU; OLIGOMERS; PATHOLOGY; MODEL; SYNAPTOPHYSIN AB As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (A beta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of AB, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain AB within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated AB reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD. C1 [Adlard, Paul A.; Cherny, Robert A.; Finkelstein, David I.; Robb, Elysia; Cortes, Mikhalina; Volitakis, Irene; Liu, Xiang; Smith, Jeffrey P.; Perez, Keyla; Laughton, Katrina; Li, Qiao-Xin; Wilkins, Simon; Deleva, Karolina; Lynch, Toni; Cappai, Roberto; Masters, Colin L.; Barnham, Kevin J.; Bush, Ashley I.] Mental Hlth Res Inst, Oxidat Biol Lab, Parkville, Vic 3052, Australia. [Adlard, Paul A.; Cherny, Robert A.; Laughton, Katrina; Li, Qiao-Xin; Cappai, Roberto; Barnham, Kevin J.; Bush, Ashley I.] Univ Melbourne, Dept Pathol, Melbourne, Vic 3010, Australia. [Finkelstein, David I.; Wilkins, Simon; Masters, Colin L.] Univ Melbourne, Ctr Neurosci, Melbourne, Vic 3010, Australia. [Cappai, Roberto; Barnham, Kevin J.] Univ Melbourne, Bio Mol Sci & Biotechnol Inst 21, Melbourne, Vic 3010, Australia. [Cherny, Robert A.; Gautier, Elisabeth; Kok, Gaik] Prana Biotechnol Ltd, Parkville, Vic 3052, Australia. [Charman, Susan A.; Nicolazzo, Joseph A.] Monash Univ, Monash Inst Pharmaceut Sci, Ctr Drug Candidate Optimisat, Parkville, Vic 3052, Australia. [Ritchie, Craig W.] UCL Royal Free & Univ Coll Med Sch, Dept Mental Hlth Sci, Metab & Clin Trials Unit, London WC1E 6BT, England. [Tanzi, Rudolph E.] Massachusetts Gen Hosp, Genet & Aging Res Unit, Charlestown, MA 02129 USA. RP Bush, AI (reprint author), Mental Hlth Res Inst, Oxidat Biol Lab, Parkville, Vic 3052, Australia. EM abush@mhri.edu.au RI Charman, Susan/E-2221-2011; Wilkins, Simon/D-1174-2009; Bush, Ashley/A-1186-2007; OI Charman, Susan/0000-0003-1753-8213; Wilkins, Simon/0000-0001-7712-4114; Bush, Ashley/0000-0001-8259-9069; /0000-0002-8167-4917 NR 45 TC 363 Z9 373 U1 6 U2 42 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 10 PY 2008 VL 59 IS 1 BP 43 EP 55 DI 10.1016/j.neuron.2008.06.018 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 327KU UT WOS:000257728800007 PM 18614028 ER PT J AU Harris, JB Michelow, IC Westra, SJ Kradin, RL AF Harris, Jason B. Michelow, Ian C. Westra, Sjirk J. Kradin, Richard L. TI A boy with fever and pulmonary infiltrates - Necrotizing granulomatous pneumonitis due to A-terreus, complicating chronic granulomatous disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ASPERGILLUS-TERREUS; CLINICAL-FEATURES; P22(PHOX) SUBUNIT; FLAVOCYTOCHROME-B; TRANSPLANTATION; EPIDEMIOLOGY; TUBERCULOSIS; INFECTION; CHILDREN C1 [Harris, Jason B.; Michelow, Ian C.] Massachusetts Gen Hosp, Dept Pediat Pediat Infect Dis, Boston, MA 02114 USA. [Westra, Sjirk J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kradin, Richard L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Harris, Jason B.; Michelow, Ian C.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Westra, Sjirk J.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kradin, Richard L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Harris, JB (reprint author), Massachusetts Gen Hosp, Dept Pediat Pediat Infect Dis, Boston, MA 02114 USA. NR 20 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 10 PY 2008 VL 359 IS 2 BP 178 EP 187 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 323PJ UT WOS:000257459000011 PM 18614786 ER PT J AU Cavallari, JM Eisen, EA Fang, SC Schwartz, J Hauser, R Herrick, RF Christiani, DC AF Cavallari, Jennifer M. Eisen, Ellen A. Fang, Shona C. Schwartz, Joel Hauser, Russ Herrick, Robert F. Christiani, David C. TI PM(2.5) metal exposures and nocturnal heart rate variability: a panel study of boilermaker construction workers SO ENVIRONMENTAL HEALTH LA English DT Article ID PARTICULATE AIR-POLLUTION; CARDIOVASCULAR-DISEASE; TRANSITION-METALS; MATTER; PARTICLES; NICKEL; FINE AB Background: To better understand the mechanism(s) of particulate matter (PM) associated cardiovascular effects, research priorities include identifying the responsible PM characteristics. Evidence suggests that metals play a role in the cardiotoxicity of fine PM (PM(2.5)) and in exposure-related decreases in heart rate variability (HRV). We examined the association between daytime exposure to the metal content of PM(2.5) and night HRV in a panel study of boilermaker construction workers exposed to metal-rich welding fumes. Methods: Twenty-six male workers were monitored by ambulatory electrocardiogram (ECG) on a workday while exposed to welding fume and a non-workday (baseline). From the ECG, rMSSD (square root of the mean squared differences of successive intervals) was summarized over the night (0: 00-7:00). Workday, gravimetric PM(2.5) samples were analyzed by x-ray fluorescence to determine metal content. We used linear mixed effects models to assess the associations between night rMSSD and PM(2.5) metal exposures both with and without adjustment for total PM(2.5). Matched ECG measurements from the non-workday were used to control for individual cardiac risk factors and models were also adjusted for smoking status. To address collinearity between PM(2.5) and metal content, we used a two-step approach that treated the residuals from linear regression models of each metal on PM(2.5) as surrogates for the differential effects of metal exposures in models for night rMSSD. Results: The median PM(2.5) exposure was 650 mu g/m(3); median metal exposures for iron, manganese, aluminum, copper, zinc, chromium, lead, and nickel ranged from 226 mu g/m(3) to non-detectable. We found inverse linear associations in exposure- response models with increased metal exposures associated with decreased night rMSSD. A statistically significant association for manganese was observed, with a decline of 0.130 msec (95% CI: -0.162, -0.098) in night rMSSD for every 1 mu g/m(3) increase in manganese. However, even after adjusting for individual metals, increases in total PM(2.5) exposures were associated with declines in night rMSSD. Conclusion: These results support the cardiotoxicity of PM(2.5) metal exposures, specifically manganese. However the metal component alone did not account for the observed declines in night HRV. Therefore, results suggest the importance of other PM elemental components. C1 [Cavallari, Jennifer M.; Eisen, Ellen A.; Fang, Shona C.; Schwartz, Joel; Hauser, Russ; Herrick, Robert F.; Christiani, David C.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Christiani, David C.] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Cavallari, JM (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 665 Huntington Ave, Boston, MA 02115 USA. EM jcavalla@hsph.harvard.edu; eeisen@hsph.harvard.edu; sfang@hsph.harvard.edu; jschwrtz@hsph.harvard.edu; rhauser@hohp.harvard.edu; herrick@hsph.harvard.edu; dchristi@hsph.harvard.edu FU NIEHS NIH HHS [ES00002, R01 ES009860, ES009860, P30 ES000002, T32 ES 07069, T32 ES007069]; NIOSH CDC HHS [T42 OH008416] NR 28 TC 55 Z9 60 U1 1 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD JUL 9 PY 2008 VL 7 AR 36 DI 10.1186/1476-069X-7-36 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 331RJ UT WOS:000258030000001 PM 18613971 ER PT J AU Gorrindo, T Groves, JE AF Gorrindo, Tristan Groves, James E. TI Web searching for information about physicians SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID PATIENT; CARE C1 [Gorrindo, Tristan; Groves, James E.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Gorrindo, Tristan; Groves, James E.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Gorrindo, T (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Wang ACC 812, Boston, MA 02114 USA. EM tristan.gorrindo@mgh.harvard.edu NR 8 TC 29 Z9 29 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 9 PY 2008 VL 300 IS 2 BP 213 EP 215 DI 10.1001/jama.2008.44 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 323GV UT WOS:000257435500027 PM 18612120 ER PT J AU Dittman, JS Kaplan, JM AF Dittman, Jeremy S. Kaplan, Joshua M. TI Behavioral impact of neurotransmitter-activated G-protein-coupled receptors: Muscarinic and GABA(B) receptors regulate Caenorhabditis elegans locomotion SO JOURNAL OF NEUROSCIENCE LA English DT Article DE C. elegans; feedback; GABA(B) receptor; GPCR; locomotion; muscarinic ID ACETYLCHOLINE-RECEPTOR; SYNAPTIC-TRANSMISSION; GLUTAMATE SPILLOVER; CEREBELLAR SYNAPSE; C-ELEGANS; G(Q)ALPHA; MICE; LOCALIZATION; INTERNEURONS; G(O)ALPHA AB Neurotransmitter released from presynaptic terminals activates both ligand-gated ion channels (ionotropic receptors) and a variety of G-protein-coupled receptors (GPCRs). These neurotransmitter receptors are expressed on both presynaptic and postsynaptic cells. Thus, each neurotransmitter acts on multiple receptor classes, generating a large repertoire of physiological responses. The impact of many ionotropic receptors on neuronal activity and behavior has been clearly elucidated; however, much less is known about how neurotransmitter-gated GPCRs regulate neurons and circuits. In Caenorhabditis elegans, both acetylcholine (ACh) and GABA are released in the nerve cord and mediate fast neuromuscular excitation and inhibition during locomotion. Here we identify a muscarinic receptor (GAR-2) and the GABA(B) receptor dimer (GBB-1/2) that detect synaptically released ACh and GABA, respectively. Both GAR-2 and GBB-1/2 inhibited cholinergic motor neurons when ACh and GABA levels were enhanced. Loss of either GPCR resulted in movement defects, suggesting that these receptors are activated during locomotion. When the negative feedback provided by GAR-2 was replaced with positive feedback, animals became highly sensitive to ACh levels and locomotion was severely impaired. Thus, conserved GPCRs act in the nematode motor circuit to provide negative feedback and to regulate locomotory behaviors that underlie navigation. C1 [Dittman, Jeremy S.; Kaplan, Joshua M.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Kaplan, JM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Simches Res Bldg,7th Floor,185 Cambridge St, Boston, MA 02114 USA. EM kaplan@molbio.mgh.harvard.edu OI Dittman, Jeremy S./0000-0002-3850-9078 FU NIGMS NIH HHS [R01 GM054728-10, R01 GM054728, R01 GM054728-08, R01 GM054728-07, R01 GM054728-09, GM54728, R01 GM054728-11] NR 48 TC 32 Z9 39 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 9 PY 2008 VL 28 IS 28 BP 7104 EP 7112 DI 10.1523/JNEUROSCI.0378-08.2008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 323TT UT WOS:000257472000011 PM 18614679 ER PT J AU He, X Fan, HY Garlick, JD Kingston, RE AF He, Xi Fan, Hua-Ying Garlick, Joseph D. Kingston, Robert E. TI Diverse regulation of SNF2h chromatin remodeling by noncatalytic subunits SO BIOCHEMISTRY LA English DT Article ID RIBOSOMAL-RNA GENE; ISWI; DNA; COMPLEX; TRANSCRIPTION; ACF1; NUCLEOSOMES; NORC; INTERACTS; PROTEINS AB SNF2h-based ATP-dependent chromatin remodeling complexes diverge in composition, nuclear localization, and biological function. Such differences have led to the hypothesis that SNF2h complexes differ mechanistically. One proposal is that the complexes have different functional interactions with the naked DNA adjacent to the nucleosome. We have used a series of templates with defined nucleosomal position and differing amounts and placement of adjacent DNA to compare the relative activities of SNF2h and SNF2h complexes. The complexes hACF, CHRAC, WICH, and RSF all displayed differences in functional interactions with these templates, which we attribute to the differences in the noncatalytic subunit. We suggest that the ability to sense adjacent DNA is a general property of the binding partners of SNF2h and that each partner provides distinct regulation that contributes to distinct cellular function. C1 [Kingston, Robert E.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Kingston, RE (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM Kingston@molbio.mgh.harvard.edu NR 52 TC 25 Z9 25 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 8 PY 2008 VL 47 IS 27 BP 7025 EP 7033 DI 10.1021/bi702304p PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 320TE UT WOS:000257257100007 PM 18553938 ER PT J AU Cappuzzo, F Varella-Garcia, M Finocchiaro, G Skokan, M Gajapathy, S Carnaghi, C Rimassa, L Rossi, E Ligorio, C Di Tommaso, L Holmes, AJ Toschi, L Tallini, G Destro, A Roncalli, M Santoro, A Janne, PA AF Cappuzzo, F. Varella-Garcia, M. Finocchiaro, G. Skokan, M. Gajapathy, S. Carnaghi, C. Rimassa, L. Rossi, E. Ligorio, C. Di Tommaso, L. Holmes, A. J. Toschi, L. Tallini, G. Destro, A. Roncalli, M. Santoro, A. Janne, P. A. TI Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients SO BRITISH JOURNAL OF CANCER LA English DT Article DE cetuximab; EGFR; KRAS; BRAF; MET; IGF1R ID GROWTH-FACTOR-I; FACTOR SCATTER FACTOR; GENE COPY NUMBER; FACTOR-RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; LUNG-CANCER; 1ST-LINE TREATMENT; MUTATION STATUS; C-MET; EXPRESSION AB The impact of KRAS mutations on cetuximab sensitivity in epidermal growth factor receptor fluorescence in situ hybridisation-positive ( EGFR FISH+) metastatic colorectal cancer patients (mCRC) has not been previously investigated. In the present study, we analysed KRAS, BRAF, P13KCA, MET, and IGF1R in 85 mCRC treated with cetuximab-based therapy in whom EGFR status was known. KRAS mutations (52.5%) negatively affected response only in EGFR FISH + patients. EGFR FISH+/KRAS mutated had a significantly lower response rate (P=0.04) than EGFR FISH+/KRAS wild type patients. Four EGFR FISH + patients with KRAS mutations responded to cetuximab therapy. BRAF was mutated in 5.0% of patients and none responded to the therapy. P13KCA mutations (17.7%) were not associated to cetuximab sensitivity. Patients overexpressing IGF1R (74.3%) had significantly longer survival than patients with low IGF1R expression (P=0.006), with no difference in response rate. IGF1R gene amplification was not detected, and only two (2.6%) patients, both responders, had MET gene amplification. In conclusion, KRAS mutations are associated with cetuximab failure in EGFR FISH+ mCRC, even if it does not preclude response. The rarity of MET and IGF1R gene amplification suggests a marginal role inprimary resistance. The potential prognostic implication of IGF1R expression merits further evaluation. C1 [Cappuzzo, F.; Finocchiaro, G.; Carnaghi, C.; Rimassa, L.; Ligorio, C.; Di Tommaso, L.; Destro, A.; Santoro, A.] Univ Milan, Dept Med Oncol, Ist Clin Humanitas IRCCS, I-20089 Rozzano, Italy. [Varella-Garcia, M.; Finocchiaro, G.; Skokan, M.; Gajapathy, S.] Univ Colorado, Ctr Canc, Dept Med Med Oncol, Aurora, CO USA. [Rossi, E.] CINECA Interuniv Consortium, Bologna, Italy. [Ligorio, C.; Tallini, G.] Univ Bologna, Pathol Unit, Bellaria Hosp, Bologna, Italy. [Holmes, A. J.; Toschi, L.; Janne, P. A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Roncalli, M.] Univ Milan, Ist Clin Humanitas IRCCS, Pathol Unit, Rozzano, Italy. RP Cappuzzo, F (reprint author), Univ Milan, Dept Med Oncol, Ist Clin Humanitas IRCCS, Via Manzoni 56, I-20089 Rozzano, Italy. EM federico.cappuzzo@humanitas.it RI Rimassa, Lorenza/N-4884-2016; OI Rimassa, Lorenza/0000-0001-9957-3615; Tallini, Giovanni/0000-0003-0113-6682; di tommaso, luca/0000-0002-9013-4728; Cappuzzo, Federico/0000-0002-6295-6767; Roncalli, Massimo/0000-0002-7901-8910 NR 47 TC 120 Z9 122 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 EI 1532-1827 J9 BRIT J CANCER JI Br. J. Cancer PD JUL 8 PY 2008 VL 99 IS 1 BP 83 EP 89 DI 10.1038/sj.bjc.6604439 PG 7 WC Oncology SC Oncology GA 321RU UT WOS:000257325000014 PM 18577988 ER PT J AU Lewis, GD Asnani, A Gerszten, RE AF Lewis, Gregory D. Asnani, Aarti Gerszten, Robert E. TI Application of metabolomics to cardiovascular biomarker and pathway discovery SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; CITRIC-ACID CYCLE; FUNCTIONAL GENOMICS; MYOCARDIAL-ISCHEMIA; MUSCLE; IDENTIFICATION; CHROMATOGRAPHY; TECHNOLOGIES; METABONOMICS; REPERFUSION AB Emerging technologies based on mass spectrometry and nuclear magnetic resonance enable the monitoring of hundreds of metabolites from tissues or body fluids, that is, "metabolomics." Because metabolites change rapidly in response to physiologic perturbations, they represent proximal reporters of disease phenotypes. The profiling of low molecular weight biochemicals, including lipids, sugars, nucleotides, organic acids, and amino acids, that serve as substrates and products in metabolic pathways is particularly relevant to cardiovascular diseases. In addition to serving as disease biomarkers, circulating metabolites may participate in previously unanticipated roles as regulatory signals with hormone-like functions. Cellular metabolic pathways are highly conserved among species, facilitating complementary functional studies in model organisms to provide insight into metabolic changes identified in humans. Although metabolic profiling technologies and methods of pattern recognition and data reduction remain under development, the coupling of metabolomics with other functional genomic approaches promises to extend our ability to elucidate biological pathways and discover biomarkers of human disease. C1 [Lewis, Gregory D.; Asnani, Aarti; Gerszten, Robert E.] Massachusetts Gen Hosp E, Ctr Immunol & Inflammatory Dis, Charlestown, MA USA. [Lewis, Gregory D.; Asnani, Aarti; Gerszten, Robert E.] Massachusetts Gen Hosp E, Div Cardiol, Charlestown, MA USA. [Lewis, Gregory D.; Asnani, Aarti; Gerszten, Robert E.] Harvard Univ, Sch Med, Div Cardiol, Boston, MA USA. [Lewis, Gregory D.; Asnani, Aarti; Gerszten, Robert E.] Harvard Univ, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USA. [Lewis, Gregory D.; Asnani, Aarti; Gerszten, Robert E.] Broad Inst MIT & Harvard, Cambridge, MA USA. RP Gerszten, RE (reprint author), Massachusetts Gen Hosp E 8307, Div Cardiol, 149 13th St, Charlestown, MA 02129 USA. EM rgerszten@partners.org FU NHLBI NIH HHS [R01 HL083141, U01HL083141, R01 HL072872] NR 39 TC 103 Z9 107 U1 3 U2 33 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 8 PY 2008 VL 52 IS 2 BP 117 EP 123 DI 10.1016/j.jacc.2008.03.043 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 321FT UT WOS:000257290800005 PM 18598890 ER PT J AU Antoniades, C Shirodaria, C Van Assche, T Cunnington, C Tegeder, I Lotsch, J Guzik, TJ Leeson, P Diesch, J Tousoulis, D Stefanadis, C Costigan, M Woolf, CJ Alp, NJ Channon, KM AF Antoniades, Charalambos Shirodaria, Cheerag Van Assche, Tim Cunnington, Colin Tegeder, Irmgard Loetsch, Joern Guzik, Tomasz J. Leeson, Paul Diesch, Jonathan Tousoulis, Dimitris Stefanadis, Christodoulos Costigan, Michael Woolf, Clifford J. Alp, Nicholas J. Channon, Keith M. TI GCH1 haplotype determines vascular and plasma biopterin availability in coronary artery disease - Effects on vascular superoxide production and endothelial function SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; GTP-CYCLOHYDROLASE-I; FOLIC-ACID; OXIDATIVE STRESS; NAD(P)H OXIDASE; DEFICIENT MICE; RISK-FACTORS; TETRAHYDROBIOPTERIN; DYSFUNCTION; CELLS AB Objectives This study sought to determine the effects of endogenous tetrahydrobiopterin (BH4) bioavailability on endothelial nitric oxide synthase (eNOS) coupling, nitric oxide (NO) bioavailability, and vascular superoxide production in patients with coronary artery disease (CAD). Background GTP-cyclohydrolase I, encoded by the GCH1 gene, is the rate-limiting enzyme in the biosynthesis of BH4, an eNOS cofactor important for maintaining enzymatic coupling. We examined the associations between haplotypes of the GCH1 gene, GCH1 expression and biopterin levels, and the effects on endothelial function and vascular superoxide production. Methods Blood samples and segments of internal mammary arteries and saphenous veins were obtained from patients with CAD undergoing coronary artery bypass grafting (n = 347). The GCH1 haplotypes were defined by 3 polymorphisms: rs8007267G < A, rs3783641A < T, and rs10483639C < G (X haplotype: A, T, G; O haplotype: any other combination). Vascular superoxide (+/- the eNOS inhibitor NG-nitro-L-arginine methyl ester [L-NAME]) was measured by lucigenin-enhanced chemiluminescence, whereas the vasorelaxations of saphenous veins to acetylcholine were evaluated ex vivo. Results Haplotype frequencies were OO 70.6%, XO 27.4%, and XX 2.0%. The X haplotype was associated with significantly lower vascular GCH1 messenger ribonucleic acid expression and substantial reductions in both plasma and vascular BH4 levels. In X haplotype carriers both vascular superoxide and L-NAME-inhibitable superoxide were significantly increased, and were associated with reduced vasorelaxations to acetylcholine. Conclusions GCH1 gene expression, modulated by a particular GCH1 haplotype, is a major determinant of BH4 bioavailability both in plasma and in the vascular wall in patients with CAD. Genetic variation in GCH1 underlies important differences in endogenous BH4 availability and is a determinant of eNOS coupling, vascular redox state, and endothelial function in human vascular disease. C1 [Antoniades, Charalambos; Shirodaria, Cheerag; Van Assche, Tim; Cunnington, Colin; Guzik, Tomasz J.; Leeson, Paul; Diesch, Jonathan; Alp, Nicholas J.; Channon, Keith M.] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Tegeder, Irmgard; Woolf, Clifford J.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Boston, MA 02114 USA. [Tegeder, Irmgard; Woolf, Clifford J.] Harvard Univ, Sch Med, Boston, MA USA. [Tegeder, Irmgard; Loetsch, Joern] Goethe Univ Frankfurt, Inst Clin Pharmacol, Pharmazentrum Frankfurt ZAFES, Frankfurt, Germany. [Guzik, Tomasz J.] Jagiellonian Univ, Dept Med, Krakow, Poland. [Guzik, Tomasz J.] Jagiellonian Univ, Dept Pharmacol, Krakow, Poland. [Tousoulis, Dimitris; Stefanadis, Christodoulos] Univ Athens, Sch Med, Hippokrat Hosp, Dept Cardiol 1, GR-11527 Athens, Greece. RP Channon, KM (reprint author), Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. EM keith.channon@cardiov.ox.ac.uk RI Leeson, Paul/K-6964-2012; OI Lotsch, Jorn/0000-0002-5818-6958; Tegeder, Irmgard/0000-0001-7524-8025 FU British Heart Foundation [FS/03/105/16340, RG/02/006, RG/07/003/23133]; NINDS NIH HHS [R01 NS058870, R01 NS058870-01A1] NR 40 TC 56 Z9 58 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 8 PY 2008 VL 52 IS 2 BP 158 EP 165 DI 10.1016/j.jacc.2007.12.062 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 321FT UT WOS:000257290800011 PM 18598896 ER PT J AU Silbert, LC Nelson, C Howieson, DB Moore, MM Kaye, JA AF Silbert, L. C. Nelson, C. Howieson, D. B. Moore, M. M. Kaye, J. A. TI Impact of white matter hyperintensity volume progression on rate of cognitive and motor decline SO NEUROLOGY LA English DT Article ID AUSTRIAN STROKE PREVENTION; HEALTHY OLDEST-OLD; CARDIOVASCULAR HEALTH; ELDERLY-PATIENTS; RATING-SCALE; MRI; LESIONS; BRAIN; PEOPLE; PERFORMANCE AB Background: White matter hyperintensity (WMH) change on brain MRI is observed with increased frequency in the elderly and has been independently associated with neurologic decline. The degree to which the location and rate of volume increase in WMH affects other structural brain changes along with cognitive and motor performance over time may determine subsequent degrees of risk for dementia and other syndromes of aging. Methods: One hundred four cognitively intact men and women followed longitudinally for up to 13 years underwent at least three MRIs with corresponding annual cognitive and neurologic assessments. Brain volume, ventricular CSF (vCSF), and total periventricular (PV) and subcortical WMH volumes were measured. Progression of MRI volumes was examined in relation to rates of cognitive, motor, and cerebral volume change based on slopes of outcomes. Results: Higher initial total and PV WMH volume was associated with total WMH, PV WMH, and vCSF progression, and with increased time and number of steps to walk 30 feet. Progression of PV WMH volume was associated with increased time to walk 30 feet. Progression of subcortical WMH volume was associated with decreased performance on logical memory testing and increased rate of vCSF volume change. Conclusion: Increased total and periventricular (PV) white matter hyperintensity (WMH) burden and progression of PV WMH burden are associated with decreased gait performance over time, while progression of subcortical WMH volume is associated with memory decline in cognitively intact elderly. Greater progression of WMH burden is associated with an increased risk of memory and gait dysfunction, and thus should not be considered a benign process. C1 [Silbert, L. C.; Nelson, C.; Howieson, D. B.; Moore, M. M.; Kaye, J. A.] Oregon Hlth & Sci Univ, Dept Neurol, Layton Aging & Alzheimers Dis Ctr, Portland, OR 97201 USA. [Silbert, L. C.; Kaye, J. A.] Portland VA Med Ctr, Portland, OR USA. RP Silbert, LC (reprint author), Oregon Hlth & Sci Univ, Dept Neurol, Layton Aging & Alzheimers Dis Ctr, CR 131,3181 SW Sam Jackson Pk Rd, Portland, OR 97201 USA. EM silbertl@ohsu.edu OI Kaye, Jeffrey/0000-0002-9971-3478 NR 34 TC 95 Z9 97 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 8 PY 2008 VL 71 IS 2 BP 108 EP 113 DI 10.1212/01.wnl.0000316799.86917.37 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 322WV UT WOS:000257406900007 PM 18606964 ER PT J AU Mehta, BP Shmerling, RH AF Mehta, Brijesh P. Shmerling, Robert H. TI Teaching NeuroImage: Cerebrotendinous xanthomatosis SO NEUROLOGY LA English DT Editorial Material C1 [Mehta, Brijesh P.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Brigham & Womens Hosp,Dept Neurol, Boston, MA 02115 USA. [Shmerling, Robert H.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Div Rheumatol, Boston, MA 02115 USA. RP Mehta, BP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Brigham & Womens Hosp,Dept Neurol, Boston, MA 02115 USA. EM bmehta@partners.org NR 2 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 8 PY 2008 VL 71 IS 2 BP E4 EP E4 DI 10.1212/01.wnl.0000316806.01406.74 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 322WV UT WOS:000257406900034 PM 18606959 ER PT J AU Diederichs, S Jung, S Rothenberg, SM Smolen, GA Mlody, BG Habert, DA AF Diederichs, Sven Jung, Stephanie Rothenberg, S. Michael Smolen, Gromoslaw A. Mlody, Barbara G. Habert, Daniel A. TI Coexpression of Argonaute-2 enhances RNA interference toward perfect match binding sites SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microRNA; RNAi screening; shRNA; siRNA; Ago2 ID SHORT HAIRPIN RNAS; PASSENGER-STRAND; NUCLEAR EXPORT; HUMAN-CELLS; SCREEN; GENE; MICRORNAS; CLEAVAGE; CANCER; SIRNA AB RNAi is widely applied to inhibit expression of specific genes, but it is limited by variable efficiency and specificity of empirically designed siRNA or shRNA constructs. This complicates studies targeting individual genes and significantly impairs large-scale screens using genome-wide knockdown libraries. Here, we show that ectopic expression of the RISC slicer Argonaute-2 (Ago2, eIF2C2) dramatically enhances RNAi specifically for mRNA targets with perfectly matched binding sites. This effect depends on its endonuclease activity and is uncoupled from its regulation of microRNA expression. To model the application of Ago2 coexpression with shRNA knockdown, we targeted the EGF receptor (EGFR) in lung cancer cells exhibiting oncogene addiction to EGFR. Whereas multiple empirically designed shRNA constructs exhibited highly divergent efficiencies in mediating EGFR knockdown and cell killing, coexpression of Ago2 resulted in uniform and highly specific target gene suppression and apoptosis in EGFR-dependent cells. Codelivery of Ago2 with shRNA constructs or siRNA duplexes thus provides a strategy to enhance the efficacy and the specificity of RNAi in experimental and potentially therapeutic settings. C1 [Diederichs, Sven; Jung, Stephanie; Rothenberg, S. Michael; Smolen, Gromoslaw A.; Mlody, Barbara G.; Habert, Daniel A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Charlestown, MA 02129 USA. RP Diederichs, S (reprint author), German Canc Res Ctr, Mol RNA Biol & Canc Grp, D-69120 Heidelberg, Germany. EM s.diederichs@dkfz.de; haber@helix.mgh.harvard.edu RI Diederichs, Sven/J-6237-2012; Jung, Stephanie/D-1351-2013 OI Diederichs, Sven/0000-0001-7901-4752; FU NCI NIH HHS [R37 CA058596-15, R37 CA058596] NR 27 TC 57 Z9 60 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2008 VL 105 IS 27 BP 9284 EP 9289 DI 10.1073/pnas.0800803105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 326GA UT WOS:000257645400029 PM 18591665 ER PT J AU Zha, S Sekiguchi, J Brush, JW Bassing, CH Alt, FW AF Zha, Shan Sekiguchi, JoAnn Brush, James W. Bassing, Craig H. Alt, Frederick W. TI Complementary functions of ATM and H2AX in development and suppression of genomic instability SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA repair; embryonic lethality; oxidative DNA damage ID DOUBLE-STRAND BREAKS; HEMATOPOIETIC STEM-CELLS; HISTONE H2AX; DNA-DAMAGE; IONIZING-RADIATION; DEFICIENT MICE; ATAXIA-TELANGIECTASIA; OXIDATIVE STRESS; LYMPHOCYTES; STABILITY AB Upon DNA damage, histone H2AX is phosphorylated by ataxia-telangiectasia mutated (ATM) and other phosphoinositide 3-kinase-related protein kinases. To elucidate further the potential overlapping and unique functions of ATM and H2AX, we asked whether they have synergistic functions in the development and maintenance of genomic stability by inactivating both genes in mouse germ line. Combined ATM/H2AX deficiency caused embryonic lethality and dramatic cellular genomic instability. Mechanistically, severe genomic instability in the double-deficient cells is associated with a requirement for H2AX to repair oxidative DNA damage resulting from ATM deficiency. We discuss these findings in the context of synergies between ATM and other repair factors. C1 [Alt, Frederick W.] Harvard Univ, Howard Hughes Med Inst, Childrens Hosp, Immune Dis Inst,Med Sch, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Howard Hughes Med Inst, Childrens Hosp, Immune Dis Inst,Med Sch, 300 Longwood Ave, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu OI Sekiguchi, JoAnn/0000-0002-7178-4258 FU Howard Hughes Medical Institute; NCI NIH HHS [R01 CA125195-02, R01 CA125195, 5P01CA92625-06, P01 CA092625, 5P01 CA109901-03, 5P01 CA92625-06, P01 CA109901, 5R01 CA125195-02] NR 30 TC 52 Z9 56 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 8 PY 2008 VL 105 IS 27 BP 9302 EP 9306 DI 10.1073/pnas.0803520105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 326GA UT WOS:000257645400032 PM 18599436 ER PT J AU Zarrin, AA Goff, PH Senger, K Alt, FW AF Zarrin, Ali A. Goff, Peter H. Senger, Kate Alt, Frederick W. TI S gamma 3 switch sequences function in place of endogenous S gamma 1 to mediate antibody class switching SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HEAVY-CHAIN GENES; C-H TRANSCRIPTION; B-CELLS; SOMATIC HYPERMUTATION; RECOMBINATION SITES; SELECTIVE DEFECTS; REGION; SPECIFICITY; DNA; MECHANISM AB Immunoglobulin heavy chain (IgH) class switch recombination (CSR) replaces the initially expressed IgH C mu exons with a set of downstream IgH constant region (C H) exons. Individual sets of C H exons are flanked upstream by long (1-10-kb) repetitive switch (S) regions, with CSR involving a deletional recombination event between the donor S mu region and a downstream S region. Targeting CSR to specific S regions might be mediated by S region-specific factors. To test the role of endogenous S region sequences in targeting specific CSR events, we generated mutant B cells in which the endogenous 10-kb S gamma 1 region was replaced with wild-type (WT) or synthetic 2-kb S gamma 3 sequences or a synthetic 2-kb S gamma 1 sequence. We found that both the inserted endogenous and synthetic S gamma 3 sequences functioned similarly to a size-matched synthetic S gamma 1 sequence to mediate substantial CSR to IgG1 in mutant B cells activated under conditions that stimulate IgG1 switching in WT B cells. We conclude that S gamma 3 can function similarly to S gamma 1 in mediating endogenous CSR to IgG1. The approach that we have developed will facilitate assays for IgH isotype-specifi c functions of other endogenous S regions. C1 [Zarrin, Ali A.; Goff, Peter H.; Alt, Frederick W.] Harvard Univ, Sch Med, Immune Dis Inst, Childrens Hosp,Howard Hughes Med Inst, Boston, MA 02115 USA. [Zarrin, Ali A.; Goff, Peter H.; Alt, Frederick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Senger, Kate] Genentech Inc, Immunol Discovery Grp, San Francisco, CA 94080 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, Childrens Hosp,Howard Hughes Med Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu FU National Institutes of Health [AI31541]; Howard Hughes Medical Institute FX We thank Yuko Fujiwara and Nicole Stokes for generating RAG chimeras and Ming Tian for technical advice. We are grateful to Cherry Lei and Bill Forrest for statistical analyses.; This work was supported by National Institutes of Health grant AI31541 (to F.W. Alt). F.W. Alt is an Investigator of the Howard Hughes Medical Institute.; The authors have no conflicting financial interests. NR 29 TC 7 Z9 7 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 7 PY 2008 VL 205 IS 7 BP 1567 EP 1572 DI 10.1084/jem.20080451 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 338RS UT WOS:000258527000009 PM 18541713 ER PT J AU Peng, L Gardecki, JA Bouma, BE Tearney, GJ AF Peng, Leilei Gardecki, Joseph A. Bouma, Brett E. Tearney, Guillermo J. TI Fourier fluorescence spectrometer for excitation emission matrix measurement SO OPTICS EXPRESS LA English DT Article ID SPECTROFLUOROMETER; SPECTROSCOPY; TRANSFORM; TISSUE; DIAGNOSIS; FILTERS; SYSTEM AB We demonstrate a fluorescence spectrometer that utilizes principles of Fourier transform spectroscopy to measure excitation emission matrices (EEM) rapidly and with high spectral resolution. For this EEM fluorometer, incoherent excitation light is first input into a differential-delay scanning Michelson interferometer. Light from the output port excites sample fluorescence. The fluorescence remitted from the sample is directed to a second Michelson interferometer, whose differential-delay scanning is synchronized with the first interferometer. The EEM is obtained by two-dimensional Fourier analysis of the detected signal from the output port of the second interferometer. EEM results from the system are verified by comparing with results from a standard spectrometer. The system provides a wide spectral range, adjustable spectral resolution, and fast EEM acquisition speed, which allows EEM's to be acquired in 40 seconds at a spectral resolution of 81-cm(-1). (c) 2008 Optical Society of America. C1 Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. RP Peng, L (reprint author), Harvard Univ, Sch Med, 55 Fruit St,BAR 708, Boston, MA 02114 USA. EM lpeng1@partners.org NR 19 TC 4 Z9 4 U1 4 U2 6 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUL 7 PY 2008 VL 16 IS 14 BP 10493 EP 10500 DI 10.1364/OE.16.010493 PG 8 WC Optics SC Optics GA 325BV UT WOS:000257564100055 PM 18607462 ER PT J AU Song, Q Risco, R Latina, M Berthiaume, F Nahmias, Y Yarmush, ML AF Song, Q. Risco, R. Latina, M. Berthiaume, F. Nahmias, Y. Yarmush, M. L. TI Selective targeting of pigmented retinal pigment epithelial (RPE) cells by a single pulsed laser irradiation: an in vitro study SO OPTICS EXPRESS LA English DT Article AB This work describes the selective targeting of pigmented retinal pigment epithelial (RPE) cells by a single pulsed laser irradiation. We observed: (1) single pulsed laser irradiation caused cellular damages on pigmented, and not on non-pigmented RPE cells at laser radiant exposure up to 2550 mJ/cm(2); (2) in the mixture of pigmented and non-pigmented RPE cells, single pulsed laser-induced damage was confined to pigmented RPE cells. This study demonstrates that the pigmented RPE cells can be selectively damaged, using a single pulsed laser irradiation, without thermal coagulation to adjacent non-pigmented RPE cells. (c) 2008 Optical Society of America. C1 [Song, Q.; Latina, M.; Berthiaume, F.; Nahmias, Y.; Yarmush, M. L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Song, Q.; Latina, M.; Berthiaume, F.; Nahmias, Y.; Yarmush, M. L.] Shriners Burns Hosp, Boston, MA 02114 USA. [Risco, R.] Univ Seville, Escuela Super Ingn, Seville 41092, Spain. RP Yarmush, ML (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org RI Song, Qing/D-3509-2012; Nahmias, Yaakov/H-4725-2013; OI Risco Delgado, Ramon/0000-0001-5995-6590; Nahmias, Yaakov/0000-0002-6051-616X NR 17 TC 5 Z9 5 U1 0 U2 0 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD JUL 7 PY 2008 VL 16 IS 14 BP 10518 EP 10528 DI 10.1364/OE.16.010518 PG 11 WC Optics SC Optics GA 325BV UT WOS:000257564100058 PM 18607465 ER PT J AU Park, SJ Ionascu, D Killoran, J Mamede, M Gerbaudo, VH Chin, L Berbeco, R AF Park, Sang-June Ionascu, Dan Killoran, Joseph Mamede, Marcelo Gerbaudo, Victor H. Chin, Lee Berbeco, Ross TI Evaluation of the combined effects of target size, respiratory motion and background activity on 3D and 4D PET/CT images SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID CELL LUNG-CANCER; POSITRON-EMISSION-TOMOGRAPHY; DUAL-MODALITY PET/CT; BREATH-HOLD PET/CT; GROSS TUMOR VOLUME; ATTENUATION CORRECTION; COMPUTED-TOMOGRAPHY; F-18-FDG PET; AVERAGED CT; FDG-PET AB Gated (4D) PET/CT has the potential to greatly improve the accuracy of radiotherapy at treatment sites where internal organ motion is significant. However, the best methodology for applying 4D-PET/CT to target definition is not currently well established. With the goal of better understanding how to best apply 4D information to radiotherapy, initial studies were performed to investigate the effect of target size, respiratory motion and target-to-background activity concentration ratio (TBR) on 3D (ungated) and 4D PET images. Using a PET/CT scanner with 4D or gating capability, a full 3D-PET scan corrected with a 3D attenuation map from 3D-CT scan and a respiratory gated (4D) PET scan corrected with corresponding attenuation maps from 4D-CT were performed by imaging spherical targets (0.5-26.5 mL) filled with 18F-FDG in a dynamic thorax phantom and NEMA IEC body phantom at different TBRs (infinite, 8 and 4). To simulate respiratory motion, the phantoms were driven sinusoidally in the superior-inferior direction with amplitudes of 0, 1 and 2 cm and a period of 4.5 s. Recovery coefficients were determined on PET images. In addition, gating methods using different numbers of gating bins (1-20 bins) were evaluated with image noise and temporal resolution. For evaluation, volume recovery coefficient, signal-to-noise ratio and contrast-to-noise ratio were calculated as a function of the number of gating bins. Moreover, the optimum thresholds which give accurate moving target volumes were obtained for 3D and 4D images. The partial volume effect and signal loss in the 3D-PET images due to the limited PET resolution and the respiratory motion, respectively were measured. The results show that signal loss depends on both the amplitude and pattern of respiratory motion. However, the 4D-PET successfully recovers most of the loss induced by the respiratory motion. The 5-bin gating method gives the best temporal resolution with acceptable image noise. The results based on the 4D scan protocols can be used to improve the accuracy of determining the gross tumor volume for tumors in the lung and abdomen. C1 [Park, Sang-June; Ionascu, Dan; Killoran, Joseph; Chin, Lee; Berbeco, Ross] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. [Park, Sang-June; Ionascu, Dan; Killoran, Joseph; Chin, Lee; Berbeco, Ross] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Mamede, Marcelo; Gerbaudo, Victor H.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Nucl Med,Dept Radiol, Boston, MA 02115 USA. RP Park, SJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. EM spark@lroc.harvard.edu RI Mamede, Marcelo/A-1751-2014 OI Mamede, Marcelo/0000-0001-5818-0954 NR 39 TC 65 Z9 66 U1 0 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2008 VL 53 IS 13 BP 3661 EP 3679 DI 10.1088/0031-9155/53/13/018 PG 19 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 319YL UT WOS:000257200800019 PM 18562782 ER PT J AU Xu, XG Bednarz, B Paganetti, H AF Xu, X. George Bednarz, Bryan Paganetti, Harald TI A review of dosimetry studies on external-beam radiation treatment with respect to second cancer induction SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Review ID ATOMIC-BOMB SURVIVORS; NEUTRON DOSE-EQUIVALENT; INTENSITY-MODULATED RADIOTHERAPY; MEDICAL ELECTRON-ACCELERATORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; GAMMA-KNIFE RADIOSURGERY; MONTE-CARLO-SIMULATION; MV LINEAR-ACCELERATOR; LONG-TERM SURVIVORS; ENERGY X-RAYS AB It has been long known that patients treated with ionizing radiation carry a risk of developing a second cancer in their lifetimes. Factors contributing to the recently renewed concern about the second cancer include improved cancer survival rate, younger patient population as well as emerging treatment modalities such as intensity-modulated radiation treatment (IMRT) and proton therapy that can potentially elevate secondary exposures to healthy tissues distant from the target volume. In the past 30 years, external-beam treatment technologies have evolved significantly, and a large amount of data exist but appear to be difficult to comprehend and compare. This review article aims to provide readers with an understanding of the principles and methods related to scattered doses in radiation therapy by summarizing a large collection of dosimetry and clinical studies. Basic concepts and terminology are introduced at the beginning. That is followed by a comprehensive review of dosimetry studies for external-beam treatment modalities including classical radiation therapy, 3D-conformal x-ray therapy, intensity-modulated x-ray therapy (IMRT and tomotherapy) and proton therapy. Selected clinical data on second cancer induction among radiotherapy patients are also covered. Problems in past studies and controversial issues are discussed. The needs for future studies are presented at the end. C1 [Xu, X. George; Bednarz, Bryan] Rensselaer Polytech Inst, Troy, NY 12180 USA. [Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Xu, XG (reprint author), Rensselaer Polytech Inst, Troy, NY 12180 USA. FU NCI NIH HHS [R01CA116743, R01 CA116743] NR 295 TC 161 Z9 161 U1 2 U2 36 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD JUL 7 PY 2008 VL 53 IS 13 BP R193 EP R241 DI 10.1088/0031-9155/53/13/R01 PG 49 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 319YL UT WOS:000257200800001 PM 18540047 ER PT J AU Djebbari, A Quackenbush, J AF Djebbari, Amira Quackenbush, John TI Seeded Bayesian Networks: Constructing genetic networks from microarray data SO BMC SYSTEMS BIOLOGY LA English DT Article ID EXPRESSION DATA; RB/E2F PATHWAY; LEUKEMIA; CLASSIFICATION; INFORMATION; CANCER; TM4 AB Background: DNA microarrays and other genomics-inspired technologies provide large datasets that often include hidden patterns of correlation between genes reflecting the complex processes that underlie cellular metabolism and physiology. The challenge in analyzing large-scale expression data has been to extract biologically meaningful inferences regarding these processes - often represented as networks - in an environment where the datasets are often imperfect and biological noise can obscure the actual signal. Although many techniques have been developed in an attempt to address these issues, to date their ability to extract meaningful and predictive network relationships has been limited. Here we describe a method that draws on prior information about gene-gene interactions to infer biologically relevant pathways from microarray data. Our approach consists of using preliminary networks derived from the literature and/or protein-protein interaction data as seeds for a Bayesian network analysis of microarray results. Results: Through a bootstrap analysis of gene expression data derived from a number of leukemia studies, we demonstrate that seeded Bayesian Networks have the ability to identify high-confidence gene-gene interactions which can then be validated by comparison to other sources of pathway data. Conclusion: The use of network seeds greatly improves the ability of Bayesian Network analysis to learn gene interaction networks from gene expression data. We demonstrate that the use of seeds derived from the biomedical literature or high-throughput protein-protein interaction data, or the combination, provides improvement over a standard Bayesian Network analysis, allowing networks involving dynamic processes to be deduced from the static snapshots of biological systems that represent the most common source of microarray data. Software implementing these methods has been included in the widely used TM4 microarray analysis package. C1 [Quackenbush, John] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Quackenbush, J (reprint author), Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. EM amirad@gmail.com; johnq@jimmy.harvard.edu NR 38 TC 48 Z9 50 U1 0 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD JUL 4 PY 2008 VL 2 AR 57 DI 10.1186/1752-0509-2-57 PG 13 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 328NB UT WOS:000257804000001 PM 18601736 ER PT J AU Kim, MH Choi, BH Jung, SR Sernka, TJ Kim, S Kim, KT Hille, B Nguyen, TD Koh, DS AF Kim, Mean-Hwan Choi, Bo-Hwa Jung, Seung-Ryoung Sernka, Thomas J. Kim, Seunghwan Kim, Kyong-Tai Hille, Bertil Nguyen, Toan D. Koh, Duk-Su TI Protease-activated receptor-2 increases exocytosis via multiple signal transduction pathways in pancreatic duct epithelial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOLECULAR-CLONING; SECRETION; AMPEROMETRY; CA2+; MECHANISMS; PROTECTION AB Protease-activated receptor-2 (PAR-2) is activated when trypsin cleaves its NH2 terminus to expose a tethered ligand. We previously demonstrated that PAR-2 activates ion channels in pancreatic duct epithelial cells (PDEC). Using real-time optical fluorescent probes, cyan fluorescence protein-Epac1-yellow fluorescence protein for cAMP, PHPLC-delta 1-enhanced green fluorescent protein for phosphatidylinositol 4,5-bisphosphate, and protein kinase C gamma (PKC gamma)-C1-yellow fluorescence protein for diacylglycerol, we now define the signaling pathways mediating PAR-2 effect in dog PDEC. Although PAR-2 activation does not stimulate acAMPincrease, it induces phospholipase C to hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate and diacylglycerol. Intracellular Ca2+ mobilization from inositol 1,4,5-trisphosphate- sensitive Ca2+ stores and a subsequent Ca2+ influx through store-operated Ca2+ channels cause a biphasic increase in intracellular Ca2+ concentration ([Ca2+](i)), measured with Indo-1 dye. Single-cell amperometry demonstrated that this increase in [Ca2+] i in turn causes a biphasic increase in exocytosis. A protein kinase assay revealed that trypsin also activates PKC isozymes to stimulate additional exocytosis. Paralleling the increased exocytosis, mucin secretion from PDEC was also induced by trypsin or the PAR-2 activating peptide. Consistent with the serosal localization of PAR-2, 1 mu M luminal trypsin did not induce exocytosis in polarized PDEC monolayers; on the other hand, 10 mu M trypsin at 37 degrees C damaged the epithelial barrier sufficiently so that it could reach and activate the serosal PAR-2 to stimulate exocytosis. Thus, in PDEC, PAR-2 activation increases [Ca2+](i) and activates PKC to stimulate exocytosis and mucin secretion. These functions may mediate the reported protective role of PAR-2 in different models of pancreatitis. C1 [Koh, Duk-Su] Univ Washington, Sch Med, Dept Physiol & Biophys, Seattle, WA 98195 USA. [Kim, Mean-Hwan; Jung, Seung-Ryoung; Kim, Seunghwan; Koh, Duk-Su] POSTECH, Dept Phys, Pohang 790784, South Korea. [Choi, Bo-Hwa; Kim, Kyong-Tai] POSTECH, Dept Life Sci, Pohang 790784, South Korea. [Sernka, Thomas J.; Nguyen, Toan D.] Univ Washington, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. [Nguyen, Toan D.] Univ Washington, Dept Med, Seattle, WA 98195 USA. RP Koh, DS (reprint author), Univ Washington, Sch Med, Dept Physiol & Biophys, Hlth Sci Bldg, Seattle, WA 98195 USA. EM koh@u.washington.edu FU NIDDK NIH HHS [DK55885]; NIGMS NIH HHS [GM083913] NR 29 TC 17 Z9 18 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 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 4 PY 2008 VL 283 IS 27 BP 18711 EP 18720 DI 10.1074/jbc.M801655200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 319LR UT WOS:000257165600028 PM 18448425 ER PT J AU Sugiura, T Nakanishi, H Roberts, JD AF Sugiura, Takahiro Nakanishi, Hidehiko Roberts, Jesse D., Jr. TI Proteolytic processing of cGMP-dependent protein kinase I mediates nuclear cGMP signaling in vascular smooth muscle cells SO CIRCULATION RESEARCH LA English DT Article DE cGKI; guanylate cyclase; gene expression regulation; signal transduction; vascular disease ID CYCLIC-GMP; GENE-EXPRESSION; GOLGI-COMPLEX; FOS PROMOTER; NITRIC-OXIDE; ACTIVATION; TRANSCRIPTION; IDENTIFICATION; TRANSLOCATION; TRANSDUCTION AB Cyclic GMP modulates gene expression in vascular smooth muscle cells (SMCs) in part by stimulating cGMP-dependent protein kinase I (PKGI) and the phosphorylation of transcription factors. In some cells, cGMP increases nuclear translocation of PKGI and PKGI-dependent phosphorylation of transcription regulators; however, these observations have been variable, and the mechanisms mediating nuclear PKGI translocation are incompletely understood. We tested the hypothesis that proteolytic cleavage of PKGI is required for cGMP-stimulated nuclear compartmentation of PKGI and phosphorylation of transcription factors. We detected an NH(2)-terminal PKGI fragment with leucine zipper domain immunoreactivity in the cytosol and endoplasmic reticulum of SMCs, but only a COOH-terminal PKGI fragment containing the catalytic region (now termed PKGI gamma) was observed in the Golgi apparatus (GA) and nucleoplasm. Posttranslational PKGI processing in the GA was critical for nuclear compartmentation of PKGI gamma because GA disruption with nocodazol or brefeldin A inhibited PKGI gamma nuclear localization. PKGI gamma immunoreactivity was particularly abundant in the nucleolus of interphase SMCs where its colocalization with the nucleolar dense fibrillar component protein fibrillarin closely matched the level of nucleolar assembly. Purified nucleolar PKGI gamma enzyme activity was insensitive to cGMP stimulation, which is consistent with its lack of the NH(2)-terminal autoinhibitory domain. Mutation of a putative proteolytic cleavage region in PKGI inhibited cGMP-mediated phosphorylation of cAMP response element-binding protein, cAMP response element-dependent transcription, and nuclear localization of PKGI gamma. These observations suggest that posttranslational modification of PKGI critically influences the nuclear translocation of PKGI and activities of cGMP in SMCs. C1 [Sugiura, Takahiro; Nakanishi, Hidehiko; Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Dept Anesthesia, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Roberts, Jesse D., Jr.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Roberts, JD (reprint author), MGH-E,CVRC 4th Floor,149 13th St, Charlestown, MA 02129 USA. EM roberts@cvrc.mgh.harvard.edu FU NHLBI NIH HHS [R01 HL080316-04, R01 HL080316, HL080316] NR 40 TC 8 Z9 8 U1 0 U2 1 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 JUL 3 PY 2008 VL 103 IS 1 BP 53 EP 60 DI 10.1161/CIRCRESAHA.108.176321 PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 321WR UT WOS:000257337700010 PM 18535260 ER PT J AU Mikkelsen, TS Hanna, J Zhang, XL Ku, MC Wernig, M Schorderet, P Bernstein, BE Jaenisch, R Lander, ES Meissner, A AF Mikkelsen, Tarjei S. Hanna, Jacob Zhang, Xiaolan Ku, Manching Wernig, Marius Schorderet, Patrick Bernstein, Bradley E. Jaenisch, Rudolf Lander, Eric S. Meissner, Alexander TI Dissecting direct reprogramming through integrative genomic analysis SO NATURE LA English DT Article ID PLURIPOTENT STEM-CELLS; HUMAN SOMATIC-CELLS; DEFINED FACTORS; HUMAN FIBROBLASTS; GENERATION; MOUSE; MYC; EXPRESSION; INDUCTION; STATE AB Somatic cells can be reprogrammed to a pluripotent state through the ectopic expression of defined transcription factors. Understanding the mechanism and kinetics of this transformation may shed light on the nature of developmental potency and suggest strategies with improved efficiency or safety. Here we report an integrative genomic analysis of reprogramming of mouse fibroblasts and B lymphocytes. Lineage- committed cells show a complex response to the ectopic expression involving induction of genes downstream of individual reprogramming factors. Fully reprogrammed cells show gene expression and epigenetic states that are highly similar to embryonic stem cells. In contrast, stable partially reprogrammed cell lines show reactivation of a distinctive subset of stem- cell- related genes, incomplete repression of lineage- specifying transcription factors, and DNA hypermethylation at pluripotency- related loci. These observations suggest that some cells may become trapped in partially reprogrammed states owing to incomplete repression of transcription factors, and that DNA de- methylation is an inefficient step in the transition to pluripotency. We demonstrate that RNA inhibition of transcription factors can facilitate reprogramming, and that treatment with DNA methyltransferase inhibitors can improve the overall efficiency of the reprogramming process. C1 [Mikkelsen, Tarjei S.; Zhang, Xiaolan; Bernstein, Bradley E.; Lander, Eric S.; Meissner, Alexander] MIT, Broad Inst, Cambridge, MA 02142 USA. [Mikkelsen, Tarjei S.; Zhang, Xiaolan; Bernstein, Bradley E.; Lander, Eric S.; Meissner, Alexander] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Mikkelsen, Tarjei S.] MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Jaenisch, Rudolf; Lander, Eric S.] MIT, Dept Biol, Cambridge, MA 02139 USA. [Hanna, Jacob; Wernig, Marius; Schorderet, Patrick; Jaenisch, Rudolf; Lander, Eric S.] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Ku, Manching; Bernstein, Bradley E.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Ku, Manching; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Bernstein, Bradley E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Lander, Eric S.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02114 USA. [Meissner, Alexander] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Meissner, A (reprint author), MIT, Broad Inst, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM alex@broad.mit.edu RI Mikkelsen, Tarjei/A-1306-2007; jia, xu/A-8386-2016; HANNA, JACOB/K-1339-2012 OI Mikkelsen, Tarjei/0000-0002-8133-3135; HANNA, JACOB/0000-0003-2042-9974 FU NHGRI NIH HHS [U54 HG003067, U54 HG003067-04] NR 33 TC 845 Z9 901 U1 3 U2 74 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 3 PY 2008 VL 454 IS 7200 BP 49 EP U1 DI 10.1038/nature07056 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 321MC UT WOS:000257308300033 PM 18509334 ER PT J AU Zhou, B Ma, Q Rajagopal, S Wu, SM Domian, I Rivera-Feliciano, J Jiang, DW von Gise, A Ikeda, S Chien, KR Pu, WT AF Zhou, Bin Ma, Qing Rajagopal, Satish Wu, Sean M. Domian, Ibrahim Rivera-Feliciano, Jose Jiang, Dawei von Gise, Alexander Ikeda, Sadakatsu Chien, Kenneth R. Pu, William T. TI Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart SO NATURE LA English DT Article ID SMOOTH-MUSCLE-CELLS; CARDIOVASCULAR PROGENITORS; PERICARDIAL MESODERM; REPORTER STRAIN; EXPRESSION; ORIGIN; MOUSE; NEOVASCULARIZATION; DIFFERENTIATION; POPULATION AB The heart is formed from cardiogenic progenitors expressing the transcription factors Nkx2-5 and Isl1 ( refs 1 and 2). These multipotent progenitors give rise to cardiomyocyte, smooth muscle and endothelial cells, the major lineages of the mature heart(3,4). Here we identify a novel cardiogenic precursor marked by expression of the transcription factor Wt1 and located within the epicardium - an epithelial sheet overlying the heart. During normal murine heart development, a subset of these Wt1(+) precursors differentiated into fully functional cardiomyocytes. Wt1(+) proepicardial cells arose from progenitors that express Nkx2-5 and Isl1, suggesting that they share a developmental origin with multipotent Nkx2-5(+) and Isl1(+) progenitors. These results identify Wt1(+) epicardial cells as previously unrecognized cardiomyocyte progenitors, and lay the foundation for future efforts to harness the cardiogenic potential of these progenitors for cardiac regeneration and repair. C1 [Zhou, Bin; Ma, Qing; Rajagopal, Satish; Jiang, Dawei; von Gise, Alexander; Ikeda, Sadakatsu; Pu, William T.] Childrens Hosp, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Zhou, Bin; Ma, Qing; Rajagopal, Satish; Jiang, Dawei; von Gise, Alexander; Ikeda, Sadakatsu; Pu, William T.] Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. [Zhou, Bin; Ma, Qing; Rajagopal, Satish; Rivera-Feliciano, Jose; von Gise, Alexander; Ikeda, Sadakatsu; Pu, William T.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Wu, Sean M.; Domian, Ibrahim; Chien, Kenneth R.] Harvard Univ, Harvard Stem Cell Inst, Boston, MA 02114 USA. [Wu, Sean M.; Domian, Ibrahim; Chien, Kenneth R.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [von Gise, Alexander] Charite Univ Med Berlin, Clin Neonatol, D-10117 Berlin, Germany. RP Pu, WT (reprint author), Childrens Hosp, Harvard Stem Cell Inst, 300 Longwood Ave, Boston, MA 02115 USA. EM wpu@enders.tch.harvard.edu FU NHLBI NIH HHS [P50 HL074734, P50 HL074734-05] NR 36 TC 461 Z9 477 U1 4 U2 40 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 3 PY 2008 VL 454 IS 7200 BP 109 EP U5 DI 10.1038/nature07060 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 321MC UT WOS:000257308300047 PM 18568026 ER PT J AU Mansy, SS Schrum, JP Krishnamurthy, M Tobe, S Treco, DA Szostak, JW AF Mansy, Sheref S. Schrum, Jason P. Krishnamurthy, Mathangi Tobe, Sylvia Treco, Douglas A. Szostak, Jack W. TI Template-directed synthesis of a genetic polymer in a model protocell SO NATURE LA English DT Article ID FATTY-ACID VESICLES; MONOCARBOXYLIC ACIDS; BILAYERS; GROWTH; OLIGOMERIZATION; ENCAPSULATION; PHOSPHATES; STABILITY; LIPOSOMES; ALCOHOLS AB Contemporary phospholipid- based cell membranes are formidable barriers to the uptake of polar and charged molecules ranging from metal ions to complex nutrients. Modern cells therefore require sophisticated protein channels and pumps to mediate the exchange of molecules with their environment. The strong barrier function of membranes has made it difficult to understand the origin of cellular life and has been thought to preclude a heterotrophic lifestyle for primitive cells. Although nucleotides can cross dimyristoyl phosphatidylcholine membranes through defects formed at the gel- to- liquid transition temperature(1,2), phospholipid membranes lack the dynamic properties required for membrane growth. Fatty acids and their corresponding alcohols and glycerol monoesters are attractive candidates for the components of protocell membranes because they are simple amphiphiles that form bilayer membrane vesicles(3-5) that retain encapsulated oligonucleotides(3,6) and are capable of growth and division(7-9). Here we show that such membranes allow the passage of charged molecules such as nucleotides, so that activated nucleotides added to the outside of a model protocell spontaneously cross the membrane and take part in efficient template copying in the protocell interior. The permeability properties of prebiotically plausible membranes suggest that primitive protocells could have acquired complex nutrients from their environment in the absence of any macromolecular transport machinery; that is, they could have been obligate heterotrophs. C1 [Mansy, Sheref S.; Schrum, Jason P.; Krishnamurthy, Mathangi; Tobe, Sylvia; Treco, Douglas A.; Szostak, Jack W.] Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA. [Mansy, Sheref S.; Schrum, Jason P.; Krishnamurthy, Mathangi; Tobe, Sylvia; Treco, Douglas A.; Szostak, Jack W.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Howard Hughes Med Inst, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu RI Mansy, Sheref/E-6266-2010; OI Mansy, Sheref/0000-0003-2382-198X FU Howard Hughes Medical Institute; NIGMS NIH HHS [F32 GM074506-01, F32 GM07450601] NR 34 TC 297 Z9 307 U1 18 U2 135 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 3 PY 2008 VL 454 IS 7200 BP 122 EP U10 DI 10.1038/nature07018 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 321MC UT WOS:000257308300050 PM 18528332 ER PT J AU Palevsky, PM Zhang, JHY O'Connor, TZ Chertow, GM Crowley, ST Choudhury, D Finkel, K Kellum, JA Paganini, E Schein, RMH Smith, MW Swanson, KM Thompson, BT Vijayan, A Watnick, S Star, RA Peduzzi, P AF Palevsky, Paul M. Zhang, Jane Hongyuan O'Connor, Theresa Z. Chertow, Glenn M. Crowley, Susan T. Choudhury, Devasmita Finkel, Kevin Kellum, John A. Paganini, Emil Schein, Roland M. H. Smith, Mark W. Swanson, Kathleen M. Thompson, B. Taylor Vijayan, Anitha Watnick, Suzanne Star, Robert A. Peduzzi, Peter CA VA NIH Acute Renal Failure Trial TI Intensity of renal support in critically ill patients with acute kidney injury SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONTINUOUS VENOVENOUS HEMOFILTRATION; REPLACEMENT THERAPY; CARE-UNIT; RANDOMIZED-TRIAL; FAILURE; MULTICENTER; EXPERIENCE; MANAGEMENT; MORTALITY; SURVIVAL AB Background: The optimal intensity of renal-replacement therapy in critically ill patients with acute kidney injury is controversial. Methods: We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. Results: Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P=0.47). There was no significant difference between the two groups in the duration of renal-replacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. Conclusions: Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.). C1 [Palevsky, Paul M.] VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. [Chertow, Glenn M.] Stanford Univ, Palo Alto, CA 94304 USA. [Zhang, Jane Hongyuan; O'Connor, Theresa Z.; Crowley, Susan T.; Peduzzi, Peter] VA Connecticut Healthcare Syst, CSP Coordinating Ctr, West Haven, CT USA. [Choudhury, Devasmita] VA N Texas Healthcare Syst, Dallas, TX USA. [Kellum, John A.] Univ Pittsburgh, Pittsburgh, PA USA. [Paganini, Emil] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Schein, Roland M. H.] Miami VA Healthcare Syst, Miami, FL USA. [Smith, Mark W.] VA Palo Alto Hlth Care Syst, Hlth Econ Resource Ctr, Menlo Pk, CA USA. [Swanson, Kathleen M.] Clin Res Pharm Coordinating Ctr, CSP, Albuquerque, NM USA. [Thompson, B. Taylor] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Star, Robert A.] NIDDK, Bethesda, MD 20892 USA. RP Palevsky, PM (reprint author), VA Pittsburgh Healthcare Syst, Rm 7E123 111F-U,Univ Dr, Pittsburgh, PA 15240 USA. EM palevsky@pitt.edu RI Smith, Mark/G-1522-2012 OI Smith, Mark/0000-0002-4582-9088 NR 31 TC 624 Z9 673 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 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 3 PY 2008 VL 359 IS 1 BP 7 EP 20 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 320PB UT WOS:000257246000003 ER PT J AU Sherman, SI Wirth, LJ Droz, JP Hofmann, M Bastholt, L Martins, RG Licitra, L Eschenberg, MJ Sun, YN Juan, T Stepan, DE Schlumberger, MJ AF Sherman, Steven I. Wirth, Lori J. Droz, Jean-Pierre Hofmann, Michael Bastholt, Lars Martins, Renato G. Licitra, Lisa Eschenberg, Michael J. Sun, Yu-Nien Juan, Todd Stepan, Daniel E. Schlumberger, Martin J. CA Motesanib Thyroid Canc Study Grp TI Motesanib diphosphate in progressive differentiated thyroid cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; PHASE-II TRIAL; MULTIKINASE INHIBITOR; SOLID TUMORS; FACTOR VEGF; CARCINOMA; PAPILLARY; EXPRESSION; THERAPY; HYPOTHYROIDISM AB Background: The expression of vascular endothelial growth factor (VEGF) is characteristic of differentiated thyroid cancer and is associated with aggressive tumor behavior and a poor clinical outcome. Motesanib diphosphate (AMG 706) is a novel oral inhibitor of VEGF receptors, platelet-derived growth-factor receptor, and KIT. Methods: In an open-label, single-group, phase 2 study, we treated 93 patients who had progressive, locally advanced or metastatic, radioiodine-resistant differentiated thyroid cancer with 125 mg of motesanib diphosphate, administered orally once daily. The primary end point was an objective response as assessed by an independent radiographic review. Additional end points included the duration of the response, progression-free survival, safety, and changes in serum thyroglobulin concentration. Results: Of the 93 patients, 57 (61%) had papillary thyroid carcinoma. The objective response rate was 14%. Stable disease was achieved in 67% of the patients, and stable disease was maintained for 24 weeks or longer in 35%; 8% had progressive disease as the best response. The Kaplan-Meier estimate of the median duration of the response was 32 weeks (the lower limit of the 95% confidence interval [CI] was 24; the upper limit could not be estimated because of an insufficient number of events); the estimate of median progression-free survival was 40 weeks (95% CI, 32 to 50). Among the 75 patients in whom thyroglobulin analysis was performed, 81% had decreased serum thyroglobulin concentrations during treatment, as compared with baseline levels. The most common treatment-related adverse events were diarrhea (in 59% of the patients), hypertension (56%), fatigue (46%), and weight loss (40%). Conclusions: Motesanib diphosphate can induce partial responses in patients with advanced or metastatic differentiated thyroid cancer that is progressive. (ClinicalTrials.gov number, NCT00121628.). C1 [Sherman, Steven I.] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Unit 435, Houston, TX 77230 USA. [Wirth, Lori J.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Droz, Jean-Pierre] Ctr Leon Berard, F-69373 Lyon, France. [Hofmann, Michael] Med Sch Bern, Bern, Switzerland. [Bastholt, Lars] Odense Univ Hosp, DK-5000 Odense, Denmark. [Martins, Renato G.] Univ Washington, Seattle, WA 98195 USA. [Licitra, Lisa] Ist Nazl Tumori, I-20133 Milan, Italy. [Eschenberg, Michael J.; Sun, Yu-Nien; Juan, Todd; Stepan, Daniel E.] Amgen Inc, Thousand Oaks, CA USA. [Schlumberger, Martin J.] Univ Paris 11, Inst Gustave Roussy, Villejuif, France. RP Sherman, SI (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Unit 435, 1515 Holcombe Blvd,POB 301402, Houston, TX 77230 USA. EM sisherma@mdanderson.org RI Licitra, Lisa/C-6271-2017; OI Licitra, Lisa/0000-0003-0623-4118; Sherman, Steven/0000-0002-3079-5153 FU Associazione Italiana per la Ricerca sul Cancro NR 29 TC 287 Z9 296 U1 0 U2 16 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 3 PY 2008 VL 359 IS 1 BP 31 EP 42 DI 10.1056/NEJMoa075853 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 320PB UT WOS:000257246000005 PM 18596272 ER PT J AU DesRoches, CM Campbell, EG Rao, SR Donelan, K Ferris, TG Jha, A Kaushal, R Levy, DE Rosenbaum, S Shields, AE Blumenthal, D AF DesRoches, Catherine M. Campbell, Eric G. Rao, Sowmya R. Donelan, Karen Ferris, Timothy G. Jha, Ashish Kaushal, Rainu Levy, Douglas E. Rosenbaum, Sara Shields, Alexandra E. Blumenthal, David TI Electronic health records in ambulatory care - A national survey of physicians SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SYSTEMS; COSTS AB Background: Electronic health records have the potential to improve the delivery of health care services. However, in the United States, physicians have been slow to adopt such systems. This study assessed physicians' adoption of outpatient electronic health records, their satisfaction with such systems, the perceived effect of the systems on the quality of care, and the perceived barriers to adoption. Methods: In late 2007 and early 2008, we conducted a national survey of 2758 physicians, which represented a response rate of 62%. Using a definition for electronic health records that was based on expert consensus, we determined the proportion of physicians who were using such records in an office setting and the relationship between adoption and the characteristics of individual physicians and their practices. Results: Four percent of physicians reported having an extensive, fully functional electronic-records system, and 13% reported having a basic system. In multivariate analyses, primary care physicians and those practicing in large groups, in hospitals or medical centers, and in the western region of the United States were more likely to use electronic health records. Physicians reported positive effects of these systems on several dimensions of quality of care and high levels of satisfaction. Financial barriers were viewed as having the greatest effect on decisions about the adoption of electronic health records. Conclusions: Physicians who use electronic health records believe such systems improve the quality of care and are generally satisfied with the systems. However, as of early 2008, electronic systems had been adopted by only a small minority of U.S. physicians, who may differ from later adopters of these systems. C1 [DesRoches, Catherine M.; Campbell, Eric G.; Rao, Sowmya R.; Donelan, Karen; Levy, Douglas E.; Shields, Alexandra E.; Blumenthal, David] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Ferris, Timothy G.] Massachusetts Gen Hosp, Massachusetts Gen Phys Org, Boston, MA 02114 USA. [Jha, Ashish] Harvard Univ, Sch Med, Boston, MA USA. [Kaushal, Rainu] Weill Cornell Med Coll, New York, NY USA. [Rosenbaum, Sara] George Washington Univ, Dept Hlth Policy, Washington, DC USA. RP DesRoches, CM (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, Suite 900,50 Staniford St, Boston, MA 02114 USA. EM cdesroches@partners.org RI Chang, Shulan/H-2270-2011 NR 17 TC 544 Z9 550 U1 4 U2 57 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUL 3 PY 2008 VL 359 IS 1 BP 50 EP 60 DI 10.1056/NEJMsa0802005 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 320PB UT WOS:000257246000007 PM 18565855 ER PT J AU O'Donoghue, M Boden, WE Braunwald, E Cannon, CP Clayton, TC de Winter, RJ Fox, KAA Lagerqvist, B McCullough, PA Murphy, SA Spacek, R Swahn, E Wallentin, L Windhausen, F Sabatine, MS AF O'Donoghue, Michelle Boden, William E. Braunwald, Eugene Cannon, Christopher P. Clayton, Tim C. de Winter, Robbert J. Fox, Keith A. A. Lagerqvist, Bo McCullough, Peter A. Murphy, Sabina A. Spacek, Rudolf Swahn, Eva Wallentin, Lars Windhausen, Fons Sabatine, Marc S. TI Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction - A meta-analysis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID ACUTE CORONARY SYNDROMES; RITA-3 RANDOMIZED-TRIAL; ARTERY-BYPASS-SURGERY; INTERVENTIONAL STRATEGY; CLINICAL-TRIALS; TIMI IIIB; MORTALITY; MULTICENTER; DISEASE; REVASCULARIZATION AB Context Although an invasive strategy is frequently used in patients with non - ST-segment elevation acute coronary syndromes ( NSTE ACS), data from some trials suggest that this strategy may not benefit women. Objective To conduct a meta- analysis of randomized trials to compare the effects of an invasive vs conservative strategy in women and men with NSTE ACS. Data Sources Trials were identified through a computerized literature search of the MEDLINE and Cochrane databases ( 1970- April 2008) using the search terms invasive strategy, conservative strategy, selective invasive strategy, acute coronary syndromes, non- ST- elevation myocardial infarction, and unstable angina. Study Selection Randomized clinical trials comparing an invasive vs conservative treatment strategy in patients with NSTE ACS. Data Extraction The principal investigators for each trial provided the sex- specific incidences of death, myocardial infarction ( MI), and rehospitalization with ACS through 12 months of follow- up. Data Synthesis Data were combined across 8 trials ( 3075 women and 7075 men). The odds ratio ( OR) for the composite of death, MI, or ACS for invasive vs conservative strategy in women was 0.81 ( 95% confidence interval [ CI], 0.65- 1.01; 21.1% vs 25.0%) and in men was 0.73 ( 95% CI, 0.55- 0.98; 21.2% vs 26.3%) without significant heterogeneity between sexes ( P for interaction=. 26). Among biomarker- positive women, an invasive strategy was associated with a 33% lower odds of death, MI, or ACS ( OR, 0.67; 95% CI, 0.50- 0.88) and a nonsignificant 23% lower odds of death or MI ( OR, 0.77; 95% CI, 0.47- 1.25). In contrast, an invasive strategy was not associated with a significant reduction in the triple composite end point in biomarker- negative women ( OR, 0.94; 95% CI, 0.61- 1.44; P for interaction=. 36) and was associated with a nonsignificant 35% higher odds of death or MI ( OR, 1.35; 95% CI, 0.78- 2.35; P for interaction=. 08). Among men, the OR for death, MI, or ACS was 0.56 ( 95% CI, 0.46- 0.67) if biomarker- positive and 0.72 ( 95% CI, 0.51- 1.01) if biomarker- negative ( P for interaction=. 09). Conclusions In NSTE ACS, an invasive strategy has a comparable benefit in men and high- risk women for reducing the composite end point of death, MI, or rehospitalization with ACS. In contrast, our data provide evidence supporting the new guideline recommendation for a conservative strategy in low- risk women. C1 [O'Donoghue, Michelle; Braunwald, Eugene; Cannon, Christopher P.; Murphy, Sabina A.; Sabatine, Marc S.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [O'Donoghue, Michelle] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Boden, William E.] Buffalo Gen Hosp, Buffalo, NY 14203 USA. [Clayton, Tim C.] London Sch Hyg & Trop Med, London WC1, England. [de Winter, Robbert J.; Windhausen, Fons] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Fox, Keith A. A.] Univ Edinburgh, Edinburgh, Midlothian, Scotland. [Fox, Keith A. A.] Royal Infirm, Edinburgh, Midlothian, Scotland. [Lagerqvist, Bo; Wallentin, Lars] Univ Uppsala Hosp, Uppsala, Sweden. [McCullough, Peter A.] William Beaumont Hosp, Royal Oak, MI 48072 USA. [Spacek, Rudolf] Hosp Na Frantisku, Prague, Czech Republic. [Swahn, Eva] Linkoping Univ Hosp, S-58185 Linkoping, Sweden. RP O'Donoghue, M (reprint author), Brigham & Womens Hosp, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM modonoghue@partners.org FU NHLBI NIH HHS [U01 HL083-1341] NR 40 TC 172 Z9 180 U1 2 U2 11 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUL 2 PY 2008 VL 300 IS 1 BP 71 EP 80 DI 10.1001/jama.300.1.71 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 320NW UT WOS:000257242800026 PM 18594042 ER PT J AU Dusek, JA Otu, HH Wohlhueter, AL Bhasin, M Zerbini, LF Joseph, MG Benson, H Libermann, TA AF Dusek, Jeffery A. Otu, Hasan H. Wohlhueter, Ann L. Bhasin, Manoj Zerbini, Luiz F. Joseph, Marie G. Benson, Herbert Libermann, Towia A. TI Genomic Counter-Stress Changes Induced by the Relaxation Response SO PLOS ONE LA English DT Article AB Background: Mind-body practices that elicit the relaxation response (RR) have been used worldwide for millennia to prevent and treat disease. The RR is characterized by decreased oxygen consumption, increased exhaled nitric oxide, and reduced psychological distress. It is believed to be the counterpart of the stress response that exhibits a distinct pattern of physiology and transcriptional profile. We hypothesized that RR elicitation results in characteristic gene expression changes that can be used to measure physiological responses elicited by the RR in an unbiased fashion. Methods/Principal Findings: We assessed whole blood transcriptional profiles in 19 healthy, long-term practitioners of daily RR practice (group M), 19 healthy controls (group N(1)), and 20 N(1) individuals who completed 8 weeks of RR training (group N(2)). 2209 genes were differentially expressed in group M relative to group N(1) (p < 0.05) and 1561 genes in group N(2) compared to group N(1) (p, 0.05). Importantly, 433 (p, 10210) of 2209 and 1561 differentially expressed genes were shared among long-term (M) and short-term practitioners (N(2)). Gene ontology and gene set enrichment analyses revealed significant alterations in cellular metabolism, oxidative phosphorylation, generation of reactive oxygen species and response to oxidative stress in long-term and short-term practitioners of daily RR practice that may counteract cellular damage related to chronic psychological stress. A significant number of genes and pathways were confirmed in an independent validation set containing 5 N(1) controls, 5 N(2) short-term and 6 M long-term practitioners. Conclusions/Significance: This study provides the first compelling evidence that the RR elicits specific gene expression changes in short-term and long-term practitioners. Our results suggest consistent and constitutive changes in gene expression resulting from RR may relate to long term physiological effects. Our study may stimulate new investigations into applying transcriptional profiling for accurately measuring RR and stress related responses in multiple disease settings. C1 [Dusek, Jeffery A.; Wohlhueter, Ann L.; Benson, Herbert] Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Chestnut Hill, MA USA. [Dusek, Jeffery A.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA USA. [Dusek, Jeffery A.; Otu, Hasan H.; Bhasin, Manoj; Zerbini, Luiz F.; Benson, Herbert; Libermann, Towia A.] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Division of Interdisciplinary Med & Biotechnol, Boston, MA USA. [Otu, Hasan H.; Bhasin, Manoj; Zerbini, Luiz F.; Joseph, Marie G.; Libermann, Towia A.] Beth Israel Deaconess Med Ctr, BIDMC Genom Ctr, Boston, MA USA. [Benson, Herbert] Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. [Dusek, Jeffery A.] Abbott NW Hosp, Inst Hlth & Healing, Minneapolis, MN USA. RP Dusek, JA (reprint author), Massachusetts Gen Hosp, Benson Henry Inst Mind Body Med, Chestnut Hill, MA USA. EM hbenson@partners.org; tliberma@bidmc.harvard.edu RI Zerbini, Luiz /B-7720-2015; OI Libermann, Towia/0000-0002-4006-8179; Dusek, Jeffery/0000-0001-9581-0564; Otu, Hasan/0000-0002-9253-8152 FU Centers for Disease Control and Prevention (CDC) [H75/CCH 19124, H75/CCH 123424, R01 DP000339]; National Institutes of Health [M01 RR01032] FX The study was funded by grants H75/CCH 19124, H75/CCH 123424 and R01 DP000339 (HB) from the Centers for Disease Control and Prevention (CDC) and M01 RR01032 (HB) from the National Institutes of Health (to Harvard-Thorndike BIDMC GCRC). NR 38 TC 81 Z9 81 U1 3 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 2 PY 2008 VL 3 IS 7 AR e2576 DI 10.1371/journal.pone.0002576 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 406IM UT WOS:000263288200041 PM 18596974 ER PT J AU Singh, AK Gervais, DA Hahn, PF Mueller, PR AF Singh, Ajay K. Gervais, Debra A. Hahn, Peter F. Mueller, Peter R. TI Neoplastic iliopsoas masses in oncology patients: CT findings SO ABDOMINAL IMAGING LA English DT Article ID SKELETAL-MUSCLE METASTASES; COMPARTMENT; CARCINOMA; ABSCESS; DISEASE AB The aim of this study is to evaluate the imaging features of neoplastic iliopsoas masses detected on abdominal CT and determine the association with other metastatic sites in the abdomen. Thirty-three patients with a neoplastic mass detected in the iliopsoas muscles on a CT were included in this study. The CT were evaluated for imaging features of the focal psoas lesion and for the presence of additional metastatic disease in the abdomen. All 33 patients had a history of primary neoplasm. The most common primary neoplasms were renal in five, melanoma in four, lung in three, pharyngeal in three, colorectal in two, ovarian in two and other neoplasms in 14 patients. Although the majority of the iliopsoas masses were of lower density than the muscle, four patients had a mass with hyperdense ring and four other patients had a uniformly hyperdense mass on contrast enhanced CT. Eight (24%) patients had gluteal muscle metastases and 6 (18%) had subcutaneous metastases. Secondary iliopsoas neoplasms are most commonly hypodense lesions and are most commonly due to primary neoplasm from renal, lung, pharyngeal, ovarian, colorectal neoplasm and melanoma. The detection of an iliopsoas mass warrants a careful search for gluteal muscles and subcutaneous metastases. C1 [Singh, Ajay K.] Univ Massachusetts, Med Ctr, Dept Radiol, Worcester, MA 01655 USA. [Singh, Ajay K.; Gervais, Debra A.; Hahn, Peter F.; Mueller, Peter R.] Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent Radiol, Boston, MA 02114 USA. RP Singh, AK (reprint author), Univ Massachusetts, Med Ctr, Dept Radiol, Worcester, MA 01655 USA. EM dgervais@partners.org NR 13 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0942-8925 J9 ABDOM IMAGING JI Abdom. Imaging PD JUL PY 2008 VL 33 IS 4 BP 493 EP 497 DI 10.1007/s00261-007-9274-5 PG 5 WC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging SC Gastroenterology & Hepatology; Radiology, Nuclear Medicine & Medical Imaging GA 302UW UT WOS:000255996300019 PM 17639377 ER PT J AU Swierczewska, M Hajicharalambous, CS Janorkar, AV Megeed, Z Yarmush, ML Rajagopalan, P AF Swierczewska, M. Hajicharalambous, C. S. Janorkar, A. V. Megeed, Z. Yarmush, M. L. Rajagopalan, P. TI Cellular response to nanoscale elastin-like polypeptide polyelectrolyte multilayers SO ACTA BIOMATERIALIA LA English DT Article DE elastin-like polypeptides; polyelectrolyte multilayers; fibroblasts ID INVERSE TEMPERATURE TRANSITION; DIFFERENTIAL SCANNING CALORIMETRY; PROTEIN-BASED POLYMERS; ALPHA-ELASTIN; EXTRACELLULAR-MATRIX; PHYSICAL-PROPERTIES; ENDOTHELIAL-CELLS; MOLECULAR-WEIGHT; SMOOTH-MUSCLE; THIN-FILMS AB Ionic elastin-like polypeptide (ELP) conjugates are a new class of biocompatible, self-assembling biomaterials. ELPs composed of the repeat unit (GVGVP), are derived from the primary sequence of mammalian elastin and produced in Escherichia coli. These biopolymers exhibit an inverse transition temperature that renders them extremely useful for applications in cell-sheet engineering. Cationic and anionic conjugates were synthesized by the chemical coupling of ELP to polyethyleneimine (PEI) and polyacrylic acid (PAA). The self-assembly of ELP-PEI and ELP-PAA using the layer-by-layer deposition of alternately charged polyelectrolytes is a simple, versatile technique to generate bioactive and biomimetic surfaces with the ability to modulate cell-substratum interactions. Our studies are focused on cellular response to self-assembled multilayers of ionic (GVGVP)(40) incorporated within the polymeric sequence H2N-MVSACRGPG(GVGVP)(40) WP-COOH. Angle-dependent XPS studies indicated a difference in the chemical composition at the surface (similar to 10 angstrom below the surface) and subsurface regions. These studies provided additional insight into the growth of the nanoscale multilayer assembly as well as the chemical environment that the cells can sense. Overall, cellular response was enhanced on glass substrata coated with ELP conjugates compared with uncoated surfaces. We report significant differences in cell proliferation, focal adhesions and cytoskeletal organization as a function of the number of bilayers in each assembly. These multilayer assemblies have the potential to be successfully utilized in the rational design of coatings on biomaterials to elicit a desired cellular response. (c) 2007 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. C1 [Swierczewska, M.; Hajicharalambous, C. S.] Lehigh Univ, Bioengn & Life Sci Program, Bethlehem, PA 18015 USA. [Janorkar, A. V.; Megeed, Z.; Yarmush, M. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Shriners Burns Hosp,Ctr Engn Med, Boston, MA 02114 USA. [Rajagopalan, P.] Lehigh Univ, Dept Chem Engn, Bethlehem, PA 18015 USA. RP Rajagopalan, P (reprint author), Virginia Polytech Inst & State Univ, Dept Chem Engn, Blacksburg, VA 24061 USA. EM padmar@vt.edu FU NIBIB NIH HHS [P41 EB 002503]; NIDDK NIH HHS [F32 DK 070496] NR 56 TC 26 Z9 26 U1 4 U2 27 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1742-7061 J9 ACTA BIOMATER JI Acta Biomater. PD JUL PY 2008 VL 4 IS 4 BP 827 EP 837 DI 10.1016/j.actbio.2007.11.004 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 320WQ UT WOS:000257266300007 PM 18178532 ER PT J AU Waxman, EA Duda, JE Giasson, BI AF Waxman, Elisa A. Duda, John E. Giasson, Benoit I. TI Characterization of antibodies that selectively detect alpha-synuclein in pathological inclusions SO ACTA NEUROPATHOLOGICA LA English DT Article DE alpha-synuclein; antibodies; fibrillization; Lewy bodies; Parkinson's disease ID MULTIPLE SYSTEM ATROPHY; FAMILIAL PARKINSONS-DISEASE; LEWY BODIES; IN-VITRO; FIBRIL FORMATION; PROTEIN DOMAINS; TRANSGENIC MICE; DEMENTIA; MUTATION; AGGREGATION AB Sensitive detection of alpha-synuclein (alpha-syn) pathology is important in the diagnosis of disorders like Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy and in providing better insights into the etiology of these diseases. Several monoclonal antibodies that selectively react with aggregated alpha-syn in pathological inclusions and reveal extensive and underappreciated alpha-syn pathology in the brains of diseased patients were previously reported by Duda et al. (Ann Neurol 52:205-210, 2002). We sought to characterize the specificity of some of these antibodies (Syn 505, Syn 506 and Syn 514); using C-terminal and N-terminal truncations of alpha-syn, all three antibodies were determined to require N-terminal epitopes that minimally comprise amino acids 2-4, but possibly extend to amino acid 12 of alpha-syn. The selectivity of these antibodies was further assessed using biochemical analysis of human brains and reactivity to altered recombinant alpha-syn proteins with duplication variants of amino acids 1-12. In addition, by expressing wild-type or a double mutant (E46K/A53T) of alpha-syn in cultured cells and by comparing their immunoreactivities to another antibody (SNL-4), which has a similar primary epitope, it was determined that Syn 505, Syn 506 and Syn 514 recognize conformational variants of alpha-syn that is enhanced by the presence of the double mutations. These studies indicate that antibodies Syn 505, Syn 506 and Syn 514 preferentially recognize N-terminal epitopes in complex conformations, consistent with the dramatic conformational change associated with the polymerization of alpha-synuclein into amyloid fibrils that form pathological inclusions. C1 [Waxman, Elisa A.; Giasson, Benoit I.] Univ Penn, Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA. [Duda, John E.] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Duda, John E.] Philadelphia Vet Affairs Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA 19104 USA. RP Giasson, BI (reprint author), Univ Penn, Sch Med, Dept Pharmacol, 3620 Hamilton Walk,123 John Morgan Bldg, Philadelphia, PA 19104 USA. EM giassonb@mail.med.upenn.edu FU NIA NIH HHS [AG09215, P01 AG009215, T32 AG000255, T32 AG000255-11A1, T32 AG00255]; NINDS NIH HHS [NS053488, P50 NS053488] NR 52 TC 34 Z9 34 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD JUL PY 2008 VL 116 IS 1 BP 37 EP 46 DI 10.1007/s00401-008-0375-1 PG 10 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 324UF UT WOS:000257544200004 PM 18414880 ER PT J AU Holtzman, D AF Holtzman, David TI Autistic spectrum disorders and mitochondrial encephalopathies SO ACTA PAEDIATRICA LA English DT Editorial Material ID DYSFUNCTION C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Holtzman, David] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. [Holtzman, David] Harvard Univ, Sch Med, Boston, MA USA. RP Holtzman, D (reprint author), Massachusetts Gen Hosp, Dept Neurol, 175 Cambridge St, Boston, MA 02114 USA. EM dholtzman1@partners.org NR 20 TC 10 Z9 10 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD JUL PY 2008 VL 97 IS 7 BP 859 EP 860 DI 10.1111/j.1651-2227.2008.00883.x PG 2 WC Pediatrics SC Pediatrics GA 308MS UT WOS:000256395300009 PM 18532934 ER PT J AU Ostacher, MJ Nierenberg, AA Iosifescu, DV Eidelman, P Lund, HG Ametrano, RM Kaczynski, R Calabrese, J Miklowitz, DJ Sachs, GS Perlick, DA Gro, SBFECS AF Ostacher, M. J. Nierenberg, A. A. Iosifescu, D. V. Eidelman, P. Lund, H. G. Ametrano, R. M. Kaczynski, R. Calabrese, J. Miklowitz, D. J. Sachs, G. S. Perlick, D. A. Gro, STEP-BD Family Experience Collaborative Study TI Correlates of subjective and objective burden among caregivers of patients with bipolar disorder SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE bipolar disorder; depression; interpersonal relations; social environment ID TREATMENT ENHANCEMENT PROGRAM; WEEKLY SYMPTOMATIC STATUS; FAMILY BURDEN; NATURAL-HISTORY; STEP-BD; RELIABILITY; RATIONALE; INTERVIEW; IMPACT; SCALE AB Objective: We examined the relationship between mood symptoms and episodes in patients with bipolar disorder and burden reported by their primary caregivers. Method: Data on subjective and objective burden reported by 500 primary caregivers for 500 patients with bipolar disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were collected using semistructured interviews. Patient data were collected prospectively over 1 year. The relationship between patient course and subsequent caregiver burden was examined. Results: Episodes of patient depression, but not mood elevation, were associated with greater objective and subjective caregiver burden. Burden was associated with fewer patient days well over the previous year. Patient depression was associated with caregiver burden even after controlling for days well. Conclusion: Patient depression, after accounting for chronicity of symptoms, independently predicts caregiver burden. This study underscores the important impact of bipolar depression on those most closely involved with those whom it affects. C1 [Ostacher, M. J.; Nierenberg, A. A.; Iosifescu, D. V.; Eidelman, P.; Lund, H. G.; Ametrano, R. M.; Sachs, G. S.] Massachusetts Gen Hosp, Bipolar Clin & Res Program, Boston, MA 02114 USA. [Kaczynski, R.] Yale Univ, Dept Psychiat, Sch Med, New Haven, CT 06520 USA. [Calabrese, J.] Case Western Reserve Univ, Dept Psychiat, Cleveland, OH 44106 USA. [Miklowitz, D. J.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Perlick, D. A.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Ostacher, M. J.; Nierenberg, A. A.; Sachs, G. S.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Ostacher, MJ (reprint author), Massachusetts Gen Hosp, Bipolar Clin & Res Program, 50 Staniford St,Suite 580, Boston, MA 02114 USA. EM mostacher@partners.org OI Ostacher, Michael/0000-0003-0353-7535 FU NIMH NIH HHS [N01MH-8001, R01MH-65015] NR 22 TC 23 Z9 24 U1 2 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD JUL PY 2008 VL 118 IS 1 BP 49 EP 56 DI 10.1111/j.1600-0447.2008.01201.x PG 8 WC Psychiatry SC Psychiatry GA 312PT UT WOS:000256684000007 PM 18582347 ER PT J AU Yarlagadda, SG Klein, CL Jani, A AF Yarlagadda, Sri G. Klein, Christina L. Jani, Alkesh TI Long-term renal outcomes after delayed graft function SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE delayed graft function; graft survival; outcomes; kidney function ID ACUTE TUBULAR-NECROSIS; HEART-BEATING DONORS; KIDNEY-TRANSPLANTATION; RISK-FACTORS; ACUTE REJECTION; CARDIAC DEATH; ALLOGRAFT SURVIVAL; COLD ISCHEMIA; PULSATILE PRESERVATION; PREDICTIVE FACTORS AB Delayed graft function (DGF) describes dysfunction of the kidney allograft immediately after transplantation and is the most common complication in the immediate posttransplantation period. Although a standardized definition for DGF is lacking, it is most commonly defined as the need for dialysis within the first week after transplant. DGF is caused by a variety of factors related to the donor and recipient as well as organ procurement techniques. The occurrence of DGF affects both allograft and patient outcomes. In addition to prolonging hospital stay and increasing the costs associated with transplantation, DGF is associated with an increased incidence of acute rejection after transplantation and is associated with poorer long-term graft outcomes. Both immunologic and nonimmunologic mechanisms contribute to DGF. The risk factors for DGF that have been identified are reviewed as well as the impact of DGF on long-term outcomes. (C) 2008 by the National Kidney Foundation, Inc. All rights reserved. C1 Yale Univ, Sch Med, Dept Med, Nephrol Sect, New Haven, CT 06510 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Nephrol Sect, Denver, CO 80262 USA. RP Jani, A (reprint author), Denver Vet Affairs Med Ctr, Mail Code 111C,1055 Clermont, Denver, CO 80220 USA. EM Alkesh.jani@uchsc.edu FU NIDDK NIH HHS [1 K08 DK069512-01] NR 77 TC 30 Z9 34 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1548-5595 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD JUL PY 2008 VL 15 IS 3 BP 248 EP 256 DI 10.1053/j.ackd.2008.04.005 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 322YH UT WOS:000257410700006 PM 18565476 ER PT J AU Doupis, J Veves, A AF Doupis, John Veves, Aristidis TI DPP4 Inhibitors: a new approach in diabetes treatment SO ADVANCES IN THERAPY LA English DT Review DE diabetes; dipeptidyl peptidase-IV; DPP4; sitagliptin; vildagliptin ID DIPEPTIDYL-PEPTIDASE-IV; GLUCAGON-LIKE PEPTIDE-1; INITIAL COMBINATION THERAPY; METFORMIN-TREATED PATIENTS; IMPROVES GLYCEMIC CONTROL; DRUG-NAIVE PATIENTS; BETA-CELL FUNCTION; DOUBLE-BLIND; IN-VITRO; INTRAVENOUS GLUCOSE AB The role of dipeptidyl peptidase-IV (DPP4) as both a regulatory enzyme and a signalling factor has been evaluated and described in many studies. DPP4 inhibition results in increased blood concentration of the incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). This causes an increase in glucose-dependent stimulation of insulin secretion, resulting in a lowering of blood glucose levels. Recent studies have shown that DPP4 inhibitors can induce a significant reduction in glycosylated haemoglobin (HbA(1c)) levels, either as monotherapy or as a combination with other antidiabetic agents. Research has also demonstrated that DPP4 inhibitors portray a very low risk of hypoglycaemia development. This review article focuses on the two leading agents of this category (sitagliptin and vildagliptin), providing an overview of their function along with the latest data regarding their clinical efficacy as antidiabetic agents. C1 [Doupis, John] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Veves, Aristidis] Harvard Univ, Sch Med, Microcirculat Lab, Boston, MA USA. [Veves, Aristidis] Joslin Beth Israel Deaconess Foot Ctr, Boston, MA USA. RP Veves, A (reprint author), Beth Israel Deaconess Med Ctr, Microcirculat Lab, Palmer 317,West Campus,1 Deaconess Rd, Boston, MA 02215 USA. EM aveves@caregroup.harvard.edu OI Veves, Aristidis/0000-0002-3901-4405 NR 73 TC 39 Z9 41 U1 1 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0741-238X J9 ADV THER JI Adv. Ther. PD JUL PY 2008 VL 25 IS 7 BP 627 EP 643 DI 10.1007/s12325-008-0076-1 PG 17 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 340NR UT WOS:000258652800001 PM 18641927 ER PT J AU Walley, AY Krupitsky, EM Cheng, DM Raj, A Edwards, EM Bridden, C Egorova, VY Zvartau, EE Woody, GE Samet, JH AF Walley, Alexander Y. Krupitsky, Evgeny M. Cheng, Debbie M. Raj, Anita Edwards, Erika M. Bridden, Carly Egorova, Valentina Y. Zvartau, Edwin E. Woody, George E. Samet, Jeffrey H. TI Implications of cannabis use and heavy alcohol use on HIV drug risk behaviors in Russian heroin users SO AIDS AND BEHAVIOR LA English DT Article DE cannabis; alcohol; Russia; HIV; risk behaviors ID ST-PETERSBURG; INJECTION RISK; SUBSTANCE USE; DEPENDENCE; WOMEN; MEN; METHAMPHETAMINE; ASSOCIATION; NALTREXONE; ADDICTION AB Cannabis and heavy alcohol use potentially increase HIV transmission by increasing risky drug behaviors. We studied 404 subjects entering treatment for heroin dependence, in St. Petersburg, Russia. We used the HIV Risk Assessment Battery (RAB) drug subscale to measure risky drug behavior. Although all heavy alcohol users had risky drug behaviors, their drug RAB scores did not differ from non-heavy alcohol users in unadjusted or adjusted analyses. Cannabis use was significantly associated with drug RAB scores in unadjusted analyses (mean difference 1.7 points) and analyses adjusted for age, sex, and employment (mean difference 1.3 points). When also adjusting for stimulant use, the impact of cannabis use was attenuated and no longer statistically significant (mean difference 1.1 points). Because of the central role of risky drug behaviors in the Russian HIV epidemic, it is important to understand how the use of multiple substances, including cannabis and alcohol, impacts risky drug behaviors. C1 [Walley, Alexander Y.; Cheng, Debbie M.; Bridden, Carly; Samet, Jeffrey H.] Boston Univ, Med Ctr, Clin Addict Res & Educ Unit, Sect Gen Internal Med,Dept Med, Boston, MA 02118 USA. [Walley, Alexander Y.; Cheng, Debbie M.; Bridden, Carly; Samet, Jeffrey H.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Krupitsky, Evgeny M.; Egorova, Valentina Y.; Zvartau, Edwin E.] Pavlov State Med Univ St Petersburg, St Petersburg Sci Res Ctr Addict & Psychopharmaco, St Petersburg, Russia. [Cheng, Debbie M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Raj, Anita; Samet, Jeffrey H.] Boston Univ, Sch Publ Hlth, Dept Social & Behav Sci, Boston, MA USA. [Edwards, Erika M.] Boston Univ, Sch Publ Hlth, Data Coordinating Ctr, Boston, MA USA. [Woody, George E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. [Woody, George E.] Univ Penn, Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Walley, AY (reprint author), Boston Univ, Med Ctr, Clin Addict Res & Educ Unit, Sect Gen Internal Med,Dept Med, 91 E Concord St,Suite 200, Boston, MA 02118 USA. EM awalley@bu.edu OI Samet, Jeffrey/0000-0002-0897-3400; Bridden, Carly/0000-0002-7208-7235; Walley, Alexander/0000-0002-8158-4882 FU NIAAA NIH HHS [R21-AA014821, K24 AA015674, K24-AA015674, R21 AA014821]; NIAID NIH HHS [T32 AI052074, T32 AI052074-05, T32-AI52074 04]; NIDA NIH HHS [K05 DA017009, K05 DA017009-06, K05-DA 17009, R25 DA013582, R25-DA13582, U10 DA013043, U10 DA013043-05, U10-DA13043] NR 43 TC 9 Z9 9 U1 3 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD JUL PY 2008 VL 12 IS 4 BP 662 EP 669 DI 10.1007/s10461-007-9243-6 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 315VJ UT WOS:000256908000016 PM 17487577 ER PT J AU Nijhawan, AE Zachary, KC Kwara, A Venna, N AF Nijhawan, Ank E. Zachary, Kimon C. Kwara, Awewura Venna, Nagagopal TI Status epilepticus resulting from severe efavirenz toxicity in an HIV-infected patient SO AIDS READER LA English DT Article DE HIV/AIDS; efavirenz; toxicity ID NEUROPSYCHIATRIC ADVERSE EVENTS; POPULATION PHARMACOKINETICS; HIV-1-INFECTED PATIENTS; PHARMACOGENETICS; VARIABILITY; THERAPY; CYP2B6; INDIVIDUALS; TENOFOVIR; UTILITY AB We present the case of an HIV-infected patient with cirrhosis in whom severe neuropsychiatric signs and symptoms developed in the setting of a significantly elevated plasma efavirenz level. Although mild neuropsychiatric symptoms are a well-known adverse effect of this medication, to our knowledge, this is the first report of status epilepticus with routine efavirenz dosing. This case raises several significant questions regarding the adverse effects and dosing of this medication, including which patient characteristics predispose to efavirenz toxicity, the relevance of the CYP2B6 mutation, and indications for therapeutic drug monitoring. C1 [Kwara, Awewura] Brown Univ, Sch Med, Div Infect Dis, Providence, RI 02912 USA. [Zachary, Kimon C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Venna, Nagagopal] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Venna, Nagagopal] Massachusetts Gen Hosp, Neurol Clin, Boston, MA 02114 USA. NR 23 TC 5 Z9 5 U1 0 U2 1 PU CLIGGOTT PUBLISHING CO PI DARIEN PA 330 BOSTON POST RD, DARIEN, CT 06820 USA SN 1053-0894 J9 AIDS READ JI Aids Read. PD JUL PY 2008 VL 18 IS 7 BP 386 EP + PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 327VR UT WOS:000257757100007 PM 18655316 ER PT J AU Abraham, NS Castillo, DL Hartman, C AF Abraham, N. S. Castillo, D. L. Hartman, C. TI National mortality following upper gastrointestinal or cardiovascular events in older veterans with recent nonsteroidal anti-inflammatory drug use SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; PEPTIC-ULCER DISEASE; PRIMARY PREVENTION; ELDERLY PERSONS; RISK; INHIBITORS; OUTCOMES; ASPIRIN; DEATH; PRESCRIPTION AB Background Upper gastrointestinal events (UGIE), myocardial infarction (MI) and cerebrovascular accident (CVA) are known morbities among recent NSAID users. Aim To assess all-cause mortality following UGIE, MI or CVA among recent NSAID users. Methods Veterans > 65 prescribed an NSAID at any Veterans Affairs (VA) facility were identified using prescription fill data and their records linked to a merged VA-Medicare database. Each person-day was assessed for NSAID, coxib or proton pump inhibitor (PPI) exposure. Incidence density ratios and hazard rates of death were calculated following UGIE, MI and CVA adjusting for demographics, co-morbidity, prescription channeling, geographic location and pharmacological covariates. Results Among 474 495 patients [97.8% male; 85.3% white; 73.9 years (s.d. 5.6)], death followed at a rate of 5.5 per 1000 person-years (95% CI: 5.4-5.6) post-UGIE, 17.7 per 1000 person-years (95% CI: 17.5-17.9) post-MI and 21.8 per 1000 person-years (95% CI: 21.6-22.0) post-CVA. CVA was associated with greatest risk of death [hazard ratio (HR) 12.4; 95% CI: 10.9-14.3] followed by MI (HR 10.7; 95% CI: 9.2-11.6) and UGIE (HR 3.3; 95% CI: 2.8-3.9). Predictors of mortality were advancing age and co-morbidity, increased use of coxibs and failure to ensure adequate gastroprotection. Conclusion Among elderly veterans with recent NSAID use, an UGIE, MI or CVA is a clinically relevant premorbid event. C1 [Abraham, N. S.; Castillo, D. L.; Hartman, C.] Houston Ctr Qual Care & Utilizat Studies, Houston, TX USA. [Abraham, N. S.] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Abraham, N. S.] Baylor Coll Med, Houston, TX 77030 USA. RP Abraham, NS (reprint author), DeBakey Vet Affairs Med Ctr, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM nabraham@bcm.edu NR 32 TC 17 Z9 17 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD JUL 1 PY 2008 VL 28 IS 1 BP 97 EP 106 DI 10.1111/j.1365-2036.2008.03706.x PG 10 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 308MT UT WOS:000256395400009 PM 18397385 ER PT J AU Atri, A Shaughnessy, LW Locascio, JJ Growdon, JH AF Atri, Alireza Shaughnessy, Lynn W. Locascio, Joseph J. Growdon, John H. TI Long-term course and effectiveness of combination therapy in Alzheimer disease SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE treatment efficacy; modeling progression; cholinesterase inhibitor; memantine; memory; cognition and function in dementia ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; CLINICAL-TRIALS; DOUBLE-BLIND; OPEN-LABEL; CHOLINESTERASE-INHIBITORS; DONEPEZIL TREATMENT; FOLLOW-UP; GALANTAMINE; MEMANTINE AB Objective: To compare the real-world clinical effectiveness and long-term clinical trajectory in patients with Alzheimer disease (AD) treated with combination (COMBO) therapy consisting of cholinesterase-inhibitor (Cl) plus memantine (MEM) versus Cl alone versus no treatment with either. Methods: Three hundred eighty-two subjects with probable AD underwent serial clinical evaluations at a memory disorders unit. Cognition was assessed by the Information-Memory-Concentration subscale of the Blessed Dementia Scale (BDS) and function was assessed by the Weintraub Activities of Daily Living Scale (ADL) at 6-month intervals. One hundred forty-four subjects received standard care without CI or MEM (NORX), 122 received CI monotherapy, and 116 received COMBO therapy with Cl plus MEM. Mean follow-up was 30 months (4.1 visits) and mean cumulative medication treatment time was 22.5 months. Rates of decline were analyzed using mixed-effects regression models, and Cohen's d effect sizes were calculated annually for years 1 to 4. Results: Covarying for baseline scores, age, education, and duration of illness, the COMBO group had significantly lower mean annualized rates of deterioration in BDS and ADL scores compared with the CI (P < 0.001; Cohen's d(BDS) = 0.10 - 0.34 and (IADL = 0.23 - 0.46 at 1 to 2 y) and NO-RX groups (P < 0.001; Cohen's d(BDS) = 0.56 - 0.73 and d(ADL) = 0.32 - 0.48 at 1 to 2y). For the COMBO group, Cohen's d effect sizes increased with treatment duration. Similar comparisons significantly favored the CI over the NO-RX group on the BDS. Conclusions: COMBO therapy slows cognitive and functional decline in AD compared with Cl monotherapy and no treatment. These benefits had small-to-medium effect sizes that increased with time on treatment and were sustained for years. C1 [Atri, Alireza] Massachusetts Gen Hosp, Memory Disorders Unit, Dept Neurol, Boston, MA 02114 USA. [Atri, Alireza; Shaughnessy, Lynn W.; Locascio, Joseph J.; Growdon, John H.] Massachusetts Gen Hosp, Massachusetts Alzheimers Dis Res Ctr, Boston, MA 02114 USA. [Atri, Alireza; Shaughnessy, Lynn W.; Locascio, Joseph J.; Growdon, John H.] Harvard Univ, Sch Med, Boston, MA USA. [Shaughnessy, Lynn W.] Massachusetts Sch Profess Psychol, W Roxbury, MA USA. RP Atri, A (reprint author), Massachusetts Gen Hosp, Memory Disorders Unit, Dept Neurol, 15 Parkman St,WACC 715, Boston, MA 02114 USA. EM aatri@partners.org OI Atri, Alireza/0000-0003-4405-6973 FU the National Institutes of Aging [1K23 AG27171-01, 5P50 AG05134]; Massachusetts Alzheimer's Disease Research Center (MADRC)]; he NIH Loan Repayment Program FX Supported by the National Institutes of Aging through grants 1K23 AG27171-01 (A.A.) and 5P50 AG05134 [J.H.G. and B.T.H.; Massachusetts Alzheimer's Disease Research Center (MADRC)], and the NIH Loan Repayment Program (A.A.). NR 53 TC 111 Z9 115 U1 4 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2008 VL 22 IS 3 BP 209 EP 221 DI 10.1097/WAD.0b013e31816653bc PG 13 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 352UA UT WOS:000259521700004 PM 18580597 ER PT J AU Hirschman, KB Kapo, JM Karlawish, JHT AF Hirschman, Karen B. Kapo, Jennifer M. Karlawish, Jason H. T. TI Identifying the factors that facilitate or hinder advance planning by persons with dementia SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE advance care planning; Alzheimer disease; decision making; advance directives ID ALZHEIMERS-DISEASE; DECISION; CARE; DIRECTIVES; DIAGNOSIS; SURVIVAL; ILLNESS; PATIENT; ADULTS AB members of patients with advanced dementia to identify the factors that facilitate or hinder advance planning by persons with dementia. All interviews were analyzed using qualitative data analysis techniques. The majority (77%) of family members reported that their relative had some form of written advance directive, and at least half reported previous discussions about health care preferences (57%), living situation or placement issues (50%), and finances or estate planning (60%) with the patient. Family members reported some themes that prompted planning and others that were barriers to planning. Events that most often triggered planning were medical, living situation, or financial issues associated with a friend or family member of the patient (57%). Barriers to planning included both passive and active avoidance. The most common form of passive avoidance was not realizing the importance of planning until it was too late to have the discussion (63%). The most common form of active avoidance was avoiding the discussion (53%). These data suggest potentially remediable strategies to address barriers to advance planning discussions. C1 [Hirschman, Karen B.] Univ Penn, Sch Nursing, Div Behav & Hlth Sci, Philadelphia, PA 19104 USA. [Hirschman, Karen B.] Univ Penn, NewCourtland Ctr Transit & Hlth, Philadelphia, PA 19104 USA. [Kapo, Jennifer M.; Karlawish, Jason H. T.] Univ Penn, Dept Med, Div Geriatr, Philadelphia, PA 19104 USA. [Hirschman, Karen B.; Kapo, Jennifer M.; Karlawish, Jason H. T.] Univ Penn, Inst Aging, Philadelphia, PA 19104 USA. [Karlawish, Jason H. T.] Univ Penn, Alzheimers Dis Ctr, Philadelphia, PA 19104 USA. [Karlawish, Jason H. T.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Kapo, Jennifer M.; Karlawish, Jason H. T.] Univ Penn, Ctr Bioeth, Philadelphia, PA 19104 USA. [Kapo, Jennifer M.] Philadelphia VA Med Ctr, Philadelphia, PA USA. RP Hirschman, KB (reprint author), Univ Penn, Sch Nursing, Div Behav & Hlth Sci, 3615 Chestnut St,Ralston House, Philadelphia, PA 19104 USA. EM hirschk@nursing.upenn.edu FU Age-Related Neurodegenerative Diseases [NIH/NIA T32 AG-00255]; Alzheimer's Association [NIRG-05-13570]; the NIA [1R01AG025524-01A2, R01-AG020627, P30-AG10124]; HRSA Geriatric Academic Career Award [1 K01 HP 00099-01]; Greenwall Faculty Scholars Award in Bioethics FX Supported through a training grant in Age-Related Neurodegenerative Diseases (NIH/NIA T32 AG-00255; K.B.H.). Dr Karen B. Hirschman is supported by grants from the Alzheimer's Association (NIRG-05-13570), the NIA (1R01AG025524-01A2), and the Marian S. Ware Alzheimer Program. Dr Jennifer M. Kapo is supported by a HRSA Geriatric Academic Career Award (1 K01 HP 00099-01). Dr Jason H. T. Karlawish is supported by a Greenwall Faculty Scholars Award in Bioethics and NIA grants R01-AG020627 and P30-AG10124 and the Marian S. Ware Alzheimer Program. NR 25 TC 21 Z9 21 U1 1 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2008 VL 22 IS 3 BP 293 EP 298 DI 10.1097/WAD.0b013e318169d669 PG 6 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 352UA UT WOS:000259521700015 PM 18580595 ER PT J AU Zhu, CW Scarmeas, N Stavitsky, K Albert, M Brandt, J Blacker, D Sano, M Stern, Y AF Zhu, Carolyn W. Scarmeas, Nikolaos Stavitsky, Karina Albert, Marilyn Brandt, Jason Blacker, Deborah Sano, Mary Stern, Yaakov TI Comparison of costs of care between patients with Alzheimer's disease and dementia with Lewy bodies SO ALZHEIMERS & DEMENTIA LA English DT Article DE dementia; Alzheimer's disease; dementia with Lewy bodies; cost of care; economics ID PREDICTORS; MULTICENTER; DIAGNOSIS; SCALE; AD AB Background: The objective of this study was to compare total costs of care and its major components for community- living patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB). This cross-sectional analysis of baseline data from the Predictors 11 Study took place in three university-based AD centers in the U.S. Methods: Community-living patients clinically diagnosed with probable AD (n = 170) or DLB (n = 25) with a modified Mini-Mental State examination (mMMS) score >= 30, equivalent to a score of approximately >= 16 on the Folstein Mini-Mental State Examination (MMSE), participated in this study. Patient and informant reported on patients' use of direct medical care, direct nonmedical care, and informal care. Patients' clinical and demographic characteristics included global cognitive status (measured by MMSE), functional capacity (measured by Blessed Dementia Rating Scale), psychotic symptoms, behavioral problems, depressive symptoms, extrapyramidal signs, comorbidities, age, and sex. Costs were compared by using covariate matching methods. Results: Unadjusted total costs and direct medical costs were not significantly different between AD and DLB patients. Compared with AD patients, unadjusted indirect costs were significantly higher and unadjusted direct nonmedical costs were significantly lower among DLB patients. After adjusting for age, sex, cognitive and functional status, differences in all cost components between DLB and AD patients were no longer statistically significant. Conclusions: Apparent cost differences were largely attributed to differences in patients' cognitive and functional status. However, the small sample size for DLB patients might have limited power to detect statistically significant differences in costs of care between these groups. (C) 2008 The Alzheimer's Association. All rights reserved. C1 [Zhu, Carolyn W.; Sano, Mary] James J Peters VA Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. [Zhu, Carolyn W.; Sano, Mary] James J Peters VA Med Ctr, Program Res Serious Phys & Mental Illness, TREP, Bronx, NY USA. [Zhu, Carolyn W.] Mt Sinai Sch Med, Brookdale Dept Geriatr, New York, NY USA. [Scarmeas, Nikolaos; Stavitsky, Karina; Stern, Yaakov] Columbia Univ, Med Ctr, Taub Inst Res Alzheimers Dis & Aging Brain, Cognit Neurosci Div, New York, NY USA. [Scarmeas, Nikolaos; Stavitsky, Karina; Stern, Yaakov] Columbia Univ, Gertrude H Sergievsky Ctr, Med Ctr, New York, NY 10027 USA. [Scarmeas, Nikolaos; Stavitsky, Karina; Stern, Yaakov] Columbia Univ, Med Ctr, Dept Neurol, New York, NY USA. [Albert, Marilyn; Brandt, Jason] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. [Blacker, Deborah] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. [Sano, Mary] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Zhu, CW (reprint author), James J Peters VA Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. EM carolyn.zhu@mssm.edu OI Brandt, Jason/0000-0001-7381-6244 FU NCRR NIH HHS [M01 RR000645, M01 RR000645-260594, RR00645]; NIA NIH HHS [R01 AG007370, R01 AG007370-15, U01 AG010483, Z01 AG007370] NR 21 TC 7 Z9 7 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD JUL PY 2008 VL 4 IS 4 BP 280 EP 284 DI 10.1016/j.jalz.2008.02.008 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 326NC UT WOS:000257665200008 PM 18631979 ER PT J AU La Rue, A Hermann, B Jones, JE Johnson, S Asthana, S Sager, MA AF La Rue, Asenath Hermann, Bruce Jones, Jana E. Johnson, Sterling Asthana, Sanjay Sager, Mark A. TI Effect of parental family history of Alzheimer's disease on serial position profiles SO ALZHEIMERS & DEMENTIA LA English DT Article DE Alzheimer's disease; memory; serial position effect; prospective study; family history of dementia ID APOLIPOPROTEIN-E; COGNITIVE IMPAIRMENT; GENETIC RISK; LATE-LIFE; MEMORY; DEMENTIA; METAANALYSIS; PERFORMANCE; DIAGNOSIS; RELATIVES AB Background: An exaggerated recency effect (ie, disproportionate recall of last-presented items) has been consistently observed in the word list learning of patients with Alzheimer's disease (AD). Our study sought to determine whether there were similar alterations in serial position learning among asymptomatic persons at risk for AD as a result of parental family history. Methods: Subjects included 623 asymptomatic middle-aged children of patients with AD (median, 53 years) and 157 control participants whose parents survived to at least age 70 without AD or other memory disorders. All participants were administered the Rey Auditory Verbal Learning Test, which requires learning and recall of 15 unrelated nouns. Results: There was no significant difference in total words recalled between the AD children and control groups. However, compared with controls, AD children exhibited a significantly greater tendency to recall words from the end (recency) versus beginning (primacy) of the list. Serial position effects were unrelated to apolipoprotein allele epsilon 4 or depressive symptoms. Conclusions: Asymptomatic persons at risk for AD by virtue of family history do not show a difference in total words recalled compared with controls, but they exhibit a distinctly different serial position curve, suggesting greater reliance on immediate as opposed to episodic memory. This is the same serial position pattern observed in mild AD, seen here in reduced severity. Longitudinal follow-up is planned to determine whether changes in serial position patterns are a meaningful marker for preclinical detection of AD. (C) 2008 The Alzheimer's Association. All rights reserved. C1 [La Rue, Asenath; Hermann, Bruce; Jones, Jana E.; Johnson, Sterling; Asthana, Sanjay; Sager, Mark A.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Wisconsin Alzheimers Inst, Madison, WI 53706 USA. [Hermann, Bruce; Jones, Jana E.] Univ Wisconsin, Dept Neurol, Sch Med & Publ Hlth, Madison, WI 53706 USA. [Johnson, Sterling; Asthana, Sanjay; Sager, Mark A.] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Sect Geriatr & Gerontol, Madison, WI USA. [Johnson, Sterling; Asthana, Sanjay] William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. RP La Rue, A (reprint author), Univ Wisconsin, Sch Med & Publ Hlth, Dept Med, Wisconsin Alzheimers Inst, Madison, WI 53706 USA. EM larue@wisc.edu OI Johnson, Sterling/0000-0002-8501-545X FU NCRR NIH HHS [M01 RR003186, M01RR03186]; NIA NIH HHS [R01 AG027161-02, K07 AG021582, K07 AG021582-03, R01 AG027161] NR 38 TC 44 Z9 44 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD JUL PY 2008 VL 4 IS 4 BP 285 EP 290 DI 10.1016/j.jalz.2008.03.009 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 326NC UT WOS:000257665200009 PM 18631980 ER PT J AU Yoshida, M Booth, SL Meigs, JB Saltzman, E Jacques, PF AF Yoshida, Makiko Booth, Sarah L. Meigs, James B. Saltzman, Edward Jacques, Paul F. TI Phylloquinone intake, insulin sensitivity, and glycemic status in men and women SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID VITAMIN-K INTAKE; FOOD FREQUENCY QUESTIONNAIRE; DEPENDENT DIABETES-MELLITUS; YOUNG MALE-VOLUNTEERS; GLUCOSE-TOLERANCE; SECRETORY DYSFUNCTION; RESISTANCE; DIETARY; REPRODUCIBILITY; MENAQUINONE-4 AB Background: Limited evidence suggests that vitamin K may have a beneficial role in glucose homeostasis. No observational data exist on the associations between vitamin K intake and insulin sensitivity. Objective: We aimed to examine associations between vitamin K intake and measures of insulin sensitivity and glycemic status in men and women aged 26-81 y. Design: We assessed the cross-sectional associations of self-reported phylloquinone (vitamin K(1)) intake with insulin sensitivity and glycemic status in the Framingham Offspring Cohort. Dietary and supplemental phylloquinone intakes were assessed by using a food-frequency questionnaire. Insulin sensitivity was measured by fasting and 2-h post-oral-glucose-tolerance test (OGTT) insulin, the homeostasis model assessment of insulin resistance (HOMA-IR), and the insulin sensitivity index (ISI(0,120)). Glycemic status was assessed by fasting and 2-h post-OGTT glucose and glycated hemoglobin (HbA(1c)). Results: Higher phylloquinone intake was associated with greater insulin sensitivity and glycemic status, as measured by 2-h post-OGTT insulin and glucose and ISI(0,121), after adjustment for age, sex, waist circumference, lifestyle characteristics, and diet quality [2-h post-OGTT insulin: lowest and highest quintile, 81.0 and 72.7 mu U/mL, respectively (P for trend = 0.003); 2-h post-OGTT glucose: 106.3 and 101.9 mg/dL, respectively (P for trend = 0.009); ISI(0,120): 26.3 and 27.3 mg . L(2)/mmol . mU . min (P for trend = 0.009)]. Phylloquinone intake was not associated with fasting insulin and glucose concentrations, HOMA-IR, or HbA(1c). Conclusion: Our findings support a potential beneficial role for phylloquinone in glucose homeostasis in men and women. C1 [Yoshida, Makiko; Booth, Sarah L.; Saltzman, Edward; Jacques, Paul F.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr, Boston, MA 02111 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Jacques, PF (reprint author), Tufts Univ, USDA, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM paul.jacques@tufts.edu FU NHLBI NIH HHS [N01-HC-25195, N01HC25195, N01 HC025195]; NIDDK NIH HHS [K24 DK080140] NR 25 TC 39 Z9 41 U1 1 U2 6 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD JUL PY 2008 VL 88 IS 1 BP 210 EP 215 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 326FH UT WOS:000257643300028 PM 18614743 ER PT J AU Streim, JE Porsteinsson, AP Breder, CD Swanink, R Marcus, R McQuade, R Carson, WH AF Streim, Joel E. Porsteinsson, Anton P. Breder, Christopher D. Swanink, Rene Marcus, Ronald McQuade, Robert Carson, William H. TI A randomized, double-blind, placebo-controlled study of aripiprazole for the treatment of psychosis in nursing home patients with Alzheimer disease SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE aripiprazole; Alzheimer disease; dementia; behavioral symptoms; psychotic symptoms ID MANSFIELD AGITATION INVENTORY; BEHAVIORAL DISTURBANCES; CEREBROVASCULAR EVENTS; PSYCHIATRIC-SYMPTOMS; ATYPICAL ANTIPSYCHOTICS; LONGITUDINAL EVALUATION; EXTRAPYRAMIDAL SIGNS; CONTROLLED TRIALS; CAREGIVER BURDEN; ELDERLY-PATIENTS AB Objective: To evaluate the efficacy and safety of aripiprazole treatment for psychotic symptoms associated with Alzheimer disease (AD). Methods: In this parallel group, randomized, double-blind, placebo-controlled, flexible-dose trial, institutionalized subjects with AD and psychotic symptoms were randomized to aripiprazole (n = 131) or placebo (n = 125) for 10 weeks. The aripiprazole starting dose was 2 mg/day, and could be titrated to higher doses ( 5, 10, and 15 mg/day) based on efficacy and tolerability. Results: No significant differences in mean change [2 X SD] from baseline between aripiprazole ( mean dose similar to 9 mg/day at endpoint; range = 0.7-15.0 mg) and placebo were detected in the coprimary efficacy endpoints of Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) Psychosis score ( aripiprazole, -4.53 [9.23]; placebo, -4.62 [9.56]; F = 0.02, df = 1, 222, p = 0.883 [ANCOVA]) and Clinical Global Impression (CGI)-Severity score ( aripiprazole, -0.57 [1.63]; placebo, -0.43 [1.65]; F = 1.67, df = 1, 220, p = 0.198 [ANCOVA]) at endpoint. However, improvements in several secondary efficacy measures (NPI-NH Total, Brief Psychiatric Rating Scale Total, CGI - improvement, Cohen-Mansfield Agitation Inventory and Cornell Depression Scale scores) indicated that aripiprazole may confer clinical benefits beyond the primary outcome measures. Treatment-emergent adverse events (AEs) were similar in both groups, except for somnolence ( aripiprazole, 14%; placebo, 4%). Somnolence with aripiprazole was of mild or moderate intensity, and not associated with accidental injury. Incidence of AEs related to extrapyramidal symptoms was low with aripiprazole (5%) and placebo (4%). Conclusions: In nursing home residents with AD and psychosis, aripiprazole did not confer specific benefits for the treatment of psychotic symptoms; but psychological and behavioral symptoms, including agitation, anxiety, and depression, were improved with aripiprazole, with a low risk of AEs. C1 [Streim, Joel E.] Univ Penn, Sect Geriatr Psychiat, Philadelphia, PA 19104 USA. [Streim, Joel E.] Philadelphia Vet Affairs Med Ctr, VISN Mental Illness Res Educ & Clin Ctr 4, Philadelphia, PA USA. [Porsteinsson, Anton P.] Res & Educ Program AD CARE, Program Neurobehav Therapeut Alzheimers Dis Care, Rochester, NY USA. [Breder, Christopher D.; Marcus, Ronald] Bristol Myers Squibb Co, Wallingford, CT 06492 USA. [Swanink, Rene] Bristol Myers Squibb Co, Braine lAlleud, Belgium. [McQuade, Robert; Carson, William H.] Otsuka Amer Pharmaceut Inc, Princeton, NJ USA. RP Streim, JE (reprint author), Univ Penn, Sect Geriatr Psychiat, 3535 Market St,Room 3053, Philadelphia, PA 19104 USA. EM jstreim@mail.med.upenn.edu NR 56 TC 37 Z9 38 U1 4 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 EI 1545-7214 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD JUL PY 2008 VL 16 IS 7 BP 537 EP 550 DI 10.1097/JGP.0b013e318165db77 PG 14 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 321FJ UT WOS:000257289800003 PM 18591574 ER PT J AU