FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kim, YB AF Kim, Young Bae TI Improved trimethoprim-resistance cassette for prokaryotic selections SO JOURNAL OF BIOSCIENCE AND BIOENGINEERING LA English DT Article DE Dihydrofolate reductase (dfr); Trimethoprim (Tmp); Cloning vector; Plasmid construction; Transformation; Selectable marker; Antibiotic resistance ID DIHYDROFOLATE-REDUCTASE GENE; NUCLEOTIDE-SEQUENCE; VECTORS; PBR322; COPY AB Many of the antibiotic resistance elements used in molecular biology have idiosyncratic limitations. For example, beta-lactam selections rely on. antibiotics that are unstable to hydrolysis and allow satellite colonies to form upon extended incubation, and tetracycline selections typically give rise to widely varying colony sizes and lower transformation efficiencies. Although prokaryotic Type II dihydrofolate reductase (dfr) genes have long been considered to have potential utility for the selection of plasmids and mobile elements in bacteria, practical limitations to the quality of those selections, mostly relating to background and inefficiency, have led for the most part to their underuse. I describe here the construction of a Type Ila dfr prokaryotic expression cassette that confers strong resistance against trimethoprim (Tmp), a bactericidal dfr inhibiting antibiotic. The Tmp-resistance cassette provides consistent and efficient selections and plasmid transformation frequencies equivalent to those encountered with beta-lactamases. (C) 2009, The Society for Biotechnology, Japan. All rights reserved. C1 [Kim, Young Bae] Massachusetts Gen Hosp, CCIB, Boston, MA 02114 USA. [Kim, Young Bae] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Kim, YB (reprint author), Massachusetts Gen Hosp, CCIB, 185 Cambridge St, Boston, MA 02114 USA. EM ykim@ccib.mgh.harvard.edu FU Sundry Seed Lab FX I thank Dr. Brian Seed for his support and encouragement during this work. This work was supported by the Sundry Seed Lab Research Fund. I also thank Dr. Eun-Kyung Suh (Harvard Medical School), Ms. Aimee Landry (CCIB, MGH) and particularly Dr. Linda Chun (CCIB, MGH) for helpful suggestions on the manuscript, and Seed lab members for testing and making use of the materials. NR 15 TC 2 Z9 2 U1 1 U2 6 PU SOC BIOSCIENCE BIOENGINEERING JAPAN PI OSAKA PA OSAKA UNIV, FACULTY ENGINEERING, 2-1 YAMADAOKA, SUITA, OSAKA, 565-0871, JAPAN SN 1389-1723 J9 J BIOSCI BIOENG JI J. Biosci. Bioeng. PD NOV PY 2009 VL 108 IS 5 BP 441 EP 445 DI 10.1016/j.jbiosc.2009.05.015 PG 5 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 539IN UT WOS:000273247700017 PM 19804872 ER PT J AU Souer, JS Ring, D Jupiter, JB Matschke, S Audige, L Marent-Huber, M AF Souer, J. Sebastiaan Ring, David Jupiter, Jesse B. Matschke, Stefan Audige, Laurent Marent-Huber, Marta CA AOCID Prospective ORIF Distal Radi TI Comparison of AO Type-B and Type-C Volar Shearing Fractures of the Distal Part of the Radius SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID LUNATE FACET; FIXATION; ADULTS; SF-36 AB Background: Fractures of the volar articular margin of the distal part of the radius with volar radiocarpal subluxation (volar shearing, or Barton, fractures) can be accompanied by a fracture of the dorsal metaphyseal cortex. We tested the null hypothesis that there is no difference in wrist function or health status after open reduction and plate-and-screw fixation between volar shearing fractures with a dorsal cortical fracture (complete articular, AO Type C) and those without :I dorsal cortical fracture (partial articular, AO Type B). Methods: In a multicenter cohort study, fifty-seven patients with a volar marginal shearing fracture of the distal part of the radius and volar radiocarpal subluxation were followed for at least one year following plate-and-screw fixation. Thirty-seven patients who also had a dorsal metaphyseal cortical fracture (Type-C fracture) were compared with twenty patients who had a partial articular (Type-B) fracture. The two cohorts were analyzed for differences in wrist and forearm motion,; grip strength, pain, and the Gartland and Werley, Disabilities of the Arm, Shoulder and Hand (DASH), and Short Form-36 (SF-36) scores at six, twelve, and twenty-four months postoperatively. Differences in mean values and their change over time were determined. Results: There were no significant differences between patients with a Type-B fracture and those with a Type-C fracture with respect to motion, grip strength, or the Gartland and Werley or DASH score at any time point. At six months after the surgery, the patients with a Type-B volar shearing fracture reported a mean score for pain in motion of 0.5 point on a 10-point visual analogue scale compared with 2.2 points for patients with a Type-C fracture (difference in means, 1.7 points [95% confidence interval, 0.7 to 2.6 points]; p < 0.001), but no significant difference was seen at twelve or twenty-four months. Conclusions: Volar shearing fractures are usually complete articular, Type-C injuries. Patients with a Type-C volar shearing fracture experience more pain during early recovery, but ultimately their outcome is comparable with that for patients with a Type-B (partial articular) volar shearing fracture. C1 [Souer, J. Sebastiaan] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Souer, JS (reprint author), Massachusetts Gen Hosp, Yawkey 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org RI AOCID, AO Foundation/R-6455-2016 FU AO Clinical Investigation and Documentation (AOCID); Small Bone Innovations; Smith and Nephew Richards; Wright Medical; Tornier; Acumed; Joint Active Systems; Biomet; Stryker; DePuy; Hand Innovations; Skeletal Dynamics; Illuminos; Mimedex FX In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from AO Clinical Investigation and Documentation (AOCID). In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benefits in excess of $10,000 (in total) or a commitment or agreement to provide such benefits from commercial entities (Small Bone Innovations, Smith and Nephew Richards, Wright Medical, Tornier, Acumed, Joint Active Systems, Biomet, Stryker, DePuy, Hand Innovations, Skeletal Dynamics, Illuminos, and Mimedex). NR 16 TC 11 Z9 11 U1 0 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD NOV PY 2009 VL 91A IS 11 BP 2605 EP 2611 DI 10.2106/JBJS.H.01479 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 518DZ UT WOS:000271671800011 PM 19884434 ER PT J AU Jupiter, JB Fernandez, DL Levin, LS Wysocki, RW AF Jupiter, Jesse B. Fernandez, Diego L. Levin, L. Scott Wysocki, Robert W. TI Reconstruction of Posttraumatic Disorders of the Forearm SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID VASCULARIZED FIBULAR GRAFT; ULNAR TORSION PROFILES; DONOR-SITE MORBIDITY; ONE-BONE FOREARM; SEGMENTAL DEFECTS; PLATE FIXATION; INTEROSSEOUS MEMBRANE; MALUNITED FRACTURES; LONG BONES; ANTERIOR DISLOCATION RP Jupiter, JB (reprint author), Massachusetts Gen Hosp, Hand & Upper Limb Serv, Yawkey Bldg,Suite 2100,55 Parknian St, Boston, MA 02114 USA. EM jjupiter1@partners.org; diegof@bluewin.ch; scott.levin@uphs.upenn.edu; robertwysocki@mac.com NR 86 TC 4 Z9 5 U1 0 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD NOV PY 2009 VL 91A IS 11 BP 2730 EP 2739 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 518DZ UT WOS:000271671800027 PM 19884450 ER PT J AU Friedman, DJ Afkarian, M Tamez, H Bhan, I Isakova, T Wolf, M Ankers, E Ye, J Tonelli, M Zoccali, C Kuro-o, M Moe, O Karumanchi, SA Thadhani, R AF Friedman, David J. Afkarian, Maryam Tamez, Hector Bhan, Ishir Isakova, Tamara Wolf, Myles Ankers, Elizabeth Ye, Jun Tonelli, Marcello Zoccali, Carmine Kuro-o, Makoto Moe, Orson Karumanchi, S. Ananth Thadhani, Ravi TI Klotho Variants and Chronic Hemodialysis Mortality SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE Klotho; hemodialysis; mortality; vitamin D; fibroblast growth factor-23; HapMap; end-stage renal disease; polymorphism ID POSTMENOPAUSAL WOMEN; FUNCTIONAL VARIANT; GENE-EXPRESSION; TRPV5 CHANNEL; BONE-DENSITY; ASSOCIATION; MICE; POLYMORPHISMS; MUTATION; RECEPTOR AB Patients with end-stage renal disease (ESRD) suffer exceptionally high mortality rates in their first year of chronic hemodialysis. Both vitamin D and fibroblast growth factor (FGF)-23 levels correlate with survival in these patients. Klotho is a protein in the vitamin D/FGF-23 signaling pathway that has been linked with accelerated aging and early mortality in animal models. We therefore hypothesized that genetic variation in the Klotho gene might be associated with survival in subjects with ESRD. We tested the association between 12 single nucleotide polymorphisms (SNPs) in the Klotho gene and mortality in a cohort of ESRD patients during their first year on hemodialysis (n =1307 white and Asian). We found a significant association between the CC genotype of one tag SNP, rs577912, and increased risk for 1-yr mortality (RR, 1.76; 95% CI, 1.19-2.59; p = 0.003). This effect was even more marked among patients who were not treated with activated vitamin D supplementation (HR, 2.51; 95% CI, 1.18-5.34; p = 0.005). In lymphoblastoid cell lines derived from HapMap subjects, the CC genotype was associated with a 16-21% lower Klotho expression compared with the AA/AC genotype. Our data suggest that a specific Klotho variant (rs577912) is linked to survival in ESRD patients initiating chronic hemodialysis and that therapy with activated vitamin D may modify this risk. J Bone Miner Res 2009;24:1847-1855. Published online on May 4, 2009; doi: 10.1359/JBMR.090516 C1 [Afkarian, Maryam; Tamez, Hector; Bhan, Ishir; Isakova, Tamara; Ankers, Elizabeth; Ye, Jun; Thadhani, Ravi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Friedman, David J.; Karumanchi, S. Ananth] Harvard Univ, Sch Med, Dept Med, Beth Israel Deaconess Med Ctr,Ctr Vasc Biol Res, Boston, MA 02114 USA. [Wolf, Myles] Univ Miami, Sch Med, Miami, FL USA. [Tonelli, Marcello] Univ Alberta, Dept Med, Edmonton, AB, Canada. [Zoccali, Carmine] Osped Riuniti, CNR, IBIM Clin Epidemiol Renal Dis & Hypertens, Calabria, Italy. [Karumanchi, S. Ananth] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. RP Thadhani, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Bullfinch 127,55 Fruit St, Boston, MA 02114 USA. EM rthadhani@partners.org RI Tonelli, Marcello/B-3028-2009; OI Zoccali, Carmine/0000-0002-6616-1996 FU NIH [DK076868]; National Institutes of Health [DK71674, DK076116, HL093954] FX D.F. is supported by DK076868 (NIH). R.T. is supported by DK71674, DK076116, and HL093954, all by the National Institutes of Health. NR 28 TC 27 Z9 29 U1 0 U2 2 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD NOV PY 2009 VL 24 IS 11 BP 1847 EP 1855 DI 10.1359/JBMR.090516 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 518XU UT WOS:000271730200010 PM 19419323 ER PT J AU Aono, Y Yamazaki, Y Yasutake, J Kawata, T Hasegawa, H Urakawa, I Fujita, T Wada, M Yamashita, T Fukumoto, S Shimada, T AF Aono, Yukiko Yamazaki, Yuji Yasutake, Junichi Kawata, Takehisa Hasegawa, Hisashi Urakawa, Itaru Fujita, Toshiro Wada, Michihito Yamashita, Takeyoshi Fukumoto, Seiji Shimada, Takashi TI Therapeutic Effects of Anti-FGF23 Antibodies in Hypophosphatemic Rickets/Osteomalacia SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE fibroblast growth factor 23; X-linked hypophosphatemia; phosphatonin; neutralizing antibody; novel therapy ID X-LINKED HYPOPHOSPHATEMIA; VITAMIN-D METABOLISM; HYP-MICE; IN-VIVO; PHOSPHATE HOMEOSTASIS; PROTEOLYTIC CLEAVAGE; PARATHYROID-HORMONE; PHYSIOLOGICAL-ROLE; PEX GENE; FGF23 AB X-linked hypophosphatemia (XLH), characterized by renal phosphate wasting, is the most common cause of vitamin D-resistant rickets. It has been postulated that some phosphaturic factor plays a causative role in XLH and its murine homolog, the Hyp mouse. Fibroblast growth factor 23 (FGF23) is a physiological phosphaturic factor; its circulatory level is known to be high in most patients with XLH and Hyp mice, suggesting its pathophysiological role in this disease. To test this hypothesis, we treated Hyp mice with anti-FGF23 antibodies to inhibit endogenous FGF23 action. A single injection of the antibodies corrected the hypophosphatemia and inappropriately normal serum 1,25-dihydroxyvitamin D. These effects were accompanied by increased expressions of type IIa sodium-phosphate cotransporter and 25-hydroxyvitamin-D-1 alpha-hydroxylase and a suppressed expression of 24-hydroxylase in the kidney. Repeated injections during the growth period ameliorated the rachitic bone phenotypes typically observed in Hyp mice, such as impaired longitudinal elongation, defective mineralization, and abnormal cartilage development. Thus, these results indicate that excess actions of FGF23 underlie hypophosphatemic rickets in Hyp mice and suggest a novel therapeutic potential of the FGF23 antibodies for XLH. J Bone Miner Res 2009;24:1879-1888. Published online on May 4, 2009; doi: 10.1359/JBMR.090509 C1 [Fukumoto, Seiji] Tokyo Univ Hosp, Dept Med, Div Nephrol & Endocrinol, Bunkyo Ku, Tokyo 1138655, Japan. [Yamazaki, Yuji; Yasutake, Junichi; Urakawa, Itaru; Yamashita, Takeyoshi; Shimada, Takashi] Tokyo Univ Hosp, Innovat Drug Res Labs, Tokyo 1138655, Japan. [Aono, Yukiko; Kawata, Takehisa; Hasegawa, Hisashi; Wada, Michihito] Tokyo Univ Hosp, Pharmacol Res Labs, Tokyo 1138655, Japan. [Shimada, Takashi] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Endocrine Unit, Boston, MA USA. RP Fukumoto, S (reprint author), Tokyo Univ Hosp, Dept Med, Div Nephrol & Endocrinol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan. EM fukumoto-tky@umin.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labor and Welfare of Japan FX The authors thank K. Ono, R. Hino, N. Kobayashi, S. Miyata, S. Wakita, and M. Abe for excellent technical assistance and Drs. T. Sakai and M. Paskewitz for fruitful discussion. This work was partly supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and from the Ministry of Health, Labor and Welfare of Japan. NR 39 TC 98 Z9 99 U1 4 U2 17 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD NOV PY 2009 VL 24 IS 11 BP 1879 EP 1888 DI 10.1359/JBMR.090509 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 518XU UT WOS:000271730200013 PM 19419316 ER PT J AU Izamis, ML Uygun, K Uygun, B Yarmush, ML Berthiaume, F AF Izamis, Maria-Louisa Uygun, Korkut Uygun, Basak Yarmush, Martin L. Berthiaume, Francois TI Effects of Burn Injury on Markers of Hypermetabolism in Rats SO JOURNAL OF BURN CARE & RESEARCH LA English DT Article ID THERMAL-INJURY; MUSCLE CATABOLISM; FLUID RETENTION; RESISTANCE; CHILDREN; OUTCOMES; AGE; SURVIVAL; TRAUMA; GENDER AB The basic metrics of hypermetabolism have not been thoroughly characterized in rat burn injury models. We examined three models expected to differ in sensitivity to burn injury to identify that which group(s) exhibited the most clinically relevant metabolic response. Six and 12 weeks old male CD (6 week mCD and 12 week mCD) rats, and 12 weeks old female Fischer (12 week fFI) rats received a 20% total body surface area burn, followed by saline resuscitation. Activity, core body temperature, heart rate (via implanted telemetry devices), body weight, food and water intake, and fecal output were measured daily for 1 week before and after burn. Rats lost weight initially postburn but resumed weight gain by 1 week, except for 12 week mCD rats. Core body temperature increased above normal 2 days postburn and returned to baseline by 1 week. Food intake, normalized to body weight, remained unchanged postburn for 12 week mCD rats, but decreased in 6 week mCD rats and increased in 12 week fFI rats. Heart rate in the 12 week mCD and 12 week fFI rats remained at 10 to 15% above baseline, whereas, in 6 week mCD, heart rates returned to baseline after 4 days. Activity levels were unchanged for 12 week fFI and 6 week mCD rats postburn, but decreased for 12 week mCD rats. Postburn hypermetabolism was most significant and sustained in 12 week mCD rats, of least consequence and brief in 6 week mCD rats, and intermediate in 12 week tFI rats. The disparate responses indicate that the choice of animal model should be carefully considered in hypermetabolism studies. (J Burn Care Res 2009;30:993-1001) C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med Surg Serv, Boston, MA USA. Shriners Hosp Children, Boston, MA USA. RP Berthiaume, F (reprint author), Shriners Burns Hosp, 51 Blossom St, Boston, MA 02114 USA. RI Uygun, Basak/I-1792-2012 OI Uygun, Basak/0000-0002-2600-7900 FU Shriners Hospitals for Children [8640, 8450, 8460, 8490, 8496, 8503] FX Supported by the Shriners Hospitals for Children grants 8640, 8450, 8460, 8490, for this work, and Shriners Hospitals for Children Fellowships 8496 (to K. U.) and 8503 (to B. U.). NR 32 TC 5 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1559-047X J9 J BURN CARE RES JI J. Burn Care Res. PD NOV-DEC PY 2009 VL 30 IS 6 BP 993 EP 1001 DI 10.1097/BCR.0b013e3181bfb7b4 PG 9 WC Emergency Medicine; Dermatology; Surgery SC Emergency Medicine; Dermatology; Surgery GA 518BS UT WOS:000271665700009 PM 19898103 ER PT J AU Haime, M AF Haime, Miguel TI Right Atrial Myxoma SO JOURNAL OF CARDIAC SURGERY LA English DT Editorial Material AB (J Card Surg 009;24:691-692). C1 Harvard Univ, Sch Med, VA Boston Healthcare Syst, W Roxbury, MA 02132 USA. RP Haime, M (reprint author), Harvard Univ, Sch Med, VA Boston Healthcare Syst, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM miguel.haime@med.va.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0886-0440 J9 J CARDIAC SURG JI J. Card. Surg. PD NOV PY 2009 VL 24 IS 6 BP 691 EP 692 DI 10.1111/j.1540-8191.2009.00903.x PG 2 WC Cardiac & Cardiovascular Systems; Surgery SC Cardiovascular System & Cardiology; Surgery GA 516EB UT WOS:000271523400020 PM 19793251 ER PT J AU Ramlawi, B Otu, H Russo, MJ Novick, RJ Bianchi, C Sellke, FW AF Ramlawi, Basel Otu, Hasan Russo, Mark J. Novick, Richard J. Bianchi, Cesario Sellke, Frank W. TI Aprotinin Attenuates Genomic Expression Variability Following Cardiac Surgery SO JOURNAL OF CARDIAC SURGERY LA English DT Article ID BYPASS GRAFT-SURGERY; SERINE-PROTEASE INHIBITORS; CARDIOPULMONARY BYPASS; OLIGONUCLEOTIDE; OUTCOMES; MICROARRAYS; ACTIVATION; DISEASE; INJURY; SAFETY AB P>Background: Aprotinin was the subject of recent controversy regarding adverse clinical outcomes following cardiac surgery. We compared the role of Aprotinin and epsilon-aminocaproic acid on clinical outcomes and the attenuation of the postcardiopulmonary bypass (CPB) response at the genomic expression and cytokine (protein) level. Methods: Thirty-nine low-risk patients undergoing coronary revascularization (CABG) and/or valve procedures using cardiopulmonary CPB were enrolled into a prospective cohort study. Aprotinin or epsilon-aminocaproic acid was administered to patients. Gene expression was assessed from whole blood mRNA samples collected preoperatively (PRE) and 6 hours (6H) postoperatively. Validation of gene expression was performed with SYBR Green real-time polymerase chain reaction. Cytokine values were quantified from serum preoperatively and postoperatively at 6 H and 4 days and analyzed in a blinded fashion. Results: No difference was detected in baseline characteristics. Inflammatory markers measured did not reveal significant difference between patients receiving Aprotinin (APR) and those receiving epsilon-aminocaproic acid (Amicar). Intraoperative parameters and postoperative outcomes were not significantly different. Compared with PRE samples, 6H samples had 264 upregulated and 548 downregulated genes uniquely in the APR group compared to 4826 upregulated and 1114 downregulated genes uniquely in the Amicar group (p < 0.001). Compared to patients in the Amicar group, APR patients had significantly different gene expression pathways involving NF-kappa beta regulation, programmed cell death and cell-cell adhesion. None of the patients developed postoperative stroke, myocardial infarction, or systemic infections. Conclusions: Aprotinin leads to significantly less genomic expression variability following CPB compared to Amicar and has a differential effect on specific genomic pathways. (J Card Surg 2009;24:772-780). C1 [Bianchi, Cesario; Sellke, Frank W.] Harvard Univ, Div Cardiothorac Surg, Sch Med, BIDMC, Boston, MA 02215 USA. [Ramlawi, Basel; Russo, Mark J.] Columbia Univ, Columbia Presbyterian Med Ctr, Div Cardiothorac Surg, New York, NY 10032 USA. [Otu, Hasan] Harvard Univ, Sch Med, Genom Ctr, BIDMC, Boston, MA 02215 USA. [Novick, Richard J.] Univ Western Ontario, Div Cardiac Surg, London, ON N6A 3K7, Canada. RP Sellke, FW (reprint author), Harvard Univ, Div Cardiothorac Surg, Sch Med, BIDMC, LMOB 2A,110 Francis St, Boston, MA 02215 USA. EM fsellke@caregroup.harvard.edu RI bianchi, cesario/H-6238-2012; OI Otu, Hasan/0000-0002-9253-8152 FU Irving Bard Memorial Fellowship; NIH [HL04095-06, HL-46716]; CIHR/Canadian Stroke Network Postdoctoral Research Fellowship FX Financial Support: Research supported by the Irving Bard Memorial Fellowship. Dr. Basel Ramlawi is supported by grant HL04095-06 from the NIH as well as a CIHR/Canadian Stroke Network Postdoctoral Research Fellowship. Dr. Frank Sellke is supported by grant HL-46716 from the NIH. NR 37 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0886-0440 J9 J CARDIAC SURG JI J. Card. Surg. PD NOV PY 2009 VL 24 IS 6 BP 772 EP 780 DI 10.1111/j.1540-8191.2009.00924.x PG 9 WC Cardiac & Cardiovascular Systems; Surgery SC Cardiovascular System & Cardiology; Surgery GA 516EB UT WOS:000271523400042 PM 19754679 ER PT J AU Todani, A Melki, SA AF Todani, Amit Melki, Samir A. TI Late-onset epithelial ingrowth after laser in situ keratomileusis SO JOURNAL OF CATARACT AND REFRACTIVE SURGERY LA English DT Article ID PREVENTION AB We report a case of late-onset epithelial ingrowth that occurred between 17 months and 20 months after an uneventful laser in situ keratomileusis (LASIK) enhancement. The patient denied a history of trauma or symptoms consistent with epithelial disruption. Post-LASIK treatment had included lifting the flap and scraping the epithelial cells followed by placement of corneal flap sutures for several weeks and a bandage contact lens for 3 days. Gradual regression of epithelial cells was noted. The last recorded uncorrected distance visual acuity 24 months after scraping was 20/25. Epithelial ingrowth can occur many months after LASIK even in the absence of predisposing factors such as trauma or recurrent erosion syndrome. J Cataract Refract Surg 2009; 35:2022-2023 (C) 2009 ASCRS and ESCRS C1 [Melki, Samir A.] Harvard Univ, Cornea & Refract Surg Serv, Sch Med, Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Boston Eye Grp, Brookline, MA USA. RP Melki, SA (reprint author), Harvard Univ, Cornea & Refract Surg Serv, Sch Med, Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. EM samir_melki@meei.harvard.edu NR 7 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0886-3350 J9 J CATARACT REFR SURG JI J. Cataract. Refract. Surg. PD NOV PY 2009 VL 35 IS 11 BP 2022 EP 2023 DI 10.1016/j.jcrs.2009.05.044 PG 2 WC Ophthalmology; Surgery SC Ophthalmology; Surgery GA 518WF UT WOS:000271725600028 PM 19878839 ER PT J AU Fangusaro, J Chi, S AF Fangusaro, Jason Chi, Susan TI Introduction to a Special Issue on Pediatric Neuro-Oncology SO JOURNAL OF CHILD NEUROLOGY LA English DT Editorial Material ID LONG-TERM SURVIVORS; BRAIN-TUMORS; EPIDEMIOLOGY; CHILDHOOD; CHILDREN; ADOLESCENCE C1 [Fangusaro, Jason] Childrens Mem Hosp, Dept Hematol Oncol Stem Cell Transplantat, Chicago, IL 60614 USA. [Chi, Susan] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Fangusaro, J (reprint author), Childrens Mem Hosp, Dept Hematol Oncol Stem Cell Transplantat, Chicago, IL 60614 USA. NR 18 TC 3 Z9 3 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD NOV PY 2009 VL 24 IS 11 BP 1341 EP 1342 DI 10.1177/0883073809338959 PG 2 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 510RP UT WOS:000271109100002 PM 19841423 ER PT J AU Hoffman, KE Yock, TI AF Hoffman, Karen E. Yock, Torunn I. TI Radiation Therapy for Pediatric Central Nervous System Tumors SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE primary central nervous system neoplasms; radiotherapy; proton radiation ID LOW-GRADE GLIOMAS; CHILDHOOD MEDULLOBLASTOMA; PHOTON RADIOTHERAPY; PROTON RADIOTHERAPY; CLINICAL-OUTCOMES; BRAIN-TUMORS; SURVIVORS; CANCER; CHEMOTHERAPY; EPENDYMOMA AB Radiation therapy is an important component of treatment of many pediatric central nervous system tumors. The radiation treatment target is determined by tumor histology, extent of disease, anticipated pattern of spread, and expected pattern of failure. Children cured of their tumors live to experience the long-term sequelae of radiation treatment, including developmental, neurocognitive, neuroendocrine, and hearing late effects The development of more conformal radiation techniques has decreased inadvertent radiation dose to normal tissues and should decrease long-term treatment sequelae that are the result of normal tissue radiation Intensity-modulated radiation therapy improves treatment conformity and decreases high dose to nearby normal tissues. however, it delivers a larger volume of low- and intermediate-dose radiation. Proton radiation eliminates exit dose to normal tissues, thereby eliminating approximately 50% of unnecessary radiation to normal tissues. The long-term clinical benefits of proton radiation in the pediatric population are just beginning to be reported in the literature. C1 [Yock, Torunn I.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Hoffman, Karen E.] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. RP Yock, TI (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, 100 Blossom St,Cox 341, Boston, MA 02114 USA. EM tyock@partners.org NR 31 TC 28 Z9 28 U1 0 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD NOV PY 2009 VL 24 IS 11 BP 1387 EP 1396 DI 10.1177/0883073809342275 PG 10 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 510RP UT WOS:000271109100006 PM 19841427 ER PT J AU Ullrich, NJ AF Ullrich, Nicole J. TI Neurologic Sequelae of Brain Tumors in Children SO JOURNAL OF CHILD NEUROLOGY LA English DT Article DE brain tumors; late effects; neurologic sequelae; chemotherapy; headache; hydrocephalus ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CENTRAL-NERVOUS-SYSTEM; QUALITY-OF-LIFE; RADIATION-THERAPY; PUNCTURE HEADACHE; CHILDHOOD-CANCER; SURVIVORS; SEIZURES; MEDULLOBLASTOMA; CHEMOTHERAPY AB Neurologic signs and symptoms are often the initial presenting features of a primary brain tumor and may also emerge during the course of therapy of as late effects of the tumor and its treatment. Variables that influence the development of such neurologic complications include the type, size, and location of the tumor, the patient's age at diagnosis, and the treatment modalities used. Heightened surveillance and improved neuroimaging modalities have been instrumental in detecting and addressing such complications, which are often not appreciated until many years after completion of therapy. As Current brain tumor therapies arc continually refined and newer targeted therapies are developed, it will be important for future cooperative group studies to include systematic assessments to determine the incidence of neurologic complications and to provide a framework for the development of novel strategies for prevention and intervention. C1 [Ullrich, Nicole J.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. [Ullrich, Nicole J.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Ullrich, NJ (reprint author), Childrens Hosp, Dept Neurol, 300 Longwood Ave, Boston, MA 02115 USA. EM nicole.ullrich@childrens.harvard.edu NR 50 TC 22 Z9 22 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD NOV PY 2009 VL 24 IS 11 BP 1446 EP 1454 DI 10.1177/0883073809342491 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 510RP UT WOS:000271109100012 PM 19841432 ER PT J AU Turner, CD Rey-Casserly, C Liptak, CC Chordas, C AF Turner, Christopher D. Rey-Casserly, Celiane Liptak, Cori C. Chordas, Christine TI Late Effects of Therapy for Pediatric Brain Tumor Survivors SO JOURNAL OF CHILD NEUROLOGY LA English DT Review DE late effects, brain tumors; survivorship, neurological deficits; neurocognitive deficits; psychosocial, quality of life, outcomes; transitions ID CHILDHOOD-CANCER SURVIVOR; LONG-TERM SURVIVORS; CENTRAL-NERVOUS-SYSTEM; QUALITY-OF-LIFE; CEREBELLAR MUTISM SYNDROME; ADULT SURVIVORS; COGNITIVE FUNCTION; CRANIOSPINAL IRRADIATION; CRANIAL IRRADIATION; CHILDRENS ONCOLOGY AB Approximately 2 of every 3 of all pediatric patients with brain tumors will be long-term survivors. However, there is a steep cost for pediatric brain tumor survivors, and the group as a whole faces significantly more late effects than many other survivors of pediatric cancers. Most of these effects can be attributed to direct neurologic damage to the developing brain caused by the tumor and its removal, the long-term toxicity of chemotherapy, or the effects of irradiation on the central nervous system. The late effects experienced by childhood brain tumor survivors involve multiple domains. This article will review the significant late effects that occur within the medical, neurocognitive, psychosocial, and economic domains of the survivorship experience. We conclude by discussing how the late effects in different domains often coexist and can create a complex set of obstacles that pose significant challenges for a survivor of a pediatric brain tumor on a daily basis. C1 [Turner, Christopher D.; Chordas, Christine] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Rey-Casserly, Celiane] Childrens Hosp, Neuropsychol Program, Dept Psychiat, Boston, MA 02115 USA. [Liptak, Cori C.] Dana Farber Canc Inst, Dept Psychosocial Oncol & Palliat Care, Boston, MA 02115 USA. RP Turner, CD (reprint author), Dana Farber Childrens Hosp Canc Care, Pediat Neurooncol Outcomes Program, 44 Binney St,SW 331, Boston, MA 02115 USA. NR 117 TC 48 Z9 48 U1 4 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0883-0738 J9 J CHILD NEUROL JI J. Child Neurol. PD NOV PY 2009 VL 24 IS 11 BP 1455 EP 1463 DI 10.1177/0883073809341709 PG 9 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 510RP UT WOS:000271109100013 PM 19841433 ER PT J AU Bergwitz, C Banerjee, S Abu-Zahra, H Kaji, H Miyauchi, A Sugimoto, T Juppner, H AF Bergwitz, Clemens Banerjee, Santanu Abu-Zahra, Hilal Kaji, Hiroshi Miyauchi, Akimitsu Sugimoto, Toshitsugu Jueppner, Harald TI Defective O-Glycosylation due to a Novel Homozygous S129P Mutation Is Associated with Lack of Fibroblast Growth Factor 23 Secretion and Tumoral Calcinosis SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MISSENSE MUTATION; FGF23; FIBROBLAST-GROWTH-FACTOR-23; HYPERPHOSPHATEMIA; DISORDER; PROTEIN; GALNT3 AB Background: Homozygous mutations in fibroblast growth factor (FGF23) have recently been described as the genetic cause of one form of hyperphosphatemic tumoral calcinosis (HFTC). However, it remained unclear to date how these mutations lead to loss of biologically active FGF23 in the circulation. Methods: We here report a novel homozygous mutation, c. 385T > C in FGF23 exon 2, which changes codon 129 from serine to proline (S129P) in a previously described individual affected by HFTC. The S129P mutation as well as two known FGF23 mutations, S71G and S129F, were introduced into an expression vector encoding wild-type (wt) human (h) FGF23 to yield [P129]hFGF23, [F129]hFGF23, and [G71] hFGF23; whole lysates, glycoprotein fractions, and conditioned media from HEK293 and COS-7 cells expressing these constructs were subjected to Western blot analysis using affinity-purified goat anti-hFGF23(51-69) and anti-hFGF23(206-222) antibodies. Results: We detected 25-and 32-kDa protein species in total lysates of HEK293 cells expressing wt-hFGF23. The 32-kDa band, representing O-glycosylated hFGF23, was not detectable in the glycoprotein fraction of lysates from HEK293 cells expressing [P129] hFGF23, and in comparison with wt-FGF23 only small amounts of [P129] hFGF23 were secreted into the medium. Similar results were obtained for cells expressing [G71] hFGF23 and [F129] hFGF23. Conclusion: Our data for the first time directly show that FGF23 mutations associated with HFTC impair O-glycosylation in vitro resulting in poor secretion of the mutant hormone thereby explaining the characteristic hyperphosphatemic phenotype of homozygous carriers in vivo. (J Clin Endocrinol Metab 94: 4267-4274, 2009) C1 [Bergwitz, Clemens; Banerjee, Santanu; Abu-Zahra, Hilal; Jueppner, Harald] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. [Jueppner, Harald] Massachusetts Gen Hosp, Pediat Nephrol Unit, Boston, MA 02114 USA. [Kaji, Hiroshi] Kobe Univ, Grad Sch Med, Dept Internal Med, Div Endocrinol Diabet & Metab, Kobe, Hyogo 6500017, Japan. [Sugimoto, Toshitsugu] Shimane Univ, Fac Med, Matsue, Shimane 6938501, Japan. RP Bergwitz, C (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Thier 1038, Boston, MA 02114 USA. EM cbergwitz@partners.org FU National Institutes of Health [PO1 DK11794, 1K08 DK078361]; National Kidney Foundation; American Association for Clinical Investigation FX This work was supported by the National Institutes of Health Grants PO1 DK11794, Project IV (to H. J.), and 1K08 DK078361; Young Investigator Awards by the National Kidney Foundation and the American Association for Clinical Investigation (to C. B.). NR 26 TC 38 Z9 39 U1 0 U2 0 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 NOV PY 2009 VL 94 IS 11 BP 4267 EP 4274 DI 10.1210/jc.2009-0961 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 515LD UT WOS:000271470800019 PM 19837926 ER PT J AU Raivio, T Sidis, Y Plummer, L Chen, HB Ma, JH Mukherjee, A Jacobson-Dickman, E Quinton, R Van Vliet, G Lavoie, H Hughes, VA Dwyer, A Hayes, FJ Xu, SY Sparks, S Kaiser, UB Mohammadi, M Pitteloud, N AF Raivio, Taneli Sidis, Yisrael Plummer, Lacey Chen, Huaibin Ma, Jinghong Mukherjee, Abir Jacobson-Dickman, Elka Quinton, Richard Van Vliet, Guy Lavoie, Helene Hughes, Virginia A. Dwyer, Andrew Hayes, Frances J. Xu, Shuyun Sparks, Susan Kaiser, Ursula B. Mohammadi, Moosa Pitteloud, Nelly TI Impaired Fibroblast Growth Factor Receptor 1 Signaling as a Cause of Normosmic Idiopathic Hypogonadotropic Hypogonadism SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GONADOTROPIN-RELEASING-HORMONE; KALLMANN-SYNDROME; LUTEINIZING-HORMONE; PEPTIDE RECEPTOR; MUTATIONS; GENE; FGFR1; DEFICIENCY; FIBROBLAST-GROWTH-FACTOR-RECEPTOR-1; SPECTRUM AB Context: FGFR1 mutations have been identified in about 10% of patients with Kallmann syndrome. Recently cases of idiopathic hypogonadotropic hypogonadism (IHH) with a normal sense of smell (nIHH) have been reported. Aims: The objective of the study was to define the frequency of FGFR1 mutations in a large cohort of nIHH, delineate the spectrum of reproductive phenotypes, assess functionality of the FGFR1 mutant alleles in vitro, and investigate genotype-phenotype relationships. Design: FGFR1 sequencing of 134 well-characterized nIHH patients (112 men and 22 women) and 270 healthy controls was performed. The impact of the identified mutations on FGFR1 function was assessed using structural prediction and in vitro studies. Results: Nine nIHH subjects (five males and four females; 7%) harbor a heterozygous mutation in FGFR1 and exhibit a wide spectrum of pubertal development, ranging from absent puberty to reversal of IHH in both sexes. All mutations impair receptor function. The Y99C, Y228D, and I239T mutants impair the tertiary folding, resulting in incomplete glycosylation and reduced cell surface expression. The R250Q mutant reduces receptor affinity for FGF. The K618N, A671P, and Q680X mutants impair tyrosine kinase activity. However, the degree of functional impairment of the mutant receptors did not always correlate with the reproductive phenotype, and variable expressivity of the disease was noted within family members carrying the same FGFR1 mutation. These discrepancies were partially explained by additional mutations in known IHH loci. Conclusions: Loss-of-function mutations in FGFR1 underlie 7% of nIHH with different degrees of impairment in vitro. These mutations act in concert with other gene defects in several cases, consistent with oligogenicity. (J Clin Endocrinol Metab 94: 4380-4390, 2009) C1 [Raivio, Taneli; Sidis, Yisrael; Plummer, Lacey; Mukherjee, Abir; Jacobson-Dickman, Elka; Hughes, Virginia A.; Dwyer, Andrew; Hayes, Frances J.; Pitteloud, Nelly] Massachusetts Gen Hosp, Harvard Ctr Reprod Endocrine Sci, Boston, MA 02114 USA. [Raivio, Taneli; Sidis, Yisrael; Plummer, Lacey; Mukherjee, Abir; Jacobson-Dickman, Elka; Hughes, Virginia A.; Dwyer, Andrew; Hayes, Frances J.; Pitteloud, Nelly] Massachusetts Gen Hosp, Reprod Endocrine Unit, Dept Med, Boston, MA 02114 USA. [Xu, Shuyun; Kaiser, Ursula B.] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02114 USA. [Chen, Huaibin; Ma, Jinghong; Mohammadi, Moosa] NYU, Sch Med, Dept Pharmacol, New York, NY 10016 USA. [Quinton, Richard] Newcastle Univ, Inst Human Genet, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. [Van Vliet, Guy] Hop St Justine, Montreal, PQ H3T 1C5, Canada. [Lavoie, Helene] Ctr Hosp Univ Montreal, Montreal, PQ H2W 1T8, Canada. [Lavoie, Helene] Procrea Clin, Montreal, PQ H2W 1T8, Canada. [Sparks, Susan] Childrens Natl Med Ctr, Dept Genet & Metab, Washington, DC 20010 USA. [Raivio, Taneli] Univ Helsinki, Inst Biomed Physiol, FIN-00014 Helsinki, Finland. RP Pitteloud, N (reprint author), Massachusetts Gen Hosp, Harvard Ctr Reprod Endocrine Sci, Bartlett Hall Extens 5, Boston, MA 02114 USA. EM pitteloud.nelly@mgh.harvard.edu RI Dwyer, Andrew/D-8099-2012; PITTELOUD, Nelly/K-2709-2014; OI Dwyer, Andrew/0000-0002-7023-6794; Mohammadi, Moosa/0000-0003-2434-9437 FU National Institutes of Health [R01 HD015788-21, R01 HD19938, U54HD028138-16, R01 DE13686-09]; Foundation for Pediatric Research, Finland; Academy of Finland FX This work was supported by National Institutes of Health Grants R01 HD015788-21, R01 HD19938, U54HD028138-16, and R01 DE13686-09; Foundation for Pediatric Research, Finland; and the Academy of Finland. NR 53 TC 43 Z9 45 U1 1 U2 2 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 NOV PY 2009 VL 94 IS 11 BP 4380 EP 4390 DI 10.1210/jc.2009-0179 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 515LD UT WOS:000271470800033 PM 19820032 ER PT J AU Ix, JH Wassel, CL Chertow, GM Koster, A Johnson, KC Tylavsky, FA Cauley, JA Cummings, SR Harris, TB Shlipak, MG AF Ix, Joachim H. Wassel, Christina L. Chertow, Glenn M. Koster, Annemarie Johnson, Karen C. Tylavsky, Frances A. Cauley, Jane A. Cummings, Steven R. Harris, Tamara B. Shlipak, Michael G. CA Hlth Aging Body Composition Study TI Fetuin-A and Change in Body Composition in Older Persons SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID INCIDENT DIABETES-MELLITUS; TYROSINE KINASE INHIBITOR; INSULIN-RECEPTOR; MYOCARDIAL-INFARCTION; RESISTANCE; PLASMA; ADULTS; ADIPOCYTOKINES; GLYCOPROTEIN; ASSOCIATION AB Context: Fetuin-A inhibits the insulin receptor in vitro. Higher serum fetuin-A concentrations are associated with type 2 diabetes longitudinally and greater adiposity in cross-sectional analyses. Whether higher fetuin-A concentrations are associated with accumulation of adiposity over time is unknown. Objective: To determine the association of fetuin-A levels with changes in body composition over 5 yr. Study Design: Observational cohort study nested in the Health Aging and Body Composition Study. Predictor: Serum fetuin-A levels. Outcomes: Visceral adipose tissue (VAT), abdominal sc adipose tissue, and thigh muscle area by computed tomography, and waist circumference and body mass index were measured at baseline and again after 5 yr. Percent change and extreme change (>1.5 SDs) in each measure were calculated. Results: Over 5 yr, subjects lost body mass in each measure, including 6% decline in VAT. Yet each SD (0.42 g/liter) higher fetuin-A concentration was associated with a 5.5% increase in VAT over 5 yr (95% confidence interval 1.9-9.2%; P = 0.003) in models adjusted for age, sex, race, clinical site, diabetes, physical activity, triglycerides, kidney function, and the baseline VAT score. Similarly, higher fetuin-A concentrations were associated with extreme VAT gain (relative risk 1.70, 95% confidence interval 1.12-2.60, P = 0.01). Fetuin-A concentrations were not statistically significant associated with change in any other measures of body composition (P > 0.20). Conclusions: Higher fetuin-A concentrations are associated with the accumulation of VAT in well-functioning, community-living older persons. The mechanisms linking fetuin-A, VAT, and insulin resistance remain to be determined. (J Clin Endocrinol Metab 94: 4492-4498, 2009) C1 [Ix, Joachim H.] Univ Calif San Diego, Div Nephrol, Dept Med, San Diego, CA 92161 USA. [Ix, Joachim H.; Wassel, Christina L.] Univ Calif San Diego, Div Prevent Med, Dept Family & Prevent Med, San Diego, CA 92161 USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, Nephrol Sect, San Diego, CA 92161 USA. [Chertow, Glenn M.] Stanford Univ, Dept Med, Div Nephrol, Stanford, CA 94305 USA. [Koster, Annemarie; Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Johnson, Karen C.; Tylavsky, Frances A.] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN 38163 USA. [Cauley, Jane A.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Cummings, Steven R.] Calif Pacific Med Ctr, Dept Med, San Francisco, CA 94120 USA. [Cummings, Steven R.] San Francisco Coordinating Ctr, San Francisco, CA 94107 USA. [Cummings, Steven R.; Shlipak, Michael G.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Shlipak, Michael G.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, Gen Internal Med Sect, San Francisco, CA 94121 USA. RP Ix, JH (reprint author), Univ Calif San Diego, Dept Med, Div Nephrol & Hypertens, 3350 La Jolla Village Dr,Mail Code 111-H, San Diego, CA 92161 USA. EM joeix@ucsd.edu RI Koster, Annemarie/E-7438-2010; Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU American Diabetes Association (ADA); Association of Subspecialty Professors (ASP); Atlantic Philanthropies; John A. Hartford Foundation; American Heart Association; National Institutes of Health, National Institute on Aging (NIA); [N01-AG-6-2101]; [N01-AG6-2103]; [N01-AG-6-2106] FX This study was supported by an American Diabetes Association (ADA) -Association of Subspecialty Professors (ASP) Young Investigator Innovation Award in Geriatric Endocrinology sponsored by the Atlantic Philanthropies, ADA, the John A. Hartford Foundation, and ASP, an American Heart Association Fellow to Faculty Transition Award (J. H. I.). The Health ABC study was supported by contracts N01-AG-6-2101, N01-AG6-2103, and N01-AG-6-2106 and by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (NIA). The funding sources played no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data, nor in the preparation of the manuscript. The NIA reviewed and approved this manuscript prior to submission. NR 27 TC 25 Z9 25 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 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD NOV PY 2009 VL 94 IS 11 BP 4492 EP 4498 DI 10.1210/jc.2009-0916 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 515LD UT WOS:000271470800048 PM 19820014 ER PT J AU Cefalu, AB Noto, D Arpi, ML Yin, F Spina, R Hilden, H Barbagallo, CM Carroccio, A Tarugi, P Squatrito, S Vigneri, R Taskinen, MR Peterfy, M Averna, MR AF Cefalu, Angelo B. Noto, Davide Arpi, Maria Luisa Yin, Fen Spina, Rossella Hilden, Hannele Barbagallo, Carlo M. Carroccio, Antonio Tarugi, Patrizia Squatrito, Sebastiano Vigneri, Riccardo Taskinen, Marja-Riitta Peterfy, Miklos Averna, Maurizio R. TI Novel LMF1 Nonsense Mutation in a Patient with Severe Hypertriglyceridemia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ANGIOPOIETIN-LIKE PROTEIN-4; COMBINED LIPASE DEFICIENCY; LIPOPROTEIN-LIPASE; ENDOPLASMIC-RETICULUM; MICE; CLD; DYSLIPIDEMIA; MATURATION AB Context: Lipase maturation factor 1 (LMF1) gene is a novel candidate gene in severe hypertriglyceridemia. Lmf1 is involved in the maturation of lipoprotein lipase (LPL) and hepatic lipase in endoplasmic reticulum. To date only one patient with severe hypertriglyceridemia and related disorders was found to be homozygous for a nonsense mutation in LMF1 gene (Y439X). Objective: The objective of the study was to investigate LMF1 gene in hypertriglyceridemic patients in whom mutations in LPL, APOC2, and APOA5 genes had been excluded. Results: The resequencing of LMF1 gene led to the discovery of a novel homozygous nonsense mutation in one patient with severe hypertriglyceridemia and recurrent episodes of pancreatitis. The mutation causes a G > A substitution in exon 9 (c. 1395G > A), leading to a premature stop codon (W464X). LPL activity and mass were reduced by 76 and 50%, respectively, compared with normolipidemic controls. The proband over the years has shown a good response to treatment. The proband's son, heterozygous for the W464X, shows normal plasma triglyceride levels. Conclusions: We identified the second novel pathogenic mutation in LMF1 gene in a patient with severe hypertriglyceridemia. LPL deficiency in our patient was milder than in the carrier of the Y439X previously described. (J Clin Endocrinol Metab 94: 4584-4590, 2009) C1 [Averna, Maurizio R.] Univ Palermo, Policlin Paolo Giaccone, Dept Clin Med & Emerging Dis, I-90127 Palermo, Italy. [Arpi, Maria Luisa; Squatrito, Sebastiano; Vigneri, Riccardo] Univ Catania, Dept Internal Med, Endocrinol Unit, I-95125 Catania, Italy. [Yin, Fen; Peterfy, Miklos] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. [Yin, Fen; Peterfy, Miklos] Vet Affairs Greater Los Angeles Healthcare Syst, Lipid Res Lab, Los Angeles, CA 90073 USA. [Yin, Fen; Peterfy, Miklos] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Hilden, Hannele; Taskinen, Marja-Riitta] Helsinki Univ Hosp, Dept Med, FI-00029 Helsinki, Finland. [Tarugi, Patrizia] Univ Modena & Reggio Emilia, Dept Biomed Sci, I-41100 Modena, Italy. RP Averna, MR (reprint author), Univ Palermo, Policlin Paolo Giaccone, Dept Clin Med & Emerging Dis, Via Vespro 141, I-90127 Palermo, Italy. EM avernam@unipa.it RI Tarugi, Patrizia/D-2179-2015; Carroccio, Antonio/K-4484-2016; OI Tarugi, Patrizia/0000-0001-6864-7853; Carroccio, Antonio/0000-0001-8913-7916; Noto, Davide/0000-0002-5346-2829; Barbagallo, Carlo M./0000-0002-4114-038X; Cefalu', Angelo Baldassare/0000-0003-1259-8284; Averna, Maurizio/0000-0003-3558-9209 FU University of Palermo; Cedars-Sinai Medical Center; National Institutes of Health [HL28481] FX This work was supported by contract grants from the University of Palermo (60% to M. R. A. and C. M. B.), the Cedars-Sinai Medical Center, and Grant HL28481 from the National Institutes of Health (to M. P.). NR 27 TC 27 Z9 27 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 NOV PY 2009 VL 94 IS 11 BP 4584 EP 4590 DI 10.1210/jc.2009-0594 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 515LD UT WOS:000271470800059 PM 19820022 ER PT J AU Kostis, WJ Kostis, JB AF Kostis, William J. Kostis, John B. TI Age-Neutral Guidelines for the Primary Prevention of Cardiovascular Disease SO JOURNAL OF CLINICAL HYPERTENSION LA English DT Editorial Material ID HIGH BLOOD CHOLESTEROL; ADULTS; RISK; HYPERTENSION; PREVALENCE; AWARENESS; TRENDS; COSTS; WOMEN AB Use of common guidelines for primary prevention of cardiovascular events based on 10-year risk results in undertreatment of younger individuals, especially women, since age and sex are major determinants of global risk. Women in their late 40s have a 10-year risk lower than the 10% threshold used for cholesterol-lowering treatment even in the presence of marked elevations of blood pressure or cholesterol. Removal of age from risk algorithms and use of lifetime global risk to treat individuals according to the degree of their modifiable risk factors rather than demographics has been proposed. Initiation of therapy at younger ages, aiming at "primordial'' prevention of atherosclerotic disease rather than focusing on cardiovascular events, will result in saving more quality-adjusted life-years. Generic medications can be obtained at an affordable cost, and concerns about long-term safety and efficacy can be tested in a clinical trial of younger individuals at low 10-year risk but high lifetime risk. J Clin Hypertens (Greenwich). 2009;11:644-645. (C) 2009 Wiley Periodicals, Inc. C1 [Kostis, William J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Kostis, John B.] UMDNJ, Dept Med, Robert Wood Johnson Med Sch, New Brunswick, NJ USA. RP Kostis, WJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, 55 Fruit St, Boston, MA 02114 USA. EM wkostis@partners.org NR 19 TC 3 Z9 3 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 NOV PY 2009 VL 11 IS 11 BP 644 EP 645 DI 10.1111/j.1751-7176.2009.00162.x PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 509ZM UT WOS:000271057800006 PM 19878373 ER PT J AU Chen, L Periquet, M Wang, X Negro, A McLean, PJ Hyman, BT Feany, MB AF Chen, Li Periquet, Magali Wang, Xu Negro, Alessandro McLean, Pamela J. Hyman, Bradley T. Feany, Mel B. TI Tyrosine and serine phosphorylation of alpha-synuclein have opposing effects on neurotoxicity and soluble oligomer formation SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID FAMILIAL PARKINSONS-DISEASE; DROSOPHILA MODEL; LEWY BODIES; TRANSGENIC MICE; CELL-DEATH; RAT MODEL; NEURODEGENERATION; MUTATION; AGGREGATION; DIAGNOSIS AB Mutations in the neuronal protein alpha-synuclein cause familial Parkinson disease. Phosphorylation of alpha-synuclein at serine 129 is prominent in Parkinson disease and influences alpha-synuclein neurotoxicity. Here we report that alpha-synuclein is also phosphorylated at tyrosine 125 in transgenic Drosophila expressing wildtype human alpha-synuclein and that this tyrosine phosphorylation protects from alpha-synuclein neurotoxicity in a Drosophila model of Parkinson disease. Western blot analysis of fly brain homogenates showed that levels of soluble oligomeric species of alpha-synuclein were increased by phosphorylation at serine 129 and decreased by tyrosine 125 phosphorylation. Tyrosine 125 phosphorylation diminished during the normal aging process in both humans and flies. Notably, cortical tissue from patients with the Parkinson disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at tyrosine 125. Our findings suggest that alpha-synuclein neurotoxicity in Parkinson disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of serine 129 phosphorylation and a neuroprotective action of tyrosine 125 phosphorylation that inhibits toxic oligomer formation. C1 [Chen, Li; Periquet, Magali; Feany, Mel B.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Wang, Xu] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wang, Xu] Harvard Univ, Sch Med, Boston, MA USA. [Negro, Alessandro] Univ Padua, Dept Biochem, Padua, Italy. [McLean, Pamela J.; Hyman, Bradley T.] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. RP Feany, MB (reprint author), Brigham & Womens Hosp, Dept Pathol, 77 Louis Pasteur Ave,Room 630, Boston, MA 02115 USA. EM mel_feany@hms.harvard.edu FU NIH [R01-NS41536, P50-NS38372]; Parkinson's Disease Foundation FX We thank D. Rennie (Cutaneous Biology Research Center, Massachusetts General Hospital) for fly embryo injection. We also acknowledge the Massachusetts General Hospital ADRC Brain Bank. We appreciate the assistance of Katherine Sharpe and Paola Merlo with real-time PCR measurements. This work was supported by NIH grants R01-NS41536 (to M.B. Feany) and P50-NS38372 (to B.T Hyman) and by the Parkinson's Disease Foundation (to L. Chen). NR 55 TC 86 Z9 88 U1 2 U2 11 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 NOV PY 2009 VL 119 IS 11 BP 3257 EP 3265 DI 10.1172/JCI39088 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 517CC UT WOS:000271589400010 PM 19855133 ER PT J AU Wang, LJ Harrington, L Trebicka, E Shi, HN Kagan, JC Hong, CC Lin, HY Babitt, JL Cherayil, BJ AF Wang, Lijian Harrington, Lynne Trebicka, Estela Shi, Hai Ning Kagan, Jonathan C. Hong, Charles C. Lin, Herbert Y. Babitt, Jodie L. Cherayil, Bobby J. TI Selective modulation of TLR4-activated inflammatory responses by altered iron homeostasis in mice SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID TOLL-LIKE RECEPTOR; HEREDITARY HEMOCHROMATOSIS; SALMONELLA INFECTION; HEPCIDIN EXPRESSION; VIBRIO-VULNIFICUS; SIGNALING PATHWAY; C282Y MUTATION; PROTEIN; HOST; HFE AB Mice deficient in the hemochromatosis gene, Hfe, have attenuated inflammatory responses to Salmonella infection associated with decreased macrophage TNF-alpha and IL-6 biosynthesis after exposure to LPS. In this study, we show that the abnormal cytokine production is related to impaired TLR4 signaling. Despite their abnormal response to LPS, Hfe KO macrophages produced amounts of TNF-alpha similar to those in WT cells after TLR2 stimulation. Consistent with this finding, LPS-induced activation of Mal/MyD88-dependent events was normal in the mutant macrophages. However, LPS-induced IFN-beta expression, a TRAM/TRIF-dependent response activated by TLR4, was reduced by Hfe deficiency. This reduction could be replicated in WT macrophages with the use of iron chelators. In contrast, TLR3-activated expression of IFN-beta, a TRIF-dependent response, was normal in Hfe KO macrophages and was unaffected by iron chelation. Our data suggest that low intracellular iron selectively impairs signaling via the TLR4/TRAM/TRIF pathway proximal to TRIF and results in reduced LPS-induced cytokine expression. Furthermore, by mimicking the altered iron metabolism associated with Hfe deficiency, we found that 3 different inhibitors of hepcidin attenuated Salmonella-induced and noninfectious enterocolitis. Thus, manipulation of iron homeostasis could represent a new therapeutic approach to controlling inflammation. C1 [Wang, Lijian; Harrington, Lynne; Trebicka, Estela; Shi, Hai Ning; Cherayil, Bobby J.] Massachusetts Gen Hosp, Mucosal Immunol Lab, Charlestown, MA 02129 USA. [Wang, Lijian] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Shi, Hai Ning; Cherayil, Bobby J.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Kagan, Jonathan C.] Childrens Hosp, Dept Gastroenterol, Boston, MA 02115 USA. [Hong, Charles C.] Vanderbilt Univ, Med Ctr, Div Cardiovasc Med, Nashville, TN USA. [Lin, Herbert Y.; Babitt, Jodie L.] Massachusetts Gen Hosp, Program Membrane Biol, Div Nephrol, Boston, MA 02114 USA. [Lin, Herbert Y.; Babitt, Jodie L.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. RP Cherayil, BJ (reprint author), Massachusetts Gen Hosp, Mucosal Immunol Lab, Bldg 114,16th St, Charlestown, MA 02129 USA. EM cherayil@helix.mgh.harvard.edu RI Hong, Charles/C-9989-2010 FU Broad Medical Research Program [TBD-0253]; Wyeth Nutrition; Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders; National Institute of Diabetes and Digestive and Kidney Diseases, NIH [R01-071837] FX This work was supported by funds from the Broad Medical Research Program (grant no. TBD-0253) to Bobby J. Cherayil and from Wyeth Nutrition to L. Wang. C.C. Hong received support from the Center for Research in Fibrodysplasia Ossificans Progressiva and Related Disorders. H.Y. Lin was supported in part by grant R01-071837 from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. We are grateful to Nancy Andrews for providing the Hfe KO mice and to Prem Ponka for the gift of SIH. We thank Sarah A. Faasse for technical assistance with iron assays. NR 44 TC 76 Z9 78 U1 0 U2 9 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 NOV PY 2009 VL 119 IS 11 BP 3322 EP 3328 DI 10.1172/JCI39939 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 517CC UT WOS:000271589400016 PM 19809161 ER PT J AU Mareninova, OA Hermann, K French, SW O'Konski, MS Pandol, SJ Webster, P Erickson, AH Katunuma, N Gorelick, FS Gukovsky, I Gukovskaya, AS AF Mareninova, Olga A. Hermann, Kip French, Samuel W. O'Konski, Mark S. Pandol, Stephen J. Webster, Paul Erickson, Ann H. Katunuma, Nobuhiko Gorelick, Fred S. Gukovsky, Ilya Gukovskaya, Anna S. TI Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CERULEIN-INDUCED PANCREATITIS; CATHEPSIN-B; HEREDITARY PANCREATITIS; LYSOSOMAL-ENZYMES; EARLY EVENTS; MONITORING AUTOPHAGY; ZYMOGEN ACTIVATION; RAT HEPATOCYTES; IN-VITRO; DISEASE AB The pathogenic mechanisms underlying acute pancreatitis are not clear. Two key pathologic acinar cell responses of this disease are vacuole accumulation and trypsinogen activation. We show here that both result from defective autophagy, by comparing the autophagic responses in rodent models of acute pancreatitis to physiologic autophagy triggered by fasting. Pancreatitis-induced vacuoles in acinar cells were greater in number and much larger than those induced with fasting. Degradation of long-lived proteins, a measure of autophagic efficiency, was markedly inhibited in in vitro pancreatitis, while it was stimulated by acinar cell starvation. Further, processing of the lysosomal proteases cathepsin L (CatL) and CatB into their fully active, mature forms was reduced in pancreatitis, as were their activities in the lysosome-enriched subcellular fraction. These findings indicate that autophagy is retarded in pancreatitis due to deficient lysosomal degradation caused by impaired cathepsin processing. Trypsinogen activation occurred in pancreatitis but not with fasting and was prevented by inhibiting autophagy. A marker of trypsinogen activation partially localized to autophagic vacuoles, and pharmacologic inhibition of CatL increased the amount of active trypsin in acinar cells. The results suggest that retarded autophagy is associated with an imbalance between CatL, which degrades trypsinogen and trypsin, and CatB, which converts trypsinogen into trypsin, resulting in intra-acinar accumulation of active trypsin in pancreatitis. Thus, deficient lysosomal degradation may be a dominant mechanism for increased intra-acinar trypsin in pancreatitis. C1 [Mareninova, Olga A.; Hermann, Kip; Pandol, Stephen J.; Gukovsky, Ilya; Gukovskaya, Anna S.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Mareninova, Olga A.; Hermann, Kip; Pandol, Stephen J.; Gukovsky, Ilya; Gukovskaya, Anna S.] Univ Calif Los Angeles, Los Angeles, CA USA. [French, Samuel W.] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [O'Konski, Mark S.] Digest Hlth Phys, Ft Myers, FL USA. [Webster, Paul] House Ear Res Inst, Los Angeles, CA USA. [Erickson, Ann H.] Univ N Carolina, Chapel Hill, NC USA. [Katunuma, Nobuhiko] Tokushima Bunri Univ, Tokushima, Japan. [Gorelick, Fred S.] Vet Affairs Med Ctr, West Haven, CT USA. [Gorelick, Fred S.] Yale Univ, West Haven, CT USA. RP Gukovskaya, AS (reprint author), UCLA Vet Affairs Greater Los Angeles Healthcare S, W Los Angeles Vet Affairs Healthcare Ctr, 11301 Wilshire Blvd,Blg 258,Rm 340, Los Angeles, CA 90073 USA. EM igukovsk@ucla.edu; agukovsk@ucla.edu FU Department of Veterans Affairs; NIH [DK59936, P60 AA11999]; American Gastroenterology Association Foundation Designated Research Scholar Award in Pancreaeitis FX This study was supported by the Department of Veterans Affairs, the NIH grants DK59936 (to A.S. Gukovskaya) and P60 AA11999 (to A.S. Gukovskaya and SJ. Pandol), and, in part, by the American Gastroenterology Association Foundation Designated Research Scholar Award in Pancreaeitis (to O.A. Mareninova). The authors thank Noboru Mizushima (Tokyo Medical and Dental University, Tokyo, Japan) and RIKEN BioResourse Center (Koyadai, Japan) for providing the GFP-LC3 transgenic mice and D.S. Longnecker (Dartmouth Medical School, USA) for providing H&E images of pancreatic tissue from patients with acute pancreatitis. The authors also thank the UCLA Microscopic Techniques Core (Marianne Cilluffo) for expert help with immunolabeling, Moses A. Lee for help with Western blot densicometry, and Tina Feng for help with quantification of vacuoles. NR 69 TC 91 Z9 97 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 NOV PY 2009 VL 119 IS 11 BP 3340 EP 3355 DI 10.1172/JCI38674 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 517CC UT WOS:000271589400018 PM 19805911 ER PT J AU Fox, JG Shen, Z Muthupalani, S Rogers, AR Kirchain, SM Dewhirst, FE AF Fox, J. G. Shen, Z. Muthupalani, S. Rogers, A. R. Kirchain, S. M. Dewhirst, F. E. TI Chronic Hepatitis, Hepatic Dysplasia, Fibrosis, and Biliary Hyperplasia in Hamsters Naturally Infected with a Novel Helicobacter Classified in the H. bilis Cluster SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; SYRIAN GOLDEN-HAMSTERS; RIBOSOMAL-RNA GENE; HUMAN-LIVER FLUKE; OPISTHORCHIS-VIVERRINI; N-NITROSODIMETHYLAMINE; SPONTANEOUS TUMORS; COMMON DISEASES; SP-NOV; BACTERIAL-INFECTION AB We recently described helicobacter-associated progressive, proliferative, and dysplastic typhlocolitis in aging (18- to 24-month-old) Syrian hamsters. Other pathogens associated with typhlocolitis in hamsters, Clostridium difficile, Lawsonia intracellularis, and Giardia spp., were not indentified. The presence of Helicobacter genus-specific DNA was noted by PCR in cecal and paraffin-embedded liver samples from aged hamsters by the use of Helicobacter-specific PCR primers. By 16S rRNA analysis, the Helicobacter sp. isolated from the liver tissue was identical to the cecal isolates from hamsters. The six hamster 16S rRNA sequences form a genotypic cluster most closely related to Helicobacter sp. Flexispira taxon 8, part of the Helicobacter bilis/H. cinaedi group. Livers from aged helicobacter-infected hamsters showed various stages of predominantly portocentric and, to a lesser extent, perivenular fibrosis. Within nodules, there was cellular atypia consistent with nodular dysplasia. The livers also exhibited a range of chronic active portal/interface and lobular inflammation, with significant portal hepatitis being present. The inflammation was composed of a mixture of lymphocytes, neutrophils, and macrophages, indicative of its chronic-active nature in these aged hamsters infected with Helicobacter spp. The isolation of novel Helicobacter spp., their identification by PCR from the diseased livers of aged hamsters, and their taxonomic classification as belonging to the Helicobacter bilis cluster strengthen the argument that H. bilis and closely related Helicobacter spp. play an etiological role in hepatobiliary disease in both animals and humans. C1 [Fox, J. G.; Shen, Z.; Muthupalani, S.; Rogers, A. R.; Kirchain, S. M.] MIT, Div Comparat Med, Cambridge, MA 02139 USA. [Dewhirst, F. E.] Forsyth Inst, Dept Mol Genet, Boston, MA 02115 USA. RP Fox, JG (reprint author), MIT, Div Comparat Med, 77 Massachusetts Ave,Bldg 16-825, Cambridge, MA 02139 USA. EM jgfox@mit.edu FU NIH [R01CA67529, P30ES102109, RR07036, DE016937] FX This work was supported by NIH grants R01CA67529 (to J. G. F.), P30ES102109 (to J. G. F.), RR07036 (to J. G. F.), and DE016937 (to F. E. D.). NR 52 TC 19 Z9 19 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 NOV PY 2009 VL 47 IS 11 BP 3673 EP 3681 DI 10.1128/JCM.00879-09 PG 9 WC Microbiology SC Microbiology GA 514CZ UT WOS:000271373000043 PM 19759229 ER PT J AU Castellon, SA Ganz, PA AF Castellon, Steven A. Ganz, Patricia A. TI Exploring the Impact of the Hormonal Milieu on Cognitive Functioning SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID STAR P-2 TRIAL; BREAST-CANCER; TAMOXIFEN; CHEMOTHERAPY; PERFORMANCE; RALOXIFENE; THERAPY; BRAIN; NSABP C1 [Castellon, Steven A.] Univ Calif Los Angeles, David Geffen Sch Med, Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90095 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Med, Los Angeles, CA 90024 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Publ Hlth, Los Angeles, CA 90024 USA. RP Castellon, SA (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA 90095 USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2009 VL 27 IS 31 BP 5119 EP 5121 DI 10.1200/JCO.2009.24.3329 PG 5 WC Oncology SC Oncology GA 512TS UT WOS:000271274300003 PM 19770364 ER PT J AU Liebig, C Ayala, G Wilks, J Verstovsek, G Liu, H Agarwal, N Berger, DH Albo, D AF Liebig, Catherine Ayala, Gustavo Wilks, Jonathan Verstovsek, Gordana Liu, Hao Agarwal, Neeti Berger, David H. Albo, Daniel TI Perineural Invasion Is an Independent Predictor of Outcome in Colorectal Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROSTATE-CANCER; NEURAL INVASION; HIGH-RISK; PANCREATIC-CANCER; COLON-CANCER; PROGNOSTIC-SIGNIFICANCE; RECTAL-CANCER; NEEDLE-BIOPSY; CARCINOMA; STAGE AB Purpose Perineural invasion (PNI) is associated with decreased survival in several malignancies, but its significance in colorectal cancer (CRC) remains to be clearly defined. We evaluated PNI as a potential prognostic indicator in CRC, focusing on its significance in node-negative patients. Patients and Methods We identified 269 consecutive patients who had CRC resected at our institution. Tumors were rereviewed for PNI by a pathologist blinded to the patients' outcomes. Overall and disease-free survivals were determined using the Kaplan-Meier method, with differences determined by multivariate analysis using the Cox multiple hazards model. Results were compared using the log-rank test. Results PNI was identified in less than 0.5% of the initial pathology reports. On rereview, 22% of tumors in our series were found to be PNI positive. The 5-year disease-free survival rate was four-fold greater for patients with PNI-negative tumors versus those with PNI-positive tumors (65% v 16%, respectively; P < .0001). The 5-year overall survival rate was 72% for PNI-negative tumors versus 25% for PNI-positive tumors. On multivariate analysis, PNI was an independent prognostic factor for both cancer-specific overall and disease-free survival. In a subset analysis comparing patients with node-negative disease with patients with stage III disease, the 5-year disease-free survival rate was 56% for stage III patients versus 29% for patients with node-negative, PNI-positive tumors (P = .0002). Similar results were seen for overall survival. Conclusion PNI is grossly underreported in CRC and could serve as an independent prognostic factor of outcomes in these patients. PNI should be considered when stratifying CRC patients for adjuvant treatment. C1 [Albo, Daniel] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. Baylor Coll Med, Micheal E DeBakey Dept Surg, Dept Pathol, Houston, TX 77030 USA. Baylor Coll Med, Div Biostat, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. RP Albo, D (reprint author), Michael E DeBakey Vet Affairs Med Ctr, 2002 Holcombe Blvd,OCL 112-A, Houston, TX 77030 USA. EM dalbo@bcm.edu NR 45 TC 110 Z9 124 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2009 VL 27 IS 31 BP 5131 EP 5137 DI 10.1200/JCO.2009.22.4949 PG 7 WC Oncology SC Oncology GA 512TS UT WOS:000271274300006 PM 19738119 ER PT J AU Lewis, NL Lewis, LD Eder, JP Reddy, NJ Guo, F Pierce, KJ Olszanski, AJ Cohen, RB AF Lewis, Nancy L. Lewis, Lionel D. Eder, Joseph P. Reddy, Nandi J. Guo, Feng Pierce, Kristen J. Olszanski, Anthony J. Cohen, Roger B. TI Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PDGF RECEPTORS; TARGETS; TUMORS AB Purpose This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596. Patients and Methods Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups. Results Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased gamma-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months). Conclusion CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted. C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Dartmouth Med Sch, Lebanon, NH USA. Norris Cotton Canc Ctr, Lebanon, NH USA. Dana Farber Canc Ctr, Boston, MA USA. Pfizer Oncol, New London, CT USA. RP Lewis, NL (reprint author), Cooper Canc Inst, 900 Centennial Blvd,Ste A, Voorhees, NJ 08043 USA. EM lewis-nancy@cooperhealth.edu FU Pfizer Oncology; National Cancer Institute [CA06927] FX Supported by Pfizer Oncology and by Grant No. CA06927 from the National Cancer Institute. NR 15 TC 39 Z9 40 U1 0 U2 5 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD NOV 1 PY 2009 VL 27 IS 31 BP 5262 EP 5269 DI 10.1200/JCO.2009.21.8487 PG 8 WC Oncology SC Oncology GA 512TS UT WOS:000271274300025 PM 19738123 ER PT J AU Martin, JE Wagner, AJ Murphy, GF Pinkus, GS Wang, LC AF Martin, Julie E. Wagner, Andrew J. Murphy, George F. Pinkus, Geraldine S. Wang, Linda C. TI Granuloma Annulare Heralding Angioimmunoblastic T-Cell Lymphoma in a Patient With a History of Epstein-Barr Virus-Associated B-Cell Lymphoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HODGKINS-DISEASE; INITIAL MANIFESTATION; CUTANEOUS INVOLVEMENT; LABORATORY FINDINGS; MALIGNANT-LYMPHOMA; MYCOSIS-FUNGOIDES; LEUKEMIA; IMMUNODEFICIENCY; LYMPHADENOPATHY; INFECTION C1 [Martin, Julie E.; Wang, Linda C.] Harvard Univ, Brigham & Womens Hosp, Dept Dermatol, Sch Med, Boston, MA 02115 USA. [Murphy, George F.; Pinkus, Geraldine S.] Harvard Univ, Brigham & Womens Hosp, Dept Pathol, Sch Med, Boston, MA 02115 USA. [Wagner, Andrew J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Martin, JE (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Dermatol, Sch Med, Boston, MA 02115 USA. NR 38 TC 5 Z9 5 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 NOV 1 PY 2009 VL 27 IS 31 BP E168 EP E171 DI 10.1200/JCO.2009.23.0409 PG 4 WC Oncology SC Oncology GA 512TS UT WOS:000271274300030 PM 19770367 ER PT J AU Surman, CBH Adamson, JJ Petty, C Biederman, J Kenealy, DC Levine, M Mick, E Faraone, SV AF Surman, Craig B. H. Adamson, Joel J. Petty, Carter Biederman, Joseph Kenealy, Deborah C. Levine, Madeleine Mick, Eric Faraone, Stephen V. TI Association Between Attention-Deficit/Hyperactivity Disorder and Sleep Impairment in Adulthood: Evidence From a Large Controlled Study SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; SUBTHRESHOLD DIAGNOSES; LATE-ONSET; ADHD ADULTS; CHILDREN; SYMPTOMS; COMORBIDITY; ALERTNESS; QUALITY AB Objective: To examine whether sleep impairment is associated with attention-deficit/hyperactivity disorder (ADHD) in adults. Method: In a study conducted from 1998 to 2003, we identified sleep characteristics in a community sample of 182 cases of DSM-IV ADHD or ADHD not otherwise specified and 117 non-ADHD controls aged 18 to 55 years. Attention-deficit/hyperactivity disorder status, current and lifetime psychiatric comorbidity, and pharmacologic treatment of ADHD were identified with the Structured Clinical Interview for DSM-IV and with modules from the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version. Sleep problems were characterized by self-report. We separately accounted for the contribution of age at ADHD onset, ADHD pharmacotherapy, lifetime bipolar disorder, and the following lifetime and current comorbidities: depression, generalized anxiety, substance abuse, and multiple anxiety disorders. Results: Adults with ADHD went to bed later than control subjects and had a wider range of bedtimes (mean +/- SD = 18 +/- 92 min vs 54 +/- 69 min before midnight; P < .001), were more likely to take over an hour to fall asleep (OR = 5.22, P = .001), and were more likely (P < .003) to experience difficulty going to bed, going to sleep, sleeping restfully, or waking in the morning. Adults with ADHD experienced daytime sleepiness more often (OR = 2.23, P = .003) and reported more sleep problems (mean +/- SD = 6.7 +/- 2.5 vs 4.3 +/- 2.2; P < .001) than controls. All sleep impairments were significantly associated with ADHD independent of contributions to sleep disruption from ADHD pharmacotherapy, comorbidities likely to contribute to sleep disturbance, and age at ADHD onset. Conclusion: Sleep disturbances that are not attributable to comorbid mental health conditions or ADHD pharmacotherapy are associated with ADHD in adulthood. Clinicians and researchers should consider the potential contribution of sleep disruption to the clinical presentation of adults with ADHD. J Clin Psychiatry 2009,70(11):1523-1529 (C) Copyright 2009 Physicians Postgraduate Press, Inc. C1 [Surman, Craig B. H.; Adamson, Joel J.; Petty, Carter; Biederman, Joseph; Kenealy, Deborah C.; Levine, Madeleine; Mick, Eric] Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol & Adult, Pediat Psychopharmacol Unit, Yawkey Ctr Outpatient Care, Boston, MA 02114 USA. [Faraone, Stephen V.] NYU, Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [Faraone, Stephen V.] NYU, Upstate Med Univ, Dept Neurosci & Physiol, Syracuse, NY USA. RP Surman, CBH (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol & Adult, Suite 2000,185 Alewife Brook Pkwy, Cambridge, MA 02138 USA. EM csurman@partners.org OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU Abbott; Alza; Cephalon; Eli Lilly; Hilda and Preston Davis Foundation; McNeil; Merck; New River; National Institutes of Health (NIH) [R01MH57934]; AstraZeneca; Bristol-Myers Squibb; Organon; Otsuka; Shire; National Institute of Child Health and Human Development; Celltech; Glaxo; Gliatech; Janssen; NARSAD; National Institute on Drug Abuse; NeuroSearch; Pfizer; Pharmacia; The Prechter Foundation; The Stanley Foundation; UCB Pharma; Wyeth; Ortho-McNeil-Janssen SA; Shire Pharmaceuticals FX Funding/support. This study was supported in part by a grant to Dr Faraone from NIH (R01MH57934) and by a grant to Dr Mick from Shire Pharmaceuticals. NR 36 TC 26 Z9 26 U1 2 U2 4 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 NOV PY 2009 VL 70 IS 11 BP 1523 EP 1529 DI 10.4088/JCP.08m04514 PG 7 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 525HQ UT WOS:000272206200006 PM 19646365 ER PT J AU Wilens, TE Biederman, J Faraone, SV Martelon, M Westerberg, D Spencer, TJ AF Wilens, Timothy E. Biederman, Joseph Faraone, Stephen V. Martelon, MaryKate Westerberg, Diana Spencer, Thomas J. TI Presenting ADHD Symptoms, Subtypes, and Comorbid Disorders in Clinically Referred Adults With ADHD SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; AGE-DEPENDENT DECLINE; UTAH RATING-SCALE; PSYCHIATRIC COMORBIDITY; FOLLOW-UP; SURVEY REPLICATION; CONDUCT DISORDER; CHILDREN; SAMPLE AB Objective: Despite the increasing presentation of attention-deficit/hyperactivity disorder (ADHD) in adults, many practitioners remain reluctant to assess individuals for ADHD, in part related to the relative lack of data on the presenting symptoms of ADHD in adulthood. Comorbidity among adults with ADHD is also of great interest due to the high rates of psychiatric comorbidity, which can lead to a more persistent ADHD among adults. Method: We assessed 107 adults with ADHD of both sexes (51% female; mean +/- SD of 37 +/- 10.4 years) using structured diagnostic interviews. Using DSM-IV symptoms, we determined DSM-IV subtypes. The study was conducted from 1998 to 2003. Results: Inattentive symptoms were most frequently endorsed (> 90%) in adults with ADHD. Using current symptoms, 62% of adults had the combined subtype, 31% the inattentive only subtype, and 7% the hyperactive/impulsive only subtype. Adults with the combined subtype had relatively more psychiatric comorbidity compared to those with the predominately inattentive subtype. Women were similar to men in the presentation of ADHD. Conclusion: Adults with ADHD have prominent inattentive symptoms of ADHD, necessitating careful questioning of these symptoms when evaluating these individuals. J Clin Psychiatry 2009,70(11):1557-1562 (C) Copyright 2009 Physicians Postgraduate Press, Inc. C1 [Wilens, Timothy E.] Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Pediat Psychopharmacol Clin, Boston, MA 02114 USA. [Wilens, Timothy E.; Biederman, Joseph; Martelon, MaryKate; Westerberg, Diana; Spencer, Thomas J.] Massachusetts Gen Hosp, ADHD Program, Boston, MA 02114 USA. [Wilens, Timothy E.; Biederman, Joseph; Martelon, MaryKate; Westerberg, Diana; Spencer, Thomas J.] Harvard Univ, Sch Med, Boston, MA USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Psychiat, Albany, NY USA. [Faraone, Stephen V.] SUNY Upstate Med Univ, Dept Neurosci & Physiol, Albany, NY USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Pediat Psychopharmacol Clin, YAW 6A,55 Fruit St, Boston, MA 02114 USA. EM twilens@partners.org OI Faraone, Stephen/0000-0002-9217-3982 FU Abbott; McNeil; Eli Lilly; National Institutes of Health [RO1 DA12945, K24 DA016264]; Merck; Shire; Alza; AstraZeneca; Bristol-Myers Squibb; Janssen; Organon; Otsuka; National Institute of Mental Health (NIMH); National Institute of Child Health and Human Development; Celltech; Cephalon; Esai; Forest; GlaxoSmithKline; Gliatech; NARSAD; NIDA; New River; Novartis; Noven; Neurosearch; Pfizer; Pharmacia; The Prechter Foundation; The Stanley Foundation; UCB Pharma FX Dr Wilens receives grant support from Abbott, McNeil, Eli Lilly, National Institutes of Health (National Institute on Drug Abuse; NIH (NIDA]), Merck, and Shire; is a speaker for the speakers' bureaus of Eli Lilly, McNeil, Novartis, and Shire; is a consultant for Abbott, AstraZeneca, McNeil, Eli Lilly, NIH (NIDA), Novartis, Merck, and Shire; and has a published book with Guilford Press, Straight Talk About Psychiatric Medications for Kids. Dr Biederman is currently receiving research support from Alza, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, McNeil, Merck, Organon, Otsuka, Shire, the National Institute of Mental Health (NIMH), and the National Institute of Child Health and Human Development; is currently a consultant/advisory board member for Janssen, McNeil, Novartis, and Shire; is currently a speaker for the speakers' bureaus of Janssen, McNeil, Novartis, Shire, UCB Pharma, Inc, Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association; and in previous years has received research support, consultation fees, or speaker's fees from Abbott, AstraZeneca, Celltech, Cephalon, Eli Lilly, Esai, Forest, GlaxoSmithKline, Gliatech, NARSAD, NIDA, New River, Novartis, Noven, Neurosearch, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, and Wyeth. Dr Faraone has received consulting fees, been on the advisory boards for, or been a speaker for Eli Lilly, Shire, McNeil, Janssen, Novartis, and Pfizer and has received research support from Eli Lilly, Pfizer, Shire, and the NIH. Dr Spencer receives research support from Shire, Cephalon, Eli Lilly, GlaxoSmithKline, Janssen, McNeil, Novartis, Pfizer, and NIMH; has been a speaker for the speakers' bureaus of Shire, Eli Lilly, GlaxoSmithKline, Janssen, McNeil, and Novartis; and is on the advisory board for Shire, Cephalon, Eli Lilly, GlaxoSmithKline, Janssen, McNeil, Novartis, and Pfizer. Mss Martelon and Westerberg have no personal affiliations or financial relationships with any commercial interest to disclose relative to the article.; Funding/support: This study was supported by National Institutes of Health grants RO1 DA12945 (Dr Wilens) and K24 DA016264 (Dr Wilens). NR 40 TC 67 Z9 67 U1 1 U2 15 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 NOV PY 2009 VL 70 IS 11 BP 1557 EP 1562 DI 10.4088/JCP.08m04785pur PG 6 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 525HQ UT WOS:000272206200012 PM 20031097 ER PT J AU Simon, NM Otto, MW Worthington, JJ Hoge, EA Thompson, EH LeBeau, RT Moshier, SJ Zalta, AK Pollack, MH AF Simon, Naomi M. Otto, Michael W. Worthington, John J. Hoge, Elizabeth A. Thompson, Elizabeth H. LeBeau, Richard T. Moshier, Samantha J. Zalta, Alyson K. Pollack, Mark H. TI Next-Step Strategies for Panic Disorder Refractory to Initial Pharmacotherapy: A 3-Phase Randomized Clinical Trial SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID COGNITIVE-BEHAVIOR THERAPY; COMORBIDITY SURVEY REPLICATION; SEVERITY SCALE; DOUBLE-BLIND; AGORAPHOBIA; MEDICATION; EFFICACY; PLACEBO; PSYCHOTHERAPY; IMPROVEMENT AB Background: More data are needed to guide next-step interventions for panic disorder refractory to initial intervention. Method: This 24-week randomized clinical trial (RCT) enrolled 46 patients with DSM-IV-defined panic disorder from November 2000 to April 2005 and consisted of 3 phases. Patients who failed to meet remission criteria were eligible for randomization in the next treatment phase. Phase I was a 6-week lead-in with open-label sertraline flexibly dosed to 100 mg (or escitalopram equivalent) to prospectively define treatment refractoriness (lack of remission). Phase 2 was a 6-week double-blind RCT of (1) increased-dose selective serotonin re-uptake inhibitor (SSRI) versus (2) continued SSRI plus placebo. Phase 3 was a 12-week RCT of added cognitive-behavioral therapy (CBT) compared to 11 medication optimization" with SSRI plus clonazepam. Primary endpoints were remission and change in Panic Disorder Severity Scale (PDSS) score in the intent-to-treat sample in each phase. Results: In phase 1, 20.5% (8/39) of the patients achieved remission, and only baseline severity predicted endpoint PDSS score (beta [SE] = 1.04 [0.15], t = 6.76, P < .001). In phase 2, increasing the SSRI dose did not result in greater improvement or remission rates (placebo 15% [n = 2] vs increased dose 9% [n = 1]: Fisher exact test P = NS). In phase 3, remission was minimal (medication optimization = 11% [n = 1]; CBT = 10% [n = 1]), with a lack of group difference in PDSS score reduction (t(17) = 0.51, P > .60) consistent with a small effect size (d = 0.24). Conclusions: Although power was limited and larger studies are needed, we failed to find evidence for greater benefit of increased SSRI dose versus continuation of current dose for panic disorder symptomatic after 6 weeks at moderate dose. Further, augmentation with CBT or medication optimization with clonazepam augmentation in nonremitted panic after 12 weeks of an SSRI did not differ, suggesting that both are reasonable next-step options. However, low overall remission rates in this comorbid refractory population suggest that better predictors of response to specific treatments over time and additional interventions are needed. C1 [Simon, Naomi M.] Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Boston, MA 02114 USA. [Simon, Naomi M.; Worthington, John J.; Hoge, Elizabeth A.; Thompson, Elizabeth H.; LeBeau, Richard T.; Moshier, Samantha J.; Zalta, Alyson K.; Pollack, Mark H.] Harvard Univ, Sch Med, Boston, MA USA. [Otto, Michael W.] Boston Univ, Boston, MA 02215 USA. RP Simon, NM (reprint author), Massachusetts Gen Hosp, Ctr Anxiety & Traumat Stress Disorders, Simches Res Bldg,2nd Floor,185 Cambridge St, Boston, MA 02114 USA. EM nsimon@partners.org RI Hoge, Elizabeth/H-5879-2012; OI Hoge, Elizabeth/0000-0002-5513-2292; Zalta, Alyson/0000-0002-5159-8431 FU Abbott; McNeil; Eli Lilly; National Institutes of Health; Merck; Shire; AstraZeneca; Alza; Bristol-Myers Squibb; Janssen; Organon; Otsuka; National Institute of Mental Health (NIMH) [K23 MH 01831]; National Institute of Child Health and Human Development; Celltech; Cephalon; Esai; Forest; GlaxoSmithKline; Gliatech; NARSAD; NIDA; New River; Novartis; Noven; Neurosearch; Pfizer; Pharmacia; The Prechter Foundation; The Stanley Foundation; UCB Pharma FX Funding/support. This study was supported by a Career Development Award from the National Institute of Mental Health (K23 MH 01831) to Dr Simon. NR 43 TC 19 Z9 20 U1 2 U2 5 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 NOV PY 2009 VL 70 IS 11 BP 1563 EP 1570 DI 10.4088/JCP.08m04485blu PG 8 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 525HQ UT WOS:000272206200013 PM 19814948 ER PT J AU Wingo, AP Wingo, TS Harvey, PD Baldessarini, RJ AF Wingo, Aliza P. Wingo, Thomas S. Harvey, Philip D. Baldessarini, Ross J. TI Effects of Lithium on Cognitive Performance: A Meta-Analysis SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 47th Annual Meeting of the American-College-of-Neuropsychopharmacology CY DEC 07-11, 2008 CL Scottsdale, AZ SP Amer Coll Neuropsychopharmacol ID EUTHYMIC BIPOLAR PATIENTS; N-ACETYL-ASPARTATE; ALZHEIMERS-DISEASE; NEUROCOGNITIVE IMPAIRMENT; HEALTHY-ADULTS; DOUBLE-BLIND; II DISORDER; MEMORY; CARBONATE; MOOD AB Background: Cognitive impairment is under-recognized among patients with bipolar disorder and may represent not only effects of the illness but also adverse effects of its treatments. Among these, lithium is the best-studied mood stabilizer. As its cognitive effects are mixed and not well-known, we assessed reported effects of lithium on cognitive performance. Data sources: MEDLINE, PsycINFO, and EMBASE databases (1950 to December 2008) were queried with the keywords lithium, cognit*, neurocognit*, neuropsych*, psycholog*, attention, concentration, processing speed, memory, executive, and learning. Database searches were supplemented with bibliographic cross-referencing by hand. The literature search was conducted independently by 2 authors (A.P.W. and T.S.W) during August and September 2008, and questions about appropriate inclusion or exclusion were resolved between them by consensus. Study selection: Of 586 reports initially identified as being of potential interest, 12, involving 539 subjects, met our inclusion criteria: (1) cognitive performance compared between subjects taking lithium and comparable subjects not taking lithium; comparability was assured by: (2) patients with the same affective disorder diagnoses in euthymic or remitted status or healthy volunteers; (3) groups of similar age and sex; (4) similar intelligence, education, or occupation; (5) similar distribution of other concurrent psychotropic drugs; and (6) cognitive abilities (outcomes) assessed with performance-based measures. Data extraction: Standardized mean-difference effect size (ES), corrected for small-sample bias (Hedges g), was computed for cognitive tasks in each study. ES estimates were transformed so that positive values indicate poorer performance by lithium-treated subjects. Infrequently, when means and standard deviations were not provided, ES was estimated from reported values of t, F, or z tests. For analysis, similar neurocognitive tests were grouped a priori based on the cognitive domains they aimed to assess. Data synthesis. We identified 12 studies involving 276 lithium-treated and 263 similar or the same subjects, lithium-free. Lithium was taken for a mean duration of 3.9 years by affective disorder patients and 2.5 weeks by healthy volunteers, yielding a mean daily trough serum concentration of 0.80 mEq/L. Overall, lithium treatment was associated with small but significant impairment in immediate verbal learning and memory (ES = 0.24; 95% Cl, 0.05-0.43) and creativity (ES = 0.33; 95% Cl, 0.02-0.64), whereas delayed verbal memory, visual memory, attention, executive function, processing speed, and psychomotor performance were not significantly affected. Selectively, among the 326 affective-disorder patients, in addition to these overall impairments, long-term lithium treatment also was associated with even greater impairment in psychomotor performance (ES = 0.62; 95% Cl, 0.27-0.97), with no evidence of cognitive improvements. Conclusions: Lithium treatment appears to have only few and minor negative effects on cognition. J Clin Psychiatry 2009,70(11):1588-1597 (C) Copyright 2009 Physicians Postgraduate Press, Inc. C1 [Wingo, Aliza P.; Harvey, Philip D.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Wingo, Aliza P.] Emory Univ, Dept Neurol, Atlanta, GA 30322 USA. [Baldessarini, Ross J.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Baldessarini, Ross J.] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. [Baldessarini, Ross J.] Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Psychopharmacol Program, Belmont, MA USA. [Baldessarini, Ross J.] Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Int Consortium Bipolar Disorder Res, Belmont, MA USA. RP Wingo, AP (reprint author), Emory Univ, Dept Psychiat & Behav Sci, 101 Woodruff Circle NE Suite 4000, Atlanta, GA 30322 USA. EM aliza.wingo@emory.edu NR 75 TC 98 Z9 99 U1 4 U2 30 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 NOV PY 2009 VL 70 IS 11 BP 1588 EP 1597 DI 10.4088/JCP.08r04972 PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 525HQ UT WOS:000272206200017 PM 19689922 ER PT J AU Gross, AF Wiechers, IR Stern, TA AF Gross, Anne F. Wiechers, Ilse R. Stern, Theodore A. TI Peer Review by Early Career Psychiatrists: An Opportunity for Development SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Editorial Material C1 [Gross, Anne F.; Wiechers, Ilse R.; Stern, Theodore A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Stern, TA (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Warren 605,55 Fruit St, Boston, MA 02114 USA. EM tstern@partners.org NR 0 TC 5 Z9 5 U1 0 U2 0 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 NOV PY 2009 VL 70 IS 11 BP 1600 EP 1601 DI 10.4088/JCP.09com05635whi PG 2 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 525HQ UT WOS:000272206200021 PM 20031102 ER PT J AU Holt, DJ Lynn, SK Kuperberg, GR AF Holt, Daphne J. Lynn, Spencer K. Kuperberg, Gina R. TI Neurophysiological Correlates of Comprehending Emotional Meaning in Context SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID EVENT-RELATED POTENTIALS; LANGUAGE COMPREHENSION; BRAIN POTENTIALS; ERP ANALYSIS; EVALUATIVE CATEGORIZATIONS; NEURAL MECHANISMS; LIFE EVENTS; WORDS; ATTENTION; STIMULI AB Although the neurocognitive mechanisms of nonaffective language comprehension have been studied extensively, relatively less is known about how the emotional meaning of language is processed. In this study, electrophysiological responses to affectively positive, negative, and neutral words, presented within nonconstraining, neutral contexts, were evaluated under conditions of explicit evaluation of emotional content ( Experiment 1) and passive reading ( Experiment 2). In both experiments, a widely distributed Late Positivity was found to be larger to negative than to positive words ( a "negativity bias''). In addition, in Experiment 2, a small, posterior N400 effect to negative and positive ( relative to neutral) words was detected, with no differences found between N400 magnitudes to negative and positive words. Taken together, these results suggest that comprehending the emotional meaning of words following a neutral context requires an initial semantic analysis that is relatively more engaged for emotional than for nonemotional words, whereas a later, more extended, attention-modulated process distinguishes the specific emotional valence ( positive vs. negative) of words. Thus, emotional processing networks within the brain appear to exert a continuous influence, evident at several stages, on the construction of the emotional meaning of language. C1 [Holt, Daphne J.; Kuperberg, Gina R.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lynn, Spencer K.] McLean Hosp, Belmont, MA 02178 USA. [Kuperberg, Gina R.] Tufts Univ, Medford, MA 02155 USA. RP Holt, DJ (reprint author), Massachusetts Gen Hosp E, Dept Psychiat, 149 13th St, Charlestown, MA 02129 USA. EM dholt@partners.org FU NIMH [R01 MH071635, K23-MH076054]; NARSAD; Sidney R. Baer, Jr. Foundation; Institute for Mental Illness and Neuroscience Discovery ( MIND); Clinical Research Training Program; GlaxoSmithKline Severe Mental Illness Award; Jerome Lyle Rappaport Charitable Foundation; Office of Juvenile Justice and Delinquency Prevention; USDOJ; Harvard Medical School Center for Mental Health and Media FX We thank Abigail Swain, Tatiana Sitnikova, Molly Butterworth, Catherine Garth, and George Nitzburg for their invaluable technical assistance and Jos Van Berkum and two anonymous reviewers for their helpful comments on the manuscript. This research was funded by grants from NIMH [ R01 MH071635 ( G. R. K.), K23-MH076054 ( D. J. H.)], NARSAD ( D. J. H., G. R. K.), the Sidney R. Baer, Jr. Foundation ( D. J. H., G. R. K.), and the Institute for Mental Illness and Neuroscience Discovery ( MIND). D. J. H. was also supported by the Clinical Research Training Program, the GlaxoSmithKline Severe Mental Illness Award, and the Jerome Lyle Rappaport Charitable Foundation. S. K. L. was supported by a grant from the Office of Juvenile Justice and Delinquency Prevention, USDOJ, to the Harvard Medical School Center for Mental Health and Media. NR 93 TC 44 Z9 45 U1 3 U2 10 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 NOV PY 2009 VL 21 IS 11 BP 2245 EP 2262 DI 10.1162/jocn.2008.21151 PG 18 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 505ZL UT WOS:000270741300016 PM 18855550 ER PT J AU Marvizon, JCG Chen, WL Murphy, N AF Marvizon, Juan Carlos G. Chen, Wenling Murphy, Niall TI Enkephalins, Dynorphins, and beta-Endorphin in the Rat Dorsal Horn: An Immunofluorescence Colocalization Study SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE calcitonin gene-related peptide; dorsal root ganglia; mu-opioid receptor; prodynorphin; spinal cord; substance P ID MU-OPIOID RECEPTOR; CENTRAL-NERVOUS-SYSTEM; GENE-RELATED PEPTIDE; ACTIVITY MODIFYING PROTEIN-1; SPINAL-CORD; SUBSTANCE-P; ROOT-GANGLIA; IMMUNOHISTOCHEMICAL LOCALIZATION; IMMUNOREACTIVE DYNORPHIN; METHIONINE-ENKEPHALIN AB To characterize neuronal pathways that release opioid peptides in the rat dorsal horn, multiple-label immunohistochemistry, confocal microscopy, and computerized colocalization measures were used to characterize opioid-containing terminals and cells. An antibody that selectively recognized beta-endorphin labeled fibers and neurons in the ventral horn as well as fibers in the lateral funiculus and lamina X, but practically no fibers in the dorsal horn. An anti-enkephalin antibody, which recognized Leu-, Met-, and Phe-Arg-Met-enkephalin, labeled the dorsolateral funiculus and numerous puncta in laminae I-III and V of the dorsal horn. An antibody against Phe-Arg-Met-enkephalin, which did not recognize Leu- and Met-enkephalin, labeled the same puncta. Antibodies against dynorphin and prodynorphin labeled puncta and fibers in laminae I, II, and V, as well as some fibers in the rest of the dorsal horn. Dynorphin and prodynorphin immunoreactivities colocalized in some puncta and fibers, but the prodynorphin antibody additionally labeled cell bodies. There was no colocalization of dynorphin (or prodynorphin) with enkephalin (or Phe-Arg-Met-enkephalin). Enkephalin immunoreactivity did not colocalize with the C-fiber markers calcitonin gene-related peptide (CGRP), substance P, and isolectin B4. In contrast, there was some colocalization of dynorphin and prodynorphin with CGRP and substance P, but not with isolectin B4. Both enkephalin and dynorphin partly colocalized with vesicular glutamate transporter 2, a marker of glutamatergic terminals. The prodynorphin-positive neurons in the dorsal horn were distinct from neurons expressing mu-opioid receptors, neurokinin 1 receptors, and protein kinase C-gamma. These results show that enkephalins and dynorphins are present in different populations of dorsal horn neurons. In addition, dynorphin is present in some C-fibers. J. Comp. Neurol. 517:51-68, 2009. Published 2009 Wiley-Liss, Inc. C1 [Marvizon, Juan Carlos G.] VA Greater Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Marvizon, Juan Carlos G.; Chen, Wenling] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Ctr Neurobiol Stress,Div Digest Dis, Los Angeles, CA 90095 USA. [Murphy, Niall] RIKEN, Brain Sci Inst, Mol Neuropathol Grp, Wako, Saitama 3510198, Japan. RP Marvizon, JCG (reprint author), VA Greater Angeles Healthcare Syst, Bldg 115,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM marvizon@ucla.edu FU National Institutes of Health [R01-DA-012609]; Department of Veterans Affairs [B47661] FX Grant sponsor: the National Institutes of Health; Grant number: R01-DA-012609 to (J.C.M.); Grant sponsor: the Department of Veterans Affairs; Grant number: B47661 (to J.C.M.). NR 74 TC 31 Z9 31 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD NOV 1 PY 2009 VL 517 IS 1 BP 51 EP 68 DI 10.1002/cne.22130 PG 18 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 494VV UT WOS:000269848300004 PM 19711397 ER PT J AU Chen, JL Luviano, DM Chen, JC Yu, F Sarraf, D AF Chen, Jessica L. Luviano, Damien M. Chen, John C. Yu, Fei Sarraf, David TI Comparison of diabetic retinopathy phenotype between Latinos and Blacks SO JOURNAL OF DIABETES AND ITS COMPLICATIONS LA English DT Article CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 06-10, 2007 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol DE Diabetic retinopathy phenotype; Latino; Black ID VEGF GENE; MACULAR DEGENERATION; UNITED-STATES; PREVALENCE; ASSOCIATION; POLYMORPHISM; POPULATION; WHITES; ADULTS; RISK AB Objective: The objective of this study was to delineate the difference in the phenotype of diabetic retinopathy (DR) in Latinos versus Blacks using characteristics shown on fundus photography (FP) and fluorescein angiography (FA). Research Design and Methods: This was a retrospective chart review of 203 adult Black and Latino diabetic patients from the King-Drew Medical Center eye clinic from January 1998 to March 2005. Systemic risk factors such as HbA(1c) and kidney function data were collected. FP and FA were analyzed and graded according to Early Treatment of Diabetic Retinopathy Study criteria. Statistical analysis was performed to determine whether a given lesion type was more characteristic of a particular racial group. Results: Gender, age, median microalbumin-to-creatinine ratio (ACR), and aver-age HbA(1c) values were not significantly different between the groups. The presence of clinically significant macular edema (CSME), focal or diffuse, was very high in both groups (44% in Latinos and 46% in Blacks), and the overall DR grades were similar. However, upon individual lesion analysis, the Latinos were noted to have more prevalent intraretinal hemorrhages involving a greater area of the retina (P=.046). Conclusions: Although Latinos and Blacks of comparable age and glycemic control are equally at risk for CSME and proliferative retinopathy, Latinos may be at greater risk for a specific phenotype of DR characterized by extravasation of intraretinal hemorrhages, which is associated with poor prognosis. Further prospective studies may uncover racial differences that may have implications for prognosis and therapy. Published by Elsevier Inc. C1 [Yu, Fei; Sarraf, David] Univ Calif Los Angeles, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Chen, Jessica L.] Drew UCLA Med Educ Program, Los Angeles, CA USA. [Luviano, Damien M.; Sarraf, David] Charles R Drew Univ Med & Sci, Dept Ophthalmol, Los Angeles, CA 90059 USA. [Chen, John C.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Sarraf, David] Greater Los Angeles Vet Adm Healthcare Syst, Los Angeles, CA USA. RP Sarraf, D (reprint author), Univ Calif Los Angeles, Jules Stein Eye Inst, Oph Box 957006,1-165 JSEI, Los Angeles, CA 90095 USA. EM dsarraf@ucla.edu NR 23 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 1056-8727 J9 J DIABETES COMPLICAT JI J. Diabetes Complications PD NOV-DEC PY 2009 VL 23 IS 6 BP 371 EP 375 DI 10.1016/j.jdiacomp.2008.05.001 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 519TM UT WOS:000271791300001 PM 18599323 ER PT J AU Singh, B AF Singh, Bramah TI Atrial fibrillation: from ion channels to bedside treatment options SO JOURNAL OF ELECTROCARDIOLOGY LA English DT Review DE Atrial fibrillation; Ion channels; Antiarrhythmic ID PEPTIDE ROTIGAPTIDE ZP123; GAP-JUNCTION MODIFIER; ANTIARRHYTHMIC COMPOUND AZD7009; STERILE PERICARDITIS MODEL; REDUCES INFARCT SIZE; TORSADES-DE-POINTES; OPEN-CHEST DOGS; CLASS IC DRUGS; SINUS RHYTHM; IN-VITRO AB Atrial fibrillation is now the most common arrhythmia in clinical practice. Recent understanding of the abnormalities in ion flow that underlie atrial fibrillation has led to the search for new treatment options with improved efficacy and tolerability. The purpose of this article is to review the role of ion channels in the development of atrial fibrillation and discuss the nature of their inhibition by investigational antiarrhythmic agents. Novel treatments include the benzofuran derivative dronedarone, atrial-selective compounds (eg, vernakalant), multichannel blocking agents (eg, tedisamil), and gap junction modifiers (eg, rotigaptide). Targeted antiarrhythmic therapies have the potential to provide safer and more effective management options for patients with atrial fibrillation. (C) 2009 Published by Elsevier Inc. C1 Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. RP Singh, B (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, VA Greater Los Angeles Hlth Care Syst, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM bsingh@ucla.edu FU Sanofi-Aventis US; Bridgewater, New Jersey, USA FX Funding for editorial support was provided by Sanofi-Aventis US, Bridgewater, New Jersey, USA. NR 102 TC 6 Z9 7 U1 0 U2 12 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 0022-0736 J9 J ELECTROCARDIOL JI J. Electrocardiol. PD NOV-DEC PY 2009 VL 42 IS 6 BP 660 EP 670 DI 10.1016/j.jelectrocard.2009.04.002 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 515SZ UT WOS:000271494500032 PM 19520377 ER PT J AU Wilcox, SR Arbelaez, C Nadel, ES Brown, DFM AF Wilcox, Susan R. Arbelaez, Christian Nadel, Eric S. Brown, David F. M. TI FOREIGN BODY ASPIRATION AFTER HIGH-VELOCITY TRAUMA SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article C1 [Wilcox, Susan R.; Nadel, Eric S.; Brown, David F. M.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Wilcox, Susan R.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care, Boston, MA 02114 USA. [Wilcox, Susan R.; Arbelaez, Christian; Nadel, Eric S.; Brown, David F. M.] Harvard Univ, Sch Med, Div Emergency Med, Boston, MA USA. [Arbelaez, Christian; Nadel, Eric S.] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. RP Brown, DFM (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Founders 114,Fruit St, Boston, MA 02114 USA. NR 14 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 0736-4679 J9 J EMERG MED JI J. Emerg. Med. PD NOV PY 2009 VL 37 IS 4 BP 411 EP 414 PG 4 WC Emergency Medicine SC Emergency Medicine GA 530BJ UT WOS:000272563600013 PM 19836919 ER PT J AU Xu, Y Young, MJ Battaglino, RA Morse, LR Fontana, CR Pagonis, TC Kent, R Soukos, NS AF Xu, Yan Young, Mark J. Battaglino, Ricardo A. Morse, Leslie R. Fontana, Carla Raquel Pagonis, Tom C. Kent, Ralph Soukos, Nikolaos S. TI Endodontic Antimicrobial Photodynamic Therapy: Safety Assessment in Mammalian Cell Cultures SO JOURNAL OF ENDODONTICS LA English DT Article DE Endodontic disinfection; mammalian cells; methylene blue; photodynamic therapy; safety ID LIGHT-ACTIVATED DISINFECTION; KERATINOCYTES IN-VITRO; METHYLENE-BLUE; SODIUM-HYPOCHLORITE; TOLUIDINE-BLUE; ENTEROCOCCUS-FAECALIS; ROOT CANALS; DNA-DAMAGE; APOPTOSIS; VIVO AB Objectives: The purpose of this study was to assess the in vitro synergistic effect of methylene blue (MB) and red light on human gingival fibroblasts and osteoblasts with parameters similar to those that may be applied in a clinical setting for endodontic disinfection. Materials and Methods: Both cell types were sensitized with 50 mu g/mL MB followed by exposure to red light at 665 nm for 5 minutes with an irradiance of 10, 20, and 40 mW/cm(2). After photodynamic therapy (PDT), cell viability and mitochondrial activity were evaluated by the neutral red and MTT assay, respectively. The assessment of PDT-induced apoptosis was investigated by western blot analysis using cleaved poly(ADPribose) polymerase-specific antibodies. Results: Light at 20 and 40 mW/cm(2) with MB had modest effects at 24 hours on osteoblasts in both assays, whereas sodium hypochlorite completely eliminated cells. Western blot analysis revealed no signs of apoptosis in either cell type. Conclusion: The data suggest that there is a safe therapeutic window whereby PDT can inactivate endodontic pathogens without affecting host cell viability. (J Endod 2009;35:1567-1572) C1 [Xu, Yan; Fontana, Carla Raquel; Soukos, Nikolaos S.] Forsyth Inst, Appl Mol Photomed Lab, Boston, MA 02115 USA. [Young, Mark J.; Pagonis, Tom C.] Harvard Univ, Sch Dent Med, Dept Adv Grad Endodont, Div Endodont, Boston, MA 02115 USA. [Battaglino, Ricardo A.] Forsyth Inst, Dept Cytokine Biol, Boston, MA 02115 USA. [Kent, Ralph] Forsyth Inst, Dept Biostat, Boston, MA 02115 USA. [Morse, Leslie R.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA USA. RP Soukos, NS (reprint author), Forsyth Inst, Appl Mol Photomed Lab, 140 Fenway, Boston, MA 02115 USA. EM nsoukos@forsyth.org RI Fontana, Carla/C-2033-2012; battaglino, ricardo/D-2892-2015; Morse, Leslie/C-9442-2015 OI Fontana, Carla/0000-0002-9135-3690; Morse, Leslie/0000-0002-7426-6341 FU NIDCR [R01-DE-16922] FX Supported by NIDCR grant R01-DE-16922. NR 40 TC 38 Z9 39 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0099-2399 J9 J ENDODONT JI J. Endod. PD NOV PY 2009 VL 35 IS 11 BP 1567 EP 1572 DI 10.1016/j.joen.2009.08.002 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 518YB UT WOS:000271730900017 PM 19840649 ER PT J AU Sugimoto, M Furuta, T Yamaoka, Y AF Sugimoto, Mitsushige Furuta, Takahisa Yamaoka, Yoshio TI Influence of inflammatory cytokine polymorphisms on eradication rates of Helicobacter pylori SO JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY LA English DT Review DE eradication therapy; Helicobacter pylori; IL-1 beta; inflammatory cytokine; polymorphism; TNF-alpha ID NECROSIS-FACTOR-ALPHA; INTERLEUKIN-1-BETA GENETIC-POLYMORPHISM; RANDOMIZED CONTROLLED-TRIAL; GASTRIC-ACID INHIBITION; PROTON PUMP INHIBITOR; TRIPLE THERAPY; GENOTYPIC DIFFERENCES; INCREASED RISK; CURE RATES; ENDOSCOPIC RESECTION AB Pro-inflammatory cytokines and anti-inflammatory cytokines are produced in gastric mucosa from inflammatory cells activated by Helicobacter pylori (H. pylori) infection. Of the inflammatory cytokines, interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha have a potent inhibitive effect on gastric acid production. Polymorphisms in these genes are associated with individual differences in cytokine messenger RNA levels, which result in different gastric mucosal inflammation, different acid inhibition and different gastroduodenal disease risks in response to H. pylori infection. The sustained higher intragastric pH during an eradication therapy is known to be one of the therapeutic determinants of the H. pylori eradication as well as antibiotics resistance and poor compliance. The IL-1B-511 polymorphism is related to eradication rate, and, in combined analysis of previous reports, the eradication rate in patients with the IL-1B-511 C/C genotype (77.4%, 209/270), low IL-1 beta producer genotype, is lower than that of the IL-1B-511 C/T and T/T genotypes (87.2%, 631/724) (Odds ratio for eradication failure: 1.98, 95% confidence interval: 1.38-2.84, P = 0.0002). Moreover, the odds ratio of combined CYP2C19 rapid metabolizer-IL-1B-511 C/C type for eradication failure is 11.15 (5.23-23.78) times that of the CYP2C19 poor metabolizer-IL-1B-511 non-C/C type. However, there is no positive data indicating the role of other inflammatory cytokine polymorphisms (e.g. IL-1RN, TNF-A or IL-10) in eradication therapy. Nevertheless, the studies show that inflammatory cytokine polymorphisms, especially the IL-1B-511 T/T genotype, are the determinants of eradication by affecting gastric acid secretion and mucosal inflammation. Therefore, the tailored eradication therapy, considering inflammatory cytokine polymorphisms, may be effective for the higher eradication rates. C1 [Sugimoto, Mitsushige] Hamamatsu Univ Sch Med, Clin Res Ctr, Higashi Ku, Hamamatsu, Shizuoka 4313192, Japan. [Sugimoto, Mitsushige; Yamaoka, Yoshio] Michael E DeBakey Vet Affairs Med Ctr, Dept Med Gastroenterol, Houston, TX USA. [Sugimoto, Mitsushige; Yamaoka, Yoshio] Baylor Coll Med, Houston, TX 77030 USA. [Yamaoka, Yoshio] Oita Univ, Dept Environm & Prevent Med, Fac Med, Yufu, Japan. RP Sugimoto, M (reprint author), Hamamatsu Univ Sch Med, Clin Res Ctr, Higashi Ku, 1-20-1 Handayama, Hamamatsu, Shizuoka 4313192, Japan. EM mitsuhamamed@yahoo.co.jp FU National Institute of Health [R01 DK62813] FX We thank Jared Pinkston for his advice and grammatical editing of this paper. This study is supported by Grant Number R01 DK62813 (National Institute of Health). None of the authors had conflicts of interest related to this study. NR 74 TC 21 Z9 22 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0815-9319 J9 J GASTROEN HEPATOL JI J. Gastroenterol. Hepatol. PD NOV PY 2009 VL 24 IS 11 BP 1725 EP 1732 DI 10.1111/j.1440-1746.2009.06047.x PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512KQ UT WOS:000271248000007 PM 20136959 ER PT J AU Bausch, D Mino-Kenudson, M Fernandez-del Castillo, C Warshaw, AL Kelly, KA Thayer, SP AF Bausch, Dirk Mino-Kenudson, Mari Fernandez-del Castillo, Carlos Warshaw, Andrew L. Kelly, Kimberly A. Thayer, Sarah P. TI Plectin-1 is a Biomarker of Malignant Pancreatic Intraductal Papillary Mucinous Neoplasms SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article CT 50th Annual Meeting of the Society-for-Surgery-of-the-Alimentary-Tract CY JUN 01, 2009 CL Chicago, IL SP Soc Surg Alimentary Tract DE Plectin-1; Biomarker; Malignant IPMN; Benign IPMN ID UPDATED EXPERIENCE; FLUID ANALYSIS; IN-SITU; DUCT; RESECTION; TUMORS; MANAGEMENT; ADENOCARCINOMA; PREDICTORS; CARCINOMAS AB Pancreatic intraductal papillary mucinous neoplasms (IPMN) are now identified with increasing frequency. The detection of carcinoma in IPMN is difficult and suffers from high false-positive and false-negative rates, often resulting in inappropriate treatment decisions. Improved detection of malignancy using novel biomarkers may therefore improve diagnostic accuracy. One such promising novel biomarker is Plectin-1 (Plec-1). Using immunohistochemistry, Plec-1 expression was assayed in benign (low and moderate dysplasia, n = 6) as well as malignant IPMN (high-grade dysplasia and invasive carcinoma, n = 31) and lymph node metastases from carcinoma arising in IPMN (n = 12). Furthermore, cyst fluids from benign (n = 3) and malignant IPMN (n = 4) were evaluated for Plec-1 expression. Twenty-six of 31 malignant IPMN and all 12 lymph node metastases were Plec-1 positive. In contrast, only one of six benign IPMN expressed Plec-1. The specificity of Plec-1 in distinguishing malignant IPMN from benign IPMN was 83% and its sensitivity 84%. Furthermore, all (four out of four) cyst fluids from malignant IPMN, but none of the three benign IPMN, were Plec-1 positive. These data support Plec-1 as an excellent biomarker for the early detection of carcinoma arising in IPMN. C1 [Bausch, Dirk; Fernandez-del Castillo, Carlos; Warshaw, Andrew L.; Thayer, Sarah P.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, Mari] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Thayer, Sarah P.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Kelly, Kimberly A.] Univ Virginia, Dept Biomed Engn, Charlottesville, VA 22908 USA. RP Thayer, SP (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St,WAC 460, Boston, MA 02114 USA. EM sthayer@partners.org FU NCI NIH HHS [R01 CA137071, P50 CA127003, R01 CA137071-03]; NIDDK NIH HHS [K08 DK071329] NR 32 TC 26 Z9 26 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD NOV PY 2009 VL 13 IS 11 BP 1948 EP 1953 DI 10.1007/s11605-009-1001-9 PG 6 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 510QS UT WOS:000271106200010 PM 19760374 ER PT J AU Vollmer, CM AF Vollmer, Charles M., Jr. TI Unexpected Identification of Gallbladder Carcinoma During Cholecystectomy SO JOURNAL OF GASTROINTESTINAL SURGERY LA English DT Article CT SSAT/AHPBA Joint Symposium on Current Approach to Carcinoma of the Gallbladder CY MAY, 2008 CL San Diego, CA SP Soc Surg Alimentary Tract, AHPBA DE Gallbladder carcinoma; Incidental gallbladder cancer; Laparoscopic cholecystectomy; Stop rules ID STAGING LAPAROSCOPY C1 Beth Israel Deaconess Med Ctr, Dept Surg, Div Gen Surg, Boston, MA 02215 USA. RP Vollmer, CM (reprint author), Beth Israel Deaconess Med Ctr, Dept Surg, Div Gen Surg, 330 Brookline Ave,Stoneman 9, Boston, MA 02215 USA. EM cvollmer@bidmc.harvard.edu NR 6 TC 2 Z9 3 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1091-255X J9 J GASTROINTEST SURG JI J. Gastrointest. Surg. PD NOV PY 2009 VL 13 IS 11 BP 2034 EP 2036 DI 10.1007/s11605-009-0808-8 PG 3 WC Gastroenterology & Hepatology; Surgery SC Gastroenterology & Hepatology; Surgery GA 510QS UT WOS:000271106200027 PM 19238496 ER PT J AU Saylor, PJ Keating, NL Smith, MR AF Saylor, Philip J. Keating, Nancy L. Smith, Matthew R. TI Prostate Cancer Survivorship: Prevention and Treatment of the Adverse Effects of Androgen Deprivation Therapy SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE prostate cancer; survivorship; GnRH agonists; osteoporosis; bisphosphonates; diabetes; obesity; cardiovascular disease ID RANDOMIZED CONTROLLED-TRIAL; BONE-MINERAL DENSITY; CORONARY-HEART-DISEASE; HORMONE AGONIST THERAPY; LEAN BODY-MASS; FRACTURE RISK; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; SUPPRESSION THERAPY; ARTERIAL STIFFNESS AB More than one-third of the estimated 2 million prostate cancer survivors in the United States receive androgen deprivation therapy (ADT). This population of mostly older men is medically vulnerable to a variety of treatment-associated adverse effects. Androgen-deprivation therapy (ADT) causes loss of libido, vasomotor flushing, anemia, and fatigue. More recently, ADT has been shown to accelerate bone loss, increase fat mass, increase cholesterol and triglycerides, and decrease insulin sensitivity. Consistent with these adverse metabolic effects, ADT has also recently been associated with greater risks for fractures, diabetes and cardiovascular disease. Primary care clinicians and patients should be aware of the potential benefits and harms of ADT. Screening and intervention to prevent treatment-related morbidity should be incorporated into the routine care of prostate cancer survivors. Evidence-based guidelines to prevent fractures, diabetes, and cardiovascular disease in prostate cancer survivors represent an important unmet need. We recommend the adapted use of established practice guidelines designed for the general population. C1 [Saylor, Philip J.; Smith, Matthew R.] Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Boston, MA 02114 USA. [Keating, Nancy L.] Brigham & Womens Hosp, Div Gen Internal Med, Boston, MA 02115 USA. [Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Saylor, PJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol Oncol, Massachusetts Gen Hosp Lawrence House,POB 2nd Flo, Boston, MA 02114 USA. EM psaylor@partners.org FU NIH [5K24CA121990-02]; Prostate Cancer Foundation; Lance Armstrong Foundation FX R. Smith is supported by an NIH K24 Midcareer Investigator Award (5K24CA121990-02) and grants from the Prostate Cancer Foundation and Lance Armstrong Foundation. NR 87 TC 24 Z9 24 U1 2 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2009 VL 24 BP 389 EP 394 DI 10.1007/s11606-009-0968-y PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 507ZB UT WOS:000270894400003 ER PT J AU Park, ER Bober, SL Campbell, EG Recklitis, CJ Kutner, JS Diller, L AF Park, Elyse R. Bober, Sharon L. Campbell, Eric G. Recklitis, Christopher J. Kutner, Jean S. Diller, Lisa TI General Internist Communication about Sexual Function with Cancer Survivors SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE general internist; survivorship; sexuality communication ID HEALTH; DYSFUNCTION; BARRIERS; ISSUES; HELP; CARE AB Sexual dysfunction is an important issue that affects many cancer survivors who are increasingly being cared for by internists. To examine the attitudes and reported practices of internists regarding survivorship care as it pertains to sexual dysfunction. Surveys were sent to 406 physicians affiliated with the Department of Internal Medicine at the University of Colorado Denver School of Medicine. Of the 319 eligibles, 227 were returned (71% RR). Of the 227 responders, 46% were "somewhat/very" likely to initiate a conversation about sexual dysfunction; 62% "never/rarely" addressed sexual dysfunction. Each additional weekly hour spent in patient care was associated with a 2% increase in the likelihood of sexual dysfunction being addressed or discussions about sexual dysfunction being initiated. Reported inadequate preparation/formal training around survivorship issues was associated with sexual dysfunction being addressed less often (odds ratio [OR] = 0.45). Perception of patient anxiety or fears about health was associated with sexual dysfunction being addressed more often (OR = 2.38). Perceived preparedness to evaluate long-term effects was associated with a greater likelihood of physicians initiating discussions about sexual functioning (OR = 2.49). Cancer survivors receive their long-term care from internists. Our results suggest that sexual dysfunction is often not addressed during their follow-up care. Additional training is needed to prepare physicians to negotiate this difficult issue. C1 [Park, Elyse R.; Campbell, Eric G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Hlth Policy, Boston, MA 02114 USA. [Bober, Sharon L.; Recklitis, Christopher J.; Diller, Lisa] Harvard Univ, Sch Med, Dana Farber Canc Inst, Perini Family Survivors Ctr, Boston, MA 02115 USA. [Kutner, Jean S.] Univ Colorado, Sch Med, Denver, CO USA. RP Park, ER (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM epark@partners.org FU Swim Across America Foundation; American Cancer Society FX We are grateful to the Swim Across America Foundation and the American Cancer Society for supporting this work. We thank Sowmya Rao, PhD, for her statistical assistance. We would like to acknowledge and thank Monica Rothwell, Laura Fox, and Jennifer Pandiscio for their assistance with preparation of these data and the manuscript. NR 20 TC 22 Z9 22 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2009 VL 24 BP 407 EP 411 DI 10.1007/s11606-009-1026-5 PG 5 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 507ZB UT WOS:000270894400006 ER PT J AU McQueen, A Bartholomew, LK Greisinger, AJ Medina, GG Hawley, ST Haidet, P Bettencourt, JL Shokar, NK Ling, BS Vernon, SW AF McQueen, Amy Bartholomew, L. Kay Greisinger, Anthony J. Medina, Gilda G. Hawley, Sarah T. Haidet, Paul Bettencourt, Judith L. Shokar, Navkiran K. Ling, Bruce S. Vernon, Sally W. TI Behind Closed Doors: Physician-Patient Discussions About Colorectal Cancer Screening SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article DE colorectal cancer screening; physician-patient communication; shared decision-making; qualitative research; interventions ID INFORMED DECISION-MAKING; SELF-EXEMPTING BELIEFS; SERVICES TASK-FORCE; FECAL OCCULT BLOOD; PRIMARY-CARE; RANDOMIZED-TRIAL; UNITED-STATES; HEALTH; RECOMMENDATION; COLONOSCOPY AB Despite the availability of multiple effective screening tests for colorectal cancer, screening rates remain suboptimal. The literature documents patient preferences for different test types and recommends a shared decision-making approach for physician-patient colorectal cancer screening (CRCS) discussions, but it is unknown whether such communication about CRCS preferences and options actually occurs in busy primary-care settings. Describe physician-patient CRCS discussions during a wellness visit. Cross-sectional; patients audio-recorded with physicians. A subset of patients (N = 64) participating in a behavioral intervention trial designed to increase CRCS who completed a wellness visit during the trial with a participating physician (N = 8). Transcripts were analyzed using qualitative methods. Physicians in this sample consistently recommended CRCS, but focused on colonoscopy. Physicians did not offer a fecal occult blood test alone as a screening choice, which may have created missed opportunities for some patients to get screened. In this single visit, physicians' communication processes generally precluded discussion of patients' test preferences and did not facilitate shared decision-making. Patients' questions indicated their interest in different CRCS test types and appeared to elicit more information from physicians. Some patients remained resistant to CRCS after discussing it with a physician. If a preference for colonoscopy is widespread among primary-care physicians, the implications for intervention are either to prepare patients for this preference or to train physicians to offer options when recommending screening to patients. C1 [McQueen, Amy] Washington Univ, Sch Med, Div Hlth Behav Res, St Louis, MO 63108 USA. [Bartholomew, L. Kay; Medina, Gilda G.; Bettencourt, Judith L.; Vernon, Sally W.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Greisinger, Anthony J.] Kelsey Res Fdn, Houston, TX USA. [Hawley, Sarah T.] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Haidet, Paul] DeBakey VA Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Houston, TX USA. [Haidet, Paul] Baylor Coll Med, Houston, TX 77030 USA. [Shokar, Navkiran K.] Univ Texas Med Branch, Galveston, TX USA. [Ling, Bruce S.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP McQueen, A (reprint author), Washington Univ, Sch Med, Div Hlth Behav Res, 4444 Forest Pk Ave, St Louis, MO 63108 USA. EM amcqueen@dom.wustl.edu FU National Cancer Institute [097263]; American Cancer Society Mentored Research Scholar [CPPB113766] FX This research was supported by a National Cancer Institute R01 grant (no. 097263; PI: Sally W. Vernon) and an American Cancer Society Mentored Research Scholar Grant (CPPB113766; PI: Amy McQueen). We gratefully acknowledge the support of the physicians and patients in the Family Medicine and Internal Medicine Departments at Kelsey-Seybold Clinic. We also thank Nicholas Solomos, MD, for his insightful comments on the manuscript. NR 61 TC 57 Z9 57 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD NOV PY 2009 VL 24 IS 11 BP 1228 EP 1235 DI 10.1007/s11606-009-1108-4 PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 514VA UT WOS:000271422600009 PM 19763699 ER PT J AU Jupiter, JB AF Jupiter, Jesse B. TI Commentary: The Effect of Ulnar Styloid Fractures on Patient-Rated Outcomes After Volar Locking Plating of Distal Radius Fractures SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Editorial Material ID SYSTEM C1 Massachusetts Gen Hosp, Dept Hand Surg, Boston, MA 02114 USA. RP Jupiter, JB (reprint author), Massachusetts Gen Hosp, Dept Hand Surg, Boston, MA 02114 USA. EM jjupiter1@partners.org NR 6 TC 15 Z9 17 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD NOV PY 2009 VL 34A IS 9 BP 1603 EP 1604 DI 10.1016/j.jhsa.2009.06.022 PG 2 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 517FG UT WOS:000271598000002 PM 19896005 ER PT J AU Guitton, TG Ring, D Kloen, P AF Guitton, Thierry G. Ring, David Kloen, Peter TI Long-Term Evaluation of Surgically Treated Anterior Monteggia Fractures in Skeletally Mature Patients SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Dislocation; elbow; fracture; Monteggia ID RADIAL HEAD; EQUIVALENT LESIONS; ELBOW; DISLOCATIONS; CHILDREN; OLECRANON; FOREARM; ULNA; ADULTS AB Purpose The purpose of this retrospective study was to evaluate the functional and radiological long-term outcome of open reduction and internal fixation of skeletally mature patients with a Bado type 1 Monteggia fracture. Methods We identified 11 consecutive skeletally mature patients who had surgical treatment of an anterior (Bado type 1) Monteggia fracture. Long-term evaluation at a median of 20 years after injury (range, 7-34 years) was compared with an early evaluation at a median of 13 months after injury (range, 11-32 months). The early and long-term results were evaluated radiographically and according to the system of Broberg and Morrey. The long-term result was also evaluated according to the Mayo Elbow Performance Index, the American Shoulder and Elbow Surgeons, and the Disabilities of the Arm Should and Hand scores. Results Two patients had subsequent surgery to address a nonunion and 3 elbows had radiographic signs of arthrosis. The mean arc of elbow flexion increased from 110 degrees degrees (range, 35 degrees to 140 degrees) at early follow-up to 120 degrees (range, 40 degrees to 150 degrees) at late follow-up. The mean arc of forearm rotation increased from 145 degrees (range, 90 degrees to 180 degrees) to 149 degrees (range, 90 degrees to 180 degrees). The mean Broberg and Morrey score increased from 89 points (range, 62-100 points) to 94 points (range, 76-100 points). The median DASH score was 7 points (range, 0-34 points) at long-term follow-up. There was no statistical difference between early and late range of motion or Broberg and Morrey score. Conclusions The results of open reduction and internal fixation of anterior Monteggia fractures in skeletally mature patients are maintained over long-term follow-up. (J Hand Surg 2009;34A:1618-1624. (c) 2009 Published by Elsevier Inc. on behalf of the American Society for Surgery of the Hand.) C1 [Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, Boston, MA 02114 USA. Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, NL-1105 AZ Amsterdam, Netherlands. RP Ring, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv,Yawkey Ctr, Suite 2100,55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org OI Guitton, Thierry/0000-0002-2599-1985 FU Acumed; Tornier; Wright Medical FX D.R. is a consultant for and has received unrestricted research grants from Acumed, Tornier, and Wright Medical. NR 42 TC 8 Z9 8 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD NOV PY 2009 VL 34A IS 9 BP 1618 EP 1624 DI 10.1016/j.jhsa.2009.06.026 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 517FG UT WOS:000271598000005 PM 19896007 ER PT J AU Lindenhovius, A Karanicolas, PJ Bhandari, M van Dijk, N Ring, D AF Lindenhovius, Anneluuk Karanicolas, Paul Jack Bhandari, Mohit van Dijk, Nick Ring, David CA Collaboration Outcome Assessment TI Interobserver Reliability of Coronoid Fracture Classification: Two-Dimensional Versus Three-Dimensional Computed Tomography SO JOURNAL OF HAND SURGERY-AMERICAN VOLUME LA English DT Article DE Computed tomography; coronoid; fracture; interobserver; reliability ID TERRIBLE-TRIAD INJURIES; ANTEROMEDIAL FACET; RADIAL HEAD; ELBOW; DISLOCATION; RECONSTRUCTIONS; ULNA AB Purpose This study tests the hypothesis that 3-dimensional computed tomography (CT) reconstructions improve interobserver agreement on classification and treatment of coronoid fractures compared with 2-dimensional CT. Methods A total of 29 orthopedic surgeons evaluated 10 coronoid fractures on 2 occasions (first with radiographs and 2-dimensional CT and then with radiographs and 3-dimensional CT), separated by a minimum of 2 weeks. Surgeons classified fractures according to the classifications of Regan and Morrey and of O'Driscoll et al., identified specific characteristics, recommended the most appropriate treatment approach, and made treatment recommendations. The kappa multirater measure (kappa) was calculated to estimate agreement between observers. Results Regardless of the imaging modality used, there was fair to moderate agreement for most of the observations. Three-dimensional CT improved interobserver agreement in Regan and Morrey's classsication (kappa(3-dimensional) = 0.51 vs kappa(2-dimensionol) = 0.40; p < .001) and O'Driscoll et al.'s classifications (kappa(3-dimensional) = 0.48 vs kappa(2-dimensional) = 0.42; p = .009). There were trends toward better reliability for 3-dimensional reconstruction in recognition of coronoid tip fractures (kappa(3-dimensional) = 0.19, kappa(2-dimensional) = 0.03; p = .268), comminution (kappa(3-dimensional) = 0.41 vs kappa(2-dimensional) = 0.29; p = .133), and impacted fragments (kappa(3-dimensional) = 0.39 vs kappa(2-dimensional) = 0.27; p = .094), and in surgeons' opinions on the need for something other than screws or plate for surgical fixation (kappa(3-dimensional) = 0.31 vs kappa(2-dimensional) = 0.15; p = .138). Interobserver agreement on treatment approach was better with 2-dimensional CT (kappa(3-dimensional) = 0.27, kappa(2-dimensional) = 0.32; p = .015). Conclusions Three-dimensional CT reconstructions improve Interobserver agreement with respect to fracture classification compared with 2-dimensional CT. (J Hand Surg 2009;34A: 1640-1646. (c) 2009 Published by Elsevier Inc. on behalf of the American Society,for Surgery of the Hand.) C1 [Ring, David] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, Boston, MA 02114 USA. Univ Western Ontario, Dept Surg, London, ON N6A 3K7, Canada. McMaster Univ, Hamilton, ON, Canada. Univ Amsterdam, Acad Med Ctr, Dept Orthopaed Surg, NL-1012 WX Amsterdam, Netherlands. RP Ring, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Orthopaed Hand & Upper Extrem Serv, 55 Fruit St, Boston, MA 02114 USA. EM dring@partners.org RI Kampen, A./H-8056-2014; Page, Richard/K-6327-2015; OI Page, Richard/0000-0002-2225-7144; Frihagen, Frede/0000-0002-4811-669X FU Wright Medical and Skeletal Dynamics FX D.R. isa consultant for Wright Medical, Acumed, and Tornier. He received unrestricted research grants from Acumed and Tornier, and he receives royalties from Wright Medical and Skeletal Dynamics. NR 26 TC 24 Z9 25 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 0363-5023 J9 J HAND SURG-AM JI J. Hand Surg.-Am. Vol. PD NOV PY 2009 VL 34A IS 9 BP 1640 EP 1646 DI 10.1016/j.jhsa.2009.07.009 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 517FG UT WOS:000271598000008 PM 19833449 ER PT J AU Rivard, AL Bartel, T Bianco, RW O'Donnell, KS Bonatti, J Dichtl, W Cury, RC Feuchtner, GM AF Rivard, Andrew L. Bartel, Thomas Bianco, Richard W. O'Donnell, Kasia Simura Bonatti, Johannes Dichtl, Wolfgang Cury, Ricardo C. Feuchtner, Gudrun M. TI Evaluation of Aortic Root and Valve Calcifications by Multi-Detector Computed Tomography SO JOURNAL OF HEART VALVE DISEASE LA English DT Article; Proceedings Paper CT 3rd Annual Scientific Meeting of the Society-for-Cardiovascular-Computed-Tomography CY JUL 17-20, 2008 CL Orlando, FL SP Soc Cardiovasc Computed Tomog ID PERCUTANEOUS TRANSCATHETER IMPLANTATION; HIGH-RISK PATIENTS; HEART-VALVE; COREVALVE PROSTHESIS; POSITION STATEMENT; BALLOON VALVOTOMY; FOLLOW-UP; STENOSIS; REPLACEMENT; EXPERIENCE AB Background and aim of the study: In percutaneous aortic valve replacement (AVR), whilst calcifications are used as landmarks in fluoroscopic placement of the stent, they may also complicate stent placement. In response to this problem, the study aim was to examine severe aortic root calcification by using multi-detector computed tomography (MDCT), to better understand the pathology complicating percutaneous valve placement. Methods: In 33 patients with severe aortic stenosis and scheduled for surgery, the 'inner orifice' and,outer fibrous' annulus diameter and area (with and without calcification) were measured, in addition to the distances of the calcifications and coronary ostia from the annulus, using by ECG-gated 64-slice MDCT. Aortic root calcification was evaluated as minimal (<25% of total circumference), mild (25-50%), moderate (50-75%), and severe (75-100%). Results: The inner orifice annulus area was 5.9 +/- 1.9 cm 2 (range: 1.4-10.1 cm(2)), while the outer fibrous area was 7.5 +/- 1.8 cm(2) (range: 4.7-11.5 cm(2)). The proximal-to-distal extent of valve calcification from the annulus in the mid-center of leaflets was 0.8 +/- 0.26 cm. In 36% of patients, valvular calcification extended +/-3 mm within the coronary-ostium level. The distance of the coronary ostia from the annulus was variable, with a mean of 1.3 +/- 0.35 cm (range: 0.6-2.4 cm) for the left coronary artery. In 42% of patients, a 'low coro- nary ostium' (<= 1.1 cm), and in 6% a 'critical-low-coronary ostium' (<= 8 mm) was identified. Annulus calcification was present in 100% of cases, but the severity varied widely (severe 50%, moderate 35%, mild 15%). In 36% of cases, the aortic annulus calcification extended caudally into the membranous part of the interventricular septum (and thus into the left ventricular outflow tract), and in 42% of cases (n = 14) into the anterior mitral valve leaflet. Conclusion: The present results indicated that cardiac MDCT may qualify as a primary pre-procedural imaging modality to select patients for percutaneous AVR, based on the measurement and characterization of the aortic root and valve calcification. In comparison to echocardiography, CT will reduce - if not eliminate - difficulties in visualizing the aortic orifice area in heavily calcified valves. Furthermore, knowledge of the exact location of calcific deposits provides a distinct advantage to the fluroscopist for precise placement of the percutaneous aortic valve. Likewise, knowledge of the coronary arteries orifice in relation to the valve plane is critical to prevent inadvertent coronary artery occlusion, and would clearly be beneficial when planning future valve designs. C1 [Rivard, Andrew L.] Univ Florida, Dept Radiol, Gainesville, FL 32610 USA. [Rivard, Andrew L.; Bianco, Richard W.; O'Donnell, Kasia Simura] Univ Minnesota, Dept Surg, Expt Surg Serv, Minneapolis, MN 55455 USA. [Bartel, Thomas; Bonatti, Johannes; Dichtl, Wolfgang; Feuchtner, Gudrun M.] Innsbruck Med Univ, Dept Radiol & Cardiol 2, Innsbruck, Austria. [Cury, Ricardo C.; Feuchtner, Gudrun M.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Cury, Ricardo C.] Baptist Cardiac & Vasc Inst, Miami, FL USA. RP Rivard, AL (reprint author), Univ Florida, Dept Radiol, POB 100374, Gainesville, FL 32610 USA. EM arivard@ufl.edu NR 33 TC 15 Z9 15 U1 1 U2 3 PU I C R PUBLISHERS PI NORTHWOOD PA CRISPIN HOUSE, 12/A SOUTH APPROACH, MOOR PARK, NORTHWOOD HA6 2ET, ENGLAND SN 0966-8519 J9 J HEART VALVE DIS JI J. Heart Valve Dis. PD NOV PY 2009 VL 18 IS 6 BP 662 EP 670 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 537SP UT WOS:000273134600011 PM 20099715 ER PT J AU Domart, MC Degli Esposti, D Sebagh, M Olaya, N Harper, F Pierron, G Franc, B Tanabe, KK Debuire, B Azoulay, D Brenner, C Lemoine, A AF Domart, Marie-Charlotte Degli Esposti, Davide Sebagh, Mylene Olaya, Natalia Harper, Francis Pierron, Gerard Franc, Brigitte Tanabe, Kenneth K. Debuire, Brigitte Azoulay, Daniel Brenner, Catherine Lemoine, Antoinette TI Concurrent induction of necrosis, apoptosis, and autophagy in ischemic preconditioned human livers formerly treated by chemotherapy SO JOURNAL OF HEPATOLOGY LA English DT Article DE Cell death; Ischemia/reperfusion; Ischemic preconditioning; Chemotherapy; Bcl-2; Beclin-1; Autophagy; Liver ID MOUSE-LIVER; PREOPERATIVE CHEMOTHERAPY; REPERFUSION INJURY; COLORECTAL-CANCER; CELL-DEATH; IN-VIVO; BCL-2; METASTASES; OXALIPLATIN; MECHANISMS AB Background/Aims: Liver pathology induced by chemotherapy (steatosis or vascular injury) is known to increase the liver's sensitivity to ischemia/reperfusion (I/R) injury, thereby increasing morbidity and mortality after liver resection. Our aim was to assess whether ischemic preconditioning (IP) reduces I/R injury to livers with chemotherapy-induced pathology. Methods: We analyzed a series of livers from patients treated with chemotherapy for colorectal cancer who underwent IP (n = 30) or not (n = 31) before hepatectomy. All but one of the livers exhibited chemotherapy-induced steatosis and/or peliosis before the I/R insult. Results: Necrosis was less frequent (p = 0.038) in livers with IP than in the others. IP had no influence on apoptosis as assessed by terminal transferase uridyl nick-end labeling (TUNEL) assay or caspase-3, -8 and -9 expression. I P induced a twofold increase in B-cell leukemia/lymphoma 2 (Bcl-2; p < 0.05), which was localized to hepatocytes of centrolobular and peliotic areas and colocalized with the autophagy protein beclin-1 in livers with IP, suggesting their coordinated role in autophagy. Increased expression of the phosphorylated Bcl-2 was observed in preconditioned livers and was associated with a decreased immunoprecipitation of beclin-1 and the increased expression of light chain 3 type II (LC3-II). The increased number of autophagic vacuoles seen by electron microscopy confirmed an association of autophagy in chemotherapy-injured livers following I P. However, the differences in protein expression were not reflected in postresection liver-injury tests or measure of patient morbidity. Conclusions: IP is associated with a reduction in necrosis of hepatocytes already damaged by chemotherapy and an activation of autophagy. Bcl-2 and beclin-1 could be major targets in the regulation of cell death during I/R injury. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. C1 [Domart, Marie-Charlotte; Degli Esposti, Davide; Olaya, Natalia; Debuire, Brigitte; Lemoine, Antoinette] Hop Paul Brousse, AP HP, Serv Biochim & Biol Mol, F-94804 Villejuif, France. [Domart, Marie-Charlotte; Degli Esposti, Davide; Olaya, Natalia] Univ Paris 11, INSERM, Inst Andre Lwoff IFR89, PRES Universud Paris,U602, Villejuif, France. [Degli Esposti, Davide; Lemoine, Antoinette] Univ Paris 11, Fac Pharm, Lab Biochim & Biol Cellulaire, F-92290 Chatenay Malabry, France. [Sebagh, Mylene] Univ Paris 11, AP HP, Hop Paul Brousse, Inst Andre Lwoff,Serv Anat Pathol,Inserm U785, F-94804 Villejuif, France. [Harper, Francis; Pierron, Gerard] Inst Andre Lwoff, Lab Replicat ADN & Ultrastruct Noyau, UPR 1983, Villejuif, France. [Franc, Brigitte] Univ Versailles St Quentin, Hop Ambroise Pare, AP HP, Serv Anat Pathol,PRES Universud Paris, Versailles, France. [Tanabe, Kenneth K.] Massachusetts Gen Hosp, Ctr Canc, Div Surg Oncol, Boston, MA USA. [Tanabe, Kenneth K.] Harvard Univ, Sch Med, Boston, MA USA. [Azoulay, Daniel] Univ Paris 11, Hop Paul Brousse, AP HP, Ctr Hepatobiliaire, Villejuif, France. [Brenner, Catherine] Univ Versailles St Quentin, CNRS, PRES Univsud Paris, UMR 8159, Versailles, France. RP Lemoine, A (reprint author), Hop Paul Brousse, AP HP, Serv Biochim & Biol Mol, 14 Ave Paul Vaillant Couturier, F-94804 Villejuif, France. EM antoinette.lemoine@pbr.aphp.fr RI Ji, Haofeng/G-6206-2012; degli esposti, davide/M-1917-2015 OI degli esposti, davide/0000-0003-1390-4845 FU Ligue Nationale Contre le Cancer (comite de l'Essonne); NRB-Vaincre le Cancer; Groupement Cooperatif de Transplantation de I'lle de France; Colciencias (Colombia) FX Marie-Charlotte Dorriart is a fellow of Ligue Nationale Contre le Cancer (comite de l'Essonne). Davide Degli Esposti is a fellow of NRB-Vaincre le Cancer and Groupement Cooperatif de Transplantation de I'lle de France. Natalia Olaya was supported by a grant from Colciencias (Colombia). NR 36 TC 28 Z9 31 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD NOV PY 2009 VL 51 IS 5 BP 881 EP 889 DI 10.1016/j.jhep.2009.06.028 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 519IY UT WOS:000271760800007 PM 19765849 ER PT J AU Thierman, S Dhaliwal, G Sooriash, L Baudendistel, T AF Thierman, Sara Dhaliwal, Gurpreet Sooriash, Lailey Baudendistel, Thomas TI Flushing Out the Diagnosis SO JOURNAL OF HOSPITAL MEDICINE LA English DT Editorial Material ID ANTICONVULSANT-HYPERSENSITIVITY-SYNDROME; SYSTEMIC SYMPTOMS; PHYSICAL-EXAMINATION; DRESS SYNDROME; DRUG RASH; MANAGEMENT; EOSINOPHILIA; HISTORY C1 [Thierman, Sara; Sooriash, Lailey] Calif Pacific Med Ctr, Dept Med, San Francisco, CA 94115 USA. [Thierman, Sara] SUNY Downstate Med Ctr, Dept Dermatol, Brooklyn, NY 11203 USA. [Dhaliwal, Gurpreet] San Francisco VA Med Ctr, Dept Med, San Francisco, CA USA. [Baudendistel, Thomas] Kaiser Permanente, Dept Med, Oakland, CA USA. RP Thierman, S (reprint author), Calif Pacific Med Ctr, Dept Med, 2333 Buchanan, San Francisco, CA 94115 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1553-5592 J9 J HOSP MED JI J. Hosp. Med. PD NOV-DEC PY 2009 VL 4 IS 9 BP 569 EP 573 DI 10.1002/jhm.603 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 540FD UT WOS:000273315800008 PM 20013860 ER PT J AU Stephen, TL Tikhonova, A Riberdy, JM Laufer, TM AF Stephen, Tom Li Tikhonova, Anastasia Riberdy, Janice M. Laufer, Terri M. TI The Activation Threshold of CD4(+) T Cells Is Defined by TCR/Peptide-MHC Class II Interactions in the Thymic Medulla SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROMISCUOUS GENE-EXPRESSION; ANTIGEN PRESENTATION; THYMOCYTE SENSITIVITY; TYROSINE-PHOSPHATASE; POSITIVE SELECTION; CENTRAL TOLERANCE; EPITHELIAL-CELLS; PROTEIN-KINASE; IN-VIVO; SELF AB Immature thymocytes that are positively selected based upon their response to self-peptide-MHC complexes develop into mature T cells that are not overtly reactive to those same complexes. Developmental tuning is the active process through which TCR-associated signaling pathways of single-positive thymocytes are attenuated to respond appropriately to the peptide-MHC molecules that will be encountered in the periphery. In this study, we explore the mechanisms that regulate the tuning of CD4(+) single-positive T cells to MHC class II encountered in the thymic medulla. Experiments with murine BM chimeras demonstrate that tuning can be mediated by MHC class II expressed by either thymic medullary epithelial cells or thymic dendritic cells. Tuning does not require the engagement of CD4 by MHC class II on stromal cells. Rather, it is mediated by interactions between MHC class 11 and the TCR. To understand the molecular changes that distinguish immature hyperactive T cells from tuned mature CD4(+) T cells, we compared their responses to TCR stimulation. The altered response of mature CD4 single-positive thymocytes is characterized by the inhibition of ERK activation by low-affinity self-ligands and increased expression of the inhibitory tyrosine phosphatase SHP-1. Thus, persistent TCR engagement by peptide-MHC class II on thymic medullary stroma inhibits reactivity to self-Ags and prevents autoreactivity in the mature repertoire. The Journal of Immunology, 2009,183: 5554-5562. C1 [Stephen, Tom Li; Tikhonova, Anastasia; Laufer, Terri M.] Univ Penn, Dept Med, Sch Med, Philadelphia, PA 19104 USA. [Riberdy, Janice M.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Laufer, Terri M.] Philadelphia Vet Affairs Med Ctr, Dept Med, Philadelphia, PA 19104 USA. RP Laufer, TM (reprint author), Univ Penn, Dept Med, Sch Med, 753 Biomed Res Bldg 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. EM tlaufer@mail.med.upenn.edu RI Tikhonova, Anastasia/F-1186-2015 FU National Institutes of Health [R01 AI068819]; Arthritis Foundation postdoctoral fellowship FX This work was supported by National Institutes of Health Grant R01 AI068819 (to T.M.L.) and an Arthritis Foundation postdoctoral fellowship (to T.L.S.). NR 48 TC 11 Z9 11 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 NOV 1 PY 2009 VL 183 IS 9 BP 5554 EP 5562 DI 10.4049/jimmunol.0901104 PG 9 WC Immunology SC Immunology GA 515QU UT WOS:000271488500017 PM 19843939 ER PT J AU Sullivan, RJ Hoshida, Y Brunet, JP Aldridge, J Tahan, S Cho, D Mier, JW McDermott, DF Golub, T Atkins, MB AF Sullivan, Ryan J. Hoshida, Yujin Brunet, Jean-Philippe Aldridge, Julie Tahan, Steven Cho, Daniel Mier, James W. McDermott, David F. Golub, Todd Atkins, Michael B. TI Update on the Predictive Nature of a Novel Melanocytic Gene Expression Signature for Outcome to High-dose Interleukin-2 Treatment in Patients With Adavnced Melanoma SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract CT 24th Annual Meeting of the International-Society-for-Biology-Therapy-of-Cancer CY OCT 29-31, 2009 CL Washington, DC SP Int Soc Biol Therapy Canc C1 Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA USA. [Tahan, Steven] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA USA. [Aldridge, Julie] Dana Farber Canc Inst, Boston, MA 02115 USA. Broad Inst, Cambridge, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2009 VL 32 IS 9 BP 962 EP 962 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 510RX UT WOS:000271110100072 ER PT J AU Arredouani, MS Tseng-Rogenski, S Hollenbeck, B Defeo-Jones, D Hwang, C Sanda, MG AF Arredouani, M. Simo Tseng-Rogenski, Stephanie Hollenbeck, Brent Defeo-Jones, Deborah Hwang, Clara Sanda, Martin G. TI Androgen Ablation Augments Cellular Immune Responses to PSA in a Humanized PSA/HLA-A2.1 Transgenic Mouse Model SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract CT 24th Annual Meeting of the International-Society-for-Biology-Therapy-of-Cancer CY OCT 29-31, 2009 CL Washington, DC SP Int Soc Biol Therapy Canc C1 [Arredouani, M. Simo; Sanda, Martin G.] Harvard Univ, Sch Med, BIDMC, Boston, MA USA. [Tseng-Rogenski, Stephanie; Hollenbeck, Brent; Hwang, Clara] Univ Michigan, Sch Med, Ann Arbor, MI USA. [Defeo-Jones, Deborah] Merck Labs, Whitehouse Stn, NJ USA. RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2009 VL 32 IS 9 BP 966 EP 966 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 510RX UT WOS:000271110100083 ER PT J AU Haggerty, TJ Newton, E Dunn, IS Rose, LB Kurnick, JT AF Haggerty, Timothy J. Newton, Estelle Dunn, Ian S. Rose, Lenota B. Kurnick, James T. TI A High-throughput Screening Assay to Identify Agents That Enhance T-cell Recognition of Human Melanomas SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract CT 24th Annual Meeting of the International-Society-for-Biology-Therapy-of-Cancer CY OCT 29-31, 2009 CL Washington, DC SP Int Soc Biol Therapy Canc C1 [Haggerty, Timothy J.; Newton, Estelle; Dunn, Ian S.; Rose, Lenota B.; Kurnick, James T.] CvtoCure, Beverly, MA USA. [Haggerty, Timothy J.; Kurnick, James T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2009 VL 32 IS 9 BP 971 EP 971 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 510RX UT WOS:000271110100098 ER PT J AU Zaupa, C Rabkin, S AF Zaupa, Cecile Rabkin, Samuel TI Oncolytic Herpes Simplex Virus Activation of FLT3-ligand Generated Dendritic Cells for Cancer Immunity SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract CT 24th Annual Meeting of the International-Society-for-Biology-Therapy-of-Cancer CY OCT 29-31, 2009 CL Washington, DC SP Int Soc Biol Therapy Canc C1 [Zaupa, Cecile; Rabkin, Samuel] Massachusetts Gen Hosp, Brain Tumor Res Ctr, Boston, MA 02114 USA. [Zaupa, Cecile; Rabkin, Samuel] Harvard Univ, Sch Med, Boston, MA USA. RI rabkin, samuel/C-2443-2012 OI rabkin, samuel/0000-0003-2344-2795 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2009 VL 32 IS 9 BP 979 EP 980 PG 2 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 510RX UT WOS:000271110100123 ER PT J AU Zuleger, CL Bostwick, BL Macklin, MD Pei, QL Newton, MA Albertini, MR AF Zuleger, Cindav L. Bostwick, Biet L. Macklin, Michael D. Pei, Qinglin Newton, Michael A. Albertini, Mark R. TI Similar T-cell Receptor-beta Sequences Identified in Melanoma-reactive T Cells and In Vivo 6-thioguanine-resistant T Cells From Melanoma Patients SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract CT 24th Annual Meeting of the International-Society-for-Biology-Therapy-of-Cancer CY OCT 29-31, 2009 CL Washington, DC SP Int Soc Biol Therapy Canc C1 [Zuleger, Cindav L.; Macklin, Michael D.; Newton, Michael A.; Albertini, Mark R.] Univ Wisconsin, Carboae Comprehens Canc Ctr, Madison, WI USA. Univ Wisconsin, Sch Med & Publ Hlth, Madison, WI USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2009 VL 32 IS 9 BP 986 EP 986 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 510RX UT WOS:000271110100144 ER PT J AU Dranoff, G AF Dranoff, Glenn TI Enhancing Cancer Vaccines SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract CT 24th Annual Meeting of the International-Society-for-Biology-Therapy-of-Cancer CY OCT 29-31, 2009 CL Washington, DC SP Int Soc Biol Therapy Canc C1 [Dranoff, Glenn] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2009 VL 32 IS 9 BP 993 EP 993 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 510RX UT WOS:000271110100165 ER PT J AU Zheng, LZ Rai, P Evans, C Spring, B Hasan, T AF Zheng, Lei Z. Rai, Prakash Evans, Conoi Spring, Bryan Hasan, Tayyaba TI Nanocell Delivery of PHA-665752 and Cetuximab Enables High-Efficacy Photodynamic Therapy Combination Treatment for Pancreatic Cancer in Preclinical Mice Model SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract CT 24th Annual Meeting of the International-Society-for-Biology-Therapy-of-Cancer CY OCT 29-31, 2009 CL Washington, DC SP Int Soc Biol Therapy Canc C1 [Zheng, Lei Z.; Rai, Prakash; Evans, Conoi; Spring, Bryan; Hasan, Tayyaba] Massachusetts Gen Hosp, Wellman Ctr Photomed, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2009 VL 32 IS 9 BP 995 EP 995 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 510RX UT WOS:000271110100171 ER PT J AU Rahmanzadeh, R Rai, P Abu-Yousif, A Rizyi, I Celli, J Baron-Luhr, B Gerdes, J Hasan, T AF Rahmanzadeh, Ramtin Rai, Prakash Abu-Yousif, Adnan Rizyi, Imran Celli, Jon Baron-Luhr, Bettina Gerdes, Johannes Hasan, Tayyaba TI KI-67 as a Target for Nanotechnology-mediated Light Activatable Cancer Therapy SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract CT 24th Annual Meeting of the International-Society-for-Biology-Therapy-of-Cancer CY OCT 29-31, 2009 CL Washington, DC SP Int Soc Biol Therapy Canc C1 [Rai, Prakash; Abu-Yousif, Adnan; Rizyi, Imran; Celli, Jon] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA USA. [Baron-Luhr, Bettina; Gerdes, Johannes; Hasan, Tayyaba] Leibniz Res Ctr Borstel, Dept Immunol & Cell Biol, Borstel, Germany. RI Rahmanzadeh, Ramtin/L-7941-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2009 VL 32 IS 9 BP 1008 EP 1008 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 510RX UT WOS:000271110100212 ER PT J AU Dranoff, G AF Dranoff, Glenn TI Targets of Protective Tumor Immunity SO JOURNAL OF IMMUNOTHERAPY LA English DT Meeting Abstract CT 24th Annual Meeting of the International-Society-for-Biology-Therapy-of-Cancer CY OCT 29-31, 2009 CL Washington, DC SP Int Soc Biol Therapy Canc C1 [Dranoff, Glenn] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD NOV-DEC PY 2009 VL 32 IS 9 BP 1011 EP 1011 PG 1 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 510RX UT WOS:000271110100221 ER PT J AU Meffert, SM Marmar, CR AF Meffert, Susan M. Marmar, Charles R. TI Darfur Refugees in Cairo Mental Health and Interpersonal Conflict in the Aftermath of Genocide SO JOURNAL OF INTERPERSONAL VIOLENCE LA English DT Article DE refugee; trauma; violence; Sudan; Darfur ID POSTTRAUMATIC-STRESS-DISORDER; MALE VIETNAM VETERANS; QUALITATIVE RESEARCH; PTSD SYMPTOMS; TRAUMA; RECONCILIATION; DEPRESSION; ATTITUDES AB Hundreds of thousands of Darfur people affected by the Sudanese genocide have fled to Cairo, Egypt, in search of assistance. Collaborating with Africa and Middle East Refugee Assistance (AMERA), the authors conducted a mental health care needs assessment among Darfur refugees in Cairo. Information was collected using individual and focus group interviews to identify gaps in mental health care and develop understandings of emotional and relationship problems. The refugee mental health care system has a piecemeal structure with gaps in outpatient services. There is moderate to severe emotional distress among many Darfur refugees, including symptoms of depression and trauma, and interpersonal conflict, both domestic violence and broader community conflict, elevated relative to pregenocide levels. Given the established relationships between symptoms of depression/traumatic stress and interpersonal violence, improving mental health is important for both preventing mental health decompensation and stemming future cycles of intra- and intergroup conflict. C1 [Meffert, Susan M.; Marmar, Charles R.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Marmar, Charles R.] San Francisco Vet Adm Med Ctr, San Francisco, CA 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 OI meffert, susan/0000-0002-5882-7102 FU NIMH NIH HHS [R25 MH060482] NR 26 TC 10 Z9 11 U1 0 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0886-2605 J9 J INTERPERS VIOLENCE JI J. Interpers. Violence PD NOV PY 2009 VL 24 IS 11 BP 1835 EP 1848 DI 10.1177/0886260508325491 PG 14 WC Criminology & Penology; Family Studies; Psychology, Applied SC Criminology & Penology; Family Studies; Psychology GA 500TI UT WOS:000270327400004 PM 18945917 ER PT J AU Feramisco, JD Sadreyev, RI Murray, ML Grishin, NV Tsao, H AF Feramisco, Jamison D. Sadreyev, Ruslan I. Murray, Mitzi L. Grishin, Nick V. Tsao, Hensin TI Phenotypic and Genotypic Analyses of Genetic Skin Disease through the Online Mendelian Inheritance in Man (OMIM) Database SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID ATAXIA TELANGIECTASIA AB Despite unprecedented gains in genomic technologies and genotype resolution, there remain tremendous challenges in our ability to capture disease "phenomes.'' We propose a previously unreported method for deconvolving human disease into elemental features, thereby creating a third space that interacts with both the disease and genotypic spaces. Using cutaneous and noncutaneous clinical findings available through Johns Hopkins University's Online Mendelian Inheritance in Man (OMIM) database, we set out to deconstruct genetic skin disease (GSD) into its various components, to more fully explore the relationship between these features within the complex phenotypic space and to characterize the genotypic space within which these disorders exist. Using OMIM, we defined the current state of GSD as including 560 distinct disorders associated with 501 unique protein-encoding genes. The most common elemental skin features included cornifying, erosive, and hair/nail phenotypes, and the most common systemic features included those associated with developmental, musculoskeletal, and neurological systems. As a proof of principle, we focused on a single skin feature-cafe-au-lait macules-and partitioned the disease space into hierarchical groupings on the basis of this finding. Finally, functional analyses among GSD loci were mapped back to skin features, providing insights into pigmentary and auditory features. Phenotypic deconvolution provides a framework for analyzing medical disorders and can aid in the organization and elucidation of biological mechanisms related to human disease. C1 [Tsao, Hensin] Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Boston, MA 02114 USA. [Feramisco, Jamison D.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [Sadreyev, Ruslan I.; Grishin, Nick V.] Univ Texas SW Med Ctr Dallas, Howard Hughes Med Inst, Dallas, TX 75390 USA. [Sadreyev, Ruslan I.; Grishin, Nick V.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Murray, Mitzi L.] Univ Washington, Dept Med Genet, Seattle, WA 98195 USA. [Tsao, Hensin] Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Wellman Ctr Photomed, Bartlett 622,48 Blossom St, Boston, MA 02114 USA. EM htsao@partners.org FU American Cancer Society; Massachusetts General Hospital (MGH) Institutional FX This work was supported in part by the American Cancer Society, Massachusetts General Hospital (MGH) Institutional start-up funds, and generous philanthropic donors to the MGH ( all to H. T.). NR 9 TC 23 Z9 25 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD NOV PY 2009 VL 129 IS 11 BP 2628 EP 2636 DI 10.1038/jid.2009.108 PG 9 WC Dermatology SC Dermatology GA 509AJ UT WOS:000270982900016 PM 19536140 ER PT J AU Yin, F Doolittle, MH Peterfy, M AF Yin, Fen Doolittle, Mark H. Peterfy, Miklos TI A quantitative assay measuring the function of lipase maturation factor 1 SO JOURNAL OF LIPID RESEARCH LA English DT Article DE combined lipase deficiency; hypertriglyceridemia; lipoprotein lipase; genetic complementation ID LIPOPROTEIN-LIPASE; ENDOPLASMIC-RETICULUM; DEFICIENCY; MUTATIONS; LETHAL; MICE; CLD AB Newly synthesized lipoprotein lipase (LPL) and related members of the lipase gene family require an endoplasmic reticulum maturation factor for attainment of enzyme activity. This factor has been identified as lipase maturation factor 1 (Lmf1), and mutations affecting its function and/or expression result in combined lipase deficiency (cld) and hypertriglyceridemia. To assess the functional impact of Lmf1 sequence variations, both naturally occurring and induced, we report the development of a cell-based assay using LPL activity as a quantitative reporter of Lmf1 function. The assay uses a cell line homozygous for the cld mutation, which renders endogenous Lmf1 nonfunctional. LPL transfected into the mutant cld cell line fails to attain activity; however, cotransfection of LPL with wildtype Lmf1 restores its ability to support normal lipase maturation. In this report, we describe optimized conditions that ensure the detection of a complete range of Lmf1 function ( full, partial, or complete loss of function) using LPL activity as the quantitative reporter. To illustrate the dynamic range of the assay, we tested several novel mutations in mouse Lmf1. Our results demonstrate the ability of the assay to detect and analyze Lmf1 mutations having a wide range of effects on Lmf1 function and protein expression.Yin, F., M. H. Doolittle, and M. Peterfy. A quantitative assay measuring the function of lipase maturation factor 1. J. Lipid Res. 2009. 50: 2265-2269. C1 [Yin, Fen; Doolittle, Mark H.; Peterfy, Miklos] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Yin, Fen; Doolittle, Mark H.; Peterfy, Miklos] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. [Yin, Fen; Peterfy, Miklos] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. RP Doolittle, MH (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. EM markdool@ucla.edu; mpeterfy@ucla.edu FU Cedars-Sinai Medical Center, the Department of Veterans Affairs; National Institutes of Health [HL-24841] FX This work was supported by the Cedars-Sinai Medical Center, the Department of Veterans Affairs, and Grant HL-24841 from the National Institutes of Health. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 10 TC 9 Z9 9 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 NOV PY 2009 VL 50 IS 11 BP 2265 EP 2269 DI 10.1194/jlr.M900196-JLR200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 507NJ UT WOS:000270860900015 PM 19471043 ER PT J AU Ikeda, H Shiojima, I Ozasa, Y Yoshida, M Holzenberger, M Kahn, CR Walsh, K Igarashi, T Abel, ED Komuro, I AF Ikeda, Hiroyuki Shiojima, Ichiro Ozasa, Yukako Yoshida, Masashi Holzenberger, Martin Kahn, C. Ronald Walsh, Kenneth Igarashi, Takashi Abel, E. Dale Komuro, Issei TI Interaction of myocardial insulin receptor and IGF receptor signaling in exercise-induced cardiac hypertrophy SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE Insulin-like growth factor receptor; Insulin receptor; Exercise; Cardiac hypertrophy; Tyrosine phosphorylation ID TRANSGENIC MICE; HEART-FAILURE; GROWTH; EXPRESSION; PATHWAY; SIZE; CARDIOMYOPATHY; ANGIOGENESIS; DELETION; GENE AB Insulin-like growth factor-1 (IGF-1) signaling has recently been implicated in the development of cardiac hypertrophy after long-term endurance training, via mechanisms that may involve energetic stress. Given the potential overlap of insulin and IGF-1 signaling we sought to determine if both signaling pathways could contribute to exercise-induced cardiac hypertrophy following shorter-term exercise training. Studies were performed in mice with cardiac-specific IGF-1 receptor (IGF1R) knockout (CIGFRKO), mice with cardiac-specific insulin receptor (IR) knockout (CIRKO), CIGFRKO mice that lacked one IR allele in cardiomyocytes (IGFR-/-IR+/-), and CIRKO mice that lacked one IGF1R allele in cardiomyocytes (IGFR+/-IR-/-) Intravenous administration of IGF-1 or 75 hours of swimming over 4 weeks increased IGF1R tyrosine phosphorylation in the heart in control and CIRKO mice but not in CIGFRKO mice. Intriguingly, IR tyrosine phosphorylation in the heart was also increased following IGF-1 administration or exercise training in control and CIGFRKO mice but not in CIRKO mice. The extent of cardiac hypertrophy following exercise training in CIGFRKO and CIRKO mice was comparable to that in control mice. In contrast, exercise-induced cardiac hypertrophy was significantly attenuated in IGFR-/-IR+/- and IGFR+/-IR-/- mice. Thus, IGF-1 and exercise activates both IGF1R and IR in the heart, and IGF1R- and IR-mediated signals may serve redundant roles in the hypertrophic responses of the heart to exercise training. (C) 2009 Elsevier Inc. All rights reserved. C1 [Ikeda, Hiroyuki; Shiojima, Ichiro; Ozasa, Yukako; Yoshida, Masashi; Komuro, Issei] Chiba Univ, Dept Cardiovasc Sci & Med, Grad Sch Med, Chiba, Japan. [Ikeda, Hiroyuki; Igarashi, Takashi] Univ Tokyo, Dept Pediat, Grad Sch Med, Tokyo, Japan. [Shiojima, Ichiro; Komuro, Issei] Osaka Univ, Dept Cardiovasc Med, Grad Sch Med, Suita, Osaka, Japan. [Holzenberger, Martin] Hop St Antoine, INSERM, UMR893, F-75571 Paris, France. [Kahn, C. Ronald] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. [Kahn, C. Ronald] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Walsh, Kenneth] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Abel, E. Dale] Univ Utah, Sch Med, Program Mol Med, Salt Lake City, UT USA. [Abel, E. Dale] Univ Utah, Sch Med, Div Endocrinol Diabet & Metab, Salt Lake City, UT USA. RP Komuro, I (reprint author), Chiba Univ, Dept Cardiovasc Sci & Med, Grad Sch Med, Chiba, Japan. EM komuro-tky@umin.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology (MEXT); NIH [RO1HL070070] FX We thank E. Fujita, R. Kobayashi, and Y Ishiyama for technical assistance. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to I.K. and by NIH grant RO1HL070070 to E.D.A. NR 32 TC 21 Z9 22 U1 0 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD NOV PY 2009 VL 47 IS 5 BP 664 EP 675 DI 10.1016/j.yjmcc.2009.08.028 PG 12 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 510RG UT WOS:000271108000013 PM 19744489 ER PT J AU Ogino, S Irahara, N Nosho, K Lindeman, N Hazra, A Hunters, D Fuchs, C AF Ogino, S. Irahara, N. Nosho, K. Lindeman, N. Hazra, A. Hunters, D. Fuchs, C. TI Precision of Pyrosequencing Assay to Measure LINE-1 Methylation Level in Paraffin-Embedded Colorectal Cancer and Normal Colon Specimens and Blood Cells SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology CY NOV 19-22, 2009 CL Orlando, FL SP Assoc Mole Pathol C1 [Ogino, S.; Lindeman, N.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Hazra, A.; Hunters, D.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2009 VL 11 IS 6 BP 657 EP 657 PG 1 WC Pathology SC Pathology GA 518HK UT WOS:000271681400179 ER PT J AU Barletta, JA Xiao, Y Joshi, VA Jackman, DM Janne, PA Lee, C Lindeman, NI AF Barletta, J. A. Xiao, Y. Joshi, V. A. Jackman, D. M. Janne, P. A. Lee, C. Lindeman, N. I. TI MET Copy-Number Status in Lung Adenocarcinomas with EGFR Alterations SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology CY NOV 19-22, 2009 CL Orlando, FL SP Assoc Mole Pathol C1 [Barletta, J. A.; Xiao, Y.; Lee, C.; Lindeman, N. I.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Barletta, J. A.; Xiao, Y.; Joshi, V. A.; Jackman, D. M.; Janne, P. A.; Lee, C.; Lindeman, N. I.] Harvard Univ, Sch Med, Boston, MA USA. [Joshi, V. A.] Partners Ctr Personalized Genet Med, Mol Med Lab, Cambridge, MA USA. [Jackman, D. M.; Janne, P. A.] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2009 VL 11 IS 6 BP 664 EP 664 PG 1 WC Pathology SC Pathology GA 518HK UT WOS:000271681400209 ER PT J AU Dias-Santagata, DC Akhavanfard, S David, SS Vemovsky, K Kuhlmann, G Boisvert, SL Settleman, J Sequist, LV Engelman, JA Louis, DN Ellisen, LW Borger, DR Iafrate, AJ AF Dias-Santagata, D. C. Akhavanfard, S. David, S. S. Vemovsky, K. Kuhlmann, G. Boisvert, S. L. Settleman, J. Sequist, L. V. Engelman, J. A. Louis, D. N. Ellisen, L. W. Borger, D. R. Iafrate, A. J. TI Real Time Targeted Mutational Analysis of Human Tumors: a Clinical Platform to Guide Personalized Cancer Medicine SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology CY NOV 19-22, 2009 CL Orlando, FL SP Assoc Mole Pathol C1 [Akhavanfard, S.; David, S. S.; Vemovsky, K.; Boisvert, S. L.; Settleman, J.; Sequist, L. V.; Engelman, J. A.; Ellisen, L. W.; Borger, D. R.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Dias-Santagata, D. C.; Settleman, J.; Engelman, J. A.; Louis, D. N.; Ellisen, L. W.; Borger, D. R.; Iafrate, A. J.] Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2009 VL 11 IS 6 BP 666 EP 666 PG 1 WC Pathology SC Pathology GA 518HK UT WOS:000271681400217 ER PT J AU Wildemore, BM Cook, J Fiorentino, M Wu, L Bailey, D Brown, M Loda, M AF Wildemore, B. M. Cook, J. Fiorentino, M. Wu, L. Bailey, D. Brown, M. Loda, M. TI Immunohistochemistry Used for the Better Identification of the Atypical Cells in Lymphangioleiomyomatosis SO JOURNAL OF MOLECULAR DIAGNOSTICS LA English DT Meeting Abstract CT Annual Meeting of the Association-for-Molecular-Pathology CY NOV 19-22, 2009 CL Orlando, FL SP Assoc Mole Pathol C1 [Wildemore, B. M.] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Loda, M.] Dana Farber Canc Inst, Ctr Oncol Pathol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 1525-1578 J9 J MOL DIAGN JI J. Mol. Diagn. PD NOV PY 2009 VL 11 IS 6 BP 669 EP 669 PG 1 WC Pathology SC Pathology GA 518HK UT WOS:000271681400228 ER PT J AU Piccirillo, SGM Binda, E Fiocco, R Vescovi, AL Shah, K AF Piccirillo, Sara G. M. Binda, Elena Fiocco, Roberta Vescovi, Angelo L. Shah, Khalid TI Brain cancer stem cells SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Review DE Neural stem cells; Cancer stem cells; Glioblastoma multiforme; Tumorigenicity; Brain tumor; Glioblastoma; Cancer therapy ID TUMOR-INITIATING CELLS; ACUTE MYELOID-LEUKEMIA; IN-VIVO; HUMAN GLIOBLASTOMA; MOUSE MODELS; GROWTH; IDENTIFICATION; TEMOZOLOMIDE; HEDGEHOG; RENEWAL AB Cancers comprise heterogeneous cells, ranging from highly proliferative immature precursors to more differentiated cell lineages. In the last decade, several groups have demonstrated the existence of cancer stem cells in both nonsolid solid tumors, including some of the brain: glioblastoma multiforme (GBM), medulloblastoma, and ependymoma. These cells, like their normal counterpart in homologous tissues, are multipotent, undifferentiated, self-sustaining, yet transformed cells. In particular, glioblastoma-stem like cells (GBSCs) self-renew under clonal conditions and differentiate into neuron- and glia-like cells, with aberrant, mixed neuronal/astroglial phenotypes. Remarkably, upon subcutaneous and intracerebral transplantation in immunosuppressed mice, GBSCs are able to form secondary tumors that closely resemble the human pathology, a property retained also throughout serial transplantation. The search is up for the identification of the markers and the molecular mechanisms that underpin the tumorigenic potential of these cells. This is critical if we aim at defining new therapeutic approaches for the treatment of malignant brain tumors. Lately, it has been shown that some key regulatory system that plays pivotal roles in neural stem cell physiology can also regulate the tumorigenic ability of cancer stem cells in GBMs. This suggests that the study of cancer stem cells in brain tumors might help to identify new and more specific therapeutic molecular effectors, with the cancer stem cells themselves representing one of the main targets, in fact the Holy Grail, in cancer cell therapy. This review includes a summary review on brain cancer cells and their usefulness as emerging targets in cancer cell therapy. C1 [Piccirillo, Sara G. M.; Vescovi, Angelo L.] Univ Milano Bicocca, Dept Biosci & Biotechnol, I-20126 Milan, Italy. [Binda, Elena; Fiocco, Roberta; Vescovi, Angelo L.] StemGen SpA, I-20126 Milan, Italy. [Shah, Khalid] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. RP Vescovi, AL (reprint author), Univ Milano Bicocca, Dept Biosci & Biotechnol, Piazza Sci 2,Bldg U3, I-20126 Milan, Italy. EM vescovi@tin.it; kshah@helix.mgh.harvard.edu RI Binda, Elena/B-2650-2017; OI Binda, Elena/0000-0002-8750-2905; Piccirillo, Sara Grazia Maria/0000-0003-4109-1992; Vescovi, Angelo Luigi/0000-0002-1742-4112 FU Associazione Italiana Ricerca sul Cancro (AIRC) FX ALV is an awardee of a grant from Associazione Italiana Ricerca sul Cancro (AIRC). NR 66 TC 39 Z9 41 U1 0 U2 15 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0946-2716 J9 J MOL MED-JMM JI J. Mol. Med. PD NOV PY 2009 VL 87 IS 11 BP 1087 EP 1095 DI 10.1007/s00109-009-0535-3 PG 9 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 514RI UT WOS:000271412300008 PM 19784875 ER PT J AU Germano, PM Lieu, SN Xue, JJ Cooke, HJ Christofi, FL Lu, YX Pisegna, JR AF Germano, Patrizia M. Lieu, Sandy N. Xue, Janjing Cooke, Helen J. Christofi, Fievos L. Lu, Yuxin Pisegna, Joseph R. TI PACAP Induces Signaling and Stimulation of 5-Hydroxytryptamine Release and Growth in Neuroendocrine Tumor Cells SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE BON cell; Carcinoid tumor; PACAP ID CYCLASE-ACTIVATING POLYPEPTIDE; LUNG-CANCER CELLS; VASOACTIVE INTESTINAL POLYPEPTIDE; CARCINOID BON CELLS; PROTEIN-KINASE-C; ADENYLATE-CYCLASE; FUNCTIONAL EXPRESSION; NEUROTENSIN SECRETION; RECEPTOR ANTAGONIST; CHROMAFFIN CELLS AB Neuroendocrine tumors, although rare, are currently diagnosed with increasing frequency, owing to improved imaging techniques and a greater clinical awareness of this condition. To date, BON is a very well established and characterized human pancreatic neuroendocrine tumor cell line used to study the signal transduction and genetic regulation of neuroendocrine tumors secretion and growth. The secretory activity of BON cells is known to release peptides, such as chromogranin A, neurotensin, and biogenic amines, as 5-HT, permitting an assessment of their biological activity. The neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP), released from the enteric neurons in the gastrointestinal tract by binding to its high affinity receptor PAC1, has been previously shown to regulate the secretory activity and growth of the neuroendocrine-derived enterochromaffin-like cells in the stomach. This led us to speculate that PACAP might also play an important role in regulating the growth of human neuroendocrine tumors. Accordingly, in the current study, we have shown that BON cells express PAC1 receptors, which are rapidly internalized upon PACAP activation. Furthermore, PAC1 receptor activation, in BON cells, couple to intracellular Ca(2+) as well as cAMP responses and induce the release of intracellular 5-HT, activate mitogen activated protein kinases, and stimulate cellular growth. These data indicate that PACAP functionally can stimulate 5-HT release and promote the growth of the BON neuroendocrine tumor cell line. Therefore, PACAP and its receptors regulate neuroendocrine tumor secretory activity and growth in vivo, and this knowledge will permit the development of novel diagnostic and therapeutic targets for managing neuroendocrine tumors in humans. C1 [Germano, Patrizia M.; Lieu, Sandy N.; Lu, Yuxin; Pisegna, Joseph R.] Univ Calif Los Angeles, CURE Digest Dis Res Ctr, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90073 USA. [Xue, Janjing; Cooke, Helen J.; Christofi, Fievos L.] Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA. [Xue, Janjing; Cooke, Helen J.; Christofi, Fievos L.] Ohio State Univ, Dept Anesthesiol, Columbus, OH 43210 USA. RP Germano, PM (reprint author), Univ Calif Los Angeles, CURE Digest Dis Res Ctr, VA Greater Los Angeles Healthcare Syst, 11301 Wilshire Blvd,Bldg 115,Room 316, Los Angeles, CA 90073 USA. EM pgermano@ucla.edu FU Department of Veterans Affairs; National Institutes of Health [DK37240] FX This work was supported by the Department of Veterans Affairs Merit Review Grant (JRP) and National Institutes of Health DK37240 (HJC). NR 51 TC 9 Z9 9 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD NOV PY 2009 VL 39 IS 3 BP 391 EP 401 DI 10.1007/s12031-009-9283-7 PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 505YZ UT WOS:000270739700012 PM 19701709 ER PT J AU Pallast, S Arai, K Wang, XY Lo, EH van Leyen, K AF Pallast, Stefanie Arai, Ken Wang, Xiaoying Lo, Eng H. van Leyen, Klaus TI 12/15-Lipoxygenase targets neuronal mitochondria under oxidative stress SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE cytochrome c; glutathione; lipoxygenase; mitochondria; reactive oxygen species ID GLUTATHIONE DEPLETION; CELL-DEATH; GLUTAMATE TOXICITY; ORGANELLE DEGRADATION; CORTICAL-NEURONS; BRAIN; 12-LIPOXYGENASE; CULTURES; LIPOXYGENASE; INHIBITION AB 12/15-Lipoxygenase (12/15-LOX) is an important mediator of brain injury following experimental stroke in rodents. It contributes to neuronal death, but the underlying mechanism remains unclear. We demonstrate here that in neuronal HT22 cells subjected to glutamate-induced oxidative stress, 12/15-LOX damages mitochondria, and this represents the committed step that condemns the cell to die. Importantly these events, including breakdown of the mitochondrial membrane potential, the production of reactive oxygen species, and cytochrome c release, can all be replicated by incubation of 12/15-LOX with mitochondria in vitro, without the need to add other cytosolic factors. Proteasome activity is required downstream of mitochondrial damage to complete the cell death cascade, but proteasome inhibition is only partially protective. These findings position 12/15-LOX as the central executioner in an oxidative stress-related neuronal death program. C1 [Pallast, Stefanie; Arai, Ken; Wang, Xiaoying; Lo, Eng H.; van Leyen, Klaus] Massachusetts Gen Hosp, Neuroprotect Res Lab, Charlestown, MA 02129 USA. RP van Leyen, K (reprint author), Massachusetts Gen Hosp, Neuroprotect Res Lab, 149 13th St,R 2401, Charlestown, MA 02129 USA. EM klaus_vanleyen@hms.harvard.edu RI van Leyen, Klaus/C-9126-2013 FU NIH [R01NS049430, R01NS53560, P01NS555104]; American Heart Association FX Support through grants from the NIH (R01NS049430 to K.v.L., R01NS53560 and P01NS555104 to E.H.L.), and a Scientist Development Grant from the American Heart Association (to K.v.L.), is gratefully acknowledged. The authors declare no conflict of interest. NR 34 TC 42 Z9 45 U1 1 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD NOV PY 2009 VL 111 IS 3 BP 882 EP 889 DI 10.1111/j.1471-4159.2009.06379.x PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 505VY UT WOS:000270728600024 PM 19737346 ER PT J AU Dickey, MW Thompson, CK AF Dickey, Michael Walsh Thompson, Cynthia K. TI Automatic processing of wh- and NP-movement in agrammatic aphasia: Evidence from eyetracking SO JOURNAL OF NEUROLINGUISTICS LA English DT Article DE Aphasia; Agrammatism; Eyetracking; Filler-gap dependencies; NP-movement; Sentence comprehension; wh-movement ID EMPTY CATEGORIES; EYE-MOVEMENTS; TIME-COURSE; SENTENCE COMPREHENSION; BROCAS APHASIA; ALTERED SPEECH; DEPENDENCIES; TRACKING; ASSIGNMENT; PREFERENCE AB Individuals with agrammatic Broca's aphasia show deficits in comprehension of non-canonical wh-movement and NP-movement sentences. Previous work using eyetracking has found that agrammatic and unimpaired listeners show very similar patterns of automatic processing for wh-movement sentences. The current study attempts to replicate this finding for sentences with wh-movement (in object relatives in the Current study) and to extend it to sentences with NP-movement (passives). For wh-movement sentences, aphasic and control participants' eye-movements differed most dramatically in late regions of the sentence and post-offset, with aphasic participants exhibiting lingering attention to a salient but grammatically impermissible competitor. The eye-movement differences between correct and incorrect trials for wh-movement sentences were similar. with incorrect trials also exhibiting competition from an impermissible interpretation late in the sentence. Furthermore, the two groups exhibited similar eye-movement patterns in response to passive NP-movement sentences, but showed little evidence of gap-filling for passives. The results suggest that aphasic and unimpaired individuals may generate similar representations during comprehension, but that aphasics are highly vulnerable to interference from alternative interpretations (Ferreira, F. (2003). The misinterpretation of non-canonical sentences. Cognitive Psychology, 47(2),164-203). (C) 2009 Elsevier Ltd. All rights reserved. C1 [Dickey, Michael Walsh] Univ Pittsburgh, Dept Commun Sci & Disorders, Pittsburgh, PA 15260 USA. [Dickey, Michael Walsh] VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. [Thompson, Cynthia K.] Northwestern Univ, Aphasia & Neurolinguist Res Lab, Evanston, IL USA. [Thompson, Cynthia K.] Northwestern Univ, Dept Commun Sci & Disorders, Evanston, IL USA. [Thompson, Cynthia K.] Northwestern Univ, Dept Neurol, Evanston, IL USA. [Thompson, Cynthia K.] Northwestern Univ, Cognit Neurol & Alzheimers Dis Ctr, Evanston, IL USA. RP Dickey, MW (reprint author), Univ Pittsburgh, Dept Commun Sci & Disorders, 4032 Forbes Tower, Pittsburgh, PA 15260 USA. EM mdickey@pitt.edu OI Dickey, Michael Walsh/0000-0002-9068-3313 FU NIDCD NIH HHS [R01 DC001948, R01 DC001948-14] NR 56 TC 25 Z9 26 U1 2 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0911-6044 J9 J NEUROLINGUIST JI J. Neurolinguist. PD NOV PY 2009 VL 22 IS 6 BP 563 EP 583 DI 10.1016/j.jneuroling.2009.06.004 PG 21 WC Linguistics; Neurosciences; Psychology, Experimental SC Linguistics; Neurosciences & Neurology; Psychology GA 500PN UT WOS:000270315700004 PM 20161014 ER PT J AU Healy, B Valsasina, P Filippi, M Bakshi, R AF Healy, B. Valsasina, P. Filippi, M. Bakshi, R. TI Sample size requirements for treatment effects using gray matter, white matter and whole brain volume in relapsing-remitting multiple sclerosis SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Article ID COGNITIVE IMPAIRMENT; ATROPHY; MS; DISABILITY; NEUROPROTECTION; DISEASE; MRI; T2 AB Objective: To compare the sample size requirements for a neuroprotection trial with change in cerebral gray matter volume (GMV), white matter volume (WMV) or whole brain parenchymal volume (BPV) as outcome measures in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Two datasets with longitudinal MRI measures of untreated patients with RRMS (n = 116 and n = 26) and one dataset of treated patients with RRMS (n = 109) were investigated. In each dataset, normalised GMV, normalised WMV and normalised BPV were analysed using a random intercepts and slopes model to estimate the variance components and per cent change. The required sample size to observe a 33%, 50% and 90% reduction in the per cent change was calculated for each dataset using both a constant per cent change for each measurement and the estimated per cent change for each dataset. Results: The per cent change was greatest in GMV but all variance components were smallest in BPV. Using the estimated per cent change, the sample size required in the untreated cohorts was similar for GMV and BPV, and both were lower than WMV. In the treated cohort, the sample size for GMV was the smallest of all measures. Including additional scans reduced the sample size but increasing the length of the trial and clustering scans led to greater reductions. Conclusions: Cerebral GMV may be a viable outcome measure for clinical trials investigating neuroprotection in RRMS patients, especially considering that the treatment effect may be larger on GMV compared with BPV. However, GMV was somewhat limited by increased variability versus BPV. C1 [Healy, B.; Bakshi, R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol,Partners MS Ctr,Lab Neuroimaging Res, Brookline, MA 02445 USA. [Healy, B.] Massachusetts Gen Hosp, Dept Neurol, Ctr Biostat, Boston, MA 02114 USA. [Valsasina, P.; Filippi, M.] Univ Osped San Raffaele, Milan, Italy. [Valsasina, P.; Filippi, M.] Inst Sci, Neuroimaging Res Unit, Milan, Italy. [Bakshi, R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Brookline, MA 02445 USA. RP Bakshi, R (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurol,Partners MS Ctr,Lab Neuroimaging Res, 1 Brookline Pl,Suite 602, Brookline, MA 02445 USA. EM rbakshi@bwh.harvard.edu RI Valsasina, Paola/K-5820-2016 OI Valsasina, Paola/0000-0001-5390-2655 FU Partners MS Center; National Institutes of Health [1R01NS055083-01]; National Multiple Sclerosis Society [RG3705A1, RG3798A2] FX BH acknowledges support from the Partners MS Center. RB acknowledges support of research grants from the National Institutes of Health (1R01NS055083-01) and National Multiple Sclerosis Society (RG3705A1; RG3798A2). Teva kindly accepted to use the placebo and treated data of the European/Canadian MRI trial of Copaxone in MS. NR 28 TC 11 Z9 11 U1 0 U2 2 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 NOV PY 2009 VL 80 IS 11 BP 1218 EP 1223 DI 10.1136/jnnp.2008.154732 PG 6 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 512PE UT WOS:000271261400200 PM 19204021 ER PT J AU Prerau, MJ Smith, AC Eden, UT Kubota, Y Yanike, M Suzuki, W Graybiel, AM Brown, EN AF Prerau, M. J. Smith, A. C. Eden, Uri T. Kubota, Y. Yanike, M. Suzuki, W. Graybiel, A. M. Brown, E. N. TI Characterizing Learning by Simultaneous Analysis of Continuous and Binary Measures of Performance SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID BEHAVIORAL-EXPERIMENTS; PROSTHETIC DEVICES; PREFRONTAL CORTEX; ACQUISITION; MEMORY; HIPPOCAMPUS; ALGORITHM; NEURONS; LESIONS; DESIGN AB Prerau MJ, Smith AC, Eden UT, Kubota Y, Yanike M, Suzuki W, Graybiel AM, Brown EN. Characterizing learning by simultaneous analysis of continuous and binary measures of performance. J Neurophysiol 102: 3060-3072, 2009. First published August 19, 2009; doi:10.1152/jn.91251.2008. Continuous observations, such as reaction and run times, and binary observations, such as correct/incorrect responses, are recorded routinely in behavioral learning experiments. Although both types of performance measures are often recorded simultaneously, the two have not been used in combination to evaluate learning. We present a state-space model of learning in which the observation process has simultaneously recorded continuous and binary measures of performance. We use these performance measures simultaneously to estimate the model parameters and the unobserved cognitive state process by maximum likelihood using an approximate expectation maximization (EM) algorithm. We introduce the concept of a reaction-time curve and reformulate our previous definitions of the learning curve, the ideal observer curve, the learning trial and between-trial comparisons of performance in terms of the new model. We illustrate the properties of the new model in an analysis of a simulated learning experiment. In the simulated data analysis, simultaneous use of the two measures of performance provided more credible and accurate estimates of the learning than either measure analyzed separately. We also analyze two actual learning experiments in which the performance of rats and of monkeys was tracked across trials by simultaneously recorded reaction and run times and the correct and incorrect responses. In the analysis of the actual experiments, our algorithm gave a straightforward, efficient way to characterize learning by combining continuous and binary measures of performance. This analysis paradigm has implications for characterizing learning and for the more general problem of combining different data types to characterize the properties of a neural system. C1 [Brown, E. N.] Massachusetts Gen Hosp, Neurosci Stat Res Lab, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Graybiel, A. M.; Brown, E. N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Kubota, Y.; Graybiel, A. M.] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Yanike, M.; Suzuki, W.] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Brown, E. N.] Harvard Univ, Sch Med, Div Hlth Sci & Technol, MIT, Cambridge, MA 02138 USA. [Eden, Uri T.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Prerau, M. J.; Eden, Uri T.] Boston Univ, Program Neurosci, Boston, MA 02215 USA. RP Brown, EN (reprint author), Massachusetts Gen Hosp, Neurosci Stat Res Lab, Dept Anesthesia & Crit Care, 55 Fruit St,Clin 3, Boston, MA 02114 USA. EM brown@neurostat.mgh.harvard.edu FU National Institutes of Health [DA-015644, DPI0D003646, MH-59733, MH-071847, P50 NS-38372] FX Support was provided by National Institutes of Health Grants DA-015644 to E. N. Brown and W. Suzuki, DPI0D003646, MH-59733 and MH-071847 to E. N. Brown, and P50 NS-38372 to A. M. Graybiel. NR 42 TC 10 Z9 10 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD NOV PY 2009 VL 102 IS 5 BP 3060 EP 3072 DI 10.1152/jn.91251.2008 PG 13 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 515JZ UT WOS:000271467300044 PM 19692505 ER PT J AU Mitha, AP Reichardt, B Grasruck, M Macklin, E Bartling, S Leidecker, C Schmidt, B Flohr, T Brady, TJ Ogilvy, CS Gupta, R AF Mitha, Alim P. Reichardt, Benjamin Grasruck, Michael Macklin, Eric Bartling, Soenke Leidecker, Christianne Schmidt, Bernhard Flohr, Thomas Brady, Thomas J. Ogilvy, Christopher S. Gupta, Rajiv TI Dynamic imaging of a model of intracranial saccular aneurysms using ultra-high-resolution flat-panel volumetric computed tomography SO JOURNAL OF NEUROSURGERY LA English DT Article DE intracranial aneurysm; aneurysm model; flat-panel volumetric computed tomography; high spatial resolution; dynamic computed tomography ID CT-SCANNER; RUPTURE; DESIGN AB Object. Imaging of intracranial aneurysms using conventional multidetector CT (MDCT) is limited because of nonvisualization of features such as perforating vessels, pulsatile blebs, and neck remnants after clip placement or coil embolization. In this study, a model of intracranial saccular aneurysms in rabbits was used to assess the ultra-high resolution and dynamic scanning capabilities of a prototype flat-panel volumetric CT (fpVCT) scanner in demonstrating these features. Methods. Ten New Zealand white rabbits underwent imaging before and after clipping or coil embolization of surgically created aneurysms in the proximal right carotid artery. Imaging was performed using a prototype fpVCT scanner, a 64-slice MDCT scanner, and traditional catheter angiography. In addition to the slice data and 3D views, 4D dynamic views, a capability unique to fpVCT, were also created and reviewed. The images were subjectively compared on 1) 4 image quality metrics ( spatial resolution, noise, motion artifacts, and aneurysm surface features); 2) 4 posttreatment features reflecting the metal artifact profile of the various imaging modalities ( visualization of clip or coil placement, perianeurysmal clip/coil anatomy, neck remnant, and white-collar sign); and 3) 2 dynamic features ( blood flow pattern and aneurysm pulsation). Results. Flat-panel volumetric CT provided better image resolution than MDCT and was comparable to traditional catheter angiography. The surface features of aneurysms were demonstrated with much higher resolution, detail, and clarity by fpVCT compared with MDCT and angiography. Flat-panel volumetric CT was inferior to both MDCT and angiography in terms of image noise and motion artifacts. In fpVCT images, the metallic artifacts from clips and coils were significantly fewer than those in MDCT images. As a result, clinically important information about posttreatment aneurysm neck remnants could be derived from fpVCT images but not from MDCT images. Time-resolved dynamic sequences were judged slightly inferior to conventional angiography but superior to static MDCT images. Conclusions. The spatial resolution, surface anatomy visualization, metal artifact profile, and 4D dynamic images from fpVCT are superior to those from MDCT. Flat-panel volumetric CT demonstrates aneurysm surface features to better advantage than angiography and is comparable to angiography in metal artifact profile. Even though the temporal resolution of fpVCT is not quite as good as that of angiography, fpVCT images yield clinically important anatomical information about aneurysm surface features and posttreatment neck remnants not attainable with either angiography or MDCT images. (DOI: 10.3171/2009.2.JNS08828) C1 [Reichardt, Benjamin; Brady, Thomas J.; Gupta, Rajiv] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mitha, Alim P.; Ogilvy, Christopher S.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. [Macklin, Eric] Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. [Mitha, Alim P.] Foothills Med Ctr, Div Neurosurg, Calgary, AB, Canada. [Grasruck, Michael; Leidecker, Christianne; Schmidt, Bernhard; Flohr, Thomas] Siemens Med Solut, Forchheim, Germany. [Bartling, Soenke] German Canc Res Ctr, D-6900 Heidelberg, Germany. RP Gupta, R (reprint author), Massachusetts Gen Hosp, Dept Radiol, Room 273A,55 Fruit St, Boston, MA 02114 USA. EM rgupta1@partners.org RI Macklin, Eric/E-2955-2013 OI Macklin, Eric/0000-0003-1618-3502 NR 11 TC 5 Z9 5 U1 0 U2 1 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD NOV PY 2009 VL 111 IS 5 BP 947 EP 957 DI 10.3171/2009.2.JNS08828 PG 11 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 514DW UT WOS:000271375500015 PM 19374491 ER PT J AU Garces-Ambrossi, GL McGirt, MJ AF Garces-Ambrossi, Giannina L. McGirt, Matthew J. TI Factors predicting the resectability of intramedullary spinal cord tumors and the progression-free survival following microsurgical treatment Response SO JOURNAL OF NEUROSURGERY-SPINE LA English DT Editorial Material C1 [Garces-Ambrossi, Giannina L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. [McGirt, Matthew J.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. RP Garces-Ambrossi, GL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02163 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC NEUROLOGICAL SURGEONS PI ROLLING MEADOWS PA 5550 MEADOWBROOK DRIVE, ROLLING MEADOWS, IL 60008 USA SN 1547-5654 J9 J NEUROSURG-SPINE JI J. Neurosurg.-Spine PD NOV PY 2009 VL 11 IS 5 BP 590 EP 590 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 512JM UT WOS:000271244200017 ER PT J AU Tejima, E Guo, SZ Murata, Y Arai, K Lok, J van Leyen, K Rosell, A Wang, XY Lo, EH AF Tejima, Emiri Guo, Shuzhen Murata, Yoshihiro Arai, Ken Lok, Josephine van Leyen, Klaus Rosell, Anna Wang, Xiaoying Lo, Eng H. TI Neuroprotective Effects of Overexpressing Tissue Inhibitor of Metalloproteinase TIMP-1 SO JOURNAL OF NEUROTRAUMA LA English DT Article DE blood-brain barrier; neuroprotection; neurovascular unit; stroke; traumatic brain injury ID FOCAL CEREBRAL-ISCHEMIA; BLOOD-BRAIN-BARRIER; GENE KNOCK-OUT; MATRIX METALLOPROTEINASES; ALZHEIMERS-DISEASE; CELL-DEATH; PLASMINOGEN-ACTIVATOR; MMP-9/TIMP-1 RATIO; REPERFUSION INJURY; ENDOTHELIAL-CELLS AB Accumulating data suggest that matrix metalloproteinases (MMPs) may be important mediators in the pathophysiology of acute brain injury after trauma or stroke. Here, we test the hypothesis that the endogenous tissue inhibitor of metalloproteinase (TIMP-1) is neuroprotective in vitro and in vivo. For in vitro studies, primary cortical neuronal cultures were subjected to hypoxia and reoxygenation. Treatment with recombinant TIMP-1 protein significantly decreased neuronal death. In vivo studies in models of brain trauma and stroke supported these cell culture results. After controlled cortical impact, 24-h MMP-9 levels were significantly reduced in transgenic mice overexpressing TIMP-1 compared to wild-type mice. And at 7 days post-trauma, brain lesion volumes were also significantly decreased by TIMP-1 overexpression as well. In a model of transient 2-h focal cerebral ischemia, MMP-9 levels were lower in TIMP-1 transgenic mice compared with wild-types. Correspondingly, blood-brain barrier leakage was ameliorated by TIMP-1 overexpression, and 24-h infarction volumes were also reduced. Taken together, these cell culture and in vivo data provide initial proof-of-principle that TIMP-1 is neuroprotective against traumatic and ischemic brain injury in mice. C1 [Tejima, Emiri; Guo, Shuzhen; Murata, Yoshihiro; Arai, Ken; Lok, Josephine; van Leyen, Klaus; Rosell, Anna; Wang, Xiaoying; Lo, Eng H.] Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, Charlestown, MA 02129 USA. [Tejima, Emiri; Guo, Shuzhen; Murata, Yoshihiro; Arai, Ken; Lok, Josephine; van Leyen, Klaus; Rosell, Anna; Wang, Xiaoying; Lo, Eng H.] Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA 02129 USA. [Tejima, Emiri; Guo, Shuzhen; Murata, Yoshihiro; Arai, Ken; Lok, Josephine; van Leyen, Klaus; Wang, Xiaoying; Lo, Eng H.] Harvard Univ, Sch Med, Program Neurosci, Charlestown, MA USA. [Lok, Josephine] Harvard Univ, Sch Med, Boston, MA USA. [Lok, Josephine] Massachusetts Gen Hosp, Dept Pediat, Boston, MA 02114 USA. RP Lo, EH (reprint author), Massachusetts Gen Hosp, Neuroprotect Res Lab, Dept Neurol, MGH E 149-2401, Charlestown, MA 02129 USA. EM Lo@helix.mgh.harvard.edu RI van Leyen, Klaus/C-9126-2013 FU NINDS; American Stroke Association FX This research was supported in part by grants from NINDS and a Bugher award from the American Stroke Association. NR 49 TC 52 Z9 55 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0897-7151 J9 J NEUROTRAUM JI J. Neurotrauma PD NOV PY 2009 VL 26 IS 11 BP 1935 EP 1941 DI 10.1089/neu.2009.0959 PG 7 WC Critical Care Medicine; Clinical Neurology; Neurosciences SC General & Internal Medicine; Neurosciences & Neurology GA 523CO UT WOS:000272049600009 PM 19469687 ER PT J AU Abukawa, H Phelps, M Jackson, P Smith, RM Vacanti, JP Kaban, LB Troulis, MJ AF Abukawa, Harutsugi Phelps, Maynard Jackson, Pamela Smith, R. Malcolm Vacanti, Joseph P. Kaban, Leonard B. Troulis, Maria J. TI Effect of Ibuprofen on Osteoblast Differentiation of Porcine Bone Marrow-Derived Progenitor Cells SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; MESENCHYMAL STEM-CELLS; MINERAL DENSITY; OLDER WOMEN; IN-VITRO; SELECTIVITY; RATS; CYCLOOXYGENASE; CONDYLE; ASPIRIN AB Purpose: Nonsteroidal anti-inflammatory drugs are commonly prescribed to reduce inflammation and pain. However, little is known about the direct effect of these drugs on the differentiation of bone marrow-derived progenitor cells into osteoblasts. The purpose of this Study was to determine the effect of ibuprofen on osteoblast differentiation and proliferation in a minipig model Materials and Methods: Bone marrow was aspirated from the minipig ilium,and porcine bone marrow-derived progenitor cells (pBMPCs) were isolated and expanded in standard culture medium The pBMPCs were replated and differentiated into osteoblasts by use of osteogenic supplements (OS). Five groups were studied: negative control-pBMPCs in standard medium only; positive control-pBMPCs, standard culture medium, and OS; and 3 experimental groups-PBMPCs, standard culture medium, OS, and ibuprofen added in doses of 0.1, 10, and 3.0 mmol/L. Cell cultures were evaluated quantitatively by alkaline phosphatase (ALP) stain, von Kossa stain, and deoxyribonucleic acid (DNA) content. Results: pBMPCs cultured with OS and low-dose ibuprofen (0 1 mmol/l.) showed ALP stain, von Kossa stain, and DNA content similar to pBMPCs cultured in OS (positive control) pBMPCs cultured in higher doses of ibuprofen (1.0 and 3.0 mmol/L) produced significantly less positive staining of ALP and von Kossa and decreased DNA content Conclusion: The results indicate that high-dose ibuprofen has a deleterious effect on pBMPC differentiation into osteoblasts whereas low-dose ibuprofen does not. The low dose of 0.1 mmol/L is the typical serum level when prescribed for clinical use (C) 2009 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 67-2412-2417, 2009 C1 [Troulis, Maria J.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Minimally Invas Oral & Maxillofacial Surg Program, Boston, MA 02114 USA. [Troulis, Maria J.] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Residency Program, Boston, MA 02114 USA. [Phelps, Maynard; Kaban, Leonard B.; Troulis, Maria J.] Harvard Univ, Sch Dent Med, Boston, MA 02115 USA. [Abukawa, Harutsugi] Tokyo Med Univ, Dept Oral & Maxillofacial Surg, Tokyo, Japan. [Smith, R. Malcolm] Massachusetts Gen Hosp, Orthoped Trauma Serv, Boston, MA 02114 USA. [Smith, R. Malcolm; Vacanti, Joseph P.] Harvard Univ, Sch Med, Boston, MA USA. [Vacanti, Joseph P.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Vacanti, Joseph P.] Massachusetts Gen Hosp, Tissue Engn & Organ Fabricat Lab, Boston, MA 02114 USA. RP Troulis, MJ (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Minimally Invas Oral & Maxillofacial Surg Program, Warren Bldg 1201,55 Fruit St, Boston, MA 02114 USA. NR 32 TC 12 Z9 13 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 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD NOV PY 2009 VL 67 IS 11 BP 2412 EP 2417 DI 10.1016/j.joms.2009.05.434 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 512JC UT WOS:000271243100014 PM 19837310 ER PT J AU Williams, WB Jiang, YD AF Williams, W. Bradford Jiang, Yandong TI Management of a Difficult Airway With Direct Ventilation Through Nasal Airway Without Facemask SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID GENERAL-ANESTHESIA C1 [Jiang, Yandong] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Williams, W. Bradford] Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. [Jiang, Yandong] Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02115 USA. RP Jiang, YD (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St,Jackson 422, Boston, MA 02114 USA. NR 7 TC 2 Z9 2 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 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD NOV PY 2009 VL 67 IS 11 BP 2541 EP 2543 DI 10.1016/j.joms.2009.04.092 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 512JC UT WOS:000271243100037 PM 19837332 ER PT J AU Glatt, V Kwong, FN Park, K Parry, N Griffin, D Vrahas, M Evans, CH Harris, M AF Glatt, Vaida Kwong, Francois N. Park, Kichul Parry, Nicola Griffin, Damian Vrahas, Mark Evans, Christopher H. Harris, Mitchel TI Ability of Recombinant Human Bone Morphogenetic Protein 2 to Enhance Bone Healing in the Presence of Tobramycin: Evaluation in a Rat Segmental Defect Model SO JOURNAL OF ORTHOPAEDIC TRAUMA LA English DT Article DE tobramycin; BMP-2; Segmental defect; rat model ID OPEN FRACTURES; ANTIBIOTIC-THERAPY; DELIVERY; FEMUR; BEADS; MANAGEMENT; INFECTION; TOXICITY; RHBMP-2 AB Objective: To determine whether locally applied tobramycin influences the ability of recombinant human bone morphogenetic protein 2 (rhBMP-2) to heal a segmental defect in the rat femur. Methods: The influence of tobramycin on the osteogenic differentiation of mesenchymal stein cells was first evaluated in vitro. For the subsequent, in vivo experiments, a 5-mm segmental defect was created in the right femur of each of 25 Sprague-Dawley rats and stabilized with an external fixator and four Kirschner wires. Rats were divided in four groups: empty control, tobramycin (11 mg)/absorbable collagen sponge, rhBMP-2 (11 p,g)/absorbable collagen sponge, and rhBMP-2/absorbable collagen sponge with tobramycin. Bone healing was monitored by radiography at 3 and 8 weeks. Animals were euthanized at 8 weeks and the properties of the defect were compared with the intact contralateral femur. Bone formation in the defect region was assessed by dual-energy x-ray absorptiometry, microcomputed tomography, histology, and mechanical testing. Results: Tobramycin exerted a dose-dependent inhibition of alkaline phosphatase induction and calcium deposition by mesenchymal stein cells cultured under osteogenic conditions. The inhibition was reversed in the presence of 500 ng/mL of rhBMP-2. Segmental defects in the rat femora failed to heal in the absence of rhBMP-2. Tobramycin exerted no inhibitory effects on the ability of rhBMP-2 to heal these defects and increased the bone area of the defects treated with rhBMP-2. Data obtained from all other parameters of healing, including dual-energy x-ray absorptiometry, microcomputed tomography, histology, and mechanical testing, were unaffected by tobramycin. Conclusions: Although our in vitro results suggested that tobramycin inhibits the osteogenic differentiation of mesenchymal stein cells, this could be overcome by rhBMP-2. Tobramycin did not impair the ability of rhBMP-2 to heal critical-sized femoral defects in rats. Indeed, bone area was increased by nearly 20% in the rhBMP-2 group treated with tobramycin. This study shows that locally applied tobramycin can be used in conjunction with rhBMP-2 to enhance bone formation at fracture sites. C1 [Glatt, Vaida] Harvard Univ, Beth Israel Deaconess Med Ctr, Orthopaed Biomech Lab, Sch Med, Boston, MA 02215 USA. [Glatt, Vaida; Kwong, Francois N.; Griffin, Damian] Univ Warwick, Dept Orthopaed Surg, Warwick Med Sch, Coventry CV4 7AL, W Midlands, England. [Kwong, Francois N.; Evans, Christopher H.] Harvard Univ, Sch Med, Ctr Mol Orthoped, Brigham & Womens Hosp, Boston, MA 02215 USA. [Vrahas, Mark; Harris, Mitchel] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Partners Orthoped Trauma Serv, Boston, MA USA. [Parry, Nicola] Tufts Univ, Cummings Sch Vet Med, Sect Pathol, North Grafton, MA USA. RP Evans, CH (reprint author), Harvard Univ, Sch Med, Ctr Mol Orthoped, Brigham & Womens Hosp, BIDMC RN 115,300 Brookline Ave, Boston, MA 02215 USA. EM cevans@bidmc.harvard.edu FU Medtronic FX This work was financially supported by Medtronic. NR 27 TC 12 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-5339 J9 J ORTHOP TRAUMA JI J. Orthop. Trauma PD NOV-DEC PY 2009 VL 23 IS 10 BP 693 EP 701 PG 9 WC Orthopedics; Sport Sciences SC Orthopedics; Sport Sciences GA 513HO UT WOS:000271313500002 PM 19858977 ER PT J AU Heath, JA Clarke, NE McCarthy, M Donath, SM Anderson, VA Wolfe, J AF Heath, John A. Clarke, Naomi E. McCarthy, Maria Donath, Susan M. Anderson, Vicki A. Wolfe, Joanne TI Quality of care at the end of life in children with cancer SO JOURNAL OF PAEDIATRICS AND CHILD HEALTH LA English DT Article DE childhood cancer; palliative care; quality of life ID PEDIATRIC PALLIATIVE CARE; FAMILY PERSPECTIVES; PARENTS; INTEGRATION; PROGNOSIS; IMPACT AB Aim: Current Australian guidelines for the provision of paediatric palliative care highlight the importance of services being focused on the needs of the child and family. We aimed to establish parents' level of satisfaction with the quality of care currently being provided to children dying of cancer. Methods: We interviewed 96 parents of children who died of cancer in Melbourne, Australia between 1996 and 2004 to ascertain how they rated the care provided to their child during the end-of-life period. Results: A majority of parents were satisfied with the care provided by their primary oncologist, local doctors, palliative care services and home-care nurses. Most parents felt that discussions about key medical and treatment decisions were appropriate and clearly understood. Parents were generally satisfied with the leadership roles undertaken in decision-making in the end-of-life period; however, parents who were not satisfied indicated that they would like additional involvement of their primary oncologist. Conclusions: Current approaches to end-of-life care in children with cancer appear to be satisfactory. The main focus should continue to be on open and honest communication. C1 [Heath, John A.; Clarke, Naomi E.; McCarthy, Maria] Univ Melbourne, Royal Childrens Hosp, Childrens Canc Ctr, Melbourne, Vic, Australia. [Heath, John A.; Clarke, Naomi E.; Donath, Susan M.; Anderson, Vicki A.] Univ Melbourne, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Heath, John A.; Clarke, Naomi E.; Donath, Susan M.; Anderson, Vicki A.] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia. [Wolfe, Joanne] Childrens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Wolfe, Joanne] Harvard Univ, Dept Pediat, Cambridge, MA 02138 USA. RP Heath, JA (reprint author), Royal Childrens Hosp, Flemington Rd, Parkville, Vic 3052, Australia. EM john.heath@rch.org.au NR 23 TC 17 Z9 17 U1 0 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1034-4810 J9 J PAEDIATR CHILD H JI J. Paediatr. Child Health PD NOV PY 2009 VL 45 IS 11 BP 656 EP 659 DI 10.1111/j.1440-1754.2009.01590.x PG 4 WC Pediatrics SC Pediatrics GA 513HY UT WOS:000271314500008 PM 19903251 ER PT J AU Tilden, LB Williams, BR Tucker, RO MacLennan, PA Ritchie, CS AF Tilden, Lauren B. Williams, Beverly R. Tucker, Rodney O. MacLennan, Paul A. Ritchie, Christine S. TI Surgeons' Attitudes and Practices in the Utilization of Palliative and Supportive Care Services for Patients with a Sudden Advanced Illness SO JOURNAL OF PALLIATIVE MEDICINE LA English DT Article ID OUTCOMES; UNIT AB Background: There is growing interest in the interface between palliative care and other medical specialties, yet little is known about decision-making processes characterizing such collaborations. At the University of Alabama at Birmingham (UAB), the trauma-burn surgery and neurosurgery services frequently request consults from the palliative care team for patients with a sudden advanced illness from catastrophic injuries or physiologic insult. Objective: We explored surgeons' attitudes and decision-making practices regarding utilization of palliative and supportive care for patients with a sudden advanced illness from traumatic injury or physiologic insult at UAB Hospital, an American College of Surgeons certified level 1 trauma center. Design and Analysis: We conducted face-to-face, open-ended interviews with nine attending trauma-burn surgeons and neurosurgeons at UAB, utilizing a grounded theory approach to discover salient themes in surgeons' accounts of the palliative care consultative process. Surgeons' descriptions of exemplary cases provided the context for elucidating the larger dynamic involved in assessing patients' situations and identifying the need for palliative and supportive care services. Results: We organized the data using decision-making diagrams, identifying multiple pathways within the larger consultative framework. Although case-based responses exhibited variations in surgeons diagnostic or prognostic criteria, patient's location in the illness/injury trajectory, and surgeon's goals/desired outcomes; a general decision-making pathway emerged. Conclusions: Through collaboration with the palliative care service at UAB, trauma-burn surgeons and neurosurgeons are better equipped to manage the multidimensional nature of suffering and provide a holistic approach to care for patients and families dealing with a sudden advanced illness. C1 [Williams, Beverly R.; Ritchie, Christine S.] Birmingham VA Med Ctr, Birmingham Atlanta VA Geriatr Res Educ & Clin Ctr, Birmingham, AL 35233 USA. [Tilden, Lauren B.; Williams, Beverly R.; Tucker, Rodney O.; Ritchie, Christine S.] Univ Alabama, Dept Gerontol Geriatr Palliat Care, Birmingham, AL USA. [Tilden, Lauren B.; Williams, Beverly R.; Tucker, Rodney O.; Ritchie, Christine S.] Univ Alabama, Ctr Palliat Care, Birmingham, AL USA. [MacLennan, Paul A.] Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. RP Williams, BR (reprint author), Birmingham VA Med Ctr, Birmingham Atlanta VA Geriatr Res Educ & Clin Ctr, 700 19th St S, Birmingham, AL 35233 USA. EM beverly.williams3@va.gov NR 13 TC 10 Z9 10 U1 3 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1096-6218 J9 J PALLIAT MED JI J. Palliat. Med. PD NOV PY 2009 VL 12 IS 11 BP 1037 EP 1042 DI 10.1089/jpm.2009.0120 PG 6 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 521IS UT WOS:000271914900011 PM 19663713 ER PT J AU Ayyanar, K Blackman, SC Chordas, C Frazier, L Kieran, MW AF Ayyanar, Kanyalakshmi Blackman, Samuel C. Chordas, Christine Frazier, Lindsay Kieran, Mark W. TI Metachronous Mediastinal Seminoma Occurring After Intracranial Germinoma in an Adolescent SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE germinoma; metachronous; germ cell tumor; brain tumor ID GERM-CELL TUMORS; OF-THE-LITERATURE; KLINEFELTERS-SYNDROME; TESTICULAR SEMINOMA; SYNCHRONOUS LESIONS; SUPRASELLAR REGIONS; RADIATION-THERAPY; PINEAL GERMINOMA; METASTASIS; ORIGIN AB We report a case of a mediastinal seminoma occurring 19 months after the resolution of a pineal germinoma. A 15-yearold boy with headaches and Visual changes was diagnosed with a pineal germinoma by biopsy and mildly elevated beta-human chorionic gonadatropin (beta-HCG) in serum and cerebral spinal fluid. Radiation therapy leads to the resolution of his pineal germinoma and normalization of the beta-HCG. A mediastinal seminoma (germinoma) was diagnosed nearly 2),cars later because of rising serum beta-HCG. There was no evidence of recurrent central nervous system disease. The patient underwent systemic chemotherapy with the complete resolution of the mediastinal seminoma. C1 [Ayyanar, Kanyalakshmi] Univ Louisville, Kosair Childrens Hosp, Div Pediat Hematol Oncol, Louisville, KY 40202 USA. [Blackman, Samuel C.; Chordas, Christine; Frazier, Lindsay; Kieran, Mark W.] Dana Farber Canc Inst, Div Pediat Oncol, Boston, MA 02115 USA. [Blackman, Samuel C.; Chordas, Christine; Frazier, Lindsay; Kieran, Mark W.] Childrens Hosp, Boston, MA 02115 USA. RP Ayyanar, K (reprint author), Univ Louisville, Kosair Childrens Hosp, Div Pediat Hematol Oncol, 571 S Floyd St,Suite 445, Louisville, KY 40202 USA. EM k0ayya01@louisville.edu OI Kieran, Mark/0000-0003-2184-7692 NR 26 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD NOV PY 2009 VL 31 IS 11 BP 861 EP 864 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 519JZ UT WOS:000271763900015 PM 19779380 ER PT J AU Wang, LY Martin, B Brenneman, R Luttrell, LM Maudsley, S AF Wang, Liyun Martin, Bronwen Brenneman, Randall Luttrell, Louis M. Maudsley, Stuart TI Allosteric Modulators of G Protein-Coupled Receptors: Future Therapeutics for Complex Physiological Disorders SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Review ID BETA(2) ADRENERGIC-RECEPTOR; MUSCARINIC ACETYLCHOLINE-RECEPTORS; AGONIST-DIRECTED TRAFFICKING; DELTA-OPIOID RECEPTORS; SIGNAL-TRANSDUCTION; BETA(2)-ADRENERGIC RECEPTOR; DRUG DISCOVERY; IN-VIVO; FUNCTIONAL SELECTIVITY; MOLECULAR-MECHANISM AB G protein-coupled receptors (GPCRs) are one of the most important classes of proteins in the genome, not only because of their tremendous molecular diversity but because they are the targets of nearly 50% of current pharmacotherapeutics. The majority of these drugs affect GPCR activity by binding to a similar molecular site as the endogenous cognate ligand for the receptor. These "orthosterically" targeted drugs currently dominate the existing pharmacopeia. Over the past two decades, novel opportunities for drug discovery have risen from a greater understanding of the complexity of GPCR signaling. A striking example of this is the appreciation that many GPCRs possess functional allosteric binding sites. Allosteric modulator ligands bind receptor domains topographically distinct from the orthosteric site, altering the biological activity of the orthosteric ligand by changing its binding affinity, functional efficacy, or both. This additional receptor signaling complexity can be embraced and exploited for the next generation of GPCR-targeted therapies. Despite the challenges associated with detecting and quantifying the myriad of possible allosteric effects on GPCR activity, allosteric ligands offer the prospect of engendering a facile stimulus-bias in orthosteric ligand signaling, paving the way for not only receptor-selective but also signaling pathway-selective therapies. Allosteric modulators possess specific advantages when considering the treatment of multifactorial syndromes, such as metabolic diseases or age-related cognitive impairment, because they may not greatly affect neurotransmitter or hormone release patterns, thus maintaining the integrity of complex signaling networks that underlie perception, memory patterns, or neuroendocrinological axes while introducing therapeutically beneficial signal bias. C1 [Maudsley, Stuart] NIA, Biomed Res Ctr, Receptor Pharmacol Unit, NIH, Baltimore, MD 21224 USA. [Martin, Bronwen] NIA, Metab Unit, NIH, Baltimore, MD 21224 USA. [Brenneman, Randall] Univ Miami, Miller Sch Med, Canc Biol Program, Miami, FL 33136 USA. [Luttrell, Louis M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. [Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Div Endocrinol, Charleston, SC 29425 USA. RP Maudsley, S (reprint author), NIA, Biomed Res Ctr, Receptor Pharmacol Unit, NIH, Room 5C228,251 Bayview Blvd, Baltimore, MD 21224 USA. EM maudsleyst@mail.nih.gov FU National Institutes of Health National Institute on Aging; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK055524]; Research Service of the Ralph H. Johnson Veterans Affairs Medical Center FX This research was supported in part by the Intramural Research Program of the National Institutes of Health National Institute on Aging; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK055524] (L. M. L.); and the Research Service of the Ralph H. Johnson Veterans Affairs Medical Center (L. M. L.). NR 109 TC 56 Z9 56 U1 0 U2 5 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD NOV PY 2009 VL 331 IS 2 BP 340 EP 348 DI 10.1124/jpet.109.156380 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 509HR UT WOS:000271006200001 PM 19667132 ER PT J AU Zhou, JY Petritis, BO Petritis, K Norbeck, AD Weitz, KK Moore, RJ Camp, DG Kulkarni, RN Smith, RD Qian, WJ AF Zhou, Jian-Ying Petritis, Brianne O. Petritis, Konstantinos Norbeck, Angela D. Weitz, Karl K. Moore, Ronald J. Camp, David G., II Kulkarni, Rohit N. Smith, Richard D. Qian, Wei-Jun TI Mouse-Specific Tandem IgY7-SuperMix Immunoaffinity Separations for Improved LC-MS/MS Coverage of the Plasma Proteome SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE Immunoaffinity separation; LC-MS/MS; Proteomics; Mouse plasma; SuperMix ID MASS-SPECTROMETRY; BREAST-CANCER; PROTEINS; MODEL; CHROMATOGRAPHY; IDENTIFICATIONS; BIOMARKERS; DISCOVERY; DEPLETION; STRATEGY AB We report on a mouse specific SuperMix immunoaffinity separation system for separating low-abundance proteins from high and moderate abundance proteins in mouse plasma. When applied in tandem with a mouse IgY7 column that removes the seven most abundant proteins in plasma, the SuperMix column captures more than 100 additional moderate abundance proteins, thus allowing significant enrichment of low-abundance proteins in the flow-through fraction. A side-by-side comparison of results obtained from 2D-LC-MS/MS analyses of flow-through samples from IgY7 and SuperMix columns revealed a nearly 2-fold improvement in the overall proteome coverage. Detection of low-abundance proteins was also enhanced, as evidenced by a more than 2-fold increase in the coverage of cytokines, growth factors, and other low-abundance proteins. Moreover, the tandem separations are automated, reproducible, and allow effective identification of protein abundance differences from LC-MS/MS analyses. Considering the overall reproducibility and increased sensitivity using the IgY7-SuperMix separation system, we anticipate broad applications of this strategy for biomarker discovery using mouse models. C1 [Zhou, Jian-Ying; Petritis, Brianne O.; Petritis, Konstantinos; Norbeck, Angela D.; Weitz, Karl K.; Moore, Ronald J.; Camp, David G., II; Smith, Richard D.; Qian, Wei-Jun] Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. [Zhou, Jian-Ying; Petritis, Brianne O.; Petritis, Konstantinos; Norbeck, Angela D.; Weitz, Karl K.; Moore, Ronald J.; Camp, David G., II; Smith, Richard D.; Qian, Wei-Jun] Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Div Cell & Mol Biol, Joslin Diabet Ctr,Dept Med, Boston, MA 02215 USA. RP Qian, WJ (reprint author), Pacific NW Natl Lab, Environm Mol Sci Lab, POB 999,MSIN K8-98, Richland, WA 99352 USA. RI Petritis, Konstantinos/F-2156-2010; Zhou, Jian-Ying/B-1336-2011; Qian, Weijun/C-6167-2011; Zhou, Jian-Ying/D-1308-2012; Smith, Richard/J-3664-2012 OI Smith, Richard/0000-0002-2381-2349 FU National Institutes of Health [R01 DK074795, RR018522] FX Portions of this research were supported by National Institutes of Health grants R01 DK074795 and RR018522. Experimental work was performed in the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy (DOE) Office of Biological and Environmental Research national scientific user facility on the Pacific Northwest National Laboratory (PNNL) campus PNNL is multiprogram national laboratory operated by Battelle for the DOE under Contract No DE-AC05-76RLO 1830 NR 29 TC 12 Z9 12 U1 2 U2 7 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 NOV PY 2009 VL 8 IS 11 BP 5387 EP 5395 DI 10.1021/pr900564f PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 586XV UT WOS:000276949600048 PM 19722698 ER PT J AU Boynton, L Bentley, J Strachan, E Barbato, A Raskind, M AF Boynton, Lorin Bentley, Jacob Strachan, Eric Barbato, Anna Raskind, Murray TI Preliminary Findings Concerning the Use of Prazosin for the Treatment of Posttraumatic Nightmares in a Refugee Population SO JOURNAL OF PSYCHIATRIC PRACTICE LA English DT Article DE posttraumatic stress disorder; prazosin; nightmares; refugees; global concern ID STRESS-DISORDER; SLEEP DISTURBANCE; TRAUMA NIGHTMARES; COMBAT VETERANS; PTSD; SYMPTOMS AB Prazosin, a centrally active alpha-1 adrenergic receptor antagonist, has reduced nightmares and sleep disturbances in placebo-controlled studies involving patients with combat and civilian related posttraumatic stress disorder (PTSD). In this retrospective chart review, we analyzed data from 23 refugees diagnosed with chronic PTSD who were treated with prazosin. The recurrent distressing dreams item of the Clinician Administered PTSD Scale (CAPS) was used to quantify nightmare severity. A Clinical Global Impressions-Change (CGI-C) score assessed change in overall PTSD severity exclusive of nightmares. Using a paired-samples t-test, we found that CAPS scores decreased significantly (p < 0.0005) from baseline after 8 weeks of treatment with a stable dose of prazosin. Overall PTSD severity was "markedly improved" in 6 patients, "moderately improved" in 11 patients, and "minimally improved" in 6 patients. These data provide preliminary support for the use of prazosin in targeting reduction of trauma-related nightmares and promoting improvement of global clinical status within an international sample of severely traumatized refugee patients. (Journal of Psychiatric Practice 2009;15:454-459) C1 [Boynton, Lorin] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Bentley, Jacob] Seattle Pacific Univ, Seattle, WA USA. [Barbato, Anna] Univ Hawaii, Hilo, HI 96720 USA. [Raskind, Murray] VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Boynton, L (reprint author), Univ Washington, Harborview Med Ctr, 325 9Th Ave,Box 359896, Seattle, WA 98104 USA. EM loring@u.washington.edu NR 17 TC 15 Z9 15 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1527-4160 J9 J PSYCHIATR PRACT JI J. Psychiatr. Pract. PD NOV PY 2009 VL 15 IS 6 BP 454 EP 459 PG 6 WC Psychiatry SC Psychiatry GA 525GZ UT WOS:000272204400005 PM 19934720 ER PT J AU Riedl, A Maass, J Fliege, H Stengel, A Schmidtmann, M Klapp, BF Monnikes, H AF Riedl, Andrea Maass, Julia Fliege, Herbert Stengel, Andreas Schmidtmann, Marco Klapp, Burghard F. Moennikes, Hubert TI Subjective theories of illness and clinical and psychological outcomes in patients with irritable bowel syndrome SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE IBS; Quality of life; Subjective theories of illness ID QUALITY-OF-LIFE; SYNDROME IBS; SYMPTOMS; IMPACT; REPRESENTATION; ATTRIBUTIONS; PERSONALITY; PERCEPTION; DISORDERS; DISEASES AB Objectives: Patients' ideas about the nature, cause, and treatment of their illnesses are pail of the complex process of coping with illness. To date, limited research on subjective theories of illness in patients with irritable bowel syndrome (IBS) has been performed. The aim of the study was to investigate patients' subjective theories of illness and how these are related to clinical and psychological outcome criteria, in particular IBS symptom severity and quality of life. Methods: Eighty-eight patients with IBS, as defined by Rome III criteria, were administered a battery of questionnaires to collect the following data: sociodemographic variables, subjective theories of illness (Subjektive Krankheitstheorien, Cause Questionnaire), anxiety (Hospital Anxiety and Depression Scale), depression (Beck Depression Inventory), quality of life (SF-12), and IBS symptoms (Questionnaire for Gastrointestinal Symptoms). Results: Almost all patients reported theories of illness reflecting their subjective causal assumptions. The most frequently mentioned causal factors were physical illness, intrapsychic factors, and stress. Patients with mainly somatic attributions had higher IBS symptoms scores (P<.05) and reduced physical quality of life. Intrapsychic attributions were associated with reduced mental quality of life and enhanced physical quality of life (P<.01). All correlations were independent of gender, age, and irritable bowel subgroups. Conclusions: Subjective theories of illness can have significant implications for IBS symptom severity, as well as for physical and mental quality of life. (C) 2009 Elsevier Inc. All rights reserved. C1 [Riedl, Andrea; Fliege, Herbert; Schmidtmann, Marco] Charite, Dept Med, Div Psychosomat Med & Psychotherapy, D-10117 Berlin, Germany. [Riedl, Andrea; Maass, Julia; Schmidtmann, Marco; Klapp, Burghard F.] Charite, Dept Med, Div Hepatol Gastroenterol & Endocrinol, D-10117 Berlin, Germany. [Stengel, Andreas] Univ Calif Los Angeles, David Geffen Sch Med, CURE Digest Dis Res Ctr, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Stengel, Andreas] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Neurobiol Stress, Digest Dis Div,Dept Med,VA Greater Los Angeles He, Los Angeles, CA 90095 USA. [Moennikes, Hubert] Martin Luther Hosp, Dept Med, Berlin, Germany. [Moennikes, Hubert] Martin Luther Hosp, Inst Neurogastroenterol, Berlin, Germany. RP Riedl, A (reprint author), Charite, Dept Med, Div Psychosomat Med & Psychotherapy, Luisenstr 13A, D-10117 Berlin, Germany. EM andrea.riedl@charite.de NR 37 TC 14 Z9 14 U1 3 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD NOV PY 2009 VL 67 IS 5 BP 449 EP 455 DI 10.1016/j.jpsychores.2009.02.001 PG 7 WC Psychiatry SC Psychiatry GA 513TZ UT WOS:000271348000011 PM 19837208 ER PT J AU Mori, S Lu, HM Wolfgang, JA Choi, NC Chen, GTY AF Mori, Shinichiro Lu, Hsiao-Ming Wolfgang, John A. Choi, Noah C. Chen, George T. Y. TI Effects of Interfractional Anatomical Changes on Water-Equivalent Pathlength in Charged-Particle Radiotherapy of Lung Cancer SO JOURNAL OF RADIATION RESEARCH LA English DT Article DE Charged-particle; Four-dimensional; Lung cancer; Lung density; Radiotherapy planning; Beam range variation; Tumor shrinkage ID 4-DIMENSIONAL COMPUTED-TOMOGRAPHY; BEAM RADIOTHERAPY; TUMOR-TRACKING; ORGAN MOTION; IRRADIATION; REGRESSION AB Intrafractional motion and interfractional changes affect the accuracy of the delivered dose in radio- therapy, particularly in charged-particle radiotherapy. Most recent studies are focused oil intrafractional motion (respiratory motion). Here, we report a quantitative Simulation analysis of the effects of interfractional changes oil water-equivalent pathlength (WEL) in charged-particle lung therapy. Serial four-, dimensional (4D) CT scans were performed under free breathing conditions; the time span between the first and second 4DCT scans was five weeks. We quantified WEL changes between the first and second CT scans due to interfractional changes (turner shrinkage and tissue density changes) and compared the particle-beam-stopping point between the serial 4DCT scans with use of the same initial bolus. Both tumor-shrinkage and lung-density changes were observed in a single patient over the course of therapy. The lung density decreased by approximately 0.1 g/cm(3) between the first and second-CT scans, resulting in a 1.5 cm WEL changes. Tumor shrinkage resulted in approximately 3 cm WEL changes. If the same initial bolus and plan were used through the treatment Course. an unexpected significant beam overshoot would occur by interfractional changes due to tumor shrinkage and king density variation. C1 [Mori, Shinichiro; Lu, Hsiao-Ming; Wolfgang, John A.; Choi, Noah C.; Chen, George T. Y.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Cambridge, MA 02138 USA. RP Mori, S (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Cambridge, MA 02138 USA. EM shinshin@nirs.go.jp OI Mori, Shinichiro/0000-0002-0412-4399 NR 19 TC 6 Z9 6 U1 0 U2 2 PU JAPAN RADIATION RESEARCH SOC PI CHIBA PA C/O NAT INST RADIOLOGICAL SCI 9-1 ANAGAWA-4-CHOME INAGE-KU, CHIBA, 263, JAPAN SN 0449-3060 J9 J RADIAT RES JI J. Radiat. Res. PD NOV PY 2009 VL 50 IS 6 BP 513 EP 519 DI 10.1269/jrr.09032 PG 7 WC Biology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Radiology, Nuclear Medicine & Medical Imaging GA 537RO UT WOS:000273131700004 PM 19959880 ER PT J AU Omurtag, KR Styer, AK Session, D Toth, TL AF Omurtag, Kenan R. Styer, Aaron K. Session, Donna Toth, Thomas L. TI Economic Implications of Insurance Coverage for in Vitro Fertilization in the United States A Review SO JOURNAL OF REPRODUCTIVE MEDICINE LA English DT Article; Proceedings Paper CT 63rd Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 13-17, 2007 CL Washington, DC SP Amer Soc Reprod Med DE fertilization, in vitro; health policy; infertility; insurance health; mandated benefits ID ASSISTED-REPRODUCTIVE-TECHNOLOGY; SINGLE-BLASTOCYST TRANSFER; MULTIPLE BIRTHS; OVARIAN STIMULATION; COST-EFFECTIVENESS; INFERTILITY; TRENDS; CARE; PREGNANCY; MEDICINE AB OBJECTIVE: To analyze cost-effectiveness studies in regard to the costs of in vitro fertilization (IVF) and discuss specific economic trends that may affect the future utilization of IVF in the United States. STUDY DESIGN: Health economics. A Pub Med literature review and the Centers for Disease Control's (CDC) Fertility Clinic Success Rate registry served to access cost analyses and trends, respectively. RESULTS: The average cost of an IVF cycle in the U.S. is $9,226. Among policies that provide IVF set-vices, the increase in premium pet, month ranges front $0.67 to $14. CONCLUSION: When IVF is provided as a health benefit, the cost increases can be variable. As utilization increases, contemporary cost analyses and outcomes research will aid providers, third-party payers and policymakers in better understanding the economic impact of IVF. (J Reprod Med 2009;54:661-668) C1 [Omurtag, Kenan R.] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA 30303 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Vincent Obstet & Gynecol Serv, Boston, MA USA. RP Omurtag, KR (reprint author), Emory Univ, Sch Med, Dept Gynecol & Obstet, Glenn Bldg,4th Floor,69 Jesse Hill Dr, Atlanta, GA 30303 USA. EM komurta@emory.edu NR 42 TC 6 Z9 6 U1 1 U2 7 PU J REPROD MED INC PI ST LOUIS PA 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0024-7758 J9 J REPROD MED JI J. Reprod. Med. PD NOV-DEC PY 2009 VL 54 IS 11-12 BP 661 EP 668 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 540CR UT WOS:000273308900001 PM 20120898 ER PT J AU Campbell, R Cooper, GS Gilkeson, GS AF Campbell, Robert, Jr. Cooper, Glinda S. Gilkeson, Gary S. TI The Impact of Systemic Lupus Erythematosus on Employment SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE JOB LOSS; LOST WAGES; SYSTEMIC LUPUS ERYTHEMATOSUS; CAROLINA LUPUS STUDY; ARTHRITIS; PLEURITIS ID RHEUMATOID-ARTHRITIS PATIENTS; SOUTHEASTERN UNITED-STATES; WORK DISABILITY; REVISED CRITERIA; RISK-FACTORS; CLASSIFICATION; POPULATION; COSTS; RACE AB Objective. Our primary objective was to examine work status (e.g., job loss, changes in amount worked) and predictors of job loss in patients with systemic lupus erythematosus (SLE). Methods. Recently diagnosed SLE patients were enrolled in the Carolina Lupus Study between 1997 and 1999: ail age-, sex-, and state-matched control group selected through driver's license registries for the 60-county study area was also enrolled. In 2001, a followup study of both groups was conducted (median 4 yrs since diagnosis). Work history data were obtained in ail in-person interview at enrollment and a telephone interview at followup. Results. Fifty-one patients (26%) and 26 controls (9%) (p < 0.0001) who were working the year before diagnosis (or for controls, it corresponding reference year) were no longer working at followup; 92% of patients compared with 40% of controls who were no longer working indicated that they had stopped working because of their health (p < 0.0001). College graduates were less likely to quit their jobs due to health compared to non-college graduates (adjusted OR = 0.27, 95% CI 0.09, 0.84). SLE patients with arthritis were 3 times more likely to have left their jobs due to health reasons compared to those who didn't have arthritis (adjusted OR = 3.3. 95% CI 1.2, 8.8); ail association was also seen with pleuritis (adjusted OR 2.3, 95% CI 1.1, 4.6). Conclusion. The burden expressed as work cessation due to health, especially among lesser educated patients and those with arthritis or pleuritis, is significant even early in the disease process. (First Release Oct 1 2009; J Rheumatol 2009;36:2470-5, doi: 10.3899/jrheum.080586) C1 [Campbell, Robert, Jr.] Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, Charleston, SC 29425 USA. NIEHS, NIH, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Cooper, Glinda S.] US EPA, Washington, DC 20460 USA. [Gilkeson, Gary S.] Ralph H Johnson Vet Adm Med Ctr, Charleston, SC USA. RP Campbell, R (reprint author), Med Univ S Carolina, Dept Med, Div Rheumatol & Immunol, 96 Jonathan Lucas St,Suite 912, Charleston, SC 29425 USA. EM campber@musc.edu FU Intramural NIH HHS; NIAMS NIH HHS [2R01-AR045476, 1T32-AR050958, P60-AR049459] NR 28 TC 12 Z9 12 U1 0 U2 0 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD NOV PY 2009 VL 36 IS 11 BP 2470 EP 2475 DI 10.3899/jrheum.080586 PG 6 WC Rheumatology SC Rheumatology GA 517DP UT WOS:000271593700016 PM 19273454 ER PT J AU La Fountaine, MF Radulovic, M Cardozo, CP Spungen, AM DeMeersman, RE Bauman, WA AF La Fountaine, Michael F. Radulovic, Miroslav Cardozo, Christopher P. Spungen, Ann M. DeMeersman, Ronald E. Bauman, William A. TI Effects of Acute Nitric Oxide Synthase Inhibition on Lower Leg Vascular Function in Chronic Tetraplegia SO JOURNAL OF SPINAL CORD MEDICINE LA English DT Article DE Spinal cord injuries; L-NAME; Nitric oxide synthase; Tetraplegia; Vascular resistance; Vasoregulation ID SPINAL-CORD-INJURY; BLOOD-PRESSURE; L-NAME; PLASMA-CATECHOLAMINES; SKELETAL-MUSCLE; NERVOUS-SYSTEM; RESPONSES; HUMANS; TONE; PLETHYSMOGRAPHY AB Background/Objective: To improve our understanding of the lower-leg vascular responses of nitric oxide synthase inhibition in persons with tetraplegia. Participants: Six people with chronic tetraplegia and 6 age-matched controls. Methods: Lower-leg relative vascular resistance and venous volume variation were obtained by venous occlusion plethysmography and blood pressure by auscultation at baseline. Postintravenous infusion of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine-methyl-ester (1 mg.kg(-1)) or placebo on separate days. Results: At baseline in the group with tetraplegia compared with controls, mean arterial pressure and relative vascular resistance of the leg were significantly lower. After nitric oxide synthase inhibition, mean arterial pressure and lower leg vascular resistance were significantly elevated in both groups. There were no group or intervention differences in venous volume variation. Conclusion: These preliminary results suggest that nitric oxide synthase inhibition with I mg.kg-1 N(G)-nitro-L-arginine-methyl-ester normalizes seated blood pressure and lower leg vascular resistance to control group baseline levels. C1 [La Fountaine, Michael F.; Radulovic, Miroslav; Cardozo, Christopher P.; Spungen, Ann M.; Bauman, William A.] James J Peters VA Med Ctr, VA Ctr Excellence Med Consequences Spinal Cord In, Bronx, NY 10468 USA. [DeMeersman, Ronald E.] Columbia Univ, Teachers Coll, Dept Biobehav Sci, New York, NY 10027 USA. RP La Fountaine, MF (reprint author), James J Peters VA Med Ctr, VA Ctr Excellence Med Consequences Spinal Cord In, SCI Room 1E-02,130 W Kingsbridge Rd, Bronx, NY 10468 USA. EM michael.lafountaineg@gmail.com FU Veterans Affairs Rehabilitation Research and Development Service [B4335V, 3755, B4162C]; James J. Peters VA Medical Center; VIDDA Foundation FX This research was supported by the Veterans Affairs Rehabilitation Research and Development Service (#B4335V, ARCD #3755 and #B4162C), James J. Peters VA Medical Center, and VIDDA Foundation. NR 44 TC 2 Z9 2 U1 0 U2 0 PU AMER PARAPLEGIA SOC PI JACKSON HWIGHTS PA 75-20 ASTORIA BLVD, JACKSON HWIGHTS, NY 11370-1177 USA SN 1079-0268 J9 J SPINAL CORD MED JI J. Spinal Cord. Med. PD NOV PY 2009 VL 32 IS 5 BP 538 EP 544 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 534JX UT WOS:000272893500004 PM 20025149 ER PT J AU Liu, M Gu, M Wu, YC Zhu, PC Zhang, W Yin, CJ Zhang, WJ AF Liu, Min Gu, Min Wu, Yichao Zhu, Pengcheng Zhang, Wei Yin, Changjun Zhang, Wei (J) TI Therapeutic Effect of Y-27632 on Chronic Allograft Nephropathy in Rats SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE kidney transplantation; chronic allograft nephropathy; Rho-kinase; Y-27632, fibrosis AB Background. Chronic allograft nephropathy (CAN) is a major cause of late allograft loss. Recent evidences suggest that Rho and its downstream effector ROCK may be greatly involved in the progression of renal fibrosis. Inhibition of Rho/ROCK pathway might interact with the inflammatory process in the renal interstitium, and antagonize the process of epithelial-to-mesenchymal transition (EMT). We hypothesized that Y-27632 could inhibit the chronic inflammatory process and prevent the progression of CAN. Materials and Methods. Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. Lewis to Lewis rat kidney transplantation was served as the syngeneic control (Syn group). Allograft recipients were randomized and treated with either cyclosporine A alone (Allo group), or in combination with Y-27632 (30 mg/kg body weight/d intragastric, Y-27632 group). Renal function and urine protein excretion levels of the rats were analyzed. Animals were sacrificed 12 wk post-transplantation for histological and immunohistochemical studies, as well as analysis of the expression levels of chemokines, transforming growth factor (TGF-beta) 1 and alpha smooth muscle actin (alpha-SMA). Results. Renal function deteriorated progressively in the Allo group, and there was typical CAN morphology in the kidneys. However, Y-27632-treatment significantly prevented the deterioration of graft function, lessened the level of urine protein excretion, and preserved the renal structure. Attenuation of ED1 positive mononuclear cell infiltration and amelioration of tubulointerstitial fibrosis were achieved by Y-27632 intervention. This was associated with down-regulation of the expression of tubular monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and phosphorylated NF-kappa B (which was a marker for activation). Profibrotic protein (TGF-beta 1) and alpha-SMA, a marker of EMT, were significantly down-regulated by Y-27632 treatment as well. Conclusions. The Rho/ROCK pathway plays an important role in the progression of CAN, and specific inhibition of Rho activity by Y-27632 showed favorable effects on blocking renal interstitial inflammation and fibrosis, thus efficiently retarding the development of CAN, which might provide us with a novel strategy to improve long-term renal graft survival. (C) 2009 Elsevier Inc. All rights reserved. C1 [Liu, Min; Gu, Min; Zhang, Wei; Yin, Changjun; Zhang, Wei (J)] Nanjing Med Univ, Affiliated Hosp 1, Div Urol & Kidney Transplantat, Nanjing 210029, Jiangsu, Peoples R China. [Wu, Yichao; Zhu, Pengcheng] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA USA. RP Zhang, WJ (reprint author), Nanjing Med Univ, Affiliated Hosp 1, Div Urol & Kidney Transplantat, Nanjing 210029, Jiangsu, Peoples R China. EM Kidneyliu@163.com OI Liu, Min/0000-0002-8117-4808 NR 33 TC 11 Z9 13 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 0022-4804 J9 J SURG RES JI J. Surg. Res. PD NOV PY 2009 VL 157 IS 1 BP E117 EP E127 DI 10.1016/j.jss.2008.10.018 PG 11 WC Surgery SC Surgery GA V17NW UT WOS:000207944900015 PM 19589538 ER PT J AU Favero, M AF Favero, Marcus TI Child and Adolescent Neurology for Psychiatrists SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Book Review C1 [Favero, Marcus] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Favero, M (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM mfavero@partners.org NR 1 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD NOV PY 2009 VL 48 IS 11 BP 1130 EP 1132 DI 10.1097/01.CHI.0000359012.71922.50 PG 3 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 510DL UT WOS:000271068100022 ER PT J AU Clark, D AF Clark, Deborah TI Handbook of Depression in Adolescents SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Book Review C1 [Clark, Deborah] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Clark, D (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. EM DAClark@partners.org NR 1 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD NOV PY 2009 VL 48 IS 11 BP 1132 EP 1133 DI 10.1097/01.CHI.0000359013.66084.16 PG 2 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 510DL UT WOS:000271068100023 ER PT J AU Merkow, RP Bilimoria, KY Cohen, ME Richards, K Ko, CY Hall, BL AF Merkow, Ryan P. Bilimoria, Karl Y. Cohen, Mark E. Richards, Karen Ko, Clifford Y. Hall, Bruce L. TI Variability in Reoperation Rates at 182 Hospitals: A Potential Target for Quality Improvement SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Article ID OPERATING-ROOM; UNPLANNED RETURN; SURGICAL CARE; SURGERY; OUTCOMES; RISK; INDICATOR; PROGRAM; FUTURE; NSQIP AB BACKGROUND: Reoperation rate has gained increasing attention as a potential indicator of surgical quality. Objectives of this study were to examine the feasibility of assessing reoperation rates at 182 hospitals to identify institutions with Outlying performance, to examine potentially modifiable factors that are associated with reoperations, and to determine if a more parsimonious logistic regression model effectively predicts reoperations. STUDY DESIGN: Patients were identified who underwent colorectal procedures at 182 hospitals participating in the American College of Surgeon's National Surgical Quality Improvement Program in 2006-2007. Risk-adjusted regression models for reoperation were developed to identify hospitals that had ratios of observed-to-expected events that were substantial outliers. RESULTS: Of 23,098 patients identified, 1,320 (5.7%) required reoperations. Reoperation occurred significantly more often than expected in 16 hospitals and less often than expected in 7 hospitals (P 0.05). Factors that were associated with all increased risk of reoperation were advanced American Society of Anesthesiologists class, male gender, contaminated wounds, surgical extent, Surgical indication, smoking, poor functional status, disseminated cancer, COPD, steroid dependence, anemia, body mass index (calculated as kg/m(2)) >35 or <= 18.5, and hypertension. Compared with the full logistic regression model, there was a high degree of correlation with the more parsimonious logistic model containing only the first six variables (r = 0.996). CONCLUSIONS: There is considerable variability in reoperation rates at American College of Surgeon's National Surgical Quality Improvement Program hospitals. American College of Surgeon's National Surgical Quality Improvement Program data call be used to provide individual hospitals with risk-adjusted self-assessment data on reoperations to potentially identify quality-improvement opportunities. (J Am Coll Surg 2009;209:557-564. (C) 2009 by the American College of Surgeons) C1 [Bilimoria, Karl Y.; Cohen, Mark E.; Richards, Karen; Ko, Clifford Y.] Amer Coll Surg, Div Res & Optimal Patient Care, Chicago, IL 60611 USA. [Merkow, Ryan P.] Univ Colorado, Denver Sch Med, Dept Surg, Aurora, CO USA. [Bilimoria, Karl Y.] Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. [Ko, Clifford Y.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. [Ko, Clifford Y.] Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Hall, Bruce L.] Washington Univ, Sch Med, Dept Surg, John Cochran St Louis Vet Affairs Med Ctr,Ctr Hlt, St Louis, MO 63110 USA. [Hall, Bruce L.] Washington Univ, John M Olin Sch Business, St Louis, MO 63130 USA. RP Bilimoria, KY (reprint author), Amer Coll Surg, Div Res & Optimal Patient Care, 633 N St Clair St,22nd Fl, Chicago, IL 60611 USA. EM kbilimoria@facs.org NR 26 TC 28 Z9 29 U1 1 U2 1 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 NOV PY 2009 VL 209 IS 5 BP 557 EP 564 DI 10.1016/j.jamcollsurg.2009.07.003 PG 8 WC Surgery SC Surgery GA 520VB UT WOS:000271876400002 PM 19854394 ER PT J AU Itani, KMF Fitzgibbons, R Awad, SS Duh, QY Ferzli, GS AF Itani, Kamal M. F. Fitzgibbons, Robert, Jr. Awad, Samir S. Duh, Quan-Yang Ferzli, George S. TI Management of Recurrent Inguinal Hernias SO JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS LA English DT Review ID LAPAROSCOPIC TRANSABDOMINAL PREPERITONEAL; PROSPECTIVE RANDOMIZED-TRIAL; MESH PLUG MIGRATION; GROIN HERNIA; FEMORAL HERNIA; CLINICAL-TRIAL; REPAIR; HERNIORRHAPHY; REOPERATION; EXPERIENCE AB The ultimate measure of success of inguinal hernia repair is the rate of recurrence. Although other procedure-related complications are important and have been shown to affect health-related quality-of-life parameters,(1) recurrence is more challenging for the patients and the surgeon. From the patients' perspective, the initial physical and mental investment in the operation has failed. A new investment has to be made, with fewer guarantees for success, more risks for more serious complications, and more time off from work. For the surgeon, repair of a recurrent inguinal hernia is technically more demanding because scar tissue causes the inguinal canal to be obscured and distorted. In addition, the tissue tends to be weaker than at the time of primary repair, resulting in a substantially higher risk for complications or development: of another recurrence. Although much has been published about primary repair of inguinal hernias, less is known about the best approach to address a recurrent hernia. In this review, we address the "pros and cons" of popular surgical approaches and watchful waiting for recurrent inguinal hernias and indications for each. In the absence of best evidence in this field, the authors present an opinion based on their experience and a review of the available literature primarily extracted from large trials and large cohorts for inguinal hernia repair in general. C1 [Itani, Kamal M. F.] Boston Vet Affairs Hlth Care Syst, Dept Surg, Boston, MA USA. [Itani, Kamal M. F.] Boston Univ, Boston, MA 02215 USA. [Fitzgibbons, Robert, Jr.] Creighton Univ, Dept Surg, Omaha, NE 68178 USA. [Awad, Samir S.] Michael E DeBakey Vet Affairs Med Ctr, Dept Surg, Houston, TX USA. [Awad, Samir S.] Baylor Coll Med, Houston, TX 77030 USA. [Duh, Quan-Yang] San Francisco VA Med Ctr, Dept Surg, San Francisco, CA USA. [Duh, Quan-Yang] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ferzli, George S.] SUNY Hlth Sci Ctr, Dept Surg, Brooklyn, NY 11203 USA. [Ferzli, George S.] Lutheran Med Ctr, Brooklyn, NY USA. RP Itani, KMF (reprint author), Boston Vet Affairs Hlth Care Syst 112A, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM kitani@va.gov OI Ferzli, George/0000-0003-0095-6216 FU Lifecell Corporation FX Dr Irani received research support from Lifecell Corporation. Dr Fitzgibbons is a consultant and receives research support from Lifecell Corporation and royalties from Cook Surgical for the Fitzgibbons-Jenkins Multi Purpose Common Bile Duct Catheter. Dr Duh is on the clinical advisory board of Covidien. Dr Awad is a speaker and ad hoc consultant and has received research support from Lifecell Corporation. Dr Ferzli has nothing to disclose. NR 49 TC 12 Z9 18 U1 0 U2 2 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 NOV PY 2009 VL 209 IS 5 BP 653 EP 658 DI 10.1016/j.jamcollsurg.2009.07.015 PG 6 WC Surgery SC Surgery GA 520VB UT WOS:000271876400016 PM 19854408 ER PT J AU Wang, LY Larson, EB Sonnen, JA Shofer, JB McCormick, W Bowen, JD Montine, TJ Li, G AF Wang, Lucy Y. Larson, Eric B. Sonnen, Joshua A. Shofer, Jane B. McCormick, Wayne Bowen, James D. Montine, Thomas J. Li, Ge TI Blood Pressure and Brain Injury in Older Adults: Findings from a Community-Based Autopsy Study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE dementia; blood pressure; hypertension; neuropathology; autopsy ID ALZHEIMERS-DISEASE; RISK-FACTORS; NEUROFIBRILLARY TANGLES; CARDIOVASCULAR HEALTH; ATHEROSCLEROSIS RISK; CEREBRAL INFARCTION; PROSPECTIVE COHORT; DEMENTIA; POPULATION; PATHOLOGY AB OBJECTIVES To examine correlations between blood pressure (BP) and dementia-related pathological brain changes in a community-based autopsy sample. DESIGN Prospective cohort study. SETTING A large health maintenance organization in Seattle, Washington. PARTICIPANTS A cohort of 250 participants aged 65 and older and cognitively normal at time of enrollment in the Adult Changes in Thought (ACT) Study and who underwent autopsy. MEASUREMENTS BP and history of antihypertensive treatment were taken at enrollment. A linear regression model was used to examine the relationship between BP (systolic (SBP) and diastolic (DBP)) at enrollment and pathological changes in the cerebrum (cystic macroscopic infarcts, microinfarcts, neuritic plaques, neurofibrillary tangles, and cortical Lewy bodies). RESULTS The presence of more than 2 microinfarcts, but not any other pathological change, was independently associated with SBP in younger participants (65-80, n=137) but not in older participants (> 80, n=91). The relative risk (RR) for more than two microinfarcts with each 10-mmHg increase in SBP was 1.15 (95% confidence interval (CI)=1.00-1.33) in the younger participants, adjusted for age at entry, sex, and time to death. This RR was particularly strong in younger participants not taking antihypertensive medications (RR=1.48, 95% CI=1.21, 1.81); significant associations were not observed in participants treated for hypertension. Findings for DBP were negative. CONCLUSION The association between high SBP and cerebrovascular damage in untreated older adults (65-80) suggests that adequate hypertension treatment may reduce dementia risk by minimizing microvascular injury to cerebrum. C1 [Wang, Lucy Y.; Li, Ge] Vet Affairs Puget Sound Healthcare Syst, Mental Illness Res & Educ Clin Ctr, Seattle, WA USA. [Wang, Lucy Y.; Shofer, Jane B.; Li, Ge] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Larson, Eric B.; McCormick, Wayne] Univ Washington, Dept Med, Seattle, WA USA. [Sonnen, Joshua A.; Montine, Thomas J.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Bowen, James D.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Larson, Eric B.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. RP Wang, LY (reprint author), 1660 S Columbian Way,S-116-6E, Seattle, WA 98108 USA. EM wanglucy@u.washington.edu RI Sonnen, 37382016/H-3738-2016 OI Sonnen, 37382016/0000-0001-9267-8705 FU National Institute on Aging [AG020020, AG006781, AG023801, AG005136]; Nancy and Buster Alvord Endowment; Department of Veterans Affairs Mental Illness Research, Education, and Clinical Center Special Fellowship in Advanced Psychiatry FX We thank all of the faculty and staff who worked on this study and made this article possible. Specifically, we gratefully acknowledge Mary Lou Thompson, PhD, for providing statistical consultation. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. This material is the result of work supported by resources from the Veterans Affairs Puget Sound Health Care System, Seattle, Washington. This work was supported by Grants AG020020, AG006781, AG023801, and AG005136 from the National Institute on Aging, the Nancy and Buster Alvord Endowment, and the Department of Veterans Affairs Mental Illness Research, Education, and Clinical Center Special Fellowship in Advanced Psychiatry. Author Contributions: Study concept and design: LY Wang, JA Sonnen, TJ Montine, G Li, EB Larson, acquisition of study participants and data: JD Bowen, W McCormick, EB Larson, JA Sonnen, TJ Montine, analysis and interpretation of data: JB Shofer, preparation of manuscript: LY Wang, JA Sonnen, TJ Montine, G Li, and critical review of the manuscript: LY Wang, EB Larson, JA Sonnen, JB Shofer, W McCormick, JD Bowen, TJ Montine, G Li. Sponsor's Role: The funding sources had no role in the design, methodology, data analysis, or preparation of this manuscript. NR 46 TC 27 Z9 29 U1 1 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD NOV PY 2009 VL 57 IS 11 BP 1975 EP 1981 DI 10.1111/j.1532-5415.2009.02493.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 512KU UT WOS:000271248500001 PM 19793158 ER PT J AU Hernandez, RK Farwell, W Cantor, MD Lawler, EV AF Hernandez, Rohini K. Farwell, Wildon Cantor, Michael D. Lawler, Elizabeth V. TI Cholinesterase Inhibitors and Incidence of Bradycardia in Patients with Dementia in the Veterans Affairs New England Healthcare System SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE cholinesterase inhibitors; bradycardia; dementia; Alzheimer's disease ID ALZHEIMERS-DISEASE; HEART-RATE; DONEPEZIL; SAFETY; SYNCOPE; TOLERABILITY; HYPERTENSION AB OBJECTIVES To quantify the association between cholinesterase inhibitors (ChE-Is) and a new diagnosis of bradycardia and to evaluate the clinical significance of bradycardia. DESIGN Cox proportional hazards with time-dependent exposures were used to evaluate the association and examine the dose effect for donepezil and bradycardia. SETTING New England Veterans Affairs Healthcare System. PARTICIPANTS Patients with dementia who received care between January 1999 and June 2007 (N=11,328). MEASUREMENTS Bradycardia was defined using three methods using a combination of International Classification of Diseases, Ninth Revision, codes and recorded heart rates of less than 60 beats per minute. RESULTS A greater risk for bradycardia was found in patients taking any ChE-Is than in the no-treatment group (adjusted hazard ratio (HR)=1.4, 95% confidence interval (CI)=1.1-1.6). A dose-response effect was observed for donepezil, with the highest-dose group at greatest risk (HR=2.1, 95% CI=1.5-2.9). Results were consistent regardless of bradycardia definition. Patients with bradycardia were more likely to fall, experience syncope, or need a pacemaker implantation than those without. CONCLUSION Using a large cohort, a modestly greater risk of bradycardia was found in patients with dementia taking ChE-Is than in those not taking these drugs. In patients taking donepezil, the risk of bradycardia may increase with increasing doses. Because of the potential clinical consequences, monitoring for bradycardia may be warranted in patients with dementia treated with ChE-Is. C1 [Hernandez, Rohini K.; Farwell, Wildon; Lawler, Elizabeth V.] VA Boston Healthcare Syst, MAVERIC, Cooperat Studies Program, Boston, MA 02130 USA. [Hernandez, Rohini K.; Lawler, Elizabeth V.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Farwell, Wildon; Lawler, Elizabeth V.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Aging, Boston, MA 02115 USA. [Cantor, Michael D.] Tufts Univ, Sch Med, Tufts Med Ctr, Dept Med, Boston, MA 02111 USA. RP Lawler, EV (reprint author), VA Boston Healthcare Syst, MAVERIC, Cooperat Studies Program, 150 S Huntington Ave,151 MAV, Boston, MA 02130 USA. EM Elizabeth.Lawler@va.gov FU VA Healthcare System Boston; VA Cooperative Studies Program FX This study was conducted using the facilities and resources of the VA Healthcare System Boston and the VA Cooperative Studies Program. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: All authors made substantial contributions to conception and design, acquisition of data, analysis and interpretation of data, and preparation of the manuscript. Sponsor's Role: Not applicable. NR 21 TC 42 Z9 44 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD NOV PY 2009 VL 57 IS 11 BP 1997 EP 2003 DI 10.1111/j.1532-5415.2009.02488.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 512KU UT WOS:000271248500004 PM 19793162 ER PT J AU Min, L Yoon, W Mariano, J Wenger, NS Elliott, MN Kamberg, C Saliba, D AF Min, Lillian Yoon, William Mariano, Jeff Wenger, Neil S. Elliott, Marc N. Kamberg, Caren Saliba, Debra TI The Vulnerable Elders-13 Survey Predicts 5-Year Functional Decline and Mortality Outcomes in Older Ambulatory Care Patients SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE vulnerable elder; functional decline; survival ID QUALITY INDICATORS; ELDERLY-PATIENTS; PEOPLE; DISABILITY; COMMUNITY; CANCER; INTERVENTION; DEMENTIA; DEATH; LIFE AB OBJECTIVES To test the predictive properties of the Vulnerable Elders-13 Survey (VES-13) a short tool that predicts functional decline and mortality over a 1- to 2-year follow-up interval over a 5-year interval. DESIGN Longitudinal evaluation with mean follow-up of 4.5 years. SETTING Two managed-care organizations. PARTICIPANTS Six hundred forty-nine community-dwelling older adults (>= 75) enrolled in the Assessing Care of Vulnerable Elders observational study who screened positive for symptoms of falls or fear of falling, bothersome urinary incontinence, or memory problems. MEASUREMENTS VES-13 score (range 1-10, higher score indicates worse prognosis), functional decline (decline in count of 5 activities of daily living or nursing home entry), and deaths. RESULTS Higher VES-13 scores were associated with greater predicted probability of death and decline in older patients over a mean observation period of 4.5 years. For each additional VES-13 point, the odds of the combined outcome of functional decline or death was 1.37 (95% confidence interval (CI)=1.25-1.50), and the area under the receiver operating curve was 0.75 (95% CI=0.71-0.80). In the Cox proportional hazards model predicting time to death, the hazard ratio was 1.23 (95% CI=1.19-1.27) per additional VES-13 point. CONCLUSION This study extends the utility of the VES-13 to clinical decisions that require longer-term prognostic estimates of functional status and survival. C1 [Min, Lillian; Mariano, Jeff; Saliba, Debra] Univ Calif Los Angeles, Div Geriatr, Los Angeles, CA USA. [Wenger, Neil S.] Univ Calif Los Angeles, Div Gen Internal Med & Hlth Serv Res, Los Angeles, CA USA. [Yoon, William] Virginia Commonwealth Univ, Sch Med, Richmond, VA 23284 USA. [Wenger, Neil S.; Elliott, Marc N.; Kamberg, Caren; Saliba, Debra] RAND Corp, Santa Monica, CA USA. [Saliba, Debra] Vet Affairs Greater Los Angeles Healthcare Syst, Geriatr Res Educ & Clin Care Ctr, Los Angeles, CA USA. [Saliba, Debra] Univ Calif Los Angeles, Jewish Homes Borun Ctr Gerontol Res, Los Angeles, CA USA. RP Min, L (reprint author), 10945 Le Conte Ave,Suite 2339,Box 951687, Los Angeles, CA 90095 USA. EM lmin@mednet.ucla.edu FU Agency for Healthcare Research and Quality [R21 HS017621-01]; National Institute on Aging (NIA)-UCLA [K12 AG001004]; Donald W. Reynolds Foundation; University of California at Los Angeles (UCLA) Older Americans Independence Center (Pepper Center) FX Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Dr. Min is supported by grants from the Agency for Healthcare Research and Quality (R21 HS017621-01) and National Institute on Aging (NIA)-UCLA (K12 AG001004). Mr. Yoon was a NIA/American Federation for Aging Research and Lillian R. Gleitsman Medical Student Training in Aging Research Program Scholar in 2008. Dr. Mariano was supported by a Faculty Development to Advance Geriatric Education award from the Donald W. Reynolds Foundation. This project also received support from the University of California at Los Angeles (UCLA) Older Americans Independence Center (Pepper Center). This paper was presented as an abstract at the 2009 American Geriatrics Society Scientific Meeting. Author Contributions: Lillian Min, Neil S. Wenger, and Debra Saliba: concept and design, acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript. William Yoon: acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript. Jeff Mariano: concept and design, acquisition of subjects and data, and preparation of manuscript. Marc Elliot: concept and design, analysis and interpretation of data, and preparation of manuscript. Caren Kamberg: concept and design, acquisition of subjects and data. Sponsor's Role: Pfizer Inc. supported the recruitment of the original ACOVE-2 cohort but had no role in obtaining outcomes data, data analysis, or preparation of this manuscript. The UCLA Older Americans Independence Center (Pepper Center) provided support for statistical analysis. NR 22 TC 51 Z9 53 U1 1 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD NOV PY 2009 VL 57 IS 11 BP 2070 EP 2076 DI 10.1111/j.1532-5415.2009.02497.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 512KU UT WOS:000271248500013 PM 19793154 ER PT J AU Kirk, JB Goetz, MB AF Kirk, Jason B. Goetz, Matthew Bidwell TI Human Immunodeficiency Virus in an Aging Population, a Complication of Success SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE human immunodeficiency virus; acquired immunodeficiency syndrome; antiretroviral therapy; immune activation ID HIV-INFECTED PATIENTS; ACTIVE ANTIRETROVIRAL THERAPY; REVERSE-TRANSCRIPTASE INHIBITORS; MULTICENTER AIDS COHORT; HEALTH-CARE SETTINGS; D-A-D; MYOCARDIAL-INFARCTION; MEDICINE ASSOCIATION; LIFE EXPECTANCY; PATIENTS OLDER AB The proportion of human immunodeficiency virus (HIV)-infected patients aged 50 and older has greatly increased since the beginning of the epidemic, particularly since 1996, when combination antiretroviral therapy became available. By 2015, 50% of HIV-infected individuals in the United States are likely to be aged 50 and older. The rate of progression of untreated HIV disease, response to therapy, and complicating effects of comorbidities differ in older and younger patients. Older untreated patients with HIV demonstrate faster rates of CD4+ cell loss and more rapid progression to acquired immunodeficiency syndrome (AIDS) and death than younger individuals. Synergistic deleterious effects of chronic immune activation on the course of HIV infection with the immune senescence of aging may promote this accelerated course. Despite the increasing prevalence in older patients and cost-effectiveness analyses that favor HIV testing, older patients are less likely to be routinely evaluated for HIV infection. Consequently, when diagnosed, older patients have more-advanced disease than do younger patients and, upon presentation with AIDS-defining conditions, are less likely to receive timely appropriate therapy. The treatment of older HIV-infected patients is complicated by preexisting comorbid conditions, including cardiovascular, hepatic, and metabolic complications, which in turn may be exacerbated by the effects of HIV infection per se, modest immunodeficiency (i.e., at CD4+ counts > 350 cells/mu L), and the metabolic and other adverse effects of combination antiretroviral therapy. Nevertheless, older patients derive substantial benefit from combination antiretroviral therapy despite having less of an immunological response than expected given their adherence to therapy and excellent virological responses. C1 VA Greater Los Angeles Healthcare Syst, Infect Dis Sect, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 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 69 TC 85 Z9 86 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD NOV PY 2009 VL 57 IS 11 BP 2129 EP 2138 DI 10.1111/j.1532-5415.2009.02494.x PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 512KU UT WOS:000271248500022 PM 19793157 ER PT J AU Braddy, KK Imam, SN Palla, KR Lee, TA AF Braddy, Kathryn K. Imam, Syed N. Palla, Kavita R. Lee, Todd A. TI Vitamin D Deficiency/Insufficiency Practice Patterns in a Veterans Health Administration Long-Term Care Population: A Retrospective Analysis SO JOURNAL OF THE AMERICAN MEDICAL DIRECTORS ASSOCIATION LA English DT Article DE Vitamin D; long-term care; vitamin D insufficiency; vitamin D deficiency ID D DEFICIENCY; SECONDARY HYPERPARATHYROIDISM; D INADEQUACY; PREVALENCE; METAANALYSIS; FRACTURES AB Objectives: To evaluate the prevalence of vitamin D deficiency/insufficiency in long-term care patients at a Veterans Health Administration (VHA) hospital and to assess treatment and follow-up of low vitamin D levels. Design: Observational cohort study. Setting: VA hospital extended care center (ECC). Participants: 2218 ECC patients between January 2001 and December 2006 were screened. Measurement: Serum 25-hydroxyvitamin D (25[OH]D) level, vitamin D therapy regimen, time to follow-up, documented adverse event to vitamin D therapy. Results: Of 2218 patients admitted to the ECC during the study period, 229 (10%) had a vitamin D level measured. Among these 229 patients, 49% were vitamin D sufficient (25[OH]D >= 30 ng/mL), 14% were insufficient (25[OH]D = 21-29 ng/mL), and 37% were deficient (25[OH]D <= 20 ng/mL). Sixty-nine percent of patients with low vitamin D levels received some form of vitamin D therapy, whereas 43% received treatment as well as follow-up evaluation of vitamin D status within 3 months. Only 13% received a formulation of vitamin D appropriate for the severity of their deficiency/insufficiency with concurrent calcium supplementation and had a repeat vitamin D level within 3 months. Conclusion: Vitamin D levels were measured infrequently in long-term care patients. Among those monitored, the rate of vitamin D deficiency/insufficiency is high. Few patients with low vitamin D status received proper treatment and follow-up. These data support the need to educate physicians regarding the high prevalence of vitamin D insufficiency/deficiency among long-term care patients to ensure that patients with low vitamin D levels are identified and treated appropriately. (J Am Med Dir Assoc 2009; 10: 653-657) C1 [Braddy, Kathryn K.] VA Maryland Hlth Care Syst, Baltimore, MD 21201 USA. [Braddy, Kathryn K.; Imam, Syed N.; Palla, Kavita R.; Lee, Todd A.] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. RP Braddy, KK (reprint author), VA Maryland Hlth Care Syst, 10 N Greene St,119, Baltimore, MD 21201 USA. EM kathryn.kuhn@va.gov NR 13 TC 44 Z9 44 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1525-8610 J9 J AM MED DIR ASSOC JI J. Am. Med. Dir. Assoc. PD NOV PY 2009 VL 10 IS 9 BP 653 EP 657 DI 10.1016/j.jamda.2009.08.010 PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 524NQ UT WOS:000272150400012 PM 19883889 ER PT J AU Hua, LQ Walker, JD Adams, MS Marshall, JE Picard, MH Passeri, JJ AF Hua, Lanqi Walker, Jennifer D. Adams, Mark S. Marshall, Jane E. Picard, Michael H. Passeri, Jonathan J. TI Unusual Position of a Prosthetic Mitral Valve SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article DE Calcified mitral annulus; Mitral regurgitation; Prosthetic mitral valve ID EXTENSIVE CALCIFICATION; ANNULUS; ANULUS AB Extensive calcification of the mitral annulus in patients who require mitral valvereplacement presents a significant challenge to the surgeon. Several techniques, includingdebridement of the calcium, reconstruction of the annulus, and insertion of the prosthesis in a locationother than the annulus, have been used in such patients. We report the echocardiographictechniques used to evaluate the case of a woman with an unusually positioned prosthetic mitralvalve. (J Am Soc Echocardiogr 2009;22:1309.e7-1309.e9.) C1 [Hua, Lanqi] Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Hua, LQ (reprint author), Massachusetts Gen Hosp, Cardiac Ultrasound Lab, 55 Fruit St 260, Boston, MA 02114 USA. EM lhua1@partners.org OI Picard, Michael/0000-0002-9264-3243 NR 8 TC 0 Z9 0 U1 0 U2 18 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD NOV PY 2009 VL 22 IS 11 AR 1309.e7 DI 10.1016/j.echo.2009.05.025 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 513TL UT WOS:000271346300019 PM 19647402 ER PT J AU Smith, RG Rubin, SA Ellestad, MH AF Smith, Ryan G. Rubin, Stanley A. Ellestad, Myrvin H. TI Exercise hypertension: an adverse prognosis? SO JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION LA English DT Review DE Exercise hypertension; prognosis; hypertension; cardiovascular events ID BLOOD-PRESSURE RESPONSE; CORONARY-ARTERY-DISEASE; MIDDLE-AGED MEN; LEFT-VENTRICULAR MASS; MYOCARDIAL-INFARCTION; CARDIOVASCULAR MORTALITY; RISK; INCREASE AB We sought to clarify the prognostic importance of an "exaggerated" or "hypertensive" systolic blood pressure response to exercise during an exercise test. Studies evaluating the prognosis for cardiovascular events and cardiovascular mortality in those with hypertension during exercise testing were systematically reviewed. Fourteen studies were identified. Six studies were of healthy volunteers or hypertensives. Eight studies were in subjects with known or suspected heart disease. Without established heart disease, exercise hypertension predicted cardiovascular events and cardiovascular death. However, two of the six studies included a multivariate analysis; both demonstrated no independent association. Studies in subjects with known or suspected heart disease demonstrated that exercise hypertension predicted fewer cardiac events and lesser mortality or, after multivariate adjustment, no associated risk. In a healthy population, a higher exercise blood pressure may indicate hypertension or prehypertension, instead of normal vascular function, and an associated long-term adverse prognosis. In a population with a high burden of heart disease, the highest risk subjects with the most extensive cardiac disease may not be capable of generating pressure or workload to allow the manifestation of exercise systolic hypertension. By comparison, therefore, those with exercise hypertension have a better prognosis. J Am Soc Hypertens 2009;3(6):366-373. (C) 2009 American Society of Hypertension. All rights reserved. C1 [Smith, Ryan G.; Rubin, Stanley A.] Univ Calif Los Angeles, Sch Med Los Angeles, Los Angeles, CA 90024 USA. [Smith, Ryan G.; Rubin, Stanley A.] Greater Los Angeles, Vet Adm, Los Angeles, CA USA. [Ellestad, Myrvin H.] UCI Sch Med, Irvine, CA USA. [Ellestad, Myrvin H.] Long Beach Mem Hosp Med Ctr, Long Beach, CA USA. RP Smith, RG (reprint author), VA Greater Los Angeles Healthcare Syst, Div Cardiol 111E, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM smithryang@ucla.edu NR 28 TC 14 Z9 15 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-1711 J9 J AM SOC HYPERTENS JI J. Am. Soc. Hypertens. PD NOV-DEC PY 2009 VL 3 IS 6 BP 366 EP 373 DI 10.1016/j.jash.2009.10.003 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 589ZV UT WOS:000277193700003 PM 20409979 ER PT J AU Palevsky, PM Weisbord, SD AF Palevsky, Paul M. Weisbord, Steven D. TI Critical Care Nephrology: It's Not Just Acute Kidney Injury SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material ID STAGE RENAL-DISEASE; CLINICAL-FEATURES; UNIT; DIALYSIS; FAILURE C1 [Palevsky, Paul M.; Weisbord, Steven D.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA 15240 USA. [Weisbord, Steven D.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. [Palevsky, Paul M.; Weisbord, Steven D.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA USA. RP Palevsky, PM (reprint author), VA Pittsburgh Healthcare Syst, Renal Sect, Room 7E123 111F-U,Univ Dr, Pittsburgh, PA 15240 USA. EM palevsky@pitt.edu OI Palevsky, Paul/0000-0002-7334-5400 NR 11 TC 0 Z9 0 U1 0 U2 1 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 NOV PY 2009 VL 20 IS 11 BP 2281 EP 2282 DI 10.1681/ASN.2009080875 PG 2 WC Urology & Nephrology SC Urology & Nephrology GA 526BD UT WOS:000272261600003 PM 19797471 ER PT J AU Thadhani, R AF Thadhani, Ravi TI Is Calcitriol Life-Protective for Patients with Chronic Kidney Disease? SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID VITAMIN-D DEFICIENCY; STAGE RENAL-DISEASE; MAINTENANCE HEMODIALYSIS-PATIENTS; CORONARY-HEART-DISEASE; D-RECEPTOR ACTIVATORS; VASCULAR CALCIFICATION; SECONDARY HYPERPARATHYROIDISM; INTRAVENOUS CALCITRIOL; DIALYSIS PATIENTS; KNOCKOUT MICE C1 Harvard Univ, Massachusetts Gen Hosp, Dept Med, Sch Med,Renal Unit, Boston, MA 02114 USA. RP Thadhani, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Med, Sch Med,Renal Unit, Bulfinch 127,55 Fruit St, Boston, MA 02114 USA. EM thadhani.ravi@mgh.harvard.edu FU National Institutes of Health [DK 071674, HL 093954, DK 084974] FX R.T. is supported by Grants DK 071674, HL 093954, and DK 084974 from the National Institutes of Health. NR 81 TC 6 Z9 6 U1 0 U2 2 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 EI 1533-3450 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD NOV PY 2009 VL 20 IS 11 BP 2285 EP 2290 DI 10.1681/ASN.2009050494 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 526BD UT WOS:000272261600005 PM 19679671 ER PT J AU Wang, WC Chen, HJ Tseng, YH Lai, YC AF Wang, Wen-Chung Chen, Hui-Ju Tseng, Yu-Hua Lai, Yen-Chein TI Identification of Somatic Mutations in the von Hippel-Lindau (VHL) Gene in a Patient With Renal Cell Carcinoma SO JOURNAL OF THE FORMOSAN MEDICAL ASSOCIATION LA English DT Article DE mutation; renal cell carcinoma; Taiwan; von Hippel-Lindau gene ID TUMOR-SUPPRESSOR GENE; GERMLINE MUTATIONS; DISEASE; DELETIONS; RFLP AB One of the known causal molecular events in renal cell carcinoma is somatic mutation in the von Hippel-Lindau (VHL) gene. Our study describes a 51-year-old Taiwanese man who had bilateral renal cell carcinoma. The patient underwent radical nephrectomy without postoperative chemotherapy or radiotherapy, and is still alive after renal transplantation without tumor recurrence after > 5 years. To clarify his predisposition for bilateral tumors, we performed molecular genetic analysis of the VHL gene in this study. Polymerase chain reaction-single-strand conformation polymorphism and direct sequencing were performed on DNA of blood samples and paraffin-embedded tumor specimens from this patient. DNA from peripheral blood lymphocytes tested negative for germline mutations. However, there were two heterozygous alleles in the promoter and 3' untranslated regions of this gene. Nonetheless, the DNA from his tumors showed loss of heterozygosity (LOH) in these two loci. In addition to the LOH, we identified some different somatic mutations in his tumor tissues: C287T and G460A in the right-sided tumor, and G244A and C390A in the left-sided tumor. The possible roles of these genetic polymorphisms and point mutations in his renal tumorigenesis are discussed. This report provides new insights into renal cell carcinoma that result from VHL gene alterations in Taiwan. [J Formos Med Assoc 2009; 108(11):886-893] C1 [Chen, Hui-Ju; Lai, Yen-Chein] Chung Shan Med Univ, Sch Med Lab & Biotechnol, Taichung 402, Taiwan. [Wang, Wen-Chung] Jen Ai Hosp, Dept Obstet & Gynecol, Taichung, Taiwan. [Tseng, Yu-Hua] Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res,Dept Med, Boston, MA 02115 USA. RP Lai, YC (reprint author), Chung Shan Med Univ, Sch Med Lab & Biotechnol, 110,Sect 1,Chien Kuo N Rd, Taichung 402, Taiwan. EM yenchein@csmu.edu.tw NR 25 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SINGAPORE PTE LTD PI SINGAPORE PA 3 KILLINEY ROAD 08-01, WINSLAND HOUSE 1, SINGAPORE, 239519, SINGAPORE SN 0929-6646 J9 J FORMOS MED ASSOC JI J. Formos. Med. Assoc. PD NOV PY 2009 VL 108 IS 11 BP 886 EP 893 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 535HK UT WOS:000272957800010 PM 19933033 ER PT J AU Vasterling, JJ Verfaellie, M AF Vasterling, Jennifer J. Verfaellie, Mieke TI Posttraumatic stress disorder: A neurocognitive perspective INTRODUCTION SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Editorial Material ID PREFRONTAL CORTEX; MEMORY; PTSD; VETERANS; VULNERABILITY; AMYGDALA; VOLUME; SELF C1 [Vasterling, Jennifer J.] Psychol Serv, Boston, MA 02130 USA. [Vasterling, Jennifer J.] VA Boston Healthcare Syst, VA Natl Ctr PTSD, Boston, MA USA. [Vasterling, Jennifer J.; Verfaellie, Mieke] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Verfaellie, Mieke] VA Boston Healthcare Syst, Memory Disorders Res Ctr, Boston, MA USA. [Verfaellie, Mieke] VA Boston Healthcare Syst, Psychol Serv, Boston, MA USA. RP Vasterling, JJ (reprint author), Psychol Serv, 150 S Huntington Ave, Boston, MA 02130 USA. EM jennifer.vasterling@va.gov; verf@bu.edu NR 30 TC 19 Z9 19 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD NOV PY 2009 VL 15 IS 6 BP 826 EP 829 DI 10.1017/S1355617709990683 PG 4 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 523ZV UT WOS:000272114500002 PM 19891816 ER PT J AU Woodward, SH Kaloupek, DG Grande, LJ Stegman, WK Kutter, CJ Leskin, L Prestel, R Schaer, M Reiss, AL Eliez, S AF Woodward, Steven H. Kaloupek, Danny G. Grande, Laura J. Stegman, Wendy K. Kutter, Catherine J. Leskin, Loraine Prestel, Rebecca Schaer, Marie Reiss, Allan L. Eliez, Stephan TI Hippocampal volume and declarative memory function in combat-related PTSD SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE PTSD; Memory; Cognition; Hippocampus; Neocortex; Magnetic resonance imaging ID POSTTRAUMATIC-STRESS-DISORDER; CHILDHOOD SEXUAL-ABUSE; SURFACE-BASED ANALYSIS; HUMAN CEREBRAL-CORTEX; CORTICAL SURFACE; ALZHEIMERS-DISEASE; COORDINATE SYSTEM; VERBAL MEMORY; AREA CA3; MRI AB The proposition that declarative memory deficits are systematically related to smaller hippocampal Volume was tested in a relatively large sample (n = 95) of U.S. military veterans with and without combat-related posttraumatic stress disorder. This correlative analysis was extended by including multiple measures of verbal and visual declarative memory and multiple memory-relevant regional brain volumes that had been shown to exhibit main effects of PTSD in prior work. Small-to-moderate effects were observed on verbal declarative memory in line with a recent meta-analysis; nevertheless, little or no evidence of systematic linear covariation between memory measures and brain Volumes was observed. (JINS, 2009, 15, 830-839.) C1 [Woodward, Steven H.] VA Palo Alto Hlth Care Syst, Disseminat & Training Div, Natl Ctr PTSD, Palo Alto, CA 94304 USA. [Kaloupek, Danny G.; Prestel, Rebecca] VA New England Hlth Care Syst, Behav Sci Div, Natl Ctr PTSD, Boston, MA USA. [Kaloupek, Danny G.] Boston Univ, Sch Med, Div Psychiat, Boston, MA 02118 USA. [Grande, Laura J.] VA New England Hlth Care Syst, Psychol Serv, Boston, MA USA. [Stegman, Wendy K.] Earth Syst, Melbourne, Vic, Australia. [Kutter, Catherine J.] White River Junct Vet Affairs Med Ctr, Psychol Serv, White River Jct, VT USA. [Leskin, Loraine] VA Greater Los Angeles Hlth Care System, Psychol Serv, Los Angeles, CA USA. [Schaer, Marie; Eliez, Stephan] Univ Geneva, Dept Psychiat, Geneva, Switzerland. [Schaer, Marie] Swiss Fed Inst Technol, Signal Proc Lab, CH-1015 Lausanne, Switzerland. [Reiss, Allan L.] Stanford Univ, Dept Psychiat & Behav Sci, Sch Med, Stanford, CA 94305 USA. RP Woodward, SH (reprint author), VA Palo Alto Hlth Care Syst, Disseminat & Training Div, Natl Ctr PTSD, Mail Code 334 PTSD,3801 Miranda Ave, Palo Alto, CA 94304 USA. EM steve.woodward@va.gov OI Kaloupek, Danny/0000-0002-0795-593X FU National Institute on Alcohol Abuse and Alcoholism [K23AA13149]; Swiss National Fund for Research Career Development [32-63135-00, PP00B-102864/1] FX Major funding for this work was provided under a VA/DoD assistance agreement to Drs. Woodward and Kaloupek from the U.S. Army Medical Research and Materiel Command (DoD) administered through the Institute for Medical Research (VA). Special thanks are due to Stephen Grate and Lori Moll who facilitated the necessary arrangements at those institutions. Support was also provided by a National Institute on Alcohol Abuse and Alcoholism award (K23AA13149) and a VA Career Development Award to Dr. Streeter. Support for Dr. Eliez was provided by the Swiss National Fund for Research Career Development Award (32-63135-00 and PP00B-102864/1). The authors wish to thank the Research Services of the VA Palo Alto and VA Boston Healthcare Systems for their support. Important institutional and technical support was also provided by the following individuals: at the VA Palo Alto HCS, John E. Drace, Patricia Spezia, Carla Ambriz, and Gary E. Gold; at the VA Boston HCS, Chris C. Streeter, Kelly Teresi, Frederick Kanter, Steven Blank, Susan Proctor, and Erica Stone; at Stanford University, Thomas J. Brosnan, Anil Patwardhan, and Eric Schmitt; at McLean Hospital, Perry Renshaw, Blaise Frederick, Rosemond Villafuerte, Ann Smith, and Eileen Connolly; and at the Defense Manpower Database Command, Michael A. Dove. The authors are also grateful for the guidance provided by Kelvin O. Lim, Stephen E. Lindley, Craig Rosen, and H. Stefan Bracha. The neuropsychological assessment results and relations to neuroimaging have not been published either electronically or in print. No authors have conflicts of interest in relation to the findings published in this article. NR 69 TC 19 Z9 19 U1 3 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD NOV PY 2009 VL 15 IS 6 BP 830 EP 839 DI 10.1017/S1355617709990476 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 523ZV UT WOS:000272114500003 PM 19703322 ER PT J AU Marx, BP Doron-Lamarca, S Proctor, SP Vasterling, JJ AF Marx, Brian P. Doron-Lamarca, Susan Proctor, Susan P. Vasterling, Jennifer J. TI The influence of pre-deployment neurocognitive functioning on post-deployment PTSD symptom outcomes among Iraq-deployed Army soldiers SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Visual memory; Verbal memory; Attention; Neurocognitive functioning; PTSD; Combat ID POSTTRAUMATIC-STRESS-DISORDER; GULF-WAR VETERANS; PREFRONTAL CORTEX; COGNITIVE-ABILITY; VIETNAM VETERANS; RISK-FACTORS; AUTOBIOGRAPHICAL MEMORY; PSYCHOMETRIC PROPERTIES; HIPPOCAMPAL VOLUME; TWINS DISCORDANT AB This study evaluated associations between pre-deployment neurocognitive performance and post-deployment posttraumatic stress disorder (PTSD) symptoms in a sample of deployed active duty Army soldiers. As part of a larger longitudinal study, each participant completed baseline measures of memory, executive attention, and response inhibition, and baseline and post-deployment self-report measures of PTSD symptom severity. Data were subjected to multiple regression analyses that examined associations between baseline neurocognitive performances and longitudinal PTSD symptom outcome. Results revealed that pre-trauma immediate recall Of Visual information was associated with post-deployment PTSD symptom severity, even after controlling for pre-deployment PTSD symptom levels, combat intensity, age, gender, and test-retest interval. There was also an interaction between pre-deployment PTSD symptom severity and pre-deployment immediate visual recall and Verbal learning, indicating that neurocognitive performances were more strongly (and negatively) associated with residualized post-deployment PTSD symptoms at higher levels of pre-deployment PTSD symptoms. These findings highlight the potential role of pre-trauma neurocognitive functioning in moderating the effects of trauma exposure on PTSD symptoms. (JINS, 2009 15, 840-852.) C1 [Marx, Brian P.; Doron-Lamarca, Susan; Vasterling, Jennifer J.] VA Boston Healthcare Syst, Behav Sci Div, Natl Ctr PTSD, Boston, MA 02130 USA. [Marx, Brian P.; Doron-Lamarca, Susan; Proctor, Susan P.; Vasterling, Jennifer J.] VA Boston Healthcare Syst, Dept Psychol, Boston, MA 02130 USA. [Marx, Brian P.; Doron-Lamarca, Susan; Vasterling, Jennifer J.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. [Proctor, Susan P.] USA, Environm Med Res Inst, Mil Performance Div, Natick, MA 01760 USA. [Proctor, Susan P.] Boston Univ, Sch Med, Dept Environm Hlth, Boston, MA 02118 USA. RP Marx, BP (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD 116B2, 150 S Huntington Ave, Boston, MA 02130 USA. EM brain.marx@va.gov FU U.S. Army Medical Research and Materiel Command [17-03-0020, A-11815]; VA Clinical Sciences Research and Development; South Central Mental Illness Research, Education, and Clinical Center; U.S. Army Research Institute for Environmental Medicine; U.S. Army Medical Research Acquisition Activity [DAMD 17-03-0020] FX This work was Supported by the U.S. Army Medical Research and Materiel Command (DAMD 17-03-0020; HSRRB Log No. A-11815) and VA Clinical Sciences Research and Development awards. The work also was Supported in part by resources provided by the South Central Mental Illness Research, Education, and Clinical Center and U.S. Army Research Institute for Environmental Medicine. Some of the work was completed at the Southeast Louisiana Veterans Healthcare System and Tulane University. The U.S. Army Medical Research Acquisition Activity (Fort Detrick, MD) is the awarding and administering acquisition office for DAMD 17-03-0020 NR 88 TC 31 Z9 31 U1 3 U2 13 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD NOV PY 2009 VL 15 IS 6 BP 840 EP 852 DI 10.1017/S1355617709990488 PG 13 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 523ZV UT WOS:000272114500004 PM 19891817 ER PT J AU Samuelson, KW Neylan, TC Lenoci, M Metzler, TJ Cardenas, V Weiner, MW Marmar, CR AF Samuelson, Kristin W. Neylan, Thomas C. Lenoci, Maryanne Metzler, Thomas J. Cardenas, Valerie Weiner, Michael W. Marmar, Charles R. TI Longitudinal effects of PTSD on memory functioning SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Veterans; Neuropsychology; Verbal learning; Delayed memory; Immediate recall; Aging ID POSTTRAUMATIC-STRESS-DISORDER; CHILDHOOD SEXUAL-ABUSE; SHORT-TERM-MEMORY; HOLOCAUST SURVIVORS; DECLARATIVE MEMORY; COMBAT VETERANS; PERFORMANCE; ATTENTION; WOMEN; DEFICITS AB Numerous Studies have demonstrated explicit and working memory deficits related to posttraumatic stress disorder (PTSD), but few have addressed longitudinal changes in memory functioning. There is some evidence to Suggest in interactive effect of PTSD and aging on verbal memory decline in Holocaust Survivors (Yehuda et al., 2006). However. the longitudinal trajectory of neuropsychologgical functioning has not been investigated in Vietnam veterans, a younger but substantial population of aging trauma Survivors. We administered tests 017 Visual and verbal memory, and working memory to derive different dependent measures in veterans between the ages of 41 and 63, the majority of whom served in the Vietnam War. Twenty-five veterans with PTSD and 22 veterans without PTSD were assessed over two time points (mean age at follow-up = 54.0; mean inter-test interval = 34 months). The PTSD+group, consisting of veterans with chronic, primarily combat-related PTSD, did not show a significant change in PTSD symptoms over time. Compared to veterans without PTSD. veterans with PTSD showed it greater decline in delayed facial recognition only, and this decline was extremely Subtle. (JINS, 2009, 15, 853-861.) C1 [Samuelson, Kristin W.] Alliant Int Univ, Calif Sch Profess Psychol, San Francisco, CA 94133 USA. [Samuelson, Kristin W.; Neylan, Thomas C.; Lenoci, Maryanne; Metzler, Thomas J.; Cardenas, Valerie; Weiner, Michael W.; Marmar, Charles R.] San Francisco VA Med Ctr, Mental Hlth Serv, San Francisco, CA USA. [Neylan, Thomas C.; Metzler, Thomas J.; Weiner, Michael W.; Marmar, Charles R.] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Cardenas, Valerie; Weiner, Michael W.] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. RP Samuelson, KW (reprint author), Alliant Int Univ, Calif Sch Profess Psychol, 1 Beach St,Suite 100, San Francisco, CA 94133 USA. EM ksamuelson@alliant.edu FU Sierra Pacific (VISN 21) Mental Illness Research, Education, and Clinical Center (MIRECC); Department of Defense FX This study was supported by the Sierra Pacific (VISN 21) Mental Illness Research, Education, and Clinical Center (MIRECC) and the Department of Defense. The authors do not have any conflicts of interest that might be interpreted as influencing the research. NR 48 TC 13 Z9 14 U1 1 U2 11 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD NOV PY 2009 VL 15 IS 6 BP 853 EP 861 DI 10.1017/S1355617709990282 PG 9 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 523ZV UT WOS:000272114500005 PM 19703319 ER PT J AU Benge, JF Perrier, ND Massman, PJ Meyers, CA Kayl, AE Wefel, JS AF Benge, Jared F. Perrier, Nancy D. Massman, Paul J. Meyers, Christina A. Kayl, Anne E. Wefel, Jeffrey S. TI Cognitive and affective sequelae of primary hyperparathyroidism and early response to parathyroidectomy SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE Hyperparathyroidism; Parathyroidectomy; Cognition; Depression; Neuropsychology; Surgery ID ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM; TEST-RETEST RELIABILITY; NORMATIVE DATA; HYPER-PARATHYROIDISM; HORMONE; BRAIN; DYSFUNCTION; EDUCATION; BEHAVIOR; DEFICITS AB Cognitive and affective complaints are common in patients with primary hyperparathyroidism (PHPT), but few studies have used psychometric testing to document these symptoms and their response to parathyroidectomy. The current Study sought to clarify the nature of cognitive and affective impairments in PHPT and changes postparathyroidectomy. One hundred eleven patients with PHPT underwent neuropsychological evaluation prior to parathyroidectomy with 68 returning for an early postsurgical evaluation. Changes in cognition were assessed using practice effect corrected reliable change indices. Biochemical and anesthesia variables were compared between groups who improved and declined. In a subset of patients, assessment revealed a significant pattern of cognitive slowing, reductions in psychomotor speed, memory impairment, and depression prior to parathyroidectomy. Postsurgical evaluations revealed a trend for improvements on timed tests and depression but a decline in memory. Older patients responded less well to surgical intervention, as did patients who experienced more dramatic changes in biochemical status following surgery. Cognitive changes early postparathyroidectomy are characterized by improved information processing speed and decline in verbal memory, with younger patients more likely to recover during this acute phase. The need for longer-term follow-up studies and increasing utilization of neuropsychological assessments in this population are discussed. (JINS, 2009, 15, 1002-1011.) C1 [Wefel, Jeffrey S.] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Unit 431, Sect Neuropsychol, Houston, TX 77230 USA. [Benge, Jared F.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Benge, Jared F.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Perrier, Nancy D.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77230 USA. [Massman, Paul J.] Univ Houston, Dept Psychol, Houston, TX USA. RP Wefel, JS (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Unit 431, Sect Neuropsychol, POB 301402, Houston, TX 77230 USA. EM jwefel@mdanderson.org FU American Geriatric Society, Jahnigan FX No pharmaceutical or corporate funding was used in the preparation of this manuscript or collection of data. Support was in part funded by the American Geriatric Society, Jahnigan Scholars grant. Portions of this work were presented previously as a poster at the 36th Annual Meeting of the International Neuropsychological Society, Waikoloa, HI. NR 51 TC 16 Z9 17 U1 1 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD NOV PY 2009 VL 15 IS 6 BP 1002 EP 1011 DI 10.1017/S1355617709990695 PG 10 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 523ZV UT WOS:000272114500022 PM 19807940 ER PT J AU Burstein, HJ AF Burstein, Harold J. TI Screening Contretemps: The Real Issue in the Mammogram Guideline Debate SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Editorial Material C1 [Burstein, Harold J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Burstein, Harold J.] Dana Farber Canc Inst, Boston, MA USA. [Burstein, Harold J.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Burstein, HJ (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV PY 2009 VL 7 IS 10 BP 1039 EP 1040 PG 2 WC Oncology SC Oncology GA 527SH UT WOS:000272386300002 PM 19930972 ER PT J AU Bevers, TB Anderson, BO Bonaccio, E Buys, S Daly, MB Dempsey, PJ Farrar, WB Fleming, I Garber, JE Harris, RE Heerdt, AS Helvie, M Huff, JG Khakpour, N Khan, SA Krontiras, H Lyman, G Rafferty, E Shaw, S Smith, ML Tsangaris, TN Williams, C Yaneeklov, T AF Bevers, Therese B. Anderson, Benjamin O. Bonaccio, Ermelinda Buys, Sandra Daly, Mary B. Dempsey, Peter J. Farrar, William B. Fleming, Irving Garber, Judy E. Harris, Randall E. Heerdt, Alexandra S. Helvie, Mark Huff, John G. Khakpour, Nazanin Khan, Seema A. Krontiras, Helen Lyman, Gary Rafferty, Elizabeth Shaw, Sara Smith, Mary Lou Tsangaris, Theodore N. Williams, Cheryl Yaneeklov, Thomas TI Breast Cancer Screening and Diagnosis SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review DE NCCN Clinical Practice Guidelines; breast carcinoma; carcinoma in situ; screening; diagnosis; mammography; risk assessment; biopsy; hyperplasia ID CORE-NEEDLE-BIOPSY; FIELD DIGITAL MAMMOGRAPHY; CARCINOMA IN-SITU; ATYPICAL LOBULAR HYPERPLASIA; CHILDHOOD HODGKINS-DISEASE; BRCA2 MUTATION CARRIERS; HIGH FAMILIAL RISK; NIPPLE DISCHARGE; FILM MAMMOGRAPHY; FOLLOW-UP C1 [Bevers, Therese B.; Dempsey, Peter J.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Anderson, Benjamin O.] Fred Hutchinson Canc Res Ctr, Seattle Canc Care Alliance, Seattle, WA USA. [Bonaccio, Ermelinda] Roswell Pk Canc Inst, Buffalo, NY USA. [Buys, Sandra] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT 84112 USA. [Daly, Mary B.] Fox Chase Canc Ctr, Philadelphia, PA USA. [Farrar, William B.; Harris, Randall E.] Ohio State Univ, Ctr Comprehens Canc, James Canc Hosp, Columbus, OH 43210 USA. [Fleming, Irving] Univ Tennessee, Inst Canc, St Jude Childrens Res Hosp, Knoxville, TN 37996 USA. [Garber, Judy E.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. [Heerdt, Alexandra S.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Helvie, Mark] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. [Huff, John G.] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Khakpour, Nazanin] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Khan, Seema A.] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Evanston, IL 60208 USA. [Krontiras, Helen] Univ Alabama, Ctr Comprehens Canc, Birmingham, AL USA. [Lyman, Gary] Duke Comprehens Canc Ctr, Durham, NC 27705 USA. [Rafferty, Elizabeth] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Shaw, Sara] City Hope Comprehens Canc Ctr, Duarte, CA 91010 USA. [Williams, Cheryl] Nebraska Med Ctr, UNMC Eppley Canc Ctr, Omaha, NE USA. [Yaneeklov, Thomas] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. RP Bevers, TB (reprint author), Univ Texas MD Anderson Canc Ctr, Houston, TX USA. NR 108 TC 137 Z9 143 U1 0 U2 11 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV PY 2009 VL 7 IS 10 BP 1060 EP 1096 PG 37 WC Oncology SC Oncology GA 527SH UT WOS:000272386300005 PM 19930975 ER PT J AU Ng, AK Travis, LB AF Ng, Andrea K. Travis, Lois B. TI Radiation Therapy and Breast Cancer Risk SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Article DE Breast cancer; second malignant neoplasm; radiation therapy ID ATOMIC-BOMB SURVIVORS; ACUTE POSTPARTUM MASTITIS; CASE-CONTROL INTERVIEW; 2ND PRIMARY BREAST; CONTRALATERAL BREAST; HODGKINS-DISEASE; FOLLOW-UP; CHILDHOOD-CANCER; YOUNG-WOMEN; ADJUVANT RADIOTHERAPY AB Exposure to ionizing radiation has clearly been established as one of the risk factors for the development of breast cancer. Much data on the relationship between radiation exposures and subsequent breast cancer are derived from atomic bomb survivors and women who received medical exposures either for diagnostic or therapeutic purposes. Although these populations differ in background breast cancer risks and the dose, quality, and timing of radiation, consistent findings include an increased risk with younger age at exposure, long latency to breast cancer development, and increasing risk with increasing radiation dose. Although therapeutic radiation is rarely used to treat benign conditions, it remains an important and effective treatment modality for a wide range of cancers. Increased knowledge of radiation-related breast cancer and modifying influences plays an important role in guiding the initial treatment approach for young women and optimizing long-term follow-up care. (JNCCN 2009;7:1121-1128) C1 [Ng, Andrea K.] Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Ng, Andrea K.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Travis, Lois B.] Univ Rochester, Med Ctr, James P Wilmot Canc Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. [Travis, Lois B.] Univ Rochester, Med Ctr, Rubin Ctr Canc Survivorship, Rochester, NY 14642 USA. RP Ng, AK (reprint author), Harvard Univ, Sch Med, Dept Radiat Oncol, Dana Farber Canc Inst, 75 Francis St,ASB1-L2, Boston, MA 02115 USA. EM ang@lroc.harvard.edu NR 65 TC 7 Z9 7 U1 0 U2 0 PU HARBORSIDE PRESS PI COLD SPRING HARBOR PA 37 MAIN ST, COLD SPRING HARBOR, NY 11724 USA SN 1540-1405 EI 1540-1413 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV PY 2009 VL 7 IS 10 BP 1121 EP 1128 PG 8 WC Oncology SC Oncology GA 527SH UT WOS:000272386300008 PM 19930978 ER PT J AU Mitsiades, CS Anderson, KC AF Mitsiades, Constantine S. Anderson, Kenneth C. TI Epigenetic Modulation in Hematologic Malignancies: Challenges and Progress SO JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK LA English DT Review DE Epigenetics; hematologic malignancy ID HISTONE DEACETYLASE INHIBITOR; ACUTE MYELOID-LEUKEMIA; T-CELL LYMPHOMA; SUBEROYLANILIDE HYDROXAMIC ACID; HUMAN HEPATOCELLULAR-CARCINOMA; CHRONIC MYELOGENOUS LEUKEMIA; TUMOR-SUPPRESSOR GENE; HYPERMETHYLATION-ASSOCIATED INACTIVATION; RISK MYELODYSPLASTIC SYNDROMES; ACUTE LYMPHOBLASTIC-LEUKEMIA AB Genetic alterations, including gene mutations, and chromosomal amplifications, deletions, inversions, and translocations, are hallmarks of the molecular biology of cancer. These events lead to oncogene activation, formation of chimeric oncoproteins, and/or inactivation of tumor suppressor genes. Such genetic changes contribute to the neoplastic transformation of cells, as well as the eventual acquisition by malignant cells of a more aggressive biologic and clinical behavior. However, in recent years, it has become apparent that these genetic events are not the sole determinants of the biologic behavior of tumor cells. Indeed, it is becoming increasingly apparent that tumor cells with a given genotype exhibit a differential phenotype depending on the microenvironment in which they reside. Furthermore, extensive data have shown that derivative daughter cells of neoplastic, as well as normal cells, inherit changes in the patterns of gene expression that are not associated with changes in the primary DNA sequence but are instead related to changes in chromatin structure and its accessibility for transcriptional activity. These heritable gene expression changes that are not associated with changes in the primary nucleotide sequence are referred to as epigenetic changes. This review provides an overview of the regulation of the "epigenome" in neoplastic cells, with particular emphasis on DNA methylation and histone acetylation as therapeutic targets for hematologic malignancies. (JNCCN 2009;7[Suppl 8]:S1-S12) C1 [Mitsiades, Constantine S.] Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. [Mitsiades, Constantine S.] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. [Anderson, Kenneth C.] Dana Farber Canc Inst, Div Hematol Neoplasia, Boston, MA 02115 USA. RP Mitsiades, CS (reprint author), Harvard Univ, Sch Med, Dept Med Oncol, Boston, MA 02115 USA. NR 140 TC 4 Z9 4 U1 0 U2 1 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1540-1405 J9 J NATL COMPR CANC NE JI J. Natl. Compr. Cancer Netw. PD NOV PY 2009 VL 7 BP S1 EP S12 PG 12 WC Oncology SC Oncology GA 518TU UT WOS:000271717400001 PM 19930971 ER PT J AU Raemer, DB AF Raemer, Daniel B. TI Simulation in cardiothoracic surgery: A paradigm shift in education? SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Editorial Material C1 [Raemer, Daniel B.] Ctr Med Simulat, Cambridge, MA 02139 USA. [Raemer, Daniel B.] Soc Simulat Healthcare, Cambridge, MA USA. [Raemer, Daniel B.] Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. [Raemer, Daniel B.] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. RP Raemer, DB (reprint author), Ctr Med Simulat, 65 Landsdowne St, Cambridge, MA 02139 USA. EM draemer@partners.org NR 9 TC 3 Z9 3 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5223 J9 J THORAC CARDIOV SUR JI J. Thorac. Cardiovasc. Surg. PD NOV PY 2009 VL 138 IS 5 BP 1065 EP 1066 DI 10.1016/j.jtcvs.2009.07.056 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 507RG UT WOS:000270871700004 PM 19837214 ER PT J AU Dwyer, HA Matthews, PB Azadani, A Ge, L Guy, TS Tseng, EE AF Dwyer, Harry A. Matthews, Peter B. Azadani, Ali Ge, Liang Guy, T. Sloane Tseng, Elaine E. TI Migration forces of transcatheter aortic valves in patients with noncalcific aortic insufficiency SO JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY LA English DT Article ID PERCUTANEOUS HEART-VALVE; HIGH-RISK PATIENTS; BLOOD-FLOW; IMPLANTATION; PROSTHESIS; STENOSIS; MODEL; EXPERIENCE; FEASIBILITY; REPLACEMENT AB Objective: Transcatheter aortic valves have been successfully implanted into the calcified leaflets of patients with severe aortic stenosis. However, their stability in patients with noncalcified aortic insufficiency is unknown. Similar to thoracic and abdominal aortic stent grafts, transcatheter aortic valves are subjected to antegrade ejection forces during systole. However, retrograde migration forces into the left ventricle are also generated by the diastolic pressure gradient across the closed valve. It has been suggested that leaflet calcification anchors the prosthesis, and measurements of migration forces should be considered before clinical trials in noncalcified aortic insufficiency. The objective of this study was to use computational fluid dynamics simulations to quantify forces that could potentially dislodge the prosthesis. Methods: A computational fluid dynamics model was developed to simulate systolic flow through a geometric mesh of the aortic root and transcatheter aortic valves. Hemodynamic measurements were made at discrete moments during ejection. Unsteady control volume analysis was used for calculations of force on the mesh. Results: Results of the simulation indicate that a total force of 0.602 N acts on the transcatheter aortic valves during systole, 99% of which is in the direction of axial flow. The largest contributor to force was the dynamic pressure gradient through the transcatheter aortic valves. This antegrade force is approximately 10 times smaller than the retrograde force (6.01 N) on the closed valve during diastole. Conclusion: Our model simulated systolic flow through a transcatheter aortic valve and demonstrated migration into the left ventricle to be of greater concern than antegrade ejection. C1 [Tseng, Elaine E.] UCSF Med Ctr, Div Cardiothorac Surg, Dept Surg, San Francisco, CA 94143 USA. [Dwyer, Harry A.] Univ Calif Davis, Dept Mech & Aeronaut Engn, Davis, CA 95616 USA. [Matthews, Peter B.; Azadani, Ali; Ge, Liang; Guy, T. Sloane; Tseng, Elaine E.] San Francisco VA Med Ctr, San Francisco, CA USA. RP Tseng, EE (reprint author), UCSF Med Ctr, Div Cardiothorac Surg, Dept Surg, 500 Parnassus Ave,Suite W405,Box 0118, San Francisco, CA 94143 USA. EM elaine.tseng@ucsfmedctr.org FU American Heart Association Beginning [0565148Y]; Northern California Institute for Research and Education FX This work was supported by the American Heart Association Beginning Grant-in-Aid 0565148Y (Burlingame, Calif) and the Northern California Institute for Research and Education (San Francisco, Calif). The authors have no financial conflicts of interest to disclose. NR 25 TC 22 Z9 22 U1 1 U2 4 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 NOV PY 2009 VL 138 IS 5 BP 1227 EP 1233 DI 10.1016/j.jtcvs.2009.02.057 PG 7 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 507RG UT WOS:000270871700026 PM 19748632 ER PT J AU Abbott, GF Rosado-de-Christenson, ML Rossi, SE Suster, S AF Abbott, Gerald F. Rosado-de-Christenson, Melissa L. Rossi, Santiago E. Suster, Saul TI Imaging of Small Airways Disease SO JOURNAL OF THORACIC IMAGING LA English DT Article DE small airways disease; bronchioles; bronchiolitis; constrictive bronchiolitis ID HIGH-RESOLUTION CT; THIN-SECTION CT; BRONCHIOLITIS OBLITERANS SYNDROME; LUNG-TRANSPLANT RECIPIENTS; CHRONIC OCCULT ASPIRATION; HYPERSENSITIVITY PNEUMONITIS; COMPUTED-TOMOGRAPHY; DISORDERS; DIAGNOSIS; SPECTRUM AB Small airways disease includes a spectrum of inflammatory and fibrotic pulmonary diseases centered on the small conducting airways. High-resolution computed tomography plays a key role in the detection and classification of small airways disease and, when combined with relevant clinical and pathologic findings, leads to a more accurate diagnosis. The imaging manifestations of small airways disease on high-resolution Computed tomography may be direct or indirect signs of small airway involvement and include centrilobular nodules and branching nodular (tree-in-bud) opacities, or the demonstration of mosaic attenuation that is typically exaggerated on expiratory computed tomography. This article reviews the normal anatomy and histology of bronchioles and the clinical, pathologic, and imaging features of small airways diseases. C1 [Abbott, Gerald F.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Rosado-de-Christenson, Melissa L.] Uniformed Serv Univ Hlth Sci, Dept Radiol & Nucl Med, Bethesda, MD 20814 USA. [Rosado-de-Christenson, Melissa L.] St Lukes Hosp Kansas City, Dept Radiol, Kansas City, MO USA. [Rosado-de-Christenson, Melissa L.] Univ Missouri, Dept Radiol, Kansas City, MO 64110 USA. [Rossi, Santiago E.] Ctr Diagnost Dr Enrique Rossi, Dept Radiol, Buenos Aires, DF, Argentina. [Suster, Saul] Med Coll Wisconsin, Dept Pathol & Lab Med, Milwaukee, WI 53226 USA. RP Abbott, GF (reprint author), Massachusetts Gen Hosp, Dept Radiol, Thorac Radiol FND 202,55 Fruit St, Boston, MA 02114 USA. EM GABBOTT@PARTNERS.ORG NR 50 TC 10 Z9 10 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 NOV PY 2009 VL 24 IS 4 BP 285 EP 298 PG 14 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 528XW UT WOS:000272481300006 PM 19935225 ER PT J AU Sequist, LV Fidias, PM Temel, JS Kolevska, T Rabin, MS Boccia, RV Burris, HA Belt, RJ Huberman, MS Melnyk, O Mills, GM Englund, CW Caldwell, DC Keck, JG Meng, L Jones, M Brown, GL Edelman, MJ Lynch, TJ AF Sequist, Lecia V. Fidias, Panos M. Temel, Jennifer S. Kolevska, Tatjana Rabin, Michael S. Boccia, Ralph V. Burris, Howard A. Belt, Robert J. Huberman, Mark S. Melnyk, Ostap Mills, Glenn M. Englund, Craig W. Caldwell, David C. Keck, James G. Meng, Lisa Jones, Marsha Brown, Gail L. Edelman, Martin J. Lynch, Thomas J. TI Phase 1-2a Multicenter Dose-Ranging Study of Canfosfamide in Combination with Carboplatin and Paclitaxel as First-Line Therapy for Patients with Advanced Non-small Cell Lung Cancer SO JOURNAL OF THORACIC ONCOLOGY LA English DT Article DE Canfosfamide; Carboplatin; Paclitaxel; NSCLC; Phase 2 ID GLUTATHIONE-S-TRANSFERASE; CHEMOTHERAPY-NAIVE PATIENTS; III TRIAL; PLUS CARBOPLATIN; DRUG-RESISTANCE; ONCOLOGY-GROUP; GEMCITABINE; CISPLATIN; CISPLATIN/VINORELBINE; MALIGNANCIES AB Introduction: We aimed to evaluate the safety and efficacy of canfosfamide in combination with carboplatin and paclitaxel as first-line therapy in patients with locally advanced or metastatic non-small cell lung cancer. Methods: This was a phase 1-2a, multicenter, dose-ranging trial that enrolled patients with stage IIIB or IV non-small cell lung cancer with measurable disease. Patients received canfosfamide in doses ranging from 400 to 1000 mg/m(2) intravenously (IV) with carboplatin at area under the curve 6 IV and paclitaxel at 200 mg/m(2) IV day I every 3 weeks. The primary end point was objective response rate, and the secondary endpoints were safety and progression-free survival. Results: One hundred twenty-nine patients were treated with canfosfamide at dose levels of 400 (n = 3), 500 (n = 51), 750 (n = 54), and 1000 mg/m(2) (n = 21). Objective tumor responses by RECIST were observed in 40 patients [34% (95% confidence interval [CI], 26-44)], the median progression-free survival was 4.3 months (95% Cl, 3.7-5.2) and the median survival 9.9 months (95% Cl, 7.7-11.9). The percent of patients alive at I year was 43.1%. The overall safety profile of the combination was acceptable and consistent with the profiles of the individual agents. In an exploratory analysis, patients receiving the optional maintenance canfosfamide therapy had a prolonged median Survival of 16.8 months compared with those eligible for but not receiving maintenance therapy at 8.8 months (hazard ratio = 0.38, p < 0.001). Conclusions: The combination of canfosfamide with carboplatin and paclitaxel chemotherapy is well tolerated and active. Maintenance canfosfamide may further improve outcomes. This regimen is worthy of additional study. C1 [Sequist, Lecia V.; Fidias, Panos M.; Temel, Jennifer S.; Lynch, Thomas J.] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Kolevska, Tatjana] Kaiser Permanente Med Ctr, Vallejo, CA USA. [Rabin, Michael S.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Boccia, Ralph V.] Ctr Canc & Blood Disorders, Bethesda, MD USA. [Burris, Howard A.] Sarah Cannon Canc Ctr, Nashville, TN USA. [Belt, Robert J.] Kansas City Canc Ctr, Kansas City, MO USA. [Huberman, Mark S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Melnyk, Ostap] Bay Area Canc Res Grp LLC, Concord, CA USA. [Englund, Craig W.] Florida Well Care, Inverness, FL USA. [Caldwell, David C.] Danville Hematol & Oncol Inc, Danville, VA USA. [Keck, James G.; Meng, Lisa; Jones, Marsha; Brown, Gail L.] Telik Inc, Palo Alto, CA USA. [Edelman, Martin J.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Sequist, LV (reprint author), Massachusetts Gen Hosp, Ctr Canc, 55 Fruit St, Boston, MA 02114 USA. EM lvsequist@partners.org FU Telik, Inc.; Palo Alto, CA. FX Supported by Telik, Inc., Palo Alto, CA. NR 39 TC 10 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1556-0864 J9 J THORAC ONCOL JI J. Thorac. Oncol. PD NOV PY 2009 VL 4 IS 11 BP 1389 EP 1396 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 514KT UT WOS:000271394000016 PM 19701107 ER PT J AU Sequist, LV AF Sequist, Lecia V. TI Protein Degradation/Chaperone System and Histone Deacetylase Pathway SO JOURNAL OF THORACIC ONCOLOGY LA English DT Editorial Material ID GROWTH-FACTOR RECEPTORS; CANCER; CHAPERONE; THERAPY C1 Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA. RP Sequist, LV (reprint author), Massachusetts Gen Hosp, Ctr Canc, Dept Med, 55 Fruit St,POB 212, Boston, MA 02114 USA. EM LVSequist@partners.org NR 9 TC 1 Z9 1 U1 0 U2 0 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 NOV PY 2009 VL 4 IS 11 BP S1077 EP S1078 PG 2 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 514KU UT WOS:000271394100011 PM 19861924 ER PT J AU Moreira, DM Presti, JC Aronson, WJ Terris, MK Kane, CJ Amling, CL Freedland, SJ AF Moreira, Daniel M. Presti, Joseph C., Jr. Aronson, William J. Terris, Martha K. Kane, Christopher J. Amling, Christopher L. Freedland, Stephen J. TI Natural History of Persistently Elevated Prostate Specific Antigen After Radical Prostatectomy: Results From the SEARCH Database SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; mortality; prostate-specific antigen; prostatectomy ID BIOCHEMICAL RECURRENCE; DOUBLING TIME; FREE SURVIVAL; CANCER; PSA; RISK; PROGRESSION; MORTALITY; PREDICTS; RELAPSE AB Purpose: We examined natural history, predictors of biochemical recurrence and all cause mortality in patients with persistently elevated prostate specific antigen after radical prostatectomy in the Shared Equal Access Regional Cancer Hospital cohort. Materials and Methods: We reviewed data on 1,156 men treated with radical prostatectomy after 1997. Prostate specific antigen persistence was defined as failure to achieve prostate specific antigen less than 0.03 ng/ml within 6 months postoperatively. Disease-free and overall survival was compared between men with and without persistence using the log rank test. Predictors of biochemical recurrence and all cause death were analyzed using the Cox model. Results: A total of 291 men (25%) had persistence, which was associated with increased biochemical recurrence and all cause death (p <0.001 and 0.041, respectively). In patients with persistence 1 and 5-year biochemical recurrence-free survival was 68% and 36%, significantly lower than 95% and 72%, respectively, in men without persistence. Ten-year overall survival in patients with vs without persistence was 63% vs 80%. In men with persistence independent predictors of prostate specific antigen recurrence were higher prostate specific antigen nadir (HR 2.19, p <0.001), positive surgical margins (HR 1.75, p = 0.022) and high pathological Gleason score (8-10 vs 2-6 HR 2.40, p = 0.026). Independent predictors of overall mortality were a higher prostate specific antigen nadir (HR 1.46, p = 0.013) and seminal vesicle invasion (HR 3.15, p = 0.047). Conclusions: Prostate specific antigen persistence is associated with increased biochemical recurrence and overall mortality. In men with persistence the prostate specific antigen nadir is an independent predictor of recurrence and mortality. Thus, prostate specific antigen persistence and nadir are important tools for early postoperative risk stratification. C1 [Freedland, Stephen J.] Duke Univ, Sch Med, Div Urol, Dept Pathol, Durham, NC 27710 USA. [Moreira, Daniel M.; Freedland, Stephen J.] Duke Univ, Sch Med, Div Urol Surg, Dept Surg, Durham, NC 27710 USA. [Moreira, Daniel M.; Freedland, Stephen J.] Duke Univ, Sch Med, Duke Prostate Ctr, Durham, NC 27710 USA. [Moreira, Daniel M.; Freedland, Stephen J.] Vet Affairs Med Ctr Durham, Urol Sect, Durham, NC USA. [Presti, Joseph C., Jr.; Aronson, William J.] Stanford Univ, Med Ctr, Dept Urol, Palo Alto, CA 94304 USA. [Presti, Joseph C., Jr.] Vet Affairs Med Ctr, Urol Sect, Dept Surg, Palo Alto, CA 94304 USA. [Aronson, William J.] Univ Calif Los Angeles, Med Ctr, Dept Surg, Urol Sect,W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90024 USA. [Aronson, William J.] Univ Calif Los Angeles, Med Ctr, Dept Urol, Los Angeles, CA 90024 USA. [Kane, Christopher J.] Univ Calif San Diego, Med Ctr, Dept Surg, Div Urol, San Diego, CA 92103 USA. [Terris, Martha K.] Vet Affairs Med Ctr, Urol Sect, Div Surg, Augusta, GA USA. [Terris, Martha K.] Med Coll Georgia, Dept Surg, Div Urol Surg, Augusta, GA 30912 USA. [Amling, Christopher L.] Univ Alabama, Dept Surg, Div Urol, Birmingham, AL 35294 USA. RP Freedland, SJ (reprint author), Duke Univ, Sch Med, Div Urol, Dept Pathol, Box 2626 DUMC, Durham, NC 27710 USA. EM steve.freedland@duke.edu OI Terris, Martha/0000-0002-3843-7270 FU Department of Veterans Affairs; National Institute of Health [R01CA100938]; National Institutes of Health Specialized Programs of Research Excellence [P50 CA92131-01A1]; Georgia Cancer Coalition (MKT); Department of Defense; Prostate Cancer Research Program (SJF); American Urological Association Foundation; Astellas Rising Star in Urology Award (SJF) FX Supported by Department of Veterans Affairs, National Institute of Health R01CA100938 WIN, National Institutes of Health Specialized Programs of Research Excellence Grant P50 CA92131-01A1 (WJA), Georgia Cancer Coalition (MKT), Department of Defense, Prostate Cancer Research Program (SJF) and American Urological Association Foundation/Astellas Rising Star in Urology Award (SJF). NR 18 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD NOV PY 2009 VL 182 IS 5 BP 2250 EP 2255 DI 10.1016/j.juro.2009.07.022 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 506EO UT WOS:000270756900049 PM 19758614 ER PT J AU Bhoopalam, N Campbell, SC Moritz, T Broderick, WR Iyer, P Arcenas, AG Van Veldhuizen, PJ Friedman, N Reda, D Warren, S Garewal, H AF Bhoopalam, Nirmala Campbell, Steven C. Moritz, Thomas Broderick, William R. Iyer, Padmini Arcenas, Anthony G. Van Veldhuizen, Peter J. Friedman, Nicholas Reda, Domenic Warren, Stuart Garewal, Harinder TI Intravenous Zoledronic Acid to Prevent Osteoporosis in a Veteran Population With Multiple Risk Factors for Bone Loss on Androgen Deprivation Therapy SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; androgen antagonists; zoledronic acid; osteoporosis ID RANDOMIZED CONTROLLED-TRIAL; PROSTATE-CANCER; MINERAL DENSITY; CLINICAL FRACTURES; MEN; HEALTH AB Purpose: Androgen deprivation therapy for prostate cancer is associated with osteoporosis and increased fracture risk. Previous studies of zoledronic acid demonstrated bone loss prevention in patients initiating androgen deprivation therapy. There are limited data on patients on prolonged androgen deprivation therapy or in Veterans Affairs patients with multiple risk factors for osteoporosis. Methods: We randomized 93 patients with MO prostate cancer in this placebo controlled trial in the Veterans Affairs health care system. Preplanned strata included 50 patients on androgen deprivation therapy for less than 1 year (stratum 1) and 43 on androgen deprivation therapy for greater than 1 year (stratum 2). In each stratum patients were randomized to 4 mg zoledronic acid intravenously every 3 months for 4 treatments or intravenous placebo. The primary end point was the percent change in bone mineral density at the lumbar spine at 12 months. Results: Age, race, body mass index and osteoporosis risk factors were similar for the 2 treatments. Most patients were former smokers, had moderate alcohol intake, were not on calcium/vitamin D supplements and were relatively sedentary at baseline. In stratum 1 spine bone mineral density increased 5.95% in the zoledronic acid arm and decreased 3.23% in the placebo arm (p = 0.0044). In stratum 2 spine bone mineral density increased 6.08% in the zoledronic acid arm and only increased 1.57% in the placebo arm (p = 0.0005). Treatment was well tolerated with minimal impact on renal function. Conclusions: Zoledronic acid improved bone mineral density in patients with MO prostate cancer on androgen deprivation therapy for 1 year or less, or greater than 1 year. This finding indicates that bisphosphonate therapy remains effective when initiated later in the course of androgen deprivation therapy and is efficacious in Veterans Affairs patients with multiple risk factors for osteoporosis. C1 [Bhoopalam, Nirmala; Campbell, Steven C.; Moritz, Thomas; Broderick, William R.; Friedman, Nicholas; Reda, Domenic] US Dept Vet Affairs, Vet Affairs Edward Hines Jr Hosp, Hines, IL 60141 USA. [Iyer, Padmini] Vet Affairs Long Beach Healthcare Syst, Washington, DC USA. [Arcenas, Anthony G.] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Van Veldhuizen, Peter J.] Kansas City Vet Affairs, Kansas City, MO USA. [Warren, Stuart] Cooperat Studies Clin Res Pharm Coordinating Ctr, Albuquerque, NM USA. [Garewal, Harinder] So Arizona Vet Affairs Healthcare Syst, Tucson, AZ USA. RP Bhoopalam, N (reprint author), Loyola Univ Chicago, Edward Hines Vet Affairs Hosp, Stritch Sch Med, Bldg 200,Room 910,5000 S 5th Ave, Hines, IL 60141 USA. EM nirmala.bhoopalam@va.gov FU Novartis Pharmaceutical Corp., East Hanover, New Jersey FX Supported by a grant from Novartis Pharmaceutical Corp., East Hanover, New Jersey. NR 24 TC 29 Z9 29 U1 0 U2 6 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 NOV PY 2009 VL 182 IS 5 BP 2257 EP 2264 DI 10.1016/j.juro.2009.07.046 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 506EO UT WOS:000270756900052 PM 19758618 ER PT J AU Hirata, H Kawamoto, K Kikuno, N Kawakami, T Kawakami, K Saini, S Yamamura, S Dahiya, R AF Hirata, Hiroshi Kawamoto, Ken Kikuno, Nobuyuki Kawakami, Toshifumi Kawakami, Kazumori Saini, Sharanjot Yamamura, Soichiro Dahiya, Rajvir TI Restoring Erectile Function by Antioxidant Therapy in Diabetic Rats SO JOURNAL OF UROLOGY LA English DT Article DE penis; diabetes mellitus; gene expression; tempol; insulin ID OXIDATIVE STRESS; DYSFUNCTION; APOPTOSIS; IMPACT; PENIS; EXPRESSION; PROTEIN; MUSCLE; INJURY AB Purpose: Diabetes mediates an increase in reactive oxygen species that can lead to impaired endothelial function, decreased smooth muscle in the diabetic corpus cavernosum and increased apoptosis. We hypothesized that antioxidant therapy may restore erectile function by inhibiting apoptosis in diabetic rat crura. Materials and Methods: A total of 40 male Sprague-Dawley rats were randomized to 5 groups of 8 each, including healthy controls, rats with diabetes, and rats with diabetes with the antioxidant tempol. (4-hydroxytetramethyl-piperidine-1-oxyl) (Sigma-Aldrich (R)), with insulin, and with tempol and insulin. Intracavernous pressure was measured for functional analysis. Smooth muscle and collagen fiber levels in the rat penile corpus cavernosum were assessed by hematoxylin and eosin, and Masson's trichrome staining. Endothelial cells were assessed by CD31 staining. Reactive oxygen species related genes were analyzed by cDNA microarray. We confirmed mRNA and protein expression profiles for these genes in diabetic and treated rats using real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. TUNEL assay was done to analyze apoptosis status. Results: Intracavernous pressure in diabetic rats was significantly decreased vs controls. After treatment with tempol or insulin alone intracavernous pressure was significantly increased compared to that in untreated diabetic rats. In the diabetic group mean smooth muscle area significantly decreased but was restored after combined tempol and insulin. Endothelial cell area in diabetic rats significantly decreased and was not restored by any treatments. However, apoptosis was restored to normal by combined insulin and tempol. Of 84 reactive oxidative stress and antioxidant genes 32 were identified specific to diabetic rats compared to healthy controls. UCP3 expression was significantly increased in diabetic rats and normal levels were restored by all treatments. Conclusions: To our knowledge this is the first report that tempol and insulin can restore erectile function in diabetic rats by inhibiting apoptosis. C1 San Francisco VA Med Ctr, Dept Urol, San Francisco, CA USA. Univ Calif San Francisco, San Francisco, CA 94121 USA. RP Dahiya, R (reprint author), Vet Affairs Med Ctr, Urol Res Ctr, 112F,4150 Clement St, San Francisco, CA 94121 USA. EM rdahiya@urology.ucsf.edu FU NIDDK NIH HHS [R01DK075524] NR 21 TC 15 Z9 19 U1 0 U2 6 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 NOV PY 2009 VL 182 IS 5 BP 2518 EP 2525 DI 10.1016/j.juro.2009.07.009 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 506EO UT WOS:000270756900142 PM 19765757 ER PT J AU Groeneveld, PW Yang, L Greenhut, A Yang, FF AF Groeneveld, Peter W. Yang, Lin Greenhut, Alexis Yang, Feifei TI Comparative effectiveness of carotid arterial stenting versus endarterectomy SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID HIGH-RISK PATIENTS; RANDOMIZED-TRIAL; CLINICAL-TRIAL; STENOSIS AB Background Carotid arterial stent (CAS) systems are an alterative to carotid endarterectomy for the treatment of moderate to severe carotid stenosis, but the effectiveness of CAS compared to endarterectomy in preventing stroke and death is uncertain. This study's objective was to compare the clinical outcomes among Medicare beneficiaries undergoing carotid revascularization before and after CAS became widely available. Objectives. This observational, retrospective cohort study compared 46,784 patients undergoing carotid revascularization from August 2005-March 2006 (the coverage era) to propensity-score-matched patients undergoing carotid revascularization between October 2002-September 2004 (the pre-coverage era), before widespread Medicare coverage of CAS. Methods. Mortality was compared at 90 and 270 days after revascularization, as were the combined outcomes of periprocedural acute myocardial infarction and any stroke or death within 90 and 270 days after revascularization, between the two eras. Comparisons were also made between localities with high (23% of carotid procedures being CAS) and lower (9% of carotid procedures being CAS) adoption rates of carotid stents during the coverage era. Results: There were no significant differences in 90-day mortality (2.2% vs; 2.2%; P = .79), 90-day combined outcomes (4.5% vs 4.3%; P = .13), or 270-day mortality (4.8% vs 4.6%; P = .17) between the coverage and pre-coverage eras, but there were more 270-day combined outcomes in the coverage era (7.7% vs 7.3%; P = .03). In localities with higher adoption of carotid stents, there was higher 90-day mortality (adjusted odds ratio [OR] 1.15; P = .16), 90-day combined outcomes (OR = 1.17; P = .03), 270-day mortality (OR = 1.13; P = .07), and 270-day combined outcomes (OR = 1.10; P = .09) in the coverage era. There were no differences in event rates between eras in areas with lower carotid stent adoption. Conclusion: The adoption of carotid stents for treatment of carotid stenosis was associated with increased rates of adverse clinical outcomes after carotid revascularization. (J Vasc Surg 2009;50:1040-8.) C1 [Groeneveld, Peter W.] Philadelphia Vet Affairs Med Ctr, Dept Med, Philadelphia, PA USA. [Groeneveld, Peter W.; Yang, Lin; Greenhut, Alexis; Yang, Feifei] Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA 19104 USA. [Groeneveld, Peter W.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. RP Groeneveld, PW (reprint author), 1229 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM peter.groeneveld@va.gov FU NHLBI NIH HHS [1-R01-HL086919, R01 HL086919-02, R01 HL086919] NR 22 TC 10 Z9 10 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD NOV PY 2009 VL 50 IS 5 BP 1040 EP 1048 DI 10.1016/j.jvs.2009.05.054 PG 9 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 514JL UT WOS:000271390300011 PM 19628358 ER PT J AU Hovav, AH Santosuosso, M Bivas-Benita, M Plair, A Cheng, A Elnekave, M Righi, E Chen, T Kashiwagi, S Panas, MW Xiang, SH Furmanov, K Letvin, NL Poznansky, MC AF Hovav, Avi-Hai Santosuosso, Michael Bivas-Benita, Maytal Plair, Andre Cheng, Alex Elnekave, Mazal Righi, Elda Chen, Tao Kashiwagi, Satoshi Panas, Michael W. Xiang, Shi-Hua Furmanov, Karina Letvin, Norman L. Poznansky, Mark C. TI X4 Human Immunodeficiency Virus Type 1 gp120 Down-Modulates Expression and Immunogenicity of Codelivered Antigens SO JOURNAL OF VIROLOGY LA English DT Article ID CD8(+) T-CELLS; IMMUNE-RESPONSES; ENVELOPE PROTEIN; HIV-1 ENVELOPE; DNA VACCINATION; IN-VIVO; GAG-POL; GLYCOPROTEIN; PROGRESSION; ANTIBODIES AB In order to increase the immune breadth of human immunodeficiency virus (HIV) vaccines, strategies such as immunization with several HIV antigens or centralized immunogens have been examined. HIV-1 gp120 protein is a major immunogen of HIV and has been routinely considered for inclusion in both present and future AIDS vaccines. However, recent studies proposed that gp120 interferes with the generation of immune response to codelivered antigens. Here, we investigate whether coimmunization with plasmid-encoded gp120 alters the immune response to other coadministered plasmid encoded antigens such as luciferase or ovalbumin in a mouse model. We found that the presence of gp120 leads to a significant reduction in the expression level of the codelivered antigen in vivo. Antigen presentation by antigen-presenting cells was also reduced and resulted in the induction of weak antigen-specific cellular and humoral immune responses. Importantly, gp120-mediated immune interference was observed after administration of the plasmids at the same or at distinct locations. To characterize the region in gp120 mediating these effects, we used plasmid constructs encoding gp120 that lacks the V1V2 loops (Delta V1V2) or the V3 loop (Delta V3). After immunization, the Delta V1V2, but not the Delta V3 construct, was able to reduce antigen expression, antigen presentation, and subsequently the immunogenicity of the codelivered antigen. The V3 loop dependence of this phenomenon seems to be limited to V3 loops known to interact with the CXCR4 molecule but not with CCR5. Our study presents a novel mechanism by which HIV-1 gp120 interferes with the immune response against coadministered antigen in a polyvalent vaccine preparation. C1 [Hovav, Avi-Hai] Hebrew Univ Jerusalem, Hadassah Fac Dent Med, Inst Dent Sci, Hadassah Sch Dent Med, IL-91120 Jerusalem, Israel. [Santosuosso, Michael; Plair, Andre; Cheng, Alex; Righi, Elda; Chen, Tao; Kashiwagi, Satoshi; Poznansky, Mark C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Partners AIDS Res Ctr,Dept Infect Dis, Charlestown, MA 02129 USA. [Bivas-Benita, Maytal; Panas, Michael W.; Letvin, Norman L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02115 USA. [Xiang, Shi-Hua] Dana Farber Canc Inst, Canc Immunol & AIDS, Boston, MA 02115 USA. RP Hovav, AH (reprint author), Hebrew Univ Jerusalem, Hadassah Fac Dent Med, Inst Dent Sci, Hadassah Sch Dent Med, POB 122722, IL-91120 Jerusalem, Israel. EM avihaih@ekmd.huji.ac.il FU Israeli Ministry of Health [300000-4790]; National Institutes of Health [RO1 AI49757]; National Institute of Allergy and Infection Diseases Center for HIV/AIDS Vaccine Immunology [AI067854]; Canadian Institutes of Heath Research FX This study received financial support from the Israeli Ministry of Health (300000-4790 [A.-H. H.]). M. C. P. was supported by National Institutes of Health grant RO1 AI49757, N. L. L. was supported by the National Institute of Allergy and Infection Diseases Center for HIV/AIDS Vaccine Immunology (AI067854), and M. S. was funded by the Canadian Institutes of Heath Research. NR 29 TC 10 Z9 10 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD NOV PY 2009 VL 83 IS 21 BP 10941 EP 10950 DI 10.1128/JVI.00394-09 PG 10 WC Virology SC Virology GA 504FW UT WOS:000270602300009 PM 19692474 ER PT J AU Li, Y Kar, AK Sodroski, J AF Li, Yuan Kar, Alak Kanti Sodroski, Joseph TI Target Cell Type-Dependent Modulation of Human Immunodeficiency Virus Type 1 Capsid Disassembly by Cyclophilin A SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; TRIM5-ALPHA RESTRICTION FACTOR; CYCLOSPORINE-A-RESISTANT; OLD-WORLD MONKEY; GAG PROTEIN; REVERSE TRANSCRIPTION; RETROVIRUS INFECTION; VIRAL REPLICATION; HIV-1 INFECTIVITY; TERMINAL DOMAIN AB The binding of cyclophilin A (CypA) to the human immunodeficiency virus type 1 (HIV-1) capsid protein (CA protein) is required soon after virus entry into natural target cells. In Jurkat T lymphocytes, disrupting CypA-CA interaction either by cyclosporine (Cs) treatment or by alteration (e. g., P90A) of the CA inhibits HIV-1 infection. In HeLa cells, however, treatment with Cs or Cs analogues minimally inhibits the early phase of HIV-1 infection but selects for a Cs-dependent virus with a change (A92E) in CA. To understand these phenomena, we examined the effects of the P90A and A92E changes in the HIV-1 CA protein on the stability of capsid complexes assembled in vitro and on capsid disassembly in the cytosol of virus-exposed target cells. The A92E change impaired CA-CA interactions in vitro and decreased the amount of particulate capsids in the cytosol of HeLa target cells. Reducing the binding of CypA to the A92E mutant capsid, either by Cs treatment or by an additional P90A change in the CA protein, increased the amount of particulate capsids and viral infectivity in HeLa cells. In contrast, reduction of the binding of CypA to HIV-1 capsids in Jurkat T lymphocytes resulted in a decrease in the amount of particulate capsids and infectivity. Thus, depending on the capsid and the target cell, CypA-CA binding either stabilized or destabilized the capsid, indicating that CypA modulates HIV-1 capsid disassembly. In both cell types examined, decreased stability of the capsid was associated with a decrease in the efficiency of HIV-1 infection. C1 [Li, Yuan; Kar, Alak Kanti; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Div AIDS, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Div AIDS, 44 Binney St,CLS 1010, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu RI Li, Yuan/B-4098-2013 FU National Institutes of Health [AI063987, AI076094]; Center for AIDS Research Award [AI06354]; International AIDS Vaccine Initiative FX This study was supported by the National Institutes of Health (AI063987 and AI076094), Center for AIDS Research Award AI06354, the International AIDS Vaccine Initiative, and the late William F. McCarty-Cooper. NR 61 TC 62 Z9 62 U1 2 U2 5 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 NOV PY 2009 VL 83 IS 21 BP 10951 EP 10962 DI 10.1128/JVI.00682-09 PG 12 WC Virology SC Virology GA 504FW UT WOS:000270602300010 PM 19656870 ER PT J AU Cohen, MH Fabri, M Cai, XT Shi, QH Hoover, DR Binagwaho, A Culhane, MA Mukanyonga, H Karegeya, DK Anastos, K AF Cohen, Mardge H. Fabri, Mary Cai, Xiaotao Shi, Qiuhu Hoover, Donald R. Binagwaho, Agnes Culhane, Melissa A. Mukanyonga, Henriette Karegeya, Davis Ksahaka Anastos, Kathryn TI Prevalence and Predictors of Posttraumatic Stress Disorder and Depression in HIV-Infected and At-Risk Rwandan Women SO JOURNAL OF WOMENS HEALTH LA English DT Article ID INTIMATE-PARTNER VIOLENCE; MENTAL-HEALTH; SOUTH-AFRICA; POSTWAR AFGHANISTAN; DOMESTIC VIOLENCE; SYMPTOMS; HIV/AIDS; MORTALITY; ABUSE; PROGRESSION AB Objective: During the 1994 Rwandan genocide, rape was used as a weapon of war to transmit HIV. This study measures trauma experiences of Rwandan women and identifies predictors associated with posttraumatic stress disorder (PTSD) and depressive symptoms. Methods: The Rwandan Women's Interassociation Study and Assessment (RWISA) is a prospective observational cohort study designed to assess effectiveness and toxicity of antiretroviral therapy in HIV-infected Rwandan women. In 2005, a Rwandan-adapted Harvard Trauma Questionnaire (HTQ) and the Center for Epidemiologic Studies Depression Scale (CES-D) were used to assess genocide trauma events and prevalence of PTSD (HTQ mean > 2) and depressive symptoms (CES-D >= 16) for 850 women (658 HIV-positive and 192 HIV-negative). Results: PTSD was common in HIV-positive (58%) and HIV-negative women (66%) (p - 0.05). Women with HIV had a higher prevalence of depressive symptoms than HIV-negative women (81% vs. 65%, p<0.0001). Independent predictors for increased PTSD were experiencing more genocide-related trauma events and having more depressive symptoms. Independent predictors for increased depressive symptoms were making <$18 a month, HIV infection (and, among HIV-positive women, having lower CD4 cell counts), a history of genocidal rape, and having more PTSD symptoms. Conclusions: The prevalence of PTSD and depressive symptoms is high in women in the RWISA cohort. Four of five HIV-infected women had depressive symptoms, with highest rates among women with CD4 cell counts <200. In addition to treatment with antiretroviral therapy, economic empowerment and identification and treatment of depression and PTSD may reduce morbidity and mortality among women in postconflict countries. C1 [Cohen, Mardge H.] John Stroger Hosp, Dept Med, Chicago, IL USA. [Cohen, Mardge H.] Rush Univ, Dept Med, Chicago, IL 60612 USA. [Fabri, Mary] Heartland Alliance Marjorie Kovler Ctr, Chicago, IL USA. [Cai, Xiaotao] Data Solut LLC, Bronx, NY USA. [Shi, Qiuhu] New York Med Coll, Sch Publ Hlth, Valhalla, NY 10595 USA. [Hoover, Donald R.] Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, New Brunswick, NJ 08903 USA. [Hoover, Donald R.] Rutgers State Univ, Dept Stat & Biostat, New Brunswick, NJ 08903 USA. [Culhane, Melissa A.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Mukanyonga, Henriette] Rwanda Womens Interassoc Study & Assessment, Kigali, Rwanda. [Karegeya, Davis Ksahaka] Forum Activistes Torture Rwanda, Kigali, Rwanda. [Anastos, Kathryn] Montefiore Med Ctr, Dept Med, Bronx, NY 10467 USA. [Anastos, Kathryn] Montefiore Med Ctr, Dept Epidemiol, Bronx, NY 10467 USA. [Anastos, Kathryn] Montefiore Med Ctr, Dept Populat Hlth, Bronx, NY 10467 USA. [Anastos, Kathryn] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Cohen, MH (reprint author), 2020 W Harrison, Chicago, IL 60612 USA. EM mardge.cohen@gmail.com FU NIAID NIH HHS [AI-51519, U01-AI-35004]; NIDDK NIH HHS [DK54615]; PHS HHS [U01-A1- 34993] NR 45 TC 19 Z9 19 U1 1 U2 10 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD NOV PY 2009 VL 18 IS 11 BP 1783 EP 1791 DI 10.1089/jwh.2009.1367 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 525XH UT WOS:000272250500008 PM 19951212 ER PT J AU Galofre, JC Davies, TF AF Galofre, Juan C. Davies, Terry F. TI Autoimmune Thyroid Disease in Pregnancy: A Review SO JOURNAL OF WOMENS HEALTH LA English DT Review ID SUBCLINICAL HYPOTHYROIDISM; ENDOCRINE-SOCIETY; LEVOTHYROXINE REQUIREMENTS; CLINICAL ENDOCRINOLOGISTS; AMERICAN ASSOCIATION; FETAL MICROCHIMERISM; JOINT STATEMENT; DYSFUNCTION; MANAGEMENT; WOMEN AB The maternal physiological changes that occur in normal pregnancy induce complex endocrine and immune responses. During a normal pregnancy, thyroid gland volume may enlarge, and thyroid hormone production increases. Hence, the interpretation of thyroid function during gestation needs to be adjusted according to pregnancy-specific ranges. The elevated prevalence of gestation-related thyroid disorders (10%-15%) and the important repercussions for both mother and fetus reported in multiple studies throughout the world denote, in our opinion, the necessity for routine thyroid function screening both before and during pregnancy. Once thyroid dysfunction is suspected or confirmed, management of the thyroid disorder necessitates regular monitoring in order to ensure a successful outcome. The aim of treating hyperthyroidism in pregnancy with antithyroid drugs is to maintain serum thyroxine (T-4) in the upper normal range of the assay used with the lowest possible dose of drug, whereas in hypothyroidism, the goal is to return serum thyroid-stimulating hormone (TSH) to the range between 0.5 and 2.5mU/L. C1 [Galofre, Juan C.; Davies, Terry F.] Mt Sinai Hosp, Mt Sinai Sch Med, Thyroid Res Unit, New York, NY 10029 USA. [Galofre, Juan C.; Davies, Terry F.] James J Peters VA Med Ctr, New York, NY 10029 USA. [Galofre, Juan C.] Univ Navarra, Dept Endocrinol & Nutr, Clin Univ, E-31080 Pamplona, Spain. RP Davies, TF (reprint author), Mt Sinai Med Ctr, Box 1055,1 Gustave L Levy Pl, New York, NY 10029 USA. EM terry.davies@mssm.edu NR 74 TC 14 Z9 14 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 EI 1931-843X J9 J WOMENS HEALTH JI J. Womens Health PD NOV PY 2009 VL 18 IS 11 BP 1847 EP 1856 DI 10.1089/jwh.2008.1234 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 525XH UT WOS:000272250500017 PM 19951221 ER PT J AU VanSwearingen, JM Perera, S Brach, JS Cham, R Rosano, C Studenski, SA AF VanSwearingen, Jessie M. Perera, Subashan Brach, Jennifer S. Cham, Rakie Rosano, Caterina Studenski, Stephanie A. TI A Randomized Trial of Two Forms of Therapeutic Activity to Improve Walking: Effect on the Energy Cost of Walking SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article DE Exercise; Gait; Energy cost ID DWELLING OLDER-ADULTS; HEMIPARETIC STROKE PATIENTS; LOWER-EXTREMITY FUNCTION; STEP WIDTH VARIABILITY; PHYSICAL PERFORMANCE; GAIT VARIABILITY; AEROBIC EXERCISE; FALL RISK; METABOLIC COST; HEART-RATE AB Background. Therapeutic activities to improve mobility often include walking practice and exercises to improve deficits in endurance, strength. and balance. Because walking may also be energy inefficient in people with decreased mobility, another approach is to reduce energy cost by improving timing and coordination (TC) of movement. Methods. This pilot randomized trial of older adults with slow and variable gait offered two types of therapeutic activity over 12 weeks. One addressed Walking, Endurance, Balance, and Strength (WEBS) and the other focused on TC. Outcomes were energy cost of walking and measures of mobility. Results. Of 50 participants (mean age. 77.2 +/- 5.5 years, 65% women). 47 completed the study. Baseline gait speed was 0.85 +/- 0.13 m/s and energy cost of walking was 0.30 +/- 0.10 mL/kg/m, nearly twice normal. Both interventions increased gait speed (TC by 0.21 m/s and WEBS by 0.14 m/s, p < .001). TC reduced the energy cost of walking 0.10 +/- 0.03 mL/kg/m more than WEBS (p < .001) and reduced the modified Gait Abnormalities Rating Scale 1.5 +/- 0.6 more points than WEBS (p < .05). TC had a 9.8 +/- 3.5 points greater gain than WEBS in self-reported confidence in walking (p < .01). Conclusions. In older adults with slow and variable gait, activity focused on TC reduced the energy cost of walking and improved confidence in walking more than WEBS while generating at least equivalent gains in mobility. To optimize mobility, future larger studies should assess various combinations of TC and WEBS over longer periods of time. C1 [VanSwearingen, Jessie M.; Brach, Jennifer S.] Univ Pittsburgh, Dept Phys Therapy, Sch Hlth & Rehabil Sci, Pittsburgh, PA 15260 USA. [Perera, Subashan; Studenski, Stephanie A.] Univ Pittsburgh, Sch Med, Dept Med, Div Geriatr Med, Pittsburgh, PA 15260 USA. [Cham, Rakie] Univ Pittsburgh, Sch Engn, Dept Bioengn, Pittsburgh, PA 15260 USA. [Rosano, Caterina] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. [Studenski, Stephanie A.] VA Pittsburgh Healthcare Syst, GRECC, Pittsburgh, PA USA. RP VanSwearingen, JM (reprint author), Univ Pittsburgh, Dept Phys Therapy, Sch Hlth & Rehabil Sci, 6035 Forbes Tower, Pittsburgh, PA 15260 USA. EM jessievs@pitt.edu RI Perera, Subashan/D-7603-2014 FU NIA NIH HHS [AG023641, 1 K23 AG026766-01, P30 AG024827, 1 P30 AG024827] NR 84 TC 36 Z9 36 U1 7 U2 12 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 NOV PY 2009 VL 64 IS 11 BP 1190 EP 1198 DI 10.1093/gerona/glp098 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 509UU UT WOS:000271044900015 PM 19643842 ER PT J AU Siedlecki, KL Tatarina, O Sanders, L Albert, M Blacker, D Dubois, B Brandt, J Stern, Y AF Siedlecki, Karen L. Tatarina, Oksana Sanders, Linda Albert, Marilyn Blacker, Deborah Dubois, Bruno Brandt, Jason Stern, Yaakov TI Comparison of Patient and Caregiver Reports of Patient Activity Participation and Its Relationship to Mental Health in Patients With Alzheimer's Disease SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article DE Activities; Alzheimer's disease; Invariance analyses; Structural equation modeling ID QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIAL; EVENTS SCHEDULE-AD; COGNITIVE IMPAIRMENT; DEMENTIA; MULTICENTER; DEPRESSION; PREDICTORS; CARE AB The relationship between engagement in pleasant activities as rated by the patient and as rated by the caregiver from the patient's perspective was examined using structural equation modeling in a sample of patients (N=277) diagnosed with mild to moderate Alzheimer's disease. The two activity participation ratings were only moderately related to one another. Furthermore, depression was the only significant predictor of the patient-rated activity participation, whereas severity of depression, degree of personality change, level of dependence, and cognition were all significant predictors of caregiver-rated activity participation. These findings suggest that caregivers consider a wider range of variables when evaluating the patient's engagement in activities than does the patient. Predictors of patient-rated activity participation did not differ as a function of age or cognition. C1 [Siedlecki, Karen L.; Tatarina, Oksana; Sanders, Linda; Stern, Yaakov] Columbia Univ, Cognit Neurosci Div, Taub Inst, New York, NY 10032 USA. [Albert, Marilyn] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Blacker, Deborah] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Dubois, Bruno] Hop La Pitie Salpetriere, Dept Neurol, Paris, France. RP Siedlecki, KL (reprint author), Columbia Univ, Cognit Neurosci Div, Taub Inst, 630 W 168th St, New York, NY 10032 USA. EM ks2513@columbia.edu OI Brandt, Jason/0000-0001-7381-6244 FU National Institute of Health [AG07370, RR00645]; NIMH [T32MH020004-09] FX This study was supported by National Institute of Health federal grants AG07370 and RR00645. KLS is supported as a trainee by a grant (T32MH020004-09) from the NIMH. NR 29 TC 9 Z9 9 U1 0 U2 3 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD NOV PY 2009 VL 64 IS 6 BP 687 EP 695 DI 10.1093/geronb/gbp071 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 518TY UT WOS:000271718200001 PM 19805487 ER PT J AU Mehrotra, R Kermah, DA Salusky, IB Wolf, MS Thadhani, RI Chiu, YW Martins, D Adler, SG Norris, KC AF Mehrotra, Rajnish Kermah, Dulcie A. Salusky, Isidro B. Wolf, Myles S. Thadhani, Ravi I. Chiu, Yi-Wen Martins, David Adler, Sharon G. Norris, Keith C. TI Chronic kidney disease, hypovitaminosis D, and mortality in the United States SO KIDNEY INTERNATIONAL LA English DT Article DE cardiovascular; chronic kidney disease; mortality; non-cardiovascular; vitamin D ID SERUM 25-HYDROXYVITAMIN-D STATUS; VITAMIN-D DEFICIENCY; HEMODIALYSIS-PATIENTS; ASSOCIATION; SURVIVAL; RISK; NEPHROPATHY; POPULATION; PREVALENCE; EXPRESSION AB Low serum 25-hydroxy vitamin D (25OHD) predicts a higher cardiovascular risk in the general population. Because patients with chronic kidney disease are more likely to have low serum 25OHD, we determined the relationship between hypovitaminosis D and death in this group. Analysis was done using a cohort composed of 3011 patients from the Third National Health and Nutrition Examination Survey who had chronic kidney disease but were not on dialysis and who had a mean follow-up of 9 years. In analyses adjusted for demographics, cardiovascular risk factors, serum phosphorus, albumin, hemoglobin, stage of chronic kidney disease, albuminuria, and socioeconomic status, individuals with serum 25OHD levels less than 15 ng/ml had an increased risk for all-cause mortality when compared to those with levels over 30 ng/ml. This significantly higher risk for death with low serum 25OHD was evident in 15 of the 23 subgroups. The higher risk for cardiovascular and non-cardiovascular mortality became statistically nonsignificant on multivariable adjustment. The trend for higher mortality in patients with 25OHD levels 15-30 ng/ml was not statistically significant. Our results indicate there is a graded relationship between serum 25OHD and the risk for death among subjects with chronic kidney disease who are not undergoing dialysis. Randomized, controlled trials are needed to conclusively determine whether vitamin D supplementation reduces mortality. Kidney International (2009) 76, 977-983; doi:10.1038/ki.2009.288; published online 5 August 2009 C1 [Mehrotra, Rajnish; Adler, Sharon G.] Los Angeles Biomed Res Inst, Div Nephrol & Hypertens, Dept Med, Torrance, CA 90502 USA. [Mehrotra, Rajnish; Salusky, Isidro B.; Adler, Sharon G.; Norris, Keith C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. [Mehrotra, Rajnish; Salusky, Isidro B.; Adler, Sharon G.; Norris, Keith C.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA. [Kermah, Dulcie A.; Martins, David; Norris, Keith C.] Charles Drew Univ, Dept Med, Los Angeles, CA USA. [Wolf, Myles S.] Univ Miami, Miller Sch Med, Dept Med, Miami, FL 33136 USA. [Thadhani, Ravi I.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Renal Unit, Boston, MA USA. [Chiu, Yi-Wen] Kaohsiung Med Univ, Dept Med, Kaohsiung, Taiwan. RP Mehrotra, R (reprint author), Los Angeles Biomed Res Inst, Div Nephrol & Hypertens, Dept Med, 1124 W Carson St, Torrance, CA 90502 USA. EM rmehrotra@labiomed.org RI Chiu, Yi-Wen/D-5041-2009 FU NIH [RR18298, RR019234, RR14616, RR11145, MD00182]; NIDDK [35423, 67563, HL 093954]; NCRR [RR 00865]; [R01DK076116]; [R01DK081374] FX Rajnish Mehrotra is supported by a grant from the NIH (RR18298 and RR019234) and DaVita. Isidro B. Salusky is supported by grants from NIDDK (35423 and 67563) and NCRR (RR 00865), Myles Wolf by R01DK076116 and R01DK081374, and Ravi Thadhani by a grant from NIDDK (HL 093954). Dulcie Kermah, David Martins, and Keith Norris are supported by NIH grants RR14616, RR11145, RR019234, and MD00182. NR 30 TC 114 Z9 124 U1 0 U2 4 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 NOV PY 2009 VL 76 IS 9 BP 977 EP 983 DI 10.1038/ki.2009.288 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 507LC UT WOS:000270853800010 PM 19657329 ER PT J AU Johansen, KL Zhang, R Huang, YJ Chen, SC Blagg, CR Goldfarb-Rumyantzev, AS Hoy, CD Lockridge, RS Miller, BW Eggers, PW Kutner, NG AF Johansen, Kirsten L. Zhang, Rebecca Huang, Yijian Chen, Shu-Cheng Blagg, Christopher R. Goldfarb-Rumyantzev, Alexander S. Hoy, Chistopher D. Lockridge, Robert S., Jr. Miller, Brent W. Eggers, Paul W. Kutner, Nancy G. TI Survival and hospitalization among patients using nocturnal and short daily compared to conventional hemodialysis: a USRDS study SO KIDNEY INTERNATIONAL LA English DT Article DE daily hemodialysis; hospitalization; survival; USRDS ID LEFT-VENTRICULAR HYPERTROPHY; QUALITY-OF-LIFE; IN-CENTER HEMODIALYSIS; VASCULAR ACCESS; HOME HEMODIALYSIS; DAILY DIALYSIS; LONG-TERM; COST; MORTALITY; TRIAL AB We estimated the survival and hospitalization among frequent hemodialysis users in comparison to those patients undergoing thrice-weekly conventional hemodialysis. All patients had similar characteristics and medical histories. In this cohort study of frequent hemodialysis users and propensity score-matched controls, the collaborating clinicians identified 94 patients who used nocturnal hermodialysis (NHD) and 43 patients who used short-duration daily hemodialysis (SDHD) for a minimum of 60 days. Ten propensity score-matched control patients for each NHD and SDHD patient were identified from the United States Renal Data System database. Primary outcomes were risk for all-cause mortality and risk for the composite outcome of mortality or major morbid event (acute myocardial infarction or stroke) estimated using Cox proportional hazards models. Risks for all-cause, cardiovascular-related, infection-related, and vascular access-related hospital admissions were also studied. Nocturnal hemodialysis was associated with significant reductions in mortality risk and risk for mortality or major morbid event when compared to conventional hemodialysis. There was a reduced but non-significant risk of death for patients using SDHD compared to controls. All-cause and specific hospitalizations did not differ significantly between NHD and SDHD patients and their matched control cohorts. Our study suggests that NHD may improve patient survival. Kidney International (2009) 76, 984-990; doi:10.1038/ki.2009.291; published online 19 August 2009 C1 [Kutner, Nancy G.] Emory Univ, Dept Rehabil Med, USRDS Rehabil QoL Special Studies Ctr, Atlanta, GA 30322 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Nephrol Sect, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. [Johansen, Kirsten L.] Univ Calif San Francisco, Div Nephrol, San Francisco, CA 94143 USA. [Chen, Shu-Cheng] USRDS Coordinating Ctr, Minneapolis, MN USA. [Blagg, Christopher R.] NW Kidney Ctr, Seattle, WA USA. [Goldfarb-Rumyantzev, Alexander S.] Harvard Univ, Sch Med, Boston, MA USA. [Hoy, Chistopher D.] Rubin Dialysis Ctr, Saratoga Springs, NY USA. [Lockridge, Robert S., Jr.] Lynchburg Nephrol Dialysis, Lynchburg, VA USA. [Miller, Brent W.] Washington Univ, Sch Med, St Louis, MO USA. [Eggers, Paul W.] NIDDK, NIH, Bethesda, MD USA. RP Kutner, NG (reprint author), Emory Univ, Dept Rehabil Med, USRDS Rehabil QoL Special Studies Ctr, 1441 Clifton Rd NE, Atlanta, GA 30322 USA. EM nkutner@emory.edu FU National Institutes of Health [N01-DK-1-2471, HHSN267200715004C] FX This study was supported by the National Institutes of Health contracts N01-DK-1-2471 and HHSN267200715004C, ADB No. N01-DK-7-5004. The interpretation and reporting of the data presented here are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the United States government. An abstract was presented in poster form at the annual meeting of the American Society of Nephrology; 3 November 2007, San Francisco, CA, USA. NR 37 TC 101 Z9 101 U1 0 U2 2 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 NOV PY 2009 VL 76 IS 9 BP 984 EP 990 DI 10.1038/ki.2009.291 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 507LC UT WOS:000270853800011 PM 19692997 ER PT J AU Shakespeare, T Lezzoni, LI Groce, NE AF Shakespeare, Tom Lezzoni, Lisa I. Groce, Nora E. TI The art of medicine Disability and the training of health professionals SO LANCET LA English DT Editorial Material C1 [Shakespeare, Tom] WHO, Dept Violence & Injury Prevent & Disabil, CH-1211 Geneva 27, Switzerland. [Lezzoni, Lisa I.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Groce, Nora E.] UCL, Leonard Cheshire Ctr Disabil & Inclus Dev, London, England. RP Shakespeare, T (reprint author), WHO, Dept Violence & Injury Prevent & Disabil, CH-1211 Geneva 27, Switzerland. EM shakespearet@who.int NR 8 TC 47 Z9 47 U1 0 U2 8 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 NOV-DEC PY 2009 VL 374 IS 9704 BP 1815 EP 1816 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 527MC UT WOS:000272370200017 PM 19957403 ER PT J AU Burns, JA Kim, KH Kobler, JB deBoer, JF Lopez-Guerra, G Zeitels, SM AF Burns, James A. Kim, Ki Hean Kobler, James B. deBoer, Johannes F. Lopez-Guerra, Gerardo Zeitels, Steven M. TI Real-Time Tracking of Vocal Fold Injections With Optical Coherence Tomography SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT 130th Annual Meeting of the American-Laryngological-Association Combined Otolaryngology Spring Meeting CY MAY 28, 2009 CL Phoenix, AZ SP Amer Laryngol Assoc DE Optical coherence tomography; larynx; glottis; vocal fold; vocal fold injection ID IN-VIVO AB Objectives/Hypothesis: Optical coherence tomography (OCT) is a promising new imaging modality that can help discern the layered microstructure of vocal folds. In the future, subepithelial injections of implants will improve vocal fold pliability where there is stiffness of phonatory mucosa. Using OCT both to delineate the depth of subepithelial injections real-time and to serially image the implant over time would be valuable, and has not been demonstrated previously. Study Design: Ex vivo study using excised calf larynges and survival study using canines in vivo. Methods: An investigation was done employing real-time OCT imaging of subepithelial injection pulses into phonatory mucosa of four calf larynges ex vivo to track the presence of subepithelial implants in phonatory mucosa in a survival study using an in vivo canine model. Results: OCT readily identified polyethylene glycol (PEG)-based hydrogel in the subepithelial plane in both the ex vivo calf study and the in vivo canine study. Ex vivo calf images correlated with histological specimens obtained immediately postinjection. Images obtained in this study provide confirmation of the hydrogel injection depth in real time, and allow for the implant to be tracked during a canine survival study. Conclusions: OCT can confirm subepithelial placement of hydrogel implant in the vocal fold with sufficient resolution to provide instantaneous feedback of an injection pulse. Survival studies in an in vivo canine model indicate that OCT can potentially be helpful in monitoring rheologically appropriate implants within the superficial lamina propria. C1 [Burns, James A.; Kobler, James B.; Lopez-Guerra, Gerardo; Zeitels, Steven M.] Harvard Univ, Sch Med, Ctr Laryngeal Surg & Voice Rehabil, Dept Surg, Boston, MA 02114 USA. [Kim, Ki Hean] Harvard Univ, Sch Med, Wellman Ctr Photomed, Massachusetts Gen Hosp, Boston, MA 02114 USA. [deBoer, Johannes F.] Vrije Univ Amsterdam, Dept Phys, Amsterdam, Netherlands. RP Burns, JA (reprint author), Harvard Univ, Sch Med, Ctr Laryngeal Surg & Voice Rehabil, Massachusetts Gen Hosp, 1 Bowdoin Sq,11th Floor, Boston, MA 02114 USA. EM burns.james@mgh.harvard.edu RI de Boer, Johannes/B-7590-2012; OI de Boer, Johannes/0000-0003-1253-4950; Lopez-Guerra, Gerardo/0000-0003-0305-4680 NR 18 TC 16 Z9 18 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2009 VL 119 IS 11 BP 2182 EP 2186 DI 10.1002/lary.20654 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 518LG UT WOS:000271692900018 PM 19676103 ER PT J AU Herrera, VLM Viereck, JC Lopez-Guerra, G Kumai, Y Kobler, J Karajanagi, S Park, H Hillman, R Zeitels, SM AF Herrera, Victoria L. M. Viereck, Jason C. Lopez-Guerra, Gerardo Kumai, Yoshihiko Kobler, James Karajanagi, Sandeep Park, Hyoungshin Hillman, Robert Zeitels, Steven M. TI 11.7 Tesla Magnetic Resonance Microimaging of Laryngeal Tissue Architecture SO LARYNGOSCOPE LA English DT Article DE 11.7 T MRI; microimaging; VF implants; vocal fold scar ID MRI AB Objectives/Hypothesis: High-resolution imaging of vocal folds that distinguishes vocal fold (VF) layered microstructure and VF implants would provide a key experimental tool for translational research investigating biomaterial-based interventions to treat vocal fold scar. To establish proof of concept, we studied whether 11.7 Tesla (T) magnetic resonance (MR) microimaging provides the needed resolution to resolve vocal fold tissue architecture. Study Design: We performed ex vivo MR microimaging of fixed ferret and canine larynges to determine whether changes in the layered architecture can be detected in the presence of scar and subsequent to biomaterial injections into the vocal folds. Serial section histological analyses were done to corroborate MR microimaging findings. Methods: Multiple axial and transverse/coronal 300-mu m slices were obtained using an 11.7 T MR speetrometer/500 MHz for proton with gradient-recalled echo and rapid acquisition with relaxation enhancement imaging sequences. Results: High-resolution (39 mu m/pixel) MR microimages distinguished VF epithelium, lamina propria, muscle, and cartilage in ferret and canine larynges. In ferret scarred VFs (n = 25), collagen-rich dense scar tissue was distinguishable from contralateral nonscarred VFs and from normal ferret VFs (n = 25), as confirmed on histology. MR microimaging accurately detected injected autologous fat, hyaluronic acid-based and polyethylene glycol (PEG)based implants injected into both ferret and canine VFs. Importantly, MRI accurately showed resorption of PEG implants in ferrets and canines, as confirmed on histology. Additionally, ex vivo MR spectroscopy distinguished fat from PEG-based implants. Conclusions: Ex vivo 11.7 T MR microimaging provided high-resolution images of ferret and canine laryngeal tissue microstructure, although the superficial lamina propria could not be distinguished. Histology confirmed MR microimaging findings, indicating utility of MR microimaging of modeled scar, implant residence time, and tissue responses, thus providing integrative insight relevant to translational research. C1 [Herrera, Victoria L. M.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Viereck, Jason C.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Lopez-Guerra, Gerardo; Kumai, Yoshihiko; Kobler, James; Karajanagi, Sandeep; Park, Hyoungshin; Hillman, Robert; Zeitels, Steven M.] Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Herrera, VLM (reprint author), Boston Univ, Sch Med, Dept Med, 700 Albany St,Room W-609, Boston, MA 02118 USA. EM vherrera@bu.edu OI Lopez-Guerra, Gerardo/0000-0003-0305-4680 FU Institute of Laryngeal and Voice Restoration; Eugene B. Casey Foundation FX This work was supported by the Institute of Laryngeal and Voice Restoration and the Eugene B. Casey Foundation. NR 16 TC 9 Z9 10 U1 0 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2009 VL 119 IS 11 BP 2187 EP 2194 DI 10.1002/lary.20643 PG 8 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 518LG UT WOS:000271692900019 PM 19824052 ER PT J AU Quesnel, AM Hartnick, CJ AF Quesnel, Alicia M. Hartnick, Christopher J. TI A Contemporary Review of Voice and Airway After Laryngeal Trauma in Children SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT Eastern Section Meeting of the Triological-Society CY JAN 24-25, 2009 CL Boston, MA SP Triol Soc DE Pediatric airway; voice; laryngeal trauma ID LARYNGOTRACHEAL TRAUMA; MANAGEMENT AB Objectives/Hypothesis: To discuss three cases of pediatric laryngeal trauma that highlight current techniques in diagnosis and treatment of the voice following laryngeal trauma. To examine the diagnostic utility of "chip tip" video laryngoscopy and to explore the current uses for open, endoscopic, or combined approaches within the context of these cases. Study Design: Case series with review of contemporary techniques. Methods: A case series of three children who sustained laryngeal trauma is presented. Ages range from 6 weeks to 17 years. The diagnostic evaluation and treatment strategies are reviewed with a focus on contemporary techniques. Results: A 15-year-old boy who sustained blunt neck trauma was diagnosed with a vocal fold avulsion on video laryngoscopy with digital image processing and a significant mucosal tear with exposure of the paraglottic space on direct laryngoscopy. Anatomical reapproximation required a combined open and endoscopic repair. A 17-year-old football player developed a glottic hematoma after blunt cervical trauma. This was managed conservatively with serial chip tip video laryngoscopy that provided high fidelity images and facilitated proper and timely diagnosis and treatment. A 6-week-old male suffered vocal fold avulsion from a traumatic intubation. Laryngofissure with reattachment of the vocal fold resolved his aspiration and reconstructed the laryngeal anatomy. Conclusions: Enhanced imaging via chip tip video laryngoscopy, compared to conventional fiberoptic endoscopy, might provide additional diagnostic information in pediatric patients with laryngeal trauma. Additionally, there could be a role for video strobolaryngoscopy in selected laryngeal trauma patients. Open, endoscopic, and combined approaches could be used to optimize voice and swallowing outcomes in pediatric laryngeal trauma. C1 [Hartnick, Christopher J.] Massachusetts Eye & Ear Infirm, Div Pediat Otolaryngol, Dept Otol & Laryngol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Hartnick, CJ (reprint author), Massachusetts Eye & Ear Infirm, Div Pediat Otolaryngol, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM christopher_hartnick@meei.harvard.edu NR 13 TC 5 Z9 5 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD NOV PY 2009 VL 119 IS 11 BP 2226 EP 2230 DI 10.1002/lary.20492 PG 5 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 518LG UT WOS:000271692900025 PM 19434680 ER PT J AU Zelickson, BD Walgrave, SE Al-Arashi, MYH Altshuler, GB Yaroslavsky, IV Childs, JJ Cohen, RH Erofeev, AV Depina, EF Smirnov, MZ Kist, DA Tabatadze, DR AF Zelickson, Brian D. Walgrave, Susan E. Al-Arashi, Munir Yahya H. Altshuler, Gregory B. Yaroslavsky, Ilya V. Childs, James J. Cohen, Rich H. Erofeev, Andrei V. Depina, Erminaldo F. Smirnov, Mikhail Z. Kist, David A. Tabatadze, David R. TI Semi-Automated Method of Analysis of Horizontal Histological Sections of Skin for Objective Evaluation of Fractional Devices SO LASERS IN SURGERY AND MEDICINE LA English DT Article DE fractional lasers; columns of micro-damage; histological evaluation ID OPTICAL COHERENCE TOMOGRAPHY; LASER; PHOTOTHERMOLYSIS; TISSUE AB Background and Objective: The treatment of skin with fractional devices creates columns of micro-ablation or micro-denaturation depending on the device. Since the geometric profiles of thermal damage depend on the treatment parameters or physical properties of the treated tissue, the size of these columns may vary from a few microns to a few millimeters. For objective evaluation of the damage profiles generated by fractional devices, this report describes an innovative and efficient method of processing and evaluating horizontal sections of skin using a novel software program. Materials and Methods: Ex vivo porcine skin was treated with the Lux1540/10, Lux1540 Zoom and Lux2940 with 500 optics. Horizontal (radial) sections of biopsies were obtained and processed with H&E and NBTC staining. Digital images of the histologic sections were taken in either transmission or reflection illumination and were processed using the SAFHIR program. Results: NBTC- and H&E-stained horizontal sections of ex vivo skin treated with ablative and non-ablative fractional devices were obtained. Geometric parameters, such as depth, diameter, and width of the coagulated layer (if applicable), and micro-columns of thermal damage, were evaluated using the SAFHIR software. The feasibility of objective comparison of the performance of two different fractional devices was demonstrated. Conclusion: The proposed methodology provides a comprehensive, objective, and efficient approach for the comparison of various fractional devices. Correlation of device settings with the objective dimensions of post-treatment damage profiles serve as a powerful tool for the prediction and modulation of clinical response. Lasers Surg. Med. 41:634-642, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Zelickson, Brian D.; Walgrave, Susan E.] Zel Skin & Laser Specialists, Edina, MN 55424 USA. [Zelickson, Brian D.; Kist, David A.] Univ Minnesota, Dept Dermatol, Minneapolis, MN 55455 USA. [Al-Arashi, Munir Yahya H.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Al-Arashi, Munir Yahya H.; Altshuler, Gregory B.; Yaroslavsky, Ilya V.; Childs, James J.; Cohen, Rich H.; Erofeev, Andrei V.; Depina, Erminaldo F.; Smirnov, Mikhail Z.; Tabatadze, David R.] Palomar Med Technol Inc, Burlington, MA 01803 USA. RP Zelickson, BD (reprint author), Zel Skin & Laser Specialists, 4100 W 50th St, Edina, MN 55424 USA. EM zelic002@earthlink.net NR 15 TC 11 Z9 11 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-8092 J9 LASER SURG MED JI Lasers Surg. Med. PD NOV PY 2009 VL 41 IS 9 BP 634 EP 642 DI 10.1002/lsm.20843 PG 9 WC Dermatology; Surgery SC Dermatology; Surgery GA 515VB UT WOS:000271499900005 PM 19816914 ER PT J AU Lacy, MQ Jacobus, S Blood, EA Kay, NE Rajkumar, SV Greipp, PR AF Lacy, Martha Q. Jacobus, Susanna Blood, Emily A. Kay, Neil E. Rajkumar, S. Vincent Greipp, Philip R. TI Phase II study of interleukin-12 for treatment of plateau phase multiple myeloma (E1A96): A trial of the Eastern Cooperative Oncology Group SO LEUKEMIA RESEARCH LA English DT Article DE Multiple myeloma; Interleukin-12; Immunomodulatory therapy ID MAINTENANCE THERAPY; RANDOMIZED TRIALS; INTERFERON; COMBINATION; PREDNISONE; RITUXIMAB; LYMPHOMA AB The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of interleukin-12 (IL-12) for plateau phase multiple myeloma. Patients were initially treated with IL-12 250 ng/kg I.V. daily for 5 days every 3 weeks. The trial was modified due to toxicity after the first 16 patients. IL-12 was given 300 ng/kg subcutaneously twice weekly for 24 weeks. Of 48 eligible patients, there were 4 objective responses (8.3%), all CR. The median survival and progression-free survival were 42.8 and 11.4 months. Unacceptable grade 3 or 4 non-hematologic toxicity (31% with IL-12 subcutaneously and 63% with IL-12 intravenously) was observed. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Lacy, Martha Q.] Mayo Clin, Div Hematol, Rochester, MN 55905 USA. [Jacobus, Susanna; Blood, Emily A.] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Lacy, MQ (reprint author), Mayo Clin, Div Hematol, 200 1st St SW, Rochester, MN 55905 USA. EM lacy.martha@mayo.edu OI Rajkumar, S. Vincent/0000-0002-5862-1833 FU Celgene Corporation; Millennium; Takeda Oncology Company; Genzyme FX Dr. Lacy: Grant/Research Support: Celgene Corporation, Millennium, The Takeda Oncology Company, and Genzyme. NR 14 TC 18 Z9 20 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD NOV PY 2009 VL 33 IS 11 BP 1485 EP 1489 DI 10.1016/j.leukres.2009.01.020 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 495DM UT WOS:000269870400012 PM 19243818 ER PT J AU Schiodt, FV Chung, RT Schilsky, ML Hay, JE Christensen, E Lee, WM AF Schiodt, Frank V. Chung, Raymond T. Schilsky, Michael L. Hay, J. Eileen Christensen, Erik Lee, William M. CA Acute Liver Failure Study Grp TI Outcome of Acute Liver Failure in the Elderly SO LIVER TRANSPLANTATION LA English DT Article ID FULMINANT HEPATIC-FAILURE; SINGLE-CENTER EXPERIENCE; REGENERATING RAT LIVER; AGE-RELATED-CHANGES; EARLY INDICATORS; UNITED-STATES; BLOOD-FLOW; DONOR AGE; TRANSPLANTATION; PROGNOSIS AB Older age is considered a poor prognostic factor in acute liver failure (ALF) and may still be considered a relative contraindication for liver transplantation for ALF. We aimed to evaluate the impact of older age, defined as age >= 60 years, on outcomes in patients with ALF. One thousand one hundred twenty-six consecutive prospective patients from the US Acute Liver Failure Study Group registry were studied. The median age was 38 years (range, 15-81 years). One thousand sixteen patients (90.2%) were younger than 60 years (group 1), and 499 (49.1%) of these had acetaminophen-induced ALF; this rate of acetaminophen-induced ALF was significantly higher than that in patients >= 60 years (group 2; n = 110; 23.6% with acetaminophen-induced ALF, P < 0.001). The overall survival rate was 72.7% in group 1 and 60.0% in group 2 (not significant) for acetaminophen patients and 67.9% in group 1 and 48.2% in group 2 for non-acetaminophen patients (P < 0.001). The spontaneous survival rate (ie, survival without liver transplantation) was 64.9% in group 1 and 60.0% in group 2 (not significant) for acetaminophen patients and 30.8% in group 1 and 24.7% in group 2 for non-acetaminophen patients (P = 0.27). Age was not a significant predictor of spontaneous survival in multiple logistic regression analyses. Group 2 patients were listed for liver transplantation significantly less than group 1 patients. Age was listed as a contraindication for transplantation in 5 patients. In conclusion, in contrast to previous studies, we have demonstrated a relatively good spontaneous survival rate for older patients with ALF when it is corrected for etiology. However, overall survival was better for younger non-acetaminophen patients. Fewer older patients were listed for transplantation. Liver Transpl 15:1481-1487, 2009. (C) 2009 AASLD. C1 [Schiodt, Frank V.; Christensen, Erik] Bispebjerg Hosp, Dept Internal Med 1, DK-2400 Copenhagen NV, Denmark. [Schiodt, Frank V.; Lee, William M.] Univ Texas SW Med Ctr Dallas, Div Digest & Liver Dis, Dallas, TX 75390 USA. [Chung, Raymond T.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Schilsky, Michael L.] Yale New Haven Transplant Ctr, New Haven, CT USA. [Hay, J. Eileen] Mayo Clin, Rochester, MN USA. RP Schiodt, FV (reprint author), Bispebjerg Hosp, Dept Internal Med 1, Bispebjerg Bakke 23, DK-2400 Copenhagen NV, Denmark. EM schiodt@get2net.dk FU National Institute of Diabetes and Digestive and Kidney Diseases for the Acute Liver Failure Study Group [DK U-01 58369]; Tips Fund of the Northwestern Medical Foundation; Jeanne Roberts and Rollin and Mary Ella King Funds of the Southwestern Medical Foundation FX This study was funded by a National Institutes of Health grant (DK U-01 58369) provided by the National Institute of Diabetes and Digestive and Kidney Diseases for the Acute Liver Failure Study Group. Additional funding was provided by the Tips Fund of the Northwestern Medical Foundation and the Jeanne Roberts and Rollin and Mary Ella King Funds of the Southwestern Medical Foundation. NR 36 TC 11 Z9 11 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1527-6465 J9 LIVER TRANSPLANT JI Liver Transplant. PD NOV PY 2009 VL 15 IS 11 BP 1481 EP 1487 DI 10.1002/lt.21865 PG 7 WC Gastroenterology & Hepatology; Surgery; Transplantation SC Gastroenterology & Hepatology; Surgery; Transplantation GA 517HQ UT WOS:000271604400015 PM 19877205 ER PT J AU Cooley, ME Sarna, L Kotlerman, J Lukanich, JM Jaklitsch, M Green, SB Bueno, R AF Cooley, Mary E. Sarna, Linda Kotlerman, Jenny Lukanich, Jeanne M. Jaklitsch, Michael Green, Sarah B. Bueno, Raphael TI Smoking cessation is challenging even for patients recovering from lung cancer surgery with curative intent SO LUNG CANCER LA English DT Article DE Lung cancer; Thoracic surgery; Smoking cessation; Symptom management; Tobacco dependence; Nicotine dependence treatment; Smoking; Cancer treatment ID QUALITY-OF-LIFE; CONTINUED TOBACCO USE; LONG-TERM SURVIVORS; DEPENDENCE TREATMENT; NICOTINE DEPENDENCE; CLINICAL-TRIALS; PREVALENCE; PREDICTORS; ABSTINENCE; SMOKERS AB Background: Although it is recommended that smokers undergoing surgery for lung cancer quit smoking to reduce post-operative complications, few studies have examined patterns of smoking in the peri-operative period. The goals of this study were to determine: (1) patterns of smoking during post-operative recovery, (2) types of cessation strategies used to quit smoking, and (3) factors related to smoking after lung cancer surgery. Methods: Data were collected from 94 patients through chart review, tobacco, health status, and symptom questionnaires at 1, 2, and 4 months after surgery. Smoking status was assessed through self-report and urinary cotinine measurement. Results: Eighty-four patients (89%)were ever-smokers and 35 (37%) reported smoking at diagnosis. Thirty-nine (46%) ever-smokers remained abstinent, 13 (16%) continued smoking at all time-points, and 32 (38%) relapsed. Ten (46%) of those who relapsed were former-smokers and had not smoked for at least 1 year. Sixteen (46%) of those who were smoking at diagnosis received cessation assistance with pharmacotherapy being the most common strategy. Factors associated with smoking during recovery were younger age and quitting smoking <6 months before the diagnosis of lung cancer. Factors that were marginally significant were lower educational level, male gender, lower number of comorbidities, and the presence of pain. Conclusion: Only half of those who were smoking received assistance to quit prior to surgery. Some patients were unable to quit and relapse rates post-surgery were high even among those who quit more than 1 year prior. Innovative programs incorporating symptom management and relapse prevention may enhance smoking abstinence during post-operative care. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Cooley, Mary E.; Green, Sarah B.] Dana Farber Canc Inst, Phyllis F Cantor Ctr, Boston, MA 02115 USA. [Cooley, Mary E.] Univ Massachusetts, Coll Nursing & Hlth Sci, Boston, MA 02125 USA. [Sarna, Linda] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA. [Kotlerman, Jenny] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Lukanich, Jeanne M.; Jaklitsch, Michael; Bueno, Raphael] Brigham & Womens Hosp, Div Thorac Surg, Boston, MA 02115 USA. RP Cooley, ME (reprint author), Dana Farber Canc Inst, Phyllis F Cantor Ctr, 44 Binney St,CP 302, Boston, MA 02115 USA. EM mary_cooley@dfci.harvard.edu; lsarna@sonnet.ucla.edu; jkotlerman@mednet.ucla.edu; jlukanich@partners.org; Mjaklitsch@partners.org; rbueno@partners.org FU National Cancer Institute [1 K07 CA92696-02]; James B. Gillen Thoracic Oncology Research Fund; Dana-Farber Cancer Institute; Oncology Nursing Foundation Center for Leadership, Information, and Research [018652] FX Funding from the National Cancer Institute 1 K07 CA92696-02 and James B. Gillen Thoracic Oncology Research Fund, Dana-Farber Cancer Institute (Mary E. Cooley) and Oncology Nursing Foundation Center for Leadership, Information, and Research (#018652) (PI: Linda Sarna). NR 53 TC 41 Z9 41 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0169-5002 J9 LUNG CANCER JI Lung Cancer PD NOV PY 2009 VL 66 IS 2 BP 218 EP 225 DI 10.1016/j.lungcan.2009.01.021 PG 8 WC Oncology; Respiratory System SC Oncology; Respiratory System GA 527ME UT WOS:000272370400012 PM 19321223 ER PT J AU Liu, S Gonen, O Fleysher, R Fleysher, L Babb, JS Soher, BJ Joo, CG Ratai, EM Gonzalez, RG AF Liu, Songtao Gonen, Oded Fleysher, Roman Fleysher, Lazar Babb, James S. Soher, Brian J. Joo, Chan-Gyu Ratai, Eva-Maria Gonzalez, R. Gilberto TI Metabolite Proton T-2 Mapping in the Healthy Rhesus Macaque Brain at 3 T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE animal models; brain metabolites; high magnetic field; MR spectroscopic imaging; rhesus macaque; transverse relaxation time ID AUTOMATED SPECTRAL-ANALYSIS; RELAXATION-TIMES; MR SPECTROSCOPY; ACQUISITION STRATEGY; MAGNETIC-FIELDS; TESLA; RESOLUTION; DISEASE; MODEL; WATER AB The structure and metabolism of the rhesus macaque brain, an advanced model for neurologic diseases and their treatment response, is often studied noninvasively with MRI and H-1-MR spectroscopy. Due to the shorter transverse relaxation time (T-2) at the higher magnetic fields these studies favor, the echo times used in H-1-MR spectroscopy subject the metabolites to unknown T-2 weighting, decreasing the accuracy of quantification which is key for inter- and intra-animal comparisons. To establish the "baseline" (healthy animal) T-2 values, we mapped them for the three main metabolites' T(2)s at 3 T in four healthy rhesus macaques and tested the hypotheses that their mean values are similar (i) among animals; and (ii) to analogs regions in the human brain. This was done with three-dimensional multivoxel H-1-MR spectroscopy at (0.6 x 0.6 x 0.5 cm)(3) = 180 mu L spatial resolution over a 4.2 x 3.0 x 2.0 = 25 cm(3) (similar to 30%) of the macaque brain in a two-point protocol that optimizes T-2 precision per unit time. The estimated T(2)s in several gray and white matter regions are all within 10% of those reported in the human brain (mean +/- standard error of the mean): N-acetylaspartate = 316 +/- 7, creatine = 177 +/- 3, and choline = 264 +/- 9 ms, with no statistically significant gray versus white matter differences. Magn Reson Med 62:1292-1299, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Liu, Songtao; Gonen, Oded; Fleysher, Roman; Fleysher, Lazar; Babb, James S.] NYU, Sch Med, Dept Radiol, New York, NY 10016 USA. [Joo, Chan-Gyu; Ratai, Eva-Maria; Gonzalez, R. Gilberto] Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Joo, Chan-Gyu; Ratai, Eva-Maria; Gonzalez, R. Gilberto] Massachusetts Gen Hosp, Neuroradiol Div, Charlestown, MA USA. [Soher, Brian J.] Duke Univ, Med Ctr, Dept Radiol, Ctr Adv MR Dev, Durham, NC 27710 USA. RP Gonen, O (reprint author), NYU, Sch Med, Dept Radiol, 660 1st Ave,4th Floor, New York, NY 10016 USA. EM oded.gonen@med.nyu.edu OI Gonen, Oded/0000-0002-3148-2028 FU National Institutes of Health [EB01015, NS050520, NS050041, NS051129, NS059331, P51RR000168, A1028691, NS040237]; National Center for Research Resources [P41RR14075] FX Grant sponsor: National Institutes of Health; Grant numbers: EB01015, NS050520, NS050041, NS051129, NS059331, P51RR000168, A1028691 and NS040237; National Center for Research Resources; Grant number: P41RR14075. NR 25 TC 2 Z9 2 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD NOV PY 2009 VL 62 IS 5 BP 1292 EP 1299 DI 10.1002/mrm.22117 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 514XX UT WOS:000271431200023 PM 19780178 ER PT J AU Kressin, NR Nunn, ME Singh, H Orner, MB Pbert, L Hayes, C Culler, C Glicken, SR Palfrey, S Geltman, PL Cadoret, C Henshaw, MM AF Kressin, Nancy R. Nunn, Martha E. Singh, Harpreet Orner, Michelle B. Pbert, Lori Hayes, Catherine Culler, Corinna Glicken, Stephan R. Palfrey, Sean Geltman, Paul L. Cadoret, Cynthia Henshaw, Michelle M. TI Pediatric Clinicians Can Help Reduce Rates of Early Childhood Caries Effects of a Practice Based Intervention SO MEDICAL CARE LA English DT Article DE early childhood caries; physician-patient relations; physicians,'; practice patterns; intervention studies ID WORCESTER-AREA TRIAL; ORAL-HEALTH; HYPERLIPIDEMIA WATCH; SMOKING INTERVENTION; PRESCHOOL-CHILDREN; CARE PROVIDERS; DENTAL-CARIES; PREVALENCE; RESIDENTS; ETHNICITY AB Objective: Early childhood caries (ECC) is a serious and preventable disease which pediatric clinicians can help address by counseling to reduce risk. Research Design: We implemented a multifaceted practice-based intervention in a pediatric outpatient clinic treating children vulnerable to ECC (N = 635), comparing results to those from a similar nearby clinic providing usual care (N = 452). Intervention: We provided communication skills training using the approach of patient centered counseling, edited the electronic medical record to prompt counseling, and provided parents/caregivers with an educational brochure. Outcome Measures: We assessed changes in provider knowledge about ECC after the intervention, and examined providers' counseling practices and incidence of ECC over time by site, controlling for baseline ECC, patient sociodemographics and parents'/caregivers' practice of risk factors (diet, oral hygiene, tooth-monitoring), among 1045 children with complete data. Results: Provider knowledge about ECC increased after the intervention training (percentage correct answers improved from 66% to 79%). Providers at the intervention site used more counseling strategies, which persisted after adjustment for socio-demographic characteristics. Children at the intervention site had a 77% reduction in risk for developing ECC at follow up, after controlling for age and race/ethnicity, sociodemographics and ECC risk factors; P <= 0.004. Conclusions: The multifaceted intervention was associated with increased provider knowledge and counseling, and significantly attenuated incidence of ECC. If validated by additional studies, similar interventions could have the potential to make a significant public health impact on reducing ECC among young children. C1 [Kressin, Nancy R.] Boston Univ, Gen Internal Med Sect, Crosstown Ctr, HealthCare Dispar Res Program,Sch Med, Boston, MA 02118 USA. [Kressin, Nancy R.; Nunn, Martha E.; Singh, Harpreet; Orner, Michelle B.; Hayes, Catherine; Culler, Corinna; Geltman, Paul L.; Cadoret, Cynthia; Henshaw, Michelle M.] NE Ctr Res Evaluate & Eliminate Dent Dispar, Boston, MA USA. [Kressin, Nancy R.] VA Boston Healthcare Syst, Boston, MA USA. [Kressin, Nancy R.; Orner, Michelle B.] VAMC, Ctr Hlth Qual Outcomes & Econ Res, Bedford, MA USA. [Nunn, Martha E.; Singh, Harpreet; Culler, Corinna; Cadoret, Cynthia; Henshaw, Michelle M.] Boston Univ, Sch Dent Med, Boston, MA 02118 USA. [Pbert, Lori] Univ Massachusetts, Sch Med, Dept Med, Div Prevent & Behav Med, Worcester, MA 01605 USA. [Hayes, Catherine] Tufts Univ, Sch Dent Med, Boston, MA 02111 USA. [Glicken, Stephan R.] Allegheny Gen Hosp, Dept Pediat, Pittsburgh, PA 15212 USA. [Palfrey, Sean; Geltman, Paul L.] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. RP Kressin, NR (reprint author), Boston Univ, Gen Internal Med Sect, Crosstown Ctr, HealthCare Dispar Res Program,Sch Med, 2nd Floor,801 Massachusetts Ave, Boston, MA 02118 USA. EM nkressin@bu.edu OI Culler, Corinna/0000-0003-4680-0436 FU NCRR NIH HHS [U54 RR024381]; NIDCR NIH HHS [U54 DE019275, U54 DE14264-S2, K23 DE00454, U54 DE014264-020002, K24 DE000419, K24 DE00419, U54 DE014264, K23 DE000454] NR 34 TC 22 Z9 22 U1 1 U2 7 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 NOV PY 2009 VL 47 IS 11 BP 1121 EP 1128 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 515DM UT WOS:000271447000003 PM 19786919 ER PT J AU Sidky, EY Pan, XC Reiser, IS Nishikawa, RM Moore, RH Kopans, DB AF Sidky, Emil Y. Pan, Xiaochuan Reiser, Ingrid S. Nishikawa, Robert M. Moore, Richard H. Kopans, Daniel B. TI Enhanced imaging of microcalcifications in digital breast tomosynthesis through improved image-reconstruction algorithms SO MEDICAL PHYSICS LA English DT Article DE digital breast tomosynthesis; iterative image-reconstruction; total-variation; nonconvex optimization ID MINIMIZATION; TOMOGRAPHY AB Purpose: The authors develop a practical, iterative algorithm for image-reconstruction in under-sampled tomographic systems, such as digital breast tomosynthesis (DBT). Methods: The algorithm controls image regularity by minimizing the image total p variation (TpV), a function that reduces to the total variation when p=1.0 or the image roughness when p=2.0. Constraints on the image, such as image positivity and estimated projection-data tolerance, are enforced by projection onto convex sets. The fact that the tomographic system is undersampled translates to the mathematical property that many widely varied resultant volumes may correspond to a given data tolerance. Thus the application of image regularity serves two purposes: (1) Reduction in the number of resultant volumes out of those allowed by fixing the data tolerance, finding the minimum image TpV for fixed data tolerance, and (2) traditional regularization, sacrificing data fidelity for higher image regularity. The present algorithm allows for this dual role of image regularity in undersampled tomography. Results: The proposed image-reconstruction algorithm is applied to three clinical DBT data sets. The DBT cases include one with microcalcifications and two with masses. Conclusions: Results indicate that there may be a substantial advantage in using the present image-reconstruction algorithm for microcalcification imaging. (C) 2009 American Association of Physicists in Medicine. [DOI: 10.1118/1.3232211] C1 [Sidky, Emil Y.; Pan, Xiaochuan; Reiser, Ingrid S.; Nishikawa, Robert M.] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Moore, Richard H.; Kopans, Daniel B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Sidky, EY (reprint author), Univ Chicago, Dept Radiol, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM sidky@uchicago.edu; xpan@uchicago.edu OI Nishikawa, Robert/0000-0001-7720-9951 FU NIH R01 [CA120540, EB000225]; Illinois Department of Public Health Ticket for the Cure; NIH SPORE [CA125183-03]; NIH [R33 CA109963, R21 EB8801, S10 RR021039, P30 CA14599]; US ARMY [DAMD1798-8309]; NIH-NCI [5R33CA107863-01] FX Two of the authors (E.Y.S. and X.P.) were supported in part by NIH R01 Grant Nos. CA120540 and EB000225 and by an Illinois Department of Public Health Ticket for the Cure Grant. E.Y.S. was also supported in part by a Career Development Award from NIH SPORE grant CA125183-03. Other two authors (I.S.R. and R.M.N.) were supported in part by NIH Grant Nos. R33 CA109963 and R21 EB8801. The original MGH-GE instrument was funded by the US ARMY via Clinical translational research (CTR) DAMD1798-8309, GE provided the current clinical prototype system designated DBT Senographe DS. NIH-NCI funded the use of this instrument to acquire 3000 screening studies as 5R33CA107863-01. Computations for this work were performed on a cluster, partially funded by NIH Grant Nos. S10 RR021039 and P30 CA14599. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 17 TC 98 Z9 99 U1 0 U2 13 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD NOV PY 2009 VL 36 IS 11 BP 4920 EP 4932 DI 10.1118/1.3232211 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 512BR UT WOS:000271217900011 PM 19994501 ER PT J AU Moriyama, K Wiener-Kronish, JP Sawa, T AF Moriyama, Kiyoshi Wiener-Kronish, Jeanine P. Sawa, Teiji TI Protective effects of affinity-purified antibody and truncated vaccines against Pseudomonas aeruginosa V-antigen in neutropenic mice SO MICROBIOLOGY AND IMMUNOLOGY LA English DT Article DE affinity-purified antibody; component vaccine; Pseudomonas aeruginosa PcrV ID YERSINIA-PESTIS; MONOCLONAL-ANTIBODY; PASTEURELLA-PESTIS; PASSIVE-IMMUNITY; VIRULENCE; PCRV; IMMUNIZATION; PNEUMONIA; INFECTION; STRAINS AB Virulent P. aeruginosa strainsexpress PcrV, one of the translocational components of the type III secretion system. PcrV has been reported to be a protective antigen against lethal P. aeruginosa infection. The PcrV region, which contributes to protective immunity against P. aeruginosa infection, was investigated by using genetically engineered, truncated PcrV proteins and affinity-purified anti-PcrV antibodies against the truncated PcrV proteins. The efficacy of active and passive immunization against PcrV was tested in mice with cyclophosphamide-induced immunosuppression by intraabdominal challenge of P. aeruginosa. Active immunization with either full-length PcrV1-294 or PcrV139-294 significantly improved the survival of mice infected with P. aeruginosa, while PcrV139-258, PcrV139-234, PcrV197-294, and PcrV261-294 were not protective. These results suggest that an effective PcrV vaccine needs to contain not only the Mab166 epitope (PcrV144-257) but also the carboxyl terminal tail of PcrV. In the case of passive immunization, administration of affinity-purified anti-PcrV IgG against either PcrV1-294 or PcrV139-258 showed significantly higher efficacy against lethal P. aeruginosa infection than did original anti-PcrV IgG and Mab166. The increased efficacy of affinity-purified anti-PcrV IgG implies that more potent anti-PcrV strategies are possible. The results of this study are crucial to the development of an effective PcrV vaccine for active immunization and to an appropriate blocking anti-PcrV antibody against P. aeruginosa infection in humans. C1 [Moriyama, Kiyoshi] Kyorin Univ, Sch Med, Dept Anesthesiol, Tokyo 1818611, Japan. [Sawa, Teiji] Kyoto First Red Cross Hosp, Dept Anesthesiol, Kyoto 6050981, Japan. [Moriyama, Kiyoshi; Wiener-Kronish, Jeanine P.; Sawa, Teiji] Univ Calif San Francisco, Dept Anesthesia & Perioperat Care, San Francisco, CA 94143 USA. [Wiener-Kronish, Jeanine P.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Wiener-Kronish, Jeanine P.] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. [Wiener-Kronish, Jeanine P.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA USA. RP Moriyama, K (reprint author), Kyorin Univ, Sch Med, Dept Anesthesiol, 6-20-2 Shinkawa, Tokyo 1818611, Japan. EM mokiyokeio@gmail.com FU American Lung Association [RG004N]; National Institutes of Health [HL067600, HL59239, AI44101] FX This work was supported in part by American Lung Association RG004N (to T. S.), National Institutes of Health HL067600 (to T. S), and HL59239, AI44101 (to J.P.W.-K.). NR 30 TC 12 Z9 14 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0385-5600 J9 MICROBIOL IMMUNOL JI Microbiol. Immunol. PD NOV PY 2009 VL 53 IS 11 BP 587 EP 594 DI 10.1111/j.1348-0421.2009.00165.x PG 8 WC Immunology; Microbiology SC Immunology; Microbiology GA 510BO UT WOS:000271063200001 PM 19903258 ER PT J AU Gariti, KO Sadeghi, L Joisa, SD Holmes, WC AF Gariti, Katherine O. Sadeghi, Leila Joisa, Sowmya D. Holmes, William C. TI Veterans' Distress Related to Participation in a Study About Detainee Abuse SO MILITARY MEDICINE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; TRAUMA-FOCUSED RESEARCH; RISK-FACTORS; LOCUS; BENEFITS AB Unintended consequences of participating in research studies are not well characterized, particularly in veterans who are frequent study participants. Our objective, then, was to assess the rate of and variables associated with distress resulting from veterans' participation in a study on a sensitive subject. Veterans Administration (VA) hospital outpatients were administered questionnaires with three increasingly severe scenarios of a U.S. soldier abusing a detainee. Distress-upset requiring clinical intervention-was assessed, as were sociodemographic characteristics, post-traumatic stress disorder (PTSD), depression, and locus of control (LOC). Three hundred fifty-one veterans participated. Forty-three (12%) became distressed. Modeling indicated distress was associated with minority status (odds ratio [OR] = 5.72, 95% confidence interval [CI] = 1.59, 20.58), PTSD (OR = 2.66, 95% CI = 1.12, 6.29), and external LOC (OR = 6.27, 95% CI = 2.82, 13.90). Distress related to study participation was high in this veteran sample. Higher rates in some subgroups suggested that some individuals may not be able to accurately anticipate risk for harm in sensitive studies. C1 [Gariti, Katherine O.] Philadelphia Vet Affairs Med Ctr, Mental Hlth Clin, Philadelphia, PA 19104 USA. [Sadeghi, Leila] NYU Langone Med Ctr, Dept Pediat, New York, NY 10016 USA. [Joisa, Sowmya D.] Good Samaritan Hosp, Lebanon, PA 17042 USA. [Holmes, William C.] Philadelphia Vet Affairs Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA 19104 USA. RP Gariti, KO (reprint author), Philadelphia Vet Affairs Med Ctr, Mental Hlth Clin, Univ & Woodland Ave, Philadelphia, PA 19104 USA. NR 17 TC 1 Z9 1 U1 1 U2 1 PU ASSOC MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 EI 1930-613X J9 MIL MED JI Milit. Med. PD NOV PY 2009 VL 174 IS 11 BP 1149 EP 1154 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 601LL UT WOS:000278060900005 PM 19960821 ER PT J AU Zhu, Y Li, Q Chen, ZY Kun, Y Liu, LJ Liu, X Yuan, HJ Zhai, SQ Han, DY Dai, P AF Zhu, Yuhua Li, Qi Chen, Zhengyi Kun, Yao Liu, Lijia Liu, Xin Yuan, Huijun Zhai, Suoqiang Han, Dongyi Dai, Pu TI Mitochondrial haplotype and phenotype of 13 Chinese families may suggest multi-original evolution of mitochondrial C1494T mutation SO MITOCHONDRION LA English DT Article DE Hearing loss; Aminoglycosides; Mitochondrial DNA; Haplotype; 12S rRNA mutation; Penetrance ID 12S RIBOSOMAL-RNA; NONSYNDROMIC HEARING-LOSS; COMPLETE NUCLEOTIDE-SEQUENCE; A1555G MUTATION; AMINOGLYCOSIDE OTOTOXICITY; MOLECULAR ANALYSIS; T7511C MUTATION; GJB2 MUTATION; DEAFNESS; GENE AB Mutations in mitochondrial DNA (mtDNA) are associated with sensorineural hearing loss. In this study, we traced the origin of the 12S rRNA C1494T mutation through analysis of the clinical, genetic, and molecular characteristics of 13 Han Chinese pedigrees with aminoglycoside-induced and non-syndromic bilateral hearing loss that were selected by C1494T screening in 3133 subjects with non-syndromic hearing impairment from 27 regions of China (13/3133). Clinical evaluation revealed the variable phenotypes of hearing impairment including severity, age-of-onset, and audiometric configuration in these subjects. Through the whole mitochondrial genome DNA sequence analysis, we identified two evolutionarily conservative variants in protein-coding genes: tRNA(Ala) T 5628C and tRNA(Tyr) A5836G mutations. However, the pedigrees with these mutations did not have a higher or lower penetrance of deafness than in other pedigrees. These results suggested that both T 5628C and A5836G mutations might not significantly modify the manifestation of the C1494T mutation. Sequencing analysis of the whole mitochondrial genome of the probands showed that 13 pedigrees from seven different provinces were classified into 10 haplogroups by the distinct sets of mtDNA polymorphisms, including haplogroups A, B, D, D4, D4b2, F1, M, M7c, N9a1, and H2b. This result suggested that the C1494T mutation occurred sporadically with multi-origins through the evolution of the mtDNA in China, and these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the C1494T mutation in these Chinese families with different penetrance of hearing loss. In addition, the lack of a significant mutation in the GJB2 gene ruled out the possible involvement of GJB2 in the phenotypic expression of the C1494T mutation in those affected subjects. Therefore, the aminoglycosides is solo well-established factor to contribute to the deafness manifestation of the C1494T mutation, and prevention by avoiding the administration of aminoglycosides in individuals carrying C1494T mutation is the most effective way to protect their vulnerability to deafness. (C) 2009 Elsevier B.V. and Mitochondria Research Society. All rights reserved. C1 [Zhu, Yuhua; Li, Qi; Liu, Xin; Yuan, Huijun; Zhai, Suoqiang; Han, Dongyi; Dai, Pu] Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol, Beijing, Peoples R China. [Li, Qi] Nanjing Childrens Hosp, Dept Otolaryngol, Nanjing, Jiangsu, Peoples R China. [Chen, Zhengyi] Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. [Chen, Zhengyi] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Kun, Yao] Fuyang Peoples Hosp, Dept Otolaryngol, Fuyang, Anhui, Peoples R China. [Liu, Lijia] Mudanjiang First Hosp, Dept Otolaryngol, Mudanjiang, Heilongjiang, Peoples R China. RP Zhai, SQ (reprint author), Chinese Peoples Liberat Army Gen Hosp, Dept Otolaryngol, 28 Fuxing Road, Beijing, Peoples R China. EM zhaisq@plagh.com.cn; hdy301@263.net; daipu301@vip.sina.com FU Chinese National Nature Science Foundation Research [30728030, 30872862]; Chinese Capital Medical Development Scientific Funding [2005-1032]; [2007BAI18B12]; [2006BAI02B06] FX This work was supported by the Chinese National Nature Science Foundation Research Grant 30728030, 30872862 to Pu Dai and Zhengyi Chen, and Chinese Capital Medical Development Scientific Funding 2005-1032 and 11th 5 Year Supporting Funding 2007BAI18B12, 2006BAI02B06 to Dongyi Han and Suoqiang Zhai. NR 34 TC 18 Z9 27 U1 0 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD NOV PY 2009 VL 9 IS 6 BP 418 EP 428 DI 10.1016/j.mito.2009.07.006 PG 11 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 523RW UT WOS:000272093200006 PM 19682603 ER PT J AU Nath, SD He, X Voruganti, VS Blangero, J MacCluer, JW Comuzzie, AG Arar, NH Abboud, HE Thameem, F AF Nath, Subrata D. He, Xin Voruganti, V. Saroja Blangero, John MacCluer, Jean W. Comuzzie, Anthony G. Arar, Nedal H. Abboud, Hanna E. Thameem, Farook TI The 27-bp repeat polymorphism in intron 4 (27 bp-VNTR) of endothelial nitric oxide synthase (eNOS) gene is associated with albumin to creatinine ratio in Mexican Americans SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE eNOS; Genetic polymorphisms; Association analyses; ACR; Triglycerides; Mexican Americans ID GLOMERULAR-FILTRATION-RATE; WIDE LINKAGE SCANS; TRANSMISSION DISEQUILIBRIUM; DIABETIC-NEPHROPATHY; RISK-FACTORS; DISEASE; KIDNEY; ECNOS; GENOTYPE; REGION AB The T-786C, Glu298Asp, and 27 bp variable number of tandem repeats (27 bp-VNTR-a/b) polymorphsims of the endothelial nitric oxide synthase (eNOS) gene are thought to alter nitric oxide production and contribute to the development of vascular and renal disease risk. The objective of this study is to investigate whether these three polymorphisms examined previously by others are associated with cardiovascular and renal disease risk in Mexican Americans. Study participants (N = 848; 21 families) were genotyped for T-786C, Glu298Asp, and 27 bp-VNTR-a/b polymorphisms by PCR followed by restriction digestion. Association analyses were performed by a measured genotype approach implemented in the program SOLAR. Of the phenotypes (type 2 diabetes, hypertension, body mass index, waist circumference, total cholesterol, high density lipoprotein cholesterol, triglycerides, systolic and diastolic blood pressure, albumin to creatinine ratio (ACR), and estimated glomerular filtration rate) examined for association, the 27 bp-VNTR-a/b variant exhibited statistically significant association with ACR (P = 0.047) after accounting for the trait specific covariate effects. In addition, the promoter variant (T-786C) showed a significant association with triglycerides (P = 0.034) after accounting for covariate influences. In conclusion, the present study adds evidence to the role of eNOS candidate gene polymorphisms in modulating the risk factors related to cardiovascular-renal disease in Mexican Americans although the magnitude of the genetic effect is small. C1 [Nath, Subrata D.; He, Xin; Arar, Nedal H.; Abboud, Hanna E.; Thameem, Farook] Univ Texas Hlth Sci Ctr San Antonio, Div Nephrol, Dept Med, San Antonio, TX 78229 USA. [Arar, Nedal H.; Abboud, Hanna E.] S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. [Voruganti, V. Saroja; Blangero, John; MacCluer, Jean W.; Comuzzie, Anthony G.] SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78227 USA. RP Thameem, F (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Div Nephrol, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM thameem@uthscsa.edu FU American Heart Association; Carl W. Gottschalk Research Scholars of the American Society of Nephrology; George O'Brien Kidney Research Center [P50 DK061597]; Satellite Healthcare; San Antonio Area Foundation; NIH [P01 HL45522]; National Center for Research Resources [UL1 RR025767, KL2 RR025766]; [R01 MH59490] FX We thank the members of SAFHS for their participation and cooperation. This study was supported by the Grant-in-Aid from the American Heart Association (FT), Carl W. Gottschalk Research Scholars of the American Society of Nephrology (FT), George O'Brien Kidney Research Center (P50 DK061597; HEA, FT), Norman S. Coplan grant from the Satellite Healthcare (FT), San Antonio Area Foundation (FT), VA-MERIT Review (HEA, NHA). The SAFHS is supported by NIH grant P01 HL45522. The development of SOLAR was supported by R01 MH59490. This work was supported by the National Center for Research Resources contracts UL1 RR025767 and KL2 RR025766 for the Institute for Integration of Medicine and Science. NR 29 TC 9 Z9 10 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD NOV PY 2009 VL 331 IS 1-2 BP 201 EP 205 DI 10.1007/s11010-009-0159-5 PG 5 WC Cell Biology SC Cell Biology GA 513FN UT WOS:000271308000023 PM 19468830 ER PT J AU Minamishima, YA Moslehi, J Padera, RF Bronson, RT Liao, R Kaelin, WG AF Minamishima, Yoji Andrew Moslehi, Javid Padera, Robert F. Bronson, Roderick T. Liao, Ronglih Kaelin, William G., Jr. TI A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PAS DOMAIN PROTEIN; INDUCIBLE-FACTOR; VASCULAR TUMORS; TRANSCRIPTIONAL ACTIVITY; MITOCHONDRIAL AUTOPHAGY; MYOCARDIAL-INFARCTION; MOUSE MODEL; HIF; INACTIVATION; HEART AB Hypoxia-inducible factor (HIF), consisting of a labile alpha subunit and a stable beta subunit, is a master regulator of hypoxia-responsive mRNAs. HIF alpha undergoes oxygen-dependent prolyl hydroxylation, which marks it for polyubiquitination by a complex containing the von Hippel-Lindau protein (pVHL). Among the three Phd family members, Phd2 appears to be the primary HIF prolyl hydroxylase. Phd3 is induced by HIF and, based on findings from in vitro studies, may participate in a HIF-regulatory feedback loop. Here, we report that Phd3 loss exacerbates the HIF activation, hepatic steatosis, dilated cardiomyopathy, and premature mortality observed in mice lacking Phd2 alone and produces a closer phenocopy of the changes seen in mice lacking pVHL than the loss of Phd2 alone. Importantly, the degree to which Phd3 can compensate for Phd2 loss and the degree to which the combined loss of Phd2 and Phd3 resembles pVHL loss appear to differ for different HIF-responsive genes and in different tissues. These findings highlight that the responses of different HIF target genes to changes in prolyl hydroxylase activity differ, quantitatively and qualitatively, in vivo and have implications for the development of paralog-specific prolyl hydroxylase inhibitors as therapeutic agents. C1 [Minamishima, Yoji Andrew; Moslehi, Javid; Kaelin, William G., Jr.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Moslehi, Javid; Liao, Ronglih] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Cardiovasc Med, Boston, MA 02115 USA. [Padera, Robert F.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kaelin, William G., Jr.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Kaelin, WG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM william_kaelin@dfci.harvard.edu RI Minamishima, Yoji/E-5380-2010 OI Minamishima, Yoji/0000-0001-7995-9318 FU NIH [T32]; Fibrogen, Inc. FX J. M. was supported by an NIH Clinical Research Training Program (T32) for cardiovascular medicine. W. G. K. was supported by NIH, is a Howard Hughes Medical Institute (HHMI) Investigator, and is a Doris Duke Distinguished Clinical Scientist. W. G. K. has a financial interest in Fibrogen, Inc., which is developing prolyl hydroxylase inhibitors as drugs. NR 55 TC 77 Z9 80 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV 1 PY 2009 VL 29 IS 21 BP 5729 EP 5741 DI 10.1128/MCB.00331-09 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 505SV UT WOS:000270716800009 PM 19720742 ER PT J AU Rhodes, J Amsterdam, A Sanda, T Moreau, LA McKenna, K Heinrichs, S Ganem, NJ Ho, KW Neuberg, DS Johnston, A Ahn, Y Kutok, JL Hromas, R Wray, J Lee, C Murphy, C Radtke, I Downing, JR Fleming, MD MacConaill, LE Amatruda, JF Gutierrez, A Galinsky, I Stone, RM Ross, EA Pellman, DS Kanki, JP Look, AT AF Rhodes, Jennifer Amsterdam, Adam Sanda, Takaomi Moreau, Lisa A. McKenna, Keith Heinrichs, Stefan Ganem, Neil J. Ho, Karen W. Neuberg, Donna S. Johnston, Adam Ahn, Yebin Kutok, Jeffery L. Hromas, Robert Wray, Justin Lee, Charles Murphy, Carly Radtke, Ina Downing, James R. Fleming, Mark D. MacConaill, Laura E. Amatruda, James F. Gutierrez, Alejandro Galinsky, Ilene Stone, Richard M. Ross, Eric A. Pellman, David S. Kanki, John P. Look, A. Thomas TI Emi1 Maintains Genomic Integrity during Zebrafish Embryogenesis and Cooperates with p53 in Tumor Suppression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ANAPHASE-PROMOTING COMPLEX/CYCLOSOME; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; TOPOISOMERASE-II; INSERTIONAL MUTAGENESIS; MAMMALIAN-CELLS; DNA-DAMAGE; INHIBITION; PROGRESSION; CHECKPOINT AB A growing body of evidence indicates that early mitotic inhibitor 1 (Emi1) is essential for genomic stability, but how this function relates to embryonic development and cancer pathogenesis remains unclear. We have identified a zebrafish mutant line in which deficient emi1 gene expression results in multilineage hematopoietic defects and widespread developmental defects that are p53 independent. Cell cycle analyses of Emi1-depleted zebrafish or human cells showed chromosomal rereplication, and metaphase preparations from mutant zebrafish embryos revealed rereplicated, unsegregated chromosomes and polyploidy. Furthermore, EMI1-depleted mammalian cells relied on topoisomerase II alpha-dependent mitotic decatenation to progress through metaphase. Interestingly, the loss of a single emi1 allele in the absence of p53 enhanced the susceptibility of adult fish to neural sheath tumorigenesis. Our results cast Emi1 as a critical regulator of genomic fidelity during embryogenesis and suggest that the factor may act as a tumor suppressor. C1 [Rhodes, Jennifer; Ross, Eric A.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Amsterdam, Adam] MIT, Cambridge, MA 02139 USA. [Sanda, Takaomi; Moreau, Lisa A.; McKenna, Keith; Heinrichs, Stefan; Ganem, Neil J.; Ho, Karen W.; Neuberg, Donna S.; Johnston, Adam; Ahn, Yebin; MacConaill, Laura E.; Gutierrez, Alejandro; Galinsky, Ilene; Stone, Richard M.; Pellman, David S.; Kanki, John P.; Look, A. Thomas] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kutok, Jeffery L.; Lee, Charles; Murphy, Carly] Brigham & Womens Hosp, Boston, MA 02115 USA. [Hromas, Robert; Wray, Justin] Univ New Mexico, Ctr Canc, Albuquerque, NM 87131 USA. [Radtke, Ina; Downing, James R.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Fleming, Mark D.] Childrens Hosp, Boston, MA 02115 USA. [Amatruda, James F.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. RP Rhodes, J (reprint author), Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA. EM Jennifer.Rhodes@fccc.edu OI Gutierrez, Alejandro/0000-0002-0249-9007 FU NIH [R01 CA93152, K01 DK69672, P01 CA66996-11A1, R01 CA111560, R01 RR12589] FX This work was supported by NIH grants R01 CA93152 (A. T. L.), K01 DK69672 (J. R.), P01 CA66996-11A1 (R. M. S. and J. D. Griffin), R01 CA111560 (C. L.), and R01 RR12589 (A. A. and Nancy Hopkins). NR 42 TC 24 Z9 24 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV 1 PY 2009 VL 29 IS 21 BP 5911 EP 5922 DI 10.1128/MCB.00558-09 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 505SV UT WOS:000270716800023 PM 19704007 ER PT J AU Saydam, O Shen, YP Wurdinger, T Senol, O Boke, E James, MF Tannous, BA Stemmer-Rachamimov, AO Yi, M Stephens, RM Fraefel, C Gusella, JF Krichevsky, AM Breakefield, XO AF Saydam, Okay Shen, Yiping Wuerdinger, Thomas Senol, Ozlem Boke, Elvan James, Marianne F. Tannous, Bakhos A. Stemmer-Rachamimov, Anat O. Yi, Ming Stephens, Robert M. Fraefel, Cornel Gusella, James F. Krichevsky, Anna M. Breakefield, Xandra O. TI Downregulated MicroRNA-200a in Meningiomas Promotes Tumor Growth by Reducing E-Cadherin and Activating the Wnt/beta-Catenin Signaling Pathway SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MIR-200 FAMILY; MESENCHYMAL TRANSITION; COLORECTAL-CANCER; REPRESSORS ZEB1; GENETIC MODEL; BETA-CATENIN; IN-VIVO; CELLS; EXPRESSION; NF2 AB Meningiomas, one of the most common human brain tumors, are derived from arachnoidal cells associated with brain meninges, are usually benign, and are frequently associated with neurofibromatosis type 2. Here, we define a typical human meningioma microRNA (miRNA) profile and characterize the effects of one downregulated miRNA, miR-200a, on tumor growth. Elevated levels of miR-200a inhibited meningioma cell growth in culture and in a tumor model in vivo. Upregulation of miR-200a decreased the expression of transcription factors ZEB1 and SIP1, with consequent increased expression of E-cadherin, an adhesion protein associated with cell differentiation. Downregulation of miR-200a in meningiomas and arachnoidal cells resulted in increased expression of beta-catenin and cyclin D1 involved in cell proliferation. miR-200a was found to directly target beta-catenin mRNA, thereby inhibiting its translation and blocking Wnt/beta-catenin signaling, which is frequently involved in cancer. A direct correlation was found between the downregulation of miR-200a and the upregulation of beta-catenin in human meningioma samples. Thus, miR-200a appears to act as a multifunctional tumor suppressor miRNA in meningiomas through effects on the E-cadherin and Wnt/beta-catenin signaling pathways. This reveals a previously unrecognized signaling cascade involved in meningioma tumor development and highlights a novel molecular interaction between miR-200a and Wnt signaling, thereby providing insights into novel therapies for meningiomas. C1 [Saydam, Okay; Wuerdinger, Thomas; Senol, Ozlem; Boke, Elvan; Tannous, Bakhos A.; Breakefield, Xandra O.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02129 USA. [Saydam, Okay; Wuerdinger, Thomas; Senol, Ozlem; Boke, Elvan; Tannous, Bakhos A.; Breakefield, Xandra O.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02129 USA. [Saydam, Okay; Wuerdinger, Thomas; Senol, Ozlem; Boke, Elvan; Tannous, Bakhos A.; Breakefield, Xandra O.] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02129 USA. [Shen, Yiping; James, Marianne F.; Gusella, James F.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res,Mol Neurogenet Unit, Boston, MA 02114 USA. [Wuerdinger, Thomas] Vrije Univ Amsterdam, Med Ctr, Dept Neurosurg, Neurooncol Res Grp, Amsterdam, Netherlands. [Stemmer-Rachamimov, Anat O.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02129 USA. [Stemmer-Rachamimov, Anat O.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mol Neurooncol Lab, Boston, MA 02129 USA. [Yi, Ming; Stephens, Robert M.] NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. [Fraefel, Cornel] Univ Zurich, Inst Virol, CH-8057 Zurich, Switzerland. [Krichevsky, Anna M.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Breakefield, XO (reprint author), Harvard Univ, Massachusetts Gen Hosp, Mol Neurogenet Unit, Sch Med, E 13th St,Bldg 149, Charlestown, MA 02129 USA. EM breakefield@hms.harvard.edu RI huang, nqi/F-7238-2011 FU Children's Tumor Foundation [2007-01-043, 2005-01-004, NINDS NS24279, NCI CA69246, CA86355]; Brain Tumor Society; American Brain Tumor Society; Cancer League of Canton Zurich; Neurofibromatosis Inc.-New England; S. Sydney De Young Foundation FX We thank Anita Lal for meningioma cell lines SF4433 and SF4068. We also thank Casey A. Maguire for critical reading of the manuscript, Arda Mizrak for assistance, Suzanne McDavitt for skilled editorial assistance, and Applied Biosystems for supplying the miRNA qRT-PCR primers. NR 46 TC 126 Z9 144 U1 1 U2 19 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD NOV 1 PY 2009 VL 29 IS 21 BP 5923 EP 5940 DI 10.1128/MCB.00332-09 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 505SV UT WOS:000270716800024 PM 19703993 ER PT J AU Jha, AR Pillai, SK York, VA Sharp, ER Storm, EC Wachter, DJ Martin, JN Deeks, SG Rosenberg, MG Nixon, DF Garrison, KE AF Jha, Aashish R. Pillai, Satish K. York, Vanessa A. Sharp, Elizabeth R. Storm, Emily C. Wachter, Douglas J. Martin, Jeffrey N. Deeks, Steven G. Rosenberg, Michael G. Nixon, Douglas F. Garrison, Keith E. TI Cross-Sectional Dating of Novel Haplotypes of HERV-K 113 and HERV-K 115 Indicate These Proviruses Originated in Africa before Homo sapiens SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE insertion frequencies; haplotype; HERV-K113 and HERV-K115; hervotype; human evolution; Homo erectus ID ENDOGENOUS RETROVIRUS FAMILY; BREAST-CANCER PATIENTS; INSERTIONAL POLYMORPHISMS; REVERSE-TRANSCRIPTASE; EVOLUTIONARY DYNAMICS; RHEUMATOID-ARTHRITIS; SUBSTITUTION RATES; HUMAN-POPULATIONS; MOLECULAR CLOCK; MIDDLE-AWASH AB The human genome, human endogenous retroviruses (HERV), of which HERV-K 113 and HERV-K 115 are the only known full-length proviruses that are insertionally polymorphic. Although a handful of previously published papers have documented their prevalence in the global population; to date, there has been no report on their prevalence in the United States population. Here, we studied the geographic distribution of K113 and K115 among 156 HIV-1+ subjects from the United States, including African Americans, Hispanics, and Caucasians. In the individuals studied, we found higher insertion frequencies of K113 (21%) and K115 (35%) in African Americans compared with Caucasians (K113 9% and K115 6%) within the United States. We also report the presence of three single nucleotide polymorphism sites in the K113 5' long terminal repeats (LTRs) and four in the K115 5' LTR that together constituted four haplotypes for K113 Lind five haplotypes for K115. HERV insertion times can be estimated from the sequence differences between the 5' and 3' LTR of each insertion, but this dating method cannot be used with HERV-K115. We developed a method to estimate insertion times by applying coalescent inference to 5' LTR sequences within our study population and validated this approach using an independent estimate derived from the genetic distance between K113 5' and 3' LTR sequences. Using our method, we estimated the insertion dates of K113 and K115 to be it minimum of 800,000 and 1.1 million years ago, respectively. Both these insertion dates predate the emergence of anatomically modern Homo sapiens. C1 [Jha, Aashish R.; York, Vanessa A.; Sharp, Elizabeth R.; Storm, Emily C.; Wachter, Douglas J.; Nixon, Douglas F.; Garrison, Keith E.] Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA. [Jha, Aashish R.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Pillai, Satish K.] Univ Calif San Francisco, Dept Med, San Francisco Vet Affairs Med Ctr, Div Infect Dis, San Francisco, CA USA. [Martin, Jeffrey N.; Deeks, Steven G.] Univ Calif San Francisco, Dept Med, Div HIV AIDS, San Francisco Gen Hosp, San Francisco, CA USA. [Rosenberg, Michael G.] Albert Einstein Coll Med, Jacobi Med Ctr, Bronx, NY 10467 USA. [Garrison, Keith E.] St Marys Coll, Moraga, CA 94575 USA. RP Jha, AR (reprint author), Univ Calif San Francisco, Div Expt Med, San Francisco, CA 94143 USA. EM nepaliaashish@gmail.com OI Nixon, Douglas/0000-0002-2801-1786 FU UCSF AIDS Research Institute; Pfizer, Inc.,; National Institutes of Health [1KO1DA024654, A176059]; University of California San Francisco AIDS Research Institute FX This study was conducted in part from funds from the UCSF AIDS Research Institute, a sponsored research agreement from Pfizer, Inc., and National Institutes of Health grants 1KO1DA024654 (S.K.P.) and A176059 (D.F.N.). This study was conducted in part from funds from the University of California San Francisco AIDS Research Institute, a sponsored research agreement from Pfizer, Inc., and National Institutes of Health grants 1KO1DA024654 (S.K.P.) and A176059 (D.F.N.). NR 48 TC 19 Z9 19 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD NOV PY 2009 VL 26 IS 11 BP 2617 EP 2626 DI 10.1093/molbev/msp180 PG 10 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 514UX UT WOS:000271422300020 PM 19666991 ER PT J AU Kong, TQ Xu, DS Yu, WF Takakura, A Boucher, I Tran, M Kreidberg, JA Shah, J Zhou, J Denker, BM AF Kong, Tianqing Xu, Daosong Yu, Wanfeng Takakura, Ayumi Boucher, Ilene Tran, Mei Kreidberg, Jordan A. Shah, Jagesh Zhou, Jing Denker, Bradley M. TI G alpha 12 Inhibits alpha 2 beta 1 Integrin-mediated Madin-Darby Canine Kidney Cell Attachment and Migration on Collagen-I and Blocks Tubulogenesis SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID FOCAL ADHESION KINASE; HETEROTRIMERIC G-PROTEINS; SRC TYROSINE KINASE; BREAST-CANCER; BRANCHING MORPHOGENESIS; PHOSPHATASE-ACTIVITY; EPITHELIAL-CELLS; BINDING PROTEIN; G(12) FAMILY; G12 FAMILY AB Regulation of epithelial cell attachment and migration are essential for normal development and maintenance of numerous tissues. G proteins and integrins are critical signaling proteins regulating these processes, yet in polarized cells little is known about the interaction of these pathways. Herein, we demonstrate that G alpha 12 inhibits interaction of MDCK cells with collagen-I, the major ligand for alpha 2 beta 1 integrin. Activating G alpha 12 (QL point mutation or stimulating endogenous G alpha 12 with thrombin) inhibited focal adhesions and lamellipodia formation and led to impaired cell migration. Consistent with G alpha 12-regulated attachment to collagen-I, G alpha 12-silenced MDCK cells revealed a more adherent phenotype. Inhibiting Rho kinase completely restored normal attachment in G alpha 12-activated cells, and there was partial recovery with inhibition of Src and protein phosphatase pathways. G alpha 12 activation led to decreased phosphorylation of focal adhesion kinase and paxillin with displacement of alpha 2 integrin from the focal adhesion protein complex. Using the MDCK cell 3D-tubulogenesis assay, activated G alpha 12 inhibited tubulogenesis and led to the formation of cyst-like structures. Furthermore, G alpha 12-silenced MDCK cells were resistant to thrombin-stimulated cyst development. Taken together, these studies provide direct evidence for G alpha 12-integrin regulation of epithelial cell spreading and migration necessary for normal tubulogenesis. C1 [Kong, Tianqing; Yu, Wanfeng; Takakura, Ayumi; Boucher, Ilene; Tran, Mei; Shah, Jagesh; Zhou, Jing; Denker, Bradley M.] Brigham & Womens Hosp, Div Renal, Harvard Inst Med, Boston, MA 02115 USA. [Xu, Daosong] Dana Farber Canc Inst, Boston, MA 02115 USA. [Kreidberg, Jordan A.] Childrens Hosp, Boston, MA 02115 USA. RP Denker, BM (reprint author), Brigham & Womens Hosp, Div Renal, Harvard Inst Med, Boston, MA 02115 USA. EM bdenker@rics.bwh.harvard.edu RI yu, wanfeng/G-2915-2013 FU [P50 DK074030]; [R01 KD40703]; [R01 GM5223]; [K01 DK080179] FX We thank members of the Harvard Polycystic Kidney Disease Center for helpful comments and suggestions, Dr. Gunaratnam for providing G alpha 12-expressing PK1 cells, and Sarah Beaudry for her outstanding technical assistance. This work was supported by Grants P50 DK074030 to J.Z. (PI) and B.M.D. (Project 1). J.Z. is also supported by R01 KD40703 and B. M. D. by R01 GM5223, and Grant K01 DK080179 to T. K. NR 48 TC 12 Z9 12 U1 0 U2 3 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 NOV 1 PY 2009 VL 20 IS 21 BP 4596 EP 4610 DI 10.1091/mbc.E09-03-0220 PG 15 WC Cell Biology SC Cell Biology GA 514DL UT WOS:000271374400012 PM 19776354 ER PT J AU Liu, BL Ordonez-Ercan, D Fan, ZY Huang, XP Edgerton, SM Yang, XH Thor, AD AF Liu, Bolin Ordonez-Ercan, Dalia Fan, Zeying Huang, Xiaoping Edgerton, Susan M. Yang, XiaoHe Thor, Ann D. TI Estrogenic Promotion of ErbB2 Tyrosine Kinase Activity in Mammary Tumor Cells Requires Activation of ErbB3 Signaling SO MOLECULAR CANCER RESEARCH LA English DT Article ID HUMAN-BREAST-CARCINOMA; MESSENGER RIBONUCLEIC-ACID; GROWTH-FACTOR RECEPTOR; TRANSGENIC MICE; ENDOCRINE RESISTANCE; ADJUVANT THERAPY; NEU ONCOGENE; CANCER CELLS; C-NEU; EXPRESSION AB Increasing evidence suggests molecular interactions between erbB2 and other receptor tyrosine kinases, and estrogenic compounds and their cognate receptors. We have recently reported that downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. On the basis of these data, we hypothesized that erbB3 may play a major role connecting these two sentinel pathways. Interactions were studied using mammary/breast cancer cell lines from wild-type rat c-neu gene transgenic mice and humans. Estradiol promoted cell proliferation and activated erbB2/neu tyrosine kinase, Akt, and mitogen-activated protein kinase signaling exclusively in mammary and breast epithelial cell lines with coexpression of both erbB2 and erbB3. Estradiol action was independent of the transgene promoter (MMTV-LTR) activity, both in vitro and in vivo, as well as c-neu transgene or endogenous erbB2 gene expression. Estrogen induction of cell growth promotion, erbB2/neu activation, and downstream signaling was abrogated by blockade of estrogen receptor (ER) with the pure ER antagonist ICI 182,780 or knockdown of erbB3 expression via specific siRNA. These data suggest that activation of both ER and erbB2/erbB3 signaling is requisite for estrogen-induced mitogenesis and erbB2/neu tyrosine kinase activation. (Mol Cancer Res 2009;7(11):1882-92) C1 [Liu, Bolin; Fan, Zeying; Huang, Xiaoping; Edgerton, Susan M.; Thor, Ann D.] Univ Colorado, Dept Pathol, Denver Sch Med, Aurora, CO 80045 USA. [Ordonez-Ercan, Dalia] Dana Farber Canc Inst, Boston, MA 02115 USA. [Yang, XiaoHe] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. RP Thor, AD (reprint author), Univ Colorado, Dept Pathol, Denver Sch Med, MS B2116,POB 6511, Aurora, CO 80045 USA. EM ann.thor@uchsc.edu RI Yang, Jim/B-3776-2010 NR 45 TC 14 Z9 15 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1541-7786 J9 MOL CANCER RES JI Mol. Cancer Res. PD NOV PY 2009 VL 7 IS 11 BP 1882 EP 1892 DI 10.1158/1541-7786.MCR-08-0509 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 522NZ UT WOS:000272006300014 PM 19861407 ER PT J AU Joshi, MD Ahmad, R Yin, L Raina, D Rajabi, H Bubley, G Kharbanda, S Kufe, D AF Joshi, Maya Datt Ahmad, Rehan Yin, Li Raina, Deepak Rajabi, Hasan Bubley, Glenn Kharbanda, Surender Kufe, Donald TI MUC1 oncoprotein is a druggable target in human prostate cancer cells SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID RECEPTOR TRANSCRIPTIONAL ACTIVITY; EPIDERMAL-GROWTH-FACTOR; ANDROGEN-RECEPTOR; BETA-CATENIN; SURVIVAL RESPONSE; OXIDATIVE STRESS; CARCINOMA ANTIGEN; C-SRC; ACTIVATION; DEATH AB Human prostate cancers are dependent on the androgen receptor for their progression. The MUC1 heterodimeric oncoprotein is aberrantly overexpressed in prostate cancers; however, it is not known if MUC1 is of functional importance to these tumors. To assess dependence on MUC1, we synthesized an inhibitor, designated GO-201, which interacts directly with the MUC1-C subunit at its oligomerization domain. Treatment of MUC1-positive DU145 and PC3 prostate cancer cells with GO-201, and not an altered version, resulted in inhibition of proliferation. GO-201 also induced necrotic cell death that was associated with increases in reactive oxygen species, loss of mitochondrial transmembrane potential, and depletion of ATP. By contrast, GO-201 had no effect against MUC1-negative LNCaP, CWR22Rv1, and MDA-PCa-2b prostate cancer cells. Significantly, GO-201 treatment of DU145 and PC3 xenografts growing in nude mice resulted in complete tumor regression and prolonged lack of recurrence. These findings indicate that certain prostate cancer cells are dependent on MUC1-C for growth and survival and that directly targeting MUC1-C results in their death in vitro and in tumor models. [Mol Cancer Ther 2009;(11):3056-65] C1 [Joshi, Maya Datt; Ahmad, Rehan; Yin, Li; Rajabi, Hasan; Kufe, Donald] Dana Farber Canc Inst, Boston, MA 02115 USA. [Bubley, Glenn] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. RP Kufe, D (reprint author), Dana Farber Canc Inst, 44 Binney St,Dana 830, Boston, MA 02115 USA. EM donald_kufe@dfci.harvard.edu FU Dana-Farber/Harvard Cancer Center Nodal [2006-11-NN]; Department of Defense Prostate Cancer Idea [W81XWH-08-1-0093]; National Cancer Institute [CA97098, CA42802] FX Dana-Farber/Harvard Cancer Center Nodal grant 2006-11-NN, Department of Defense Prostate Cancer Idea Award W81XWH-08-1-0093, and National Cancer Institute grants CA97098 and CA42802. NR 50 TC 39 Z9 39 U1 0 U2 8 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 NOV PY 2009 VL 8 IS 11 BP 3056 EP 3065 DI 10.1158/1535-7163.MCT-09-0646 PG 10 WC Oncology SC Oncology GA 519XE UT WOS:000271802100009 PM 19887552 ER PT J AU Ficicioglu, C Mandell, R Shih, VE AF Ficicioglu, C. Mandell, R. Shih, V. E. TI Argininosuccinate lyase deficiency: Longterm outcome of 13 patients detected by newborn screening SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Argininosuccinate lyase deficiency; Argininosuccinic aciduria; Newborn screening; Urea cycle disorder; Outcome; Hyperammonemia ID DIETARY-MANAGEMENT; ACIDURIA; DISORDERS AB Argininosuccinate lyase deficiency is a urea cycle disorder which can present in the neonatal period with hyperammonemic encephalopathy, or later in childhood with episodic vomiting, growth and developmental delay. Abnormal hair, hepatomegaly, and hepatic fibrosis are unique features of this disorder. Twelve patients with argininosuccinate lyase deficiency were ascertained between 4 and 6 weeks of age by urine amino acid screening. One infant in a previously identified family was diagnosed shortly after birth. Diagnosis was confirmed by enzyme assay in red blood cells and/or skin fibroblasts. At the time of last follow-up, patients had been followed for 13-33 years. All patients were asymptomatic at detection, 7 had slightly increased blood ammonia, and all were initially treated with low-protein diet. Utilization of (14)C-citrulline by intact skin fibroblasts measured by (14)C incorporation into macromolecules was 74-135% of the control mean for 7 of the 8 patients studied. Nine patients had normal development. 4 had learning disability, 6 had EEG abnormalities, 3 had seizure disorder. None had any episodes of hyperammonemic coma. None had hepatomegaly. Patients detected by screening had higher enzyme activity measured by the (14)C-citrulline incorporation assay than comparison groups of patients with neonatal-onset and with late-onset detected by clinical disease. The ability to utilize (14)C-citrulline by intact fibroblasts seems to correlate with clinical outcome and may have prognostic value. It is likely that early diagnosis and treatment contributed to the relatively mild clinical course of the study group. (C) 2009 Elsevier Inc. All rights reserved. C1 [Ficicioglu, C.; Mandell, R.; Shih, V. E.] Massachusetts Gen Hosp, Amino Acid Disorders Lab, Boston, MA 02114 USA. RP Shih, VE (reprint author), Massachusetts Gen Hosp, Amino Acid Disorders Lab, 55 Fruit St,GRJ239, Boston, MA 02114 USA. EM vshih@partners.org OI Ficicioglu, Can/0000-0002-8331-9804 FU Massachusetts General Hospital FX Supported in part by the Mary L. Efron Fund, Massachusetts General Hospital. NR 11 TC 22 Z9 23 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD NOV PY 2009 VL 98 IS 3 BP 273 EP 277 DI 10.1016/j.ymgme.2009.06.011 PG 5 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 513BG UT WOS:000271296400006 PM 19635676 ER PT J AU Zhong, Q Simonis, N Li, QR Charloteaux, B Heuze, F Klitgord, N Tam, S Yu, HY Venkatesan, K Mou, D Swearingen, V Yildirim, MA Yan, H Dricot, A Szeto, D Lin, CW Hao, T Fan, CY Milstein, S Dupuy, D Brasseur, R Hill, DE Cusick, ME Vidal, M AF Zhong, Quan Simonis, Nicolas Li, Qian-Ru Charloteaux, Benoit Heuze, Fabien Klitgord, Niels Tam, Stanley Yu, Haiyuan Venkatesan, Kavitha Mou, Danny Swearingen, Venus Yildirim, Muhammed A. Yan, Han Dricot, Amelle Szeto, David Lin, Chenwei Hao, Tong Fan, Changyu Milstein, Stuart Dupuy, Denis Brasseur, Robert Hill, David E. Cusick, Michael E. Vidal, Marc TI Edgetic perturbation models of human inherited disorders SO MOLECULAR SYSTEMS BIOLOGY LA English DT Article DE binary protein interaction; genotype-to-phenotype relationships; human Mendelian disorders; network perturbation ID PROTEIN-PROTEIN INTERACTIONS; BETA-ACTIN; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; HUMAN GENES; WEB TOOLS; DISEASE; DATABASE; GENOME; IMPROVEMENTS AB Cellular functions are mediated through complex systems of macromolecules and metabolites linked through biochemical and physical interactions, represented in interactome models as 'nodes' and 'edges', respectively. Better understanding of genotype-to-phenotype relationships in human disease will require modeling of how disease-causing mutations affect systems or interactome properties. Here we investigate how perturbations of interactome networks may differ between complete loss of gene products ('node removal') and interaction-specific or edge-specific ('edgetic') alterations. Global computational analyses of similar to 50 000 known causative mutations in human Mendelian disorders revealed clear separations of mutations probably corresponding to those of node removal versus edgetic perturbations. Experimental characterization of mutant alleles in various disorders identified diverse edgetic interaction profiles of mutant proteins, which correlated with distinct structural properties of disease proteins and disease mechanisms. Edgetic perturbations seem to confer distinct functional consequences from node removal because a large fraction of cases in which a single gene is linked to multiple disorders can be modeled by distinguishing edgetic network perturbations. Edgetic network perturbation models might improve both the understanding of dissemination of disease alleles in human populations and the development of molecular therapeutic strategies. Molecular Systems Biology 5: 321; published online 3 November 2009; doi: 10.1038/msb.2009.80 C1 [Vidal, Marc] Dana Farber Canc Inst, Dept Canc Biol, Ctr Canc Syst Biol, Boston, MA 02115 USA. [Zhong, Quan; Simonis, Nicolas; Li, Qian-Ru; Charloteaux, Benoit; Heuze, Fabien; Klitgord, Niels; Tam, Stanley; Yu, Haiyuan; Venkatesan, Kavitha; Mou, Danny; Swearingen, Venus; Yildirim, Muhammed A.; Yan, Han; Dricot, Amelle; Szeto, David; Lin, Chenwei; Hao, Tong; Fan, Changyu; Milstein, Stuart; Dupuy, Denis; Hill, David E.; Cusick, Michael E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Charloteaux, Benoit; Heuze, Fabien; Brasseur, Robert] Fac Univ Sci Agronom Gembloux, Ctr Biophys Mol Numer, Gembloux, Wallonia, Belgium. RP Vidal, M (reprint author), Dana Farber Canc Inst, Dept Canc Biol, Ctr Canc Syst Biol, 44 Binney St,Smith 858, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu RI Klitgord, Niels/B-5121-2009; Simonis, Nicolas/E-5124-2010; Hill, David/B-6617-2011; Yildirim, Muhammed/J-3695-2014; Dupuy, Denis/M-7299-2014 OI Yildirim, Muhammed/0000-0003-2826-1766; FU Ellison Foundation; WM Keck Foundation (MV), NIH [R01-HG001715]; NHGRI [U01-CA105423, U54-CA112952, R33-CA132073]; NCI; Institute Sponsored Research funds from the DanaFarber Cancer Institute Strategic Initiative; NIH NRSA training [T32-CA09361]; Belgian Program on Interuniversity Attraction Poles initiated by the Federal Office for Scientific, Technical and Cultural Affairs [IAPP6/19 PROFUSA]; Honorary Research Associate' and 'Research Director'; Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium) FX We thank all members of the Vidal Lab and the Center for Cancer Systems Biology (CCSB), Dr Patricia K Donahoe and Dr Roseann Mulloy for helpful suggestions; Ines M Pinto for help with experiments. This study was supported by the Ellison Foundation and the WM Keck Foundation (MV), NIH grants R01-HG001715 from NHGRI (MVand F Roth), U01-CA105423 (PI, S Orkin, project leader, MV), U54CA112952 (PI, J Nevins, subcontract, MV) and R33-CA132073 (MV) from NCI, and by Institute Sponsored Research funds from the DanaFarber Cancer Institute Strategic Initiative awarded to CCSB. KV was supported by an NIH NRSA training grant fellowship (T32-CA09361). BC was supported by the Belgian Program on Interuniversity Attraction Poles initiated by the Federal Office for Scientific, Technical and Cultural Affairs (IAPP6/19 PROFUSA). MVand RB are 'Honorary Research Associate' and 'Research Director' from the Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium), respectively. NR 37 TC 163 Z9 163 U1 1 U2 8 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 NOV PY 2009 VL 5 AR 321 DI 10.1038/msb.2009.80 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 526QY UT WOS:000272308900005 PM 19888216 ER PT J AU Heinlen, LD McClain, MT Gross, T Anderson, J Pachner, A Harley, JB James, JA AF Heinlen, Latisha D. McClain, Micah T. Gross, Tim Anderson, Jourdan Pachner, Andrew Harley, John B. James, Judith A. TI Multiple sclerosis patients make antibodies against a unique sequence of EBNA-1 that cross reacts with myelin basic protein SO MULTIPLE SCLEROSIS LA English DT Meeting Abstract CT 14th Annual Meeting of the Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/Cons ortium-for-Multiple-Sclerosis-Centers CY MAY 27-30, 2009 CL Atlanta, GA SP Amer Comm Treatment & Res Multiple Sclerosis, Consortium Multiple Sclerosis Ctr C1 [Heinlen, Latisha D.; McClain, Micah T.; Gross, Tim; Anderson, Jourdan; James, Judith A.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma Med Res Fdn, Dept Clin Immunol, Oklahoma City, OK USA. [Pachner, Andrew] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Neurol & Neurosci, Newark, NJ 07103 USA. [Harley, John B.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma Med Res Fdn, Dept Arthrit & Immunol,US Dept Vet Affairs, Oklahoma City, OK USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1352-4585 J9 MULT SCLER JI Mult. Scler. PD NOV PY 2009 VL 15 IS 11 BP 1389 EP 1389 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 516IU UT WOS:000271536400027 ER PT J AU Salameh, JS Atassi, N David, WS AF Salameh, Johnny S. Atassi, Nazem David, William S. TI SOD1 (A4V)-MEDIATED ALS PRESENTING WITH LOWER MOTOR NEURON FACIAL DIPLEGIA AND UNILATERAL VOCAL CORD PARALYSIS SO MUSCLE & NERVE LA English DT Article DE amyotrophic lateral sclerosis; ALS; SOD1; A4V; motor neuron disease; Madras motor neuron disease; Brown-Vialetto-Van Laere Syndrome; facial diplegia ID AMYOTROPHIC-LATERAL-SCLEROSIS; SUPEROXIDE-DISMUTASE GENE; MUSCULAR-ATROPHY; DISEASE MMND; MUTATIONS AB Amyotrophic lateral sclerosis (ALS) is a progressive degenerative neuromuscular disease that presents with upper and lower motor neuron signs. Although the majority of ALS cases are sporadic, 10% are familial, of which 20%-25% result from mutations in the superoxide dismutase (SOD1) gene. We describe a novel case of SOD1 (A4V)-mediated ALS that presented with lower motor neuron facial diplegia and unilateral vocal cord paralysis. This case expands the phenotypic expression of the A4V mutation. Muscle Nerve 40: 880-882, 2009 C1 [Salameh, Johnny S.; Atassi, Nazem; David, William S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Salameh, JS (reprint author), Massachusetts Gen Hosp, Dept Neurol, 165 Cambridge St,Suite 820, Boston, MA 02114 USA. EM johnnysalameh@hotmail.com NR 14 TC 5 Z9 6 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-639X J9 MUSCLE NERVE JI Muscle Nerve PD NOV PY 2009 VL 40 IS 5 BP 880 EP 882 DI 10.1002/mus.21321 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 511OF UT WOS:000271174400018 PM 19618436 ER PT J AU Chan, EM Ratanasirintrawoot, S Park, IH Manos, PD Loh, YH Huo, HG Miller, JD Hartung, O Rho, J Ince, TA Daley, GQ Schlaeger, TM AF Chan, Elayne M. Ratanasirintrawoot, Sutheera Park, In-Hyun Manos, Philip D. Loh, Yuin-Han Huo, Hongguang Miller, Justine D. Hartung, Odelya Rho, Junsung Ince, Tan A. Daley, George Q. Schlaeger, Thorsten M. TI Live cell imaging distinguishes bona fide human iPS cells from partially reprogrammed cells SO NATURE BIOTECHNOLOGY LA English DT Article ID PLURIPOTENT STEM-CELLS; HUMAN SOMATIC-CELLS; DEFINED FACTORS; FIBROBLASTS; GENERATION; EXPRESSION; SYSTEM; MOUSE AB Somatic cells can be reprogrammed into induced pluripotent stem (iPS) cells by enforced expression of transcription factors. Using serial live imaging of human fibroblasts undergoing reprogramming, we identified distinct colony types that morphologically resemble embryonic stem (ES) cells yet differ in molecular phenotype and differentiation potential. By analyzing expression of pluripotency markers, methylation at the OCT4 and NANOG promoters and differentiation into teratomas, we determined that only one colony type represents true iPS cells, whereas the others represent reprogramming intermediates. Proviral silencing and expression of TRA-1-60, DNMT3B and REX1 can be used to distinguish the fully reprogrammed state, whereas alkaline phosphatase, SSEA-4, GDF3, hTERT and NANOG are insufficient as markers. We also show that reprogramming using chemically defined medium favors formation of fully reprogrammed over partially reprogrammed colonies. Our data define molecular markers of the fully reprogrammed state and highlight the need for rigorous characterization and standardization of putative iPS cells. C1 [Chan, Elayne M.; Ratanasirintrawoot, Sutheera; Park, In-Hyun; Manos, Philip D.; Loh, Yuin-Han; Huo, Hongguang; Miller, Justine D.; Hartung, Odelya; Rho, Junsung; Daley, George Q.; Schlaeger, Thorsten M.] Childrens Hosp, Div Pediat Hematol Oncol, Boston, MA 02115 USA. [Chan, Elayne M.; Ratanasirintrawoot, Sutheera; Park, In-Hyun; Manos, Philip D.; Loh, Yuin-Han; Huo, Hongguang; Miller, Justine D.; Hartung, Odelya; Rho, Junsung; Daley, George Q.; Schlaeger, Thorsten M.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Chan, Elayne M.; Park, In-Hyun; Loh, Yuin-Han; Daley, George Q.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Ratanasirintrawoot, Sutheera; Manos, Philip D.; Huo, Hongguang; Miller, Justine D.; Hartung, Odelya; Daley, George Q.; Schlaeger, Thorsten M.] Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA. [Ince, Tan A.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Daley, George Q.; Schlaeger, Thorsten M.] Harvard Stem Cell Inst, Cambridge, MA USA. [Daley, George Q.] Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. [Daley, George Q.] Brigham & Womens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Daley, George Q.] Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA 02115 USA. RP Daley, GQ (reprint author), Childrens Hosp, Div Pediat Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. EM george.daley@childrens.harvard.edu; schlaeger@enders.tch.harvard.edu RI Loh, Yuin-Han/E-1096-2014 OI Loh, Yuin-Han/0000-0002-4715-6454 FU National Institutes of Health (NIH); Burroughs Wellcome Fund; Leukemia and Lymphoma Society; Harvard Stem Cell Institute; Agency of Science, Technology and Research International Fellowship; Institute of Medical Biology, Singapore; Canadian Institutes of Health Research; Breast Cancer Research Foundation, NY; Department of Defense; Congressionally Directed Medical Research Programs (CDMRPs); Breast Cancer Research Program (BCRP) FX G. Q. D. was supported by grants from the National Institutes of Health (NIH), the NIH Director's Pioneer Award of the NIH Roadmap for Medical Research, and private funds contributed to the Harvard Stem Cell Institute and the Children's Hospital Stem Cell Program. G. Q. D. is a recipient of Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society, and is an investigator of the Howard Hughes Medical Institute. T. M. S. was supported by the Harvard Stem Cell Institute and the Children's Hospital Stem Cell Program. Y.-H. L. is funded by the Agency of Science, Technology and Research International Fellowship and the Institute of Medical Biology, Singapore. E. M. C. was funded by The Canadian Institutes of Health Research. T. A. I. was supported by Breast Cancer Research Foundation, NY, and Department of Defense, Congressionally Directed Medical Research Programs (CDMRPs) and Breast Cancer Research Program (BCRP). We thank T. Woo (BWH) for her assistance with immnuhistopathological stains of the teratoma sections. NR 24 TC 284 Z9 286 U1 1 U2 32 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 NOV PY 2009 VL 27 IS 11 BP 1033 EP U100 DI 10.1038/nbt.1580 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 516EM UT WOS:000271524700024 PM 19826408 ER PT J AU Sun, YL Jiang, XF Xu, Y Ayrapetov, MK Moreau, LA Whetstine, JR Price, BD AF Sun, Yingli Jiang, Xiaofeng Xu, Ye Ayrapetov, Marina K. Moreau, Lisa A. Whetstine, Johnathan R. Price, Brendan D. TI Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60 SO NATURE CELL BIOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; ATM KINASE-ACTIVITY; CHROMATIN; ACETYLATION; BINDING; GENOME; REPAIR; GENE; HETEROCHROMATIN; DEMETHYLASES AB DNA double-strand break (DSB) repair involves complex interactions between chromatin and repair proteins, including Tip60, a tumour suppressor(1). Tip60 is an acetyltransferase that acetylates both histones(2-5) and ATM (ataxia telangiectasia mutated) kinase(6,7). Inactivation of Tip60 leads to defective DNA repair(2-4) and increased cancer risk(8-11). However, how DNA damage activates the acetyltransferase activity of Tip60 is not known. Here, we show that direct interaction between the chromodomain of Tip60 and histone H3 trimethylated on lysine 9 (H3K9me3) at DSBs activates the acetyltransferase activity of Tip60. Depletion of intracellular H3K9me3 blocks activation of the acetyltransferase activity of Tip60, resulting in defective ATM activation and widespread defects in DSB repair. In addition, the ability of Tip60 to access H3K9me3 is dependent on the DNA damage-induced displacement of HP1 beta (heterochromatin protein 1 beta) from H3K9me3. Finally, we demonstrate that the Mre11-Rad50-Nbs1 (MRN) complex targets Tip60 to H3K9me3, and is required to activate the acetyltransferase activity of Tip60. These results reveal a new function for H3K9me3 in coordinating activation of Tip60-dependent DNA repair pathways, and imply that aberrant patterns of histone methylation may contribute to cancer by altering the efficiency of DSB repair. C1 [Sun, Yingli; Jiang, Xiaofeng; Xu, Ye; Ayrapetov, Marina K.; Moreau, Lisa A.; Price, Brendan D.] Harvard Univ, Sch Med, Div Genom Stabil & DNA Repair, Dept Radiat Oncol,Dana Farber Canc Inst, Boston, MA 02115 USA. [Whetstine, Johnathan R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Price, BD (reprint author), Harvard Univ, Sch Med, Div Genom Stabil & DNA Repair, Dept Radiat Oncol,Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM brendan_price@dfci.harvard.edu FU NCI [CA64585, CA93602]; DOD Breast Cancer Program; NIAID [U19AI067751]; [T32 CA09078] FX We thank T. Jenuwein for providing Suv39h1/2 cells, D. Ferguson for providing Rad50-deficient HCT116 cells, and H. Chan, J. Cote, D. Chowdhury and A. D'Andrea for critical discussions and reading of the manuscript. This work was supported by grants from the NCI (CA64585 and CA93602) and the DOD Breast Cancer Program to B. D. P., and by NCI training grants to Y.S. and M. K. A. (T32 CA09078). Y.X. is supported by a U19 Center grant from NIAID (U19AI067751). NR 38 TC 172 Z9 178 U1 2 U2 14 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 NOV PY 2009 VL 11 IS 11 BP 1376 EP U273 DI 10.1038/ncb1982 PG 18 WC Cell Biology SC Cell Biology GA 514WC UT WOS:000271425800019 PM 19783983 ER PT J AU Yang, XHR Ng, D Alcorta, DA Liebsch, NJ Sheridan, E Li, SF Goldstein, AM Parry, DM Kelley, MJ AF Yang, Xiaohong R. Ng, David Alcorta, David A. Liebsch, Norbert J. Sheridan, Eamonn Li, Sufeng Goldstein, Alisa M. Parry, Dilys M. Kelley, Michael J. TI T (brachyury) gene duplication confers major susceptibility to familial chordoma SO NATURE GENETICS LA English DT Article ID COPY-NUMBER VARIATION; GENOMIC REARRANGEMENTS; DISORDERS; PROTEIN; DISEASE; LOCUS AB Using high-resolution array-CGH, we identified unique duplications of a region on 6q27 in four multiplex families with at least three cases of chordoma, a cancer of presumed notochordal origin. The duplicated region contains only the T (brachyury) gene, which is important in notochord development and is expressed in most sporadic chordomas. Our findings highlight the value of screening for complex genomic rearrangements in searches for cancer-susceptibility genes. C1 [Yang, Xiaohong R.; Ng, David; Goldstein, Alisa M.; Parry, Dilys M.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Alcorta, David A.; Li, Sufeng; Kelley, Michael J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Liebsch, Norbert J.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Sheridan, Eamonn] St James Univ Hosp, Leeds LS9 7TF, W Yorkshire, England. [Li, Sufeng; Kelley, Michael J.] Durham Vet Affairs Med Ctr, Durham, NC USA. RP Parry, DM (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM parryd@mail.nih.gov OI Kelley, Michael/0000-0001-9523-6080 FU US National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Institutes of Health; Department of Veterans Affairs, Veterans Health Administration; Office of Research and Development, Biomedical Laboratory Research and Development program; Chordoma Foundation FX We thank D. Zametkin for her outstanding skills as a research nurse; G. M. Glenn and M. L. McMaster for their careful clinical evaluations of affected individuals and family members; N. J. Patronas for reviewing the MRIs; A. Bergen and S. Chanock for SNP genotyping; K. Haque and D. Maeder for technical assistance; and, especially, the affected individuals and their families for their participation. This work was supported by the intramural research program of the US National Cancer Institute, Division of Cancer Epidemiology and Genetics, National Institutes of Health; by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development program; and by a grant from the Chordoma Foundation (M. J. K.). NR 13 TC 104 Z9 111 U1 0 U2 6 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 NOV PY 2009 VL 41 IS 11 BP 1176 EP 1178 DI 10.1038/ng.454 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 512KM UT WOS:000271247600008 PM 19801981 ER PT J AU Soranzo, N Spector, TD Mangino, M Kuhnel, B Rendon, A Teumer, A Willenborg, C Wright, B Chen, L Li, MY Salo, P Voight, BF Burns, P Laskowski, RA Xue, YL Menzel, S Altshuler, D Bradley, JR Bumpstead, S Burnett, MS Devaney, J Doring, A Elosua, R Epstein, SE Erber, W Falchi, M Garner, SF Ghori, MJR Goodall, AH Gwilliam, R Hakonarson, HH Hall, AS Hammond, N Hengstenberg, C Illig, T Konig, IR Knouff, CW McPherson, R Melander, O Mooser, V Nauck, M Nieminen, MS O'Donnell, CJ Peltonen, L Potter, SC Prokisch, H Rader, DJ Rice, CM Roberts, R Salomaa, V Sambrook, J Schreiber, S Schunkert, H Schwartz, SM Serbanovic-Canic, J Sinisalo, J Siscovick, DS Stark, K Surakka, I Stephens, J Thompson, JR Volker, U Volzke, H Watkins, NA Wells, GA Wichmann, HE Van Heel, DA Tyler-Smith, C Thein, SL Kathiresan, S Perola, M Reilly, MP Stewart, AFR Erdmann, J Samani, NJ Meisinger, C Greinacher, A Deloukas, P Ouwehand, WH Gieger, C AF Soranzo, Nicole Spector, Tim D. Mangino, Massimo Kuehnel, Brigitte Rendon, Augusto Teumer, Alexander Willenborg, Christina Wright, Benjamin Chen, Li Li, Mingyao Salo, Perttu Voight, Benjamin F. Burns, Philippa Laskowski, Roman A. Xue, Yali Menzel, Stephan Altshuler, David Bradley, John R. Bumpstead, Suzannah Burnett, Mary-Susan Devaney, Joseph Doering, Angela Elosua, Roberto Epstein, Stephen E. Erber, Wendy Falchi, Mario Garner, Stephen F. Ghori, Mohammed J. R. Goodall, Alison H. Gwilliam, Rhian Hakonarson, Hakon H. Hall, Alistair S. Hammond, Naomi Hengstenberg, Christian Illig, Thomas Koenig, Inke R. Knouff, Christopher W. McPherson, Ruth Melander, Olle Mooser, Vincent Nauck, Matthias Nieminen, Markku S. O'Donnell, Christopher J. Peltonen, Leena Potter, Simon C. Prokisch, Holger Rader, Daniel J. Rice, Catherine M. Roberts, Robert Salomaa, Veikko Sambrook, Jennifer Schreiber, Stefan Schunkert, Heribert Schwartz, Stephen M. Serbanovic-Canic, Jovana Sinisalo, Juha Siscovick, David S. Stark, Klaus Surakka, Ida Stephens, Jonathan Thompson, John R. Voelker, Uwe Voelzke, Henry Watkins, Nicholas A. Wells, George A. Wichmann, H-Erich Van Heel, David A. Tyler-Smith, Chris Thein, Swee Lay Kathiresan, Sekar Perola, Markus Reilly, Muredach P. Stewart, Alexandre F. R. Erdmann, Jeanette Samani, Nilesh J. Meisinger, Christa Greinacher, Andreas Deloukas, Panos Ouwehand, Willem H. Gieger, Christian TI A genome-wide meta-analysis identifies 22 loci associated with eight hematological parameters in the HaemGen consortium SO NATURE GENETICS LA English DT Article ID CORONARY-HEART-DISEASE; MEAN PLATELET VOLUME; MYOCARDIAL-INFARCTION; COMMON VARIANTS; NOONAN-SYNDROME; RISK; GENE; EXPRESSION; MUTATIONS; SELECTION AB The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease and myocardial infarction in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations. C1 [Soranzo, Nicole; Xue, Yali; Bumpstead, Suzannah; Ghori, Mohammed J. R.; Gwilliam, Rhian; Hammond, Naomi; Potter, Simon C.; Rice, Catherine M.; Tyler-Smith, Chris; Deloukas, Panos; Ouwehand, Willem H.] Wellcome Trust Sanger Inst, Hinxton, England. [Soranzo, Nicole; Spector, Tim D.; Mangino, Massimo; Falchi, Mario] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Kuehnel, Brigitte; Doering, Angela; Illig, Thomas; Wichmann, H-Erich; Meisinger, Christa; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Rendon, Augusto; Burns, Philippa; Garner, Stephen F.; Sambrook, Jennifer; Serbanovic-Canic, Jovana; Stephens, Jonathan; Watkins, Nicholas A.; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Rendon, Augusto; Burns, Philippa; Garner, Stephen F.; Sambrook, Jennifer; Serbanovic-Canic, Jovana; Stephens, Jonathan; Watkins, Nicholas A.; Ouwehand, Willem H.] Natl Hlth Serv Blood & Transplant, Cambridge, England. [Teumer, Alexander; Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Willenborg, Christina; Koenig, Inke R.] Med Univ Lubeck, Inst Med Biometrie & Stat, D-23538 Lubeck, Germany. [Willenborg, Christina; Schunkert, Heribert; Erdmann, Jeanette] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Wright, Benjamin; Thompson, John R.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Chen, Li; McPherson, Ruth; Roberts, Robert; Wells, George A.; Stewart, Alexandre F. R.] Univ Ottawa, Inst Heart, John & Jennifer Ruddy Canadian Cardiovasc Genet C, Ottawa, ON, Canada. [Li, Mingyao] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Salo, Perttu; Peltonen, Leena; Salomaa, Veikko; Perola, Markus] Natl Inst Hlth & Welf, Helsinki, Finland. [Salo, Perttu; Peltonen, Leena; Salomaa, Veikko; Surakka, Ida; Perola, Markus] Univ Helsinki, Inst Mol Med, FIN-00014 Helsinki, Finland. [Voight, Benjamin F.; Altshuler, David] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Voight, Benjamin F.; Altshuler, David] MIT & Harvard, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Laskowski, Roman A.] European Bioinformat Inst, Hinxton, England. [Menzel, Stephan; Thein, Swee Lay] Kings Coll London, Dept Haematol, London WC2R 2LS, England. [Altshuler, David] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Altshuler, David; O'Donnell, Christopher J.; Kathiresan, Sekar] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Altshuler, David] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Bradley, John R.] Univ Cambridge, Sch Clin Med, Dept Med, Addenbrookes Hosp, Cambridge, England. [Burnett, Mary-Susan; Devaney, Joseph; Epstein, Stephen E.] Washington Hosp Ctr, MedStar Res Inst, Cardiovasc Res Inst, Washington, DC 20010 USA. [Elosua, Roberto] Inst Municipal Invest Med, E-08003 Barcelona, Spain. [Elosua, Roberto] CIBER Epidemiol & Salud Publ, E-08003 Barcelona, Spain. [Erber, Wendy] Cambridge Univ Hosp NHS Fdn Trust, Dept Haematol, Cambridge, England. [Falchi, Mario] Univ London Imperial Coll Sci Technol & Med, Sect Genom Med, London, England. [Goodall, Alison H.; Samani, Nilesh J.] Univ Leicester, Glenfield Hosp, Leicester, Leics, England. [Hakonarson, Hakon H.] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA. [Hall, Alistair S.] Leeds Gen Infirm, BHF Heart Res Ctr, Leeds, W Yorkshire, England. [Hengstenberg, Christian; Stark, Klaus] Univ Regensburg, Klin & Poliklin Innere Med 2, Regensburg, Germany. [Knouff, Christopher W.; Mooser, Vincent] GlaxoSmithKline Inc, Div Genet, King Of Prussia, PA USA. [Melander, Olle] Lund Univ, Dept Clin Sci Hypertens & Cardiovasc Dis, Malmo Univ Hosp, Malmo, Sweden. [Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Inst Klin Chem & Lab Med, Greifswald, Germany. [Nieminen, Markku S.; Sinisalo, Juha] Univ Helsinki, Cent Hosp, Dept Med, Div Cardiol, Helsinki, Finland. [O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Prokisch, Holger] Tech Univ Munich, Klinikum Rechts Isar, Dept Human Genet, D-8000 Munich, Germany. [Prokisch, Holger] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Rader, Daniel J.; Reilly, Muredach P.] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Schreiber, Stefan] Univ Kiel, Inst Klin Mol Biol, Kiel, Germany. [Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Schwartz, Stephen M.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Wichmann, H-Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H-Erich] Univ Munich, Klinikum Grosshadern, D-8000 Munich, Germany. [Van Heel, David A.] Queen Mary Univ London, Inst Cell & Mol Sci, Barts & London Sch Med & Dent, London, England. [Greinacher, Andreas] Ernst Moritz Arndt Univ Greifswald, Inst Immunol & Transfus Med, Greifswald, Germany. RP Soranzo, N (reprint author), Wellcome Trust Sanger Inst, Genome Campus, Hinxton, England. EM ns6@sanger.ac.uk RI Konig, Inke/A-4544-2009; Erdmann, Jeanette/A-4417-2009; Erdmann, Jeanette/P-7513-2014; Schreiber, Stefan/B-6748-2008; van Heel, David/A-8005-2011; Altshuler, David/A-4476-2009; Voight, Benjamin/F-1775-2011; Stark, Klaus/D-3813-2009; Stewart, Alexandre/A-5677-2011; Falchi, Mario/F-5956-2013; Prokisch, Holger/N-8964-2013; Erber, Wendy/A-1955-2012; Meisinger, Christine/B-5358-2014; Willenborg, Christina/D-2668-2012; Spector, Tim/F-6533-2012; Deloukas, Panos/B-2922-2013; mangino, massimo/F-5134-2011 OI Bradley, John/0000-0002-7774-8805; Perola, Markus/0000-0003-4842-1667; Sinisalo, Juha/0000-0002-0169-5137; Soranzo, Nicole/0000-0003-1095-3852; Meisinger, Christa/0000-0002-9026-6544; ELOSUA, ROBERTO/0000-0001-8235-0095; Rendon, Augusto/0000-0001-8994-0039; van Heel, David/0000-0002-0637-2265; Stewart, Alexandre/0000-0003-2673-9164; Erdmann, Jeanette/0000-0002-4486-6231; Gieger, Christian/0000-0001-6986-9554; Laskowski, Roman/0000-0001-5528-0087; Schreiber, Stefan/0000-0003-2254-7771; Altshuler, David/0000-0002-7250-4107; Stark, Klaus/0000-0002-7832-1942; Willenborg, Christina/0000-0001-5217-6882; Deloukas, Panos/0000-0001-9251-070X; mangino, massimo/0000-0002-2167-7470 FU Wellcome Trust [UKBS-CC1]; EU [HEALTH-F2-2008-ENGAGE, QLG2-CT-2002-01254, LSHM-CT-2006-037593]; National Institute for Health Research of England (NIHR) (TwinsUK); Helmholtz Zentrum Munchen; German Research Center for Environmental Health, Neuherberg, Germany; German Federal Ministry of Education and Research (BMBF); German National Genome Research Network (NGFN); Munich Center of Health Sciences (MC Health) (KORA); Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs, Social Ministry of the Federal State of Mecklenburg-West Pomerania; Deutsche Forschungsgemeinschaft [SFB TR 19]; Siemens Healthcare, Erlangen, Germany; Federal State of Mecklenburg-West Pomerania (SHIP); NIHR, CBMRC, NHSBT, (CBR); Deutsche Forschungsgemeinschaft; German Federal Ministry of Education and Research (BMBF) [NGFN-2]; Leicester NIHR Biomedical Research Unit in Cardiovascular Disease; EU-FP6 [LSHM-CT-2004-503485]; Cardiovascular Institute (University of Pennsylvania); GlaxoSmithKline; MedSTAR Research Institute (PennCATH/MedSTAR); US National Institutes of Health (NIH); National Heart, Lung, and Blood Institute (STAMPEED); National Center for Research Resource [U54 RR020278]; Canadian Institutes of Health Research [MOP82810, NA6650, MOP77682]; Canada Foundation for Innovation and Ontario Research Foundation [11966]; Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation (COROGENE); Juvenile Diabetes Research Foundation/Wellcome Trust [T1D] FX The Wellcome Trust, EU (HEALTH-F2-2008-ENGAGE, QLG2-CT-2002-01254), National Institute for Health Research of England (NIHR) (TwinsUK); The Wellcome Trust (UKBS-CC1); Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany, the German Federal Ministry of Education and Research (BMBF), the German National Genome Research Network (NGFN), Munich Center of Health Sciences (MC Health) (KORA); Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103 and 01ZZ0403), Ministry of Cultural Affairs, Social Ministry of the Federal State of Mecklenburg-West Pomerania, Deutsche Forschungsgemeinschaft (grant SFB TR 19), the Federal Ministry of Education and Research (grant no. 03ZIK012); a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania (SHIP); NIHR, CBMRC, NHSBT, (CBR); Deutsche Forschungsgemeinschaft, the German Federal Ministry of Education and Research (BMBF) (NGFN-2 and NGFN-plus), EU (LSHM-CT-2006-037593) (GerMIFS I and II); BHF and the UK MRC, the Wellcome Trust, Leicester NIHR Biomedical Research Unit in Cardiovascular Disease and EU-FP6 (LSHM-CT-2004-503485) (WTCCC-CAD); Cardiovascular Institute (University of Pennsylvania), GlaxoSmithKline, MedSTAR Research Institute (PennCATH/MedSTAR); US National Institutes of Health (NIH) and National Heart, Lung, and Blood Institute (STAMPEED), National Center for Research Resource (U54 RR020278) (MIGen); Canadian Institutes of Health Research (MOP82810, NA6650 and MOP77682), Canada Foundation for Innovation and Ontario Research Foundation (# 11966) (OHGS); Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation (COROGENE); Juvenile Diabetes Research Foundation/Wellcome Trust (T1D). NR 52 TC 288 Z9 298 U1 1 U2 19 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 NOV PY 2009 VL 41 IS 11 BP 1182 EP U38 DI 10.1038/ng.467 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 512KM UT WOS:000271247600010 PM 19820697 ER PT J AU Ganesh, SK Zakai, NA van Rooij, FJA Soranzo, N Smith, AV Nalls, MA Chen, MH Kottgen, A Glazer, NL Dehghan, A Kuhnel, B Aspelund, T Yang, Q Tanaka, T Jaffe, A Bis, JCM Verwoert, GC Teumer, A Fox, CS Guralnik, JM Ehret, GB Rice, K Felix, JF Rendon, A Eiriksdottir, G Levy, D Patel, KV Boerwinkle, E Rotter, JI Hofman, A Sambrook, JG Hernandez, DG Zheng, G Bandinelli, S Singleton, AB Coresh, J Lumley, T Uitterlinden, AG vanGils, JM Launer, LJ Cupples, LA Oostra, BA Zwaginga, JJ Ouwehand, WH Thein, SL Meisinger, C Deloukas, P Nauck, M Spector, TD Gieger, C Gudnason, V van Duijn, CM Psaty, BM Ferrucci, L Chakravarti, A Greinacher, A O'Donnell, CJ Witteman, JCM Furth, S Cushman, M Harris, TB Lin, JP AF Ganesh, Santhi K. Zakai, Neil A. van Rooij, Frank J. A. Soranzo, Nicole Smith, Albert V. Nalls, Michael A. Chen, Ming-Huei Kottgen, Anna Glazer, Nicole L. Dehghan, Abbas Kuhnel, Brigitte Aspelund, Thor Yang, Qiong Tanaka, Toshiko Jaffe, Andrew Bis, Joshua C. M. Verwoert, Germaine C. Teumer, Alexander Fox, Caroline S. Guralnik, Jack M. Ehret, Georg B. Rice, Kenneth Felix, Janine F. Rendon, Augusto Eiriksdottir, Gudny Levy, Daniel Patel, Kushang V. Boerwinkle, Eric Rotter, Jerome I. Hofman, Albert Sambrook, Jennifer G. Hernandez, Dena G. Zheng, Gang Bandinelli, Stefania Singleton, Andrew B. Coresh, Josef Lumley, Thomas Uitterlinden, Andre G. vanGils, Janine M. Launer, Lenore J. Cupples, L. Adrienne Oostra, Ben A. Zwaginga, Jaap-Jan Ouwehand, Willem H. Thein, Swee-Lay Meisinger, Christa Deloukas, Panos Nauck, Matthias Spector, Tim D. Gieger, Christian Gudnason, Vilmundur van Duijn, Cornelia M. Psaty, Bruce M. Ferrucci, Luigi Chakravarti, Aravinda Greinacher, Andreas O'Donnell, Christopher J. Witteman, Jacqueline C. M. Furth, Susan Cushman, Mary Harris, Tamara B. Lin, Jing-Ping TI Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium SO NATURE GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BLOOD-PRESSURE; HEMOGLOBIN CONCENTRATION; HEMOCHROMATOSIS GENE; HEREDITARY HEMOCHROMATOSIS; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; FETAL-HEMOGLOBIN; CELIAC-DISEASE; C-MYB AB Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures. C1 [Ganesh, Santhi K.] NHGRI, Div Intramural Res, Bethesda, MD 20892 USA. [Ganesh, Santhi K.; Fox, Caroline S.; Levy, Daniel] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Ganesh, Santhi K.; Ehret, Georg B.; Chakravarti, Aravinda] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Zakai, Neil A.; Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Zakai, Neil A.; Cushman, Mary] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [van Rooij, Frank J. A.; Dehghan, Abbas; Verwoert, Germaine C.; Felix, Janine F.; Hofman, Albert; Uitterlinden, Andre G.; Oostra, Ben A.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [van Rooij, Frank J. A.; Dehghan, Abbas; Verwoert, Germaine C.; Felix, Janine F.; Hofman, Albert; Uitterlinden, Andre G.; Oostra, Ben A.; van Duijn, Cornelia M.; Witteman, Jacqueline C. M.] NCHA, NGI, Leiden, Netherlands. [Soranzo, Nicole; Ouwehand, Willem H.; Deloukas, Panos] Wellcome Trust Sanger Inst, Hinxton, England. [Soranzo, Nicole; Cupples, L. Adrienne; Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Smith, Albert V.; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Hernandez, Dena G.] NIA, Intramural Res Program, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Chen, Ming-Huei; Yang, Qiong; Fox, Caroline S.; Levy, Daniel; Cupples, L. Adrienne; O'Donnell, Christopher J.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Kottgen, Anna; Jaffe, Andrew; Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Glazer, Nicole L.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Glazer, Nicole L.; Bis, Joshua C. M.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Kuhnel, Brigitte; Meisinger, Christa; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Tanaka, Toshiko] MedStar Res Inst, Hyattsville, MD USA. [Verwoert, Germaine C.; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Teumer, Alexander] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Guralnik, Jack M.; Patel, Kushang V.; Launer, Lenore J.; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Ehret, Georg B.] Univ Hosp Geneva, Ctr Cardiol, Geneva, Switzerland. [Rice, Kenneth; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Rendon, Augusto; Sambrook, Jennifer G.; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge, England. [Rendon, Augusto; Sambrook, Jennifer G.; Ouwehand, Willem H.] Natl Hlth Serv Blood & Transplant, Cambridge, England. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Zheng, Gang; Lin, Jing-Ping] NHLBI, Off Biostat Res, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Bandinelli, Stefania] Geriatr Unit ASF, Florence, Italy. [Uitterlinden, Andre G.] Erasmus MC, Dept Clin Chem, Rotterdam, Netherlands. [Zwaginga, Jaap-Jan] Leiden Univ, Med Ctr, Dept Immunohematol & Blood Transfus, Leiden, Netherlands. [Oostra, Ben A.] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands. [Zwaginga, Jaap-Jan] Sanquin Res, Dept Expt Immunohematol, Amsterdam, Netherlands. [Thein, Swee-Lay] Kings Coll London, Dept Haematol, London WC2R 2LS, England. [Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Inst Klin Chem & Lab Med, Greifswald, Germany. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA. [Greinacher, Andreas] Ernst Moritz Arndt Univ Greifswald, Inst Immunol & Transfus Med, Greifswald, Germany. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Furth, Susan] Johns Hopkins Sch Med, Dept Pediat, Baltimore, MD USA. RP Ganesh, SK (reprint author), NHGRI, Div Intramural Res, Bethesda, MD 20892 USA. EM ganeshs@mail.nih.gov; odonnellc@mail.nih.gov RI Yang, Qiong/G-5438-2014; Gudnason, Vilmundur/K-6885-2015; Smith, Albert/K-5150-2015; Singleton, Andrew/C-3010-2009; Aspelund, Thor/F-4826-2011; Aspelund, Thor/C-5983-2008; EHRET, Georg/A-9532-2009; Kottgen, Anna/D-2920-2012; Spector, Tim/F-6533-2012; Rice, Kenneth/A-4150-2013; Deloukas, Panos/B-2922-2013; Meisinger, Christine/B-5358-2014 OI Felix, Janine/0000-0002-9801-5774; Rendon, Augusto/0000-0001-8994-0039; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Meisinger, Christa/0000-0002-9026-6544; Dehghan, Abbas/0000-0001-6403-016X; Gudnason, Vilmundur/0000-0001-5696-0084; Smith, Albert/0000-0003-1942-5845; Cupples, L. Adrienne/0000-0003-0273-7965; Aspelund, Thor/0000-0002-7998-5433; EHRET, Georg/0000-0002-5730-0675; Rice, Kenneth/0000-0001-5779-4495; Deloukas, Panos/0000-0001-9251-070X; FU Medical Research Council [G0000111]; NHLBI NIH HHS [R01 HL086694, R01 HL086694-01A1, R01 HL086694-02, R01 HL086694-03]; NIDDK NIH HHS [P30 DK063491-049004, K24 DK078737, P30 DK063491, P30 DK063491-019004, P30 DK063491-029004, P30 DK063491-039004, P30 DK063491-05, U01 DK066174] NR 65 TC 190 Z9 196 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD NOV PY 2009 VL 41 IS 11 BP 1191 EP U48 DI 10.1038/ng.466 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 512KM UT WOS:000271247600011 PM 19862010 ER PT J AU McCarthy, SE Makarov, V Kirov, G Addington, AM McClellan, J Yoon, S Perkins, DO Dickel, DE Kusenda, M Krastoshevsky, O Krause, V Kumar, RA Grozeva, D Malhotra, D Walsh, T Zackai, EH Kaplan, P Ganesh, J Krantz, ID Spinner, NB Roccanova, P Bhandari, A Pavon, K Lakshmi, B Leotta, A Kendall, J Lee, YH Vacic, V Gary, S Iakoucheva, LM Crow, TJ Christian, SL Lieberman, JA Stroup, TS Lehtimaki, T Puura, K Haldeman-Englert, C Pearl, J Goodell, M Willour, VL DeRosse, P Steele, J Kassem, L Wolff, J Chitkara, N McMahon, FJ Malhotra, AK Potash, JB Schulze, TG Nothen, MM Cichon, S Rietschel, M Leibenluft, E Kustanovich, V Lajonchere, CM Sutcliffe, JS Skuse, D Gill, M Gallagher, L Mendell, NR Craddock, N Owen, MJ O'Donovan, MC Shaikh, TH Susser, E DeLisi, LE Sullivan, PF Deutsch, CK Rapoport, J Levy, DL King, MC Sebat, J AF McCarthy, Shane E. Makarov, Vladimir Kirov, George Addington, Anjene M. McClellan, Jon Yoon, Seungtai Perkins, Diana O. Dickel, Diane E. Kusenda, Mary Krastoshevsky, Olga Krause, Verena Kumar, Ravinesh A. Grozeva, Detelina Malhotra, Dheeraj Walsh, Tom Zackai, Elaine H. Kaplan, Paige Ganesh, Jaya Krantz, Ian D. Spinner, Nancy B. Roccanova, Patricia Bhandari, Abhishek Pavon, Kevin Lakshmi, B. Leotta, Anthony Kendall, Jude Lee, Yoon-ha Vacic, Vladimir Gary, Sydney Iakoucheva, Lilia M. Crow, Timothy J. Christian, Susan L. Lieberman, Jeffrey A. Stroup, T. Scott Lehtimaki, Terho Puura, Kaija Haldeman-Englert, Chad Pearl, Justin Goodell, Meredith Willour, Virginia L. DeRosse, Pamela Steele, Jo Kassem, Layla Wolff, Jessica Chitkara, Nisha McMahon, Francis J. Malhotra, Anil K. Potash, James B. Schulze, Thomas G. Noethen, Markus M. Cichon, Sven Rietschel, Marcella Leibenluft, Ellen Kustanovich, Vlad Lajonchere, Clara M. Sutcliffe, James S. Skuse, David Gill, Michael Gallagher, Louise Mendell, Nancy R. Craddock, Nick Owen, Michael J. O'Donovan, Michael C. Shaikh, Tamim H. Susser, Ezra DeLisi, Lynn E. Sullivan, Patrick F. Deutsch, Curtis K. Rapoport, Judith Levy, Deborah L. King, Mary-Claire Sebat, Jonathan CA Wellcome Trust Case Control Consor TI Microduplications of 16p11.2 are associated with schizophrenia SO NATURE GENETICS LA English DT Article ID PERVASIVE DEVELOPMENTAL DISORDERS; AUTISM SPECTRUM DISORDER; HEAD CIRCUMFERENCE; RECURRENT REARRANGEMENTS; HUMAN GENOME; 1ST YEAR; INDIVIDUALS; DISRUPTION; DELETIONS; GENES AB Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders(1-3). We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007). C1 [McCarthy, Shane E.; Makarov, Vladimir; Yoon, Seungtai; Kusenda, Mary; Malhotra, Dheeraj; Roccanova, Patricia; Bhandari, Abhishek; Pavon, Kevin; Lakshmi, B.; Leotta, Anthony; Kendall, Jude; Lee, Yoon-ha; Vacic, Vladimir; Gary, Sydney; Sebat, Jonathan] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Kirov, George; Grozeva, Detelina; Craddock, Nick; Owen, Michael J.; O'Donovan, Michael C.] Cardiff Univ, MRC, Ctr Neuropsychiat Genet & Genom, Dept Psychol Med & Neurol,Sch Med, Cardiff, S Glam, Wales. [Addington, Anjene M.; Rapoport, Judith] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [McClellan, Jon] Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Dickel, Diane E.; Walsh, Tom; King, Mary-Claire] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Kusenda, Mary] SUNY Stony Brook, Grad Program Genet, Stony Brook, NY 11794 USA. [Krastoshevsky, Olga; Krause, Verena; Levy, Deborah L.] McLean Hosp, Psychol Res Lab, Belmont, MA 02178 USA. [Kumar, Ravinesh A.; Christian, Susan L.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Zackai, Elaine H.; Krantz, Ian D.; Spinner, Nancy B.; Haldeman-Englert, Chad; Shaikh, Tamim H.] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA. [Kaplan, Paige; Ganesh, Jaya] Childrens Hosp Philadelphia, Sect Biochem Genet, Philadelphia, PA 19104 USA. [Lakshmi, B.] Ontario Inst Canc Res, Toronto, ON, Canada. [Iakoucheva, Lilia M.] Rockefeller Univ, Lab Stat Genet, New York, NY 10021 USA. [Crow, Timothy J.] Warneford Hosp, Prince Wales Int Ctr SANE Res, Oxford OX3 7JX, England. [Lieberman, Jeffrey A.; Stroup, T. Scott; Susser, Ezra] Columbia Univ, Columbia Univ Coll Phys & Surg, New York, NY USA. [Lieberman, Jeffrey A.] New York State Psychiat Hosp, New York, NY USA. [Lehtimaki, Terho] Tampere Univ, Dept Clin Chem, FIN-33101 Tampere, Finland. [Puura, Kaija] Tampere Univ, Dept Child Psychiat, FIN-33101 Tampere, Finland. [Puura, Kaija] Univ Hosp, Tampere, Finland. [Pearl, Justin; Steele, Jo; Kassem, Layla; Wolff, Jessica; McMahon, Francis J.; Schulze, Thomas G.] NIMH, Genet Basis Mood & Anxiety Disorders Unit, NIH, Bethesda, MD 20892 USA. [Goodell, Meredith; Willour, Virginia L.; Potash, James B.] Johns Hopkins Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. [DeRosse, Pamela; Chitkara, Nisha; Malhotra, Anil K.] Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY USA. [Schulze, Thomas G.; Rietschel, Marcella] Heidelberg Univ, Cent Inst Mental Hlth, Dept Genet Epidemiol Psychiat, D-6800 Mannheim, Germany. [Noethen, Markus M.; Cichon, Sven] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. [Noethen, Markus M.; Cichon, Sven] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. [Rietschel, Marcella] Univ Bonn, Dept Psychiat & Psychotherapy, D-5300 Bonn, Germany. [Leibenluft, Ellen] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Kustanovich, Vlad; Lajonchere, Clara M.] Autism Speaks, Autism Genet Resource Exchange, Los Angeles, CA USA. [Sutcliffe, James S.] Vanderbilt Univ, Ctr Mol Neurosci, Nashville, TN USA. [Skuse, David] UCL, Behav Sci Unit, Inst Child Hlth, London, England. [Gill, Michael; Gallagher, Louise] Trinity Coll Dublin, Sch Med, Dept Psychiat, Dublin, Ireland. [Mendell, Nancy R.] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. [DeLisi, Lynn E.; Deutsch, Curtis K.; Levy, Deborah L.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [DeLisi, Lynn E.] VA Boston Healthcare Syst, Brockton, MA USA. [Sullivan, Patrick F.] Univ N Carolina, Dept Genet, Chapel Hill, NC USA. [Deutsch, Curtis K.] Univ Massachusetts, Sch Med, Eunice Kennedy Shriver Ctr, Waltham, MA USA. RP Sebat, J (reprint author), Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA. EM sebat@cshl.edu RI Stroup, Thomas/F-9188-2014; turton, miranda/F-4682-2011; Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Sutcliffe, James/C-1348-2012; OI Gallagher, Louise/0000-0001-9462-2836; Stroup, Thomas/0000-0002-3123-0672; Gill, Michael/0000-0003-0206-5337; Vacic, Vladimir/0000-0001-6571-2293; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Sutcliffe, James/0000-0001-5200-6007; Sebat, Jonathan/0000-0002-9087-526X; Walsh, Tom/0000-0002-8875-0310; O'Donovan, Michael/0000-0001-7073-2379; Iakoucheva, Lilia/0000-0002-4542-5219; McMahon, Francis/0000-0002-9469-305X; Dickel, Diane/0000-0001-5497-6824; Nothen, Markus/0000-0002-8770-2464 FU National Institute of Mental Health (NIMH) [R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289, U01 MH46318, U01 MH79469, U01 MH79470] FX Funding support for the genome-wide association of schizophrenia study was provided by the National Institute of Mental Health (NIMH) (R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289, U01 MH46318, U01 MH79469 and U01 MH79470), and the genotyping of samples was provided through the genetic association information network (GAIN). The datasets used for the analyses described in this manuscript were obtained from the database of genotype and phenotype (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000021.v2.p1. Samples and associated phenotype data for the genome-wide association of schizophrenia study were provided by the Molecular Genetics of Schizophrenia Collaboration (PI: P. V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, Illinois, USA). NR 41 TC 345 Z9 352 U1 4 U2 28 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD NOV PY 2009 VL 41 IS 11 BP 1223 EP U85 DI 10.1038/ng.474 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 512KM UT WOS:000271247600015 PM 19855392 ER PT J AU Bass, AJ Watanabe, H Mermel, CH Yu, SY Perner, S Verhaak, RG Kim, SY Wardwell, L Tamayo, P Gat-Viks, I Ramos, AH Woo, MS Weir, BA Getz, G Beroukhim, R O'Kelly, M Dutt, A Rozenblatt-Rosen, O Dziunycz, P Komisarof, J Chirieac, LR LaFargue, CJ Scheble, V Wilbertz, T Ma, CQ Rao, S Nakagawa, H Stairs, DB Lin, L Giordano, TJ Wagner, P Minna, JD Gazdar, AF Zhu, CQ Brose, MS Cecconello, I Ribeiro, U Marie, SK Dahl, O Shivdasani, RA Tsao, MS Rubin, MA Wong, KK Regev, A Hahn, WC Beer, DG Rustgi, AK Meyerson, M AF Bass, Adam J. Watanabe, Hideo Mermel, Craig H. Yu, Soyoung Perner, Sven Verhaak, Roel G. Kim, So Young Wardwell, Leslie Tamayo, Pablo Gat-Viks, Irit Ramos, Alex H. Woo, Michele S. Weir, Barbara A. Getz, Gad Beroukhim, Rameen O'Kelly, Michael Dutt, Amit Rozenblatt-Rosen, Orit Dziunycz, Piotr Komisarof, Justin Chirieac, Lucian R. LaFargue, Christopher J. Scheble, Veit Wilbertz, Theresia Ma, Changqing Rao, Shilpa Nakagawa, Hiroshi Stairs, Douglas B. Lin, Lin Giordano, Thomas J. Wagner, Patrick Minna, John D. Gazdar, Adi F. Zhu, Chang Qi Brose, Marcia S. Cecconello, Ivan Ribeiro, Ulysses, Jr. Marie, Suely K. Dahl, Olav Shivdasani, Ramesh A. Tsao, Ming-Sound Rubin, Mark A. Wong, Kwok K. Regev, Aviv Hahn, William C. Beer, David G. Rustgi, Anil K. Meyerson, Matthew TI SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomas SO NATURE GENETICS LA English DT Article ID FOREGUT ENDODERM; MOUSE TRACHEA; CANCER; GENE; EXPRESSION; REVEALS; ADENOCARCINOMAS; DIFFERENTIATION; IDENTIFICATION; AMPLIFICATION AB Lineage-survival oncogenes are activated by somatic DNA alterations in cancers arising from the cell lineages in which these genes play a role in normal development(1,2). Here we show that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas (SCCs) of the lung and esophagus contains the transcription factor gene SOX2, which is mutated in hereditary human esophageal malformations(3), is necessary for normal esophageal squamous development(4), promotes differentiation and proliferation of basal tracheal cells(5) and cooperates in induction of pluripotent stem cells(6-8). SOX2 expression is required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 here cooperated with FOXE1 or FGFR2 to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors show expression of markers of both squamous differentiation and pluripotency. These characteristics identify SOX2 as a lineage-survival oncogene in lung and esophageal SCC. C1 [Bass, Adam J.; Watanabe, Hideo; Mermel, Craig H.; Yu, Soyoung; Verhaak, Roel G.; Kim, So Young; Wardwell, Leslie; Ramos, Alex H.; Woo, Michele S.; Weir, Barbara A.; Beroukhim, Rameen; Dutt, Amit; Rozenblatt-Rosen, Orit; Dziunycz, Piotr; Komisarof, Justin; Shivdasani, Ramesh A.; Wong, Kwok K.; Hahn, William C.; Meyerson, Matthew] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bass, Adam J.; Beroukhim, Rameen; Shivdasani, Ramesh A.; Wong, Kwok K.; Hahn, William C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Bass, Adam J.; Watanabe, Hideo; Mermel, Craig H.; Yu, Soyoung; Verhaak, Roel G.; Kim, So Young; Wardwell, Leslie; Ramos, Alex H.; Woo, Michele S.; Weir, Barbara A.; Beroukhim, Rameen; Dutt, Amit; Rozenblatt-Rosen, Orit; Hahn, William C.; Meyerson, Matthew] Dana Farber Canc Inst, Ctr Canc Genome Discovery, Boston, MA 02115 USA. [Bass, Adam J.; Watanabe, Hideo; Mermel, Craig H.; Verhaak, Roel G.; Tamayo, Pablo; Gat-Viks, Irit; Ramos, Alex H.; Woo, Michele S.; Weir, Barbara A.; Getz, Gad; Beroukhim, Rameen; O'Kelly, Michael; Dutt, Amit; Regev, Aviv; Hahn, William C.; Meyerson, Matthew] Broad Inst, Cambridge, MA USA. [Perner, Sven; LaFargue, Christopher J.; Wagner, Patrick; Rubin, Mark A.] Cornell Univ, Dept Pathol, Weill Med Coll, New York, NY 10021 USA. [Perner, Sven; Scheble, Veit; Wilbertz, Theresia] Univ Tubingen Hosp, Inst Pathol, Ctr Comprehens Canc, Tubingen, Germany. [Chirieac, Lucian R.; Meyerson, Matthew] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Ma, Changqing; Rao, Shilpa; Nakagawa, Hiroshi; Stairs, Douglas B.; Brose, Marcia S.; Rustgi, Anil K.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Nakagawa, Hiroshi; Stairs, Douglas B.; Rustgi, Anil K.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Lin, Lin; Beer, David G.] Univ Michigan, Dept Surg, Thorac Surg Sect, Ann Arbor, MI 48109 USA. [Giordano, Thomas J.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Minna, John D.; Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Zhu, Chang Qi; Tsao, Ming-Sound] Univ Hlth Network, Toronto, ON, Canada. [Zhu, Chang Qi; Tsao, Ming-Sound] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Brose, Marcia S.] Univ Penn, Dept Otorhinolaryngol, Philadelphia, PA 19104 USA. [Cecconello, Ivan; Ribeiro, Ulysses, Jr.; Marie, Suely K.] Univ Sao Paulo, Sch Med, Bauru, SP, Brazil. [Dahl, Olav] Univ Bergen, Sect Oncol, Bergen, Norway. [Rustgi, Anil K.] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. RP Meyerson, M (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM matthew_meyerson@dfci.harvard.edu RI Meyerson, Matthew/E-7123-2012; Dutt, Amit/I-1911-2013; Marie, Suely/D-1870-2012; Ribeiro Jr, Ulysses/G-5942-2012; Cecconello, Ivan/A-3918-2013; OI Rubin, Mark/0000-0002-8321-9950; Giordano, Thomas/0000-0003-0641-8873; Dutt, Amit/0000-0002-1119-4774; Cecconello, Ivan/0000-0002-3535-4170; Ribeiro Junior, Ulysses/0000-0003-1711-7347 FU Ruth L. Kirschstein NRSA; KWF Kankerbestrijding; US Department of Defense; National Cancer Institute [K08CA134931, P50CA70907, R33CA128625, R01CA071606-12, P01CA098101-05, R01CA109038, P50CA90578]; Genentech, Inc.; Sara Thomas Monopoli Lung Cancer Research Fund; Seaman Corporation Fund for Lung Cancer Research FX We thank J. Francis, J. Cho, A. Schinzel, R. Firestein, I. Guney and J. Boehm for technical advice and discussions. A. J. B. is supported by the Harvard Clinical Investigator Training Program and American Society of Clinical Oncology. H. W. is supported by a Ruth L. Kirschstein NRSA T32 institutional training grant. R. G. V. is supported by the KWF Kankerbestrijding. The Morphology, Molecular Biology and Cell Culture Core of 5P01CA098101-05 (A. K. R.) provided tissue processing for this project. This work was supported by US Department of Defense VITAL grant (J. D. M, A. F. G.) and by National Cancer Institute grants K08CA134931 (A. J. B.), P50CA70907 (J. D. M, A. F. G.), R33CA128625 (W. C. H.), R01CA071606-12 (D. G. B.), P01CA098101-05 (A. K. R.) and R01CA109038 and P50CA90578 (M. M.). Funding for lung SCC SNP arrays was provided by Genentech, Inc. Funding was provided by the Sara Thomas Monopoli Lung Cancer Research Fund and the Seaman Corporation Fund for Lung Cancer Research. NR 38 TC 437 Z9 455 U1 1 U2 42 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 NOV PY 2009 VL 41 IS 11 BP 1238 EP U105 DI 10.1038/ng.465 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 512KM UT WOS:000271247600018 PM 19801978 ER PT J AU Wucherpfennig, KW Gagnon, E AF Wucherpfennig, Kai W. Gagnon, Etienne TI Positively selecting peptides: their job does not end in the thymus SO NATURE IMMUNOLOGY LA English DT Editorial Material ID T-CELL-RECEPTOR; SENSITIVITY AB Peptides able to positively select major histocompatibility complex class II-restricted thymocytes have not yet been defined. Two new reports identify and ascribe important extrathymic functions to several positively selecting peptides for CD4(+) T cells. C1 [Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. [Wucherpfennig, Kai W.] Harvard Univ, Sch Med, Program Immunol, Boston, MA 02115 USA. RP Wucherpfennig, KW (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. EM kai_wucherpfennig@dfci.harvard.edu NR 10 TC 4 Z9 4 U1 0 U2 0 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 NOV PY 2009 VL 10 IS 11 BP 1143 EP 1144 DI 10.1038/ni1109-1143 PG 3 WC Immunology SC Immunology GA 508SO UT WOS:000270955900005 PM 19841646 ER PT J AU Geraldes, P Hiraoka-Yamamoto, J Matsumoto, M Clermont, A Leitges, M Marette, A Aiello, LP Kern, TS King, GL AF Geraldes, Pedro Hiraoka-Yamamoto, Junko Matsumoto, Motonobu Clermont, Allen Leitges, Michael Marette, Andre Aiello, Lloyd P. Kern, Timothy S. King, George L. TI Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy SO NATURE MEDICINE LA English DT Article ID PROTEIN-KINASE-C; ENDOTHELIAL GROWTH-FACTOR; SMOOTH-MUSCLE-CELLS; MOTH-EATEN MICE; TYROSINE-PHOSPHATASE; INTENSIVE TREATMENT; FACTOR RECEPTOR; BETA-INHIBITOR; COMPLICATIONS; GLUCOSE AB Cellular apoptosis induced by hyperglycemia occurs in many vascular cells and is crucial for the initiation of diabetic pathologies. In the retina, pericyte apoptosis and the formation of acellular capillaries, the most specific vascular pathologies attributed to hyperglycemia, is linked to the loss of platelet-derived growth factor (PDGF)-mediated survival actions owing to unknown mechanisms. Here we show that hyperglycemia persistently activates protein kinase C-delta (PKC-delta, encoded by Prkcd) and p38 alpha mitogen-activated protein kinase (MAPK) to increase the expression of a previously unknown target of PKC-delta signaling, Src homology-2 domain-containing phosphatase-1 (SHP-1), a protein tyrosine phosphatase. This signaling cascade leads to PDGF receptor-beta dephosphorylation and a reduction in downstream signaling from this receptor, resulting in pericyte apoptosis independently of nuclear factor-kappa B (NF-kappa B) signaling. We observed increased PKC-delta activity and an increase in the number of acellular capillaries in diabetic mouse retinas, which were not reversible with insulin treatment that achieved normoglycemia. Unlike diabetic age-matched wild-type mice, diabetic Prkcd(-/-) mice did not show activation of p38 alpha MAPK or SHP-1, inhibition of PDGF signaling in vascular cells or the presence of acellular capillaries. We also observed PKC-delta, p38 alpha MAPK and SHP-1 activation in brain pericytes and in the renal cortex of diabetic mice. These findings elucidate a new signaling pathway by which hyperglycemia can induce PDGF resistance and increase vascular cell apoptosis to cause diabetic vascular complications. C1 [Geraldes, Pedro; Hiraoka-Yamamoto, Junko; Matsumoto, Motonobu; Clermont, Allen; Aiello, Lloyd P.; King, George L.] Joslin Diabet Ctr, Dianne Nunnally Hoppes Lab Diabet Complicat, Boston, MA 02215 USA. [Aiello, Lloyd P.] Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02215 USA. [Leitges, Michael] Univ Oslo, Biotechnol Ctr Oslo, Oslo, Norway. [Marette, Andre] Univ Laval, Dept Anat & Physiol, Quebec City, PQ, Canada. [Aiello, Lloyd P.] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Kern, Timothy S.] Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. [King, George L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP King, GL (reprint author), Joslin Diabet Ctr, Dianne Nunnally Hoppes Lab Diabet Complicat, Boston, MA 02215 USA. EM george.king@joslin.harvard.edu RI Marette, Andre/E-9342-2013 FU US National Eye Institute [5R01EY016150-02]; Canadian Institute of Health Research [165453] FX Prkcd-/- mice were provided by M. Leitges (University of Oslo). Adenoviral vectors expressing dominant-negative p38 alpha and p38 beta MAPK were generously provided by Y. Wang (University of California, Los Angeles). Adenoviral vector expressing dominant-negative of SHP-1 (Ad-DN SHP-1) was generously provided by A. Marette (University of Laval). P. G. is a recipient of awards from the Juvenile Diabetes Research Foundation. This study was supported by the US National Eye Institute (grant 5R01EY016150-02 to G. L. K.) and by the Canadian Institute of Health Research (grant 165453) to A. M. We thank W.-C. Li and S. Bonner-Weir for the technical support on confocal microscopy imaging. NR 44 TC 158 Z9 170 U1 2 U2 21 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 NOV PY 2009 VL 15 IS 11 BP 1298 EP U133 DI 10.1038/nm.2052 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 516LM UT WOS:000271543700018 PM 19881493 ER PT J AU Cheng, ZY Guo, SD Copps, K Dong, XC Kollipara, R Rodgers, JT Depinho, RA Puigserver, P White, MF AF Cheng, Zhiyong Guo, Shaodong Copps, Kyle Dong, Xiaochen Kollipara, Ramya Rodgers, Joseph T. Depinho, Ronald A. Puigserver, Pere White, Morris F. TI Foxo1 integrates insulin signaling with mitochondrial function in the liver SO NATURE MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR FOXO1; HEPATIC GLUCOSE-PRODUCTION; HUMAN SKELETAL-MUSCLE; LIFE-SPAN; MICE; DYSFUNCTION; RESISTANCE; INDUCTION; OXIDATION; RECEPTOR AB Type 2 diabetes is a complex disease that is marked by the dysfunction of glucose and lipid metabolism. Hepatic insulin resistance is especially pathogenic in type 2 diabetes, as it dysregulates fasting and postprandial glucose tolerance and promotes systemic dyslipidemia and nonalcoholic fatty liver disease(1,2). Mitochondrial dysfunction is closely associated with insulin resistance and might contribute to the progression of diabetes(3,4). Here we used previously generated mice(5) with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD(+)/NADH ratio and ATP production. Although peroxisome proliferator-activated receptor-gamma coactivator-1 gamma (Ppargc-1 alpha) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD(+)/NADH ratio, reduced Ppargc-1 alpha acetylation and restored mitochondrial oxidative metabolism and biogenesis. Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome. C1 [Cheng, Zhiyong; Guo, Shaodong; Copps, Kyle; Dong, Xiaochen; White, Morris F.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Div Endocrinol,Childrens Hosp Boston, Boston, MA 02115 USA. [Kollipara, Ramya; Depinho, Ronald A.] Harvard Univ, Sch Med, Dept Med, Dept Med Oncol,Belfer Inst Appl Canc Sci, Boston, MA USA. [Kollipara, Ramya; Depinho, Ronald A.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Rodgers, Joseph T.; Puigserver, Pere] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol,Dept Cell Biol, Boston, MA 02115 USA. RP White, MF (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Div Endocrinol,Childrens Hosp Boston, Boston, MA 02115 USA. EM morris.white@childrens.harvard.edu FU US National Institutes of Health [DK38712, DK55326]; American Diabetes Association [7-08-MN-63, JF-7-07-27] FX We thank B. Spiegelman and L. M. Rohas for help with respiration assays, S. Orkin for help with fluorescent assays and R. de Cabo for the communication on flow cytometric assay. We are also grateful to Y. Long for his valuable comments and discussion. This project was supported by US National Institutes of Health grants DK38712 and DK55326 (M. F. W.), American Diabetes Association Mentor-Based Postdoctoral Fellowship 7-08-MN-63 (M. F. W. and Z.C.) and American Diabetes Association Junior Faculty Grant JF-7-07-27 (S. G.). NR 34 TC 121 Z9 124 U1 4 U2 18 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 NOV PY 2009 VL 15 IS 11 BP 1307 EP U105 DI 10.1038/nm.2049 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 516LM UT WOS:000271543700019 PM 19838201 ER PT J AU Dreze, M Charloteaux, B Milstein, S Vidalain, PO Yildirim, MA Zhong, Q Svrzikapa, N Romero, V Laloux, G Brasseur, R Vandenhaute, J Boxem, M Cusick, ME Hill, DE Vidal, M AF Dreze, Matija Charloteaux, Benoit Milstein, Stuart Vidalain, Pierre-Olivier Yildirim, Muhammed A. Zhong, Quan Svrzikapa, Nenad Romero, Viviana Laloux, Geraldine Brasseur, Robert Vandenhaute, Jean Boxem, Mike Cusick, Michael E. Hill, David E. Vidal, Marc TI 'Edgetic' perturbation of a C. elegans BCL2 ortholog SO NATURE METHODS LA English DT Article ID PROGRAMMED CELL-DEATH; REVERSE 2-HYBRID SYSTEM; PROTEIN-PROTEIN INTERACTIONS; CAENORHABDITIS-ELEGANS; CED-3 ACTIVATION; GENETIC-CONTROL; APOPTOSIS; YEAST; SELECTION; NETWORK AB Genes and gene products do not function in isolation but within highly interconnected 'interactome' networks, modeled as graphs of nodes and edges representing macromolecules and interactions between them, respectively. We propose to investigate genotype-phenotype associations by methodical use of alleles that lack single interactions, while retaining all others, in contrast to genetic approaches designed to eliminate gene products completely. We describe an integrated strategy based on the reverse yeast two-hybrid system to isolate and characterize such edge-specific, or 'edgetic', alleles. We established a proof of concept with CED-9, a Caenorhabditis elegans BCL2 ortholog. Using ced-9 edgetic alleles, we uncovered a new potential functional link between apoptosis and a centrosomal protein. This approach is amenable to higher throughput and is particularly applicable to interactome network analysis in organisms for which transgenesis is straightforward. C1 [Dreze, Matija; Charloteaux, Benoit; Milstein, Stuart; Vidalain, Pierre-Olivier; Yildirim, Muhammed A.; Zhong, Quan; Svrzikapa, Nenad; Romero, Viviana; Laloux, Geraldine; Boxem, Mike; Cusick, Michael E.; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, CCSB, Boston, MA 02115 USA. [Dreze, Matija; Charloteaux, Benoit; Milstein, Stuart; Vidalain, Pierre-Olivier; Yildirim, Muhammed A.; Zhong, Quan; Svrzikapa, Nenad; Romero, Viviana; Laloux, Geraldine; Boxem, Mike; Cusick, Michael E.; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Dreze, Matija; Charloteaux, Benoit; Milstein, Stuart; Vidalain, Pierre-Olivier; Yildirim, Muhammed A.; Zhong, Quan; Svrzikapa, Nenad; Romero, Viviana; Laloux, Geraldine; Boxem, Mike; Cusick, Michael E.; Hill, David E.; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Dreze, Matija; Laloux, Geraldine; Vandenhaute, Jean] Fac Univ Notre Dame Paix, Unite Rech & Biol Mol, Namur, Wallonia, Belgium. [Charloteaux, Benoit; Brasseur, Robert] Fac Univ Sci Agronom Gembloux, Ctr Biophys Mol Numer, Gembloux, Wallonia, Belgium. RP Vidal, M (reprint author), Harvard Univ, Sch Med, CCSB, Boston, MA 02115 USA. EM marc_vidal@dfci.harvard.edu RI Boxem, Mike/B-8857-2011; Hill, David/B-6617-2011; Yildirim, Muhammed/J-3695-2014; OI Boxem, Mike/0000-0003-3966-4173; Yildirim, Muhammed/0000-0003-2826-1766; , /0000-0001-7002-8488 FU US National Institutes of Health (NIH), National Human Genomics Research Institute (NHGRI) and National Institute of General Medical Sciences (NIGMS) [HG001715]; US National Cancer Institute (NCI) [R33 CA105405, R33 CA132073, R21/R33 CA081658, U01 CA105423]; Dana-Farber Cancer Institute Strategic Initiative; Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium); Federal Office for Scientific, Technical and Cultural Affairs [IAP P6/19 PROFUSA]; NIH National Research Service [T32CA09361]; European Molecular Biology Organization [61-2002]; Leukemia Research Foundation; 'Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium)' FX This paper is dedicated to the memory of Stan Korsmeyer. We thank the members of the Vidal Lab and of the Dana-Farber Cancer Institute CCSB and particularly A.-R. Carvunis for helpful discussions. This work was supported by US National Institutes of Health (NIH) grants R01 HG001715 from the National Human Genomics Research Institute (NHGRI) and National Institute of General Medical Sciences (NIGMS) and grants R33 CA105405, R33 CA132073 and R21/R33 CA081658 from the US National Cancer Institute (NCI) (M. V.), U01 CA105423 from the NCI (principal investigator, S. Orkin; project leader, M. V.) and by Institute Sponsored Research funds from the Dana-Farber Cancer Institute Strategic Initiative awarded to CCSB. M. D. and G. L. were supported by a 'Research Fellow' fellowship from the Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium). B. C. was supported by the Belgian Program on Interuniversity Attraction Poles initiated by the Federal Office for Scientific, Technical and Cultural Affairs (IAP P6/19 PROFUSA). S. M. was supported by an NIH National Research Service Award training grant fellowship (T32CA09361). P.-O.V. was supported by a European Molecular Biology Organization long-term fellowship 61-2002. Support was provided by the Leukemia Research Foundation to M. B. M. V. and R. B. thank the 'Fonds de la Recherche Scientifique (FRS-FNRS, French Community of Belgium)'. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI, NHGRI, NIGMS or the official views of the NCI, NHGRI, NIGMS or the NIH. NR 44 TC 45 Z9 54 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD NOV PY 2009 VL 6 IS 11 BP 843 EP U89 DI 10.1038/NMETH.1394 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 512KI UT WOS:000271247200019 PM 19855391 ER PT J AU Ruggiero, NJ Jaff, MR AF Ruggiero, Nicholas J. Jaff, Michael R. TI INTERVENTIONAL CARDIOLOGY Renal artery stenting-which patients will benefit? SO NATURE REVIEWS CARDIOLOGY LA English DT Editorial Material ID STENOSIS; GUIDELINES; MANAGEMENT C1 [Ruggiero, Nicholas J.; Jaff, Michael R.] Massachusetts Gen Hosp, Sect Vasc Med, Div Cardiovasc Med, Boston, MA 02114 USA. RP Jaff, MR (reprint author), Jaff 55 Fruit St,GB 800, Boston, MA 02114 USA. EM mjaff@partners.org NR 7 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-5002 J9 NAT REV CARDIOL JI Nat. Rev. Cardiol. PD NOV PY 2009 VL 6 IS 11 BP 675 EP 676 DI 10.1038/nrcardio.2009.173 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 508RJ UT WOS:000270950600002 PM 19851345 ER PT J AU Pillai, S Cariappa, A AF Pillai, Shiv Cariappa, Annaiah TI The follicular versus marginal zone B lymphocyte cell fate decision SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID NF-KAPPA-B; ANTIGEN RECEPTOR SIGNALS; IN-VIVO; BONE-MARROW; IMMUNE-RESPONSES; CORROSION CASTS; MICROCIRCULATORY PATHWAYS; POSITIVE SELECTION; SURVIVAL SIGNALS; DISTINCT ROLES AB Bone marrow-derived B cells make an important cell fate choice to develop into either follicular B cells or marginal zone B cells in the spleen, which depends on signalling through the B cell receptor, Notch2, the receptor for B cell-activating factor and the canonical nuclear factor-kappa B pathway, as well as signals involved in the migration and anatomical retention of marginal zone B cells. Recent information discussed in this Review reconciles some of the controversies regarding the role of the B cell receptor in this cell fate decision and a clearer picture has also emerged regarding the anatomical location of ligands for Notch2 in the spleen. This cell fate decision could provide mechanistic insights that are relevant to other commitment events in lymphocytes. C1 [Pillai, Shiv] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Pillai, S (reprint author), Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02129 USA. EM pillai@helix.mgh.harvard.edu FU US National Institutes of Health. [AI064930, AO076505, AR058481] FX This work was supported by grants AI064930, AO076505, and AR058481 from the US National Institutes of Health. NR 105 TC 195 Z9 201 U1 1 U2 15 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 NOV PY 2009 VL 9 IS 11 BP 767 EP 777 DI 10.1038/nri2656 PG 11 WC Immunology SC Immunology GA 510GG UT WOS:000271075500010 PM 19855403 ER PT J AU Norden, AD Drappatz, J Wen, PY AF Norden, Andrew D. Drappatz, Jan Wen, Patrick Y. TI Antiangiogenic therapies for high-grade glioma SO NATURE REVIEWS NEUROLOGY LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; PHASE-II TRIAL; BEVACIZUMAB PLUS IRINOTECAN; RECURRENT GLIOBLASTOMA-MULTIFORME; NEWLY-DIAGNOSED GLIOBLASTOMA; CANCER STEM-CELLS; MALIGNANT GLIOMAS; TUMOR ANGIOGENESIS; BRAIN-TUMORS; IN-VIVO AB High-grade gliomas (HGGs) are vascular tumors that represent attractive targets for antiangiogenic therapies. In this Review, we present the rationale and clinical trial evidence for targeting angiogenesis in HGGs, focusing predominantly on agents that target vascular endothelial growth factor (VEGF) and its receptors. Bevacizumab, a humanized monoclonal antibody against VEGF, was recently approved by the FDA for treatment of recurrent glioblastoma. Bevacizumab prolongs progress ion-free survival and controls peritumoral edema, but its effects on overall survival remain to be determined. Other inhibitors of VEGF, VEGF receptors and other proangiogenic signaling pathways are being evaluated. Antiangiogenic therapies are well tolerated, although potentially serious adverse events can occasionally occur, and resistance to antiangiogenic therapy inevitably develops. Mechanisms of resistance include upregulation of alternative proangiogenic pathways, and increased perivascular tumor growth. Tumor progression on antiangiogenic agents is a challenging problem for which no effective salvage therapy has been identified. Combining these agents with radiation therapy, cytotoxic chemotherapy, other targeted molecular agents, or anti-invasion therapies could be helpful. The international Response Assessment in Neuro-Oncology Working Group has developed consensus treatment response criteria for HGG that account for the complex effects of antiangiogenic drugs. C1 [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Dana Farber Canc Inst, Ctr Neurooncol, Dept Med Oncol, Boston, MA 02115 USA. [Norden, Andrew D.; Drappatz, Jan; Wen, Patrick Y.] Brigham & Womens Hosp, Dept Neurol, Div Neurooncol, Boston, MA 02115 USA. RP Wen, PY (reprint author), Dana Farber Brigham & Womens Canc Ctr, Dana Farber Canc Inst, Ctr Neurooncol, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM pwen@partners.org NR 123 TC 141 Z9 146 U1 2 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1759-4758 J9 NAT REV NEUROL JI Nat. Rev. Neurol. PD NOV PY 2009 VL 5 IS 11 BP 610 EP 620 DI 10.1038/nrneurol.2009.159 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 512WJ UT WOS:000271282100009 PM 19826401 ER PT J AU Li, XY Sapp, E Chase, K Comer-Tierney, LA Masso, N Alexander, J Reeves, P Kegel, KB Valencia, A Esteves, M Aronin, N DiFiglia, M AF Li, Xueyi Sapp, Ellen Chase, Kathryn Comer-Tierney, Laryssa A. Masso, Nicholas Alexander, Jonathan Reeves, Patrick Kegel, Kimberly B. Valencia, Antonio Esteves, Miguel Aronin, Neil DiFiglia, Marian TI Disruption of Rab11 activity in a knock-in mouse model of Huntington's disease SO NEUROBIOLOGY OF DISEASE LA English DT Article DE Huntingtin; Knock-in mouse; Rab11 ID UBIQUITIN-PROTEASOME SYSTEM; GUANINE-NUCLEOTIDE-EXCHANGE; MUTANT HUNTINGTIN; AXONAL-TRANSPORT; TRANSCRIPTIONAL REPRESSION; MITOCHONDRIAL DYSFUNCTION; OXIDATIVE STRESS; NERVOUS-SYSTEM; AMPA RECEPTORS; FRONTAL-CORTEX AB The Huntington's disease (HD) mutation causes polyglutamine expansion in huntingtin (Htt) and neurodegeneration. Htt interacts with a complex containing Rab11GDP and is involved in activation of Rab11, which functions in endosomal recycling and neurite growth and long-term potentiation. Like other Rab proteins, Rab11GDP undergoes nucleotide exchange to Rab11 GTP for its activation. Here we show that striatal membranes of HD(140Q/140Q) knock-in mice are impaired in supporting conversion of Rab11GDP to Rab11GTP. Dominant negative Rab11 expressed in the striatum and cortex of normal mice caused neuropathology and motor dysfunction, suggesting that a deficiency in Rab11 activity is pathogenic in vivo. Primary cortical neurons from HD(140Q/140Q) Mice were delayed in recycling transferrin receptors back to the plasma membrane. Partial rescue from glutamate-induced cell death occurred in HD neurons expressing dominant active Rab11. We propose a novel mechanism of HD pathogenesis arising from diminished Rab11 activity at recycling endosomes. (C) 2009 Elsevier Inc. All rights reserved. C1 [DiFiglia, Marian] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cellular Neurobiol Lab,Dept Neurol, Charlestown, MA 02129 USA. [Li, Xueyi; Sapp, Ellen; Comer-Tierney, Laryssa A.; Masso, Nicholas; Alexander, Jonathan; Reeves, Patrick; Kegel, Kimberly B.; Valencia, Antonio; Esteves, Miguel; DiFiglia, Marian] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Chase, Kathryn; Aronin, Neil] Univ Massachusetts, Sch Med, Dept Med & Cell Biol, Worcester, MA 01655 USA. RP DiFiglia, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cellular Neurobiol Lab,Dept Neurol, Charlestown, MA 02129 USA. EM xlil2@partners.org; difiglia@helix.mgh.harvard.edu FU Hereditary Disease Foundation; High Q/CHDI Foundation; NIH [NS35711, NS38194] FX X.L. was supported by a John J. Wasmuth Postdoctoral Fellowship from the Hereditary Disease Foundation. Other support included grants from High Q/CHDI Foundation to M. D, Huntington's Disease Society of America to M.D. and from NIH (NS35711 to M.D. and NS38194 to N.A.). We are indebted to Dr. William E. Balch (The Scripps Research Institute, La Jolla, CA) for his generous gift of GST-RabGDI. NR 59 TC 27 Z9 27 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD NOV PY 2009 VL 36 IS 2 BP 374 EP 383 DI 10.1016/j.nbd.2009.08.003 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 513AD UT WOS:000271293000015 PM 19699304 ER PT J AU Chan, ST Tang, SW Tang, KW Lee, WK Lo, SS Kwong, KK AF Chan, Suk-tak Tang, Sze-wing Tang, Kwok-wing Lee, Wing-kit Lo, Shing-shun Kwong, Kenneth K. TI Hierarchical coding of characters in the ventral and dorsal visual streams of Chinese language processing SO NEUROIMAGE LA English DT Article ID WORD FORM AREA; POSTERIOR PARIETAL CORTEX; HUMAN OBJECT AREAS; EVENT-RELATED FMRI; FUNCTIONAL MRI; TOP-DOWN; DISCONNEXION SYNDROMES; FUSIFORM GYRUS; BRAIN-FUNCTION; ACTIVATION AB Functional and spatial hierarchical organization of increasingly language-like word forms has been proposed for alphabetic languages at the occipitotemporal cortex for visual word recognition. In the logographic Chinese language system, similar functional and spatial hierarchical presentations of brain responses to sublexical orthographic structure are beginning to be explored. In this study, we used whole-brain fMRI to show that a hierarchical coding of increasingly language-like character type is present in multiple Chinese language processing areas. Fluent Chinese readers were presented with Chinese synonyms/non-synonym pairs, identical/non-identical non-pronounceable pseudo-character pairs constructed with Chinese radicals, and identical/non-identical Korean character pairs. We observed the presence of a spatial gradient for increasing language-like character types in the ventral and dorsal visual streams of the cortex. At the left occipitotemporal cortex of the ventral visual stream, we observed a posterior-to-anterior gradient of character type selectivity with the anterior fusiform region being more selective for real Chinese characters and the posterior fusiform region being more selective for Korean characters. At the left and right intraparietal sulci of the dorsal visual stream, a medial-to-lateral gradient of character type selectivity was observed, with the lateral edge being more selective for real Chinese characters, the medial edge being more selective for pseudo-characters, and with less activation attributable to Korean characters. Spatial gradients of selecting character type were also identified in prefrontal cortex, dorsal striatum and lateral temporal cortex. The results suggest that the left occipitotemporal cortex and both left and right intraparietal sulci are tuned with a functional and spatial hierarchical sensitivity to the presence of semantic elements as well as different orthographic structures. (C) 2009 Elsevier Inc. All rights reserved. C1 [Chan, Suk-tak; Lee, Wing-kit] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. [Tang, Sze-wing] Hong Kong Polytech Univ, Dept Chinese & Bilingual Studies, Hong Kong, Hong Kong, Peoples R China. [Tang, Kwok-wing] Queen Elizabeth Hosp, Dept Diagnost Radiol & Imaging, Hong Kong, Hong Kong, Peoples R China. [Lo, Shing-shun] United Christian Hosp, Dept Radiol & Organ Imaging, Hong Kong, Hong Kong, Peoples R China. [Kwong, Kenneth K.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Chan, ST (reprint author), Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. EM htphoebe@inet.polyu.edu.hk RI Chan, Suk-tak/G-5846-2015 FU Hong Kong Research Grants Council [PolyU 5403/04M]; Hong Kong Polytechnic University FX This research was supported by the Hong Kong Research Grants Council (PolyU 5403/04M) and The Hong Kong Polytechnic University. We thank the radiographers at the United Christian Hospital and the Queen Elizabeth Hospital for their assistance in data collection. NR 80 TC 12 Z9 13 U1 3 U2 12 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 NOV 1 PY 2009 VL 48 IS 2 BP 423 EP 435 DI 10.1016/j.neuroimage.2009.06.078 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 558EP UT WOS:000274723900013 PM 19591947 ER PT J AU Costello, DJ Eichler, AF Eichler, FS AF Costello, Daniel J. Eichler, April F. Eichler, Florian S. TI Leukodystrophies Classification, Diagnosis, and Treatment SO NEUROLOGIST LA English DT Review DE leukodystrophy; X-linked adrenoleukodystrophy; metachromatic leukodystrophy; vanishing white matter disease; Alexander disease; Krabbe disease; magnetic resonance imaging ID X-LINKED ADRENOLEUKODYSTROPHY; GLOBOID-CELL LEUKODYSTROPHY; VANISHING WHITE-MATTER; PROTEOLIPID PROTEIN GENE; ADULT METACHROMATIC LEUKODYSTROPHY; PELIZAEUS-MERZBACHER-DISEASE; AICARDI-GOUTIERES-SYNDROME; MEGALENCEPHALIC LEUKOENCEPHALOPATHY; SUBCORTICAL CYSTS; KRABBE-DISEASE AB Background: The leukodystrophies are a heterogeneous group of diseases, which primarily affect white matter. Symptomatic patients are frequently misdiagnosed and the leukodystrophies are collectively under recognized. However, with ongoing research and increased availability of neuroimaging, our understanding of these diseases is increasing at a steady rate. Recent advances in the diagnosis and treatment of certain forms of leukodystrophy should prompt increased awareness of these diseases in clinical practice. Review Summary: The clinical features, pathophysiology, and therapeutic approach to these diseases are described. Particular emphasis is placed on genetic and pathophysiologic mechanisms, imaging patterns, screening of other family members and, where available, treatment options and resources, Conclusions: With more widespread use of neuroimaging, both pediatric and adult neurologists will increasingly be confronted with white matter disorders. Neurologists should have an approach to the recognition, diagnosis, and management of white matter diseases in general and the leukodystrophies in specific. C1 [Costello, Daniel J.; Eichler, Florian S.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Eichler, April F.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA. RP Eichler, FS (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA. EM feichler@partners.org FU NINDS [1K08N552550-01A1] FX Supported by NINDS, grant 1K08N552550-01A1 (to F.S.E). NR 67 TC 41 Z9 41 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1074-7931 J9 NEUROLOGIST JI Neurologist PD NOV PY 2009 VL 15 IS 6 BP 319 EP 328 DI 10.1097/NRL.0b013e3181b287c8 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 518KA UT WOS:000271688900003 PM 19901710 ER PT J AU Schnyer, DM Maddox, WT Ell, S Davis, S Pacheco, C Verfaellie, M AF Schnyer, David M. Maddox, W. Todd Ell, Shawn Davis, Sarah Pacheco, Clenni Verfaellie, Mieke TI Prefrontal contributions to rule-based and information-integration category learning SO NEUROPSYCHOLOGIA LA English DT Article DE Category learning; Prefrontal cortex; Feedback processing ID CARD SORTING TEST; DECISION BOUND MODELS; BASAL GANGLIA; ORBITOFRONTAL CORTEX; PERCEPTUAL PROCESSES; PARKINSONS-DISEASE; FRONTAL-CORTEX; CATEGORIZATION; SYSTEMS; IDENTIFICATION AB Previous research revealed that the basal ganglia play a critical role in category learning [Ell, S. W., Marchant, N. L., & Ivry, R. B. (2006). Focal putamen lesions impair learning in rule-based, but not information-integration categorization tasks. Neuropsychologia, 44(10),1737-1751; Maddox, W. T. & Filoteo, J. V. (2007). Modeling visual attention and category learning in amnesiacs, striatal-damaged patients and normal aging. In Advances in Clinical-cognitive science: formal modeling and assessment of processes and symptoms (pp. 113-146). Washington DC: American Psychological Association] but less is known about the specific role of prefrontal cortical (PFC) regions in category learning. The current study examined rule-based (RB) and information-integration (II) category learning in 13 patients with damage primarily to ventral PFC regions. After 600 learning trials with feedback, patients were significantly less accurate than matched controls on both RB and II learning. Model-based analysis identified subgroups of patients whose impaired performance in each task was due to the use of sub-optimal learning strategies. Those patients impaired at either II or RB learning, performed significantly worse on the Wisconsin Card Sorting Test, a test of abstract rule formation and the ability to shift and maintain rules. Lesion analysis pointed to damage in a fairly circumscribed region of ventral medial prefrontal cortex as common to the impaired group of patients and those patients without ventral PFC damage mostly performed normally. These results provide further evidence that the ventromedial prefrontal cortex is critically important for the ability to monitor and integrate feedback in order to select and maintain optimal learning strategies. (c) 2009 Elsevier Ltd. All rights reserved. C1 [Schnyer, David M.; Maddox, W. Todd; Pacheco, Clenni] Univ Texas Austin, Dept Psychol, Inst Neurosci, Austin, TX 78712 USA. [Ell, Shawn] Univ Maine, Dept Psychol, Grad Sch Biomed Sci, Orono, ME 04469 USA. [Davis, Sarah] Univ Rochester, Dept Brain & Cognit Sci, Rochester, NY USA. [Verfaellie, Mieke] VA Boston Healthcare Syst, Boston, MA USA. [Verfaellie, Mieke] Boston Univ, Sch Med, Boston, MA 02118 USA. RP Schnyer, DM (reprint author), Univ Texas Austin, Dept Psychol, Inst Neurosci, Austin, TX 78712 USA. EM schnyer@psy.utexas.edu OI Verfaellie, Mieke/0000-0001-5535-4584 FU NIMH [MH077708]; NINDS [NS047884, MH071783]; The University of Texas at Austin [W911NF-07-2-0023]; Medical Research Service of the Department of Veterans Affairs FX We would like to thank Ginette Lafleche, Ph.D. and Michael Alexander, M.D. for the neuropsychological testing and assessment of the patients. We would also like to thank Caitlin Tenison, Natalie Dailey, Maria Olivares, and Sasha Wolosin for their assistance in testing normal control participants. This research was supported by NIMH grants MH077708 to WTM, NINDS grant NS047884 to SWE, MH071783 to MV, and Army grant #W911NF-07-2-0023 to DMS through the Center for Strategic and Innovative Technologies at The University of Texas at Austin, and by the Medical Research Service of the Department of Veterans Affairs. NR 80 TC 21 Z9 21 U1 2 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3932 J9 NEUROPSYCHOLOGIA JI Neuropsychologia PD NOV PY 2009 VL 47 IS 13 BP 2995 EP 3006 DI 10.1016/j.neuropsychologia.2009.07.011 PG 12 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 510DB UT WOS:000271067100037 PM 19643119 ER PT J AU Walcott, BP Bamber, NI Anderson, DE AF Walcott, Brian P. Bamber, Norman I. Anderson, Douglas E. TI SUCCESSFUL TREATMENT OF CHRONIC PAROXYSMAL HEMICRANIA WITH POSTERIOR HYPOTHALAMIC STIMULATION: TECHNICAL CASE REPORT SO NEUROSURGERY LA English DT Article DE Deep brain stimulation; Functional; Headache; Hypothalamus; Paroxysmal hemicrania; Stereotactic; Target AB OBJECTIVE: Chronic paroxysmal hemicrania (CPH) is a rare, unilateral primary headache syndrome. Recent studies suggest hypothalamic dysfunction as the likely cause of CPH. Therapeutic response to deep brain stimulation of the hypothalamus has been observed in the treatment of related trigeminal autonomic cephalgias. We explored the therapeutic effectiveness of posterior hypothalamic Stimulation for the treatment of CPH in a patient intolerant of medical management. CLINICAL PRESENTATION: A 43-year-old woman with CPH reported acute onset of lancinating, unilateral headache pain focused about the right orbit. These debilitating headaches were accompanied by ipsilateral nasal congestion, conjunctival injection, tearing, and ptosis lasting minutes before resolving spontaneously. The patient exhausted attempts at medical management. TECHNIQUE: A deep brain stimulator microelectrode was placed under stereotactic guidance. The posterior hypothalamic target was 3 mm posterior, 5 mm inferior, and 2 mm ipsilateral to the midcommissural point. The electrode was connected to a standard pulse generator and set to final amplitude of 1.5 V, a pulse width of 60 microseconds, and a frequency of 185 Hz. CONCLUSION: The patient's headache symptoms were durably alleviated with intraoperative activation. NO complications were observed. This preliminary success suggests a role for posterior hypothalamic stimulation as a safe and effective treatment in patients with medically refractory CPH. As a therapeutic incremental innovation, this off-label use of technology for symptomatic therapy contributes to results of studies that support a central pathophysiological role for hypothalamic dysfunction in headaches classified among the trigeminal autonomic cephalgias. C1 [Walcott, Brian P.] Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. [Walcott, Brian P.] Harvard Univ, Sch Med, Dept Neurosurg, Boston, MA USA. [Bamber, Norman I.; Anderson, Douglas E.] Loyola Univ, Med Ctr, Dept Neurosurg, Maywood, IL 60153 USA. RP Walcott, BP (reprint author), Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. NR 0 TC 29 Z9 31 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD NOV PY 2009 VL 65 IS 5 BP 997 EP 997 DI 10.1227/01.NEU.0000345937.05186.73 PG 1 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 507SX UT WOS:000270876100038 PM 19834392 ER PT J AU Ott, KM Haddock, KS Fox, SE Shinn, JK Walters, SE Hardin, JW Durand, K Harris, JL AF Ott, Karen M. Haddock, K. Sue Fox, Sandra E. Shinn, Julie K. Walters, Sandra E. Hardin, James W. Durand, Kerri Harris, James L. TI The Clinical Nurse Leader(SM): Impact On Practice Outcomes in the Veterans Health Administration SO NURSING ECONOMICS LA English DT Article ID HEART-FAILURE AB The Clinical Nurse Leader (CNL) role was designed to meet an identified need for expert clinical leadership at the point of care. The Veterans Health Administration (VHA) became early adopters of the CNL role, foreseeing the value of this pivotal clinical leader at the point of care to meet the complex health care needs of America's veterans and shape health care delivery. Impact data were collected and assimilated from seven Veterans Administration Medical Centers to support how CNLs impact the delivery of quality and safe patient care and how practice changes could be sustained. Data collection and analyses resulted in many lessons learned. The new CNL role was implemented in a variety of settings in the VHA system. Integration of the CNL role in all areas of practice in every care setting has the promise of streamlining coordination of care for veterans across all spectrums in the provision of care. C1 [Ott, Karen M.] Vet Hlth Adm, Natl CNL, Off Nursing Serv, Washington, DC USA. [Haddock, K. Sue] Vet Hlth Adm, CNL Evaluat Program, Off Nursing Serv, Washington, DC USA. [Haddock, K. Sue; Durand, Kerri] William Jennings Bryan Dorn VA Med Ctr, Columbia, SC USA. [Fox, Sandra E.] VA Tennessee Valley Healthcare Syst, Surg Serv, Nashville, TN USA. [Shinn, Julie K.] William S Middleton Mem Vet Adm Med Ctr, Inpatient Nursing Serv, Madison, WI USA. [Walters, Sandra E.] VA Tennessee Valley Healthcare Syst, Educ Affiliat & Res, Nashville, TN USA. [Hardin, James W.] Univ S Carolina, Biostat Collaborat Unit, Columbia, SC 29208 USA. [Hardin, James W.] Univ S Carolina, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. RP Ott, KM (reprint author), Vet Hlth Adm, Natl CNL, Off Nursing Serv, Washington, DC USA. RI Hardin, James/Q-7617-2016 OI Hardin, James/0000-0003-0506-5500 NR 19 TC 13 Z9 13 U1 0 U2 5 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD NOV-DEC PY 2009 VL 27 IS 6 BP 363 EP + PG 9 WC Nursing SC Nursing GA 531KJ UT WOS:000272664600002 PM 20050486 ER PT J AU Buerhaus, PI Donelan, K DesRoches, C Hess, R AF Buerhaus, Peter I. Donelan, Karen DesRoches, Catherine Hess, Robert TI Registered Nurses' Perceptions of Nurse Staffing Ratios and New Hospital Payment Regulations SO NURSING ECONOMICS LA English DT Article ID PATIENT OUTCOMES; CARE AB Two regulatory initiatives weigh heavily on the nursing workforce: establishing minimum patient-to-nurse staffing ratios in hospitals and payment policy that eliminates payment to hospitals for negative consequences of care. Although the majority of RNs favor ratios, results also indicate that a good number of RNs either do not support ratios or are unsure, which suggests that while strong support for ratios exists, the support is not universal. With regard to the Centers for Medicare and Medicaid Services hospital payment regulations, while many RNs expect that this policy change will increase the emphasis on prevention and additional education and training, RNs also believe they will be blamed if adverse patient conditions occur. A clear majority think that their work will increase, and only a small percentage of RNs think the regulations will lead to added respect, more staffing, higher pay, or raise their status. Beyond affecting the clinical environment, both regulations will impact RNs' economic value in the eyes of the hospitals that employ them. C1 [Buerhaus, Peter I.] Vanderbilt Univ, Med Ctr, Ctr Interdisciplinary Hlth Workforce Studies, Inst Med & Publ Hlth, Nashville, TN 37203 USA. [DesRoches, Catherine] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Hess, Robert] Gannett Healthcare Grp, Falls Church, VA USA. RP Buerhaus, PI (reprint author), Vanderbilt Univ, Med Ctr, Ctr Interdisciplinary Hlth Workforce Studies, Inst Med & Publ Hlth, Nashville, TN 37203 USA. NR 14 TC 7 Z9 7 U1 0 U2 2 PU JANNETTI PUBLICATIONS, INC PI PITMAN PA EAST HOLLY AVENUE, BOX 56, PITMAN, NJ 08071-0056 USA SN 0746-1739 J9 NURS ECON JI Nurs. Econ. PD NOV-DEC PY 2009 VL 27 IS 6 BP 372 EP 376 PG 5 WC Nursing SC Nursing GA 531KJ UT WOS:000272664600003 PM 20050487 ER PT J AU Kong, A Neuthouser, ML Xiao, LR Ulrich, CM McTiernan, A Foster-Schubert, KE AF Kong, Angela Neuthouser, Marian L. Xiao, Liren Ulrich, Cornelia M. McTiernan, Anne Foster-Schubert, Karen E. TI Higher habitual intake of dietary fat and carbohydrates are associated with lower leptin and higher ghrelin concentrations in overweight and obese postmenopausal women with elevated insulin levels SO NUTRITION RESEARCH LA English DT Article DE Ghrelin; Leptin; Insulin; Dietary carbohydrates; Dietary fats; Dietary habits; Obesity; Women ID INCREASES FOOD-INTAKE; PLASMA LEPTIN; CIRCULATING GHRELIN; BODY-WEIGHT; HEALTHY-MEN; GLUCOSE; SENSITIVITY; HUMANS; ENERGY; SECRETION AB A highly regulated homeostatic system governs body weight; however, it is possible that this system might be impaired by the sustained intake of highly palatable foods. Short-term feeding studies suggest that the appetite-stimulating hormone ghrelin is suppressed less effectively by dietary fat intake, and diets high in sucrose decrease levels of the adipose hormone leptin. We hypothesized that higher habitual intake of dietary fat and carbohydrate (CHO) would be associated with elevated concentrations of circulating plasma ghrelin and lower circulating leptin in humans, a hormonal profile that could promote weight gain. To test our hypothesis, we examined the cross-sectional associations of ghrelin and leptin with the habitual macronutrient intake of 165 healthy overweight and obese sedentary women and tested the modifying role of insulin in these associations. We observed a significant inverse association between leptin concentrations and percentage energy from CHO independent of body mass index, percentage body fat, age, and intraabdominal fat (beta = -0.11 P = .04). No significant associations were observed between ghrelin and macronutrients or their subtypes among the total cohort. Among women with insulin concentrations at or greater than the median, we found a statistically significant positive association between intake of saturated fat and ghrelin concentrations, as well as additional statistically significant associations between leptin concentrations and macronutrients not observed among the total cohort. Our results provide some evidence that diets higher in fat and CHO are associated with a hormonal profile (ie, lower leptin and higher ghrelin concentrations), which could enhance weight gain, particularly among individuals with higher circulating insulin concentrations. (C) 2009 Elsevier Inc. All rights reserved. C1 [Foster-Schubert, Karen E.] Univ Washington, Dept Med, Seattle, WA 98109 USA. [Foster-Schubert, Karen E.] VA Puget Sound Hlth Care Syst, Seattle, WA 98109 USA. [Kong, Angela; Foster-Schubert, Karen E.] Univ Washington, Nutr Sci Program, Seattle, WA 98109 USA. [Kong, Angela; Neuthouser, Marian L.; Xiao, Liren; Ulrich, Cornelia M.; McTiernan, Anne; Foster-Schubert, Karen E.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98109 USA. RP Foster-Schubert, KE (reprint author), Univ Washington, Nutr Sci Program, Seattle, WA 98109 USA. EM kfoster@u.washington.edu FU Transdisciplinary Research in Energetics and Cancer [U54 CA116847]; National Cancer Institute [R25 CA94880, R01 CA69334]; National Center for Research Resources [5 KL2 RR025015-03] FX This study was supported by the Transdisciplinary Research in Energetics and Cancer (U54 CA116847), National Cancer Institute (Grant R25 CA94880), National Cancer Institute (R01 CA69334), and National Center for Research Resources (Grant 5 KL2 RR025015-03). NR 50 TC 13 Z9 13 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0271-5317 J9 NUTR RES JI Nutr. Res. PD NOV PY 2009 VL 29 IS 11 BP 768 EP 776 DI 10.1016/j.nutres.2009.10.013 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 531KG UT WOS:000272664300003 PM 19932865 ER PT J AU Kabrhel, C Varraso, R Goldhaber, SZ Rimm, EB Camargo, CA AF Kabrhel, Christopher Varraso, Raphaelle Goldhaber, Samuel Z. Rimm, Eric B. Camargo, Carlos A. TI Prospective Study of BMI and the Risk of Pulmonary Embolism in Women SO OBESITY LA English DT Article ID DEEP-VEIN THROMBOSIS; VENOUS THROMBOEMBOLISM; CARDIOVASCULAR RISK; OLDER-ADULTS; OBESITY; HYPERTENSION; PREVALENCE; WEIGHT; EPIDEMIOLOGY; OVERWEIGHT AB Pulmonary embolism (PE) is common and associated with significant morbidity and mortality. An association between obesity and PE has been suggested, but the nature of the association has not been well defined. We performed a prospective cohort study of 87,226 women in the Nurses' Health Study (1984-2002) to define the association between BMI and the risk of incident PE. Primary exposure was BMI (<22.5, 22.5-24.9, 25.0-27.4, 27.5-29.9, 30.0-34.9, and >= 35.0kg/m(2)). Primary outcome was idiopathic PE (medical record confirmed cases of PE not associated with prior surgery, trauma, or malignancy). Secondary analysis of nonidiopathic PE was also performed. Multivariable Cox proportional hazards models were controlled for age, physical activity, caloric intake, smoking, pack-years, race, spouse's educational attainment, parity, menopause, nonaspirin nonsteroidal anti-inflammatory drugs, warfarin, multivitamin supplements, hypertension, coronary heart disease, and rheumatological disease. There were 157 incident idiopathic PE and 338 nonidiopathic PE. There was a strong positive association between BMI, the risk of idiopathic PE (relative risk (RR) = 1.08 (95% confidence interval (CI), 1.06-1.10) per 1 kg/m(2) increase in BMI, P < 0.001) and nonidiopathic PE (RR = 1.08 (95% Cl, 1.07-1.10), P < 0.001). The association was linear, and apparent even with modest increases in BMI (22.5-25kg/m(2)). The risk increased nearly sixfold among subjects with BMI >= 35kg/m(2), and was present in multiple subgroups. Increasing BMI has a strong, linear association with the development of PE in women. Clinicians should consider BMI when assessing the risk of PE in their patients. C1 [Kabrhel, Christopher; Camargo, Carlos A.] Harvard Univ, Dept Emergency Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. [Varraso, Raphaelle] Inst Municipal Invest Med, Ctr Res Environm Epidemiol, E-08003 Barcelona, Spain. [Varraso, Raphaelle] Univ Paris Sud, Villejuif, France. [Varraso, Raphaelle] INSERM, U780, Villejuif, France. [Goldhaber, Samuel Z.] Harvard Univ, Brigham & Womens Hosp, Dept Med, Div Cardiovasc,Med Sch, Boston, MA 02115 USA. [Rimm, Eric B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Rimm, Eric B.; Camargo, Carlos A.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. RP Kabrhel, C (reprint author), Harvard Univ, Dept Emergency Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RI Varraso, Raphaelle/R-8740-2016; OI Varraso, Raphaelle/0000-0002-3338-7825; Kabrhel, Christopher/0000-0002-8699-7176 FU NIH [R21AG031079] FX The Nurses' Health Study is coordinated at the Channing Laboratory. Brigham and Women's Hospital, Boston, Massachusetts This work was supported by NIH R21AG031079 (National Institute of Aging, National Institutes of Health, Bethesda, Maryland) NR 31 TC 32 Z9 32 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD NOV PY 2009 VL 17 IS 11 BP 2040 EP 2046 DI 10.1038/oby.2009.92 PG 7 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 512HT UT WOS:000271237700013 PM 19373223 ER PT J AU Parikh, NI Keyes, MJ Larson, MG Pou, KA Hamburg, NA Vita, JA O'Donnell, CJ Vasan, RS Mitchell, GF Hoffmann, U Fox, CS Benjamin, EJ AF Parikh, Nisha I. Keyes, Michelle J. Larson, Martin G. Pou, Karla A. Hamburg, Naomi A. Vita, Joseph A. O'Donnell, Christopher J. Vasan, Ramachandran S. Mitchell, Gary F. Hoffmann, Udo Fox, Caroline S. Benjamin, Emelia J. TI Visceral and Subcutaneous Adiposity and Brachial Artery Vasodilator Function SO OBESITY LA English DT Article ID FLOW-MEDIATED DILATION; CORONARY-HEART-DISEASE; METABOLIC RISK-FACTORS; BODY-FAT DISTRIBUTION; C-REACTIVE PROTEIN; INSULIN-RESISTANCE; ENDOTHELIAL DYSFUNCTION; JAPANESE-AMERICANS; TISSUE; WOMEN AB Endothelial dysfunction may link obesity to cardiovascular disease (CVD). We tested the hypothesis that visceral abdominal tissue (VAT) as compared with subcutaneous adipose tissue (SAT) is more related to endothelium-dependent vasodilation. Among Framingham Offspring and Third Generation cohorts (n = 3,020, mean age 50 years, 47% women), we used multivariable linear regression adjusted for CVD and its risk factors to relate computed tomography (CT)-assessed VAT and SAT, BMI, and waist circumference (WC), with brachial artery measures. In multivariable-adjusted models, Bill WC, VAT, and SAT were positively related to baseline artery diameter and baseline mean flow velocity (all P < 0.001), but not hyperemic mean flow velocity. In multivariable-adjusted models, BMI (P = 0.002), WC (P = 0.001), and VAT (P = 0.01), but not SAT (P = 0.24) were inversely associated with percentage of flow-mediated dilation (FMD%). However, there was little incremental increase in the proportion of variability explained by VAT (R(2) = 0.266) as compared to SAT (R(2) = 0.265), above and beyond traditional risk factors. VAT, but not SAT was associated with FMD% after adjusting for clinical covariates. Nevertheless, the differential association with VAT as compared to SAT was minimal. C1 [Parikh, Nisha I.; Keyes, Michelle J.; Larson, Martin G.; O'Donnell, Christopher J.; Vasan, Ramachandran S.; Fox, Caroline S.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Keyes, Michelle J.; Larson, Martin G.] Boston Univ, Sch Med, Math & Stat Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Pou, Karla A.; Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Hamburg, Naomi A.; Vita, Joseph A.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Cardiol Sect, Boston, MA 02118 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [Mitchell, Gary F.] Cardiovasc Engn Inc, Holiston, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Benjamin, EJ (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. OI Hamburg, Naomi/0000-0001-5504-5589; Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195, RO1 HL70100, 1 RO1 HL60040]; NHLBI/NIH [2K24HL04334] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (N01-HC-25195, RO1 HL70100, 1 RO1 HL60040) Dr Vasan is supported in part by 2K24HL04334 (NHLBI/NIH). NR 38 TC 33 Z9 34 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD NOV PY 2009 VL 17 IS 11 BP 2054 EP 2059 DI 10.1038/oby.2009.60 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 512HT UT WOS:000271237700015 PM 19282819 ER PT J AU Fowler-Brown, AG Bennett, GG Goodman, MS Wee, CC Corbie-Smith, GM James, SA AF Fowler-Brown, Angela G. Bennett, Gary G. Goodman, Melody S. Wee, Christina C. Corbie-Smith, Giselle M. James, Sherman A. TI Psychosocial Stress and 13-year BMI Change Among Blacks: The Pitt County Study SO OBESITY LA English DT Article ID CORONARY-HEART-DISEASE; PERCEIVED STRESS; SOCIOECONOMIC POSITION; GENDER DIFFERENCES; HEALTH BEHAVIORS; ALLOSTATIC LOAD; SOCIAL SUPPORT; LIFE EVENTS; ADULTS; HYPERTENSION AB Adverse psychosocial exposures may partially drive the high rates of obesity among blacks. The objective of this study was to prospectively examine the relationship between perceived psychosocial stress and percent change in BMI among adult black men and women. We used data from 756 women and 416 men who were participants in the Pitt County Study, a community-based, prospective cohort study of blacks in eastern North Carolina. Participants were aged 25-50 years of age on entry into the study in 1988 and follow-up was obtained in 2001. Using multivariable linear regression, we calculated the adjusted mean percentage change in BMI over the follow-up period for each tertile of baseline measures of the Perceived Stress Scale (low, medium, and high), adjusted for potential confounders. For black women, higher levels of psychosocial stress at baseline predicted higher adjusted percentage increase in BMI over the 13-year follow-up: low stress 12.0% (95% Cl 9.6-14.4), medium stress 16.3% (95% Cl 13.7-18.9), and high stress 15.5% (95% Cl 13.1-17.8). For black men, perceived stress was not associated with percent BMI change. These data suggest that interventions targeting obesity in black women should consider the potential impact of emotional stress on weight change. C1 [Fowler-Brown, Angela G.; Wee, Christina C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care,Med Sch, Boston, MA 02215 USA. [Bennett, Gary G.] Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Soc Human Dev & Hlth,Ctr Community Based Res, Boston, MA 02115 USA. [Goodman, Melody S.] SUNY Stony Brook, Dept Prevent Med, Div Evaluat Sci, Med Ctr, Stony Brook, NY USA. [Corbie-Smith, Giselle M.] Univ N Carolina, Dept Social Med, Chapel Hill, NC USA. [James, Sherman A.] Duke Univ, Terry Sanford Inst Publ Policy, Durham, NC USA. RP Fowler-Brown, AG (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Med, Div Gen Med & Primary Care,Med Sch, Boston, MA 02215 USA. RI Goodman, Melody/F-6768-2011 OI Goodman, Melody/0000-0001-8932-624X FU National Institutes of Health (NIH) [R01 DK071083-01A1, HL 65645] FX This work was primarily funded by an administrative supplement to National Institutes of Health (NIH) grant R01 DK071083-01A1 (Dr Fowler-Brown) Data collection for this study was supported by the NIH (grant HL 65645). NR 36 TC 32 Z9 32 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD NOV PY 2009 VL 17 IS 11 BP 2106 EP 2109 DI 10.1038/oby.2009.130 PG 4 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 512HT UT WOS:000271237700024 PM 19407807 ER PT J AU Broughton, DE Beigi, RH Switzer, GE Raker, CA Anderson, BL AF Broughton, D. E. Beigi, R. H. Switzer, G. E. Raker, C. A. Anderson, B. L. TI Obstetric Health Care Workers' Attitudes and Beliefs Regarding Influenza Vaccination in Pregnancy SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID WOMEN; IMMUNIZATION; KNOWLEDGE AB OBJECTIVE: To explore obstetric health care workers' attitudes and beliefs regarding influenza vaccination in pregnancy. METHODS: A survey consisting of 16 multiple-choice questions was administered to nurses, medical and nursing assistants, receptionists, and clinical administrators in obstetric settings. Survey questions addressed general knowledge of influenza and recommendations for vaccination during pregnancy, as well as personal beliefs about the acceptability of the vaccine in the pregnant population. The study was conducted at two sites, Women & Infants Hospital in Providence, III, and Magee-Women's Hospital in Pittsburgh, PA. Variables were compared by Fisher exact test. RESULTS: Two hundred sixty-seven completed surveys were available for analysis, with a completion rate of 85%. Almost one third of health care workers surveyed do not believe that vaccines are a safe and effective way to decrease infections (31%) and a minority believe that vaccines are safe in pregnancy (36%). just over half of health care workers know that pregnant women are at increased risk of complications from the flu (56.6%). Only 46% were able to correctly identify influenza symptoms, and only 65% would recommend influenza vaccination to a pregnant woman if indicated. A small percentage would be willing to give an avian influenza vaccine to pregnant women during a pandemic if it had not been tested in pregnancy (12.3%). CONCLUSION: Many obstetric health care workers lack knowledge regarding the safety and importance of influenza vaccination during pregnancy. Misinformed or inadequately informed health care workers may represent a barrier to influenza vaccine coverage of pregnant women. This lack of knowledge among the health care workforce takes on added importance in the setting of the H1N1 2009 swine-origin influenza pandemic. (Obstet Gynecol 2009,114:981-7) C1 [Broughton, D. E.] Brown Univ, Women & Infants Hosp, Alpert Med Sch, Dept Obstet & Gynecol, Providence, RI 02912 USA. Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. Magee Womens Hosp, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Ctr Hlth Equ & Promot, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. RP Broughton, DE (reprint author), Brown Univ, Alpert Med Sch, MS3,Box 8191,75 Waterman St, Providence, RI 02912 USA. EM darcy.e.broughton@gmail.com FU Alpert Medical School Scholarly Concentration in Women's Reproductive Health, Freedom Rights; Brown University Women's Reproductive Health Research scholar program [5K12-HD050108-04]; Department of Obstetrics, Gynecolog and Reproductive Sciences; Magee-Women's Hospital of the University of Pittsburgh Medical Center FX 1) Alpert Medical School Scholarly Concentration in Women's Reproductive Health, Freedom & Rights; 2) Brown University Women's Reproductive Health Research scholar program, 5K12-HD050108-04; and 3) Departmental funding. Department of Obstetrics, Gynecolog and Reproductive Sciences, Magee-Women's Hospital of the University of Pittsburgh Medical Center NR 16 TC 38 Z9 40 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD NOV PY 2009 VL 114 IS 5 BP 981 EP 987 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 513AH UT WOS:000271293500004 PM 20168097 ER PT J AU Cortot, AB Janne, PA AF Cortot, Alexis B. Jaenne, Pasi A. TI Histology... For Want of Anything Better? SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID CELL LUNG-CANCER; THYMIDYLATE SYNTHASE; TUMOR CAVITATION; GEFITINIB; THERAPY; ADENOCARCINOMA; CARBOPLATIN; PACLITAXEL; RESISTANCE; EXPRESSION C1 [Cortot, Alexis B.; Jaenne, Pasi A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Lowe Ctr Thorac Oncol,Dept Med Oncol, Boston, MA 02115 USA. RP Cortot, AB (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Lowe Ctr Thorac Oncol,Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD NOV PY 2009 VL 23 IS 13 BP 1140 EP 1141 PG 2 WC Oncology SC Oncology GA V18PW UT WOS:000208017700002 PM 20043462 ER PT J AU Gangaputra, S Newcomb, CW Liesegang, TL Kacmaz, RO Jabs, DA Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Suhler, EB Thorne, JE Foster, CS Kempen, JH AF Gangaputra, Sapna Newcomb, Craig W. Liesegang, Teresa L. Kacmaz, R. Oktay Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Suhler, Eric B. Thorne, Jennifer E. Foster, C. Stephen Kempen, John H. CA Systemic Immunosuppressive Therapy TI Methotrexate for Ocular Inflammatory Diseases SO OPHTHALMOLOGY LA English DT Article ID LOW-DOSE METHOTREXATE; JUVENILE RHEUMATOID-ARTHRITIS; CORTICOSTEROID-SPARING THERAPY; IDIOPATHIC ARTHRITIS; IMMUNOSUPPRESSIVE THERAPY; INDUCED PNEUMONITIS; INTRAOCULAR LEVELS; OPTIC NEUROPATHY; CHRONIC UVEITIS; TOXICITY AB Purpose: To evaluate the outcome of treatment with methotrexate for noninfectious ocular inflammation. Design: Retrospective cohort study. Participants: Patients with noninfectious ocular inflammation managed at 4 tertiary ocular inflammation clinics in the United States observed to add methotrexate as a single, noncorticosteroid immunosuppressive agent to their treatment regimen, between 1979 and 2007, inclusive. Methods: Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage, route of administration of methotrexate, and main outcome measures, were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. Main Outcome Measures: Control of inflammation, corticosteroid-sparing effects, and incidence of and reason for discontinuation of therapy. Results: Among 384 patients (639 eyes) observed from the point of addition of methotrexate to an anti-inflammatory regimen, 32.8%, 9.9%, 21.4%, 14.6%, 15.1%, and 6.3%, respectively, had anterior uveitis, intermediate uveitis, posterior or panuveitis, scleritis, ocular mucous membrane pemphigoid, and other forms of ocular inflammation. In these groups, complete suppression of inflammation sustained for 28 days was achieved within 6 months in 55.6%, 47.4%, 38.6%, 56.4%, 39.5%, and 76.7%, respectively. Corticosteroid-sparing success (sustained suppression of inflammation with prednisone <= 10 mg/d) was achieved within 6 months among 46.1%, 41.3%, 20.7%, 37.3%, 36.5%, and 50.9%, respectively. Overall, success within 12 months was 66% and 58.4% for sustained control and corticosteroid sparing (<= 10 mg), respectively. Methotrexate was discontinued within 1 year by 42% of patients. It was discontinued owing to ineffectiveness in 50 patients (13%); 60 patients (16%) discontinued because of side effects, which typically were reversible with dose reduction or discontinuation. Remission was seen in 43 patients, with 7.7% remitting within 1 year of treatment. Conclusions: Our data suggest that adding methotrexate to an anti-inflammatory regimen not involving other noncorticosteroid immunosuppressive drugs is moderately effective for management of inflammatory activity and for achieving corticosteroid-sparing objectives, although many months may be required for therapeutic success. Methotrexate was well tolerated by most patients, and seems to convey little risk of serious side effects during treatment. Financial Disclosure(s): The authors have no proprietary or commercial interests in any of the materials discussed in this article. Ophthalmology 2009,116:2188-2198 (C) 2009 by the American Academy of Ophthalmology. C1 [Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Philadelphia, PA 19104 USA. [Gangaputra, Sapna] Univ Wisconsin, Dept Ophthalmol, Fundus Photograph Reading Ctr, Madison, WI USA. [Gangaputra, Sapna; Jabs, Douglas A.; Thorne, Jennifer E.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Jabs, Douglas A.; Thorne, Jennifer E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Newcomb, Craig W.; Kempen, John H.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Newcomb, Craig W.; Kempen, John H.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Liesegang, Teresa L.; Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Kacmaz, R. Oktay; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Kacmaz, R. Oktay; Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu FU National Eye Institute [EY014943]; Paul and Evanina Mackall Foundation; Research to Prevent Blindness James S. Adams Special Scholar Award; Senior Scientific Investigator Award; Prevent Blindness Harrington Special Scholar Award FX Supported primarily by National Eye Institute Grant EY014943 (JHK). Additional support was provided by Research to Prevent Blindness and the Paul and Evanina Mackall Foundation. Dr Kempen is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. Drs Jabs and Rosenbaum are Research to Prevent Blindness Senior Scientific Investigator Award recipients. Dr Thorne is a Research to Prevent Blindness Harrington Special Scholar Award recipient. Dr Levy-Clarke was previously supported by and Dr Nussenblatt continues to be supported by intramural funds of the National Eye Institute. NR 49 TC 80 Z9 82 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2009 VL 116 IS 11 BP 2188 EP 2198 DI 10.1016/j.ophtha.2009.04.020 PG 11 WC Ophthalmology SC Ophthalmology GA 512ZQ UT WOS:000271291600022 PM 19748676 ER PT J AU Lane, AM Egan, KM Harmon, D Holbrook, A Munzenrider, JE Gragoudas, ES AF Lane, Anne Marie Egan, Kathleen M. Harmon, David Holbrook, Amy Munzenrider, John E. Gragoudas, Evangelos S. TI Adjuvant Interferon Therapy for Patients with Uveal Melanoma at High Risk of Metastasis SO OPHTHALMOLOGY LA English DT Article ID RENAL-CELL CARCINOMA; COOPERATIVE-ONCOLOGY-GROUP; DISSEMINATED MALIGNANT-MELANOMA; LEUKOCYTE-A INTERFERON; OCULAR MELANOMA; C-MYC; CUTANEOUS MELANOMA; RANDOMIZED-TRIAL; PHASE-II; RECOMBINANT INTERFERON-ALPHA-2A AB Purpose: To examine whether interferon (IFN)-alfa-2a treatment after radiation or enucleation reduces death rates in patients with uveal melanoma. Design: Interventional, comparative case series. Participants: Subjects were identified through the ocular oncology clinic of the Massachusetts Eye and Ear Infirmary. Patients eligible for the study were at increased risk of metastasis because of the presence of at least one of the following characteristics: age >= 65 years, largest tumor diameter (LTD) >= 15 mm, ciliary body involvement of the tumor, or extrascleral tumor extension. Methods: Between May 1995 and June 1999, 121 patients with choroidal or ciliary body melanoma began a 2-year course of therapy (3 MIU IFN-alfa-2a subcutaneously 3 times per week), initiated within 3 years of primary therapy. All patients underwent regular monitoring for drug toxicity. To evaluate IFN-alfa-2a efficacy, we selected a series of historical controls frequency-matched (2:1) to IFN-alfa-2a-treated patients on age (+/-5 years), LTD (+/-3 mm), gender, and survival time between primary therapy and initiation of IFN therapy. Survival status was ascertained for all patients through December 2006. Main Outcome Measures: Melanoma-related mortality, metastasis, IFN-related toxicities. Results: Fifty-five patients (45%) completed therapy; the median dose for IFN-alfa-2a-treated patients was 792 MIU (85% of the theoretic dose). The median follow-up time in the IFN-alfa-2a-treated group was approximately 9 years. Treatment and control groups were similar with respect to age (P = 0.78), LTD (P = 0.38), and gender (P = 1.0). Of 363 patients, 108 developed metastasis under observation; 42 of these were IFN-alfa-2a-treated patients. Cumulative 5-year melanoma-related death rates were 17% in the radiation or enucleation-only group, 15% in those who completed the entire IFN-alfa-2a course, and 35% in those who discontinued IFN-alfa-2a therapy. In multivariate Cox regression, IFN-alfa-2a had no significant influence on melanoma-related mortality (rate ratio = 1.02, 95% confidence interval, 0.68-1.5, P = 0.91) or all-cause mortality (rate ratio = 0.84, 95% confidence interval, 0.58-1.2, P = 0.34). Conclusions: Interferon-alfa-2a has no material influence on survival in patients with choroidal melanoma. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2009; 116:2206-2212 (C) 2009 by the American Academy of Ophthalmology. C1 [Lane, Anne Marie; Holbrook, Amy; Gragoudas, Evangelos S.] Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. [Egan, Kathleen M.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. [Harmon, David] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. [Munzenrider, John E.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Lane, AM (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. EM alane@meei.harvard.edu FU Roche Laboratories; Nutley; New Jersey; Massachusetts Eye and Ear Infirmary Melanoma Research Fund FX Evangelos Gragoudas is a paid consultant for and has an equity ownership in Jerini Ophthalmics. This research was conducted with funding from Roche Laboratories, Nutley, New Jersey, and the Massachusetts Eye and Ear Infirmary Melanoma Research Fund. The funding organization approved the design of the study and the study manuscript. No other authors have any financial interests to disclose. NR 41 TC 21 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD NOV PY 2009 VL 116 IS 11 BP 2206 EP 2212 DI 10.1016/j.ophtha.2009.04.044 PG 7 WC Ophthalmology SC Ophthalmology GA 512ZQ UT WOS:000271291600024 PM 19744725 ER PT J AU Bouchard, C Troulis, MJ Kaban, LB AF Bouchard, Carl Troulis, Maria J. Kaban, Leonard B. TI Management of Obstructive Sleep Apnea: Role of Distraction Osteogenesis SO ORAL AND MAXILLOFACIAL SURGERY CLINICS OF NORTH AMERICA LA English DT Article DE Distraction osteogenesis; Obstructive sleep apnea; Orthognathic surgery; Maxillomandibular advancement; Respiratory disturbance index AB Distraction osteogenesis to expand the facial skeleton is an alternative to standard orthognathic surgery for selected patients with obstructive sleep apnea. For children with congenital micrognathia or midface hypoplasia, distraction osteogenesis allows large advancements without the need for bone grafting and with less risk of relapse. For later-onset obstructive sleep apnea, distraction osteogenesis may represent an alternative when acute bone movement is expected to be difficult (scarring from previous surgery or radiation therapy) or when the risk for inferior alveolar nerve damage is unacceptable (patients older than 40 years). C1 [Bouchard, Carl; Troulis, Maria J.; Kaban, Leonard B.] Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Bouchard, C (reprint author), Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. EM carlbouch@hotmail.com FU AO Foundation (Berne, Switzerland); Synthes CMF (West Chester, PA); MGH Department of OMFS Education Research; Hanson Foundation (Boston, MA) FX This project was funded in part by the AO Foundation (Berne, Switzerland); Synthes CMF (West Chester, PA); MGH Department of OMFS Education & Research Fund; and the Hanson Foundation (Boston, MA). NR 112 TC 10 Z9 10 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1042-3699 J9 ORAL MAXIL SURG CLIN JI Oral Maxillofac. Surg. Clin. N. Am. PD NOV PY 2009 VL 21 IS 4 BP 459 EP + DI 10.1016/j.coms.2009.07.001 PG 18 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA V20LG UT WOS:000208140900011 PM 19944346 ER PT J AU Marple, BF Stringer, SP Batra, PS Bhattacharyya, N Chiu, AG Citardi, MJ Han, JK Kern, RC Kingdom, TT Lane, AP Orlandi, RR Ryan, MW Senior, BA Stewart, MG AF Marple, Bradley F. Stringer, Scott P. Batra, Pete S. Bhattacharyya, Neil Chiu, Alexander G. Citardi, Martin J. Han, Joseph K. Kern, Robert C. Kingdom, Todd T. Lane, Andrew P. Orlandi, Richard R. Ryan, Matthew W. Senior, Brent A. Stewart, Michael G. CA Task Force Rhinology Paranasal Sin TI Going to the next level: Health care's evolving expectations for evidence SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Editorial Material AB Rhinologic literature has historically relied oil lower levels of evidence to make prescriptive recommendations for use of new technology and procedures However, as the medical profession has moved to embrace the principles of evidence-based medicine, expectations for minimum standards of evidence have risen The resulting high-quality efficacy Outcomes data have become the linchpin of informed decision making by physicians, payers, and health care systems. While many challenges remain in this transition to higher evidence expectations, none are insurmountable. It has become the responsibility of the organized medical profession to play a role in influencing and supporting production of high-quality outcomes research (C) 2009 American Academy of Otolaryngology-Head and Neck Surgery Foundation All rights reserved C1 [Marple, Bradley F.; Batra, Pete S.; Ryan, Matthew W.] Univ Texas SW Med Ctr Dallas, Dept Otolaryngol Head & Neck Surg, Dallas, TX 75390 USA. [Stringer, Scott P.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Bhattacharyya, Neil] Dana Farber Brigham & Womens Canc Ctr, Head & Neck Oncol Program, Boston, MA USA. [Chiu, Alexander G.] Hosp Univ Penn, Dept Otorhinolaryngol Head & Neck Surg, Philadelphia, PA 19104 USA. [Citardi, Martin J.] Univ Texas Houston, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Houston, TX USA. [Han, Joseph K.] E Virginia Med Sch, Dept Otolaryngol Head & Neck Surg, Norfolk, VA USA. [Kern, Robert C.] Northwestern Univ, Sinus & Allergy Ctr, Chicago, IL 60611 USA. [Kingdom, Todd T.] Univ Colorado, Hlth Sci Ctr, Dept Otolaryngol, Aurora, CO USA. [Lane, Andrew P.] Johns Hopkins Univ Hosp, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. [Orlandi, Richard R.] Univ Utah, Dept Otolaryngol Head & Neck Surg, Salt Lake City, UT USA. [Senior, Brent A.] Univ N Carolina, Sch Med, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC USA. [Stewart, Michael G.] Cornell Univ, Dept Otorhinolaryngol, Weill Med Coll, New York, NY 10021 USA. RP Marple, BF (reprint author), Univ Texas SW Med Ctr Dallas, Dept Otolaryngol Head & Neck Surg, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. RI Chiu, Alexander/J-1230-2014 OI Chiu, Alexander/0000-0002-7592-6575 NR 10 TC 3 Z9 3 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0194-5998 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD NOV PY 2009 VL 141 IS 5 BP 551 EP 554 DI 10.1016/j.otohns.2009.07.013 PG 4 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 512DI UT WOS:000271223300001 PM 19861188 ER PT J AU Morone, NE Rollman, BL Moore, CG Qin, L Weiner, DK AF Morone, Natalia E. Rollman, Bruce L. Moore, Charity G. Qin, Li Weiner, Debra K. TI A Mind-Body Program for Older Adults with Chronic Low Back Pain: Results of a Pilot Study SO PAIN MEDICINE LA English DT Article DE Low Back Pain; Mindfulness; Meditation; Mind-Body; Aged AB Objectives. Determine the impact of an 8-week mindfulness meditation program on disability, psychological function, and pain severity in community-dwelling older adults with chronic low back pain, and to test the education control program for feasibility. Design. Randomized controlled trial. Participants. Forty community-dwelling older adults with moderate low back pain or greater for at least the previous 3 months. Intervention. Participants were randomized to an 8-week meditation program or an 8-week education control program. Outcome Measures. Disability, psychological function, and pain severity were assessed. The same measures were obtained for both groups at baseline, at the end of the program, and 4 months after program completion. Results. Sixteen participants (80%) completed the meditation program and 19 (95%) completed the education program. Both the meditation and control group improved on measures of disability, pain, and psychological function, both at program completion and 4-month follow-up. The differences between the two groups did not reach statistical significance. The meditation group practiced mindfulness meditation a mean of 5 days/week (range 1-7) and mean of 31 minutes/session (range 22-48). At 4 months follow-up 14/16 (88%) participants continued to meditate. Conclusion. Both the intervention group and the education control group improved on outcome measures suggesting both programs had a beneficial effect. Participants continued to meditate on 4-month follow-up. The control program was feasible but not inert. Piloting the control program in mind-body research can inform the design of larger clinical trials. C1 [Morone, Natalia E.; Rollman, Bruce L.; Moore, Charity G.; Qin, Li] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Dept Med, Div Geriatr Med, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA USA. [Weiner, Debra K.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Weiner, Debra K.] VA Pittsburgh Healthcare Syst, Geriatr Res Educ & Clin Ctr, Pittsburgh, PA USA. RP Morone, NE (reprint author), 230 McKee Pl,Suite 600, Pittsburgh, PA 15213 USA. EM moronene@upmc.edu OI Moore, Charity/0000-0002-0060-0124 FU NIH [1KL2RR024154-04]; National Center for Research Resources (NCRR), a component of the NIH [UL1RR024153]; NIH Roadmap for Medical Research FX During the time of this work Dr. Morone was funded by the NIH Roadmap Multidisciplinary Clinical Research Career Development Award Grant (1KL2RR024154-04) from the National Institutes of Health (NIH). This publication was also made possible by Grant Number UL1RR024153 from the National Center for Research Resources (NCRR), a component of the NIH and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Special thanks to Daniel Schenck, DC for co-teaching the mindfulness meditation program and to Vinny Losasso for assistance in data collection and preparation of the manuscript. NR 37 TC 47 Z9 47 U1 3 U2 12 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1526-2375 J9 PAIN MED JI Pain Med. PD NOV-DEC PY 2009 VL 10 IS 8 BP 1395 EP 1407 DI 10.1111/j.1526-4637.2009.00746.x PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA V20FE UT WOS:000208125100008 PM 20021599 ER PT J AU Manchikanti, L Derby, R Wolfer, L Singh, V Datta, S Hirsch, JA AF Manchikanti, Laxmaiah Derby, Richard Wolfer, Lee Singh, Vijay Datta, Sukdeb Hirsch, Joshua A. TI Evidence-Based Medicine, Systematic Reviews, and Guidelines in Interventional Pain Management: Part 7: Systematic Reviews and Meta-Analyses of Diagnostic Accuracy Studies SO PAIN PHYSICIAN LA English DT Review DE Diagnostic accuracy studies; evidence-based medicine; systematic reviews; meta-analysis; comparative effectiveness studies; interventional pain management; Standards for the Reporting of Diagnostic Accuracy Studies (STARD) ID LOW-BACK-PAIN; FACET JOINT PAIN; RANDOMIZED CONTROLLED-TRIALS; CAUDAL EPIDURAL INJECTIONS; CHRONIC SPINAL PAIN; LOCAL-ANESTHETIC BLOCKS; MEDIAL BRANCH BLOCKS; 2000-2010 TASK-FORCE; RADIOFREQUENCY DENERVATION SUCCESS; VERTEBRAL COMPRESSION FRACTURES AB Appropriate diagnosis is essential in providing proper and effective therapy. The field of diagnostic accuracy tests is dynamic with new tests being developed at a fast pace along with improvement in technology of existing tests on a continuous basis. Well-designed diagnostic test accuracy studies can help in making appropriate health care decisions, provided that they transparently and fully report their participants, tests, methods, and results. Exaggerated and biased results from poorly designed and reported diagnostic test studies can trigger their premature dissemination and lead physicians into making incorrect treatment decisions. Consequently, a diagnostic test is useful only to the extent that it distinguishes between conditions or disorders that might otherwise be confused. Since it is unlikely that clinicians, patients, and policy makers have the time, skills, and resources to find, appraise, and interpret the evidence and incorporate it into their health care decisions, systematic reviews and meta-analysis provide an accurate and reliable synthesis of vast quantities of data. A systematic review can identify what is known and what is unknown, giving guidance for future research. Systematic reviews have been considered as a vital link in the great chain of evidence that stretches from the laboratory to the bedside by helping to separate the insignificant, unsound, or redundant deadwood from the salient and critical studies that are worthy of reflection. A dangerous discrepancy exists between experts and evidence with all types of evidence. Historically, it has been reported that in only 15% of all cases can a pathoanatomical explanation be found for patients with chronic low back pain of more than 3 months resulting in the assumption that very little can be done in our present state of ignorance to treat these patients and improve their natural histories. On the other end of the spectrum, due to lack of sound diagnostic information, excessive health care is utilized with exploding costs. The validity of all diagnostic techniques has been described with variable accuracy and reliability Lack of understanding of reference standards and their unavailability with interventional diagnostic techniques and misinterpretation secondary to interpretation bias may adversely influence the applicability of diagnostic interventions. This manuscript provides a review of the literature, a checklist, and a flow diagram describing the preferred way to present the abstract, introduction, methods, results, and discussion sections of the report of an analysis in a systematic review of diagnostic accuracy studies. C1 [Manchikanti, Laxmaiah] Pain Management Ctr Paducah, Paducah, KY USA. [Derby, Richard; Wolfer, Lee] Spinal Diagnost & Treatment Ctr, Daly City, CA USA. [Datta, Sukdeb] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Hirsch, Joshua A.] Harvard Univ, Sch Med, Boston, MA USA. [Hirsch, Joshua A.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Singh, Vijay] Pain Diagnost Associates, Niagara, WI USA. RP Manchikanti, L (reprint author), 2831 Lone Oak Rd, Paducah, KY 42003 USA. EM drlm@thepainmd.co NR 298 TC 36 Z9 36 U1 1 U2 7 PU AM SOC INTERVENTIONAL PAIN PHYSICIANS PI PADUCAH PA 81 LAKEVIEW DR, PADUCAH, KY 42001 USA SN 1533-3159 J9 PAIN PHYSICIAN JI Pain Physician PD NOV-DEC PY 2009 VL 12 IS 6 BP 929 EP 963 PG 35 WC Anesthesiology; Clinical Neurology SC Anesthesiology; Neurosciences & Neurology GA 537EQ UT WOS:000273096200003 PM 19935980 ER PT J AU Warshaw, AL AF Warshaw, Andrew L. TI 2009 American Pancreatic Association Presidential Address On Our 40th Birthday SO PANCREAS LA English DT Editorial Material C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Warshaw, AL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, 55 Fruit St,WHT506, Boston, MA 02114 USA. EM awarshaw@partners.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 844 EP 844 DI 10.1097/MPA.0b013e3181bd0fa9 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300002 PM 19855230 ER PT J AU Thrower, EC Wang, J Cheriyan, S Lugea, A Kolodecik, TR Yuan, JZ Reeve, JR Gorelick, FS Pandol, SJ AF Thrower, Edwin C. Wang, Jeffrey Cheriyan, Salim Lugea, Aurelia Kolodecik, Thomas R. Yuan, Jingzhen Reeve, Joseph R., Jr. Gorelick, Fred S. Pandol, Stephen J. TI Protein Kinase C delta-Mediated Processes in Cholecystokinin-8-Stimulated Pancreatic Acini SO PANCREAS LA English DT Article DE amylase secretion; genetic deletion; trypsinogen ID DAMAGE-INDUCED APOPTOSIS; KAPPA-B ACTIVATION; PKC-DELTA; TYROSINE PHOSPHORYLATION; AMYLASE RELEASE; CELLS; ROTTLERIN; EPSILON; MECHANISM; ISOFORMS AB Objectives: To define the role of protein kinase C delta (PKC delta) in acinar cell responses to the hormone cholecystokinin-8 (CCK) using isoform-specific inhibitors and a previously unreported genetic deletion model. Methods: Pancreatic acinar cells were isolated from (1) rat, and pretreated with a PKC delta-specific inhibitor or (2) PKC delta-deficient and wild type mice. Isolated cells were stimulated with CCK (0.001-100 nmol/L) and cell responses were measured. Results: The PKC delta inhibitor did not affect stimulated amylase secretion from rat pancreatic acinar cells. Cholecystokinin-8 stimulation induced a typical biphasic dose-response curve for amylase secretion in acinar cells isolated from both PKC delta(-/-) and wild type mice, with maximal stimulation at 10-pmol/L CCK. Cholecystokinin-8 (100 nmol/L) induced zymogen and nuclear factor kappa B activation in both PKC delta(-/-) and wild type mice, although it was up to 50% less in PKC delta(-/-). Conclusions: In contrast to previous studies, this study has used specific and complementary approaches to examine PKC delta-mediated acinar cell responses. We could not confirm that it mediates amylase release but corroborated its role in the early stages of acute pancreatitis. C1 [Thrower, Edwin C.; Cheriyan, Salim; Kolodecik, Thomas R.; Gorelick, Fred S.] Vet Adm Connecticut Healthcare, Sect Digest Dis, Dept Internal Med, West Haven, CT USA. [Thrower, Edwin C.; Cheriyan, Salim; Kolodecik, Thomas R.; Gorelick, Fred S.] Yale Univ, Sch Med, New Haven, CT USA. [Wang, Jeffrey; Lugea, Aurelia; Yuan, Jingzhen; Reeve, Joseph R., Jr.; Pandol, Stephen J.] Vet Affairs Greater Los Angeles Hlth Care Syst, Res Ctr Alcohol Liver & Pancreat Dis, Los Angeles, CA USA. [Wang, Jeffrey; Lugea, Aurelia; Yuan, Jingzhen; Reeve, Joseph R., Jr.; Pandol, Stephen J.] Univ Calif Los Angeles, Los Angeles, CA USA. RP Thrower, EC (reprint author), Vet Adm Med Ctr, 950 Campbell Ave,Bldg 4, West Haven, CT 06516 USA. EM edwin.thrower@yale.edu FU National Institutes of Health [R21 DK69702, RO1 DK33850, DK54021]; USC-UCLA Research Center for Alcoholic Liver and Pancreatic Injury [5 P60 AA11999]; Veterans Administration Merit and Senior Career Development Award FX This work was supported by a National Institutes of Health grant R21 (DK69702 to E. C. T.), National Institutes of Health Grants RO1 (DK33850 to J. R. R., Jr; DK54021 to F. S. G.), USC-UCLA Research Center for Alcoholic Liver and Pancreatic Injury grant (5 P60 AA11999 from NIAAA; Tsukamoto; to S. J. P.), and a Veterans Administration Merit and Senior Career Development Award (to F. S. G.). NR 34 TC 20 Z9 20 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 930 EP 935 DI 10.1097/MPA.0b013e3181b8476a PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300014 PM 19752773 ER PT J AU Boni, A Thayer, SP Ferrone, C Bausch, D Neyhard, N Cogdill, A Fernandez-del-Castillo, CF Warshaw, AL Wargo, JA AF Boni, A. Thayer, S. P. Ferrone, C. Bausch, D. Neyhard, N. Cogdill, A. Fernandez-del-Castillo, C. F. Warshaw, A. L. Wargo, J. A. TI Immunotherapeutic and Epigenetic Approaches Targeting Cancer-Testis Antigens in the Treatment of Pancreatic Cancer SO PANCREAS LA English DT Meeting Abstract C1 [Boni, A.; Thayer, S. P.; Ferrone, C.; Bausch, D.; Neyhard, N.; Cogdill, A.; Fernandez-del-Castillo, C. F.; Warshaw, A. L.; Wargo, J. A.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 985 EP 985 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300045 ER PT J AU Correa-Gallego, C Ferrone, C Thayer, SP Wargo, JA Warshaw, AL Fernandez-del Castillo, C AF Correa-Gallego, C. Ferrone, C. Thayer, S. P. Wargo, J. A. Warshaw, A. L. Fernandez-del Castillo, C. TI Are Multifocal Pancreatic Cysts an Indolent Condition? SO PANCREAS LA English DT Meeting Abstract C1 [Correa-Gallego, C.; Ferrone, C.; Thayer, S. P.; Wargo, J. A.; Warshaw, A. L.; Fernandez-del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 991 EP 991 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300072 ER PT J AU Correa-Gallego, C Mino-Kenudson, M Ferrone, C Thayer, SP Wargo, JA Warshaw, AL Fernandez-del Castillo, C AF Correa-Gallego, C. Mino-Kenudson, M. Ferrone, C. Thayer, S. P. Wargo, J. A. Warshaw, A. L. Fernandez-del Castillo, C. TI Non-Neoplastic Cysts Comprise 8% of Resected Pancreatic Cysts Presumed to Be Neoplastic SO PANCREAS LA English DT Meeting Abstract C1 [Correa-Gallego, C.; Ferrone, C.; Thayer, S. P.; Wargo, J. A.; Warshaw, A. L.; Fernandez-del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mino-Kenudson, M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 991 EP 991 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300073 ER PT J AU Ferrone, CR Konstantinidis, IT Fernandez-del Castillo, C Wargo, J Thayer, SP Warshaw, AL AF Ferrone, C. R. Konstantinidis, I. T. Fernandez-del Castillo, C. Wargo, J. Thayer, S. P. Warshaw, A. L. TI Fifteen Years of the Warshaw Technique SO PANCREAS LA English DT Meeting Abstract C1 [Ferrone, C. R.; Konstantinidis, I. T.; Fernandez-del Castillo, C.; Wargo, J.; Thayer, S. P.; Warshaw, A. L.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 995 EP 995 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300094 ER PT J AU Furukawa, T Hatori, T Fujita, I Yamamoto, M Kobayashi, M Ohike, N Morohoshi, T Egawa, S Unno, M Takao, S Osako, M Yonezawa, S Mino-Kenudson, M Lauwers, GY Yamaguchi, H Ban, S Shimizu, M AF Furukawa, T. Hatori, T. Fujita, I. Yamamoto, M. Kobayashi, M. Ohike, N. Morohoshi, T. Egawa, S. Unno, M. Takao, S. Osako, M. Yonezawa, S. Mino-Kenudson, M. Lauwers, G. Y. Yamaguchi, H. Ban, S. Shimizu, M. TI Prognostic Relevance of Morphologic Types of Intraductal Papillary Mucinous Neoplasms of the Pancreas SO PANCREAS LA English DT Meeting Abstract C1 [Furukawa, T.] Tokyo Womens Med Univ, Int Res Edu Inst Integ Med Sci, Tokyo, Japan. [Hatori, T.; Fujita, I.; Yamamoto, M.] Tokyo Womens Med Univ, Dept Surg, Inst Gastroenterol, Tokyo, Japan. [Kobayashi, M.] Tokyo Womens Med Univ, Dept Path, Tokyo, Japan. [Kobayashi, M.] Tokyo Womens Med Univ, Dept Surg Path, Tokyo, Japan. [Ohike, N.; Morohoshi, T.] Showa Univ, Sch Med, Dept Path 1, Tokyo 142, Japan. [Egawa, S.; Unno, M.] Tohoku Univ, Grad Sch Med, Div Hepbilpanc Surg, Sendai, Miyagi 980, Japan. [Takao, S.] Kagoshima Univ, Front Sci Res Ctr, Kagoshima 890, Japan. [Osako, M.] Kagoshima Shi Med Assoc Hosp, Dept Surg, Kagoshima, Japan. [Yonezawa, S.] Kagoshima Univ, Grad Sch Med Dent Sci, Dept Hum Path, Kagoshima 890, Japan. [Mino-Kenudson, M.; Lauwers, G. Y.] Massachusetts Gen Hosp, Dept Path, Boston, MA 02114 USA. [Yamaguchi, H.; Ban, S.; Shimizu, M.] Saitama Med Univ, Int Med Ctr, Dept Path, Hidaka, Japan. RI Unno, Michiaki/A-8633-2010 OI Unno, Michiaki/0000-0002-2145-6416 NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 998 EP 998 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300106 ER PT J AU Hui, H Tang, YG Zhu, L Khoury, N Wang, KY Perfetti, R Pandol, SJ Go, VLW AF Hui, H. Tang, Y. G. Zhu, L. Khoury, N. Wang, K. Y. Perfetti, R. Pandol, S. J. Go, V. L. W. TI GLP-1 Directed Human Embryonic Stem Cells Differentiation Into Insulin Producing Cells Via Hedgehog, CAMP, PI3K Pathways SO PANCREAS LA English DT Meeting Abstract C1 [Hui, H.; Wang, K. Y.; Pandol, S. J.; Go, V. L. W.] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Ctr Excellence Pancreat Dis, Los Angeles, CA 90095 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Hui, H.; Tang, Y. G.; Zhu, L.; Khoury, N.; Perfetti, R.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 1005 EP 1005 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300139 ER PT J AU Hui, H Tang, YG Wang, KY Pandol, SJ Go, VLW AF Hui, H. Tang, Y. G. Wang, K. Y. Pandol, S. J. Go, V. L. W. TI Inhibitory Effects of GLP-1 on Proliferation and Tumiorgenicisty of Pancreatic Cancer Stem Cells In Vitro SO PANCREAS LA English DT Meeting Abstract C1 [Hui, H.; Wang, K. Y.; Pandol, S. J.; Go, V. L. W.] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Ctr Excellence Pancreat Dis, Los Angeles, CA 90095 USA. [Hui, H.; Pandol, S. J.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Tang, Y. G.] Cedars Sinai Med Ctr, Div Med Genet, Los Angeles, CA 90048 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 1005 EP 1005 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300138 ER PT J AU Mino-Kenudson, M Warshaw, AL Correa-Gallego, C Muzikansky, A Androutsopoulos, V Deshpande, V Pitman, MB Thayer, SP Lauwers, GY Fernandez-del Castillo, C AF Mino-Kenudson, M. Warshaw, A. L. Correa-Gallego, C. Muzikansky, A. Androutsopoulos, V. Deshpande, V. Pitman, M. B. Thayer, S. P. Lauwers, G. Y. Fernandez-del Castillo, C. TI Intraductal Papillary Mucinous Neoplasm - Associated Invasive Carcinoma (IPMN-INV) Has Favorable Survival After Resection SO PANCREAS LA English DT Meeting Abstract C1 [Mino-Kenudson, M.; Deshpande, V.; Pitman, M. B.; Lauwers, G. Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Warshaw, A. L.; Correa-Gallego, C.; Androutsopoulos, V.; Thayer, S. P.; Fernandez-del Castillo, C.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Muzikansky, A.] Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 1028 EP 1028 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300246 ER PT J AU Sloss, CM Wang, F Palladino, M Cusack, JC AF Sloss, C. M. Wang, F. Palladino, M. Cusack, J. C. TI Proteasome Inhibition Activates EGFR in an HB-EGF Dependant Manner in Pancreatic Cancer Cells SO PANCREAS LA English DT Meeting Abstract C1 [Sloss, C. M.; Wang, F.; Cusack, J. C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Palladino, M.] Nereus Pharmaceut, San Diego, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 1049 EP 1049 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300343 ER PT J AU Thrower, E Yuan, J Usmani, A Jones, C Ireson, C Pandol, S Guha, S AF Thrower, E. Yuan, J. Usmani, A. Jones, C. Ireson, C. Pandol, S. Guha, S. TI Protein Kinase D Regulates Secretagogue-Induced Amylase Secretion and Zymogen Activation SO PANCREAS LA English DT Meeting Abstract C1 [Thrower, E.; Usmani, A.; Jones, C.] VA Connecticut Healthcare, Sect Digest Dis, West Haven, CT USA. [Thrower, E.; Usmani, A.; Jones, C.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Yuan, J.; Pandol, S.] VA Greater LA Hlth Care Syst, Los Angeles, CA USA. [Yuan, J.; Pandol, S.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Ireson, C.] Canc Res Technol, London, England. [Guha, S.] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 1056 EP 1056 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300376 ER PT J AU Yuan, J Liu, Y Shalbueva, N Tan, T Gukovskaya, AS Pandol, SJ AF Yuan, J. Liu, Y. Shalbueva, N. Tan, T. Gukovskaya, A. S. Pandol, S. J. TI Protein Kinase C Epsilon Mediates Ethanol and Carbachol-Induced Depolarization in Pancreatic Acinar Cells SO PANCREAS LA English DT Meeting Abstract C1 VA Greater LA Hlth Care Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 1066 EP 1066 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300424 ER PT J AU Yuan, J Liu, Y Pandol, SJ Gukovskaya, AS Tan, T Thrower, E Guha, S AF Yuan, J. Liu, Y. Pandol, S. J. Gukovskaya, A. S. Tan, T. Thrower, E. Guha, S. TI Protein Kinase D Regulates Cell Death Pathways in Acute Pancreatitis SO PANCREAS LA English DT Meeting Abstract C1 [Yuan, J.; Pandol, S. J.; Gukovskaya, A. S.] VA Greater LA Hlth Care Syst, Los Angeles, CA USA. [Yuan, J.; Pandol, S. J.; Gukovskaya, A. S.] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Liu, Y.] Beijing Hosp, Beijing, Peoples R China. [Thrower, E.] VA Connecticut Healthcare, West Haven, CT USA. [Thrower, E.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Guha, S.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD NOV PY 2009 VL 38 IS 8 BP 1066 EP 1066 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 512DZ UT WOS:000271225300423 ER PT J AU Wolfe, J AF Wolfe, Joanne TI SYMPTOMS AND SUFFERING IN CHILDREN WITH CANCER AT THE END OF LIFE SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 [Wolfe, Joanne] Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 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 NOV PY 2009 VL 53 IS 5 BP 704 EP 704 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 499XS UT WOS:000270260700009 ER PT J AU Kapoor, R Hoffstad, O Bilker, W Margolis, DJ AF Kapoor, Roger Hoffstad, Ole Bilker, Warren Margolis, David J. TI The Frequency and Intensity of Topical Pimecrolimus Treatment in Children with Physician-Confirmed Mild to Moderate Atopic Dermatitis SO PEDIATRIC DERMATOLOGY LA English DT Article ID CALCINEURIN INHIBITORS; SKIN-CANCER; ASSOCIATION; EXPOSURE; DISEASES; ASTHMA; RISK; AGE; PREVALENCE; CHILDHOOD AB Atopic dermatitis (AD) is often treated with multiple modalities, including topical medications such as corticosteroids and topical calcineurin inhibitors (TCIs). The aim of this study was to describe the natural history of the utilization characteristics of topical treatment in those with AD. We conducted a longitudinal study of the first 4,105 children with physician-confirmed mild to moderate AD enrolled in an ongoing postmarketing safety study of pimecrolimus. Information was obtained from participants every six months using a questionnaire. Drug utilization was solely determined by the physician and patient. Over the three years of our study, an increasing number of individuals reported at least 6 months of complete control of their disease, without the continued use of a topical medication. While all study participants used pimecrolimus at the start of the study less than 40% continued to use it after 3 years of study participation. If an individual was still using a topical medication after three years of follow-up, it was most likely a topical corticosteroid. For those who continued to use pimecrolimus, the use was limited to about 60 grams of pimecrolimus in 6 months. Community-based use of topical pimecrolimus to treat AD is limited both with respect to the duration of exposure and amount or total dose of the exposure. If a topical therapy is persistent, it is most likely to a topical corticosteroid. C1 [Kapoor, Roger] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, Boston, MA 02114 USA. [Hoffstad, Ole; Bilker, Warren; Margolis, David J.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Margolis, David J.] Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. RP Kapoor, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol, 55 Fruit St, Boston, MA 02114 USA. FU Novartis Pharmaceuticals FX This study was sponsored by a grant from Novartis Pharmaceuticals to the Trustees of the University of Pennsylvania. NR 22 TC 9 Z9 9 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0736-8046 J9 PEDIATR DERMATOL JI Pediatr. Dermatol. PD NOV-DEC PY 2009 VL 26 IS 6 BP 682 EP 687 DI 10.1111/j.1525-1470.2009.01013.x PG 6 WC Dermatology; Pediatrics SC Dermatology; Pediatrics GA 535XZ UT WOS:000273006600003 PM 20199441 ER PT J AU Tanaka, N Thiele, EA Madsen, JR Bourgeois, BF Stufflebeam, SM AF Tanaka, Naoaki Thiele, Elizabeth A. Madsen, Joseph R. Bourgeois, Blaise F. Stufflebeam, Steven M. TI Magnetoencephalographic Analysis in Patients With Vagus Nerve Stimulator SO PEDIATRIC NEUROLOGY LA English DT Article ID SIGNAL-SPACE SEPARATION; INTERFERENCE; ARTIFACTS; EPILEPSY; MEG AB The objective of this study was to assess the feasibility of magnetoencephalography in epilepsy patients with a vagus nerve stimulator. Magnetoencephalography was performed in two patients with medically intractable epilepsy who had a vagus nerve stimulator. Because of the artifacts caused by the vagus nerve stimulator, no spikes could be identified in the original magnetoencephalographic data in either patient. The temporally extended signal space separation method was used to remove artifacts. After processing by this method, left temporoparietal spikes were clearly identified in patient 1. Equivalent current dipoles calculated from these spikes were localized in the left posterior-temporal and parietal lobes. The location of the dipoles was consistent with the spike distribution on intracranial electroencephalography. In patient 2, bilateral diffuse spikes were seen in the processed data. The contour maps demonstrated a bilateral pattern, not in agreement with a single focal source. These findings supported the diagnosis of symptomatic generalized epilepsy in this patient. Magnetoencephalography may thus be a useful option for evaluating patients with intractable epilepsy who have a vagus nerve stimulator. (C) 2009 by Elsevier Inc. All rights reserved. C1 [Tanaka, Naoaki; Stufflebeam, Steven M.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Thiele, Elizabeth A.] Massachusetts Gen Hosp, Dept Neurol, Pediat Epilepsy Program, Boston, MA 02114 USA. [Madsen, Joseph R.] Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA. [Bourgeois, Blaise F.] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. RP Tanaka, N (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM naoro@nmr.mgh.harvard.edu FU U.S. National Institutes of Health [P41RR14075, R01NS037462-07]; Mental Illness and Neuroscience Discovery Institute; NARSAD FX The authors thank Seppo P. Ahlfors, PhD, Matti S. Hamalainen, PhD, and Samu Taulu, PhD, for their helpful comments on the manuscript. This work was supported by U.S. National Institutes of Health (P41RR14075, R01NS037462-07), Mental Illness and Neuroscience Discovery Institute, and a NARSAD Young Investigatons Award. NR 9 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0887-8994 J9 PEDIATR NEUROL JI Pediatr. Neurol. PD NOV PY 2009 VL 41 IS 5 BP 383 EP 387 DI 10.1016/j.pediatrneurol.2009.06.007 PG 5 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 510GY UT WOS:000271077300013 PM 19818944 ER PT J AU Mansbach, JM Ginde, AA Camargo, CA AF Mansbach, Jonathan M. Ginde, Adit A. Camargo, Carlos A., Jr. TI Serum 25-Hydroxyvitamin D Levels Among US Children Aged 1 to 11 Years: Do Children Need More Vitamin D? SO PEDIATRICS LA English DT Article DE vitamin D; deficiency; prevalence; supplementation ID D DEFICIENCY; NUTRITIONAL RICKETS; HEALTHY-CHILDREN; EARLY-CHILDHOOD; CANCER-RISK; INFANTS; ADOLESCENTS; SKIN; SUPPLEMENTATION; PREVALENCE AB OBJECTIVE: Single-center studies have suggested that hypovitaminosis D is widespread. Our objective was to determine the serum levels of 25-hydroxyvitamin D (25[OH] D) in a nationally representative sample of US children aged 1 to 11 years. METHODS: Data were obtained from the 2001-2004 National Health and Nutrition Examination Survey. Serum 25(OH) D levels were determined by radioimmunoassay and categorized as <25, <50, and <75 nmol/L. National estimates were obtained by using assigned patient visit weights and reported with 95% confidence intervals (CIs). RESULTS: During the 2001-2004 time period, the mean serum 25(OH) D level for US children aged 1 to 11 years was 70 nmol/L (95% CI: 68-73). Children aged 6 to 11 years had lower mean levels of 25(OH) D ( 68 nmol/L [95% CI: 65-71]) compared with children aged 1 to 5 years (74 nmol/L [95% CI: 71-77]). Overall, the prevalence of levels at <25 nmol/L was 0.7% (95% CI: 0.4-1.3), <50 nmol/L was 15% (95% CI: 12-18), and <75 nmol/L was 65% (95% CI: 58-71). The prevalence of serum 25(OH) D levels of <75 nmol/L was higher among children aged 6 to 11 years (71%) compared with children aged 1 to 5 years (56%); girls (67%) compared with boys (62%); and non- Hispanic black (89%) and Mexican American (77%) children compared with non- Hispanic white children (54%). CONCLUSIONS: On the basis of a nationally representative sample of US children aged 1 to 11 years, millions of children may have suboptimal levels of 25(OH) D, especially non- Hispanic black and Mexican American children. More data in children are needed not only to understand better the health implications of specific serum levels of 25(OH) D but also to determine the appropriate vitamin D supplement requirements for children. Pediatrics 2009; 124: 1404-1410 C1 [Mansbach, Jonathan M.] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Med, Boston, MA 02115 USA. [Ginde, Adit A.] Univ Colorado Denver, Sch Med, Dept Emergency Med, Aurora, CO USA. [Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02115 USA. RP Mansbach, JM (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Med, Main Clin Bldg 9 S 9157, Boston, MA 02115 USA. EM jonathan.mansbach@childrens.harvard.edu RI Siry, Bonnie/D-7189-2017 FU Massachusetts General Hospital Center for D-receptor Activation Research ( Boston, MA); [R01-HL84401] FX Dr Camargo was supported by the Massachusetts General Hospital Center for D-receptor Activation Research ( Boston, MA) and grant R01-HL84401 ( Bethesda, MD). NR 52 TC 133 Z9 140 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 J9 PEDIATRICS JI Pediatrics PD NOV PY 2009 VL 124 IS 5 BP 1404 EP 1410 DI 10.1542/peds.2008-2041 PG 7 WC Pediatrics SC Pediatrics GA 510MH UT WOS:000271092100020 PM 19951983 ER PT J AU Rudolph, JL Babikian, VL Treanor, P Pochay, VE Wigginton, JB Crittenden, MD Marcantonio, ER AF Rudolph, James L. Babikian, Viken L. Treanor, Patrick Pochay, Val E. Wigginton, Jeremy B. Crittenden, Michael D. Marcantonio, Edward R. TI Microemboli are not associated with delirium after coronary artery bypass graft surgery SO PERFUSION-UK LA English DT Article DE microembolism; aged; delirium; coronary artery bypass graft; carotid stenosis; transcranial doppler ID CONFUSION ASSESSMENT METHOD; POSTOPERATIVE DELIRIUM; CARDIOPULMONARY BYPASS; CARDIAC-SURGERY; TRANSCRANIAL DOPPLER; CEREBRAL MICROEMBOLI; COGNITIVE CHANGE; PREDICTION RULE; PATIENT; VALIDATION AB Delirium is an acute change in cognition which occurs frequently after coronary artery bypass graft (CABG) surgery. Cerebral microemboli, from plaque, air, or thrombus, have been hypothesized to contribute to delirium and cognitive decline after CABG. The purpose of this study was to determine if there was an association between cerebral microemboli and delirium after cardiac surgery. Non-delirious patients (n=68) were prospectively enrolled and underwent intraoperative monitoring of the middle cerebral arteries with transcranial Doppler (TCD). TCD signals were saved and analyzed postoperatively for microemboli manually, according to established criteria. Postoperatively, patients were assessed for delirium with a standardized battery. Thirty-three patients (48.5%) developed delirium after surgery. Microemboli counts (mean +/- SD) were not significantly different in those with and without delirium (303 +/- 449 vs. 299 +/- 350; p= 0.97). While intraoperative microemboli were not associated with delirium after CABG, further investigation into the source and composition of microemboli can further elucidate the long-term clinical impact of microemboli. C1 [Rudolph, James L.] Boston VA Healthcare Syst, GRECC, Boston, MA 02130 USA. [Babikian, Viken L.; Pochay, Val E.] Boston VA Healthcare Syst, Dept Neurol, Boston, MA 02130 USA. [Treanor, Patrick; Crittenden, Michael D.] Boston VA Healthcare Syst, Div Cardiac Surg, Boston, MA 02130 USA. [Wigginton, Jeremy B.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Crittenden, Michael D.] St Louis VA Med Ctr, Dept Surg, St Louis, MO USA. [Marcantonio, Edward R.] Beth Israel Deaconess Med Ctr, Div Gerontol, Boston, MA 02215 USA. [Marcantonio, Edward R.] Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. [Rudolph, James L.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Babikian, Viken L.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. RP Rudolph, JL (reprint author), Boston VA Healthcare Syst, GRECC, JP-182 150 S Huntington Ave, Boston, MA 02130 USA. EM jrudolph@partners.org FU Harvard Older Americans Independence Center [AG08812-14, AG029861-02]; Harvard - Hartford Junior Faculty Development FX Dr Rudolph is supported by a VA Rehabilitation Career Development Award. This work was funded by the Harvard Older Americans Independence Center AG08812-14 and AG029861-02. Additional support was provided by a Harvard - Hartford Junior Faculty Development Grant and an American NR 42 TC 13 Z9 15 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0267-6591 J9 PERFUSION-UK JI Perfusion-UK PD NOV PY 2009 VL 24 IS 6 BP 409 EP 415 DI 10.1177/0267659109358207 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 545XJ UT WOS:000273770000007 PM 20093336 ER PT J AU Samie, MA Grimm, C Evans, JA Curcio-Morelli, C Heller, S Slaugenhaupt, SA Cuajungco, MP AF Samie, Mohammad A. Grimm, Christian Evans, Jeffrey A. Curcio-Morelli, Cyntia Heller, Stefan Slaugenhaupt, Susan A. Cuajungco, Math P. TI The tissue-specific expression of TRPML2 (MCOLN-2) gene is influenced by the presence of TRPML1 SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE TRP ion channel; TRPML2; Mucolipidosis type IV; Mucolipin-2; Lysosomal storage disorder; TRPML1 knock out mouse ID MUCOLIPIDOSIS TYPE-IV; ADENINE-DINUCLEOTIDE PHOSPHATE; VARITINT-WADDLER PHENOTYPE; RECEPTOR POTENTIAL CHANNEL; NAADP MOBILIZES CALCIUM; CATION CHANNEL; MEMBRANE-PROTEIN; RELEASE CHANNEL; T-LYMPHOCYTES; MUTATION AB Mucolipidosis type IV is a lysosomal storage disorder caused by the loss or dysfunction of the mucolipin-1 (TRPML1) protein. It has been suggested that TRPML2 could genetically compensate (i.e., become upregulated) for the loss of TRPML1. We thus investigated this possibility by first studying the expression pattern of mouse TRPML2 and its basic channel properties using the varitint-waddler (Va) model. Here, we confirmed the presence of long variant TRPML2 (TRPML2lv) and short variant (TRPML2sv) isoforms. We showed for the first time that, heterologously expressed, TRPML2lv-Va is an active, inwardly rectifying channel. Secondly, we quantitatively measured TRPML2 and TRPML3 mRNA expressions in TRPML1(-/-) null and wild-type (Wt) mice. In wild-type mice, the TRPML2lv transcripts were very low while TRPML2sv and TRPML3 transcripts have predominant expressions in lymphoid and kidney organs. Significant reductions of TRPML2sv, but not TRPML2lv or TRPML3 transcripts, were observed in lymphoid and kidney organs of TRPML1(-/-) mice. RNA interference of endogenous human TRPML1 in HEK-293 cells produced a comparable decrease of human TRPML2 transcript levels that can be restored by overexpression of human TRPML1. Conversely, significant upregulation of TRPML2sv transcripts was observed when primary mouse lymphoid cells were treated with nicotinic acid adenine dinucleotide phosphate, or N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinoline sulfonamide, both known activators of TRPML1. In conclusion, our results indicate that TRPML2 is unlikely to compensate for the loss of TRPML1 in lymphoid or kidney organs and that TRPML1 appears to play a novel role in the tissue-specific transcriptional regulation of TRPML2. C1 [Samie, Mohammad A.; Evans, Jeffrey A.; Cuajungco, Math P.] Calif State Univ Fullerton, Dept Biol Sci, Fullerton, CA 92831 USA. [Samie, Mohammad A.; Evans, Jeffrey A.; Cuajungco, Math P.] Calif State Univ Fullerton, Ctr Appl Biotechnol Studies, Fullerton, CA 92831 USA. [Grimm, Christian; Heller, Stefan] Stanford Univ, Sch Med, Dept Otolaryngol & Mol & Cellular Physiol, Stanford, CA 94305 USA. [Curcio-Morelli, Cyntia; Slaugenhaupt, Susan A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Curcio-Morelli, Cyntia; Slaugenhaupt, Susan A.] Harvard Univ, Sch Med, Boston, MA USA. [Cuajungco, Math P.] Mental Hlth Res Inst, Melbourne, Vic, Australia. RP Cuajungco, MP (reprint author), Calif State Univ Fullerton, Dept Biol Sci, 800 N State Coll Blvd, Fullerton, CA 92831 USA. EM mcuajungco@fullerton.edu RI Cuajungco, Math/B-2647-2008; di Ronza, Alberto/H-7674-2016 OI Cuajungco, Math/0000-0003-0749-9564; di Ronza, Alberto/0000-0002-9813-5143 FU Howard Hughes Medical Institute; California State University Program for Education and Research in Biotechnology (CSUPERB); CSUF Junior Faculty Intramural Research; CSUF Associated Students Inc.; Nagel-CSUPERB; NIH [DC004563, NS39995] FX We are grateful for the technical support given by Tony Ricci, Michael Schnee, Simone Jors, and James Mull. We also thank Breck Wheelock for his help on tissue dissection and primary mouse lymphoid cell culture. We thank Dr. Rosa Puertollano (NIH/NHLBI) for providing the human TRPML2 expression plasmid and Dr. Kirill Kiselyov for the human anti-TRPML1 polyclonal antibodies. MPC is partly supported by the Howard Hughes Medical Institute under the HHMI Undergraduate Research Program and a recipient of the California State University Program for Education and Research in Biotechnology (CSUPERB) Faculty-Student Collaborative Research Grant and CSUF Junior Faculty Intramural Research Grant. M. A. S. is a Coppel Graduate Student Science scholar and is a recipient of a research grant from the CSUF Associated Students Inc. JAE is a Howell-CSUPERB scholar, and a recipient of the Nagel-CSUPERB travel award and the CSUF Associated Students Inc. research grant. SH is funded by NIH grant (DC004563). SAS is funded by NIH grant (NS39995). NR 65 TC 27 Z9 27 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD NOV PY 2009 VL 459 IS 1 BP 79 EP 91 DI 10.1007/s00424-009-0716-5 PG 13 WC Physiology SC Physiology GA 509OZ UT WOS:000271028700008 PM 19763610 ER PT J AU Choi, WS Mitsumoto, A Kochevar, IE AF Choi, Won Seon Mitsumoto, Atsushi Kochevar, Irene E. TI Involvement of Reactive Oxygen Species in TGF-beta 1-induced Tropoelastin Expression by Human Dermal Fibroblasts SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; HUMAN ELASTIN PROMOTER; GENE-EXPRESSION; NADPH OXIDASE; HUMAN SKIN; SIGNAL-TRANSDUCTION; MESSENGER-RNA; IN-VITRO; TRANSCRIPTION FACTORS; DEPENDENT MECHANISM AB Chronic exposure to solar UV radiation causes marked changes in the dermal extracellular matrix that underlie the loss of resiliency and increased laxity observed in photoaged skin. In particular, the dermal elastin content increases substantially and the normal, well-organized elastic fibers are replaced by amorphous elastotic material. Transforming growth factor-beta 1 (TGF-beta 1) stimulates synthesis of elastin by dermal fibroblasts and may mediate the increase in elastin in chronically photo-damaged skin. We investigated pathways involved in the TGF-beta 1-induced increase in tropoelastin (TE), the soluble elastin monomer and assessed the role of reactive oxygen species (ROS) in the regulation of TE mRNA. Antioxidants and an inhibitor of NADPH oxidase blocked TGF-beta 1-induced TE mRNA increase even when added 1.5 h after TGF-beta 1, although ROS were detected for only 30 min. The TE mRNA increase required activation of Smad4, shown using Smad4 siRNA, and also involved the ERK1/2, p38 and JNK MAP kinases but not PI3K. ROS did not enhance signaling through Smad2 but did enhance activation of p38 and ERK1/2 at 10 min after TGF-beta 1. These results indicate that Smad and MAPK pathways mediate TGF-beta 1-induced TE expression and that ROS are required for both early signal transduction and later steps that increase elastin. C1 [Choi, Won Seon; Mitsumoto, Atsushi; Kochevar, Irene E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02163 USA. [Choi, Won Seon] MIT, Cambridge, MA 02139 USA. RP Kochevar, IE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed, Boston, MA 02163 USA. EM kochevar@helix.mgh.harvard.edu FU National Institutes of Health [RO1 AR43895] FX We gratefully acknowledge support for this research by grant RO1 AR43895 from the National Institutes of Health. NR 54 TC 10 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD NOV-DEC PY 2009 VL 85 IS 6 BP 1425 EP 1433 DI 10.1111/j.1751-1097.2009.00611.x PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 509UX UT WOS:000271045200018 PM 19709383 ER PT J AU Wooten, K AF Wooten, Karen TI Clinical Features and Electrodiagnosis of Diabetic Peripheral Neuropathy in the Dysvascular Patient SO PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA LA English DT Article DE Neuropathy; Electrodiagnosis; Diabetes; Dysvascular; Amputee; Diabetic peripheral neuropathy; Polyneuropathy ID DISTAL SYMMETRIC POLYNEUROPATHY; ACADEMY-OF-NEUROLOGY; AUTONOMIC NEUROPATHY; NERVE-CONDUCTION; CLASSIFICATION; ASSOCIATION; MELLITUS; CACHEXIA AB Diabetic peripheral neuropathy (DPN) is a common disorder that can lead to limb loss and death. Up to 50% of DPN patients can be asymptomatic. This fact contributes to making DPN the leading cause of lower limb amputation. The degree of heterogeneity in the clinical manifestations of DPN makes diagnosing this condition difficult. This article reviews the characteristics, diagnosis, electrodiagnosis, classification, pathogenesis, and treatment of DPN. C1 [Wooten, Karen] Vet Affairs Puget Sound Hlth Care Syst, Rehabilitat Care Serv S117, Seattle, WA 98108 USA. [Wooten, Karen] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. RP Wooten, K (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Rehabilitat Care Serv S117, 1660 S Columbian Way, Seattle, WA 98108 USA. EM Karen.wooten@va.gov NR 35 TC 7 Z9 9 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 1047-9651 J9 PHYS MED REHABIL CLI JI Phys. Med. Rehabil. Clin. N. Am. PD NOV PY 2009 VL 20 IS 4 BP 657 EP + DI 10.1016/j.pmr.2009.06.011 PG 21 WC Rehabilitation SC Rehabilitation GA 509NI UT WOS:000271024300006 PM 19781504 ER PT J AU Hakimi, KN AF Hakimi, Kevin N. TI Pre-Operative Rehabilitation Evaluation of the Dysvascular Patient Prior to Amputation SO PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA LA English DT Article DE Amputation; Rehabilitation; Diabetes mellitus; Diabetes complications; Peripheral vascular diseases ID LOWER-LIMB AMPUTATION; LOWER-EXTREMITY AMPUTATIONS; OUTCOMES; AMPUTEE; 10-YEAR AB Lower-extremity amputation secondary to dysvascular disease, including diabetes and peripheral vascular disease, is a major health problem in the United States. Due to the increased comorbidities in this patient population, pre-operative rehabilitation evaluation by a multidisciplinary team is crucial to ensure optimal patient outcomes. This article discusses the key factors that may affect functional outcomes in this patient population and outlines important history and physical examination components that should be evaluated pre-operatively. C1 [Hakimi, Kevin N.] VA Puget Sound Hlth Care Syst, Rehabil Care Serv, Seattle, WA 98108 USA. [Hakimi, Kevin N.] Univ Washington, Sch Med, Dept Rehabil Med, Seattle, WA 98159 USA. RP Hakimi, KN (reprint author), VA Puget Sound Hlth Care Syst, Rehabil Care Serv, RCS 117,1660 S Columbian Way, Seattle, WA 98108 USA. EM khakimi@u.washington.edu NR 20 TC 5 Z9 5 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1047-9651 J9 PHYS MED REHABIL CLI JI Phys. Med. Rehabil. Clin. N. Am. PD NOV PY 2009 VL 20 IS 4 BP 677 EP + DI 10.1016/j.pmr.2009.06.015 PG 13 WC Rehabilitation SC Rehabilitation GA 509NI UT WOS:000271024300007 PM 19781505 ER PT J AU Won, S Wilk, JB Mathias, RA O'Donnell, CJ Silverman, EK Barnes, K O'Connor, GT Weiss, ST Lange, C AF Won, Sungho Wilk, Jemma B. Mathias, Rasika A. O'Donnell, Christopher J. Silverman, Edwin K. Barnes, Kathleen O'Connor, George T. Weiss, Scott T. Lange, Christoph TI On the Analysis of Genome-Wide Association Studies in Family-Based Designs: A Universal, Robust Analysis Approach and an Application to Four Genome-Wide Association Studies SO PLOS GENETICS LA English DT Article ID QUANTITATIVE TRAITS; UNIFIED APPROACH; GENERAL-CLASS; TESTS; POWER; STRATIFICATION; REGRESSION; LINKAGE; ASTHMA AB For genome-wide association studies in family-based designs, we propose a new, universally applicable approach. The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information. The approach is suitable for the analysis of almost any trait type, e. g. binary, continuous, time-to-onset, multivariate, etc., and combinations of those. We use simulation studies to verify all theoretically derived properties of the approach, estimate its power, and compare it with other standard approaches. We illustrate the practical implications of the new analysis method by an application to a lung-function phenotype, forced expiratory volume in one second (FEV1) in 4 genome-wide association studies. C1 [Won, Sungho] Chung Ang Univ, Dept Stat, Seoul 156756, South Korea. [Won, Sungho] Chung Ang Univ, Res Ctr Data Sci, Seoul 156756, South Korea. [Wilk, Jemma B.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Mathias, Rasika A.] NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [O'Donnell, Christopher J.] NHLBI, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, Bethesda, MD USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Silverman, Edwin K.; Weiss, Scott T.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Silverman, Edwin K.] Brigham & Womens Hosp, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Barnes, Kathleen] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [O'Connor, George T.] Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. [Weiss, Scott T.; Lange, Christoph] Brigham & Womens Hosp, Ctr Genom Med, Boston, MA 02115 USA. [Lange, Christoph] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Won, S (reprint author), Chung Ang Univ, Dept Stat, Seoul 156756, South Korea. EM clange@hsph.harvard.edu OI O'Connor, George/0000-0002-6476-3926 FU National Heart, Lung, and Blood Institute, National Institutes of Health [U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, T32 HL07427]; National Institutes of Health [R01MH081862]; Medic Research Council [G00000934]; Wellcome Trust [068545/Z/02] FX The CAMP Genetics Ancillary Study is supported by U01 HL075419, U01 HL65899, P01 HL083069, R01 HL086601, and T32 HL07427 from the National Heart, Lung, and Blood Institute, National Institutes of Health. CL is supported by the National Institutes of Health grant R01MH081862. Framingham Heart Study genotype and phenotype data are publicly available through the NHLBI's SNP Health Association Resource (SHARe) initiative (http://public.nhlbi.nih.gov/GeneticsGenomics/home/share.aspx). The British 1958 Birth Cohort DNA collection is funded by the Medic Research Council grant G00000934 and the Wellcome Trust grant 068545/Z/02. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 26 Z9 27 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2009 VL 5 IS 11 AR e1000741 DI 10.1371/journal.pgen.1000741 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 528CW UT WOS:000272419500036 PM 19956679 ER PT J AU Hammond, MC AF Hammond, Margaret C. TI Honoring Those Who Have Served SO PM&R LA English DT Editorial Material C1 VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Hammond, MC (reprint author), VA Puget Sound Hlth Care Syst, 1660 S Columbian Way,128N, Seattle, WA 98108 USA. EM margaret.hammond@va.gov NR 7 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 1934-1482 J9 PM&R JI PM&R PD NOV PY 2009 VL 1 IS 11 BP 991 EP 992 DI 10.1016/j.pmrj.2009.10.009 PG 2 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA V24LO UT WOS:000208412100001 PM 19942183 ER PT J AU Gaynes, BN Warden, D Trivedi, MH Wisniewski, SR Fava, M Rush, AJ AF Gaynes, Bradley N. Warden, Diane Trivedi, Madhukar H. Wisniewski, Stephen R. Fava, Maurizio Rush, A. John TI What Did STAR*D Teach Us? Results From a Large-Scale, Practical, Clinical Trial for Patients With Depression SO PSYCHIATRIC SERVICES LA English DT Article ID MEASUREMENT-BASED CARE; SEQUENCED TREATMENT ALTERNATIVES; FAILED MEDICATION TREATMENTS; 2ND-STEP TREATMENTS; OUTPATIENTS; AUGMENTATION; OUTCOMES; EPIDEMIOLOGY; MIRTAZAPINE; RATIONALE AB The authors provide an overview of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (www.star-d.org), a large-scale practical clinical trial to determine which of several treatments are the most effective "next-steps" for patients with major depressive disorder whose symptoms do not remit or who cannot tolerate an initial treatment and, if needed, ensuing treatments. Entry criteria were broadly defined and inclusive, and patients were enrolled from psychiatric and primary care clinics. All participants began on citalopram and were managed by clinic physicians, who followed an algorithm-guided acute-phase treatment through five visits over 12 weeks. At the end of each sequence, patients whose depression had not fully remitted were eligible for subsequent randomized trials in a sequence of up to three clinical trials. In general, remission rates in the study clinics were lower than expected, suggesting the need for several steps to achieve remission for most patients. There was no clear medication "winner" for patients whose depression did not remit after one or more aggressive medication trials. Both switching and augmenting appeared to be reasonable options when an initial antidepressant treatment failed, although these two strategies could not be directly compared. Further, the likelihood of remission after two vigorous medication trials substantially decreased, and remission would likely require more complicated medication regimens for which the existing evidence base is quite thin. STAR*D demonstrated that inclusion of more real-world patients in clinical trials is both feasible and informative. Policy implications of the findings, as well as the study's limitations, are discussed. (Psychiatric Services 60: 1439-1445, 2009) C1 [Gaynes, Bradley N.] Univ N Carolina, Dept Psychiat, Sch Med, Chapel Hill, NC 27599 USA. [Warden, Diane; Trivedi, Madhukar H.; Rush, A. John] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX USA. [Wisniewski, Stephen R.] Univ Pittsburgh, Grad Sch Publ Hlth, Epidemiol Data Ctr, Pittsburgh, PA 15260 USA. [Fava, Maurizio] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Depress Clin & Res Program, Boston, MA USA. RP Gaynes, BN (reprint author), Univ N Carolina, Dept Psychiat, Sch Med, CB 7160, Chapel Hill, NC 27599 USA. EM bgaynes@med.unc.edu OI Wisniewski, Stephen/0000-0002-3877-9860; Gaynes, Bradley/0000-0002-8283-5030; Rush, Augustus/0000-0003-2004-2382 FU National Institute of Mental Health (NIMH) [N01MH90003]; Bristol-Myers Squibb and Novartis; Targacept FX Dr. Gaynes has received grants and research support from Bristol-Myers Squibb and Novartis and has served as an advisor for Bristol-Myers Squibb. Dr. Warden has owned stock in Pfizer in the past year. Dr. Trivedi has received consulting fees from AstraZeneca, Bristol-Myers Squibb, Cephalon, Inc., Eli Lilly and Company, Evotec, Fabre-Kramer Pharmaceuticals, Forest Pharmaceuticals, GlaxoSmithKline, Janssen, Johnson and Johnson, Medtronic, Neuronetics, Otsuka Pharmaceuticals, Pfizer, Shire, and Wyeth-Ayerst Laboratories. He has received research support from Targacept. Dr. Wisniewski has received consultant fees from Cyberonics Inc. The other authors report no competing interests. NR 27 TC 114 Z9 116 U1 0 U2 5 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 NOV PY 2009 VL 60 IS 11 BP 1439 EP 1445 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 514KM UT WOS:000271393200006 PM 19880458 ER PT J AU Laje, G Perlis, RH Rush, AJ McMahon, FJ AF Laje, Gonzalo Perlis, Roy H. Rush, A. John McMahon, Francis J. TI Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results SO PSYCHIATRIC SERVICES LA English DT Article ID SEQUENCED TREATMENT ALTERNATIVES; FACTOR GENETIC-POLYMORPHISM; EMERGENT SUICIDAL IDEATION; MAJOR DEPRESSIVE DISORDER; GENOME-WIDE ASSOCIATION; ELEMENT-BINDING PROTEIN; ANTIDEPRESSANT TREATMENT; NEUROTROPHIC-FACTOR; D COHORT; SEROTONIN TRANSPORTER AB Several lines of evidence support an important genetic contribution to the wide individual variation in therapeutic response to antidepressant medications. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study provided the largest cohort assembled to date of DNA from patients with nonpsychotic major depressive disorder, uniformly treated with citalopram and followed prospectively for up to 12 weeks. This pivotal study changed the face of pharmacogenetics research by increasing the sample size by an order of magnitude as well as by providing detailed prospective information about antidepressant response and tolerability. Several groups have identified markers in genes and tested the replication of previous findings of genes associated with outcome and side effects of antidepressant treatment. Variants in HTR2A, GRIK4, and KCNK2 were associated with citalopram treatment outcome. Replication was achieved in markers in the FKBP5 gene. Other findings in PDE11A and BDNF were not successfully replicated, and reports of potential confounders in previous associations with serotonin transporter variation (SLC6A4) were identified. Polymorphisms in pharmacokinetic genes involved in metabolism and transmembrane transport were also not associated with antidepressant response. Adverse events were also tested. Treatment-emergent suicidal ideation was associated with GRIK2, GRIA3, PAPLN, IL28RA, and CREB1. Sexual dysfunction was linked with variation in GRIN3A, GRIA1 GRIA3, and GRIK2. Reported and future findings of pharmacogenetics studies in STAR*D could help elucidate pathways involved in major depression and those pertinent to antidepressant outcome and side effects. Replication of these findings in independent samples could lead to the development of new treatments and to optimization of available treatments. (Psychiatric Services 60: 1446-1457, 2009) C1 [Laje, Gonzalo; McMahon, Francis J.] NIMH, Genet Basis Mood & Anxiety Disorders Unit, Bethesda, MD 20892 USA. [Perlis, Roy H.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rush, A. John] Duke Natl Univ Singapore, Singapore, Singapore. RP Laje, G (reprint author), NIMH, Genet Basis Mood & Anxiety Disorders Unit, 35 Convent Dr,MSC 3719,Bldg 35-1A207, Bethesda, MD 20892 USA. EM gonzalo.laje@nih.gov RI Laje, Gonzalo/L-2654-2014; OI Laje, Gonzalo/0000-0003-2763-3329; Rush, Augustus/0000-0003-2004-2382; McMahon, Francis/0000-0002-9469-305X FU NIMH [N01 MH-90003, K23MH67060]; National Institutes of Health (NIH); U.S. Department of Health and Human Services (DHHS); NARSAD Young Investigator/Sidney R. Baer Jr. Foundation; Bowman Family Foundation FX STAR*D is supported by federal funds from NIMH under contract N01 MH-90003 to the University of Texas-Southwestern Medical Center at Dallas (Dr. Rush, principal investigator). This study was funded by the Intramural Research Program of NIMH, National Institutes of Health (NIH), U.S. Department of Health and Human Services (DHHS), NIMH grant K23MH67060, a NARSAD Young Investigator/Sidney R. Baer Jr. Foundation Award, and a Bowman Family Foundation award. The content of this publication does not necessarily reflect the views or policies of DHHS nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 67 TC 51 Z9 52 U1 0 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 NOV PY 2009 VL 60 IS 11 BP 1446 EP 1457 PG 12 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 514KM UT WOS:000271393200007 PM 19880459 ER PT J AU Ong, MK Rubenstein, LV AF Ong, Michael K. Rubenstein, Lisa V. TI Wishing Upon a STAR*D: The Promise of Ideal Depression Care by Primary Care Providers SO PSYCHIATRIC SERVICES LA English DT Editorial Material ID DISSEMINATING QUALITY IMPROVEMENT; RANDOMIZED CONTROLLED-TRIAL; COLLABORATIVE CARE; OUTCOMES; PREFERENCES; INCENTIVES; MANAGEMENT; VISITS; IMPACT; TIME AB The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial found that after initial treatment, depressed patients treated in primary care settings had the same or slightly better outcomes than those treated in specialty care settings. The authors describe challenges to using the STAR*D approach and protocols in usual primary care settings. These include inadequate availability of appointments, insufficient resources for care management and treatment monitoring, and lack of payment to primary care providers for providing mental health care. Substantial reengineering of payment and delivery systems is needed in order for the STAR*D approach to be viable in primary care clinics. (Psychiatric Services 60: 1460-1462, 2009) C1 [Ong, Michael K.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Rubenstein, Lisa V.] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. RP Ong, MK (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, 911 Broxton Ave,1st Floor, Los Angeles, CA 90024 USA. EM michael.ong@ucla.edu RI Ong, Michael/F-7397-2013 FU NIMH NIH HHS [P30 MH068639, P30-MH082760, P30 MH082760] NR 24 TC 3 Z9 3 U1 0 U2 0 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 NOV PY 2009 VL 60 IS 11 BP 1460 EP 1462 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 514KM UT WOS:000271393200009 PM 19880461 ER PT J AU Cully, JA Johnson, M Moffett, ML Khan, M Deswal, A AF Cully, Jeffrey A. Johnson, Michael Moffett, Maurice L. Khan, Myrna Deswal, Anita TI Depression and Anxiety in Ambulatory Patients With Heart Failure SO PSYCHOSOMATICS LA English DT Article ID PRIMARY-CARE PATIENTS; QUALITY-OF-CARE; PULMONARY-DISEASE; COMPETING DEMANDS; RISK; SYMPTOMS; PREVALENCE; PREDICTORS; OUTCOMES; IDENTIFICATION AB Background: Depression and anxiety are common in heart failure, but the prevalence, incidence, and relationship of these conditions to health service use and mortality remains uncertain. Objective: The authors sought to delineate these parameters and identify patient factors predicting hospitalizations for heart failure and mortality 12 months after their initial diagnosis of heart failure. Method: The authors utilized a retrospective database cohort of 12,028 ambulatory patients with newly diagnosed heart failure to examine diagnosed depression and anxiety and the relationship of these conditions to health service use and all-cause mortality. Results: Patients with diagnosed depression and/or anxiety (18% of the cohort) were frequently identified by providers within the first 30 days after a heart failure diagnosis. They subsequently utilized twice as many health services, but they did not show increased mortality risk. Discussion: Although mental health intervention data for heart failure patients are limited, the prevalence and impact of depression and anxiety in these patients suggest that assessment and intervention efforts appear warranted early in the heart failure process. (Psychosomatics 2009; 50: 592-598) C1 Michael E DeBakey Vet Affairs Med Ctr, Hlth Serv Res & Dev Serv, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Vet Affairs S Cent Mental Illness Res Educ & Clin, Houston, TX USA. Baylor Coll Med, Winters Ctr Heart Failure Res, Cardiol Sect, Houston, TX 77030 USA. RP Cully, JA (reprint author), 2002 Holcombe 152, Houston, TX 77030 USA. EM jcully@bcm.edu NR 33 TC 12 Z9 12 U1 1 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD NOV-DEC PY 2009 VL 50 IS 6 BP 592 EP 598 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 529AU UT WOS:000272488900007 PM 19996230 ER PT J AU Nejad, SH Gandhi, RT Freudenreich, O AF Nejad, Shamim Hashemi Gandhi, Rajesh T. Freudenreich, Oliver TI Clozapine Use in HIV-Infected Schizophrenia Patients: A Case-Based Discussion and Review SO PSYCHOSOMATICS LA English DT Article ID SERIOUS MENTAL-ILLNESS; ACQUIRED IMMUNODEFICIENCY SYNDROME; PNEUMOCYSTIS-CARINII PNEUMONIA; TRIMETHOPRIM-SULFAMETHOXAZOLE; ANTIRETROVIRAL THERAPY; DEPRESSIVE SYMPTOMS; METABOLIC SYNDROME; CONTROLLED-TRIAL; DOUBLE-BLIND; HEPATITIS-C AB Background: Schizophrenia is a common neuropsychiatric disorder that is associated with an increased risk for HIV infection. Because schizophrenia may affect the ability of HIV-infected patients to adhere to their antiretroviral regimen, optimal management of their mental illness is a high priority in such individuals. However, 20% to 30% of patients with schizophrenia are refractory to first-line antipsychotics. Objective: Given the frequency of comorbid HIV infection and schizophrenia, the authors investigated the potential role of clozapine, with the idea that this medication may be considered for use in this particular patient population. Method: The authors present histories of clozapine treatment in two patients with schizophrenia and comorbid HIV illness. The use of clozapine in this population, along with potential pharmacodynamic and pharmacokinetic drug interactions are discussed. Results: Management and information regarding the use of clozapine in patients with schizophrenia and comorbid HIV illness are presented. Discussion: Clozapine can be used successfully in HIV-infected individuals, with control of viral replication an achievable goal, particularly for those patients in whom there is some external oversight of medication adherence. A multidisciplinary approach must be adopted, with the consultation psychiatrist providing the best possible control of psychiatric problems so that infectious-disease doctors can achieve the goal of HIV replication control. (Psychosomatics 2009; 50: 626-632) C1 [Nejad, Shamim Hashemi] Massachusetts Gen Hosp, Schizophrenia Program, Div Psychiat & Med, Div Infect Dis, Boston, MA 02114 USA. Massachusetts Gen Hosp, Schizophrenia Program, Partners AIDS Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Nejad, SH (reprint author), Massachusetts Gen Hosp, Schizophrenia Program, Div Psychiat & Med, Div Infect Dis, 55 Fruit St,WRN 605, Boston, MA 02114 USA. EM snejad@partners.org NR 50 TC 5 Z9 5 U1 2 U2 5 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0033-3182 J9 PSYCHOSOMATICS JI Psychosomatics PD NOV-DEC PY 2009 VL 50 IS 6 BP 626 EP 632 PG 7 WC Psychiatry; Psychology SC Psychiatry; Psychology GA 529AU UT WOS:000272488900012 PM 19996235 ER PT J AU Hennessey, KA Bangsberg, DR Weinbaum, C Hahn, JA AF Hennessey, Karen A. Bangsberg, David R. Weinbaum, Cindy Hahn, Judith A. TI Hepatitis A Seroprevalence and Risk Factors Among Homeless Adults in San Francisco: Should Homelessness Be Included in the Risk-Based Strategy for Vaccination? SO PUBLIC HEALTH REPORTS LA English DT Article ID INJECTION-DRUG USERS; VIRAL-HEPATITIS; POPULATION; INFECTION; VIRUS; MEN; OUTBREAK AB Objectives. Homeless adults have an increased risk of infectious diseases due to sexual and drug-related behaviors and substandard living conditions. We investigated the prevalence and risk factors for presence of hepatitis A virus (HAV) antibodies among homeless and marginally housed adults. Methods. We analyzed serologic and questionnaire data from a study of marginally housed and homeless adults in San Francisco from April 1999 to March 2000. We tested seroprevalance for total antibodies to HAV (anti-HAV) and analyzed data using Chi-square tests and logistic regression. Results. Of the 1,138 adults in the study, 52% were anti-HAV positive. The anti-HAV prevalence in this study population was 58% higher than the expected prevalence based on age-specific prevalence rates from the general population. Number of years of homelessness (<= 1, 2-4, and; >= 5 years) was associated with anti-HAV prevalence (46%, 50%, and 61%, respectively, p<0.001). We found other differences in anti-HAV prevalence (p<0.05) for ever having injected drugs (63% vs. 42% for non-injectors), being foreign-born (75% vs. 51% among U.S.-born), race/ethnicity (72%, 53%, and 45% for Hispanic, white, and black people, respectively), and increasing age (38%, 49%, and 62% among those aged <35, 35-45, and >45 years, respectively). These variables all remained significant in a multivariate model. Conclusions. We found overall anti-HAV prevalence elevated in this San Francisco homeless population compared with the general U.S. population. These data show that anti-HAV was associated with homelessness independent of other known risk factors, such as being foreign-born, race/ethnicity, and injection drug use. This increase indicates an excess risk of HAV infection and the potential need to offer hepatitis A vaccination as part of homeless services. C1 [Hennessey, Karen A.; Weinbaum, Cindy] Ctr Dis Control & Prevent, Div Viral Hepatitis, Atlanta, GA 30333 USA. [Bangsberg, David R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Harvard Initiat Global Hlth, Cambridge, MA 02138 USA. [Hahn, Judith A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Hennessey, KA (reprint author), Ctr Dis Control & Prevent, Div Viral Hepatitis, 1600 Clifton Rd,E-05, Atlanta, GA 30333 USA. EM keh7@cdc.gov FU NIDA NIH HHS [K01 DA023365, K01 DA023365-03]; NIMH NIH HHS [R01 MH054907]; PHS HHS [K-24 015287, R01-1 54907] NR 18 TC 6 Z9 6 U1 0 U2 0 PU ASSOC SCHOOLS PUBLIC HEALTH PI WASHINGTON PA 1101 15TH ST NW, STE 910, WASHINGTON, DC 20005 USA SN 0033-3549 J9 PUBLIC HEALTH REP JI Public Health Rep. PD NOV-DEC PY 2009 VL 124 IS 6 BP 813 EP 817 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 504IG UT WOS:000270608900008 PM 19894423 ER PT J AU Brown, CA Cheng, EM Hays, RD Vassar, SD Vickrey, BG AF Brown, Carlos A. Cheng, Eric M. Hays, Ron D. Vassar, Stefanie D. Vickrey, Barbara G. TI SF-36 includes less Parkinson Disease (PD)-targeted content but is more responsive to change than two PD-targeted health-related quality of life measures SO QUALITY OF LIFE RESEARCH LA English DT Article DE Health-related quality of life; Parkinson Disease; PDQUALIF; PDQ-39; Responsiveness; SF-36 ID PATIENT-REPORTED OUTCOMES; MULTIPLE-SCLEROSIS; INSTRUMENTS; SCALE; DISABILITY AB To compare validity including responsiveness, and internal consistency reliability and scaling assumptions of a generic (SF-36) and Parkinson Disease (PD)-targeted (PDQ-39; PDQUALIF) health-related quality of life (HRQOL) measures. Ninety-six PD patients were administered for all HRQOL measures by telephonic interview at baseline and 18 months. Relative efficiency and responsiveness were compared relative to four external criteria (self-ratings of PD's daily effects, global Quality of Life, PD symptom severity, and a depression screener). We examined whether PD-targeted measures explained unique variance beyond the SF-36 by regressing criterion variables on HRQOL scales/items. Adequacy of PD-targeted measures' original scaling was explored by item-scale correlations. Relative efficiency estimates were similar for generic and PD-targeted measures across all criteria. Responsiveness analyses showed that the SF-36 yielded large (> 0.8) effect sizes (ES) for three of eight scales for each of two criterion variables, compared to only one large ES for any scale in either PD-targeted measure. Adjusted R (2) increased from 14 to 27% in regression models that included PD-targeted items compared to models with only SF-36 scales. Item-scale correlations showed significant cross-loading of items across scales of the PD-targeted measures. SF-36 responsiveness was better than that of two PD-targeted measures, yet those measures had content that significantly explains PD patients' HRQOL. C1 [Brown, Carlos A.; Cheng, Eric M.; Vassar, Stefanie D.; Vickrey, Barbara G.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90024 USA. RP Cheng, EM (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90024 USA. EM eric.cheng@va.gov RI Hays, Ronald/D-5629-2013 FU Department of Veterans Affairs, Veterans Health Administration; VA Health Services Research & Development Service [PDI 01-158]; NIH/NINDS [NS038367]; NINDS [K23NS058571] FX We acknowledge with thanks Michele Maines, MSG, Sunberri Murphy, and Amelia Mittleman for bibliographic support, and Harvey Lopez and Jessika Herrera for their administrative assistance. Erin Jacob assisted in the data collection. We thank Drs. Jeff Bronstein, Yvette Bordelon, and Indu Subramanian for recruitment of patients. The research presented here was supported by the Department of Veterans Affairs, Veterans Health Administration, VA Health Services Research & Development Service project number PDI 01-158, and by NIH/NINDS NS038367 for the UCLA UDALL Parkinson Disease Center of Excellence. Eric Cheng was supported by an NINDS career development award (K23NS058571). NR 34 TC 22 Z9 24 U1 1 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD NOV PY 2009 VL 18 IS 9 BP 1219 EP 1237 DI 10.1007/s11136-009-9530-y PG 19 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 504XH UT WOS:000270650900010 PM 19714487 ER PT J AU Catalano, OA Sahani, DV Forcione, DG Czermak, B Liu, CH Soricelli, A Arellano, RS Mueller, PR Hahn, PF AF Catalano, Onofrio A. Sahani, Dushyant V. Forcione, David G. Czermak, Benedikt Liu, Chang-Hsien Soricelli, Andrea Arellano, Ronald S. Mueller, Peter R. Hahn, Peter F. TI Biliary Infections: Spectrum of Imaging Findings and Management SO RADIOGRAPHICS LA English DT Article ID RECURRENT PYOGENIC CHOLANGITIS; HEPATOSPLENIC SCHISTOSOMIASIS-MANSONI; MAGNETIC-RESONANCE CHOLANGIOGRAPHY; ACUTE SUPPURATIVE CHOLANGITIS; BILE-DUCT STONES; LIVER-TRANSPLANTATION; RISK-FACTORS; NONSUPPURATIVE CHOLANGITIS; SCLEROSING CHOLANGITIS; PERCUTANEOUS DRAINAGE AB Infectious cholangitides encompass a wide spectrum of infectious processes affecting the biliary tree. They can have protean clinical and imaging appearances. Some manifest as an acute medical emergency with high mortality if not properly and emergently managed. Others are chronic processes that may predispose a patient to liver failure or cholangiocarcinoma. The clinical and imaging features and the subsequent therapy are dictated by the pathogens involved, the immune status of the host, and the degree and distribution of biliary obstruction. Bacteria cause most cases of infectious cholangitis in Western countries. In other parts of the world, parasites play an important role, either as causative agents or in predisposing the host to bacterial superinfection. Viral cholangitides primarily affect immunocompromised patients. The clinical and imaging features of cholangitis differ between immunocompetent and immunocompromised patients. Imaging plays a pivotal role in diagnosis of infectious cholangitis, helps identify predisposing causes, and demonstrates complications. Moreover, interventional radiology provides tools to treat acute life-threatening biliary infections, chronic entities, and complications. (C) RSNA, 2009.radiographics.rsna.org C1 [Catalano, Onofrio A.; Sahani, Dushyant V.; Arellano, Ronald S.; Mueller, Peter R.; Hahn, Peter F.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Forcione, David G.] Harvard Univ, Sch Med, Dept Gastroenterol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. [Czermak, Benedikt] Univ Innsbruck, Dept Radiol, Sch Med, A-6020 Innsbruck, Austria. [Liu, Chang-Hsien] Tri Serv Gen Hosp, Dept Radiol, Taipei, Taiwan. [Liu, Chang-Hsien] Natl Def Med Ctr, Taipei, Taiwan. [Soricelli, Andrea] Univ Naples Parthenope, Dept Radiol, Naples, Italy. [Soricelli, Andrea] SDN Fdn IRCCS, Naples, Italy. RP Catalano, OA (reprint author), Harvard Univ, Sch Med, Dept Radiol, 55 Fruit St, Boston, MA 02114 USA. EM ocatalano@partners.org RI soricelli, andrea/C-1133-2009 OI soricelli, andrea/0000-0001-7011-7667 NR 77 TC 21 Z9 24 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD NOV PY 2009 VL 29 IS 7 BP 2059 EP U269 DI 10.1148/rg.297095051 PG 23 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 521UF UT WOS:000271949200016 PM 19926762 ER PT J AU Levine, D Bankier, AA Halpern, EF AF Levine, Deborah Bankier, Alexander A. Halpern, Elkan F. TI Submissions to Radiology: Our Top 10 List of Statistical Errors SO RADIOLOGY LA English DT Editorial Material ID SAMPLE-SIZE ESTIMATION; DIAGNOSTIC-ACCURACY; PROPORTIONS; REGRESSION; AGREEMENT; QUALITY C1 [Levine, Deborah; Bankier, Alexander A.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Levine, D (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA. EM dlevine@bidmc.harvard.edu OI Levine, Deborah/0000-0001-7761-6493 NR 23 TC 9 Z9 9 U1 0 U2 3 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD NOV PY 2009 VL 253 IS 2 BP 288 EP 290 DI 10.1148/radiol.2532090759 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 512UH UT WOS:000271275800003 ER PT J AU Sistrom, CL Dreyer, KJ Dang, PP Weilburg, JB Boland, GW Rosenthal, DI Thrall, JH AF Sistrom, Christopher L. Dreyer, Keith J. Dang, Pragya P. Weilburg, Jeffrey B. Boland, Giles W. Rosenthal, Daniel I. Thrall, James H. TI Recommendations for Additional Imaging in Radiology Reports: Multifactorial Analysis of 5.9 Million Examinations SO RADIOLOGY LA English DT Article ID P-VALUE FALLACY; CT; COST AB Purpose: To quantify the rates of recommendation for additional imaging (RAI) in a large number of radiology reports of different modalities and to estimate the effects of 11 clinically relevant factors. Materials and Methods: This HIPAA compliant research was approved by the institutional review board under an expedited protocol for analyzing anonymous aggregated radiology data. All diagnostic imaging examinations (n = 5 948 342) interpreted by radiologists between 1995 and 2008 were studied. A natural language processing technique specifically designed to extract information about any recommendations from radiology report texts was used. The analytic data set included three quantitative variables: the interpreting radiologist's experience, the year of study, and patient age. Categoric variables described patient location (inpatient, outpatient, emergency department), whether a resident dictated the case, patient sex, modality, body area studied, ordering service, radiologist's specialty division, and whether the examination result was positive. A multivariable logistic regression model was used to determine the effect of each of these factors on likelihood of RAI while holding all others equal. Results: Recommendations increased during the 13 years of study, with the unadjusted rate rising from roughly 6% to 12%. After accounting for all other factors, the odds of any one examination resulting in an RAI increased by 2.16 times (95% confidence interval: 2.12, 2.21) from 1995 to 2008. As radiologist experience increased, the odds of an RAI decreased by about 15% per decade. Studies that had positive findings were more likely (odds ratio = 5.03; 95% confidence interval: 4.98, 5.07) to have an RAI. The remaining factors also had significant effects on the tendency for an RAI. Conclusion: The likelihood of RAI increased by 15% for each decade of radiologist experience and roughly doubled over 13 years of study. (C) RSNA, 2009 C1 [Sistrom, Christopher L.; Dreyer, Keith J.; Dang, Pragya P.; Boland, Giles W.; Rosenthal, Daniel I.; Thrall, James H.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Weilburg, Jeffrey B.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Sistrom, CL (reprint author), Univ Florida, Ctr Hlth, Dept Radiol, POB 100374, Gainesville, FL 32610 USA. EM sistrc@radiology.ufl.edu NR 16 TC 50 Z9 51 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 NOV PY 2009 VL 253 IS 2 BP 453 EP 461 DI 10.1148/radiol.2532090200 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 512UH UT WOS:000271275800021 PM 19710005 ER PT J AU Holloway, CL Racine, ML Cormack, RA O'Farrell, DA Viswanathan, AN AF Holloway, Caroline L. Racine, Marie-Lynn Cormack, Robert A. O'Farrell, Desmond A. Viswanathan, Akila N. TI Sigmoid dose using 3D imaging in cervical-cancer brachytherapy SO RADIOTHERAPY AND ONCOLOGY LA English DT Article DE Cervical cancer; Brachytherapy; Normal tissue dose ID INTRACAVITARY BRACHYTHERAPY; VOLUME PARAMETERS; UTERINE CERVIX; RADIATION-THERAPY; CARCINOMA; RADIOTHERAPY; BLADDER; RECTUM; RECOMMENDATIONS; COMPLICATIONS AB Background and Purpose: To evaluate the proximity. variance, predictors of dose, and complications to the sigmoid in cervical-cancer brachytherapy using 3D planning. Materials and methods: Over 36 months, 50 patients were treated for cervical cancer with either low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. The distance from the central tandem to the sigmoid, the D0.1cc and the D2cc to the sigmoid, rectum and bladder doses, and toxicity were analyzed. Results: The median sigmoid EQD2 D0.1cc and D2cc were 84 Gy and 68.3 Gy for HDR versus 71.1 Gy and 65.9 Gy for LDR (p = 0.02 and 0.98, respectively). Twenty percent of the HDR fractions required manipulation of the superior dwell positions to decrease the sigmoid dose. The median distance from the sigmoid to the tandem was 1.7 cm (range [rg], 0.1-6.16 cm) for HDR and 2.7 cm (rg, 1.17-4.52 cm) for LDR; from the sigmoid to the 100% isodose region the median distances were -0.1 cm (rg, -1.4 to 2.5 cm) and 0.44 cm (rg. -0.73-5.2 cm), respectively. The proximity of the sigmoid to the tandem is significantly related to sigmoid dose (p<0.0001). Within-patient (among-fraction) variation in sigmoid-to-tandem distance during HDR was substantial (coefficient of variation =40%). No grade 3-4 sigmoid toxicity was seen after a median 31-month follow-up period. Conclusions: 3D imaging in cervical-cancer brachytherapy shows the sigmoid in close proximity to the tandem. The sigmoid-to-tandem distance varies substantially between fractions, indicating the importance of sigmoid dose-volume evaluation with each fraction. (C) 2009 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 93 (2009) 307-310 C1 [Holloway, Caroline L.; Racine, Marie-Lynn; Cormack, Robert A.; O'Farrell, Desmond A.; Viswanathan, Akila N.] Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Viswanathan, AN (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, Dana Farber Canc Inst, 75 Francis St,L2, Boston, MA 02115 USA. EM aviswanathan@lroc.harvard.edu OI Cormack, Robert/0000-0001-5553-9984 FU NCI NIH HHS [K07 CA117979-01, K07 CA117979-04, K07 CA117979-03, K07 CA117979, K07 CA117979-02] NR 30 TC 27 Z9 29 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD NOV PY 2009 VL 93 IS 2 BP 307 EP 310 DI 10.1016/j.radonc.2009.06.032 PG 4 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 523RT UT WOS:000272092900025 PM 19665244 ER PT J AU Huang, CYC Pelaez, D Bendala, JD Garcia-Godoy, F Cheung, HS AF Huang, C-Y Charles Pelaez, Daniel Bendala, Juan Dominguez Garcia-Godoy, Franklin Cheung, Herman S. TI Plasticity of stem cells derived from adult periodontal ligament SO REGENERATIVE MEDICINE LA English DT Article DE adult stem cells; neural crest; periodontal ligament; pluripotent stem cells ID CARDIAC NEURAL CREST; HUMAN SOMATIC-CELLS; IN-VITRO; PROGENITOR CELLS; ENDOCRINE PANCREAS; HUMAN FIBROBLASTS; DEFINED FACTORS; SELF-RENEWAL; BONE-MARROW; DIFFERENTIATION AB Background: The neural crest contains pluripotent cells that can give rise to neurons and glial cells of the peripheral nervous system, endocrine cells, connective tissue cells, muscle cells and pigment cells during embryonic development. Stem cells derived from the neural crest may still reside in neural crest derivatives including the periodontal ligament (PDL). However, the pluripotency of PDL-derived stem cells has not been investigated. Aim: To identify subpopulations of stem cells from the adult PDL and study their pluripotency. Human PDLs were harvested from impacted wisdom teeth (patients aged 19-22 years). Results: This study demonstrated that subpopulations of PDL cells expressed embryonic stem cell markers (Oct4, Sox2, Nanog and Klf4) and a subset of neural crest markers (Nestin, Slug, p75 and Sox10). Such PDL cell subpopulations exhibited the potential to differentiate into neurogenic, cardiomyogenic, chondrogenic and osteogenic lineages. Furthermore, preliminary evidence suggesting insulin production of PDL cells might be indicative of the generation of cells of the endodermal lineage. Conclusion: These findings suggest that the PDL may contain pluripotent stem cells that originate from the neural crest. Our observations open the door to prospective autologous therapeutic applications for a variety of conditions. C1 [Huang, C-Y Charles; Pelaez, Daniel; Cheung, Herman S.] Univ Miami, Dept Biomed Engn, Coral Gables, FL 33124 USA. [Huang, C-Y Charles] Nova SE Univ, Craniofacial Res Lab, Coll Dent Med, Ft Lauderdale, FL 33314 USA. [Pelaez, Daniel; Cheung, Herman S.] Miami VA Med Ctr, Miami, FL 33125 USA. [Bendala, Juan Dominguez] Univ Miami, Sch Med, Diabet Res Inst, Miami, FL USA. [Garcia-Godoy, Franklin] Univ Miami, Biosci Res Ctr, Coll Dent, Coral Gables, FL 33124 USA. [Garcia-Godoy, Franklin] Forsyth Inst, Boston, MA USA. RP Cheung, HS (reprint author), Univ Miami, Dept Biomed Engn, Coral Gables, FL 33124 USA. EM hcheung@med.miami.edu NR 59 TC 63 Z9 65 U1 0 U2 6 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0751 J9 REGEN MED JI Regen. Med. PD NOV PY 2009 VL 4 IS 6 BP 809 EP 821 DI 10.2217/RME.09.55 PG 13 WC Cell & Tissue Engineering; Engineering, Biomedical SC Cell Biology; Engineering GA 522PJ UT WOS:000272010000008 PM 19903001 ER PT J AU Hausmann, LRM Ye, FF Schofield, JW Woods, RL AF Hausmann, Leslie R. M. Ye, Feifei Schofield, Janet Ward Woods, Rochelle L. TI Sense of Belonging and Persistence in White and African American First-Year Students SO RESEARCH IN HIGHER EDUCATION LA English DT Article DE Sense of belonging; Persistence; Intentions; Intervention ID CAMPUS RACIAL CLIMATE; REDUCING INTERGROUP BIAS; COLLEGE-STUDENTS; PREDOMINANTLY WHITE; MINORITY-STUDENTS; HIGHER-EDUCATION; SOCIAL INTEGRATION; THEORETICAL-MODEL; ETHNIC-MINORITY; CAUSAL MODEL AB The authors argue for the inclusion of students' subjective sense of belonging in an integrated model of student persistence (Cabrera et al., J Higher Educ 64:123-139, 1993). The effects of sense of belonging and a simple intervention designed to increase sense of belonging are tested in the context of this model. The intervention increased sense of belonging for white students, but not for African American students. However, sense of belonging had direct effects on institutional commitment and indirect effects on intentions to persist and actual persistence behavior for both white and African American students. C1 [Hausmann, Leslie R. M.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Ye, Feifei] Univ Pittsburgh, Dept Educ Psychol, Pittsburgh, PA USA. [Schofield, Janet Ward] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. [Schofield, Janet Ward] Univ Pittsburgh, Ctr Learning Res & Dev, Pittsburgh, PA 15260 USA. [Woods, Rochelle L.] Univ Michigan, Off Acad Multicultural Initiat, Ann Arbor, MI 48109 USA. RP Hausmann, LRM (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr 151C H, Pittsburgh, PA 15206 USA. EM leslie.hausmann@gmail.com NR 56 TC 24 Z9 26 U1 7 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0361-0365 J9 RES HIGH EDUC JI Res. High. Educ. PD NOV PY 2009 VL 50 IS 7 BP 649 EP 669 DI 10.1007/s11162-009-9137-8 PG 21 WC Education & Educational Research SC Education & Educational Research GA 480YQ UT WOS:000268773600002 ER PT J AU MacDonald, AW Thermenos, HW Barch, DM Seidman, LJ AF MacDonald, Angus W., III Thermenos, Heidi W. Barch, Deanna M. Seidman, Larry J. TI Imaging Genetic Liability to Schizophrenia: Systematic Review of fMRI Studies of Patients' Nonpsychotic Relatives SO SCHIZOPHRENIA BULLETIN LA English DT Review DE schizophrenia; neuroimaging; fMRI; relatives; family study; cognitive control; working memory; memory; language; review ID DORSOLATERAL PREFRONTAL CORTEX; WORKING-MEMORY PERFORMANCE; EVENT-RELATED FMRI; 1ST-DEGREE RELATIVES; VERBAL FLUENCY; LANGUAGE LATERALIZATION; BRAIN ACTIVATION; FUNCTIONAL MRI; UNAFFECTED RELATIVES; THALAMIC ACTIVATION AB There is a growing literature on brain activity in the non-psychotic first-degree relatives of patients with schizophrenia as measured using functional imaging. This systematic review examined 20 studies in 4 domains of cognition, including cognitive control (7 samples), working memory (5 samples), long-term memory (4 samples), and language (4 samples). While the literature was widely divergent, these studies did consistently find activation differences between patients' relatives and controls. The most consistent increases in activation within hemisphere were found in right ventral prefrontal cortex (PFC) and right parietal cortex. Abnormal activity, defined as significant increases or decreases in activation relative to controls irrespective of hemisphere, was found in about two-thirds of contrasts in the cerebellum, dorsal prefrontal, lateral temporal, and parietal cortices, and thalamus, with basal ganglia and ventral PFC showing abnormalities in approximately half of those contrasts. Anterior cingulate was generally spared in patients' relatives. The diversity of findings in studies of patients' relatives may derive from differences between the cognitive demands across studies. We identify avenues for building a more accurate and cumulative literature, including symmetrical inclusion criteria for relatives and controls, recording in-scanner responses, using both a priori and whole-brain tests, explicitly reporting threshold values, reporting main effects of task, reporting effect sizes, and quantifying the risk of false negatives. While functional imaging in the relatives of schizophrenia patients remains a promising methodology for understanding the impact of the unexpressed genetic liability to schizophrenia, no single region or mechanism of abnormalities has yet emerged. C1 [MacDonald, Angus W., III] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [MacDonald, Angus W., III] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Thermenos, Heidi W.; Seidman, Larry J.] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Psychiat,Med Sch, Massachusetts Mental Hlth Ctr,Publ Psychiat Div, Cambridge, MA 02138 USA. [Thermenos, Heidi W.; Seidman, Larry J.] Harvard Univ, Sch Med, Dept Psychiat, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. [Thermenos, Heidi W.; Seidman, Larry J.] MIT, MGH, HMS, Athinoula A Martinos Ctr Funct & Struct Biomed Im, Cambridge, MA 02139 USA. [Barch, Deanna M.] Washington Univ, Dept Psychol, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. [Barch, Deanna M.] Washington Univ, Dept Radiol, St Louis, MO 63130 USA. RP MacDonald, AW (reprint author), Univ Minnesota, Dept Psychol, N218 Elliott Hall,75 E River Rd, Minneapolis, MN 55455 USA. EM angus@umn.edu RI Barch, Deanna/G-8638-2013; MacDonald, Angus/M-9855-2016 OI MacDonald, Angus/0000-0003-4588-931X FU National Alliance for Research in Schizophrenia and Affective Disorders; University of Minnesota's McKnight-Land Grant Fellowship; National Institute of Mental Health [MH 18269, MH 79262]; National Institute of Mental Health Conte Center [MH 71616]; Commonwealth Research Center of the Massachusetts Department of Mental Health and National Institute of Mental Health [MH 43518, MH 63951, MH 65562]; Center grant [P50 MH080272] FX National Alliance for Research in Schizophrenia and Affective Disorders (to A.W.M. III, D.M.B., and L.J.S.); the University of Minnesota's McKnight-Land Grant Fellowship and National Institute of Mental Health (grants MH 18269 and MH 79262 to A.W.M. 111); National Institute of Mental Health Conte Center (grant MH 71616 to D.M.B.); the Commonwealth Research Center of the Massachusetts Department of Mental Health and National Institute of Mental Health (grants MH 43518. MH 63951, and MH 65562); Center grant (P50 MH080272 to H.W.T. and L.J.S.). NR 113 TC 78 Z9 78 U1 1 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD NOV PY 2009 VL 35 IS 6 BP 1142 EP 1162 DI 10.1093/schbul/sbn053 PG 21 WC Psychiatry SC Psychiatry GA 518UG UT WOS:000271719200014 PM 18556667 ER PT J AU Walker, EF Cornblatt, BA Addington, J Cadenhead, KS Cannon, TD McGlashan, TH Perkins, DO Seidman, LJ Tsuang, MT Woods, SW Heinssen, R AF Walker, Elaine F. Cornblatt, Barbara A. Addington, Jean Cadenhead, Kristin S. Cannon, Tyrone D. McGlashan, Thomas H. Perkins, Diana O. Seidman, Larry J. Tsuang, Ming T. Woods, Scott W. Heinssen, Robert TI The relation of antipsychotic and antidepressant medication with baseline symptoms and symptom progression: A naturalistic study of the North American Prodrome Longitudinal Sample SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Psychosis; Prodrome; Medication ID RANDOMIZED CONTROLLED-TRIAL; ULTRA-HIGH RISK; SCHIZOPHRENIA PRODROME; FOLLOW-UP; PSYCHOSIS; PEOPLE; PHASE; NEURODEVELOPMENT; INTERVENTIONS; OLANZAPINE AB A substantial number of patients who meet criteria for a prodromal syndrome for first psychosis are treated with antipsychotic and/or antidepressant medications. There is suggestive evidence that both classes of medication may reduce prodromal symptoms. This longitudinal study examined the relation of antipsychotic and antidepressant medication with prodromal symptom severity at baseline and 6-month follow-up. Participants met Structured Interview for Prodromal Syndromes (SIPS) criteria for the prodrome, and were evaluated at eight centers as part of the North American Prodrome Longitudinal Study (NAPLS). Symptom ratings (positive, negative, disorganized and general) and data on antipsychotics, SSRIs, and other antidepressant medications were obtained at baseline and 6-month follow-up. Analyses revealed that all symptom dimensions declined in severity over time, but there were differences in the magnitude of the decline as a function of antipsychotic medication. Those never on antipsychotics showed less reduction in positive and disorganized symptoms over time. SSRIs and other antidepressants were not linked with declines in symptom severity. Consistent with findings from small-sample, clinical trials, the present results suggest that atypical antipsychotics may be effective in reducing the severity of attenuated positive symptoms associated with the prodrome to psychotic disorders. Limitations of the present study are noted, including the fact that it is not a randomized trial, and data on duration and dosage of medication and 2-year follow-up were not available for most participants. The results are discussed in light of the relative risks and benefits of preventive interventions, both medication and cognitive therapies, and the importance of future clinical trials. (C) 2009 Elsevier B.V. All rights reserved. C1 [Walker, Elaine F.] Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. [Walker, Elaine F.] Emory Univ, Dept Psychiat, Atlanta, GA 30322 USA. [Cornblatt, Barbara A.] Zucker Hillside Hosp, Dept Psychiat, Long Isl City, NY USA. [Addington, Jean] Univ Calgary, Dept Psychiat, Calgary, AB, Canada. [Cannon, Tyrone D.] Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. [Cannon, Tyrone D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [McGlashan, Thomas H.; Woods, Scott W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [Perkins, Diana O.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Seidman, Larry J.; Tsuang, Ming T.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Seidman, Larry J.; Tsuang, Ming T.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cadenhead, Kristin S.; Tsuang, Ming T.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Heinssen, Robert] NIMH, Schizophrenia Spectrum Res Program, Div Adult Translat Res, Bethesda, MD 20892 USA. RP Walker, EF (reprint author), Emory Univ, Dept Psychol, 36 Eagle Row, Atlanta, GA 30322 USA. EM psyefw@emory.edu FU NCATS NIH HHS [UL1 TR000454]; NIMH NIH HHS [K24 MH076191-05, R01 MH060720, U01 MH081944, U01 MH081944-05, R01 MH060720-10, U01 MH081988, U01 MH081988-02, K24 MH076191, U01 MH081988-01A1, K23 MH001905] NR 22 TC 33 Z9 34 U1 5 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 NOV PY 2009 VL 115 IS 1 BP 50 EP 57 DI 10.1016/j.schres.2009.07.023 PG 8 WC Psychiatry SC Psychiatry GA 518JD UT WOS:000271686400008 PM 19709859 ER PT J AU Asif, A Salman, L Carrillo, RG Garisto, JD Lopera, G Barakat, U Lenz, O Yevzlin, A Agarwal, A Gadalean, F Sachdeva, B Vachharajani, TJ Wu, S Maya, ID Abreo, K AF Asif, Arif Salman, Loay Carrillo, Roger G. Garisto, Juan D. Lopera, Gustavo Barakat, Urwa Lenz, Oliver Yevzlin, Alexander Agarwal, Anil Gadalean, Florin Sachdeva, Bharat Vachharajani, Tushar J. Wu, Steven Maya, Ivan D. Abreo, Ken TI Patency Rates for Angioplasty in the Treatment of Pacemaker-Induced Central Venous Stenosis in Hemodialysis Patients: Results of a Multi-Center Study SO SEMINARS IN DIALYSIS LA English DT Article ID SUBCLAVIAN VEIN STENOSIS; TRANSVENOUS PACEMAKER; FOLLOW-UP; OCCLUSION; OBSTRUCTION; FISTULA; WALLSTENTS; PLACEMENT; INSERTION; SALVAGE AB While hemodialysis access ligation has been used to manage pacemaker (PM) and implantable cardioverter-defibrillator (ICD) lead-induced central venous stenosis (CVS), percutaneous transluminal balloon angioplasty (PTA) has also been employed to manage this complication. The advantages of PTA include minimal invasiveness and preservation of arteriovenous access for hemodialysis therapy. In this multi-center study we report the patency rates for PTA to manage lead-induced CVS. Consecutive PM/ICD chronic hemodialysis patients with an arteriovenous access referred for signs and symptoms of CVS due to lead-induced CVS were included in this analysis. PTA was performed using the standard technique. Technical and clinical success was examined. Technical success was defined as the ability to successfully perform the procedure. Clinical success was defined as the ability to achieve amelioration of the signs and symptoms of CVS. Both primary and secondary patency rates were also analyzed. Twenty-eight consecutive patients underwent PTA procedure. Technical success was 95%. Postprocedure clinical success was achieved in 100% of the cases where the procedure was successful. The primary patency rates were 18% and 9% at 6 and 12 months, respectively. The secondary patency rates were 95%, 86%, and 73% at 6, 12, and 24 months, respectively. On average, 2.1 procedures/year were required to maintain secondary patency. There were no procedure-related complications. This study finds PTA to be a viable option in the management of PM/ICD lead-induced CVS. Additional studies with appropriate design and sample size are required to conclusively establish the role of PTA in the management of this problem. C1 [Asif, Arif; Salman, Loay; Carrillo, Roger G.; Garisto, Juan D.; Lopera, Gustavo; Barakat, Urwa; Lenz, Oliver] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Yevzlin, Alexander] Univ Wisconsin, Madison, WI USA. [Agarwal, Anil] Ohio Univ, Columbus, OH USA. [Gadalean, Florin] Nephrol Associates Cent Florida, Intervent Nephrol, Orlando, FL USA. [Sachdeva, Bharat; Abreo, Ken] Louisiana State Univ, Shreveport, LA 71105 USA. [Vachharajani, Tushar J.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Wu, Steven] Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Maya, Ivan D.] Univ Alabama, Birmingham, AL USA. RP Asif, A (reprint author), 1600 NW 10th Ave R 7168, Miami, FL 33136 USA. EM aasif@med.miami.edu RI Carrillo, Roger/C-2231-2015; Lenz, Oliver/M-4672-2016 OI Carrillo, Roger/0000-0002-0443-8689; Lenz, Oliver/0000-0003-2997-3976 NR 27 TC 20 Z9 22 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0894-0959 J9 SEMIN DIALYSIS JI Semin. Dial. PD NOV-DEC PY 2009 VL 22 IS 6 BP 671 EP 676 DI 10.1111/j.1525-139X.2009.00636.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 528NO UT WOS:000272452800014 PM 19799756 ER PT J AU Choudhury, D Tuncel, M Levi, M AF Choudhury, Devasmita Tuncel, Meryem Levi, Moshe TI Disorders of Lipid Metabolism and Chronic Kidney Disease in the Elderly SO SEMINARS IN NEPHROLOGY LA English DT Review DE Lipid disorder; elderly; chronic kidney disease; end-stage renal disease; dyslipidemia ID CHRONIC-RENAL-FAILURE; CORONARY-HEART-DISEASE; HMG-COA REDUCTASE; AGE-RELATED HYPERCHOLESTEROLEMIA; NUTRITION EXAMINATION SURVEY; ELEMENT-BINDING PROTEINS; WHITE ADIPOSE-TISSUE; 3RD NATIONAL-HEALTH; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION C1 [Choudhury, Devasmita] Univ Texas SW Med Ctr Dallas, Inctr & Home Dialysis, Dallas VA Med Ctr, Dallas, TX 75390 USA. [Tuncel, Meryem] Texas Tech Univ, Hlth Sci Ctr, Dept Hypertens & Nephrol, Lubbock, TX 79430 USA. [Levi, Moshe] Univ Colorado, Dept Med, Denver VA Med Ctr, Denver, CO USA. RP Levi, M (reprint author), 12700 E 19th Ave,Res 2,Room 7002, Aurora, CO 80045 USA. EM moshe.levi@UCHSC.edu OI Levi, Moshe/0000-0002-6225-946X FU NIA NIH HHS [R01 AG026529-01A2, R01 AG026529] NR 90 TC 5 Z9 7 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD NOV PY 2009 VL 29 IS 6 BP 610 EP 620 DI 10.1016/j.semnephrol.2009.07.006 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 617CD UT WOS:000279257500009 PM 20006793 ER PT J AU Li, YQ Liu, BL Zhao, H Sailhamer, EA Fukudome, EY Zhang, XB Kheirbek, T Finkelstein, RA Velmahos, GC deMoya, M Hales, CA Alam, HB AF Li, Yongqing Liu, Baoling Zhao, Hang Sailhamer, Elizabeth A. Fukudome, Eugene Y. Zhang, Xiaobo Kheirbek, Tareq Finkelstein, Robert A. Velmahos, George C. deMoya, Marc Hales, Charles A. Alam, Hasan B. TI PROTECTIVE EFFECT OF SUBEROYLANILIDE HYDROXAMIC ACID AGAINST LPS-INDUCED SEPTIC SHOCK IN RODENTS SO SHOCK LA English DT Article; Proceedings Paper CT 94th Annual Clinical Congress of the American-College-of-Surgeons/63rd Annual Sessions of the Owen H Wangensteen Forum on Fundamental Surgical Problems CY OCT 12-16, 2008 CL San Francisco, CA SP Amer Coll Surg DE Septic shock; acetylation; LPS; suberoylanilide hydroxamic acid; histone; survival; lung; macrophage ID HISTONE DEACETYLASE INHIBITOR; ACUTE LUNG INJURY; RESUSCITATION STRATEGIES; HEMORRHAGIC-SHOCK; CARDIAC HISTONES; GENE-EXPRESSION; VALPROIC ACID; ACETYLATION; RECEPTOR; RECRUITMENT AB We have recently found that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lethal model of hemorrhagic shock in rats. The purpose of the present study was to determine whether SAHA treatment would prevent LPS-induced septic shock and improve the survival in a murine model. C57BL/6J mice were randomly divided into two groups. Experimental mice were given intraperitoneal SAHA (50 mg/kg) in vehicle dimethyl sulfoxide fluid (n = 10). The control mice (n = 10) received vehicle dimethyl sulfoxide only. They were injected with LIDS (20 mg/kg, i.p.) 2 h later, and the animals from the treatment group were given a second dose of SAHA. Survival was monitored during the next 7 days. In a parallel study, mice treated with or without SAHA were subjected to LPS insult while normal (sham) mice serviced as controls. 1) Lungs were harvested at 3 and 48 h for analysis of gene expression and pathologic changes, respectively; 2) spleens were isolated for analysis of neutrophilic cell population. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA on LPS-induced inflammation in vitro. All mice in the control group that were subjected to LIDS challenge died in less than 48 h. However, SAHA-treated animals displayed a significantly higher 1-week survival rate (87.5%) compared with the control group (0%). Moreover, LPS insult decreased the acetylation of histone proteins (H2A, H2B, and H3), elevated the levels of TNF-alpha in vivo (circulation) and in vitro (culture medium), increased the neutrophilic cell population in the spleen, enhanced the expression of TNF-alpha and IL-1 beta genes in lung tissue, and augmented the pulmonary neutrophil infiltration. In contrast, SAHA treatment markedly attenuated all of these LPS-induced alterations. We report for the first time that administration of SAHA (50 mg/kg) significantly attenuates a variety of inflammatory markers and improves long-term survival after a lethal LPS insult. C1 [Li, Yongqing; Liu, Baoling; Sailhamer, Elizabeth A.; Fukudome, Eugene Y.; Kheirbek, Tareq; Finkelstein, Robert A.; Velmahos, George C.; deMoya, Marc; Alam, Hasan B.] Harvard Univ, Div Trauma Emergency Surg & Surg Crit Care, Massachusetts Gen Hosp, Dept Surg,Med Sch, Boston, MA 02114 USA. [Zhao, Hang; Hales, Charles A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit,Dept Med, Boston, MA 02114 USA. [Zhang, Xiaobo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. [Finkelstein, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pediat,Div Crit Care, Boston, MA 02114 USA. RP Alam, HB (reprint author), Harvard Univ, Div Trauma Emergency Surg & Surg Crit Care, Massachusetts Gen Hosp, Dept Surg,Med Sch, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM hbalam@partners.org FU NHLBI NIH HHS [R01 HL039150] NR 30 TC 41 Z9 43 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD NOV PY 2009 VL 32 IS 5 BP 517 EP 523 DI 10.1097/SHK.0b013e3181a44c79 PG 7 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 514QJ UT WOS:000271409700010 PM 19295477 ER PT J AU Torriani, M Gupta, R Donahue, DM AF Torriani, Martin Gupta, Rajiv Donahue, Dean M. TI Sonographically guided anesthetic injection of anterior scalene muscle for investigation of neurogenic thoracic outlet syndrome SO SKELETAL RADIOLOGY LA English DT Article DE Thoracic outlet syndrome; Anterior scalene; Brachial plexus; Ultrasound; Percutaneous block ID CLINICAL-SIGNIFICANCE; BRACHIAL-PLEXUS AB To describe the technique and complications of sonographically guided anesthetic injection of the anterior scalene muscle in patients being investigated for neurogenic thoracic outlet syndrome. Subjects were identified via a retrospective review of medical records. For the procedure a 25-gauge needle was introduced into the anterior scalene muscle under real-time ultrasound guidance followed by injection of local anesthetic. The procedures were evaluated for technical success, which was defined as satisfactory identification of anterior scalene muscle, intramuscular needle placement, and intramuscular delivery of medication. There was a short-term follow-up to determine procedure-related complications and rate of unintended brachial plexus (BP) block, manifested by upper extremity paresthesias and/or weakness. Twenty-six subjects with suspected neurogenic thoracic outlet syndrome underwent 29 injections (three subjects received bilateral injections). Technical success was achieved in all procedures. The mean duration of the procedure was 30 min, and there were no cases of intravascular needle placement or neurogenic pain during the injection. No major complications occurred. Temporary symptoms of partial BP block occurred after nine injections (9/29, 31%), and a temporary complete BP block occurred after one injection (1/29, 3%). Sonographically guided anesthetic injection of the anterior scalene muscle is a safe and well-tolerated diagnostic test for patients being investigated for neurogenic thoracic outlet syndrome. C1 [Torriani, Martin] Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Radiol, Boston, MA 02114 USA. [Torriani, Martin; Gupta, Rajiv; Donahue, Dean M.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Donahue, Dean M.] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. RP Torriani, M (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Musculoskeletal Radiol, 55 Fruit St,YAW 6048, Boston, MA 02114 USA. EM mtorriani@hms.harvard.edu NR 9 TC 13 Z9 13 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD NOV PY 2009 VL 38 IS 11 BP 1083 EP 1087 DI 10.1007/s00256-009-0714-x PG 5 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 500TB UT WOS:000270326700009 PM 19440705 ER PT J AU Gray, ST Chen, YL Lin, DT AF Gray, Stacey Tutt Chen, Yen-Lin Lin, Derrick T. TI Efficacy of Proton Beam Therapy in the Treatment of Ewing's Sarcoma of the Paranasal Sinuses and Anterior Skull Base SO SKULL BASE-AN INTERDISCIPLINARY APPROACH LA English DT Article CT 7th International Conference on Head and Neck Cancer CY JUL 19-23, 2008 CL San Francisco, CA SP Amer Head & Neck Soc DE Ewing's sarcoma; anterior skull base; proton beam; endoscopic surgery ID SARCOMA/PRIMITIVE NEUROECTODERMAL TUMOR; COMBINED-MODALITY THERAPY; TERM-FOLLOW-UP; ADJUVANT CHEMOTHERAPY; MULTIMODAL THERAPY; RADIATION-THERAPY; MAXILLARY SINUS; NASAL FOSSA; NO BENEFIT; BONE AB Ewing's sarcoma involving the sinonasal cavity and anterior skull base is very rare. The purpose of this article is to present our experience with two such cases, which were both treated with combined chemotherapy and proton beam radiation therapy. The patients were selected from a retrospective medical record analysis that was conducted of all patients who were diagnosed with Ewing's sarcoma of the sinonasal cavity at the Massachusetts Eye & Ear Infirmary/Massachusetts General Hospital Cranial Base Center from 2004 to 2008. One of the patients underwent pretreatment endoscopic subtotal resection to facilitate proton beam radiation therapy. Response to treatment was assessed, post-treatment endoscopic biopsies were performed to assure eradication of disease, and treatment complications were recorded. Both patients completed chemotherapy and proton beam radiation therapy without complication. One patient completed treatment in December 2006 and remains disease free. The second patient completed treatment in March 2007 and remains disease free. Both patients developed headaches accompanied by frontal sinus opacification after treatment that required endoscopic drainage. After endoscopic drainage, the opacification and symptoms resolved. C1 [Gray, Stacey Tutt; Lin, Derrick T.] Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. [Chen, Yen-Lin] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Gray, ST (reprint author), Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. EM stacey_gray@meei.harvard.edu NR 35 TC 12 Z9 13 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1531-5010 J9 SKULL BASE-INTERD AP JI Skull Base-Interdiscip. Appr. PD NOV PY 2009 VL 19 IS 6 BP 409 EP 416 DI 10.1055/s-0029-1220207 PG 8 WC Clinical Neurology; Otorhinolaryngology; Surgery SC Neurosciences & Neurology; Otorhinolaryngology; Surgery GA 521EX UT WOS:000271904200004 PM 20436842 ER PT J AU Collins, ME Block, SD Arnold, RM Christakis, NA AF Collins, Molly E. Block, Susan D. Arnold, Robert M. Christakis, Nicholas A. TI On the prospects for a blame-free medical culture SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE USA; Blame-free culture; Medical errors; Physicians; Palliative care ID PATIENT SAFETY; MISTAKES; ERRORS; PHYSICIANS; DOCTORS; DEATHS; VICTIM; IMPACT AB Official policy-making bodies and experts in medical error have called for a shift in perspective to a blame-free culture within medicine, predicated on the basis that errors are largely attributable to systems rather than individuals. However, little is known about how the lived experience of blame in medical care relates to prospects for such a shift. In this essay we explore the benefits and costs of blame in medical culture. Our observations are informed by our clinical experience and supported by interview data from a study in which 163 American physicians were interviewed about caring for a total of 66 dying patients in two institutions. We observe three ways in which blame is invoked: (1) self-blame, (2) blame of impersonal forces or the "system," and (3) blame of others. Physicians articulate several important functions of blame: as a stimulus for learning and improvement; as a way to empathically allow physicians to forgive mistakes when others accept responsibility using self-blame; and as a way to achieve control over clinical outcomes. We argue that, since error is viewed as a personal failing and tends to evoke substantial self-blame, physicians do not tend to think of errors in a systems context. Given that physicians' ideology of self-blame is ingrained, accompanied by benefits, and limits a systems perspective on error, it may subvert attempts to establish a blame-free culture. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Collins, Molly E.] Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Block, Susan D.] Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. [Block, Susan D.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Block, Susan D.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Block, Susan D.] Harvard Univ, Sch Med, Ctr Palliat Care, Boston, MA USA. [Arnold, Robert M.] Univ Pittsburgh, Inst Doctor Patient Commun, Pittsburgh, PA 15260 USA. [Christakis, Nicholas A.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Christakis, Nicholas A.] Mt Auburn Hosp, Dept Med, Boston, MA USA. [Christakis, Nicholas A.] Harvard Univ, Dept Sociol, Boston, MA 02115 USA. RP Collins, ME (reprint author), Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA. EM molly_collins@post.harvard.edu RI Christakis, Nicholas/C-3205-2009 NR 33 TC 13 Z9 15 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2009 VL 69 IS 9 BP 1287 EP 1290 DI 10.1016/j.socscimed.2009.08.033 PG 4 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 518LU UT WOS:000271694700001 PM 19766373 ER PT J AU Collins, ME Block, SD Arnold, RM Christakis, NA AF Collins, Molly E. Block, Susan D. Arnold, Robert M. Christakis, Nicholas A. TI Responsibility and reflection: Understanding our responses to perceived errors. A response to Woodward, Lemer and Wu SO SOCIAL SCIENCE & MEDICINE LA English DT Editorial Material DE Blame-free culture; Medical errors; USA; Physicians ID MISTAKES C1 [Collins, Molly E.] Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Block, Susan D.] Dana Farber Canc Inst, Ctr Psychooncol & Palliat Care Res, Boston, MA 02115 USA. [Block, Susan D.] Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA. [Block, Susan D.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Block, Susan D.] Harvard Univ, Sch Med, Ctr Palliat Care, Boston, MA USA. [Arnold, Robert M.] Inst Enhance Palliat Care, Sect Palliat Care & Med Eth, Div Gen Internal Med, Pittsburgh, PA USA. [Arnold, Robert M.] Univ Pittsburgh, Inst Doctor Patient Commun, Pittsburgh, PA USA. [Christakis, Nicholas A.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Christakis, Nicholas A.] Mt Auburn Hosp, Dept Med, Cambridge, MA USA. [Christakis, Nicholas A.] Harvard Univ, Dept Sociol, Cambridge, MA 02138 USA. RP Collins, ME (reprint author), Hosp Univ Penn, Dept Med, Philadelphia, PA 19104 USA. EM molly_collins@post.harvard.edu RI Christakis, Nicholas/C-3205-2009 NR 6 TC 1 Z9 1 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2009 VL 69 IS 9 BP 1294 EP 1295 DI 10.1016/j.socscimed.2009.08.007 PG 2 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 518LU UT WOS:000271694700003 PM 19766370 ER PT J AU Hinton, DE Rasmussen, A Nou, L Pollack, MH Good, MJ AF Hinton, Devon E. Rasmussen, Andrew Nou, Leakhena Pollack, Mark H. Good, Mary-Jo TI Anger, PTSD, and the nuclear family: A study of Cambodian refugees SO SOCIAL SCIENCE & MEDICINE LA English DT Article DE Anger; PTSD; Family; Catastrophic cognitions; Cambodian refugees; Acculturation; USA ID POSTTRAUMATIC-STRESS-DISORDER; ANXIETY DISORDERS; PSYCHOMETRIC PROPERTIES; COMBAT VETERANS; MENTAL-HEALTH; PANIC-ATTACKS; SOCIAL COURSE; TRAUMA; SCALE; WAR AB This study profiles the family-directed anger of traumatized Cambodian refugees, all survivors of the Pol Pot genocide (1975-1979), who were patients at a psychiatric clinic in Lowell, MA, USA. We focus on the nuclear family (NF) unit, the NF unit defined as the patient's "significant other" (i.e. spouse or boyfriend/girlfriend) and children. Survey data were collected from a convenience sample of 143 Cambodian refugee patients from October 2006 to August 2007. The study revealed that 48% (68/143) of the patients had anger directed toward a NF member in the last month, with anger directed toward children being particularly common (64 of the 143 patients, or 49% [64/131] of the patients with children). NF-type anger was severe, for example, almost always resulting in somatic arousal (e.g., causing palpitations in 91% [62/68] of the anger episodes) and often in trauma recall and fears of bodily dysfunction. Responses to open-ended questions revealed the causes of anger toward a significant other and children, the content of anger-associated trauma recall, and what patients did to gain relief from anger. A type of cultural gap, namely, a linguistic gap (i.e., the parent's lack of English language skills and the child's lack of Khmer language skills), seemingly played a role in generating conflict and anger. NF-type anger was associated with PTSD presence. The effect of anger on PTSD severity resulted in part from anger-associated trauma recall and fears of bodily dysfunction, with 54% of the variance in PTSD severity explained by that regression model. The study: 1) suggests that among traumatized refugees, family-related anger is a major clinical concern; 2) illustrates how family-related anger may be profiled and investigated in trauma-exposed populations; and 3) gives insights into how family-related anger is generated in such populations. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Hinton, Devon E.; Pollack, Mark H.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02115 USA. [Hinton, Devon E.] Arbour Counseling, SE Asian Clin, Lowell, MA USA. [Rasmussen, Andrew] NYU, Sch Med, Div Gen Internal Med, New York, NY 10003 USA. [Nou, Leakhena] Calif State Univ Long Beach, Dept Sociol, Long Beach, CA 90840 USA. [Good, Mary-Jo] Harvard Univ, Cambridge, MA 02138 USA. RP Hinton, DE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, 15 Parkman St,WACC 812, Boston, MA 02115 USA. EM devon_hinton@hms.harvard.edu FU NIMH NIH HHS [R01 MH079032, R01 MH079032-01A1, R01 MH094312] NR 42 TC 36 Z9 36 U1 2 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0277-9536 J9 SOC SCI MED JI Soc. Sci. Med. PD NOV PY 2009 VL 69 IS 9 BP 1387 EP 1394 DI 10.1016/j.socscimed.2009.08.018 PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 518LU UT WOS:000271694700015 PM 19748169 ER PT J AU Stowell, CP Jones, SC Enny, C Langholff, W Leitz, G AF Stowell, Christopher P. Jones, Stanley C. Enny, Christopher Langholff, Wayne Leitz, Gerhard TI An Open-Label, Randomized, Parallel-Group Study of Perioperative Epoetin Alfa Versus Standard of Care for Blood Conservation in Major Elective Spinal Surgery Safety Analysis SO SPINE LA English DT Article DE erythropoietin; epoetin alfa; surgery; deep vein thrombosis; thrombovascular events ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; VENOUS THROMBOEMBOLISM; REPLACEMENT; OUTCOMES; HIP AB Study Design. Prospective, open-label, randomized, parallel-group study at 80 centers. Objective. To demonstrate there is no clinically important additional risk for deep vein thrombosis with perioperative use of epoetin alfa versus standard of care in spine surgery without prophylactic anticoagulation. Summary of Background Data. Trials of epoetin alfa in orthopedic surgery that demonstrated no additional risk of thrombovascular events included perioperative pharmacologic anticoagulation. Methods. Subjects received epoetin alfa 600 U/kg subcutaneously once weekly starting 3 weeks before spinal surgery plus standard of care for blood conservation, or standard of care alone. Perioperative anticoagulation therapy was not permitted; mechanical deep vein thrombosis prophylaxis was allowed. Doppler imaging for deep vein thrombosis was done on postoperative day 4 (or day of discharge), or for suspected deep vein thrombosis. Deep vein thrombosis was diagnosed by Doppler result or adverse event report. The criterion for no additional risk of deep vein thrombosis was a 1-sided 97.5% upper confidence limit <= 4% between groups. Results. Of the 680 subjects analyzed (340 in each treatment group), 16 (4.7%) in the epoetin alfa group and 7 (2.1%) in the standard of care group had a diagnosis of deep vein thrombosis either by Doppler or by adverse event report with normal Doppler. The between-group difference was 2.6% (97.5% upper confidence limit, 5.4%). Deep vein thrombosis confirmed by Doppler (4.1% vs. 2.1%), other clinically relevant thrombovascular events (1.5% vs. 0.9%), and all adverse events combined (76.5% vs. 73.2%) occurred with similar frequency in the 2 treatment groups. Conclusion. This study documented a higher incidence of deep vein thrombosis and similar rates of other clinically relevant thrombovascular events with epoetin alfa versus standard of care for blood conservation in subjects who did not receive prophylactic anticoagulation before spinal surgery. Antithrombotic prophylaxis should be considered when erythropoietin is used in the surgical setting. C1 [Stowell, Christopher P.] Harvard Univ, Sch Med, Blood Transfus Serv, Massachusetts Gen Hosp, Boston, MA 02114 USA. [Jones, Stanley C.] Spine Care, Houston, TX USA. [Enny, Christopher; Langholff, Wayne; Leitz, Gerhard] Centocor Ortho Biotech Serv LLC, Med Affairs, Bridgewater, NJ USA. RP Stowell, CP (reprint author), Harvard Univ, Sch Med, Blood Transfus Serv, Massachusetts Gen Hosp, Boston, MA 02114 USA. EM cstowell@partners.org FU Centocor Ortho Biotech Services LLC [PR97-19-002] FX Supported by Centocor Ortho Biotech Services LLC (Protocol #PR97-19-002). NR 18 TC 45 Z9 46 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD NOV 1 PY 2009 VL 34 IS 23 BP 2479 EP 2485 DI 10.1097/BRS.0b013e3181bd163f PG 7 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 515CT UT WOS:000271444900001 PM 19927096 ER PT J AU Kim, JH Deasy, BM Seo, HY Studer, RK Vo, NV Georgescu, HI Sowa, GA Kang, JD AF Kim, Joo Han Deasy, Bridget M. Seo, Hyoung Yeon Studer, Rebecca K. Vo, Nam V. Georgescu, Helga I. Sowa, Gwendolyn A. Kang, James D. TI Differentiation of Intervertebral Notochordal Cells Through Live Automated Cell Imaging System In Vitro SO SPINE LA English DT Article DE notochordal cells; chondrocyte-like cells; live automated cell imager; (35)S sulfate incorporation; RT-PCR ID NUCLEUS PULPOSUS; EXTRACELLULAR-MATRIX; CULTURE SYSTEM; DISC; EXPRESSION; PROLIFERATION; CHONDROCYTES; SOX9 AB Study Design. We demonstrated the differentiation of notochordal cells by direct observation using a live automated cell imaging system. We also hypothesized that notochordal cells have characteristics of chondrocyte-like cells. Objective. To determine characteristics of notochordal cells by matrix protein expression and their differentiation using a live automated cell imager. Summary of Background Data. Although notochordal cells are critical to homeostasis of intervertebral disc, their fate has not been extensively studied and there is little evidence of notochordal cells as progenitors. Methods. Notochordal cells purified from rabbit nucleus pulposus were isolated after serial filtration. Notochordal cells in 3-dimensional culture were compared to chondrocyte-like cells by (35)S sulfate incorporation into proteoglycan and reverse transcription polymerase chain reaction for gene expression(collagen II and aggrecan). Notochordal cells in 2-D culture were used for immunocytochemical staining (collagen II, aggrecan, and SOX9) and time-lapsed cell tracking study. Results. Notochordal cells were capable of proteoglycan production at a rate comparable to chondrocyte-like cells (108% +/- 22.6% to chondrocyte-like cells) and expressed collagen II, aggrecan, and SOX9. In time- lapsed cell tracking analysis, notochordal cells were slower in population doubling time than chondrocyte-like cells and differentiated into 3 morphologically distinct cell types: vacuolated cells (area: 2392 +/- 507.1 mu m(2), velocity: 0.09 +/- 0.01 mu m/min); giant cells (area: 12678 +/- 1637.0 mu m(2), velocity: 0.08 +/- 0.01 mu m/min) which grew rapidly without cell division; polygonal cells (area: 3053 +/- 751.2 mu m(2), 0.14 +/- 0.01 mu m/min) morphologically similar to typical differentiation type of chondrocyte-like cells ( area: 2671 +/- 235.6 mu m(2), 0.19 +/- 0.01 mu m/min). Rarely, notochordal cells formed clusters analogous to that observed in vivo. Conclusion. These studies demonstrate a chondrocyte phenotype of notochordal cells and are the first direct evidence of notochordal cell differentiation, suggesting that they may act as progenitor cells, which has the potential to lead to their use in novel approaches to regeneration of degenerative intervertebral disc. C1 [Sowa, Gwendolyn A.] Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, Pittsburgh, PA 15261 USA. [Kim, Joo Han; Deasy, Bridget M.; Vo, Nam V.; Georgescu, Helga I.; Kang, James D.] Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Pittsburgh, PA 15261 USA. [Kim, Joo Han] Korea Univ, Coll Med, Dept Neurosurg, Seoul 136705, South Korea. [Seo, Hyoung Yeon] Chonnam Natl Univ, Dept Orthopaed Surg, Coll Med, Kwangju, South Korea. [Studer, Rebecca K.] Univ Pittsburgh, Sch Med, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15261 USA. RP Sowa, GA (reprint author), Univ Pittsburgh, Sch Med, Dept Phys Med & Rehabil, 200 Lothrop St,E1658,Biomed Sci Tower, Pittsburgh, PA 15261 USA. EM sowaga@upmc.edu RI Kim, Joo Han/B-8129-2014 OI Kim, Joo Han/0000-0002-4747-9763 FU Pittsburgh Foundation at Department of Orthopedic Surgery; University of Pittsburgh FX Supported by the Pittsburgh Foundation at Department of Orthopedic Surgery, University of Pittsburgh. NR 26 TC 35 Z9 40 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD NOV 1 PY 2009 VL 34 IS 23 BP 2486 EP 2493 DI 10.1097/BRS.0b013e3181b26ed1 PG 8 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 515CT UT WOS:000271444900002 PM 19841610 ER PT J AU Sims, JR Lee, SW Topalkara, K Qiu, JH Xu, J Zhou, ZP Moskowitz, MA AF Sims, John R. Lee, Sae-Won Topalkara, Kamil Qiu, Jianhua Xu, Jian Zhou, Zhipeng Moskowitz, Michael A. TI Sonic Hedgehog Regulates Ischemia/Hypoxia-Induced Neural Progenitor Proliferation SO STROKE LA English DT Article DE brain ischemia; dentate gyrus; gene expression; Sonic hedgehog; stem cell ID ADULT BRAIN; IN-VIVO; CELLS; DIFFERENTIATION; EXPRESSION; NEUROGENESIS AB Background and Purpose - Sonic hedgehog (Shh) protein is required for the maintenance of neural progenitor cells (NPCs) in the embryonic and adult hippocampus. Brain ischemia causes increased proliferation of hippocampal NPCs. We therefore examined whether Shh regulates the increase in proliferation of NPCs after ischemia/hypoxia. Methods - Male SV129 mice were exposed to a 20-minute middle cerebral artery occlusion; hippocampi were then analyzed for Shh mRNA and protein expression by real-time polymerase chain reaction, immunoblot, and immunohistochemistry. Primary cell cultures of neurons, astrocytes, and NPCs were exposed to 16 hours of hypoxia (1% O-2) and analyzed by real-time polymerase chain reaction and immunoblot for Shh expression. Proliferation of NPCs, in vivo and in vitro, was measured by bromodeoxyuridine incorporation. Results - Among the cell types examined in vitro, only NPC and neurons increased Shh mRNA under hypoxic conditions. Furthermore, hypoxia increased proliferation of NPCs and this proliferation was enhanced by the addition of recombinant Shh or blocked by the pathway- specific inhibitor, cyclopamine. Middle cerebral artery occlusion was associated with a transient 2-fold increase in the mRNA encoding both Shh and its transcription factor, Gli1, 0.5 days after ischemia. Within the hippocampus, Shh protein was increased approximately 3-fold 3 and 7 days after ischemia and was observed predominantly within cells in the CA3 and hilar regions. Shh was expressed only in mature neurons. In vivo, cyclopamine suppressed ischemia- induced proliferation of subgranular NPCs. Conclusion - The Shh pathway plays a role in the proliferation of NPCs induced by ischemia/hypoxia and might participate in injury remodeling. (Stroke. 2009; 40: 3618- 3626.) C1 [Sims, John R.; Lee, Sae-Won; Topalkara, Kamil; Qiu, Jianhua; Zhou, Zhipeng; Moskowitz, Michael A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Dept Radiol, Charlestown, MA 02129 USA. [Sims, John R.; Lee, Sae-Won; Topalkara, Kamil; Qiu, Jianhua; Zhou, Zhipeng; Moskowitz, Michael A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Neurosci Ctr, Charlestown, MA 02129 USA. [Sims, John R.; Xu, Jian] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Dept Neurol, Charlestown, MA 02129 USA. [Sims, John R.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Dept Neurosurg, Charlestown, MA 02129 USA. RP Sims, JR (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab,Dept Radiol, CNY149 Room 6403, Charlestown, MA 02129 USA. EM jsims@partners.org FU National Institutes of Health (NIH) [NS045776, P30 NS045776, K08 NS04924]; Cardiovascular Foundation; Craig H. Neilsen Foundation; American Heart Association, National Scientist Development [0335154N, 0535138N]; NIH Interdepartmental Stroke Program [5 P50 NS10828] FX Real-time polymerase chain reaction work was supported by a National Institutes of Health (NIH) Nucleic Acid Quantitation Core Grant NS045776. Image analysis data obtained with NIH core grant support P30 NS045776. This work was supported by grants from the Stanely J. Sarnoff Cardiovascular Foundation (J. R. S.), Craig H. Neilsen Foundation (J. R. S.), American Heart Association, National Scientist Development Grants, 0335154N (J. Q.) and 0535138N (J. R. S.), National Institutes of Health (NIH) K08 NS049241 (J. R. S.), and NIH Interdepartmental Stroke Program Project 5 P50 NS10828 (M. A. M.). NR 23 TC 68 Z9 87 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD NOV PY 2009 VL 40 IS 11 BP 3618 EP 3626 DI 10.1161/STROKEAHA.109.561951 PG 9 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 511JM UT WOS:000271160300035 PM 19762700 ER PT J AU Schwaitzberg, SD Kochman, ML Hawes, RH Rattner, DW AF Schwaitzberg, Steven D. Kochman, Michael L. Hawes, Robert H. Rattner, David W. TI Natural orifice translumenal endoscopic surgery (NOTES): Is it time for introduction to clinical practice? SO SURGERY LA English DT Editorial Material C1 [Schwaitzberg, Steven D.] Cambridge Hlth Alliance, Dept Surg, Boston, MA USA. [Kochman, Michael L.] Univ Penn Hlth Syst, Div Gastroenterol, Philadelphia, PA USA. [Hawes, Robert H.] Med Univ S Carolina, Div Gastroenterol & Hepatol, Charleston, SC 29425 USA. [Rattner, David W.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. RP Schwaitzberg, SD (reprint author), Cambridge Hlth Alliance, 1493 Cambridge St, Cambridge, MA 02139 USA. EM sschwaitzberg@challiance.org NR 2 TC 5 Z9 5 U1 0 U2 0 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 NOV PY 2009 VL 146 IS 5 BP 841 EP 842 DI 10.1016/j.surg.2009.06.015 PG 2 WC Surgery SC Surgery GA 514TX UT WOS:000271419600002 PM 19744446 ER PT J AU Mekel, M Stephen, AE Gaz, RD Perry, ZH Hodin, RA Parangi, S AF Mekel, Michal Stephen, Antonia E. Gaz, Randall D. Perry, Zvi H. Hodin, Richard A. Parangi, Sareh TI Thyroid surgery in octogenarians is associated with higher complication rates SO SURGERY LA English DT Article ID ELDERLY-PATIENTS; MALE GENDER; OUTCOMES; CANCER; MANAGEMENT; MORBIDITY; NODULES; DISEASE; RISK; AGE AB Background. The incidence of thyroid nodules increases with age and little information is available regarding the risks of thyroid surgery in elderly patients. The aim of this study was to determine whether thyroid surgery in patients : 80 is associated with higher complication rates. Methods. Out of 3,568 patients undergoing thyroid surgery between July 2001 and October 2007 at a single institution., the records of 90 consecutive patients 80 years were reviewed retrospectively and compared with a cohort of 242 randomly selected patients aged 18-79, who underwent thyroid surgery during the same time period. Clinical variables included age, gender, pre-operative diagnosis, substernal component, previous surgery, final pathology, length of stay, comorbidities, American Society of Anesthesiologists (ASA) score, body mass index, postoperative complications, and mortality. Results. Preoperative indications for surgery included benign disease in 51% vs 39%, suspected malignancy in 19% vs 26%, and suspected follicular neoplasms in 30% vs 35% in the octogenarian patient group (>= 80 years old) vs the younger patient cohort (P = NS). Octogenarians had 20% significant malignancy on final pathology vs 27% in the younger cohort (P = NS). The overall complication rate in the octogenarian group was 24% vs 9% in the younger cohort (P < .001). Male gender and ASA >= 3 were found to be independent fisk factors for Perioperative complications after thyroid surgery, while age alone was not. Conclusion. Age >= 80 is associated with higher morbidity after thyroid surgery, although not independently. Earlier operative intervention may be advised in those at high risk for disease progression, whereas follow-up strategies without operation may be advised for others. (Surgery 2009;146:913-21.) C1 [Mekel, Michal; Stephen, Antonia E.; Gaz, Randall D.; Hodin, Richard A.; Parangi, Sareh] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Mekel, Michal; Stephen, Antonia E.; Gaz, Randall D.; Hodin, Richard A.; Parangi, Sareh] Massachusetts Gen Hosp, Endocrine Surg Unit, Boston, MA 02114 USA. [Mekel, Michal; Stephen, Antonia E.; Gaz, Randall D.; Hodin, Richard A.; Parangi, Sareh] Harvard Univ, Sch Med, Boston, MA USA. [Perry, Zvi H.] Tufts Med Ctr, Surg Res Lab, Boston, MA USA. RP Parangi, S (reprint author), Massachusetts Gen Hosp, Dept Surg, 15 Parkman St,Wang ACC 460, Boston, MA 02114 USA. EM sparangi@partners.org OI Perry, Zvi/0000-0002-1131-5230 FU NCI NIH HHS [R01 CA149738] NR 25 TC 16 Z9 17 U1 0 U2 1 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 NOV PY 2009 VL 146 IS 5 BP 913 EP 921 DI 10.1016/j.surg.2009.05.004 PG 9 WC Surgery SC Surgery GA 514TX UT WOS:000271419600011 PM 19744461 ER PT J AU Livhits, M Mercado, C Yermilov, I Parikh, JA Dutson, E Mehran, A Ko, CY Gibbons, MM AF Livhits, Masha Mercado, Cheryl Yermilov, Irina Parikh, Janak A. Dutson, Erik Mehran, Amir Ko, Clifford Y. Gibbons, Melinda Maggard TI Does weight loss immediately before bariatric surgery improve outcomes: a systematic review SO SURGERY FOR OBESITY AND RELATED DISEASES LA English DT Review DE Bariatric surgery; Predictors; Weight loss; Preoperative weight loss; Outcomes AB Background: Preoperative weight loss before bariatric surgery has been proposed as a predictive factor for improved patient compliance and the degree of excess weight loss achieved after surgery. In the present study, we sought to determine the effect of preoperative weight loss on postoperative outcomes. Methods: A search of MEDLINE was completed to identify the patient factors associated with weight loss after bariatric surgery. Of the 909 screened reports, 15 had reported on preoperative weight loss and the degree of postoperative weight loss achieved. A meta-analysis was performed that compared the postoperative weight loss and perioperative outcomes in patients who had lost weight preoperatively compared to those who had not. Results: Of the 15 articles (n = 3404 patients) identified, 5 found a positive effect of preoperative weight loss on postoperative weight loss, 2 found a positive short-term effect that was not sustained long term, 5 did not find an effect difference, and 1 found a negative effect. A meta-analysis revealed a significant increase in the 1-year postoperative weight loss (mean difference of 5% EWL, 95% confidence interval 2.68-7.32) for patients who had lost weight preoperatively. A meta-analysis of other outcomes revealed a decreased operative time for patients who had lost weight preoperatively (mean difference 23.3 minutes, 95% confidence interval 13.8-32.8). Conclusion: Preoperative weight loss before bariatric surgery appears to be associated with greater weight loss postoperatively and might help to identify patients who would have better compliance after surgery. (C) 2009 American Society for Metabolic and Bariatric Surgery. All rights reserved. C1 [Livhits, Masha; Mercado, Cheryl; Yermilov, Irina; Parikh, Janak A.; Dutson, Erik; Mehran, Amir; Ko, Clifford Y.; Gibbons, Melinda Maggard] Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, Los Angeles, CA 90095 USA. [Livhits, Masha; Yermilov, Irina; Parikh, Janak A.; Ko, Clifford Y.; Gibbons, Melinda Maggard] Vet Affairs Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. [Gibbons, Melinda Maggard] Olive View Univ Calif, Dept Surg, Sylmar, CA USA. RP Livhits, M (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Surg, 10833 LeComte Ave,72-215 CHS, Los Angeles, CA 90095 USA. EM mlivhits@mednet.ucla.edu NR 35 TC 45 Z9 47 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1550-7289 EI 1878-7533 J9 SURG OBES RELAT DIS JI Surg. Obes. Relat. Dis. PD NOV-DEC PY 2009 VL 5 IS 6 BP 713 EP 721 DI 10.1016/j.soard.2009.08.014 PG 9 WC Surgery SC Surgery GA V30LE UT WOS:000208816700017 PM 19879814 ER PT J AU Izci, Y Seckin, H Ates, O Baskaya, MK AF Izci, Yusuf Seckin, Hakan Ates, Oezkan Baskaya, Mustafa K. TI Supracerebellar transtentorial transcollateral sulcus approach to the atrium of the lateral ventricle: microsurgical anatomy and surgical technique in cadaveric dissections SO SURGICAL NEUROLOGY LA English DT Article DE Atrium; Collateral sulcus; Lateral ventricle; Supracerebellar approach ID ARTERIOVENOUS-MALFORMATIONS; TEMPORAL-LOBE; FIBER DISSECTION; TUMORS AB Background: Access to lesions located in the atrium of the lateral ventricle without causing neurologic deficit can be challenging. Here, we demonstrate the supracerebellar transtentorial transcollateral sulcus (STTS) approach as an alternative route to the atrium of the lateral ventricle using anatomical dissections in cadavers. Methods: Suboccipital craniotomy with extension above the transverse sinus was performed in 5 arterial and venous latex-injected cadaveric heads (10 hemispheres). After the dural opening, arachnoidal dissection of the supracerebellar space was performed, and the tentorium cerebelli was cut from lateral to medial. This revealed the parahippocampal and fusiform gyri and collateral sulcus (CS). The distance from the CS to the atrium was measured. Results: The atrium of the lateral ventricle was entered through the CS in each specimen. The cerebral hemispheres were removed from each cadaveric specimen, and dissections were performed. The distance from the CS to the atrium was 1.30 cm on the right side and 1.31 cm on the left. The CS was bifurcated in 62% of the hemispheres, whereas it was single in 38%. Through this approach, only the "u" fibers of the CS were damaged, and the fibers of the optic radiation in the inferolateral wall of the atrium were preserved. Conclusion: The STTS approach may be an effective alternative approach to lesions located in the medioposterior aspect of the atrium of the lateral ventricle in selected cases. Further clinical studies to evaluate the safety and efficacy of this approach are needed. (C) 2009 Elsevier Inc. All rights reserved. C1 [Baskaya, Mustafa K.] Univ Wisconsin, Dept Neurol Surg, Madison, WI 53792 USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI 53792 USA. RP Baskaya, MK (reprint author), Univ Wisconsin, Dept Neurol Surg, Madison, WI 53792 USA. EM m.baskaya@neurosurg.wisc.edu NR 16 TC 12 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-3019 J9 SURG NEUROL JI Surg. Neurol. PD NOV PY 2009 VL 72 IS 5 BP 509 EP 514 DI 10.1016/j.surneu.2009.01.025 PG 6 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 616TX UT WOS:000279233800014 PM 19328525 ER PT J AU Carty, SE Cooper, DS Doherty, GM Duh, QY Kloos, RT Mandel, SJ Randolph, GW Stack, BC Steward, DL Terris, DJ Thompson, GB Tufano, RP Tuttle, RM Udelsman, R AF Carty, Sally E. Cooper, David S. Doherty, Gerard M. Duh, Quan-Yang Kloos, Richard T. Mandel, Susan J. Randolph, Gregory W. Stack, Brendan C., Jr. Steward, David L. Terris, David J. Thompson, Geoffrey B. Tufano, Ralph P. Tuttle, R. Michael Udelsman, Robert CA Amer Thyroid Assoc Surg Working Gr TI Consensus Statement on the Terminology and Classification of Central Neck Dissection for Thyroid Cancer SO THYROID LA English DT Review ID SURGERY; ACADEMY; HEAD AB Background: The primary goals of this interdisciplinary consensus statement are to review the relevant anatomy of the central neck compartment, to identify the nodal subgroups within the central compartment commonly involved in thyroid cancer, and to define a consistent terminology relevant to the central compartment neck dissection. Summary: The most commonly involved central lymph nodes in thyroid carcinoma are the prelaryngeal (Delphian), pretracheal, and the right and left paratracheal nodal basins. A central neck dissection includes comprehensive, compartment-oriented removal of the prelaryngeal and pretracheal nodes and at least one paratracheal lymph node basin. A designation should be made as to whether a unilateral or bilateral dissection is performed and on which side (left or right) in unilateral cases. Lymph node "plucking" or "berry picking" implies removal only of the clinically involved nodes rather than a complete nodal group within the compartment and is not recommended. A therapeutic central compartment neck dissection implies that nodal metastasis is apparent clinically (preoperatively or intraoperatively) or by imaging (clinically N1a). A prophylactic/elective central compartment dissection implies nodal metastasis is not detected clinically or by imaging (clinically N0). Conclusion: Central neck dissection at a minimum should consist of removal of the prelaryngeal, pretracheal, and paratracheal lymph nodes. The description of a central neck dissection should include both the indication (therapeutic vs. prophylactic/elective) and the extent of the dissection (unilateral or bilateral). C1 [Steward, David L.] Univ Cincinnati, Coll Med, Dept Otolaryngol Head & Neck Surg, Cincinnati, OH 45267 USA. [Carty, Sally E.] Univ Pittsburgh, Sch Med, Dept Surg, Sect Endocrine Surg, Pittsburgh, PA USA. [Cooper, David S.] Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Baltimore, MD USA. [Doherty, Gerard M.] Univ Michigan Hlth Syst, Dept Surg, Ann Arbor, MI USA. [Duh, Quan-Yang] Vet Affairs Med Ctr, Surg Serv, San Francisco, CA 94121 USA. [Duh, Quan-Yang] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kloos, Richard T.] Ohio State Univ, Arthur G James Canc Hosp, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Kloos, Richard T.] Ohio State Univ, Arthur G James Canc Hosp, Div Nucl Med, Columbus, OH 43210 USA. [Kloos, Richard T.] Ohio State Univ, Arthur G James Canc Hosp, Dept Internal Med, Columbus, OH 43210 USA. [Kloos, Richard T.] Ohio State Univ, Arthur G James Canc Hosp, Dept Radiol, Columbus, OH 43210 USA. [Kloos, Richard T.] Ohio State Univ, Richard J Solove Res Inst, Columbus, OH 43210 USA. [Kloos, Richard T.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Mandel, Susan J.] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. [Randolph, Gregory W.] Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. [Stack, Brendan C., Jr.] Univ Arkansas Med Sci, Dept Otolaryngol Head & Neck Surg, Little Rock, AR 72205 USA. [Terris, David J.] Med Coll Georgia, Dept Otolaryngol Head & Neck Surg, Augusta, GA 30912 USA. [Thompson, Geoffrey B.] Mayo Clin, Rochester, MN USA. [Tufano, Ralph P.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Tuttle, R. Michael] Mem Sloan Kettering Canc Ctr, Dept Endocrinol, New York, NY 10021 USA. [Udelsman, Robert] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA. RP Steward, DL (reprint author), Univ Cincinnati, Coll Med, Dept Otolaryngol Head & Neck Surg, 231 Albert B Sabin Way, Cincinnati, OH 45267 USA. EM david.steward@uc.edu OI Doherty, Gerard/0000-0002-1685-9552 NR 5 TC 156 Z9 170 U1 2 U2 16 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD NOV PY 2009 VL 19 IS 11 BP 1153 EP 1158 DI 10.1089/thy.2009.0159 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 515BB UT WOS:000271440100005 ER PT J AU Yagi, H Parekkadan, B Suganuma, K Soto-Gutierrez, A Tompkins, RG Tilles, AW Yarmush, ML AF Yagi, Hiroshi Parekkadan, Biju Suganuma, Kazuhiro Soto-Gutierrez, Alejandro Tompkins, Ronald G. Tilles, Arno W. Yarmush, Martin L. TI Long-Term Superior Performance of a Stem Cell/Hepatocyte Device for the Treatment of Acute Liver Failure SO TISSUE ENGINEERING PART A LA English DT Article ID INTERLEUKIN-1 RECEPTOR ANTAGONIST; FULMINANT HEPATIC-FAILURE; BIOARTIFICIAL LIVER; IN-VITRO; PORCINE HEPATOCYTES; SUPPORT-SYSTEMS; PHASE-I; CELLS; EXPRESSION; RATS AB Cell-based technologies to support/restore organ function represent one of the most promising avenues in the treatment of acute liver failure (ALF). Recently, mesenchymal stem cells (MSCs) have been reported as a new therapeutic for inflammatory conditions. Here, we demonstrate the efficacy of MSCs, when cocultured with hepatocytes, to provide combination hepatic and antiinflammatory therapy in the setting of ALF. MSCs were shown to have multiple beneficial effects in vitro that were relevant in a therapeutic context, including (1) hepatocellular functional support, (2) secretion of molecules that inhibit hepatocyte apoptosis, and (3) modulation of an acute phase response by hepatocytes cultured in ALF-induced serum. In addition, we show that the MSC secretome is dynamically changed in response to serum exposure from ALF rats. We then conducted a therapeutic trial of liver assist devices (LADs). LADs containing cocultures of MSCs and hepatocytes provided a greater survival benefit compared to other coculture and monocellular control LADs. Treatment with MSC-hepatocyte devices was associated with specific improvements in hepatic functional and histological parameters as well as decreasing inflammatory serum cytokine levels, validating a combined therapeutic effect. Moreover, MSC coculture reduced the overall cell mass of the device by an order of magnitude. These findings demonstrate the importance of nonparenchymal cells in the cellular composition of LADs, and strongly support the integration of MSCs into hepatocyte-coculture-based LADs as a potential destination therapy for ALF. C1 [Yagi, Hiroshi; Parekkadan, Biju; Soto-Gutierrez, Alejandro; Tompkins, Ronald G.; Tilles, Arno W.; Yarmush, Martin L.] Massachusetts Gen Hosp, Ctr Engn Med, Shriners Hosp Children, Boston, MA 02114 USA. [Yagi, Hiroshi; Parekkadan, Biju; Soto-Gutierrez, Alejandro; Tompkins, Ronald G.; Tilles, Arno W.; Yarmush, Martin L.] Massachusetts Gen Hosp, Surg Serv, Shriners Hosp Children, Boston, MA 02114 USA. [Yagi, Hiroshi; Parekkadan, Biju; Soto-Gutierrez, Alejandro; Tompkins, Ronald G.; Tilles, Arno W.; Yarmush, Martin L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Yagi, Hiroshi; Suganuma, Kazuhiro] Keio Univ, Sch Med, Dept Surg, Tokyo 160, Japan. RP Yarmush, ML (reprint author), Massachusetts Gen Hosp, Ctr Engn Med, Shriners Hosp Children, 51 Blossom St, Boston, MA 02114 USA. EM ireis@sbi.org FU Shriners Hospitals for Children; National Institutes of Health [R01 DK43371, K08 DK66040] FX The authors acknowledge the technical assistance of Carley Shulman for isolation of hepatocytes, Don Poulsen for help with illustrations, and Bob Crowther for preparing histological slides. We are grateful to Dr. Richard Hurley and Angela Heiser (Center for Comparative Medicine, Massachusetts General Hospital, Charlestown, MA) for their assistance in animal care. Also we thank Dr. Yaakov Nahmias and Dr. Srivatsan Kidambi (Center for Engineering in Medicine, Massachusetts General Hospital, Boston, MA) for assistance in Cytochrome P450 assay. This work was partially supported by grants from Shriners Hospitals for Children and National Institutes of Health (contract grant numbers: R01 DK43371 and K08 DK66040). NR 37 TC 34 Z9 36 U1 0 U2 6 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD NOV PY 2009 VL 15 IS 11 BP 3377 EP 3388 DI 10.1089/ten.tea.2008.0681 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 519EC UT WOS:000271746800016 PM 19397469 ER PT J AU Dennis, JW Lau, KS Demetriou, M Nabi, IR AF Dennis, James W. Lau, Ken S. Demetriou, Michael Nabi, Ivan R. TI Adaptive Regulation at the Cell Surface by N-Glycosylation SO TRAFFIC LA English DT Review DE N-glycosylation; Golgi; endocytosis; galectins; signaling; computational modeling ID GROWTH-FACTOR RECEPTOR; PLASMA-MEMBRANE; BREAST-CANCER; EGF RECEPTORS; TUMOR-CELLS; ACETYLGLUCOSAMINYLTRANSFERASE-V; REDOX REGULATION; ENZYMATIC BASIS; DOWN-REGULATION; LIGAND-BINDING AB The association of receptors and solute transporters with components of the endocytic machinery regulates their surface levels, and thereby cellular sensitivity to cytokines, ligands and nutrients in the extracellular environment. Most transmembrane receptors and solute transporters are glycoproteins, and the Asn (N)-linked oligosaccharides (N-glycans) can bind animal lectins, forming multivalent lattices or microdomains that regulate glycoprotein mobility in the plane of membrane. The N-glycan number (sequence-encoded NXS/T) and context-dependent Golgi N-glycan branching cooperate to regulate glycoprotein affinities for the galectin family of lectins. Galectin-3 binding reduces EGF receptor trafficking into clathrin-coated pits and caveolae lipid rafts, decreases ligand-independent receptor activation and promotes alpha 5 beta 1 integrin remodelling in focal adhesions. N-glycan branching in the medial Golgi increases glycan affinity for galectins, and the Golgi pathway is sensitive to uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) supply, in turn hexosamine pathway metabolites (fructose-6-P, glutamine and acetyl-CoA). Thus, lattice avidity and cellular responsiveness to extracellular cues are regulated in an adaptive manner by metabolism and Golgi modification to glycoproteins. Computational modelling of the hexosamine/Golgi/lattice has provided new insight on cell surface adaptation in cancer and autoimmune disease. C1 [Dennis, James W.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Dennis, James W.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A1, Canada. [Dennis, James W.] Univ Toronto, Dept Lab Med & Pathol, Toronto, ON M5S 1A1, Canada. [Lau, Ken S.] Massachusetts Gen Hosp, Dept Pathol, Charlestown, MA USA. [Demetriou, Michael] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA. [Demetriou, Michael] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. [Nabi, Ivan R.] Univ British Columbia, Inst Life Sci, Dept Cellular & Physiol Sci, Vancouver, BC V5Z 1M9, Canada. RP Dennis, JW (reprint author), Mt Sinai Hosp, Samuel Lunenfeld Res Inst, 600 Univ Ave R988, Toronto, ON M5G 1X5, Canada. EM dennis@mshri.on.ca RI Dennis, James/E-7268-2013; OI Lau, Ken/0000-0001-8438-0319 FU Genome Canada through the OGI; CIHR [MOP-79405, MOP-62975, MOP-43938] FX Research was supported by grants from Genome Canada through the OGI, and funding from CIHR (MOP-79405 and MOP-62975), and to J. W. D. and I. R. N. (MOP-43938). NR 96 TC 98 Z9 100 U1 1 U2 19 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD NOV PY 2009 VL 10 IS 11 BP 1569 EP 1578 DI 10.1111/j.1600-0854.2009.00981.x PG 10 WC Cell Biology SC Cell Biology GA 505CH UT WOS:000270665300002 PM 19761541 ER PT J AU Liu, YY Liao, SK Huang, CC Tsai, YH Quinn, DA Li, LF AF Liu, Yung-Yang Liao, Shuen-Kuei Huang, Chung-Chi Tsai, Ying-Huang Quinn, Deborah A. Li, Li-Fu TI Role for nuclear factor-kappa B in augmented lung injury because of interaction between hyperoxia and high stretch ventilation SO TRANSLATIONAL RESEARCH LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; NECROSIS-FACTOR-ALPHA; RESPIRATORY-DISTRESS-SYNDROME; CONTROLLED ANIMAL-EXPERIMENT; LOWER TIDAL VOLUMES; MECHANICAL VENTILATION; ENDOTHELIAL-CELLS; PAI-1 EXPRESSION; TISSUE FACTOR; NITRIC-OXIDE AB High-tidal-volume mechanical ventilation and hyperoxia used in patients with acute lung injury (ALI) can induce alveolar coagulopathy and fibrin depositions within the airways. Hyperoxia has been shown to increase ventilator-induced lung injury (VILI), but the mechanisms that regulate interaction between high-tidal-volume mechanical ventilation and hyperoxia are unclear. We hypothesized that mechanical stretch with hyperoxia synergistically augmented neutrophil infiltration and production of plasminogen activator inhibitor-1 (PAI-1) via the nuclear factor-kappa B (NF-kappa B) pathway. C57BL/6 mice (n = 5 per group) were exposed to high-tidal-volume (30mL/kg) or low-tidal-volume (6mL/kg) mechanical ventilation with room air or hyperoxia for 1 to 5h after 2-mu g/g NF-kappa B inhibitor (SN-50) administration. Nonventilated mice with room air or hyperoxia served as control groups. Evans blue dye, myeloperoxidase, electrophoretic mobility shifting of nuclear protein, and inflammatory cytokine were measured. The expression of tumor necrosis factor-alpha (TNF-alpha) and PAI-1 were studied by immunohistochemistry. The addition of hyperoxia to high-tidal-volume ventilation-augmented lung injury, as demonstrated by increased microvascular leak, neutrophil migration into the lung, TNF-alpha and active PAI-1 production, DNA binding activity of NF-kappa B, and NF-kappa B activation. No statistically significant increase of neutrophil infiltration and inflammatory cytokine production was found in the mice ventilated at 6mL/kg using hyperoxia. Hyperoxia-induced augmentation of VILI was attenuated in mice with pharmacologic inhibition of NF-kappa B activity by SN-50. We conclude that hyperoxia increased high-tidal-volume-induced cytokine production and neutrophil influx through activation of the NF-kappa B pathway. (Translational Research 2009; 154:228-240) C1 [Huang, Chung-Chi; Tsai, Ying-Huang; Li, Li-Fu] Chang Gung Mem Hosp, Div Pulm & Crit Care Med, Tao Yuan 333, Taiwan. [Liu, Yung-Yang] Taipei Vet Gen Hosp, Chest Dept, Taipei, Taiwan. [Liu, Yung-Yang] Natl Yang Ming Univ, Sch Med, Taipei 112, Taiwan. [Liao, Shuen-Kuei] Chang Gung Univ, Grad Inst Clin Med Sci, Tao Yuan, Taiwan. [Huang, Chung-Chi; Tsai, Ying-Huang; Li, Li-Fu] Chang Gung Mem Hosp, Dept Resp Therapy, Tao Yuan 333, Taiwan. [Quinn, Deborah A.] Massachusetts Gen Hosp, Dept Med, Pulm Unit, Boston, MA 02114 USA. [Quinn, Deborah A.] Massachusetts Gen Hosp, Dept Med, Crit Care Unit, Boston, MA 02114 USA. [Quinn, Deborah A.] Harvard Univ, Sch Med, Boston, MA USA. [Quinn, Deborah A.] Novartis Inst Biomed Res, Cambridge, MA USA. [Huang, Chung-Chi; Tsai, Ying-Huang; Li, Li-Fu] Chang Gung Univ, Taoyuan, Taiwan. RP Li, LF (reprint author), Chang Gung Mem Hosp, Div Pulm & Crit Care Med, 5 Fu Hsing St, Tao Yuan 333, Taiwan. EM lfp3434@adm.cgmh.org.tw FU Chang Gung Medical Research [MRPG361412] FX Supported by Grant MRPG361412 from the Chang Gung Medical Research Project. NR 37 TC 38 Z9 44 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-5244 EI 1878-1810 J9 TRANSL RES JI Transl. Res. PD NOV PY 2009 VL 154 IS 5 BP 228 EP 240 DI 10.1016/j.trsl.2009.06.006 PG 13 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 515QA UT WOS:000271485900003 PM 19840764 ER PT J AU Messmer-Blust, A An, XJ Li, J AF Messmer-Blust, Angela An, Xiaojin Li, Jian TI Hypoxia-Regulated Angiogenic Inhibitors SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; CELL-DEATH; APOPTOSIS; HIF-1-ALPHA; EXPRESSION; ENDOSTATIN; GENE; VEGF; P53; ANGIOPOIETIN-2 AB The regulation of angio genesis by hypoxia is an essential homeostatic mechanism that depends on a precise balance between positive and negative angiogenic regulatory molecules. Proangiogenic factors are well characterized; however, several in vivo and in vitro studies indicate that there are feedback mechanisms in place to inhibit angiogenesis during hypoxia. Understanding the signaling pathways leading to the negative feedback of angiogenesis will undoubtedly provide important tools to develop novel therapeutic strategies not only to enhance the angiogenic response in coronary artery disease but also to hinder deregulated angiogenesis in tumorigenesis. (Trends Cardiovasc Med 2009;19:252-256) 2009, Elsevier Inc. C1 [Messmer-Blust, Angela; An, Xiaojin; Li, Jian] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Cardiovasc Inst, Boston, MA 02215 USA. RP Li, J (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Cardiovasc Med, 3 Blackfan Circle, Boston, MA 02115 USA. EM jli@bidmc.harvard.edu FU National Institutes of Health [HLR01082837, HL007917] FX The authors thank Ms. Brittany L. Cully for editing the manuscript. This work was supported by National Institutes of Health grants HLR01082837 (Li) and T32 training award HL007917 (Messmer-Blust). NR 34 TC 17 Z9 19 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD NOV PY 2009 VL 19 IS 8 BP 252 EP 256 AR PII S1050-1738(10)00008-3 DI 10.1016/j.tcm.2010.02.006 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 596PY UT WOS:000277698500002 PM 20447566 ER PT J AU Kirchhausen, T AF Kirchhausen, Tom TI Imaging endocytic clathrin structures in living cells SO TRENDS IN CELL BIOLOGY LA English DT Review ID RECEPTOR-MEDIATED ENDOCYTOSIS; MEMBRANE-ASSOCIATED CLATHRIN; INTERACTING PROTEIN-1 HIP1; POLARIZED EPITHELIAL-CELLS; COATED PITS; FLUORESCENCE MICROSCOPY; ACTIN CYTOSKELETON; PLASMA-MEMBRANE; ELECTRON CRYOMICROSCOPY; MAMMALIAN-CELLS AB Our understanding of the clathrin-dependent endocytic pathway owes much to new visualization techniques. Budding coated pits and clathrin-coated structures are transient molecular machines with distinctive morphological characteristics, and fluorescently labeled versions of a variety of marker proteins have given us a tantalizing glimpse of the dynamics of the system in living cells. Recent live-cell imaging studies have revealed unexpected modes of coat assembly, with distinct kinetics, distinct recruitment of associated proteins, distinct requirements for the participation of actin and its accessory proteins, and apparently distinct mechanisms of membrane deformation. A crucial issue is to connect the events detected by light microscopy with the structures and properties of the molecular constituents. Here, I outline descriptions of coat assembly in different circumstances that are consistent with what is known from X-ray crystallography and electron microscopy. C1 Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. RP Kirchhausen, T (reprint author), Harvard Univ, Sch Med, Immune Dis Inst, W Alpert Bldg Room 128,200 Longwood Ave, Boston, MA 02115 USA. EM kirchhausen@crystal.harvard.edu FU NIH [GM075252]; NERCE [U54 A1057159] FX I thank the members of my laboratory, current and past, for helping create and sustain a stimulating environment. I thank my colleagues, Stephen C. Harrison in particular, for the opportunity to share good science and for many enlightening discussions. Our visualization efforts have been supported by NIH grants GM075252 and NERCE U54 A1057159. Finally, I apologize to colleagues whose work I have inadvertently failed to quote. NR 79 TC 89 Z9 92 U1 1 U2 17 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD NOV PY 2009 VL 19 IS 11 BP 596 EP 605 DI 10.1016/j.tcb.2009.09.002 PG 10 WC Cell Biology SC Cell Biology GA 523FM UT WOS:000272057500006 PM 19836955 ER PT J AU Bar, M AF Bar, Moshe TI A cognitive neuroscience hypothesis of mood and depression SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID TREATMENT-RESISTANT DEPRESSION; DEEP BRAIN-STIMULATION; POSTTRAUMATIC-STRESS-DISORDER; CONSCIOUS RESTING STATE; MAJOR DEPRESSION; HIPPOCAMPAL NEUROGENESIS; ANTIDEPRESSANT TREATMENT; NEGATIVE MOOD; THOUGHT SPEED; MEMORY AB Although mood has a direct impact on mental and physical health, our understanding of the mechanisms underlying mood regulation is limited. Here, I propose that there is a direct reciprocal relation between the cortical activation of associations and mood regulation, whereby positive mood promotes associative processing, and associative processing promotes positive mood. This relation might stem from an evolutionary pressure for learning and predicting. Along these lines, one can think of mood as a reward mechanism that guides individuals to use their brains in the most productive manner. The proposed framework has many implications, most notably for diagnosing and treating mood disorders such as depression; for elucidating the role of inhibition in the regulation of mood; for contextualizing adult hippocampal neurogenesis; and for a general, non-invasive improvement of well-being. C1 Harvard Univ, Sch Med, Martinos Ctr, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Bar, M (reprint author), Harvard Univ, Sch Med, Martinos Ctr, Massachusetts Gen Hosp, 149 13th St, Charlestown, MA 02129 USA. EM bar@nmr.mgh.harvard.edu FU NIH [R01NS050615] FX I thank L. Barrett, L. Barsalou, D. Carney, J. Denninger, M. Fava, M. Fenske, D. Gilbert, A. Harvey, M. Mason, J. Matthews, H. Mayberg, K. Shepherd, C. Thomas and D. Wegner for stimulating discussions, constructive comments and help with the article. I was supported by NIH grant R01NS050615. NR 76 TC 53 Z9 53 U1 2 U2 20 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD NOV PY 2009 VL 13 IS 11 BP 456 EP 463 DI 10.1016/j.tics.2009.08.009 PG 8 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 522MT UT WOS:000272002900002 PM 19819753 ER PT J AU Lerner, LB Tyson, MD AF Lerner, Lori B. Tyson, Mark D. TI Holmium Laser Applications of the Prostate SO UROLOGIC CLINICS OF NORTH AMERICA LA English DT Article DE Holmium laser enucleation of the prostate; Holmium; Laser; Prostate; Surgery; Laser physics ID RANDOMIZED PROSPECTIVE TRIAL; TRANSURETHRAL RESECTION; LEARNING-CURVE; CLINICAL-EXPERIENCE; SEXUAL FUNCTION; FOLLOW-UP; ENUCLEATION; HYPERPLASIA; ADENOMA; ELECTROCAUTERY AB The high-powered holmium laser is an excellent tool for the surgical treatment of benign prostatic hyperplasia. This article discusses the background of holmium use in the prostate and describes the surgical techniques of holmium laser ablation of the prostate and holmium laser enucleation of the prostate. Operative challenges are reviewed with suggestions as to how to avoid these problems or deal with them when they arise. Surgical outcomes and a thorough literature review are both presented. C1 [Lerner, Lori B.] Boston Univ, Sch Med, Boston, MA 02043 USA. [Tyson, Mark D.] Dartmouth Med Sch, Hanover, NH 03755 USA. [Lerner, Lori B.] VA Boston Healthcare Syst, Urol Sect, Boston, MA USA. RP Lerner, LB (reprint author), Boston Univ, Sch Med, 12 Water St, Boston, MA 02043 USA. EM lerner_lori@hotmail.com FU Lumenis, Inc; Preceptor, Consultant; Boston Scientific, Inc FX Financial Disclosures: Dr Lerner has the following financial disclosures: Lumenis, Inc: Preceptor, Consultant; Boston Scientific, Inc: NR 35 TC 11 Z9 12 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0094-0143 J9 UROL CLIN N AM JI Urol. Clin. N. Am. PD NOV PY 2009 VL 36 IS 4 BP 485 EP + DI 10.1016/j.ucl.2009.07.005 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 617CK UT WOS:000279258200008 PM 19942047 ER PT J AU Lu, B Maqsodi, B Yang, W McMaster, GK Perner, S Regan, M Bubley, GJ Balk, SP Rubin, M Sanda, MG AF Lu, Bin Maqsodi, Botoul Yang, Wen McMaster, Gary K. Perner, Sven Regan, Meredith Bubley, Glenn J. Balk, Steven P. Rubin, Mark Sanda, Martin G. TI Detection of TMPRSS2-ERG Fusion Gene Expression in Prostate Cancer Specimens by a Novel Assay Using Branched DNA SO UROLOGY LA English DT Article ID OVEREXPRESSION; TRANSCRIPTS AB OBJECTIVES To develop a novel assay that uses branched DNA technology to measure TMPRSS2-ERG fusion, as genetic rearrangement of TMPRSS2 regulatory sequences and coding sequences of the ERG gene has been detected in nearly half of prostate cancers, but quantitative assays to detect Such TMPRSS2-ERG gene fusion have been limited to real-time polymerase chain reaction (PCR) techniques that rely on reverse transcriptase-based amplification. METHODS Branched DNA probes were designed to detect TMPRSS2-ERG gene fusion in prostate cancer cell lines. Nonquantitative nested reverse transcription (RT)-PCR and fluorescence in situ hybridization (FISH) were used to ascertain TMPRSS2-ERG gene fusion status in prostate tissues. RESULTS The branched DNA assay detected TMPRSS2-ERG gene fusion from less than 200 pg of prostate cancer RNA, whereas more than 600 pg of RNA was required for fusion gene detection by one step real-time RT-PCR. In evaluation of clinical prostatectomy specimens, the branched DNA assay showed a concordant detectable fusion signal in all 9 clinical samples that had fusion detected by nested RT-PCR or FISH. Moreover, branched DNA detected gene fusion in 2 of 16 prostate cancer tissue specimens that was not detected by FISH or nested RT-PCR. CONCLUSIONS Our findings demonstrate a branched DNA assay that is effective for detection of TMPRSS2-ERG gene fusion in prostate cancer clinical specimens, thus providing an alternative method to ascertain TMPRSS2-ERG gene fusion in human prostate cancer tissue. UROLOGY 74: 1156-1162, 2009. (C) 2009 Elsevier Inc. C1 [Sanda, Martin G.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Urol, Boston, MA 02115 USA. Affymetrix Inc, Fremont, CA USA. Cornell Univ, Dept Pathol & Lab Med, New York, NY 10021 USA. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. Univ Hosp Ulm, Dept Pathol, Ulm, Germany. RP Sanda, MG (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Urol, Rabb 440,330 Brookline Ave, Boston, MA 02115 USA. EM msanda@bidmc.harvard.edu RI Sanda, Martin/A-6202-2013; Sanda, Martin/B-2023-2015; OI Rubin, Mark/0000-0002-8321-9950 FU NIH-NCI Early Detection Research Network [UO1-CA11391] FX Funded by NIH-NCI Early Detection Research Network Grant UO1-CA11391. NR 22 TC 9 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD NOV PY 2009 VL 74 IS 5 BP 1156 EP 1161 DI 10.1016/j.urology.2009.01.087 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 522IZ UT WOS:000271992400080 PM 19647299 ER PT J AU Johnson, ML Crown, W Martin, BC Dormuth, CR Siebert, U AF Johnson, Michael L. Crown, William Martin, Bradley C. Dormuth, Colin R. Siebert, Uwe TI Good Research Practices for Comparative Effectiveness Research: Analytic Methods to Improve Causal Inference from Nonrandomized Studies of Treatment Effects Using Secondary Data Sources: The ISPOR Good Research Practices for Retrospective Database Analysis Task Force Report-Part III SO VALUE IN HEALTH LA English DT Article DE causal inference; comparative effectiveness; nonrandomized studies; research methods; secondary databases ID MARGINAL STRUCTURAL MODELS; INSTRUMENTAL VARIABLE REGRESSION; PROPENSITY SCORE METHODS; SAMPLE SELECTION; SENSITIVITY-ANALYSIS; HEALTH; OUTCOMES; BIAS; HETEROGENEITY; ADJUSTMENTS AB Objectives: Most contemporary epidemiologic studies require complex analytical methods to adjust for bias and confounding. New methods are constantly being developed, and older more established methods are yet appropriate. Careful application of statistical analysis techniques can improve causal inference of comparative treatment effects from nonrandomized studies using secondary databases. A Task Force was formed to offer a review of the more recent developments in statistical control of confounding. Methods: The Task Force was commissioned and a chair was selected by the ISPOR Board of Directors in October 2007. This Report, the third in this issue of the journal, addressed methods to improve causal inference of treatment effects for nonrandomized studies. Results: The Task Force Report recommends general analytic techniques and specific best practices where consensus is reached including: use of stratification analysis before multivariable modeling, multivariable regression including model performance and diagnostic testing, propensity scoring, instrumental variable, and structural modeling techniques including marginal structural models, where appropriate for secondary data. Sensitivity analyses and discussion of extent of residual confounding are discussed. Conclusions: Valid findings of causal therapeutic benefits can be produced from nonrandomized studies using an array of state-of-the-art analytic techniques. Improving the quality and uniformity of these studies will improve the value to patients, physicians, and policymakers worldwide. C1 [Johnson, Michael L.] Univ Houston, Coll Pharm, Dept Clin Sci & Adm, Houston, TX 77030 USA. [Johnson, Michael L.] Michael E DeBakey VA Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Dept Vet Affairs, Houston, TX USA. [Crown, William] i3 Innovus, Waltham, MA USA. [Martin, Bradley C.] Univ Arkansas Med Sci, Div Pharmaceut Evaluat & Policy, Coll Pharm, Little Rock, AR 72205 USA. [Dormuth, Colin R.] Univ British Columbia, Dept Anesthesiol Pharmacol & Therapeut, Vancouver, BC V5Z 1M9, Canada. [Siebert, Uwe] Univ Hlth Sci Med Informat & Technol, Dept Publ Hlth Informat Syst & Hlth Technol Asses, Hall In Tirol, Austria. [Siebert, Uwe] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Inst Technol Assessment, Boston, MA USA. [Siebert, Uwe] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Siebert, Uwe] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Dormuth, Colin R.] Therapeut Initiat, Pharmacoepidemiol Grp, Vancouver, BC, Canada. RP Johnson, ML (reprint author), Univ Houston, Coll Pharm, Dept Clin Sci & Adm, Houston, TX 77030 USA. EM mikejohnson@uh.edu FU Department of Veteran Affairs [HFP020-90] FX This work was supported in part by the Department of Veteran Affairs Health Services Research and Development grant HFP020-90. The views expressed are those of the authors and do not necessarily reflect the views of the Department of Veteran Affairs. NR 63 TC 92 Z9 94 U1 3 U2 22 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-3015 EI 1524-4733 J9 VALUE HEALTH JI Value Health PD NOV-DEC PY 2009 VL 12 IS 8 BP 1062 EP 1073 DI 10.1111/j.1524-4733.2009.00602.x PG 12 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 515TH UT WOS:000271495300005 PM 19793071 ER PT J AU Chami, HA Keyes, MJ Vita, JA Mitchell, GF Larson, MG Fan, SX Vasan, RS O'Connor, GT Benjamin, EJ Gottlieb, DJ AF Chami, Hassan A. Keyes, Michelle J. Vita, Joseph A. Mitchell, Gary F. Larson, Martin G. Fan, Shuxia Vasan, Ramachandran S. O'Connor, George T. Benjamin, Emelia J. Gottlieb, Daniel J. TI Brachial artery diameter, blood flow and flow-mediated dilation in sleep-disordered breathing SO VASCULAR MEDICINE LA English DT Article DE epidemiology; obstructive sleep apnea; vascular endothelium; vascular remodeling ID POSITIVE AIRWAY PRESSURE; VASCULAR ENDOTHELIAL FUNCTION; HEART HEALTH; CARDIOVASCULAR-DISEASE; SHEAR-STRESS; APNEA; ASSOCIATION; COMMUNITY; ATHEROSCLEROSIS; HYPERTENSION AB Clinic-based, case-control studies linked sleep-disordered breathing (SDB) to markers of endothelial dysfunction. We attempted to validate this association in a large community-based sample, and evaluate the relation of SDB to arterial diameter and peripheral blood flow. This community-based, cross-sectional observational study included 327 men and 355 women, aged 42-83 years, from the Framingham Heart Study site of the Sleep Heart Health Study. The polysomnographically derived apnea-hypopnea index and the hypoxemia index (percent sleep time with oxyhemoglobin saturation below 90%) were used to quantify the severity of SDB. Brachial artery ultrasound measurements included baseline diameter, percent flow-mediated dilation, and baseline and hyperemic flow velocity and volume. The baseline brachial artery diameter was significantly associated with both the apnea-hypopnea index and the hypoxemia index. The association was diminished by adjustment for body mass index, but remained significant for the apnea-hypopnea index. Age-, sex-, race-and body mass index-adjusted mean diameters were 4.32, 4.33, 4.33, 4.56, 4.53 mm for those with apnea-hypopnea index < 1.5, 1.5-4.9, 5-14.9, 15-29.9, = 30, respectively; p = 0.03. Baseline flow measures were associated with the apnea-hypopnea index but this association was non-significant after adjusting for body mass index. No significant association was observed between measures of SDB and percent flow-mediated dilation or hyperemic flow in any model. In conclusion, this study supports a moderate association of SDB and larger baseline brachial artery diameter, which may reflect SDB-induced vascular remodeling. This study does not support a link between SDB and endothelial dysfunction as measured by brachial artery flow-mediated dilation. C1 [Chami, Hassan A.] Boston Univ, Sch Med, Ctr Pulm, Dept Med, Boston, MA 02118 USA. [Chami, Hassan A.; Gottlieb, Daniel J.] VA Boston Healthcare Syst, Boston, MA USA. [Keyes, Michelle J.; Larson, Martin G.] Boston Univ, Sch Publ Hlth, Dept Math & Stat, Boston, MA 02118 USA. [Keyes, Michelle J.; Larson, Martin G.; Fan, Shuxia; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Vita, Joseph A.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02118 USA. RP Chami, HA (reprint author), Boston Univ, Sch Med, Ctr Pulm, Dept Med, 715 Albany St,R-304, Boston, MA 02118 USA. EM hchami@bu.edu OI Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Chami, Hassan/0000-0002-9239-2528; O'Connor, George/0000-0002-6476-3926; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC 25195, HL60040, HL70100, K24-HL-04334]; National Heart, Lung and Blood Institute's Sleep Heart Health Study [U01-HL53941]; Donald W. Reynolds Foundation FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC 25195, HL60040, HL70100, K24-HL-04334(RSV), the National Heart, Lung and Blood Institute's Sleep Heart Health Study U01-HL53941 and the Donald W. Reynolds Foundation. Cardiovascular Engineering provided image capture software. NR 36 TC 17 Z9 17 U1 0 U2 2 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 NOV PY 2009 VL 14 IS 4 BP 351 EP 360 DI 10.1177/1358863X09105132 PG 10 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 503NZ UT WOS:000270544900008 PM 19808720 ER PT J AU Islam, MA Rosenfield, K Maree, AO Patel, PM Jaff, MR AF Islam, M. Ashequl Rosenfield, Kenneth Maree, Andrew O. Patel, Pranav M. Jaff, Michael R. TI Percutaneous revascularization of occluded renal arteries in the setting of acute renal failure SO VASCULAR MEDICINE LA English DT Article DE renal angioplasty; stenting ID ATHEROSCLEROTIC RENOVASCULAR DISEASE; DEPENDENT ISCHEMIC NEPHROPATHY; NATURAL-HISTORY; DIALYSIS; STENOSIS; HYPERTENSION; MANAGEMENT; OCCLUSION; RECANALIZATION; INSUFFICIENCY AB We report the case of a 60-year-old patient with acute renal failure and occluded bilateral renal arteries presenting with acute pulmonary edema and non-ST segment elevation myocardial infarction. The patient required renal replacement therapy with hemodialysis and was subsequently successfully treated with bilateral renal artery stent placement. Marked improvement in renal function was noted within 1 week with freedom from the need for renal replacement therapy at 4 months of follow-up. C1 [Rosenfield, Kenneth; Jaff, Michael R.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Islam, M. Ashequl] Baystate Med Ctr, Div Cardiol, Springfield, MA 01199 USA. [Rosenfield, Kenneth] Massachusetts Gen Hosp, Div Cardiovasc Med, Boston, MA 02114 USA. [Maree, Andrew O.] Boston Univ, Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Patel, Pranav M.] Univ Calif Irvine, Div Cardiol, Irvine, CA USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Vasc Ctr, Boston, MA 02114 USA. RP Jaff, MR (reprint author), Harvard Univ, Sch Med, Boston, MA 02114 USA. EM mjaff@partners.org NR 28 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 NOV PY 2009 VL 14 IS 4 BP 365 EP 369 DI 10.1177/1358863X09103200 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 503NZ UT WOS:000270544900010 PM 19808722 ER PT J AU Zamani, P Kaufman, J Kinlay, S AF Zamani, Payman Kaufman, James Kinlay, Scott TI Ischemic steal syndrome following arm arteriovenous fistula for hemodialysis SO VASCULAR MEDICINE LA English DT Article DE angioplasty; fistula; gangrene; ischemia; peripheral vascular diseases; subclavian artery; vascular fistula ID REVASCULARIZATION-INTERVAL LIGATION; VASCULAR ACCESS; DIALYSIS ACCESS; MONOMELIC NEUROPATHY; HAND ISCHEMIA; LIMB SALVAGE; EXTREMITY; ANGIOACCESS; MAINTENANCE; MANAGEMENT AB Arteriovenous fistulae in the arm are commonly used for hemodialysis in end-stage renal disease. Although physiological steal with reverse flow in the artery distal to the fistula is common, hand ischemia or infarction are rare. The ischemic steal syndrome (hand or forearm ischemia) is usually a result of arterial disease proximal or distal to the fistula and/or poor collateral supply to the hand. The diagnosis is primarily clinical; however, markedly reduced digital pressures and pulse volume recordings support the diagnosis. Management requires imaging for focal stenoses or disease in arteries proximal and distal to the fistula from the aorta to the hand. We present a case caused by subclavian artery occlusion that was initially missed due to focusing investigation only on the fistula. We describe the percutaneous treatments and surgical revisions that attempt to restore flow to the hand without compromising the fistula. C1 [Kinlay, Scott] VA Boston Healthcare Syst, Div Cardiovasc, Cardiac Catheterizat Lab & Vasc Med, W Roxbury, MA 02132 USA. [Zamani, Payman; Kinlay, Scott] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Zamani, Payman; Kinlay, Scott] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Kaufman, James] VA Boston Healthcare Syst, Div Renal, W Roxbury, MA 02132 USA. [Kaufman, James] Boston Univ, Sch Med, Boston, MA 02215 USA. [Kinlay, Scott] VA Boston Healthcare Syst, Div Cardiovasc, W Roxbury, MA 02132 USA. RP Kinlay, S (reprint author), VA Boston Healthcare Syst, Div Cardiovasc, Cardiac Catheterizat Lab & Vasc Med, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM scott.kinlay@va.gov NR 33 TC 11 Z9 13 U1 1 U2 2 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 NOV PY 2009 VL 14 IS 4 BP 371 EP 376 DI 10.1177/1358863X09102293 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 503NZ UT WOS:000270544900011 PM 19808723 ER PT J AU Honings, J Gaissert, HA Ruangchira-Urai, R Wain, JC Wright, CD Mathisen, DJ Mark, EJ AF Honings, Jimmie Gaissert, Henning A. Ruangchira-Urai, Ruchira Wain, John C. Wright, Cameron D. Mathisen, Douglas J. Mark, Eugene J. TI Pathologic characteristics of resected squamous cell carcinoma of the trachea: prognostic factors based on an analysis of 59 cases SO VIRCHOWS ARCHIV LA English DT Article DE Trachea; Squamous cell carcinoma; Airway resection; Pathologic staging; Histologic features of invasion ID TUMORS AB While squamous cell carcinoma (SCC) is the most common tracheal malignancy, few reports describe the pathologic considerations that may guide intraoperative decisions and prognostic assessment. We reviewed 59 tracheal SCC treated between 1985 and 2008 by segmental resection of the trachea, including resection of the carina in 24% and inferior larynx in 14%. We classified these tumors by grading histologic differentiation and microscopic features used in SCC of other sites. Of 59 tumors, 24% (14 of 59) were well differentiated, 49% (29 of 59) were moderately differentiated, and 27% (16 of 59) were poorly differentiated. Unfavorable prognostic factors were tumor extension into the thyroid gland (all of five so-afflicted patients died of tumor progression within 3 years) and lymphatic invasion (mean survival 4.6 versus 7.6 years). Keratinization, dyskeratosis, acantholysis, necrosis, and tumor thickness did not predict prognosis. As surgical resection is the only curative treatment; the surgeon should establish clean lines of resection using, as appropriate, intraoperative frozen section. The pathologist can provide additional important prognostic information, including tumor differentiation and extent, invasion of surgical margins, and extension into the thyroid. C1 [Honings, Jimmie; Gaissert, Henning A.; Wain, John C.; Wright, Cameron D.; Mathisen, Douglas J.] Massachusetts Gen Hosp, Div Thorac Surg, Boston, MA 02114 USA. [Honings, Jimmie; Gaissert, Henning A.; Wain, John C.; Wright, Cameron D.; Mathisen, Douglas J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Ruangchira-Urai, Ruchira; Mark, Eugene J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Gaissert, HA (reprint author), Massachusetts Gen Hosp, Div Thorac Surg, 32 Fruit St,Blake 1570, Boston, MA 02114 USA. EM hgaissert@partners.org RI Honings, Jimmie/B-3639-2016 OI Honings, Jimmie/0000-0001-5077-3472 NR 7 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD NOV PY 2009 VL 455 IS 5 BP 423 EP 429 DI 10.1007/s00428-009-0843-6 PG 7 WC Pathology SC Pathology GA 514RQ UT WOS:000271413100003 PM 19838727 ER PT J AU Butt, MU Velmahos, GC Zacharias, N Alam, HB de Moya, M King, DR AF Butt, Muhammad U. Velmahos, George C. Zacharias, Nikos Alam, Hasan B. de Moya, Marc King, David R. TI Adhesional Small Bowel Obstruction in the Absence of Previous Operations: Management and Outcomes SO WORLD JOURNAL OF SURGERY LA English DT Article ID INTESTINAL-OBSTRUCTION; SURGERY; BAND AB Background The majority of small bowel obstructions (SBO) are the result of adhesions caused by a previous abdominal operation. On rare occasions, adhesional SBO occurs in the absence of such an operation. Our objective was to describe the management, findings, and outcomes of unexplained adhesional SBO (UA-SBO) and examine whether preoperative diagnostic uncertainty leads to delays in therapy and complications. Methods The medical records of all adhesional SBO patients admitted to the Massachusetts General Hospital between January 1, 1997 and December 31, 2007 were screened. UA-SBO records were reviewed in detail. Each UA-SBO patient was matched with an adhesional SBO patient with abdominal surgical history (SH-SBO) according to gender, age (+/- 7 years), white blood cell count (+/- 3000/mm(3)), time interval from the onset of symptoms to the time of admission (+/- 24 h), and year of admission (+/- 4 years). Outcomes included time from admission to operation, morbidity, mortality, and length of hospital stay. Results Of 1,036 patients with adhesional SBO, 34 (3.3%) had UA-SBO. Adhesiolysis was sufficient in 31 patients, whereas 3 required an enterectomy. UA-SBO patients were similar in terms of demographics, clinical presentation, and initial laboratory tests with SH-SBO patients. There was no difference in any of the outcomes between the two groups. Conclusions In this study of UA-SBO, diagnostic delays were not found and patient outcomes were similar to those of patients with SH-SBO. C1 [Butt, Muhammad U.; Velmahos, George C.; Zacharias, Nikos; Alam, Hasan B.; de Moya, Marc; King, David R.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Butt, Muhammad U.; Velmahos, George C.; Zacharias, Nikos; Alam, Hasan B.; de Moya, Marc; King, David R.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Velmahos, GC (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Suite 810, Boston, MA 02114 USA. EM gvelmahos@partners.org OI King, David/0000-0003-1028-1478 NR 10 TC 5 Z9 6 U1 0 U2 0 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 NOV PY 2009 VL 33 IS 11 BP 2368 EP 2371 DI 10.1007/s00268-009-0200-6 PG 4 WC Surgery SC Surgery GA 505HE UT WOS:000270682200016 PM 19756860 ER PT J AU Nellore, A Fishman, J AF Nellore, Anoma Fishman, Jay TI Pandemic Swine Flu 2009 SO XENOTRANSPLANTATION LA English DT Editorial Material ID INFLUENZA-A VIRUSES; TRANSPLANT RECIPIENTS; VACCINATION; RESPONSES; PIGS C1 [Nellore, Anoma; Fishman, Jay] Massachusetts Gen Hosp, Transplant Infect Dis Program, Boston, MA 02114 USA. RP Nellore, A (reprint author), Massachusetts Gen Hosp, Transplant Infect Dis Program, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM jfishman@partners.org NR 21 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD NOV-DEC PY 2009 VL 16 IS 6 BP 463 EP 465 DI 10.1111/j.1399-3089.2009.00559.x PG 3 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 535YH UT WOS:000273007400001 PM 20042043 ER PT J AU Schuetz, C Lee, KM Eliades, P Machaidze, Z Tokiya, A Bautista, P Yagi, Y Deng, SP Markmann, JF AF Schuetz, Christian Lee, Kang Mi Eliades, Philip Machaidze, Zurab Tokiya, Abe Bautista, Pinky Yagi, Yukako Deng, Shaoping Markmann, James F. TI Diabetogenic immunosuppression: effects of drugs commonly used in islet transplantation SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the International-Pancreas-and-Islet-Transplant-Association/International-Xe notransplanation-Association CY OCT 12-16, 2009 CL Venice, ITALY SP Absorber AB, Astellas Pharma, Biorep Technol, Biotest Italia SRL, Natl Transplant Ctr, Covidien, Daibetes Wellness & Res Fdn, Ethicon, Fond L Incremento Trapianti Organo E Di Tessuti, Genzyne Transplant Europe, GTI ITALIA SRL, Johnson & Johnson Med, Juvenile Diabetes Res Fdn, Lagitre s r l, Novartis, One Lambda Inc, Prodo Lab, Roche, Serva Electrophores GMBH, SRT Transplantat Reg Syst, Storz Med, Trumpf MRD Italia, VitaCyte LLC, Wisepress, Wyeth Italia, Zaccanti SPA C1 Massachusetts Gen Hosp, Transplant Surg Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RI Schuetz, Christian/K-5234-2013 OI Schuetz, Christian/0000-0002-6828-4543 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD NOV-DEC PY 2009 VL 16 IS 6 BP 541 EP 542 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 535YH UT WOS:000273007400014 ER PT J AU Wong, J Sibani, S Lokko, NN LaBaer, J Anderson, KS AF Wong, Jessica Sibani, Sahar Lokko, Naa Norkor LaBaer, Joshua Anderson, Karen S. TI Rapid detection of antibodies in sera using multiplexed self-assembling bead arrays SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Autoantibodies; Tumor antigen; Biomarker; Luminex; Multiplex immunoassay; EBV ID EPSTEIN-BARR-VIRUS; PROTEIN MICROARRAYS; BREAST-CANCER; NEUTRALIZING EPITOPES; IMMUNOLOGICAL STATUS; RESPONSES; ASSAY; IMMUNOASSAY; OPTIMIZATION; DIAGNOSIS AB Rapid detection of antibody immunity in serum or plasma, whether to pathogenic antigens, tumor antigens, or autoimmune antigens, is critical for diagnosis, monitoring, and biomarker assessment of the immune response. Individual or multiplexed ELISAs that use purified recombinant proteins are dependent on a prior! protein purification, a labor-intensive process that may take months to obtain proteins of sufficient purity and stability for serologic assays. We developed a programmable multiplexed immunoassay for the rapid monitoring of humoral immunity using the Luminex suspension bead array platform. In this approach, epitope-tagged antigens (GST- or FLAG-tagged) are expressed using in vitro transcription and translation, and captured onto anti-epitope-coupled Luminex SeroMap beads. The antigen-loaded beads are mixed, serum is added, and human IgG is detected with standard secondary detection reagents. By coupling high-throughput DNA preparation of cDNA ORFs with antigen expression/capture, we demonstrate that 71/72 (98.6%) of GST-tagged proteins can be expressed and specifically detected on the bead ELISA. Detection of antibodies to the test viral antigen EBNA-I in human sera is highly reproducible, with intra-assay variation of 3-8%, inter-assay variation of 5%, and with stability over I I months. The specificity and limits of detection of the bead ELISAs for the tumor antigen p53 are comparable to both standard protein ELISAs and plate-based programmable (RAPID) ELISAs, and are also comparable to the detection of directly-conjugated p53 protein. Multiplexing a panel of analytes does not impair the sensitivity of antibody detection. Immunity to a panel of EBV-derived antigens (EBNA-1, EBNA-3A, EBNA-3B, and LMP-2) is specifically and differentially detected within healthy donor sera. This method allows for rapid conversion of ORFeome-derived cDNAs to a multiplexed bead ELISA to detect antibody immunity to both infectious and tumor antigens. (C) 2009 Elsevier B.V. All rights reserved. C1 [Wong, Jessica; Lokko, Naa Norkor; Anderson, Karen S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, Boston, MA 02115 USA. [Sibani, Sahar; LaBaer, Joshua] Harvard Univ, Sch Med, Harvard Inst Prote, Cambridge, MA 02138 USA. [Anderson, Karen S.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. RP Anderson, KS (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Canc Vaccine Ctr, HIM416,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM kanderson@partners.org FU NCI Early Detection Research Network [5U01CA117374-02] FX We thank Dr. Niroshan Ramachandran for assistance in setting up the Luminex system. This study was supported by a research grant from the NCI Early Detection Research Network 5U01CA117374-02. NR 30 TC 36 Z9 37 U1 0 U2 18 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD OCT 31 PY 2009 VL 350 IS 1-2 BP 171 EP 182 DI 10.1016/j.jim.2009.08.013 PG 12 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 519JA UT WOS:000271761100020 PM 19732778 ER PT J AU Kotagal, M Lee, P Habiyakare, C Dusabe, R Kanama, P Epino, HM Rich, ML Farmer, PE AF Kotagal, Meera Lee, Patrick Habiyakare, Caste Dusabe, Raymond Kanama, Philibert Epino, Henry M. Rich, Michael L. Farmer, Paul E. TI Quality Improvement Report Improving quality in resource poor settings: observational study from rural Rwanda SO BRITISH MEDICAL JOURNAL LA English DT Article ID HEALTH; PROGRAM AB Problem Hospitals in rural Africa, such as in Rwanda, often lack electricity, supplies, and staff. In our setting, basic care processes, such monitoring vital signs, giving drugs, and laboratory testing, were performed unreliably, resulting in delays in treatment owing to lack of information needed for clinical decision making. Design Simple quality improvement tools, including plan-do-study-act cycles and process maps, were used to improve system level processes in a stepwise fashion; resources were augmented where necessary. Setting 50 bed district hospital in rural Rwanda. Measurement of improvement Three key indicators ( percentage of vital signs taken by 9 am, drugs given as prescribed, and laboratory tests performed and documented) were tracked daily. Data were collected from a random sample of 25 charts from six inpatient wards. Strategy for change Our intervention had two components: staff education on quality improvement and routine care processes, and stepwise implementation of system level interventions. Real time performance data were reported to staff daily, with a goal of 95% performance for each indicator within two weeks. A Rwandan quality improvement team was trained to run the hospital's quality improvement initiatives. Effects of changes Within two weeks, all indicators achieved the 95% goal. The data for the three objectives were analysed by using time series analysis. Progress was compared against time by using run chart rules for statistical significance of improvement, showing significant improvement for all indicators. Doctors and nurses subjectively reported improved patient care and higher staff morale. Lessons learnt Four lessons are highlighted: making data visible and using them to inform subsequent interventions can promote change in resource poor settings; improvements can be made in advance of resource inputs, but sustained change in resource poor settings requires additional resources; local leadership is essential for success; and early successes were crucial for encouraging staff and motivating buy-in. C1 [Kotagal, Meera; Lee, Patrick; Epino, Henry M.; Farmer, Paul E.] Partners Hlth, Boston, MA 02215 USA. [Farmer, Paul E.] Harvard Univ, Sch Med, Dept Global Hlth & Social Med, Boston, MA 02115 USA. [Lee, Patrick] Newton Wellesley Hosp, Newton, MA 02462 USA. [Habiyakare, Caste; Dusabe, Raymond; Kanama, Philibert] Partners Hlth, Rwanda Minist Hlth, Kirehe Dist Hosp, Kigali, Rwanda. [Epino, Henry M.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Farmer, Paul E.] Brigham & Womens Hosp, Div Global Hlth Equ, Boston, MA 02115 USA. RP Kotagal, M (reprint author), Univ Washington, Dept Surg, Box 356410, Seattle, WA 98195 USA. EM mkotagal@post.harvard.edu FU Harvard University Committee on General Scholarships; Sinclair Kennedy travelling fellowship FX Harvard University Committee on General Scholarships; MK received a Sinclair Kennedy travelling fellowship. NR 20 TC 14 Z9 14 U1 1 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD OCT 30 PY 2009 VL 339 AR b3488 DI 10.1136/bmj.b3488 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 514AQ UT WOS:000271366100001 PM 19880528 ER PT J AU Srinivasan, L Sasaki, Y Calado, DP Zhang, BC Paik, JH DePinho, RA Kutok, JL Kearney, JF Otipoby, KL Rajewsky, K AF Srinivasan, Lakshmi Sasaki, Yoshiteru Calado, Dinis Pedro Zhang, Baochun Paik, Ji Hye DePinho, Ronald A. Kutok, Jeffrey L. Kearney, John F. Otipoby, Kevin L. Rajewsky, Klaus TI PI3 Kinase Signals BCR-Dependent Mature B Cell Survival SO CELL LA English DT Article ID NF-KAPPA-B; FOXO TRANSCRIPTION FACTORS; CLASS-SWITCH RECOMBINATION; ANTIGEN RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; MARGINAL ZONE; POSITIVE SELECTION; CRITICAL ROLES; LYMPHOCYTES; ACTIVATION AB Previous work has shown that mature B cells depend upon survival signals delivered to the cells by their antigen receptor (BCR). To identify the molecular nature of this survival signal, we have developed a genetic approach in which ablation of the BCR is combined with the activation of specific, BCR dependent signaling cascades in mature B cells in vivo. Using this system, we provide evidence that the survival of BCR deficient mature B cells can be rescued by a single signaling pathway downstream of the BCR, namely PI3K signaling, with the FOXO1 transcription factor playing a central role. C1 [Srinivasan, Lakshmi; Sasaki, Yoshiteru; Calado, Dinis Pedro; Zhang, Baochun; Otipoby, Kevin L.; Rajewsky, Klaus] Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Srinivasan, Lakshmi; Sasaki, Yoshiteru; Calado, Dinis Pedro; Zhang, Baochun; Otipoby, Kevin L.; Rajewsky, Klaus] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA. [Paik, Ji Hye; DePinho, Ronald A.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kutok, Jeffrey L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Kearney, John F.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. RP Rajewsky, K (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. EM rajewsky@idi.harvard.edu OI Zhang, Baochun/0000-0003-1759-1161 FU NIH [AI054636, CA092625, AI014782-31]; Leukemia and Lymphoma Society; European Union through MUGEN; Hematology and Transfusion Medicine at Harvard Medical School; Portuguese Foundation for Science and Technology; Robert A. and Renee E. Belfer Foundation FX We thank D. Ghitza, A. Pellerin, A. Monti, A. Tetreault, J. Grundy, J. Wang, J. Xia and W. F. Jia for expert technical assistance; E. Derudder for reagents; all Rajewsky lab members for discussions; and M. Janz for critical reading of the manuscript; A. Klippel for the MP110* cDNA; and K. Kaibuchi for Rac1DA cDNA. K. R. is supported by NIH grants AI054636 and CA092625, the Leukemia and Lymphoma Society and the European Union through MUGEN; L. S. by the T32 training grant of the Joint Program in Hematology and Transfusion Medicine at Harvard Medical School; J. F. K. by NIH grant AI014782-31; D. P. C. by a postdoctoral fellowship from the Portuguese Foundation for Science and Technology (FCT-MCES); B. Z. by a postdoctoral fellowship of the Leukemia and Lymphoma Society; and RAD by the NIH and the Robert A. and Renee E. Belfer Foundation. NR 58 TC 271 Z9 276 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 30 PY 2009 VL 139 IS 3 BP 573 EP 586 DI 10.1016/j.cell.2009.08.041 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 512ON UT WOS:000271259600021 PM 19879843 ER PT J AU Palijan, A Fernandes, I Bastien, Y Tang, LQ Verway, M Kourelis, M Tavera-Mendoza, LE Li, Z Bourdeau, V Mader, S Yang, XJ White, JH AF Palijan, Ana Fernandes, Isabelle Bastien, Yolande Tang, Liqun Verway, Mark Kourelis, Maria Tavera-Mendoza, Luz E. Li, Zhi Bourdeau, Veronique Mader, Sylvie Yang, Xiang Jiao White, John H. TI Function of Histone Deacetylase 6 as a Cofactor of Nuclear Receptor Coregulator LCoR SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; TRANSCRIPTIONAL REPRESSION; HORMONE-RECEPTORS; GENE-EXPRESSION; CO-REPRESSOR; N-COR; COREPRESSOR; RECRUITMENT; HDAC6; ALPHA AB Ligand-dependent corepressor LCoR was identified as a protein that interacts with the estrogen receptor alpha(ER alpha) ligand binding domain in a hormone-dependent manner. LCoR also interacts directly with histone deacetylase 3 (HDAC3) and HDAC6. Notably, HDAC6 has emerged as a marker of breast cancer prognosis. However, although HDAC3 is nuclear, HDAC6 is cytoplasmic in many cells. We found that HDAC6 is partially nuclear in estrogen-responsive MCF7 cells, colocalizes with LCoR, represses transactivation of estrogen- inducible reporter genes, and augments corepression by LCoR. In contrast, no repression was observed upon HDAC6 expression in COS7 cells, where it is exclusively cytoplasmic. LCoR binds to HDAC6 in vitro via a central domain, and repression by LCoR mutants lacking this domain was attenuated. Kinetic chromatin immunoprecipitation assays revealed hormone-dependent recruitment of LCoR to promoters of ER alpha-induced target genes in synchrony with ER alpha. HDAC6 was also recruited to these promoters, and repeat chromatin immunoprecipitation experiments confirmed the corecruitment of LCoR with ER alpha and with HDAC6. Remarkably, however, although we find evidence for corecruitment of LCoR and ER alpha on genes repressed by the receptor, LCoR and HDAC6 failed to coimmunoprecipitate, suggesting that they are part of distinct complexes on these genes. Although small interfering RNA-mediated knockdown of LCoR or HDAC6 augmented expression of an estrogen-sensitive reporter gene in MCF7 cells, unexpectedly their ablation led to reduced expression of some endogenous estrogen target genes. Taken together, these data establish that HDAC6 can function as a cofactor of LCoR but suggest that they may act in enhance expressing some target genes. C1 [Palijan, Ana; Fernandes, Isabelle; Bastien, Yolande; Tang, Liqun; Verway, Mark; Kourelis, Maria; Li, Zhi; White, John H.] McGill Univ, Dept Physiol, Montreal, PQ H3G 1Y6, Canada. [Yang, Xiang Jiao; White, John H.] McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada. [Tavera-Mendoza, Luz E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. [Bourdeau, Veronique; Mader, Sylvie] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada. [Bourdeau, Veronique; Mader, Sylvie] Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada. RP White, JH (reprint author), McGill Univ, Dept Physiol, 3655 Drummond St, Montreal, PQ H3G Y6, Canada. EM john.white@mcgill.ca OI White, John/0000-0002-4785-2687 FU Canadian Institutes of Health [MT-11704]; Canadian Cancer Society [018362] FX This work was supported by Canadian Institutes of Health Research Grant MT-11704 ( to J.H.W.) and a grant from the Canadian Cancer Society (018362 to X.J.Y.). NR 52 TC 26 Z9 28 U1 2 U2 7 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 OCT 30 PY 2009 VL 284 IS 44 BP 30264 EP 30274 DI 10.1074/jbc.M109.045526 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 510LM UT WOS:000271090000030 PM 19744931 ER PT J AU Palijan, A Fernandes, I Verway, M Kourelis, M Bastien, Y Tavera-Mendoza, LE Sacheli, A Bourdeau, V Mader, S White, JH AF Palijan, Ana Fernandes, Isabelle Verway, Mark Kourelis, Maria Bastien, Yolande Tavera-Mendoza, Luz E. Sacheli, Aaron Bourdeau, Veronique Mader, Sylvie White, John H. TI Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TERMINAL BINDING-PROTEIN; RECEPTOR-INTERACTING PROTEIN; BOUND NUCLEAR RECEPTORS; TRANSCRIPTIONAL COREPRESSOR; PIPSQUEAK PROTEIN; STEROID-HORMONES; TARGET GENES; CANCER-CELLS; ESTROGEN; CTBP AB Ligand-dependent corepressor LCoR interacts with the progesterone receptor (PR) and estrogen receptor ER alpha in the presence of hormone. LCoR contains tandem N-terminal PXDLS motifs that recruit C-terminal-binding protein (CtBP) corepressors as well as a C-terminal helix-turn-helix (HTH) domain. Here, we analyzed the function of these domains in coregulation of PR- and ER alpha-regulated gene expression. LCoR and CtBP1 colocalize in nuclear bodies that also contain CtBP-interacting protein CtIP and polycomb group repressor complex marker BMI1. Coexpression of CtBP1 in MCF7 or T47D breast cancer cells augmented corepression by LCoR, whereas coexpression of CtIP did not, consistent with direct interaction of LCoR with CtBP1, but not CtIP. The N-terminal region containing the PXDLS motifs is necessary and sufficient for CTBP1 recruitment and essential for full corepression. However, LCoR function was also strongly dependent on the helix-turn-helix domain, as its deletion completely abolished corepression. LCoR, CtBP, and CtIP were recruited to endogenous PR- and ER alpha-stimulated genes in a hormone-dependent manner. Similarly, LCoR was recruited to estrogen-repressed genes, whereas hormone treatment reduced CtBP1 binding. Small interfering RNA-mediated knockdown of LCoR or CtBP1 augmented expression of progesterone- and estrogen-stimulated reporter genes as well as endogenous progesterone- stimulated target genes. In contrast, their ablation had gene-specific effects on ER alpha-regulated transcription that generally led to reduced gene expression. Taken together, these results show that multiple domains contribute to LCoR function. They also reveal a role for LCoR and CtBP1 as attenuators of progesterone-regulated transcription but suggest that LCoR and CtBP1 can act to enhance transcription of some genes. C1 [Palijan, Ana; Fernandes, Isabelle; Verway, Mark; Kourelis, Maria; Bastien, Yolande; Sacheli, Aaron; White, John H.] McGill Univ, Dept Physiol, Montreal, PQ H3G 1Y6, Canada. [White, John H.] McGill Univ, Dept Med, Montreal, PQ H3G 1Y6, Canada. [Tavera-Mendoza, Luz E.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. [Bourdeau, Veronique; Mader, Sylvie] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada. [Bourdeau, Veronique; Mader, Sylvie] Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada. RP White, JH (reprint author), McGill Univ, Dept Physiol, 3655 Drummond St, Montreal, PQ H3G 1Y6, Canada. EM john.white@mcgill.ca OI White, John/0000-0002-4785-2687 FU Canadian Institutes of Health [MT-11704] FX This work was supported by Canadian Institutes of Health Research Grant MT-11704 (to J. H. W.). NR 54 TC 14 Z9 14 U1 1 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 30 PY 2009 VL 284 IS 44 BP 30275 EP 30287 DI 10.1074/jbc.M109.051201 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 510LM UT WOS:000271090000031 PM 19744932 ER PT J AU Zhuang, J Jiang, GC Willers, H Xia, F AF Zhuang, Jing Jiang, Guochun Willers, Henning Xia, Fen TI Exonuclease Function of Human Mre11 Promotes Deletional Nonhomologous End Joining SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STRAND-BREAK REPAIR; DEPENDENT PROTEIN-KINASE; DNA END; CELL-CYCLE; HOMOLOGOUS RECOMBINATION; CHECKPOINT CONTROL; MAMMALIAN-CELLS; COMPLEX; MECHANISMS; NUCLEASE AB DNAdouble-stranded breaks (DSBs) are lethal if not repaired and are highly mutagenic if misrepaired. Nonhomologous end joining (NHEJ) is one of the major DSB repair pathways and can rejoin the DSB ends either precisely or with mistakes. Recent evidence suggests the existence of two NHEJ subpathways: conservative NHEJ (C-NHEJ), which does not require microhomology and can join ends precisely; and deletional NHEJ (D-NHEJ), which utilizes microhomology to join the ends with small deletions. Little is known about how these NHEJ subpathways are regulated. Mre11 has been implicated in DNA damage response, thus we investigated whether Mre11 function also extended to NHEJ. We utilized an intrachromosomal NHEJ substrate in which DSBs are generated by the I-SceI to address this question. The cohesive ends are fully complementary and were either repaired by C-NHEJ or D-NHEJ with similar efficiency. We found that disruption of Mre11 by RNA interference in human cells led to a 10-fold decrease in the frequency of D-NHEJ compared with cells with functional Mre11. Interestingly, C-NHEJ was not affected by Mre11 status. Expression of wild type but not exonuclease-defective Mre11 mutants was able to rescue D-NHEJ in Mre11-deficient cells. Further mutational analysis suggested that additional mechanisms associated with methylation of Mre11 at the C-terminal glycine-arginine-rich domain contributed to the promotion of D-NHEJ by Mre11. This study provides new insights into the mechanisms by which Mre11 affects the accuracy of DSB end joining specifically through control of the D-NHEJ subpathway, thus illustrating the complexity of the Mre11 role in maintaining genomic stability. C1 [Zhuang, Jing; Jiang, Guochun; Xia, Fen] Vanderbilt Univ, Dept Radiat Oncol, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Zhuang, Jing; Jiang, Guochun; Xia, Fen] Vanderbilt Univ, Dept Canc Biol, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. [Willers, Henning] Massachusetts Gen Hosp, Lab Cellular & Mol Radiat Oncol, Ctr Canc, Boston, MA 02114 USA. RP Xia, F (reprint author), Vanderbilt Univ, Dept Radiat Oncol, Med Ctr, Nashville, TN 37232 USA. EM fen.xia@vanderbilt.edu RI Xia, Fen/G-3708-2013 FU National Institutes of Health [R01 CA118158-02] FX This work was supported, in whole or in part, by National Institutes of Health Grant R01 CA118158-02 ( to F. X.). NR 47 TC 37 Z9 38 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 30 PY 2009 VL 284 IS 44 BP 30565 EP 30573 DI 10.1074/jbc.M109.059444 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 510LM UT WOS:000271090000059 PM 19744924 ER PT J AU De Rosa, L Antonini, D Ferone, G Russo, MT Yu, PB Han, R Missero, C AF De Rosa, Laura Antonini, Dario Ferone, Giustina Russo, Monia T. Yu, Paul B. Han, Rong Missero, Caterina TI p63 Suppresses Non-epidermal Lineage Markers in a Bone Morphogenetic Protein-dependent Manner via Repression of Smad7 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OSTEOGENIC PROTEIN-1; HAIR FOLLICLE; SIGNALING PATHWAYS; GENE-EXPRESSION; I RECEPTORS; P53 HOMOLOG; STEM-CELLS; MOUSE; DIFFERENTIATION; TARGET AB p63, a p53 family member, plays an essential role in epidermal development by regulating its transcriptional program. Here we report a previously uncovered role of p63 in controlling bone morphogenetic protein (BMP) signaling, which is required for maintaining low expression levels of several non-epidermal genes. p63 represses transcription of the inhibitory Smad7 and activates Bmp7, thereby sustaining BMP signaling. In the absence of p63, compromised BMP signaling leads to inappropriate non-epidermal gene expression in postnatal mouse keratinocytes and in embryonic epidermis. Reactivation of BMP signaling by Smad7 knockdown and/or, to a lesser extent, by BMP treatment suppresses expression of non-epidermal genes in the absence of p63. Canonical BMP/Smad signaling is essential for control of non-epidermal genes as use of a specific inhibitor, or simultaneous knockdown of Smad1 and Smad5 counteract suppression of non-epidermal genes. Our data indicate that p63 prevents ectopic expression of non-epidermal genes by a mechanism involving Smad7 repression and, to a lesser extent, Bmp7 induction, with consequent enhancement of BMP/Smad signaling. C1 [De Rosa, Laura; Antonini, Dario; Ferone, Giustina; Russo, Monia T.; Missero, Caterina] CEINGE Biotecnol Avanzate, I-80145 Naples, Italy. [De Rosa, Laura; Missero, Caterina] IRCCS Fdn SDN, I-80143 Naples, Italy. [Yu, Paul B.] Harvard Univ, Div Cardiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Han, Rong] Harvard Univ, Cutaneous Biol Res Ctr, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. RP Missero, C (reprint author), CEINGE Biotecnol Avanzate, Via Comunale Margherita 482, I-80145 Naples, Italy. EM missero@ceinge.unina.it RI russo, monia /Q-5774-2016; De Rosa, Laura/H-7504-2015; OI russo, monia /0000-0003-2001-5384; Han, Rong/0000-0002-5766-8277; De Rosa, Laura/0000-0001-9020-8451; Missero, Caterina/0000-0003-0905-5123; Yu, Paul/0000-0003-2145-4944 FU Italian Telethon Foundation [GGP06243]; National Foundation for Ectodermal Dysplasia FX This work was supported in part by Italian Telethon Foundation Grant GGP06243 and the National Foundation for Ectodermal Dysplasia. NR 54 TC 20 Z9 20 U1 2 U2 4 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 OCT 30 PY 2009 VL 284 IS 44 BP 30574 EP 30582 DI 10.1074/jbc.M109.049619 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 510LM UT WOS:000271090000060 PM 19717565 ER PT J AU Kuter, DJ Mufti, GJ Bain, BJ Hasserjian, RP Davis, W Rutstein, M AF Kuter, David J. Mufti, Ghulam J. Bain, Barbara J. Hasserjian, Robert P. Davis, Wende Rutstein, Mark TI Evaluation of bone marrow reticulin formation in chronic immune thrombocytopenia patients treated with romiplostim SO BLOOD LA English DT Article ID FAMILIAL ESSENTIAL THROMBOCYTHEMIA; LONG-TERM TREATMENT; PURPURA ITP; IN-VITRO; THROMBOPOIETIN GENE; OPEN-LABEL; MICE; GROWTH; MEGAKARYOCYTES; MYELOFIBROSIS AB Romiplostim is a thrombopoietin receptor agonist that increases platelet counts in patients with chronic immune thrombocytopenia (ITP). Thrombopoietin receptor agonists are reported to increase the risk for reticulin fiber deposition within bone marrow. This report describes bone marrow findings from romiplostim-treated rats, a retrospective analysis of reticulin observed in romiplostim ITP clinical trials, and a prospective clinical study of the effects of romiplostim on bone marrow morphology. In rats, romiplostim produced a dose-dependent increase in bone marrow fibrosis that resolved after treatment withdrawal. Of 271 ITP patients in romiplostim clinical trials, 10 were reported to have reticulin deposition; reticulin grade was increased in 4 of 5 patients with both pretreatment and on-treatment bone marrow results. Reticulin grade often decreased soon after romiplostim discontinuation. In the prospective study, reticulin grade during romiplostim treatment remained within the normal range for all patients and was increased in only 1 of 6 patients with pretreatment and on-treatment bone marrow results. This report suggests that romiplostim produces reversible, dose-dependent bone marrow changes in rats and produces modest increases in bone marrow reticulin in some ITP patients that decrease when therapy is discontinued. These studies were registered at www.clinicaltrials.gov as # NCT00102323, # NCT00102336, # NCT00861224, and # NCT00116688. (Blood. 2009; 114: 3748-3756) C1 [Kuter, David J.; Hasserjian, Robert P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mufti, Ghulam J.] Kings Coll Hosp, London, England. [Bain, Barbara J.] St Marys Hosp, London, England. [Davis, Wende; Rutstein, Mark] Amgen Inc, Thousand Oaks, CA 91320 USA. RP Kuter, DJ (reprint author), Massachusetts Gen Hosp, 55 Fruit St, Boston, MA 02114 USA. EM kuter.david@MGH.harvard.edu FU Amgen Inc. FX This work was supported by Amgen Inc. In collaboration with the investigators, Amgen designed the studies and conducted statistical analyses. Writing assistance was provided by Amy Lindsay, who was funded by Amgen Inc. Animal pathology specimens were analyzed by Margarita Gruebbel, Experimental Pathology Laboratories Inc. NR 44 TC 84 Z9 88 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 29 PY 2009 VL 114 IS 18 BP 3748 EP 3756 DI 10.1182/blood-2009-05-224766 PG 9 WC Hematology SC Hematology GA 512RO UT WOS:000271268100008 PM 19671919 ER PT J AU van der Linden, MH Valsecchi, MG De Lorenzo, P Moricke, A Janka, G Leblanc, TM Felice, M Biondi, A Campbell, M Hann, I Rubnitz, JE Stary, J Szczepanski, T Vora, A Ferster, A Hovi, L Silverman, LB Pieters, R AF van der Linden, Marieke H. Valsecchi, Maria Grazia De Lorenzo, Paola Moericke, Anja Janka, Gritta Leblanc, Thierry M. Felice, Maria Biondi, Andrea Campbell, Myriam Hann, Ian Rubnitz, Jeffrey E. Stary, Jan Szczepanski, Tomasz Vora, Ajay Ferster, Alina Hovi, Liisa Silverman, Lewis B. Pieters, Rob TI Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol SO BLOOD LA English DT Article ID ONCOLOGY-GROUP; PROGNOSTIC-FACTORS; INFANTS; EXPERIENCE; THERAPY; TRIAL AB Acute lymphoblastic leukemia (ALL) diagnosed in the first month of life (congenital ALL) is very rare. Although congenital ALL is often assumed to be fatal, no studies have been published on outcome except for case reports. The present study reports the outcome of 30 patients with congenital ALL treated with the uniform Interfant-99 protocol, a hybrid regimen combining ALL treatment with elements designed for treatment of acute myeloid leukemia. Congenital ALL was characterized by a higher white blood cell count and a strong trend for higher incidence of MLL rearrangements and CD10-negative B-lineage ALL compared with older infants. Induction failure rate was 13% and not significantly different from that in older infants (7%, P = .14), but relapse rate was significantly higher in congenital ALL patients (2-year cumulative incidence [SE] was 60.0 [9.3] vs 34.2 [2.3], P < .001). Two-year event-free survival and survival of congenital ALL patients treated with this protocol was 20% (SE 9.1%). Early death in complete remission and treatment delays resulting from toxicity were not different. The survival of 17% after last follow-up, combined with a toxicity profile comparable with that in older infants, justifies treating congenital ALL with curative intent. This trial was registered at www.clinicaltrials.gov as no. NCT 00015873, and at www.controlled-trials.com as no. ISRCTN24251487. (Blood. 2009; 114: 3764-3768) C1 [Pieters, Rob] Erasmus MC Sophia Childrens Hosp, Dept Paediat Oncol & Haematol, NL-3015 GJ Rotterdam, Netherlands. [Valsecchi, Maria Grazia; De Lorenzo, Paola] Univ Milano Bicocca, Dept Clin Med & Prevent, Milan, Italy. [Moericke, Anja] Univ Med Ctr Schleswig Holstein, Kiel, Germany. [Janka, Gritta] Univ Hosp Hamburg Eppendorf, Cooperat Study Grp Treatment ALL, Hamburg, Germany. [Leblanc, Thierry M.] Hop St Louis, French ALL Grp, Paris, France. [Felice, Maria] Argentina Hosp Pediat, Buenos Aires, DF, Argentina. [Biondi, Andrea] Univ Milano Bicocca, Assoc Italiana Ematol Oncol Pediat, Monza, Italy. [Campbell, Myriam] Hosp Roberto Del Rio, Programa Infantil Nacl Drogas Antineplasicas, Santiago, Chile. [Hann, Ian] Great Ormond St Hosp Sick Children, UK Childrens Canc Study Grp, London WC1N 3JH, England. [Rubnitz, Jeffrey E.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Stary, Jan] Charles Univ Prague, Czech Paediat Haematol, Univ Hosp Motol, Prague, Czech Republic. [Stary, Jan] Charles Univ Prague, Sch Med 2, Prague, Czech Republic. [Szczepanski, Tomasz] Med Univ Silesia, Polish Paediat Leukemia & Lymphoma Study Grp, Zabrze, Poland. [Vora, Ajay] Sheffield Childrens Hosp, Sheffield, S Yorkshire, England. [Ferster, Alina] Hop Univ Enfants Reine Fabiola, Childrens Leukemia Grp, Brussels, Belgium. [Hovi, Liisa] Univ Helsinki, Nord Soc Paediat Haematol & Oncol, Helsinki, Finland. [Silverman, Lewis B.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Pieters, Rob] Dutch Childhood Oncol Grp, The Hague, Netherlands. RP Pieters, R (reprint author), Erasmus MC Sophia Childrens Hosp, Dept Paediat Oncol & Haematol, Dr Molewaterpl 60, NL-3015 GJ Rotterdam, Netherlands. EM rob.pieters@erasmusmc.nl FU KiKa; Associazione Italiana Ricerca sul Cancro Regional [Cod 1105]; Fondazione Tettamanti and Comitato MM Verga; Polish Ministry of Science and Higher Education [2 P054 095 30]; Czech Ministry of Education [MSM0021620813]; Deutsche Krebshilfe FX M. H. v. d. L. is supported by KiKa. The many participating institutes of all study groups are acknowledged for their support. This study in Associazione Italiana Ematologia Oncologia Pediatrica is partially supported by Associazione Italiana Ricerca sul Cancro Regional Grant Cod 1105 (to A. B. and M. G. V.). The international study operating center was partially supported by Fondazione Tettamanti and Comitato MM Verga (to M. G. V. and P. D. L.). T. S. was supported by the Polish Ministry of Science and Higher Education (grant 2 P054 095 30). Czech Paediatric Haematology was supported by the Czech Ministry of Education (grant MSM0021620813). Berlin-Frankfurt-Munster Germany was supported by Deutsche Krebshilfe. NR 20 TC 32 Z9 33 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 29 PY 2009 VL 114 IS 18 BP 3764 EP 3768 DI 10.1182/blood-2009-02-204214 PG 5 WC Hematology SC Hematology GA 512RO UT WOS:000271268100010 PM 19657114 ER PT J AU Beekman, JM Verhagen, LP Geijsen, N Coffer, PJ AF Beekman, Jeffrey M. Verhagen, Liesbeth P. Geijsen, Niels Coffer, Paul J. TI Regulation of myelopoiesis through syntenin-mediated modulation of IL-5 receptor output SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; EOSINOPHIL DIFFERENTIATION; FUNCTIONAL-PROPERTIES; SIGNAL-TRANSDUCTION; CYTOKINE RECEPTORS; CRYSTAL-STRUCTURE; CELL-DEVELOPMENT; BONE-MARROW; PDZ TANDEM; B-1 CELLS AB The granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin (IL)-3/IL-5 receptor family regulates the production and function of myeloid cells. These cytokines signal through receptor complexes that consist of unique ligand-binding alpha-chains and common signaling beta-chains. IL-5 is distinct from IL-3 and GM-CSF in its capacity to induce eosinophil development, however, the molecular mechanisms that generate functional diversity within this receptor family are mostly unknown. Here, we characterized the selective IL-5R alpha-binding adapter protein syntenin in IL-5R function. Syntenin and IL-5R alpha colocalize at the plasma membrane and in early endosomal compartments. Manipulation of syntenin expression by ectopic expression or knockdown selectively modulated IL-5R but not GM-CSF receptor signaling, and severely affected IL-5-induced eosinophil differentiation from primary human CD34(+) hematopoietic progenitor cells. We found syntenin upregulated during eosinophilopoiesis but down-regulated during neutropoiesis. Syntenin forms complexes with multiple IL-5R alpha chains, suggesting that syntenin-enhanced IL-5R output may result from stabilization of an IL-5-induced oligomeric receptor complex. These data demonstrate that cytokine-specific functions can be transduced by unique receptor alpha-chain-associating adapter proteins. (Blood. 2009;114:3917-3927) C1 [Beekman, Jeffrey M.; Verhagen, Liesbeth P.; Coffer, Paul J.] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Mol Immunol Lab, Dept Immunol, NL-3584 EA Utrecht, Netherlands. [Beekman, Jeffrey M.; Coffer, Paul J.] Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Dept Pediat Immunol, NL-3584 EA Utrecht, Netherlands. [Geijsen, Niels] Massachusetts Gen Hosp, Harvard Stem Cell Inst, Ctr Regenerat Med, Boston, MA 02114 USA. RP Coffer, PJ (reprint author), Univ Med Ctr Utrecht, Wilhelmina Childrens Hosp, Mol Immunol Lab, Dept Immunol, Lundlaan 6, NL-3584 EA Utrecht, Netherlands. EM p.j.coffer@umcutrecht.nl RI Beekman, Jeffrey/I-7781-2014 OI Beekman, Jeffrey/0000-0003-4886-3756 FU Dutch Scientific Organization (NWO) [917.36.316] FX J.M.B. was supported by a grant from the Dutch Scientific Organization (NWO 917.36.316). NR 54 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 29 PY 2009 VL 114 IS 18 BP 3917 EP 3927 DI 10.1182/blood-2009-03-208850 PG 11 WC Hematology SC Hematology GA 512RO UT WOS:000271268100027 PM 19654410 ER PT J AU Meems, H Meijer, AB Cullinan, DB Mertens, K Gilbert, GE AF Meems, Henriet Meijer, Alexander B. Cullinan, David B. Mertens, Koen Gilbert, Gary E. TI Factor VIII C1 domain residues Lys 2092 and Phe 2093 contribute to membrane binding and cofactor activity SO BLOOD LA English DT Article ID COAGULATION-FACTOR-VIII; VON-WILLEBRAND-FACTOR; HEMOPHILIA-A; C2 DOMAIN; FACTOR-X; FACTOR-IXA; PHOSPHOLIPID-MEMBRANES; FACTOR-V; ACTIVATION; COMPLEX AB Binding of factor VIII to membranes containing phosphatidyl-L-serine (Ptd-L-Ser) is mediated, in part, by a motif localized to the C2 domain. We evaluated a putative membrane-binding role of the C1 domain using an anti-C1 antibody fragment, KM33(scFv), and factor VIII mutants with an altered KM33 epitope. We prepared a dual mutant Lys2092/Phe2093 -> Ala/Ala (fVIII(YFP) (2092/93)) and 2 single mutants Lys2092 -> Ala and Phe2093 -> Ala. KM33(scFv) inhibited binding of fluorescein-labeled factor VIII to synthetic membranes and inhibited at least 95% of factor Xase activity. fVIII(YFP 2092/93) had 3-fold lower affinity for membranes containing 15% Ptd-L-Ser but more than 10-fold reduction in affinity for membranes with 4% Ptd-L-Ser. In a microtiter plate, KM33(scFv) was additive with an anti-C2 antibody for blocking binding to vesicles of 15% Ptd-L-Ser, whereas either antibody blocked binding to vesicles of 4% Ptd-L-Ser. KM33(scFv) inhibited binding to platelets and fVIII(YFP 2092/93) had reduced binding to A23187-stimulated platelets. fVIII(YFP 2092) exhibited normal activity at various Ptd-L-Ser concentrations, whereas fVIII(YFP 2093) showed a reduction of activity with Ptd-L-Ser less than 12%. fVIII(YFP 2092/93) had a greater reduction of activity than either single mutant. These results indicate that Lys 2092 and Phe 2093 are elements of a membrane-binding motif on the factor VIII C1 domain. (Blood. 2009;114:3938-3946) C1 [Cullinan, David B.; Gilbert, Gary E.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Dept Med, W Roxbury, MA 02132 USA. [Cullinan, David B.; Gilbert, Gary E.] Brigham & Womens Hosp, VA Boston Healthcare Syst, Dept Res, W Roxbury, MA 02132 USA. [Cullinan, David B.; Gilbert, Gary E.] Harvard Univ, Sch Med, Boston, MA USA. [Meijer, Alexander B.; Mertens, Koen] Univ Utrecht, Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands. [Meems, Henriet; Mertens, Koen] UMC Utrecht & Sanquin, Creveld Lab, Amsterdam, Netherlands. [Meems, Henriet; Meijer, Alexander B.; Mertens, Koen] Dept Plasma Prot, Amsterdam, Netherlands. RP Gilbert, GE (reprint author), Brigham & Womens Hosp, VA Boston Healthcare Syst, Dept Med, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM Gary_Gilbert@hms.harvard.edu NR 45 TC 39 Z9 40 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 29 PY 2009 VL 114 IS 18 BP 3938 EP 3946 DI 10.1182/blood-2009-01-197707 PG 9 WC Hematology SC Hematology GA 512RO UT WOS:000271268100030 PM 19687511 ER PT J AU Koreth, J Stevenson, KE Kim, HT Garcia, M Ho, VT Armand, P Cutler, C Ritz, J Antin, JH Soiffer, RJ Alyea, EP AF Koreth, John Stevenson, Kristen E. Kim, Haesook T. Garcia, Michael Ho, Vincent T. Armand, Philippe Cutler, Corey Ritz, Jerome Antin, Joseph H. Soiffer, Robert J. Alyea, Edwin P., III TI Bortezomib, tacrolimus, and methotrexate for prophylaxis of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation from HLA-mismatched unrelated donors SO BLOOD LA English DT Article ID NF-KAPPA-B; PROTEASOME INHIBITOR BORTEZOMIB; ACTIVATION; DEPLETION; GROWTH; GVHD AB Graft-versus-host disease (GVHD) is a significant complication of allogeneic stem cell transplantation (alloSCT). The proteasome inhibitor bortezomib has immunomodulatory properties of potential benefit for GVHD control. We undertook a phase 1 trial of bortezomib, tacrolimus, and methotrexate for GVHD prophylaxis after reduced-intensity conditioning alloSCT using human leukocyte antigen-mismatched unrelated donors. Twenty-three patients were enrolled. Bortezomib dose levels of 1, 1.3, and 1.5 mg/m(2) were evaluated with 5, 3, and 5 patients, respectively. Ten additional patients were accrued at the 1.3 mg/m(2) bortezomib dose level. Bortezomib-related toxicity was minimal. With a 12-month median follow-up, grade II-IV acute GVHD occurred in 3 patients, a 180-day cumulative incidence of 13%. Chronic GVHD occurred in 9 patients, a 1-year cumulative incidence of 41%. At 1-year, the nonrelapse mortality was zero, cumulative incidence of relapse/progression was 29%, and overall, progression-free, and event-free survival were 75%, 64%, and 59%, respectively. Bortezomib is a promising novel immunomodulatory agent in allogeneic transplantation. This study was registered at http://www.clinicaltrials.gov as # NCT00369226. (Blood. 2009;114:3956-3959) C1 [Koreth, John; Garcia, Michael; Ho, Vincent T.; Armand, Philippe; Cutler, Corey; Ritz, Jerome; Antin, Joseph H.; Soiffer, Robert J.; Alyea, Edwin P., III] Dana Farber Canc Inst, Div Hematol Malignancies, Boston, MA 02115 USA. [Stevenson, Kristen E.; Kim, Haesook T.] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. RP Koreth, J (reprint author), Dana Farber Canc Inst, Div Hematol Malignancies, 44 Binney St, Boston, MA 02115 USA. EM jkoreth@partners.org FU Millennium Pharmaceuticals Inc; National Institutes of Health [P01 CA142106] FX This study was supported in part by Millennium Pharmaceuticals Inc and by the National Institutes of Health (P01 CA142106). NR 14 TC 52 Z9 53 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 29 PY 2009 VL 114 IS 18 BP 3956 EP 3959 DI 10.1182/blood-2009-07-231092 PG 4 WC Hematology SC Hematology GA 512RO UT WOS:000271268100032 PM 19713456 ER PT J AU Parikh, JR Askenazi, M Ficarro, SB Cashorali, T Webber, JT Blank, NC Zhang, Y Marto, JA AF Parikh, Jignesh R. Askenazi, Manor Ficarro, Scott B. Cashorali, Tanya Webber, James T. Blank, Nathaniel C. Zhang, Yi Marto, Jarrod A. TI multiplierz: an extensible API based desktop environment for proteomics data analysis SO BMC BIOINFORMATICS LA English DT Article ID TANDEM MASS-SPECTROMETRY; NEXT-GENERATION; IDENTIFICATION; ALGORITHM; PEPTIDES; SPECTRA AB Background: Efficient analysis of results from mass spectrometry-based proteomics experiments requires access to disparate data types, including native mass spectrometry files, output from algorithms that assign peptide sequence to MS/MS spectra, and annotation for proteins and pathways from various database sources. Moreover, proteomics technologies and experimental methods are not yet standardized; hence a high degree of flexibility is necessary for efficient support of high-and low-throughput data analytic tasks. Development of a desktop environment that is sufficiently robust for deployment in data analytic pipelines, and simultaneously supports customization for programmers and non-programmers alike, has proven to be a significant challenge. Results: We describe multiplierz, a flexible and open-source desktop environment for comprehensive proteomics data analysis. We use this framework to expose a prototype version of our recently proposed common API (mzAPI) designed for direct access to proprietary mass spectrometry files. In addition to routine data analytic tasks, multiplierz supports generation of information rich, portable spreadsheet-based reports. Moreover, multiplierz is designed around a "zero infrastructure" philosophy, meaning that it can be deployed by end users with little or no system administration support. Finally, access to multiplierz functionality is provided via high-level Python scripts, resulting in a fully extensible data analytic environment for rapid development of custom algorithms and deployment of high-throughput data pipelines. Conclusion: Collectively, mzAPI and multiplierz facilitate a wide range of data analysis tasks, spanning technology development to biological annotation, for mass spectrometry-based proteomics research. C1 [Askenazi, Manor; Ficarro, Scott B.; Cashorali, Tanya; Webber, James T.; Blank, Nathaniel C.; Zhang, Yi; Marto, Jarrod A.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Parikh, Jignesh R.] Boston Univ, Bioinformat Program, Boston, MA 02115 USA. [Askenazi, Manor; Ficarro, Scott B.; Cashorali, Tanya; Webber, James T.; Blank, Nathaniel C.; Zhang, Yi; Marto, Jarrod A.] Dana Farber Canc Inst, Blais Prote Ctr, Boston, MA 02115 USA. [Askenazi, Manor; Ficarro, Scott B.; Marto, Jarrod A.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Askenazi, Manor] Hebrew Univ Jerusalem, Dept Biol Chem, IL-91904 Jerusalem, Israel. RP Marto, JA (reprint author), Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St,Smith 1158A, Boston, MA 02115 USA. EM jparikh@bu.edu; manor_askenazi@dfci.harvard.edu; scott_ficarro@dfci.harvard.edu; tanya@gnsbiotech.com; jamest_webber@dfci.harvard.edu; nate.blank@centre.edu; yi_zhang@dfci.harvard.edu; jarrod_marto@dfci.harvard.edu OI Webber, James/0000-0001-8594-9888 FU NHGRI NIH HHS [P50 HG004233, P50HG004233] NR 29 TC 36 Z9 36 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 29 PY 2009 VL 10 AR 364 DI 10.1186/1471-2105-10-364 PG 16 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 519KN UT WOS:000271765400002 PM 19874609 ER PT J AU Maslowski, KM Vieira, AT Ng, A Kranich, J Sierro, F Yu, D Schilter, HC Rolph, MS Mackay, F Artis, D Xavier, RJ Teixeira, MM Mackay, CR AF Maslowski, Kendle M. Vieira, Angelica T. Ng, Aylwin Kranich, Jan Sierro, Frederic Yu, Di Schilter, Heidi C. Rolph, Michael S. Mackay, Fabienne Artis, David Xavier, Ramnik J. Teixeira, Mauro M. Mackay, Charles R. TI Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43 SO NATURE LA English DT Article ID CHAIN FATTY-ACIDS; DISTAL ULCERATIVE-COLITIS; NF-KAPPA-B; FUNCTIONAL-CHARACTERIZATION; INTESTINAL MICROBIOTA; BOWEL-DISEASE; MICE; EOSINOPHILS; IRRIGATION; INHIBITION AB The immune system responds to pathogens by a variety of pattern recognition molecules such as the Toll-like receptors (TLRs), which promote recognition of dangerous foreign pathogens. However, recent evidence indicates that normal intestinal microbiota might also positively influence immune responses, and protect against the development of inflammatory diseases(1,2). One of these elements may be short-chain fatty acids (SCFAs), which are produced by fermentation of dietary fibre by intestinal microbiota. A feature of human ulcerative colitis and other colitic diseases is a change in 'healthy' microbiota such as Bifidobacterium and Bacteriodes(3), and a concurrent reduction in SCFAs(4). Moreover, increased intake of fermentable dietary fibre, or SCFAs, seems to be clinically beneficial in the treatment of colitis(5-9). SCFAs bind the G-protein-coupled receptor 43 (GPR43, also known as FFAR2)(10,11), and here we show that SCFA-GPR43 interactions profoundly affect inflammatory responses. Stimulation of GPR43 by SCFAs was necessary for the normal resolution of certain inflammatory responses, because GPR43-deficient (Gpr43(-/-)) mice showed exacerbated or unresolving inflammation in models of colitis, arthritis and asthma. This seemed to relate to increased production of inflammatory mediators by Gpr43(-/-) immune cells, and increased immune cell recruitment. Germ-free mice, which are devoid of bacteria and express little or no SCFAs, showed a similar dysregulation of certain inflammatory responses. GPR43 binding of SCFAs potentially provides a molecular link between diet, gastrointestinal bacterial metabolism, and immune and inflammatory responses. C1 [Maslowski, Kendle M.; Vieira, Angelica T.; Kranich, Jan; Sierro, Frederic; Yu, Di; Schilter, Heidi C.; Rolph, Michael S.; Mackay, Fabienne; Mackay, Charles R.] St Vincents Hosp, Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia. [Maslowski, Kendle M.; Kranich, Jan; Schilter, Heidi C.; Rolph, Michael S.; Mackay, Charles R.] Cooperat Res Ctr Asthma & Airways, Camperdown, NSW 2050, Australia. [Maslowski, Kendle M.; Schilter, Heidi C.; Mackay, Charles R.] Univ New S Wales, St Vincents Clin Sch, Sydney, NSW 2010, Australia. [Vieira, Angelica T.; Teixeira, Mauro M.] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biochem & Immunol, BR-31270901 Belo Horizonte, MG, Brazil. [Ng, Aylwin; Xavier, Ramnik J.] Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Massachusetts Gen Hosp, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. [Ng, Aylwin; Xavier, Ramnik J.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mackay, Fabienne; Mackay, Charles R.] Monash Univ, Fac Med, Clayton, Vic 3800, Australia. [Artis, David] Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. [Xavier, Ramnik J.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Xavier, Ramnik J.] Harvard Univ, Cambridge, MA 02142 USA. RP Mackay, CR (reprint author), St Vincents Hosp, Garvan Inst Med Res, 384 Victoria St, Darlinghurst, NSW 2010, Australia. EM charles.mackay@med.monash.edu.au RI Mackay, Charles/A-9673-2008; Sierro, Frederic/B-9742-2009; Yu, Di/C-2163-2009; Mackay, Fabienne/B-7440-2008; Vieira, Angelica/A-6227-2015; Osborne, Nicholas/N-4915-2015; OI Mackay, Charles/0000-0002-6338-7340; Sierro, Frederic/0000-0001-5004-8414; Yu, Di/0000-0003-1721-8922; Mackay, Fabienne/0000-0002-6074-2693; Vieira, Angelica/0000-0002-4556-7671; Osborne, Nicholas/0000-0002-6700-2284; Maslowski, Kendle/0000-0003-1995-5424 FU Australian NHMRC; CRC for Asthma and Airways; Crohn's and Colitis Foundation of America; Cancer Institute NSW FX The authors thank P. Silvera and S. Tangye for supply of certain Genechip data sets, L. Tsai for help with heatmaps, and D. Kobuley, J. Nicoli and M. Abt for help in the germ-free animal facilities. K. M. M. and C. R. M. are supported by the Australian NHMRC, and the CRC for Asthma and Airways. A. N. is a recipient of a Fellowship award from the Crohn's and Colitis Foundation of America. F. S. and D. Y. are Cancer Institute NSW Fellows. NR 44 TC 800 Z9 834 U1 26 U2 206 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 29 PY 2009 VL 461 IS 7268 BP 1282 EP U119 DI 10.1038/nature08530 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 511TF UT WOS:000271190800049 PM 19865172 ER PT J AU Taylor, CR Gandhi, RT Handwerker, J Duncan, LM AF Taylor, Charles R. Gandhi, Rajesh T. Handwerker, Jason Duncan, Lyn M. TI A Man with Sore Throat, Fever, and Rash PLEVA (pityriasis lichenoides et varioliformis acuta) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MUCHA-HABERMANN-DISEASE; ARCANOBACTERIUM-HAEMOLYTICUM C1 [Taylor, Charles R.] Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. [Gandhi, Rajesh T.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Handwerker, Jason] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Duncan, Lyn M.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Taylor, Charles R.] Harvard Univ, Sch Med, Dept Dermatol, Cambridge, MA 02138 USA. [Gandhi, Rajesh T.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Handwerker, Jason] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Duncan, Lyn M.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Taylor, CR (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. FU Tibotec FX Dr. Gandhi reports receiving lecture fees from GlaxoSmithKline and grant support from Tibotec. No other potential conflict of interest relevant to this article was reported. NR 19 TC 1 Z9 2 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 29 PY 2009 VL 361 IS 18 BP 1787 EP 1796 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 511RY UT WOS:000271185600013 PM 19864678 ER PT J AU Yotsumoto, Y Chang, LH Watanabe, T Sasaki, Y AF Yotsumoto, Yuko Chang, Li-hung Watanabe, Takeo Sasaki, Yuka TI Interference and feature specificity in visual perceptual learning SO VISION RESEARCH LA English DT Article DE Perceptual learning; Roving; Interference; Feature specificity ID HUMAN MOTOR MEMORY; TIME-COURSE; CONTRAST DISCRIMINATION; TEXTURE-DISCRIMINATION; MOTION DISCRIMINATION; SPATIAL-FREQUENCY; CONSOLIDATION; ORIENTATION; SLEEP; TASK AB Perceptual learning (PL) often shows specificity to a trained feature. We investigated whether feature specificity is related to disruption in PL using the texture discrimination task (TDT), which shows learning specificity to background element but not to target element. Learning was disrupted when orientations of background elements were changed in two successive training sessions (interference) but not in a random order from trial to trial (roving). The presentation of target elements seemed to have reversed effect; learning occurred in two-parts training but not with roving. These results suggest that interference in TDT is feature specific while disruption by roving is not. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Yotsumoto, Yuko; Chang, Li-hung; Sasaki, Yuka] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. [Yotsumoto, Yuko; Chang, Li-hung; Watanabe, Takeo] Boston Univ, Dept Psychol, Boston, MA 02215 USA. [Yotsumoto, Yuko; Sasaki, Yuka] Harvard Univ, Sch Med, Dept Radiol, Charlestown, MA 02129 USA. RP Sasaki, Y (reprint author), Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Charlestown, MA 02129 USA. EM yuka@nmr.mgh.harvard.edu FU NIH [EY01 9466, EY01 5980]; Japan Society for the Promotion of Science; ERATO FX This work was supported by NIH (EY01 9466 and EY01 5980) to TW. YY is supported by Japan Society for the Promotion of Science. YS is supported by ERATO Shimojo Implicit brain function project, Japan Science Technology. We thank Nichole Eusemann for her careful editing our manuscript. NR 43 TC 17 Z9 18 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD OCT 29 PY 2009 VL 49 IS 21 BP 2611 EP 2623 DI 10.1016/j.visres.2009.08.001 PG 13 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 517GE UT WOS:000271600500011 PM 19665036 ER PT J AU Carlson, BA Yoo, MH Sano, Y Sengupta, A Kim, JY Irons, R Gladyshev, VN Hatfield, DL Park, JM AF Carlson, Bradley A. Yoo, Min-Hyuk Sano, Yasuyo Sengupta, Aniruddha Kim, Jin Young Irons, Robert Gladyshev, Vadim N. Hatfield, Dolph L. Park, Jin Mo TI Selenoproteins regulate macrophage invasiveness and extracellular matrix-related gene expression SO BMC IMMUNOLOGY LA English DT Article ID SELENOCYSTEINE TRANSFER-RNA; SIGNAL-TRANSDUCTION; INNATE IMMUNITY; KAPPA-B; ACTIVATION; SELENIUM; MICE; INHIBITION; TRSP AB Background: Selenium, a micronutrient whose deficiency in diet causes immune dysfunction and inflammatory disorders, is thought to exert its physiological effects mostly in the form of selenium-containing proteins (selenoproteins). Incorporation of selenium into the amino acid selenocysteine (Sec), and subsequently into selenoproteins is mediated by Sec tRNA([Ser]Sec). Results: To define macrophage-specific selenoprotein functions, we generated mice with the Sec tRNA([Ser]Sec) gene specifically deleted in myeloid cells. These mutant mice were devoid of the "selenoproteome" in macrophages, yet exhibited largely normal inflammatory responses. However, selenoprotein deficiency led to aberrant expression of extracellular matrix-related genes, and diminished migration of macrophages in a protein gel matrix. Conclusion: Selenium status may affect immune defense and tissue homeostasis through its effect on selenoprotein expression and the trafficking of tissue macrophages. C1 [Carlson, Bradley A.; Yoo, Min-Hyuk; Sengupta, Aniruddha; Kim, Jin Young; Irons, Robert; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Sano, Yasuyo; Park, Jin Mo] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Sano, Yasuyo; Park, Jin Mo] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM carlsonb@mail.nih.gov; yoom@mail.nih.gov; yasuyo.sano@cbrc2.mgh.harvard.edu; sengupta@mail.nih.gov; glory80@snu.ac.kr; robert@veirons.com; vgladysh@unlnotes.unl.edu; hatfield@mail.nih.gov; jmpark@cbrc2.mgh.harvard.edu RI Gladyshev, Vadim/A-9894-2013 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and Center for Cancer Research, and in addition, a specific grant from the Office of Dietary Supplements, NCI, NIH and the Cutaneous Biology Research Center through the Massachusetts General Hospital/Shiseido Co. Ltd. Agreement to JMP and NIH grants awarded to VNG. NR 26 TC 35 Z9 36 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD OCT 28 PY 2009 VL 10 AR 57 DI 10.1186/1471-2172-10-57 PG 12 WC Immunology SC Immunology GA 521LY UT WOS:000271924100001 PM 19863805 ER PT J AU Kastrinos, F Mukherjee, B Tayob, N Wang, F Sparr, J Raymond, VM Bandipalliam, P Stoffel, EM Gruber, SB Syngal, S AF Kastrinos, Fay Mukherjee, Bhramar Tayob, Nabihah Wang, Fei Sparr, Jennifer Raymond, Victoria M. Bandipalliam, Prathap Stoffel, Elena M. Gruber, Stephen B. Syngal, Sapna TI Risk of Pancreatic Cancer in Families With Lynch Syndrome SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NONPOLYPOSIS COLORECTAL-CANCER; MSH2 MUTATION CARRIERS; PEUTZ-JEGHERS-SYNDROME; MISMATCH REPAIR GENE; MEDULLARY CARCINOMA; ENDOMETRIAL CANCER; HISTORY; ACCURACY; HNPCC; INDIVIDUALS AB Context Lynch syndrome is an inherited cause of colorectal cancer caused by mutations of DNA mismatch repair (MMR) genes. A number of extracolonic tumors have been associated with the disorder, including pancreatic cancer; however, the risk of pancreatic cancer in Lynch syndrome is uncertain and not quantified. Objective To estimate pancreatic cancer risk in families with germline MMR gene mutations. Design, Setting, and Patients Cancer histories of probands and their relatives were evaluated in MMR gene mutation carriers in the familial cancer registries of the Dana-Farber Cancer Institute (n=80), Boston, Massachusetts, and University of Michigan Comprehensive Cancer Center (n=67), Ann Arbor, Michigan. Families enrolled before the study start date ( June 2008) were eligible. Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk were calculated and compared with the general population using modified segregation analysis, with correction for ascertainment. Main Outcome Measures Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk. Results Data on 6342 individuals from 147 families with MMR gene mutations were analyzed. Thirty-one families (21.1%) reported at least 1 case of pancreatic cancer. Forty-seven pancreatic cancers were reported ( 21 men and 26 women), with no sex-related difference in age of diagnosis (51.5 vs 56.5 years for men and women, respectively). The cumulative risk of pancreatic cancer in these families with gene mutations was 1.31% (95% confidence interval [CI], 0.31%-2.32%) up to age 50 years and 3.68% ( 95% CI, 1.45%-5.88%) up to age 70 years, which represents an 8.6-fold increase ( 95% CI, 4.7-15.7) compared with the general population. Conclusions Among 147 families with germline MMR gene mutations, the risk of pancreatic cancer was increased compared with the US population. Individuals with MMR gene mutations and a family history of pancreatic cancer are appropriate to include in studies to further define the risk of premalignant and malignant pancreatic neoplasms and potential benefits and limitations of surveillance. JAMA. 2009; 302(16):1790-1795 www.jama.com C1 [Sparr, Jennifer; Bandipalliam, Prathap; Stoffel, Elena M.; Syngal, Sapna] Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA. [Kastrinos, Fay; Stoffel, Elena M.; Syngal, Sapna] Brigham & Womens Hosp, Dept Internal Med, Boston, MA 02115 USA. [Kastrinos, Fay] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, New York, NY USA. [Mukherjee, Bhramar; Tayob, Nabihah; Wang, Fei] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Raymond, Victoria M.; Gruber, Stephen B.] Univ Michigan, Sch Publ Hlth, Dept Internal Med, Ann Arbor, MI 48109 USA. [Gruber, Stephen B.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol & Human Genet, Ann Arbor, MI 48109 USA. RP Syngal, S (reprint author), Dana Farber Canc Inst, Div Populat Sci, 1 Jimmy Fund Way,SM 209, Boston, MA 02115 USA. EM sgruber@med.umich.edu; ssyngal@partners.org FU National Cancer Institute [R01CA81488, K24CA113433, R01CA97075, 5P30CA46592]; The Karp Family; H. H. & M. Metals Inc Fund; Leake Gift for Pancreatic Cancer Research FX This work was supported in part by the grants R01CA81488, K24CA113433, R01CA97075, and 5P30CA46592 from the National Cancer Institute, The Karp Family, H. H. & M. Metals Inc Fund, and the Leake Gift for Pancreatic Cancer Research. NR 38 TC 143 Z9 145 U1 1 U2 4 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 OCT 28 PY 2009 VL 302 IS 16 BP 1790 EP 1795 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 511FW UT WOS:000271150300022 PM 19861671 ER PT J AU Ross, JS Detsky, AS AF Ross, Joseph S. Detsky, Allan S. TI Health Care Choices and Decisions in the United States and Canada SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Detsky, Allan S.] Mt Sinai Hosp, Dept Med, Toronto, ON M5G 1X5, Canada. [Detsky, Allan S.] Univ Toronto, Dept Hlth Policy, Toronto, ON, Canada. [Detsky, Allan S.] Univ Toronto, Dept Management, Toronto, ON, Canada. [Detsky, Allan S.] Univ Toronto, Dept Evaluat & Med, Toronto, ON, Canada. [Detsky, Allan S.] Univ Hlth Network, Toronto, ON, Canada. [Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr, New York, NY USA. [Ross, Joseph S.] Mt Sinai Sch Med, Dept Palliat Care & Med, New York, NY USA. [Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Hlth Serv Res & Dev Res Enhancement Award Program, Bronx, NY USA. [Ross, Joseph S.] James J Peters Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. RP Detsky, AS (reprint author), Mt Sinai Hosp, Dept Med, 429-600 Univ Ave, Toronto, ON M5G 1X5, Canada. EM adetsky@mtsinai.on.ca FU NIA NIH HHS [K08 AG032886-01, K08 AG032886] NR 8 TC 3 Z9 3 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 OCT 28 PY 2009 VL 302 IS 16 BP 1803 EP 1804 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 511FW UT WOS:000271150300024 PM 19861673 ER PT J AU Campbell, EG Rosenthal, M AF Campbell, Eric G. Rosenthal, Meredith TI Reform of Continuing Medical Education Investments in Physician Human Capital SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Campbell, Eric G.] Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. [Rosenthal, Meredith] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Campbell, EG (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, 50 Stanford St,9th Floor, Boston, MA 02114 USA. EM ecampbell@partners.org OI Rosenthal, Meredith/0000-0003-3410-0184 NR 8 TC 6 Z9 6 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 OCT 28 PY 2009 VL 302 IS 16 BP 1807 EP 1808 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 511FW UT WOS:000271150300026 PM 19861675 ER PT J AU Ran, CZ Xu, XY Raymond, SB Ferrara, BJ Neal, K Bacskai, BJ Medarova, Z Moore, A AF Ran, Chongzhao Xu, Xiaoyin Raymond, Scott B. Ferrara, Brian J. Neal, Krista Bacskai, Brian J. Medarova, Zdravka Moore, Anna TI Design, Synthesis, and Testing of Difluoroboron-Derivatized Curcumins as Near-Infrared Probes for in Vivo Detection of Amyloid-beta Deposits SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID PITTSBURGH COMPOUND-B; ALZHEIMERS-DISEASE; MOUSE MODEL; TRANSGENIC MICE; CONTRAST AGENT; ZUR KENNTNIS; PLAQUES; BRAIN; PHOSPHORESCENCE; FLUORESCENCE AB Amyloid-beta (A beta) deposits have been identified as key players in the progression of Alzheimer's disease (AD). Recent evidence indicates that the deposits probably precede and induce the neuronal atrophy. Therefore, methods that enable monitoring the pathology before clinical symptoms are observed would be beneficial for early AD detection. Here, we report the design, synthesis, and testing of a curcumin-derivatized near-infrared (NIR) probe, CRANAD-2. Upon interacting with A beta aggregates, CRANAD-2 undergoes a range of changes, which include a 70-fold fluorescence intensity increase, a 90 nm blue shift (from 805 to 715 nm), and a large increase in quantum yield. Moreover, this probe also shows a high affinity for A beta aggregates (K(d) = 38.0 nM), a reasonable log P value (log P = 3), considerable stability in serum, and a weak interaction with albumin. After intravenous injection of this probe, 19-month-old Tg2576 mice exhibited significantly higher relative signal than that of the control mice over the same period of time. In summary, CRANAD-2 meets all the requirements for a NIR contrast agent for the detection of A beta plaques both in vitro and in vivo. Our data point toward the feasibility of monitoring the progress of the disease by NIR imaging with CRANAD-2. In addition, we believe that our probe could be potentially used as a tool for drug screening. C1 [Ran, Chongzhao; Medarova, Zdravka; Moore, Anna] Harvard Univ, Sch Med, Massachusetts Gen Hosp,Mol Imaging Lab,Dept Radio, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA 02129 USA. [Xu, Xiaoyin] Brigham & Womens Hosp, Dept Radiol, Opt Imaging Lab, Boston, MA 02115 USA. [Raymond, Scott B.; Ferrara, Brian J.; Neal, Krista; Bacskai, Brian J.] Massachusetts Gen Hosp, Dept Neurol, Alzheimers Dis Res Unit, Boston, MA 02114 USA. RP Moore, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp,Mol Imaging Lab,Dept Radio, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Room 2301,Bldg 149, Charlestown, MA 02129 USA. EM amoore@helix.mgh.harvard.edu OI Raymond, Scott/0000-0001-7008-8974 FU NIH [AG026240, CA113672] FX This work was partially supported by the NIH Program Project Grants AG026240 (B.J.B.) and CA113672 (A.M.). NR 39 TC 131 Z9 134 U1 8 U2 64 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 28 PY 2009 VL 131 IS 42 BP 15257 EP 15261 DI 10.1021/ja9047043 PG 5 WC Chemistry, Multidisciplinary SC Chemistry GA 512SX UT WOS:000271272000044 PM 19807070 ER PT J AU Lim, LY Vidnovic, N Ellisen, LW Leong, CO AF Lim, L. Y. Vidnovic, N. Ellisen, L. W. Leong, C-O TI Mutant p53 mediates survival of breast cancer cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE p53; breast cancer; gain of function; p63; p73; apoptosis ID LI-FRAUMENI-SYNDROME; WILD-TYPE P53; TUMOR-SUPPRESSOR P53; GAIN-OF-FUNCTION; P73-DEPENDENT APOPTOSIS; FUNCTION MUTATIONS; TP53 GENOTYPE; P73; P63; FAMILY AB BACKGROUND: p53 is the most commonly mutated tumour-suppressor gene in human cancers. Unlike other tumour-suppressor genes, most p53 cancer mutations are missense mutations within the core domain, leading to the expression of a full-length mutant p53 protein. Accumulating evidence has indicated that p53 cancer mutants not only lose tumour suppression activity but also gain new oncogenic activities to promote tumourigenesis. METHODS: The endogenous mutant p53 function in human breast cancer cells was studied using RNA interference (RNAi). Gene knockdown was confirmed by quantitative PCR and western blotting. Apoptosis was evaluated by morphological changes of cells, their PARP cleavage and annexin V staining. RESULTS: We show that cancer-associated p53 missense mutants are required for the survival of breast cancer cells. Inhibition of endogenous mutant p53 by RNAi led to massive apoptosis in two mutant p53-expressing cell lines, T47D and MDA-MB-468, but not in the wild-type p53-expressing cells, MCF-7 and MCF-10A. Reconstitution of an RNAi-insensitive mutant p53 in MDA-MB-468 cells completely abolished the apoptotic effects after silencing of endogenous mutant p53, suggesting the specific survival effects of mutant p53. The apoptotic effect induced by mutant p53 ablation, however, is independent of p63 or p73 function. CONCLUSION: These findings provide clear evidence of a pro-survival 'gain-of-function' property of a subset of p53 cancer mutants in breast cancer cells. British Journal of Cancer ( 2009) 101, 1606-1612. doi: 10.1038/sj.bjc.6605335 www.bjcancer.com Published online 22 September 2009 (C) 2009 Cancer Research UK C1 [Lim, L. Y.; Leong, C-O] Int Med Univ, Kuala Lumpur 57000, Malaysia. [Vidnovic, N.; Ellisen, L. W.] Harvard Univ, Massachusetts Gen Hosp, Ctr Canc, Sch Med, Boston, MA 02114 USA. RP Leong, CO (reprint author), Int Med Univ, 126 Jalan 19-155B,Bukit Jalil, Kuala Lumpur 57000, Malaysia. EM cheeonn_leong@imu.edu.my FU MAKNA Cancer Research Award, Malaysia; Ministry of Science, Technology and Innovation, Malaysia [02-02-09-SF0010]; International Medical University Research Fund [IMU-168-2008, BMS I02-2008(03)] FX This work was supported by a grant from the MAKNA Cancer Research Award, Malaysia, and by-Science Fund 02-02-09-SF0010 from the Ministry of Science, Technology and Innovation, Malaysia (to COL); and by the International Medical University Research Fund IMU-168-2008 (to COL) and BMS I02-2008(03) ( to LYL). No sponsors of this work had any function in the design or conduct of the study, in the collection, analysis, and interpretation of data, or in the preparation, review, or approval of the paper. NR 51 TC 61 Z9 62 U1 0 U2 9 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 OCT 27 PY 2009 VL 101 IS 9 BP 1606 EP 1612 DI 10.1038/sj.bjc.6605335 PG 7 WC Oncology SC Oncology GA 512KO UT WOS:000271247800017 PM 19773755 ER PT J AU Thatte, HS Rousou, L Hussaini, BE Lu, XG Treanor, PR Khuri, SF AF Thatte, Hemant S. Rousou, Laki Hussaini, Bader E. Lu, Xiu-Gui Treanor, Patrick R. Khuri, Shukri F. TI Development and Evaluation of a Novel Solution, Somah, for the Procurement and Preservation of Beating and Nonbeating Donor Hearts for Transplantation SO CIRCULATION LA English DT Article DE endothelium; myocytes; nitric oxide synthase; transplantation ID GAP-JUNCTIONAL HEMICHANNELS; SAPHENOUS-VEIN; GLUCOSE-METABOLISM; ATP; CARDIOPROTECTION; DICHLOROACETATE; REPERFUSION; GLYCOLYSIS; PHYSIOLOGY; INSULIN AB Background-Injury to myocytes, endocardium, and the coronary endothelium during harvesting and storage can compromise outcomes after heart transplantation. Safeguarding of structure and function of cardiomyocytes and endothelium in donor hearts may lead to improved patient survival after transplantation. Information gained from porcine hearts stored in standard transplant solution was used to design a superior preservation solution that would optimally protect and maintain organs from beating heart and/or nonbeating heart donors during long-term storage. Methods and Results-Multiphoton microscopy was used to image deep within cardiac biopsies and coronary artery tissue harvested from porcine hearts obtained from beating heart and nonbeating heart donors for analysis of myocyte and endothelial cell structure and function. Cell structural integrity and viability, calcium mobilization, and nitric oxide generation were determined with fluorescence viability markers, immunofluorescence, and Western blots. During hypothermic storage in standard preservation solution, Celsior, myocyte, and endothelial viability was markedly attenuated in hearts obtained from beating heart donors. In contrast, hearts from beating and nonbeating heart donors stored in the newly formulated Somah solution demonstrated an increase in high-energy phosphate levels, protection of cardiac myocyte viability, mitochondrial membrane polarization, and structural proteins. Similarly, coronary artery endothelial organization and function, calcium mobilization, and nitric oxide generation were well maintained during temporal storage in Somah. Conclusions-The Celsior preservation solution in clinical use today has led to a profound decline in cardiomyocyte and endothelial cell viability, whereas the newly designed Somah solution has safeguarded myocyte and endothelial integrity and function during organ storage. Use of Somah as a storage medium may lead to optimized graft function and long-term patient survival after transplantation. (Circulation. 2009;120:1704-1713.) C1 Harvard Univ, Sch Med, Dept Surg, Cardiothorac Div,VA Boston Healthcare Syst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Thatte, HS (reprint author), VA Boston Healthcare Syst, Dept Surg 112, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. EM Hemant_thatte@hms.harvard.edu FU National Institutes of Health [T32] FX This work was supported by grants from DoD/ONR (Dr Thatte) and VA Medical Research Service (Drs Khuri and Thatte). Dr Rousou was supported by the T32 National Institutes of Health training grant. NR 40 TC 15 Z9 16 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 27 PY 2009 VL 120 IS 17 BP 1704 EP 1713 DI 10.1161/CIRCULATIONAHA.108.808907 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 511HB UT WOS:000271153500010 PM 19822811 ER PT J AU Saam, T Raya, JG Cyran, CC Bochmann, K Meimarakis, G Dietrich, O Clevert, DA Frey, U Yuan, C Hatsukami, TS Werf, A Reiser, MF Nikolaou, K AF Saam, Tobias Raya, Jose G. Cyran, Clemens C. Bochmann, Katja Meimarakis, Georgios Dietrich, Olaf Clevert, Dirk A. Frey, Ute Yuan, Chun Hatsukami, Thomas S. Werf, Abe Reiser, Maximilian F. Nikolaou, Konstantin TI High resolution carotid black-blood 3T MR with parallel imaging and dedicated 4-channel surface coils SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article ID RISK-ASSESSMENT STRATEGIES; MAGNETIC-FIELD STRENGTHS; RICH NECROTIC CORE; IN-VIVO; ATHEROSCLEROTIC PLAQUE; QUANTITATIVE ASSESSMENT; VULNERABLE PATIENT; LESIONS; REPRODUCIBILITY; ULTRASOUND AB Background: Most of the carotid plaque MR studies have been performed using black-blood protocols at 1.5 T without parallel imaging techniques. The purpose of this study was to evaluate a multi-sequence, black-blood MR protocol using parallel imaging and a dedicated 4-channel surface coil for vessel wall imaging of the carotid arteries at 3 T. Materials and methods: 14 healthy volunteers and 14 patients with intimal thickening as proven by duplex ultrasound had their carotid arteries imaged at 3 T using a multi-sequence protocol (time-of-flight MR angiography, pre-contrast T1w-, PDw- and T2w sequences in the volunteers, additional post-contrast T1w- and dynamic contrast enhanced sequences in patients). To assess intrascan reproducibility, 10 volunteers were scanned twice within 2 weeks. Results: Intrascan reproducibility for quantitative measurements of lumen, wall and outer wall areas was excellent with Intraclass Correlation Coefficients >0.98 and measurement errors of 1.5%, 4.5% and 1.9%, respectively. Patients had larger wall areas than volunteers in both common carotid and internal carotid arteries and smaller lumen areas in internal carotid arteries (p < 0.001). Positive correlations were found between wall area and cardiovascular risk factors such as age, hypertension, coronary heart disease and hypercholesterolemia (Spearman's r = 0.45-0.76, p < 0.05). No significant correlations were found between wall area and body mass index, gender, diabetes or a family history of cardiovascular disease. Conclusion: The findings of this study indicate that high resolution carotid black-blood 3 T MR with parallel imaging is a fast, reproducible and robust method to assess carotid atherosclerotic plaque in vivo and this method is ready to be used in clinical practice. C1 [Saam, Tobias; Raya, Jose G.; Dietrich, Olaf] Univ Munich, Dept Clin Radiol, Josef Lissner Lab Biomed Imaging, Munich, Germany. [Meimarakis, Georgios; Frey, Ute] Univ Munich, Dept Surg, Munich, Germany. [Yuan, Chun] Univ Washington, Dept Radiol, Seattle, WA 98195 USA. [Hatsukami, Thomas S.] VA Puget Sound Hlth Care Syst, Seattle Div, Seattle, WA 98108 USA. [Hatsukami, Thomas S.] Univ Washington, Dept Surg, Seattle, WA 98195 USA. [Werf, Abe] Machnet BV, Td Eelde, Netherlands. RP Saam, T (reprint author), Univ Munich, Dept Clin Radiol, Josef Lissner Lab Biomed Imaging, Grosshadern Campus, Munich, Germany. EM Tobias.Saam@med.uni-muenchen.de; Jose.Raya@med.uni-muenchen.de; Clemens.Cyran@med.uni-muenchen.de; katja.bochmann@med.uni-muenchen.de; Georgios.Meimarakis@med.uni-muenchen.de; Olaf.Dietrich@med.uni-muenchen.de; Dirk.Clevert@med.uni-muenchen.de; Ute.Frey@med.uni-muenchen.de; cyuan@u.washington.edu; tomhat@u.washington.edu; avanderwerf@machnet.nl; Maximilian.Reiser@med.uni-muenchen.de; Nikolaou@med.uni-muenchen.de RI Dietrich, Olaf/C-4696-2014; OI Dietrich, Olaf/0000-0001-6182-5039; Nikolaou, Konstantin/0000-0003-2668-7325; Clevert, Dirk Andre/0000-0003-3889-5447 NR 30 TC 25 Z9 26 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD OCT 27 PY 2009 VL 11 AR 41 DI 10.1186/1532-429X-11-41 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 516FY UT WOS:000271528700001 PM 19860875 ER PT J AU Qureshi, AH Chaoji, V Maiguel, D Faridi, MH Barth, CJ Salem, SM Singhal, M Stoub, D Krastins, B Ogihara, M Zaki, MJ Gupta, V AF Qureshi, Amir H. Chaoji, Vineet Maiguel, Dony Faridi, Mohd Hafeez Barth, Constantinos J. Salem, Saeed M. Singhal, Mudita Stoub, Darren Krastins, Bryan Ogihara, Mitsunori Zaki, Mohammed J. Gupta, Vineet TI Proteomic and Phospho-Proteomic Profile of Human Platelets in Basal, Resting State: Insights into Integrin Signaling SO PLOS ONE LA English DT Article ID 2-DIMENSIONAL GEL-ELECTROPHORESIS; FLOW-CYTOMETRIC ANALYSIS; ACTIVATED PLATELETS; MASS-SPECTROMETRY; THREONINE PHOSPHORYLATION; AFFINITY-CHROMATOGRAPHY; PROTEIN INTERACTIONS; INTERACTION NETWORKS; IDENTIFICATION; INTERACTOME AB During atherogenesis and vascular inflammation quiescent platelets are activated to increase the surface expression and ligand affinity of the integrin alpha IIb beta 3 via inside-out signaling. Diverse signals such as thrombin, ADP and epinephrine transduce signals through their respective GPCRs to activate protein kinases that ultimately lead to the phosphorylation of the cytoplasmic tail of the integrin alpha IIb beta 3 and augment its function. The signaling pathways that transmit signals from the GPCR to the cytosolic domain of the integrin are not well defined. In an effort to better understand these pathways, we employed a combination of proteomic profiling and computational analyses of isolated human platelets. We analyzed ten independent human samples and identified a total of 1507 unique proteins in platelets. This is the most comprehensive platelet proteome assembled to date and includes 190 membrane-associated and 262 phosphorylated proteins, which were identified via independent proteomic and phospho-proteomic profiling. We used this proteomic dataset to create a platelet protein-protein interaction (PPI) network and applied novel contextual information about the phosphorylation step to introduce limited directionality in the PPI graph. This newly developed contextual PPI network computationally recapitulated an integrin signaling pathway. Most importantly, our approach not only provided insights into the mechanism of integrin alpha IIb beta 3 activation in resting platelets but also provides an improved model for analysis and discovery of PPI dynamics and signaling pathways in the future. RP Qureshi, AH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Nephrol, Boston, MA 02115 USA. EM vgupta2@med.miami.edu OI Zaki, Mohammed/0000-0003-4711-0234; Gupta, Vineet/0000-0001-6987-2550 FU NIBIB NIH HHS [1R01EB0080161]; NIDDK NIH HHS [K01 DK068253, K01DK068253]; NINDS NIH HHS [R03 NS053659, R03NS053659] NR 67 TC 54 Z9 57 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 27 PY 2009 VL 4 IS 10 AR e7627 DI 10.1371/journal.pone.0007627 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 511ET UT WOS:000271147400019 PM 19859549 ER PT J AU Chaturvedi, CP Hosey, AM Palii, C Perez-Iratxeta, C Nakatani, Y Ranish, JA Dilworth, FJ Brand, M AF Chaturvedi, Chandra-Prakash Hosey, Alison M. Palii, Carmen Perez-Iratxeta, Carolina Nakatani, Yoshihiro Ranish, Jeffrey A. Dilworth, F. Jeffrey Brand, Marjorie TI Dual role for the methyltransferase G9a in the maintenance of beta-globin gene transcription in adult erythroid cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chromatin; histone methylation; UTX; NF-E2 ID LOCUS-CONTROL REGION; HISTONE H3; LYSINE-9 METHYLATION; HUMAN GENOME; CHROMATIN; DIFFERENTIATION; RECRUITMENT; ACTIVATION; COMPLEX; PROTEIN AB Using a proteomics screen, we have identified the methyltransferase G9a as an interacting partner of the hematopoietic activator NF-E2. We show that G9a is recruited to the beta-globin locus in a NF-E2-dependent manner and spreads over the entire locus. While G9a is often regarded as a corepressor, knocking down this protein in differentiating adult erythroid cells leads to repression of the adult beta(maj) globin gene and aberrant reactivation of the embryonic beta-like globin gene E(y). While in adult cells G9a maintains E(y) in a repressed state via dimethylation of histone H3 at lysines 9 and 27, it activates beta(maj) transcription in a methyltransferase-independent manner. Interestingly, the demethylase UTX is recruited to the beta(maj) (but not the Ey) promoter where it antagonizes G9a-dependent H3K27 dimethylation. Collectively, these results reveal a dual role for G9a in maintaining proper expression (both repression and activation) of the beta-globin genes in differentiating adult erythroid cells. C1 [Chaturvedi, Chandra-Prakash; Hosey, Alison M.; Palii, Carmen; Perez-Iratxeta, Carolina; Dilworth, F. Jeffrey; Brand, Marjorie] Ottawa Hosp, Res Inst, Regenerat Med Program, Sprott Ctr Stem Cell Res, Ottawa, ON K1H 8L6, Canada. [Nakatani, Yoshihiro] Dana Farber Canc Inst, Boston, MA 02115 USA. [Ranish, Jeffrey A.] Inst Syst Biol, Seattle, WA 98103 USA. [Dilworth, F. Jeffrey; Brand, Marjorie] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8L6, Canada. RP Brand, M (reprint author), Ottawa Hosp, Res Inst, Regenerat Med Program, Sprott Ctr Stem Cell Res, Ottawa, ON K1H 8L6, Canada. EM mbrand@ohri.ca FU Canadian Institutes of Health Research; Terry Fox Foundation (Canadian Cancer Society Research Institute); CIHR/Thalassemia Foundation of Canada fellowship FX We thank A. Dean and M. Lorincz for critically reading the manuscript; P. Chambon, S. Pradhan, P. Rakopoulos (The Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON Canada), Y. Shinkai, and L. Tora for providing reagents; A. Desjardins for technical help; G. Palidwor for microarray data analysis; and F. Dumas for Edman sequencing. This project was funded with grants from the Canadian Institutes of Health Research and the Terry Fox Foundation (Canadian Cancer Society Research Institute) (to to M. B.) and a CIHR/Thalassemia Foundation of Canada fellowship (to C-P. C.). M. B. holds the Canadian Research Chair in the regulation of gene expression. NR 35 TC 43 Z9 43 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 27 PY 2009 VL 106 IS 43 BP 18303 EP 18308 DI 10.1073/pnas.0906769106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 512DB UT WOS:000271222500048 PM 19822740 ER PT J AU Zhang, HM Liu, JH Yang, W Springer, T Shimaoka, M Wang, JH AF Zhang, Hongmin Liu, Jin-huan Yang, Wei Springer, Timothy Shimaoka, Motomu Wang, Jia-huai TI Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell adhesion; crystal structure; ICAM-1 ID I-DOMAIN; HIGH-AFFINITY; CRYSTAL-STRUCTURE; DISULFIDE BOND; COMPLEX; ICAM-1; CONFORMATION; RECOGNITION; CD11B/CD18; ADHESION AB The activity of integrin LFA-1 (alpha(L)beta(2)) to its ligand ICAM-1 is regulated through the conformational changes of its ligand-binding domain, the I domain of alpha(L) chain, from an inactive, low-affinity closed form (LA), to an intermediate-affinity form (IA), and then finally, to a high-affinity open form (HA). A ligand-mimetic human monoclonal antibody AL-57 (activated LFA-1 clone 57) was identified by phage display to specifically recognize the affinity-upregulated I domain. Here, we describe the crystal structures of the Fab fragment of AL-57 in complex with IA, as well as in its unligated form. We discuss the structural features conferring AL-57's strong selectivity for the high affinity, open conformation of the I domain. The AL-57-binding site overlaps the ICAM-1 binding site on the I domain. Furthermore, an antibody Asp mimics an ICAM Glu by forming a coordination to the metal-ion dependent adhesion site (MIDAS). The structure also reveals better shape complementarity and a more hydrophobic interacting interface in AL-57 binding than in ICAM-1 binding. The results explain AL-57's antagonistic mimicry of LFA-1's natural ligands, the ICAM molecules. C1 [Yang, Wei; Springer, Timothy; Shimaoka, Motomu] Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. [Springer, Timothy; Shimaoka, Motomu] Childrens Hosp Boston, Program Cellular & Mol Med, Boston, MA 02115 USA. [Zhang, Hongmin; Liu, Jin-huan; Wang, Jia-huai] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat, Boston, MA 02115 USA. [Zhang, Hongmin; Liu, Jin-huan; Wang, Jia-huai] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Yang, Wei; Springer, Timothy] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Shimaoka, Motomu] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. RP Springer, T (reprint author), Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. EM springer@idi.harvard.edu; jwang@red.dfci.harvard.edu RI Zhang, Hongmin/C-4503-2009 OI Zhang, Hongmin/0000-0001-6357-4106 FU National Institutes of Health [HL48675, CA31798, AI063421] FX This work has been supported by National Institutes of Health Grants HL48675 (to J. H. W. and M. S.), CA31798 (to T. A. S.), and AI063421 (to M. S.). NR 26 TC 10 Z9 10 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 OCT 27 PY 2009 VL 106 IS 43 BP 18345 EP 18350 DI 10.1073/pnas.0909301106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 512DB UT WOS:000271222500055 PM 19805116 ER PT J AU Sos, ML Fischer, S Ullrich, R Peifer, M Heuckmann, JM Koker, M Heynck, S Stuckrath, I Weiss, J Fischer, F Michel, K Goel, A Regales, L Politi, KA Perera, S Getlik, M Heukamp, LC Ansen, S Zander, T Beroukhim, R Kashkar, H Shokat, KM Sellers, WR Rauh, D Orr, C Hoeflich, KP Friedman, L Wong, KK Pao, W Thomas, RK AF Sos, Martin L. Fischer, Stefanie Ullrich, Roland Peifer, Martin Heuckmann, Johannes M. Koker, Mirjam Heynck, Stefanie Stueckrath, Isabel Weiss, Jonathan Fischer, Florian Michel, Kathrin Goel, Aviva Regales, Lucia Politi, Katerina A. Perera, Samanthi Getlik, Matthaeus Heukamp, Lukas C. Ansen, Sascha Zander, Thomas Beroukhim, Rameen Kashkar, Hamid Shokat, Kevan M. Sellers, William R. Rauh, Daniel Orr, Christine Hoeflich, Klaus P. Friedman, Lori Wong, Kwok-Kin Pao, William Thomas, Roman K. TI Identifying genotype-dependent efficacy of single and combined PI3K-and MAPK-pathway inhibition in cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer genomics; combination therapy; high-throughput cell line screening; oncogene dependency ID CELL LUNG-CANCER; ACQUIRED-RESISTANCE; MEK INHIBITORS; BCR-ABL; IN-VIVO; KINASE; MUTATIONS; GEFITINIB; ACTIVATION; RAPAMYCIN AB In cancer, genetically activated proto-oncogenes often induce "upstream'' dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce "downstream'' dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials. C1 [Sos, Martin L.; Fischer, Stefanie; Ullrich, Roland; Peifer, Martin; Heuckmann, Johannes M.; Koker, Mirjam; Heynck, Stefanie; Stueckrath, Isabel; Weiss, Jonathan; Fischer, Florian; Michel, Kathrin; Thomas, Roman K.] Univ Cologne, Max Planck Inst Neurol Res, D-50931 Cologne, Germany. [Sos, Martin L.; Fischer, Stefanie; Ullrich, Roland; Peifer, Martin; Heuckmann, Johannes M.; Koker, Mirjam; Heynck, Stefanie; Stueckrath, Isabel; Weiss, Jonathan; Fischer, Florian; Michel, Kathrin; Thomas, Roman K.] Univ Cologne, Klaus Joachim Zulch Labs, Max Planck Soc, D-50931 Cologne, Germany. [Sos, Martin L.; Fischer, Stefanie; Ullrich, Roland; Peifer, Martin; Heuckmann, Johannes M.; Koker, Mirjam; Heynck, Stefanie; Stueckrath, Isabel; Weiss, Jonathan; Fischer, Florian; Michel, Kathrin; Thomas, Roman K.] Univ Cologne, Fac Med, D-50931 Cologne, Germany. [Goel, Aviva; Regales, Lucia; Politi, Katerina A.] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA. [Perera, Samanthi; Beroukhim, Rameen; Wong, Kwok-Kin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Getlik, Matthaeus; Rauh, Daniel; Thomas, Roman K.] Max Planck Soc, Chem Genom Ctr, D-44227 Dortmund, Germany. [Heukamp, Lukas C.] Univ Hosp Bonn Med Sch, Dept Pathol, D-53127 Bonn, Germany. [Ansen, Sascha; Zander, Thomas; Thomas, Roman K.] Univ Cologne, Fac Med, Dept Internal Med, D-50924 Cologne, Germany. [Ansen, Sascha; Zander, Thomas; Thomas, Roman K.] Univ Cologne, Fac Med, Ctr Integrated Oncol Cologne Bonn, D-50924 Cologne, Germany. [Kashkar, Hamid] Univ Cologne, Fac Med, Inst Med Microbiol Immunol & Hyg, D-50924 Cologne, Germany. [Beroukhim, Rameen] Harvard & MIT, Broad Inst, Cambridge, MA 02141 USA. [Shokat, Kevan M.] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA. [Shokat, Kevan M.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA. [Shokat, Kevan M.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Sellers, William R.] Novartis Inst BioMed Res, Cambridge, MA 02139 USA. [Orr, Christine; Hoeflich, Klaus P.; Friedman, Lori] Genentech Inc, Dept Canc Signaling & Translat Oncol, San Francisco, CA 94070 USA. [Wong, Kwok-Kin] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Wong, Kwok-Kin] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Pao, William] Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. RP Thomas, RK (reprint author), Univ Cologne, Max Planck Inst Neurol Res, Gleueler Str 50, D-50931 Cologne, Germany. EM nini@nf.mpg.de RI Rauh, Daniel/G-1595-2013; Heukamp, Lukas/A-8338-2013; OI Rauh, Daniel/0000-0002-1970-7642; wong, kwok kin/0000-0001-6323-235X FU Deutsche Krebshilfe [107954]; Fritz-Thyssen-Stiftung [10.08.2.175]; German Ministry of Science and Education NGFNplus-program BMBF [01GS08100]; Deutsche Forschungsgemeinschaft [SFB832]; National Cancer Institute [R01 CA121210]; Cologne Fortune Program/Faculty of Medicine, University of Cologne FX This work was supported by Deutsche Krebshilfe Grant 107954, Fritz-Thyssen-Stiftung Grant 10.08.2.175, and German Ministry of Science and Education NGFNplus-program BMBF Grant 01GS08100 (to R. K. T.), by the Deutsche Forschungsgemeinschaft through SFB832 (to R. K. T. and L. C. H.), and National Cancer Institute Grant R01 CA121210 (to W. P.). S. F. holds a scholarship of the Cologne Fortune Program/Faculty of Medicine, University of Cologne. NR 39 TC 156 Z9 156 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 27 PY 2009 VL 106 IS 43 BP 18351 EP 18356 DI 10.1073/pnas.0907325106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 512DB UT WOS:000271222500056 PM 19805051 ER PT J AU Bastani, S Sherman, W Schnickel, GT Hsieh, GR Bhatia, R Fishbein, MC Ardehali, A AF Bastani, Sam Sherman, William Schnickel, Gabriel T. Hsieh, George R. Bhatia, Rubina Fishbein, Michael C. Ardehali, Abbas TI Chemokine Receptor Blockade With a Synthetic Nonpeptide Compound Attenuates Cardiac Allograft Vasculopathy SO TRANSPLANTATION LA English DT Article DE Chemokines; Transplantation; T-lymphocytes ID CHRONIC REJECTION; SMALL-MOLECULE; IFN-GAMMA; INDUCIBLE PROTEIN-10; CYTOKINE PRODUCTION; CCR5 ANTAGONIST; CARBON-MONOXIDE; TARGETING CCR5; CXCR3; PATHOGENESIS AB Background. Recruitment of recipient mononuclear cells to the donor heart is a central event in the development of cardiac allograft vasculopathy (CAV). The role of individual chemokine receptors in this process is incompletely defined. TAK-779 (N,N-dimethyl-N-[4-[[[2-(4-methylphen)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetra-hydro-2H-pyran-4-aminium chloride) is a synthetic nonpeptide antagonist of CCR5 and CXCR3. The purpose of this study is to determine if combined CCR5 and CXCR3 blockade by TAK-779 would attenuate CAV in an experimental model. Methods. We used a previously characterized murine model of CAV. Recipient mice were treated with TAK-779 or vehicle control. Donor hearts were harvested on day 24 posttransplantation and analyzed for intimal thickening and cellular infiltration. Recipient splenocytes were analyzed for proliferative response and interferon (IFN)-gamma production by enzyme-linked immunosorbent spot assay. The donor hearts were also examined for heme oxygenase-1 (HO-1) gene induction. Results. CCR5 and CXCR3 blockade by TAK-779 reduced the severity of intimal lesions (53 +/- 10% vs. 16 +/- 2%; P<0.05) and decreased the number of graft infiltrating CCR5(+) and CXCR3(+) CD4 and CD8 lymphocytes. Moreover, treatment with TAK-779 (a) decreased alloantigen-specific T-lymphocyte proliferation and number of IFN-gamma producing cells and (b) increased HO-1 gene transcript level in the allografts. Conclusions. Antagonism of CCR5 and CXCR3 by TAK-779 is effective in controlling CAV. The beneficial effects of TAK-779 maybe because of (a) reduction in CCR5(+) and CXCR3(+) T-lymphocyte subset infiltration into the graft, (b) attenuation of alloantigen-specific T-lymphocyte proliferative response and IFN-gamma production, and (c) induction of HO-1 gene. This compound may offer a novel approach in clinical management of CAV. C1 [Ardehali, Abbas] Univ Calif Los Angeles, Med Ctr, Dept Surg, David Geffen Sch Med,Div Cardiothorac Surg, Los Angeles, CA 90024 USA. [Bastani, Sam; Schnickel, Gabriel T.; Hsieh, George R.; Ardehali, Abbas] W Los Angeles VA Med Ctr, Los Angeles, CA USA. [Fishbein, Michael C.] Univ Calif Los Angeles, Dept Pathol & Lab Med, David Geffen Sch Med, Los Angeles, CA 90024 USA. RP Ardehali, A (reprint author), Univ Calif Los Angeles, Med Ctr, Dept Surg, David Geffen Sch Med,Div Cardiothorac Surg, 62-186 CHS,10833 Le Conte Ave, Los Angeles, CA 90024 USA. EM aardehali@mednet.ucla.edu OI Schnickel, Gabriel/0000-0003-4392-2200 FU American Heart Association; Veterans Administration Research FX This work was supported by the American Heart Association and Veterans Administration Research services grants. NR 35 TC 13 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD OCT 27 PY 2009 VL 88 IS 8 BP 995 EP 1001 DI 10.1097/TP.0b013e3181b9ccd5 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 511MP UT WOS:000271169700009 PM 19855245 ER PT J AU Balcioglu, A AF Balcioglu, Ayguel TI IDENTIFYING TARGETS FOR THE TREATMENT OF DYSTONIA AND PRECLINICALTESTING OF THE LEAD COMPOUNDS SO EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Meeting Abstract C1 [Balcioglu, Ayguel] Harvard Univ, Sch Med, Dept Neurol, Massachusetts Gen Hosp, Boston, MA 02115 USA. NR 7 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0928-0987 EI 1879-0720 J9 EUR J PHARM SCI JI Eur. J. Pharm. Sci. PD OCT 26 PY 2009 VL 38 IS 1 SU S MA O32 BP 53 EP 54 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V38LW UT WOS:000209345900034 ER PT J AU Kalashnikov, M Choi, W Yu, CC Sung, YJ Dasari, RR Badizadegan, K Feld, MS AF Kalashnikov, Maxim Choi, Wonshik Yu, Chung-Chieh Sung, Yongjin Dasari, Ramachandra R. Badizadegan, Kamran Feld, Michael S. TI Assessing light scattering of intracellular organelles in single intact living cells SO OPTICS EXPRESS LA English DT Article ID LOW-COHERENCE INTERFEROMETRY; SCANNING FLOW-CYTOMETRY; EPITHELIAL-CELLS; IN-SITU; SPECTROSCOPY; MICROSCOPY AB This report presents a model-independent method of assessing contributions to the light scattering from individual organelles in single intact cells. We first measure the 3D index map of a living cell, and then modify the map in such a way so as to eliminate contrast due to a particular intracellular organelle. By calculating and comparing the light scattering distributions calculated from the original and modified index maps using the Rytov approximation, we extract the light scattering contribution from the particular organelle of interest. The relative contributions of the nucleus and nucleolus to the scattering of the entire cell are thus determined, and the applicability of the homogeneous spherical model to non-spherical and heterogeneous organelles in forward scattering is evaluated. (C) 2008 Optical Society of America C1 [Kalashnikov, Maxim; Choi, Wonshik; Yu, Chung-Chieh; Sung, Yongjin; Dasari, Ramachandra R.; Badizadegan, Kamran; Feld, Michael S.] MIT, George R Harrison Spect Lab, Cambridge, MA 02139 USA. [Choi, Wonshik] Korea Univ, Dept Phys, Seoul 136701, South Korea. [Badizadegan, Kamran] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Badizadegan, Kamran] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Kalashnikov, M (reprint author), MIT, George R Harrison Spect Lab, Cambridge, MA 02139 USA. EM wonshik@mit.edu FU National Center for Research Resources of the National Institutes of Health [P41-RR02594-18]; National Science Foundation [DBI-0754339]; Hamamatsu Corporation FX This work was funded by the National Center for Research Resources of the National Institutes of Health (P41-RR02594-18), the National Science Foundation (DBI-0754339) and Hamamatsu Corporation. NR 25 TC 16 Z9 16 U1 1 U2 10 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 1094-4087 J9 OPT EXPRESS JI Opt. Express PD OCT 26 PY 2009 VL 17 IS 22 BP 19674 EP 19681 DI 10.1364/OE.17.019674 PG 8 WC Optics SC Optics GA 517PS UT WOS:000271629200035 PM 19997187 ER PT J AU Fang, QQ Boas, DA AF Fang, Qianqian Boas, David A. TI Monte Carlo Simulation of Photon Migration in 3D Turbid Media Accelerated by Graphics Processing Units SO OPTICS EXPRESS LA English DT Article ID DOMAIN FLUORESCENCE TOMOGRAPHY; DIFFUSION-APPROXIMATION; HETEROGENEOUS TISSUES; LIGHT TRANSPORT; HEAD MODELS; SCATTERING; ADULT; CODE; SPECTROSCOPY; PROPAGATION AB We report a parallel Monte Carlo algorithm accelerated by graphics processing units (GPU) for modeling time-resolved photon migration in arbitrary 3D turbid media. By taking advantage of the massively parallel threads and low-memory latency, this algorithm allows many photons to be simulated simultaneously in a GPU. To further improve the computational efficiency, we explored two parallel random number generators (RNG), including a floating-point-only RNG based on a chaotic lattice. An efficient scheme for boundary reflection was implemented, along with the functions for time-resolved imaging. For a homogeneous semi-infinite medium, good agreement was observed between the simulation output and the analytical solution from the diffusion theory. The code was implemented with CUDA programming language, and benchmarked under various parameters, such as thread number, selection of RNG and memory access pattern. With a low-cost graphics card, this algorithm has demonstrated an acceleration ratio above 300 when using 1792 parallel threads over conventional CPU computation. The acceleration ratio drops to 75 when using atomic operations. These results render the GPU-based Monte Carlo simulation a practical solution for data analysis in a wide range of diffuse optical imaging applications, such as human brain or small-animal imaging. (C) 2009 Optical Society of America C1 [Fang, Qianqian; Boas, David A.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Fang, QQ (reprint author), Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, 149 13th St, Charlestown, MA 02129 USA. FU NIH [R01-EB006385] FX The authors would like to acknowledge Eric Mills for developing and sharing the shared-memory version of MT19976 random number generator. QF would like to thank Stefan Carp and Anand Kumar for the discussions on fluence normalization, and Jay Dubb for processing the brain MRI atlas. We acknowledge funding support from NIH R01-EB006385 and the valuable feedback from anonymous reviewers. NR 35 TC 209 Z9 220 U1 7 U2 50 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 OCT 26 PY 2009 VL 17 IS 22 BP 20178 EP 20190 DI 10.1364/OE.17.020178 PG 13 WC Optics SC Optics GA 517PS UT WOS:000271629200090 PM 19997242 ER PT J AU Moriarty, AT Laucirica, R Auger, M Souers, RJ Chmara, BA Wilbur, DC AF Moriarty, Ann T. Laucirica, Rodolfo Auger, Manon Souers, Rhona J. Chmara, Beth Anne Wilbur, David C. TI Granulomatous Inflammation: An Underestimated Cause of False Positive Diagnoses in Lung Fine Needle Aspirates Observations from the College of American Pathologists Non Gynecologic Cytopathology (NGC) Interlaboratory Comparison Program SO CANCER CYTOPATHOLOGY LA English DT Meeting Abstract C1 [Moriarty, Ann T.] AmeriPath Indiana, Indianapolis, IN USA. [Laucirica, Rodolfo] Baylor Coll Med, Houston, TX 77030 USA. [Auger, Manon] McGill Univ, Montreal, PQ, Canada. [Souers, Rhona J.; Chmara, Beth Anne] Coll Amer Pathologists, Northfield, IL USA. [Wilbur, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD OCT 25 PY 2009 VL 117 IS 5 BP 350 EP 350 PG 1 WC Oncology; Pathology SC Oncology; Pathology GA 510HM UT WOS:000271078800004 ER PT J AU Ducatman, BS Bentz, JS Moriarty, AT Souers, RJ Fatheree, LA Booth, CN Wilbur, DC AF Ducatman, Barbara S. Bentz, Joel S. Moriarty, Ann T. Souers, Rhona J. Fatheree, Lisa A. Booth, Christine Noga Wilbur, David C. TI Performance in Gynecologic Cytology Proficiency Testing: What Have We Learned? SO CANCER CYTOPATHOLOGY LA English DT Meeting Abstract C1 [Ducatman, Barbara S.] W Virginia Univ Hosp, Indianapolis, WV USA. [Bentz, Joel S.] Univ Utah, Salt Lake City, UT USA. [Moriarty, Ann T.] AmeriPath Indiana, Indianapolis, IN USA. [Souers, Rhona J.; Fatheree, Lisa A.] Coll Amer Pathologists, Northfield, IL USA. [Booth, Christine Noga] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44106 USA. [Wilbur, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD OCT 25 PY 2009 VL 117 IS 5 BP 352 EP 353 PG 2 WC Oncology; Pathology SC Oncology; Pathology GA 510HM UT WOS:000271078800008 ER PT J AU Qayyum, S Yagi, Y Wilbur, DC AF Qayyum, Sohail Yagi, Yukako Wilbur, David C. TI Optimization of Whole Slide Imaging Parameters for Liquid-Based Cervical Cytology Slides SO CANCER CYTOPATHOLOGY LA English DT Meeting Abstract C1 [Qayyum, Sohail; Yagi, Yukako; Wilbur, David C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD OCT 25 PY 2009 VL 117 IS 5 BP 353 EP 354 PG 2 WC Oncology; Pathology SC Oncology; Pathology GA 510HM UT WOS:000271078800010 ER PT J AU Sweeney, BJ Wilbur, D Arpin, RN Nave, JO Tambouret, R AF Sweeney, Brenda J. Wilbur, David Arpin, Ronald N., III Nave, Jolanta O. Tambouret, Rosemary TI Cell Cycle Markers in Urinary Cytology: Preliminary Studies Show Promise for the Triage of Equivocal Specimens SO CANCER CYTOPATHOLOGY LA English DT Meeting Abstract C1 [Sweeney, Brenda J.; Wilbur, David; Arpin, Ronald N., III; Nave, Jolanta O.; Tambouret, Rosemary] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD OCT 25 PY 2009 VL 117 IS 5 BP 371 EP 371 PG 1 WC Oncology; Pathology SC Oncology; Pathology GA 510HM UT WOS:000271078800037 ER PT J AU Sweeney, BJ Wilbur, D Arpin, R Tambouret, R AF Sweeney, Brenda J. Wilbur, David Arpin, Ronald Tambouret, Rosemary TI Testing for High Risk Human Papillomavirus, p16 and ProEx (TM) C on Cervico-vaginal Cytology SO CANCER CYTOPATHOLOGY LA English DT Meeting Abstract C1 [Sweeney, Brenda J.; Wilbur, David; Arpin, Ronald; Tambouret, Rosemary] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD OCT 25 PY 2009 VL 117 IS 5 BP 386 EP 386 PG 1 WC Oncology; Pathology SC Oncology; Pathology GA 510HM UT WOS:000271078800062 ER PT J AU Roh, MH Jo, VY Stelow, EB Faquin, WC Alexander, EK Benson, CB Frates, MC Gawande, A Larsen, PR Marqusee, E Moore, FD Cibas, ES AF Roh, Michael H. Jo, Vickie Y. Stelow, Edward B. Faquin, William C. Alexander, Erik K. Benson, Carol B. Frates, Mary C. Gawande, Atul Larsen, P. Reed Marqusee, Ellen Moore, Francis D., Jr. Cibas, Edmund S. TI The Predictive Value of the Fine Needle Aspiration Diagnosis "Suspicious for a Hurthle Cell Neoplasm" in Patients with Hashimoto Thyroiditis SO CANCER CYTOPATHOLOGY LA English DT Meeting Abstract C1 [Alexander, Erik K.; Benson, Carol B.; Frates, Mary C.; Gawande, Atul; Larsen, P. Reed; Marqusee, Ellen; Moore, Francis D., Jr.; Cibas, Edmund S.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Jo, Vickie Y.; Stelow, Edward B.] Univ Virginia Hlth Syst, Charlottesville, VA USA. [Faquin, William C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1934-662X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD OCT 25 PY 2009 VL 117 IS 5 BP 434 EP 435 PG 2 WC Oncology; Pathology SC Oncology; Pathology GA 510HM UT WOS:000271078800142 ER PT J AU Franciosi, S Sosa, MAG English, DF Oler, E Oung, T Janssen, WGM De Gasperi, R Schmeidler, J Dickstein, DL Schmitz, C Gandy, S Hof, PR Buxbaum, JD Elder, GA AF Franciosi, Sonia Sosa, Miguel A. Gama English, Daniel F. Oler, Elizabeth Oung, Twethida Janssen, William G. M. De Gasperi, Rita Schmeidler, James Dickstein, Dara L. Schmitz, Christoph Gandy, Sam Hof, Patrick R. Buxbaum, Joseph D. Elder, Gregory A. TI Novel cerebrovascular pathology in mice fed a high cholesterol diet SO MOLECULAR NEURODEGENERATION LA English DT Article ID DENSITY-LIPOPROTEIN RECEPTOR; ALZHEIMERS-DISEASE; MICROVASCULAR RESPONSES; METABOLIC SYNDROME; APOLIPOPROTEIN-E; KNOCKOUT MICE; RISK-FACTOR; LOW-FAT; HYPERCHOLESTEROLEMIA; ATHEROSCLEROSIS AB Background: Hypercholesterolemia causes atherosclerosis in medium to large sized arteries. Cholesterol is less known for affecting the microvasculature and has not been previously reported to induce microvascular pathology in the central nervous system (CNS). Results: Mice with a null mutation in the low-density lipoprotein receptor (LDLR) gene as well as C57BL/6J mice fed a high cholesterol diet developed a distinct microvascular pathology in the CNS that differs from cholesterol-induced atherosclerotic disease. Microvessel diameter was increased but microvascular density and length were not consistently affected. Degenerative changes and thickened vascular basement membranes were present ultrastructurally. The observed pathology shares features with the microvascular pathology of Alzheimer's disease (AD), including the presence of string-like vessels. Brain apolipoprotein E levels which have been previously found to be elevated in LDLR-/- mice were also increased in C57BL/6J mice fed a high cholesterol diet. Conclusion: In addition to its effects as an inducer of atherosclerosis in medium to large sized arteries, hypercholesterolemia also induces a microvascular pathology in the CNS that shares features of the vascular pathology found in AD. These observations suggest that high cholesterol may induce microvascular disease in a range of CNS disorders including AD. C1 [Franciosi, Sonia; Sosa, Miguel A. Gama; English, Daniel F.; De Gasperi, Rita; Schmeidler, James; Gandy, Sam; Buxbaum, Joseph D.; Elder, Gregory A.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Franciosi, Sonia; English, Daniel F.; Buxbaum, Joseph D.] Mt Sinai Sch Med, Lab Mol Neuropsychiat, New York, NY 10029 USA. [Franciosi, Sonia; Sosa, Miguel A. Gama; De Gasperi, Rita] Vet Affairs Med Ctr, James J Peters Dept, Res & Dev Serv, Bronx, NY 10468 USA. [Oler, Elizabeth; Oung, Twethida; Janssen, William G. M.; Dickstein, Dara L.; Schmitz, Christoph; Hof, Patrick R.; Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Dickstein, Dara L.; Hof, Patrick R.] Mt Sinai Sch Med, Computat Neurobiol & Imaging Ctr, New York, NY 10029 USA. [Gandy, Sam; Elder, Gregory A.] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA. [Gandy, Sam; Elder, Gregory A.] Vet Affairs Med Ctr, James J Peters Dept, Neurol Serv, Bronx, NY 10468 USA. [Hof, Patrick R.] Mt Sinai Sch Med, Dept Geriatr & Adult Dev, New York, NY 10029 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. RP Elder, GA (reprint author), Mt Sinai Sch Med, Dept Psychiat, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM sfranciosi@cmmt.ubc.ca; miguel.gama-sosa@mssm.edu; englishdaniel@gmail.com; lizoler@gmail.com; twethida.oung@mssm.edu; bill.janssen@mssm.edu; rita.de-gasperi@mssm.edu; james.schmeidler@mssm.edu; dara.dickstein@mssm.edu; cs.999@gmx.net; samuel.gandy@mssm.edu; patrick.hof@mssm.edu; joseph.buxbaum@mssm.edu; gregory.elder@mssm.edu RI Dickstein, Dara/F-3036-2013; OI Buxbaum, Joseph/0000-0001-8898-8313 FU NIH [AG02219, AG05138] FX We thank Bridget Wicinski for expert technical assistance. This work was supported by NIH grants AG02219 and AG05138. NR 53 TC 11 Z9 11 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD OCT 24 PY 2009 VL 4 AR 42 DI 10.1186/1750-1326-4-42 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 517JG UT WOS:000271608800001 PM 19852847 ER PT J AU Choi, AI Shlipak, MG Hunt, PW Martin, JN Deeks, SG AF Choi, Andy I. Shlipak, Michael G. Hunt, Peter W. Martin, Jeffrey N. Deeks, Steven G. TI HIV-infected persons continue to lose kidney function despite successful antiretroviral therapy SO AIDS LA English DT Article DE antiretroviral therapy; glomerular filtration rate; HIV; kidney diseases; viral load ID IMPROVES RENAL-FUNCTION; RISK-FACTORS; SERUM CREATININE; DISEASE; NEPHROPATHY; WOMEN; ASSOCIATION; FAILURE; RECOMMENDATIONS; PROTEINURIA AB Objective: To identify risk factors associated with kidney function decline in a contemporary cohort of treated and untreated HIV-infected patients. Methods: We followed individuals enrolled in the Study of the Consequences Of the Protease inhibitor Era cohort for longitudinal changes in kidney function, defined as glomerular filtration rate estimated from serum creatinine (eGFR). eGFR slope was calculated using linear mixed effects models adjusted for age, sex, race, and time-updated CD4 cell count, viral load, antiretroviral therapy (ART), and comorbid conditions. Results: We followed 615 patients for a mean of 3.4 (+/- 2.5) years. In multivariable adjusted analyses, predictors of eGFR decline included female sex, diabetes, and hyperlipidemia; CD4 cell count and viral load were not associated with eGFR loss. Among patients who initiated treatment, antiretroviral exposure was associated with a +2.8 (95% confidence interval 0.8-4.7) ml/min per 1.73 m(2) per year effect on eGFR slope. Although these patients appeared to benefit from ART based on the slowing of their eGFR decline, they continued to lose kidney function at a rate of -1.9 (95% confidence interval -3.7 to -0.1) ml/min per 1.73 m(2) per year. In the subgroup of individuals receiving suppressive ART with viral loads maintained below 500 copies/ml, intermittent viremic episodes (blips) were strongly associated with more rapid rates of eGFR loss [-6.7 (95% confidence interval -11.1 to -2.4) ml/min per 1.73 m2 per year]. Conclusion: Although ART appears to help curb kidney function decline, patients who achieved durable viral suppression continue to manifest substantial loss of eGFR. Loss of kidney function may be attributable to treatment-related factors, intermittent viremia, and traditional risk factors for kidney disease. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Choi, Andy I.; Shlipak, Michael G.] San Francisco VA Med Ctr, Dept Med, San Francisco, CA 94121 USA. [Choi, Andy I.; Shlipak, Michael G.; Martin, Jeffrey N.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Hunt, Peter W.; Deeks, Steven G.] San Francisco Gen Hosp, Posit Hlth Program, San Francisco, CA 94110 USA. [Martin, Jeffrey N.] Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. RP Choi, AI (reprint author), San Francisco VA Med Ctr, Dept Med, Box 111J,4150 Clement St, San Francisco, CA 94121 USA. EM andy.choi@ucsf.edu FU National Institutes of Health [K23DK080645-01A1, K23AI65244, K24AI069994, R01 DK066488-01]; Centers for AIDS Research at UCSF [A127763, MH59037]; UCSF Clinical and Translational Science Institute [UL1 RR024131-01]; National Center for Research Resources [KL2 RR024130]; American Heart Association Early Investigator Award; American Foundation for AIDS Research [106710-40-RGRL] FX This study was supported by grants from the National Institutes of Health (K23DK080645-01A1, K23AI65244, K24AI069994, and R01 DK066488-01), the Centers for AIDS Research at UCSF (A127763 and MH59037), the UCSF Clinical and Translational Science Institute (UL1 RR024131-01), the National Center for Research Resources (KL2 RR024130), the American Heart Association Early Investigator Award, and the American Foundation for AIDS Research (106710-40-RGRL). These funding sources had no involvement in the design or execution of this study. NR 38 TC 53 Z9 54 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 OCT 23 PY 2009 VL 23 IS 16 BP 2143 EP 2149 DI 10.1097/QAD.0b013e3283313c91 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 517FS UT WOS:000271599200009 PM 19684507 ER PT J AU Snow, JW Orkin, SH AF Snow, Jonathan W. Orkin, Stuart H. TI Translational Isoforms of FOG1 Regulate GATA1-interacting Complexes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; ZINC-FINGER PROTEIN; ERYTHROID-CELLS; CO-REPRESSOR; NORMAL ERYTHROPOIESIS; MAMMALIAN-CELLS; BINDING-PROTEIN; GENE-EXPRESSION; MESSENGER-RNA; ACTIVATION AB Erythropoietic and megakaryocytic programs are directed by the transcription factor GATA1. Friend of GATA1 (FOG1), a protein interaction partner of GATA1, is critical for GATA1 function in multiple contexts. Previous work has shown that FOG1 recruits two multi-protein complexes, the nucleosome remodeling domain (NuRD) complex and a C-terminal binding protein (CTBP)-containing complex, into association with GATA1 to mediate activation and repression of target genes. To elucidate mechanisms that might differentially regulate the association of FOG1, as well as GATA1, with these two complexes, we characterized a previously unrecognized translational isoform of FOG1. We found that an N-terminally truncated version of FOG1 is produced from an internal ATG and that this isoform, designated FOG1S, lacks the nucleosome remodeling domain-binding domain, altering the complexes with which it interacts. Both isoforms interact with the C-terminal binding protein complex, which we show also contains lysine-specific demethylase 1 (LSD1). FOG1S is preferentially excluded from the nucleus by unknown mechanisms. These data reveal two novel mechanisms for the regulation of GATA1 interaction with FOG1-dependent protein complexes through the production of two translational isoforms with differential interaction profiles and independent nuclear localization controls. C1 [Snow, Jonathan W.; Orkin, Stuart H.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. [Snow, Jonathan W.; Orkin, Stuart H.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Snow, Jonathan W.; Orkin, Stuart H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Orkin, Stuart H.] Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Childrens Hosp, Div Hematol, 300 Longwood Ave, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu FU National Institutes of Health [HL32259, HL32262] FX This work was supported, in whole or in part, by National Institutes of Health Grants HL32259 and HL32262 (to S. H. O.). NR 52 TC 13 Z9 13 U1 0 U2 4 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 OCT 23 PY 2009 VL 284 IS 43 BP 29310 EP 29319 DI 10.1074/jbc.M109.043497 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 507ZW UT WOS:000270896800010 PM 19654328 ER PT J AU Xu, HM Eleswarapu, S Geiger, H Szczur, K Daria, D Zheng, Y Settleman, J Srour, EF Williams, DA Filippi, MD AF Xu, Haiming Eleswarapu, Satyam Geiger, Hartmut Szczur, Kathleen Daria, Deidre Zheng, Yi Settleman, Jeffrey Srour, Edward F. Williams, David A. Filippi, Marie-Dominique TI Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential SO BLOOD LA English DT Article ID SELF-RENEWAL; BONE-MARROW; FETAL LIVER; CYCLE TRANSIT; LIFE-SPAN; PROLIFERATION; QUIESCENCE; MICE; NICHE; CDC42 AB Hematopoietic stem cell (HSC) engraftment is a multistep process involving HSC homing to bone marrow, self-renewal, proliferation, and differentiation to mature blood cells. Here, we show that loss of p190-B RhoGTPase activating protein, a negative regulator of Rho GTPases, results in enhanced long-term engraftment during serial transplantation. This effect is associated with maintenance of functional HSC-enriched cells. Furthermore, loss of p190-B led to marked improvement of HSC in vivo repopulation capacity during ex vivo culture without altering proliferation and multilineage differentiation of HSC and progeny. Transcriptional analysis revealed that p190-B deficiency represses the up-regulation of p16(Ink4a) in HSCs in primary and secondary transplantation recipients, providing a possible mechanism of p190-B-mediated HSC functions. Our study defines p190-B as a critical transducer element of HSC self-renewal activity and long-term engraftment, thus suggesting that p190-B is a target for HSC-based therapies requiring maintenance of engraftment phenotype. (Blood. 2009;114:3557-3566) C1 [Xu, Haiming; Eleswarapu, Satyam; Geiger, Hartmut; Szczur, Kathleen; Daria, Deidre; Zheng, Yi; Williams, David A.; Filippi, Marie-Dominique] Cincinnati Childrens Res Fdn, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Xu, Haiming] Univ Cincinnati, Coll Med, Cell & Mol Biol Grad Program, Cincinnati, OH 45221 USA. [Geiger, Hartmut] Univ Ulm, Dept Dermatol & Allerg Dis Aging Res, Ulm, Germany. [Settleman, Jeffrey] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Settleman, Jeffrey] Harvard Univ, Sch Med, Boston, MA USA. [Srour, Edward F.] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN USA. RP Filippi, MD (reprint author), Cincinnati Childrens Res Fdn, Div Expt Hematol & Canc Biol, S7-605, Cincinnati, OH 45229 USA. EM DAWilliams@childrens.harvard.edu; Marie-Dominique.Filippi@cchmc.org RI Xu, Haiming/A-2238-2014; Zheng, Yi/J-7235-2015 OI Zheng, Yi/0000-0001-7089-6074 FU Board of Trustee Cincinnati Children's Hospital Medical Center Award (M.-D.F.); American Heart Association Scientific and Development; National Institutes of Health [DK62757] FX The work was supported in part by a Board of Trustee Cincinnati Children's Hospital Medical Center Award (M.-D.F.), an American Heart Association Scientific and Development Grant Award (M.-D.F.), and the National Institutes of Health (DK62757) (D.A.W.). NR 59 TC 13 Z9 13 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 22 PY 2009 VL 114 IS 17 BP 3557 EP 3566 DI 10.1182/blood-2009-02-205815 PG 10 WC Hematology SC Hematology GA 509NK UT WOS:000271024500009 PM 19713466 ER PT J AU Pitsouli, C Apidianakis, Y Perrimon, N AF Pitsouli, Chrysoula Apidianakis, Yiorgos Perrimon, Norbert TI Homeostasis in Infected Epithelia: Stem Cells Take the Lead SO CELL HOST & MICROBE LA English DT Review ID UROPATHOGENIC ESCHERICHIA-COLI; DROSOPHILA MIDGUT; BACTERIAL-INFECTION; URINARY-TRACT; HOST DEFENSES; SELF-RENEWAL; PROLIFERATION; REGENERATION; ACTIVATION; INTESTINE AB To maintain tissue homeostasis and avoid disease, epithelial cells damaged by pathogens need to be readily replenished, and this is mainly achieved by the activation of stem cells. In this Short Review, we discuss recent developments in the exciting field of host epithelia-pathogen interaction in Drosophila as well as in mammals. C1 [Pitsouli, Chrysoula; Perrimon, Norbert] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Perrimon, Norbert] Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. [Apidianakis, Yiorgos] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Apidianakis, Yiorgos] Massachusetts Gen Hosp, Shriners Burns Inst, Boston, MA 02114 USA. RP Perrimon, N (reprint author), Harvard Univ, Sch Med, Dept Genet, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM perrimon@receptor.med.harvard.edu OI Apidianakis, Yiorgos/0000-0002-7465-3560 FU Howard Hughes Medical Institute NR 32 TC 18 Z9 18 U1 0 U2 5 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 OCT 22 PY 2009 VL 6 IS 4 BP 301 EP 307 DI 10.1016/j.chom.2009.10.001 PG 7 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 512EQ UT WOS:000271227700006 PM 19837370 ER PT J AU Joubert, PE Meiffren, G Gregoire, IP Pontini, G Richetta, C Flacher, M Azocar, O Vidalain, PO Vidal, M Lotteau, V Codogno, P Rabourdin-Combe, C Faure, M AF Joubert, Pierre-Emmanuel Meiffren, Gregory Gregoire, Isabel Pombo Pontini, Guillemette Richetta, Clemence Flacher, Monique Azocar, Olga Vidalain, Pierre-Olivier Vidal, Marc Lotteau, Vincent Codogno, Patrice Rabourdin-Combe, Chantal Faure, Mathias TI Autophagy Induction by the Pathogen Receptor CD46 SO CELL HOST & MICROBE LA English DT Article ID COFACTOR PROTEIN CD46; MEASLES-VIRUS; CELLULAR RECEPTOR; MONITORING AUTOPHAGY; ADAPTIVE IMMUNITY; 3-KINASE COMPLEX; INNATE IMMUNITY; HOST-CELL; RECOGNITION; BINDING AB Autophagy is a highly regulated self-degradative mechanism required at a basal level for intracellular clearance and recycling of cytoplasmic contents. Upon intracellular pathogen invasion, autophagy can be induced as an innate immune mechanism to control infection. Nevertheless, pathogens have developed strategies to avoid or hijack autophagy for their own benefit. The molecular pathways inducing autophagy in response to infection remain poorly documented. We report here that the engagement of CD46, a ubiquitous human surface receptor able to bind several different pathogens, is sufficient to induce autophagy. CD46-Cyt-1, one of the two C-terminal splice variants of CD46, is linked to the autophagosome formation complex VPS34/Beclin1 via its interaction with the scaffold protein GOPC. Measles virus and group A Streptococcus, two CD46-binding pathogens, induce autophagy through a CD46-Cyt-1/GOPC pathway. Thus, upon microorganism recognition, a cell surface pathogen receptor can directly trigger autophagy, a critical step to control infection. C1 [Joubert, Pierre-Emmanuel; Meiffren, Gregory; Gregoire, Isabel Pombo; Pontini, Guillemette; Richetta, Clemence; Flacher, Monique; Azocar, Olga; Lotteau, Vincent; Rabourdin-Combe, Chantal; Faure, Mathias] Univ Lyon, F-69003 Lyon, France. [Joubert, Pierre-Emmanuel; Meiffren, Gregory; Gregoire, Isabel Pombo; Pontini, Guillemette; Richetta, Clemence; Flacher, Monique; Azocar, Olga; Lotteau, Vincent; Rabourdin-Combe, Chantal; Faure, Mathias] INSERM, U851, F-69007 Lyon, France. [Joubert, Pierre-Emmanuel; Meiffren, Gregory; Gregoire, Isabel Pombo; Pontini, Guillemette; Richetta, Clemence; Flacher, Monique; Azocar, Olga; Lotteau, Vincent; Rabourdin-Combe, Chantal; Faure, Mathias] Univ Lyon 1, IFR128, F-69007 Lyon, France. [Vidalain, Pierre-Olivier; Vidal, Marc] Harvard Univ, Sch Med, CCSB, Boston, MA 02115 USA. [Vidalain, Pierre-Olivier; Vidal, Marc] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Vidalain, Pierre-Olivier; Vidal, Marc] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Vidalain, Pierre-Olivier] Inst Pasteur, CNRS, URA 3015, F-75724 Paris 15, France. [Codogno, Patrice] Univ Paris 11, Fac Pharm, F-92296 Chatenay Malabry, France. [Codogno, Patrice] INSERM, U756, F-92296 Chatenay Malabry, France. RP Faure, M (reprint author), Univ Lyon, F-69003 Lyon, France. EM mathias.faure@inserm.fr RI Codogno, Patrice/G-1384-2013; FAURE, Mathias/M-5627-2014; lotteau, vincent/M-8143-2014 OI Codogno, Patrice/0000-0002-5492-3180; FU INSER; UCBLyon-1; Institut National du Cancer- Canceropole; Ministere de l'Enseignement Superieur et de la Recherche; [INCA ACI-63-04]; [ARC 3949]; [ANR-08-JCJC-0064-01] FX We thank Dr. Gregoire Lauvau and Dr. Christophe Viret for critical comments on the manuscript. We thank Drs. C. Delprat and L. Genestier for discussion and M. Le Breton and A. Deloire for experimental help. We thank, from the IFR128, A. Chaboud (protein production and analysis), F. Simian-Lerme, C. Lionnet (Imaging PLATIM), and C. Bella (Flux cytometry). We are grateful to Pr. C. Poyart, Dr. T. Yoshimori, Dr. B. Loveland, and Dr. R. ucklan or providing us with materials. This work was supported by INSER, UCBLyon-1, and Institut National du Cancer- Canceropole, INCA ACI-63-04, ARC 3949, and ANR-08-JCJC-0064-01. G.M. and P.-E.J. are recipients of a fellowship from the Ministere de l'Enseignement Superieur et de la Recherche. NR 57 TC 112 Z9 120 U1 0 U2 8 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 OCT 22 PY 2009 VL 6 IS 4 BP 354 EP 366 DI 10.1016/j.chom.2009.09.006 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 512EQ UT WOS:000271227700011 PM 19837375 ER PT J AU Sidransky, E Nalls, MA Aasly, JO Aharon-Peretz, J Annesi, G Barbosa, ER Bar-Shira, A Berg, D Bras, J Brice, A Chen, CM Clark, LN Condroyer, C De Marco, EV Durr, A Eblan, MJ Fahn, S Farrer, MJ Fung, HC Gan-Or, Z Gasser, T Gershoni-Baruch, R Giladi, N Griffith, A Gurevich, T Januario, C Kropp, P Lang, AE Lee-Chen, GJ Lesage, S Marder, K Mata, IF Mirelman, A Mitsui, J Mizuta, I Nicoletti, G Oliveira, C Ottman, R Orr-Urtreger, A Pereira, LV Quattrone, A Rogaeva, E Rolfs, A Rosenbaum, H Rozenberg, R Samii, A Samaddar, T Schulte, C Sharma, M Singleton, A Spitz, M Tan, EK Tayebi, N Toda, T Troiano, AR Tsuji, S Wittstock, M Wolfsberg, TG Wu, YR Zabetian, CP Zhao, Y Ziegler, SG AF Sidransky, E. Nalls, M. A. Aasly, J. O. Aharon-Peretz, J. Annesi, G. Barbosa, E. R. Bar-Shira, A. Berg, D. Bras, J. Brice, A. Chen, C. -M. Clark, L. N. Condroyer, C. De Marco, E. V. Duerr, A. Eblan, M. J. Fahn, S. Farrer, M. J. Fung, H. -C. Gan-Or, Z. Gasser, T. Gershoni-Baruch, R. Giladi, N. Griffith, A. Gurevich, T. Januario, C. Kropp, P. Lang, A. E. Lee-Chen, G. -J. Lesage, S. Marder, K. Mata, I. F. Mirelman, A. Mitsui, J. Mizuta, I. Nicoletti, G. Oliveira, C. Ottman, R. Orr-Urtreger, A. Pereira, L. V. Quattrone, A. Rogaeva, E. Rolfs, A. Rosenbaum, H. Rozenberg, R. Samii, A. Samaddar, T. Schulte, C. Sharma, M. Singleton, A. Spitz, M. Tan, E. -K. Tayebi, N. Toda, T. Troiano, A. R. Tsuji, S. Wittstock, M. Wolfsberg, T. G. Wu, Y. -R. Zabetian, C. P. Zhao, Y. Ziegler, S. G. TI Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson's Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LEWY BODY DISORDERS; GAUCHER-DISEASE; GENE-MUTATIONS; EARLY-ONSET; RISK-FACTOR; GBA; SUSCEPTIBILITY; MANIFESTATIONS; POLYMORPHISM; ASSOCIATION AB Background Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. Methods Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. Results All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Conclusions Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease. C1 [Sidransky, E.; Eblan, M. J.; Samaddar, T.; Tayebi, N.; Ziegler, S. G.] NHGRI, Sect Mol Neurogenet, Med Genet Branch, Bethesda, MD 20892 USA. [Nalls, M. A.; Bras, J.; Samii, A.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Wolfsberg, T. G.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Aasly, J. O.] St Olavs Hosp, Dept Neurol, Trondheim, Norway. [Aasly, J. O.] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway. [Aharon-Peretz, J.] Technion Israel Inst Technol, Cognit Neurol & Movement Disorder Unit, Haifa, Israel. [Gershoni-Baruch, R.] Technion Israel Inst Technol, Human Genet Rambam Med Ctr, Haifa, Israel. [Gershoni-Baruch, R.] Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel. [Rosenbaum, H.] Technion Israel Inst Technol, Dept Hematol, IL-31096 Haifa, Israel. [Rosenbaum, H.] Technion Israel Inst Technol, Dept Bone Marrow Transplant, IL-31096 Haifa, Israel. [Nicoletti, G.; Quattrone, A.] Magna Graecia Univ Catanzaro, Dept Med Sci, Inst Neurol, Catanzaro, Italy. [Annesi, G.; De Marco, E. V.; Nicoletti, G.; Quattrone, A.] CNR, Inst Neurol Sci, Cosenza, Italy. [Barbosa, E. R.; Spitz, M.] Univ Sao Paulo, Sch Med, Dept Neurol, Movement Disorders Unit, Sao Paulo, Brazil. [Pereira, L. V.; Rozenberg, R.] Univ Sao Paulo, Biosci Inst, Dept Genet & Evolutionary Biol, Mol Genet Lab, Sao Paulo, Brazil. [Bar-Shira, A.; Gan-Or, Z.; Orr-Urtreger, A.] Tel Aviv Univ, Genet Inst, IL-69978 Tel Aviv, Israel. [Giladi, N.; Gurevich, T.; Mirelman, A.] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Dept Neurol, Movement Disorders Unit,Parkinson Ctr, IL-69978 Tel Aviv, Israel. [Gan-Or, Z.; Giladi, N.; Gurevich, T.; Orr-Urtreger, A.] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. [Berg, D.; Gasser, T.; Schulte, C.; Sharma, M.] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany. [Bras, J.; Oliveira, C.] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Januario, C.; Oliveira, C.] Univ Coimbra Hosp, Neurol Serv, Coimbra, Portugal. [Brice, A.; Condroyer, C.; Duerr, A.; Lesage, S.] Univ Paris 06, INSERM, Ctr Rech,Inst Cerveau & Moelle Epiniere, Unite Mixte Rech S679, Paris, France. [Brice, A.; Duerr, A.] Grp Hosp Pitie Salpetriere, AP HP, F-75634 Paris, France. [Brice, A.; Duerr, A.] Grp Hosp Pitie Salpetriere, Dept Genet & Cytogenet, F-75634 Paris, France. [Chen, C. -M.; Fung, H. -C.; Wu, Y. -R.] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp, Dept Neurol, Taipei, Taiwan. [Clark, L. N.; Marder, K.] Columbia Univ Coll Phys & Surg, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY 10032 USA. [Clark, L. N.] Columbia Univ Coll Phys & Surg, Ctr Human Genet, New York, NY 10032 USA. [Clark, L. N.] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. [Fahn, S.; Marder, K.; Ottman, R.] Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. [Marder, K.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Marder, K.; Ottman, R.] Columbia Univ Coll Phys & Surg, Gertrude H Sergievsky Ctr, New York, NY 10032 USA. [Ottman, R.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Ottman, R.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Farrer, M. J.] Mayo Clin, Coll Med, Dept Neurosci, Neurogenet Lab, Jacksonville, FL 32224 USA. [Griffith, A.] Evergreen Hosp Med Ctr, Booth Gardner Parkinsons Care Ctr, Kirkland, WA USA. [Kropp, P.] Univ Rostock, Inst Med Psychol, Rostock, Germany. [Rolfs, A.] Univ Rostock, Albrecht Kossel Inst Neuroregenerat, Rostock, Germany. [Wittstock, M.] Univ Rostock, Dept Neurol, Rostock, Germany. [Lang, A. E.] Toronto Western Hosp, Movement Disorders Ctr, Div Neurol, Dept Med, Toronto, ON M5T 2S8, Canada. [Rogaeva, E.] Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. [Lee-Chen, G. -J.] Natl Taiwan Normal Univ, Dept Life Sci, Taipei, Taiwan. [Mata, I. F.; Samii, A.; Zabetian, C. P.] VA Puget Sound Hlth Care Syst, Parkinsons Dis & Geriatr Res Educ & Clin Ctr, Seattle, WA USA. [Mata, I. F.; Samii, A.; Zabetian, C. P.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Mitsui, J.; Tsuji, S.] Univ Tokyo, Grad Sch Med, Dept Neurol, Tokyo, Japan. [Mizuta, I.; Toda, T.] Kobe Univ, Grad Sch Med, Div Neurol & Mol Brain Sci, Kobe, Hyogo 657, Japan. [Tan, E. -K.] Singapore Gen Hosp, Natl Inst Neurosci, Singapore 0316, Singapore. [Tan, E. -K.] Duke NUS Grada Med Sch, Singapore, Singapore. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, Rm 1A213,35 Convent Dr, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov RI Bras, Jose/D-3366-2009; Bras, Jose/A-1428-2011; Singleton, Andrew/C-3010-2009; Mitsui, Jun/B-5455-2012; Pereira, Lygia/C-1049-2012; Kropp, Peter/B-8132-2012; Barbosa, Egberto/G-7763-2012; Ottman, Ruth/O-2371-2013; QUATTRONE, Aldo/A-6734-2016; OI Gan-Or, Ziv/0000-0003-0332-234X; Zabetian, Cyrus/0000-0002-7739-4306; Mitsui, Jun/0000-0001-7425-4765; Pereira, Lygia/0000-0002-0002-725X; QUATTRONE, Aldo/0000-0003-2001-957X; Schulte, Claudia/0000-0003-4006-1265; Oliveira, Catarina/0000-0001-6942-4328; DEMARCO, ELVIRAVALERIA/0000-0002-4947-8481 FU National Institutes of Health [Z01AG000957-05]; National Institute of Neurological Disorders and Stroke and the National Center for Research Resources [NS050487, NS060113, NS40256]; Parkinson's Disease Foundation; Department of Veterans Affairs, Seattle; German National Genome Network, German Ministry for Education and Research [01GS08134]; French Parkinson's Disease Genetics Study Group; Duke-National University of Singapore (NUS) Graduate Medical School, National Medical Research Council, Biomedical Research Council, Singapore Millennium Foundation; SingHealth, Singapore General Hospital, National Neuroscience Institute; Tel Aviv Sourasky Medical Center Grant of Excellence; Wolfson and Kahn Foundations; Portuguese Fundacao para a Ciencia e a Tecnologia; National Science Council, Executive Yuan, Taiwan [NSC-95-2314-B-182A-061]; Ministry of Education, Culture, Sports, Science and Technology of Japan FX Supported in part by the Intramural Research Programs of NHGRI and the National Institute on Aging (project Z01AG000957-05), National Institutes of Health; grants from the National Institute of Neurological Disorders and Stroke and the National Center for Research Resources (NS050487, NS060113, and NS40256); grants from the Parkinson's Disease Foundation; a Merit Review Award from the Department of Veterans Affairs, Seattle; a grant from the German National Genome Network, German Ministry for Education and Research (01GS08134); a grant from the French Parkinson's Disease Genetics Study Group; a grant from the Duke-National University of Singapore (NUS) Graduate Medical School, National Medical Research Council, Biomedical Research Council, Singapore Millennium Foundation; a grant from SingHealth, Singapore General Hospital, National Neuroscience Institute; the Tel Aviv Sourasky Medical Center Grant of Excellence; grants from the Wolfson and Kahn Foundations; a grant from the Portuguese Fundacao para a Ciencia e a Tecnologia; a grant from the National Science Council, Executive Yuan, Taiwan (NSC-95-2314-B-182A-061); and a Grant-in-Aid for Scientific Research on Priority Areas, Applied Genomics, and Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 44 TC 550 Z9 558 U1 4 U2 29 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 OCT 22 PY 2009 VL 361 IS 17 BP 1651 EP 1661 DI 10.1056/NEJMoa0901281 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 508YW UT WOS:000270977400007 PM 19846850 ER PT J AU de Moya, MA del Carmen, MG Allain, RM Hirschberg, RE Shepard, JAO Kradin, RL AF de Moya, Marc A. del Carmen, Marcela G. Allain, Rae M. Hirschberg, Ronald E. Shepard, Jo-Anne O. Kradin, Richard L. TI A Woman with Fever, Abdominal Pain, and Hypotension after Cesarean SectionCase 33-2009: A 35-Year-Old Woman with Fever, Abdominal Pain, and Hypotension after Cesarean Section SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TOXIC-SHOCK-SYNDROME; A STREPTOCOCCUS INFECTIONS; SOFT-TISSUE INFECTION; TUMOR-NECROSIS-FACTOR; NECROTIZING FASCIITIS; SEPTIC SHOCK; SEVERE SEPSIS; MANAGEMENT; PYOGENES; THERAPY C1 [de Moya, Marc A.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [del Carmen, Marcela G.] Massachusetts Gen Hosp, Div Gynecol Oncol, Boston, MA 02114 USA. [Allain, Rae M.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Hirschberg, Ronald E.] Massachusetts Gen Hosp, Dept Phys Med & Rehabil, Boston, MA 02114 USA. [Shepard, Jo-Anne O.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kradin, Richard L.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Kradin, Richard L.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Hirschberg, Ronald E.] Spaulding Rehabil Hosp, Dept Phys Med & Rehabil, Boston, MA USA. [de Moya, Marc A.] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. [del Carmen, Marcela G.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. [Allain, Rae M.] Harvard Univ, Sch Med, Dept Anesthesia, Boston, MA 02115 USA. [Hirschberg, Ronald E.] Harvard Univ, Sch Med, Dept Phys Med & Rehabil, Boston, MA 02115 USA. [Shepard, Jo-Anne O.] Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. [Kradin, Richard L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Kradin, Richard L.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP de Moya, MA (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. NR 24 TC 3 Z9 3 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 22 PY 2009 VL 361 IS 17 BP 1689 EP 1697 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 508YW UT WOS:000270977400013 PM 19846855 ER PT J AU Palevsky, PM AF Palevsky, Paul M. TI Renal Support in Acute Kidney Injury - How Much Is Enough? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CRITICALLY-ILL PATIENTS; CONTINUOUS VENOVENOUS HEMOFILTRATION; RANDOMIZED-TRIAL; FAILURE; SURVIVAL; DIALYSIS; THERAPY C1 [Palevsky, Paul M.] VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. [Palevsky, Paul M.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA USA. RP Palevsky, PM (reprint author), VA Pittsburgh Healthcare Syst, Renal Sect, Pittsburgh, PA USA. OI Palevsky, Paul/0000-0002-7334-5400 NR 11 TC 8 Z9 16 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 OCT 22 PY 2009 VL 361 IS 17 BP 1699 EP 1701 DI 10.1056/NEJMe0907831 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 508YW UT WOS:000270977400014 PM 19846856 ER PT J AU Albert, NM Yancy, CW Liang, L Zhao, X Hernandez, AF Peterson, ED Cannon, CP Fonarow, GC AF Albert, Nancy M. Yancy, Clyde W. Liang, Li Zhao, Xin Hernandez, Adrian F. Peterson, Eric D. Cannon, Christopher P. Fonarow, Gregg C. TI Use of Aldosterone Antagonists in Heart Failure SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID RENAL-INSUFFICIENCY; SPIRONOLACTONE; HYPERKALEMIA; GUIDELINES; DYSFUNCTION; ASSOCIATION; MANAGEMENT; POTASSIUM; DIAGNOSIS; UPDATE AB Context Aldosterone antagonists are recommended for patients with moderate to severe heart failure (HF) and systolic dysfunction. Prior studies suggest underuse of aldosterone antagonists in eligible patients as well as overuse in settings in which therapy may be harmful. Objective To examine aldosterone antagonist prescription based on HF management guideline criteria, investigator-defined appropriateness criteria, and trends over time in patients hospitalized with heart failure. Design, Setting, and Patients Observational analysis of 43 625 patients admitted with HF and discharged home from 241 hospitals participating in the Get With The Guidelines-HF quality improvement registry between January 2005 and December 2007. Main Outcome Measures Prescription and predictors of use of aldosterone antagonists, based on guideline criteria. Results Among 12 565 patients eligible for aldosterone antagonist therapy, 4087 (32.5%) received an aldosterone antagonist at discharge, and treatment increased modestly from 28% to 34% over the study period. There was also wide variation in aldosterone antagonist use among hospitals (0%-90.6%). Aldosterone antagonist use in eligible patients was associated with younger age (adjusted odds ratio [OR], 0.85; 95% confidence interval [CI], 0.82-0.88), African American race/ethnicity (adjusted OR, 1.17; 95% CI, 1.04-1.32), lower systolic blood pressure (adjusted OR, 0.94; 95% CI, 0.92-0.95), history of implantable cardioverter-defibrillator use (adjusted OR, 1.51; 95% CI, 1.34-1.69), depression (adjusted OR, 1.15; 95% CI, 1.01-1.30), alcohol use (adjusted OR, 1.23; 95% CI, 1.02-1.50), and pacemaker implantation (adjusted OR, 1.21; 95% CI, 1.06-1.38), and with having no history of renal insufficiency (adjusted OR, 0.85; 95% CI, 0.75-0.96). Applying serum creatinine and potassium appropriateness criteria, inappropriate and potentially inappropriate use of aldosterone antagonist therapy was low and did not change over the 3-year study period. Conclusions Less than one-third of eligible patients hospitalized for HF and participating in a quality improvement registry received HF guideline-recommended aldosterone antagonist therapy. Use of aldosterone antagonist therapy among patients with documented contraindications was low. JAMA. 2009;302(15):1658-1665 C1 [Albert, Nancy M.] Cleveland Clin, Nursing Inst, Cleveland, OH 44106 USA. [Albert, Nancy M.] Cleveland Clin, Kaufman Ctr Heart Failure, Cleveland, OH 44106 USA. [Yancy, Clyde W.] Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA. [Liang, Li; Zhao, Xin; Hernandez, Adrian F.; Peterson, Eric D.] Duke Clin Res Inst, Durham, NC USA. [Cannon, Christopher P.] Brigham & Womens Hosp, TIMI Study Grp, Boston, MA 02115 USA. [Fonarow, Gregg C.] Univ Calif Los Angeles, Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. RP Albert, NM (reprint author), 9500 Euclid Ave,Mail Code J3-4, Cleveland, OH 44195 USA. EM albertn@ccf.org RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 FU American Heart Association; GlaxoSmithKline; Medtronic FX The Get With The GuidelinesHeart Failure program is sponsored by the American Heart Association and receives funding in part from GlaxoSmithKline and Medtronic. NR 25 TC 123 Z9 124 U1 0 U2 4 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 OCT 21 PY 2009 VL 302 IS 15 BP 1658 EP 1665 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 508NX UT WOS:000270941200020 PM 19843900 ER PT J AU Pedrini, S Thomas, C Brautigam, H Schmeidler, J Ho, L Fraser, P Westaway, D Hyslop, PSG Martins, RN Buxbaum, JD Pasinetti, GM Dickstein, DL Hof, PR Ehrlich, ME Gandy, S AF Pedrini, Steve Thomas, Carlos Brautigam, Hannah Schmeidler, James Ho, Lap Fraser, Paul Westaway, David Hyslop, Peter St George Martins, Ralph N. Buxbaum, Joseph D. Pasinetti, Giulio M. Dickstein, Dara L. Hof, Patrick R. Ehrlich, Michelle E. Gandy, Sam TI Dietary composition modulates brain mass and solubilizable A levels in a mouse model of aggressive Alzheimer's amyloid pathology SO MOLECULAR NEURODEGENERATION LA English DT Article ID INSULIN-RESISTANCE; TRANSGENIC MICE; DISEASE; DEMENTIA; NEUROPATHOLOGY; CHOLESTEROL; ACID; ACCUMULATION; DEFICITS AB Objective: Alzheimer's disease (AD) is a progressive neurodegenerative disease of the central nervous system (CNS). Recently, an increased interest in the role diet plays in the pathology of AD has resulted in a focus on the detrimental effects of diets high in cholesterol and fat and the beneficial effects of caloric restriction. The current study examines how dietary composition modulates cerebral amyloidosis and neuronal integrity in the TgCRND8 mouse model of AD. Methods: From 4 wks until 18 wks of age, male and female TgCRND8 mice were maintained on one of four diets: (1) reference (regular) commercial chow; (2) high fat/low carbohydrate custom chow (60 kcal% fat/30 kcal% protein/10 kcal% carbohydrate); (3) high protein/low carbohydrate custom chow (60 kcal% protein/30 kcal% fat/10 kcal% carbohydrate); or (4) high carbohydrate/low fat custom chow (60 kcal% carbohydrate/30 kcal% protein/10 kcal% fat). At age 18 wks, mice were sacrificed, and brains studied for (a) wet weight; (b) solubilizable A beta content by ELISA; (c) amyloid plaque burden; (d) stereologic analysis of selected hippocampal subregions. Results: Animals receiving a high fat diet showed increased brain levels of solubilizable A beta, although we detected no effect on plaque burden. Unexpectedly, brains of mice fed a high protein/low carbohydrate diet were 5% lower in weight than brains from all other mice. In an effort to identify regions that might link loss of brain mass to cognitive function, we studied neuronal density and volume in hippocampal subregions. Neuronal density and volume in the hippocampal CA3 region of TgCRND8 mice tended to be lower in TgCRND8 mice receiving the high protein/low carbohydrate diet than in those receiving the regular chow. Neuronal density and volume were preserved in CA1 and in the dentate gyrus. Interpretation: Dissociation of A beta changes from brain mass changes raises the possibility that diet plays a role not only in modulating amyloidosis but also in modulating neuronal vulnerability. However, in the absence of a study of the effects of a high protein/low carbohydrate diet on nontransgenic mice, one cannot be certain how much, if any, of the loss of brain mass exhibited by high protein/low carbohydrate diet-fed TgCRND8 mice was due to an interaction between cerebral amyloidosis and diet. Given the recent evidence that certain factors favor the maintenance of cognitive function in the face of substantial structural neuropathology, we propose that there might also exist factors that sensitize brain neurons to some forms of neurotoxicity, including, perhaps, amyloid neurotoxicity. Identification of these factors could help reconcile the poor clinicopathological correlation between cognitive status and structural neuropathology, including amyloid pathology. C1 [Pedrini, Steve; Gandy, Sam] Thomas Jefferson Univ, Jefferson Med Coll, Farber Inst Neurosci, Philadelphia, PA 19107 USA. [Thomas, Carlos; Brautigam, Hannah; Schmeidler, James; Ho, Lap; Buxbaum, Joseph D.; Pasinetti, Giulio M.; Dickstein, Dara L.; Hof, Patrick R.; Ehrlich, Michelle E.; Gandy, Sam] Mt Sinai Sch Med, Alzheimers Dis Res Ctr, New York, NY USA. [Thomas, Carlos; Brautigam, Hannah; Schmeidler, James; Ho, Lap; Buxbaum, Joseph D.; Pasinetti, Giulio M.; Gandy, Sam] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Thomas, Carlos; Brautigam, Hannah; Ho, Lap; Pasinetti, Giulio M.; Ehrlich, Michelle E.; Gandy, Sam] Mt Sinai Sch Med, Dept Neurol, New York, NY USA. [Thomas, Carlos; Brautigam, Hannah; Ho, Lap; Pasinetti, Giulio M.; Gandy, Sam] James J Peters Vet Affairs Med Ctr, Bronx, NY USA. [Fraser, Paul; Hyslop, Peter St George] Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. [Westaway, David] Univ Alberta, Ctr Prions & Prot Folding Dis, Edmonton, AB, Canada. [Hyslop, Peter St George] Univ Cambridge, Cambridge, England. [Martins, Ralph N.] Edith Cowan Univ, Joondalup, WA, Australia. [Brautigam, Hannah; Dickstein, Dara L.; Hof, Patrick R.] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. [Ehrlich, Michelle E.] Mt Sinai Sch Med, Dept Pediat, New York, NY USA. RP Gandy, S (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Farber Inst Neurosci, Philadelphia, PA 19107 USA. EM steve.pedrini@jefferson.edu; carlos.thomas@mssm.edu; hannah.brautigam@mssm.edu; james.schmeidler@mssm.edu; lap.ho@mssm.edu; paul.fraser@utoronto.ca; david.westaway@ualberta.ca; p.hyslop@utoronto.ca; r.martins@ecu.edu.au; joseph.buxbaum@mssm.edu; giulio.pasinetti@mssm.edu; dara.dickstein@mssm.edu; patrick.hof@mssm.edu; michelle.ehrlich@mssm.edu; samuel.gandy@mssm.edu RI Dickstein, Dara/F-3036-2013; OI Buxbaum, Joseph/0000-0001-8898-8313 FU Dr. Robert C. and Veronica Atkins Foundation; NIH [P01 AG10491, P01 AG02219, P50 AG05138] FX This work was supported by the Dr. Robert C. and Veronica Atkins Foundation (S.G., S.P., C.T., G.M.P., L.H.) and NIH grants P01 AG10491 (S.G., S.P., C.T., H.B., J.D.B., R.N.M., M.E.E.; S. Gandy, Program Director), P01 AG02219 (P.R.H., J.D.B., J.S., G.M.P., D.L.D.; H. Haroutunian, Program Director), and P50 AG05138 (P.R.H., J.D.B., J.S., G.M.P., D.L.D.; M. Sano, Program Director). NR 25 TC 16 Z9 18 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-1326 J9 MOL NEURODEGENER JI Mol. Neurodegener. PD OCT 21 PY 2009 VL 4 AR 40 DI 10.1186/1750-1326-4-40 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 517JD UT WOS:000271608500001 PM 19845940 ER PT J AU Brenner, DJ Elliston, CD Hall, EJ Paganetti, H AF Brenner, David J. Elliston, Carl D. Hall, Eric J. Paganetti, Harald TI Reduction of the secondary neutron dose in passively scattered proton radiotherapy, using an optimized pre-collimator/collimator SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MODULATED RADIATION-THERAPY; MONTE-CARLO SIMULATIONS; BEAM DELIVERY-SYSTEM; PROSTATE-CANCER; STRAY RADIATION; HUMAN-LYMPHOCYTES; BOMB SURVIVORS; 2ND CANCERS; EQUIVALENT; COLLIMATOR AB Proton radiotherapy represents a potential major advance in cancer therapy. Most current proton beams are spread out to cover the tumor using passive scattering and collimation, resulting in an extra whole-body high-energy neutron dose, primarily from proton interactions with the final collimator. There is considerable uncertainty as to the carcinogenic potential of low doses of high-energy neutrons, and thus we investigate whether this neutron dose can be significantly reduced without major modifications to passively scattered proton beam lines. Our goal is to optimize the design features of a patient-specific collimator or pre-collimator/collimator assembly. There are a number of often contradictory design features, in terms of geometry and material, involved in an optimal design. For example, plastic or hybrid plastic/metal collimators have a number of advantages. We quantify these design issues, and investigate the practical balances that can be achieved to significantly reduce the neutron dose without major alterations to the beamline design or function. Given that the majority of proton therapy treatments, at least for the next few years, will use passive scattering techniques, reducing the associated neutron-related risks by simple modifications of the collimator assembly design is a desirable goal. C1 [Brenner, David J.; Elliston, Carl D.; Hall, Eric J.] Columbia Univ, Med Ctr, Ctr Radiol Res, New York, NY 10032 USA. [Paganetti, Harald] Massachusetts Gen Hosp, Dept Radiat Oncol, Francis H Burr Proton Therapy Ctr, Boston, MA 02114 USA. RP Brenner, DJ (reprint author), Columbia Univ, Med Ctr, Ctr Radiol Res, 630 W 168th St, New York, NY 10032 USA. EM djb3@columbia.edu FU NIH [P41-EB002033, PO1-CA49062, R01-CA088074]; DOE [DE-FG02-03ER63441, DE-FG02-03ER63629] FX This work was supported in part by NIH grants P41-EB002033, PO1-CA49062 and R01-CA088074, and DOE grants DE-FG02-03ER63441 and DE-FG02-03ER63629. NR 60 TC 19 Z9 19 U1 0 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2009 VL 54 IS 20 BP 6065 EP 6078 DI 10.1088/0031-9155/54/20/003 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 503TO UT WOS:000270563300003 PM 19779218 ER PT J AU Raymond, SB Kumar, ATN Boas, DA Bacskai, BJ AF Raymond, S. B. Kumar, A. T. N. Boas, D. A. Bacskai, B. J. TI Optimal parameters for near infrared fluorescence imaging of amyloid plaques in Alzheimer's disease mouse models SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID DIFFUSE OPTICAL TOMOGRAPHY; MULTIPHOTON MICROSCOPY; MOLECULAR TOMOGRAPHY; BETA PLAQUES; HUMAN BRAIN; HUMAN HEAD; MICE; TISSUES; TRANSPORT; RANGE AB Amyloid-beta plaques are an Alzheimer's disease biomarker which present unique challenges for near-infrared fluorescence tomography because of size (< 50 mu m diameter) and distribution. We used high-resolution simulations of fluorescence in a digital Alzheimer's disease mouse model to investigate the optimal fluorophore and imaging parameters for near-infrared fluorescence tomography of amyloid plaques. Fluorescence was simulated for amyloid-targeted probes with emission at 630 and 800 nm, plaque-to-background ratios from 1-1000, amyloid burden from 0-10%, and for transmission and reflection measurement geometries. Fluorophores with high plaque-to-background contrast ratios and 800 nm emission performed significantly better than current amyloid imaging probes. We tested idealized fluorophores in transmission and full-angle tomographic measurement schemes (900 source-detector pairs), with and without anatomical priors. Transmission reconstructions demonstrated strong linear correlation with increasing amyloid burden, but underestimated fluorescence yield and suffered from localization artifacts. Full-angle measurements did not improve upon the transmission reconstruction qualitatively or in semi-quantitative measures of accuracy; anatomical and initial-value priors did improve reconstruction localization and accuracy for both transmission and full-angle schemes. Region-based reconstructions, in which the unknowns were reduced to a few distinct anatomical regions, produced highly accurate yield estimates for cortex, hippocampus and brain regions, even with a reduced number of measurements (144 source-detector pairs). C1 [Raymond, S. B.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Raymond, S. B.; Bacskai, B. J.] Massachusetts Gen Hosp, Dept Neurol, Alzheimers Res Unit, Charlestown, MA 02129 USA. [Kumar, A. T. N.; Boas, D. A.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Raymond, SB (reprint author), MIT, Harvard Mit Div Hlth Sci & Technol, 77 Mass Ave,E25-519, Cambridge, MA 02139 USA. EM bbacskai@partners.org OI Raymond, Scott/0000-0001-7008-8974 FU NIH [EB000768, P41-RR14075, AG026240, T32 EB001680] FX This research was supported by NIH EB000768, P41-RR14075 and AG026240. S B Raymond was supported by NIH T32 EB001680. NR 41 TC 5 Z9 5 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 EI 1361-6560 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 21 PY 2009 VL 54 IS 20 BP 6201 EP 6216 DI 10.1088/0031-9155/54/20/011 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 503TO UT WOS:000270563300011 PM 19794239 ER PT J AU Mulley, AG AF Mulley, Albert G. TI Inconvenient truths about supplier induced demand and unwarranted variation in medical practice SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID REGIONAL-VARIATIONS; CONTROLLED-TRIAL; HEALTH OUTCOMES; DECISION AIDS; PRIMARY-CARE; QUALITY; PROSTATECTOMY; INTENSITY; PROGRAM C1 [Mulley, Albert G.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Mulley, Albert G.] Harvard Univ, Sch Med, Boston, MA USA. RP Mulley, AG (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St, Boston, MA 02114 USA. EM amulley@partners.org NR 26 TC 25 Z9 25 U1 3 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD OCT 20 PY 2009 VL 339 AR b4073 DI 10.1136/bmj.b4073 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 510PJ UT WOS:000271102100002 PM 19843566 ER PT J AU MacDonald, S Taghian, AG AF MacDonald, Shannon Taghian, Alphonse G. TI Prognostic Factors for Local Control After Breast Conservation: Does Margin Status Still Matter? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID 20-YEAR FOLLOW-UP; CONSERVING THERAPY; RADIATION-THERAPY; PROGESTERONE-RECEPTOR; ESTROGEN-RECEPTOR; RANDOMIZED-TRIAL; CANCER; RECURRENCE; SURGERY; CARCINOMA C1 [MacDonald, Shannon; Taghian, Alphonse G.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. RP MacDonald, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. NR 19 TC 11 Z9 12 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 OCT 20 PY 2009 VL 27 IS 30 BP 4929 EP 4030 DI 10.1200/JCO.2009.23.6679 PG 2 WC Oncology SC Oncology GA 507SN UT WOS:000270875100001 PM 19720895 ER PT J AU Zietman, A AF Zietman, Anthony TI Evidence-Based Medicine, Conscience-Based Medicine, and the Management of Low-Risk Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ACTIVE SURVEILLANCE; MORTALITY; TRIAL; MEN C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP Zietman, A (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. NR 13 TC 9 Z9 9 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 OCT 20 PY 2009 VL 27 IS 30 BP 4935 EP 4936 DI 10.1200/JCO.2009.24.4533 PG 2 WC Oncology SC Oncology GA 507SN UT WOS:000270875100004 PM 19720880 ER PT J AU Brachtel, EF Rusby, JE Michaelson, JS Chen, LL Muzikansky, A Smith, BL Koerner, FC AF Brachtel, Elena F. Rusby, Jennifer E. Michaelson, James S. Chen, L. Leon Muzikansky, Alona Smith, Barbara L. Koerner, Frederick C. TI Occult Nipple Involvement in Breast Cancer: Clinicopathologic Findings in 316 Consecutive Mastectomy Specimens SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SKIN-SPARING MASTECTOMY; NEOPLASTIC INVOLVEMENT; AREOLA COMPLEX; FOLLOW-UP; CARCINOMA; RECONSTRUCTION; SECTIONS; RISK AB Purpose Although breast-conserving surgery is a standard approach for patients with breast cancer, mastectomy often becomes necessary. Surgical options now include nipple-sparing mastectomy but its oncological safety is still controversial. This study evaluates frequency and patterns of occult nipple involvement in a large contemporary cohort of patients with the retroareolar margin as possible indicator of nipple involvement. Patients and Methods Three hundred sixteen consecutive mastectomy specimens (232 therapeutic, 84 prophylactic) with grossly unremarkable nipples were evaluated by coronal sections through the entire nipple and subareolar tissue. Extent and location of nipple involvement by carcinoma was assessed with the tissue deep to the skin as potential retroareolar en-face resection margin. Results Seventy-one percent of nipples from therapeutic mastectomies showed no pathologic abnormality, 21% had ductal carcinoma in situ (DCIS), invasive carcinoma (IC), or lymphovascular invasion (LVI), and 8% lobular neoplasia (lobular carcinoma in situ). Human epidermal growth factor receptor 2 amplification, tumor size, and tumor-nipple distance were associated with nipple involvement by multivariate analysis (P = .0047, .0126, and .0176); histologic grade of both DCIS (P = .002) and IC (P = .03), LVI (P = .03), and lymph node involvement (P = .02) by univariate analysis. Nipple involvement by IC or DCIS was identified in the retroareolar margin with a sensitivity of 0.8 and a negative predictive value of 0.96. None of the 84 prophylactic mastectomies showed nipple involvement by IC or DCIS. Conclusion Nipple-sparing mastectomy may be suitable for selected cases of breast carcinoma with low probability of nipple involvement by carcinoma and prophylactic procedures. A retroareolar en-face margin may be used to test for occult involvement in patients undergoing nipple-sparing mastectomy. C1 [Brachtel, Elena F.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Brachtel, EF (reprint author), Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN 2, Boston, MA 02114 USA. EM ebrachtel@partners.org NR 30 TC 69 Z9 78 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X EI 1527-7755 J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2009 VL 27 IS 30 BP 4948 EP 4954 DI 10.1200/JCO.2008.20.8785 PG 7 WC Oncology SC Oncology GA 507SN UT WOS:000270875100007 PM 19720921 ER PT J AU Gray, R Bhattacharya, S Bowden, C Miller, K Comis, RL AF Gray, Robert Bhattacharya, Suman Bowden, Christopher Miller, Kathy Comis, Robert L. TI Independent Review of E2100: A Phase III Trial of Bevacizumab Plus Paclitaxel Versus Paclitaxel in Women With Metastatic Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CAPECITABINE AB Purpose E2100, an open-label, randomized, phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG), demonstrated a significant improvement in progression-free survival (PFS) and overall response rate (ORR) with paclitaxel plus bevacizumab compared with paclitaxel alone as initial chemotherapy for patients with HER2-negative metastatic breast cancer. Methods An independent, blinded review of radiologic and clinical data was performed, assessing progression and response according to Response Evaluation Criteria in Solid Tumors. In addition, ECOG's investigator assessments were reanalyzed using the same methods applied to the independent review. The primary end point was PFS as assessed by an independent review facility (IRF). Results The addition of bevacizumab to paclitaxel resulted in a statistically significant improvement in PFS using both the IRF and investigator assessments. Hazard ratios for PFS (0.48, 95% CI, 0.385 to 0.607; P < .0001 for the IRF v 0.42,95% CI, 0.34 to 0.52; P < .0001 for ECOG investigators) and the improvement in median PFS (11.3 v 5.8 months for the IRF v 11.4 v 5.8 months for ECOG investigators) were similar. Among patients with measurable disease at baseline, the IRF-assessed ORR was significantly higher in patients treated with paclitaxel and bevacizumab (48.9% v 22.2%; P < .0001). Conclusion The risk of progression was reduced by more than half and the ORR more than doubled with the addition of bevacizumab to weekly paclitaxel in both analyses, confirming a substantial and robust bevacizumab treatment effect. The consistency between the IRF and ECOG analyses validates the original data previously reported by ECOG in this open-label trial. C1 [Gray, Robert] Dana Farber Canc Inst, Boston, MA 02115 USA. Genentech Inc, San Francisco, CA 94080 USA. Indiana Univ, Melvin & Bren Simon Canc Ctr, Indianapolis, IN 46204 USA. Drexel Univ, Clin Trials Res Ctr, Philadelphia, PA 19104 USA. RP Gray, R (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. EM gray@jimmy.harvard.edu FU Genentech, South San Francisco, CA; United States Department of Health and Human Services; National Institutes of Health [CA23318, CA66636, CA21115] FX Supported by Genentech, South San Francisco, CA; by the United States Department of Health and Human Services; and by National Institutes of Health Grants No. CA23318 (to the Eastern Cooperative Oncology Group [ECOG] statistical center), CA66636 (to the ECOG data management center), and CA21115 (to the ECOG coordinating center). NR 4 TC 152 Z9 159 U1 1 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 20 PY 2009 VL 27 IS 30 BP 4966 EP 4972 DI 10.1200/JCO.2008.21.6630 PG 7 WC Oncology SC Oncology GA 507SN UT WOS:000270875100010 PM 19720913 ER PT J AU Saad, AG Alyea, EP Wen, PY DeGirolami, U Kesari, S AF Saad, Ali G. Alyea, Edwin P., III Wen, Patrick Y. DeGirolami, Umberto Kesari, Santosh TI Graft-Versus-Host Disease of the CNS After Allogeneic Bone Marrow Transplantation SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; COMPLICATIONS; PATHOGENESIS; PATHOLOGY; ANGIITIS; PATIENT C1 [Saad, Ali G.] Arkansas Childrens Hosp, Dept Pathol, Little Rock, AR 72202 USA. [Saad, Ali G.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Alyea, Edwin P., III; Wen, Patrick Y.; Kesari, Santosh] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Alyea, Edwin P., III; Wen, Patrick Y.; DeGirolami, Umberto; Kesari, Santosh] Harvard Univ, Sch Med, Boston, MA USA. [Wen, Patrick Y.; Kesari, Santosh] Brigham & Womens Hosp, Dept Neurol, Boston, MA 02115 USA. [DeGirolami, Umberto] Brigham & Womens Hosp, Dept Pathol, Div Neuropathol, Boston, MA 02115 USA. RP Saad, AG (reprint author), Arkansas Childrens Hosp, Dept Pathol, 800 Marshall St, Little Rock, AR 72202 USA. RI Kesari, Santosh/E-8461-2013 NR 21 TC 10 Z9 11 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 OCT 20 PY 2009 VL 27 IS 30 BP E147 EP E149 DI 10.1200/JCO.2009.21.7919 PG 3 WC Oncology SC Oncology GA 507SN UT WOS:000270875100032 PM 19667266 ER PT J AU Gao, X Simon, KC Han, J Schwarzschild, MA Ascherio, A AF Gao, X. Simon, K. C. Han, J. Schwarzschild, M. A. Ascherio, A. TI Family history of melanoma and Parkinson disease risk SO NEUROLOGY LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; CANCER-RISK; TOBACCO USE; LEVODOPA; QUESTIONNAIRE; METAANALYSIS; CONSUMPTION; INHIBITION; APOPTOSIS; NEURONS AB Background: Co-occurrence of Parkinson disease (PD) and melanoma has been reported in numerous studies. If this was due to common genetic mechanisms, a positive family history of melanoma would be associated with an excessive PD risk, independent of environmental risk factors for PD. Methods: We prospectively examined associations between a family history of melanoma and PD among 157,036 men and women free of PD at baseline (1990 for men and 1982 for women) who participated in 2 ongoing US cohorts: the Health Professional Follow-up Study and the Nurses' Health Study. Information on family history of melanoma in parents or siblings was assessed via questionnaire. Relative risks and 95% confidence intervals were estimated using Cox proportional hazards models and pooled using a fixed-effects model. Results: During 14-20 years follow-up, we identified 616 incident PD cases. A family history of melanoma in a first-degree relative was associated with a higher risk of PD (multivariate relative risk = 1.85; 95% confidence interval: 1.2, 2.8; p = 0.004), after adjusting for smoking, ethnicity, caffeine intake, and other covariates. In contrast, we did not observe significant associations between a family history of colorectal, lung, prostate, or breast cancer and PD risk. Interactions between melanoma family history and age, smoking, or caffeine intake were not significant and subgroup analyses according to these factors generated similar results. Conclusions: Our findings support the notion that melanoma and Parkinson disease (PD) share common genetic components. The genetic determinants of melanoma could therefore be explored as susceptibility candidate genes for PD. Neurology (R) 2009;73:1286-1291 C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gao, X.; Han, J.; Ascherio, A.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Ascherio, A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gao, X.; Simon, K. C.; Ascherio, A.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Schwarzschild, M. A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Gao, X (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM xiang.gao@channing.harvard.edu FU NIH/NINDS [R01 NS048517]; Parkinson Study Group; Parkinson's Disease Foundation's Advancing Parkinson's Treatments Innovations Grant FX The study was supported by NIH/NINDS grant R01 NS048517, and the Parkinson Study Group and the Parkinson's Disease Foundation's Advancing Parkinson's Treatments Innovations Grant. NR 34 TC 51 Z9 51 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 20 PY 2009 VL 73 IS 16 BP 1286 EP 1291 DI 10.1212/WNL.0b013e3181bd13a1 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 508GU UT WOS:000270918800007 PM 19841380 ER PT J AU Tamietto, M Castelli, L Vighetti, S Perozzo, P Geminiani, G Weiskrantz, L de Gelder, B AF Tamietto, Marco Castelli, Lorys Vighetti, Sergio Perozzo, Paola Geminiani, Giuliano Weiskrantz, Lawrence de Gelder, Beatrice TI Unseen facial and bodily expressions trigger fast emotional reactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE affective blindsight; electromyography; emotional body language; motor resonance; emotional contagion; face ID AFFECTIVE BLINDSIGHT; RIGHT AMYGDALA; BODY LANGUAGE; FACES; FEAR; RECOGNITION; AWARENESS AB The spontaneous tendency to synchronize our facial expressions with those of others is often termed emotional contagion. It is unclear, however, whether emotional contagion depends on visual awareness of the eliciting stimulus and which processes underlie the unfolding of expressive reactions in the observer. It has been suggested either that emotional contagion is driven by motor imitation (i.e., mimicry), or that it is one observable aspect of the emotional state arising when we see the corresponding emotion in others. Emotional contagion reactions to different classes of consciously seen and "unseen" stimuli were compared by presenting pictures of facial or bodily expressions either to the intact or blind visual field of two patients with unilateral destruction of the visual cortex and ensuing phenomenal blindness. Facial reactions were recorded using electromyography, and arousal responses were measured with pupil dilatation. Passive exposure to unseen expressions evoked faster facial reactions and higher arousal compared with seen stimuli, therefore indicating that emotional contagion occurs also when the triggering stimulus cannot be consciously perceived because of cortical blindness. Furthermore, stimuli that are very different in their visual characteristics, such as facial and bodily gestures, induced highly similar expressive responses. This shows that the patients did not simply imitate the motor pattern observed in the stimuli, but resonated to their affective meaning. Emotional contagion thus represents an instance of truly affective reactions that may be mediated by visual pathways of old evolutionary origin bypassing cortical vision while still providing a cornerstone for emotion communication and affect sharing. C1 [Tamietto, Marco; de Gelder, Beatrice] Tilburg Univ, Cognit & Affect Neurosci Lab, NL-5000 LE Tilburg, Netherlands. [Vighetti, Sergio] Univ Torino, Dept Neurosci, I-10126 Turin, Italy. [Tamietto, Marco] Inst Sci Interchange ISI Fdn, I-10133 Turin, Italy. [Tamietto, Marco; Castelli, Lorys; Geminiani, Giuliano] Univ Torino, Dept Psychol, I-10123 Turin, Italy. [Perozzo, Paola] Fdn Carlo Molo, Ctr Ric Neurosci, I-10123 Turin, Italy. [Weiskrantz, Lawrence] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [de Gelder, Beatrice] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Tamietto, M (reprint author), Tilburg Univ, Cognit & Affect Neurosci Lab, POB 90153, NL-5000 LE Tilburg, Netherlands. EM m.tamietto@uvt.nl; larry.weiskrantz@psy.ox.ac.uk; degelder@nmr.mgh.harvard.edu RI Castelli, Lorys/G-9973-2012; OI Castelli, Lorys/0000-0001-5009-2271; Tamietto, Marco/0000-0002-8815-8499 FU Netherlands Organization for Scientific Research [451-07-032]; Fondazione Carlo Molo; EU [FP6-2005-NEST-Path]; Italian Ministry for University Education and Research [PRIN 2007]; McDonnell Oxford Cognitive Neuroscience Centre FX This study is dedicated to the precious memory of our dear friend and colleague Luca Latini Corazzini, whose assistance during the testing sessions was vital to this work. Wethank D. B. and G. Y. for their patient collaboration and J. LeDoux and G. Berlucchi for valuable and constructive comments. Thanks are also due to A. Avenanti, C. Sinigaglia, and C. Urgesi for helpful discussions. M. T. was supported by a Veni grant (451-07-032) from the Netherlands Organization for Scientific Research, and partly by the Fondazione Carlo Molo. B. d. G. was supported by a Communication with Emotional Body Language (COBOL) grant from EU FP6-2005-NEST-Path, and by Netherlands Organization for Scientific Research. G. G., L. C., and P. P. were supported by the PRIN 2007 from Italian Ministry for University Education and Research, and by the Fondazione Carlo Molo. L. W. was supported by the McDonnell Oxford Cognitive Neuroscience Centre. NR 38 TC 115 Z9 121 U1 7 U2 40 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 OCT 20 PY 2009 VL 106 IS 42 BP 17661 EP 17666 DI 10.1073/pnas.0908994106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 508UR UT WOS:000270963100013 PM 19805044 ER PT J AU Dar, MJ Monel, B Krishnan, L Shun, MC Di Nunzio, F Helland, DE Engelman, A AF Dar, Mohd J. Monel, Blandine Krishnan, Lavanya Shun, Ming-Chieh Di Nunzio, Francesca Helland, Dag E. Engelman, Alan TI Biochemical and virological analysis of the 18-residue C-terminal tail of HIV-1 integrase SO RETROVIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DNA-BINDING DOMAIN; PHOTO-CROSS-LINKING; PROTEIN IN-VITRO; PREINTEGRATION COMPLEXES; REVERSE-TRANSCRIPTASE; RETROVIRAL INTEGRASE; NUCLEAR-LOCALIZATION; CRYSTAL-STRUCTURE; CATALYTIC DOMAIN AB Background: The 18 residue tail abutting the SH3 fold that comprises the heart of the C-terminal domain is the only part of HIV-1 integrase yet to be visualized by structural biology. To ascertain the role of the tail region in integrase function and HIV-1 replication, a set of deletion mutants that successively lacked three amino acids was constructed and analyzed in a variety of biochemical and virus infection assays. HIV-1/2 chimers, which harbored the analogous 23-mer HIV-2 tail in place of the HIV-1 sequence, were also studied. Because integrase mutations can affect steps in the replication cycle other than integration, defective mutant viruses were tested for integrase protein content and reverse transcription in addition to integration. The F185K core domain mutation, which increases integrase protein solubility, was furthermore analyzed in a subset of mutants. Results: Purified proteins were assessed for in vitro levels of 3' processing and DNA strand transfer activities whereas HIV-1 infectivity was measured using luciferase reporter viruses. Deletions lacking up to 9 amino acids (1-285, 1-282, and 1-279) displayed near wild-type activities in vitro and during infection. Further deletion yielded two viruses, HIV-1(1-276) and HIV-1(1-273), that displayed approximately two and 5-fold infectivity defects, respectively, due to reduced integrase function. Deletion mutant HIV-1(1-270) and the HIV-1/2 chimera were non-infectious and displayed approximately 3 to 4-fold reverse transcription in addition to severe integration defects. Removal of four additional residues, which encompassed the C-terminal. strand of the SH3 fold, further compromised integrase incorporation into virions and reverse transcription. Conclusion: HIV-1(1-270), HIV-1(1-266), and the HIV-1/2 chimera were typed as class II mutant viruses due to their pleiotropic replication defects. We speculate that residues 271-273 might play a role in mediating the known integrase-reverse transcriptase interaction, as their removal unveiled a reverse transcription defect. The F185K mutation reduced the in vitro activities of 1-279 and 1-276 integrases by about 25%. Mutant proteins 1-279/F185K and 1-276/F185K are therefore highlighted as potential structural biology candidates, whereas further deleted tail variants (1-273/F185K or 1-270/F185K) are less desirable due to marginal or undetectable levels of integrase function. C1 [Dar, Mohd J.; Monel, Blandine; Krishnan, Lavanya; Shun, Ming-Chieh; Di Nunzio, Francesca; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol, Boston, MA 02115 USA. [Dar, Mohd J.; Monel, Blandine; Krishnan, Lavanya; Shun, Ming-Chieh; Di Nunzio, Francesca; Engelman, Alan] Dana Farber Canc Inst, AIDS, Boston, MA 02115 USA. [Helland, Dag E.] Univ Bergen, Inst Mol Biol, N-5020 Bergen, Norway. RP Engelman, A (reprint author), Dana Farber Canc Inst, Dept Canc Immunol, 44 Binney St, Boston, MA 02115 USA. EM mjd82+@pitt.edu; Blandine_Monel@dfci.harvard.edu; lavanya_krishnan@dfci.harvard.edu; michelle_shun@dfci.harvard.edu; Francesca_DiNunzio@dfci.harvard.edu; Helland@mbi.uib.no; alan_engelman@dfci.harvard.edu RI Di Nunzio, Francesca/A-6153-2014 OI Di Nunzio, Francesca/0000-0003-2879-3164 FU US NIH [AI039394, AI070042]; Harvard University Center for AIDS Research (CFAR); NIH [P30AI060354]; NIAID; NCI; NIMH; NIDA; NICHD; NHLBI; NCCAM FX The authors thank Nan Yan for valuable technical advice. This work was supported by US NIH grants AI039394 and AI070042 ( to AE) and the Harvard University Center for AIDS Research (CFAR), an NIH funded program (P30AI060354) that is supported by the following NIH Institutes and Centers: NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NCCAM. The contents of this manuscript do not necessarily reflect the views of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government. NR 67 TC 20 Z9 20 U1 0 U2 4 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 OCT 19 PY 2009 VL 6 AR 94 DI 10.1186/1742-4690-6-94 PG 13 WC Virology SC Virology GA 518FC UT WOS:000271675000001 PM 19840380 ER PT J AU Feuerer, M Shen, YL Littman, DR Benoist, C Mathis, D AF Feuerer, Markus Shen, Yuelei Littman, Dan R. Benoist, Christophe Mathis, Diane TI How Punctual Ablation of Regulatory T Cells Unleashes an Autoimmune Lesion within the Pancreatic Islets SO IMMUNITY LA English DT Article ID NONOBESE DIABETIC MICE; NATURAL-KILLER-CELLS; NOD MICE; IFN-GAMMA; LYMPH-NODES; CROSS-TALK; ANTIGEN; FOXP3; COSTIMULATION; ENTEROPATHY AB CD4(+)Foxp3(+) regulatory T cells (Treg cells) are known to control the progression of autoimmune diabetes, but when, where, and how they exert their influence in this context are questions still under vigorous debate. Exploiting a transgene encoding the human diphtheria toxin receptor, we punctually and specifically ablated Foxp3(+) cells in the BCD2.5/NOD mouse model of autoimmune diabetes. Strikingly, overt disease developed within 3 days. The earliest detectable event was the activation of natural killer (NK) cells directly within the insulitic lesion, particularly the induction of Ifng gene expression within 7 hours of Treg cell ablation. Interferon-gamma had a strong impact on the gene-expression program of the local CD4(+) T effector cell population, unleashing it to aggressively attack the islets, which was required for the development of diabetes. Thus, Treg cells regulate pancreatic autoimmunity in situ through control of a central innate immune system player, NK cells. C1 [Feuerer, Markus; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Feuerer, Markus; Benoist, Christophe; Mathis, Diane] Harvard Univ, Sch Med, Joslin Diabet Ctr, Sect Immunol & Immunogenet, Boston, MA 02115 USA. [Mathis, Diane] Harvard Univ, Sch Med, Harvard Stem Cell Inst, Boston, MA 02115 USA. [Shen, Yuelei; Littman, Dan R.] NYU, Sch Med, Kimmel Ctr Biol & Med, New York, NY 10016 USA. [Shen, Yuelei; Littman, Dan R.] NYU, Sch Med, Skirball Inst, New York, NY 10016 USA. [Shen, Yuelei; Littman, Dan R.] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. RP Benoist, C (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM cbdm@hms.harvard.edu; cbdm@hms.harvard.edu RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X FU Juvenile Diabetes Research Foundation [4-2007-1057]; NIH [R01 DK59658]; Asthma Research and the National Multiple Sclerosis Society; NIDDK-funded Diabetes and Endocrinology Research Center; German Research Foundation [FE 801/1-1] FX We thank J. Stockton for producing the DTR transgenics; J. LaVecchio and G. Buruzala for flow cytometry; J. Hill, J. Perez, and K. Leatherbee for help with the microarray analyses; and H.-J. Wu for the IFN-gamma signature. This work was supported by grants from the Juvenile Diabetes Research Foundation (4-2007-1057) and the NIH (R01 DK59658) to D.M. and C.B.; by grants from the Sandler Program in Asthma Research and the National Multiple Sclerosis Society to D.R.L.; and by the core facilities of Joslin Diabetes Center's NIDDK-funded Diabetes and Endocrinology Research Center. M.F. was supported by postdoctoral fellowships from the German Research Foundation (Emmy-Noether Fellowship, FE 801/1-1) and the Charles A. King Trust. NR 44 TC 117 Z9 119 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 OCT 16 PY 2009 VL 31 IS 4 BP 654 EP 664 DI 10.1016/j.immuni.2009.08.023 PG 11 WC Immunology SC Immunology GA 514OI UT WOS:000271403900016 PM 19818653 ER PT J AU Choi, Y Seeliger, MA Panjarian, SB Kim, H Deng, X Sim, T Couch, B Koleske, AJ Smithgall, TE Gray, NS AF Choi, Yongmun Seeliger, Markus A. Panjarian, Shoghag B. Kim, Hakjoong Deng, Xianming Sim, Taebo Couch, Brian Koleske, Anthony J. Smithgall, Thomas E. Gray, Nathanael S. TI N-Myristoylated c-Abl Tyrosine Kinase Localizes to the Endoplasmic Reticulum upon Binding to an Allosteric Inhibitor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; BCR-ABL; GENE-PRODUCT; PROTEIN; ACTIN; PROLIFERATION; TRANSLOCATION; ACTIVATION; EXPRESSION; LEUKEMIA AB Allosteric kinase inhibitors hold promise for revealing unique features of kinases that may not be apparent using conventional ATP-competitive inhibitors. Here we explore the activity of a previously reported allosteric inhibitor of BCR-Abl kinase, GNF-2, against two cellular isoforms of Abl tyrosine kinase: one that carries a myristate in the N terminus and the other that is deficient in N-myristoylation. Our results show that GNF-2 inhibits the kinase activity of non-myristoylated c-Abl more potently than that of myristoylated c-Abl by binding to the myristate-binding pocket in the C-lobe of the kinase domain. Unexpectedly, indirect immunofluorescence reveals a translocation of myristoylated c-Abl to the endoplasmic reticulum in GNF-2-treated cells, whereas GNF-2 has no detectable effect on the localization of non-myristoylated c-Abl. These results indicate that GNF-2 competes with the NH(2)-terminal myristate for binding to the c-Abl kinase myristate-binding pocket and that the exposed myristoyl group accounts for the localization to the endoplasmic reticulum. We also demonstrate that GNF-2 can inhibit enzymatic and cellular kinase activity of Arg, a kinase highly homologous to c-Abl, which is also likely to be regulated through intramolecular binding of an NH(2)-terminal myristate lipid. These results suggest that non-ATP-competitive inhibitors, such as GNF-2, can serve as chemical tools that can discriminate between c-Abl isoform-specific behaviors. C1 [Gray, Nathanael S.] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Choi, Yongmun; Deng, Xianming; Gray, Nathanael S.] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. [Seeliger, Markus A.] Univ Calif Berkeley, Howard Hughes Med Inst, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Seeliger, Markus A.] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. [Panjarian, Shoghag B.; Smithgall, Thomas E.] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA 15261 USA. [Couch, Brian; Koleske, Anthony J.] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. RP Gray, NS (reprint author), AGM 628A,250 Longwood Ave, Boston, MA 02115 USA. EM nathanael_gray@dfci.harvard.edu RI Seeliger, Markus/D-6409-2013 FU National Institutes of Health [R01 CA130876-01A1, NS39475, MH77306, R01 CA101828]; Novartis Institute of Biomedical Research FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 CA130876-01A1; NS39475 and MH77306 (to A. J. K.); and R01 CA101828 (to T. E. S.). This work was also supported by the Novartis Institute of Biomedical Research (to N. S. G.). NR 31 TC 26 Z9 26 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 16 PY 2009 VL 284 IS 42 BP 29005 EP 29014 DI 10.1074/jbc.M109.026633 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 505GD UT WOS:000270678900058 PM 19679652 ER PT J AU Domian, IJ Chiravuri, M van der Meer, P Feinberg, AW Shi, X Shao, Y Wu, SM Parker, KK Chien, KR AF Domian, Ibrahim J. Chiravuri, Murali van der Meer, Peter Feinberg, Adam W. Shi, Xi Shao, Ying Wu, Sean M. Parker, Kevin Kit Chien, Kenneth R. TI Generation of Functional Ventricular Heart Muscle from Mouse Ventricular Progenitor Cells SO SCIENCE LA English DT Article ID MAMMALIAN HEART; SMOOTH-MUSCLE; ISL1; DIFFERENTIATION; TRANSCRIPTION; EXPRESSION; LINEAGES; FIELD; MEF2C AB The mammalian heart is formed from distinct sets of first and second heart field (FHF and SHF, respectively) progenitors. Although multipotent progenitors have previously been shown to give rise to cardiomyocytes, smooth muscle, and endothelial cells, the mechanism governing the generation of large numbers of differentiated progeny remains poorly understood. We have employed a two-colored fluorescent reporter system to isolate FHF and SHF progenitors from developing mouse embryos and embryonic stem cells. Genome-wide profiling of coding and noncoding transcripts revealed distinct molecular signatures of these progenitor populations. We further identify a committed ventricular progenitor cell in the Islet 1 lineage that is capable of limited in vitro expansion, differentiation, and assembly into functional ventricular muscle tissue, representing a combination of tissue engineering and stem cell biology. C1 [Domian, Ibrahim J.; Chiravuri, Murali; van der Meer, Peter; Shi, Xi; Shao, Ying; Wu, Sean M.; Chien, Kenneth R.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Domian, Ibrahim J.; Wu, Sean M.; Parker, Kevin Kit; Chien, Kenneth R.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [van der Meer, Peter] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [Feinberg, Adam W.; Parker, Kevin Kit] Harvard Univ, Sch Engn & Appl Sci, Dis Biophys Grp, Cambridge, MA 02138 USA. [Parker, Kevin Kit] Harvard Univ, Wyss Inst Biologically Inspired Engn, Boston, MA 02115 USA. [Chien, Kenneth R.] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. RP Chien, KR (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charles River Plaza,CPZN 3200,185 Cambridge St, Boston, MA 02114 USA. EM krchien@partners.org RI Feinberg, Adam/A-7103-2009 OI Feinberg, Adam/0000-0003-3338-5456 FU NHLBI NIH HHS [K08 HL081086, K08 HL081086-01, K08 HL091209, R01 HL079126, R01 HL079126-01A1, T32 HL002807] NR 21 TC 124 Z9 126 U1 1 U2 17 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 OCT 16 PY 2009 VL 326 IS 5951 BP 426 EP 429 DI 10.1126/science.1177350 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 506ZM UT WOS:000270818600053 PM 19833966 ER PT J AU Sahin, NT Pinker, S Cash, SS Schomer, D Halgren, E AF Sahin, Ned T. Pinker, Steven Cash, Sydney S. Schomer, Donald Halgren, Eric TI Sequential Processing of Lexical, Grammatical, and Phonological Information Within Broca's Area SO SCIENCE LA English DT Article ID WORD FORM AREA; BRAIN; LANGUAGE; MODEL; COMPREHENSION; FREQUENCY; REGION; NOUNS; VERBS; FMRI AB Words, grammar, and phonology are linguistically distinct, yet their neural substrates are difficult to distinguish in macroscopic brain regions. We investigated whether they can be separated in time and space at the circuit level using intracranial electrophysiology (ICE), namely by recording local field potentials from populations of neurons using electrodes implanted in language-related brain regions while people read words verbatim or grammatically inflected them (present/past or singular/plural). Neighboring probes within Broca's area revealed distinct neuronal activity for lexical (similar to 200 milliseconds), grammatical (similar to 320 milliseconds), and phonological (similar to 450 milliseconds) processing, identically for nouns and verbs, in a region activated in the same patients and task in functional magnetic resonance imaging. This suggests that a linguistic processing sequence predicted on computational grounds is implemented in the brain in fine-grained spatiotemporally patterned activity. C1 [Sahin, Ned T.; Halgren, Eric] Univ Calif San Diego, Dept Radiol, La Jolla, CA 92037 USA. [Sahin, Ned T.; Pinker, Steven] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Cash, Sydney S.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Schomer, Donald] Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. RP Sahin, NT (reprint author), Univ Calif San Diego, Dept Radiol, La Jolla, CA 92037 USA. EM sahin@post.harvard.edu FU NIH [NS18741, NS44623, HD18381, T32-MH070328, NCRR P41-RR14075]; Mental Illness and Neuroscience Discovery (MIND) Institute; Sackler Scholars Programme in Psychobiology; Harvard Mind/Brain/Behavior Initiative FX Supported by NIH grants NS18741 (E. H.), NS44623 (E. H.), HD18381 (S. P.), T32-MH070328 (N. T. S.), NCRR P41-RR14075; and the Mental Illness and Neuroscience Discovery (MIND) Institute (N. T. S.), Sackler Scholars Programme in Psychobiology (N. T. S.), and Harvard Mind/Brain/Behavior Initiative (N. T. S.). We heartily thank the patients. We also thank E. Papavassiliou and J. Wu for access to their patients; S. Narayanan, N. Dehghani, M. T. Wheeler, F. Kampmann, and L. Gruber for assistance with intracranial electrophysiological data; R. Raizada for manuscript suggestions; N. M. Sahin; and two anonymous reviewers whose suggestions and encouragement greatly improved this paper. NR 31 TC 167 Z9 168 U1 2 U2 43 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 OCT 16 PY 2009 VL 326 IS 5951 BP 445 EP 449 DI 10.1126/science.1174481 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 506ZM UT WOS:000270818600059 PM 19833971 ER PT J AU Jneid, H Cruz-Gonzalez, I Sanchez-Ledesma, M Maree, AO Cubeddu, RJ Leon, ML Rengifo-Moreno, P Otero, JP Inglessis, I Sanchez, PL Palacios, IF AF Jneid, Hani Cruz-Gonzalez, Ignacio Sanchez-Ledesma, Maria Maree, Andrew O. Cubeddu, Roberto J. Leon, Milton L. Rengifo-Moreno, Pablo Otero, Juan Pal Inglessis, Ignacio Sanchez, Pedro L. Palacios, Igor F. TI Impact of Pre- and Postprocedural Mitral Regurgitation on Outcomes After Percutaneous Mitral Valvuloplasty for Mitral Stenosis SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID BALLOON VALVOTOMY; PREDICTORS; VARIABLES AB Percutaneous mitral valvuloplasty (PMV) is an effective therapy in patients with significant mitral stenosis. Few studies have examined the effect of mitral regurgitation (MR), a frequent periprocedural finding, on PMV outcomes. We examined the effects of pre- and postprocedural MR after PMV. Contrast left ventriculography was performed before and after PMV, and the MR severity was assessed using Sellers' classification. Clinical, hemodynamic, and morphologic variables were collected for all patients. Consecutive patients (n = 876) undergoing a first PMV procedure at a single tertiary center were evaluated. An increasing preprocedural MR severity was associated with reduced PMV success (no MR, 75%; 1+ MR, 65%; 2+ MR, 44%; p <0.0001), increased in-hospital mortality (0.6% vs 2.8% vs 4.9%, respectively; p = 0.007), and other complications. Increasing grades of pre- and postprocedural MR predicted, independently and in a grade-dependent manner, the composite outcome of mortality, mitral valve surgery, or redo PMV (preprocedural MR >= 1+, relative risk [RR] 1.4, 95% confidence interval [CI] 1.2 to 1.8; preprocedural MR >= 2+, RR 1.6, 95% CI 1.1 to 2.4; postprocedural MR >= 1+, RR 1.6,95% CI 1.2 to 2.0; postprocedural MR >= 2+, RR 2.2, 95% CI 1.7 to 2.7; and postprocedural MR >= 3+, RR 4.6, 95% CI 3.4 to 6.2, respectively). In conclusion, increasing pre- and postprocedural MR grades independently predicted the long-term clinical outcomes after PMV. Patients with moderate preprocedural MR, in particular, appeared to have suboptimal short- and long-term outcomes, necessitating careful monitoring and early referral for mitral valve surgery, when appropriate. Published by Elsevier Inc. (Am J Cardiol 2009;104:1122-1127) C1 [Jneid, Hani] Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Cardiol Sect, Houston, TX USA. [Jneid, Hani] Baylor Coll Med, Houston, TX 77030 USA. [Cruz-Gonzalez, Ignacio; Sanchez-Ledesma, Maria; Maree, Andrew O.; Cubeddu, Roberto J.; Leon, Milton L.; Rengifo-Moreno, Pablo; Otero, Juan Pal; Inglessis, Ignacio; Palacios, Igor F.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Unit, Boston, MA USA. [Sanchez, Pedro L.] Gregorio Maranon Univ Hosp, Div Cardiol, Madrid, Spain. RP Jneid, H (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Dept Med, Cardiol Sect, Houston, TX USA. EM jneid@bcm.edu RI 2009, Secribsal/A-1266-2012; OI Sanchez, Pedro L/0000-0002-4288-345X NR 13 TC 12 Z9 13 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD OCT 15 PY 2009 VL 104 IS 8 BP 1122 EP 1127 DI 10.1016/j.amjcard.2009.06.008 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 507OS UT WOS:000270864600020 PM 19801035 ER PT J AU Joo, C Ozkumur, E Unlu, MS de Boer, JF AF Joo, Chulmin Ozkumur, Emre Unlu, M. Selim de Boer, Johannes F. TI Spectral-domain optical coherence phase microscopy for label-free multiplexed protein microarray assay SO BIOSENSORS & BIOELECTRONICS LA English DT Article DE Optical interferometer; Optical coherence tomography; Label-free; Microarray; Proteomics ID INTERFEROMETRY; TOMOGRAPHY AB Quantitative measurement of affinities and kinetics of various biomolecular interactions such as protein-protein, protein-DNA and receptor-ligand is central to our understanding of basic molecular and cellular functions and is useful for therapeutic evaluation. Here, we describe a laser-scanning quantitative imaging method, referred to as spectral-domain optical coherence phase microscopy, as an optical platform for label-free detection of biomolecular interactions. The instrument is based on a confocal interferometric microscope that enables depth-resolved quantitative phase measurements on sensor surface with high spatial resolution and phase stability. We demonstrate picogram per square millimeter surface mass sensitivity, and show its sensing capability by presenting static and dynamic detection of multiplexed protein microarray as immobilized antigens capture their corresponding antibodies. (C) 2009 Elsevier B.V. All rights reserved. C1 [Joo, Chulmin; de Boer, Johannes F.] Harvard Univ, Sch Med, Wellman Ctr Photomed, Boston, MA 02114 USA. [Joo, Chulmin; de Boer, Johannes F.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Joo, Chulmin] MIT, Dept Mech Engn, Cambridge, MA 02139 USA. [Ozkumur, Emre; Unlu, M. Selim] Boston Univ, Dept Elect & Comp Engn, Boston, MA 02139 USA. [de Boer, Johannes F.] Vrije Univ Amsterdam, Dept Phys & Astron, NL-1081 HV Amsterdam, Netherlands. RP Joo, C (reprint author), GE Global Res, 1 Res Circle, Niskayuna, NY 12309 USA. EM jooc@ge.com; jfdeboer@few.vu.nl RI de Boer, Johannes/B-7590-2012; Unlu, Selim/B-4244-2013; OI de Boer, Johannes/0000-0003-1253-4950; Joo, Chulmin/0000-0002-1812-2976 FU National Institute of Health [R01 RR19768, EY14975]; U.S. Department of Defense [F4 9620-01-1-0014]; Army Research Laboratory [W911NF-06-2-0040]; Center for Integration of Medicine and Innovative Technology; Wellman Graduate Fellowship; MIT Department of Mechanical Engineering FX This work was supported by grants from National Institute of Health (R01 RR19768, EY14975 to J.F.dB), the U.S. Department of Defense (F4 9620-01-1-0014 to M.S.U.), Army Research Laboratory (W911NF-06-2-0040 to M.S.U.), and the Center for Integration of Medicine and Innovative Technology. The authors are grateful to Drs. Ki Hean Kim and Conor Evans for their contributions to the system setup. C.J. would like to thank the support through Wellman Graduate Fellowship and Hatsopoulous Innovation Award from the MIT Department of Mechanical Engineering. NR 30 TC 12 Z9 12 U1 0 U2 6 PU ELSEVIER ADVANCED TECHNOLOGY PI OXFORD PA OXFORD FULFILLMENT CENTRE THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-5663 J9 BIOSENS BIOELECTRON JI Biosens. Bioelectron. PD OCT 15 PY 2009 VL 25 IS 2 BP 275 EP 281 DI 10.1016/j.bios.2009.06.028 PG 7 WC Biophysics; Biotechnology & Applied Microbiology; Chemistry, Analytical; Electrochemistry; Nanoscience & Nanotechnology SC Biophysics; Biotechnology & Applied Microbiology; Chemistry; Electrochemistry; Science & Technology - Other Topics GA 506GY UT WOS:000270764300002 PM 19674885 ER PT J AU Bergman, J Gore, JL Saigal, CS Kwan, L Litwin, MS AF Bergman, Jonathan Gore, John L. Saigal, Christopher S. Kwan, Lorna Litwin, Mark S. TI Partnership and Outcomes in Men With Prostate Cancer SO CANCER LA English DT Article DE prostatic neoplasms; quality of life; marital relationship; outcome assessment; neoplasms ID QUALITY-OF-LIFE; BREAST-CANCER; PSYCHOLOGICAL DISTRESS; ERECTILE DYSFUNCTION; COUPLES; HEALTH; SUPPORT; CARCINOMA; VALIDITY; WOMEN AB BACKGROUND: Being in a supportive relationship may have improved the health-related quality of life (HRQOL) of men with prostate cancer, if the support was strong and positive. In the current study, the authors sought to examine the impact of partnership status on the mental health of men treated for localized prostate cancer. METHODS: Participants had clinically localized prostate cancer and chose treatment with radical prostatectomy (n=307), external-beam radiotherapy (n=78), or brachytherapy (n=91). The authors prospectively assessed subject characteristics and HRQOL outcomes and evaluated associations between partnership outcomes and HRQOL measures. Two multivariate linear regression models were then created, I for baseline HRQOL outcomes and 1 for change in HRQOL from baseline to 12 months, with partnership status as the main predictor and subject characteristics as covariates. RESULTS: Partnership status was not found to be associated with either baseline physical or mental health, but partnered participants had less bowel bother (P=.02) and a lower fear of recurrence (P=.03) at baseline than did unpartnered subjects. Men with fewer comorbid conditions scored better across almost all baseline HRQOL domains. Primary treatment type was significantly associated with changes in physical HRQOL, with men undergoing radical prostatectomy describing better changes in physical health than those treated with brachytherapy (P=.04) or those receiving external-beam radiotherapy (P <=.01). CONCLUSIONS: Physical and mental health was found to be comparable in the study cohort of partnered and unpartnered men treated for prostate cancer. The universally high socioeconomic status of the current study cohort may mitigate differences in HRQOL by partnership status. Cancer 2009;115:4688-94. (C) 2009 American Cancer Society. C1 [Bergman, Jonathan; Gore, John L.] Univ Calif Los Angeles, Dept Urol, Robert Wood Johnson Clin Scholars Program, Los Angeles, CA 90095 USA. [Gore, John L.; Saigal, Christopher S.] Vet Adm Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA. [Saigal, Christopher S.; Litwin, Mark S.] Univ Calif Los Angeles, Dept Hlth Serv, Los Angeles, CA 90095 USA. [Saigal, Christopher S.; Kwan, Lorna; Litwin, Mark S.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90095 USA. RP Bergman, J (reprint author), Univ Calif Los Angeles, Dept Urol, Robert Wood Johnson Clin Scholars Program, Box 951738, Los Angeles, CA 90095 USA. EM jbergman@mednet.ucla.edu OI Gore, John/0000-0002-2847-5062 NR 27 TC 11 Z9 12 U1 2 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD OCT 15 PY 2009 VL 115 IS 20 BP 4688 EP 4694 DI 10.1002/cncr.24544 PG 7 WC Oncology SC Oncology GA 505ZJ UT WOS:000270740900008 PM 19626653 ER PT J AU Firestein, R Hahn, WC AF Firestein, Ron Hahn, William C. TI Revving the Throttle on an Oncogene: CDK8 Takes the Driver Seat SO CANCER RESEARCH LA English DT Review ID BETA-CATENIN; MEDIATOR COMPLEX; GENE-EXPRESSION; TRANSCRIPTION; ACTIVATION; PHOSPHORYLATION; SUBCOMPLEX; PYGOPUS; MED12 AB The Wnt/beta-catenin pathway plays an important role in initiation in most, if not all, colon cancers. Prior work has provided important insights into the regulation of beta-catenin stability in the cytoplasm; however, relatively little is known about the mechanism by which beta-catenin activates gene transcription in the nucleus. Using genetic approaches, studies in human colon cancers and Drosophila have identified CDK8 as a colon cancer oncogene that regidates beta-catenin transcriptional activity. These convergent observations provide new insights into the regulation of nuclear beta-catenin activity and identify a novel therapeutic target for beta-catenin-driven malignancies. [Cancer Res 2009;69(20):7899-901] C1 [Firestein, Ron; Hahn, William C.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Firestein, Ron] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Hahn, William C.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Hahn, William C.] Broad Inst Harvard & MIT, Cambridge, MA USA. RP Hahn, WC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Dana 1538, Boston, MA 02115 USA. EM william_hahn@dfci.harvard.edu FU U.S. National Institutes of Health [R33 CA128625] FX Grant support: U.S. National Institutes of Health (R33 CA128625). NR 20 TC 23 Z9 25 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2009 VL 69 IS 20 BP 7899 EP 7901 DI 10.1158/0008-5472.CAN-09-1704 PG 3 WC Oncology SC Oncology GA 508MM UT WOS:000270935500002 PM 19808961 ER PT J AU Xu, L Duda, DG di Tomaso, E Ancukiewicz, M Chung, DC Lauwers, GY Samuel, R Shellito, P Czito, BG Lin, PC Poleski, M Bentley, R Clark, JW Willett, CG Jain, RK AF Xu, Lei Duda, Dan G. di Tomaso, Emmanuelle Ancukiewicz, Marek Chung, Daniel C. Lauwers, Gregory Y. Samuel, Rekha Shellito, Paul Czito, Brian G. Lin, Pei-Chun Poleski, Martin Bentley, Rex Clark, Jeffrey W. Willett, Christopher G. Jain, Rakesh K. TI Direct Evidence that Bevacizumab, an Anti-VEGF Antibody, Up-regulates SDF1 alpha, CXCR4, CXCL6, and Neuropilin 1 in Tumors from Patients with Rectal Cancer SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; ANTIANGIOGENIC THERAPY; CELL-MIGRATION; COLORECTAL-CANCER; ANGIOGENESIS; VASCULATURE; METASTASIS; EXPRESSION AB Clinical studies converge on the observation that circulating cytokines are elevated in most cancer patients by anti-vascular endothelial growth factor (VEGF) therapy. However, the source of these molecules and their relevance in tumor escape remain unknown. We examined the gene expression profiles of cancer cells and tumor-associated macrophages in tumor biopsies before and 12 days after monotherapy with the anti-VEGF antibody bevacizumab in patients with rectal carcinoma. Bevacizumab up-regulated stromal cell-derived factor 1 alpha. (SDF1 alpha), its receptor CXCR4, and CXCL6, and down-regulated PIGF, Ang1, and Ang2 in cancer cells. In addition, bevacizumab decreased Ang1 and induced neuropilin 1 (NRP1) expression in tumor-associated macrophages. Higher SDF1 alpha plasma levels during bevacizumab treatment significantly associated with distant metastasis at three years. These data show that VEGF blockade up-regulates inflammatory pathways and NRP1, which should be evaluated as potential targets for improving anti-VEGF therapy. [Cancer Res 2009;69(20):7905-10] C1 [Jain, Rakesh K.] Massachusetts Gen Hosp, EL Steele Lab, Dept Radiat Oncol, Boston, MA 02114 USA. [Chung, Daniel C.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Lauwers, Gregory Y.; Samuel, Rekha] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Shellito, Paul] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Clark, Jeffrey W.] Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. [Czito, Brian G.; Willett, Christopher G.] Duke Univ, Med Ctr, Div Radiat Oncol, Durham, NC 27710 USA. [Poleski, Martin] Duke Univ, Med Ctr, Dept Gastroenterol, Durham, NC 27710 USA. [Bentley, Rex] Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, EL Steele Lab, Dept Radiat Oncol, 100 Blossom St,Cox 734, Boston, MA 02114 USA. EM christopher.willett@duke.edu; jain@steele.mgh.harvard.edu RI Lin, Pei-Chun/A-3200-2013 FU NIH [R21-CA99237, P01-CA80124, R01-CA115767, R01-CA85140, R01-CA126CA2]; Federal Share/National Cancer Institute Proton Beam Program Income; National Foundation for Cancer Research FX Grant support: NIH grants R21-CA99237, P01-CA80124, R01-CA115767, R01-CA85140, and R01-CA126CA2; Federal Share/National Cancer Institute Proton Beam Program Income grants; and by the National Foundation for Cancer Research. NR 20 TC 96 Z9 100 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2009 VL 69 IS 20 BP 7905 EP 7910 DI 10.1158/0008-5472.CAN-09-2099 PG 6 WC Oncology SC Oncology GA 508MM UT WOS:000270935500003 PM 19826039 ER PT J AU Wang, X Sansam, CG Thom, CS Metzger, D Evans, JA Nguyen, PTL Roberts, CWM AF Wang, Xi Sansam, Courtney G. Thom, Christopher S. Metzger, Daniel Evans, Julia A. Nguyen, Phuong T. L. Roberts, Charles W. M. TI Oncogenesis Caused by Loss of the SNF5 Tumor Suppressor Is Dependent on Activity of BRG1, the ATPase of the SWI/SNF Chromatin Remodeling Complex SO CANCER RESEARCH LA English DT Article ID CANCER CELL-LINES; ACUTE LYMPHOBLASTIC-LEUKEMIA; SOFT-TISSUE SARCOMAS; RHABDOID TUMORS; PROTEIN EXPRESSION; GERMLINE MUTATION; INI1 EXPRESSION; BREAST-CANCER; GENE; CYCLE AB Alterations in chromatin play an important role in oncogenic transformation, although the underlying mechanisms are often poorly understood. The SWI/SNF complex contributes to epigenetic regulation by using the energy of ATP hydrolysis to remodel chromatin and thus regulate transcription of target genes. SNF5, a core subunit of the SWI/SNF complex, is a potent tumor suppressor that is specifically inactivated in several types of human cancer. However, the mechanism by which SNF5 mutation leads to cancer and the role of SNF5 within the SWI/SNF complex remain largely unknown. It has been hypothesized that oncogenesis in the absence of SNF5 occurs due to a loss of function of the SWI/SNF complex. Here, we show, however, distinct effects for inactivation of Snf5 and the ATPase subunit Brg1 in primary cells. Further, using both human cell lines and mouse models, we show that cancer formation in the absence of SNF5 does not result from SWI/SNF inactivation but rather that oncogenesis is dependent on continued presence of BRG1. Collectively, our results show that cancer formation in the absence of SNF5 is dependent on the activity of the residual BRG1-containing SWI/SNF complex. These findings suggest that, much like the concept of oncogene addiction, targeted inhibition of SWI/SNF ATPase activity may be an effective therapeutic approach for aggressive SNF5-deficient human tumors. [Cancer Res 2009; 69(20):8094-101] C1 [Wang, Xi; Sansam, Courtney G.; Thom, Christopher S.; Evans, Julia A.; Nguyen, Phuong T. L.; Roberts, Charles W. M.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Wang, Xi; Sansam, Courtney G.; Thom, Christopher S.; Evans, Julia A.; Nguyen, Phuong T. L.; Roberts, Charles W. M.] Harvard Univ, Sch Med, Dept Pediat, Childrens Hosp Boston,Div Hematol Oncol, Boston, MA USA. [Metzger, Daniel] Univ Strasbourg 1, INSERM, CNRS, Inst Genet & Biol Mol & Cellulaire, Illkirch Graffenstaden, France. RP Roberts, CWM (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Mayer 657,44 Binney St, Boston, MA 02115 USA. EM charles_roberts@dfci.harvard.edu FU Garrett B. Smith Foundation; Claudia Adams Barr Foundation; Sarcoma Foundation of America; PHS award [R01CA113794, F32CA123776]; Flope Street Kids Foundation FX Grant support: Garrett B. Smith Foundation, the Claudia Adams Barr Foundation, the Sarcoma Foundation of America, and PHS award R01CA113794 (C.W.M. Roberts) and PHS awards F32CA123776 and Flope Street Kids Foundation (C.G. Sansam). NR 50 TC 54 Z9 56 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2009 VL 69 IS 20 BP 8094 EP 8101 DI 10.1158/0008-5472.CAN-09-0733 PG 8 WC Oncology SC Oncology GA 508MM UT WOS:000270935500026 PM 19789351 ER PT J AU Kreeger, PK Mandhana, R Alford, SK Haigis, KM Lauffenburger, DA AF Kreeger, Pamela K. Mandhana, Roli Alford, Shannon K. Haigis, Kevin M. Lauffenburger, Douglas A. TI RAS Mutations Affect Tumor Necrosis Factor-Induced Apoptosis in Colon Carcinoma Cells via ERK-Modulatory Negative and Positive Feedback Circuits Along with Non-ERK Pathway Effects SO CANCER RESEARCH LA English DT Article ID INDUCIBLE AUTOCRINE CASCADE; LEAST-SQUARES REGRESSION; GROWTH-FACTOR RECEPTOR; ONCOGENIC K-RAS; N-RAS; GENETIC ALTERATIONS; ULCERATIVE-COLITIS; COLORECTAL-CANCER; EPITHELIAL-CELLS; SIGNAL AB More than 40% of colon cancers have a mutation in K-RAS or N-RAS, GTPases that operate as central hubs for multiple key signaling pathways within the cell. Utilizing an isogenic panel of colon carcinoma cells with K-RAS or N-RAS variations, we observed differences in tumor necrosis factor-alpha (TNF alpha)-induced apoptosis. When the dynamics of phosphorylated ERK response to TNF alpha were examined, K-RAS mutant cells showed lower activation whereas N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERK-modulatory circuits: negative feedback mediated by dual-specificity phosphatase 5 and positive feedback by autocrine transforming growth factor-alpha. Moreover, in the various RAS mutant colon carcinoma lines, the transforming growth factor-alpha autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite effects on apoptosis. Although the apoptotic responses of the RAS mutant panel to TNF alpha treatment showed significant dependence on the respective phosphorylated ERK dynamics, successful prediction across the various cell lines required contextual information concerning additional pathways including IKK and p38. A quantitative computational model based on weighted linear combinations of these pathway activities successfully predicted not only the spectrum of cell death responses but also the corresponding chemokine production responses. Our findings indicate that diverse RAS mutations yield differential cell behavioral responses to inflammatory cytokine exposure by means of (a) differential effects on ERK activity via multiple feedback circuit mechanisms, and (b) differential effects on other key signaling pathways contextually modulating ERK-related dependence. [Cancer Res 2009;69(20):8191-9] C1 [Kreeger, Pamela K.; Mandhana, Roli; Alford, Shannon K.; Lauffenburger, Douglas A.] MIT, Dept Biol Engn, Cambridge, MA 02139 USA. [Lauffenburger, Douglas A.] MIT, Ctr Canc Res, Cambridge, MA 02139 USA. [Haigis, Kevin M.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Haigis, Kevin M.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA USA. [Haigis, Kevin M.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA USA. RP Lauffenburger, DA (reprint author), MIT, Dept Biol Engn, 77 Massachusetts Ave,16-343, Cambridge, MA 02139 USA. EM kreeger@wisc.edu; lauffen@mit.edu OI Hughes, Shannon/0000-0002-9778-140X; Kreeger, Pamela/0000-0001-8193-1007 FU NIH [U54-CA112967, P50-GM68762]; American Cancer Society [PF-08-026-01-CCG] FX Grant support: NIH grants U54-CA112967 and P50-GM68762, and by the American Cancer Society, PF-08-026-01-CCG (P.K. Kreeger). NR 40 TC 32 Z9 34 U1 1 U2 8 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 OCT 15 PY 2009 VL 69 IS 20 BP 8191 EP 8199 DI 10.1158/0008-5472.CAN-09-1921 PG 9 WC Oncology SC Oncology GA 508MM UT WOS:000270935500038 PM 19789336 ER PT J AU Zhao, JJ Silver, DP AF Zhao, Jean J. Silver, Daniel P. TI Estrogen Receptor-Negative Breast Cancer: New Insights into Subclassification and Targeting SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID ADJUVANT CHEMOTHERAPY; TRASTUZUMAB; SUBTYPES AB Classification schemes for disease states can help identify distinctions with useful implications for therapy and prognosis. Speers and colleagues provide a new subclassification scheme for estrogen receptor-negative breast cancer based upon kinome-wide gene expression profiling with interesting findings that are potentially relevant for both treatment and clinical outcome. (Clin Cancer Res 2009;15(20):6309-10) C1 [Zhao, Jean J.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. [Zhao, Jean J.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Silver, Daniel P.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Silver, Daniel P.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. RP Silver, DP (reprint author), 1 Jimmy Fund Way, Boston, MA 02115 USA. EM daniel_silver@dfci.harvard.edu FU NCI NIH HHS [P50 CA089393, P50 CA089393-090010] NR 13 TC 1 Z9 2 U1 0 U2 0 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 OCT 15 PY 2009 VL 15 IS 20 BP 6309 EP 6310 DI 10.1158/1078-0432.CCR-09-2010 PG 2 WC Oncology SC Oncology GA 509UI UT WOS:000271043500001 PM 19825953 ER PT J AU Speers, C Tsimelzon, A Sexton, K Herrick, AM Gutierrez, C Culhane, A Quackenbush, J Hilsenbeck, S Chang, J Brown, P AF Speers, Corey Tsimelzon, Anna Sexton, Krystal Herrick, Ashley M. Gutierrez, Carolina Culhane, Aedin Quackenbush, John Hilsenbeck, Susan Chang, Jenny Brown, Powel TI Identification of Novel Kinase Targets for the Treatment of Estrogen Receptor-Negative Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION PATTERNS; AFRICAN-AMERICAN; CELL-LINES; PROGNOSIS; SUBTYPES; SURVIVAL; TUMOR; SIGNATURE; CARCINOMA; DOCETAXEL AB Purpose: Previous gene expression profiling studies of breast cancer have focused on the entire genome to identify genes differentially expressed between estrogen receptor (ER) a-positive and ER-a-negative cancers. Experimental Design: Here, we used gene expression microarray profiling to identify a distinct kinase gene expression profile that identifies ER-negative breast tumors and subsets ER-negative breast tumors into four distinct subtypes. Results: Based on the types of kinases expressed in these clusters, we identify a cell cycle regulatory subset, a S6 kinase pathway cluster, an immunomodulatory kinase-expressing cluster, and a mitogen-activated protein kinase pathway cluster. Furthermore, we show that this specific kinase profile is validated using independent sets of human tumors and is also seen in a panel of breast cancer cell lines. Kinase expression knockdown studies show that many of these kinases are essential for the growth of ER-negative, but not ER-positive, breast cancer cell lines. Finally, survival analysis of patients with breast cancer shows that the S6 kinase pathway signature subtype of ER-negative cancers confers an extremely poor prognosis, whereas patients whose tumors express high levels of immunomodulatory kinases have a significantly better prognosis. Conclusions: This study identifies a list of kinases that are prognostic and may serve as druggable targets for the treatment of ER-negative breast cancer. (Clin Cancer Res 2009; 15(20):63 27-40) C1 [Brown, Powel] Baylor Coll Med, Breast Ctr, Dept Med, Houston, TX 77030 USA. [Speers, Corey; Herrick, Ashley M.] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Tsimelzon, Anna; Sexton, Krystal; Gutierrez, Carolina; Hilsenbeck, Susan; Chang, Jenny; Brown, Powel] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Houston, TX 77030 USA. [Culhane, Aedin; Quackenbush, John] Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Brown, P (reprint author), Baylor Coll Med, Breast Ctr, Dept Med, 1 Baylor Plaza,BCM 600, Houston, TX 77030 USA. EM pbrown@breastcenter.tmc.edu FU NCI NIH HHS [P50 CA058183, P50 CA058183-090011, P50 CA 58183] NR 46 TC 47 Z9 48 U1 0 U2 2 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 OCT 15 PY 2009 VL 15 IS 20 BP 6327 EP 6340 DI 10.1158/1078-0432.CCR-09-1107 PG 14 WC Oncology SC Oncology GA 509UI UT WOS:000271043500005 PM 19808870 ER PT J AU Ogino, S Nosho, K Irahara, N Meyerhardt, JA Baba, Y Shima, K Glickman, JN Ferrone, CR Mino-Kenudson, M Tanaka, N Dranoff, G Giovannucci, EL Fuchs, CS AF Ogino, Shuji Nosho, Katsuhiko Irahara, Natsumi Meyerhardt, Jeffrey A. Baba, Yoshifumi Shima, Kaori Glickman, Jonathan N. Ferrone, Cristina R. Mino-Kenudson, Mari Tanaka, Noriko Dranoff, Glenn Giovannucci, Edward L. Fuchs, Charles S. TI Lymphocytic Reaction to Colorectal Cancer Is Associated with Longer Survival, Independent of Lymph Node Count, Microsatellite Instability, and CpG Island Methylator Phenotype SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; POPULATION-BASED SAMPLE; COLON-CANCER; PROGNOSTIC-SIGNIFICANCE; LINE-1 HYPOMETHYLATION; MISMATCH REPAIR; BRAF MUTATION; T-CELLS; CARCINOMA; NUMBER AB Purpose: Host immune response to tumor may be an important prognostic factor for colon cancer patients. However, little is known on prognostic significance of histopathologic lymphoid reaction to tumor, independent of the number of lymph nodes examined and tumoral molecular alterations, including microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), both of which are associated with lymphocytic reaction and clinical outcome. Experimental Design: Using 843 colorectal cancer patients in two independent prospective cohorts, we examined patient prognosis in relation to four components of lymphocytic reaction (i.e., Crohn's-like reaction, peritumoral reaction, intratumoral periglandular reaction, and tumor-infiltrating lymphocytes) and overall lymphocytic score (0-12). CIMP was determined using eight markers including CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1. Cox proportional hazard models computed hazard ratio for mortality, adjusted for covariates including tumor stage, body mass index, lymph node count, KRAS, BRAF, p53, cyclooxygenase-2 (PTGS2), MSI, CIMP, and LINE-1 methylation. Results: Increasing overall lymphocytic reaction score including tumor-infiltrating lymphocytes was associated with a significant improvement in colorectal cancer-specific and overall survival (log-rank P < 0.003). These findings remained significant (adjusted hazard ratio estimates, 0.49-0.71; P(trend) < 0.009) in multivariate models that adjusted for covariates, including body mass index, MSI, CIMP, LINE-1 hypomethylation, and cyclooxygenase-2. The beneficial effect of tumoral lymphocytic reaction was consistent across strata of clinical, pathologic, and molecular characteristics. Conclusions: Lymphocytic reactions to tumor were associated with improved prognosis among colorectal cancer patients, independent of lymph node count and other clinical, pathologic, and molecular characteristics. (Clin Cancer Res 2009;15(20): 6412-20) C1 [Ogino, Shuji] Harvard Univ, Sch Med, Brigham & Womens Hosp,Dept Pathol, Dana Farber Canc Inst,Ctr Mol Oncol Pathol, Boston, MA 02115 USA. [Ogino, Shuji; Nosho, Katsuhiko; Irahara, Natsumi; Meyerhardt, Jeffrey A.; Baba, Yoshifumi; Shima, Kaori; Ferrone, Cristina R.; Mino-Kenudson, Mari; Dranoff, Glenn; Giovannucci, Edward L.; Fuchs, Charles S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Giovannucci, Edward L.; Fuchs, Charles S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ogino, Shuji; Nosho, Katsuhiko; Irahara, Natsumi; Meyerhardt, Jeffrey A.; Baba, Yoshifumi; Shima, Kaori; Dranoff, Glenn; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA. [Ferrone, Cristina R.; Mino-Kenudson, Mari] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Ogino, Shuji; Tanaka, Noriko; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Ogino, S (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp,Dept Pathol, Dana Farber Canc Inst,Ctr Mol Oncol Pathol, Room JF 215C,44 Binney St, Boston, MA 02115 USA. EM shuji_ogino@dfci.harvard.edu FU U.S. NIH [P01 CA87969, P01 CA55075, P50 CA127003, K07 CA122826]; Bennett Family Fund; Entertainment Industry Foundation National Colorectal Cancer Research Alliance; Japan Society for Promotion of Science FX U.S. NIH grants P01 CA87969 IS. Hankinson), P01 CA55075 (W. Willett), P50 CA127003 (C.S. Fuchs), and K07 CA122826 IS. Ogino); the Bennett Family Fund; the Entertainment Industry Foundation National Colorectal Cancer Research Alliance; and a fellowship grant from the Japan Society for Promotion of Science (K. Nosho). The content is solely the responsibility of the authors and does not necessarily represent the official views of National Cancer Institute or NIH. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript. The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and analysis. 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 50 TC 127 Z9 127 U1 1 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 OCT 15 PY 2009 VL 15 IS 20 BP 6412 EP 6420 DI 10.1158/1078-0432.CCR-09-1438 PG 9 WC Oncology SC Oncology GA 509UI UT WOS:000271043500015 PM 19825961 ER PT J AU Snuderl, M Eichler, AF Ligon, KL Vu, QU Silver, M Betensky, RA Ligon, AH Wen, PY Louis, DN Iafrate, AJ AF Snuderl, Matija Eichler, April F. Ligon, Keith L. Vu, Quynh U. Silver, Michael Betensky, Rebecca A. Ligon, Azra H. Wen, Patrick Y. Louis, David N. Iafrate, A. John TI Polysomy for Chromosomes 1 and 19 Predicts Earlier Recurrence in Anaplastic Oligodendrogliomas with Concurrent 1p/19q Loss SO CLINICAL CANCER RESEARCH LA English DT Article ID IN-SITU HYBRIDIZATION; TUMOR-SUPPRESSOR GENE; PROGNOSTIC VALUE; TRANSCRIPT MAP; ALLELIC LOSSES; DELETIONS; SURVIVAL; GLIOMAS; KI-67; OLIGOASTROCYTOMAS AB Purpose: Loss of chromosome arms 1 p and 19q is a molecular feature of oligodendroglial tumors characterized by responsiveness to chemotherapy and a favorable prognosis. The purpose of this study was to evaluate the prognostic significance of polysomy of chromosomes 1 and 19 in the setting of lp/19q codeletion. Experimental Design: We analyzed 64 anaplastic oligodendrogliomas with 1p/19q loss or maintenance diagnosed at Massachusetts General Hospital and Brigham and Women's Hospital from 1996 to 2005; fluorescence in situ hybridization for lp/19q and Ki-67 immunohistochemistry was done. Polysomy was defined as more than two 1q and 19p signals in >30% of the cells with concurrent 1p/19q deletion. Tumors were divided into groups based on their 1p/19q status and compared for progression-free survival, overall survival, and 5-year survival probabilities. Results: Forty-six tumors (72%) in our cohort had lp/19q loss and 18 (28%) had lp/19q maintenance. Of those with loss, 19 (41%) had concurrent polysomy and 27 (59%) lacked polysomy. In agreement with previous studies, the group of anaplastic oligodendrogliomas with 1p/19q loss had significantly better progression-free survival and overall survival than anaplastic oligodendrogliomas with 1p/19q maintenance (P = 0.0009 and P < 0.0003, respectively). Among anaplastic oligodendrogliomas with lp/19q loss, those with polysomy showed shorter progression-free survival than those with 1p/19q loss without polysomy (P = 0.0048). Overall survival was similar in tumors with and without polysomy. The Ki-67 labeling index was not associated with polysomy and did not have prognostic significance. Conclusion: The presence of polysomy in anaplastic oligodendrogliomas with deletion of 1p/19q is a marker of earlier recurrence. (Clin Cancer Res 2009;15(20):6430-7) C1 [Snuderl, Matija; Vu, Quynh U.; Louis, David N.; Iafrate, A. John] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Eichler, April F.] Massachusetts Gen Hosp, Pappas Ctr Neurooncol, Boston, MA 02114 USA. [Silver, Michael] Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. [Ligon, Keith L.; Ligon, Azra H.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Betensky, Rebecca A.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. [Wen, Patrick Y.] Dana Farber Brigham & Womens Canc Ctr, Ctr Neurooncol, Boston, MA USA. RP Iafrate, AJ (reprint author), Massachusetts Gen Hosp, Pathol Serv, 55 Fruit St,Wrn 501, Boston, MA 02114 USA. EM aiafrate@partners.org OI Snuderl, Matija/0000-0003-0752-0917 FU NCI NIH HHS [R01 CA057683, R01 CA057683-16] NR 32 TC 42 Z9 44 U1 0 U2 0 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 OCT 15 PY 2009 VL 15 IS 20 BP 6430 EP 6437 DI 10.1158/1078-0432.CCR-09-0867 PG 8 WC Oncology SC Oncology GA 509UI UT WOS:000271043500017 PM 19808867 ER PT J AU Kim, M Suh, J Romano, D Truong, MH Mullin, K Hooli, B Norton, D Tesco, G Elliott, K Wagner, SL Moir, RD Becker, KD Tanzi, RE AF Kim, Minji Suh, Jaehong Romano, Donna Truong, Mimy H. Mullin, Kristina Hooli, Basavaraj Norton, David Tesco, Giuseppina Elliott, Kathy Wagner, Steven L. Moir, Robert D. Becker, K. David Tanzi, Rudolph E. TI Potential late-onset Alzheimer's disease-associated mutations in the ADAM10 gene attenuate alpha-secretase activity SO HUMAN MOLECULAR GENETICS LA English DT Article ID AMYLOID PRECURSOR PROTEIN; CONVERTING-ENZYME TACE; CYSTEINE SWITCH; KINASE-C; DISINTEGRIN METALLOPROTEASE; BETA-SECRETASE; CLEAVAGE; FAMILY; ACTIVATION; PRODOMAIN AB ADAM10, a member of a disintegrin and metalloprotease family, is an alpha-secretase capable of anti-amyloidogenic proteolysis of the amyloid precursor protein. Here, we present evidence for genetic association of ADAM10 with Alzheimer's disease (AD) as well as two rare potentially disease-associated non-synonymous mutations, Q170H and R181G, in the ADAM10 prodomain. These mutations were found in 11 of 16 affected individuals (average onset age 69.5 years) from seven late-onset AD families. Each mutation was also found in one unaffected subject implying incomplete penetrance. Functionally, both mutations significantly attenuated alpha-secretase activity of ADAM10 (> 70% decrease), and elevated A beta levels (1.5-3.5-fold) in cell-based studies. In summary, we provide the first evidence of ADAM10 as a candidate AD susceptibility gene, and report two potentially pathogenic mutations with incomplete penetrance for late-onset familial AD. C1 [Kim, Minji; Suh, Jaehong; Romano, Donna; Truong, Mimy H.; Mullin, Kristina; Hooli, Basavaraj; Norton, David; Tesco, Giuseppina; Moir, Robert D.; Tanzi, Rudolph E.] Massachusetts Gen Hosp, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Kim, Minji; Suh, Jaehong; Romano, Donna; Truong, Mimy H.; Mullin, Kristina; Hooli, Basavaraj; Norton, David; Tesco, Giuseppina; Moir, Robert D.; Tanzi, Rudolph E.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Elliott, Kathy; Wagner, Steven L.; Becker, K. David] TorreyPines Therapeut, La Jolla, CA 92037 USA. RP Tanzi, RE (reprint author), Massachusetts Gen Hosp, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Bldg 114,16th St C3009, Charlestown, MA 02129 USA. EM tanzi@helix.mgh.harvard.edu FU Cure Alzheimer's Fund; National Institute of Mental Health [R37 MH60009] FX This work was supported by the Cure Alzheimer's Fund and the National Institute of Mental Health (R37 MH60009). NR 48 TC 80 Z9 82 U1 0 U2 7 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 OCT 15 PY 2009 VL 18 IS 20 BP 3987 EP 3996 DI 10.1093/hmg/ddp323 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 499KF UT WOS:000270218300018 PM 19608551 ER PT J AU Bertram, L Tanzi, RE AF Bertram, Lars Tanzi, Rudolph E. TI Genome-wide association studies in Alzheimer's disease SO HUMAN MOLECULAR GENETICS LA English DT Review ID SYSTEMATIC METAANALYSES; SUSCEPTIBILITY GENE; APOLIPOPROTEIN-E; EXPRESSION; PROTEIN; BETA; APOE; POLYMORPHISMS; HYPOTHESIS; EPSILON-4 AB Genome-wide association studies (GWAS) have gained considerable momentum over the last couple of years for the identification of novel complex disease genes. In the field of Alzheimer's disease (AD), there are currently eight published and two provisionally reported GWAS, highlighting over two dozen novel potential susceptibility loci beyond the well-established APOE association. On the basis of the data available at the time of this writing, the most compelling novel GWAS signal has been observed in GAB2 (GRB2-associated binding protein 2), followed by less consistently replicated signals in galanin-like peptide (GALP), piggyBac transposable element derived 1 (PGBD1), tyrosine kinase, non-receptor 1 (TNK1). Furthermore, consistent replication has been recently announced for CLU (clusterin, also known as apolipoprotein J). Finally, there are at least three replicated loci in hitherto uncharacterized genomic intervals on chromosomes 14q32.13, 14q31.2 and 6q24.1 likely implicating the existence of novel AD genes in these regions. In this review, we will discuss the characteristics and potential relevance to pathogenesis of the outcomes of all currently available GWAS in AD. A particular emphasis will be laid on findings with independent data in favor of the original association. C1 [Bertram, Lars] Max Planck Inst Mol Genet, Neuropsychiat Genet Grp, D-14195 Berlin, Germany. [Tanzi, Rudolph E.] Massachusetts Gen Hosp, Dept Neurol, Genet & Aging Res Unit, Charlestown, MA USA. RP Bertram, L (reprint author), Max Planck Inst Mol Genet, Neuropsychiat Genet Grp, Ihnestr 63,Room 204-1, D-14195 Berlin, Germany. EM lbertram@molgen.mpg.de RI Bertram, Lars/K-3889-2015 OI Bertram, Lars/0000-0002-0108-124X FU Cure Alzheimer's Fund; NIMH; NIA; German Federal Ministry of Education and Research (BMBF) FX This work was made possible by support from the Cure Alzheimer's Fund, NIMH, NIA, and the German Federal Ministry of Education and Research (BMBF). The AlzGene database is funded by the Cure Alzheimer's Fund. NR 40 TC 92 Z9 92 U1 1 U2 8 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 OCT 15 PY 2009 VL 18 BP R137 EP R145 DI 10.1093/hmg/ddp406 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 512QR UT WOS:000271265600003 PM 19808789 ER PT J AU Janakiraman, A Fixen, KR Gray, AN Niki, H Goldberg, MB AF Janakiraman, Anuradha Fixen, Kathryn R. Gray, Andrew N. Niki, Hironori Goldberg, Marcia B. TI A Genome-Scale Proteomic Screen Identifies a Role for DnaK in Chaperoning of Polar Autotransporters in Shigella SO JOURNAL OF BACTERIOLOGY LA English DT Article ID SURFACE PROTEIN ACTA; ESCHERICHIA-COLI; FLEXNERI 2A; UNIPOLAR LOCALIZATION; FLUORESCENT PROTEIN; CRYSTAL-STRUCTURE; BACTERIAL-GROWTH; GENE-EXPRESSION; VIRULENCE GENE; CELL-DIVISION AB Autotransporters are outer membrane proteins that are widely distributed among gram-negative bacteria. Like other autotransporters, the Shigella autotransporter IcsA, which is required for actin assembly during infection, is secreted at the bacterial pole. In the bacterial cytoplasm, IcsA localizes to poles and potential cell division sites independent of the cell division protein FtsZ. To identify bacterial proteins involved in the targeting of IcsA to the pole in the bacterial cytoplasm, we screened a genome-scale library of Escherichia coli proteins tagged with green fluorescent protein (GFP) for those that displayed a localization pattern similar to that of IcsA-GFP in cells that lack functional FtsZ using a strain carrying a temperature-sensitive ftsZ allele. For each protein that mimicked the localization of IcsA-GFP, we tested whether IcsA localization was dependent on the presence of the protein. Although these approaches did not identify a polar receptor for IcsA, the cytoplasmic chaperone DnaK both mimicked IcsA localization at elevated temperatures as a GFP fusion and was required for the localization of IcsA to the pole in the cytoplasm of E. coli. DnaK was also required for IcsA secretion at the pole in Shigella flexneri. The localization of DnaK-GFP to poles and potential cell division sites was dependent on elevated growth temperature and independent of the presence of IcsA or functional FtsZ; native DnaK was found to be enhanced at midcell and the poles. A second Shigella autotransporter, SepA, also required DnaK for secretion, consistent with a role of DnaK more generally in the chaperoning of autotransporter proteins in the bacterial cytoplasm. C1 [Janakiraman, Anuradha; Goldberg, Marcia B.] Massachusetts Gen Hosp, Div Infect Dis, Cambridge, MA 02139 USA. [Janakiraman, Anuradha] CUNY City Coll, Dept Biol, New York, NY 10031 USA. [Janakiraman, Anuradha] CUNY, Grad Ctr, New York, NY 10031 USA. [Fixen, Kathryn R.; Gray, Andrew N.; Goldberg, Marcia B.] Harvard Univ, Dept Microbiol & Mol Genet, Sch Med, Boston, MA 02115 USA. [Niki, Hironori] Natl Inst Genet, Radioisotope Ctr, Genet Strains Res Ctr, Shizuoka, Japan. [Niki, Hironori] Natl Inst Genet, Microbial Genet Lab, Genet Strains Res Ctr, Shizuoka, Japan. RP Goldberg, MB (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 65 Landsdowne St, Cambridge, MA 02139 USA. EM mgoldberg1@partners.org FU American Heart Association [0425855T]; National Institute of General Medical Sciences [GM082336]; Ministry of Education, Culture, Sports, Science, and Technology of Japan; National Institutes of Allergy and Infectious Diseases (NIH) [AI035817] FX This research was supported by a fellowship from the American Heart Association (0425855T) to A.J., a grant from the National Institute of General Medical Sciences (GM082336) to A. J., a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan to H. N., and a grant from the National Institutes of Allergy and Infectious Diseases (NIH AI035817) to M. B. G. NR 79 TC 15 Z9 16 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT 15 PY 2009 VL 191 IS 20 BP 6300 EP 6311 DI 10.1128/JB.00833-09 PG 12 WC Microbiology SC Microbiology GA 499NG UT WOS:000270227500012 PM 19684128 ER PT J AU Zalutskaya, AA Cox, MK Demay, MB AF Zalutskaya, Alena A. Cox, Megan K. Demay, Marie B. TI Phosphate Regulates Embryonic Endochondral Bone Development SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE PHOSPHATE; EMBRYONIC; BONE; DEVELOPMENT ID GROWTH-FACTOR RECEPTOR-3; CHONDROCYTE PROLIFERATION; PARATHYROID-HORMONE; APOPTOSIS; MICE; DIFFERENTIATION; CASPASES; PLATE; STAT1; FGF AB Phosphate is required for terminal differentiation of hypertrophic chondrocytes during postnatal growth plate maturation. in vitro models of chondrocyte differentiation demonstrate that 7 mM phosphate, a concentration analogous to that of the late gestational fetus, activates the mitochondrial apoptotic pathway in hypertrophic chondrocytes. This raises the question as to whether extracellular phosphate modulates chondrocyte differentiation and apoptosis during embryonic endochondral bone formation. To address this question, we performed investigations in the mouse metatarsal culture model that recapitulates in vivo bone development. Metatarsals were cultured for 4, 8, and 12 days with 1.25 and 7 mM phosphate. Metatarsals cultured with 7 mM phosphate showed a decrease in proliferation compared to those cultured in 1.25 mM phosphate. This decrease in proliferation was accompanied by an early enhancement in hypertrophic chondrocyte differentiation, associated with an increase in FGF18 expression. By 8 days in culture, an increase caspase-9 activation and apoptosis of hypertrophic chondrocytes was observed in the metatarsals cultured in 7 mM phosphate. Immunohistochemical analyses of embryonic bones demonstrated activation of caspase-9 in hypertrophic chondrocytes, associated with vascular invasion. Thus, these investigations demonstrate that phosphate promotes chondrocyte differentiation during embryonic development and implicate a physiological role for phosphate activation of the mitochondrial apoptotic pathway during embryonic endochondral bone formation. J. Cell. Biochem. 108: 668674, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Zalutskaya, Alena A.; Cox, Megan K.; Demay, Marie B.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Demay, MB (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Thier 11, Boston, MA 02114 USA. EM demay@helix.mgh.harvard.edu FU NIH [R01DK46974, T32DK007028] FX Grant sponsor: NIH; Grant numbers: R01DK46974, T32DK007028. NR 24 TC 6 Z9 6 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT 15 PY 2009 VL 108 IS 3 BP 668 EP 674 DI 10.1002/jcb.22302 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 503UU UT WOS:000270567100014 PM 19681042 ER PT J AU Smith, AC Shah, SA Hudson, AE Purpura, KP Victor, JD Brown, EN Schiff, ND AF Smith, Anne C. Shah, Sudhin A. Hudson, Andrew E. Purpura, Keith P. Victor, Jonathan D. Brown, Emery N. Schiff, Nicholas D. TI A Bayesian statistical analysis of behavioral facilitation associated with deep brain stimulation SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Deep brain stimulation; State-space models; Bayesian estimation; Behavior; Model selection; Logistic regression ID PARKINSONS-DISEASE; DYNAMIC-ANALYSIS; MONTE-CARLO; PERFORMANCE; CONSCIOUSNESS; ENHANCEMENT; ALGORITHMS; DISORDERS; CAUDATE; NUCLEUS AB Deep brain stimulation (DBS) is an established therapy for Parkinson's Disease and is being investigated as a treatment for chronic depression, obsessive compulsive disorder and for facilitating functional recovery of patients in minimally conscious states following brain injury. For all of these applications, quantitative assessments of the behavioral effects of DBS are crucial to determine whether the therapy is effective and, if so, how stimulation parameters can be optimized. Behavioral analyses for DBS are challenging because subject performance is typically assessed from only a small set of discrete measurements made on a discrete rating scale, the time course of DBS effects is unknown, and between-subject differences are often large. We demonstrate how Bayesian state-space methods can be used to characterize the relationship between DBS and behavior comparing our approach with logistic regression in two experiments: the effects of DBS on attention of a macaque monkey performing a reaction-time task, and the effects of DBS on motor behavior of a human patient in a minimally conscious state. The state-space analysis can assess the magnitude of DBS behavioral facilitation (positive or negative) at specific time points and has important implications for developing principled strategies to optimize DBS paradigms. (C) 2009 Elsevier B.V. All rights reserved. C1 [Smith, Anne C.] Univ Calif Davis, Dept Anesthesiol & Pain Med, Davis, CA 95616 USA. [Shah, Sudhin A.] Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10065 USA. [Hudson, Andrew E.] Weill Cornell Med Coll, Dept Anesthesiol, New York, NY 10065 USA. [Purpura, Keith P.; Victor, Jonathan D.; Schiff, Nicholas D.] Weill Cornell Med Coll, Dept Neurol & Neurosci, New York, NY 10065 USA. [Brown, Emery N.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neurosci Stat Res Lab, Boston, MA 02114 USA. [Brown, Emery N.] MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. [Brown, Emery N.] MIT, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Smith, AC (reprint author), Univ Calif Davis, Dept Anesthesiol & Pain Med, TB-170,1 Shields Ave, Davis, CA 95616 USA. EM annesmith@ucdavis.edu RI Victor, Jonathan/D-2931-2009; Hudson, Andrew/B-6152-2016 OI Hudson, Andrew/0000-0001-7292-5406 FU IntElect Medical; [R01 MH-071847]; [DP1 OD003646]; [NS02172] FX This research was supported by R01 MH-071847 (ENB, ACS), DP1 OD003646 (ENB), NS02172 (NDS) and IntElect Medical (NDS, KPP, SAS). NR 45 TC 21 Z9 22 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD OCT 15 PY 2009 VL 183 IS 2 BP 267 EP 276 DI 10.1016/j.jneumeth.2009.06.028 PG 10 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 502SD UT WOS:000270479500020 PM 19576932 ER PT J AU Diaz-Griffero, F Qin, XR Hayashi, F Kigawa, T Finzi, A Sarnak, Z Lienlaf, M Yokoyama, S Sodroski, J AF Diaz-Griffero, Felipe Qin, Xu-rong Hayashi, Fumiaki Kigawa, Takanori Finzi, Andres Sarnak, Zoe Lienlaf, Maritza Yokoyama, Shigeyuki Sodroski, Joseph TI A B-Box 2 Surface Patch Important for TRIM5 alpha Self-Association, Capsid Binding Avidity, and Retrovirus Restriction SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; MONKEY TRIM5-ALPHA; NMR STRUCTURE; RING; DOMAIN; PROTEIN; HIV-1; TRIMCYP; B-BOX-2; FAMILY AB TRIM5 alpha is a tripartite motif (TRIM) protein that consists of RING, B-box 2, coiled-coil, and B30.2(SPRY) domains. The TRIM5 alpha(rh) protein from rhesus monkeys recognizes the human immunodeficiency virus type 1 (HIV-1) capsid as it enters the host cell and blocks virus infection prior to reverse transcription. HIV-1-restricting ability can be eliminated by disruption of the B-box 2 domain. Changes in the TRIM5 alpha(rh) B-box 2 domain have been associated with alterations in TRIM5 alpha(rh) turnover, the formation of cytoplasmic bodies and higher-order oligomerization. We present here the nuclear magnetic resonance structure of the TRIM5 B-box 2 domain and identify an unusual hydrophobic patch (cluster 1) on the domain surface. Alteration of cluster 1 or the flanking arginine 121 resulted in various degrees of inactivation of HIV-1 restriction, in some cases depending on compensatory changes in other nearby charged residues. For this panel of TRIM5 alpha(rh) B-box 2 mutants, inhibition of HIV-1 infection was strongly correlated with higher-order self-association and binding affinity for capsid complexes but not with TRIM5 alpha(rh) half-life or the formation of cytoplasmic bodies. Thus, promoting cooperative TRIM5 alpha(rh) interactions with the HIV-1 capsid represents a major mechanism whereby the B-box 2 domain potentiates HIV-1 restriction. C1 [Diaz-Griffero, Felipe; Finzi, Andres; Sarnak, Zoe; Lienlaf, Maritza; Sodroski, Joseph] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Pathol,Div AIDS, Boston, MA 02115 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. [Qin, Xu-rong; Hayashi, Fumiaki; Kigawa, Takanori; Yokoyama, Shigeyuki] RIKEN, Yokohama Inst, Syst & Struct Biol Ctr, Yokohama, Kanagawa 2300445, Japan. [Kigawa, Takanori] Tokyo Inst Technol, Interdisciplinary Grad Sch Sci & Engn, Dept Computat Intelligence & Syst Sci, Meguro Ku, Tokyo 1528550, Japan. [Yokoyama, Shigeyuki] Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Bunko Ku, Tokyo 1130032, Japan. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS,Dept Pathol,Div AIDS, 44 Binney St,CLSB 1010, Boston, MA 02115 USA. EM joseph_sodroski@dfci.harvard.edu RI Kigawa, Takanori/A-7679-2010; Yokoyama, Shigeyuki/N-6911-2015 OI Kigawa, Takanori/0000-0003-0146-9719; Yokoyama, Shigeyuki/0000-0003-3133-7338 FU National Institutes of Health [1K99MH086162-01]; American Foundation for AIDS Research Mathilde Krim [106987-43-RFHF]; Dana-Farber Cancer Institute; Riken Structural Genomics/Proteomics Initiative of the National Project on Protein Structural and Functional Analyses, Ministry of Education, Culture, Sports, Science, and Technology of Japan; [K99/R00] FX We acknowledge the National Institutes of Health (grants AI063987 and AI076094 and a Center for AIDS Research Award AI60354), the International AIDS Vaccine Initiative, the Bristol-Myers Squibb Foundation, and the late William F. McCarty-Cooper for research funding. F. D.- G. is a recipient of a K99/R00 Pathway to Independence Award from the National Institutes of Health (1K99MH086162-01), an American Foundation for AIDS Research Mathilde Krim fellowship in basic biomedical research (106987-43-RFHF), and a Claudia Adams Barr award from the Dana-Farber Cancer Institute. The B-box 2 structure determination was supported by the Riken Structural Genomics/Proteomics Initiative of the National Project on Protein Structural and Functional Analyses, Ministry of Education, Culture, Sports, Science, and Technology of Japan. NR 62 TC 83 Z9 88 U1 0 U2 15 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 OCT 15 PY 2009 VL 83 IS 20 BP 10737 EP 10751 DI 10.1128/JVI.01307-09 PG 15 WC Virology SC Virology GA 498FC UT WOS:000270121600039 PM 19656869 ER PT J AU Pogoda, TK Cramer, IE Meterko, M Lin, H Hendricks, A Holloway, RG Chams, MP AF Pogoda, Terri K. Cramer, Irene E. Meterko, Mark Lin, Hai Hendricks, Ann Holloway, Robert G. Chams, Martin P. TI Patient and Organizational Factors Related to Education and Support Use by Veterans with Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; education; social support; multidisciplinary care; specialty centers ID QUALITY-OF-LIFE; MULTIDISCIPLINARY TREATMENT PROGRAM; HEALTH SURVEY SF-36; SELF-MANAGEMENT; PRIMARY-CARE; CENTERED CARE; SOCIAL CARE; INDIVIDUALS; PEOPLE; EFFICACY AB Patient education and support services are recognized in the Department of Veterans Affairs (VA) as important to the patient-centered treatment of Parkinson's disease. Indeed, educating patients is one of the missions of the VA's six specialty Parkinson's Disease Research, Education and Clinical Centers (PADRECCs). We compared VA education/support services utilization by whether or not a patient's VA Medical Center (VAMC) contained a PADRECC. Our sample included Parkinson's disease patients from VAMCs with (n = 882) and without (n = 1,448) PADRECCs. Patients completed surveys that asked about demographic/individual characteristics, health status/function, and education/support utilization. Results showed that 15.8% (n = 354) of all patients utilized education/support services. Patients at PADRECC VAMCs were generally healthier and more educated than other VAMC patients. After statistically controlling for these differences, however, being a patient at a PADRECC VAMC site and using only VA providers (as compared to a combination of VA and non-VA providers) were significant predictors of education/support utilization. Further, proportionally more PADRECC VAMC site patients reported higher satisfaction and receiving a broad range of information from different modalities as compared to other VAMC patients. These findings suggest that PADRECC C 41 VAMCs are providing educational/support activities consistent with these specialty centers' goals. (C) 2009 Movement Disorder Society C1 [Pogoda, Terri K.] VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Dept Vet Affairs, Boston, MA 02130 USA. [Cramer, Irene E.; Meterko, Mark; Hendricks, Ann; Chams, Martin P.] Boston Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA USA. [Lin, Hai] Brown Univ, Women & Infants Hosp Rhode Isl, Brown Ctr Study Children Risk, Warren Alpert Med Sch, Providence, RI 02912 USA. [Hendricks, Ann] Dept Vet Affairs, Boston, MA USA. [Holloway, Robert G.] Univ Rochester, Sch Med & Dent, Dept Neurol, Rochester, NY 14642 USA. RP Pogoda, TK (reprint author), VA Boston Healthcare Syst, Ctr Org Leadership & Management Res, Dept Vet Affairs, 150 S Huntington Ave 152M, Boston, MA 02130 USA. EM terri.pogoda@va.gov OI Charns, Martin/0000-0002-7102-5331 NR 40 TC 2 Z9 2 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD OCT 15 PY 2009 VL 24 IS 13 BP 1916 EP 1924 DI 10.1002/mds.22516 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 516PW UT WOS:000271555700006 PM 19606487 ER PT J AU Salat, DH Lee, SY van der Kouwe, AJ Greve, DN Fischl, B Rosas, HD AF Salat, D. H. Lee, S. Y. van der Kouwe, A. J. Greve, D. N. Fischl, B. Rosas, H. D. TI Age-associated alterations in cortical gray and white matter signal intensity and gray to white matter contrast SO NEUROIMAGE LA English DT Article DE Aging; Cerebral cortex; Cortical thickness; Gray matter; Cortical surface; Tissue contrast ID HUMAN CEREBRAL-CORTEX; MAGNETIC-RESONANCE IMAGES; SURFACE-BASED ANALYSIS; ALZHEIMERS-DISEASE; OLDER-ADULTS; HUMAN BRAIN; IN-VIVO; DIFFERENTIAL VULNERABILITY; GEOMETRICALLY ACCURATE; COGNITIVE PERFORMANCE AB Prior studies have focused on patterns of brain atrophy with aging and age-associated cognitive decline. It is possible that changes in neural tissue properties could provide an important marker of more subtle changes compared to gross morphometry. However, little is known about how MRI tissue parameters are altered in aging. We created cortical surface models of 148 individuals and mapped regional gray and white matter T1-weighted signal intensities from 3D MPRAGE images to examine patterns of age-associated signal alterations. Gray matter intensity was decreased with aging with strongest effects in medial frontal, anterior cingulate, and inferior temporal regions. White matter signal intensity decreased with aging in superior and medial frontal, cingulum, and medial and lateral temporal regions. The gray/white ratio (GWR) was altered throughout a large portion of the cortical mantle, with strong changes in superior and inferior frontal, lateral parietal, and superior temporal and precuneus regions demonstrating decreased overall contrast. Statistical effects of contrast changes were stronger than those of cortical thinning. These results demonstrate that there are strong regional changes in neural tissue properties with aging and tissue intensity measures may serve as an important biomarker of degeneration. Published by Elsevier Inc. C1 [Salat, D. H.; Lee, S. Y.; van der Kouwe, A. J.; Greve, D. N.; Fischl, B.; Rosas, H. D.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Salat, D. H.; van der Kouwe, A. J.; Greve, D. N.; Fischl, B.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. [Salat, D. H.; van der Kouwe, A. J.; Greve, D. N.; Fischl, B.] Harvard Univ, Sch Med, Boston, MA USA. [Lee, S. Y.; Rosas, H. D.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Fischl, B.] MIT, Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA. RP Salat, DH (reprint author), MGH MIT HMS, Athinoula A Martinos Ctr Biomed Imaging, Dept Radiol, Bldg 149,13th St,Mail Code 149 2301, Charlestown, MA 02129 USA. EM salat@nmr.mgh.harvard.edu FU National Institutes of Health [K01AG024898, R01NR010827, P41RR14075, BIRN002, U24RR021382, R01EB001550, R01EB006758, R01NS052585, U54EB005149]; Ellison Medical Foundation FX This work was supported by the National Institutes of Health [K01AG024898, R01NR010827, P41RR14075, BIRN002, U24RR021382, R01EB001550, R01EB006758, R01NS052585, U54EB005149]; the Athinoula A. Martinos Center for Biomedical Imaging, the Mental Illness and Neuroscience Discovery (MIND) Institute, and The Autism & Dyslexia Project funded by the Ellison Medical Foundation. We are grateful to Christina Onorato for providing assistance with data analysis. NR 66 TC 100 Z9 100 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT 15 PY 2009 VL 48 IS 1 BP 21 EP 28 DI 10.1016/j.neuroimage.2009.06.074 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 488AO UT WOS:000269321100006 PM 19580876 ER PT J AU Hinrichs, C Singh, V Mukherjee, L Xu, GF Chung, MK Johnson, SC AF Hinrichs, Chris Singh, Vikas Mukherjee, Lopamudra Xu, Guofan Chung, Moo K. Johnson, Sterling C. CA Alzheimer's Dis Neuroimaging Initi TI Spatially augmented LPboosting for AD classification with evaluations on the ADNI dataset SO NEUROIMAGE LA English DT Article ID DIMENSIONAL PATTERN-CLASSIFICATION; PRODROMAL ALZHEIMERS-DISEASE; COGNITIVE DECLINE; FEATURE-SELECTION; BRAIN ATROPHY; MR-IMAGES; DIAGNOSIS; ALGORITHM; DEMENTIA; PET AB Structural and functional brain images are playing an important role in helping us understand the changes associated with neurological disorders such as Alzheimer's disease (AD). Recent efforts have now started investigating their utility for diagnosis purposes. This line of research has shown promising results where methods from machine learning (such as Support Vector Machines) have been used to identify AD-related patterns from images, for use in diagnosing new individual subjects. In this paper, we propose a new framework for AD classification which makes use of the Linear Program (LP) boosting with novel additional regularization based on spatial "smoothness" in 3D image coordinate spaces. The algorithm formalizes the expectation that since the examples for training the classifier are images, the voxels eventually selected for specifying the decision boundary must constitute spatially contiguous chunks, i.e., "regions" must be preferred over isolated voxels. This prior belief turns out to be useful for significantly reducing the space of possible classifiers and leads to substantial benefits in generalization. In our method, the requirement of spatial contiguity (of selected discriminating voxels) is incorporated within the optimization framework directly. Other methods have made use of similar biases as a pre- or post-processing step, however, our model incorporates this emphasis on spatial smoothness directly into the learning step. We report on extensive evaluations of our algorithm on MR and FDG-PET images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, and discuss the relationship of the classification output with the clinical and cognitive biomarker data available within ADNI. (C) 2009 Elsevier Inc. All rights reserved. C1 [Hinrichs, Chris; Singh, Vikas] Univ Wisconsin, Dept Comp Sci, Madison, WI 53706 USA. [Hinrichs, Chris; Singh, Vikas; Chung, Moo K.] Univ Wisconsin, Dept Biostat & Med Informat, Madison, WI 53705 USA. [Mukherjee, Lopamudra] Univ Wisconsin, Dept Math & Comp Sci, Whitewater, WI 53190 USA. [Xu, Guofan; Johnson, Sterling C.] Univ Wisconsin, Dept Med, Madison, WI 53792 USA. [Xu, Guofan; Johnson, Sterling C.] William S Middleton Mem Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Madison, WI 53792 USA. RP Hinrichs, C (reprint author), 7645 Med Sci Ctr, Madison, WI 53706 USA. EM hinrichs@cs.wisc.edu RI Scharre, Douglas/E-4030-2011; OI Johnson, Sterling/0000-0002-8501-545X FU Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, UW ICTR through an NIH Clinical and Translational Science Award (CTSA) [1UL1RR025011]; Department of Veterans Affairs; Wisconsin Comprehensive Memory Program; NIH [AG021155, U01 AG024904]; Alzheimer's Disease Neuroimaging Initiative; National Institute on Aging; National Institute of Biomedical Imaging and Bioengineering (NIBIB); Pfizer Inc.; Wyeth Research; Bristol-Myers Squibb; Eli Lilly and Company; GlaxoSmithKline; Merck Co. Inc.; AstraZeneca AB; Novartis Pharmaceuticals Corporation; Alzheimer's Association; Eisai Global Clinical Development; Elan Corporation plc; Forest Laboratories; Institute for the Study of Aging FX This research was supported in part by the Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, UW ICTR through an NIH Clinical and Translational Science Award (CTSA) 1UL1RR025011, a Merit Review Grant from the Department of Veterans Affairs, the Wisconsin Comprehensive Memory Program, and an NIH grant AG021155. The authors also acknowledge the facilities and resources at the William S. Middleton Memorial Veterans Hospital.; Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI; Principal Investigator: Michael Weiner; NIH grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and through generous contributions from the following: Pfizer Inc., Wyeth Research, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck & Co. Inc., AstraZeneca AB, Novartis Pharmaceuticals Corporation, Alzheimer's Association, Eisai Global Clinical Development, Elan Corporation plc, Forest Laboratories, and the Institute for the Study of Aging, with participation from the U.S. Food and Drug Administration. Industry partnerships are coordinated through the Foundation for the National Institutes of Health. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory of Neuro Imaging at the University of California, Los Angeles. NR 46 TC 72 Z9 72 U1 1 U2 10 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 OCT 15 PY 2009 VL 48 IS 1 BP 138 EP 149 DI 10.1016/j.neuroimage.2009.05.056 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 488AO UT WOS:000269321100017 PM 19481161 ER PT J AU Mitchell, SL Teno, JM Kiely, DK Shaffer, ML Jones, RN Prigerson, HG Volicer, L Givens, JL Hamel, MB AF Mitchell, Susan L. Teno, Joan M. Kiely, Dan K. Shaffer, Michele L. Jones, Richard N. Prigerson, Holly G. Volicer, Ladislav Givens, Jane L. Hamel, Mary Beth TI The Clinical Course of Advanced Dementia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID NURSING-HOME RESIDENTS; LONG-TERM-CARE; ADVANCED ALZHEIMERS-DISEASE; MANAGEMENT; HOSPICE; PAIN; PATTERNS; SURVIVAL; FAILURE; HEALTH AB BACKGROUND Dementia is a leading cause of death in the United States but is underrecognized as a terminal illness. The clinical course of nursing home residents with advanced dementia has not been well described. METHODS We followed 323 nursing home residents with advanced dementia and their health care proxies for 18 months in 22 nursing homes. Data were collected to characterize the residents' survival, clinical complications, symptoms, and treatments and to determine the proxies' understanding of the residents' prognosis and the clinical complications expected in patients with advanced dementia. CONCLUSIONS Pneumonia, febrile episodes, and eating problems are frequent complications in patients with advanced dementia, and these complications are associated with high 6-month mortality rates. Distressing symptoms and burdensome interventions are also common among such patients. Patients with health care proxies who have an understanding of the prognosis and clinical course are likely to receive less aggressive care near the end of life. C1 [Mitchell, Susan L.; Kiely, Dan K.; Jones, Richard N.; Givens, Jane L.] Hebrew SeniorLife Inst Aging Res, Boston, MA USA. [Mitchell, Susan L.; Jones, Richard N.; Givens, Jane L.; Hamel, Mary Beth] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Prigerson, Holly G.] Dana Farber Canc Inst, Ctr Psychosocial Oncol & Palliat Care Res, Boston, MA 02115 USA. [Teno, Joan M.] Brown Univ, Ctr Gerontol & Hlth Care Res, Dept Community Hlth, Alpert Med Sch, Providence, RI 02912 USA. [Shaffer, Michele L.] Penn State Coll Med, Hershey, PA USA. [Volicer, Ladislav] Univ S Florida, Sch Aging Studies, Tampa, FL USA. RP Mitchell, SL (reprint author), Hebrew SeniorLife, 1200 Ctr St, Boston, MA 02131 USA. EM smitchell@hrca.harvard.edu OI Jones, Richard/0000-0002-1049-218X FU National Institute on Aging [R01 AG024091, K24 AG033640] FX Supported by a grant from the National Institute on Aging (R01 AG024091) and by a Midcareer Award in Patient Oriented Research from the National institute on Aging (K24 AG033640, to Dr. Mitchell). NR 37 TC 461 Z9 469 U1 6 U2 41 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 OCT 15 PY 2009 VL 361 IS 16 BP 1529 EP 1538 DI 10.1056/NEJMoa0902234 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 506LT UT WOS:000270777000006 PM 19828530 ER PT J AU Tamura, MK Covinsky, KE Chertow, GM Yaffe, K Landefeld, CS McCulloch, CE AF Tamura, Manjula Kurella Covinsky, Kenneth E. Chertow, Glenn M. Yaffe, Kristine Landefeld, C. Seth McCulloch, Charles E. TI Functional Status of Elderly Adults before and after Initiation of Dialysis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MINIMUM DATA SET; COMPREHENSIVE GERIATRIC ASSESSMENT; CHRONIC KIDNEY-DISEASE; STAGE RENAL-DISEASE; CARDIAC REHABILITATION; CORONARY-BYPASS; HEMODIALYSIS; SURVIVAL; OUTCOMES; HOSPITALIZATION AB BACKGROUND It is unclear whether functional status before dialysis is maintained after the initiation of this therapy in elderly patients with end-stage renal disease (ESRD). METHODS Using a national registry of patients undergoing dialysis, which was linked to a national registry of nursing home residents, we identified all 3702 nursing home residents in the United States who were starting treatment with dialysis between June 1998 and October 2000 and for whom at least one measurement of functional status was available before the initiation of dialysis. Functional status was measured by assessing the degree of dependence in seven activities of daily living (on the Minimum Data Set-Activities of Daily Living [MDS-ADL] scale of 0 to 28 points, with higher scores indication greater functional difficulty). RESULTS The median MDS-ADL score increased from 12 during the 3 months before the initiation of dialysis to 16 during the 3 months after the initiation of dialysis. Three months after the initiation of dialysis, functional status had been maintained in 39% of nursing home residents, but by 12 months after the initiation of dialysis, 58% had died and predialysis functional status had been maintained in only 13%. In a random-effects model, the initiation of dialysis was associated with a sharp declin in functional status, indicated by an increase of 2.8 points in the MDS-ADL score (95% confidence interval [CI], 2.5 to 3.0); this decline was independent of age, sex, race, and functional-status trajectory before the initiation of dialysis. The decline in functional status associated with the initiation of dialysis remained substantial (1.7 points; 95% CI, 1.4 to 2.1), even after adjustment for the presence or absence of an accelerated functional decline during the 3-month period before the initiation of dialysis. CONCLUSIONS Among nursing home residents with ESRD, the initiation of dialysis is associated with a substantial and sustained decline in functional status. C1 [Tamura, Manjula Kurella; Chertow, Glenn M.] Stanford Univ, Sch Med, Div Nephrol, Dept Med, Palo Alto, CA 94304 USA. [Covinsky, Kenneth E.; Landefeld, C. Seth] Univ Calif San Francisco, Dept Med, Div Geriatr, San Francisco, CA USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat & Neurol, San Francisco, CA 94143 USA. [Yaffe, Kristine; McCulloch, Charles E.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Covinsky, Kenneth E.; Yaffe, Kristine; Landefeld, C. Seth] San Francisco VA Med Ctr, San Francisco, CA USA. RP Tamura, MK (reprint author), Stanford Univ, Sch Med, Div Nephrol, Dept Med, 780 Welch Rd,Suite 106, Palo Alto, CA 94304 USA. EM mktamura@stanford.edu RI Kurella Tamura, Manjula/C-8284-2014 OI Kurella Tamura, Manjula/0000-0001-5227-2479 FU National Institute of Aging [K23AG028952]; National Center for Research Resources [KL2RR024130]; National Institute of Diabetes and Digestive and Kidney Diseases [N01DK12450] FX Supported by a Paul B. Beeson Career Development Award in Aging (K23AG028952, to Dr. Kurella Tamura) from the National Institute of Aging and grants from the National Center for Research Resources (KL2RR024130) and the National Institute of Diabetes and Digestive and Kidney Diseases (N01DK12450). NR 26 TC 212 Z9 223 U1 2 U2 10 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 OCT 15 PY 2009 VL 361 IS 16 BP 1539 EP 1547 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 506LT UT WOS:000270777000007 ER PT J AU Tager, AM Sharma, A Mark, EJ AF Tager, Andrew M. Sharma, Amita Mark, Eugene J. TI A Man with Progressive Dyspnea The Hermansky-Pudlak syndrome, with interstitial pulmonary fibrosis and respiratory failure SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LUNG-DISEASE; PNEUMONIA; MUTATIONS; MANIFESTATIONS; TYPE-2; FORM C1 [Tager, Andrew M.] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. [Tager, Andrew M.] Massachusetts Gen Hosp, Dept Med, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA. [Sharma, Amita] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Mark, Eugene J.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Tager, Andrew M.] Harvard Univ, Sch Med, Dept Med, Cambridge, MA 02138 USA. [Sharma, Amita] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Mark, Eugene J.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Tager, AM (reprint author), Massachusetts Gen Hosp, Pulm & Crit Care Unit, Boston, MA 02114 USA. NR 30 TC 0 Z9 1 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 15 PY 2009 VL 361 IS 16 BP 1585 EP 1593 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 506LT UT WOS:000270777000014 PM 19828536 ER PT J AU Srinivasan, VJ Sakadzic, S Gorczynska, I Ruvinskaya, S Wu, WC Fujimoto, JG Boas, DA AF Srinivasan, Vivek J. Sakadzic, Sava Gorczynska, Iwona Ruvinskaya, Svetlana Wu, Weicheng Fujimoto, James G. Boas, David A. TI Depth-resolved microscopy of cortical hemodynamics with optical coherence tomography SO OPTICS LETTERS LA English DT Article ID IN-VIVO; NEURONAL-ACTIVITY; VISUALIZATION; CORTEX AB We describe depth-resolved microscopy of cortical hemodynamics with high-speed spectral/Fourier domain optical coherence tomography (OCT). Stimulus-evoked changes in blood vessel diameter, flow, and total hemoglobin were measured in the rat somatosensory cortex. The results show OCT measurements of hemodynamic changes during functional activation and represent an important step toward understanding functional hyperemia at the microscopic level. (C) 2009 Optical Society of America C1 [Srinivasan, Vivek J.; Sakadzic, Sava; Ruvinskaya, Svetlana; Wu, Weicheng; Boas, David A.] Harvard Univ, Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Sch Med,Photon Migrat Imaging Lab, Charlestown, MA 02129 USA. [Gorczynska, Iwona; Fujimoto, James G.] MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. [Gorczynska, Iwona; Fujimoto, James G.] MIT, Elect Res Lab, Cambridge, MA 02139 USA. RP Boas, DA (reprint author), Harvard Univ, Massachusetts Gen Hosp, MGH MIT HMS Athinoula A Martinos Ctr Biomed Imagi, Sch Med,Photon Migrat Imaging Lab, Charlestown, MA 02129 USA. EM dboas@nmr.mgh.harvard.edu RI Gorczynska, Iwona/P-9367-2015 OI Gorczynska, Iwona/0000-0002-6120-8791 FU National Institutes of Health (NIH) [R01-NS057476, P01NS055104, P50NS010828, K99NS067050, R01-CA07528912]; Air Force Office of Scientific Research (AFOSR) [FA9550-07-1-0014]; Medical Free-Electron Laser Program [FA9550-07-1-0101] FX We acknowledge support by the National Institutes of Health (NIH) (R01-NS057476, P01NS055104, P50NS010828, K99NS067050, and R01-CA07528912) the Air Force Office of Scientific Research (AFOSR) FA9550-07-1-0014 and the Medical Free-Electron Laser Program FA9550-07-1-0101. NR 15 TC 21 Z9 21 U1 0 U2 1 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 OCT 15 PY 2009 VL 34 IS 20 BP 3086 EP 3088 PG 3 WC Optics SC Optics GA 514DM UT WOS:000271374500014 PM 19838234 ER PT J AU Costa, AN Castellvi, JMSI Spagnolo, AG Comoretto, N Lafitte, J Gabel, H Delmonico, FL Muehlbacher, F Schaupp, W Glazier, AK Garcia, VD Abbud, M Medina-Pestana, JO Grainer, MG Donadio, PP Guermani, A Bosco, R Giordano, F de Arroyabe, BML Brunetti, M Manyalich, M Paez, G Valero, R Matesanz, R Coll, E Dominguez-Gil, B Mahillo, B Escobar, EM Garrido, G Cantarovich, F AF Costa, Alessandro Nanni Simon i Castellvi, J. M. Spagnolo, Antonio G. Comoretto, Nunziata Lafitte, Jean Gabel, Hakan Delmonico, Francis L. Muehlbacher, Ferdinand Schaupp, Walter Glazier, Alexandra K. Garcia, Valter D. Abbud-Filho, Mario Medina-Pestana, Jose O. Grainer, Mariangela Gritta Donadio, Pier Paolo Guermani, Anna Bosco, Riccardo Giordano, Francesco de Arroyabe, Blanca Martinez Lopez Brunetti, Marco Manyalich, Marti Paez, Gloria Valero, Ricardo Matesanz, Rafael Coll, Elisabeth Dominguez-Gil, Beatriz Mahillo, Beatriz Escobar, Eduardo Martin Garrido, Gregorio Cantarovich, Felix TI A Colloquium on the Congress "A Gift for Life. Considerations on Organ Donation" SO TRANSPLANTATION LA English DT Review ID TRAUMATIC BRAIN-INJURY; DEAD DONOR RULE; QUALITY-OF-LIFE; PRESUMED CONSENT; INFORMED-CONSENT; TRANSPLANTATION TOLERANCE; LIVER-TRANSPLANTATION; HEART-TRANSPLANTATION; DEVELOPING-COUNTRIES; MEDICAL-STUDENTS C1 [Costa, Alessandro Nanni] Italian Natl Transplant Ctr, I-00161 Rome, Italy. [Abbud-Filho, Mario] Fac Med, BR-15015200 Sao Jose Do Rio Preto, SP, Brazil. [Abbud-Filho, Mario] Inst Urol Sao Jose Rio Preto, BR-15015200 Sao Jose Do Rio Preto, SP, Brazil. [Brunetti, Marco] Off Pastoral Care Hlth, Archdiocese Of Turin, Italy. [Cantarovich, Felix] Catholic Univ, Buenos Aires, DF, Argentina. [Cantarovich, Felix] Hop Necker Enfants Malad, Serv Transplantat Adultes, F-75016 Paris, France. [Spagnolo, Antonio G.; Comoretto, Nunziata] Univ Cattolica Sacro Cuore, Ctr Bioeth, I-00168 Rome, Italy. [Delmonico, Francis L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplant Ctr, Boston, MA 02114 USA. [Donadio, Pier Paolo] Univ Molinette San Giovanni Battista Torino, Piedmont Reg Organ Procurement Org Responsible, Azienda Osped, I-10126 Turin, Italy. [Glazier, Alexandra K.] New England Organ Bank Inc, Gateway Ctr 1, Newton, MA 02458 USA. [Manyalich, Marti] Univ Barcelona, Transplant Procurement Management IL3, Barcelona 08018, Spain. [de Arroyabe, Blanca Martinez Lopez] Santa Maria Misericordia Univ Hosp, Dept Anesthesiol & Intens Care Med, I-33100 Udine, Italy. [Matesanz, Rafael] ONT, Madrid 28029, Spain. [Medina-Pestana, Jose O.] Univ Fed Sao Paulo, Hosp Rim e Hipertensao, BR-04038002 Sao Paulo, Brazil. [Muehlbacher, Ferdinand] Med Univ Vienna, Dept Surg, Transplantat Unit, Gen Hosp Vienna, A-1090 Vienna, Austria. [Schaupp, Walter] Karl Franzens Univ Graz, Fac Cathol Theol, A-8010 Graz, Austria. [Spagnolo, Antonio G.] Univ Macerata, Dpt Educ Sci, Rome, Italy. RP Costa, AN (reprint author), Italian Natl Transplant Ctr, Viale Regina Elena 299, I-00161 Rome, Italy. EM cnt@iss.it; metges@federaciocristians.org; agSpagnolo@unimc.it; nunziata.comoretto@rm.unicatt.it; jlafitte@acdlife.va; hakan@Gabel.se; francis_delmonico@neob.org; ferdinand.muehlbacher@meduniwien.ac.at; walter.Schaupp@uni-graz.at; alexandra_glazier@neob.org; medina@hrim.com.br; mgrainer@interplanet.it; pdonadio@molinette.piemonte.it; aguermani@molinette.piemonte.it; rbosco@molinette.piemonte.it; blancamartinez@libero.it; salute@diocesi.torino.it; tpmproject@il3.ub.edu; rmatesanz@mps.es; felix.cantarovich@orange.fr RI Valero, Ricard/G-1770-2015 OI Valero, Ricard/0000-0001-7875-9496 NR 220 TC 5 Z9 5 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0041-1337 EI 1534-6080 J9 TRANSPLANTATION JI Transplantation PD OCT 15 PY 2009 VL 88 IS 7 SU S BP S108 EP S158 PG 51 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 507HK UT WOS:000270842600004 PM 19823162 ER PT J AU Hu, JC Gu, XM Lipsitz, SR Barry, MJ D'Amico, AV Weinberg, AC Keating, NL AF Hu, Jim C. Gu, Xiangmei Lipsitz, Stuart R. Barry, Michael J. D'Amico, Anthony V. Weinberg, Aaron C. Keating, Nancy L. TI Comparative Effectiveness of Minimally Invasive vs Open Radical Prostatectomy SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ASSISTED LAPAROSCOPIC PROSTATECTOMY; RETROPUBIC PROSTATECTOMY; SINGLE-INSTITUTION; LEARNING-CURVE; CLAIMS DATA; CANCER; OUTCOMES; ROBOT; COMPLICATIONS; EXPERIENCE AB Context Minimally invasive radical prostatectomy (MIRP) has diffused rapidly despite limited data on outcomes and greater costs compared with open retropubic radical prostatectomy (RRP). Objective To determine the comparative effectiveness of MIRP vs RRP. Design, Setting, and Patients Population-based observational cohort study using US Surveillance, Epidemiology, and End Results Medicare linked data from 2003 through 2007. We identified men with prostate cancer who underwent MIRP (n=1938) vs RRP (n=6899). Main Outcome Measures We compared postoperative 30-day complications, anastomotic stricture 31 to 365 days postoperatively, long-term incontinence and erectile dysfunction more than 18 months postoperatively, and postoperative use of additional cancer therapies, a surrogate for cancer control. Results Among men undergoing prostatectomy, use of MIRP increased from 9.2% (95% confidence interval [CI], 8.1%-10.5%) in 2003 to 43.2% (95% CI, 39.6%-46.9%) in 2006-2007. Men undergoing MIRP vs RRP were more likely to be recorded as Asian (6.1% vs 3.2%), less likely to be recorded as black (6.2% vs 7.8%) or Hispanic (5.6% vs 7.9%), and more likely to live in areas with at least 90% high school graduation rates (50.2% vs 41.0%) and with median incomes of at least $60 000 (35.8% vs 21.5%) (all P<.001). In propensity score-adjusted analyses, MIRP vs RRP was associated with shorter length of stay (median, 2.0 vs 3.0 days; P<.001) and lower rates of blood transfusions (2.7% vs 20.8%; P<.001), postoperative respiratory complications (4.3% vs 6.6%; P=.004), miscellaneous surgical complications (4.3% vs 5.6%; P=.03), and anastomotic stricture (5.8% vs 14.0%; P<.001). However, MIRP vs RRP was associated with an increased risk of genitourinary complications (4.7% vs 2.1%; P=.001) and diagnoses of incontinence (15.9 vs 12.2 per 100 person-years; P=.02) and erectile dysfunction (26.8 vs 19.2 per 100 person-years; P=.009). Rates of use of additional cancer therapies did not differ by surgical procedure (8.2 vs 6.9 per 100 person-years; P=.35). Conclusion Men undergoing MIRP vs RRP experienced shorter length of stay, fewer respiratory and miscellaneous surgical complications and strictures, and similar postoperative use of additional cancer therapies but experienced more genitourinary complications, incontinence, and erectile dysfunction. JAMA. 2009; 302(14): 1557-1564 C1 [Hu, Jim C.] Brigham & Womens Hosp, Div Neurol, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, Boston, MA 02115 USA. [Hu, Jim C.; Weinberg, Aaron C.] Div Urol Surg, Boston, MA USA. [Hu, Jim C.; Gu, Xiangmei; Lipsitz, Stuart R.; Weinberg, Aaron C.] Ctr Surg & Publ Hlth, Boston, MA USA. [D'Amico, Anthony V.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Keating, Nancy L.] Div Gen Internal Med, Boston, MA USA. [Barry, Michael J.] Massachusetts Gen Hosp, Med Practices Evaluat Ctr, Boston, MA 02114 USA. [Keating, Nancy L.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Hu, JC (reprint author), Brigham & Womens Hosp, Div Neurol, Dana Farber Canc Inst, Lank Ctr Genitourinary Oncol, 45 Francis St,ASBII 3, Boston, MA 02115 USA. EM jhu2@partners.org FU Department of Defense Prostate Cancer Physician Training Award FX This research was funded by a Department of Defense Prostate Cancer Physician Training Award to Dr Hu. NR 54 TC 429 Z9 436 U1 5 U2 27 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 OCT 14 PY 2009 VL 302 IS 14 BP 1557 EP 1564 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 505UA UT WOS:000270721800024 PM 19826025 ER PT J AU Young, AB AF Young, Anne B. TI Four Decades of Neurodegenerative Disease Research: How Far We Have Come! SO JOURNAL OF NEUROSCIENCE LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; SUBTHALAMIC NUCLEUS STIMULATION; GAMMA-AMINOBUTYRIC-ACID; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; HUNTINGTONS-DISEASE; BASAL GANGLIA; KAINIC ACID; 1-METHYL-4-PHENYLPYRIDINIUM ION; POSTEROVENTRAL PALLIDOTOMY C1 Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. RP Young, AB (reprint author), Massachusetts Gen Hosp, Neurol Serv, ACC 720, Boston, MA 02114 USA. EM abyoung@partners.org FU NIA NIH HHS [R37 AG013617-07, P01 AG011337-040001, P01 AG011337-05, P01 AG011337-050001, R01 AG013617, R01 AG013617-05, R37 AG013617, R37 AG013617-06, R37 AG013617-08, R37 AG013617-09, R37 AG013617-10, R37 AG013617-11, R37 AG013617-12, R37 AG013617-13, R37 AG013617-14, R37 AG013617-15]; NINDS NIH HHS [P50 NS038372, P50 NS038372-02, P50 NS038372-03, P50 NS038372-04, P50 NS038372-04S1, P50 NS038372-05, P50 NS038372-05S1, P50 NS038372-05S2, P50 NS038372-06A1, P50 NS038372-06A19003, P50 NS038372-06A1S1, P50 NS038372-07, P50 NS038372-08, P50 NS038372-09, P50 NS038372-10, P50 NS038372-10S1, P50 NS038372-10S2] NR 110 TC 15 Z9 15 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 14 PY 2009 VL 29 IS 41 BP 12722 EP 12728 DI 10.1523/JNEUROSCI.3767-09.2009 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 507IF UT WOS:000270845000003 PM 19828782 ER PT J AU Morfini, GA Burns, M Binder, LI Kanaan, NM LaPointe, N Bosco, DA Brown, RH Brown, H Tiwari, A Hayward, L Edgar, J Nave, KA Garberrn, J Atagi, Y Song, YY Pigino, G Brady, ST AF Morfini, Gerardo A. Burns, Matthew Binder, Lester I. Kanaan, Nicholas M. LaPointe, Nichole Bosco, Daryl A. Brown, Robert H., Jr. Brown, Hannah Tiwari, Ashutosh Hayward, Lawrence Edgar, Julia Nave, Klaus-Armin Garberrn, James Atagi, Yuka Song, Yuyu Pigino, Gustavo Brady, Scott T. TI Axonal Transport Defects in Neurodegenerative Diseases SO JOURNAL OF NEUROSCIENCE LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; HEREDITARY SPASTIC PARAPLEGIA; MOTOR-NEURON DEGENERATION; CENTRAL-NERVOUS-SYSTEM; KINESIN HEAVY-CHAIN; PELIZAEUS-MERZBACHER-DISEASE; ACTIVATED PROTEIN-KINASE; LINKED SOD1 MUTANTS; ALZHEIMERS-DISEASE; HUNTINGTONS-DISEASE AB Adult-onset neurodegenerative diseases (AONDs) comprise a heterogeneous group of neurological disorders characterized by a progressive, age-dependent decline in neuronal function and loss of selected neuronal populations. Alterations in synaptic function and axonal connectivity represent early and critical pathogenic events in AONDs, but molecular mechanisms underlying these defects remain elusive. The large size and complex subcellular architecture of neurons render them uniquely vulnerable to alterations in axonal transport (AT). Accordingly, deficits in AT have been documented in most AONDs, suggesting a common defect acquired through different pathogenic pathways. These observations suggest that many AONDs can be categorized as dysferopathies, diseases in which alterations in AT represent a critical component in pathogenesis. Topics here address various molecular mechanisms underlying alterations in AT in several AONDs. Illumination of such mechanisms provides a framework for the development of novel therapeutic strategies aimed to prevent axonal and synaptic dysfunction in several major AONDs. C1 [Morfini, Gerardo A.; Burns, Matthew; Atagi, Yuka; Song, Yuyu; Pigino, Gustavo; Brady, Scott T.] Univ Illinois, Dept Anat & Cell Biol, Chicago, IL 60612 USA. [Binder, Lester I.; Kanaan, Nicholas M.; LaPointe, Nichole] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Bosco, Daryl A.; Brown, Robert H., Jr.; Hayward, Lawrence] Univ Massachusetts, Med Ctr, Dept Neurol, Worcester, MA 01655 USA. [Brown, Hannah] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Tiwari, Ashutosh] Michigan Technol Univ, Dept Chem, Houghton, MI 49931 USA. [Edgar, Julia] Univ Glasgow, Inst Comparat Med, Div Cell Sci, Appl Neurobiol Grp, Glasgow G61 1QH, Lanark, Scotland. [Nave, Klaus-Armin] Max Planck Inst Expt Med, Dept Neurogenet, D-37075 Gottingen, Germany. [Garberrn, James] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Garberrn, James] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RP Morfini, GA (reprint author), Univ Illinois, Dept Anat & Cell Biol, MC512,909 S Wolcott St,COMRB Room 6051, Chicago, IL 60612 USA. EM gmorfini@uic.edu RI Nave, Klaus-Armin/C-8883-2011; Tiwari, Ashutosh/A-7458-2008; OI Tiwari, Ashutosh/0000-0001-7373-349X; Song, Yuyu/0000-0002-9196-1610; Kanaan, Nicholas/0000-0002-4362-2593 FU National Institutes of Health (NIH) [AG09466, T32 AG020506-07, NS23868, NS23320, NS41170]; ALS Association (ALSA); ALS Therapy Alliance; ALSA, Muscular Dystrophy Association; Multiple Sclerosis Society (Scotland); Huntington's Disease Society of America; American Parkinson Disease Association FX This work was supported by National Institutes of Health (NIH) Grants AG09466 to L. I. B. and T32 AG020506-07 to N. M. K.; ALS Association (ALSA) and ALS Therapy Alliance grants to D. A. B.; ALSA, Muscular Dystrophy Association, and NIH (NS23868, NS23320, NS41170) grants to S. T. B.; a Multiple Sclerosis Society (Scotland) grant to J. E.; and Huntington's Disease Society of America and American Parkinson Disease Association grants to G. M. NR 125 TC 222 Z9 223 U1 2 U2 29 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 OCT 14 PY 2009 VL 29 IS 41 BP 12776 EP 12786 DI 10.1523/JNEUROSCI.3463-09.2009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 507IF UT WOS:000270845000010 PM 19828789 ER PT J AU Vassar, R Kovacs, DM Yan, RQ Wong, PC AF Vassar, Robert Kovacs, Dora M. Yan, Riqiang Wong, Philip C. TI The beta-Secretase Enzyme BACE in Health and Alzheimer's Disease: Regulation, Cell Biology, Function, and Therapeutic Potential SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AMYLOID PRECURSOR PROTEIN; GATED SODIUM-CHANNELS; APP TRANSGENIC MICE; A-BETA; CLEAVING ENZYME; GAMMA-SECRETASE; KNOCKOUT MICE; GGA PROTEINS; LIPID RAFTS; ASPARTYL PROTEASE AB The beta-amyloid (A beta) peptide is the major constituent of amyloid plaques in Alzheimer's disease (AD) brain and is likely to play a central role in the pathogenesis of this devastating neurodegenerative disorder. The beta-secretase, beta-site amyloid precursor protein cleaving enzyme (BACE1; also called Asp2, memapsin 2), is the enzyme responsible for initiating A beta generation. Thus, BACE is a prime drug target for the therapeutic inhibition of A beta production in AD. Since its discovery 10 years ago, much has been learned about BACE. This review summarizes BACE properties, describes BACE translation dysregulation in AD, and discusses BACE physiological functions in sodium current, synaptic transmission, myelination, and schizophrenia. The therapeutic potential of BACE will also be considered. This is a summary of topics covered at a symposium held at the 39th annual meeting of the Society for Neuroscience and is not meant to be a comprehensive review of BACE. C1 [Vassar, Robert] Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Kovacs, Dora M.] Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Kovacs, Dora M.] Harvard Univ, Sch Med, Dept Neurol, Charlestown, MA 02129 USA. [Yan, Riqiang] Cleveland Clin, Lerner Res Inst, Dept Neurosci, Cleveland, OH 44195 USA. [Wong, Philip C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA. RP Vassar, R (reprint author), Northwestern Univ, Dept Cell & Mol Biol, Chicago, IL 60611 USA. EM r-vassar@northwestern.edu FU NIA NIH HHS [R01 AG022560-07, R01 AG022560] NR 100 TC 247 Z9 258 U1 3 U2 34 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 OCT 14 PY 2009 VL 29 IS 41 BP 12787 EP 12794 DI 10.1523/JNEUROSCI.3657-09.2009 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 507IF UT WOS:000270845000011 PM 19828790 ER PT J AU Schrum, JP Ricardo, A Krishnamurthy, M Blain, JC Szostak, JW AF Schrum, Jason P. Ricardo, Alonso Krishnamurthy, Mathangi Blain, J. Craig Szostak, Jack W. TI Efficient and Rapid Template-Directed Nucleic Acid Copying Using 2 '-Amino-2 ',3 '-dideoxyribonucleoside-5 '-Phosphorimidazolide Monomers SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CHEMICAL PRIMER EXTENSION; SELF-REPLICATION; MODEL PROTOCELL; DNA; RNA; RIBOZYME; OLIGOMERIZATION; POLYMERIZATION; EMERGENCE; ANALOGS AB The development of a sequence-general nucleic acid copying system is an essential step in the assembly of a synthetic protocell, an autonomously replicating spatially localized chemical system capable of spontaneous Darwinian evolution. Previously described nonenzymatic template-copying experiments have validated the concept of nonenzymatic replication, but have not yet achieved robust, sequence-general polynucleotide replication. The 5'-phosphorimidazolides of the 2'-amino-2',3'-dideoxyribonucleotides are attractive as potential monomers for such a system because they polymerize by forming 2'-> 5' linkages, which are favored in nonenzymatic polymerization reactions using similarly activated ribonucleotides on RNA templates. Furthermore, the 5'-activated 2'-amino nucleotides do not cyclize. We recently described the rapid and efficient nonenzymatic copying of a DNA homopolymer template (dC(15)) encapsulated within fatty acid vesicles using 2'-amino-2',3'-dideoxyguanosine-5'-phosphorimidazolide as the activated monomer. However, to realize a true Darwinian system, the template-copying chemistry must be able to copy most sequences and their complements to allow for the transmission of information from generation to generation. Here, we describe the copying of a series of nucleic acid templates using 2'-amino-2',3'-dideoxynucleotide-5'-phosphorimidazolides. Polymerization reactions proceed rapidly to completion on short homopolymer RNA and LNA templates, which favor an A-type duplex geometry. We show that more efficiently copied sequences are generated by replacing the adenine nucleobase with diaminopurine, and uracil with C5-(1-propynyl)uracil. Finally, we explore the copying of longer, mixed-sequence RNA templates to assets the sequence-general copying ability of2'-amino-2',3'-dideoxynucleoside-5'-phosphorimidazolides. Our results are a significant step forward in the realization of a self-replicating genetic polymer compatible with protocell template copying and suggest that N2'-> P5'-phosphoramidate DNA may have the potential to function as a self-replicating system. C1 [Szostak, Jack W.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Howard Hughes Med Inst, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Computat & Integrat Biol, Boston, MA 02114 USA. RP Szostak, JW (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Howard Hughes Med Inst, 185 Cambridge St, Boston, MA 02114 USA. EM szostak@molbio.mgh.harvard.edu FU NSF [CHE 0434507] FX We are grateful to Jesse J. Chen, Yollete V. Guillen-Schlippe, Ben Heuberger, Sylvia Tobe, Doug Treco, Tina Yuan, and Shenglong Zhang for helpful discussions. A.R. is a Research Associate and J.W.S. is an Investigator of the Howard Hughes Medical Institute. This work was supported in part by NSF Grant CHE 0434507 to JW.S. NR 52 TC 50 Z9 52 U1 2 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 14 PY 2009 VL 131 IS 40 BP 14560 EP 14570 DI 10.1021/ja906557v PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 512SS UT WOS:000271271500097 PM 19757789 ER PT J AU Baldys, A Raymond, JR AF Baldys, Aleksander Raymond, John R., Sr. TI Critical Role of ESCRT Machinery in EGFR Recycling SO BIOCHEMISTRY LA English DT Article ID ENDOCYTIC MEMBRANE TRAFFICKING AB The molecular mechanisms of EGFR vesicular trafficking to lysosomes have recently received considerable attention. It is now clear that endosomal sorting complexes required for transport (ESCRTs) are critical for EGFR degradation. Although an increasing number of membrane receptors also undergo recycling via specific pathways, little information is available regarding regulated recycling of EGFR. In this study, we investigated the roles of ESCRTs in EGFR recycling after stimulation with amphiregulin (AR). We used ESCRT small interfering RNA (siRNA) duplexes to demonstrate that AR-induced EGFR intracellular processing involves active sorting to the recycling pathway through specific members of the ESCRT family. C1 Med Univ S Carolina, Dept Med, Div Nephrol, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Med Serv, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Res Serv, Charleston, SC 29425 USA. RP Raymond, JR (reprint author), Room 213,Colcock Hall,179 Ashley Ave, Charleston, SC 29425 USA. EM raymondj@musc.edu FU Department of Veterans Affairs Merit; Research Enhancement Award Program; National Institutes of Health [DK052448, GM063909]; American Heart Association; Medical University of South Carolina Division of Nephrology and Dialysis Clinics, Inc. FX This work was supported by Department of Veterans Affairs Merit and Research Enhancement Award Program grants (to J.R.R.), by National Institutes of Health Grants DK052448 and GM063909 (J.R.R.), by an American Heart Association (Mid-Atlantic) fellowship (to A.B.), and by a laboratory endowment jointly supported by the Medical University of South Carolina Division of Nephrology and Dialysis Clinics, Inc. (to J.R.R.). NR 10 TC 21 Z9 21 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 13 PY 2009 VL 48 IS 40 BP 9321 EP 9323 DI 10.1021/bi900865u PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 502KU UT WOS:000270459100001 PM 19673488 ER PT J AU Rahilly-Tierney, CR Lawler, EV Scranton, RE Gaziano, JM AF Rahilly-Tierney, Catherine R. Lawler, Elizabeth V. Scranton, Richard E. Gaziano, J. Michael TI Cardiovascular Benefit of Magnitude of Low-Density Lipoprotein Cholesterol Reduction A Comparison of Subgroups by Age SO CIRCULATION LA English DT Article DE aging; lipids; lipoproteins; epidemiology; prevention ID CORONARY-HEART-DISEASE; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; PLACEBO-CONTROLLED TRIAL; LIPID-LOWERING THERAPY; OLDER PATIENTS; HYPERTENSIVE PATIENTS; PRIMARY PREVENTION; CARDIAC OUTCOMES; ELDERLY-PATIENTS AB Background-We examined the effect of the magnitude of low-density lipoprotein cholesterol (LDL-C) reduction across subjects of various ages in a retrospective cohort study. Methods and Results-We selected 20 132 male veterans at high risk for an acute cardiovascular event and who had 2 or more LDL-C measurements before their first documented acute myocardial infarction, revascularization, death, or censoring date. LDL-C reduction was categorized as no reduction (<10 mg/dL; reference), small reduction (between 10 and 40 mg/dL), moderate reduction (between 40 and 70 mg/dL), or large reduction (>= 70 mg/dL). The primary outcome was combined acute myocardial infarction or revascularization. The first and last LDL-C levels in the databases were used to calculate the LDL-C reduction in patients who experienced no outcome or who died. Within each age quartile and in a subgroup of patients >= 80 years of age, a Cox proportional hazards model was used to determine hazard ratios for each category of LDL-C reduction compared with the reference category, with adjustment for age, body mass index, current smoking status, medications, and comorbidities. In all age groups, the magnitude of LDL-C reduction was proportional to the magnitude of cardiovascular risk reduction. Risk reduction for the combined outcome in patients who achieved a large LDL-C reduction was similar in all age quartiles, with multivariate-adjusted hazard ratios of approximately 0.30. Conclusions-In a cohort of veterans at high risk for cardiovascular events, patients of all ages, including those 80 years or older, benefitted the most from large reductions in LDL-C. (Circulation. 2009;120:1491-1497.) C1 [Rahilly-Tierney, Catherine R.; Lawler, Elizabeth V.; Scranton, Richard E.; Gaziano, J. Michael] Boston VA Healthcare Syst, Massachusetts Vet Epidemiol & Res Informat Ctr, Boston, MA USA. [Rahilly-Tierney, Catherine R.; Lawler, Elizabeth V.; Scranton, Richard E.; Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Rahilly-Tierney, Catherine R.; Lawler, Elizabeth V.; Scranton, Richard E.; Gaziano, J. Michael] Brigham & Womens Hosp, Div Cardiol & Preventat Med, Boston, MA 02115 USA. [Scranton, Richard E.] VeroScience LLC, Tiverton, RI USA. RP Rahilly-Tierney, CR (reprint author), 150 S Huntington Ave,MAVERIC 13th Floor, Jamaica Plain, MA 02130 USA. EM Catherine.Rahilly@va.gov FU Epidemiology and Research Information Center of the Veterans Affairs Cooperative Studies Program. FX This research has been funded by the Epidemiology and Research Information Center of the Veterans Affairs Cooperative Studies Program. NR 30 TC 16 Z9 16 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD OCT 13 PY 2009 VL 120 IS 15 BP 1491 EP 1497 DI 10.1161/CIRCULATIONAHA.108.846931 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 505PM UT WOS:000270706500006 PM 19786636 ER PT J AU Steinhart, B Thorpe, KE Bayoumi, AM Moe, G Januzzi, JL Mazer, CD AF Steinhart, Brian Thorpe, Kevin E. Bayoumi, Ahmed M. Moe, Gordon Januzzi, James L., Jr. Mazer, C. David TI Improving the Diagnosis of Acute Heart Failure Using a Validated Prediction Model SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE acute heart failure; diagnosis; natriuretic peptide; prediction model; Bayesian theorem ID EMERGENCY-DEPARTMENT PRIDE; PULMONARY-EMBOLISM; NATRIURETIC PEPTIDE; MEDICAL LITERATURE; BIOCHEMICAL SCORE; USERS GUIDES; DYSPNEA; BNP; MANAGEMENT; RECLASSIFICATION AB Objectives We sought to derive and validate a prediction model by using N-terminal pro-B-type natriuretic peptide (NT-proBNP) and clinical variables to improve the diagnosis of acute heart failure (AHF). Background The optimal way of using natriuretic peptides to enhance the diagnosis of AHF remains uncertain. Methods Physician estimates of probability of AHF in 500 patients treated in the emergency department from the multicenter IMPROVE CHF (Improved Management of Patients With Congestive Heart Failure) trial recruited between December 2004 and December 2005 were classified into low (0% to 20%), intermediate (21% to 79%), or high (80% to 100%) probability for AHF and then compared with the blinded adjudicated AHF diagnosis. Likelihood ratios were calculated and multiple logistic regression incorporated covariates into an AHF prediction model that was validated internally by the use of bootstrapping and externally by applying the model to another 573 patients from the separate PRIDE (N-Terminal Pro-BNP Investigation of Dyspnea in the Emergency Department) study of the use of NT-proBNP in patients with dyspnea. Results Likelihood ratios for AHF with NT-proBNP were 0.11 (95% confidence interval [CI]: 0.06 to 0.19) for cut- point values < 300 pg/ml; increasing to 3.43 (95% CI: 2.34 to 5.03) for values 2,700 to 8,099 pg/ml, and 12.80 (95% CI: 5.21 to 31.45) for values >= 8,100 pg/ml. Variables used to predict AHF were age, pre-test probability, and log NT-proBNP. When applied to the external data by use of its adjudicated final diagnosis as the gold standard, the model appropriately reclassified 44% of patients by intermediate clinical probability to either low or high probability of AHF with negligible (< 2%) inappropriate redirection. Conclusions A diagnostic prediction model for AHF that incorporates both clinical assessment and NT-proBNP has been derived and validated and has excellent diagnostic accuracy, especially in cases with indeterminate likelihood for AHF. (J Am Coll Cardiol 2009; 54: 1515-21) (C) 2009 by the American College of Cardiology Foundation C1 [Steinhart, Brian; Bayoumi, Ahmed M.; Moe, Gordon] St Michaels Hosp, Dept Med, Toronto, ON M5B 1W8, Canada. [Mazer, C. David] St Michaels Hosp, Dept Anesthesia & Crit Care Med, Toronto, ON M5B 1W8, Canada. [Thorpe, Kevin E.; Bayoumi, Ahmed M.; Moe, Gordon; Mazer, C. David] St Michaels Hosp, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Steinhart, Brian] Univ Toronto, Dept Med, Div Emergency Med, Toronto, ON, Canada. [Bayoumi, Ahmed M.] Univ Toronto, Div Gen Med, Toronto, ON, Canada. [Moe, Gordon] Univ Toronto, Div Cardiol, Toronto, ON, Canada. [Mazer, C. David] Univ Toronto, Fac Med, Dept Anesthesia, Toronto, ON, Canada. [Mazer, C. David] Univ Toronto, Fac Med, Dept Physiol, Toronto, ON, Canada. [Thorpe, Kevin E.] Univ Toronto, Fac Med, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. [Bayoumi, Ahmed M.] Univ Toronto, Fac Med, Dept Hlth Policy Management & Evaluat, Toronto, ON, Canada. [Januzzi, James L., Jr.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Januzzi, James L., Jr.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Steinhart, B (reprint author), 1-008C Shuter Wing,30 Bond St, Toronto, ON M5B 1W8, Canada. EM steinhartb@smh.toronto.on.ca NR 40 TC 32 Z9 35 U1 2 U2 3 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 OCT 13 PY 2009 VL 54 IS 16 BP 1515 EP 1521 DI 10.1016/j.jacc.2009.05.065 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 503EC UT WOS:000270514400004 PM 19815122 ER PT J AU Giugliano, RP Braunwald, E AF Giugliano, Robert P. Braunwald, Eugene TI The Year in Non-ST-Segment Elevation Acute Coronary Syndrome SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE year in; non-ST-segment; coronary syndrome ID OPTICAL COHERENCE TOMOGRAPHY; GLYCOPROTEIN IIB/IIIA INHIBITORS; RESIDUAL PLATELET REACTIVITY; P2Y(12) RECEPTOR ANTAGONIST; INTENSIVE STATIN THERAPY; LOW-DENSITY-LIPOPROTEIN; TRIAGE STRATEGY TRIAL; ACUTE CHEST-PAIN; MYOCARDIAL-INFARCTION; UNFRACTIONATED HEPARIN C1 [Giugliano, Robert P.; Braunwald, Eugene] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med,TIMI Study Grp, Boston, MA 02115 USA. RP Braunwald, E (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med,TIMI Study Grp, 350 Longwood Ave,1st Floor Off, Boston, MA 02115 USA. EM ebraunwald@partners.org NR 115 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD OCT 13 PY 2009 VL 54 IS 16 BP 1544 EP 1555 DI 10.1016/j.jacc.2009.06.025 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 503EC UT WOS:000270514400009 PM 19815127 ER PT J AU Ticozzi, N Silani, V LeClerc, AL Keagle, P Gellera, C Ratti, A Taroni, F Kwiatkowski, TJ McKenna-Yasek, DM Sapp, PC Brown, RH Landers, JE AF Ticozzi, N. Silani, V. LeClerc, A. L. Keagle, P. Gellera, C. Ratti, A. Taroni, F. Kwiatkowski, T. J., Jr. McKenna-Yasek, D. M. Sapp, P. C. Brown, R. H., Jr. Landers, J. E. TI Analysis of FUS gene mutation in familial amyotrophic lateral sclerosis within an Italian cohort SO NEUROLOGY LA English DT Article ID SUPEROXIDE-DISMUTASE GENE; EXONIC SPLICING ENHANCERS; RNA-BINDING PROTEIN; TARDBP MUTATIONS; ALS; IDENTIFICATION; TDP-43; TLS; ONCOPROTEIN; TOOL AB Objective: Mutations in the FUS gene on chromosome 16 have been recently discovered as a cause of familial amyotrophic lateral sclerosis (FALS). This study determined the frequency and identities of FUS gene mutations in a cohort of Italian patients with FALS. Methods: We screened all 15 coding exons of FUS for mutations in 94 Italian patients with FALS. Results: We identified 4 distinct missense mutations in 5 patients; 2 were novel. The mutations were not present in 376 healthy Italian controls and thus are likely to be pathogenic. Conclusions: Our results demonstrate that FUS mutations cause similar to 4% of familial amyotrophic lateral sclerosis cases in the Italian population. Neurology (R) 2009; 73: 1180-1185 C1 [Ticozzi, N.; LeClerc, A. L.; Keagle, P.; McKenna-Yasek, D. M.; Sapp, P. C.; Brown, R. H., Jr.; Landers, J. E.] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. [Ticozzi, N.; Silani, V.; Ratti, A.] Univ Milan, Dept Neurol & Lab Neurosci, Ctr Dino Ferrari, IRCCS Ist Auxol Italiano, Milan, Italy. [Gellera, C.; Taroni, F.] Ist Neurol Carlo Besta, Fdn IRCCS, Unit Genet Neurodegenerat & Metab Dis, Milan, Italy. [Kwiatkowski, T. J., Jr.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Sapp, P. C.] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA. [Sapp, P. C.] MIT, Dept Biol, Cambridge, MA 02139 USA. RP Landers, JE (reprint author), LRB604,364 Plantat St, Worcester, MA 01605 USA. EM john.landers@umassmed.edu RI Ticozzi, Nicola/K-8094-2016; GELLERA, CINZIA/J-7887-2016; OI Ticozzi, Nicola/0000-0001-5963-7426; GELLERA, CINZIA/0000-0002-3582-665X; Silani, Vincenzo/0000-0002-7698-3854 FU ALS Therapy Alliance; Project ALS; Angel Fund; Pierre L. de Bourgknecht ALS Research Foundation; Al-Athel ALS Research Foundation; ALS Family Charitable Foundation; National Institute of Neurological Disorders and Stroke [NS050557, NS050641]; Italian Ministry of Health [n.533F/N1, RF2007/INN644440]; Howard Hughes Medical Institute (HHMI); Fondazione Telethon FX Supported by the ALS Therapy Alliance, Project ALS, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation, and the National Institute of Neurological Disorders and Stroke (NS050557 and NS050641). N.T., V.S., and A.R. were supported by the Italian Ministry of Health (Malattie Neurodegenerative, ex Art. 56, n.533F/N1). F. T. and C. G. were supported by the Italian Ministry of Health grant RF2007/INN644440. P.S. was supported by the Howard Hughes Medical Institute (HHMI) through the auspices of Prof. H. Robert Horvitz, an Investigator in the HHMI. R. H. B. is a cofounder of AviTx, which targets development of therapies. NR 39 TC 91 Z9 93 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 13 PY 2009 VL 73 IS 15 BP 1180 EP 1185 DI 10.1212/WNL.0b013e3181bbff05 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 505OQ UT WOS:000270704000004 PM 19741215 ER PT J AU Lee, YN Alt, FW Reyes, J Gleason, M Zarrin, AA Jung, D AF Lee, Yu Nee Alt, Frederick W. Reyes, Julia Gleason, Megan Zarrin, Ali A. Jung, David TI Differential utilization of T cell receptor TCR alpha/TCR delta locus variable region gene segments is mediated by accessibility SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epigenetic regulation; T cell development; VDJ recombination ID V(D)J RECOMBINATION; ALPHA/DELTA-LOCUS; SIGNAL SEQUENCES; LYMPHOCYTES-T; CHAIN; BETA; REARRANGEMENTS; EXPRESSION; THYMOCYTES; ENHANCER AB T cell receptor (TCR) variable region exons are assembled from germline V, (D), and J gene segments, each of which is flanked by recombination signal (RS) sequences that are composed of a conserved heptamer, a spacer of 12 or 23 bp, and a characteristic nonamer. V(D) J recombination only occurs between V, D, and J segments flanked by RS sequences that contain, respectively, 12(12-RS)- and 23(23-RS)-bp spacers (12/23 rule). Additional mechanisms can restrict joining of 12/23 RS matched segments beyond the 12/23 rule (B12/23). The TCR delta locus is contained within the TCR alpha locus; TCR alpha variable region exons are encoded by TRAV and TRAJ segments and those of TCR delta by TRDV, TRDD, and TRDJ segments. On the basis of the 12/23 rule, both TRAV and TRDV gene segments are compatible to rearrange with TRDD gene segments; however, TRAV-to-TRDD joins are not observed in vivo. Absence of TRAV-to-TRDD rearrangement might be explained either by B12/23 restriction or by differential accessibility of the TRDV versus TRAV gene segments for rearrangement to TRDD. We used in vitro substrate analysis to reveal that both TRAV and TRDV 23-RSs mediate rearrangements to the 5'TRDD1 12-RS, demonstrating that B12/23 restriction does not explain these rearrangement biases. However, targeted replacement of TRDD1 and its 12-RSs with TRAJ38 and its 12-RS showed that TRDV gene segments rearrange with the ectopic TRAJ38, whereas TRAV segments do not. Our results demonstrate that sorting of TRAV and TRDV gene segments is determined by differential locus accessibility during T cell development. C1 [Lee, Yu Nee; Alt, Frederick W.; Reyes, Julia; Gleason, Megan; Zarrin, Ali A.; Jung, David] Harvard Univ, Sch Med, Childrens Hosp Boston, Howard Hughes Med Inst,Immune Dis Inst, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Childrens Hosp Boston, Howard Hughes Med Inst,Immune Dis Inst, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu FU Human Frontiers Science Program; Medical Scientist Training Program; Harvard Medical School; National Institutes of Health [AI-20047] FX We thank Michael Krangel and Barry Sleckman for critical review of this manuscript. Y. N. L. was supported by the Human Frontiers Science Program. D. J. received support from the Medical Scientist Training Program, Harvard Medical School. F. W. A. is an investigator of the Howard Hughes Medical Institute and is supported by National Institutes of Health Grant AI-20047. NR 33 TC 8 Z9 8 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 OCT 13 PY 2009 VL 106 IS 41 BP 17487 EP 17492 DI 10.1073/pnas.0909723106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 506DS UT WOS:000270754400049 PM 19805067 ER PT J AU Duan, ZF Choy, E Hornicek, FJ AF Duan, Zhenfeng Choy, Edwin Hornicek, Francis J. TI NSC23925, Identified in a High-Throughput Cell-Based Screen, Reverses Multidrug Resistance SO PLOS ONE LA English DT Article AB Background: Multidrug resistance (MDR) is a major factor which contributes to the failure of cancer chemotherapy, and numerous efforts have been attempted to overcome MDR. To date, none of these attempts have yielded a tolerable and effective therapy to reverse MDR; thus, identification of new agents would be useful both clinically and scientifically. Methodology/Principal Findings: To identify small molecule compounds that can reverse chemoresistance, we developed a 96-well plate high-throughput cell-based screening assay in a paclitaxel resistant ovarian cancer cell line. Coincubating cells with a sublethal concentration of paclitaxel in combination with each of 2,000 small molecule compounds from the National Cancer Institute Diversity Set Library, we identified a previously uncharacterized molecule, NSC23925, that inhibits Pgp1 and reverses MDR1 (Pgp1) but does not inhibit MRP or BCRP-mediated MDR. The cytotoxic activity of NSC23925 was further evaluated using a panel of cancer cell lines expressing Pgp1, MRP, and BCRP. We found that at a concentration of >10 mu M NSC23925 moderately inhibits the proliferation of both sensitive and resistant cell lines with almost equal activity, but its inhibitory effect was not altered by co-incubation with the Pgp1 inhibitor, verapamil, suggesting that NSC23925 itself is not a substrate of Pgp1. Additionally, NSC23925 increases the intracellular accumulation of Pgp1 substrates: calcein AM, Rhodamine-123, paclitaxel, mitoxantrone, and doxorubicin. Interestingly, we further observed that, although NSC23925 directly inhibits the function of Pgp1 in a dose-dependent manner without altering the total expression level of Pgp1, NSC23925 actually stimulates ATPase activity of Pgp, a phenomenon seen in other Pgp inhibitors. Conclusions/Significance: The ability of NSC23925 to restore sensitivity to the cytotoxic effects of chemotherapy or to prevent resistance could significantly benefit cancer patients. RP Duan, ZF (reprint author), Massachusetts Gen Hosp, Ctr Sarcoma & Connect Tissue Oncol, Sarcoma Biol Lab, Boston, MA 02114 USA. EM zduan@partners.org OI Duan, Zhenfeng/0000-0002-8543-083X; Choy, Edwin/0000-0001-9896-8084 FU NCI NIH HHS [R01-CA119617, R01 CA119617] NR 45 TC 30 Z9 31 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 12 PY 2009 VL 4 IS 10 AR e7415 DI 10.1371/journal.pone.0007415 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 505VX UT WOS:000270728500014 PM 19823672 ER PT J AU Mahimainathan, L Ghosh-Choudhury, N Venkatesan, B Das, F Mandal, CC Dey, N Habib, SL Kasinath, BS Abboud, HE Choudhury, GG AF Mahimainathan, Lenin Ghosh-Choudhury, Nandini Venkatesan, Balachandar Das, Falguni Mandal, Chandi C. Dey, Nirmalya Habib, Samy L. Kasinath, Balakuntalam S. Abboud, Hanna E. Choudhury, Goutam Ghosh TI TSC2 Deficiency Increases PTEN via H1F1 alpha SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUBEROUS SCLEROSIS COMPLEX; TUMOR-SUPPRESSOR GENE; INDUCIBLE FACTOR-I; CELL-SURVIVAL; RENAL ANGIOMYOLIPOMAS; 3-KINASE/AKT PATHWAY; SIGNALING PATHWAY; MESANGIAL CELLS; DOWN-REGULATION; S6 KINASE AB Substantial evidence suggests roles of TSC2 and PTEN in the development of cancer predisposition syndromes. Loss of TSC2 results in benign tumors, neurological disorders, and angiomyolipomas. We found that PTEN mRNA and protein levels are elevated in Tsc2(-/-) mouse embryo fibroblasts with concomitant reduction in Akt phosphorylation. Reconstitution of TSC2 in Tsc2(-/-) mouse embryo fibroblasts decreases PTEN levels. Interestingly, increased HIF1 alpha activity present in Tsc2 null cells is required for PTEN transcription and protein expression. We identified a canonical hypoxia-responsive element in the PTEN promoter, which regulates the transcription of this tumor suppressor protein in a TSC2-dependent manner. Finally, we demonstrate a positive correlation between expression of HIF1 alpha and PTEN in renal angiomyolipomas from TSC patients. Our results reveal a unique function of HIF1 alpha in up-regulation of PTEN and provide a new mechanism of reduced Akt phosphorylation in Tsc2 null cells. These data suggest that PTEN may safeguard against developing malignant tumors in patients with TSC deficiency. C1 [Mahimainathan, Lenin; Venkatesan, Balachandar; Das, Falguni; Dey, Nirmalya; Kasinath, Balakuntalam S.; Abboud, Hanna E.; Choudhury, Goutam Ghosh] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini; Mandal, Chandi C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pathol, San Antonio, TX 78229 USA. [Ghosh-Choudhury, Nandini; Habib, Samy L.; Kasinath, Balakuntalam S.; Abboud, Hanna E.; Choudhury, Goutam Ghosh] S Texas Vet Hlth Care Syst, Vet Affairs Res, San Antonio, TX 78229 USA. [Habib, Samy L.; Choudhury, Goutam Ghosh] S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. RP Choudhury, GG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Mail Code 7882,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM choudhuryg@uthscsa.edu FU National Institutes of Health [RC1 DIK50190]; Juvenile Diabetes Research Foundation; Veterans Affairs Research Service Merit Review Grants FX This work was supported, in whole or in part, by National Institutes of Health Grant RC1 DIK50190. This work was also supported by the Juvenile Diabetes Research Foundation and Veterans Affairs Research Service Merit Review Grants (to G. G. C.). NR 60 TC 15 Z9 15 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 9 PY 2009 VL 284 IS 41 BP 27790 EP 27798 DI 10.1074/jbc.M109.028860 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 505FP UT WOS:000270676300005 PM 19648120 ER PT J AU Pioszak, AA Parker, NR Gardella, TJ Xu, HE AF Pioszak, Augen A. Parker, Naomi R. Gardella, Thomas J. Xu, H. Eric TI Structural Basis for Parathyroid Hormone-related Protein Binding to the Parathyroid Hormone Receptor and Design of Conformation-selective Peptides SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COUPLED-RECEPTOR; MOLECULAR RECOGNITION; EXTRACELLULAR DOMAIN; PTH/PTHRP RECEPTOR; CRYSTAL-STRUCTURE; LIGAND-BINDING; PTH; OSTEOPOROSIS; REFINEMENT; FRAGMENT AB Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are two related peptides that control calcium/phosphate homeostasis and bone development, respectively, through activation of the PTH/PTHrP receptor (PTH1R), a class B G protein-coupled receptor. Both peptides hold clinical interest for their capacities to stimulate bone formation. PTH and PTHrP display different selectivity for two distinct PTH1R conformations, but how their binding to the receptor differs is unclear. The high resolution crystal structure of PTHrP bound to the extracellular domain (ECD) of PTH1R reveals that PTHrP binds as an amphipathic a-helix to the same hydrophobic groove in the ECD as occupied by PTH, but in contrast to a straight, continuous PTH helix, the PTHrP helix is gently curved and C-terminally "unwound." The receptor accommodates the altered binding modes by shifting the side chain conformations of two residues within the binding groove: Leu-41 and Ile-115, the former acting as a rotamer toggle switch to accommodate PTH/PTHrP sequence divergence, and the latter adapting to the PTHrP curvature. Binding studies performed with PTH/PTHrP hybrid ligands having reciprocal exchanges of residues involved in different contacts confirmed functional consequences for the altered interactions and enabled the design of altered PTH and PTHrP peptides that adopt the ECD-binding mode of the opposite peptide. Hybrid peptides that bound the ECD poorly were selective for the G protein-coupled PTH1R conformation. These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics. C1 [Pioszak, Augen A.; Parker, Naomi R.; Xu, H. Eric] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA. [Gardella, Thomas J.] Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02144 USA. RP Pioszak, AA (reprint author), Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA. EM augie.pioszak@vai.org; eric.xu@vai.org FU National Institutes of Health [DK071662, DK066202, HL089301, DK-11794]; Jay and Betty Van Andel Foundation FX This work was supported, in whole or in part, by National Institutes of Health Grants DK071662, DK066202, and HL089301 (to H. E. X.), and DK-11794 (toT. J. G.).This work was also supported by the Jay and Betty Van Andel Foundation. NR 44 TC 55 Z9 57 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 9 PY 2009 VL 284 IS 41 BP 28382 EP 28391 DI 10.1074/jbc.M109.022905 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 505FP UT WOS:000270676300063 PM 19674967 ER PT J AU Yan, QS Dutt, S Xu, R Graves, K Juszczynski, P Manis, JP Shipp, MA AF Yan, Qingsheng Dutt, Shilpee Xu, Rong Graves, Katherine Juszczynski, Przemyslaw Manis, John P. Shipp, Margaret A. TI BBAP Monoubiquitylates Histone H4 at Lysine 91 and Selectively Modulates the DNA Damage Response SO MOLECULAR CELL LA English DT Article ID DOUBLE-STRAND BREAKS; B-CELL LYMPHOMAS; H2B UBIQUITYLATION; REPAIR PROTEINS; H3 METHYLATION; UBIQUITINATION; CHROMATIN; GENE; METHYLTRANSFERASE; TRANSCRIPTION AB Although the BBAP E3 ligase and its binding partner BAL are overexpressed in chemotherapy-resistant lymphomas, the role of these proteins in DNA damage responses remains undefined. Because BAL proteins modulate promoter-coupled transcription and contain structural motifs associated with chromatin remodeling and DNA repair, we reasoned that the BBAP E3 ligase might target nucleosomal proteins. Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. Because 53BP1 localizes to DNA damage sites, in part, via an interaction with dimethyl H4K20, these data directly implicate BBAP in the monoubiquitylation and additional posttranslational modification of histone H4 and an associated DNA damage response. C1 [Yan, Qingsheng; Xu, Rong; Juszczynski, Przemyslaw; Shipp, Margaret A.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Dutt, Shilpee; Graves, Katherine; Manis, John P.] Harvard Univ, Childrens Hosp Boston, Sch Med, Boston, MA 02115 USA. [Dutt, Shilpee; Graves, Katherine; Manis, John P.] Harvard Univ, Joint Program Transfus Med, Sch Med, Boston, MA 02115 USA. RP Shipp, MA (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. EM margaret_shipp@dfci.harvard.edu FU NCI NIH HHS [P01 CA092625, P01 CA092625-08, P01 CA092625-09] NR 52 TC 60 Z9 65 U1 0 U2 2 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 OCT 9 PY 2009 VL 36 IS 1 BP 110 EP 120 DI 10.1016/j.molcel.2009.08.019 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 510AN UT WOS:000271060500011 PM 19818714 ER PT J AU Amit, I Garber, M Chevrier, N Leite, AP Donner, Y Eisenhaure, T Guttman, M Grenier, JK Li, WB Zuk, O Schubert, LA Birditt, B Shay, T Goren, A Zhang, XL Smith, Z Deering, R McDonald, RC Cabili, M Bernstein, BE Rinn, JL Meissner, A Root, DE Hacohen, N Regev, A AF Amit, Ido Garber, Manuel Chevrier, Nicolas Leite, Ana Paula Donner, Yoni Eisenhaure, Thomas Guttman, Mitchell Grenier, Jennifer K. Li, Weibo Zuk, Or Schubert, Lisa A. Birditt, Brian Shay, Tal Goren, Alon Zhang, Xiaolan Smith, Zachary Deering, Raquel McDonald, Rebecca C. Cabili, Moran Bernstein, Bradley E. Rinn, John L. Meissner, Alex Root, David E. Hacohen, Nir Regev, Aviv TI Unbiased Reconstruction of a Mammalian Transcriptional Network Mediating Pathogen Responses SO SCIENCE LA English DT Article ID GENE-EXPRESSION; REGULATORS; INDUCTION; MODULE; RNA AB Models of mammalian regulatory networks controlling gene expression have been inferred from genomic data but have largely not been validated. We present an unbiased strategy to systematically perturb candidate regulators and monitor cellular transcriptional responses. We applied this approach to derive regulatory networks that control the transcriptional response of mouse primary dendritic cells to pathogens. Our approach revealed the regulatory functions of 125 transcription factors, chromatin modifiers, and RNA binding proteins, which enabled the construction of a network model consisting of 24 core regulators and 76 fine-tuners that help to explain how pathogen-sensing pathways achieve specificity. This study establishes a broadly applicable, comprehensive, and unbiased approach to reveal the wiring and functions of a regulatory network controlling a major transcriptional response in primary mammalian cells. C1 [Amit, Ido; Garber, Manuel; Leite, Ana Paula; Donner, Yoni; Guttman, Mitchell; Grenier, Jennifer K.; Zuk, Or; Shay, Tal; Goren, Alon; Zhang, Xiaolan; Smith, Zachary; Cabili, Moran; Bernstein, Bradley E.; Rinn, John L.; Meissner, Alex; Root, David E.; Hacohen, Nir; Regev, Aviv] MIT, Broad Inst, Cambridge, MA 02142 USA. [Amit, Ido; Garber, Manuel; Leite, Ana Paula; Donner, Yoni; Guttman, Mitchell; Grenier, Jennifer K.; Zuk, Or; Shay, Tal; Goren, Alon; Zhang, Xiaolan; Smith, Zachary; Cabili, Moran; Bernstein, Bradley E.; Rinn, John L.; Meissner, Alex; Root, David E.; Hacohen, Nir; Regev, Aviv] Harvard Univ, Cambridge, MA 02142 USA. [Amit, Ido; Chevrier, Nicolas; Eisenhaure, Thomas; Li, Weibo; Deering, Raquel; McDonald, Rebecca C.; Hacohen, Nir] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Charlestown, MA 02129 USA. [Amit, Ido; Chevrier, Nicolas; Eisenhaure, Thomas; Li, Weibo; Deering, Raquel; McDonald, Rebecca C.; Bernstein, Bradley E.; Hacohen, Nir] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Amit, Ido; Guttman, Mitchell; Regev, Aviv] MIT, Dept Biol, Cambridge, MA 02142 USA. [Leite, Ana Paula] MIT, Cambridge, MA 02139 USA. [Schubert, Lisa A.; Birditt, Brian] NanoString Technol, Seattle, WA 98109 USA. [Goren, Alon; Bernstein, Bradley E.] Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. [Goren, Alon; Bernstein, Bradley E.] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA. [Regev, Aviv] Howard Hughes Med Inst, Chevy Chase, MD USA. RP Hacohen, N (reprint author), MIT, Broad Inst, 7 Cambridge Ctr, Cambridge, MA 02142 USA. EM nhacohen@partners.org RI Shay, Tal/J-4028-2016; OI Shay, Tal/0000-0003-0755-1350; Leite, Ana Paula/0000-0001-5773-3211 FU American Physicians Fellowship for Medicine in Israel; NIH [R21 AI71060]; Burroughs Wellcome Fund; Sloan Foundation FX We thank E. Lander, I. Wapinski, D. Pe'er, N. Friedman, J. Kagan, A. Luster, V. Kuchroo, and A. Citri for discussions and comments; L. Gaffney for assistance with artwork; S. Gupta and the Broad Genetic Analysis Platform for microarray processing; and T. Mikkelsen and the Broad Sequencing Platform for help with the ChIP-seq experiments. Supported by the Human Frontier Science Program Organization and a Claire and Emanuel G. Rosenblatt Award from the American Physicians Fellowship for Medicine in Israel (I. A.); NIH grant R21 AI71060 and the NIH New Innovator Award (N. H.); and a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, an NIH Pioneer Award, and the Sloan Foundation (A. R.). A. R. is an Early Career Scientist of the Howard Hughes Medical Institute and an investigator of the Merkin Foundation for Stem Cell Research at the Broad Institute. Complete microarray data sets are available at the Gene Expression Omnibus (accession no. GSE17721). NR 28 TC 281 Z9 283 U1 1 U2 19 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 OCT 9 PY 2009 VL 326 IS 5950 BP 257 EP 263 DI 10.1126/science.1179050 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 504EX UT WOS:000270599500035 PM 19729616 ER PT J AU Walker, LM Phogat, SK Chan-Hui, PY Wagner, D Phung, P Goss, JL Wrin, T Simek, MD Fling, S Mitcham, JL Lehrman, JK Priddy, FH Olsen, OA Frey, SM Hammond, PW Kaminsky, S Zamb, T Moyle, M Koff, WC Poignard, P Burton, DR AF Walker, Laura M. Phogat, Sanjay K. Chan-Hui, Po-Ying Wagner, Denise Phung, Pham Goss, Julie L. Wrin, Terri Simek, Melissa D. Fling, Steven Mitcham, Jennifer L. Lehrman, Jennifer K. Priddy, Frances H. Olsen, Ole A. Frey, Steven M. Hammond, Phillip W. Kaminsky, Stephen Zamb, Timothy Moyle, Matthew Koff, Wayne C. Poignard, Pascal Burton, Dennis R. CA Protocol G Principal Investigators TI Broad and Potent Neutralizing Antibodies from an African Donor Reveal a New HIV-1 Vaccine Target SO SCIENCE LA English DT Article ID SIMIAN/HUMAN IMMUNODEFICIENCY VIRUS; MONOCLONAL-ANTIBODIES; PASSIVE TRANSFER; V2 DOMAIN; GP120; ENVELOPE; PROTECTION; MACAQUES; EPITOPE; DESIGN AB Broadly neutralizing antibodies (bNAbs), which develop over time in some HIV-1-infected individuals, define critical epitopes for HIV vaccine design. Using a systematic approach, we have examined neutralization breadth in the sera of about 1800 HIV-1-infected individuals, primarily infected with non-clade B viruses, and have selected donors for monoclonal antibody (mAb) generation. We then used a high-throughput neutralization screen of antibody-containing culture supernatants from about 30,000 activated memory B cells from a clade A-infected African donor to isolate two potent mAbs that target a broadly neutralizing epitope. This epitope is preferentially expressed on trimeric Envelope protein and spans conserved regions of variable loops of the gp120 subunit. The results provide a framework for the design of new vaccine candidates for the elicitation of bNAb responses. C1 [Phogat, Sanjay K.; Wagner, Denise; Kaminsky, Stephen; Zamb, Timothy] Int AIDS Vaccine Initiat, AIDS Vaccine Design & Dev Lab, New York, NY 11220 USA. [Walker, Laura M.; Fling, Steven; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Walker, Laura M.; Fling, Steven; Poignard, Pascal; Burton, Dennis R.] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA. [Chan-Hui, Po-Ying; Mitcham, Jennifer L.; Olsen, Ole A.; Frey, Steven M.; Hammond, Phillip W.; Moyle, Matthew] Theraclone Sci, Seattle, WA 98104 USA. [Phung, Pham; Goss, Julie L.; Wrin, Terri] Monogram Biosci Inc, San Francisco, CA 94080 USA. [Simek, Melissa D.; Lehrman, Jennifer K.; Priddy, Frances H.; Koff, Wayne C.] Int AIDS Vaccine Initiat, New York, NY 10038 USA. [Burton, Dennis R.] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02114 USA. [Burton, Dennis R.] Harvard Univ, Boston, MA 02114 USA. RP Phogat, SK (reprint author), Int AIDS Vaccine Initiat, AIDS Vaccine Design & Dev Lab, New York, NY 11220 USA. EM SPhogat@iavi.org; burton@scripps.edu RI poignard, pascal/N-6678-2013; Kaminsky, Stephen/J-5141-2016 OI Kaminsky, Stephen/0000-0003-1869-834X FU International AIDS Vaccine Initiative (IAVI); U. S. Agency for International Development (USAID); National Institute of Allergy and Infectious Diseases; NIH [AI33292] FX We thank R. Aguilar-Sino for technical assistance at The Scripps Research Institute; C. Ward, W. Cieplak, and M. Branum for technical assistance at Theraclone Sciences; R. Pejchal for assistance in structural modeling; S. M. Eagol and C. Williams for assistance with figures; E. Anton from Monogram R & D and the Monogram Clinical Reference Laboratory staff; all the study participants and research staff at each of the Protocol G clinical centers; and Protocol G project team members for all of the support that they have provided for this study (individuals and affiliations are listed in the supporting online material text as notes). We also thank A. Pinter for supplying the antibodies 10/76b and c108 g, W. Olson and J. Moore for providing the KNH1144 SOSIP trimer, and R. Wyatt for providing the YU2gp140foldon trimer. This work was supported by the International AIDS Vaccine Initiative (IAVI) through the contributions of a number of government and private donors who are listed on the Web site www. iavi. org, as well as IAVI's Innovation Fund (which is cofunded by the Bill & Melinda Gates Foundation); the U. S. Agency for International Development (USAID); and the National Institute of Allergy and Infectious Diseases, NIH, AI33292 (D. R. B.). The contents are the responsibility of the authors and do not necessarily reflect the views of USAID or the U. S. government. The authors declare competing financial interests. Protocol G Principal Investigators: G. Miiro, J. Serwanga, A. Pozniak, D. McPhee, O. Manigart, L. Mwananyanda, E. Karita, A. Inwoley, W. Jaoko, J. DeHovitz, L. G. Bekker, P. Pitisuttithum, R. Paris, and S. Allen. NR 23 TC 919 Z9 938 U1 7 U2 87 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 OCT 9 PY 2009 VL 326 IS 5950 BP 285 EP 289 DI 10.1126/science.1178746 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 504EX UT WOS:000270599500042 PM 19729618 ER PT J AU Gandhi, RT O'Neill, D Bosch, RJ Chan, ES Bucy, RP Shopis, J Baglyos, L Adams, E Fox, L Purdue, L Marshak, A Flynn, T Masih, R Schock, B Mildvan, D Schlesinger, SJ Marovich, MA Bhardwaj, N Jacobson, JM AF Gandhi, Rajesh T. O'Neill, David Bosch, Ronald J. Chan, Ellen S. Bucy, R. Pat Shopis, Janet Baglyos, Lynn Adams, Elizabeth Fox, Lawrence Purdue, Lynette Marshak, Ann Flynn, Theresa Masih, Reena Schock, Barbara Mildvan, Donna Schlesinger, Sarah J. Marovich, Mary A. Bhardwaj, Nina Jacobson, Jeffrey M. CA AIDS Clinical Trials Grp A5130 Tea TI A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy SO VACCINE LA English DT Article DE HIV-1; Dendritic cells; Canarypox; Therapeutic vaccine; Clinical trial ID CD8(+) T-CELL; VIRUS TYPE-1 HIV-1; LYMPHOCYTE RESPONSES; RECOMBINANT GP160; IMMUNIZATION; INFECTION; CD4(+); VCP1452; PROTEIN; IMMUNOGENICITY AB Targeting canarypox (CP)-HIV vaccine to dendritic cells (DCs) elicits anti-HIV-1 immune responses in vitro. We conducted a phase I/II clinical trial to evaluate whether adding DC to a CP-HIV vaccine improved virologic control during analytic treatment interruption (ATI) in HIV-1-infected subjects. Twenty-nine subjects on suppressive antiretroviral therapy were randomized to vaccination with autologous DCs infected with CP-HIV + keyhole limpet hemocyanin (KLH) (arm A, n = 14) or CP-HIV + KLH alone (arm B, n = 15). The mean viral load (VL) setpoint during ATI did not differ between subjects in arms A and B. A higher percentage of subjects in the DC group had a VL setpoint <5000 c/mL during ATI (4/13 or 31% in arm A compared with 0/13 in arm B, p = 0.096), but virologic control was transient. Subjects in arm A had a greater increase in KLH lymphoproliferative response than subjects in arm B; however. summed ELISPOT responses to HIV-1 antigens did not differ by treatment arm. We conclude that a DC-CP-HIV vaccine is well-tolerated in HIV-1-infected patients, but does not lower VL setpoint during ATI compared with CP-HIV alone. New methods to enhance the immunogenicity and antiviral efficacy of DC-based vaccines for HIV-1 infection are needed. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Gandhi, Rajesh T.; Shopis, Janet; Flynn, Theresa] Massachusetts Gen Hosp, Boston, MA 02114 USA. [O'Neill, David; Bhardwaj, Nina] NYU, Sch Med, New York, NY 10003 USA. [Bosch, Ronald J.; Chan, Ellen S.] Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. [Bucy, R. Pat] Univ Alabama, Birmingham, AL USA. [Adams, Elizabeth; Fox, Lawrence; Purdue, Lynette; Masih, Reena] NIH, Bethesda, MD 20892 USA. [Marshak, Ann; Mildvan, Donna] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Schlesinger, Sarah J.] Rockefeller Univ, New York, NY USA. [Marovich, Mary A.] Walter Reed Army Inst, Silver Spring, MD 20910 USA. [Jacobson, Jeffrey M.] Drexel Univ, Coll Med, Philadelphia, PA USA. RP Gandhi, RT (reprint author), Massachusetts Gen Hosp, 55 Fruit St,GRJ 504, Boston, MA 02114 USA. EM rgandhi@partners.org FU NIAID NIH HHS [AI38855, AI38858, AI68634, AI68636, R01 AI066992, R01 AI066992-04, R37 AI044628, R37 AI044628-08, U01 AI038855, U01 AI038858, U01 AI068634, U01 AI068634-01, U01 AI068636, U01 AI068636-01, U01 AI069472, U01 AI069472-01, UM1 AI068634, UM1 AI068636]; PHS HHS [A146370, AIO69472] NR 34 TC 48 Z9 52 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD OCT 9 PY 2009 VL 27 IS 43 BP 6088 EP 6094 DI 10.1016/j.vaccine.2009.05.016 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 511MW UT WOS:000271170500023 PM 19450647 ER PT J AU Blotta, S Tassone, P Prabhala, RH Tagliaferri, P Cervi, D Amin, S Jakubikova, J Tai, YT Podar, K Mitsiades, CS Zullo, A Franco, B Anderson, KC Munshi, NC AF Blotta, Simona Tassone, Pierfrancesco Prabhala, Rao H. Tagliaferri, Piersandro Cervi, David Amin, Samir Jakubikova, Jana Tai, Yu-Tzu Podar, Klaus Mitsiades, Constantine S. Zullo, Alessandro Franco, Brunella Anderson, Kenneth C. Munshi, Nikhil C. TI Identification of novel antigens with induced immune response in monoclonal gammopathy of undetermined significance SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; MULTIPLE-MYELOMA CELLS; CLONAL PLASMA-CELLS; PRIMARY CILIA; BONE-MARROW; LONG-TERM; EXPRESSION; CANCER; PROGNOSIS; PROTEIN AB The transformation from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is thought to be associated with changes in immune processes. We have therefore used serologic analysis of recombinant cDNA expression library to screen the sera of MGUS patients to identify tumor-associated antigens. A total of 10 antigens were identified, with specific antibody responses in MGUS. Responses appeared to be directed against intracellular proteins involved in cellular functions, such as apoptosis (SON, IFT57/HIPPI), DNA and RNA binding (ZNF292, GPATCH4), signal transduction regulators (AKAP11), transcriptional corepressor (IRF2BP2), developmental proteins (OFD1), and proteins of the ubiquitin-proteasome pathway (PSMC1). Importantly, the gene responsible for the oral-facial-digital type I syndrome (OFD1) had response in 6 of 29 (20.6%) MGUS patients but 0 of 11 newly diagnosed MM patients. Interestingly, 3 of 11 (27.2%) MM patients after autologous stem cell transplantations showed responses to OFD1. We have confirmed T-cell responses against OFD1 in MGUS and observed down-regulation of GLI1/PTCH1 and p-beta-catenin after OFD1 knock-down with specific siRNA, suggesting its functional role in the regulation of Hh and Wnt pathways. These findings demonstrate OFD1 as an important immune target and highlight its possible role in signal transduction and tumorigenesis in MGUS and MM. (Blood. 2009; 114: 3276-3284) C1 [Munshi, Nikhil C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Blotta, Simona; Prabhala, Rao H.; Cervi, David; Amin, Samir; Jakubikova, Jana; Tai, Yu-Tzu; Podar, Klaus; Mitsiades, Constantine S.; Anderson, Kenneth C.; Munshi, Nikhil C.] Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Blotta, Simona; Prabhala, Rao H.; Amin, Samir; Munshi, Nikhil C.] Harvard Univ, Sch Med, Vet Adm Boston Healthcare Syst, Boston, MA 02115 USA. [Blotta, Simona; Tassone, Pierfrancesco; Tagliaferri, Piersandro] Univ Magna Graecia & Canc Ctr, Catanzaro, Italy. [Zullo, Alessandro; Franco, Brunella] Telethon Inst Genet & Med, Naples, Italy. [Franco, Brunella] Univ Naples Federico 2, Med Genet Dept Pediat, Naples, Italy. RP Munshi, NC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Multiple Myeloma Ctr, 44 Binney St,M1B28, Boston, MA 02115 USA. EM Nikhil_Munshi@dfci.harvard.edu OI FRANCO, Brunella/0000-0001-5588-4569; Amin, Samir/0000-0002-3207-9505 FU Specialized Program of Research Excellence; National Institutes of Health (NIH) [P50CA-100707, RO1-129494, PO1-78378]; Career Development Award; Italian Telethon Foundation; Italian Association for Cancer Research, Milan, Italy; Department of Veterans Affairs; Leukemia & Lymphoma Society Scholar; Lebow Fund to Cure Myeloma FX This work was supported by the Specialized Program of Research Excellence in Myeloma, National Institutes of Health (NIH; grant P50CA-100707), a Career Development Award (S. B.), the Italian Telethon Foundation (B. F.), the Italian Association for Cancer Research, Milan, Italy (P. Tassone), the Department of Veterans Affairs merit review award, and Leukemia & Lymphoma Society Scholar in Translational Research Award and NIH (grant RO1-129494; N.C.M.), NIH grants P50CA-100707 and PO1-78378 (N.C.M., K. C. A.), and the Lebow Fund to Cure Myeloma (K. C. A.). NR 51 TC 20 Z9 21 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 8 PY 2009 VL 114 IS 15 BP 3276 EP 3284 DI 10.1182/blood-2009-04-219436 PG 9 WC Hematology SC Hematology GA 504DW UT WOS:000270595700020 PM 19587378 ER PT J AU Zhao, BQ Chauhan, AK Canault, M Patten, IS Yang, JJ Dockal, M Scheiflinger, F Wagner, DD AF Zhao, Bing-Qiao Chauhan, Anil K. Canault, Matthias Patten, Ian S. Yang, Janie J. Dockal, Michael Scheiflinger, Friedrich Wagner, Denisa D. TI vonWillebrand factor-cleaving protease ADAMTS13 reduces ischemic brain injury in experimental stroke SO BLOOD LA English DT Article ID VON-WILLEBRAND-FACTOR; THROMBOTIC THROMBOCYTOPENIC PURPURA; MOUSE MODEL; P-SELECTIN; INFLAMMATION; DISEASE; MICE; HEMOSTASIS; HEMORRHAGE; FIBRINOGEN AB Stroke is a leading cause of death and disability. The only therapy available is recombinant tissue plasminogen activator, but side effects limit its use. Platelets play a crucial role during stroke, and the inflammatory reaction promotes neurodegeneration. von Willebrand factor (VWF), an adhesion molecule for platelets, is elevated in patients with acute stroke. The activity of VWF is modulated by ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) that cleaves VWF to smaller less-active forms. We recently documented that ADAMTS13 negatively regulates both thrombosis and inflammation. We report that deficiency or reduction of VWF reduces infarct volume up to 2-fold after focal cerebral ischemia in mice, thus showing the importance of VWF in stroke injury. In contrast, ADAMTS13 deficiency results in larger infarctions, but only in mice that have VWF. Importantly, infusion of a high dose of recombinant human ADAMTS13 into a wild-type mouse immediately before reperfusion reduces infarct volume and improves functional outcome without producing cerebral hemorrhage. Furthermore, recombinant ADAMTS13 did not enhance bleeding in a hemorrhagic stroke model. Our findings show the importance of VWF in regulating infarction and suggest that recombinant ADAMTS13 could be considered as a new therapeutic agent for prevention and/or treatment of stroke. (Blood. 2009; 114: 3329-3334) C1 [Zhao, Bing-Qiao; Chauhan, Anil K.; Canault, Matthias; Patten, Ian S.; Yang, Janie J.; Wagner, Denisa D.] Immune Dis Inst, Boston, MA 02115 USA. [Zhao, Bing-Qiao; Chauhan, Anil K.; Canault, Matthias; Patten, Ian S.; Yang, Janie J.; Wagner, Denisa D.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Zhao, Bing-Qiao; Chauhan, Anil K.; Canault, Matthias; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Dockal, Michael; Scheiflinger, Friedrich] Baxter Biosci, Vienna, Austria. RP Wagner, DD (reprint author), Immune Dis Inst, 3 Blackfan Cir, Boston, MA 02115 USA. EM wagner@idi.harvard.edu RI Canault, Matthias/H-5128-2013 OI Canault, Matthias/0000-0002-7880-5250 FU NHLBI NIH HHS [R01 HL041002, R37 HL041002] NR 34 TC 110 Z9 115 U1 2 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 8 PY 2009 VL 114 IS 15 BP 3329 EP 3334 DI 10.1182/blood-2009-03-213264 PG 6 WC Hematology SC Hematology GA 504DW UT WOS:000270595700027 PM 19687510 ER PT J AU Montagut, C Settleman, J AF Montagut, Clara Settleman, Jeff TI Targeting the RAF-MEK-ERK pathway in cancer therapy SO CANCER LETTERS LA English DT Review DE RAF kinase; MEK kinase; Selective kinase inhibitors; Cancer ID SIGNAL-REGULATED KINASE; REFRACTORY SOLID TUMORS; ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; RANDOMIZED DISCONTINUATION TRIAL; INHIBITOR AZD6244 ARRY-142886; FACTOR RECEPTOR INHIBITOR; DAYS ON/7 DAYS; B-RAF; PHASE-I AB The clinical success of selective kinase inhibitors, such as imatinib and erlotinib, as therapeutic agents for several human cancers has prompted substantial interest in the further development and clinical testing of such inhibitors for a wide variety of malignancies. While much of this effort has been focused on the receptor tyrosine kinases, including EGFR, HER2, PDGF receptor, c-KIT, and MET, inhibitors of serine/threonine kinases are also beginning to emerge within discovery pipelines. Among these kinases, the RAF and MEK kinases have received substantial attention, owing largely to the relatively high frequency of activating mutations of RAS (similar to 20% of all human cancers), an upstream activator of the well established RAF-MEK-ERK signaling cascade, as well as frequent activating mutations in the BRAF kinase (similar to 7% of all human cancers). Here, we summarize the current state of development of kinase inhibitors directed at this signaling pathway, a few of which have already demonstrating favorable toxicity profiles as well as promising activity in early phase clinical studies. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Settleman, Jeff] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Settleman, Jeff] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Montagut, Clara] Hosp Mar IMIM, Dept Med Oncol, Barcelona 08003, Spain. [Montagut, Clara] Hosp Mar IMIM, Canc Res Program, Barcelona 08003, Spain. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA. EM settleman@helix.mgh.harvard.edu FU RTICC [06/0020/0109] FX C.M. has been supported by RTICC 06/0020/0109 and Fundacio Cellex (Barcelona). NR 75 TC 221 Z9 233 U1 5 U2 33 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD OCT 8 PY 2009 VL 283 IS 2 BP 125 EP 134 DI 10.1016/j.canlet.2009.01.022 PG 10 WC Oncology SC Oncology GA 498QR UT WOS:000270157800002 PM 19217204 ER PT J AU Thomas, DL Thio, CL Martin, MP Qi, Y Ge, D O'hUigin, C Kidd, J Kidd, K Khakoo, SI Alexander, G Goedert, JJ Kirk, GD Donfield, SM Rosen, HR Tobler, LH Busch, MP McHutchison, JG Goldstein, DB Carrington, M AF Thomas, David L. Thio, Chloe L. Martin, Maureen P. Qi, Ying Ge, Dongliang O'hUigin, Colm Kidd, Judith Kidd, Kenneth Khakoo, Salim I. Alexander, Graeme Goedert, James J. Kirk, Gregory D. Donfield, Sharyne M. Rosen, Hugo R. Tobler, Leslie H. Busch, Michael P. McHutchison, John G. Goldstein, David B. Carrington, Mary TI Genetic variation in IL28B and spontaneous clearance of hepatitis C virus SO NATURE LA English DT Article ID NATURAL-HISTORY; INFECTION; HEMOPHILIA; ALPHA-2A; FAMILY; HOST AB Hepatitis C virus (HCV) infection is the most common bloodborne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide(1). Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma(2). Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance(3,4). Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-lambda 3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment(5). To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection. C1 [Martin, Maureen P.; Qi, Ying; O'hUigin, Colm; Carrington, Mary] NCI Frederick, SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. [Thomas, David L.; Thio, Chloe L.] Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21205 USA. [Martin, Maureen P.; Qi, Ying; O'hUigin, Colm; Carrington, Mary] MIT, Massachusetts Gen Hosp, Ragon Inst, Boston, MA 02114 USA. [Martin, Maureen P.; Qi, Ying; O'hUigin, Colm; Carrington, Mary] Harvard Univ, Boston, MA 02114 USA. [Ge, Dongliang; Goldstein, David B.] Duke Univ, Inst Genome Sci & Policy, Ctr Human Genome Variat, Durham, NC 27708 USA. [Kidd, Judith; Kidd, Kenneth] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Alexander, Graeme] Univ Cambridge, Dept Med, Cambridge CB2 2QQ, England. [Khakoo, Salim I.] Univ London Imperial Coll Sci Technol & Med, Div Med, London W2 1NY, England. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Kirk, Gregory D.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Donfield, Sharyne M.] Rho Inc, Chapel Hill, NC 27517 USA. [Rosen, Hugo R.] Univ Colorado, Hlth Sci Ctr, Div Gastroenterol & Hepatol, Aurora, CO 80045 USA. [Tobler, Leslie H.] Blood Syst Res Inst, San Francisco, CA 94118 USA. [Busch, Michael P.] Duke Univ, Duke Clin Res Inst, Durham, NC 27705 USA. [McHutchison, John G.] Duke Univ, Sch Med, Div Gastroenterol, Durham, NC 27705 USA. RP Carrington, M (reprint author), NCI Frederick, SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. EM carringm@mail.nih.gov RI Ge, Dongliang/A-2073-2010; OI Khakoo, Salim/0000-0002-4057-9091 FU National Cancer Institute; National Institutes of Health [HHSN261200800001E, R01DA013324, R01DA004334, R01HL076902, R01DK60590, R01HD41224]; Wellcome Trust Senior Clinical Fellow 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 number HHSN261200800001E. 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 US Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This research was supported by NIH grants R01DA013324 ( D. L. T.), R01DA004334 ( G. D. K.), R01HL076902 ( M. P. B.), R01DK60590 ( H. R. R.) and R01HD41224 ( S. M. D.). S. I. K. is a Wellcome Trust Senior Clinical Fellow. NR 24 TC 1275 Z9 1331 U1 4 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 OCT 8 PY 2009 VL 461 IS 7265 BP 798 EP U52 DI 10.1038/nature08463 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 503OR UT WOS:000270547500037 PM 19759533 ER PT J AU Weiss, LA Arking, DE AF Weiss, Lauren A. Arking, Dan E. CA Johns Hopkins & Autism Consortium TI A genome-wide linkage and association scan reveals novel loci for autism SO NATURE LA English DT Article ID SPECTRUM DISORDERS; WILLIAMS-SYNDROME; GENETIC VARIANT; COMMON DISEASES; EXPRESSION; GTF2IRD1; DEFICITS; MARKERS; CNTNAP2; CORTEX AB Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success(1). Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families ( 1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 ( between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants. C1 [Weiss, Lauren A.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Weiss, Lauren A.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Weiss, Lauren A.] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. [Arking, Dan E.] Johns Hopkins Univ, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. RP Weiss, LA (reprint author), Univ Calif San Francisco, Dept Psychiat, Inst Human Genet, Ctr Neurobiol & Psychiat, San Francisco, CA 94143 USA. RI Vicente, Astrid/F-8692-2014; Monaco, Anthony/A-4495-2010; Altshuler, David/A-4476-2009; Haines, Jonathan/C-3374-2012; Howe, Jennifer/I-9013-2012; Scherer, Stephen /B-3785-2013; Pickles, Andrew/A-9625-2011; MOTTRON, Laurent/H-2020-2013; Sutcliffe, James/C-1348-2012; Bolton, Patrick/E-8501-2010; Bailey, Anthony/J-2860-2014; Tansey, Katherine/B-1033-2013; Paterson, Andrew/A-4088-2011; OI Oliveira, Guiomar Goncalves/0000-0003-4031-3880; West, Andrew/0000-0002-3034-4061; Buxbaum, Joseph/0000-0001-8898-8313; Anney, Richard/0000-0002-6083-407X; Oliveira, Guiomar/0000-0002-7049-1277; Betancur, Catalina/0000-0002-3327-4804; Fombonne, Eric/0000-0002-8605-3538; McNeil, Kirsty/0000-0003-0437-3608; Correia, Catarina/0000-0001-5481-2010; Vicente, Astrid/0000-0001-7134-8037; Gallagher, Louise/0000-0001-9462-2836; Green, Jonathan/0000-0002-0143-181X; Wijsman, Ellen/0000-0002-2725-6669; Nurnberger, John/0000-0002-7674-1767; Gill, Michael/0000-0003-0206-5337; Monaco, Anthony/0000-0001-7480-3197; Altshuler, David/0000-0002-7250-4107; Scherer, Stephen /0000-0002-8326-1999; Pickles, Andrew/0000-0003-1283-0346; Sutcliffe, James/0000-0001-5200-6007; Bolton, Patrick/0000-0002-5270-6262; Bailey, Anthony/0000-0003-4257-972X; Tansey, Katherine/0000-0002-9663-3376; Paterson, Andrew/0000-0002-9169-118X; R Magalhaes, Tiago/0000-0002-5528-2119 FU National Center for Research Resources [U54 RR020278]; National Institutes of Mental Health [MH60007, MH081754]; Simons Foundation; Autism Consortium of Boston; NIMH [1R01 MH083565, 1K23MH080954]; Nancy Lurie Marks ( NLM) Family Foundation; National Institute of Health [MH52708, MH39437, MH00219, MH00980, MH6454, MH61009, MH55135, MH55284, HD055782, NS042165]; National Health Medical Research Council [0034328]; Scottish Rite; Spunk Fund, Inc.; Rebecca and Solomon Baker Fund; APEX Foundation; National Alliance for Research in Schizophrenia and Affective Disorders ( NARSAD),; Nancy Pritzker Laboratory; Cure Autism Now Foundation; Fundacao Calouste Gulbenkian; INSERM, Fondation de France, Fondation Orange; Fondation pour la Recherche Medicale; Swedish Science Council; The Seaver Foundation; The Children's Medical & Research Foundation; Our Lady's Children's Hospital, Crumlin, Ireland; The Medical Research Council ( MRC) FX The Autism Genome Project ( AGP) work was supported by the following grants: ( 1) The Hilibrand Foundation ( Principal Investigaor Joachim F. Hallmayer); ( 2) Autism Speaks ( for the AGP); ( 3) grants from the National Institutes of Health (NIH) MH61009 ( James S. Sutcliffe), MH55135 ( Susan E. Folstein), MH55284 ( Joseph Piven), HD055782 ( Ellen M. Wijsman), NS042165 (Joachim F. Hallmayer); ( 4) Fundacao para a Ciencia e Tecnologia (POCTI/39636/ESP/2001) Fundacao Calouste Gulbenkian ( Astrid Vincente); ( 5) INSERM, Fondation de France, Fondation Orange, Fondation pour la Recherche Medicale ( Catalina Betancur, Marion Leboyer), and the Swedish Science Council ( Christopher Gillberg); ( 6) The Seaver Foundation ( Joseph D. Buxbaum); ( 7) The Children's Medical & Research Foundation ( CMRF), Our Lady's Children's Hospital, Crumlin, Ireland (Sean Ennis); ( 8) The Medical Research Council ( MRC) ( Anthony P. Monaco, Anthony J. Bailey). Fresh-frozen brain tissue samples were obtained through the Autism Tissue Program and the Harvard Brain Bank. NR 42 TC 323 Z9 335 U1 1 U2 45 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 8 PY 2009 VL 461 IS 7265 BP 802 EP U62 DI 10.1038/nature08490 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 503OR UT WOS:000270547500038 PM 19812673 ER PT J AU Okike, K Kocher, MS Wei, EX Mehlman, CT Bhandari, M AF Okike, Kanu Kocher, Mininder S. Wei, Erin X. Mehlman, Charles T. Bhandari, Mohit TI Accuracy of Conflict-of-Interest Disclosures Reported by Physicians SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CLINICAL-TRIALS; FUNDING SOURCE; PHARMACEUTICAL-INDUSTRY; ORTHOPEDIC RESEARCH; DRUG TRIALS; ASSOCIATION; SPONSORSHIP; OUTCOMES; CONCLUSIONS; IMPACT AB Background The recent public reporting of payments made to physicians by manufacturers of orthopedic devices provides an opportunity to assess the accuracy of physicians' conflict-of-interest disclosures. Methods We analyzed the reports of payments made to physicians by five manufacturers of total hip and knee prostheses in 2007. For each payment recipient who was an author of a presentation or served as a committee member or board member at the 2008 annual meeting of the American Academy of Orthopaedic Surgeons, the disclosure statement was reviewed to determine whether the payment had been disclosed. To ascertain the reasons for nondisclosure, a survey was administered to physicians who had received payments that were not disclosed. Results The overall rate of disclosure was 71.2% (245 of 344 payments). For payments that were directly related to the topic of the presentation at the meeting, the rate was 79.3% (165 of 208); for payments that were indirectly related, the rate was 50.0% (16 of 32); and for payments that were unrelated, the rate was 49.2% (29 of 59) (P = 0.008). In the multivariate analysis, payments were also more likely to have been disclosed if they exceeded $10,000 (P<0.001), were directed toward an individual physician rather than a company or organization (P=0.04), or included an in-kind component (P=0.002). Among the 36 physicians who responded to the survey regarding reasons for nondisclosure (response rate, 39.6%), the reasons most commonly given for nondisclosure were that the payment was unrelated to the topic of presentation at the annual meeting (38.9% of respondents) and that the physician had misunderstood the disclosure requirements (13.9%); 11.1% reported that the payment had been disclosed but was mistakenly omitted from the program. Conclusions In this study of self-reported conflict-of-interest disclosure by physicians at a large annual meeting, the rate of disclosure was 79.3% for directly related payments and 50.0% for indirectly related payments. C1 [Okike, Kanu] Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02114 USA. [Okike, Kanu] Brigham & Womens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Kocher, Mininder S.] Childrens Hosp, Dept Orthoped Surg, Boston, MA 02115 USA. [Kocher, Mininder S.; Wei, Erin X.] Harvard Univ, Sch Med, Boston, MA USA. [Mehlman, Charles T.] Univ Cincinnati, Med Ctr, Coll Med,Cincinnati Childrens Hosp, Div Pediat Orthoped Surg, Cincinnati, OH 45267 USA. [Bhandari, Mohit] McMaster Univ, Hamilton Gen Hosp, Dept Orthopaed Surg, Hamilton, ON, Canada. RP Okike, K (reprint author), Massachusetts Gen Hosp, Dept Orthoped Surg, 55 Fruit St, Boston, MA 02114 USA. EM okike@post.harvard.edu OI Okike, Kanu/0000-0001-9310-9969 FU ConMed Linvatec; DePuy; Smith and Nephew; Stryker; Zimmer FX Dr. Kocher reports receiving grant support from ConMed Linvatec and serving as a consultant for ConMed Linvatec, Covidien, EBI ( a subsidiary of Biomet), and Smith and Nephew; Dr. Mehlman, receiving grant support from Abbott Spine ( now part of Zimmer), DePuy Spine, Globus Medical, Medtronic, and Synthes; and Dr. Bhandari, receiving grant support from DePuy, Smith and Nephew, Stryker, and Zimmer and serving as a consultant for Amgen, Osteogenix, Pfizer, and Zelos Therapeutics. No other potential conflict of interest relevant to this article was reported. NR 40 TC 78 Z9 79 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 8 PY 2009 VL 361 IS 15 BP 1466 EP 1474 DI 10.1056/NEJMsa0807160 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 503MU UT WOS:000270540000008 PM 19812403 ER PT J AU Alam, HB Fricchione, GL Guimaraes, ASR Zukerberg, LR AF Alam, Hasan B. Fricchione, Gregory L. Guimaraes, Alexander S. R. Zukerberg, Lawrence R. TI A Man with Abdominal Distention and Shock Acute megacolon (Ogilvie's syndrome), with extensive mucosal ischemic necrosis, due to clozapine-induced gastrointestinal hypomotility. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SEPTIC SHOCK; INTRAABDOMINAL HYPERTENSION; EARLY COAGULOPATHY; TOXIC MEGACOLON; CRITICALLY-ILL; DAMAGE-CONTROL; SEVERE SEPSIS; CHLORPROMAZINE; MANAGEMENT; THERAPY C1 [Alam, Hasan B.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Fricchione, Gregory L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Guimaraes, Alexander S. R.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Zukerberg, Lawrence R.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Alam, Hasan B.] Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. [Fricchione, Gregory L.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Guimaraes, Alexander S. R.] Harvard Univ, Sch Med, Dept Radiol, Cambridge, MA 02138 USA. [Zukerberg, Lawrence R.] Harvard Univ, Sch Med, Dept Pathol, Cambridge, MA 02138 USA. RP Alam, HB (reprint author), Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. NR 30 TC 7 Z9 7 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 OCT 8 PY 2009 VL 361 IS 15 BP 1487 EP 1496 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 503MU UT WOS:000270540000013 PM 19812406 ER PT J AU Lieberman, J AF Lieberman, Judy TI Micromanaging Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID LIVER-CANCER; MICRORNAS C1 [Lieberman, Judy] Childrens Hosp, Immune Dis Inst, Boston, MA 02115 USA. [Lieberman, Judy] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Lieberman, Judy] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Lieberman, J (reprint author), Childrens Hosp, Immune Dis Inst, 300 Longwood Ave, Boston, MA 02115 USA. RI Lieberman, Judy/A-2717-2015 NR 11 TC 7 Z9 7 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 8 PY 2009 VL 361 IS 15 BP 1500 EP 1501 DI 10.1056/NEJMe0906321 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 503MU UT WOS:000270540000015 PM 19812408 ER PT J AU Chan, SY Zhang, YY Hemann, C Mahoney, CE Zweier, JL Loscalzo, J AF Chan, Stephen Y. Zhang, Ying-Yi Hemann, Craig Mahoney, Christopher E. Zweier, Jay L. Loscalzo, Joseph TI MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1/2 SO CELL METABOLISM LA English DT Article ID GENE-EXPRESSION; CELLS; OXYGEN; HIF-1; INACTIVATION; RESPIRATION; BIOGENESIS; MECHANISMS; FRATAXIN; KINASE AB Repression of mitochondrial respiration represents an evolutionarily ancient cellular adaptation to hypoxia and profoundly influences cell survival and function; however, the underlying molecular mechanisms are incompletely understood. Primarily utilizing pulmonary arterial endothelial Cells as a representative hypoxic cell type, we identify the iron-sulfur cluster assembly proteins (ISCU1/2) as direct targets for repression by the hypoxia-induced microRNA-210 (miR-210). ISCU1/2 facilitate the assembly of iron-sulfur clusters, prosthetic groups that are critical for electron transport and mitochondrial oxidation-reduction reactions. Under in vivo conditions of upregulating miR-210 and repressing ISCU1/2, the integrity of iron-sulfur clusters is disrupted. In turn, by repressing ISCU1/2 during hypoxia, miR-210 decreases the activity of prototypical iron-sulfur proteins controlling mitochondrial metabolism, including Complex I and aconitase. Consequently, miR-210 represses mitochondrial respiration and associated downstream functions. These results identify important mechanistic connections among microRNA, iron-sulfur cluster biology, hypoxia, and mitochondrial function, with broad implications for cellular metabolism and adaptation to cellular stress. C1 [Zhang, Ying-Yi; Mahoney, Christopher E.; Loscalzo, Joseph] Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, Boston, MA 02115 USA. [Chan, Stephen Y.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. [Chan, Stephen Y.; Zhang, Ying-Yi; Mahoney, Christopher E.; Loscalzo, Joseph] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hemann, Craig; Zweier, Jay L.] Ohio State Univ, Dept Med, Columbus, OH 43210 USA. RP Loscalzo, J (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, Dept Med, Boston, MA 02115 USA. EM jloscalzo@partners.org OI Hemann, Craig/0000-0002-7380-4072 FU MGH Cardiology NIH-T32; AHA [0825906D]; National Institutes of Health (NIH) [HL 61795, NO1 HV 28178, PO1 81587, U54 HL 70819] FX This work was supported by MGH Cardiology NIH-T32 grant (S.Y.C.), AHA grant 0825906D (S.Y.C.), and National Institutes of Health (NIH) grants HL 61795, NO1 HV 28178, PO1 81587, and U54 HL 70819 (J.L. and Y.-Y.Z.). We thank the Loscalzo laboratory and R. Liao for fruitful discussions; N. Kelly (bioinformatics); W. Kaelin, J. Moslehi, and Y. Minamishima (VHL WT and VHL-/- murine tissue); H. Ardehali (miR-210 expression vector); T. Rouault (ISCU expression vectors); V. Mootha (technical aid in measuring oxygen consumption); S.K. Chan and J.W. Snow (critical reading of the manuscript); and S. Tribuna (administrative assistance). NR 36 TC 234 Z9 249 U1 1 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD OCT 7 PY 2009 VL 10 IS 4 BP 273 EP 284 DI 10.1016/j.cmet.2009.08.015 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 510KE UT WOS:000271086600007 PM 19808020 ER PT J AU Granot, Z Swisa, A Magenheim, J Stolovich-Rain, M Fujimoto, W Manduchi, E Miki, T Lennerz, JK Stoeckert, CJ Meyuhas, O Seino, S Permutt, MA Piwnica-Worms, H Bardeesy, N Dor, Y AF Granot, Zvi Swisa, Avital Magenheim, Judith Stolovich-Rain, Miri Fujimoto, Wakako Manduchi, Elisabetta Miki, Takashi Lennerz, Jochen K. Stoeckert, Christian J., Jr. Meyuhas, Oded Seino, Susumu Permutt, M. Alan Piwnica-Worms, Helen Bardeesy, Nabeel Dor, Yuval TI LKB1 Regulates Pancreatic beta Cell Size, Polarity, and Function SO CELL METABOLISM LA English DT Article ID ACTIVATED PROTEIN-KINASE; STIMULATED INSULIN-SECRETION; GENE-EXPRESSION; GLUCOSE-HOMEOSTASIS; ENDOCRINE PANCREAS; LUMEN POLARITY; IN-VIVO; ISLET; PATHWAY; ENERGY AB Pancreatic beta cells, organized in the islets of Langerhans, sense glucose and secrete appropriate amounts of insulin. We have studied the roles of LKB1, a conserved kinase implicated in the control of cell polarity and energy metabolism, in adult beta cells. LKB1-deficient beta cells show a dramatic increase in insulin secretion in vivo. Histologically, LKB1-deficient beta cells have striking alterations in the localization of the nucleus and cilia relative to blood vessels, suggesting a shift from hepatocyte-like to columnar polarity. Additionally, LKB1 deficiency causes a 65% increase in beta cell volume. We show that distinct targets of LKB1 mediate these effects. LKB1 controls beta cell size, but not polarity, via the mTOR pathway. Conversely, the precise position of the beta cell nucleus, but not cell size, is controlled by the LKB1 target Par1b. Insulin secretion and content are restricted by LKB1, at least in part, via AMPK. These results expose a molecular mechanism, orchestrated by LKB1, for the coordinated maintenance of beta cell size, form, and function. C1 [Granot, Zvi; Swisa, Avital; Magenheim, Judith; Stolovich-Rain, Miri; Dor, Yuval] Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-91120 Jerusalem, Israel. [Meyuhas, Oded] Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Biochem & Mol Biol, IL-91120 Jerusalem, Israel. [Fujimoto, Wakako; Miki, Takashi; Seino, Susumu] Kobe Univ, Div Cellular & Mol Med, Grad Sch Med, Kobe, Hyogo 6500017, Japan. [Manduchi, Elisabetta; Stoeckert, Christian J., Jr.] Univ Penn, Sch Med, Ctr Bioinformat, Philadelphia, PA 19104 USA. [Manduchi, Elisabetta; Stoeckert, Christian J., Jr.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Lennerz, Jochen K.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. [Permutt, M. Alan] Washington Univ, Sch Med, Div Endocrinol Metab & Lipid Res, St Louis, MO 63110 USA. [Piwnica-Worms, Helen] Washington Univ, Sch Med, Howard Hughes Med Inst, St Louis, MO 63110 USA. [Piwnica-Worms, Helen] Washington Univ, Sch Med, Dept Cell Biol & Physiol & Med, St Louis, MO 63110 USA. [Bardeesy, Nabeel] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc,Dept Med, Boston, MA 02114 USA. RP Dor, Y (reprint author), Hebrew Univ Jerusalem, Hadassah Med Sch, Inst Med Res Israel Canada, Dept Dev Biol & Canc Res, IL-91120 Jerusalem, Israel. EM yuvald@ekmd.huji.ac.il RI Dor, Yuval/C-2405-2011; Piwnica-Worms, Helen/C-5214-2012 FU JDRF; NIH (BCBC); ISF; ICRF (Barbara Goodman PC-RCDA); European Union; NIH [R37 DK16746]; Core Research for Evolutional Science and Technology (CREST) FX We are grateful to Rachel Hertz and Jacob Bar-Tana for providing advice and generously sharing unpublished reagents. We thank Cris Welling for technical assistance; Morris Birnbaum for providing RIP-AKT mice; Bangyan Stiles for providing slides of PTEN mutant mice; Ittai Ben-Porath, Hadas Masuri, and Rotem Karni for assistance with viral infections; and Chris Wright for the gift of anti pdx1 antibodies. Y. Dor was supported by grants from JDRF, NIH (BCBC), ISF, ICRF (Barbara Goodman PC-RCDA), the Sixth Framework Programme of the European Union, and the JDRF Center for beta Cell Therapy in Diabetes. This work was supported in part by an NIH grant (R37 DK16746, to M.A. Permutt) and the Core Research for Evolutional Science and Technology (CREST) to S. Seino. The Washington University DRTC (NIH P60 DK20579) is acknowledged for assistance from the Immunoassay Core. C. Stoeckert and E. Manduchi were supported by JDRF and NIH (BCBC). NR 57 TC 78 Z9 81 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD OCT 7 PY 2009 VL 10 IS 4 BP 296 EP 308 DI 10.1016/j.cmet.2009.08.010 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 510KE UT WOS:000271086600009 PM 19808022 ER PT J AU Lau, NC Ohsumi, T Borowsky, M Kingston, RE Blower, MD AF Lau, Nelson C. Ohsumi, Toshiro Borowsky, Mark Kingston, Robert E. Blower, Michael D. TI Systematic and single cell analysis of Xenopus Piwi-interacting RNAs and Xiwi SO EMBO JOURNAL LA English DT Article DE piRNA; Piwi; Xenopus ID SMALL INTERFERING RNAS; DROSOPHILA-MELANOGASTER; EGG EXTRACTS; ENDOGENOUS SIRNAS; MITOTIC SPINDLE; DNA METHYLATION; PIRNA COMPLEX; MOUSE OOCYTES; C-ELEGANS; GERMLINE AB Piwi proteins and Piwi-interacting RNAs (piRNAs) are essential for germ cell development, but analysis of the molecular mechanisms of these ribonucleoproteins remains challenging in most animal germ cells. To address this challenge, we systematically characterized Xiwi, a Xenopus Piwi homologue, and piRNAs from Xenopus eggs and oocytes. We used the large size of Xenopus eggs to analyze small RNAs at the single cell level, and find abundant piRNAs and large piRNA clusters in the Xenopus tropicalis genome, some of which resemble the Drosophila piRNA-generating flamenco locus. Although most piRNA clusters are expressed simultaneously in an egg, individual frogs show distinct profiles of cluster expression. Xiwi is associated with microtubules and the meiotic spindle, and is localized to the germ plasm-a cytoplasmic determinant of germ cell formation. Xiwi associates with translational regulators in an RNA-dependent manner, but Xenopus tudor interacts with Xiwi independently of RNA. Our study adds insight to piRNA transcription regulation by showing that individual animals can have differential piRNA expression profiles. We suggest that in addition to regulating transposable elements, Xiwi may function in specifying RNA localization in vertebrate oocytes. The EMBO Journal (2009) 28, 2945-2958. doi: 10.1038/emboj.2009.237; Published online 27 August 2009 C1 [Lau, Nelson C.; Ohsumi, Toshiro; Borowsky, Mark; Kingston, Robert E.; Blower, Michael D.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02163 USA. [Lau, Nelson C.; Ohsumi, Toshiro; Borowsky, Mark; Kingston, Robert E.; Blower, Michael D.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Blower, MD (reprint author), Harvard Univ, Sch Med, Dept Genet, 185 Cambridge St,CPZN 7250, Boston, MA 02163 USA. EM blower@molbio.mgh.harvard.edu FU Whitney foundation fellowship; NIH FX Author Contributions: NCL and MDB designed and carried out the experiments, TO and MB provided informatics and sequencing analysis, and NCL, MDB, and REK wrote the paper. The small RNA sequencing data from this paper are deposited in the Gene Expression Omnibus under the series accession number GSE15556. NR 57 TC 52 Z9 53 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 7 PY 2009 VL 28 IS 19 BP 2945 EP 2958 DI 10.1038/emboj.2009.237 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 503DY UT WOS:000270514000009 PM 19713941 ER PT J AU Meyer-Luehmann, M Mielke, M Spires-Jones, TL Stoothoff, W Jones, P Bacskai, BJ Hyman, BT AF Meyer-Luehmann, Melanie Mielke, Matthew Spires-Jones, Tara L. Stoothoff, Will Jones, Phill Bacskai, Brian J. Hyman, Bradley T. TI A Reporter of Local Dendritic Translocation Shows Plaque-Related Loss of Neural System Function in APP-Transgenic Mice SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AMYLOID-BETA PLAQUES; ALZHEIMERS-DISEASE; PROTEIN-SYNTHESIS; MOUSE MODEL; IN-VIVO; HIPPOCAMPAL-NEURONS; DISRUPTION; ABNORMALITIES; MEMORY; EXPRESSION AB Although neuronal communication is thought to be summated within local dendritic segments, no technique is currently available to monitor activity in vivo at this level of resolution. To overcome this challenge, we developed an optical reporter of neuronal activity using the coding sequence of Venus, flanked by short stretches of the 5'- and 3'-untranslated regions from calcium/calmodulin-dependent kinase II alpha (CAMKII alpha). This reporter takes advantage of the fact that CAMKII alpha mRNA is transported to the dendrite and locally translated in an activity-dependent manner. Using adeno-associated virus, we used this reporter to study neuronal activity in adult mice. Exposure of the mice to an enriched environment led to enhancement of Venus expression in dendritic segments of somatosensory cortex, demonstrating in vivo that dendritic mRNA translocation and local translation occur in response to physiologically relevant stimuli. We then used this system to examine the impact of Alzheimer-related local amyloid-beta deposits on neural system function to test the hypothesis that plaques are toxic. In APPswe/PS1dE9 (APP/PS1) mice, neurons close to plaques, and dendritic segments close to plaques, both showed diminished fluorescent intensity and therefore neuronal activity. In contrast to wild-type mice, fluorescent intensity in neurons near plaques in transgenic mice did not increase after environmental enrichment. These data indicate that neuronal activity in dendritic segments and neurons in the vicinity of a plaque is decreased compared with wild-type mice, supporting the idea that plaques are a focal lesion leading to impaired neural system function. C1 [Meyer-Luehmann, Melanie; Mielke, Matthew; Spires-Jones, Tara L.; Stoothoff, Will; Jones, Phill; Bacskai, Brian J.; Hyman, Bradley T.] Harvard Univ, Massachusetts Gen Hosp, Alzheimers Dis Res Lab, Dept Neurol,Med Sch,MassGen Inst Neurodegenerat D, Charlestown, MA 02129 USA. [Meyer-Luehmann, Melanie] Univ Munich, Deutsch Zentrum Neurodegenerat Erkrankungen, D-80336 Munich, Germany. [Meyer-Luehmann, Melanie] Univ Munich, Adolf Butenandt Inst Biochem, D-80336 Munich, Germany. RP Hyman, BT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Alzheimers Dis Res Lab, Dept Neurol,Med Sch,MassGen Inst Neurodegenerat D, 114 16th St,Room 2009, Charlestown, MA 02129 USA. EM bhyman@partners.org OI Meyer-Luehmann, Melanie/0000-0003-3661-2220 FU National Institutes of Health [AG08487, EB000768] FX This work was supported by National Institutes of Health Grants AG08487 (to B. T. H.) and EB000768 (to B. J. B.). Wethank Kathryn Bercury, Hisatomo Kowa, Mirjam Koker, and Anne Thomas for technical help and Erin Schuman for the gift of the CAMKII alpha GFP construct. NR 23 TC 30 Z9 30 U1 0 U2 7 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 OCT 7 PY 2009 VL 29 IS 40 BP 12636 EP 12640 DI 10.1523/JNEUROSCI.1948-09.2009 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 503UX UT WOS:000270567400028 PM 19812338 ER PT J AU Hedden, T Van Dijk, KRA Becker, JA Mehta, A Sperling, RA Johnson, KA Buckner, RL AF Hedden, Trey Van Dijk, Koene R. A. Becker, J. Alex Mehta, Angel Sperling, Reisa A. Johnson, Keith A. Buckner, Randy L. TI Disruption of Functional Connectivity in Clinically Normal Older Adults Harboring Amyloid Burden SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MILD COGNITIVE IMPAIRMENT; PITTSBURGH-COMPOUND-B; DEFAULT-MODE NETWORK; PRECLINICAL ALZHEIMERS-DISEASE; RESTING-STATE NETWORKS; HUMAN BRAIN; NONDEMENTED INDIVIDUALS; SENSORY STIMULATION; CINGULATE CORTEX; PET AB Amyloid deposition is present in 20-50% of nondemented older adults yet the functional consequences remain unclear. The current study found that amyloid accumulation is correlated with functional disruption of the default network as measured by intrinsic activity correlations. Clinically normal participants (n = 38, aged 60-88 years) were characterized using (11)C-labeled Pittsburgh Compound B positron emission tomography imaging to estimate fibrillar amyloid burden and, separately, underwent functional magnetic resonance imaging (fMRI). The integrity of the default network was estimated by correlating rest-state fMRI time courses extracted from a priori regions including the posterior cingulate, lateral parietal, and medial prefrontal cortices. Clinically normal participants with high amyloid burden displayed significantly reduced functional correlations within the default network relative to participants with low amyloid burden. These reductions were also observed when amyloid burden was treated as a continuous, rather than a dichotomous, measure and when controlling for age and structural atrophy. Whole-brain analyses initiated by seeding the posterior cingulate cortex, a region of high amyloid burden in Alzheimer's disease, revealed significant disruption in the default network including functional disconnection of the hippocampal formation. C1 [Hedden, Trey; Van Dijk, Koene R. A.; Mehta, Angel; Sperling, Reisa A.; Buckner, Randy L.] Massachusetts Gen Hosp East, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. [Hedden, Trey; Becker, J. Alex; Johnson, Keith A.; Buckner, Randy L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. [Buckner, Randy L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. [Hedden, Trey; Van Dijk, Koene R. A.; Mehta, Angel] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Hedden, Trey; Van Dijk, Koene R. A.; Mehta, Angel] Harvard Univ, Ctr Brain Sci, Cambridge, MA 02138 USA. [Buckner, Randy L.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Sperling, Reisa A.; Johnson, Keith A.] Harvard Univ, Sch Med, Dept Neurol, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Hedden, T (reprint author), Massachusetts Gen Hosp East, Athinoula A Martinos Ctr Biomed Imaging, 149 13th St,Suite 2301, Charlestown, MA 02129 USA. EM hedden@nmr.mgh.harvard.edu RI Van Dijk, Koene/G-3317-2012 OI Van Dijk, Koene/0000-0001-6137-4282 FU National Institutes on Aging [AG-021910, AG-027435-S1]; Alzheimer Disease Research Center [P50AG005134]; Howard Hughes Medical Institute; Alzheimer's Association; Netherlands Organization for Scientific Research FX This research was supported by National Institutes on Aging Grants AG-021910 and AG-027435-S1, Alzheimer Disease Research Center, Grant P50AG005134, the Howard Hughes Medical Institute, and the Alzheimer's Association. K. R. A. V. D. was supported by the Netherlands Organization for Scientific Research. We thank Renee Poulin, Jeremy Caramasin, and Meghan Frey for assistance during data collection, and Tanveer Talukdar and Itamar Kahn for technical advice. The Athinoula A. Martinos Center MRI Core provided assistance with MRI imaging, and the Massachusetts General Hospital Molecular Imaging PET Core provided assistance with amyloid imaging. Bill Klunk and Chet Mathis provided assistance with PiB. Dorene Rentz and the Massachusetts Alzheimer's Disease Research Center provided assistance with clinical and neuropsychological characterization of the participants. NR 78 TC 276 Z9 283 U1 2 U2 23 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 OCT 7 PY 2009 VL 29 IS 40 BP 12686 EP 12694 DI 10.1523/JNEUROSCI.3189-09.2009 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 503UX UT WOS:000270567400033 PM 19812343 ER PT J AU Yamada, H Penney, KL Takahashi, H Katoh, T Yamano, Y Yamakado, M Kimura, T Kuruma, H Kamata, Y Egawa, S Freedman, ML AF Yamada, Hiroki Penney, Kathryn L. Takahashi, Hiroyuki Katoh, Takahiko Yamano, Yuko Yamakado, Minoru Kimura, Takahiro Kuruma, Hidetoshi Kamata, Yuko Egawa, Shin Freedman, Matthew L. TI Replication of Prostate Cancer Risk Loci in a Japanese Case-Control Association Study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENOME-WIDE ASSOCIATION; 8Q24; VARIANTS; SUSCEPTIBILITY; POPULATION AB Two prostate cancer genome-wide scans in populations of European ancestry identified several genetic variants that are strongly associated with prostate cancer risk. The effect of these risk variants and their cumulative effect in other populations are unknown. We evaluated the association of 23 risk single-nucleotide polymorphisms (SNPs) with prostate cancer risk and clinical covariates (Gleason score, tumor aggressiveness, and age at diagnosis) in men of Japanese ancestry (311 case subjects and 1035 control subjects) using unconditional logistic regression. We also used logistic regression to test the association between increasing numbers of independently associated risk alleles and the risk of prostate cancer, prostate cancer aggressiveness, and age at diagnosis. All statistical tests were two-sided. Seven of the 23 SNPs (five independent loci) were associated with prostate cancer risk (P values ranged from .0084 to 2.3 x 10(-8) and effect sizes [estimated as odds ratios, ORs] ranged from 1.35 to 1.82). None of the seven SNPs was associated with Gleason score or aggressive disease. rs6983561 and rs4430796 were associated with age at diagnosis (Ps = .0188 and .0339, respectively). Men with six or more risk alleles (27% of case patients and 11% of control subjects) had a higher risk of prostate cancer than men with two or fewer risk alleles (7% of case patients and 20% of control subjects) (OR = 6.22, P = 1.5 x 10(-12)). These results highlight the critical importance of considering ancestry in understanding how risk alleles influence disease and suggest that risk estimates and variants differ across populations. It is important to perform studies in multiple ancestral populations so that the composite genetic architecture of prostate cancer can be rigorously addressed. C1 [Freedman, Matthew L.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Yamada, Hiroki; Kimura, Takahiro; Kuruma, Hidetoshi; Kamata, Yuko; Egawa, Shin] Jikei Univ, Sch Med, Dept Urol, Tokyo, Japan. [Penney, Kathryn L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Takahashi, Hiroyuki] Jikei Univ, Dept Pathol, Sch Med, Tokyo 105, Japan. [Katoh, Takahiko] Kumamoto Univ, Grad Sch Med Sci, Dept Publ Hlth, Kumamoto, Japan. [Yamano, Yuko] Showa Univ, Sch Med, Dept Hyg & Prevent Med, Tokyo 142, Japan. [Yamakado, Minoru] Mitsui Mem Hosp, Ctr Multiphas Hlth Testing & Serv, Dept Hlth Care, Tokyo 101, Japan. RP Freedman, ML (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM s-egpro@jikei.ac.jp; freedman@broad.mit.edu NR 14 TC 47 Z9 52 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD OCT 7 PY 2009 VL 101 IS 19 BP 1330 EP 1336 DI 10.1093/jnci/djp287 PG 7 WC Oncology SC Oncology GA 505QR UT WOS:000270709900011 PM 19726753 ER PT J AU Riboldi, M Sharp, GC Baroni, G Chen, GTY AF Riboldi, M. Sharp, G. C. Baroni, G. Chen, G. T. Y. TI Four-dimensional targeting error analysis in image-guided radiotherapy SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID POINT-BASED REGISTRATION; INDUCED TUMOR MOTION; RADIATION-THERAPY; LUNG-CANCER; COMPUTED-TOMOGRAPHY; IMRT OPTIMIZATION; ORGAN MOTION; TRACKING; SYSTEM; ACCURACY AB Image-guided therapy (IGT) involves acquisition and processing of biomedical images to actively guide medical interventions. The proliferation of IGT technologies has been particularly significant in image-guided radiotherapy (IGRT), as a way to increase the tumor targeting accuracy. When IGRT is applied to moving tumors, image guidance becomes challenging, as motion leads to increased uncertainty. Different strategies may be applied to mitigate the effects of motion: each technique is related to a different technological effort and complexity in treatment planning and delivery. The objective comparison of different motion mitigation strategies can be achieved by quantifying the residual uncertainties in tumor targeting, to be detected by means of IGRT technologies. Such quantification requires an extension of targeting error theory to a 4D space, where the 3D tumor trajectory as a function of time measured (4D Targeting Error, 4DTE). Accurate 4DTE analysis can be represented by a motion probability density function, describing the statistical fluctuations of tumor trajectory. We illustrate the application of 4DTE analysis through examples, including weekly variations in tumor trajectory as detected by 4DCT, respiratory gating via external surrogates and real-time tumor tracking. C1 [Riboldi, M.; Baroni, G.] Politecn Milan Univ, Dept Bioengn, TBMLab, I-20133 Milan, Italy. [Sharp, G. C.; Chen, G. T. Y.] Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. [Sharp, G. C.; Chen, G. T. Y.] Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Riboldi, M (reprint author), Politecn Milan Univ, Dept Bioengn, TBMLab, I-20133 Milan, Italy. EM marco.riboldi@polimi.it RI Baroni, Guido/D-3012-2011; Riboldi, Marco/I-2980-2014 OI Riboldi, Marco/0000-0002-2431-4966 FU Progetto Rocca Foundation FX The authors acknowledge Lei Dong (MD Anderson Cancer Center) and Sonja Dieterich (Stanford School of Medicine) for providing data for the analysis. The work was partly supported by a post-doc grant provided by the Progetto Rocca Foundation. NR 37 TC 18 Z9 19 U1 1 U2 5 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD OCT 7 PY 2009 VL 54 IS 19 BP 5995 EP 6008 DI 10.1088/0031-9155/54/19/022 PG 14 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 497IE UT WOS:000270051600023 PM 19773606 ER PT J AU Crowley, WF Gusella, JF AF Crowley, William F., Jr. Gusella, James F. TI Changing Models of Biomedical Research SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID POLYMORPHIC DNA MARKER; AMYOTROPHIC-LATERAL-SCLEROSIS; CLINICAL-RESEARCH ENTERPRISE; CYSTIC-FIBROSIS LOCUS; HUNTINGTONS-DISEASE; GENE; LINKAGE; NEUROFIBROMATOSIS; REGION; MAPS AB Thanks to the revolutions in information technology, human "-omics" research, and intricate medical device development, academic health centers (AHCs) now have an unparalleled potential to become translational engines that both generate basic science advances and then translate them into human studies and, ultimately, into improved health care. However, AHC infrastructures have traditionally been optimized to foster basic research. Now modifications must be made to meet these expanded roles of AHCs, from providing fundamental biomedical insights to first-in-human interventions and, if warranted, to larger randomized clinical trials. Eventually, AHCs must integrate these improved treatments into patient care. Challenges to this process have been defined by the Institute of Medicine. Building the appropriate infrastructures for human investigation and stabilizing the careers of young physicians essential to these translational events have become critical needs that will require systemic investments if AHCs are to respond to these biological revolutions and fulfill their promise. C1 [Crowley, William F., Jr.] Harvard Univ, Massachusetts Gen Hosp, Dept Genet, Harvard Reprod Endocrine Sci Ctr,Dept Med,Sch Med, Boston, MA 02114 USA. [Gusella, James F.] Harvard Univ, Massachusetts Gen Hosp, Dept Genet, Ctr Human Genet Res,Sch Med, Boston, MA 02114 USA. RP Crowley, WF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Genet, Harvard Reprod Endocrine Sci Ctr,Dept Med,Sch Med, Boston, MA 02114 USA. EM wcrowley@partners.org NR 30 TC 4 Z9 4 U1 1 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 7 PY 2009 VL 1 IS 1 AR 1cm1 DI 10.1126/scitranslmed.3000124 PG 6 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 589KY UT WOS:000277147500001 PM 20368150 ER PT J AU Davies, JK Nadler, LM Guinan, EC AF Davies, Jeffrey K. Nadler, Lee M. Guinan, Eva C. TI Expansion of Allospecific Regulatory T Cells After Anergized, Mismatched Bone Marrow Transplantation SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID VERSUS-HOST-DISEASE; COSTIMULATORY BLOCKADE; ACUTE-LEUKEMIA; DONOR-PROGRAM; HLA; ALLOANTIGEN; INDUCTION; LYMPHOCYTES; ACTIVATION; DEPLETION AB Transplantation of hematopoietic stem cells from healthy donors can cure patients with many diseases. Donor T cells can protect against recurrence of infection and disease, but some of these (alloreactive) T cells recognize patient tissues as foreign, causing graft-versus-host disease. Removing T cells from donor grafts before transplantation reduces graft-versus-host disease but increases infection and disease recurrence. Inactivation of alloreactive T cells by inducing tolerance to patient cells (anergization) before transplantation preserves beneficial donor T cell effects while reducing graft-versus-host disease. We show that this approach also results in expansion of regulatory T cells that specifically suppress alloreactive donor T cell responses in the recipient. In addition to reducing graft-versus-host disease, antigen-specific regulatory T cells generated with this strategy could suppress unwanted T cell responses that cause rejection of solid organ transplants and tissue damage in autoimmune disorders. C1 [Davies, Jeffrey K.; Nadler, Lee M.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Davies, Jeffrey K.; Nadler, Lee M.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Guinan, Eva C.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Guinan, Eva C.] Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. RP Davies, JK (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM jeff_davies@dfci.harvard.edu FU NCI NIH HHS [R21 CA137645, R21 CA137645-01A1, R21 CA137645-02, U19 CA100265, U19 CA100265-03, U19 CA100265-04, U19 CA100265-05] NR 45 TC 9 Z9 9 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 7 PY 2009 VL 1 IS 1 AR 1ra3 DI 10.1126/scitranslmed.3000153 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 589KY UT WOS:000277147500002 PM 20368155 ER PT J AU Gesty-Palmer, D Flannery, P Yuan, L Corsino, L Spurney, R Lefkowitz, RJ Luttrell, LM AF Gesty-Palmer, Diane Flannery, Pat Yuan, Ling Corsino, Leonor Spurney, Robert Lefkowitz, Robert J. Luttrell, Louis M. TI A beta-Arrestin-Biased Agonist of the Parathyroid Hormone Receptor (PTH1R) Promotes Bone Formation Independent of G Protein Activation SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID OSTEOBLASTIC CELLS; KIDNEY-CELLS; KINASE; MICE; BETA-ARRESTIN2; ENDOCYTOSIS; SELECTIVITY; COMPLEXES; PATHWAYS; SIGNALS AB About 40% of the therapeutic agents in use today exert their effects through seven-transmembrane receptors (7TMRs). When activated by ligands, these receptors trigger two pathways that independently transduce signals to the cell: one through heterotrimeric GTP-binding proteins (G proteins) and one through beta-arrestins; so-called biased agonists can selectively activate these distinct pathways. Here, we investigate selective activation of these pathways through the use of a biased agonist for the type 1 parathyroid hormone (PTH)-PTH-related protein receptor (PTH1R), (D-Trp(12), Tyr(34))-PTH(7-34) (PTH-beta arr), which activates beta-arrestin but not classic G protein signaling. In mice, PTH-beta arr induces anabolic bone formation, as does the nonselective agonist PTH (1-34), which activates both mechanisms. In beta-arrestin2-null mice, the increase in bone mineral density evoked by PTH(1-34) is attenuated and that stimulated by PTH-beta arr is ablated. The beta-arrestin2-dependent pathway contributes primarily to trabecular bone formation and does not stimulate bone resorption. These results show that a biased agonist selective for the beta-arrestin pathway can elicit a response in vivo distinct from that elicited by nonselective agonists. Ligands with these properties may form the basis for improved 7TMR-directed pharmacologic agents with enhanced therapeutic specificity. C1 [Gesty-Palmer, Diane; Flannery, Pat; Yuan, Ling; Corsino, Leonor; Spurney, Robert; Lefkowitz, Robert J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Gesty-Palmer, Diane] Durham Vet Affairs Med Ctr, Durham, NC 27705 USA. [Lefkowitz, Robert J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. [Lefkowitz, Robert J.] Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA. [Luttrell, Louis M.] Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. [Luttrell, Louis M.] Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. [Luttrell, Louis M.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Lefkowitz, RJ (reprint author), Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. EM lefko001@receptor-biol.duke.edu FU Howard Hughes Medical Institute; NHLBI NIH HHS [HL70631, R01 HL070631, HL16037, R01 HL016037, R01 HL016037-37]; NICHD NIH HHS [HD043446, K12 HD043446]; NIDDK NIH HHS [DK55524, DK64353, R01 DK055524, T32 DK007012, R01 DK064353, R56 DK055524] NR 42 TC 70 Z9 70 U1 0 U2 5 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD OCT 7 PY 2009 VL 1 IS 1 AR 1ra1 DI 10.1126/scitranslmed.3000071 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 589KY UT WOS:000277147500004 PM 20368153 ER PT J AU Ward, CP McCoy, JG McKenna, JT Connolly, NP McCarley, RW Strecker, RE AF Ward, Christopher P. McCoy, John G. McKenna, James T. Connolly, Nina P. McCarley, Robert W. Strecker, Robert E. TI Spatial learning and memory deficits following exposure to 24 h of sleep fragmentation or intermittent hypoxia in a rat model of obstructive sleep apnea SO BRAIN RESEARCH LA English DT Article DE Sleep apnea; Sleep fragmentation; Intermittent hypoxia; Water maze; Spatial memory ID MORRIS WATER MAZE; NITRIC-OXIDE SYNTHASE; WORKING-MEMORY; PARADOXICAL SLEEP; OXIDATIVE STRESS; SYNAPTIC PLASTICITY; HIPPOCAMPAL-NEURONS; DEPENDENT CHANGES; CA3 REGIONS; REM-SLEEP AB Obstructive sleep apnea is primarily characterized by hypoxemia due to frequent apneic episodes and fragmentation of sleep due to the brief arousals that terminate the apneic episodes. Though neurobehavioral deficits frequently accompany sleep apnea, the relative roles of hypoxia versus sleep fragmentation are difficult to separate in apneic patients. Here, we assessed cognitive function as measured by water maze in the Fischer/Brown Norway (FBN) rat, comparing 24 h of sleep interruption (SI) to 24 h of intermittent hypoxia (IH), in order to dissociate their relative contributions to cognitive impairment. For SI, automated treadmills were used to induce brief ambulation in rats every 2 min, either prior to, or after, initial water maze acquisition training. IH was simulated by cycling environmental oxygen levels between 6% and 19% every 2 min, again either prior to, or after, acquisition. Twenty-four hours of IH exposure had no significant effect on either acquisition or retention, irrespective of whether IH occur-red prior to, or after, acquisition. To replicate previous work, another group of rats, exposed to 3 days of IH (10 h/day) prior to acquisition, had impaired performance during acquisition. A comparison of the 24 h IH and 3 day IH findings suggests that a minimum amount of IH exposure is necessary to produce detectable spatial memory impairments. Although SI before acquisition had no effect on acquisition or later retention of the hidden platform location, SI after acquisition robustly impaired retention, indicating that spatial memory consolidation is more susceptible to the effects of sleep disruption than is the acquisition (learning) of spatial information. (C) 2009 Elsevier B.V. All rights reserved. C1 [Ward, Christopher P.] Univ Houston Clear Lake City, Dept Psychol, Houston, TX 77058 USA. [Ward, Christopher P.; McCoy, John G.; McKenna, James T.; Connolly, Nina P.; McCarley, Robert W.; Strecker, Robert E.] VA Boston Healthcare Syst, Brockton, MA USA. [Ward, Christopher P.; McCoy, John G.; McKenna, James T.; Connolly, Nina P.; McCarley, Robert W.; Strecker, Robert E.] Harvard Univ, Sch Med, Neurosci Lab, Brockton, MA 02301 USA. [McCoy, John G.] Stonehill Coll, Dept Psychol, Easton, MA 02357 USA. [Connolly, Nina P.] Wheaton Coll, Dept Psychol, Norton, MA 02766 USA. RP Ward, CP (reprint author), Univ Houston Clear Lake City, Dept Psychol, 2700 Bay Area Blvd, Houston, TX 77058 USA. EM wardchris@uhcl.edu; jmccoy1@stonehill.edu; robert_strecker@hms.harvard.edu RI McCarley, Robert/N-5562-2014; OI McCarley, Robert/0000-0001-5705-7495; Ward, Christopher/0000-0001-9932-3894 FU Department of Veterans Affairs [NIH HL060292, NIH T32 HL07901, NIH F32 MH070156] FX This research was supported by the Department of Veterans Affairs (RES and RWM), NIH HL060292 (RWM and RES), NIH T32 HL07901 (JTM), and NIH F32 MH070156 (JTM). NR 57 TC 32 Z9 34 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD OCT 6 PY 2009 VL 1294 BP 128 EP 137 DI 10.1016/j.brainres.2009.07.064 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 504ZZ UT WOS:000270658500013 PM 19643093 ER PT J AU Settleman, J AF Settleman, Jeff TI A Therapeutic Opportunity in Melanoma: ErbB4 Makes a Mark on Skin SO CANCER CELL LA English DT Editorial Material ID SOMATIC MUTATIONS; CANCER AB Malignant melanomas are aggressive tumors that are largely refractory to conventional drug therapies. A recent study reported in Nature Genetics identified mutationally activated ErbB4 alleles in 20% of cases. These tumor cells exhibit ErbB4 dependency, suggesting that ErbB4 kinase inhibition may constitute an effective therapeutic strategy in this setting. C1 [Settleman, Jeff] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. [Settleman, Jeff] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Settleman, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. EM settleman@helix.mgh.harvard.edu NR 10 TC 5 Z9 5 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT 6 PY 2009 VL 16 IS 4 BP 278 EP 279 DI 10.1016/j.ccr.2009.09.013 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 506JF UT WOS:000270770400006 PM 19800573 ER PT J AU Hahn, CK Berchuck, JE Ross, KN Kakoza, RM Clauser, K Schinzel, AC Ross, L Galinsky, I Davis, TN Silver, SJ Root, DE Stone, RM DeAngelo, DJ Carroll, M Hahn, WC Carr, SA Golub, TR Kung, AL Stegmaier, K AF Hahn, Cynthia K. Berchuck, Jacob E. Ross, Kenneth N. Kakoza, Rose M. Clauser, Karl Schinzel, Anna C. Ross, Linda Galinsky, Ilene Davis, Tina N. Silver, Serena J. Root, David E. Stone, Richard M. DeAngelo, Daniel J. Carroll, Martin Hahn, William C. Carr, Steven A. Golub, Todd R. Kung, Andrew L. Stegmaier, Kimberly TI Proteomic and Genetic Approaches Identify Syk as an AML Target SO CANCER CELL LA English DT Article ID ACUTE MYELOGENOUS LEUKEMIA; ACUTE MYELOID-LEUKEMIA; TYROSINE KINASE SYK; RENAL-CELL CARCINOMA; MYELODYSPLASTIC SYNDROME; THERAPEUTIC TARGET; CYTOTOXIC ACTIVITY; SMALL MOLECULES; LUNG-CANCER; EXPRESSION AB Cell-based screening can facilitate the rapid identification of compounds inducing complex cellular phenotypes. Advancing a compound toward the clinic, however, generally requires the identification of precise mechanisms of action. We previously found that epidermal growth factor receptor (EGFR) inhibitors induce acute myeloid leukemia (AML) differentiation via a non-EGFR mechanism. In this report, we integrated proteomic and RNAi-based strategies to identify their off-target, anti-AML mechanism. These orthogonal approaches identified Syk as a target in AML. Genetic and pharmacological inactivation of Syk with a drug in clinical trial for other indications promoted differentiation of AML cells and attenuated leukemia growth in vivo. These results demonstrate the power of integrating diverse chemical, proteomic, and genomic screening approaches to identify therapeutic strategies for cancer. C1 [Hahn, Cynthia K.; Berchuck, Jacob E.; Kakoza, Rose M.; Ross, Linda; Davis, Tina N.; Golub, Todd R.; Kung, Andrew L.; Stegmaier, Kimberly] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Hahn, Cynthia K.; Berchuck, Jacob E.; Kakoza, Rose M.; Ross, Linda; Davis, Tina N.; Golub, Todd R.; Kung, Andrew L.; Stegmaier, Kimberly] Harvard Univ, Sch Med, Childrens Hosp Boston, Boston, MA 02115 USA. [Ross, Kenneth N.; Clauser, Karl; Schinzel, Anna C.; Silver, Serena J.; Root, David E.; Hahn, William C.; Carr, Steven A.; Golub, Todd R.; Stegmaier, Kimberly] Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. [Ross, Kenneth N.; Clauser, Karl; Schinzel, Anna C.; Silver, Serena J.; Root, David E.; Hahn, William C.; Carr, Steven A.; Golub, Todd R.; Stegmaier, Kimberly] MIT, Cambridge, MA 02142 USA. [Schinzel, Anna C.; Galinsky, Ilene; Stone, Richard M.; DeAngelo, Daniel J.; Hahn, William C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Carroll, Martin] Univ Penn, Div Hematol Oncol, Philadelphia, PA 19104 USA. [Golub, Todd R.] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Stegmaier, K (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. EM kimberly_stegmaier@dfci.harvard.edu OI Kung, Andrew/0000-0002-9091-488X FU National Cancer Institute [5K08 CA098444]; Howard Hughes Medical Institute; Sidney Kimmel Cancer Foundation; Claudia Adams Barr Foundation; Gloria Spivak Support Fund FX We thank Rigel Pharmaceuticals, particularly Elliott Grossbard and Polly Pine, for supplying R406 and R788 chow. We also thank Jeri Grenier for RNAi screening guidance; John Daley, Jill Angelosanto, and Kathleen Brosnahan for FACS assistance; Jinyan Du and Shao-En Ong for insight regarding the proteomics experiment; Susan Buchanan for primary sample collection; Jeff Kutock for pathology slide review; Anu Narla and Benjamin Ebert for facilitating testing of normal myeloid progenitor cells; Giovanni Roti, Dorhyun Johng, and Robin Perry for technical assistance; and Curtis Glavin for graphical design. We thank all patients and clinicians who contributed invaluable primary AML samples. This work was supported by the National Cancer Institute (NCI; 5K08 CA098444), the Howard Hughes Medical Institute, the Sidney Kimmel Cancer Foundation, the Claudia Adams Barr Foundation, and the Gloria Spivak Support Fund (K.S.). NR 41 TC 89 Z9 91 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT 6 PY 2009 VL 16 IS 4 BP 281 EP 294 DI 10.1016/j.ccr.2009.08.018 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 506JF UT WOS:000270770400007 PM 19800574 ER PT J AU Chauhan, D Singh, AV Brahmandam, M Carrasco, R Bandi, M Hideshima, T Bianchi, G Podar, K Tai, YT Mitsiades, C Raje, N Jaye, DL Kumar, SK Richardson, P Munshi, N Anderson, KC AF Chauhan, Dharminder Singh, Ajita V. Brahmandam, Mohan Carrasco, Ruben Bandi, Madhavi Hideshima, Teru Bianchi, Giada Podar, Klaus Tai, Yu-Tzu Mitsiades, Constantine Raje, Noopur Jaye, David L. Kumar, Shaji K. Richardson, Paul Munshi, Nikhil Anderson, Kenneth C. TI Functional Interaction of Plasmacytoid Dendritic Cells with Multiple Myeloma Cells: A Therapeutic Target SO CANCER CELL LA English DT Article ID INTERFERON-PRODUCING CELLS; REGULATORY T-CELLS; BONE-MARROW; NUCLEIC-ACIDS; HUMAN BLOOD; EXPRESSION; SURVIVAL; INDUCE; DIFFERENTIATION; INTERLEUKIN-6 AB Multiple myeloma (MM) remains incurable despite novel therapies, suggesting the need for further identification of factors mediating tumorigenesis and drug resistance. Using both in vitro and in vivo MM xenograft models, we show that plasmacytoid dendritic cells (pDCs) in the bone marrow (BM) microenvironment both mediate immune deficiency characteristic of MM and promote MM cell growth, survival, and drug resistance. Microarray, cell signaling, cytokine profile, and immunohistochemical analysis delineate the mechanisms mediating these sequelae. Although pDCs are resistant to novel therapies, targeting Toll-like receptors with CpG oligodeoxynucleotides both restores pDC immune function and abrogates pDC-induced MM cell growth. Our study therefore validates targeting pDC-MM interactions as a therapeutic strategy to overcome drug resistance in MM. C1 [Chauhan, Dharminder; Singh, Ajita V.; Brahmandam, Mohan; Carrasco, Ruben; Bandi, Madhavi; Hideshima, Teru; Bianchi, Giada; Podar, Klaus; Tai, Yu-Tzu; Mitsiades, Constantine; Raje, Noopur; Richardson, Paul; Anderson, Kenneth C.] Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. [Chauhan, Dharminder; Singh, Ajita V.; Brahmandam, Mohan; Carrasco, Ruben; Bandi, Madhavi; Hideshima, Teru; Bianchi, Giada; Podar, Klaus; Tai, Yu-Tzu; Mitsiades, Constantine; Raje, Noopur; Richardson, Paul; Anderson, Kenneth C.] Harvard Univ, Sch Med, Dana Farber Canc Inst, Jerome Lipper Ctr Myeloma Res,Dept Med Oncol, Boston, MA 02115 USA. [Jaye, David L.] Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Kumar, Shaji K.] Mayo Clin, Dept Hematol, Rochester, MN 55905 USA. [Munshi, Nikhil] Harvard Univ, Sch Med, Vet Adm Boston Healthcare Syst, Boston, MA 02115 USA. RP Chauhan, D (reprint author), Harvard Univ, Sch Med, LeBow Inst Myeloma Therapeut, Boston, MA 02115 USA. EM dharminder_chauhan@dfci.harvard.edu; kenneth_anderson@dfci.harvard.edu RI Kumar, Shaji/A-9853-2008 OI Kumar, Shaji/0000-0001-5392-9284 FU NIH [SPORE-P50100707, PO1-CA078378, RO1CA050947]; Myeloma Research Foundation FX This investigation was supported by NIH grants SPORE-P50100707, PO1-CA078378, and RO1CA050947, and by Myeloma Research Foundation. D.C. designed research, analyzed data, and wrote the manuscript; A.S. designed, interpreted, and performed most experiments; M.B. performed growth/survival assays; G.B. isolated normal plasma cells; R.C. and D.J. helped with IHC; T.H., S.H., P.R., Y.T., N.R., C.M., and N.M. provided clinical samples; and K.A. analyzed data and wrote the manuscript. We also thank Robert Schlossman, Bryan Ciccarelli, and Sagar Lonial for providing blood samples. We are thankful to Lay-Hong Ang for confocal microscopy, John F. Daley for FACS, and Sangeetha Battar, Gaurav Chetri, and David Vasir for technical help and insightful discussions. NR 49 TC 91 Z9 93 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT 6 PY 2009 VL 16 IS 4 BP 309 EP 323 DI 10.1016/j.ccr.2009.08.019 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 506JF UT WOS:000270770400009 PM 19800576 ER PT J AU Morley, JF Duda, JE AF Morley, James F. Duda, John E. TI Autopsy investigation of neurodegenerative disease transplant patients Hindsight is 20/20 SO NEUROLOGY LA English DT Editorial Material ID PARKINSONS-DISEASE; PATHOLOGY; NEURONS C1 [Duda, John E.] Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, Philadelphia, PA 19104 USA. [Morley, James F.] Penn Hosp, Parkinsons Dis & Movement Disorders Ctr, Philadelphia, PA 19107 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Duda, JE (reprint author), Philadelphia VA Med Ctr, Parkinsons Dis Res Educ & Clin Ctr, MS 127,3900 Woodland Ave, Philadelphia, PA 19104 USA. EM john.duda@va.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 6 PY 2009 VL 73 IS 14 BP 1086 EP 1087 DI 10.1212/WNL.0b013e3181bc6758 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 502QG UT WOS:000270474500002 PM 19726748 ER PT J AU Novak, CE Keuthen, NJ Stewart, SE Pauls, DL AF Novak, Carol E. Keuthen, Nancy J. Stewart, S. Evelyn Pauls, David L. TI A Twin Concordance Study of Trichotillomania SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE trichotillomania; hair pulling; twin; genetic; etiology; heritability ID OBSESSIVE-COMPULSIVE DISORDER; PATHOLOGICAL SKIN PICKING; MGH HAIRPULLING SCALE; FAMILIAL TRICHOTILLOMANIA; ZYGOSITY; COMORBIDITY; POPULATION; PREVALENCE; REGISTRY AB Trichotillomania (TTM) is a disorder with putative genetic underpinnings. Family studies report higher than expected rates of TTM among relatives of affected individuals, but no twin concordance studies have been completed to estimate heritability rates. Same-sex twin pairs with hair pulling in at least one co-twin were included. Subjects were recruited following phone screens and questionnaire completion for zygosity and hair pulling variables. Three sets of criteria were used to define hair pulling and TTM. Two other sets of criteria were widened to include skin picking and bothersome hair manipulation. Fisher exact tests assessed pairwise concordance rates for monozygotic and dizygotic twin pairs and heritability estimates were calculated where significant differences existed. Among 34 identified twin pairs, 24 were monozygotic (MZ) and 10 were dizygotic (DZ). Respective concordance rates for MZ and DZ twin pairs were significantly different at 38.1% and 0% for DSM-IV TTM criteria, 39.1% and 0% using modified DSM criteria, and 58.3% and 20% for noticeable non-cosmetic hair pulling (heritability estimates 76.2%). MZ and DZ concordance rates were not significantly different when broadening hair pulling criteria to include skin picking or when including bothersome hair manipulation. Concordance rates from this study suggest that genetic factors play a significant role in the etiology of TTM. Given the reported discordance rates among the MZ twins, further research is required to fully understand contributory non-genetic factors. (C) 2009 Wiley-Liss, Inc. C1 [Stewart, S. Evelyn; Pauls, David L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Keuthen, Nancy J.; Stewart, S. Evelyn] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Trichotillomania Clin, Boston, MA 02114 USA. [Novak, Carol E.] Hlth Partners, St Paul, MN USA. RP Pauls, DL (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, 185 Cambridge St,6th Floor, Boston, MA 02114 USA. EM pauls@pngu.mgh.harvard.edu RI Citations, TLC SAB/C-4006-2011; Stewart, Evelyn/K-6961-2014; OI Stewart, S. Evelyn/0000-0002-0994-6383 FU HealthPartners Research Foundation, Minneapolis, MN FX Grant sponsor: HealthPartners Research Foundation, Minneapolis, MN. NR 33 TC 27 Z9 28 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD OCT 5 PY 2009 VL 150B IS 7 BP 944 EP 949 DI 10.1002/ajmg.b.30922 PG 6 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 502FN UT WOS:000270441100007 PM 19199280 ER PT J AU Duchrow, T Shtatland, T Guettler, D Pivovarov, M Kramer, S Weissleder, R AF Duchrow, Timo Shtatland, Timur Guettler, Daniel Pivovarov, Misha Kramer, Stefan Weissleder, Ralph TI Enhancing navigation in biomedical databases by community voting and database-driven text classification SO BMC BIOINFORMATICS LA English DT Article ID DOCUMENT CLASSIFICATION; INFORMATION; ANNOTATION; PERSPECTIVE; ALGORITHMS; EXTRACTION; SEQUENCES; KNOWLEDGE; BIOLOGY; CANCER AB Background: The breadth of biological databases and their information content continues to increase exponentially. Unfortunately, our ability to query such sources is still often suboptimal. Here, we introduce and apply community voting, database-driven text classification, and visual aids as a means to incorporate distributed expert knowledge, to automatically classify database entries and to efficiently retrieve them. Results: Using a previously developed peptide database as an example, we compared several machine learning algorithms in their ability to classify abstracts of published literature results into categories relevant to peptide research, such as related or not related to cancer, angiogenesis, molecular imaging, etc. Ensembles of bagged decision trees met the requirements of our application best. No other algorithm consistently performed better in comparative testing. Moreover, we show that the algorithm produces meaningful class probability estimates, which can be used to visualize the confidence of automatic classification during the retrieval process. To allow viewing long lists of search results enriched by automatic classifications, we added a dynamic heat map to the web interface. We take advantage of community knowledge by enabling users to cast votes in Web 2.0 style in order to correct automated classification errors, which triggers reclassification of all entries. We used a novel framework in which the database "drives" the entire vote aggregation and reclassification process to increase speed while conserving computational resources and keeping the method scalable. In our experiments, we simulate community voting by adding various levels of noise to nearly perfectly labelled instances, and show that, under such conditions, classification can be improved significantly. Conclusion: Using PepBank as a model database, we show how to build a classification-aided retrieval system that gathers training data from the community, is completely controlled by the database, scales well with concurrent change events, and can be adapted to add text classification capability to other biomedical databases. C1 [Pivovarov, Misha; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Syst Biol,Dept Syst Biol, Boston, MA USA. [Duchrow, Timo; Shtatland, Timur; Guettler, Daniel; Pivovarov, Misha; Weissleder, Ralph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Charlestown, MA USA. Tech Univ Munich, Inst Informat I12, D-8046 Garching, Germany. RP Shtatland, T (reprint author), Beckman Coulter Genom Inc, Cummings Ctr 500, Suite 2450, Beverly, MA USA. EM timo.duchrow@dfki.de; tshtatland@beckman.com; dguettler@mgh.harvard.edu; mpivovarov@mgh.harvard.edu; kramer@in.tum.de; rweissleder@mgh.harvard.edu FU NIH [P50-CA86355] FX We thank Jerry Xu and Dennis Gurgul of the Enterprise Research IS group at Partners Healthcare for their excellent support and use of the HPC facilities. We also thank Vladimir Morozov and Gabriel Berriz for helpful discussions. We thank the anonymous reviewers for their comments, and the PepBank user community for support and valuable feedback. This work was supported in part by NIH grant P50-CA86355 (RW). NR 85 TC 13 Z9 13 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 3 PY 2009 VL 10 AR 317 DI 10.1186/1471-2105-10-317 PG 15 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 519IP UT WOS:000271759800001 PM 19799796 ER PT J AU Hansson, EM Lindsay, ME Chien, KR AF Hansson, Emil M. Lindsay, Mark E. Chien, Kenneth R. TI Regeneration Next: Toward Heart Stem Cell Therapeutics SO CELL STEM CELL LA English DT Review ID ACUTE MYOCARDIAL-INFARCTION; BONE-MARROW-CELLS; SKELETAL MYOBLAST TRANSPLANTATION; RANDOMIZED CONTROLLED-TRIAL; IMPROVES CARDIAC-FUNCTION; HUMAN SOMATIC-CELLS; PROGENITOR CELLS; DEFINED FACTORS; ISCHEMIC-MYOCARDIUM; ADULT MYOCARDIUM AB Stem cell biology holds great promise for a new era of cell-based therapy, sparking considerable interest among scientists, clinicians, and their patients. However, the translational arm of stem cell science is in a relatively primitive state. Although a number of clinical studies have been initiated, the early returns point to several inherent problems. In this regard, the clinical potential of stem cells can only be fully realized by the identification of the key barriers to clinical implementation. Here, we examine experimental paradigms to address the critical steps in the transition from stem cell biology to regenerative medicine, utilizing cardiovascular disease as a case study. C1 [Hansson, Emil M.; Lindsay, Mark E.; Chien, Kenneth R.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Chien, Kenneth R.] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Lindsay, Mark E.] Johns Hopkins Univ Hosp, Dept Pediat, Div Pediat Cardiol, Baltimore, MD 21205 USA. RP Chien, KR (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charles River Plaza,CPZN 3200,185 Cambridge St, Boston, MA 02114 USA. EM krchien@partners.org FU NIH; LeDucq Foundation; Harvard Stem Cell Institute FX We apologize to our colleagues whose work could not be cited due to space constraints. We thank Goran K. Hansson and B. Alexander Yi for helpful comments on the manuscript and Mattias Karlen for help with the artwork. E.M.H. is a Wenner-Gren Foundations fellow. M.E.L. is supported by a HHMI postdoctoral fellowship in the laboratory of H.C. Dietz. K.R.C. is supported by NIH, the LeDucq Foundation, and the Harvard Stem Cell Institute. NR 110 TC 107 Z9 112 U1 2 U2 15 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD OCT 2 PY 2009 VL 5 IS 4 BP 364 EP 377 DI 10.1016/j.stem.2009.09.004 PG 14 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 514NP UT WOS:000271401900009 PM 19796617 ER PT J AU Trowbridge, JJ Snow, JW Kim, J Orkin, SH AF Trowbridge, Jennifer J. Snow, Jonathan W. Kim, Jonghwan Orkin, Stuart H. TI DNA Methyltransferase 1 Is Essential for and Uniquely Regulates Hematopoietic Stem and Progenitor Cells SO CELL STEM CELL LA English DT Article ID SELF-RENEWAL; METHYLATION; DIFFERENTIATION; MAINTENANCE; SURVIVAL; DNMT3B AB DNA methylation is essential for development and in diverse biological processes. The DNA methyltransferase Dnmt1 maintains parental cell methylation patterns on daughter DNA strands in mitotic cells; however, the precise role of Dnmt1 in regulation of quiescent adult stem cells is not known. To examine the role of Dnmt1 in adult hematopoietic stem cells (HSCs), we conditionally disrupted Dnmt1 in the hematopoietic system. Defects were observed in Dnmt1 deficient HSC self-renewal, niche retention, and in the ability of Dnmt1-deficient HSCs to give rise to multilineage hematopoiesis. Loss of Dnmt1 also had specific impact on myeloid progenitor cells, causing enhanced cell cycling and inappropriate expression of mature lineage genes. Dnmt1 regulates distinct patterns of methylation and expression of discrete gene families in long-term HSCs and multipotent and lineage-restricted progenitors, suggesting that Dnmt1 differentially controls these populations. These findings establish a unique and critical role for Dnmt1 in the primitive hematopoietic compartment. C1 [Trowbridge, Jennifer J.; Snow, Jonathan W.; Kim, Jonghwan; Orkin, Stuart H.] Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. [Kim, Jonghwan; Orkin, Stuart H.] Harvard Univ, Sch Med, Howard Hughes Med Inst, Dana Farber Canc Inst, Boston, MA 02115 USA. [Trowbridge, Jennifer J.; Snow, Jonathan W.; Kim, Jonghwan; Orkin, Stuart H.] Harvard Univ, Sch Med, Childrens Hosp Boston,Div Hematol Oncol, Harvard Stem Cell Inst,Dept Pediat Oncol, Boston, MA 02115 USA. [Kim, Jonghwan; Orkin, Stuart H.] Harvard Univ, Sch Med, Childrens Hosp Boston,Div Hematol Oncol, Harvard Stem Cell Inst,Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Dept Pediat Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA. EM orkin@bloodgroup.tch.harvard.edu FU Fellows of the Leukemia & Lymphoma Society; HHMI Research Associate FX We thank Drs. C.R. Walkley, L.E. Purton, J. Xu, D.A. Williams, G.C. Yuan, and M.D. Kiers for helpful discussion and critical comments; J. Chong for technical assistance; Children's Hospital Animal Facility Staff for care of experimental animals; and J. Daley and S. Lazo-Kallanian of the DFCI HemNeo Flow Facility for cell sorting. J.J.T. and J.W.S. are Fellows of the Leukemia & Lymphoma Society, J.K. is a HHMI Research Associate, and S.H.O. is an Investigator of the HHMI. NR 16 TC 170 Z9 173 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD OCT 2 PY 2009 VL 5 IS 4 BP 442 EP 449 DI 10.1016/j.stem.2009.08.016 PG 8 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 514NP UT WOS:000271401900015 PM 19796624 ER PT J AU Chan, ST Tang, SW Lee, WK Tang, KW Lo, SS Kwong, KK AF Chan, Suk-Tak Tang, Sze-Wing Lee, Wing-Kit Tang, Kwok-Wing Lo, Shing-Shun Kwong, Kenneth K. TI Can Cantonese rhymes be used in the assessment of hemispheric dominance for language? SO NEUROSCIENCE LETTERS LA English DT Article DE Language; Cantonese; Rhyme; Hemispheric dominance ID EVENT-RELATED FMRI; AUDITORY-CORTEX; FUNCTIONAL MRI; CHINESE CHARACTERS; SPEECH-PERCEPTION; HUMAN BRAIN; VOWELS; LATERALIZATION; ORGANIZATION; ACTIVATION AB English vowels had been proposed in previous studies to be used as a simple tool for the brain mapping of language. A proper fMRI study of Cantonese rhymes, each of which being a required and fundamental unit of a Cantonese syllable, remains to be carried out. Using an auditory task with Cantonese rhymes which carry no semantic meaning, we observed a minimal amount of positive BOLD signal at the caudate nucleus when Cantonese rhymes were contrasted with their corresponding filtered sounds. Typical language activating regions of the prefrontal cortex, the medial prefrontal cortex and the lateral temporal cortex on both left and right sides were not activated by Cantonese rhymes. Based on the absence of brain activation at the typical language areas in the contrast of Cantonese rhymes relative to filtered sounds, the auditory task with Cantonese rhymes may not be a robust tool for the individual clinical assessment of hemispheric dominance for language. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Chan, Suk-Tak; Lee, Wing-Kit] Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. [Tang, Sze-Wing] Hong Kong Polytech Univ, Dept Chinese & Bilingual Studies, Hong Kong, Hong Kong, Peoples R China. [Tang, Kwok-Wing] Queen Elizabeth Hosp, Dept Diagnost Radiol & Imaging, Hong Kong, Hong Kong, Peoples R China. [Lo, Shing-Shun] United Christian Hosp, Dept Radiol & Organ Imaging, Hong Kong, Hong Kong, Peoples R China. [Kwong, Kenneth K.] Massachusetts Gen Hosp, Dept Radiol, Athinoula A Martinos Ctr Biomed Imaging, Boston, MA 02114 USA. RP Chan, ST (reprint author), Hong Kong Polytech Univ, Dept Hlth Technol & Informat, Hong Kong, Hong Kong, Peoples R China. EM htphoebe@inet.polyu.edu.hk RI Chan, Suk-tak/G-5846-2015 FU Hong Kong Research Grants Council [PolyU 5403/04M] FX This research was supported by the Hong Kong Research Grants Council (PolyU 5403/04M) and The Hong Kong Polytechnic University. We thank the radiographers at the United Christian Hospital and the Queen Elizabeth Hospital for assistance in data collection. NR 38 TC 1 Z9 1 U1 2 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 2 PY 2009 VL 463 IS 2 BP 103 EP 107 DI 10.1016/j.neulet.2009.07.057 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 494JK UT WOS:000269808700001 PM 19631717 ER PT J AU Stearns, CR Gonzales, R Camargo, CA Maselli, J Metlay, JP AF Stearns, Cordelia R. Gonzales, Ralph Camargo, Carlos A., Jr. Maselli, Judith Metlay, Joshua P. TI Antibiotic Prescriptions Are Associated with Increased Patient Satisfaction With Emergency Department Visits for Acute Respiratory Tract Infections SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE patient satisfaction; respiratory tract infections; antibacterial agents ID EXPECTATIONS; QUALITY; ACUITY AB Objectives: Health care providers cite patient satisfaction as a common reason for prescribing antibiotics for viral acute upper respiratory infections (URIs), even though quality performance measures emphasize nonantibiotic treatment for these conditions. In a secondary analysis of a cluster-randomized trial to test a combined patient and physician educational intervention to reduce antibiotic prescribing for URIs, the authors examined whether satisfaction is greater among patients diagnosed with URIs who are prescribed antibiotics in emergency department (ED) settings. Methods: This was a follow-up telephone survey of 959 patients who received care for acute respiratory infections at any of eight Veterans Administration (VA) hospital EDs or eight location-matched non-VA hospital EDs around the United States. Patients reported their satisfaction with the amount of time spent in the ED, the explanation of treatment, the provider treatment, and overall satisfaction on a five-point Likert scale. The primary measure of effect was the association between antibiotic prescription and visit satisfaction, adjusted for patient and visit characteristics. Results: Antibiotic treatment was significantly associated with increased overall visit satisfaction in non-VA EDs (adjusted odds ratio [OR] = 1.97, 95% confidence interval [CI] = 1.23 to 3.17), but not VA EDs (adjusted OR = 1.13, 95% CI = 0.81 to 1.58). Patients managed in non-VA EDs who received antibiotics were also significantly more likely to be satisfied with the explanation of treatment and the manner in which they were treated by the provider. Conclusions: Antibiotic prescriptions are associated with increased overall patient satisfaction in non-VA, but not VA, ED visits for URIs. Continued efforts to reduce unnecessary prescriptions in these settings must address ways to maintain patient satisfaction and still reduce antibiotic prescriptions. C1 [Stearns, Cordelia R.; Metlay, Joshua P.] Univ Penn, Sch Med, VA Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA 19104 USA. [Stearns, Cordelia R.; Metlay, Joshua P.] Univ Penn, Sch Med, Div Gen Internal Med, Philadelphia, PA USA. [Stearns, Cordelia R.; Metlay, Joshua P.] Univ Penn, Sch Med, Ctr Educ & Res Therapeut, Philadelphia, PA USA. [Gonzales, Ralph; Maselli, Judith] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Gonzales, Ralph; Maselli, Judith] Univ Calif San Francisco, Div Gen Internal Med, Dept Med, San Francisco, CA 94143 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. RP Metlay, JP (reprint author), Univ Penn, Sch Med, VA Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA 19104 USA. EM jmetlay@mail.med.upenn.edu FU joint Agency for Healthcare Research and Quality [1 R01 HS013915]; Veteran's Administration (VA) Health Services Research and Development Service [AVA-03-239] FX This study was conducted as part of a joint Agency for Healthcare Research and Quality (1 R01 HS013915) and Veteran's Administration (VA) Health Services Research and Development Service Award (AVA-03-239) to compare the translation of research into practice across VA and non-VA settings. NR 22 TC 20 Z9 20 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD OCT PY 2009 VL 16 IS 10 BP 934 EP 941 DI 10.1111/j.1553-2712.2009.00522.x PG 8 WC Emergency Medicine SC Emergency Medicine GA 501QP UT WOS:000270396700003 PM 19799568 ER PT J AU Newman-Toker, DE Camargo, CA Hsieh, YH Pelletier, AJ Edlow, JA AF Newman-Toker, David E. Camargo, Carlos A., Jr. Hsieh, Yu-Hsiang Pelletier, Andrea J. Edlow, Jonathan A. TI Disconnect Between Charted Vestibular Diagnoses and Emergency Department Management Decisions: A Cross-sectional Analysis From a Nationally Representative Sample SO ACADEMIC EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT 25th Barany-Society Meeting CY APR, 2008 CL Kyoto, JAPAN SP Barany Soc DE dizziness; vertigo; vestibular diseases; diagnosis; medical error; cross-sectional studies ID PAROXYSMAL POSITIONAL VERTIGO; RANDOMIZED CLINICAL-TRIAL; CEREBELLAR INFARCTION; SYMPTOM QUALITY; DIZZY PATIENTS; OLDER-ADULTS; NEURITIS; DIZZINESS; PHYSICIANS; PATIENT AB Objectives: The most common vestibular disorders seen in the emergency department (ED) are benign paroxysmal positional vertigo (BPPV) and acute peripheral vestibulopathy (APV; i.e., vestibular neuritis or labyrinthitis). BPPV and APV are two very distinct disorders that have different clinical presentations that require different diagnostic and treatment strategies. BPPV can be diagnosed without imaging and is treated with canalith-repositioning maneuvers. APV sometimes requires neuroimaging by magnetic resonance imaging (MRI) to exclude posterior fossa stroke mimics and should be treated with vestibular sedatives and corticosteroids. We sought to determine if emergency physicians (EPs) apply best practices to diagnose and treat these common vestibular disorders. Methods: This was a cross-sectional study of ED visits from the National Hospital Ambulatory Medical Care Survey (NHAMCS). A weighted sample of U.S. ED visits (1993-2005) was used. Patients at least 16 years of age who were given a final ED diagnosis of BPPV (International Classification of Diseases, 9th Revision [ICD-9], 386.11) or APV (ICD-9 386.12 or 386.3x) comprised the study population. The frequency of imaging and drug therapy in those diagnosed as BPPV or APV versus controls was the main outcome measure. Results: A total of 9,472 dizzy patient visits were sampled over 13 years (weighted estimate 33.6 million U.S. ED visits over that period). A weighted estimate of 2.5 million patients (7.4%) were given a vestibular diagnosis, mostly BPPV (weighted 0.2 million) or APV (weighted 1.9 million). Patients given BPPV (19%) and APV (19%) diagnoses were more likely to undergo imaging (all by computed tomography [CT]) than controls (7%; p < 0.001). Patients given BPPV (58%) and APV (70%) diagnoses were more likely to receive meclizine than controls (0.1%; p < 0.001). Corticosteroid administration was rarely documented (2% BPPV, 1% APV). Conclusions: Patients given a vestibular diagnosis in the ED may not be managed optimally. Patients given BPPV and APV diagnoses undergo imaging (predominantly CT) with equal frequency, suggesting overuse of CT (BPPV) and probably underuse of MRI (APV). Most patients diagnosed with BPPV are given meclizine, which is not indicated. Specific therapy for APV (corticosteroids) is probably underutilized. Educational initiatives and clinical guidelines merit consideration. ACADEMIC EMERGENCY MEDICINE 2009; 16:970-977 <(C)> 2009 by the Society for Academic Emergency Medicine. C1 [Newman-Toker, David E.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Newman-Toker, David E.] Johns Hopkins Univ, Sch Med, Dept Otolaryngol, Baltimore, MD 21205 USA. [Hsieh, Yu-Hsiang] Johns Hopkins Univ, Sch Med, Dept Emergency Med, Baltimore, MD 21205 USA. [Camargo, Carlos A., Jr.; Pelletier, Andrea J.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Edlow, Jonathan A.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Emergency Med, Boston, MA USA. RP Newman-Toker, DE (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. EM toker@jhu.edu NR 68 TC 38 Z9 39 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD OCT PY 2009 VL 16 IS 10 BP 970 EP 977 DI 10.1111/j.1553-2712.2009.00523.x PG 8 WC Emergency Medicine SC Emergency Medicine GA 501QP UT WOS:000270396700008 PM 19799573 ER PT J AU Courtney, DM Neumar, RW Venkatesh, AK Kaji, AH Cairns, CB Lavonas, E Richardson, LD AF Courtney, D. Mark Neumar, Robert W. Venkatesh, Arjun K. Kaji, Amy H. Cairns, Charles B. Lavonas, Eric Richardson, Lynne D. TI Unique Characteristics of Emergency Care Research: Scope, Populations, and Infrastructure SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE emergency care research networks ID INFORMED-CONSENT; ETHICS; FOOD AB The National Institutes of Health (NIH) Clinical and Translational Science Awards (CTSA) program and the 2006 Institute of Medicine (IOM) Report on the future of emergency care highlight the need for coordinated emergency care research (ECR) to improve the outcomes of acutely ill or injured patients. In response, the Society for Academic Emergency Medicine (SAEM) and the American College of Emergency Physicians (ACEP) sponsored the Emergency Care Research Network (ECRN) Conference in Washington, DC, on May 28, 2008. The conference objectives were to identify the unique nature of ECR and the infrastructure needed to support ECR networks and to understand the optimal role of emergency medicine (EM) and other acute care specialties in research networks. Prior to the conference, participants responded to questions addressing the relevant issues that would form the basis of breakout session discussions; two of these breakout questions are summarized in this report: 1) what makes EM research unique? and 2) what are the critical components needed to establish and maintain networked ECR? Emergency care research was defined as "the systematic examination of patient care that is expected to be continuously available to diverse populations presenting with undifferentiated symptoms of acute illness, or acutely decompensated chronic illness, and whose outcomes depend on timely diagnosis and treatment." The chain of ECR may extend beyond the physical emergency department (ED) in both place and time and integrate prehospital care, as well as short- and long-term outcome determination. ECR may extend beyond individual patients and have as the focus of investigation the actual system of emergency care delivery itself and its effects on the community with respect to access to care, use of resources, and cost. Infrastructure determinants of research network success identified by conference participants included multidisciplinary collaboration, accurate long-term outcome determination, novel information technology, intellectual infrastructure, and wider network relationships that extend beyond the ED. ACADEMIC EMERGENCY MEDICINE 2009; 16:990-994 (C) 2009 by the Society for Academic Emergency Medicine. C1 [Courtney, D. Mark] Northwestern Univ, Feinberg Sch Med, Dept Emergency Med, Chicago, IL 60611 USA. [Neumar, Robert W.] Univ Penn, Sch Med, Hosp Univ Penn, Philadelphia, PA 19104 USA. [Venkatesh, Arjun K.] Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02114 USA. [Kaji, Amy H.] Univ Calif Los Angeles, Harbor UCLA Med Ctr, Dept Emergency Med, David Geffen Sch Med, Torrance, CA USA. [Cairns, Charles B.] Univ N Carolina, Dept Emergency Med, Chapel Hill, NC USA. [Lavonas, Eric] Rocky Mt Poison & Drug Ctr, Denver, CO USA. [Lavonas, Eric] Univ Colorado, Sch Med, Dept Surg Emergency Med, Aurora, CO USA. [Richardson, Lynne D.] Mt Sinai Sch Med, Dept Emergency Med, New York, NY USA. RP Courtney, DM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Emergency Med, Chicago, IL 60611 USA. EM mcourtney@nmff.org NR 16 TC 10 Z9 10 U1 2 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD OCT PY 2009 VL 16 IS 10 BP 990 EP 994 DI 10.1111/j.1553-2712.2009.00530.x PG 5 WC Emergency Medicine SC Emergency Medicine GA 501QP UT WOS:000270396700014 PM 19799578 ER PT J AU Papa, L Kuppermann, N Lamond, K Barsan, WG Camargo, CA Ornato, JP Stiell, IG Talan, DA AF Papa, Linda Kuppermann, Nathan Lamond, Katherine Barsan, William G. Camargo, Carlos A., Jr. Ornato, Joseph P. Stiell, Ian G. Talan, David A. TI Structure and Function of Emergency Care Research Networks: Strengths, Weaknesses, and Challenges SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE research networks; emergency care; emergency research; multicenter research; collaboration; research funding ID RESUSCITATION OUTCOMES CONSORTIUM; ANIMAL EXPOSURES; MULTICENTER; MEDICINE; PROTOCOL; TRIAL; BRONCHIOLITIS; EPIDEMIOLOGY; INFECTIONS; RATIONALE AB The ability of emergency care research (ECR) to produce meaningful improvements in the outcomes of acutely ill or injured patients depends on the optimal configuration, infrastructure, organization, and support of emergency care research networks (ECRNs). Through the experiences of existing ECRNs, we can learn how to best accomplish this. A meeting was organized in Washington, DC, on May 28, 2008, to discuss the present state and future directions of clinical research networks as they relate to emergency care. Prior to the conference, at the time of online registration, participants responded to a series of preconference questions addressing the relevant issues that would form the basis of the breakout session discussions. During the conference, representatives from a number of existing ECRNs participated in discussions with the attendees and provided a description of their respective networks, infrastructure, and challenges. Breakout sessions provided the opportunity to further discuss the strengths and weaknesses of these networks and patterns of success with respect to their formation, management, funding, best practices, and pitfalls. Discussions centered on identifying characteristics that promote or inhibit successful networks and their interactivity, productivity, and expansion. Here the authors describe the current state of ECRNs and identify the strengths, weaknesses, and potential pitfalls of research networks. The most commonly cited strengths of population- or disease-based research networks identified in the preconference survey were access to larger numbers of patients; involvement of physician experts in the field, contributing to high-level study content; and the collaboration among investigators. The most commonly cited weaknesses were studies with too narrow a focus and restrictive inclusion criteria, a vast organizational structure with a risk of either too much or too little central organization or control, and heterogeneity of institutional policies and procedures among sites. Through the survey and structured discussion process involving multiple stakeholders, the authors have identified strengths and weaknesses that are consistent across a number of existing ECRNs. By leveraging the strengths and addressing the weaknesses, strategies can be adopted to enhance the scientific value and productivity of these networks and give direction to future ECRNs. ACADEMIC EMERGENCY MEDICINE 2009; 16:995-1004 (C) 2009 by the Society for Academic Emergency Medicine. C1 [Papa, Linda] Orlando Reg Med Ctr Inc, Dept Emergency Med, Orlando, FL USA. [Kuppermann, Nathan] UC Davis Hlth Syst, Dept Emergency Med, Sacramento, CA USA. [Kuppermann, Nathan] UC Davis Hlth Syst, Dept Pediat, Sacramento, CA USA. [Lamond, Katherine] Univ Penn, Sch Med, Dept Emergency Med, Philadelphia, PA 19104 USA. [Barsan, William G.] Univ Michigan, Dept Emergency Med, Ann Arbor, MI 48109 USA. [Camargo, Carlos A., Jr.] Harvard Univ, Sch Med, Boston, MA USA. [Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Ornato, Joseph P.] Virginia Commonwealth Univ Hlth Syst, Dept Emergency Med, Richmond, VA USA. [Stiell, Ian G.] Univ Ottawa, Dept Emergency Med, Ottawa, ON, Canada. [Stiell, Ian G.] Ottawa Hlth Res Inst, Ottawa, ON, Canada. [Talan, David A.] Olive View UCLA, Dept Emergency Med, Los Angeles, CA USA. RP Papa, L (reprint author), Orlando Reg Med Ctr Inc, Dept Emergency Med, Orlando, FL USA. EM lpstat@aol.com OI Stiell, Ian/0000-0002-2583-6408 NR 26 TC 7 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD OCT PY 2009 VL 16 IS 10 BP 995 EP 1004 DI 10.1111/j.1553-2712.2009.00531.x PG 10 WC Emergency Medicine SC Emergency Medicine GA 501QP UT WOS:000270396700015 PM 19799579 ER PT J AU Sullivan, AF Ginde, AA Espinola, JA Camargo, CA AF Sullivan, Ashley F. Ginde, Adit A. Espinola, Janice A. Camargo, Carlos A., Jr. TI Supply and Demand of Board-certified Emergency Physicians by US State, 2005 SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE emergency physicians; board certification; workforce; rural; staffing ID MEDICINE; WORKFORCE; DEPARTMENTS; COVERAGE; LOCATION AB Objectives: The objective was to estimate the emergency medicine (EM) board-certified emergency physician (EP) workforce supply and demand by U.S. state. Methods: The 2005 National Emergency Department Inventories-USA provided annual visit volumes for U.S. emergency departments (EDs). We estimated full-time equivalent (FTE) EP demand at each ED by dividing the actual number of visits by the estimated average EP visit volume (3,548 visits/year) and then summing FTEs by state. Our model assumed that at least one EP should be present 24/7 in each ED. The number of EM board-certified EPs per state was provided by the American Board of Medical Specialties (American Board of Emergency Medicine, American Board of Pediatrics) and the American Osteopathic Board of Emergency Medicine. We used U.S. Census Bureau civilian population estimates to calculate EP population density by state. Results: The supply of EM board-certified EPs was 58% of required FTEs to staff all EDs nationally and ranged from 10% in South Dakota to 104% in Hawai'i (i.e., there were more EPs than the estimated need). Texas and Florida had the largest absolute shortages of EM board-certified EPs (2,069 and 1,146, respectively). The number of EM board-certified EPs per 100,000 U.S. civilian population ranged from 3.6 in South Dakota to 13.8 in Washington, DC. States with a higher population density of EM board-certified EPs had higher percent high school graduates and a lower percent rural population and whites. Conclusions: The supply and demand of EM board-certified EPs varies by state. Only one state had an adequate supply of EM board-certified EPs to fully staff its EDs. C1 [Sullivan, Ashley F.; Espinola, Janice A.; Camargo, Carlos A., Jr.] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Ginde, Adit A.] Univ Colorado, Denver Sch Med, Dept Emergency Med, Aurora, CO USA. RP Camargo, CA (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. EM ccamargo@partners.org RI Siry, Bonnie/D-7189-2017 NR 26 TC 8 Z9 8 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD OCT PY 2009 VL 16 IS 10 BP 1014 EP 1018 DI 10.1111/j.1553-2712.2009.00509.x PG 5 WC Emergency Medicine SC Emergency Medicine GA 501QP UT WOS:000270396700018 PM 19719820 ER PT J AU Isaac, C Lee, B Carnes, M AF Isaac, Carol Lee, Barbara Carnes, Molly TI Interventions That Affect Gender Bias in Hiring: A Systematic Review SO ACADEMIC MEDICINE LA English DT Article AB Purpose To systematically review experimental evidence for interventions mitigating gender bias in employment. Unconscious endorsement of gender stereotypes can undermine academic medicine's commitment to gender equity. Method The authors performed electronic and hand searches for randomized controlled studies since 1973 of interventions that affect gender differences in evaluation of job applicants. Twenty-seven studies met all inclusion criteria. Interventions fell into three categories: application information, applicant features, and rating conditions. Results The studies identified gender bias as the difference in ratings or perceptions of men and women with identical qualifications. Studies reaffirmed negative bias against women being evaluated for positions traditionally or predominantly held by men (male sex-typed jobs). The assessments of male and female raters rarely differed. Interventions that provided raters with clear evidence of job-relevant competencies were effective. However, clearly competent women were rated lower than equivalent men for male sex-typed jobs unless evidence of communal qualities was also provided. A commitment to the value of credentials before review of applicants and women's presence at above 25% of the applicant pool eliminated bias against women. Two studies found unconscious resistance to "antibias" training, which could be overcome with distraction or an intervening task. Explicit employment equity policies and an attractive appearance benefited men more than women, whereas repeated employment gaps were more detrimental to men. Masculine-scented perfume favored the hiring of both sexes. Negative bias occurred against women who expressed anger or who were perceived as self-promoting. Conclusions High-level evidence exists for strategies to mitigate gender bias in hiring. Acad Med. 2009; 84: 1440-1446. C1 [Isaac, Carol; Carnes, Molly] Univ Wisconsin, Ctr Womens Hlth Res, Madison, WI 53715 USA. [Carnes, Molly] Meriter Hosp, Madison, WI USA. [Carnes, Molly] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53715 USA. [Carnes, Molly] Univ Wisconsin, Dept Psychiat, Sch Med & Publ Hlth, Madison, WI 53715 USA. [Carnes, Molly] Univ Wisconsin, Dept Ind & Syst Engn, Madison, WI 53715 USA. [Carnes, Molly] Univ Wisconsin, WISELI, Coll Engn, Madison, WI 53715 USA. [Carnes, Molly] William S Middleton Mem Vet Adm Med Ctr, Women Vet Hlth Program, Madison, WI USA. [Isaac, Carol] Univ Wisconsin, Dept Orthoped & Rehabil, Madison, WI 53715 USA. RP Carnes, M (reprint author), Univ Wisconsin, Ctr Womens Hlth Res, 700 Regent St,Suite 301, Madison, WI 53715 USA. EM mlcarnes@wisc.edu FU University of Wisconsin School of Medicine and Public Health; Meriter Hospital; National Institute on Aging [T32 AG00265] FX This research was funded by the University of Wisconsin School of Medicine and Public Health and Meriter Hospital. Dr. Isaac was supported by grant no. T32 AG00265 from the National Institute on Aging. Dr. Carnes is employed part time by the William S. Middleton Veterans Hospital. This report is GRECC manuscript no. 2000-30. NR 62 TC 44 Z9 44 U1 3 U2 38 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD OCT PY 2009 VL 84 IS 10 BP 1440 EP 1446 DI 10.1097/ACM.0b013e3181b6ba00 PG 7 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA V15EU UT WOS:000207786100032 PM 19881440 ER PT J AU Rudolph, JW Morrison, JB Carroll, JS AF Rudolph, Jenny W. Morrison, J. Bradley Carroll, John S. TI THE DYNAMICS OF ACTION-ORIENTED PROBLEM SOLVING: LINKING INTERPRETATION AND CHOICE SO ACADEMY OF MANAGEMENT REVIEW LA English DT Article ID DECISION-MAKING; CLINICAL JUDGMENT; ORGANIZATIONS; EXPLANATION; PERSPECTIVE; SENSEMAKING; HEURISTICS; PSYCHOLOGY; COLLAPSE; DISASTER AB We offer a theory of action-oriented problem solving that links interpretation and choice, processes usually separated in the sensemaking literature and decision-making literature. Through an iterative, simulation-based process we developed a formal model. Three insights emerged: (1) action-oriented problem solving includes acting. interpreting, and cultivating diagnoses; (2) feedback among these processes opens and closes windows of adaptive problem solving; and (3) reinforcing feedback and confirmation bias, usually considered dysfunctional, are helpful for adaptive problem solving. C1 [Rudolph, Jenny W.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Rudolph, Jenny W.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Morrison, J. Bradley] Brandeis Univ, Brandeis Int Business Sch, Waltham, MA 02254 USA. [Carroll, John S.] MIT, Alfred P Sloan Sch Management, Cambridge, MA 02139 USA. RP Rudolph, JW (reprint author), Harvard Univ, Sch Med, Cambridge, MA 02138 USA. EM jwrudolph@partners.org; bmorriso@brandeis.edu; jcarroll@mit.edu NR 84 TC 51 Z9 52 U1 7 U2 68 PU ACAD MANAGEMENT PI BRIARCLIFF MANOR PA PACE UNIV, PO BOX 3020, 235 ELM RD, BRIARCLIFF MANOR, NY 10510-8020 USA SN 0363-7425 J9 ACAD MANAGE REV JI Acad. Manage. Rev. PD OCT PY 2009 VL 34 IS 4 BP 733 EP 756 PG 24 WC Business; Management SC Business & Economics GA 505ZB UT WOS:000270739900009 ER PT J AU Roche-Labarbe, N Surova, A Carp, S Patel, M Boas, DA Grant, PE Franceschini, MA AF Roche-Labarbe, N. Surova, A. Carp, S. Patel, M. Boas, D. A. Grant, P. E. Franceschini, M. A. TI NON-INVASIVE OPTICAL MEASURES OF CBV, STO2, CBF INDEX, AND RCMRO2 IN PREMATURE BRAINS DURING THE FIRST 6 WEEKS OF LIFE SO ACTA PAEDIATRICA LA English DT Meeting Abstract C1 [Roche-Labarbe, N.; Surova, A.; Carp, S.; Patel, M.; Boas, D. A.; Franceschini, M. A.] Massachusetts Gen Hosp, Martinos Ctr Biomed Imaging, Charlestown, MA USA. [Grant, P. E.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Roche-Labarbe, Nadege/N-9101-2015 OI Roche-Labarbe, Nadege/0000-0002-5010-0400 NR 0 TC 1 Z9 1 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 OCT PY 2009 VL 98 SU 460 BP 48 EP 48 PG 1 WC Pediatrics SC Pediatrics GA 495AR UT WOS:000269862100120 ER PT J AU Mueser, KT Glynn, SM Cather, C Zarate, R Fox, L Feldman, J Wolfe, R Clark, RE AF Mueser, Kim T. Glynn, Shirley M. Cather, Corinne Zarate, Roberto Fox, Lindy Feldman, James Wolfe, Rosemarie Clark, Robin E. TI Family intervention for co-occurring substance use and severe psychiatric disorders: Participant characteristics and correlates of initial engagement and more extended exposure in a randomized controlled trial SO ADDICTIVE BEHAVIORS LA English DT Article DE Comorbidity; Co-occurring disorders; Dual disorders; Family therapy; Family psychoeducation; Severe mental illness; Schizophrenia ID MENTAL-HEALTH-SERVICES; GENDER DIFFERENCES; EXPRESSED EMOTION; ATTITUDE SCALE; DRUG-ABUSE; SCHIZOPHRENIA; ILLNESS; RELAPSE; PEOPLE; ALCOHOL AB Clients with severe mental illness and Substance use disorder (i.e., dual disorders) frequently have contact with family members, who may provide valuable emotional and material support, but have limited skills and knowledge to promote recovery. Furthermore, high levels of family conflict and stress are related to higher rates of relapse. The present study was a two-site randomized controlled trial comparing a comprehensive, behaviorally-based family intervention for dual disorders program (FIDD) to a shorter-term family psychoeducational program (FPE). The modal family was a single male son in his early 30s diagnosed with both alcohol and drug problems and a schizophrenia-spectrum disorder participating with his middle-aged mother, with whom he lived. Initial engagement rates following consent to participate in the study and the family intervention programs were moderately high for both programs (88% and 84%, respectively), but rates of longer term retention and exposure to the core elements of each treatment model were lower (61% and 55%, respectively). Characteristics of the relatives were the strongest predictors Of Successful initial engagement in the family programs with the most important predictor being relatives who reported higher levels of benefit related to the relationship with the client. Subsequent successful exposure to the family treatment models was more strongly associated with client factors, including less severity of drug abuse and male client gender. The results suggest that attention to issues of motivating relatives to participate in family intervention, and more focused efforts to address the disruptive effects of drug abuse on the family could improve rates of engagement and retention in family programs for dual disorders. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Mueser, Kim T.; Fox, Lindy; Wolfe, Rosemarie] Dartmouth Psychiat Res Ctr, Concord, NH 03301 USA. [Mueser, Kim T.; Fox, Lindy; Wolfe, Rosemarie] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Psychiat, Hanover, NH 03756 USA. [Mueser, Kim T.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03756 USA. [Glynn, Shirley M.] VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. [Glynn, Shirley M.; Zarate, Roberto] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Cather, Corinne] Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. [Cather, Corinne; Feldman, James] Harvard Univ, Sch Med, Boston, MA USA. [Zarate, Roberto] Pacific Clin, Los Angeles, CA USA. [Feldman, James] Massachusetts Mental Hlth Ctr, Boston, MA 02115 USA. [Clark, Robin E.] Univ Massachusetts, Sch Med, Ctr Hlth Policy & Res, Amherst, MA 01003 USA. RP Mueser, KT (reprint author), Dartmouth Psychiat Res Ctr, Main Bldg,105 Pleasant St, Concord, NH 03301 USA. EM kim.t.Mueser@dartmouth.edu RI Clark, Robin/I-7224-2012 FU National Institute of Mental Health [MH62629]; National Institute on Drug Abuse FX This research was supported by grant #MH62629 from the National Institute of Mental Health and the National Institute on Drug Abuse. This paper is subject to the National Institutes of Health Public Access Policy. An earlier version of this paper was presented at the 40th Annual Convention of the Association for Behavioral and Cognitive Therapies in Chicago, Illinois, November, 2006.; The authors appreciate the following persons for their contributions to this study: Dan Beck, Bruce Bird, Elsa Busch, Kimberly Carr, Margaret Guyer Deason, Robert E. Drake, Barbara Echevarria, Joan Friebly, Michelle Friedman-Yakoobian, Rona Gershovsky, Jennifer D. Gottlieb, Gretchen Grappone, Daniel E.Jimenez, Abigaiijudge, Lynette King, Alex Kopelowicz, Linda LaRose, Glenda Madden, Gregory McHugo, Krystal A. Murray, Noosha Niv, Thomas Quinlan, Joan Packard, Kenneth Park, Mary Parker, Jean Russo, Diane Schiavo, Melissa Stern, Shannon R. Weston, and James Wheeler. NR 62 TC 17 Z9 17 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 EI 1873-6327 J9 ADDICT BEHAV JI Addict. Behav. PD OCT PY 2009 VL 34 IS 10 SI SI BP 867 EP 877 DI 10.1016/j.addbeh.2009.03.025 PG 11 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 486BL UT WOS:000269170300012 PM 19375870 ER PT J AU Pasquale, LR Walt, JG Stern, LS Wiederkehr, D Malangone, E Dolgitser, M AF Pasquale, Louis R. Walt, John G. Stern, Lee S. Wiederkehr, Daniel Malangone, Elisabetta Dolgitser, Margarita TI Healthcare charges in patients who transition from ocular hypertension to primary open-angle glaucoma based on ophthalmic coding data SO ADVANCES IN THERAPY LA English DT Article DE healthcare economics; ocular hypertension; open-angle glaucoma; ophthalmology ID BEAVER-DAM EYE; INTRAOCULAR-PRESSURE; UNITED-STATES; ECONOMIC BURDEN; BARBADOS EYE; DIRECT COSTS; CLAIMS DATA; PREVALENCE; POPULATION; MANAGEMENT AB The purpose of this research was to assess the impact of transition from ocular hypertension (OHT) to primary open-angle glaucoma (POAG) on healthcare charges. A case-control group was identified using PharMetrics claims database (1998-2005). Cases (n=1055) had a transition from OHT to POAG based on International Classification of Disease, Ninth Edition coding (ICD-9=365.11). Controls (n=2110) retained an ICD-9 code for OHT (ICD-9=365.04) and were matched to cases (2:1) on gender, age, diagnosis year, and follow-up time post-diagnosis. The index date marked the transition for cases and a date of similar duration after OHT diagnosis for controls. Conditional logistic regression and multiple linear regression models determined the impact of transitioning on healthcare charges. Cases had significantly higher increases in ophthalmology-related charges ($797 vs. -$385, P < 0.0001) but similar total healthcare charges ($1689 vs. $1386, P=0.8277) from the year pre- to year post-index date when compared with controls. After adjusting for key covariates, cases were 1.56 times (95% CI: 1.33-1.82) more likely to have increased total charges and 5.26 times (95% CI: 4.27-6.47) more likely to have increased ophthalmology-related charges compared with controls. In multiple linear regression analyses, cases experienced $48 (55%) higher increases in ophthalmology-related charges from the year pre- to year post-index date compared with controls ($85 vs. $37, respectively; P < 0.0001). Patients with a transition from OHT to POAG based on ICD-9 coding had higher ophthalmology-related charges the year after transition compared with patients who retained a code for OHT. Prevention of this transition could result in healthcare resource savings. C1 [Stern, Lee S.; Wiederkehr, Daniel; Malangone, Elisabetta; Dolgitser, Margarita] Analyt Int, New York, NY 10018 USA. [Pasquale, Louis R.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Glaucoma Serv, Boston, MA USA. [Walt, John G.] Allergan Pharmaceut Inc, Irvine, CA 92715 USA. RP Stern, LS (reprint author), Analyt Int, 24 W 40th St,8th Floor, New York, NY 10018 USA. EM lstern@analyticaintl.com FU Allergan, Inc., Irvine, California, USA FX Editorial assistance in the preparation of this manuscript was provided by Jacob M. Willet, MPH, of Analytica International. Support for this assistance was funded by Allergan, Inc., Irvine, California, USA. NR 31 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0741-238X J9 ADV THER JI Adv. Ther. PD OCT PY 2009 VL 26 IS 10 BP 947 EP 958 DI 10.1007/s12325-009-0073-y PG 12 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 528PP UT WOS:000272459100005 PM 19907929 ER PT J AU Oliveira, RP Abate, JP Dilks, K Landis, J Ashraf, J Murphy, CT Blackwell, TK AF Oliveira, Riva P. Abate, Jess Porter Dilks, Kieran Landis, Jessica Ashraf, Jasmine Murphy, Coleen T. Blackwell, T. Keith TI Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/Nrf SO AGING CELL LA English DT Article DE aging; Caenorhabditis elegans; detoxification; insulin signaling; oxidative stress; SKN-1 ID TRANSCRIPTION FACTOR SKN-1; C-ELEGANS; OXIDATIVE-STRESS; LIFE-SPAN; MULTIDRUG-RESISTANCE; BINDING DOMAIN; DAF-16 TARGETS; INSULIN; MECHANISMS; EXPRESSION AB P>Studies in model organisms have identified regulatory processes that profoundly influence aging, many of which modulate resistance against environmental or metabolic stresses. In Caenorhabditis elegans, the transcription regulator SKN-1 is important for oxidative stress resistance and acts in multiple longevity pathways. SKN-1 is the ortholog of mammalian Nrf proteins, which induce Phase 2 detoxification genes in response to stress. Phase 2 enzymes defend against oxygen radicals and conjugate electrophiles that are produced by Phase 1 detoxification enzymes, which metabolize lipophilic compounds. Here, we have used expression profiling to identify genes and processes that are regulated by SKN-1 under normal and stress-response conditions. Under nonstressed conditions SKN-1 upregulates numerous genes involved in detoxification, cellular repair, and other functions, and downregulates a set of genes that reduce stress resistance and lifespan. Many of these genes appear to be direct SKN-1 targets, based upon presence of predicted SKN-binding sites in their promoters. The metalloid sodium arsenite induces skn-1-dependent activation of certain detoxification gene groups, including some that were not SKN-1-upregulated under normal conditions. An organic peroxide also triggers induction of a discrete Phase 2 gene set, but additionally stimulates a broad SKN-1-independent response. We conclude that under normal conditions SKN-1 has a wide range of functions in detoxification and other processes, including modulating mechanisms that reduce lifespan. In response to stress, SKN-1 and other regulators tailor transcription programs to meet the challenge at hand. Our findings reveal striking complexity in SKN-1 functions and the regulation of systemic detoxification defenses. C1 [Oliveira, Riva P.; Abate, Jess Porter; Blackwell, T. Keith] Harvard Univ, Sch Med, Harvard Stem Cell Inst,Dept Pathol, Joslin Diabet Ctr,Sect Dev & Stem Cell Biol, Boston, MA 02215 USA. [Dilks, Kieran; Landis, Jessica; Ashraf, Jasmine; Murphy, Coleen T.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Dept Mol Biol, Princeton, NJ 08544 USA. RP Blackwell, TK (reprint author), Harvard Univ, Sch Med, Harvard Stem Cell Inst,Dept Pathol, Joslin Diabet Ctr,Sect Dev & Stem Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM ctmurphy@princeton.edu; keith.blackwell@joslin.harvard.edu RI Oliveira, Riva/J-8408-2013 OI Oliveira, Riva/0000-0002-4917-7646 FU Kirchstein fellowship [GM70088, DK07260]; NIH [GM62891]; NSF; NIH National Center for Research Resources (NCRR) FX We thank Elizabeth Veal and Blackwell lab members for critically reading this manuscript, and Joe Baker and Aileen Zhen for early contributions to the study. Supported by a Kirchstein fellowship to RO (GM70088), training grant funding to RO and JPA (DK07260), NIH grant GM62891 to TKB, Pew Biomedical Scholar and Sloan Fellow funding to CTM, and an NSF Predoctoral fellowship to JL. Some nematode strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). NR 65 TC 126 Z9 130 U1 2 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD OCT PY 2009 VL 8 IS 5 BP 524 EP 541 DI 10.1111/j.1474-9726.2009.00501.x PG 18 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 498FU UT WOS:000270123400003 PM 19575768 ER PT J AU Schwer, B Eckersdorff, M Li, Y Silva, JC Fermin, D Kurtev, MV Giallourakis, C Comb, MJ Alt, FW Lombard, DB AF Schwer, Bjoern Eckersdorff, Mark Li, Yu Silva, Jeffrey C. Fermin, Damian Kurtev, Martin V. Giallourakis, Cosmas Comb, Michael J. Alt, Frederick W. Lombard, David B. TI Calorie restriction alters mitochondrial protein acetylation SO AGING CELL LA English DT Editorial Material DE calorie restriction; longevity; mass spectrometry; metabolism; mitochondria; sirtuins ID LYSINE ACETYLATION; CELLS; LIVER AB P>Calorie restriction (CR) increases lifespan in organisms ranging from budding yeast through mammals. Mitochondrial adaptation represents a key component of the response to CR. Molecular mechanisms underlying this adaptation are largely unknown. Here we show that lysine acetylation of mitochondrial proteins is altered during CR in a tissue-specific fashion. Via large-scale mass spectrometry screening, we identify 72 candidate proteins involved in a variety of metabolic pathways with altered acetylation during CR. Mitochondrial acetylation changes may play an important role in the pro-longevity CR response. C1 [Schwer, Bjoern; Giallourakis, Cosmas; Alt, Frederick W.; Lombard, David B.] Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. [Schwer, Bjoern; Giallourakis, Cosmas; Alt, Frederick W.; Lombard, David B.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Eckersdorff, Mark; Fermin, Damian; Lombard, David B.] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Lombard, David B.] Univ Michigan, Inst Gerontol, Ann Arbor, MI 48109 USA. [Li, Yu; Silva, Jeffrey C.; Comb, Michael J.] Cell Signaling Technol, Danvers, MA 01923 USA. [Kurtev, Martin V.] Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Alt, FW (reprint author), Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. EM alt@enders.tch.harvard.edu; davidlom@umich.edu FU Howard Hughes Medical Institute; NIA NIH HHS [K08 AG022325-06, AG022325, K08 AG022325]; NIGMS NIH HHS [T32 GM007753] NR 16 TC 139 Z9 145 U1 2 U2 20 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1474-9718 J9 AGING CELL JI Aging Cell PD OCT PY 2009 VL 8 IS 5 BP 604 EP 606 DI 10.1111/j.1474-9726.2009.00503.x PG 3 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 498FU UT WOS:000270123400010 PM 19594485 ER PT J AU Weiser, SD Bangsberg, DR Kegeles, S Ragland, K Kushel, MB Frongillo, EA AF Weiser, Sheri D. Bangsberg, David R. Kegeles, Susan Ragland, Kathleen Kushel, Margot B. Frongillo, Edward A. TI Food Insecurity Among Homeless and Marginally Housed Individuals Living with HIV/AIDS in San Francisco SO AIDS AND BEHAVIOR LA English DT Article DE Food insecurity; HIV/AIDS; San Francisco; Homeless ID ACTIVE ANTIRETROVIRAL THERAPY; BODY-MASS INDEX; DISEASE PROGRESSION; HIV-INFECTION; MENTAL-HEALTH; WELFARE RECIPIENTS; PATIENT POPULATION; NUTRITIONAL-STATUS; WEIGHT-LOSS; SURVIVAL AB Food insecurity is a risk factor for both HIV transmission and worse HIV clinical outcomes. We examined the prevalence of and factors associated with food insecurity among homeless and marginally housed HIV-infected individuals in San Francisco recruited from the Research on Access to Care in the Homeless Cohort. We used multiple logistic regression to determine socio-demographic and behavioral factors associated with food insecurity, which was measured using the Household Food Insecurity Access Scale. Among 250 participants, over half (53.6%) were food insecure. Higher odds of food insecurity was associated with being white, low CD4 counts, recent crack use, lack of health insurance, and worse physical and mental health. Food insecurity is highly prevalent among HIV-infected marginally housed individuals in San Francisco, and is associated with poor physical and mental health and poor social functioning. Screening for and addressing food insecurity should be a critical component of HIV prevention and treatment programs. C1 [Weiser, Sheri D.] Univ Calif San Francisco, Posit Hlth Program, San Francisco Gen Hosp, San Francisco, CA 94143 USA. [Weiser, Sheri D.; Kegeles, Susan] Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. [Bangsberg, David R.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Initiat Global Hlth, Boston, MA USA. [Ragland, Kathleen; Kushel, Margot B.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco Gen Hosp, San Francisco, CA 94143 USA. [Frongillo, Edward A.] Univ S Carolina, Dept Hlth Promot Educ & Behav, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. RP Weiser, SD (reprint author), Univ Calif San Francisco, Posit Hlth Program, San Francisco Gen Hosp, POB 0874, San Francisco, CA 94143 USA. EM Sheri.Weiser@ucsf.edu FU NCRR NIH HHS [UL1 RR024131]; NIAAA NIH HHS [K24 AA015287, K024 AA015287]; NIMH NIH HHS [K23 MH079713, K24 MH087227, R01 MH054907, K23 MH079713-01]; PHS HHS [R01 #54907] NR 54 TC 68 Z9 68 U1 1 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 OCT PY 2009 VL 13 IS 5 BP 841 EP 848 DI 10.1007/s10461-009-9597-z PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 502AI UT WOS:000270425800002 PM 19644748 ER PT J AU Mimiaga, MJ Reisner, SL Bland, S Skeer, M Cranston, K Isenberg, D Vega, BA Mayer, KH AF Mimiaga, Matthew J. Reisner, Sari L. Bland, Sean Skeer, Margie Cranston, Kevin Isenberg, Deborah Vega, Benny A. Mayer, Kenneth H. TI Health System and Personal Barriers Resulting in Decreased Utilization of HIV and STD Testing Services among At-Risk Black Men Who Have Sex with Men in Massachusetts SO AIDS PATIENT CARE AND STDS LA English DT Article ID NEW-YORK-CITY; BEHAVIORAL SURVEILLANCE SYSTEM; SEXUALLY-TRANSMITTED-DISEASES; AFRICAN-AMERICAN MEN; PACIFIC ISLANDER MEN; YOUNG MEN; CAGE QUESTIONNAIRE; PARTNER CHARACTERISTICS; PSYCHOMETRIC EVALUATION; UNITED-STATES AB Testing for HIV and other sexually transmitted diseases (STD) remains a cornerstone of public health prevention interventions. This analysis was designed to explore the frequency of testing, as well as health system and personal barriers to testing, among a community-recruited sample of Black men who have sex with men (MSM) at risk for HIV and STDs. Black MSM (n = 197) recruited via modified respondent-driven sampling between January and July 2008 completed an interviewer-administered assessment, with optional voluntary HIV counseling and testing. Logistic regression procedures examined factors associated with not having tested in the 2 years prior to study enrollment for: (1) HIV (among HIV-uninfected participants, n 145) and (2) STDs (among the entire mixed serostatus sample, n = 197). The odds ratios and their 95% confidence intervals obtained from this analysis were converted to relative risks. (1) HIV: Overall, 33% of HIV-uninfected Black MSM had not been tested for HIV in the 2 years prior to study enrollment. Factors uniquely associated with not having a recent HIV test included: being less educated; engaging in serodiscordant unprotected sex; and never having been HIV tested at a community health clinic, STD clinic, or jail. (2) STDs: Sixty percent had not been tested for STDs in the 2 years prior to study enrollment, and 24% of the sample had never been tested for STDs. Factors uniquely associated with not having a recent STD test included: older age; having had a prior STD; and never having been tested at an emergency department or urgent care clinic. Overlapping factors associated with both not having had a recent HIV or STD test included: substance use during sex; feeling that using a condom during sex is "very difficult''; less frequent contact with other MSM; not visiting a health care provider (HCP) in the past 12 months; having a HCP not recommend HIV or STD testing at their last visit; not having a primary care provider (PCP); current PCP never recommending they get tested for HIV or STDs. In multivariable models adjusting for relevant demographic and behavioral factors, Black MSM who reported that a HCP recommended getting an HIV test (adjusted relative risk [ARR] = 0.26; p = 0.01) or STD test (ARR = 0.11; p = 0.0004) at their last visit in the past 12 months were significantly less likely to have not been tested for HIV or STDs in the past 2 years. Many sexually active Black MSM do not regularly test for HIV or STDs. HCPs play a pivotal role in encouraging testing for Black MSM. Additional provider training is warranted to educate HCPs about the specific health care needs of Black MSM, in order to facilitate access to timely, culturally competent HIV and STD testing and treatment services for this population. C1 [Mimiaga, Matthew J.; Reisner, Sari L.; Bland, Sean; Skeer, Margie; Vega, Benny A.; Mayer, Kenneth H.] Fenway Hlth, Fenway Inst, Boston, MA USA. [Mimiaga, Matthew J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Mimiaga, Matthew J.; Reisner, Sari L.; Skeer, Margie] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Cranston, Kevin; Isenberg, Deborah] Massachusetts Dept Publ Hlth, Boston, MA USA. [Mayer, Kenneth H.] Miriam Hosp, Brown Med Sch, Providence, RI 02906 USA. RP Mimiaga, MJ (reprint author), Fenway Community Hlth, Fenway Inst, Prudential Tower,4th Floor,800 Boylston St, Boston, MA 02119 USA. EM mmimiaga@fenwayhealth.org FU Office of HIV/AIDS, Massachusetts Department of Public Health; National Institute on Drug Abuse (PI: M. Mimiaga) [R03DA023393] FX This work was funded by the Office of HIV/AIDS, Massachusetts Department of Public Health. Some of the investigator time on this project was supported by grant number R03DA023393 from the National Institute on Drug Abuse (PI: M. Mimiaga). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. NR 70 TC 53 Z9 56 U1 3 U2 11 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD OCT PY 2009 VL 23 IS 10 BP 825 EP 835 DI 10.1089/apc.2009.0086 PG 11 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 505VM UT WOS:000270727200005 PM 19803696 ER PT J AU Maccioni, P Carai, MAM Kaupmann, K Guery, S Froestl, W Leite-Morris, KA Gessa, GL Colombo, G AF Maccioni, Paola Carai, Mauro A. M. Kaupmann, Klemens Guery, Sebastien Froestl, Wolfgang Leite-Morris, Kimberly A. Gessa, Gian Luigi Colombo, Giancarlo TI Reduction of Alcohol's Reinforcing and Motivational Properties by the Positive Allosteric Modulator of the GABA(B) Receptor, BHF177, in Alcohol-Preferring Rats SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE GABA(B) Receptor; Positive Allosteric Modulators of the GABA(B) Receptor; BHF177; Alcohol Self-Administration; Fixed Ratio (FR) and Progressive Ratio (PR) Schedules of Reinforcement; Alcohol's Reinforcing and Motivational Properties; Sardinian Alcohol-Preferring (sP) Rats ID MIDBRAIN DOPAMINE NEURONS; AGONIST BACLOFEN; PRESYNAPTIC INHIBITION; ETHANOL SEEKING; ANIMAL-MODELS; B RECEPTORS; GS39783; SUCROSE; COCAINE; CGP7930 AB Background: The positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, have been found to reduce alcohol self-administration in alcohol-preferring rats. The present study was designed to assess the effect of the newly synthesized positive allosteric modulator of the GABA(B) receptor, BHF177, on alcohol's reinforcing and motivational properties in selectively bred Sardinian alcohol-preferring (sP) rats. Methods: sP rats were initially trained to respond on a lever [on a fixed ratio 4 (FR4) schedule of reinforcement] to orally self-administer alcohol (15%, v/v) or sucrose (1 to 3%, w/v) in daily 30-minute sessions. Once responding reached stable levels, rats were allocated to 2 different experiments: in the first experiment, rats were exposed to sessions with the FR4 schedule of reinforcement; in the second experiment, rats were exposed to sessions with a conventional progressive ratio (PR) schedule of reinforcement. In both experiments, the effect of BHF177 (0, 12.5, 25, and 50 mg/kg; i.g.) on responding for alcohol and sucrose (FR experiment: 1%, w/v; PR experiment: 3%, w/v) was determined. Results: In the FR experiment, pretreatment with 25 and 50 mg/kg BHF177 produced a 30 and 45% reduction, respectively, in responding for alcohol. In the PR experiment, pretreatment with 50 mg/kg BHF177 resulted in a 35% reduction in breakpoint for alcohol (defined as the lowest response requirement not achieved by each rat and used as index of the motivational strength of alcohol). In both experiments, the effect of BHF177 on alcohol self-administration was specific, since responding for sucrose was unaltered by BHF177 pretreatment. Conclusions: The present results extend to BHF177 the capacity of the 2 previously tested positive allosteric modulators of the GABA(B) receptor, CGP7930 and GS39783, to specifically suppress alcohol's reinforcing and motivational properties in alcohol-preferring rats. C1 [Maccioni, Paola; Carai, Mauro A. M.; Gessa, Gian Luigi; Colombo, Giancarlo] CNR, Inst Neurosci, I-09126 Cagliari, CA, Italy. [Kaupmann, Klemens] Novartis Inst BioMed Res, Basel, Switzerland. [Guery, Sebastien] IMD Int, Lausanne, Switzerland. [Froestl, Wolfgang] AC Immune SA, Lausanne, Switzerland. [Leite-Morris, Kimberly A.] Boston Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Div Psychiat, Boston, MA 02118 USA. [Leite-Morris, Kimberly A.] Boston VA Healthcare Syst, Res Serv, Boston, MA USA. RP Colombo, G (reprint author), CNR, Inst Neurosci, Viale Diaz 182, I-09126 Cagliari, CA, Italy. EM colomb@unica.it OI Leite-Morris, Kimberly/0000-0003-3407-7375 NR 37 TC 30 Z9 30 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD OCT PY 2009 VL 33 IS 10 BP 1749 EP 1756 DI 10.1111/j.1530-0277.2009.01012.x PG 8 WC Substance Abuse SC Substance Abuse GA 497OD UT WOS:000270068400011 PM 19572981 ER PT J AU Laine, L Connors, L Griffin, MR Curtis, SP Kaur, A Cannon, CP AF Laine, L. Connors, L. Griffin, M. R. Curtis, S. P. Kaur, A. Cannon, C. P. TI Prescription rates of protective co-therapy for NSAID users at high GI risk and results of attempts to improve adherence to guidelines SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; INHIBITORS; AGENTS; GASTROPROTECTION; OSTEOARTHRITIS; POPULATION; MANAGEMENT; COSTS AB P>Background Protective co-therapy is recommended in NSAID users with GI risk factors, but adherence is poor. Aim To assess the proportion of NSAID users receiving co-therapy and strategies to improve adherence. Methods Arthritis patients >= 50 years of age received etoricoxib or diclofenac in a double-blind randomized trial. Reminders that high-risk patients (age >= 65; previous ulcer/haemorrhage; corticosteroid, anticoagulant, aspirin use) should receive co-therapy were given at study initiation. Free PPI was provided. An intervention midway through the study included a written reminder and required written response regarding co-therapy. Results 16 244/23 504 (69%) patients had GI risk factors. Pre-intervention, co-therapy was most common with previous ulcer/haemorrhage [706/1107 (64%)] and 3-4 risk factors [331/519 (64%)]. In the 10 026 patients enrolled pre-intervention and remaining in the study >= 6 months after, co-therapy in high-risk patients increased from 2958/6843 (43%) to 4177/6843 (61%) (difference = 18%; 95% CI 16%,19%). The increase was greater outside the US (22%; 19%,24%) than in the US (15%; 13%,17%). Conclusions Less than 50% of NSAID users with GI risk factors are given protective co-therapy - even if prescribers are given reminders and cost is not an issue. Direct communication requiring written response significantly increased adherence to guidelines, but achieving higher levels of adherence will require additional strategies. C1 [Laine, L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Connors, L.; Curtis, S. P.; Kaur, A.] Merck Res Labs, Rahway, NJ USA. [Griffin, M. R.] Vanderbilt Univ, Med Ctr, Dept Prevent Med, Nashville, TN USA. [Cannon, C. P.] Harvard Univ, Brigham & Womens Hosp, Thrombolysis Myocardial Infarct TIMI Study Grp, Cardiovasc Div,Dept Med,Med Sch, Boston, MA 02115 USA. RP Laine, L (reprint author), Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, 2025 Zonal Ave, Los Angeles, CA 90033 USA. EM llaine@usc.edu OI Connors, Lawreen/0000-0002-4672-4296 FU TAP; Glaxo SmithKline; Merck; Pfizer; Accumetrics; AstraZeneca; Bristol-Myers Squibb/Sanofi; Merck/Schering Plough; Merck Co., Inc.; Whitehouse Station, NJ FX Declaration of personal interests: L. Laine has served as a consultant for Merck, AstraZeneca, Horizon, Santarus, Eisai, and Pozen; has received research funding from TAP and Glaxo SmithKline; and has served on a data safety and monitoring board for Pfizer and Bayer. L. Connors, S. Curtis, A. Kaur are employees of Merck and own stock and/or stock options. M. Griffin has served on a data safety and monitoring board for Merck and received research funding from Merck and Pfizer. C. Cannon has served as a consultant to Audiomedics; has received research funding from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi partnership, Glaxo Smith Kline, and Merck/Schering Plough partnership; and has equity in Audiomedics Medical Systems. Declaration of funding interests: This study was funded by Merck & Co., Inc., Whitehouse Station, NJ. The authors performed the analyses and wrote the manuscript without outside assistance or support. NR 21 TC 23 Z9 23 U1 3 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD OCT 1 PY 2009 VL 30 IS 7 BP 767 EP 774 DI 10.1111/j.1365-2036.2009.04090.x PG 8 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 490WE UT WOS:000269538000010 PM 19594486 ER PT J AU Bradford, A Kunik, ME Schulz, P Williams, SP Singh, H AF Bradford, Andrea Kunik, Mark E. Schulz, Paul Williams, Susan P. Singh, Hardeep TI Missed and Delayed Diagnosis of Dementia in Primary Care Prevalence and Contributing Factors SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Review DE dementia; diagnostic errors; primary care ID GENERAL-PRACTITIONERS; ALZHEIMERS-DISEASE; COGNITIVE IMPAIRMENT; HEALTH-CARE; ELDERLY PATIENTS; UNITED-STATES; MENTAL-STATE; PHYSICIANS; ATTITUDES; PERSPECTIVES AB Dementia is a growing public health problem for which early detection may be beneficial. Currently, the diagnosis of dementia in primary care is dependent mostly on clinical suspicion on the basis of patient symptoms or caregivers' concerns and is prone to be missed or delayed. We conducted a systematic review of the literature to ascertain the prevalence and contributing factors for missed and delayed dementia diagnoses in primary care. Prevalence of missed and delayed diagnosis was estimated by abstracting quantitative data from studies of diagnostic sensitivity among primary care providers. Possible predictors and contribution factory factors were determined from the text of quantitative and qualitative Studies of patient, caregiver, provider, and system-related barriers. Overall estimates of diagnostic sensitivity varied among studies and seemed to be in part a function of dementia severity, degree of patient impairment, dementia subtype, and frequency of patient-provider contact. Major contributory factors included problems with attitudes and patient-provider communication, educational deficits. and system resource constraints. The true prevalence of missed and delayed diagnoses of dementia is unknown but seems to be high. Until the case for dementia screening becomes more compelling, efforts to promote timely detection should focus on removing barriers to diagnosis. C1 [Bradford, Andrea] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Kunik, Mark E.] Baylor Coll Med, Houston VA HSR&D Ctr Excellence, Hlth Serv Delivery & Org Program, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Kunik, Mark E.; Singh, Hardeep] Baylor Coll Med, Sect Hlth Serv Res, Dept Med, Houston, TX 77030 USA. [Schulz, Paul] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA. [Williams, Susan P.] Baylor Coll Med, Dept Med, Sect Geriatr, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Hlth Policy & Qual Program, Houston VA HSR&D Ctr Excellence, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Singh, Hardeep] Baylor Coll Med, Ctr Inquiry Improve Outpatient Safety Effect Elec, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. RP Bradford, A (reprint author), Baylor Coll Med, Dept Psychiat & Behav Sci, VA Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM abradfor@bcm.tmc.edu OI Bradford, Andrea/0000-0002-8390-8844 FU NIH K23 career development award [K23CA125585]; Houston VA HSR&D Center of Excellence [HFP90-020] FX The study was supported by an NIH K23 career development award (K23CA125585) to Dr Singh, and in part by the Houston VA HSR&D Center of Excellence (HFP90-020). NR 76 TC 120 Z9 124 U1 4 U2 21 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 OCT-DEC PY 2009 VL 23 IS 4 BP 306 EP 314 PG 9 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 527XE UT WOS:000272403700002 PM 19568149 ER PT J AU Krueger, KR Wilson, RS Bennett, DA Aggarwal, NT AF Krueger, Kristin R. Wilson, Robert S. Bennett, David A. Aggarwal, Neelum T. TI A Battery of Tests for Assessing Cognitive Function in Older Latino Persons SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Spanish language tests; cognitive domains; cognitive function; longitudinal studies ID ALZHEIMERS-DISEASE; NEUROPSYCHOLOGICAL BATTERY; INDIVIDUAL-DIFFERENCES; SPANISH-SPEAKING; COMMUNITY; ENGLISH; PERFORMANCE; IMPAIRMENT; SYSTEMS; AGE AB With the proportion of older Latinos in the United States rapidly growing, dementia is expected to be an increasing public health problem in this segment of the population. Yet relatively few cognitive test batteries have been developed for evaluating older Spanish-speaking- persons. We selected a batter), of cognitive tests used in cognitive aging studies of English speakers, adapted it for Spanish speakers, and administered it to 66 older Latinos (mean age = 71.1, SD = 8.1). The results of a factor analysis supported grouping the tests into the same 5 functional domains identified for English speakers. Composite measures of performance in each domain were positively related to education and. with some exceptions, inversely related to age. The results suggest that this battery may be useful in epidemiologic research on cognition in older Latinos. C1 [Krueger, Kristin R.; Wilson, Robert S.; Bennett, David A.; Aggarwal, Neelum T.] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. [Krueger, Kristin R.; Wilson, Robert S.] Rush Univ, Med Ctr, Dept Behav Sci, Chicago, IL 60612 USA. [Wilson, Robert S.; Bennett, David A.; Aggarwal, Neelum T.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. RP Krueger, KR (reprint author), S Texas Vet Hlth Care Syst, Audie L Murphy Div, 7400 Merton Minter Blvd, San Antonio, TX 78229 USA. EM Kristin.Krueger@va.gov FU National Institute on Aging [P30 AG10161] FX Supported by grant P30 AG10161 from the National Institute on Aging. NR 30 TC 11 Z9 11 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD OCT-DEC PY 2009 VL 23 IS 4 BP 384 EP 388 PG 5 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 527XE UT WOS:000272403700014 PM 19561439 ER PT J AU Cannon, CP Dansky, HM Davidson, M Gotto, AM Brinton, EA Gould, AL Stepanavage, M Liu, SX Shah, S Rubino, J Gibbons, P Hermanowski-Vosatka, A Binkowitz, B Mitchel, Y Barter, P AF Cannon, Christopher P. Dansky, Hayes M. Davidson, Michael Gotto, Antonio M., Jr. Brinton, Eliot A. Gould, A. Lawrence Stepanavage, Michael Liu, Sherry Xueyu Shah, Sukrut Rubino, Joseph Gibbons, Patrice Hermanowski-Vosatka, Anne Binkowitz, Bruce Mitchel, Yale Barter, Philip CA DEFINE Investigators TI Design of the DEFINE trial: Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib SO AMERICAN HEART JOURNAL LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; ESTER TRANSFER PROTEIN; CHOLESTEROL LEVELS; THERAPEUTIC TARGET; HDL CHOLESTEROL; TORCETRAPIB; ATHEROSCLEROSIS; ATORVASTATIN; STATINS; SAFETY AB Background Residual cardiovascular (CV) risk often remains high despite statin therapy to lower low-density lipoprotein cholesterol (LDL-C). New therapies to raise high-density lipoprotein cholesterol (HDL-C) are currently being investigated. Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that raises HDL-C and reduces LDL-C when administered alone or with a statin. Adverse effects on blood pressure, electrolytes, and aldosterone levels, seen with another drug in this class, have not been noted in studies of anacetrapib to date. Methods Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib (DEFINE) is a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety profile of anacetrapib in patients with coronary heart disease (CHD) or CHID risk equivalents (clinical trials.gov NCT00685776). Eligible patients at National Cholesterol Education Program-Adult Treatment Panel III LDL-C treatment goal on a statin, with or without other lipid-modifying medications, are treated with anacetrapib, 100 mg, or placebo for 18 months, followed by a 3-month, poststudy follow-up. The primary end points are percent change from baseline in LDL-C and the safety and tolerability of anacetrapib. Comprehensive preplanned interim safety analyses will be performed at the 6- and 12-month time points to examine treatment effects on key safety end points, including blood pressure and electrolytes. A preplanned Bayesian analysis will be performed to interpret the CV event distribution, given the limited number of events expected in this study. Results A total of 2,757 patients were screened at 153 centers in 20 countries, and 1,623 patients were randomized into the trial. Lipid results, clinical CV events, and safety outcomes from this trial are anticipated in 2010. (Am Heart J 2009; 158:513-9.) C1 [Cannon, Christopher P.] Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. [Dansky, Hayes M.; Stepanavage, Michael; Liu, Sherry Xueyu; Shah, Sukrut; Gibbons, Patrice; Hermanowski-Vosatka, Anne; Binkowitz, Bruce; Mitchel, Yale] Merck Res Labs, Rahway, NJ USA. [Davidson, Michael; Brinton, Eliot A.] Radiant Res, Chicago, IL USA. [Gotto, Antonio M., Jr.] Weill Cornell Med Coll, New York, NY USA. Univ Utah, Sch Med, Salt Lake City, UT USA. [Gould, A. Lawrence; Rubino, Joseph] Merck Res Labs, Upper Gwynedd, PA USA. [Barter, Philip] Heart Res Inst, Sydney, NSW, Australia. RP Cannon, CP (reprint author), Brigham & Womens Hosp, Div Cardiovasc, TIMI Study Grp, 350 Longwood Ave,1st Floor, Boston, MA 02115 USA. EM cpcannon@partners.org FU Accumetrics, San Diego, CA; AstraZeneca, Wilmington, DE; Bristol-Myers Squibb, Princeton, NJ/Sanofi Partnership, Paris, France; Glaxo Smith Kline, Philadelphia, PA; Intekrin, Los Altos, CA; Merck, Whitehouse Station, NJ; Merck/Schering Plough Partnership, Kenilworth, NJ; Abbott; Pfizer; Sanofi-Aventis; Takeda Pharmaceuticals; Merck Research Laboratories, Rahway, NJ FX The DEFINE study and the study analyses were funded by Merck Research Laboratories, Rahway, NJ. The first draft of the manuscript was prepared by Dr Cannon, with edits and comments provided by all coauthors. The authors wish to thank Christine McCrary Sisk (Merck Research Laboratories) for her contributions in editing this manuscript. NR 22 TC 60 Z9 60 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD OCT PY 2009 VL 158 IS 4 BP 513 EP + DI 10.1016/j.ahj.2009.07.028 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 505PI UT WOS:000270706100004 PM 19781408 ER PT J AU Heidenreich, PA Lewis, WR LaBresh, KA Schwamm, LH Fonarow, GC AF Heidenreich, Paul A. Lewis, William R. LaBresh, Kenneth A. Schwamm, Lee H. Fonarow, Gregg C. TI Hospital performance recognition with the Get With The Guidelines Program and mortality for acute myocardial infarction and heart failure SO AMERICAN HEART JOURNAL LA English DT Article ID TRANSIENT ISCHEMIC ATTACK; ASSOCIATION TASK-FORCE; AMERICAN-COLLEGE; ST-ELEVATION; QUALITY; INCOME; RATES; IMPROVEMENT; MANAGEMENT; EDUCATION AB Background Many hospitals enrolled in the American Heart Association's Get With The Guidelines (GWTG) Program achieve high levels of recommended care for heart failure, acute myocardial infarction (MI) and stroke. However, it is unclear if outcomes are better in those hospitals recognized by the GWTG program for their processes of care. Methods We compared hospitals enrolled in GWTG and receiving achievement awards for high levels of recommended processes of care with other hospitals using data on risk-adjusted 30-day survival for heart failure and acute MI reported by the Center for Medicare and Medicaid Services. Results Among the 3,909 hospitals with 30-day data reported by Center for Medicare and Medicaid Services 355 (9%) received GWTG achievement awards. Risk-adjusted mortality for hospitals receiving awards was lower for both heart failure (11.0% vs 11.2%, P = .0005) and acute MI (16.1% vs 16.5%, P < .0001) compared to those not receiving awards. After additional adjustment for hospital characteristics and noncardiac performance measures, the reduction in mortality remained significantly lower for GWTG award hospitals for acute myocardial infraction (-0.19%, 95% CI -0.33 to -0.05), but not for heart failure (-0.11%, 95% CI -0.25 to 0.02). Additional adjustment for cardiac processes of care reduced the benefit of award hospitals by 28% for heart failure mortality and 43% for acute MI mortality. Conclusions Hospitals receiving achievement awards from the GWTG program have modestly lower risk adjusted mortality for acute MI and to a lesser extent, heart failure, explained in part by better process of care. (Am Heart J 2009; 158:546-53.) C1 [Heidenreich, Paul A.] VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. [Lewis, William R.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [LaBresh, Kenneth A.] RTI Int Waltham, Waltham, MA USA. [Schwamm, Lee H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Fonarow, Gregg C.] Ahmanson UCLA Cardiomyopathy Ctr, Los Angeles, CA USA. RP Heidenreich, PA (reprint author), VA Palo Alto Hlth Care Syst, 111C Cardiol,3801 Miranda Ave, Palo Alto, CA 94304 USA. EM heiden@stanford.edu RI LaBresh, Kenneth/A-6995-2017; OI LaBresh, Kenneth/0000-0001-9040-1956; Heidenreich, Paul/0000-0001-7730-8490; Schwamm, Lee/0000-0003-0592-9145 FU GlaxoSmithKline; Merck/Schering-Plough Partnership FX Program disclosure: GWTG is a program of the AHA and is Supported in part by unrestricted educational grants from GlaxoSmithKline and Merck/Schering-Plough Partnership. NR 25 TC 40 Z9 41 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD OCT PY 2009 VL 158 IS 4 BP 546 EP 553 DI 10.1016/j.ahj.2009.07.031 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 505PI UT WOS:000270706100009 PM 19781413 ER PT J AU Mahabadi, AA Bamberg, F Toepker, M Schlett, CL Rogers, IS Nagurney, JT Brady, TJ Hoffmann, U Truong, QA AF Mahabadi, Amir A. Bamberg, Fabian Toepker, Michael Schlett, Christopher L. Rogers, Ian S. Nagurney, John T. Brady, Thomas J. Hoffmann, Udo Truong, Quynh A. TI Association of aortic valve calcification to the presence, extent, and composition of coronary artery plaque burden: From the Rule Out Myocardial Infarction using Computer Assisted Tomography (ROMICAT) trial SO AMERICAN HEART JOURNAL LA English DT Article ID C-REACTIVE PROTEIN; ATHEROSCLEROTIC PLAQUE; STENOSIS; PROGRESSION; CALCIUM; INFLAMMATION; ANGIOGRAPHY; POPULATION; DISEASE AB Background Aortic valve calcification (AVC) is associated with cardiovascular risk factors and coronary artery calcification. We sought to determine whether AVC is associated with the presence and extent of overall plaque burden, as well as to plaque composition (calcified, mixed, and noncalcified). Methods We examined 357 subjects (mean age 53 12 years, 61% male) who underwent contrast-enhanced electrocardiogram-gated 64-slice multidetector computed tomography from the ROMICAT trial for the assessment of presence and extent of coronary plaque burden according to the 17-coronary segment model and presence of AVC. Results Patients with AVC (n = 37, 10%) were more likely than those without AVC (n = 320, 90%) to have coexisting presence of any coronary plaque (89% vs 46%, P < .001) and had a greater extent of coronary plaque burden (6.4 vs 1.8 segments, P < .001). Those with AVC had >3-fold increase odds of having any plaque (adjusted odds ratio [OR] 3.6, P = .047) and an increase of 2.5 segments of plaque (P < .001) as compared to those without AVC. When stratified by plaque composition, AVC was associated most with calcified plaque (OR 5.2, P = .004), then mixed plaque (OR 3.2, P = .02), but not with noncalcified plaque (P = .96). Conclusion Aortic valve calcification is associated with the presence and greater extent of coronary artery plaque burden and may be part of the later stages of the atherosclerosis process, as its relation is strongest with calcified plaque, less with mixed plaque, and nonsignificant with noncalcified plaque. If AVC is present, consideration for aggressive medical therapy may be warranted. (Am Heart J 2009;158:562-8.) C1 [Mahabadi, Amir A.; Toepker, Michael; Schlett, Christopher L.; Rogers, Ian S.; Brady, Thomas J.; Hoffmann, Udo; Truong, Quynh A.] Harvard Univ, Cardiac MR PET CT Program, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Bamberg, Fabian] Univ Munich, Klinikum Grosshadern, Dept Clin Radiol, D-8000 Munich, Germany. [Rogers, Ian S.; Truong, Quynh A.] Harvard Univ, Div Cardiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Nagurney, John T.] Harvard Univ, Dept Emergency Med, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. [Brady, Thomas J.; Hoffmann, Udo; Truong, Quynh A.] Harvard Univ, Dept Radiol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Truong, QA (reprint author), Harvard Univ, Cardiac MR PET CT Program, Massachusetts Gen Hosp, Sch Med, 165 Cambridge St,Suite 400, Boston, MA 02114 USA. EM qtruong@partners.org FU NHLBI NIH HHS [T32 HL076136, T32 HL076136-05, K23 HL098370, L30 HL093806, L30 HL093806-01, R01 HL080053, R01 HL080053-03] NR 26 TC 15 Z9 15 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD OCT PY 2009 VL 158 IS 4 BP 562 EP 568 DI 10.1016/j.ahj.2009.07.027 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 505PI UT WOS:000270706100011 PM 19781415 ER PT J AU Forman, DE Clare, R Kitzman, DW Ellis, SJ Fleg, JL Chiara, T Fletcher, G Kraus, WE AF Forman, Daniel E. Clare, Robert Kitzman, Dalane W. Ellis, Stephen J. Fleg, Jerome L. Chiara, Toni Fletcher, Gerald Kraus, William E. CA HF-ACTION Investigators TI Relationship of age and exercise performance in patients with heart failure: The HF-ACTION study SO AMERICAN HEART JOURNAL LA English DT Article ID TRIAL INVESTIGATING OUTCOMES; BODY-MASS INDEX; CHRONOTROPIC INCOMPETENCE; VENTILATORY EFFICIENCY; AEROBIC CAPACITY; EJECTION FRACTION; VE/VCO2 SLOPE; ADVANCING AGE; HEALTHY-MEN; ARTERIAL AB Background More than three fourths of patients with heart failure (HF) are 65 years and older, and older age is associated with worse symptoms and prognoses than is younger age. Reduced exercise capacity is a chief HF complaint and indicates poorer prognosis, especially among elderly persons, but the mechanisms underlying functional decline in older patients with HF are largely unknown. Methods Baseline cardiopulmonary exercise testing data from the HF-ACTION trial were assessed to clarify age effects on peak oxygen consumption (VO(2)) and ventilation-carbon dioxide production (VE/VCO(2)) slope. Results Among 2,331 New York Heart Association class II-IV patients with HF, increased age corresponded to decreased peak VO(2) (-0.14 mL kg(-1) min(-1) per year >40 years; P<.0001) and increased VE/VCO(2) slope (0.30 U/y>70years; P<.0001). In a multivariable model with 34 other potential determinants, age was the strongest independent predictor of peak VO(2) (partial R(2) 0.130, total R(2) 0.392; P<.001) and a significant but relatively weaker predictor of VE/VCO(2) slope (partial R(2) 0.037, total R(2) 0.199; P<.001). Blunted peak heart rate was also a strong predictor of peak VO(2). Although peak heart rate and age were strongly correlated, both were significant independent predictors of peak VO(2) when analyzed simultaneously in a model. Aggregate comorbidity increased significantly with age but did not account for age effects on peak VO(2). Conclusions Age is the strongest predictor of peak VO(2) and a significant predictor of VE/VCO(2) slope in the HF-ACTION population. Age-dependent comorbidities do not explain changes in peak VO(2). Age-related changes in cardiovascular physiology, potentially magnified by the HF disease state, should be considered a contributor to the pathophysiology and a target for more effective therapy in older patients with HF. (Am Heart J 2009; 1 58:S6-S15.) C1 [Kraus, William E.] Duke Univ, Med Ctr, Dept Med, Div Cardiol, Durham, NC 27710 USA. [Forman, Daniel E.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Forman, Daniel E.] VA Boston Healthcare Syst, Ctr Geriatr Res Educ & Clin, Boston, MA USA. [Clare, Robert; Ellis, Stephen J.] Duke Clin Res Inst, Durham, NC USA. [Kitzman, Dalane W.] Wake Forest Univ Hlth Sci, Dept Internal Med, Cardiol Sect, Winston Salem, NC USA. [Kitzman, Dalane W.] Wake Forest Univ Hlth Sci, Dept Internal Med, Sect Geriatr, Winston Salem, NC USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Dis, Bethesda, MD 20892 USA. [Chiara, Toni] Univ Florida, Coll Publ Hlth & Hlth Profess, Dept Phys Therapy, Malcom Randall VA Med Ctr, Gainesville, FL USA. [Fletcher, Gerald] Mayo Clin Jacksonville, Jacksonville, FL 32224 USA. RP Kraus, WE (reprint author), Duke Univ, Med Ctr, Dept Med, Div Cardiol, POB 3327, Durham, NC 27710 USA. EM william.kraus@duke.edu OI Kraus, William E/0000-0003-1930-9684 FU National Institutes of Health [5U01HL063747, 5U01HL068973, 5UO1HL066501, 5U01HL066482, 5U01HL064250, 5U01HL066494, 5U01HL064257, 5U01HL066497, 5U01HL068980, 5U01HL064265, 5U01HL066491, 5U01HL064264, R37AG18915, P60AG10484] FX A complete list of the HF-ACTION investigators is available as on appendix in the introduction of this supplement. This study was supported by National Institutes of Health grants 5U01HL063747, 5U01HL068973, 5UO1HL066501, 5U01HL066482, 5U01HL064250, 5U01HL066494, 5U01HL064257, 5U01HL066497, 5U01HL068980, 5U01HL064265, 5U01HL066491, 5U01HL064264, R37AG18915, and P60AG10484. NR 40 TC 17 Z9 18 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD OCT PY 2009 VL 158 IS 4 BP S6 EP S15 DI 10.1016/j.ahj.2009.07.018 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 505PG UT WOS:000270705800002 PM 19782790 ER PT J AU Spies, C Farzaneh-Far, R Na, B Kanaya, A Schiller, NB Whooley, MA AF Spies, Christian Farzaneh-Far, Ramin Na, Beeya Kanaya, Alka Schiller, Nelson B. Whooley, Mary A. TI Relation of Obesity to Heart Failure Hospitalization and Cardiovascular Events in Persons With Stable Coronary Heart Disease (from the Heart and Soul Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID BODY-MASS INDEX; DEPRESSIVE SYMPTOMS; ABDOMINAL OBESITY; RISK; MORTALITY; WEIGHT; DYSFUNCTION; DISORDERS; ADIPOSITY; INSULIN AB Obesity is an independent risk factor for recurrent events among patients with established coronary heart disease (CHD). The goal of the present study was to identify potential mechanisms underlying this association. We measured the waist-to-hip ratio and body mass index in 979 outpatients with stable CHD and followed them for a mean of 4.9 years. We used proportional hazards models to evaluate the extent to which the association of obesity with subsequent heart failure (HF) hospitalization or cardiovascular (CV) events (myocardial infarction, stroke, or CHD death) was explained by baseline co-morbidities, cardiac disease severity, inflammation, insulin resistance, neurohormones and adipokines. Of the 979 participants, 128 (13%) were hospitalized for HF and 152 (16%) developed a CV event. Each standard deviation (SD) increase in the waist-to-hip ratio was associated with a 30% increased risk of HF hospitalization (unadjusted hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.1 to 1.6). This association was not attenuated after adjustment for potential mediators (HR 1.6, 95% CI 1.2 to 2.1.). Likewise, each SD increase in the waist-to-hip ratio was associated with a 20% greater risk of CV events (unadjusted HR 1.2, 95% CI 1.0 to 1.4), and this remained unchanged after adjustment for potential mediators (adjusted HR 1.3, 95% CI 1.0 to 1.5). The body mass index was not associated with the risk of HF or CV events. In conclusion, abdominal obesity is an independent predictor of HF hospitalization and recurrent CV events in patients with stable CHD. This association does not appear to be mediated by co-morbid conditions, cardiac disease severity, insulin resistance, inflammation, neurohormones, or adipokines. (C) 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:883-889) C1 [Farzaneh-Far, Ramin; Na, Beeya; Whooley, Mary A.] Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. [Spies, Christian] Queens Med Ctr, Honolulu, HI USA. [Farzaneh-Far, Ramin; Kanaya, Alka; Schiller, Nelson B.; Whooley, Mary A.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Whooley, Mary A.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Farzaneh-Far, R (reprint author), Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94143 USA. EM rfarzanehfar@medicine.ucsf.edu FU Department of Veterans Affairs, Washington, DC; National Heart Lung and Blood Institute [RO 1 HL079235] FX The Heart and Soul Study was funded by the Department of Veterans Affairs, Washington, DC; the National Heart Lung and Blood Institute, Grant RO 1 HL079235, Bethesda, Maryland; the American Federation for Aging Research (Paul Beeson Scholars Program), New York, New York; the Robert Wood Johnson Foundation (Faculty Scholars Program), Princeton, New Jersey; and the Nancy Kirwan Heart Research Fund, San Francisco, California. Dr. Farzaneh-Far was supported by an American Heart Association Fellow-to-Faculty Transition Award (Dallas, Texas). NR 30 TC 11 Z9 12 U1 1 U2 4 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 OCT 1 PY 2009 VL 104 IS 7 BP 883 EP 889 DI 10.1016/j.amjcard.2009.05.027 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 503MG UT WOS:000270537800003 PM 19766751 ER PT J AU Yosefy, C Hung, J Chua, S Vaturi, M Ton-Nu, TT Handschumacher, MD Levine, RA AF Yosefy, Chaim Hung, Judy Chua, Sarah Vaturi, Mordehay Ton-Nu, Thanh-Thao Handschumacher, Mark D. Levine, Robert A. TI Direct Measurement of Vena Contracta Area by Real-Time 3-Dimensional Echocardiography for Assessing Severity of Mitral Regurgitation SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID QUANTITATIVE DOPPLER ASSESSMENT; FLOW MAPPING PREDICTS; CHRONIC ANIMAL-MODEL; COLOR DOPPLER; ORIFICE AREA; VALVULAR REGURGITATION; AORTIC REGURGITATION; JET AREA; QUANTIFICATION; VOLUME AB We tested the hypothesis that the vena contracta (VC) cross-sectional area in patients with mitral regurgitation (MR) can be reproducibly measured by real-time 3-dimensional (3D) echocardiography and correlates well with the volumetric effective regurgitant orifice area (EROA). Earlier MR repair requires accurate noninvasive measures, but practically, the VC area is difficult to image in 2-dimensional views, which are often oblique to it. 3D echocardiography can provide an otherwise unobtainable true cross-sectional view. In 45 patients with mild or greater MR, 44% eccentric, 2-dimensional and 3D VC areas were measured and correlated with the EROA derived from the regurgitant stroke volume. Real-time 3D echocardiography of the VC area correlated and agreed well with the EROA for both central and eccentric jets (r(2) = 0.86, SEE 0.02 cm(2), difference 0.04 +/- 0.06 cm(2), p = NS). For eccentric jets, 2-dimensional echocardiography overestimated the VC width compared with 3D echocardiography (p = 0.024) and correlated more poorly with the EROA (r(2) = 0.61 vs 0.85, p <0.001), causing clinical misclassification in 45% of patients with eccentric MR. The interobserver variability for the 3D VC area was 0.03 cm(2) (7.5% of the mean, r = 0.95); the intraobserver variability was 0.01 cm(2) (2.5% of the mean, r = 0.97). In conclusion, real-time 3D echocardiography accurately and reproducibly quantified the vena contracta cross-sectional area in patients with both central and eccentric MR. Rapid acquisition and intuitive analysis promote practical clinical application of this central, directly visualized, measure and its correlation with outcome. (C) 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:978-983) C1 [Yosefy, Chaim; Hung, Judy; Chua, Sarah; Vaturi, Mordehay; Ton-Nu, Thanh-Thao; Handschumacher, Mark D.; Levine, Robert A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA 02115 USA. RP Levine, RA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA 02115 USA. EM rlevine@partners.org FU NHLBI NIH HHS [K24 HL067434, K24 HL067434-08, R01 HL038176, R01 HL038176-14, R01 HL072265, R01 HL072265-04] NR 30 TC 47 Z9 49 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 OCT 1 PY 2009 VL 104 IS 7 BP 978 EP 983 DI 10.1016/j.amjcard.2009.05.043 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 503MG UT WOS:000270537800019 PM 19766767 ER PT J AU Imamura, F Lichtenstein, AH Dallal, GE Meigs, JB Jacques, PF AF Imamura, Fumiaki Lichtenstein, Alice H. Dallal, Gerard E. Meigs, James B. Jacques, Paul F. TI Generalizability of dietary patterns associated with incidence of type 2 diabetes mellitus SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; CORONARY-HEART-DISEASE; TRANS-FATTY-ACIDS; SUGAR-SWEETENED BEVERAGES; MIDDLE-AGED ADULTS; ALCOHOL-CONSUMPTION; MEAT INTAKE; INSULIN-RESISTANCE; WHITEHALL-II; RISK AB Background: Reduced rank regression (RRR) has been used to derive dietary pattern scores that predict linear combinations of disease biomarkers. The generalizability of these patterns to independent populations remains unknown. Objective: The goal was to examine the generalizability of dietary patterns from the following prior studies using RRR to predict type 2 diabetes mellitus (T2DM): the Nurses' Health Study (NHS), European Prospective Investigation into Cancer and Nutrition Germany (EPIC), and Whitehall II Study (WS). Design: The relative weights of food groups of each dietary pattern were used to generate each dietary pattern score in the Framingham Offspring Study (n = 2879). Each of the external scores (confirmatory scores) was examined to determine whether it could predict incident T2DM during 7 y of follow-up as well as scores developed internally in the Framingham Offspring Study using a Cox-proportional hazard model adjusted for T2DM risk factors. Results: Intakes of meat products, refined grains, and soft drinks (caloric and noncaloric) were found to be common predictive components of all confirmatory scores, but fried foods, eggs, and alcoholic beverages were predictive in some, but not in all, confirmatory scores. On the basis of a continuous increase in the score by 1 SD, the NHS-based confirmatory score predicted T2DM risk (hazard ratio: 1.44; 95% CI: 1.25, 1.66). However, T2DM risk was only weakly predicted by the EPIC-based score (hazard ratio: 1.14; 95% CI: 0.99, 1.32) and the WS-based score (hazard ratio: 1.16; 95% CI: 1.00, 1.35). Conclusions: The study suggested that dietary patterns that predict T2DM risk in different populations may not be generalizable to different populations. Additional dietary pattern studies should be conducted with regard to generalizability. Am J Clin Nutr 2009;90:1075-83. C1 [Imamura, Fumiaki; Lichtenstein, Alice H.; Dallal, Gerard E.; Jacques, Paul F.] Tufts Univ, Jean Meyer USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Jacques, PF (reprint author), Tufts Univ, Jean Meyer USDA, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM paul.jacques@tufts.edu OI Imamura, Fumiaki/0000-0002-6841-8396 FU US Department of Agriculture, Agricultural Research Service [58-1950-7-707]; National Institutes of Health [N01-HC-25195]; NIDDK [K24 DK080140] FX Supported in part by the US Department of Agriculture, Agricultural Research Service, under agreement no. 58-1950-7-707 and the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health (contract no. N01-HC-25195). JBM was supported by NIDDK K24 DK080140. NR 49 TC 32 Z9 32 U1 0 U2 4 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 OCT 1 PY 2009 VL 90 IS 4 BP 1075 EP 1083 DI 10.3945/ajcn.2009.28009 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 496GC UT WOS:000269956700025 PM 19710193 ER PT J AU Wagner, PL Perner, S Rickman, DS LaFargue, CJ Kitabayashi, N Johnstone, SF Weir, BA Meyerson, M Altorki, NK Rubin, MA AF Wagner, Patrick L. Perner, Sven Rickman, David S. LaFargue, Christopher J. Kitabayashi, Naoki Johnstone, Stephen F. Weir, Barbara A. Meyerson, Matthew Altorki, Nasser K. Rubin, Mark A. TI In Situ Evidence of KRAS Amplification and Association With Increased p21 Levels in Non-Small Cell Lung Carcinoma SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE Lung cancer; KRAS; EGFR; p21; Gene amplification ID COMPARATIVE GENOMIC HYBRIDIZATION; EML4-ALK FUSION; KI-RAS; GENE AMPLIFICATION; COPY NUMBER; CANCER; ADENOCARCINOMA; MUTATIONS; PROTOONCOGENES; ABERRATIONS AB Recent advances in the characterization of the lung cancer genome have suggested that KRAS may frequently be amplified, although little is known regarding the significance of this finding. This is in contrast with activating mutations of KRAS, which occur in approximately 20% of non-small cell lung carcinomas (NSCLCs). We used fluorescence in situ hybridization to provide direct evidence of KRAS amplification for the first time in clinical specimens. We detected amplification in 7 of 100 consecutive NSCLCs, with a concurrent activating KRAS mutation in 4 cases. KRAS amplification was associated with greater expression of p21 as assessed by quantitative immunohistochemical analysis (P =. 015). Our data indicate that a sizable subgroup of NSCLCs harbor KRAS amplification, some of which also contain point mutations, and suggest that an increased KRAS copy number may drive p21 overexpression. KRAS amplification may define a unique clinicopathologic subset of NSCLCs with potentially altered responsiveness to targeted therapies C1 [Wagner, Patrick L.; Perner, Sven; Rickman, David S.; LaFargue, Christopher J.; Kitabayashi, Naoki; Johnstone, Stephen F.; Rubin, Mark A.] Cornell Univ, Weill Med Coll, Dept Pathol & Lab Med, New York, NY 10021 USA. [Wagner, Patrick L.; Altorki, Nasser K.] Cornell Univ, Weill Med Coll, Dept Cardiothorac Surg, New York, NY 10021 USA. [Weir, Barbara A.; Meyerson, Matthew] Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wagner, PL (reprint author), 525 E 68 St,K-707, New York, NY 10021 USA. RI Meyerson, Matthew/E-7123-2012; OI Rubin, Mark/0000-0002-8321-9950 NR 22 TC 14 Z9 14 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD OCT PY 2009 VL 132 IS 4 BP 500 EP 505 DI 10.1309/AJCPF10ZUNSOLIFG PG 6 WC Pathology SC Pathology GA 503AQ UT WOS:000270503500002 PM 19762526 ER PT J AU Cannizzo, E Bellio, E Dorn, ME Sadowski, C Bucci, JJ Petrini, M Carulli, G Preffer, F AF Cannizzo, Elisa Bellio, Emanuele Dorn, Michelle E. Sadowski, Craig Bucci, Janessa J. Petrini, Mario Carulli, Giovanni Preffer, Frederic TI The Diagnostic Role of Multiparameter Immunophenotyping by Flow Cytometry in Multiple Myeloma: A New Model SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Meeting Abstract CT AJCP Resident Research Symposium and Poster Sessions/Annual Meeting of the American-Society-for-Clinical-Pathology CY OCT 28-NOV 01, 2009 CL Chicago, IL SP Amer Soc Clin Pathol C1 [Cannizzo, Elisa; Dorn, Michelle E.; Sadowski, Craig; Bucci, Janessa J.; Preffer, Frederic] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Cannizzo, Elisa; Dorn, Michelle E.; Sadowski, Craig; Bucci, Janessa J.; Preffer, Frederic] Harvard Univ, Sch Med, Boston, MA USA. [Cannizzo, Elisa; Bellio, Emanuele; Petrini, Mario; Carulli, Giovanni] Univ Pisa, Sect Hematol, Dept Oncol Transplants & Advances Med, Pisa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD OCT PY 2009 VL 132 IS 4 MA 39 BP 634 EP 634 PG 1 WC Pathology SC Pathology GA 503AQ UT WOS:000270503500056 ER PT J AU Coniglio, I Garcia-Godoy, F Magni, E Carvalho, CA Ferrari, M AF Coniglio, Ivanovic Garcia-Godoy, Franklin Magni, Elisa Carvalho, Carlos Augusto Ferrari, Marco TI Resin cement thickness in oval-shaped canals: Oval vs. circular fiber posts in combination with different tips/drills for post space preparation SO AMERICAN JOURNAL OF DENTISTRY LA English DT Article ID ENDODONTICALLY TREATED TEETH; CLINICAL-PERFORMANCE; ROOT CANALS; INSTRUMENTS; STRENGTH; DENTIN; LAYER; HAND AB Purpose: To evaluate the cement thickness around oval and circular posts luted in oval post spaces prepared with different drills/tips. Methods: Extracted premolars were endodontically treated and obturated, then randomly divided into three groups (n = 5) according to the tips/drills used for post-space preparation and to the type of fiber post luted: medium grit oval tip + oval posts, fine grit oval tip + oval posts, Mtwo Post File drill + circular posts. The specimens were sectioned in horizontal slices; one slice per canal third was chosen for each post-space, resulting in three slices for each specimen. The distances between the canal wall and the post perimeter were measured on SEM images of each slice. Results: The fine grit tip + oval post group obtained statistically significant lower cement thicknesses than the other groups (P < 0.05), in particular in the apical third. The MtwoPF + circular post group showed the highest cement thickness, comparable to that of the medium tip + oval post group. A good post fitting in oval-shaped canals can be obtained using a fine grit oval tip combined with oval posts. (Am J Dent 2009;22:290-294). C1 [Coniglio, Ivanovic; Magni, Elisa; Ferrari, Marco] Univ Siena, Policlin Le Scotte, Sch Dent Med, Dept Fixed Prosthodont & Dent Mat, I-53100 Siena, Italy. [Garcia-Godoy, Franklin] Univ Tennessee, Coll Dent, Biosci Res Ctr, Memphis, TN USA. [Garcia-Godoy, Franklin] Forsyth Inst, Boston, MA USA. [Carvalho, Carlos Augusto] Univ Sao Paulo, Bauru Sch Dent, Dept Operat Dent, Bauru, Brazil. [Ferrari, Marco] Univ Siena, Sch Dent Med, Dept Dent Mat & Restorat Dent, I-53100 Siena, Italy. [Ferrari, Marco] Tufts Univ, Sch Dent Med, Boston, MA 02111 USA. RP Ferrari, M (reprint author), Univ Siena, Policlin Le Scotte, Sch Dent Med, Dept Fixed Prosthodont & Dent Mat, Viale Bracci, I-53100 Siena, Italy. EM md3972@mclink.it NR 22 TC 21 Z9 25 U1 0 U2 0 PU MOSHER & LINDER, INC PI WESTON PA 318 INDIAN TRACE SUITE 500, WESTON, FL 33326 USA SN 0894-8275 J9 AM J DENT JI Am. J. Dent. PD OCT PY 2009 VL 22 IS 5 BP 290 EP 294 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 548JO UT WOS:000273958100009 PM 20225472 ER PT J AU Chapman, J Pallin, D Ferrara, L Mortell, S Pliakas, J Shear, M Thomas, S AF Chapman, Jacob Pallin, Daniel Ferrara, Larisa Mortell, Sarah Pliakas, John Shear, Melissa Thomas, Stephen TI Endotracheal tube cuff pressures in patients intubated before transport SO AMERICAN JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID BLOOD-FLOW AB Introduction: Prolonged endotracheal tube cuff pressures (ETTCPs) greater than 30 cm H(2)O cause complications ranging from sore throat to rare cases of tracheoesophageal fistula. In a series of patients, we sought to determine the proportion of patients with overinflated cuffs and to determine whether overinflation was associated with demographics, diagnostic category, or intubator credentials. Methods: Between July 2007 and April 2008, we measured cuff pressures on a convenience sample of patients drawn from 2 groups. The "helicopter group" had pressure measured before transport by a single aeromedical transport service. The "hospital group" had pressure measured upon arrival to I of 2 emergency departments after being intubated before transport. Results: Three hundred patients aged 4 to 92 years (median, 57) were studied: 59.7% were male; and diagnostic categories were neurologic (33.7%), trauma (32.7%), cardiac (12.7%), and general medical/surgical (21.0%). Intubation occurred 1 to 28 000 minutes before ETTCP assessment (median, 60). Endotracheal tube cuff pressure was greater than 30 cm H(2)O in 64.7% and ranged from 10 to 180 (median, 40). Forty-nine percent of patients had ETTCP greater than 40 cm H(2)O. There was no association between ETTCP and age group, sex, diagnostic category, ETT size, time between intubation and ETTCP assessment, or intubator credentials. Conclusions: The most compelling results of the study are the high rates of elevated ETTCPs. Furthermore, there were no clear risk factors for elevated ETTCP. Although the risk of elevated ETTCP in the prehospital to acute care time frame is unclear, it seems reasonable to measure ETTCP after intubation in all patients. (C) 2009 Elsevier Inc. All rights reserved. C1 [Chapman, Jacob; Shear, Melissa; Thomas, Stephen] Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. [Chapman, Jacob; Pallin, Daniel] Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Pallin, Daniel] Childrens Hosp, Dept Emergency Med, Boston, MA 02115 USA. [Ferrara, Larisa] Massachusetts Gen Hosp, Dept Resp Therapy, Boston, MA 02114 USA. [Mortell, Sarah] Brigham & Womens Hosp, Dept Resp Therapy, Boston, MA 02115 USA. [Pliakas, John; Thomas, Stephen] Boston MedFlight, Boston, MA USA. RP Chapman, J (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. OI Pallin, Daniel/0000-0002-8517-9702 NR 9 TC 15 Z9 16 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 0735-6757 J9 AM J EMERG MED JI Am. J. Emerg. Med. PD OCT PY 2009 VL 27 IS 8 BP 980 EP 982 DI 10.1016/j.ajem.2008.07.025 PG 3 WC Emergency Medicine SC Emergency Medicine GA 503WZ UT WOS:000270573900014 PM 19857418 ER PT J AU Singh, H Daci, K Petersen, LA Collins, C Petersen, NJ Shethia, A El-Serag, HB AF Singh, Hardeep Daci, Kuang Petersen, Laura A. Collins, Clyde Petersen, Nancy J. Shethia, Anila El-Serag, Hashem B. TI Missed Opportunities to Initiate Endoscopic Evaluation for Colorectal Cancer Diagnosis SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID IRON-DEFICIENCY ANEMIA; PRIMARY-CARE; GASTROINTESTINAL-TRACT; MALPRACTICE CLAIMS; DELAY; COLON; POPULATION; CARCINOMA; SYMPTOMS; ERRORS AB OBJECTIVES: Delayed diagnosis of colorectal cancer (CRC) is among the most common reasons for ambulatory diagnostic malpractice claims in the United States. Our objective was to describe missed opportunities to diagnose CRC before endoscopic referral, in terms of patient characteristics, nature of clinical clues, and types of diagnostic-process breakdowns involved. METHODS: We conducted a retrospective cohort study of consecutive, newly diagnosed cases of CRC between February 1999 and June 2007 at a tertiary health-care system in Texas. Two reviewers independently evaluated the electronic record of each patient using a standardized pretested data collection instrument. Missed opportunities were defined as care episodes in which endoscopic evaluation was not initiated despite the presence of one or more clues that warrant a diagnostic workup for CRC. Predictors of missed opportunities were evaluated in logistic regression. The types of breakdowns involved in the diagnostic process were also determined and described. RESULTS: Of the 513 patients with CRC who met the inclusion criteria, both reviewers agreed on the presence of at least one missed opportunity in 161 patients. Among these patients there was a mean of 4.2 missed opportunities and 5.3 clues. The most common clues were suspected or confirmed iron deficiency anemia, positive fecal occult blood test, and hematochezia. The odds of a missed opportunity were increased in patients older than 75 years (odds ratio (OR) = 2.3; 95% confidence interval (CI) 1.3-4.1) or with iron deficiency anemia (OR = 2.2; 95 % CI 1.3-3.6), whereas the odds of a missed opportunity were lower in patients with abnormal flexible sigmoidoscopy (OR = 0.06; 95 % CI 0.01-0.51), or imaging suspicious for CRC (OR = 0.3; 95 % CI 0.1-0.9). Anemia was the clue associated with the longest time to endoscopic referral (median = 393 days). Most process breakdowns occurred in the provider-patient clinical encounter and in the follow-up of patients or abnormal diagnostic test results. CONCLUSIONS: Missed opportunities to initiate workup for CRC are common despite the presence of many clues suggestive of CRC diagnosis. Future interventions are needed to reduce the process breakdowns identified. C1 [El-Serag, Hashem B.] Baylor Coll Med, Dept Med, Michael E DeBakey Vet Affairs Med Ctr, Houston VA HSR&D Ctr Excellence, Houston, TX 77030 USA. [Singh, Hardeep; Petersen, Laura A.; Petersen, Nancy J.; Shethia, Anila] Michael E DeBakey Vet Affairs Med Ctr, Ctr Inquiry Improve Outpatient Safety Effect Elec, Houston, TX USA. [Singh, Hardeep; Petersen, Laura A.; Petersen, Nancy J.; Shethia, Anila] Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [El-Serag, Hashem B.] Baylor Coll Med, Dept Med, Michael E DeBakey Vet Affairs Med Ctr, Sect Gastroenterol & Hepatol, Houston, TX 77030 USA. RP Singh, H (reprint author), VA Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM hardeeps@bcm.edu FU NIH K23 [K23CA125585]; Houston VA HSR&D Center of Excellence [HFP90-020] FX This work was supported by an NIH K23 career development award (K23CA125585) to Dr Singh, and in part by the Houston VA HSR&D Center of Excellence (HFP90-020). These sources had no role in study design or execution, collection of data, the writing of the paper, or the decision to submit the paper for publication. NR 44 TC 46 Z9 49 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 IS 10 BP 2543 EP 2554 DI 10.1038/ajg.2009.324 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507KY UT WOS:000270853300022 PM 19550418 ER PT J AU Chavalitdhamrong, D Kijsirichareanchai, K Sul, J Jutabha, R AF Chavalitdhamrong, Disaya Kijsirichareanchai, Kunut Sul, James Jutabha, Rome TI The Self-administered Capsule Endoscopy is Useful for the Obscure Gastrointestinal Bleeding Cases SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Kijsirichareanchai, Kunut; Sul, James; Jutabha, Rome] Univ Calif Los Angeles, Med Ctr, Capsule Endoscopy Serv, Los Angeles, CA 90024 USA. [Chavalitdhamrong, Disaya] Mt Sinai Sch Med Program, James J Peters Vet Affairs Med Ctr, Bronx, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1435 BP S539 EP S540 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601423 ER PT J AU Chavalitdhamrong, D Kijsirichareanchai, K Sul, J Jutabha, R AF Chavalitdhamrong, Disaya Kijsirichareanchai, Kunut Sul, James Jutabha, Rome TI Endoscopic Placement of a Capsule Endoscope by Using Mini-snare SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Kijsirichareanchai, Kunut; Sul, James; Jutabha, Rome] Univ Calif Los Angeles, Capsule Endoscopy Serv, Los Angeles, CA USA. [Chavalitdhamrong, Disaya] Mt Sinai Sch Med Program, James J Peters Vet Affairs Med Ctr, Bronx, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1066 BP S392 EP S392 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601055 ER PT J AU Flicker, M Weber, H AF Flicker, Michael Weber, Horst TI Endoscopic Hemostasis in a Case of Bleeding from Zenker's Diverticulum SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Flicker, Michael; Weber, Horst] VA Boston Healthcare Syst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1011 BP S371 EP S371 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601001 ER PT J AU Halley, L Lahr, C Subramony, C Kothari, T Schmieg, R Spree, D Eriator, I Kasser, C Kedar, A Abell, T AF Halley, Lindsey Lahr, Christopher Subramony, Charu Kothari, Truptesh Schmieg, Robert Spree, Danielle Eriator, Ike Kasser, Christine Kedar, Archana Abell, Thomas TI Pain and Gastroparesis: Not a Contraindication for a Trial of Gastric Electrical Stimulation SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Halley, Lindsey; Lahr, Christopher; Subramony, Charu; Schmieg, Robert; Spree, Danielle; Eriator, Ike; Kedar, Archana; Abell, Thomas] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Kasser, Christine] Univ Tennessee, Memphis, TN USA. [Kothari, Truptesh] James J Peters VA Med Ctr, Bronx, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 112 BP S45 EP S45 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853600112 ER PT J AU Harris, M Buscaglia, J DiMaio, C Pollack, M Shin, EJ Richards, R Chak, A Kantsevoy, S Jagannath, S Okolo, P AF Harris, Michael Buscaglia, Jonathan DiMaio, Christopher Pollack, Michael Shin, Eun Ji Richards, Robert Chak, Amitabh Kantsevoy, Sergey Jagannath, Sanjay Okolo, Patrick TI Are Large Side Holes Associated with Reduced Rates of Pancreatic Stent Occlusion? Results of a Prospective, Multi-centered Study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Buscaglia, Jonathan; Kantsevoy, Sergey; Jagannath, Sanjay; Okolo, Patrick] Johns Hopkins Sch Med, Baltimore, MD USA. [DiMaio, Christopher; Shin, Eun Ji] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. [Pollack, Michael; Chak, Amitabh] Case Western Reserve Univ, Univ Hosp Cleveland, Sch Med, Cleveland, OH 44106 USA. [Harris, Michael] Stony Brook Med Ctr, Stony Brook, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 204 BP S79 EP S80 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853600204 ER PT J AU Heyman, M Ferry, G Aronstein, W Ajayi, F Balan, G Kuzmak, B Smith-Hall, N Winter, H AF Heyman, Melvin Ferry, George Aronstein, William Ajayi, Funmi Balan, Guhan Kuzmak, Barbara Smith-Hall, Nancy Winter, Harland TI A Randomized, Open-Label, Parallel-Group Study to Determine the Pharmacokinetics (PK), Safety and Tolerability of Delayed-Release Mesalamine Tablets in Children and Adolescents with Active Ulcerative Colitis (UC) SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Heyman, Melvin] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Ferry, George] Texas Childrens Hosp, Houston, TX 77030 USA. [Aronstein, William] CTI Clin Trial & Consulting Serv Inc, Cincinnati, OH USA. [Ajayi, Funmi; Balan, Guhan; Kuzmak, Barbara; Smith-Hall, Nancy] Procter & Gamble Pharmaceut Inc, Mason, OH USA. [Winter, Harland] Mass Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1452 BP S546 EP S546 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601440 ER PT J AU Hughes, J Lahr, C Subramony, C Kothari, T Schmieg, R Spree, D Cutts, T Kedar, A Abell, T AF Hughes, Joy Lahr, Christopher Subramony, Charu Kothari, Truptesh Schmieg, Robert Spree, Danielle Cutts, Teresa Kedar, Archana Abell, Thomas TI Depression and Gastroparesis: A Histological, Physiological and Clinical Outcome Analysis in Response to Gastric Stimulation SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Hughes, Joy; Lahr, Christopher; Subramony, Charu; Schmieg, Robert; Spree, Danielle; Kedar, Archana; Abell, Thomas] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Kothari, Truptesh] James J Peters VA Med Ctr, Bronx, NY USA. [Cutts, Teresa] Univ Tennessee, Memphis, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 113 BP S45 EP S45 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853600113 ER PT J AU Isani, M Lahr, C Subramony, C Kothari, T Schmieg, R Spree, D Vedanarayanan, V Kedar, A Abell, T AF Isani, Mubina Lahr, Christopher Subramony, Charu Kothari, Truptesh Schmieg, Robert Spree, Danielle Vedanarayanan, Vetta Kedar, Archana Abell, Thomas TI Migraines and Gastroparesis: A Histologic, Physiologic, and Clinical Analysis with Temporary Gastric Stimulation SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Isani, Mubina; Lahr, Christopher; Subramony, Charu; Schmieg, Robert; Spree, Danielle; Vedanarayanan, Vetta; Kedar, Archana; Abell, Thomas] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Kothari, Truptesh] James J Peters VA Med Ctr, Bronx, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 111 BP S44 EP S44 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853600111 ER PT J AU Kane, S Panaccione, R Colombel, JF Sands, B Rubin, D Lewis, J Nag, A Hass, S Panjabi, S AF Kane, Sunanda Panaccione, Remo Colombel, Jean-Frederic Sands, Bruce Rubin, David Lewis, James Nag, Arpita Hass, Steven Panjabi, Sumeet TI TOUCH (TM) Study Patient Outcomes: The Impact of Natalizumab on Utilization of Healthcare Resources by the Patients and Their Associated Treatment Satisfaction SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Kane, Sunanda] Mayo Clin, Rochester, MN USA. [Panaccione, Remo] Univ Calgary, Rochester, AB, Canada. [Colombel, Jean-Frederic] Ctr Hosp Reg & Univ Lille, Hop Huriez, F-59037 Lille, France. [Sands, Bruce] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rubin, David] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Lewis, James] Univ Penn, Philadelphia, PA 19104 USA. [Nag, Arpita; Hass, Steven; Panjabi, Sumeet] Elan Pharmaceut Inc, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1130 BP S416 EP S416 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601119 ER PT J AU Kothari, T Hughes, J Lahr, C Subramony, C Schmieg, R Spree, D Uwaifo, G Kedar, A Abell, T AF Kothari, Truptesh Hughes, Joy Lahr, Christopher Subramony, Charu Schmieg, Robert Spree, Danielle Uwaifo, Gabriel Kedar, Archana Abell, Thomas TI Diabetes and Gastroparesis: A Histologic, Physiologic and Clinical Analysis in Response to Temporary and Subsequent Permanent Gastric Stimulation SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Hughes, Joy; Lahr, Christopher; Subramony, Charu; Schmieg, Robert; Spree, Danielle; Uwaifo, Gabriel; Kedar, Archana; Abell, Thomas] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Kothari, Truptesh] James J Peters VA Med Ctr, Bronx, NY USA. RI Uwaifo, Gabriel/M-2361-2016 OI Uwaifo, Gabriel/0000-0002-6962-9304 NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 114 BP S46 EP S46 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853600114 ER PT J AU Panaccione, R Kane, S Lewis, J Colombel, JF Sands, B Rubin, D Nag, A Hass, S Panjabi, S Eisenberg, D AF Panaccione, Remo Kane, Sunanda Lewis, James Colombel, Jean-Frederic Sands, Bruce Rubin, David Nag, Arpita Hass, Steven Panjabi, Sumeet Eisenberg, Debra TI TOUCH (TM) Study Patient Outcomes: The Impact of Natalizumab on Common Measures of Quality of Life in CD patients SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Panaccione, Remo] Univ Calgary, Calgary, AB, Canada. [Kane, Sunanda] Mayo Clin, Rochester, MN USA. [Lewis, James] Univ Penn, Philadelphia, PA 19104 USA. [Colombel, Jean-Frederic] Ctr Hosp Reg & Univ Lille, Hop Huriez, F-59037 Lille, France. [Sands, Bruce] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rubin, David] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Nag, Arpita; Hass, Steven; Panjabi, Sumeet] Elan Pharmaceut Inc, San Francisco, CA USA. [Eisenberg, Debra] HealthCore Inc, Wilmington, DE USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1135 BP S418 EP S418 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601124 ER PT J AU Ramirez, F Leung, F AF Ramirez, Francisco Leung, Felix TI Water Method for Colonoscopy in Sedated Patients is Easy to Learn for an Experienced Colonoscopist and May Minimize the Need for Technical Assistance SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Ramirez, Francisco] Carl T Hayden VA Med Ctr, Phoenix, AZ USA. [Leung, Felix] Univ Calif Los Angeles, David Geffen Sch Med, Sepulveda Ambulatory Care Ctr, VA Greater Healthcare Syst, Los Angeles, CA 90095 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1399 BP S525 EP S525 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601387 ER PT J AU Rubin, D Sands, B Lewis, J Kane, S Panaccione, R Colombel, JF Nag, A Hass, S Panjabi, S AF Rubin, David Sands, Bruce Lewis, James Kane, Sunanda Panaccione, Remo Colombel, Jean-Frederic Nag, Arpita Hass, Steven Panjabi, Sumeet TI TOUCH (TM) Study Patient Outcomes: The Impact of Natalizumab on Crohn's Disease Severity SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Rubin, David] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Sands, Bruce] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lewis, James] Univ Penn, Philadelphia, PA 19104 USA. [Kane, Sunanda] Mayo Clin, Rochester, MN USA. [Panaccione, Remo] Univ Calgary, Calgary, AB, Canada. [Colombel, Jean-Frederic] Ctr Hosp Reg & Univ Lille, Hop Huriez, F-59037 Lille, France. [Nag, Arpita; Hass, Steven; Panjabi, Sumeet] Elan Pharmaceut Inc, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1139 BP S420 EP S420 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601128 ER PT J AU Rubin, D Lewis, J Kane, S Panaccione, R Colombel, JF Sands, B Nag, A Hass, S Panjabi, S AF Rubin, David Lewis, James Kane, Sunanda Panaccione, Remo Colombel, Jean-Frederic Sands, Bruce Nag, Arpita Hass, Steven Panjabi, Sumeet TI TOUCH (TM) Study Patient Outcomes: Workforce Participation, Productivity and the Impact of Natalizumab SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Rubin, David] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Lewis, James] Univ Penn, Philadelphia, PA 19104 USA. [Kane, Sunanda] Mayo Clin, Rochester, MN USA. [Panaccione, Remo] Univ Calgary, Calgary, AB, Canada. [Colombel, Jean-Frederic] Ctr Hosp Reg & Univ Lille, Hop Huriez, F-59037 Lille, France. [Sands, Bruce] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Nag, Arpita; Hass, Steven; Panjabi, Sumeet] Elan Pharmaceut Inc, San Francisco, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1134 BP S417 EP S418 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601123 ER PT J AU Sandborn, W Kane, S Korzenik, J Lashner, B Leighton, J Mahadevan, U Marion, J Safdi, M Sninsky, C Ramsey, D AF Sandborn, William Kane, Sunanda Korzenik, Joshua Lashner, Bret Leighton, Jonathan Mahadevan, Uma Marion, James Safdi, Michael Sninsky, Charles Ramsey, David TI Once Daily Dosing of Delayed-Release Oral Mesalamine (400 mg Tablet) is as Effective as Twice Daily Dosing for Maintenance of Remission of Ulcerative Colitis: Results of the QDIEM Study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Sandborn, William; Kane, Sunanda] Mayo Clin, Rochester, MN USA. [Korzenik, Joshua] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Lashner, Bret] Cleveland Clin, Cleveland, OH 44106 USA. [Leighton, Jonathan] Mayo Clin Arizona, Scottsdale, AZ USA. [Mahadevan, Uma] Univ Calif San Francisco, Ctr Colitis & Crohns Dis, San Francisco, CA 94143 USA. [Marion, James] Mt Sinai Sch Med, New York, NY USA. [Safdi, Michael] Gastroenterol & Liver Inst, Cincinnati, OH USA. [Sninsky, Charles] Digest Dis Associates, Gainesville, FL USA. [Ramsey, David] Procter & Gamble Pharmaceut Inc, Mason, OH USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1185 BP S438 EP S439 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601174 ER PT J AU Siegel, C Sands, B Feagan, B Sandborn, W Hass, S Niecko, T AF Siegel, Corey Sands, Bruce Feagan, Brian Sandborn, William Hass, Steven Niecko, Timothy TI Natalizumab Reduces the Rate of Hospitalization in Moderate to Severe Crohn's Patients: Data from the ENACT and ENCORE Trials SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Siegel, Corey] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Sands, Bruce] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Feagan, Brian] Univ Western Ontario, Robarts Res Inst, London, ON, Canada. [Sandborn, William] Mayo Clin, Rochester, MN USA. [Hass, Steven] Elan Pharmaceut Inc, San Francisco, CA USA. [Niecko, Timothy] Niecko Hlth Econ, Escondido, CA USA. RI Feagan, Brian/M-4283-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1258 BP S470 EP S470 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601246 ER PT J AU Siegel, C Finlayson, S Sands, B Tosteson, A AF Siegel, Corey Finlayson, Samuel Sands, Bruce Tosteson, Anna TI A Decision Analysis to Define the Thresholds at Which the Risks of Combination Infliximab and Azathioprine Therapy Outweigh Its Benefits SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 74th Annual Scientific Meeting and Postgraduate Course of the American-College-of-Gastroenterology CY OCT 23-28, 2009 CL San Diego, CA SP Amer Coll Gastroenterol C1 [Siegel, Corey] Dartmouth Hitchcock Med Ctr, IBD Ctr, Lebanon, NH 03766 USA. [Finlayson, Samuel; Tosteson, Anna] Dartmouth Inst Hlth Policy & Clin Practice, Hanover, NH USA. [Sands, Bruce] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2009 VL 104 SU 3 MA 1257 BP S469 EP S470 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 507LA UT WOS:000270853601245 ER PT J AU Shah, K Qureshi, SU Johnson, M Parikh, N Schulz, PE Kunik, ME AF Shah, Kairav Qureshi, Salah U. Johnson, Michael Parikh, Niraj Schulz, Paul E. Kunik, Mark E. TI Does Use of Antihypertensive Drugs Affect the Incidence or Progression of Dementia? A Systematic Review SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Review DE incidence or progression of dementia; antihypertensive drugs ID PLACEBO-CONTROLLED TRIAL; COGNITIVE FUNCTION; BLOOD-PRESSURE; ALZHEIMERS-DISEASE; VASCULAR DEMENTIA; MEDICATION-USE; HYPERTENSION; RISK; PREVALENCE; PREVENTION AB Background: Hypertension appears to contribute to the development of dementia. Antihypertensive drugs may play an important role in altering the incidence or progression of dementia, particularly dementia of the vascular type; however, the neuroprotective effects of these agents in other types of dementia are not well characterized. Objectives: The main aims of this review were to examine the relationship between use of antihypertensive agents and the incidence and progression of Alzheimer's dementia (AD), vascular dementia (VaD), and unspecified dementia, and to consider whether these agents may be neuroprotective. Methods: A search of the English-language literature (January 1996-August 2009) was conducted using PubMed, Ovid MEDLINE, EBSCO MEDLINE, and the Cochrane Database of Systematic Reviews for publications mentioning both antihypertensive drugs and dementia. A combination of searches was performed using the following terms: antihypertensive drugs, dementia, cognitive impairment, Alzheimer's dementia, vascular dementia, progression of cognitive impairment, severity of cognitive impairment, severity of dementia, prevalence, and incidence. Searches were also performed using the names of antihypertensive drug classes. The bibliographies of all retrieved articles were reviewed for additional relevant publications. The focus was on randomized controlled trials, cohort studies, and case-control studies, excluding studies in animals, patients aged <45 years, drugs other than antihypertensive agents, and the role in cognition of hormones, receptors, and enzymes. Results: Sixty-five potentially relevant articles were identified from the 536 publications retrieved by the literature search. After application of the exclusion criteria, 12 original studies were included in the review, all published between 1999 and 2008 and most involving patients with AD or VaD. The most frequently studied antihypertensive agents were calcium channel blockers (7 studies), diuretics (6 studies), and angiotensin-converting enzyme (ACE) inhibitors (6 studies). Overall, these medications appeared to be beneficial in dementia, but only ACE inhibitors and diuretics significantly reduced the risk for and progression of dementia in the majority of studies. Conclusions: Antihypertensive medications-particularly ACE inhibitors and diuretics-may be helpful in reducing the risk for and progression of dementia. Large randomized clinical trials are warranted to further explore the relationship between antihypertensive drugs and dementia. (Am J Geriatr Pharmacother. 2009;7:250-261) (C) 2009 Excerpta Medica Inc. C1 [Shah, Kairav; Qureshi, Salah U.; Schulz, Paul E.; Kunik, Mark E.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX USA. [Shah, Kairav] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Qureshi, Salah U.; Kunik, Mark E.] Houston Ctr Qual Care & Utilizat Studies, Houston, TX USA. [Qureshi, Salah U.; Schulz, Paul E.; Kunik, Mark E.] Baylor Coll Med, Houston, TX 77030 USA. [Qureshi, Salah U.; Kunik, Mark E.] Vet Affairs S Cent Mental Illness Res Educ & Clin, Houston, TX USA. [Johnson, Michael] Univ Houston, Coll Pharm, Dept Clin Sci & Adm, Houston, TX 77030 USA. [Parikh, Niraj] Anal Grp Inc, Boston, MA USA. RP Kunik, ME (reprint author), Michael E DeBakey VAMC 151, Houston Ctr Qual Care & Utilizat Studies, 2002 Holcombe Blvd, Houston, TX 77030 USA. EM mkunik@bcm.tmc.edu FU Houston Veterans Affairs Health Services Research and Development Center of Excellence [HFP90-020] FX This work was supported in part by the Houston Veterans Affairs Health Services Research and Development Center of Excellence (HFP90-020). The views expressed are those of the authors and do not necessarily reflect those of the Department of Veterans Affairs (Baylor College of Medicine), with which 3 of the authors are affiliated. NR 34 TC 61 Z9 61 U1 3 U2 11 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD OCT PY 2009 VL 7 IS 5 BP 250 EP 261 DI 10.1016/j.amjopharm.2009.11.001 PG 12 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 525XU UT WOS:000272251900002 PM 19948301 ER PT J AU Wright, RM Sloane, R Pieper, CF Ruby-Scelsi, C Twersky, J Schmader, KE Hanlon, JT AF Wright, Rollin M. Sloane, Richard Pieper, Carl F. Ruby-Scelsi, Christine Twersky, Jack Schmader, Kenneth E. Hanlon, Joseph T. TI Underuse of Indicated Medications Among Physically Frail Older US Veterans at the Time of Hospital Discharge: Results of a Cross-Sectional Analysis of Data From the Geriatric Evaluation and Management Drug Study SO AMERICAN JOURNAL OF GERIATRIC PHARMACOTHERAPY LA English DT Article DE medication use; underutilization; comorbidity; transition of care; frail elderly ID QUALITY-OF-CARE; PHARMACOLOGICAL CARE; CONTROLLED-TRIAL; POLYPHARMACY; INPATIENTS; DISEASES; PEOPLE; COMORBIDITY; OUTPATIENTS; VALIDATION AB Background: Medication underutilization, or the omission of a potentially beneficial medication indicated for disease management, is common among older adults but poorly understood. Objectives: The aims of this work were to assess the prevalence of medication underuse and to determine whether polypharmacy or comorbidity was associated with medication underuse among physically frail older veterans transitioning from the hospital to the community. Methods: This was a cross-sectional analysis of patients who were discharged from 11 US veterans' hospitals to outpatient care, based on data from the Geriatric Evaluation and Management Drug Study, a substudy of the Veterans Affairs Cooperative Study of geriatric evaluation and management. Patients were enrolled between August 31, 1995, and January 31, 1999. To qualify for the study, patients had to be aged >= 65 years, hospitalized in a medical or surgical ward for >48 hours, and meet >= 2 of the following criteria: moderate functional disability; recent cerebrovascular accident with residual neurological deficit; history of >= 1 fall in the previous 3 months; documented difficulty with walking (ie, requiring personal assistance or equipment), not including preadmission use of a wheelchair with ability to transfer to and from chair independently; malnutrition (admission serum albumin of 3.5 g/dL, <80% of ideal body weight, or recent >= 15-lb weight loss reported in admission history); dementia; depression; documented diagnosis of new fracture or revision needed of older fracture; unplanned admission within 3 months of previous admission; and prolonged bed rest. Clinical pharmacist/physician pairs reviewed medical records and medication lists and independently applied the Assessment of Underutilization (AOU) index to determine omissions of indicated medications. Discordances in index ratings were resolved during clinical consensus conferences. The primary outcome measure was the percentage of patients with >= 1 medication omission detected by the AOU. Multivariable logistic regression analyses identified factors associated with underuse. Results: A total of 384 patients were included in the study. The majority (53.6%) were between the ages of 65 and 74 years, and the mean (SD) Charlson comorbidity index was 2.44 (1.93). Overall, 374 patients (97.4%) were men and 274 (71.4%) were white. Medication undertreatment occurred in 238 participants (62.0%). Diseases of the circulatory, endocrine/nutritional, musculoskeletal, and respiratory systems were the most commonly undertreated conditions. The indicated medications most likely to be omitted were nitrates for those with a history of myocardial infarction, multivitamins in those with malnutrition, and inhaled anticholinergics for chronic obstructive airways disease. Statistically significant factors associated with medication underuse included limitations in activities of daily living (adjusted odds ratio [AOR], 2.17 [95% CI, 1.27-3.71]; P = 0.01), being white (AOR, 1.70 [95% CI, 1.06-2.71]; P = 0.03), and Charlson comorbidity index (AOR, 1.13 for each 1-point increase [95% CI, 1.00-1.27]; P = 0.04). Discharge from a general medicine service as opposed to a surgical service was associated with lower risk of medication underuse (AOR, 0.61 [95% CI, 0.38-0.98]; P = 0.04). Conclusions: Medication underuse was relatively common in this study. Patients with greater comorbidity, but not polypharmacy, had increased odds of undertreatment. (Am J Geriatr Pharmacother 2009;7:271280) (C) 2009 Excerpta Medica Inc. C1 [Wright, Rollin M.; Ruby-Scelsi, Christine; Hanlon, Joseph T.] Univ Pittsburgh, Div Geriatr Med, Dept Med, Sch Med, Pittsburgh, PA 15213 USA. [Sloane, Richard; Pieper, Carl F.; Twersky, Jack; Schmader, Kenneth E.] Duke Univ, Med Ctr, Ctr Study Aging & Human Dev, Durham, NC 27710 USA. [Pieper, Carl F.] Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. [Ruby-Scelsi, Christine; Hanlon, Joseph T.] Univ Pittsburgh, Sch Pharm, Dept Pharm & Therapeut, Pittsburgh, PA 15261 USA. [Twersky, Jack; Schmader, Kenneth E.] Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Durham, NC USA. [Twersky, Jack; Schmader, Kenneth E.] Duke Univ, Med Ctr, Dept Med, Div Geriatr Med, Durham, NC 27710 USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Hlth Care Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Hanlon, Joseph T.] Vet Affairs Pittsburgh Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Hanlon, JT (reprint author), Univ Pittsburgh, Div Geriatr Med, Dept Med, Sch Med, Kaufmann Med Bldg,Suite 500,3471 5th Ave, Pittsburgh, PA 15213 USA. EM jth14@pitt.edu FU Veterans Affairs Cooperative Study Program 006; National Institute on Aging [R01-AG-027017, P30 AG024827]; National Institute of Allergy and Infectious Diseases [K24-AI-51324-01]; John A. Hartford Foundation Center of Excellence in Geriatrics; [R01-AG-15432] FX Financial support was provided by the grant R01-AG-15432 and the Veterans Affairs Cooperative Study Program 006. Additional support was provided by R01-AG-027017 and P30 AG024827 from the National Institute on Aging, K24-AI-51324-01 from the National Institute of Allergy and Infectious Diseases, and from the John A. Hartford Foundation Center of Excellence in Geriatrics. NR 37 TC 20 Z9 22 U1 0 U2 8 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 1543-5946 J9 AM J GERIATR PHARMAC JI Am. J. Geriatr. Pharmacother. PD OCT PY 2009 VL 7 IS 5 BP 271 EP 280 DI 10.1016/j.amjopharm.2009.11.002 PG 10 WC Geriatrics & Gerontology; Pharmacology & Pharmacy SC Geriatrics & Gerontology; Pharmacology & Pharmacy GA 525XU UT WOS:000272251900004 PM 19948303 ER PT J AU Snow, AL Chandler, JF Kunik, ME Davila, JA Balasubramanyam, V Steele, AB Morgan, RO AF Snow, A. Lynn Chandler, Joseph F. Kunik, Mark E. Davila, Jessica A. Balasubramanyam, Valli Steele, Avila B. Morgan, Robert O. TI Self-Reported Pain in Persons With Dementia Predicts Subsequent Decreased Psychosocial Functioning SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Pain; dementia; psychosocial functioning ID LOW-BACK-PAIN; QUALITY-OF-LIFE; NURSING-HOME RESIDENTS; LONG-TERM-CARE; ALZHEIMERS-DISEASE; MARITAL SATISFACTION; BEHAVIORAL TREATMENT; DEPRESSION; ASSOCIATION; AGITATION AB Objectives: Pain self-report is the assessment gold standard in cognitively intact populations but has been discouraged in persons with dementia because of significant evidence that pain intensity is often underreported by persons with dementia. However, most community-dwelling persons with dementia are cared for in primary care settings where a more in depth pain assessment is unlikely. Therefore, it is vital to know the clinical predictive value of self-report pain assessment in this population. Psychosocial functioning is a meaningful focus for clinical prediction, because psychosocial constructs are integrally related to quality of life, physical functioning, and one's ability to function in the presence of pain. The purpose of this study was to investigate the degree to which answers to simple self-report pain questions can predict changes in psychosocial functioning 4 months later in community-dwelling older adults with dementia. Design: Longitudinal. Patients and caregivers were assessed every 4 months for 24 months. Setting: Veterans Affairs Medical Center, Houston, TX. Participants: One hundred seventy-one patients over age 60 years diagnosed with dementia in the previous year and with no previous aggression were recruited from Veterans Administration clinics. Measurements: Pain, agitation, depression, involvement in pleasant events, caregiver burden, psychosis, and patient/caregiver relationship quality (mutuality). Results: Pain scores at each time period were predictive of increased agitation and depression and decreased pleasant event frequency 4 months later. Conclusions: Our results suggest that persons with dementia who affirmatively respond to pain questions are at higher risk for developing negative psychosocial states. (Am J Geriatr Psychiatry 2009; 17:873-880) C1 [Snow, A. Lynn; Chandler, Joseph F.] Univ Alabama, Ctr Mental Hlth & Aging, Dept Psychol, Tuscaloosa, AL 35487 USA. [Snow, A. Lynn] Tuscaloosa Vet Affairs Med Ctr, Res & Dev Serv, Tuscaloosa, AL USA. [Kunik, Mark E.; Davila, Jessica A.; Balasubramanyam, Valli; Steele, Avila B.] Baylor Coll Med, Houston Ctr Qual Care & Utilizat Studies, Houston, TX 77030 USA. [Kunik, Mark E.; Davila, Jessica A.; Balasubramanyam, Valli; Steele, Avila B.] Baylor Coll Med, Hlth Serv Res & Dev Serv, Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Kunik, Mark E.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. [Kunik, Mark E.; Davila, Jessica A.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Snow, A. Lynn; Kunik, Mark E.] Vet Affairs S Cent Mental Illness Res Educ & Clin, N Little Rock, AR USA. [Morgan, Robert O.] Univ Texas Sch Publ Hlth, Div Management Policy & Community Hlth, Houston, TX USA. RP Snow, AL (reprint author), Univ Alabama, Ctr Mental Hlth & Aging, Dept Psychol, 207 Osband Hall,Box 870315, Tuscaloosa, AL 35487 USA. EM LSNOW@bama.ua.edu FU Department of Veterans Affairs; Veterans Health Administration; Health Services Research and Development Service, Washington, DC [IIR 01-159-2, HFP 90-020] FX The study sponsors had no role in the design, conduct, analysis, interpretation, writing, or decision to publish this study. NR 47 TC 15 Z9 15 U1 5 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD OCT PY 2009 VL 17 IS 10 BP 873 EP 880 DI 10.1097/JGP.0b013e3181ad4f73 PG 8 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 501LG UT WOS:000270382800007 PM 19910876 ER PT J AU Schillerstrom, JE Salazar, R Regwan, H Bonugli, RJ Royall, DR AF Schillerstrom, Jason E. Salazar, Ricardo Regwan, Heather Bonugli, Rebecca J. Royall, Donald R. TI Executive Function in Self-Neglecting Adult Protective Services Referrals Compared With Elder Psychiatric Outpatients SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Adult protective services; executive function; depression ID CONSENT AB Objective: Psychometric performance, with an emphasis on executive function, was compared between adult protective services (APS) clients referred for a decision-making capacity consultation and elders seen in an outpatient geriatric psychiatry clinic. Methods: The authors performed a retrospective medical records review extracting general, executive, and visuospatial cognitive performance and depression symptom burden in APS referrals (N = 63) and geriatric psychiatry outpatients (N = 58). Results: After adjusting for age and education, APS clients had worse mean executive performance as measured by the Executive Interview (24.3 [SD 6.4] versus 17.3 [SD 7.6], F([1, 87]) 15.7, p < 0.001) and CLOX1 (7.4 [SD 4.0] versus 9.3 [SD 4.2], F([1, 92]) 4.79, p = 0.03). There were no differences in visuospatial or general cognitive abilities. The self-neglect subgroup had worse cognitive performance on each measure than other APS referrals. Conclusions: Compared with routine geriatric psychiatry patients, APS referrals are more likely to be executively impaired but less depressed. General cognitive screens do not distinguish these two groups. (Am J Geriatr Psychiatry 2009; 17:907-910) C1 [Schillerstrom, Jason E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Royall, Donald R.] S Texas Vet Healthcare Syst, Audie L Murphy Div, San Antonio, TX USA. RP Schillerstrom, JE (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM schillerstr@uthscsa.edu; royall@uthscsa.edu NR 10 TC 8 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD OCT PY 2009 VL 17 IS 10 BP 907 EP 910 DI 10.1097/JGP.0b013e3181b4bf64 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 501LG UT WOS:000270382800011 PM 19910879 ER PT J AU Aspinall, SL Banthin, JS Good, CB Miller, GE Cunningham, FE AF Aspinall, Sherrie L. Banthin, Jessica S. Good, Chester B. Miller, G. Edward Cunningham, Francesca E. TI VA Pharmacy Users: How They Differ From Other Veterans SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID MENTAL-HEALTH PROBLEMS; CARE; EXPENDITURES; MEDICARE; ACCESS; IRAQ AB Objective: To compare users and nonusers of Veterans Affairs (VA) pharmacy services by age group. Study Design: Cross-sectional. Methods: We used data on sociodemographics, health status, and medical conditions from the Medical Expenditure Panel Survey (MEPS) to compare users and nonusers of VA pharmacies for medications. Data were pooled for 2003-2005 to ensure adequate sample sizes. Student t tests were used to compare the means for each variable, and all analyses were adjusted for the complex sample design of the MEPS. Results: Among both nonelderly (18-64 years) and elderly (> 65 years) veterans, a higher proportion who used VA pharmacy services versus those who did not use VA pharmacy services (1) were black (nonelderly: 17.7% vs 7.4%, P < .001; elderly: 9.4% vs 4.7%, P < .001); (2) had no alternative insurance (nonelderly: 27.2% vs 4.8%, P < .001; elderly: 36.3% vs 19.9%, P < .001); (3) had lower incomes (nonelderly: 32.4% vs 11.5%, P < .001; elderly: 32.4% vs 25.4%, P = .01); (4) had less than a high school education (nonelderly: 13.0% vs 6.5%, P < .001; elderly: 27.5% vs 17.6%, P < .001); (5) were disabled; and (6) reported poorer health. A higher percentage of nonelderly users reported a mental health condition (31.6% vs 19.4%, P < .001). Conclusions: Veterans who use VA pharmacy services appear to be more ill than those who do not use VA pharmacy services. In addition, the VA appears to be a safety net for uninsured veterans who have mental health problems. (Am J Manag Care. 2009; 15(10): 701-708) C1 [Aspinall, Sherrie L.; Good, Chester B.] VA Pittsburgh Healthcare Syst, VA Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Aspinall, Sherrie L.; Good, Chester B.; Cunningham, Francesca E.] VA Ctr Medicat Safety, Hines, IL USA. [Aspinall, Sherrie L.; Good, Chester B.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA 15260 USA. [Good, Chester B.] Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. [Banthin, Jessica S.; Miller, G. Edward] Agcy Healthcare Res & Qual, Ctr Financing Access & Cost Trends, Washington, DC USA. RP Aspinall, SL (reprint author), VA Pittsburgh Healthcare Syst, VA Ctr Hlth Equ Res & Promot, 7180 Highland Dr, Pittsburgh, PA 15206 USA. EM sherrie.aspinall@va.gov NR 13 TC 3 Z9 3 U1 1 U2 1 PU MANAGED CARE & HEALTHCARE COMMUNICATIONS LLC PI PLAINSBORO PA 666 PLAINSBORO RD, STE 300, PLAINSBORO, NJ 08536 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD OCT PY 2009 VL 15 IS 10 BP 701 EP 708 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 508YN UT WOS:000270975300004 PM 19845422 ER PT J AU Ross, JS Keyhani, S Korenstein, D AF Ross, Joseph S. Keyhani, Salomeh Korenstein, Deborah TI Appropriateness of Collaborations between Industry and the Medical Profession: Physicians' Perceptions SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Attitude of health personnel; Biomedical research; Drug industry ID EDUCATIONAL INTERVENTION; GIFTS AB BACKGROUND: Physicians' ratings of the appropriateness of collaboration and of receiving payment for collaboration with the pharmaceutical and medical device industries may differ. METHODS: We administered an anonymous, cross-sectional survey to a convenience sample of faculty and postgraduate physicians from all departments within the 11 hospitals affiliated with the Mount Sinai School of Medicine in New York City and New Jersey. We examined 12 collaborations with the pharmaceutical and medical device industries using 4-point Likert scales, ranging from very appropriate to very inappropriate. RESULTS: Surveys were distributed to physicians within 35 departments at 11 hospitals; 590 surveys were completed by physicians at 9 hospitals, yielding a 67% response rate. Physicians' assessment of appropriateness varied among the different collaborations, ranging from nearly all rating developing a drug or device (92%) and designing a drug/device trial (91%) as appropriate to fewer rating preparing a manuscript of a drug/device trial (60%) and recruiting patients for a drug/device trial (65%) as appropriate for physicians not involved in trial design. Physicians consistently rated receiving payment for collaboration as appropriate less often than they rated the collaboration itself as appropriate and ratings varied among the collaborations. For example, 81% rated receiving payment to develop a drug or device as appropriate, whereas 38% rated receiving payment to recruit patients for a drug/device trial when the physician was not involved in trial design as appropriate. CONCLUSIONS: Physicians' broadly perceived most collaboration with the pharmaceutical and medical device industries, and of receiving payment for collaboration, as appropriate. Published by Elsevier Inc. . The American Journal of Medicine (2009) 122, 955-960 C1 [Ross, Joseph S.] Mt Sinai Sch Med, Dept Geriatr & Adult Dev, New York, NY 10029 USA. [Ross, Joseph S.; Keyhani, Salomeh] James J Peters VA Med Ctr, HSR&D Res Enhancement Award Program, Bronx, NY USA. James J Peters VA Med Ctr, Ctr Geriatr Res Educ & Clin, Bronx, NY USA. [Keyhani, Salomeh] Mt Sinai Sch Med, Dept Hlth Policy, New York, NY USA. [Korenstein, Deborah] Mt Sinai Sch Med, Dept Med, New York, NY USA. RP Ross, JS (reprint author), Mt Sinai Sch Med, Dept Geriatr & Adult Dev, 1 Gustave L Levy Pl,Box 1070, New York, NY 10029 USA. EM joseph.ross@mssm.edu FU Attorney General Consumer and Prescriber FX Data collection for this work was partially supported by the Attorney General Consumer and Prescriber Grant Program administered by the State of Oregon. Dr. Ross was compensated for his work as a consultant at the request of plaintiffs in litigation against Merck and Co., Inc. related to rofecoxib from 2006-2007. NR 14 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD OCT PY 2009 VL 122 IS 10 BP 955 EP 960 DI 10.1016/j.amjmed.2009.04.013 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 501UV UT WOS:000270409200015 PM 19786162 ER PT J AU Sampat, MP Berger, AM Healy, BC Hildenbrand, P Vass, J Meier, DS Chitnis, T Weiner, HL Bakshi, R Guttmann, CRG AF Sampat, M. P. Berger, A. M. Healy, B. C. Hildenbrand, P. Vass, J. Meier, D. S. Chitnis, T. Weiner, H. L. Bakshi, R. Guttmann, C. R. G. TI Regional White Matter Atrophy-Based Classification of Multiple Sclerosis in Cross-Sectional and Longitudinal Data SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID SPINAL-CORD ATROPHY; HUMAN CORPUS-CALLOSUM; COGNITIVE IMPAIRMENT; BRAIN ATROPHY; DIAGNOSTIC-CRITERIA; CLINICAL-RELEVANCE; SEX-DIFFERENCES; AXONAL LOSS; MRI; SECONDARY AB BACKGROUND AND PURPOSE: The different clinical subtypes of multiple sclerosis (MS) may reflect underlying differences in affected neuroanatomic regions, Our aim was to analyze the effectiveness of jointly using the inferior subolivary medulla oblongata volume (MOV) and the cross-sectional area of the corpus callosum in distinguishing patients with relapsing-remitting multiple sclerosis (RRMS), secondary-progressive multiple sclerosis (SPMS), and primary-progressive multiple sclerosis (PPMS). MATERIALS AND METHODS: We analyzed a cross-sectional dataset of 64 patients (30 RRMS, 14 SPMS, 20 PPMS) and a separate longitudinal dataset of 25 patients (114 MR imaging examinations). Twelve patients in the longitudinal dataset had converted from RRMS to SPMS. For all images, the MOV and corpus callosum were delineated manually and the corpus callosum was parcellated into 5 segments. Patients from the cross-sectional dataset were classified as FIRMS, SPMS, or PPMS by using a decision tree algorithm with the following input features: brain parenchymal fraction, age, disease duration, MOV, total corpus callosum area and areas of 5 segments of the corpus callosum. To test the robustness of the classification technique, we applied the results derived from the cross-sectional analysis to the longitudinal dataset. RESULTS: MOV and central corpus callosum segment area were the 2 features retained by the decision tree. Patients with MOV >0.94 cm(3) were classified as having RRMS. Patients with progressive MS were further subclassified as having SPMS if the central corpus callosum segment area was <55.12 mm(2), and as having PPMS otherwise. In the cross-sectional dataset, 51/64 (80%) patients were correctly classified. For the longitudinal dataset, 88/114 (77%) patient time points were correctly classified as FIRMS or SPMS. CONCLUSIONS: Classification techniques revealed differences in affected neuroanatomic regions in subtypes of multiple sclerosis. The combination of central corpus callosum segment area and MOV provides good discrimination among patients with FIRMS, SPMS, and PPMS. C1 [Sampat, M. P.; Berger, A. M.; Vass, J.; Meier, D. S.; Bakshi, R.; Guttmann, C. R. G.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Imaging, Boston, MA 02115 USA. [Healy, B. C.; Chitnis, T.; Weiner, H. L.; Bakshi, R.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Partners Multiple Sclerosis Ctr, Boston, MA 02115 USA. [Healy, B. C.] Massachusetts Gen Hosp, Dept Neurol, Ctr Biostat, Boston, MA 02114 USA. [Hildenbrand, P.] Lahey Clin Fdn, Burlington, MA USA. RP Guttmann, CRG (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Imaging, 221 Longwood Ave,RF 394, Boston, MA 02115 USA. EM guttmann@bwh.harvard.edu FU NCRR NIH HHS [P41 RR013218, P41 RR013218-010009, P41 RR13218-01] NR 56 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD OCT PY 2009 VL 30 IS 9 BP 1731 EP 1739 DI 10.3174/ajnr.A1659 PG 9 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 509PV UT WOS:000271031300021 PM 19696139 ER PT J AU Pasadhika, S Kempen, JH Newcomb, CW Liesegang, TL Pujari, SS Rosenbaum, JT Thorne, JE Foster, CS Jabs, DA Levy-Clarke, GA Nussenblatt, RB Suhler, EB AF Pasadhika, Sirichai Kempen, John H. Newcomb, Craig W. Liesegang, Teresa L. Pujari, Siddharth S. Rosenbaum, James T. Thorne, Jennifer E. Foster, C. Stephen Jabs, Douglas A. Levy-Clarke, Grace A. Nussenblatt, Robert B. Suhler, Eric B. TI Azathioprine for Ocular Inflammatory Diseases SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID LONG-TERM; IMMUNOSUPPRESSIVE THERAPY; BEHCETS-SYNDROME; CONTROLLED TRIAL; DRUGS; MANAGEMENT; PREGNANCY; ARTHRITIS; UVEITIS; AGENTS AB PURPOSE: To evaluate treatment outcomes of azathioprine for noninfectious ocular inflammatory diseases. DESIGN: Retrospective cohort study. METHODS: Medical records of 145 patients starting azathioprine as a sole noncorticosteroid immunosuppressant at 4 tertiary uveitis services were reviewed. Main outcome measures included control of ocular inflammation, sustained control after tapering prednisone to <= 10 mg/day, and discontinuation of treatment because of side effects. RESULTS: Among 145 patients (255 eyes) treated with azathioprine, 63% had uveitis, 23% had mucous membrane pemphigoid, 11% bad scleritis, and 3% had other inflammatory diseases. By Kaplan-Meier analysis, 62% (95% confidence interval [CI], 50% to 74%) of patients with active disease initially gained complete inactivity of inflammation sustained over at least 28 days within 1 year of therapy, and 47% (95% CI, 37% to 58%) tapered systemic corticosteroids to <= 10 mg daily while maintaining control of inflammation within 1 year of therapy. Treatment success was most common for intermediate uveitis (90% with sustained inactivity within 1 year; 95% CI, 64% to 99%). Over the median follow-up of 230 days (interquartile range, 62 to 679 days), azathioprine was discontinued at a rate of 0.45 per person,years (/PY): 0.16/PY because of side effects, 0.10/PY because of ineffectiveness, 0.09/PY because of disease remission, and 0.10/PY because of unspecified causes. CONCLUSIONS: Azathioprine was moderately effective as a single corticosteroid-sparing immunosuppressive agent in terms of control of inflammation and corticosteroid-sparing benefits, but required several months to achieve treatment goals; it seems especially useful for patients with intermediate uveitis. Treatment-limiting side effects occurred in approximately one-fourth of patients within 1 year, but typically were reversible. (Am J Ophthalmol 2009;148:500-509. (C) 2009 by Elsevier Inc. All rights reserved.) C1 [Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Philadelphia, PA 19104 USA. [Pasadhika, Sirichai; Liesegang, Teresa L.; Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Internal Med, Portland, OR 97201 USA. [Kempen, John H.] Univ Penn, Scheie Eye Inst, Ocular Inflammat Serv, Philadelphia, PA 19104 USA. [Kempen, John H.; Newcomb, Craig W.] Univ Penn, Ctr Clin Epidemiol & Biostat, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Pujari, Siddharth S.; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.; Jabs, Douglas A.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Tarpon Springs, FL USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu FU NATIONAL EYE INSTITUTE, BETHESDA, MARYLAND [EY-014943]; Research to Prevent Blindness; Veterans' Administration; Genentech; Eyegate; Lux Biosciences; Abbott FX THIS STUDY WAS SUPPORTED BY THE NATIONAL EYE INSTITUTE, BETHESDA, MARYLAND, GRANT NO. EY-014943 (DR KEMPEN); the Paul and Evanina Mackall Foundation, New York, New York; and Research to Prevent Blindness Inc, New York, New York. Dr Kempen is a Research to Prevent Blindness James S. Adams Special Scholar Award recipient. Drs Jabs and Rosenbaum are recipients of Research to Prevent Blindness Senior Scientific Investigator Awards. Dr Levy-Clarke previously was supported by and Dr Nussenblatt is supported by intramural funds of the National Eye Institute, Bethesda, Maryland. Dr Sublet also received support from the Veterans' Administration. Dr Foster has served as a consultant to Allergan, Bausch & Lomb, and Sirion; owns equity or stock options in Eyegate; and h is received speaking fees from Alcon, Allergan, Inspire, Ista, Bausch & Lomb, and Centocor. Dr Jabs has served as a consultant to Abbott, Genzyme Corporation, Novartis, Allergan, the Emmes Corporation (DSMC member), and the Johns Hopkins University Dana Center for Preventive Ophthalmology. Dr Kempen has served as a Consultant to Lux Biosciences and has participated in clinical trials funded by Allergan and Eyegate. Dr Rosenbaum has served as a Consultant to Abbott, Amgen, Allergan, Lux Biosciences, and Novartis; holds equity ownership/stock options in Amgen; and has received research Support from Genentech, Lux Biosciences, and Abbott. Dr Suhler has received research support from Eyegate, Genentech, Lux Biosciences, and Abbott. Involved in design of study (S.P., J.H.K., C.W.N.); conduct of study (S.P., J.H.K., E.B.S.); collection of data (S.P., J.H.K., CW.N., T.L.L., S.S.P., J.T.R., J.E.T., C.S.F., D.A.J., G.A.L.-C., R.B.N., E.B.S.); management (S.P., J.H.K., JT.R., J.E.T., C.S.F., D.A.]., G.A.L.-C., R.B.N., E.B.S.), analysis, and interpretation of data (S.P., J.H.K., CW.N., E.B.S.); and preparation (S.P., J.H.K., E.B.S.), review, and approval of the manuscript (S.P., J.H.K., C.W.N., T.L.L., S.S.P., J.T.R., J.E.T., C.S.F., D.A.J., G.A.L.-C., R.B.N., E.B.S.). The protocol was approved by Institutional Review Boards of all participating institutions and was conducted in accordance with the principles of the Declaration of Helsinki and the Health Insurance Portability and Accountability Act. NR 26 TC 68 Z9 71 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD OCT PY 2009 VL 148 IS 4 BP 500 EP 509 DI 10.1016/j.ajo.2009.05.008 PG 10 WC Ophthalmology SC Ophthalmology GA 503MI UT WOS:000270538000006 PM 19570522 ER PT J AU Taft, CT Weatherill, RP Woodward, HE Pinto, LA Watkins, LE Miller, MW Dekel, R AF Taft, Casey T. Weatherill, Robin P. Woodward, Halley E. Pinto, Lavinia A. Watkins, Laura E. Miller, Mark W. Dekel, Rachel TI Intimate Partner and General Aggression Perpetration Among Combat Veterans Presenting to a Posttraumatic Stress Disorder Clinic SO AMERICAN JOURNAL OF ORTHOPSYCHIATRY LA English DT Article DE aggression; domestic violence; veterans; posttraumatic stress disorder ID PHYSICAL AGGRESSION; RELATIONSHIP ABUSE; DOMESTIC VIOLENCE; VIETNAM VETERANS; BEHAVIOR; COUPLES; ANGER; MEN; SYMPTOMATOLOGY; CONFLICT AB This study examined rates and correlates of intimate partner and general aggression perpetration among 236 male combat veterans seeking services in a Veteran's Affairs posttraumatic stress disorder (PTSD) clinic. Approximately 33% of those in an intimate relationship reported perpetrating partner physical aggression in the previous year, and 91% reported partner psychological aggression. Comparable rates were found for general aggression perpetration among partnered and nonpartnered veterans. PTSD symptoms as well as symptoms of depression were associated with aggression across subgroups and forms of aggression, and PTSD symptoms reflecting arousal and lack of control were generally the strongest predictor of aggression. Findings indicate a need for additional aggression screening and intervention development for this population, and highlight the targeting of heightened arousal and lack of behavioral control in aggression interventions. C1 [Taft, Casey T.; Weatherill, Robin P.; Woodward, Halley E.; Pinto, Lavinia A.; Watkins, Laura E.; Miller, Mark W.] VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. [Taft, Casey T.; Weatherill, Robin P.; Miller, Mark W.] Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02215 USA. [Dekel, Rachel] Bar Ilan Univ, Louis & Gabi Weisfeld Sch Social Work, IL-52100 Ramat Gan, Israel. RP Taft, CT (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 150 S Huntington Ave, Boston, MA 02130 USA. EM casey.taft@va.gov RI Miller, Mark/G-7322-2011 OI Miller, Mark/0000-0001-6393-8563 FU NIMH NIH HHS [R01 MH079806] NR 45 TC 48 Z9 48 U1 4 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-9432 J9 AM J ORTHOPSYCHIAT JI Am. J. Orthopsychiatr. PD OCT PY 2009 VL 79 IS 4 BP 461 EP 468 DI 10.1037/a0016657 PG 8 WC Psychiatry; Social Work SC Psychiatry; Social Work GA V15HM UT WOS:000207793100005 PM 20099937 ER PT J AU Jaafar, F Righi, E Lindstrom, V Linton, C Nohadani, M Van Noorden, S Lloyd, T Poznansky, J Stamp, G Dina, R Coleman, DV Poznansky, MC AF Jaafar, Fatimah Righi, Elda Lindstrom, Victoria Linton, Christine Nohadani, Mahrokh Van Noorden, Susan Lloyd, Tyler Poznansky, Joshua Stamp, Gordon Dina, Roberto Coleman, Dulcie V. Poznansky, Mark C. TI Correlation of CXCL12 Expression and FoxP3(+) Cell Infiltration with Human Papillomavirus Infection and Clinicopathological Progression of Cervical Cancer SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID REGULATORY T-CELLS; CHEMOKINE RECEPTOR CXCR4; LYMPH-NODE METASTASIS; OVARIAN-CARCINOMA; ACTIVE MOVEMENT; TUMOR-CELLS; ADENOCARCINOMA; INVOLVEMENT; PROGNOSIS; NEOPLASIA AB Human cervical cancer is an immunogenic tumor with a defined pattern of histopathological and clinical progression. Tumor-infiltrating T cells contribute to immune control of this tumor; however, cervical cancer dysregulates this immune response both through its association with human papillomavirus (HPV) infection and by producing cytokines and chemokines. Animal tumor models have revealed associations between overproduction of the chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12) and dys-regulation of tumor-specific immunity. We therefore proposed that CXCL12 expression by cervical precancerous and cancerous lesions correlates with histopathological progression, loss of immune control of the tumor, and HPV infection. We found a significant association between cancer stage and CXCL12 expression for squamous and glandular lesions as well as with the HPV16+ (high-risk) status of the neoplastic lesions. Cancer progression was correlated with increasing levels of FoxP3 T-cell infiltration in the tumor. FoxP3 and CXCL12 expression significantly correlated for squamous and glandular neoplastic lesions. These observations were supported by enzyme-linked immunosorbent assay and Western blotting. In addition, we demonstrated CXCL12 expression by dyskaryotic cells in ThinPrep cervical smears. This study robustly links increased CXCL12 expression and FoxP3(+)-cell infiltration to HPV infection and progression of cervical cancer. It supports the detection of CXCL12 in cervical smears and biopsies as an additional biomarker for this disease. (Am J Pathol 2009, 175:1525-1535; DOI: 10.2353/ajpath.2009.090295) C1 [Righi, Elda; Lindstrom, Victoria; Linton, Christine; Poznansky, Mark C.] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. [Righi, Elda; Lindstrom, Victoria; Linton, Christine; Poznansky, Mark C.] Massachusetts Gen Hosp, Dana Farber Harvard Canc Ctr, Boston, MA 02114 USA. [Jaafar, Fatimah; Nohadani, Mahrokh; Van Noorden, Susan; Lloyd, Tyler; Poznansky, Joshua; Stamp, Gordon; Dina, Roberto; Coleman, Dulcie V.] Hammersmith Hosp, Imperial Coll, Fac Med, Dept Histopathol & Cytol, London, England. RP Poznansky, MC (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp East, 149 Bldg,13th St, Charlestown, MA 02129 USA. EM d.v.coleman@ic.ac.uk; mpoznansky@partners.org FU U.S. Public Health Service [R01 A149757]; Marsha Rivkin Center; philanthropic funds; Imperial College Trust Fund; Government of Brunei, Darussalam FX Supported by the U.S. Public Health Service (grant R01 A149757), the Marsha Rivkin Center, and philanthropic funds (M.C.P. and E.R.), the Imperial College Trust Fund (D.N.C.), and the Government of Brunei, Darussalam (F.J.). NR 33 TC 33 Z9 33 U1 1 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD OCT PY 2009 VL 175 IS 4 BP 1525 EP 1535 DI 10.2353/ajpath.2009.090295 PG 11 WC Pathology SC Pathology GA 503AM UT WOS:000270503100019 PM 19808652 ER PT J AU Ho-Tin-Noe, B Carbo, C Demers, M Cifuni, SM Goerge, T Wagner, DD AF Ho-Tin-Noe, Benoit Carbo, Carla Demers, Melanie Cifuni, Stephen M. Goerge, Tobias Wagner, Denisa D. TI Innate Immune Cells Induce Hemorrhage in Tumors during Thrombocytopenia SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HUMAN PLATELETS; NEUTROPHIL FUNCTIONS; ENDOTHELIAL BARRIER; NECROSIS-FACTOR; MICE; INFLAMMATION; ANGIOGENESIS; MACROPHAGES; RELEASE; PRODUCTS AB Platelets are crucial regulators of tumor vascular homeostasis and continuously prevent tumor hemorrhage through secretion of their granules. However, the reason for tumor bleeding in the absence of platelets remains unknown. Tumors are associated with inflammation, a cause of hemorrhage in thrombocytopenia. Here, we investigated the role of the inflamed tumor microenvironment in the induction of tumor vessel injury in thrombocytopenic mice. Using s.c. injections of vascular endothelial growth factor or tumor necrosis factor-a combined with depletion of neurtrophils, we demonstrate that enhancing the opening of endothelial cell junctions was not sufficient to cause bleeding in the absence of platelets; instead, induction of tissue hemorrhage in thrombocytopenia required recruitment of leukocytes. immunohistology revealed that thrombocytopenia-induced tumor hemorrhage occurs at sites of macrophage and neutrophil accumulation. Mice deficient in beta(2) or beta(3) integrins, which have decreased neutrophil and/or macrophage infiltration in their tumor stroma, were protected from thrombocytopenia-induced tumor hemorrhage, indicating that, in the absence of platelets, stroma-infiltrating leukocytes induced tumor vessel injury. This injury was independent of reactive oxygen species generation and of complement activation, as suggested by the persistence of tumor hemorrhage in C3- and nicotinamide adenine dinucleotide phosphate oxidase-deficient thrombocytopenic mice. Our results show that platelets counteract tumor-associated inflammation and that the absence of this platelet function elicits vascular injuries by tumor-infiltrating innate immune cells. (Am J Pathol 2009, 175:1699-1708; DOI: 10.2353/ajpath.2009.090460) C1 [Ho-Tin-Noe, Benoit; Carbo, Carla; Demers, Melanie; Cifuni, Stephen M.; Goerge, Tobias; Wagner, Denisa D.] Immune Dis Inst, Boston, MA 02115 USA. [Ho-Tin-Noe, Benoit; Carbo, Carla; Demers, Melanie; Cifuni, Stephen M.; Goerge, Tobias; Wagner, Denisa D.] Childrens Hosp, Program Cellular & Mol Med, Boston, MA 02115 USA. [Ho-Tin-Noe, Benoit; Carbo, Carla; Demers, Melanie; Goerge, Tobias; Wagner, Denisa D.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Carbo, Carla] Univ Barcelona, Hosp Clin, Serv Hemoterapia Hemostasia, Barcelona, Spain. RP Wagner, DD (reprint author), Immune Dis Inst, 3 Blackfan Circle, Boston, MA 02115 USA. EM wagner@idi.harvard.edu FU National Heart, Lung, and Blood Institute of the National Institutes of Health [R37 HL041002, P01 HI066105]; La Fonclation pour la Recherche Medicale; Terry Fox Foundation through the National Cancer Institute of Canada [TF018748]; Deutsche Forschungsgemeinschaft [GO1360/4-1] FX Supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (R37 HL041002 and P01 HI066105; to D.D.W.), La Fonclation pour la Recherche Medicale (to B.H.), the Terry Fox Foundation through the National Cancer Institute of Canada (TF018748; to M.D.), and from the Deutsche Forschungsgemeinschaft (GO1360/4-1; to T.G.). NR 58 TC 31 Z9 32 U1 1 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD OCT PY 2009 VL 175 IS 4 BP 1699 EP 1708 DI 10.2353/ajpath.2009.090460 PG 10 WC Pathology SC Pathology GA 503AM UT WOS:000270503100035 PM 19729481 ER PT J AU Jones, JA Beck, C Barbour, JR Zavadzkas, JA Mukherjee, R Spinale, FG Ikonomidis, JS AF Jones, Jeffrey A. Beck, Christy Barbour, John R. Zavadzkas, Jouzas A. Mukherjee, Rupak Spinale, Francis G. Ikonomidis, John S. TI Alterations in Aortic Cellular Constituents during Thoracic Aortic Aneurysm Development Myofibroblast-Mediated Vascular Remodeling SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MATRIX PROTEIN EXPRESSION; EXTRACELLULAR-MATRIX; ASCENDING AORTA; MURINE MODEL; MONOCLONAL-ANTIBODY; METALLOPROTEINASES; VALVE; MACROPHAGE; APOPTOSIS; PATTERNS AB The present study tested the hypothesis that changes in the resident endogenous cellular population accompany alterations in aortic collagen and elastin content during thoracic aortic aneurysm (TAA) development in a murine model. Descending thoracic aortas were analyzed at various time points (2, 4, 8, and 16 weeks) post-TAA induction (0-5 M CaCl(2), 15 minutes). Aortic tissue sections were subjected to histological staining and morphometric analysis for collagen and elastin, as well as immunostaining for cell-type-specific markers to quantify fibroblasts, myofibroblasts, and smooth-muscle cells. Results were compared with reference control mice processed in die same fashion. Aortic dilatation was accompanied by changes in the elastic architecture that included: a decreased number of elastic lamellae (from 6 to 4); altered area fraction of elastin (elevated at 4 weeks and decreased at 16 weeks); and a decreased area between elastic lamellae (minimum reached at 4 weeks). Total collagen content did not change over time. increased immunoreactivity for fibroblast and myofibroblast markers was observed at 8- and 16-week post-TAA-induction, whereas immunoreactivity for smooth-muscle cell markers peaked at 4 weeks and returned to baseline by 16 weeks. Therefore, this study demonstrated that changes in aortic elastin content were accompanied by the emergence of a subset of fibroblast-derived myofibroblasts whose altered phenotype may play a significant role in TAA development through the enhancement of extracellular matrix proteolysis. (Am J Pathol 2009, 175:1746-1756; DOI: 10.2353/ajpath.2009.081141) C1 [Jones, Jeffrey A.; Beck, Christy; Barbour, John R.; Zavadzkas, Jouzas A.; Mukherjee, Rupak; Spinale, Francis G.; Ikonomidis, John S.] Med Univ S Carolina, Dept Surg, Div Cardiothorac Surg Res, Charleston, SC 29425 USA. [Jones, Jeffrey A.; Spinale, Francis G.] Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Jones, JA (reprint author), Med Univ S Carolina, Dept Surg, Div Cardiothorac Surg Res, Strom Thurmond Res Bldg,114 Doughty St,Suite 625, Charleston, SC 29425 USA. EM jonesja@musc.edu FU National Institutes of Health/National Heart, Lung, and Blood Institute [R01 HL075488-05]; Department of Veterans Affairs [BLRD-CDA-2] FX Supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant R01 HL075488-05 and a Career Development Award (BLRD-CDA-2) from the Department of Veterans Affairs. NR 50 TC 27 Z9 28 U1 1 U2 5 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD OCT PY 2009 VL 175 IS 4 BP 1746 EP 1756 DI 10.2353/ajpath.2009.081141 PG 11 WC Pathology SC Pathology GA 503AM UT WOS:000270503100039 PM 19729479 ER PT J AU Yang, ZH Yan, K Williams, S Lew, HL AF Yang, Zhaohui Yan, Kun Williams, Steve Lew, Henry L. TI An Unusual Cause of Abdominal Pain in a Patient with Severe Traumatic Brain Injury (TBI): Intussusception of the Jejunum SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Editorial Material C1 [Yan, Kun; Lew, Henry L.] VA Boston Healthcare Syst, Phys Med & Rehabil Serv, Boston, MA 02130 USA. [Yang, Zhaohui; Williams, Steve] Boston Univ, Med Ctr, Dept Phys Med & Rehabil, Boston, MA USA. [Lew, Henry L.] Harvard Univ, Sch Med, Boston, MA USA. RP Lew, HL (reprint author), VA Boston Healthcare Syst, Phys Med & Rehabil Serv, 150 S Huntington Ave, Boston, MA 02130 USA. 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 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD OCT PY 2009 VL 88 IS 10 BP 864 EP 865 DI 10.1097/PHM.0b013e3181b32b31 PG 2 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 506FV UT WOS:000270760600011 PM 19661775 ER PT J AU Sussman, CR Zhao, JH Plata, C Lu, J Daly, C Angle, N DiPiero, J Drummond, IA Liang, JO Boron, WF Romero, MF Chang, MH AF Sussman, Caroline R. Zhao, Jinhua Plata, Consuelo Lu, Jing Daly, Christopher Angle, Nathan DiPiero, Jennifer Drummond, Iain A. Liang, Jennifer O. Boron, Walter F. Romero, Michael F. Chang, Min-Hwang TI Cloning, localization, and functional expression of the electrogenic Na+ bicarbonate cotransporter (NBCe1) from zebrafish SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE intracellular pH; acid base; membrane current; bicarbonate transport; Xenopus oocyte; teleost; Danio rerio; cellular buffering; immunohistochemistry; in situ; electrophysiology ID RENAL TUBULAR-ACIDOSIS; NA+-HCO3-COTRANSPORTER; ANION-EXCHANGER; NA+/HCO3-COTRANSPORTER; ENVIRONMENTAL HYPERCAPNIA; MISSENSE MUTATION; BRAIN VENTRICLES; INTRACELLULAR PH; BASE REGULATION; GENE SLC4A4 AB Sussman CR, Zhao J, Plata C, Lu J, Daly C, Angle N, DiPiero J, Drummond IA, Liang JO, Boron WF, Romero MF, Chang M-H. Cloning, localization, and functional expression of the electrogenic Na+ bicarbonate cotransporter (NBCe1) from zebrafish. Am J Physiol Cell Physiol 297: C865-C875, 2009. First published July 22, 2009; doi:10.1152/ajpcell.00679.2008.-Mutations in the electrogenic Na+/nHCO(3)(-) cotransporter (NBCe1, SLC4A4) cause severe proximal renal tubular acidosis, glaucoma, and cataracts in humans, indicating NBCe1 has a critical role in acid-base homeostasis and ocular fluid transport. To better understand the homeostatic roles and protein ontogeny of NBCe1, we have cloned, localized, and downregulated NBCe1 expression in zebrafish, and examined its transport characteristics when expressed in Xenopus oocytes. Zebrafish NBCe1 (zNBCe1) is 80% identical to published mammalian NBCe1 cDNAs. Like other fish NBCe1 clones, zebrafish NBCe1 is most similar to the pancreatic form of mammalian NBC (Slc4a4-B) but appears to be the dominant isoform found in zebrafish. In situ hybridization of embryos demonstrated mRNA expression in kidney pronephros and eye by 24 h postfertilization (hpf) and gill and brain by 120 hpf. Immunohistochemical labeling demonstrated expression in adult zebrafish eye and gill. Morpholino knockdown studies demonstrated roles in eye and brain development and caused edema, indicating altered fluid and electrolyte balance. With the use of microelectrodes to measure membrane potential (V-m), voltage clamp (V-C), intracellular pH (pH(i)), or intracellular Na+ activity (aNa(i)), we examined the function of zNBCe1 expressed in Xenopus oocytes. Zebrafish NBCe1 shared transport properties with mammalian NBCe1s, demonstrating electrogenic Na+ and HCO3- transport as well as similar drug sensitivity, including inhibition by 4,4'-diiso-thiocyano-2,2'-disulfonic acid stilbene and tenidap. These data indicate that NBCe1 in zebrafish shares many characteristics with mammalian NBCe1, including tissue distribution, importance in systemic water and electrolyte balance, and electrogenic transport of Na+ and HCO3-. Thus zebrafish promise to be useful model system for studies of NBCe1 physiology. C1 [Sussman, Caroline R.; Romero, Michael F.; Chang, Min-Hwang] Mayo Clin, Coll Med, Rochester, MN 55905 USA. [Sussman, Caroline R.; Plata, Consuelo; Lu, Jing; Daly, Christopher; Angle, Nathan; DiPiero, Jennifer; Liang, Jennifer O.; Boron, Walter F.; Romero, Michael F.; Chang, Min-Hwang] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Zhao, Jinhua] Cleveland Vet Affairs Med Ctr, Cleveland, OH USA. [Zhao, Jinhua; Drummond, Iain A.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Nephrol Div,Dept Med, Charlestown, MA USA. [Plata, Consuelo] Inst Nacl Ciencias Med & Nutr Nefrol & Metab Mine, Mexico City, DF, Mexico. [Lu, Jing; Daly, Christopher; Boron, Walter F.] Yale Univ, Sch Med, New Haven, CT USA. [Liang, Jennifer O.] Univ Minnesota, Duluth, MN 55812 USA. RP Chang, MH (reprint author), Mayo Clin, Coll Med, 200 1st St SW, Rochester, MN 55905 USA. EM chang.minhwang@mayo.edu RI Plata, Consuelo/M-4482-2015 OI Plata, Consuelo/0000-0001-9340-8950 FU National Institute of Diabetes and Digestive and Kidney Diseases [DK-56218, DK-60845, EY-017732, DK-30344, DK-070263]; Wadsworth Foundation New Investigator Award; American Heart Association (AHA) [SDG 06-30137N]; PKD foundation fellowship [38a2f]; AHA postdoctoral fellowships FX This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-56218, DK-60845, and EY-017732 (to M. F. Romero), DK-30344 (to W. F. Boron), DK-070263 (to I. A. Drummond), Wadsworth Foundation New Investigator Award and American Heart Association (AHA) SDG 06-30137N (to C. R. Sussman), PKD foundation fellowship 38a2f (to J. Zhao), and AHA postdoctoral fellowships (to M.-H. Chang and J. Lu). NR 52 TC 15 Z9 16 U1 3 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD OCT PY 2009 VL 297 IS 4 BP C865 EP C875 DI 10.1152/ajpcell.00679.2008 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 501KY UT WOS:000270381900009 PM 19625604 ER PT J AU Akiba, Y Watanabe, C Mizumori, M Kaunitz, JD AF Akiba, Yasutada Watanabe, Chikako Mizumori, Misa Kaunitz, Jonathan D. TI Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE intracellular alkalinization; mucus secretion; bicarbonate secretion; monosodium glutamate; taste receptor ID CALCIUM-SENSING RECEPTOR; MUCUS GEL THICKNESS; BITTER TASTE RECEPTORS; INTRACELLULAR PH; GASTROINTESTINAL-TRACT; CA2+-SENSING RECEPTOR; CARBONIC-ANHYDRASES; CHORDA TYMPANI; BLOOD-FLOW; ACID AB Akiba Y, Watanabe C, Mizumori M, Kaunitz JD. Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. Am J Physiol Gastrointest Liver Physiol 297: G781-G791, 2009. First published July 30, 2009; doi: 10.1152/ajpgi.90605.2008.-Presence of taste receptor families in the gastrointestinal mucosa suggests a physiological basis for local and early detection of a meal. We hypothesized that luminal L-glutamate, which is the primary nutrient conferring fundamental umami or proteinaceous taste, influences mucosal defense mechanisms in rat duodenum. We perfused the duodenal mucosa of anesthetized rats with L-glutamate (0.1-10 mM). Intracellular pH (pH(i)) of the epithelial cells, blood flow, and mucus gel thickness (MGT) were simultaneously and continuously measured in vivo. Some rats were pretreated with indomethacin or capsaicin. Duodenal bicarbonate secretion (DBS) was measured with flow-through pH and CO(2) electrodes. We tested the effects of agonists or antagonists for metabotropic glutamate receptor (mGluR) 1 or 4 or calcium-sensing receptor (CaSR) on defense factors. Luminal L-glutamate dose dependently increased pHi and MGT but had no effect on blood flow in the duodenum. L-glutamate (10 mM)-induced cellular alkalinization and mucus secretion were inhibited by pretreatment with indomethacin or capsaicin. L-glutamate effects on pH(i) and MGT were mimicked by mGluR4 agonists and inhibited by an mGluR4 antagonist. CaSR agonists acidified cells with increased MGT and DBS, unlike L-glutamate. Perfusion of L-glutamate with inosinate (inosine 5'-monophosphate, 0.1 mM) enhanced DBS only in combination, suggesting synergistic activation of the L-glutamate receptor, typical of taste receptor type 1. L-leucine or L-aspartate had similar effects on DBS without any effect on pHi and MGT. Preperfusion of L-glutamate prevented acid-induced cellular injury, suggesting that L-glutamate protects the mucosa by enhancing mucosal defenses. Luminal L-glutamate may activate multiple receptors and afferent nerves and locally enhance mucosal defenses to prevent subsequent injury attributable to acid exposure in the duodenum. C1 [Akiba, Yasutada; Kaunitz, Jonathan D.] Greater Los Angeles Vet Affairs Healthcare Syst, Los Angeles, CA USA. [Akiba, Yasutada; Watanabe, Chikako; Mizumori, Misa; Kaunitz, Jonathan D.] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. [Akiba, Yasutada; Watanabe, Chikako; Mizumori, Misa; Kaunitz, Jonathan D.] Brentwood Biomed Res Inst, Los Angeles, CA USA. RP Akiba, Y (reprint author), W Los Angeles Vet Affairs Med Ctr, Bldg 114,Suite 217,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM yasuakiba@hotmail.com FU Ajinomoto, Japan; Department of Veterans Affairs Merit Review Award, NIH-NIDDK [R01 DK54221, P30 DK0413] FX This work was supported by a research grant from Ajinomoto, Japan (Y. Akiba), Department of Veterans Affairs Merit Review Award, NIH-NIDDK R01 DK54221 (J. Kaunitz), and the animal core of NIH-NIDDK P30 DK0413 (J. E. Rozengurt). NR 48 TC 58 Z9 62 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD OCT PY 2009 VL 297 IS 4 BP G781 EP G791 DI 10.1152/ajpgi.90605.2008 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 498LI UT WOS:000270141400017 PM 19643955 ER PT J AU Waxman, AB Kolliputi, N AF Waxman, Aaron B. Kolliputi, Narasaiah TI IL-6 Protects against Hyperoxia-Induced Mitochondrial Damage via Bcl-2-Induced Bak Interactions with Mitofusions SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE lung injury; mitochondria; apoptosis; cytochrome c; Bax ID ACUTE LUNG INJURY; CELL-DEATH; OXYGEN-TOXICITY; GENE-EXPRESSION; DNA-DAMAGE; BCL-2; APOPTOSIS; FAMILY; INTERLEUKIN-11; INHIBITION AB overexpression of IL-6 markedly diminishes hyperoxic lung injury, hyperoxia-induced cell death, and DNA fragmentation, and enhances Bcl-2 expression. We hypothesized that changes in the interactions between Bcl-2 family members play an important role in the IL-6-mediated protective response to oxidative stress. Consistent with this hypothesis, we found that IL-6 induced Bcl-2 expression, both in vivo and in vitro, disrupted interactions between proapoptotic and antiapoptotic factors, and suppressed H(2)O(2)-induced loss of mitochondrial membrane potential in vitro. In addition, IL-6 overexpression in mice protects against hyperoxia-induced lung mitochondrial damage. The overexpression of Bcl-2 in vivo prolonged the survival of mice exposed to hyperoxia and inhibited alveolar capillary protein leakage. In addition, apoptosis-associated DNA fragmentation was substantially reduced in these animals. This IL-6-mediated protection was lost when Bcl-2 was silenced, demonstrating that Bcl-2 is an essential mediator of IL-6 cytoprotection. Finally, Bcl-2 blocked the dissociation of Bak from mitofusion protein (Mfn) 2, and inhibited the interaction between Bak and Mfn1. Taken together, our results suggest that IL-6 induces Bcl-2 expression to perform cytoprotective functions in response to oxygen toxicity, and that this effect is mediated by alterations in the interactions between Bak and Mfns. C1 [Waxman, Aaron B.; Kolliputi, Narasaiah] Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp,Pulm Crit Care Unit, Boston, MA 02114 USA. RP Waxman, AB (reprint author), Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp,Pulm Crit Care Unit, 55 Fruit St,Bulfinch 148, Boston, MA 02114 USA. EM abwaxman@partners.org RI Kolliputi, Narasaiah/I-6050-2012 OI Kolliputi, Narasaiah/0000-0002-2654-1900 FU National Institutes of Health [RO1HL074859] FX This work was supported by National Institutes of Health grant RO1HL074859 (A.B.W.). NR 32 TC 45 Z9 50 U1 0 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD OCT PY 2009 VL 41 IS 4 BP 385 EP 396 DI 10.1165/rcmb.2008-0302OC PG 12 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 499BJ UT WOS:000270191200002 PM 19168699 ER PT J AU Medoff, BD Okamoto, Y Leyton, P Weng, MQ Sandall, BP Raher, MJ Kihara, S Bloch, KD Libby, P Luster, AD AF Medoff, Benjamin D. Okamoto, Yoshihisa Leyton, Patricio Weng, Meiqian Sandall, Barry P. Raher, Michael J. Kihara, Shinji Bloch, Kenneth D. Libby, Peter Luster, Andrew D. TI Adiponectin Deficiency Increases Allergic Airway Inflammation and Pulmonary Vascular Remodeling SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE asthma; obesity; pulmonary hypertension ID ACTIVATED PROTEIN-KINASE; OBESITY HYPOVENTILATION-SYNDROME; BODY-MASS INDEX; NF-KAPPA-B; SMOOTH-MUSCLE; ARTERIAL-HYPERTENSION; EPITHELIAL-CELLS; STIMULATES ANGIOGENESIS; EOTAXIN EXPRESSION; INSULIN-RESISTANCE AB Obesity is associated with an increased incidence and severity of asthma, as well as other lung disorders, such as pulmonary hypertension. Adiponectin (APN), an antiinflammatory adipocytokine, circulates at lower levels in the obese, which is thought to contribute to obesity-related inflammatory diseases. We sought to determine the effects of APN deficiency in a murine model of chronic asthma. Allergic airway inflammation was induced in APN-deficient mice (APN(-/-)) using sensitization without adjuvant followed by airway challenge with ovalbumin. The mice were then analyzed for changes in inflammation and lung remodeling. APN(-/-) mice in this model develop increased allergic airway inflammation compared with wildtype mice, with greater accumulation of eosinophils and monocytes in the airways associated with elevated lung chemokine levels. Surprisingly, APN-/- mice developed severe pulmonary arterial muscularization and pulmonary arterial hypertension in this model, whereas wild-type mice had only mild vascular remodeling and comparatively less pulmonary arterial hypertension. Our findings demonstrate that APN modulates allergic inflammation and pulmonary vascular remodeling in a model of chronic asthma. These data provide a possible mechanism for the association between obesity and asthma, and suggest a potential novel link between obesity, inflammatory lung disease, and pulmonary hypertension. C1 [Medoff, Benjamin D.; Weng, Meiqian; Sandall, Barry P.; Luster, Andrew D.] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Charlestown, MA 02129 USA. [Medoff, Benjamin D.; Weng, Meiqian] Massachusetts Gen Hosp, Pulm & Crit Care Unit, Charlestown, MA 02129 USA. [Leyton, Patricio; Raher, Michael J.; Bloch, Kenneth D.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Leyton, Patricio; Raher, Michael J.; Bloch, Kenneth D.] Massachusetts Gen Hosp, Anesthesia Ctr Crit Care Res, Charlestown, MA 02129 USA. [Leyton, Patricio; Raher, Michael J.; Bloch, Kenneth D.] Harvard Univ, Sch Med, Charlestown, MA USA. [Okamoto, Yoshihisa; Libby, Peter] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Okamoto, Yoshihisa; Libby, Peter] Harvard Univ, Sch Med, Boston, MA USA. [Kihara, Shinji] Osaka Univ, Grad Sch Med, Dept Metab Med, Osaka, Japan. RP Medoff, BD (reprint author), Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, CNY 8301,149 13th St, Charlestown, MA 02129 USA. EM bmedoff@partners.org; aluster@mgh.harvard.edu FU National Institutes of Health [HL072775, HL088297, A140618, HL34636, HL074352]; Donald W. Reynolds Foundation; American Heart Association and Eli Lilly (International Fellowship) FX This work was supported by National Institutes of Health grants HL072775 and HL088297 (B.D.M.), A140618 (A.D.L.), HL34636 (P.L.), and HL074352 (K.D.B.), the Donald W. Reynolds Foundation (P.L.), and the American Heart Association and Eli Lilly (International Fellowship) (Y.O.). NR 86 TC 87 Z9 88 U1 1 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD OCT PY 2009 VL 41 IS 4 BP 397 EP 406 DI 10.1165/rcmb.2008-0415OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 499BJ UT WOS:000270191200003 PM 19168697 ER PT J AU Baier, ND Hahn, PF Gervais, DA Samir, A Halpern, EF Mueller, PR Harisinghani, MG AF Baier, Nina D. Hahn, Peter F. Gervais, Debra A. Samir, Anthony Halpern, Elkan F. Mueller, Peter R. Harisinghani, Mukesh G. TI Fine-Needle Aspiration Biopsy of Thyroid Nodules: Experience in a Cohort of 944 Patients SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE fine-needle aspiration biopsy; sonography; thyroid cancer; thyroid nodules; ultrasound-guided biopsy ID ULTRASONOGRAPHY; CARCINOMA; SONOGRAPHY; US; ASSOCIATION; PREVALENCE; MALIGNANCY; MANAGEMENT; DIAGNOSIS; SOLITARY AB OBJECTIVE. The objective of our study was to determine the likelihood of malignancy in thyroid nodules and the risk of a nondiagnostic fine-needle aspiration biopsy (FNAB) on the basis of the demographic characteristics of the patients and sonographic features of the nodules. MATERIALS AND METHODS. Between January 2002 and November 2007, 2,338 ultrasound-guided thyroid, thyroid bed, and cervical lymph node FNABs were performed at a tertiary referral center. Entry criteria for our retrospective study were adult patients who underwent thyroid nodule FNAB and had previously undergone diagnostic sonography. From previous reports for 944 thyroid nodules (739 nodules in women and 205 nodules in men), four sonographic features were recorded: longest dimension, morphology, presence of micro-calcifications, and presence of lymphadenopathy. The final diagnosis of each nodule was classified as benign, malignant, or nondiagnostic on the basis of surgical pathology when available and cytology otherwise and was analyzed for correlation with individual sonographic features and combinations of features. RESULTS. The prevalence of malignancy and of nondiagnostic FNAB in this study was 11.0% and 11.8%, respectively. Statistically significant (p < 0.05) findings in malignant nodules were younger patient age (<= 45 years; odds ratio [OR], 1.54) and solid nodule morphology (OR, 2.38). The significant predictors of a nondiagnostic-quality FNAB were older patient age (> 75 years; OR, 1.95) and a nodule >= 10 mm (OR, 1.45). Adding information about the other evaluated ultrasound features did not lead to a significant result. CONCLUSION. Malignant thyroid nodules tend to be solid (86.5%). Patients older than 75 years showed a clearly increased risk of nondiagnostic FNAB, but to predict a higher risk of malignancy or of nondiagnostic FNAB using ultrasound remains difficult. C1 [Baier, Nina D.; Hahn, Peter F.; Gervais, Debra A.; Samir, Anthony; Mueller, Peter R.; Harisinghani, Mukesh G.] Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, Boston, MA 02114 USA. [Halpern, Elkan F.] Massachusetts Gen Hosp, Inst Technol Assessment, Boston, MA 02114 USA. RP Baier, ND (reprint author), Massachusetts Gen Hosp, Dept Radiol, Div Abdominal Imaging & Intervent, 55 Fruit St,White 270, Boston, MA 02114 USA. OI Samir, Anthony/0000-0002-7801-8724 NR 20 TC 45 Z9 45 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2009 VL 193 IS 4 BP 1175 EP 1179 DI 10.2214/AJR.08.1840 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 497CZ UT WOS:000270033300035 PM 19770344 ER PT J AU Samphao, S Wheeler, AJ Rafferty, E Michaelson, JS Specht, MC Gadd, MA Hughes, KS Smith, BL AF Samphao, Srila Wheeler, Amanda J. Rafferty, Elizabeth Michaelson, James S. Specht, Michelle C. Gadd, Michele A. Hughes, Kevin S. Smith, Barbara L. TI Diagnosis of breast cancer in women age 40 and younger: delays in diagnosis result from underuse of genetic testing and breast imaging SO AMERICAN JOURNAL OF SURGERY LA English DT Article; Proceedings Paper CT 10th Annual Meeting of the American-Society-of-Breast-Surgeons CY APR 23, 2009 CL San Diego, CA SP Amer Soc Breast Surg DE Breast cancer; Young women; Genetic testing; Digital mammography; Magnetic resonance imaging ID HIGH FAMILIAL RISK; SOCIETY GUIDELINES; BRCA2 MUTATIONS; MAMMOGRAPHY; MRI; CARCINOMA; SENSITIVITY; PERFORMANCE; POPULATION; FEATURES AB BACKGROUND: The impact of newer breast imaging technologies and genetic testing on the detection of breast cancer in women age 40 and younger remains unknown. METHODS: A records review identified 628 women age 40 and younger diagnosed with breast cancer from 1996 to 2008. Patient and tumor characteristics, means of diagnosis, imaging results, and genetic testing were examined. RESULTS: Tumors were first detected by self-examination in 71%, with a median invasive tumor size of 2.0 cm. Imaging performed at or after diagnosis visualized most tumors; mammography visualized 86%, magnetic resonance imaging (MRI) visualized 96%, and mammography plus MRI visualized more than 98% of tumors. For 81% of patients, the mammogram at diagnosis was their first mammogram. Although 50% had a family history of breast or ovarian cancer, few underwent genetic testing before their cancer diagnosis; 61 of 247 (25%) ultimately tested had a BRCA mutation. CONCLUSIONS: Better use of genetic testing, mammography, and MRI could improve breast cancer detection in young women. (C) 2009 Elsevier Inc. All rights reserved. C1 [Samphao, Srila; Wheeler, Amanda J.; Michaelson, James S.; Specht, Michelle C.; Gadd, Michele A.; Hughes, Kevin S.; Smith, Barbara L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Surg Oncol, Boston, MA 02114 USA. [Rafferty, Elizabeth] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. [Michaelson, James S.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Smith, BL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Surg Oncol, Yawkey 9A,55 Fruit St, Boston, MA 02114 USA. EM blsmith1@partners.org OI Hughes, Kevin/0000-0003-4084-6484 NR 33 TC 27 Z9 29 U1 0 U2 5 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9610 J9 AM J SURG JI Am. J. Surg. PD OCT PY 2009 VL 198 IS 4 BP 538 EP 543 DI 10.1016/j.amjsurg.2009.06.010 PG 6 WC Surgery SC Surgery GA 509YU UT WOS:000271056000016 PM 19800464 ER PT J AU Maguire, AA Greenson, JK Lauwers, GY Ginsburg, RE Williams, GT Brown, IS Riddell, RH O'Donoghue, D Sheahan, KD AF Maguire, Aoife A. Greenson, Joel K. Lauwers, Greg Y. Ginsburg, Richard E. Williams, Geraint T. Brown, Ian S. Riddell, Robert H. O'Donoghue, Diarmuid Sheahan, Kieran D. TI Collagenous Sprue A Clinicopathologic Study of 12 Cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE collagenous sprue; complicated celiac disease; small intestine ID T-CELL LYMPHOMA; REFRACTORY CELIAC-DISEASE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; GLUTEN-FREE DIET; INTRAEPITHELIAL LYMPHOCYTES; GASTROINTESTINAL-TRACT; NEOPLASTIC POPULATION; ULCERATIVE JEJUNITIS; SMALL-INTESTINE; COLITIS AB Collagenous sprue is a rare form of small bowel enteropathy characterized by chronic diarrhea and progressive malabsorption with little data available on its natural history. The pathologic lesion consists of subepithelial collagen deposition associated with variable alterations in villous architecture. The small bowel biopsies of 12 cases were reviewed. Clinical details, celiac serology, and T-cell receptor gene rearrangement study results, when available, were collated. There were 8 females and 4 males (age ranged from 41 to 84 y) who presented with chronic diarrhea and weight loss. Small intestinal biopsies showed subepithelial collagen deposition with varying degrees of villous atrophy and varying numbers of intraepithelial lymphocytes. Four patients had previous biopsies showing enteropathic changes without collagen deposition. Seven cases were associated with collagenous colitis and I also had features of lymphocytic colitis. Three patients also had collagen deposition in gastric biopsies. One case was associated with lymphocytic gastritis. Celiac disease (CD, gluten-sensitive enteropathy) was documented in 4 patients. Five patients made a clinical improvement with combinations of a gluten-free diet and immunosuppressive therapy. Two patients died of complications of malnutrition and I of another illness. Clonal T-cell populations were identified in 5 of 6 cases tested. Four of these patients improved clinically after treatment but I has died. Collagenous sprue evolved on a background of CID in 4 cases. There was no history of CD in others and these cases may be the result of a biologic insult other than gluten sensitivity. None has developed clinical evidence of lymphoma to date. C1 [Maguire, Aoife A.; Sheahan, Kieran D.] St Vincents Univ Hosp, Dept Histopathol, Dublin 4, Ireland. [Greenson, Joel K.] Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI USA. [Lauwers, Greg Y.] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Ginsburg, Richard E.] Montgomery Gastroenterol Specialists, Montgomery, AL USA. [Williams, Geraint T.] Cardiff Univ, Sch Med, Dept Pathol, Cardiff, S Glam, Wales. [Brown, Ian S.] Sullivan Nicolaides Pathol, Brisbane, Qld, Australia. [Riddell, Robert H.] Mt Sinai Hosp, Dept Pathol & Lab Med, Toronto, ON M5G 1X5, Canada. [O'Donoghue, Diarmuid] St Vincents Univ Hosp, Dept Gastroenterol, Dublin 4, Ireland. RP Maguire, AA (reprint author), St Vincents Univ Hosp, Dept Histopathol, Elm Pk, Dublin 4, Ireland. EM Aoife.maguire@ucd.ie RI Riddell, Robert/J-5557-2016; Brown, Ian/R-7763-2016 OI Brown, Ian/0000-0001-6329-2547 NR 54 TC 20 Z9 20 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2009 VL 33 IS 10 BP 1440 EP 1449 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 501RQ UT WOS:000270399700002 PM 19641452 ER PT J AU Braaten, KM Young, RH Ferry, JA AF braaten, Kristina M. Young, Robert H. Ferry, Judith A. TI Viral-type Orchitis A Potential Mimic of Testicular Neoplasia SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE testis; orchitis; lymphoma; leukemia; intratubular neoplasia ID TESTIS; LYMPHOMA; SARCOMA; TUMORS AB Orchitis of viral or presumed viral etiology is an uncommon Cause of testicular pain or enlargement. Rarely orchitis is clinically or radiographically suggestive of neoplasia, resulting in a testicular biopsy or orchiectomy being performed. Between 1978 and 2004, 10 cases submitted in consultation were diagnosed as orchitis at the Massachusetts General Hospital. The patients were from 18 to 37 years of age and presented with testicular enlargement or a mass, pain, or both. Radiographic Studies were suspicious for a neoplasm in all 5 cases in which results were available. The patients underwent testicular biopsy (2 cases), orchiectomy (6 cases), biopsy immediately followed by orchiectomy (I case), or biopsy followed by orchiectomy 3 weeks later (I case). The cases were Submitted with diagnoses that included intratubular seminoma, intratubular germ cell neoplasia, unspecified, Sertoli cell hyperplasia, myeloid sarcoma, and lymphoma. Microscopic examination revealed preservation of the architecture of the testicular parenchyma, typically with hemorrhage and edema, with patchy inflammation in the form of a lymphohistiocytic infiltrate within seminiferous tubules and also between tubules. The intratubular infiltrate usually predominated. Immunohistochemical studies, performed in 7 cases showed a mixture of CD68+ histiocytes and CD3+ T cells, with few B cells (CD20+) and few granulocytes. Follow-up was available in 5 cases; all 5 patients were alive and well I I months to 10 years after diagnosis. In the rare instance in which a testicular specimen with orchitis is Submitted for pathologic evaluation, diagnosis may be difficult. Familiarity with the pathologic changes characteristic of orchitis will help avoid misdiagnosis. C1 [braaten, Kristina M.; Young, Robert H.; Ferry, Judith A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, James Homer Wright Pathol Labs,Dept Pathol, Boston, MA 02114 USA. RP Ferry, JA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, James Homer Wright Pathol Labs,Dept Pathol, 55 Fruit St, Boston, MA 02114 USA. EM jferry@partners.org NR 21 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2009 VL 33 IS 10 BP 1477 EP 1484 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 501RQ UT WOS:000270399700006 PM 19623033 ER PT J AU Farris, AB Hasserjian, RP Zukerberg, LR Amrein, PC Greene, RE Mark, EJ Kradin, RL AF Farris, Alton B., III Hasserjian, Robert P. zukerberg, Lawrence R. Amrein, Philip C. Greene, Reginald E. Mark, Eugene J. Kradin, Richard L. TI Diffuse Cellular and Fibrosing Interstitial Pneumonitis With Desquamative Interstitial Pneumonitis-like Features Associated With Myeloid Neoplasia SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE interstitial pneumonia; myelodysplastic syndromes; acute myeloid leukemia ID BONE-MARROW-TRANSPLANTATION; IDIOPATHIC PNEUMONIA; MYELODYSPLASTIC SYNDROME; PROGNOSTIC-SIGNIFICANCE; LUNG INJURY; LENALIDOMIDE; SPECTRUM; DISEASE AB Patients with preleukemic myeloid neoplasia can develop nonhematologic disease. Five patients with the myelodysplastic syndrome presented with interstitial lung disease that heralded acute leukemia in 3. Chest radiographs showed diffuse interstitial opacities, and the lung biopsies showed diffuse Cellular interstitial and fibrosing pneumonitis with prominent alveolar filling by macrophages. There was no evidence to support a drug-induced or infectious etiology, and all cases lacked an identifiable leukemic infiltration. The inflammatory infiltrates and fibrosis were analyzed morphometrically, and this revealed a trend toward an indirect correlation between both CD68(+) cells and MPO-positive inflammatory cells and pulmonary fibrosis. We conclude that preleukemic myeloid neoplasia can be associated with an interstitial pneumonitis with histopathologic features that are distinguishable from both leukemic infiltration and "usual" nonspecific interstitial pneumonia. C1 [Farris, Alton B., III; Hasserjian, Robert P.; zukerberg, Lawrence R.; Mark, Eugene J.; Kradin, Richard L.] Massachusetts Gen Hosp, Pathol Serv, Boston, MA 02114 USA. [Amrein, Philip C.] Massachusetts Gen Hosp, Dept Med, Hematol Oncol Unit, Boston, MA 02114 USA. [Greene, Reginald E.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Kradin, Richard L.] Massachusetts Gen Hosp, Dept Med, Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Kradin, RL (reprint author), Massachusetts Gen Hosp, Pathol Serv, 55 Fruit St,Warren 2, Boston, MA 02114 USA. EM rkradin@partners.org NR 34 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2009 VL 33 IS 10 BP 1485 EP 1493 PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 501RQ UT WOS:000270399700007 PM 19654503 ER PT J AU Hsu, M Young, RH Misdraji, J AF Hsu, Maylee Young, Robert H. Misdraji, Joseph TI Ruptured Appendiceal Diverticula Mimicking Low-grade Appendiceal Mucinous Neoplasms SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE appendix; diverticular disease; mucinous neoplasm; pseudomyxoma peritonei ID VERMIFORM APPENDIX; NEUROMAS; LESIONS AB Low-grade appendiceal mucinous neoplasms may rupture and seed the peritoneum with bland neoplastic mucinous epithelium resulting, when grossly evident, in the well-known process pseudomyxoma peritonei. Appendiceal diverticula may also rupture, resulting in mucin on the appendiceal serosa, which may raise concern for,in underlying appendiceal mucinous neoplasm. We report I I cases of ruptured appendiceal diverticula that were initially either misdiagnosed as appendiceal mucinous neoplasms, raised concern for a neoplasm, or were thought to exhibit localized pseudomyxoma peritonei. Two cases showed eversion or the appendiceal lining onto the serosa; I showed collision between the diverticulum and endosalpingiosis, and 3 had rare nonneoplastic epithelial cells in extra-appendiceal mucin. Most cases showed mucosal hyperplasia, mild crypt disarray, and variable reactive atypia. Eight cases had mucosal neuromas or other neural changes. None of the patients progressed to pseudomyxoma peritonei during the follow-up interval (mean 23 mo). Pathologists Should be aware that ruptured appendiceal diverticula may be associated with serosal mucin and even extra-appendiceal epithelium. Failure to distinguish this process from a mucosal neoplasm with rupture may result in unnecessary therapy and Cause the patient undue alarm. C1 [Misdraji, Joseph] Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs,Dept Pathol, Boston, MA 02114 USA. RP Misdraji, J (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, James Homer Wright Pathol Labs,Dept Pathol, Warren Bldg 105F, Boston, MA 02114 USA. EM jmisdraji@partners.org NR 22 TC 9 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2009 VL 33 IS 10 BP 1515 EP 1521 PG 7 WC Pathology; Surgery SC Pathology; Surgery GA 501RQ UT WOS:000270399700010 PM 19623035 ER PT J AU Jasuja, D Mor, MK Hartwig, KC Palevsky, PM Fine, MJ Weisbord, SD AF Jasuja, Deepak Mor, Maria K. Hartwig, Kathryn C. Palevsky, Paul M. Fine, Michael J. Weisbord, Steven D. TI Provider Knowledge of Contrast-Induced Acute Kidney Injury SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Contrast; Acute kidney injury; Providers; Knowledge ID RADIOCONTRAST-INDUCED NEPHROPATHY; RANDOMIZED CONTROLLED-TRIAL; ACUTE-RENAL-FAILURE; CORONARY INTERVENTION; CARDIAC ANGIOGRAPHY; RISK-FACTORS; MEDIA; PREVENTION; NEPHROTOXICITY; INSUFFICIENCY AB Background Although past research has elucidated the principal risk factors and efficacy of preventive interventions for contrast-induced acute kidney injury (CIAKI), provider awareness of this empiric evidence base is largely unknown. We sought to assess provider knowledge of the risk factors and preventive interventions for CIAKI. Methods: We asked medical providers caring for patients undergoing procedures with intravascular iodinated contrast to complete a survey designed to assess their knowledge of the risk factors and preventive interventions,for CIAKI. Results: Of the 87 participating providers, nearly all (n = 85; 98%) recognized chronic kidney disease and intravascular volume depletion as risk factors. However, 35 (41%) incorrectly identified allergy to contrast media as a risk factor and 8 (10%) incorrectly identified intravenous (IV) water as an effective preventive intervention. Compared with those with little or no prior training on CIAKI, those with substantial prior training correctly reported that peripheral vascular disease and atrial fibrillation are not risk factors and that fenoldopam and IV water are ineffective preventive interventions (P < 0.05). Trainees were more likely than those who had completed their postgraduate medical training to correctly report that IV saline and sodium bicarbonate are effective preventive interventions and that fenoldopam, dopamine, mannitol, and IV water are ineffective measures (P < 0.05). Conclusions: There is wide variability in providers' knowledge of CIAKI. Providers with more training on CIAKI and trainees had greater knowledge of the risk factors and preventive interventions for CIAKI. These findings underscore the need to standardize and intensify provider education of this costly and preventable iatrogenic condition. C1 [Mor, Maria K.; Hartwig, Kathryn C.; Fine, Michael J.; Weisbord, Steven D.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15240 USA. [Jasuja, Deepak] Univ Pittsburgh, Dept Gen Internal Med, Med Ctr McKeesport, Pittsburgh, PA USA. [Palevsky, Paul M.; Weisbord, Steven D.] VA Pittsburgh Healthcare Syst, Renal Sect, Med Specialty Serv Line, Pittsburgh, PA 15240 USA. [Palevsky, Paul M.; Weisbord, Steven D.] Univ Pittsburgh, Sch Med, Dept Med, Renal Electrolyte Div, Pittsburgh, PA USA. [Mor, Maria K.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Fine, Michael J.] Univ Pittsburgh, Sch Med, Dept Med, Div Gen Internal Med, Pittsburgh, PA USA. RP Weisbord, SD (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Mailstop 111F-U,7E Room 120, Pittsburgh, PA 15240 USA. EM weisbordsd@upmc.edu OI Palevsky, Paul/0000-0002-7334-5400 FU NIAID NIH HHS [K24 AI001769] NR 27 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD OCT PY 2009 VL 338 IS 4 BP 280 EP 286 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 511OE UT WOS:000271174300006 PM 19641454 ER PT J AU Reese, PP Feldman, HI Asch, DA Halpern, SD Blumberg, EA Thomasson, A Shults, J Bloom, RD AF Reese, P. P. Feldman, H. I. Asch, D. A. Halpern, S. D. Blumberg, E. A. Thomasson, A. Shults, J. Bloom, R. D. TI Transplantation of Kidneys from Donors at Increased Risk for Blood-Borne Viral Infection: Recipient Outcomes and Patterns of Organ Use SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE Centers for Disease Control (CDC); kidney transplantation; viral infection ID EXPANDED CRITERIA DONORS; CARDIAC DEATH; INFORMING CANDIDATES; SURVIVAL; DIALYSIS; DONATION; INMATES AB Kidney transplantation from deceased donors classified as increased risk for viral infection by the Centers for Disease Control (CDC) is controversial. Analyses of Organ Procurement and Transplantation Network (OPTN) data from 7/1/2004 to 7/1/2006 were performed. The primary cohort included 48 054 adults added to the kidney transplant wait list. Compared to receiving a standard criteria donor (SCD) kidney or remaining wait-listed, CDC recipients (HR 0.80, p = 0.18) had no significant difference in mortality. In a secondary cohort of 19 872 kidney recipients at 180 centers, SCD (reference) and CDC (HR 0.91, p = 0.16) recipients had no difference in the combined endpoint of allograft failure or death. Among centers performing > 10 kidney transplants during the study period, the median proportion of CDC transplants/total transplants was 7.2% (range 1.1-35.6%). Higher volume transplant centers were more likely to use CDC kidneys compared to low and intermediate volume centers (p < 0.01). An analysis of procured kidneys revealed that 6.8% of SCD versus 7.8% of CDC (p = 0.13) kidneys were discarded. In summary, center use of CDC kidneys varied widely, and recipients had good short-term outcomes. OPTN should collect detailed data about long-term outcomes and recipient viral testing so the potential risks of CDC kidneys can be fully evaluated. C1 [Reese, P. P.; Feldman, H. I.; Halpern, S. D.; Bloom, R. D.] Univ Penn, Dept Med, Div Renal, Philadelphia, PA 19104 USA. [Reese, P. P.; Feldman, H. I.; Halpern, S. D.; Thomasson, A.; Shults, J.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Reese, P. P.; Asch, D. A.; Halpern, S. D.] Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. [Asch, D. A.] Philadelphia VA Med Ctr, Ctr Hlth Equ Res & Promot, Philadelphia, PA USA. [Blumberg, E. A.] Univ Penn, Dept Med, Div Infect Dis, Philadelphia, PA 19104 USA. RP Reese, PP (reprint author), Univ Penn, Dept Med, Div Renal, Philadelphia, PA 19104 USA. EM peter.reese@uphs.upenn.edu OI Asch, David/0000-0002-7970-286X FU NIH [K23 - DK078688-01, K24 - DK002651]; Greenwall Foundation FX The authors acknowledge Stacey Doll for her helpful suggestions for the study. Dr. Reese is supported by NIH grant K23 - DK078688-01. Dr. Feldman is supported by NIH grant K24 - DK002651. Dr. Halpern is supported by a Greenwall Foundation Faculty Scholar Award in Bioethics. NR 23 TC 17 Z9 18 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD OCT PY 2009 VL 9 IS 10 BP 2338 EP 2345 DI 10.1111/j.1600-6143.2009.02782.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 494GY UT WOS:000269801000018 PM 19702645 ER PT J AU Rozet, I Tontisirin, N Vavilala, MS Treggiari, MM Lee, LA Lam, AM AF Rozet, Irene Tontisirin, Nuj Vavilala, Monica S. Treggiari, Miriam M. Lee, Lorri A. Lam, Arthur M. TI Prolonged Propofol Anesthesia Is Not Associated with an Increase in Blood Lactate SO ANESTHESIA AND ANALGESIA LA English DT Article ID HEPATIC GLUCOSE-PRODUCTION; FREE FATTY-ACIDS; INFUSION SYNDROME; METABOLIC-ACIDOSIS; LACTIC-ACIDOSIS; ISOFLURANE ANESTHESIA; HALOTHANE ANESTHESIA; CONSCIOUS DOGS; SEVOFLURANE; CHILDREN AB BACKGROUND: Lactic acidosis is considered an early sign of propofol infusion syndrome. In this study, we investigated the changes in lactate and pH with propofol versus volatile anesthesia (VA) of long duration. METHODS: Demographic and intraoperative data were recorded retrospectively from the anesthesia records of patients who underwent elective spine surgery longer than 8 h. Propofol patients were matched 1:2 to VA patients, based on anesthesia time (AT) (+/- 30 min) and blood loss (BL) (+/- 500 mL). RESULTS: Of 246 patients identified, 50 received propofol (AT 10 +/- 2 h, BL = 1955 +/- 1409 mL) and were matched to 100 VA cases (AT = 10 +/- 1 h, BL = 1801 +/- 1543 mL), and of those, 40 and 72 patients, respectively, had complete lactate data at baseline and at 8 h after anesthesia and were included in the main analysis. The propofol group received 8.8 +/- 2 mg.kg(-1).h(-1) of propofol. The VA group age was older than the propofol group (58 +/- 12 vs 51 +/- 15 yr, respectively, P = 0.002), but there was no difference between the groups in gender, ASA grade, intraoperative hemodynamic variables, and use of vasopressors. After 8 h, the VA group had a larger increase in arterial lactate from baseline compared with the propofol group (change from baseline: propofol, 0.48 +/- 0.72 mmol/L; VA, 1.2 +/- 1.2 mmol/L, P = 0.001). CONCLUSIONS: During prolonged spine surgery > 8 h, VA was associated with higher serum lactate, when compared with propofol infusion. Prospective studies are needed to elucidate the exact mechanisms and clinical implications of this finding. (Anesth Analg 2009;109:1105-10) C1 [Rozet, Irene] Univ Washington, Dept Anesthesiol, VA Puget Sound Hlth Care Syst, Harborview Med Ctr, Seattle, WA 98108 USA. [Vavilala, Monica S.] Univ Washington, Dept Pediat, Harborview Med Ctr, Seattle, WA 98108 USA. [Vavilala, Monica S.; Treggiari, Miriam M.; Lee, Lorri A.; Lam, Arthur M.] Univ Washington, Dept Neurol Surg, Harborview Med Ctr, Seattle, WA 98108 USA. RP Rozet, I (reprint author), Univ Washington, Dept Anesthesiol, VA Puget Sound Hlth Care Syst, Harborview Med Ctr, 1660 S Columbian Way, Seattle, WA 98108 USA. EM irozet@u.washington.edu NR 38 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD OCT PY 2009 VL 109 IS 4 BP 1105 EP 1110 DI 10.1213/ANE.0b013e3181b5a220 PG 6 WC Anesthesiology SC Anesthesiology GA 499HL UT WOS:000270209100020 PM 19641048 ER PT J AU Bartels, K Moss, DR Peterfreund, RA AF Bartels, Karsten Moss, David R. Peterfreund, Robert A. TI An Analysis of Drug Delivery Dynamics via a Pediatric Central Venous Infusion System: Quantification of Delays in Achieving Intended Doses SO ANESTHESIA AND ANALGESIA LA English DT Article ID SYRINGE PUMPS; DEAD-VOLUME; FLOW-RATE; FLUCTUATIONS AB BACKGROUND: Pediatric patients frequently receive continuous infusions of drugs via central venous catheters in the intensive care unit and the operating room. This study characterized drug delivery profiles in a quantitative laboratory model of a standard pediatric central venous infusion system. METHODS: We evaluated drug delivery via a standard pediatric 8-cm, 4-F double-lumen catheter. One syringe pump infused normal saline as the carrier fluid through a limb of a Y-piece connected to the catheter's 22-gauge distal lumen. Through the other limb of the Y-piece, a second syringe pump infused methylene blue, the model drug, at a constant rate of 0.5 mL/h. The volume delivered was collected every minute for quantitative analysis. We compared 2 mL/h and 12 mL/h total flow rates to mimic volume delivery to a 3-kg infant, and priming of the Y-piece with the model drug, to mimic resumption of a stopped drug infusion, versus no priming, to mimic a new infusion. Drug pump system start-up performance was measured to estimate this factor's contribution to infusion onset profiles. RESULTS: When initiating a new infusion of the model drug, the time to steady-state delivery at the catheter's end varied significantly among the studied scenarios as measured by the time to reach half of the targeted dose (t(50)). Onset of delivery with a low total flow was much slower (t(50) = 23.5 +/- 2.1 min) than with the high flow rate (t(50) = 15.7 +/- 2.9 min). Priming the drug limb of the connecting Y-piece with methylene blue substantially shortened the time to steady state (low flow t(50) = 12.7 +/- 0.6 min, high flow t(50) = 5.2 +/- 0.8 min). Time to cessation of drug delivery to the end of the catheter after stopping the drug pump was substantially shorter using the high carrier flow rate (t(50) = 3 +/- 0.5 min) compared with the low carrier flow rate (t(50) = 11.6 +/- 0.8 min). Drug pump system start-up performance contributed to onset delay. CONCLUSIONS: Current infusion techniques in the pediatric care setting can result in significant, unrecognized, and potentially hazardous delays in achieving delivery of intended drug doses to the patient. Total flow rate, priming of the infusion system, the dead volume of the fluid path, and the start-up performance of the infusion pump system contribute to delays in achieving targeted rates of drug delivery. (Anesth Analg 2009;109:1156-61) C1 [Bartels, Karsten; Moss, David R.; Peterfreund, Robert A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Peterfreund, RA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Jackson 439,55 Fruit St, Boston, MA 02114 USA. EM rpeterfreund@partners.org NR 8 TC 16 Z9 16 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD OCT PY 2009 VL 109 IS 4 BP 1156 EP 1161 DI 10.1213/ane.0b013e3181b220c9 PG 6 WC Anesthesiology SC Anesthesiology GA 499HL UT WOS:000270209100026 PM 19762743 ER PT J AU Rathmell, JP Miller, MJ AF Rathmell, James P. Miller, Matthew J. TI Death after Initiation of Intrathecal Drug Therapy for Chronic Pain Assessing Risk and Designing Prevention SO ANESTHESIOLOGY LA English DT Editorial Material ID RESPIRATORY DEPRESSION; CANCER PAIN; DELIVERY; MORPHINE; MANAGEMENT C1 [Rathmell, James P.] Massachusetts Gen Hosp, Div Pain Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Rathmell, James P.] Harvard Univ, Sch Med, Boston, MA USA. [Miller, Matthew J.] Harvard Univ, Sch Publ Hlth, Harvard Injury Control Res Ctr, Boston, MA 02115 USA. RP Rathmell, JP (reprint author), Massachusetts Gen Hosp, Div Pain Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. EM jrathmell@partners.org RI miller, matthew/H-4624-2011 OI miller, matthew/0000-0002-3267-6510 NR 12 TC 6 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD OCT PY 2009 VL 111 IS 4 BP 706 EP 708 PG 3 WC Anesthesiology SC Anesthesiology GA 499HS UT WOS:000270210100009 PM 20029248 ER PT J AU Zhen, Y Dong, YL Wu, X Xu, ZP Lu, Y Zhang, YY Norton, D Tian, M Li, SR Xie, ZC AF Zhen, Yu Dong, Yuanlin Wu, Xu Xu, Zhipeng Lu, Yan Zhang, Yiying Norton, David Tian, Ming Li, Shuren Xie, Zhongcong TI Nitrous Oxide Plus Isoflurane Induces Apoptosis and Increases beta-Amyloid Protein Levels SO ANESTHESIOLOGY LA English DT Article ID INHALATION ANESTHETIC ISOFLURANE; NEURONAL CELL-DEATH; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; CASPASE-3 ACTIVATION; GLYCINE RECEPTORS; PEPTIDE; GAMMA; INVOLVEMENT; EXPOSURE AB Background: Some anesthetics have been suggested to induce neurotoxicity, including promotion of Alzheimer's disease neuro-pathogenesis. Nitrous oxide and isoflurane are common anesthetics. The authors set out to assess the effects of nitrous oxide and/or isoflurane on apoptosis and beta-amyloid (A beta) levels in H4 human neuroglioma cells and primary neurons from naive mice. Methods: The cells or neurons were exposed to 70% nitrous oxide and/or 1% isoflurane for 6 h. The cells or neurons and Methods: The cells or neurons were exposed to 70% nitrous oxide and/or 1% isoflurane for 6 h. The cells or neurons and conditioned media were harvested at the end of the treatment. Caspase-3 activation, apoptosis, processing of amyloid precursor protein, and A beta levels were determined. Results: Treatment with a combination of 70% nitrous oxide and 1% isoflurane for 6 h induced caspase-3 activation and apoptosis In H4 naive cells and primary neurons from naive mice. The 70% nitrous oxide plus 1% isoflurane, but neither alone, for 6 h Induced caspase-3 activation and apoptosis, and increased levels of beta-site amyloid precursor protein-cleaving enzyme and A beta in H4-amyloid precursor protein cells. In addition, the nitrous oxide plus isoflurane-induced A beta generation was reduced by a broad caspase inhibitor, Z-VAD. Finally, the nitrous oxide plus isoflurane-induced caspase-3 activation was attenuated by gamma-secretase inhibitor L-685,458, but potentiated by exogenously added A beta. Conclusion: These results suggest that the common anesthetics nitrous oxide plus isoflurane may promote neurotoxicity by inducing apoptosis and increasing A beta levels. The generated A beta may further potentiate apoptosis to form another round of apoptosis and A beta generation. More studies, especially the in vivo confirmation of these in vitro findings, are needed. C1 [Zhen, Yu; Dong, Yuanlin; Norton, David; Xie, Zhongcong] Massachusetts Gen Hosp, Dept Anesthesia Crit Care & Pain Med, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, Charlestown, MA 02129 USA. [Zhen, Yu; Dong, Yuanlin; Norton, David; Xie, Zhongcong] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Zhen, Yu; Tian, Ming; Li, Shuren] Capital Med Univ, Beijing Friendship Hosp, Dept Anesthesia, Beijing, Peoples R China. [Wu, Xu] China Med Univ, Dept Forens Pathol, Fac Forens Med, Shenyang, Peoples R China. [Lu, Yan] China Med Univ, Affiliated Shengjing Hosp, Key Lab Hlth Minist Congenital Malformat, Shenyang, Liaoning, Peoples R China. RP Xie, ZC (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Genet & Aging Res Unit, MassGen Inst Neurodegenerat Dis, 114 16th St,3750, Charlestown, MA 02129 USA. EM zxie@partners.org FU NIA NIH HHS [R21 AG029856-01A2, R21 AG029856]; NIGMS NIH HHS [R01 GM088801-01A1, R01 GM088801]; NINDS NIH HHS [K08 NS048140-04, K08 NS048140, K08 NS048140-05] NR 61 TC 48 Z9 54 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD OCT PY 2009 VL 111 IS 4 BP 741 EP 752 PG 12 WC Anesthesiology SC Anesthesiology GA 499HS UT WOS:000270210100015 PM 19741497 ER PT J AU Desai, R Ruesch, D Forman, SA AF Desai, Rooma Ruesch, Dirk Forman, Stuart A. TI gamma-Amino Butyric Acid Type A Receptor Mutations at beta 2N265 Alter Etomidate Efficacy While Preserving Basal and Agonist-dependent Activity SO ANESTHESIOLOGY LA English DT Article ID GENERAL ANESTHETIC ETOMIDATE; NICOTINIC ACETYLCHOLINE-RECEPTORS; GATED ION CHANNELS; GABA(A) RECEPTOR; BINDING-SITE; AZI-ETOMIDATE; SUBUNIT; ACTIVATION; MECHANISMS; BENZODIAZEPINES AB Background: Etomidate acts at gamma-Aminobutyric acid type A (GABA(A)) receptors containing beta 2 or beta 3, but not beta 1 subunits. Mutations at beta residue 265 (Ser in beta 1; Asn in beta 2 or beta 3) profoundly affect etomidate sensitivity. Whether these mutations alter etomidate binding remains uncertain. Methods: Heterologously expressed alpha 1 beta 2 gamma 2L GAB(A) receptors and receptors with beta 2(N265S) or beta 2(N265M) mutations were studied electrophysiologically in both Xenopus oocytes and HEK293 cells. Experiments quantified the impact of beta 2N265 mutations or substituting beta 1 for beta 2 on basal channel activation, GABA EC(50), maximal GABA efficacy, etomidate-induced leftward shift in GABA responses, etomidate direct activation, and rapid macrocurrent kinetics. Results were analyzed in the context of an established allosteric coagonist mechanism. Results: Mutations produced only small changes in basal channel activity, GABA EC(50), maximal GABA efficacy, and macrocurrent kinetics. Relative to wild-type, beta 2(N265S) reduced etomidate enhancement of apparent GABA affinity six-fold, and it reduced etomidate direct activation efficacy 14-fold. beta 2(N265M) totally eliminated both etomidate modulation of GABA responses and direct channel activation. Mechanism-based analysis showed that the function of both mutants remains consistent with the allosteric coagonist model and that beta 2(N265S) reduced etomidate allosteric efficacy five-fold, whereas etomidate-binding affinity dropped threefold. Experiments swapping beta 2 subunits for beta 1 indicated that etomidate efficacy is reduced 34-fold, whereas binding affinity drops less than two-fold. Conclusions. Mutations at beta 2N265 profoundly alter etomidate sensitivity with only small changes in basal and GABA-dependent channel activity. Mutations at the beta 2N265 residue or replacement of beta 2 with beta 1 Influence etomidate efficacy much more than binding to inactive receptors. C1 [Forman, Stuart A.] Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. [Ruesch, Dirk] Univ Hosp Giessen Marburg, Dept Anesthesia & Crit Care, Marburg, Germany. RP Forman, SA (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. EM saforman@partners.org FU National Institutes of Health, Bethesda, Maryland [P0IGM58448, R01GM66724]; Department of Anesthesia & Critical Care, Massachusetts General Hospital, Boston, Massachusetts FX Supported by grants P0IGM58448 and R01GM66724 from the National Institutes of Health, Bethesda, Maryland, and by the Department of Anesthesia & Critical Care, Massachusetts General Hospital, Boston, Massachusetts. NR 42 TC 27 Z9 27 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD OCT PY 2009 VL 111 IS 4 BP 774 EP 784 PG 11 WC Anesthesiology SC Anesthesiology GA 499HS UT WOS:000270210100019 PM 19741491 ER PT J AU Sulemanji, D Marchese, A Garbarini, P Wysocki, M Kacmarek, RM AF Sulemanji, Demet Marchese, Andrew Garbarini, Paul Wysocki, Marc Kacmarek, Robert M. TI Adaptive Support Ventilation An Appropriate Mechanical Ventilation Strategy for Acute Respiratory Distress Syndrome? SO ANESTHESIOLOGY LA English DT Article ID ACUTE LUNG INJURY; VOLUME-CONTROLLED VENTILATION; CARDIAC-SURGERY; PROTECTIVE-VENTILATION; BREATHING PATTERN; MORTALITY; FAILURE; ARDS AB Background: Adaptive support ventilation (ASV) allows the clinician to set a maximum plateau pressure (PP) and automatically adjusts tidal volume to keep PP below the set maximum. Methods: ASV was compared to a fixed tidal volume of 6 ml/kg. ASV determined the respiratory rate and tidal volume based on its algorithms. Maximum airway pressure limit was 28 CM H(2)O in ASV. Six sets of lung mechanics were simulated for two ideal body weights: 60 kg, Group I; 80 kg, Group II. Positive end expiratory pressure was 8, 12, and 16 cm 1120, and target minute volume 120%, 150%, and 200% of predicted minute volume. Results: ASV "sacrificed" tidal volume and minute ventilation to maintain PP in 9 (17%) of 54 scenarios in Group I and 20 (37%) of 54 scenarios in Group U. In Group I, the number of scenarios with PP of 28 cm H(2)O or more was 14 for ASV (26%) and 19 for 6 ml/kg (35%). in these scenarios, mean PP were ASV 28.8 +/- 0.86 cm H(2)O (min 28, max 30.3) and 6 ml/kg 33.01 +/- 3.48 cm H(2)O (min 28, max 37.8) (P = 0.000). In group II, the number of scenarios PP of 28 cm H(2)O or more was 10 for ASV (19%) and 21 for 6 ml/kg (39%). in these cases, mean PP values were ASV 28.78 +/- 0.54 cm H(2)O (min 28, max 29.6) and 6 ml/kg 32.66 +/- 3.37 cm H(2)O (min 28.2, max 38.2) (P = 0.000). Conclusion: In a lung model with varying mechanics, ASV is better able to prevent the potential damaging effects of excessive PP (greater than 28 cm 1120) than a fixed tidal volume of 6 ml/kg by automatically adjusting airway pressure, resulting in a decreased tidal volume. C1 [Marchese, Andrew; Kacmarek, Robert M.] Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. RP Kacmarek, RM (reprint author), Massachusetts Gen Hosp, Dept Resp Care, 55 Fruit St,Ellison 401, Boston, MA 02114 USA. EM rkacmarek@partners.org NR 30 TC 16 Z9 16 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD OCT PY 2009 VL 111 IS 4 BP 863 EP 870 PG 8 WC Anesthesiology SC Anesthesiology GA 499HS UT WOS:000270210100029 PM 19741490 ER PT J AU Tsai, CL Rowe, BH Sullivan, AF Camargo, CA AF Tsai, Chu-Lin Rowe, Brian H. Sullivan, Ashley F. Camargo, Carlos A., Jr. TI Factors associated with delayed use or nonuse of systemic corticosteroids in emergency department patients with acute asthma SO ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY LA English DT Article ID MYOCARDIAL-INFARCTION; METHYLPREDNISOLONE; REPERFUSION; THERAPY AB Background: Little is known about factors associated with systemic corticosteroid (SC) use in emergency department (ED) patients with acute asthma. Objective: To determine the patient and system factors associated with delayed use or nonuse of SCs in the ED. Methods: We analyzed the asthma component of the National Emergency Department Safety Study. Patients with acute asthma in 62 urban EDs in 23 US states between 2003 and 2006 were identified. The primary outcome measure was the pattern of SC use in the ED, which was categorized as timely use (<= 60 minutes), delayed use (>60 minutes), or nonuse. Multinomial logistic regression was performed to identify factors associated with delayed use or nonuse of SCs. Results: A total of 2,559 of 3,798 patients with acute asthma (67.4%) received SCs. Of these, the median door-to-SC time was 62 minutes (interquartile range, 35-100 minutes), with 1,319 patients (51.5%) having delayed SC treatment. Nonuse of SCs was largely explained by markers of asthma exacerbations (never intubated for asthma, lower respiratory rate, and higher oxygen saturation). In contrast, in addition to these factors, delayed SC treatment was associated with age of 40 years or older, female sex, longer duration of symptoms, ED presentation between 8 Am and 11:59 Pm, and ED with a longer average patient wait time. Conclusions: Physicians in the ED seem to appropriately administer SCs to higher-acuity asthmatic patients; however, the additional nonmedical factors represent opportunities to improve the timeliness of SC treatment in the ED. Ann Allergy Asthma Immunol. 2009;103:318-324. C1 [Tsai, Chu-Lin; Sullivan, Ashley F.; Camargo, Carlos A., Jr.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. [Rowe, Brian H.] Univ Alberta, Dept Emergency Med, Edmonton, AB, Canada. [Rowe, Brian H.] Univ Alberta, Sch Publ Hlth, Edmonton, AB, Canada. RP Tsai, CL (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. OI TSAI, CHU-LIN/0000-0003-4639-1513 FU Agency for Healthcare Research and Quality [R01 HS-13099]; National Institutes of Health [R01 HL-84401]; Government of Canada FX This study was supported by grant R01 HS-13099 from the Agency for Healthcare Research and Quality, grant R01 HL-84401 from the National Institutes of Health (Dr Camargo), and a 21st Century Research Chair from the Government of Canada (Dr Rowe). NR 32 TC 4 Z9 5 U1 0 U2 0 PU AMER COLL ALLERGY ASTHMA IMMUNOLOGY PI ARLINGTON HTS PA 85 WEST ALGONQUIN RD SUITE 550, ARLINGTON HTS, IL 60005 USA SN 1081-1206 J9 ANN ALLERG ASTHMA IM JI Ann. Allergy Asthma Immunol. PD OCT PY 2009 VL 103 IS 4 BP 318 EP 324 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 509YP UT WOS:000271055500008 PM 19852196 ER PT J AU Kang, HK Bullman, TA AF Kang, Han K. Bullman, Tim A. TI Is There an Epidemic of Suicides among Current and Former US Military Personnel? SO ANNALS OF EPIDEMIOLOGY LA English DT Article ID PERSIAN-GULF-WAR; VIETNAM VETERANS; MORTALITY; RISK; ARMY C1 [Kang, Han K.; Bullman, Tim A.] Environm Epidemiol Serv, US Dept Vet Affairs, Washington, DC 20420 USA. [Kang, Han K.] DC VA Med Ctr, War Related Illness & Injury Study Ctr, Washington, DC USA. [Kang, Han K.] George Washington Univ, Washington, DC 20052 USA. RP Kang, HK (reprint author), Environm Epidemiol Serv, US Dept Vet Affairs, 810 Vermont Ave NW, Washington, DC 20420 USA. EM han.kang@va.gov NR 20 TC 34 Z9 34 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD OCT PY 2009 VL 19 IS 10 BP 757 EP 760 DI 10.1016/j.annepidem.2009.05.004 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 499BR UT WOS:000270192000011 PM 19628411 ER PT J AU Hawker, K O'Connor, P Freedman, MS Calabresi, PA Antel, J Simon, J Hauser, S Waubant, E Vollmer, T Panitch, H Zhang, JM Chin, P Smith, CH AF Hawker, Kathleen O'Connor, Paul Freedman, Mark S. Calabresi, Peter A. Antel, Jack Simon, Jack Hauser, Stephen Waubant, Emmanuelle Vollmer, Timothy Panitch, Hillel Zhang, Jiameng Chin, Peter Smith, Craig H. CA OLYMPUS Trial Grp TI Rituximab in Patients with Primary Progressive Multiple Sclerosis Results of a Randomized Double-Blind Placebo-Controlled Multicenter Trial SO ANNALS OF NEUROLOGY LA English DT Article ID INNATE IMMUNE-SYSTEM; INTERFERON BETA-1A; AGED MICE; B-CELLS; INFLAMMATION; DAMAGE; EVENT; MRI; NEUROINFLAMMATION; AUTOANTIBODIES AB Objective: Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks. Methods: Using 2:1 randomization, 439 PPMS patients received two 1,000mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans. Results: Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p = 0.14). From baseline to week 96, rituximab patients had less (p < 0.001) increase in T2 lesion volume; brain volume change was similar (p = 0.62) to placebo. Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; P = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses. Interpretation: Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions. C1 [Hawker, Kathleen] Ohio State Univ, Dept Neurol, Med Ctr, Columbus, OH 43210 USA. [O'Connor, Paul] Univ Toronto, Dept Med, Toronto, ON, Canada. [Freedman, Mark S.] Ottawa Hosp, Dept Med, Ottawa, ON, Canada. [Calabresi, Peter A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD USA. [Antel, Jack] McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada. [Simon, Jack] Portland VA Med Ctr, Dept Neurol, Portland, OR USA. [Hauser, Stephen; Waubant, Emmanuelle] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. [Vollmer, Timothy] Univ Colorado, Dept Neurol, Denver, CO 80202 USA. [Panitch, Hillel] Univ Vermont, Dept Neurol, Burlington, VT USA. [Zhang, Jiameng; Chin, Peter; Smith, Craig H.] Genentech Inc, San Francisco, CA 94080 USA. RP Hawker, K (reprint author), Eli Lilly & Co, 450 S Meridian St, Indianapolis, IN 46225 USA. EM hawkerks@lilly.com FU Clinicaltrials.gov [NCT00087529]; Genentech, Inc.; Biogen Idec, Inc. FX This study was supported by Clinicaltrials.gov under "A Study to Evaluate the Safety and Efficacy of Rituximab in Adults With Primary Progressive Multiple Sclerosis" (grant NCT00087529), by Genentech, Inc., and by Biogen Idec, Inc. NR 38 TC 245 Z9 248 U1 3 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD OCT PY 2009 VL 66 IS 4 BP 460 EP 471 DI 10.1002/ana.21867 PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 507SJ UT WOS:000270874700006 PM 19847908 ER PT J AU Jimenez, M Krall, EA Garcia, RI Vokonas, PS Dietrich, T AF Jimenez, Monik Krall, Elizabeth A. Garcia, Raul I. Vokonas, Pantel S. Dietrich, Thomas TI Periodontitis and Incidence of Cerebrovascular Disease in Men SO ANNALS OF NEUROLOGY LA English DT Article ID SERUM INFLAMMATORY MARKERS; CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; PLASMA-FIBRINOGEN; SMOKING HISTORY; ISCHEMIC-STROKE; RISK-FACTOR; POPULATION; ASSOCIATIONS AB Objective: To identify associations between periodontitis and incidence of cerebrovascular disease. Methods: We analyzed data of 1, 137 dentate men in the Veterans Affairs Normative Aging and Dental Longitudinal Study who were followed with triennial medical/dental exams for up to 34 years (mean, 24 years). We evaluated incidence of cerebrovascular events consistent with stroke or transient ischemic attack in relation to mean radiographic alveolar bone loss (a measure of periodontitis history) and cumulative periodontal probing depth (a measure of current periodontal inflammation). Cox proportional hazards models were Fit controlling for age, baseline socioeconomic status, and time-varying effects of established cardiovascular risk factors. Results: Eighty incident cases of cerebrovascular disease Occurred from 27,506 person-years. Periodontal bone loss was significantly associated with an increased hazard rate (HR) of cerebrovascular disease (HR, 3.52; 95% confidence interval [Cl], 1.59-7.81 comparing highest to lowest bone loss category; p for trend, <0.001). There was a stronger effect among men aged <65 years (HR, 5.81; 95% CI, 1.63-20.7) as compared with men aged >= 65 years (HR, 2.39; 95% CI, 0.91-6.25). Periodontal probing depth was not associated with a significantly increased rate of cerebrovascular disease in the combined or age-stratified analyses. Interpretation: These results Support an association between history of periodontitis-but not current periodontal inflammation-and incidence of cerebrovascular disease in men, independent of established cardiovascular risk factors, particularly among men aged <65 years. C1 [Dietrich, Thomas] Univ Birmingham, Sch Dent, Dept Oral Surg, Birmingham B4 6NN, W Midlands, England. [Jimenez, Monik; Krall, Elizabeth A.; Garcia, Raul I.; Dietrich, Thomas] Boston Univ, Dept Hlth Policy & Hlth Serv Res, Goldman Sch Dent Med, Boston, MA 02215 USA. [Jimenez, Monik] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Jimenez, Monik] Harvard Univ, Sch Dent Med, Dept Oral Hlth Policy & Epidemiol, Boston, MA 02115 USA. [Garcia, Raul I.; Vokonas, Pantel S.] VA Boston Healthcare Syst, VA Normat Aging Study, Boston, MA USA. [Vokonas, Pantel S.] Boston Univ, Sch Med, Dept Med, Dept Epidemiol, Boston, MA 02118 USA. RP Dietrich, T (reprint author), Univ Birmingham, Sch Dent, Dept Oral Surg, St Chads Queensway, Birmingham B4 6NN, W Midlands, England. EM t.dietrich@bham.ac.uk OI Garcia, Raul/0000-0003-2153-4629; Kaye, Elizabeth/0000-0001-7529-2501; Dietrich, Thomas/0000-0002-2557-7645 FU Veterans Affairs Cooperative Studies Program; National Institutes of Health [R03 DE016357, K24 DE00419]; National Institute of Dental and Craniofacial Research; US Department of Veterans Affairs Career Development Award in Health Services Research; Veterans Affairs Merit Review Award FX The Veterans Affairs Normative Aging Study and Veterans Affairs Dental Longitudinal Study are components of the Massachusetts Veterans Epidemiology Research and Information Center, supported by the Veterans Affairs Cooperative Studies Program. This work was supported by National Institutes of Health grant R03 DE016357 from the National Institute of Dental and Craniofacial Research (T.D.), and by a US Department of Veterans Affairs Career Development Award in Health Services Research from the Veterans Affairs Health Services Research & Development Service, a Veterans Affairs Merit Review Award, and National Institutes of Health grant K24 DE00419 from the National Institute of Dental and Craniofacial Research (R.I.G.). NR 32 TC 42 Z9 43 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD OCT PY 2009 VL 66 IS 4 BP 505 EP 512 DI 10.1002/ana.21742 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 507SJ UT WOS:000270874700010 PM 19847898 ER PT J AU Eikermann-Haerter, K Baum, MJ Ferrari, MD van den Maagdenberg, AMJM Moskowitz, MA Ayata, C AF Eikermann-Haerter, Katharina Baum, Michael J. Ferrari, Michel D. van den Maagdenberg, Arn M. J. M. Moskowitz, Michael A. Ayata, Cenk TI Androgenic Suppression of Spreading Depression in Familial Hemiplegic Migraine Type 1 Mutant Mice SO ANNALS OF NEUROLOGY LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; PYRAMIDAL CELLS; TESTOSTERONE; POPULATION; DANAZOL; 17-BETA-ESTRADIOL; SUSCEPTIBILITY; PREVALENCE; DISORDERS; MUTATIONS AB Familial hemiplegic migraine type 1 (FHM1), a severe migraine with aura variant, is caused by mutations in the CACNA1A gene. Mutant mice carrying the FHM1 R192Q mutation exhibit increased propensity for cortical spreading depression (CSD), a propagating wave of neuroglial depolarization implicated in migraine aura. The CSD phenotype is stronger in female R192Q mutants and diminishes after ovariectomy. Here, we show that orchiectomy reciprocally increases CSD susceptibility in R192Q mutant mice. Chronic testosterone replacement restores CSD susceptibility by an androgen receptor-dependent mechanism. Hence, androgens modulate genetically-enhanced CSD susceptibility and may provide a novel prophylactic target for migraine. C1 [Eikermann-Haerter, Katharina; Moskowitz, Michael A.; Ayata, Cenk] Boston Univ, Stroke & Neurovasc Regulat Lab, Dept Radiol, Boston, MA 02215 USA. [Baum, Michael J.] Boston Univ, Dept Biol, Boston, MA 02215 USA. [Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. [van den Maagdenberg, Arn M. J. M.] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [van den Maagdenberg, Arn M. J. M.] Harvard Univ, Massachusetts Gen Hosp, Stroke Serv & Neurosci Intens Care Unit, Sch Med,Dept Neurol, Charlestown, MA USA. RP Ayata, C (reprint author), Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab, 149 13th St,Room 6403, Charlestown, MA 02129 USA. EM cayata@partners.org FU Deutsche Forschungsgemeinschaft [Ha5085/1-1]; National Institutes of Health [NS061505, NS35611]; Netherlands Organization for Scientific Research [903-52-291, Vici 918-56.602]; EU [CT-2004-504837]; Centre for Medical Systems Biology (CMSB) FX This work was supported by the Deutsche Forschungsgemeinschaft (Ha5085/1-1; K.E.-H.), National Institutes of Health (NS061505, C.A.; NS35611, M.A.M), Netherlands Organization for Scientific Research (903-52-291 and Vici 918-56.602; M.D.F.), EU "EUROHEAD" grant (LSHM-CT-2004-504837; M.D.F. and A.M.J.M.v.d.M.), and the Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI). NR 30 TC 38 Z9 38 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD OCT PY 2009 VL 66 IS 4 BP 564 EP 568 DI 10.1002/ana.21779 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 507SJ UT WOS:000270874700018 PM 19847904 ER PT J AU Nannini, M Astolfi, A Pantaleo, MA Di Battista, M Santini, D Catena, F Heinrich, MC Saponara, M Lolli, C Maleddu, A Formica, S Biasco, G AF Nannini, Margherita Astolfi, Annalisa Pantaleo, Maria A. Di Battista, Monica Santini, Donatella Catena, Fausto Heinrich, Mike C. Saponara, Maristella Lolli, Cristian Maleddu, Alessandra Formica, Serena Biasco, Guido TI HIGH RESOLUTION COPY NUMBER ANALYSIS OF GASTROINTESTINAL STROMAL TUMORS (GISTs) WITH AFFYMETRIX TECHNOLOGY SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Nannini, Margherita; Pantaleo, Maria A.; Di Battista, Monica; Saponara, Maristella; Lolli, Cristian; Maleddu, Alessandra; Biasco, Guido] Univ Bologna, Dept Hematol & Oncol Sci LA Seragnoli, I-40126 Bologna, Italy. [Astolfi, Annalisa; Formica, Serena; Biasco, Guido] Univ Bologna, Interdept Ctr Canc Res G Prodi, I-40126 Bologna, Italy. [Santini, Donatella] Univ Bologna, Pathol Unit, St Orsola Malpighi Hosp, I-40126 Bologna, Italy. [Catena, Fausto] Univ Bologna, Emergency Surg & Transplant Dept, St Orsola Malpighi Hosp, I-40126 Bologna, Italy. [Heinrich, Mike C.] Oregon Hlth & Sci Univ, Dept Med, Portland VA Med Ctr, Portland, OR 97201 USA. [Heinrich, Mike C.] Oregon Hlth & Sci Univ, Oregon Hlth & Sci Univ Knight Canc Inst, Portland, OR 97201 USA. RI Saponara, Maristella/J-9904-2016; nannini, margherita/J-9866-2016 OI Saponara, Maristella/0000-0003-0715-171X; NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD OCT PY 2009 VL 20 SU 8 PG 2 WC Oncology SC Oncology GA V15CV UT WOS:000207781000221 ER PT J AU Pantaleo, MA Astolfi, A Di Battista, M Paterini, P Santini, D Catena, F Heinrich, MC Nannini, M Saponara, M Lolli, C Maleddu, A Formica, S Biasco, G AF Pantaleo, Maria A. Astolfi, Annalisa Di Battista, Monica Paterini, Paola Santini, Donatella Catena, Fausto Heinrich, Mike C. Nannini, Margherita Saponara, Maristella Lolli, Cristian Maleddu, Alessandra Formica, Serena Biasco, Guido TI IGF1R OVEREXPRESSION IN WILD TYPE GASTROINETSTINAL STROMAL TUMOR (GISTS) STUDIED WITH GENOME ARRAY ANALYSES AND WESTERN BLOTTING SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract C1 [Pantaleo, Maria A.; Di Battista, Monica; Nannini, Margherita; Saponara, Maristella; Lolli, Cristian; Maleddu, Alessandra; Biasco, Guido] Univ Bologna, Dept Hematol & Oncol Sci LA Seragnoli, I-40126 Bologna, Italy. [Astolfi, Annalisa; Paterini, Paola; Formica, Serena] Univ Bologna, Interdept Ctr Canc Res G Prodi, I-40126 Bologna, Italy. [Santini, Donatella] Univ Bologna, Pathol Unit, St Orsola Malpighi Hosp, I-40126 Bologna, Italy. [Catena, Fausto] Univ Bologna, Emergency Surg & Transplant Dept, St Orsola Malpighi Hosp, I-40126 Bologna, Italy. [Heinrich, Mike C.] Oregon Hlth & Sci Univ, Dept Med, Portland VA Med Ctr, Portland, OR 97201 USA. [Heinrich, Mike C.] Oregon Hlth & Sci Univ, Oregon Hlth & Sci Univ Knight Canc Inst, Portland, OR 97201 USA. RI Saponara, Maristella/J-9904-2016; nannini, margherita/J-9866-2016 OI Saponara, Maristella/0000-0003-0715-171X; NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD OCT PY 2009 VL 20 SU 8 PG 1 WC Oncology SC Oncology GA V15CV UT WOS:000207781000219 ER PT J AU Lin, HW Quesnel, AM Holman, AS Curry, WT Rho, MB AF Lin, Harrison W. Quesnel, Alicia M. Holman, Allison S. Curry, William T., Jr. Rho, Michael B. TI Hypertrophic Anterior Cervical Osteophytes Causing Dysphagia and Airway Obstruction SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE airway obstruction; anterior cervical osteophyte; dysphagia ID IDIOPATHIC SKELETAL HYPEROSTOSIS; FORESTIERS-DISEASE; DISH; MANIFESTATIONS; DYSPNEA AB Hyperostosis of anterior cervical vertebral osteophytes can produce otolaryngological symptoms ranging from mild dysphagia, dysphonia, and foreign body sensation to severe food impaction and stridulous dyspnea. Airway compromise necessitating a tracheostomy is very rare. We discuss the case of an elderly man who presented with progressive dysphagia and a large hypopharyngeal mass as his initial manifestations of hypertrophic anterior cervical osteophytes. After a biopsy of the mass, the patient went into airway distress due to bilateral vocal fold fixation by the enlarging mass and consequently required a surgical airway. A combined team approach to the removal of the osteophytes successfully resolved his symptoms. The clinical, diagnostic, radiologic, and therapeutic principles involved in this case are presented and discussed. The recognition of hypertrophic osteophytes as a potential cause of common otolaryngological symptoms in the elderly population is paramount, as these symptoms can rapidly progress and lead to life-threatening airway obstruction. Medical and surgical interventions can be employed for the treatment of hypertrophic anterior cervical osteophytes, and they often result in favorable outcomes. C1 [Lin, Harrison W.; Quesnel, Alicia M.; Rho, Michael B.] Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Boston, MA 02114 USA. [Lin, Harrison W.; Quesnel, Alicia M.; Rho, Michael B.] Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. [Holman, Allison S.] Massachusetts Gen Hosp, Dept Speech Language & Swallowing Disorders, Boston, MA 02114 USA. [Curry, William T., Jr.] Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. RP Lin, HW (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, 243 Charles St, Boston, MA 02114 USA. NR 22 TC 12 Z9 12 U1 0 U2 1 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD OCT PY 2009 VL 118 IS 10 BP 703 EP 707 PG 5 WC Otorhinolaryngology SC Otorhinolaryngology GA 509UZ UT WOS:000271045500004 PM 19894397 ER PT J AU Johnson, ML Petersen, LA Sundaravaradan, R Byrne, MM Hasche, JC Osemene, NI Wei, II Morgan, RO AF Johnson, Michael L. Petersen, Laura A. Sundaravaradan, Raji Byrne, Margaret M. Hasche, Jennifer C. Osemene, Nora I. Wei, Iris I. Morgan, Robert O. TI The Association of Medicare Drug Coverage with Use of Evidence-Based Medications in the Veterans Health Administration SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE managed care; Medicare; pharmacy; veterans ID ACUTE MYOCARDIAL-INFARCTION; ACCESS; VA; IDENTIFICATION; POPULATIONS; PREVALENCE; OUTCOMES; HMOS; CARE AB BACKGROUND: Veterans with Medicare managed-care plans have access to pharmacy benefits outside the Veterans Health Administration (VA), but how this coverage affects use of medications for specific disease conditions within the VA is unclear. OBJECTIVE: To examine patterns of pharmacotherapy among patients with diabetes mellitus, ischemic heart disease, and chronic heart failure enrolled in fee-for-service (FFS) or managed-care (HMO) plans and to test whether pharmacy benefit coverage within Medicare is associated with the receipt of evidence-based medications in the VA. METHODS: A retrospective analysis of veterans dually enrolled in the VA and Medicare healthcare systems was conducted. We used VA and Medicare administrative data from 2002 in multivariable logistic regression analysis to determine the unique association of enrollment in Medicare FFS or managed-care plans on the use of medications, after adjusting for sociodemographic, geographic, and patient clinical factors. RESULTS: A total of 369,697 enrollees met inclusion criteria for diabetes, ischemic heart disease, or chronic heart failure. Among patients with diabetes, adjusted odds ratios (ORs) of receiving angiotensin-converting enzyme (ACE) inhibitors and oral hypoglycemics in the FFS group were, respectively, 0.86 and 0.80 (p < 0.001). Among patients with ischemic heart disease, FFS patients were generally less likely to receive beta-blockers, antianginals, and statins. Among patients with chronic heart failure, adjusted ORs of receiving ACE inhibitors, angiotensin-receptor blockers, and statins in the FFS group were, respectively, 0.90, 0.78, and 0.79 (all p < 0.05). There were few systematic differences within HMO coverage levels. CONCLUSIONS: FFS-enrolled veterans were generally less likely to be receiving condition-related medications from the VA, compared with HMO-enrolled veterans with lower levels of prescription drug coverage. Pharmacy prescription coverage within Medicare affects the use of evidence-based medications for specific disease conditions in the VA. C1 [Johnson, Michael L.] Univ Houston, Coll Pharm, Dept Clin Sci & Adm, Houston, TX 77030 USA. [Johnson, Michael L.; Petersen, Laura A.; Sundaravaradan, Raji; Hasche, Jennifer C.; Morgan, Robert O.] Michael E DeBakey Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Houston, TX USA. [Petersen, Laura A.] Baylor Coll Med, Sect Hlth Serv Res, Houston, TX 77030 USA. [Byrne, Margaret M.] Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL USA. [Osemene, Nora I.] Texas So Univ, Coll Pharm & Hlth Sci, Houston, TX 77004 USA. [Wei, Iris I.] Ctr Medicare Serv, Off Res Dev & Informat, Res & Evaluat Grp, Div Res Hlth Plans & Drugs, Baltimore, MD USA. [Wei, Iris I.] Ctr Medicaid Serv, Off Res Dev & Informat, Res & Evaluat Grp, Div Res Hlth Plans & Drugs, Baltimore, MD USA. RP Johnson, ML (reprint author), 1441 Moursund St, Houston, TX 77030 USA. EM mikejohnson@uh.edu NR 30 TC 2 Z9 2 U1 0 U2 0 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD OCT PY 2009 VL 43 IS 10 BP 1565 EP 1575 DI 10.1345/aph.1L606 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 503YR UT WOS:000270579100001 PM 19706740 ER PT J AU Arriaga, AF Lancaster, RT Berry, WR Regenbogen, SE Lipsitz, SR Kaafarani, HMA Elbardissi, AW Desai, P Ferzoco, SJ Belday, R Breen, E Kastrinakis, WV Rubin, MS Gawande, AA AF Arriaga, Alexander F. Lancaster, Robert T. Berry, William R. Regenbogen, Scott E. Lipsitz, Stuart R. Kaafarani, Haytham M. A. Elbardissi, Andrew W. Desai, Priya Ferzoco, Stephen J. Belday, Ronald Breen, Elizabeth Kastrinakis, William V. Rubin, Marc S. Gawande, Atul A. TI The Better Colectomy Project Association of Evidence-Based Best-Practice Adherence Rates to Outcomes in Colorectal Surgery SO ANNALS OF SURGERY LA English DT Article ID QUALITY IMPROVEMENT PROGRAM; SURGERY; SAFETY; MORBIDITY; MORTALITY; CANCER AB objective: To evaluate whether adherence to evidence-based best practices in colorectal surgery predicts improved postoperative Outcomes Summary and Background Data: Over a quarter of a million colon and rectal resections are performed annually in the United States The average postoperative complication rate for these procedures approaches 3 0 Methods: A panel of colorectal and general surgeons from 3 hospitals (I academic medical center and 2 community hospitals) was assembled to ascertain a set of 37 evidence-based practices that they felt were the most pertinent to the evaluation and management of a patient undergoing a colorectal resection. Fifteen of these practices were classified as "key processes" for the prevention of complications We then retrospectively reviewed medical records for 370 consecutive patients undergoing colorectal resection at these institutions We evaluated the a. association of best-practice adherence to complications in the subset of patients with outcome data available through the American College of Surgeons National Surgical Quality Improvement Program Results: Nonadherence rates exceeded 40% for 11 practices (including 2 key processes avoidance of unnecessary blood transfusions and timely removal of central venous catheters) Among 198 patients with American College of Surgeons National Surgical Quality Improvement Program outcomes data. 38 (19%) experienced complications, of which 31 (82%) involved postoperative infection Nonadherence it) key-processes significantly predicted the occurrence of a complication (P = 0.002) Each additional process missed increased the odds of a postoperative complication by 60% (odds ratio 1:6. 95% confidence interval 1.2-2.2) Conclusions: Failures of adherence with best practices in colorectal surgery is associated with an increased occurrence of complications This study merits further research to confirm that improvement in compliance with perioperative best practices will reduce complication rates significantly C1 [Arriaga, Alexander F.; Lancaster, Robert T.; Berry, William R.; Regenbogen, Scott E.; Kaafarani, Haytham M. A.; Elbardissi, Andrew W.; Desai, Priya; Gawande, Atul A.] Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. [Arriaga, Alexander F.; Lipsitz, Stuart R.; Elbardissi, Andrew W.; Desai, Priya; Belday, Ronald; Breen, Elizabeth; Gawande, Atul A.] Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. [Lancaster, Robert T.; Regenbogen, Scott E.] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. [Kaafarani, Haytham M. A.] Vet Affairs Boston Healthcare Syst, Dept Surg, Boston, MA USA. [Ferzoco, Stephen J.] Faulkner Hosp, Dept Surg, Boston, MA USA. [Kastrinakis, William V.; Rubin, Marc S.] N Shore Med Ctr, Dept Surg, Salem, MA USA. RP Arriaga, AF (reprint author), Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, 677 Huntington Ave, Boston, MA 02115 USA. EM aarriaga@partners.org OI Gawande, Atul/0000-0002-1824-9176 NR 14 TC 29 Z9 29 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD OCT PY 2009 VL 250 IS 4 BP 507 EP 513 DI 10.1097/SLA.0b013e3181b672bc PG 7 WC Surgery SC Surgery GA 504FA UT WOS:000270599800001 PM 19734778 ER PT J AU Cobb, JP Moore, EE Hayden, DL Minei, JP Cuschieri, J Yang, JY Li, Q Lin, N Brownstein, BH Hennessy, L Mason, PH Schierding, WS Dixon, DJ Tompkins, RG Warren, HS Schoenfeld, DA Maier, RV AF Cobb, J. Perren Moore, Ernest E. Hayden, Doug L. Minei, Joseph P. Cuschieri, Joseph Yang, Jingyun Li, Qing Lin, Nan Brownstein, Bernard H. Hennessy, Laura Mason, Philip H. Schierding, William S. Dixon, David J. Tompkins, Ronald G. Warren, H. Shaw Schoenfeld, David A. Maier, Ronald V. TI Validation of the Riboleukogram to Detect Ventilator-Associated Pneumonia After Severe Injury SO ANNALS OF SURGERY LA English DT Article DE trauma; sepsis; micro array; genechip; diagnosis; RNA; glue grant ID GENE-EXPRESSION PROFILES; INTENSIVE-CARE-UNIT; SEPSIS; BLOOD; MICROARRAYS; DIAGNOSIS; RESPONSES; INFLAMMATION; ACTIVATION; PREDICTION AB Objective: We hypothesized that circulating leukocyte RNA profiles or 'riboleukograrns" detect ventulator-associaied pneumonia after blunt trauma Summary Background Data: A pilot microarray Study of 11 ventilator-associated pneumonia (VAP) patients suggested that 85 leukocyte genes can be used to diagnose VAII. Validation of this gene set to detect VAP was tested using data from an independent patient cohort Methods: A total of 158 intubated blunt trauma patients were enrolled at 5 centers. where 57 (36%) developed VAP. Patient age was 34.2 +/- 11.1 years. 65% were male Circulating leukocyte GeneChip U 133 2 0 expression values were measured at time 0.5. 1, 4, 7, 14, 21 and 28 days after injury DChip normalized leukocyte transcriptional profiles were analyzed using repeated measures logistic regression A compound covariate model based on leukocyte gene transcriptional profiles in a training subset of patients was tested to determine predictive accuracy for VAII 4 days prior to (clinical diagnosis in the test subset. Results: Using gene expression values measured on each study (lay at all FDR <0.05, 27 (32%) of the 85 genes were associated with Lhe diagnosis of VAP 1 to 4 days before diagnosis However, the compound covariate model based on these 85-genes did not predict VAP in the test cohort better than chance (P = 027) 111 contrast, a compound covariate model based upon de novo transcriptional analysis of the 158 patients predicted VAP better than chance 4 days before diagnosis with a sensitivity of 57% and a specificity of 69%. Conclusion: Our results validate those described in I pilot study, confirming that riboleukograms are associated with the development of VAP days prior to clinical diagnosis Similarly. a riboleukogram predictive model tested oil a larger cohort of 158 patients was better than chance at predicting VAP (lays prior to clinical diagnosis C1 Washington Univ, Ctr Crit Illness & Hlth Engn, St Louis, MO USA. Massachusetts Gen Hosp, NIGMS Inflammat & Host Response Injury Program, Boston, MA 02114 USA. RP Cobb, JP (reprint author), Campus Box 8109,660 S Euclid Ave, St Louis, MO 63110 USA. FU NIGMS NIH HHS [U54 GM062119, R01 GM081524, R01GM081524, R01 GM081524-04, R21 GM075023, R21GM075023, U54GM6211906] NR 53 TC 15 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD OCT PY 2009 VL 250 IS 4 BP 531 EP 539 DI 10.1097/SLA.0b013e3181b81bd5 PG 9 WC Surgery SC Surgery GA 504FA UT WOS:000270599800004 PM 19730236 ER PT J AU Gee, JR Burmeister, CB Havighurst, TC Kim, K AF Gee, Jason R. Burmeister, Corrie B. Havighurst, Thomas C. Kim, Kyungmann TI Cyclin-mediated G1 Arrest by Celecoxib Differs in Low-versus High-grade Bladder Cancer SO ANTICANCER RESEARCH LA English DT Article DE Cyclooxygenase (COX)-2; celecoxib; bladder cancer; chemoprevention ID COLON-CARCINOMA CELLS; CYCLOOXYGENASE-2 INHIBITORS; INDUCED APOPTOSIS; COX-2 EXPRESSION; INDUCE APOPTOSIS; URINARY-BLADDER; AKT ACTIVATION; LUNG-CANCER; IN-VITRO; GROWTH AB Background: Celecoxib and other non-steroidal anti-inflammatory drugs (NSAIDs) are being evaluated in the prevention of bladder and other cancers. Here we investigate molecular effects of celecoxib independent of cyclooxygenase (COX)-2 expression levels in urothelial carcinoma of the bladder. Materials and Methods: Low-grade RT-4 and high-grade UM-UC-3 bladder cancer cells were treated with 0-50,mu M celecoxib. Growth, cell cycle and apoptosis were measured by crystal violet elution and flow cytometry. Western analysis was performed for COX-2, Rb, cyclin B1/D1, and phosphocyclin B1/D1 COX-2 induction was achieved with phorbol ester. Results: Celecoxib inhibited growth of RT-4 and UM-UC-3, with G(1) cell cycle arrest and altered cyclin B1/D1 expression in RT-4, whereas Rb up-regulation occurred in UM-UC-3. Apoptosis occurred in both cell lines. Conclusion: Celecoxib induces G(1) cell cycle arrest in low- and high-grade bladder cancer by different pathways. This heterogeneous molecular response supports combination approaches to prevention and treatment. C1 [Gee, Jason R.] Univ Wisconsin, Dept Urol, Sch Med & Publ Hlth, Clin Sci Ctr G5 342, Madison, WI 53792 USA. [Havighurst, Thomas C.; Kim, Kyungmann] Univ Wisconsin, Dept Biostat & Informat, Madison, WI 53792 USA. [Gee, Jason R.] William S Middleton Mem Vet Adm Med Ctr, Dept Urol, Madison, WI USA. RP Gee, JR (reprint author), Univ Wisconsin, Dept Urol, Sch Med & Publ Hlth, Clin Sci Ctr G5 342, 600 Highland Ave, Madison, WI 53792 USA. EM Gee@urology.wisc.edu FU Office of Research and Development, Biomedical Laboratory R&D Service, Department of Veterans Affairs [P30 CA 14520] FX This work is supported by the Office of Research and Development, Biomedical Laboratory R&D Service, Department of Veterans Affairs (J.R. Gee) and by P30 CA 14520 (T. Havighurst & K. Kim). NR 40 TC 7 Z9 7 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD OCT PY 2009 VL 29 IS 10 BP 3769 EP 3775 PG 7 WC Oncology SC Oncology GA 515QL UT WOS:000271487400005 PM 19846907 ER PT J AU Rivas, DA Lessard, SJ Coffey, VG AF Rivas, Donato A. Lessard, Sarah J. Coffey, Vernon G. TI mTOR function in skeletal muscle: a focal point for overnutrition and exercise SO APPLIED PHYSIOLOGY NUTRITION AND METABOLISM-PHYSIOLOGIE APPLIQUEE NUTRITION ET METABOLISME LA English DT Review DE nutrients; insulin action; metabolism; training ID INDUCED INSULIN-RESISTANCE; FREE FATTY-ACIDS; NUTRIENT SENSING PATHWAY; P70 S6 KINASE; AMINO-ACID; MAMMALIAN TARGET; PROTEIN-SYNTHESIS; GLUCOSE-UPTAKE; ENDURANCE EXERCISE; CELL-GROWTH AB The mammalian target of rapamycin (mTOR) is a highly conserved atypical serine-threonine kinase that controls numerous functions essential for cell homeostasis and adaptation in mammalian cells via 2 distinct protein complex formations. Moreover, mTOR is a key regulatory protein in the insulin signalling cascade and has also been characterized as an insulin-independent nutrient sensor that may represent a critical mediator in obesity-related impairments of insulin action in skeletal muscle. Exercise characterizes a remedial modality that enhances mTOR activity and subsequently promotes beneficial metabolic adaptation in skeletal muscle. Thus, the metabolic effects of nutrients and exercise have the capacity to converge at the mTOR protein complexes and subsequently modify mTOR function. Accordingly, the aim of the present review is to highlight the role of mTOR in the regulation of insulin action in response to overnutrition and the capacity for exercise to enhance mTOR activity in skeletal muscle. C1 [Rivas, Donato A.; Coffey, Vernon G.] RMIT Univ, Sch Med Sci, Exercise Metab Grp, Bundoora, Vic 3083, Australia. [Lessard, Sarah J.] Harvard Univ, Sch Med, Div Res, Joslin Diabet Ctr, Boston, MA 02215 USA. [Lessard, Sarah J.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Coffey, VG (reprint author), RMIT Univ, Sch Med Sci, Exercise Metab Grp, Bundoora, Vic 3083, Australia. EM vernon.coffey@rmit.edu.au OI Rivas, Donato/0000-0002-4500-6233 NR 109 TC 19 Z9 19 U1 2 U2 11 PU NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS PI OTTAWA PA BUILDING M 55, OTTAWA, ON K1A 0R6, CANADA SN 1715-5312 J9 APPL PHYSIOL NUTR ME JI Appl. Physiol. Nutr. Metab. PD OCT PY 2009 VL 34 IS 5 BP 807 EP 816 DI 10.1139/H09-073 PG 10 WC Nutrition & Dietetics; Physiology; Sport Sciences SC Nutrition & Dietetics; Physiology; Sport Sciences GA 541LW UT WOS:000273418200001 PM 19935842 ER PT J AU Huebschmann, AG Reis, EN Emsermann, C Dickinson, LM Reusch, JEB Bauer, TA Regensteiner, JG AF Huebschmann, Amy G. Reis, Erin N. Emsermann, Caroline Dickinson, L. Miriam Reusch, Jane E. B. Bauer, Timothy A. Regensteiner, Judith G. TI Women with type 2 diabetes perceive harder effort during exercise than nondiabetic women SO APPLIED PHYSIOLOGY NUTRITION AND METABOLISM-PHYSIOLOGIE APPLIQUEE NUTRITION ET METABOLISME LA English DT Article DE ratings of perceived exertion scale of Borg; type 2 diabetes mellitus; overweight; obesity; physical activity; exercise ID HABITUAL PHYSICAL-ACTIVITY; CAUSE-SPECIFIC MORTALITY; CARDIORESPIRATORY FITNESS; GLUCOSE-TOLERANCE; SKELETAL-MUSCLE; OXYGEN-UPTAKE; US ADULTS; MEN; SCALE; PREVALENCE AB Regular exercise is a cornerstone of diabetes treatment; however, people with type 2 diabetes (T2D) are commonly sedentary. It is possible that a harder rate of perceived exertion (RPE) during exercise for those with T2D as compared with nondiabetics may be a barrier to physical activity. This study examined RPE (Borg scale, ordinal range 6-20) during submaximal exercise at identical absolute work rates to test the hypothesis that women with T2D demonstrate harder RPE during exercise than nondiabetic controls. In a prespecified analysis of existing data from equivalently sedentary women, RPE during submaximal exercise was compared among women with uncomplicated T2D (n = 13, mean body mass index (BMI) 34.2, mean hemoglobin A1c 9%), overweight controls (OC, n = 13, mean BMI 30.7), and normal-weight controls (NWC, n = 13, mean BMI 23.1). Subjects performed three 7 min, constant-load exercise tests at 20 W and 30 W. Mixed-effects general linear modeling was used to test for differences in mean RPE estimates among groups with and without adjustment for relative work intensity, age, habitual physical activity, or BMI. Subjects with T2D perceived harder effort during bicycling exercise than controls, as measured by RPE at 20 W and 30 W (p < 0.05 for T2D vs. OC and for T2D vs. NWC). Adjusting for relative work intensity eliminated significant group RPE differences at 30 W, but group RPE differences at 20 W remained significant. Harder perceived effort during exercise may be a barrier to physical activity for those with T2D. C1 [Huebschmann, Amy G.; Reis, Erin N.; Bauer, Timothy A.; Regensteiner, Judith G.] Univ Colorado, Denver Sch Med, Div Gen Internal Med, Aurora, CO 80045 USA. [Huebschmann, Amy G.; Reusch, Jane E. B.; Regensteiner, Judith G.] Univ Colorado, Denver Sch Med, Ctr Womens Hlth Res, Dept Med, Aurora, CO 80045 USA. [Emsermann, Caroline; Dickinson, L. Miriam] Univ Colorado, Denver Sch Med, Div Family Med, Aurora, CO 80045 USA. [Reusch, Jane E. B.] Univ Colorado, Denver Sch Med, Div Endocrinol, Aurora, CO 80045 USA. [Reusch, Jane E. B.] Univ Colorado, Denver Sch Med, Denver VAMC, Denver, CO 80220 USA. [Regensteiner, Judith G.] Univ Colorado, Denver Sch Med, Div Cardiol, Aurora, CO 80045 USA. RP Huebschmann, AG (reprint author), Univ Colorado, Denver Sch Med, Div Gen Internal Med, POB 6511,Mailstop B180, Aurora, CO 80045 USA. EM Amy.Huebschmann@ucdenver.edu FU General Internal Medicine Division of the University of Colorado Denver (UCD) School of Medicine; American Diabetes Association; Health Resources and Services Administration faculty development grant; UCD Center for Women's Health Research Junior Faculty Research Development Award; Armstrong Family Foundation grant; National Research Service Award [F32 DK088413-01]; American Diabetes Association award; Veteran Affairs Merit award; National Institutes of Health [DK064741] FX As noted in the manuscript, the demographic and (V) over dotO2 peak data have been published previously by Regensteiner et al. (1998). RPE data were presented in abstract form only at the 2007 American Diabetes Association 67th Scientific Sessions and the 2007 National Diabetes Health Disparities Conference. The analysis of RPE data was supported by a small grant from the General Internal Medicine Division of the University of Colorado Denver (UCD) School of Medicine, and the primary data acquisition for this study was funded by the American Diabetes Association. A. G. H. is supported by a Health Resources and Services Administration faculty development grant, by the UCD Center for Women's Health Research Junior Faculty Research Development Award, and by an Armstrong Family Foundation grant; T. A. B. is supported by National Research Service Award F32 DK088413-01; J. G. R. is supported by an American Diabetes Association award; J. E. B. R. is supported by a Veteran Affairs Merit award and National Institutes of Health grant DK064741. We are also grateful to Vermed, Inc., for their generous donation of ECG electrodes for all of our exercise studies. NR 45 TC 19 Z9 19 U1 0 U2 0 PU NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS PI OTTAWA PA BUILDING M 55, OTTAWA, ON K1A 0R6, CANADA SN 1715-5312 J9 APPL PHYSIOL NUTR ME JI Appl. Physiol. Nutr. Metab. PD OCT PY 2009 VL 34 IS 5 BP 851 EP 857 DI 10.1139/H09-074 PG 7 WC Nutrition & Dietetics; Physiology; Sport Sciences SC Nutrition & Dietetics; Physiology; Sport Sciences GA 541LW UT WOS:000273418200005 PM 19935846 ER PT J AU Shin, LM Lasko, NB Macklin, ML Karpf, RD Milad, MR Orr, SP Goetz, JM Fischman, AJ Rauch, SL Pitman, RK AF Shin, Lisa M. Lasko, Natasha B. Macklin, Michael L. Karpf, Rachel D. Milad, Mohammed R. Orr, Scott P. Goetz, Jared M. Fischman, Alan J. Rauch, Scott L. Pitman, Roger K. TI Resting Metabolic Activity in the Cingulate Cortex and Vulnerability to Posttraumatic Stress Disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID CHILDHOOD SEXUAL-ABUSE; SCRIPT-DRIVEN IMAGERY; CEREBRAL-BLOOD-FLOW; MONOZYGOTIC TWINS DISCORDANT; MEDIAL PREFRONTAL CORTEX; FUNCTIONAL MRI; COMBAT EXPOSURE; ENVIRONMENTAL-INFLUENCES; NEUROIMAGING RESEARCH; HIPPOCAMPAL FUNCTION AB Context: Recent neuroimaging research has revealed functional abnormalities in the anterior cingulate cortex, amygdala, and hippocampus in individuals with post-traumatic stress disorder (PTSD). Objective: To determine whether resting functional abnormalities found in PTSD are acquired characteristics or familial risk factors. Design: Cross-sectional design including identical twins discordant for trauma exposure. Setting: Academic medical center. Participants: Combat-exposed veterans with PTSD (n = 14) and their identical co-twins not exposed to combat (n = 14) as well as combat-exposed veterans without PTSD (n = 19) and their identical co-twins not exposed to combat (n = 19). Main Outcome Measures: We used positron emission tomography and fluorodeoxyglucose 18 to examine resting regional cerebral metabolic rate for glucose (rCMRglu). Results: Veterans with PTSD and their co-twins had significantly higher resting rCMRglu in the dorsal anterior cingulate cortex/midcingulate cortex (dACC/MCC) compared with veterans without PTSD and their co-twins. Resting rCMRglu in the dACC/MCC in unexposed co-twins was positively correlated with combat exposure severity, PTSD symptom severity, and alcohol use in their exposed twins. Conclusions: Enhanced resting metabolic activity in the dACC/MCC appears to represent a familial risk factor for developing PTSD after exposure to psychological trauma. C1 [Shin, Lisa M.] Tufts Univ, Dept Psychol, Medford, MA 02155 USA. [Shin, Lisa M.; Lasko, Natasha B.; Karpf, Rachel D.; Milad, Mohammed R.; Orr, Scott P.; Goetz, Jared M.; Rauch, Scott L.; Pitman, Roger K.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rauch, Scott L.] Harvard Univ, Sch Med, Boston, MA USA. [Lasko, Natasha B.; Macklin, Michael L.; Orr, Scott P.] Vet Affairs Res Serv, Manchester, NH USA. [Rauch, Scott L.] McLean Hosp, Dept Psychiat, Belmont, MA 02178 USA. [Fischman, Alan J.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. RP Shin, LM (reprint author), Tufts Univ, Dept Psychol, 490 Boston Ave, Medford, MA 02155 USA. EM lisa.shin@tufts.edu FU US Public Health Service [R01MH54636]; US Department of Veterans Affairs; Vietnam Era Twin Registry FX This work was supported by grant R01MH54636 from the US Public Health Service (Dr Pitman). The US Department of Veterans Affairs provided financial support for the development and maintenance of the Vietnam Era Twin Registry. Through their support of the Vietnam Era Twin Registry, numerous other US organizations also provided invaluable assistance, including the Department of Defense; National Personnel Records Center, National Archives and Records Administration; Internal Revenue Service; National Institutes of Health; National Opinion Research Center; National Research Council, National Academy of Sciences; and Institute for Survey Research, Temple University. NR 94 TC 60 Z9 63 U1 10 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2009 VL 66 IS 10 BP 1099 EP 1107 PG 9 WC Psychiatry SC Psychiatry GA 502YE UT WOS:000270496100007 PM 19805700 ER PT J AU Martell, BA Orson, FM Poling, J Mitchell, E Rossen, RD Gardner, T Kosten, TR AF Martell, Bridget A. Orson, Frank M. Poling, James Mitchell, Ellen Rossen, Roger D. Gardner, Tracie Kosten, Thomas R. TI Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone-Maintained Patients A Randomized, Double-blind, Placebo-Controlled Efficacy Trial SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID CHOLERA B-SUBUNIT; WHOLE-CELL VACCINE; CONTINGENCY MANAGEMENT; IMMUNOLOGICAL MEMORY; ACTIVE IMMUNIZATION; MONOCLONAL-ANTIBODY; SWEDISH VOLUNTEERS; SMOKING-CESSATION; IMMUNE FUNCTION; IMMUNOGENICITY AB Context: Cocaine dependence, which affects 2.5 million Americans annually, has no US Food and Drug Administration-approved pharmacotherapy. Objectives: To evaluate the immunogenicity, safety, and efficacy of a novel cocaine vaccine to treat cocaine dependence. Design: A 24-week, phase 2b, randomized, double-blind, placebo-controlled trial with efficacy assessed during weeks 8 to 20 and follow-up to week 24. Setting: Cocaine- and opioid-dependent persons recruited from October 2003 to April 2005 from greater New Haven, Connecticut. Participants: One hundred fifteen methadone-maintained subjects (67% male, 87% white, aged 18-46 years) were randomized to vaccine or placebo, and 94 subjects (82%) completed the trial. Most smoked crack cocaine along with using marijuana (18%), alcohol (10%), and nonprescription opioids (44%). Intervention: Over 12 weeks, 109 of 115 subjects received 5 vaccinations of placebo or succinylnorcocaine linked to recombinant cholera toxin B-subunit protein. Main Outcome Measure: Semiquantitative urinary cocaine metabolite levels measured thrice weekly with a positive cutoff of 300 ng/mL. Results: The 21 vaccinated subjects (38%) who attained serum IgG anticocaine antibody levels of 43 mu g/mL or higher (ie, high IgG level) had significantly more cocaine-free urine samples than those with levels less than 43 mu g/mL (ie, low IgG level) and the placebo-receiving subjects during weeks 9 to 16 (45% vs 35% cocaine-free urine samples, respectively). The proportion of subjects having a 50% reduction in cocaine use was significantly greater in the subjects with a high IgG level than in subjects with a low IgG level (53% of subjects vs 23% of subjects, respectively) (P = .048). The most common adverse effects were injection site induration and tenderness. There were no treatment-related serious adverse events, withdrawals, or deaths. Conclusions: Attaining high (>= 43 mu g/mL) IgG anticocaine antibody levels was associated with significantly reduced cocaine use, but only 38% of the vaccinated subjects attained these IgG levels and they had only 2 months of adequate cocaine blockade. Thus, we need improved vaccines and boosters. C1 [Orson, Frank M.; Rossen, Roger D.; Gardner, Tracie; Kosten, Thomas R.] Michael E DeBakey Vet Affairs Med Ctr, Houston, TX 77030 USA. [Martell, Bridget A.] Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. [Poling, James; Mitchell, Ellen] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. [Martell, Bridget A.; Poling, James; Mitchell, Ellen] Vet Affairs Connecticut Healthcare Syst, West Haven, CT USA. [Gardner, Tracie; Kosten, Thomas R.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Gardner, Tracie; Kosten, Thomas R.] Baylor Coll Med, Dept Immunol, Houston, TX 77030 USA. [Gardner, Tracie; Kosten, Thomas R.] Baylor Coll Med, Menninger Dept Psychiat & Behav Sci, Houston, TX 77030 USA. RP Kosten, TR (reprint author), Michael E DeBakey Vet Affairs Med Ctr, 2002 Holcombe,Bldg 110,Room 229, Houston, TX 77030 USA. EM kosten@bcm.edu OI Poling, James/0000-0002-0133-3136 FU National Institute on Drug Abuse [1 R01 DA15477, K05-DA 0454, P50-DA12762]; Veterans Affairs Mental Illness Research, Education, and Clinical Center (New England MIRECC); Veteran's Affairs Office of Research and Development/Cooperative Studies Program Career Development Award [733A] FX This work was supported by grants 1 R01 DA15477, K05-DA 0454 (Dr Kosten), and P50-DA12762 from the National Institute on Drug Abuse and by the Veterans Affairs Mental Illness Research, Education, and Clinical Center (New England MIRECC). Dr Martell was provided salary support by the Veteran's Affairs Office of Research and Development/Cooperative Studies Program Career Development Award CRCD # 733A at the time the research was conducted. Celtic Pharmaceuticals supplied the succinylnorcocaine recombinant cholera toxin B-subunit vaccine and gave Dr Kosten travel fees for consultative services. NR 53 TC 109 Z9 111 U1 0 U2 15 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2009 VL 66 IS 10 BP 1116 EP 1123 PG 8 WC Psychiatry SC Psychiatry GA 502YE UT WOS:000270496100009 PM 19805702 ER PT J AU Middleton, LE Yaffe, K AF Middleton, Laura E. Yaffe, Kristine TI Promising Strategies for the Prevention of Dementia SO ARCHIVES OF NEUROLOGY LA English DT Review ID COGNITIVE FUNCTION; ALZHEIMER-DISEASE; OLDER-ADULTS; PHYSICAL-ACTIVITY; RANDOMIZED-TRIAL; BLOOD-PRESSURE; RISK; IMPAIRMENT; DECLINE; MEMORY AB The incidence and prevalence of dementia are expected to increase several-fold in the coming decades. Given that the current pharmaceutical treatment of dementia can only modestly improve symptoms, risk factor modification remains the cornerstone for dementia prevention. Some of the most promising strategies for the prevention of dementia include vascular risk factor control, cognitive activity, physical activity, social engagement, diet, and recognition of depression. In observational studies, vascular risk factors including diabetes, hypertension, dyslipidemia, and obesity-are fairly consistently associated with increased risk of dementia. In addition, people with depression are at high risk for cognitive impairment. Population studies have reported that intake of antioxidants or polyunsaturated fatty acids may be associated with a reduced incidence of dementia, and it has been reported that people who are cognitively, socially, and physically active have a reduced risk of cognitive impairment. However, results from randomized trials of risk factor modification have been mixed. Most promising, interventions of cognitive and physical activity improve cognitive performance and slow cognitive decline. Future studies should continue to examine the implication of risk factor modification in controlled trials, with particular focus on whether several simultaneous interventions may have additive or multiplicative effects. Arch Neurol. 2009;66(10):1210-1215 C1 [Middleton, Laura E.; Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat, Sch Med, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Neurol, Sch Med, San Francisco, CA 94121 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Epidemiol & Biostat, Sch Med, San Francisco, CA 94121 USA. San Francisco VA Med Ctr, San Francisco, CA USA. RP Yaffe, K (reprint author), Univ Calif San Francisco, Dept Psychiat, Sch Med, 4150 Clement St,Box 181, San Francisco, CA 94121 USA. EM kristine.yaffe@ucsf.edu RI Middleton, Laura/C-6024-2009 OI Middleton, Laura/0000-0001-8624-3123 FU National Institute on Aging [AG 031155] FX This work was supported in part by grant AG 031155 from the National Institute on Aging (Dr Yaffe). NR 37 TC 169 Z9 173 U1 2 U2 33 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9942 EI 1538-3687 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD OCT PY 2009 VL 66 IS 10 BP 1210 EP 1215 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 504LA UT WOS:000270617000004 PM 19822776 ER PT J AU Lester, SC Bose, S Chen, YY Connolly, JL de Baca, ME Fitzgibbons, PL Hayes, DF Kleer, C O'Malley, FP Page, DL Smith, BL Tan, LK Weaver, DL Winer, E AF Lester, Susan C. Bose, Shikha Chen, Yunn-Yi Connolly, James L. de Baca, Monica E. Fitzgibbons, Patrick L. Hayes, Daniel F. Kleer, Celina O'Malley, Frances P. Page, David L. Smith, Barbara L. Tan, Lee K. Weaver, Donald L. Winer, Eric CA Coll Amer Pathologists TI Protocol for the Examination of Specimens From Patients With Invasive Carcinoma of the Breast SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID ESTROGEN-RECEPTOR STATUS; IN-SITU HYBRIDIZATION; NEOADJUVANT CHEMOTHERAPY; PROGESTERONE-RECEPTORS; FORMALIN FIXATION; CANCER; IMMUNOHISTOCHEMISTRY; RECOMMENDATIONS; DECALCIFICATION; CLASSIFICATION C1 [Lester, Susan C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Connolly, James L.] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. [Smith, Barbara L.] Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. [Winer, Eric] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Bose, Shikha] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA. [Chen, Yunn-Yi] UCSF Med Ctr, Dept Pathol, San Francisco, CA USA. [de Baca, Monica E.] Phys Lab, Sioux Falls, SD USA. [Fitzgibbons, Patrick L.] St Jude Med Ctr, Dept Pathol, Fullerton, CA USA. [Hayes, Daniel F.] Univ Michigan, Dept Med Oncol, Med Ctr, Ann Arbor, MI USA. [Kleer, Celina] Univ Michigan, Dept Pathol, Med Ctr, Ann Arbor, MI 48109 USA. [O'Malley, Frances P.] Mt Sinai Hosp, Dept Pathol, Toronto, ON M5G 1X5, Canada. [Page, David L.] Vanderbilt Univ, Med Ctr, Dept Pathol, Nashville, TN 37232 USA. [Tan, Lee K.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Weaver, Donald L.] Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. [Weaver, Donald L.] Univ Vermont, Vermont Canc Ctr, Burlington, VT 05405 USA. RP Lester, SC (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. EM slester@partners.org OI Fitzgibbons, Patrick/0000-0002-2998-6913 FU NCI NIH HHS [U01 CA154224] NR 47 TC 70 Z9 75 U1 0 U2 6 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD OCT PY 2009 VL 133 IS 10 BP 1515 EP 1538 PG 24 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 506ZU UT WOS:000270819500001 PM 19792042 ER PT J AU Monzon, FA Ogino, S Hammond, MEH Halling, KC Bloom, KJ Nikiforova, MN AF Monzon, Federico A. Ogino, Shuji Hammond, M. Elizabeth H. Halling, Kevin C. Bloom, Kenneth J. Nikiforova, Marina N. TI The Role of KRAS Mutation Testing in the Management of Patients With Metastatic Colorectal Cancer SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Review ID RESOLUTION MELTING ANALYSIS; KI-RAS MUTATIONS; CETUXIMAB THERAPY; SEQUENCING METHOD; PREDICT RESPONSE; LUNG-CANCER; EGFR; PANITUMUMAB; EXPRESSION; PCR AB Context.-KRAS mutations can be detected in approximately 30% to 40% of all patients with colorectal cancer. Several recent studies have shown that patients with KRAS mutations in codons 12 or 13 in metastatic tumors do not benefit from anti-epidermal growth factor receptor therapy with cetuximab or panitumumab. Objective.-To review the literature on the role of KRAS mutation testing for management of patients with metastatic colorectal cancer and to discuss testing strategies. Data Sources.-This review is based on published, peer-reviewed literature; available information from medical organizations (eg, National Comprehensive Cancer Network, American Society of Clinical Oncology, College of American Pathologists); and information from clinical laboratories conducting KRAS mutation analysis. Conclusions.-Multiple methods for detecting KRAS mutations in colorectal tumors are available, and all methods in current clinical use appear to have adequate clinical sensitivity for predicting a lack of response to cetuximab and panitumumab. Pathologist expertise is essential to quality KRAS testing and to determining effective treatment for patients with metastatic colorectal cancer. (Arch Pathol Lab Med. 2009; 133: 1600-1606) C1 [Monzon, Federico A.] Methodist Hosp, Res Inst, Dept Mol Diagnost, Houston, TX 77030 USA. [Monzon, Federico A.] Weill Cornell Med Coll, New York, NY USA. [Ogino, Shuji] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Ogino, Shuji] Harvard Univ, Sch Med, Boston, MA USA. [Ogino, Shuji] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Hammond, M. Elizabeth H.] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT USA. [Halling, Kevin C.] Mayo Clin, Dept Pathol & Lab Med, Rochester, MN USA. [Bloom, Kenneth J.] Clarient Diagnost Serv Lab, Dept Lab, Aliso Viejo, CA USA. [Nikiforova, Marina N.] Univ Pittsburgh, Dept Pathol, Med Ctr, Pittsburgh, PA USA. RP Monzon, FA (reprint author), Methodist Hosp, Res Inst, Dept Mol Diagnost, 6565 Fannin St,MS 205, Houston, TX 77030 USA. EM famonzon@tmhs.org NR 44 TC 80 Z9 83 U1 0 U2 2 PU COLL AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 EI 1543-2165 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD OCT PY 2009 VL 133 IS 10 BP 1600 EP 1606 PG 7 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 506ZU UT WOS:000270819500009 PM 19792050 ER PT J AU Arterburn, D Livingston, EH Schifftner, T Kahwati, LC Henderson, WG Maciejewski, ML AF Arterburn, David Livingston, Edward H. Schifftner, Tracy Kahwati, Leila C. Henderson, William G. Maciejewski, Matthew L. TI Predictors of Long-term Mortality After Bariatric Surgery Performed in Veterans Affairs Medical Centers SO ARCHIVES OF SURGERY LA English DT Article ID GASTRIC BYPASS-SURGERY; RISK-FACTORS; SURGICAL CARE; UNITED-STATES; DEATH RATES; OBESITY; METAANALYSIS; OVERWEIGHT; QUALITY; EXPENDITURES AB Hypothesis: The purpose of this study was to examine patient factors associated with mortality among veterans who undergo bariatric surgery. Design: Prospective study that uses data from the Veterans Affairs (VA) National Surgical Quality Improvement Program. Setting: Group Health Center for Health Studies, the VA North Texas Health Care System, the Denver VA Medical Center, and the Durham VA Medical Center. Patients: We identified 856 veterans who had undergone bariatric surgery in 1 of 12 VA bariatric centers from January 1, 2000, through December 31, 2006. Main Outcome Measures: The risk of death was estimated via Cox proportional hazards. Results: The 856 veterans had a mean body mass index (BMI) of 48.7, a mean age of 54 years, and a mean DCG score of 0.76; 73.0% were men, 83.9% were white, and 7.0% had an ASA class equal to 4. Fifty-four veterans (6.3%) had died by the end of 2006. In our Cox models, patients with a BMI greater than 50 (superobesity; hazard ratio [HR], 1.8; P=.04) or aDCGscore greater than or equal to 2 (HR, 3.4; P<.001) had an increased risk of death. Conclusion: Superobese veterans and those with a greater burden of chronic disease had a greater risk of death after bariatric surgery from 2000 through 2006. C1 [Maciejewski, Matthew L.] Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC 27705 USA. [Maciejewski, Matthew L.] Univ N Carolina, Sch Pharm, Div Pharmaceut Outcomes & Policy, Chapel Hill, NC USA. [Arterburn, David] Univ Washington, Ctr Hlth Studies, Grp Hlth, Seattle, WA 98195 USA. [Arterburn, David] Univ Washington, Dept Med, Div Gen Internal Med, Seattle, WA 98195 USA. [Livingston, Edward H.] Univ Texas SW Med Ctr Dallas, Div Gastrointestinal & Endocrine Surg, Dallas, TX 75390 USA. [Livingston, Edward H.] Vet Adm N Texas Hlth Care Syst, Dallas, TX USA. [Livingston, Edward H.] Univ Texas Arlington, Arlington, TX USA. [Schifftner, Tracy; Henderson, William G.] Univ Colorado, Denver Vet Affairs Med Ctr, Denver, CO 80202 USA. [Henderson, William G.] Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80262 USA. [Henderson, William G.] Univ Colorado, Hlth Sci Ctr, Colorado Hlth Outcomes Program, Denver, CO 80262 USA. [Kahwati, Leila C.] Off Patient Care Serv, Natl Ctr Hlth Promot & Dis Prevent, Vet Hlth Adm, Dept Vet Affairs, Durham, NC USA. RP Maciejewski, ML (reprint author), Durham VA Med Ctr, Ctr Hlth Serv Res Primary Care, Stop Code 152,508 Fulton St, Durham, NC 27705 USA. EM matthew.maciejewski@va.gov FU Office of Research and Development, Health Services Research and Development Service, Department of Veterans Affairs [IIR 05-201] FX This work was supported by the Office of Research and Development, Health Services Research and Development Service, Department of Veterans Affairs, project number IIR 05-201. NR 33 TC 26 Z9 26 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD OCT PY 2009 VL 144 IS 10 BP 914 EP 920 PG 7 WC Surgery SC Surgery GA 508JJ UT WOS:000270926400009 PM 19841358 ER PT J AU Velmahos, GC Spaniolas, K Tabbara, M Abujudeh, HH de Moya, M Gervasini, A Alam, HB AF Velmahos, George C. Spaniolas, Konstantinos Tabbara, Malek Abujudeh, Hani H. de Moya, Marc Gervasini, Alice Alam, Hasan B. TI Pulmonary Embolism and Deep Venous Thrombosis in Trauma Are They Related? SO ARCHIVES OF SURGERY LA English DT Article ID INDIRECT CT VENOGRAPHY; THROMBOEMBOLIC DISEASE; VEIN THROMBOSIS; CRITICALLY-ILL; MAJOR TRAUMA; ANGIOGRAPHY; COMPRESSION; PROPHYLAXIS; ULTRASOUND; SONOGRAPHY AB Hypothesis: Pulmonary embolism (PE) and deep venous thrombosis (DVT) in trauma are related. Design: Retrospective review of medical records. Setting: Academic level I trauma center. Patients: Trauma patients who underwent computed tomographic pulmonary angiography (CTPA) with computed tomographic venography (CTV) of the pelvic and proximal lower extremity veins over a 3-year period (January 1, 2004, to December 31, 2006) were reviewed. Data on demographics, injury type and severity, imaging findings, hospital length of stay, and mortality were collected. Main Outcome Measures: Pulmonary embolism and DVT. Results: Among 247 trauma patients undergoing CTPA/CTV, PE was diagnosed in 46 (19%) and DVT in 18 (7%). Eighteen PEs were central (main or lobar pulmonary arteries), and 28 PEs were peripheral (segmental or subsegmental branches). Pulmonary embolism occurred within the first week of injury in two-thirds of patients. Seven patients with PE (4 femoral, 2 popliteal, and 1 iliac) had DVT. Pulmonary embolism was central in 5 patients and peripheral in 2 patients. No significant differences were noted in any of the examined variables between patients with PE having DVT and those not having DVT. Conclusions: Few patients with PE have DVT of the pelvic or proximal lower extremity veins. Pulmonary embolism may not originate from these veins, as commonly believed, but instead may occur de novo in the lungs. These findings have implications for thromboprophylaxis and, particularly, the value of vena cava filters. C1 [Velmahos, George C.; Spaniolas, Konstantinos; Tabbara, Malek; de Moya, Marc; Gervasini, Alice; Alam, Hasan B.] Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, Boston, MA 02114 USA. [Abujudeh, Hani H.] Massachusetts Gen Hosp, Dept Emergency Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Velmahos, GC (reprint author), Massachusetts Gen Hosp, Div Trauma Emergency Surg & Surg Crit Care, 165 Cambridge St,Ste 810, Boston, MA 02114 USA. EM gvelmahos@partners.org NR 32 TC 39 Z9 39 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD OCT PY 2009 VL 144 IS 10 BP 928 EP 932 PG 5 WC Surgery SC Surgery GA 508JJ UT WOS:000270926400013 PM 19841360 ER PT J AU Swirski, FK Weissleder, R Pittet, MJ AF Swirski, Filip K. Weissleder, Ralph Pittet, Mikael J. TI Heterogeneous In Vivo Behavior of Monocyte Subsets in Atherosclerosis SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE monocyte; atherosclerosis; imaging ID LOW-DENSITY-LIPOPROTEIN; PROINFLAMMATORY CD14(+)CD16(+)DR(++) MONOCYTES; HUMAN PERIPHERAL-BLOOD; BONE-MARROW; T-CELLS; MONONUCLEAR PHAGOCYTES; MYOCARDIAL-INFARCTION; DENDRITIC CELLS; KNOCKOUT MICE; MACROPHAGES AB Monocytes and macrophages play active roles in atherosclerosis, a chronic inflammatory disease that is a leading cause of death in the developed world. The prevailing paradigm states that, during human atherogenesis, monocytes accumulate in the arterial intima and differentiate into macrophages, which then ingest oxidized lipoproteins, secrete a diverse array of proinflammatory mediators, and eventually become foam cells, the key constituents of a vulnerable plaque. Yet monocytes are heterogeneous. In the mouse, one subset (Ly-6C(hi)) promotes inflammation, expands in hypercholesterolemic conditions, and selectively gives rise to macrophages in atheromata. A different subset (Ly-6C(lo)) attenuates inflammation and promotes angiogenesis and granulation tissue formation in models of tissue injury, but its role in atherosclerosis is largely unknown. In the human, monocyte heterogeneity is preserved but it is still unresolved how subsets correspond functionally. The contradistinctive properties of these cells suggest commitment for specific function before infiltrating tissue. Such commitment argues for discriminate targeting of deleterious subsets while sparing host defense and repair mechanisms. In addition to advancing our understanding of atherosclerosis, the ability to target and image monocyte subsets would allow us to evaluate drugs designed to selectively inhibit monocyte subset recruitment or function, and to stratify patients at risk for developing complications such as myocardial infarction or stroke. In this review we summarize recent advances of our understanding of the behavioral heterogeneity of monocytes during disease progression and outline emerging molecular imaging approaches to address key questions in the field. (Arterioscler Thromb Vasc Biol. 2009; 29: 1424-1432.) C1 [Swirski, Filip K.; Weissleder, Ralph; Pittet, Mikael J.] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02114 USA. [Weissleder, Ralph] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA USA. RP Swirski, FK (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, Simches Res Bldg,185 Cambridge St, Boston, MA 02114 USA. EM fswirski@mgh.harvard.edu FU NIH [U01 HL080731, P50 CA86355, R24 CA69246, P01-A154904]; MGH-Center for Systems Biology FX This work was supported in part by NIH grants U01 HL080731, P50 CA86355, R24 CA69246, and P01-A154904 (to R.W.) and the MGH-Center for Systems Biology (to M.J.P.). NR 100 TC 89 Z9 92 U1 2 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2009 VL 29 IS 10 BP 1424 EP 1432 DI 10.1161/ATVBAHA.108.180521 PG 9 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 494VY UT WOS:000269848600006 PM 19372462 ER PT J AU Nahrendorf, M Waterman, P Thurber, G Groves, K Rajopadhye, M Panizzi, P Marinelli, B Aikawa, E Pittet, MJ Swirski, FK Weissleder, R AF Nahrendorf, Matthias Waterman, Peter Thurber, Greg Groves, Kevin Rajopadhye, Milind Panizzi, Peter Marinelli, Brett Aikawa, Elena Pittet, Mikael J. Swirski, Filip K. Weissleder, Ralph TI Hybrid In Vivo FMT-CT Imaging of Protease Activity in Atherosclerosis With Customized Nanosensors SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE FMT-CT; molecular imaging; atherosclerosis; protease activity; inflammation ID RAT PERITONEAL-MACROPHAGES; MATRIX METALLOPROTEINASES; PINOCYTOSED FLUID; KINETIC EVIDENCE; PLAQUE RUPTURE; CATHEPSIN-B; INFLAMMATION; MOUSE; ENDOCYTOSIS; PLASMA AB Objective-Proteases are emerging biomarkers of inflammatory diseases. In atherosclerosis, these enzymes are often secreted by inflammatory macrophages, digest the extracellular matrix of the fibrous cap, and destabilize atheromata. Protease function can be monitored with protease activatable imaging probes and quantitated in vivo by fluorescence molecular tomography (FMT). To address 2 major constraints currently associated with imaging of murine atherosclerosis (lack of highly sensitive probes and absence of anatomic information), we compared protease sensors (PS) of variable size and pharmacokinetics and coregistered FMT datasets with computed tomography (FMT-CT). Methods and Results-Coregistration of FMT and CT was achieved with a multimodal imaging cartridge containing fiducial markers detectable by both modalities. A high-resolution CT angiography protocol accurately localized fluorescence to the aortic root of atherosclerotic apoE(-/-) mice. To identify suitable sensors, we first modeled signal kinetics in-silico and then compared 3 probes with oligo-L-lysine cleavage sequences: PS-5, 5 nm in diameter containing 2 fluorochromes, PS-25, a 25-nm version with an elongated lysine chain and PS-40, a polymeric nanoparticle. Serial FMT-CT showed fastest kinetics for PS-5 but, surprisingly, highest fluorescence in lesions of the aortic root for PS-40. PS-40 robustly reported therapeutic effects of atorvastatin, corroborated by ex vivo imaging and qPCR for the model protease cathepsin B. Conclusions-FMT-CT is a robust and observer-independent tool for noninvasive assessment of inflammatory murine atherosclerosis. Reporter-containing nanomaterials may have unique advantages over small molecule agents for in vivo imaging. (Arterioscler Thromb Vasc Biol. 2009; 29: 1444-1451.) C1 [Nahrendorf, Matthias; Waterman, Peter; Thurber, Greg; Panizzi, Peter; Marinelli, Brett; Pittet, Mikael J.; Swirski, Filip K.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Syst Biol, Boston, MA 02124 USA. Harvard Univ, Sch Med, Boston, MA USA. [Nahrendorf, Matthias; Waterman, Peter; Panizzi, Peter; Aikawa, Elena; Pittet, Mikael J.; Swirski, Filip K.; Weissleder, Ralph] Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. [Groves, Kevin; Rajopadhye, Milind] VisEn Med Inc, Bedford, MA USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Ctr Syst Biol, CPZN 5206,185 Cambridge St, Boston, MA 02124 USA. EM rweissleder@mgh.harvard.edu OI Panizzi, Peter/0000-0003-0141-8807; Thurber, Greg/0000-0001-7570-2080 FU American Heart Association [0835623D]; [R24-CA92782]; [UO1-HL08073] FX This work was funded in part by R24-CA92782 and UO1-HL08073 (to R.W.) and by the American Heart Association 0835623D (to M.N.). NR 50 TC 93 Z9 93 U1 1 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2009 VL 29 IS 10 BP 1444 EP U89 DI 10.1161/ATVBAHA.109.193086 PG 16 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 494VY UT WOS:000269848600009 PM 19608968 ER PT J AU Sovershaev, MA Egorina, EM Hansen, JB Osterud, B Pacher, P Stasch, JP Evgenov, OV AF Sovershaev, Mikhail A. Egorina, Elena M. Hansen, John-Bjarne Osterud, Bjarne Pacher, Pal Stasch, Johannes-Peter Evgenov, Oleg V. TI Soluble Guanylate Cyclase Agonists Inhibit Expression and Procoagulant Activity of Tissue Factor SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE tissue factor; procoagulant activity; soluble guanylate cyclase; BAY 41-2272; BAY 58-2667 ID THP-1 MONOCYTIC CELLS; TUMOR-NECROSIS-FACTOR; FACTOR-KAPPA-B; PULMONARY-HYPERTENSION; ENDOTHELIAL-CELLS; HEART-FAILURE; NITRIC-OXIDE; CD40 LIGAND; P-SELECTIN; PLATELETS AB Objective-Tissue factor (TF), a major initiator of blood coagulation, contributes to inflammation, atherosclerosis, angiogenesis, and vascular remodeling. Pharmacological agonists of soluble guanylate cyclase (sGC) attenuate systemic and pulmonary hypertension, vascular remodeling, and platelet aggregation. However, the influence of these novel pharmacophores on TF is unknown. Methods and Results-We evaluated effects of BAY 41-2272 and BAY 58-2667 on expression and activity of TF in human monocytes and umbilical vein endothelial cells (HUVECs). Both compounds reduced expression of active TF protein in monocytes stimulated with lipopolysaccharide, as demonstrated by immunoblotting and a TF procoagulant activity assay. In-cell Western assay revealed that this effect was associated with a marked reduction of total and surface TF presentation. Furthermore, BAY 41-2272 and BAY 58-2667 decreased TF protein expression and the TF-dependent procoagulant activity in HUVECs stimulated with TNF-alpha. The sGC agonists also suppressed transcriptional activity of NF-kappa B. A siRNA-mediated knockdown of the alpha 1-subunit of sGC in monocytes and HUVECs confirmed that the inhibitory effect of BAY 41-2272 and BAY 58-2667 on TF expression is mediated through the sGC-dependent mechanisms. Conclusions-Inhibition of TF expression and activity by sGC agonists might provide therapeutic benefits in cardiovascular diseases associated with enhanced procoagulant and inflammatory response. (Arterioscler Thromb Vasc Biol. 2009;29:1578-1586.) C1 [Sovershaev, Mikhail A.; Egorina, Elena M.; Evgenov, Oleg V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA 02114 USA. [Sovershaev, Mikhail A.; Egorina, Elena M.; Osterud, Bjarne] Univ Tromso, Dept Biochem, Inst Med Biol, N-9001 Tromso, Norway. [Hansen, John-Bjarne] Univ Tromso, Ctr Atherothrombot Res, Inst Clin Med, N-9001 Tromso, Norway. [Sovershaev, Mikhail A.; Hansen, John-Bjarne] Univ Hosp No Norway, Dept Med, Tromso, Norway. [Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. [Stasch, Johannes-Peter] Bayer Schering Pharma AG, Inst Cardiovasc Res, Wuppertal, Germany. RP Evgenov, OV (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, 55 Fruit St,Gray Bigelow 444, Boston, MA 02114 USA. EM oevgenov@partners.org RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Northern Norway Regional Health Authority; NIH/NIAAA FX This work was supported in part by departmental funds, the Northern Norway Regional Health Authority ( to M. A. S. and J.B.H.), and the Intramural Research Program of NIH/NIAAA ( to P. P.). NR 39 TC 7 Z9 7 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2009 VL 29 IS 10 BP 1578 EP U446 DI 10.1161/ATVBAHA.109.192690 PG 27 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 494VY UT WOS:000269848600029 PM 19592462 ER PT J AU Deguchi, JO Yamazaki, H Aikawa, E Aikawa, M AF Deguchi, Jun-o Yamazaki, Hiroyuki Aikawa, Elena Aikawa, Masanori TI Chronic Hypoxia Activates the Akt and beta-Catenin Pathways in Human Macrophages SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE macrophages; hypoxia; inflammation; atherosclerosis; MMP ID SMOOTH-MUSCLE-CELLS; IN-VIVO; ATHEROSCLEROTIC PLAQUES; MATRIX METALLOPROTEINASE-7; COLLAGEN ACCUMULATION; INSULIN-RESISTANCE; SIGNALING PATHWAY; SURVIVAL PATHWAY; OXYGEN-TENSIONS; INFLAMMATION AB Objective-Macrophage activation contributes importantly to the pathogenesis of inflammatory diseases including atherosclerosis. Macrophages exist chronically under moderate hypoxia (2% to 5% O(2)) in inflamed tissues such as atherosclerotic plaques. However, macrophage phenotypes in such environments remain incompletely understood. This study tested the hypothesis that chronic moderate hypoxia induces macrophage activation and explored the underlying mechanisms. Methods and Results-We cultured primary human macrophages derived from peripheral blood monocytes in moderate hypoxia (2% O(2) tension) or normoxia (21% O(2)) for 10 days. Moderate hypoxia did not affect macrophage differentiation assessed via expression levels of scavenger receptor A. Chronic moderate hypoxia, but not normoxia, activated Akt and inactivated GSK-3 beta, a negative effector of Akt, thus allowing nuclear translocation of beta-catenin. 2% O(2) tension increased accumulation of hypoxia-inducible factors 1 alpha (HIF-1 alpha) transiently at 3 to 5 days. Hypoxia induced mRNA expression of the beta-catenin-associated genes: MMP-7, CD44, and c-Myc. RNAi of TCF7L2, a cofactor of beta-catenin, suppressed MMP-7 expression induced by hypoxia. Inhibition of Akt phosphorylation with LY294002 abolished hypoxia-induced GSK-3 beta inactivation, beta-catenin activation, and MMP-7 expression. Macrophages under hypoxia were more resistant for oxLDL-induced apoptosis. Moreover, phospho-Akt colocalized with MMP-7 and CD44 expression in macrophages of human atherosclerotic plaques. Conclusions-Chronic moderate hypoxia induces macrophage activation via the Akt and beta-catenin pathways, providing new insight into the pathogenesis of inflammatory diseases. (Arterioscler Thromb Vasc Biol. 2009;29:1664-1670.) C1 [Aikawa, Masanori] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Excellence Vasc Biol,Cardiovasc Div,Dept Med, Boston, MA 02115 USA. [Aikawa, Elena] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. RP Aikawa, M (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Excellence Vasc Biol,Cardiovasc Div,Dept Med, 77 Ave Louis Pasteur, Boston, MA 02115 USA. EM maikawa@rics.bwh.harvard.edu FU National Heart, Lung, and Blood Institute [HL66086]; American Heart Association; Kowa Company Ltd Tokyo, Japan; Donald W. Reynolds Foundation FX This work was supported in part by grants from the National Heart, Lung, and Blood Institute HL66086 and the American Heart Association Grant-in-Aid, an unrestricted donation from Kowa Company Ltd Tokyo, Japan ( to M. A.), and a fellowship from the Donald W. Reynolds Foundation ( to J.D.). NR 60 TC 25 Z9 25 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD OCT PY 2009 VL 29 IS 10 BP 1664 EP U628 DI 10.1161/ATVBAHA.109.194043 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 494VY UT WOS:000269848600041 PM 19644051 ER EF