FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Manco-Johnson, MJ Grabowski, EF Hellgreen, M Kemahli, AS Massicotte, MP Muntean, W Peters, M Schlegel, N Wang, M Nowak-Gottl, U AF Manco-Johnson, MJ Grabowski, EF Hellgreen, M Kemahli, AS Massicotte, MP Muntean, W Peters, M Schlegel, N Wang, M Nowak-Gottl, U TI Recommendations for tPA thrombolysis in children - On behalf of the scientific subcommittee on perinatal and pediatric thrombosis of the scientific and standardization committee of the International Society of Thrombosis and Haemostasis SO THROMBOSIS AND HAEMOSTASIS LA English DT Article ID TISSUE-PLASMINOGEN-ACTIVATOR C1 Mt States Hemophilia Ctr, Aurora, CO USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Sahlgrens Hosp E, Dept Obstet Gynecol, Gothenburg, Sweden. Ankara Univ, Dept Pediat, TR-06100 Ankara, Turkey. Univ Toronto, Div Hematol Oncol, Toronto, ON, Canada. Graz Univ, Dept Pediat, Graz, Austria. Acad Med Ctr, Dept Pediat, Amsterdam, Netherlands. Hosp Robert Debre, Lab Hematol Biol, Paris, France. RP Nowak-Gottl, U (reprint author), Univ Munster, Pediat Hosp, Albert Schweitzer Str 33, D-48149 Munster, Germany. NR 5 TC 46 Z9 47 U1 0 U2 0 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUL PY 2002 VL 88 IS 1 BP 157 EP 158 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 574BE UT WOS:000176867800028 PM 12152658 ER PT J AU Koutkia, P Mylonakis, E Levin, RM AF Koutkia, P Mylonakis, E Levin, RM TI Human immunodeficiency virus infection and the thyroid (Retracted Article. See vol 16, pg 99, 2006) SO THYROID LA English DT Review ID PNEUMOCYSTIS-CARINII INFECTION; IMMUNE-DEFICIENCY-SYNDROME; FINE-NEEDLE-ASPIRATION; OF-THE-LITERATURE; HIV-INFECTION; HYPOTHYROID PATIENT; INTERFERON-ALPHA; KAPOSIS-SARCOMA; SYNDROME AIDS; ENDOCRINE AB Abnormalities of thyroid function are associated with a number of systemic conditions, including patients infected with human immunodeficiency virus (HIV). Most patients with early HIV infection and a stable body weight have normal thyroid function. Subtle abnormalities of a number of thyroid function tests have been reported during the early asymptomatic phase of HIV disease. These include an inappropriately normal triiodothyronine (T-3) and reduced reverse triiodothyronine (rT(3)), and increased thyroxine-binding globulin (TBG) levels. Opportunistic infections involving the thyroid gland, neoplasms such as lymphoma and Kaposi's sarcoma, and medications can alter the thyroid function in individuals with more advanced HIV infection. If thyroid dysfunction is diagnosed in an HIV-infected patient, it should be treated in the usual manner. However, high index of suspicion and caution in the interpretation of thyroid function tests in patients with HIV disease are needed for optimal diagnosis and treatment. C1 Boston Univ, Med Ctr, Dept Med, Sect Endocrinol Diabet & Nutr, Boston, MA 02118 USA. Harvard Univ, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02115 USA. RP Levin, RM (reprint author), Boston Univ, Med Ctr, Dept Med, Sect Endocrinol Diabet & Nutr, Dowling 5 N 818 Harrison Ave, Boston, MA 02118 USA. EM elconnol@bmc.org NR 54 TC 9 Z9 9 U1 4 U2 8 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 EI 1557-9077 J9 THYROID JI Thyroid PD JUL PY 2002 VL 12 IS 7 BP 577 EP 582 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 578YR UT WOS:000177149100007 PM 12193301 ER PT J AU Hauser, D Gayowski, T Singh, N AF Hauser, D Gayowski, T Singh, N TI Bleeding complications precipitated by unrecognized Gingko biloba use after liver transplantation SO TRANSPLANT INTERNATIONAL LA English DT Article DE alternative therapies; transplants; herbal products ID ST-JOHNS-WORT; GINKGO-BILOBA; HYPERICUM-PERFORATUM; DRUG-INTERACTION; CYCLOSPORINE; EXTRACT; INGESTION; MEDICINE; HERBS AB Because of its neurocognitive enhancing effects, Gingko biloba has emerged as amongst the most commonly used herbal products. We report a liver transplant recipient with potentially life-threatening toxicity resulting from Gingko biloba use. Seven days after a second liver transplantation for recurrent hepatitisB virus infection, subphrenic hematoma was documented in a 59-year-old Korean patient. Failure to control bleeding with CT-guided drainage necessitated exploratory laparotomy for the evacuation of a large subphrenic hematoma. Three weeks later, an episode of vitreous hemorrhage was documented. Unbeknownst to his care providers, the patient had been consuming Gingko biloba throughout the postoperative period. No further bleeding episodes occurred after the cessation of Gingko biloba use. Unrecognized use of herbal products may be associated with serious side effects and adverse clinical sequelae in transplant recipients. Given their increasing popularity, the use of herbal products should be routinely sought as part of the history in transplant recipients. C1 VA Pittsburgh Healthcare Syst, Infect Dis Sect, Pittsburgh, PA 15240 USA. Thomas E Starzl Transplantat Inst, Pittsburgh, PA USA. RP Singh, N (reprint author), VA Pittsburgh Healthcare Syst, Infect Dis Sect, Univ Dr C, Pittsburgh, PA 15240 USA. NR 22 TC 20 Z9 20 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0934-0874 J9 TRANSPLANT INT JI Transpl. Int. PD JUL PY 2002 VL 15 IS 7 BP 377 EP 379 DI 10.1007/s00147-002-0432-y PG 3 WC Surgery; Transplantation SC Surgery; Transplantation GA 582VA UT WOS:000177370800009 PM 12122516 ER PT J AU Kyewski, B Derbinski, J Gotter, J Klein, L AF Kyewski, B Derbinski, J Gotter, J Klein, L TI Promiscuous gene expression and central T-cell tolerance: more than meets the eye SO TRENDS IN IMMUNOLOGY LA English DT Article ID THYMIC EPITHELIAL-CELLS; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; SELF-ANTIGEN; INTRATHYMIC EXPRESSION; MEDULLARY EPITHELIUM; MYASTHENIA-GRAVIS; IMMUNE-RESPONSES; STROMAL CELLS; TRANSCRIPTION; SELECTION AB Self-tolerance of the T-cell repertoire is mediated by multiple mechanisms operating both in the thymus ('central tolerance') and in peripheral lymphoid and non-lymphoid organs ('peripheral tolerance'). Based on the recent finding that tissue-specific genes are commonly expressed in the thymus, this strict delineation has been blurred. Medullary thymic epithelial cells have been identified as a unique cell type that expresses a wide range of tissue-specific genes in a 'promiscuous' manner and displays these self-antigens for intrathymic repertoire selection. The array of promiscuously expressed genes appears random rather than the result of specific selection. The gains and pitfalls of this tolerance mechanism have important implications for autoimmunity. C1 German Canc Res Ctr, Tumor Immunol Program, Div Cellular Immunol, D-69120 Heidelberg, Germany. Dana Farber Canc Inst, Dept Canc & AIDS, Boston, MA 02115 USA. RP Kyewski, B (reprint author), German Canc Res Ctr, Tumor Immunol Program, Div Cellular Immunol, INF 280, D-69120 Heidelberg, Germany. RI Klein, Ludger/G-8785-2011 NR 62 TC 148 Z9 154 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD JUL PY 2002 VL 23 IS 7 BP 364 EP 371 AR PII S1471-4906(02)02248-2 DI 10.1016/S1471-4906(02)02248-2 PG 8 WC Immunology SC Immunology GA 571CJ UT WOS:000176697000011 PM 12103357 ER PT J AU Stadler, WM Hayden, A von der Maase, H Roychowdhury, D Dogliotti, L Seymour, L Kaufmann, D Moore, M AF Stadler, WM Hayden, A von der Maase, H Roychowdhury, D Dogliotti, L Seymour, L Kaufmann, D Moore, M TI Long-term survival in phase II trials of gemcitabine plus cisplatin for advanced transitional cell cancer SO UROLOGIC ONCOLOGY LA English DT Article DE transitional cell carcinoma; bladder neoplasms; combination drug therapy; treatment outcome prognosis ID METASTATIC UROTHELIAL CANCER; BLADDER-CANCER; CARCINOMA; METHOTREXATE; VINBLASTINE; DOXORUBICIN; CHEMOTHERAPY; COMBINATION; THERAPY AB Purpose: To assess long-term survival and prognostic indicators of survival in patients with advanced urothelial cancer treated with gemcitabine and cisplatin. Materials and methods: Survival data from three previously published phase 11 trials of gemcitabine/cisplatin were updated. Baseline hemoglobin. performance status, and presence of visceral metastases, which are known prognostic factors with other regimens, were examined. Survival curves were constructed by the Kaplan-Meier method and significance assessed using the log-rank statistic. Cox's Proportional Hazards Model was used to construct univariate and multivariate survival models. Results and conclusions: Overall median survival of 121 included patients was 13.2 (11.0 to 14.9) months and estimated 4 year Survival was 13 +/- 6%. In a univariate analysis. the presence of visceral metastases and a hemoglobin <12.5 mg/dl had significant adverse prognostic implications (P<0.001 and P=0.02, respectively). Performance status was not a significant predictor of survival, perhaps due to the fact that only 14% of patients had a performance status of 2. In a multivariate analysis, only the absence of visceral metastases retained its prognostic importance with all estimated 24% 4-year Survival ill Such patients. These results lend further evidence for the clinical benefit of this regimen in advanced transitional cell cancer. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Chicago, Dept Med, Chicago, IL 60637 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. Univ Turin, San Luigi Hosp, Turin, Italy. Massachusetts Gen Hosp, Boston, MA 02114 USA. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Natl Canc Inst Canada Clin Trials Grp, Kingston, ON, Canada. RP Stadler, WM (reprint author), Univ Chicago, Dept Med, 5841 S Maryland MC2115, Chicago, IL 60637 USA. NR 17 TC 36 Z9 36 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL JI Urol. Oncol. PD JUL-AUG PY 2002 VL 7 IS 4 BP 153 EP 157 DI 10.1016/S1078-1439(02)00182-5 PG 5 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 577GF UT WOS:000177052600005 PM 12474531 ER PT J AU Shipley, WU Kaufman, DS Zehr, E Heney, NM Lane, SC Thakral, HK Althausen, AF Zietman, AL AF Shipley, WU Kaufman, DS Zehr, E Heney, NM Lane, SC Thakral, HK Althausen, AF Zietman, AL TI Selective bladder preservation by combined modality protocol treatment: Long-term outcomes of 190 patients with invasive bladder cancer SO UROLOGY LA English DT Article ID TRANSITIONAL-CELL CARCINOMA; PHASE-II TRIAL; TRANSURETHRAL RESECTION; RADICAL CYSTECTOMY; COMBINED RADIATION; FOLLOW-UP; CHEMOTHERAPY; CISPLATIN; THERAPY; RADIOTHERAPY AB Objectives. To evaluate the outcomes of patients with muscle-invasive Stage T2-4a bladder carcinoma managed by transurethral surgery and concurrent chemoradiation. Methods. A total of 190 patients were treated on institutional prospective protocols using concurrent cisplatin-containing chemotherapy and radiotherapy after rigorous transurethral resection of the bladder tumor. Patients were re-evaluated by repeated biopsy and urine cytologic analysis after 40 Gy, with the initial tumor response guiding subsequent therapy. One hundred twenty-one patients with a complete response by cytologic and histologic examination and those medically unfit for cystectomy received boost chemoradiation to 64 to 65 Gy. Those patients without a complete response were advised to undergo radical cystectomy. A total of 66 patients (35%) ultimately underwent radical cystectomy; 41 for less than a complete response and an additional 25 for recurrent invasive tumors. The median follow-up was 6.7 years for all surviving patients. Results. The 5 and 10-year actuarial overall survival rate was 54% and 36%, respectively (Stage T2, 62% and 41%; Stage T3-T4a, 47% and 31%, respectively). The 5 and 10-year disease-specific survival rate was 63% and 59% (Stage T2, 74% and 66%; Stage T3-T4a, 53% and 52%), respectively. The 5 and 10-year disease-specific survival rate for patients with an intact bladder was 46% and 45% (Stage T2, 57% and 50%; Stage T3-T4a, 35% and 34%), respectively. The pelvic failure rate was 8.4%. No patient required cystectomy because of bladder morbidity. Conclusions. The 10-year overall survival and disease-specific survival rates are comparable with the results reported for contemporary radical cystectomy for patients of similar clinical and pathologic stage. One third of patients treated on protocol with the goal of bladder sparing ultimately required a cystectomy. A trimodality approach with bladder preservation based on the initial tumor response is, therefore, safe, with most long-term survivors retaining functional bladders. (C) 2002, Elsevier Science Inc. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Urol, Boston, MA 02114 USA. RP Shipley, WU (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. NR 32 TC 196 Z9 208 U1 1 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 JUL PY 2002 VL 60 IS 1 BP 62 EP 67 AR PII S0090-4295(02)01650-3 DI 10.1016/S0090-4295(02)01650-3 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 570TR UT WOS:000176674600012 PM 12100923 ER PT J AU Freedland, SJ Csathy, GS Dorey, F Aronson, WJ AF Freedland, SJ Csathy, GS Dorey, F Aronson, WJ TI Clinical utility of percent prostate needle biopsy tissue with cancer cutpoints to risk stratify patients before radical prostatectomy SO UROLOGY LA English DT Article ID PERINEURAL INVASION; MULTIVARIATE-ANALYSIS; RADIATION-THERAPY; JAPANESE MEN; ANTIGEN; RECURRENCE; COMBINATION; PREDICTION; EXTENSION; RELAPSE AB Objectives. The percentage of total prostate needle biopsy tissue with cancer was previously found to be a stronger predictor of biochemical failure after radical prostatectomy (RIP) than either biopsy Gleason score or serum prostate-specific antigen (PSA). To improve our ability to predict preoperatively the risk of biochemical recurrence after RP, we sought to determine the cutpoints of the percentage of biopsy tissue with cancer to separate patients into low, intermediate, or high-risk groups. We then examined whether we could further stratify low, intermediate, and high-risk groups (on the basis of the PSA level and biopsy Gleason score) using the percentage of prostate needle biopsy tissue with cancer. Methods. A single pathologist reviewed the prostate needle biopsy specimens of 2 17 men who underwent RP between 1991 and 200 1. Biopsy specimens were examined for Gleason score and the percentage of total biopsy tissue with cancer. Cutpoints were identified to define patients with differing risk of biochemical recurrence after RP. These cutpoints were applied to low, intermediate, and high-risk patients, on the basis of PSA and biopsy Gleason score, to determine whether preoperative risk stratification could be improved. Results. Using the cutpoints for the percentage of prostate needle biopsy tissue with cancer of less than 20% (low risk), 20% to less than 55% (intermediate risk), and 55% or greater (high risk), patients were separated into three groups with differing risks of biochemical failure after RIP (hazard ratio 1.95, 95% confidence interval 1.37 to 2.77, P<0.001). These cutpoints further stratified patients with an intermediate (P = 0.002) or high risk (P = 0.05) of biochemical failure (on the basis of the PSA and biopsy Gleason score). However, these cutpoints provided no improvement in risk stratification for patients who were at low risk (P = 0.501) of biochemical failure (on the basis of PSA and biopsy Gleason score). Conclusions. The percentage of total prostate needle biopsy tissue with cancer can be used to stratify patients into low, intermediate, and high-risk groups preoperatively for biochemical recurrence after RIP. These cutpoints could further stratify patients preoperatively who were at intermediate or high risk of biochemical failure on the basis of PSA and biopsy Gleason score. (C) 2002, Elsevier Science Inc. C1 Univ Calif Los Angeles, Dept Urol, Sch Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90024 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Dept Pathol, Los Angeles, CA USA. Vet Affairs Greater Los Angeles Healthcare Syst, Dept Surg, Los Angeles, CA USA. RP Aronson, WJ (reprint author), Univ Calif Los Angeles, Dept Urol, Sch Med, Box 951738, Los Angeles, CA 90095 USA. NR 18 TC 12 Z9 13 U1 0 U2 0 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 JUL PY 2002 VL 60 IS 1 BP 84 EP 88 AR PII S0090-4295(02)01660-6 DI 10.1016/S0090-4295(02)01660-6 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 570TR UT WOS:000176674600018 PM 12100929 ER PT J AU Berger, DH AF Berger, DH TI Plasmin/plasminogen system in colorectal cancer SO WORLD JOURNAL OF SURGERY LA English DT Article ID UROKINASE PLASMINOGEN-ACTIVATOR; HEPATOCYTE GROWTH-FACTOR; TUMOR-CELL INVASION; INHIBITOR TYPE-1; HUMAN-COLON; LIGAND INTERACTION; PANCREATIC-CANCER; SIGNALING PATHWAY; GENE-EXPRESSION; STROMAL CELLS AB Pericellular proteolysis plays a crucial role in tumor cell invasion. The controlled degradation of the extracellular matrix by tumor cell-associated proteases allows tumor cells to invade surrounding tissues and gain access to the circulation. One of the main protease systems involved in tumor cell invasion and metastasis is the plasminogen/plasmin system (PPS). The components of the PPS include the urokinase plasminogen activator (uPA), its cell surface receptor urokinase plasminogen activator receptor (uPAR), and its naturally occurring inhibitors, plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2). Increases in tumor and serum levels of uPA, uPAR, and PAI-1 are associated with a worse prognosis in patients with colon cancer. Use of these proteins as either tumor or serum markers may allow more accurate determination of the prognosis in colon cancer patients. Furthermore, these proteins appear to be attractive as targets for the biologic therapy of colon cancer. C1 Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. Houston Vet Affairs Med Ctr, Surg Serv 112, OCL, Houston, TX 77030 USA. RP Berger, DH (reprint author), Baylor Coll Med, Michael E DeBakey Dept Surg, 1 Baylor Plaza, Houston, TX 77030 USA. NR 58 TC 87 Z9 96 U1 0 U2 3 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD JUL PY 2002 VL 26 IS 7 BP 767 EP 771 DI 10.1007/s00268-002-4050-8 PG 5 WC Surgery SC Surgery GA 570TF UT WOS:000176673300003 PM 11965442 ER PT J AU Guo, SS Wu, AY Sawicki, MP AF Guo, SS Wu, AY Sawicki, MP TI Deletion of chromosome 1, but not mutation of MEN-1, predicts prognosis in sporadic pancreatic endocrine tumors SO WORLD JOURNAL OF SURGERY LA English DT Article ID NEOPLASIA TYPE-1 GENE; SUPPRESSOR GENE; NEUROENDOCRINE TUMORS; SOMATIC MUTATIONS; GASTRINOMAS AB Pancreatic endocrine tumors (PETs) may be sporadic or inherited in the multiple endocrine neoplasia type 1 (MEN-1) syndrome. The inherited form is caused by mutations of the MEN-1 gene, which functions as a tumor suppressor gene and maps to chromosome 11q13. These tumors tend to have a better prognosis than their sporadic counterparts, which often have mutations of the MEN-1 gene. Previous molecular analyses of sporadic PETs suggest a high frequency of loss of heterozygosity (LOH) at chromosome I as well as mutation of MEN-1. In this study we correlate abnormalities of MEN-1 and chromosome 1 LOH with the biological behavior of sporadic PETs. Loss of heterozygosity for markers at chromosome 11q13 and mutation of MEN-1 were equally frequent in tumors with or without liver metastases. Mutation of MEN-1 is more frequent in gastrinomas than in non-gastrinomas. Loss of heterozygosity for markers on chromosome I is more frequent in PETs with liver metastases. These results suggest a molecular tumor model in which there is a dichotomy in the development of benign and malignant PETs. C1 W Los Angeles Vet Affairs Med Ctr, Dept Surg, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90073 USA. RP Sawicki, MP (reprint author), W Los Angeles Vet Affairs Med Ctr, Dept Surg, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 20 TC 19 Z9 19 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2313 J9 WORLD J SURG JI World J.Surg. PD JUL PY 2002 VL 26 IS 7 BP 843 EP 847 DI 10.1007/s00268-002-4062-4 PG 5 WC Surgery SC Surgery GA 570TF UT WOS:000176673300015 PM 11960210 ER PT J AU Tsou, R Fathke, C Wilson, L Wallace, K Gibran, N Isik, F AF Tsou, R Fathke, C Wilson, L Wallace, K Gibran, N Isik, F TI Retroviral delivery of dominant-negative vascular endothelial growth factor receptor type 2 to murine wounds inhibits wound angiogenesis SO WOUND REPAIR AND REGENERATION LA English DT Article ID PROLYL HYDROXYLATION; FIBROBLAST RESPONSE; GRANULATION-TISSUE; PROGENITOR CELLS; TYROSINE KINASE; TRANSGENIC MICE; EXPRESSION; REPAIR; APOPTOSIS; HYPOXIA AB Vascular endothelial growth factor (VEGF) is a potent paracrine signal for initiating angiogenesis. Although VEGF can bind to several cell surface receptors, VEGF receptor type 2 (VEGFR2, a.k.a. KDR or flk-1 ) is the primary receptor responsible for VEGF-induced endothelial cell proliferation. To determine whether the VEGF-VEGFR2 signaling axis has an important role in wound healing angiogenesis, we used a retrovirus to deliver a signaling-defective truncated VEGFR2 (tm VEGFR2) to block VEGF-VEGFR2-induced endothelial cell proliferation in murine wounds. We show that the retroviral construct effectively blocked phosphorylation of VEGFR2 in vitro and we were able to express the truncated receptor in murine wounds. We achieved significant reduction of angiogenesis and granulation tissue formation in murine wounds, but this did not lead to delayed wound closure. In contrast, there was a corresponding increase in wound contraction, showing that functional VEGFR2 intracellular signaling is not critical for normal closure of excisional dermal wounds. Our results show a novel relationship between wound bed vascularity and wound contraction. C1 Univ Washington, Med Ctr, Div Plast Surg, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Dept Surg, Seattle, WA USA. RP Isik, F (reprint author), Univ Washington, Med Ctr, Div Plast Surg, Box 356410,1959 NE Pacific St, Seattle, WA 98195 USA. FU NIGMS NIH HHS [R01-GM57426] NR 57 TC 24 Z9 24 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD JUL-AUG PY 2002 VL 10 IS 4 BP 222 EP 229 DI 10.1046/j.1524-475X.2002.10405.x PG 8 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 585UX UT WOS:000177543900005 PM 12191004 ER PT J AU Theodore, PR Simon, AR Warrens, AN Sackstein, R Sykes, M AF Theodore, PR Simon, AR Warrens, AN Sackstein, R Sykes, M TI Porcine mononuclear cells adhere to human fibronectin independently of very late antigen-5: implications for donor-specific tolerance induction in xenotransplantation SO XENOTRANSPLANTATION LA English DT Article DE adhesion molecules; bone marrow; fibronectin; human; integrins; swine; very late antigen-5; very late antigen-4; xenotransplantation ID HEMATOPOIETIC PROGENITOR CELLS; NONLETHAL PREPARATIVE REGIMEN; BONE-MARROW TRANSPLANTATION; CLASS II+ CELLS; MIXED CHIMERISM; ALPHA(5)BETA(1) INTEGRINS; NONMYELOABLATIVE REGIMEN; ADHESION MOLECULE-1; ALPHA-4 INTEGRINS; VLA4 INTEGRIN AB To combat the shortage of donor organs, transplantation across species barriers has been proposed. Induction of tolerance would overcome the substantial immunologic barriers to xenotransplantation and would avoid the chronic use of immunosuppressive agents. Successful transplantation of hematopoietic cells induces robust specific tolerance to donor antigens in allogeneic and xenogeneic models. The beta(1) integrin class of adhesion molecules and their interactions with extracellular matrix components are thought to be integral to the engraftment and maturation of hematopoietic stem cells. We therefore examined the efficacy of porcine very late antigen-5 (VLA-5) and VLA-4 interactions with the human extracellular matrix (ECM) protein, fibronectin. Peripheral blood mononuclear cells (PBMCs) from humans and miniature swine were flourochrome labeled and adhesion to plates coated with whole human fibronectin (whFN) or its 120 KDa fragment containing the VLA-5 binding region was determined. Flow cytometry and immunoprecipitation were used to identify a monoclonal antibody that cross-reacted on porcine VLA-5. Human and pig PBMC adhesion to human fibronectin (hFN) or 120 kDa fragment-coated plates was assessed following incubation with control ab, anti-VLA-4, anti-VLA-5, or soluble fibronectin. Using rabbit complement, cells expressing VLA-5 were purged from PBMC preparations before performing the adhesion assay. Porcine and human PBMC both adhered to hFN in a divalent cation-dependent and activation-dependent manner. Adhesion to hFN of human but not pig PBMC was blocked by anti-VLA-5 monoclonal antibody SAM-1, although this mAb immunoprecipitated a heterodimeric cell surface molecule (155/135 kDa) resembling VLA-5 from pig PBMC. Complement-mediated depletion of VLA-5-expressing cells ablated specific binding of human but not porcine cells to hFN and its 120 kDa fragment. Addition of soluble fibronectin was capable of blocking adhesion of PBMC of both species to hFN. Anti-VLA-4 reduced the binding of PBMC from both species to hFN to a similar extent. Human and pig cells can specifically adhere to hFN and its 120 kDa fragment, suggesting that this critical cell-ECM interaction is preserved across species. While human cells exclusively use VLA-5 for binding to the 120 kDa fragment, porcine cells could not be shown to adhere to whFN or its 120 kDa fragment via VLA-5. However, porcine VLA-4 is capable of mediating adhesion to human FN. We conclude that disparities in the adhesive interactions of beta(1) integrins may be a barrier to the use of porcine hematopoietic stem cell transplantation as a means of inducing donor-specific tolerance in the pig to human species combination. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr,Surg Serv, Boston, MA 02129 USA. RP Sykes, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr,Surg Serv, MGH E,Bldg 149-5102,13th St, Boston, MA 02129 USA. FU NHLBI NIH HHS [HL46532, HL254038] NR 61 TC 7 Z9 7 U1 0 U2 3 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD JUL PY 2002 VL 9 IS 4 BP 277 EP 289 DI 10.1034/j.1399-3089.2002.01086.x PG 13 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 565KG UT WOS:000176368500006 PM 12060464 ER PT J AU Gojo, S Harper, D Down, J Awwad, M Cooper, DKC AF Gojo, S Harper, D Down, J Awwad, M Cooper, DKC TI Differential expression of Gal alpha 1,3Gal epitopes on fetal and adult porcine hematopoietic cells SO XENOTRANSPLANTATION LA English DT Article DE bone marrow; c-kit; fetus; Gal alpha 1-3Gal epitopes; hematopoietic cells; pig ID BONE-MARROW ENGRAFTMENT; ANTIBODIES; MOBILIZATION; PIGS AB Galalpha1-3Gal (Gal) is the major epitope on pig tissues bound by human natural antibodies. Xenogeneic hematopoietic cell transplantation is being investigated to induce immunological tolerance to xenografts. We have investigated the level of Gal expression on pig hematopoietic cells. Cells were collected from pig fetal liver and bone marrow (BM), and also from adult BM and peripheral blood, before and after treatment with pig-specific hematopoietic growth factors. Fluorescent activated cell sorting (FACS) analysis was performed with the M86 monoclonal antibody (specific for Gal), lineage markers, and biotinylated stem cell factor (SCF) to detect c-kit expression. In fetal pig BM and liver, there was no significant difference in Gal expression between monocytes/macrophages (myeloid cells) and lymphocytes. In adult hematopoietic cells from all sources, Gal-positive subpopulations in T cells showed weak expression of Gal, whereas B cells demonstrated higher expression, and myeloid cells showed highest expression. Adult BM and mobilized peripheral blood progenitor cells contained small populations with very low or negligible expression of Gal. A very small population of c-kit-positive cells, indicating progenitor cells, were Gal-negative. The small Gal-negative population that exists in progenitor cells might explain why some pig colony forming units (CFU) can be resistant to human serum. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Biotransplant Inc, Charlestown, MA USA. RP Cooper, DKC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, MGH E,Bldg 149-9019,13th St, Boston, MA 02129 USA. NR 9 TC 8 Z9 8 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD JUL PY 2002 VL 9 IS 4 BP 297 EP 300 DI 10.1034/j.1399-3089.2002.01048.x PG 4 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 565KG UT WOS:000176368500008 PM 12060466 ER PT J AU Hahn, WC AF Hahn, WC TI Immortalization and transformation of human cells SO MOLECULES AND CELLS LA English DT Review DE hTERT; human cell transformation; immortalization; oncogenes; telomerase; tumor suppressor genes ID MAMMARY EPITHELIAL-CELLS; HUMAN-DIPLOID FIBROBLASTS; REPLICATIVE LIFE-SPAN; HUMAN TUMOR-CELLS; TELOMERASE ACTIVITY; HUMAN CANCER; CELLULAR SENESCENCE; CATALYTIC SUBUNIT; INK4A LOCUS; EMBRYO FIBROBLASTS AB The disruption of homeostatic mechanisms that regulate normal cell growth and proliferation is a hallmark of cancer. Experimentally, many of the same genetic changes that lead to abnormal cell proliferation conspire to confer replicative immortality upon cells in culture. Correspondingly, several lines of evidence implicate cellular immortalization as a prerequisite for cell transformation. Recently much progress has been made in elucidating the cellular machinery that regulates cell lifespan. This review summarizes,these recent advances in our understanding of these molecular mechanisms that contribute to human cell immortalization and transformation. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Hahn, WC (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [K01 CA94223] NR 108 TC 43 Z9 46 U1 1 U2 2 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1016-8478 J9 MOL CELLS JI Mol. Cells PD JUN 30 PY 2002 VL 13 IS 3 BP 351 EP 361 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 568RT UT WOS:000176557400001 PM 12132573 ER PT J AU Zhou, L Burnett, AL Huang, PL Becker, LC Kuppusamy, P Kass, DA Donahue, JK Proud, D Sham, JSK Dawson, TM Xu, KY AF Zhou, L Burnett, AL Huang, PL Becker, LC Kuppusamy, P Kass, DA Donahue, JK Proud, D Sham, JSK Dawson, TM Xu, KY TI Lack of nitric oxide synthase depresses ion transporting enzyme function in cardiac muscle SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE (Na+ + K+)-ATPase; Ca2+-ATPase; nitric oxide; NOS knockout mice; membrane ion active transport ID CALCIUM-RELEASE CHANNEL; ATP BINDING-SITE; SARCOPLASMIC-RETICULUM; SKELETAL-MUSCLE; MYOCARDIAL-ISCHEMIA; RYANODINE RECEPTOR; REPERFUSION; INJURY; SODIUM; ATTACK AB Nitric oxide (NO.) is produced endogenously from NOS isoforms bound to sarcolemmal (SL) and sarcoplasmic reticulum (SR) membranes. To investigate whether locally generated NO' directly affects the activity of enzymes mediating ion active transport, we studied whether knockout of selected NOS isoforms would affect the functions of cardiac SL (Na+ + K+)-ATPase and SR Ca2+- ATPase. Cardiac SL and SR vesicles containing either SL (Na+ + K+)-ATPase or SR Ca2+-ATPase were isolated from mice lacking either nNOS or eNOS, or both, and tested for enzyme activities. Western blot analysis revealed that absence of single or double NOS isoforms did not interrupt the protein expression of SL (Na+ + K+)-ATPase and SR Ca2+-ATPase in cardiac muscle cells. However, lack of NOS isoforms in cardiac muscle significantly altered both (Na+ + K+)-ATPase activity and SR Ca2+-ATPase function. Our experimental results suggest that disrupted endogenous NO. production may change local redox conditions and lead to an unbalanced free radical homeostasis in cardiac muscle cells which, in turn, may affect key enzyme activities and membrane ion active transport systems in the heart. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Div Publ & Crit Care Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Neurosci Inst Cell Engn, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Urol, Baltimore, MD 21205 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Univ Calgary, Resp Res Grp, Calgary, AB T2N 4N1, Canada. RP Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. EM kxu@jhmi.edu FU NHLBI NIH HHS [HL33360, HL52175]; NIDDK NIH HHS [DK02568]; NINDS NIH HHS [NS37090] NR 28 TC 31 Z9 31 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD JUN 28 PY 2002 VL 294 IS 5 BP 1030 EP 1035 AR PII S0006-291X(02)00599-5 DI 10.1016/S0006-291X(02)00599-5 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 568PJ UT WOS:000176550900017 PM 12074580 ER PT J AU Zhu, CM Mills, KD Ferguson, DO Lee, C Manins, J Fleming, J Gao, YJ Morton, CC Alt, FW AF Zhu, CM Mills, KD Ferguson, DO Lee, C Manins, J Fleming, J Gao, YJ Morton, CC Alt, FW TI Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations SO CELL LA English DT Article ID DIHYDROFOLATE-REDUCTASE GENE; WILD-TYPE P53; V(D)J RECOMBINATION; FRAGILE SITES; EMBRYONIC LETHALITY; CHROMOSOME BREAKAGE; MAMMALIAN-CELLS; HAMSTER CELLS; LIGASE-IV; REPAIR AB Amplification of large genomic regions associated with complex translocations (complicons) is a basis for tumor progression and drug resistance. We show that pro-B lymphomas in mice deficient for both p53 and nonhomologous end-joining (NHEJ) contain complicons that coamplify c-myc (chromosome 15) and IgH (chromosome 12) sequences. While all carry a translocated (12;15) chromosome, coamplified sequences are located within a separate complicon that often involves a third chromosome. Complicon formation is initiated by recombination of RAGI1/2-catalyzed IgH locus double-strand breaks with sequences downstream of c-myc, generating a dicentric (15;12) chromosome as an amplification intermediate. This recombination event employs a microhomology-based end-joining repair pathway, as opposed to classic NHEJ or homologous recombination. These findings suggest a general model for oncogenic complicon formation. C1 Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. RP Alt, FW (reprint author), Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. RI Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 FU NCI NIH HHS [CA92625]; NHLBI NIH HHS [K08 HL67580-02]; NIAID NIH HHS [AI35714] NR 60 TC 295 Z9 303 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 28 PY 2002 VL 109 IS 7 BP 811 EP 821 DI 10.1016/S0092-8674(02)00770-5 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 570KJ UT WOS:000176657200005 PM 12110179 ER PT J AU Kuppuswamy, D AF Kuppuswamy, D TI Importance of integrin signaling in myocyte growth and survival SO CIRCULATION RESEARCH LA English DT Editorial Material DE cardiomyocyte; integrins; focal adhesion kinase; hypertrophy; apoptosis ID FOCAL ADHESION KINASE; HYPERTROPHY; ACTIVATION C1 Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, Charleston, SC 29425 USA. Med Univ S Carolina, Div Cardiol, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC USA. RP Kuppuswamy, D (reprint author), Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, 114 Doughty St, Charleston, SC 29425 USA. NR 13 TC 18 Z9 22 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUN 28 PY 2002 VL 90 IS 12 BP 1240 EP 1242 DI 10.1161/01.RES.0000025080.78636.23 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 570XR UT WOS:000176686200003 PM 12089060 ER PT J AU Koipally, J Georgopoulos, K AF Koipally, J Georgopoulos, K TI Ikaros-CtIP interactions do not require C-terminal binding protein and participate in a deacetylase-independent mode of repression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTIONAL REPRESSION; HISTONE DEACETYLASE; TUMOR-SUPPRESSOR; DNA-DAMAGE; BRCA1; GENE; CTBP; COREPRESSOR; COMPLEXES; MECHANISM AB Ikaros and Aiolos are Kruppel zinc finger proteins that play key roles in hemo-lymphoid development and homeostasis. We have previously shown that they can repress transcription through the recruitment of histone deacetylases (HDACs). Here, we provide the first functional evidence that these proteins can also repress gene function in a manner that does not require deacetylase activity. This functionality can be attributed in part to Ikaros interactions with the HDAC-independent corepressor, C-terminal binding protein (CtBP). However, mutations that block Ikaros-CtBP interactions do not abolish Ikaros's repression activity, implicating the involvement of additional corepressors. Consistent with this expectation, we show that Ikaros can interact with a CtBP-interacting protein (CUP), which has also been linked to a deacetylase-independent strategy of repression. Despite being a CtBP interactor, CUP's association with Ikaros does not require CtBP but instead relies upon its Rb interaction domain. Significantly, Ikaros can interact with Rb, which itself can repress gene function in a deacetylase-independent manner. A mutation in Ikaros that abrogates CUP interactions significantly reduces repression, and a double mutation that prevents interaction with both CtIP and CtBP even further alleviates repression. Finally, we show that CtIP and CtBP can interact with the general transcription factors, TATA binding protein and transcription factor IIB, which suggests a possible mechanism for their deacetylase-independent mode of repression. C1 Massachusetts Gen Hosp East, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Med Sch, Charlestown, MA 02129 USA. RP Georgopoulos, K (reprint author), Massachusetts Gen Hosp East, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NIAID NIH HHS [R01-AI380342] NR 42 TC 46 Z9 48 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 28 PY 2002 VL 277 IS 26 BP 23143 EP 23149 DI 10.1074/jbc.M202079200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567FX UT WOS:000176475700008 PM 11959865 ER PT J AU Re, F Strominger, JL AF Re, F Strominger, JL TI Monomeric recombinant MD-2 binds Toll-like receptor 4 tightly and confers lipopolysaccharide responsiveness SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INNATE IMMUNITY; RECOGNITION; EXPRESSION; CLEARANCE; ENDOTOXIN; PROTEINS; MOLECULE; CELLS; CD14; TLR4 AB In order to mediate cellular response to lipopolysaccharide (LPS), Toll-like receptor (TLR) 4 must interact with MD-2, a secreted protein. In this study, a biochemical assay was developed to demonstrate that recombinant MD-2 can interact with the extracellular portion of TLR4 in solution. The ability of MD-2 to multimerize was confirmed, and MD-1 was also shown to possess this ability. Through site-directed mutagenesis, more than two intermolecular disulfide bonds were found to stabilize the MD-2 multimer. MD-2's abilities to confer LPS responsiveness and to bind TLR4 were strongly associated functions. Remarkably, although the majority of recombinant MD-2 exists in multimeric form, monomeric MD-2 was found to preferentially bind TLR4 and to confer LPS responsiveness more efficiently than MD-2 multimers. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Re, F (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,Dana 1414, Boston, MA 02115 USA. FU NCI NIH HHS [5R35-CA47554]; NIAID NIH HHS [N01-AI45198] NR 17 TC 87 Z9 90 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 28 PY 2002 VL 277 IS 26 BP 23427 EP 23432 DI 10.1074/jbc.M202554200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567FX UT WOS:000176475700044 PM 11976338 ER PT J AU David, G Neptune, MA DePinho, RA AF David, G Neptune, MA DePinho, RA TI SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; REPRESS TRANSCRIPTION; PROTEIN; COMPLEX; P53; GROWTH; CANCER; DIFFERENTIATION; CONJUGATION; ACTIVATION AB Histone deacetylation plays a central role in the regulation of genes linked to virtually all biological processes. This modification reaction is dependent on a family of related histone deacetylases (HDACs), which function as key components of large multiprotein complexes involved in the development of normal and neoplastic cells. The mechanisms regulating HDACs and their roles in such processes are not understood, and these form the major focus for the current study. Here, in the course of assessing possible post-translational modifications of HDAC1, we demonstrated that HDAC1 is a substrate for SUMO-1 (small ubiquitin-related modifier) modification in vitro and in vivo. The HDAC1 lysines targeted for modification were identified as C-terminal Lys-444 and Lys-476, which are also present in mammalian HDAC2 and lower vertebrate HDAC1/2 orthologs yet absent from other HDAC family members, pointing to a means of differential regulation among HDAC proteins. Mutation of these target residues (lysine to arginine substitution) profoundly reduced HDAC1-mediated transcriptional repression in reporter assays without affecting HDAC1 ability to associate with mSin3A and eliminated HDAC1-induced cell cycle and apoptotic responses upon overexpression. Together, the results demonstrate that HDAC1 is modified by SUMO-1, and this modification can dramatically affect HDAC1 activity in a number of surrogate biological assays. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St,M413, Boston, MA 02115 USA. OI , gregory/0000-0002-3371-4558 FU NCI NIH HHS [R01CA86379] NR 36 TC 154 Z9 160 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 28 PY 2002 VL 277 IS 26 BP 23658 EP 23663 DI 10.1074/jbc.M203690200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567FX UT WOS:000176475700073 PM 11960997 ER PT J AU Di Simone, N Schneyer, AL Caliandro, D Castellani, R Caruso, A AF Di Simone, N Schneyer, AL Caliandro, D Castellani, R Caruso, A TI Regulation of endometrial adenocarcinoma cell proliferation by Activin-A and its modulation by 17 beta-estradiol SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE activin; cancer; endometrium ID BINDING PROTEIN; GROWTH-FACTORS; INHIBIN-ALPHA; FOLLISTATIN; LINE; EXPRESSION; RECEPTORS; SUBUNIT; LNCAP; MICE AB A role for activins in regulating cellular transformation is suggested by the a-inhibin knockout mouse in which development of gonadal tumors is associated with elevated activin levels. It was the purpose of the current study to determine whether activin had similar actions on endometrial cell lines, specifically on a well differentiated estrogen-responsive endometrial adenocarcinoma cell line (ISH) and estrogen-unresponsive cells (HEC-50) obtained from a poorly differentiated endometrial adenocarcinoma. Activin was secreted by both adenocarcinoma cell lines. Using reverse transcription-PCR, messenger RNA type I and type II activin receptor subtypes were detected in both cell lines: expression of 113 and 1113 was approximately three- to fourfold greater in ISH cells than in HEC-50 cells, while activin receptor IA and IIA messenger RNA levels were approximately equal in both cell lines. Activin treatment (30-300 ng/ml) caused a dose- and time-dependent inhibition of ISH cells proliferation and resulted in a significant decrease in Bcl-2 protein and mRNA levels. No difference was observed in Bax expression. There was no significant effect of activin when the cultures of ISH cells were exposed to 17beta-estradiol. In contrast, activin showed a weak, but significant, mitogenic effect on HEC-50 cells without modifications in Bax and Bcl-2 mRNA and protein levels. The results demonstrate that activin is a regulator of endometrial cancer cell growth. 17beta-Estradiol may promote resistance of estrogen- responsive endometrial cancer cells to the growth-retarding effects of activin and one of the mechanisms might be a down-regulation of the activin receptors. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Cattolica Sacro Cuore, Dept Obstet & Gynecol, I-00168 Rome, Italy. Massachusetts Gen Hosp, Natl Ctr Infertil Res, Boston, MA 02114 USA. Massachusetts Gen Hosp, Reprod Endocrine Sci Ctr, Dept Med, Boston, MA 02114 USA. RP Caruso, A (reprint author), Univ Cattolica Sacro Cuore, Dept Obstet & Gynecol, Largo Gemelli 8, I-00168 Rome, Italy. NR 38 TC 16 Z9 17 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUN 28 PY 2002 VL 192 IS 1-2 BP 187 EP 195 AR PII S0303-7207(01)00648-7 DI 10.1016/S0303-7207(01)00648-7 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 571MF UT WOS:000176720600019 PM 12088879 ER PT J AU Cooper, JM Katcher, MS Orlov, MV AF Cooper, JM Katcher, MS Orlov, MV TI Current concepts - Implantable devices for the treatment of atrial fibrillation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID SICK-SINUS SYNDROME; ATRIOVENTRICULAR JUNCTION ABLATION; ARTERY BYPASS-SURGERY; TERM FOLLOW-UP; QUALITY-OF-LIFE; DUAL-SITE; CARDIOVERTER-DEFIBRILLATOR; CLINICAL-EXPERIENCE; RANDOMIZED TRIAL; SINGLE-SITE C1 VA Boston Healthcare Syst, Div Cardiol, Vet Affairs Med Ctr, W Roxbury, MA 02132 USA. Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Katcher, MS (reprint author), VA Boston Healthcare Syst, Div Cardiol, Vet Affairs Med Ctr, 111A,1400 VFW Pkwy, W Roxbury, MA 02132 USA. NR 69 TC 39 Z9 41 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 27 PY 2002 VL 346 IS 26 BP 2062 EP 2068 DI 10.1056/NEJMra012144 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 566DN UT WOS:000176411900008 PM 12087143 ER PT J AU Mathes, DW Randolph, MA Bourget, JL Nielsen, GP Ferrera, VR Arn, JS Scahs, DH Lee, WPA AF Mathes, DW Randolph, MA Bourget, JL Nielsen, GP Ferrera, VR Arn, JS Scahs, DH Lee, WPA TI Recipient bone marrow engraftment in donor tissue after long-term tolerance to a composite tissue allograft SO TRANSPLANTATION LA English DT Article ID ANTILYMPHOCYTE-SERUM; MINIATURE SWINE; TRANSPLANTATION; CHIMERISM; CELLS; ORGAN; RATS; INFUSION AB Background. An important component of a composite tissue limb allograft (CTA) is the vascularized bone marrow and bone marrow stroma, which when transplanted could create immediate marrow space and engraftment. We have previously demonstrated that tolerance to musculoskeletal allografts can be achieved with a 12-day course of cyclosporine without the presence of long-term peripheral donor cell chimerism. The objective of this study was to determine the fate of the donor bone marrow after transplantation of a limb allograft in a miniature swine model. Methods. CTAs from donor swine were heterotopically transplanted into six MHC-matched, minor-antigen-mismatched recipients, and a 12-day course of cyclosporine was given. Previous animals transplanted without cyclosporine rejected their grafts in less than 42 days. A non-MHC-linked marker, pig allelic antigen (PAA), was used to distinguish host and donor cells. Three PAA- animals received PAA+ CTAs, and three PAA+ animals received PAA- CTAs. Bone marrow was harvested from the donor limb grafts and the recipient and analyzed by flow cytometry and histology. Thymus, spleen, and mesenteric lymph nodes were also harvested from the recipient swine and evaluated for the presence of donor cells by flow cytometry. Results. All animals receiving cyclosporine demonstrated permanent tolerance to their allografts. Donor bone marrow cells were present in all grafts at the time of transplantation and during the immediate postoperative period. By 48 weeks, donor cells were no longer detectable within the marrow space of the allograft. In long-term animals host bone marrow cells replaced donor cells in the graft marrow space. No evidence of donor cell engraftment was found in recipient animals. Conclusion This study demonstrates that in long-term tolerant recipients of musculoskeletal allografts there is no evidence of persistent donor bone marrow cells in the hematopoietic tissues of the graft or the host Rather, the recipient's bone marrow cells and lymphocytes repopulate the donor marrow space of the graft. C1 Harvard Univ, Sch Med, Div Plast Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Div Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Lee, WPA (reprint author), Harvard Univ, Sch Med, Div Plast Surg, WACC-453,15 Parkman St, Boston, MA 02114 USA. OI Mathes, David/0000-0003-4388-1373 FU NCI NIH HHS [1R01 CA7988-01A1]; NHLBI NIH HHS [5R01 HL63430-02] NR 31 TC 21 Z9 23 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 JUN 27 PY 2002 VL 73 IS 12 BP 1880 EP 1885 DI 10.1097/00007890-200206270-00005 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 571CL UT WOS:000176697200005 PM 12131681 ER PT J AU Smith, RN Chang, YC Houser, S Dec, GW Grazette, L AF Smith, RN Chang, YC Houser, S Dec, GW Grazette, L TI Higher frequency of high-grade rejections in cardiac allograft patients after quilty B lesions or grade 2/4 rejections SO TRANSPLANTATION LA English DT Article ID CELLULAR HEART REJECTION; INTERNATIONAL-SOCIETY; WORKING CLASSIFICATION; CLINICAL-SIGNIFICANCE; BIOPSY SPECIMENS; TRANSPLANTATION; CYCLOSPORINE; PATHOLOGY; CRITERIA AB Background. To better understand bow different histologic patterns of allograft inflammation found on biopsies of human cardiac allografts progress to high-grade rejection, we undertook a statistical analysis of our institutional database to detect statistical patterns among different types of myocardial allograft inflammations found on sequential biopsies. Methods. Biopsies were analyzed for statistical associations between high-grade rejections (International Society of Heart and Lung Transplantation [ISHLT] grade greater than or equal to3A/4) and the type of cardiac allograft inflammation found on prior biopsies. Case cross-over and case control designs were used to compare the antecedent patterns of inflammation on biopsies with high-grade rejection compared to biopsies with low-grade rejection, all within the same subject. Quilty lesions were correlated with cyclosporine levels. Results. Patients with Quilty B lesions or ISHLT grade 2/4 rejections show an increased risk for high-grade rejection on their next biopsies (Odds ratio 5.9 to 11.2). The presence of two pathological findings, especially Quilty B and grade 2/4 rejection, creates additional risk in excess of that found independently (Odds ratio > 14). Quilty lesions are found only in cardiac allografts, and do not correlate with trough cyclosporine levels. Conclusions. The morphological patterns of several types of human cardiac allograft inflammation found on sequential protocol biopsies are not randomly associated. Patients with grade 2/4 rejections and Quilty B lesions show an increased risk for high-grade rejections on their next biopsies. Quilty B lesions, similar to ISHLT grade 2/4 rejections, may represent subclinical rejection. Both are more likely to progress to a high-grade rejection. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Smith, RN (reprint author), Massachusetts Gen Hosp, Dept Pathol, 501D Warren Bldg,Fruit St, Boston, MA 02114 USA. NR 25 TC 15 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 JUN 27 PY 2002 VL 73 IS 12 BP 1928 EP 1932 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 571CL UT WOS:000176697200014 PM 12131690 ER PT J AU Goff, DC AF Goff, DC TI A 23-year-old man with schizophrenia SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID DOUBLE-BLIND; ATYPICAL ANTIPSYCHOTICS; CORTICAL DEVELOPMENT; TARDIVE-DYSKINESIA; TREATMENT RESPONSE; CIGARETTE-SMOKING; NEGATIVE SYMPTOMS; BIPOLAR DISORDER; MENTAL-DISORDERS; OLDER PATIENTS C1 Freedom Trail Clin, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. Massachusetts Gen Hosp, Schizophrenia Program, Boston, MA 02114 USA. RP Goff, DC (reprint author), Freedom Trail Clin, 25 Staniford St, Boston, MA 02114 USA. NR 89 TC 0 Z9 0 U1 9 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD JUN 26 PY 2002 VL 287 IS 24 BP 3249 EP 3257 DI 10.1001/jama.287.24.3249 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 566FF UT WOS:000176415800030 PM 12076222 ER PT J AU Pitman, MB Cibas, ES Powers, CN Renshaw, AA Frable, WJ AF Pitman, MB Cibas, ES Powers, CN Renshaw, AA Frable, WJ TI Reducing or eliminating use of the category of atypical squamous cells of undetermined significance decreases the diagnostic accuracy of the Papanicolaou smear SO CANCER CYTOPATHOLOGY LA English DT Article DE cytology; Papanicolaou (Pap) smear; atypical squamous cells of undetermined; significance (ASCUS); accuracy; sensitivity ID CERVICAL INTRAEPITHELIAL NEOPLASIA; LARGE LOOP EXCISION; DIRECTED PUNCH BIOPSY; TRANSFORMATION ZONE; CYTOLOGIC DIAGNOSIS; CYTOPATHOLOGIC DIAGNOSES; QUALITY ASSURANCE; FOLLOW-UP; ASCUS; MANAGEMENT AB BACKGROUND. The diagnosis of "atypical squamous cells of undetermined significance" (ASCUS) is controversial, not only for the clinical utility of its subcategories (favor reactive vs. favor dysplasia), but for its very existence as an expression of uncertainty. In the current study, the authors investigated the impact of reducing and eliminating this category on the sensitivity and predictive values for detecting squamous intraepithelial lesions (SILs). METHODS. One hundred cervical Papanicolaou (Pap) smears originally diagnosed as ASCUS, all of which had histologic follow-up, were reviewed blindly and reclassified as either negative (within normal limits/benign cellular changes), low-grade SIL (LSIL), or high-grade SIL (HSIL) by 1 reviewer who eliminated ASCUS as a diagnostic possibility entirely. A second reviewer reinterpreted the cases but attempted to use the ASCUS diagnosis (favor reactive or favor dysplasia) sparingly. All histologic diagnoses were reviewed, and an adjudicated final diagnosis was established. Reviewed smear interpretations were correlated with the histologic diagnosis (original, reviewed, and adjudicated). Statistical analysis was performed using the Fisher exact test. RESULTS. Thirty-eight women had histologically confirmed SIL (21 LSIL cases and 17 HSIL cases [including 1 case of endocervical adenocarcinoma]); 31 of these 38 cases originally were classified as ASCUS, not otherwise specified, 1 case was classified as ASCUS favor reactive, and 6 cases were classified as ASCUS favor dysplasia. The reviewer who used the ASCUS diagnosis sparingly reclassified the smears as negative (62 cases); ASCUS, favor reactive (3 cases); ASCUS, favor dysplasia (13 cases); LSIL (19 cases); and HSIL (3 cases). The reviewer who eliminated the ASCUS category reclassified the smears as negative (59 cases), LSIL (29 cases), and HSIL (12 cases). The rate of SIL/HSIL in those cases interpreted as abnormal was 38%/17% originally, 42%/24% with a reduced ASCUS interpretation, and 37%/17% when the ASCUS category was eliminated. In those ASCUS smears that were reclassified as negative, the SIL/HSIL rate was 35%/13% with the reduced ASCUS interpretation and 39%/17% when the ASCUS category was eliminated. The sensitivity for detecting a SIL/HSIL was reduced from 100%/100% for the original ASCUS interpretation to 42%/53% for the reduced ASCUS interpretation to 39%/41% with the elimination of the ASCUS interpretation. CONCLUSIONS. Although in the current study utilization of the ASCUS diagnosis was found to result in a 62% negative or reactive outcome on biopsy, a significant number of patients with SIL were detected (38% in the current series, 17% with HSIL). Despite the improved correlation with negative biopsies, reducing or eliminating the ASCUS diagnosis appears to decrease the sensitivity of the Pap smear significantly and appears to be no better than chance at predicting a diagnosis of SIL on biopsy, including HSIL. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pathol, Richmond, VA 23298 USA. Baptist Hosp Miami, Dept Pathol, Miami, FL USA. RP Pitman, MB (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, 14 Fruit St, Boston, MA 02114 USA. NR 35 TC 33 Z9 33 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD JUN 25 PY 2002 VL 96 IS 3 BP 128 EP 134 DI 10.1002/cncr.10618 PG 7 WC Oncology; Pathology SC Oncology; Pathology GA 563TY UT WOS:000176272700002 PM 12115299 ER PT J AU Buono, C Come, CE Witztum, JL Maguire, GF Connelly, PW Carroll, M Lichtman, AH AF Buono, C Come, CE Witztum, JL Maguire, GF Connelly, PW Carroll, M Lichtman, AH TI Influence of C3 deficiency on atherosclerosis SO CIRCULATION LA English DT Article DE atherosclerosis; complement; inflammation ID COMPLEMENT COMPONENTS; REACTIVE PROTEIN; MICE; MECHANISMS; ANTIBODIES; PLAQUES; HYPERAPOBETALIPOPROTEINEMIA; ATHEROGENESIS; IMMUNIZATION; ACTIVATION AB Background-The influence of complement activation on atherosclerosis is not well understood. The purpose of this study was to examine the effects of C3 deficiency on the extent and phenotype of atherosclerosis. Methods and Results-Aortic atherosclerosis was analyzed in low-density lipoprotein receptor (Idlr)/C3-deficient mice (ldlr(-/-)C3(-/-)) and ldlr(-/-)C3(+/-) littermate control mice after 15 weeks on a 1.25% (wt/wt) cholesterol diet. Serum lipoprotein profiles and immunoglobulin levels were not significantly different between the 2 experimental groups. The lipid-positive en face lesional area in thoracic and abdominal aorta was greater in C3-deficient mice than in control mice (3.9% versus 2.1%, median, P=0.0076). Similarly, the lipid-positive area in aortic arch sections was greater in C3-deficient mice than in controls (0.04 mm(2) versus 0.02 mm(2), median, P=0.0089). Analysis of aortic arch sections showed greater lesional macrophage content in C3-deficient versus control mice (8.24+/-1.36% versus 5.9+/-1.63% intimal area, mean +/- SEM, P = 0.003), less smooth muscle cell content in C3-deficient versus control mice (0.06 +/- 0.05% versus 0.92+/-0.32% intimal area, mean+/-SEM, P<0.0001), and less collagen content in C3-deficient versus control mice (0.52+/-1.26% versus 11+/-10.43% intimal area, mean+/-SEM, P=0.008). Conclusions-The maturation of atherosclerotic lesions beyond the foam cell stage is strongly dependent on an intact complement system. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. St Michaels Hosp, J Alick Little Liped Res Lab, Toronto, ON M5B 1W8, Canada. RP Lichtman, AH (reprint author), Brigham & Womens Hosp, Dept Pathol, 221 Longwood Ave, Boston, MA 02115 USA. RI Connelly, Philip/B-7583-2012 OI Connelly, Philip/0000-0001-7244-6843 FU NHLBI NIH HHS [HL56985, HL48743, HL56989]; NIAID NIH HHS [AI36389] NR 30 TC 108 Z9 113 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 JUN 25 PY 2002 VL 105 IS 25 BP 3025 EP 3031 DI 10.1161/01.CIR.0000019584.04929.83 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 573FN UT WOS:000176818800028 PM 12081998 ER PT J AU Albert, CM Gaziano, JM Willett, WC Manson, JE AF Albert, CM Gaziano, JM Willett, WC Manson, JE TI Nut consumption and decreased risk of sudden cardiac death in the Physicians' Health Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 71st Scientific Session of the American-Heart-Association CY NOV 08-12, 1998 CL DALLAS, TEXAS SP Amer Heart Assoc ID CORONARY HEART-DISEASE; POLYUNSATURATED FATTY-ACIDS; MYOCARDIAL-INFARCTION; FISH CONSUMPTION; DIET; SUPPLEMENTATION; QUESTIONNAIRE; FLAVONOIDS; MEN AB Background: Dietary nut intake has been associated with a reduced risk of coronary heart disease mortality; however, the mechanism is unclear. Since components of nuts may have antiarrhythmic properties, part of the benefit may be due to a reduction in sudden cardiac death. Methods: We prospectively assessed whether increasing frequency of nut consumption, as ascertained by an abbreviated food frequency questionnaire at 12 months of follow-up, was associated with a lower risk of sudden cardiac death and other coronary heart disease end points among 21454 male participants enrolled in the US Physicians' Health Study, Participants were followed up for an average of 17 years. Results: Dietary nut intake was associated with a significantly reduced risk of sudden cardiac death after controlling for known cardiac risk factors and other dietary habits (P for trend,.01). Compared with men who rarely or never consumed nuts those who consumed nuts 2 or more times per week had reduced risks of sudden cardiac death (relative risk, 0.53; 95% confidence interval, 0.30-0.92) and total coronary heart disease death (relative risk, 0.70; 95% confidence interval, 0.50-0.98). In contrast, nut intake was not associated with significantly reduced risks of nonsudden coronary heart disease death or nonfatal myocardial infarction. Conclusion: These prospective data in US male physicians suggest that the inverse association between nut consumption and total coronary heart disease death is primarily due to a reduction in the risk of sudden cardiac death. C1 Brigham & Womens Hosp, Div Prevent Med, Dept Med, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiovasc, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Albert, CM (reprint author), Brigham & Womens Hosp, Div Prevent Med, Dept Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. FU NCI NIH HHS [CA-34944, CA-40360]; NHLBI NIH HHS [1-K08-HL-03783, HL-26490, HL-34595] NR 30 TC 201 Z9 221 U1 2 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUN 24 PY 2002 VL 162 IS 12 BP 1382 EP 1387 DI 10.1001/archinte.162.12.1382 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 564XC UT WOS:000176338000008 PM 12076237 ER PT J AU Schaefer, AW Kamei, Y Kamiguchi, H Wong, EV Rapoport, I Kirchhausen, T Beach, CM Landreth, G Lemmon, SK Lemmon, V AF Schaefer, AW Kamei, Y Kamiguchi, H Wong, EV Rapoport, I Kirchhausen, T Beach, CM Landreth, G Lemmon, SK Lemmon, V TI L1 endocytosis is controlled by a phosphorylation-dephosphorylation cycle stimulated by outside-in signaling by L1 SO JOURNAL OF CELL BIOLOGY LA English DT Article DE IGSF protein; cell adhesion; growth cones; endocytosis; tyrosine-based sorting motifs ID ADHESION MOLECULE L1; TYROSINE PHOSPHORYLATION; NEURITE OUTGROWTH; SORTING SIGNALS; KINASE-ACTIVITY; AP-2 COMPLEXES; AXON OUTGROWTH; CTLA-4 CD152; GROWTH CONES; N-CAM AB Dynamic regulation of the cell surface expression of adhesion molecules is an important mechanism for controlling neuronal growth cone motility and guidance. Clathrin-mediated vesicular internalization of L1 via the tyrosine-based endocytosis motif YRSL regulates adhesion and signaling by this Ig superfamily molecule. Here, we present evidence that tyrosine-1176 (Y1176) of the YRSL motif is phosphorylated in vivo. The nonreceptor tyrosine kinase (p60src) is implicated in L1-mediated neurite outgrowth, and we find that p60src phosphorylates Y1176 in vitro. Phosphorylation of Y1176 prevents L1 binding to AP-2, an adaptor required for clathrin-mediated internalization of L1. mAb 74-5H7 recognizes the sequence immediately NH2-terminal to the tyrosine-based motif and binds L1 only when Y1176 is dephosphorylated. 74-5H7 identifies a subset of L1 present at points of cell-cell contact and in vesicle-like structures that colocalize with an endocytosis marker. L1-L1 binding or L1 cross-linking induces a rapid increase in 74-5H7 immunoreactivity. Our data suggest a model in which homophilic binding or L1 cross-linking triggers transient dephosphorylation of the YRSL motif that makes L1 available for endocytosis. Thus, the regulation of L1 endocytosis through dephosphorylation of Y1176 is a critical regulatory point of L1-mediated adhesion and signaling. C1 Case Western Reserve Univ, Sch Med, Dept Neurosci, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Mol Biol & Microbiol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Ophthalmol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Ctr Canc, Cleveland, OH 44106 USA. Univ Kentucky, Macromol Struct Anal Facil, Lexington, KY 40536 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Lemmon, V (reprint author), Case Western Reserve Univ, Sch Med, Dept Neurosci, Rm E661,2109 Adelbert Rd, Cleveland, OH 44106 USA. RI Lemmon, Vance/A-2565-2008; Kamiguchi, Hiroyuki/N-5409-2015; Lemmon, Vance/A-7410-2010 OI Lemmon, Vance/0000-0003-3550-7576 FU NEI NIH HHS [EY-05285, EY-11373, P30 EY011373, R01 EY005285, R01 EY005285-23]; NICHD NIH HHS [R01 HD039884, R01 HD039884-06]; NIGMS NIH HHS [R01 GM036548] NR 45 TC 86 Z9 87 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD JUN 24 PY 2002 VL 157 IS 7 BP 1223 EP 1232 DI 10.1083/jcb.200203024 PG 10 WC Cell Biology SC Cell Biology GA 568EA UT WOS:000176528400011 PM 12082080 ER PT J AU Schumacher, HR Boice, JA Daikh, DI Mukhopadhyay, S Malmstrom, K Ng, J Tate, GA Molina, J AF Schumacher, HR Boice, JA Daikh, DI Mukhopadhyay, S Malmstrom, K Ng, J Tate, GA Molina, J TI Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis SO BRITISH MEDICAL JOURNAL LA English DT Article ID ORAL INDOMETHACIN; CLINICAL-TRIAL; CYCLOOXYGENASE-2; CELECOXIB; OSTEOARTHRITIS; DICLOFENAC; MANAGEMENT; EFFICACY; INHIBITOR; ROFECOXIB AB Objective To assess the safety and efficacy of etoricoxib, a selective cyclo-oxygenase-2 inhibitor, in comparison with indometacin in the treatment of acute gouty arthritis. Design Randomised, double blind, active comparator controlled trial. Setting 43 outpatient study centres in 11 countries. Participants 142 men and eight women (75 patients per treatment group) aged 18 years or over presenting with clinically diagnosed acute gout within 48 hours of onset. Interventions Etoricoxib 120 mg administered orally once daily versus indometacin 50 mg administered orally three times daily, both for 8 days Main outcome measures Patients' assessment of pain in the study joint over days 2 to 5 (primary end point); investigators' and patients' global assessments of response to treatment and tenderness of the study joint (key secondary end points). Results Etoricoxib showed efficacy comparable to indometacin. Patients' assessment of pain in the study joint (0-4 point Likert scale, "no pain" to "extreme pain") over days 2 to 5 showed a least squares mean change from baseline of - 1.72 (95% confidence interval - 1.90 to - 1.55) for etoricoxib and - 1.83 (- 2.01 to - 1.65) for indometacin. The difference between treatment groups met prespecified comparability criteria. All other efficacy end points, including those reflecting reduction in inflammation and analgesia, provided corroborative evidence of comparable efficacy. Significant pain relief was evident at the first measurement, 4 hours after the first dose of treatment. Prespecified safety analyses revealed that drug related adverse experiences occurred significantly less frequently with etoricoxib (22.7%) than with indometacin (46.7%) (P=.003), although overall adverse experience rates were similar between the two treatment groups. Conclusion Etoricoxib 120 mg once daily provides rapid and effective treatment for acute gouty arthritis comparable to indometacin 50 mg three times daily. Etoricoxib was generally safe and well tolerated in this study. C1 Merck Res Labs, Dept Clin Immunol & Analgesia, Rahway, NJ 07065 USA. Univ Penn, Sch Med, Div Rheumatol, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Merck Res Labs, Dept Clin Biostat & Res Data Syst, Rahway, NJ USA. Univ Calif San Francisco, Div Rheumatol, San Francisco, CA 94121 USA. Dept Vet Affairs Med Ctr, San Francisco, CA 94121 USA. Ctr Ospeopatias Reumatol & Invest Clin, RA-1012 Buenos Aires, DF, Argentina. Antioquia Univ, Dept Internal Med, Medellin 1226, Colombia. RP Boice, JA (reprint author), Merck Res Labs, Dept Clin Immunol & Analgesia, Rahway, NJ 07065 USA. NR 24 TC 132 Z9 138 U1 0 U2 11 PU BRITISH MED JOURNAL PUBL 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 JUN 22 PY 2002 VL 324 IS 7352 BP 1488 EP 1492 DI 10.1136/bmj.324.7352.1488 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 567ZL UT WOS:000176517900018 PM 12077033 ER PT J AU Pillai, S Moran, ST AF Pillai, S Moran, ST TI Tec kinase pathways in lymphocyte development and transformation SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE Tec kinase; lymphocyte; transformation ID BRUTONS-TYROSINE-KINASE; X-LINKED AGAMMAGLOBULINEMIA; B-CELL DEVELOPMENT; FACTOR-KAPPA-B; FAMILY KINASES; PHOSPHOINOSITIDE 3-KINASE; PHOSPHOLIPASE C-GAMMA-2; SIGNALING PATHWAY; BINDING PROTEIN; SRC FAMILY C1 Harvard Univ, Med Sch, Massachusetts Gen Hosp Canc Ctr, Boston, MA 02129 USA. RP Pillai, S (reprint author), Harvard Univ, Med Sch, Massachusetts Gen Hosp Canc Ctr, 13th St, Boston, MA 02129 USA. NR 47 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD JUN 21 PY 2002 VL 1602 IS 2 BP 162 EP 167 AR PII S0304-419X(02)00041-0 DI 10.1016/S0304-419X(02)00041-0 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA 558NG UT WOS:000175973000005 PM 12020802 ER PT J AU Lin, Y Martin, J Gruendler, C Farley, J Meng, XW Li, BY Lechleider, R Huff, C Kim, RH Grasser, W Paralkar, V Wang, TW AF Lin, Y Martin, J Gruendler, C Farley, J Meng, XW Li, BY Lechleider, R Huff, C Kim, RH Grasser, W Paralkar, V Wang, TW TI A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs) SO BMC CELL BIOLOGY LA English DT Article ID E3 UBIQUITIN LIGASE; FACTOR-BETA FAMILY; 20S PROTEASOME; DEPENDENT DEGRADATION; PRECURSOR COMPLEXES; SMAD PROTEINS; I RECEPTOR; INTERACTS; ACTIVATION; SUBUNIT AB Background The intracellular signaling events of the Bone Morphogenetic Proteins (BMPs) involve the R-Smad family members Smad1, Smad5, Smad8 and the Co-Smad, Smad4. Smads are currently considered to be DNA-binding transcriptional modulators and sown to recruit the master transcriptional co-activator CBP/p300 for transcriptional activation. SNIP1 is a recently discovered novel repressor of CBP/p300. Currently, the detailed molecular mechanisms that allow R-Smads and Co-Smad to co-operatively modulate transcription events are not fully understood. Results Here we report a novel physical and functional link between Smad1 and the 26S proteasome that contributes to Smad1- and Smad4-mediated transcriptional regulation. Smad1 forms a complex wit a proteasome beta subunit HsN3 and the ornithine decarboxylase antizyme (Az). T e interaction is enhanced upon BMP type I receptor activation and occur prior to the incorporation of HsN3 into the mature 20S proteasome. Furthermore, BMPs trigger the translocation of Smad1, HsN3 and Az into the nucleus, where the novel CBP/p300 repressor protein SNIP1 is further recruited to Smad1/HsN3/Az complex and degraded in a Smad1-, Smad4- and Az-dependent fashion. The degradation of the CBP/p300 repressor SNIP1 is likely an essential step for Smad1-, Smad4- mediated transcriptional activation, since increased SNIP1 expression inhibits BMP-induced gene responses. Conclusions Our studies thus add two additional important functional partners of Smad1 into the signaling web of BMPs and also suggest a novel mechanism for Smad1 and Smad4 to co-modulate transcription via regulating proteasomal degradation of CBP/p300 repressor SNIP1. C1 Virginia Mason Res Ctr, Seattle, WA 98101 USA. Univ Washington, Dept Immunol, Seattle, WA 98195 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg Genet, Boston, MA 02114 USA. Pfizer Inc, Dept Cardiovasc Metab Dis, Groton, CT 06340 USA. NCI, Chemoprevent Lab, Bethesda, MD 20892 USA. RP Wang, TW (reprint author), Virginia Mason Res Ctr, 1201 9th Ave, Seattle, WA 98101 USA. NR 55 TC 53 Z9 65 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD JUN 21 PY 2002 VL 3 AR 15 DI 10.1186/1471-2121-3-15 PG 55 WC Cell Biology SC Cell Biology GA 565RQ UT WOS:000176383600001 PM 12097147 ER PT J AU Silvestri, AJ Sanford, LD Ross, RJ Mann, GL Pavlock, A Morrison, AR AF Silvestri, AJ Sanford, LD Ross, RJ Mann, GL Pavlock, A Morrison, AR TI The central nucleus of the amygdala and the wake-promoting effects of modafinil SO BRAIN RESEARCH LA English DT Article DE modafinil; amygdala; wakefulness; sleep ID AGENT MODAFINIL; BRAIN-STEM; RAT; WAKEFULNESS; AMPHETAMINE; FOREBRAIN; CAT AB Modafinil, a novel non-amphetamine stimulant recently approved for the treatment of narcolepsy, has been shown to increase waking in both animals and humans. However, its mechanism of action is currently unknown. Earlier research into the brain structures responsible for the wake-producing actions of modafinil implicated the central nucleus of the amygdala (ACe) as a possible site of action [Neuroscience 87 (1998) 905-911; Neurosci. Lett. 241 (1998) 95-98]. The present experiments were designed to test the hypothesis that the ACe is, at least in pail, involved in the wake-producing actions of modafinil, In the first experiment, rats with lesions of the ACe were injected systemically with varying doses of modafinil and sleep was recorded. At the highest dose, modafinil significantly increased waking and decreased sleep. However, there was no interaction between the lesion and the effect of the drug. In the second experiment, varying doses of modafinil were injected directly into the ACe and sleep was recorded. Injection of modatinil into the ACe did not affect sleep architecture. Thus. ACe does not play a simple role in modafinil's wake-promoting action. We suggest that more complex testing will be required to elucidate its role. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Penn, Sch Vet Med, Dept Anim Biol, Lab Study Brain Sleep, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Morrison, AR (reprint author), Univ Penn, Sch Vet Med, Dept Anim Biol, Lab Study Brain Sleep, 3800 Spruce St, Philadelphia, PA 19104 USA. OI Hunter, Amy/0000-0002-4501-5578 FU NIMH NIH HHS [MH 42903]; NINDS NIH HHS [NS 35281] NR 13 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUN 21 PY 2002 VL 941 IS 1-2 BP 43 EP 52 AR PII S0006-8993(02)02547-7 DI 10.1016/S0006-8993(02)02547-7 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 564AV UT WOS:000176292300005 PM 12031546 ER PT J AU Lin, Y Martin, J Gruendler, C Farley, J Eng, XW Li, BY Lechleider, R Huff, C Kim, RH Grasser, W Paralkar, VW Wang, TW AF Lin, Y Martin, J Gruendler, C Farley, J Eng, XW Li, BY Lechleider, R Huff, C Kim, RH Grasser, W Paralkar, VW Wang, TW TI A novel link between the proteasome pathway and the signal transduction pathway of the bone morphogenetic proteins (BMPs) SO GEOCHEMISTRY GEOPHYSICS GEOSYSTEMS LA English DT Article ID E3 UBIQUITIN LIGASE; MAD-RELATED PROTEIN; FACTOR-BETA FAMILY; 20S PROTEASOME; DEPENDENT DEGRADATION; PRECURSOR COMPLEXES; SMAD PROTEINS; I RECEPTOR; INTERACTS; ACTIVATION AB Background The intracellular signaling events of the Bone Morphogenetic Proteins (BMPs) involve the R-Smad family members Smad1, Smad5, Smad8 and the Co-Smad, Smad4. Smads are currently considered to be DNA-binding transcriptional modulators and shown to recruit the master transcriptional co-activator CBP/p300 for transcriptional activation. SNIP1 is a recently discovered novel repressor of CBP/p300. Currently, the detailed molecular mechanisms that allow R-Smads and Co-Smad to co-operatively modulate transcription events are not fully understood. Results Here we report a novel physical and functional link between Smad1 and the 26S proteasome that contributes to Smad1- and Smad4-mediated transcriptional regulation. Smad1 forms a complex wit a proteasome beta subunit HsN3 and the ornithine decarboxylase antizyme (Az). The interaction is enhanced upon BMP type I receptor activation and occur prior to the incorporation of HsN3 into the mature 20S proteasome. Furthermore, BMPs trigger the translocation of Smad1, HsN3 and Az into the nucleus, where the novel CBP/p300 repressor protein SNIP1 is further recruited to Smad1/HsN3/Az complex and degraded in a Smad1-, Smad4- and Az-dependent fashion. The degradation of the CBP/p300 repressor SNIP1 is likely an essential step for Smad1-, Smad4- mediated transcriptional activation, since increased SNIP1 expression inhibits BMP-induced gene responses. Conclusions Our studies thus add two additional important functional partners of Smad1 into the signaling web of BMPs and also suggest a novel mechanism for Smad1 and Smad4 to co-modulate transcription via regulating proteasomal degradation of CBP/p300 repressor SNIP1. C1 Virginia Mason Res Ctr, Seattle, WA 98101 USA. Univ Washington, Dept Immunol, Seattle, WA 98195 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg Genet, Boston, MA 02114 USA. RP Wang, TW (reprint author), Virginia Mason Res Ctr, 1201 9th Ave, Seattle, WA 98101 USA. NR 55 TC 1 Z9 1 U1 0 U2 2 PU AMER GEOPHYSICAL UNION PI WASHINGTON PA 2000 FLORIDA AVE NW, WASHINGTON, DC 20009 USA SN 1525-2027 J9 GEOCHEM GEOPHY GEOSY JI Geochem. Geophys. Geosyst. PD JUN 21 PY 2002 VL 3 PG 55 WC Geochemistry & Geophysics SC Geochemistry & Geophysics GA 564WH UT WOS:000176336200001 ER PT J AU Cook, SA Matsui, T Li, L Rosenzweig, A AF Cook, SA Matsui, T Li, L Rosenzweig, A TI Transcriptional effects of chronic Akt activation in the heart SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SERINE-THREONINE KINASE; BETA SUPERFAMILY MEMBER; IGF-BINDING PROTEIN-5; NF-KAPPA-B; GROWTH-FACTOR; PHOSPHATIDYLINOSITOL 3-KINASE; CARDIOVASCULAR-SYSTEM; NEURONAL SURVIVAL; SIGNALING PATHWAY; CARDIAC MYOCYTES AB Akt activation reduces cardiomyocyte death and induces cardiac hypertrophy. To help identify effector mechanisms, gene expression profiles in hearts from transgenic mice with cardiac-specific expression of activated Akt (myr-Akt) were compared with littermate controls. 40 genes were identified as differentially expressed. Quantitative reverse transcription-PCR confirmed qualitative results of transcript profiling for 9 of 10 genes examined, however, there were notable quantitative discrepancies between the quantitative reverse transcription-PCR and microarray data sets. Interestingly Akt induced significant up-regulation of insulin-like growth factor-binding protein-5 (IGFBP-5), which could contribute to its anti-apoptotic effects in the heart. In addition, Akt-mediated down-regulation of peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1 (PGC-1) and PPAR-alpha may shift myocytes toward glycolytic metabolism shown to preserve cardiomyocyte function and survival during transient ischemia. IGFBP-5 transcripts also increased after adenoviral gene transfer of myr-Akt to cultured cardiomyocytes, suggesting that this represents a direct effect of Akt activation. In contrast, substantial induction of growth differentiation factor-8 (GDF-8), a highly conserved inhibitor of skeletal muscle growth, was observed in transgenic hearts but not after acute Akt activation in vitro, suggesting that GDF-8 induction may represent a secondary effect perhaps related to the cardiac hypertrophy seen in these mice. Thus, microarray analysis reveals previously unappreciated Akt regulation of genes that could contribute to the effects of Akt on cardiomyocyte survival, metabolism, and growth. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr,Program Cardiovasc Gene Therap, Boston, MA 02129 USA. RP Rosenzweig, A (reprint author), Massachusetts Gen Hosp E, Cardiovasc Res Ctr, Program Cardiovasc Gene Therapy, 114 16th St,Rm 2600, Charlestown, MA 02129 USA. RI Cook, Stuart/G-9567-2011; OI Cook, Stuart/0000-0001-6628-194X FU NHLBI NIH HHS [HL-61557, HL-59521, HL-04250] NR 44 TC 148 Z9 150 U1 1 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 JUN 21 PY 2002 VL 277 IS 25 BP 22528 EP 22533 DI 10.1074/jbc.M201462200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564KM UT WOS:000176313600056 PM 11956204 ER PT J AU Gukovskaya, AS Gukovsky, I Jung, Y Mouria, M Pandol, SJ AF Gukovskaya, AS Gukovsky, I Jung, Y Mouria, M Pandol, SJ TI Cholecystokinin induces caspase activation and mitochondrial dysfunction in pancreatic acinar cells - Roles in cell injury processes of pancreatitis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; NECROSIS-FACTOR-ALPHA; PERMEABILITY TRANSITION; INDUCED APOPTOSIS; ENZYME-SECRETION; CYCLOSPORINE-A; UP-REGULATION; DEATH; INDUCTION; CERULEIN AB Apoptosis and necrosis are critical parameters of pancreatitis, the mechanisms of which remain unknown. Many characteristics of pancreatitis can be studied in vitro in pancreatic acini treated with high doses of cholecystokinin (CCK). We show here that CCK stimulates apoptosis and death signaling pathways in rat pancreatic acinar cells, including caspase activation, cytochrome c release, and mitochondrial depolarization. The mitochondrial dysfunction is mediated by upstream caspases (possibly caspase-8) and, in turn, leads to activation of caspase-3. CCK causes mitochondrial alterations through both permeability transition pore-dependent (cytochrome c release) and permeability transition pore-independent (mitochondrial depolarization) mechanisms. Caspase activation and mitochondrial alterations also occur in untreated pancreatic acinar cells; however, the underlying mechanisms are different. In particular, caspases protect untreated acinar cells from mitochondrial damage. We found that caspases not only mediate apoptosis but also regulate other parameters of CCK-induced acinar cell injury that are characteristic of pancreatitis; in particular, caspases negatively regulate necrosis and trypsin activation in acinar cells. The results suggest that the observed signaling pathways regulate parenchymal cell injury and death in CCK-induced pancreatitis. Protection against necrosis and trypsin activation by caspases can explain why the severity of pancreatitis in experimental models correlates inversely with the extent of apoptosis. C1 Vet Affairs Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90073 USA. RP Gukovskaya, AS (reprint author), Vet Affairs Greater Los Angeles Healthcare Syst, W Los Angeles Healthcare Ctr, Dept Med, Bldg 258,Rm 340,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU PHS HHS [P50-A11999] NR 63 TC 95 Z9 99 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 21 PY 2002 VL 277 IS 25 BP 22595 EP 22604 DI 10.1074/jbc.M202929200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564KM UT WOS:000176313600066 PM 11964411 ER PT J AU Chi, YI Sadler, I Jablonski, LM Callantine, SD Deobald, CF Stauffacher, CV Bohach, GA AF Chi, YI Sadler, I Jablonski, LM Callantine, SD Deobald, CF Stauffacher, CV Bohach, GA TI Zinc-mediated dimerization and its effect on activity and conformation of staphylococcal enterotoxin type C SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TOXIC-SHOCK SYNDROME; MHC CLASS-II; CRYSTAL-STRUCTURE; CYSTEINYL LEUKOTRIENES; NUCLEOTIDE-SEQUENCE; SUPERANTIGEN; PROTEINS; BINDING; RESOLUTION; MOLECULES AB Staphylococcal enterotoxins are superantigen exotoxins that mediate food poisoning and toxic shock syndrome in humans. Despite their structural and functional similarities, superantigens display subtle differences in biological properties and modes of receptor binding as a result of zinc atoms bound differently in their crystal structures. For example, the crystal structures of the staphylococcal enterotoxins in the type C serogroup (SECs) contain a zinc atom coordinated by one aspartate and two histidine residues from one molecule and another aspartate residue from the next molecule, thus forming a dimer. This type of zinc ligation and zinc-mediated dimerization occurs in several SECs, but not in most other staphylococcal enterotoxin serogroups. This prompted us to investigate the potential importance of zinc in SEC-mediated pathogenesis. Site-directed mutagenesis was used to replace SEC zinc binding ligands with alanine. SEC mutants unable to bind zinc did not have major conformational alterations although they failed to form dimers. Zinc binding was not essential for T cell stimulation, emesis, or lethality although in general the mutants were less pyrogenic. Thus the zinc atom in SECs might represent a non-functional heavy atom in an exotoxin group that has diverged from related bacterial toxins containing crucial zinc atoms. C1 Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. Univ Idaho, Dept Microbiol Mol Biol & Biochem, Moscow, ID 83843 USA. RP Chi, YI (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. NR 51 TC 19 Z9 21 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 21 PY 2002 VL 277 IS 25 BP 22839 EP 22846 DI 10.1074/jbc.M201932200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564KM UT WOS:000176313600094 PM 11934896 ER PT J AU Matsui, T Li, L Wu, JC Cook, SA Nagoshi, T Picard, MH Liao, RL Rosenzweig, A AF Matsui, T Li, L Wu, JC Cook, SA Nagoshi, T Picard, MH Liao, RL Rosenzweig, A TI Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-B; GROWTH-FACTOR-I; NF-KAPPA-B; GLYCOGEN-SYNTHASE KINASE-3-BETA; SERINE-THREONINE KINASE; P70 S6 KINASE; CELL-SURVIVAL; PHOSPHATIDYLINOSITOL 3-KINASE; CARDIOMYOCYTE HYPERTROPHY; DEPENDENT PHOSPHORYLATION AB The serine-threonine kinase, Akt, inhibits cardiomyocyte apoptosis acutely both in vitro and in vivo. However, the effects of chronic Akt activation in the heart are unknown. To address this issue, we generated transgenic mice (TG+) with cardiac-specific expression of a constitutively active mutant of Akt (myr-Akt) driven by the myosin heavy chain-alpha promoter. Three TG+ founders (9-19 weeks) died suddenly with massive cardiac dilatation. Two viable TG+ lines (TG564 and TG20) derived from independent founders demonstrated cardiac-specific transgene expression as well as activation of Akt and p70S6 kinase. TG564 (n = 19) showed cardiac hypertrophy with a heart/body weight ratio 2.3-fold greater than littermates (n = 17, p < 0.005). TG20 (n = 18) had less marked cardiac hypertrophy with a heart/body weight ratio 1.6-fold greater than littermates (a = 17, p < 0.005). Isolated TG564 myocytes were also hypertrophic with surface areas 1.7-fold greater than littermates (p < 0.000001). Echocardiograms in both lines demonstrated concentric hypertrophy and preserved systolic function. After ischemia-reperfusion, TG+ had a 50% reduction in infarct size versus TG- (17 +/- 3% versus 34 +/- 4%, p < 0.001). Thus, chronic Akt activation is sufficient to cause a spectrum of phenotypes from moderate cardiac hypertrophy with preserved systolic function and cardioprotection to massive cardiac dilatation and sudden death. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Program Cardiovasc Gene Therapy,CVRC, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02129 USA. Boston Univ, Sch Med, Cardiac Muscle Res Lab, Boston, MA 02118 USA. RP Rosenzweig, A (reprint author), Massachusetts Gen Hosp East, Cardiovasc Res Ctr, Program Cardiovasc Gene Therapy, 114 16th St,2nd Floor,Rm 2600, Charlestown, MA 02129 USA. RI Cook, Stuart/G-9567-2011; OI Cook, Stuart/0000-0001-6628-194X; Picard, Michael/0000-0002-9264-3243 FU NHLBI NIH HHS [HL61557, HL04250, HL59521] NR 49 TC 276 Z9 284 U1 1 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 JUN 21 PY 2002 VL 277 IS 25 BP 22896 EP 22901 DI 10.1074/jbc.M200347200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564KM UT WOS:000176313600101 PM 11943770 ER PT J AU Iijima, Y Laser, M Shiraishi, H Willey, CD Sundaravadivel, B Xu, L McDermott, PJ Kuppuswamy, D AF Iijima, Y Laser, M Shiraishi, H Willey, CD Sundaravadivel, B Xu, L McDermott, PJ Kuppuswamy, D TI c-Raf/MEK/ERK pathway controls protein kinase C-mediated p70S6K activation in adult cardiac muscle cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL-REGULATED KINASE; CAP-DEPENDENT INITIATION; VIVO PRESSURE-OVERLOAD; S6 KINASE; ANGIOTENSIN-II; IN-VIVO; CYCLIC-AMP; RAT-HEART; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHORYLATION SITE AB p70S6 kinase (S6K1) plays a pivotal role in hypertrophic cardiac growth via ribosomal biogenesis. In pressure-overloaded myocardium, we show S6K1 activation accompanied by activation of protein kinase C (PKC), c-Raf, and mitogen-activated protein kinases (MAPKs). To explore the importance of the c-Raf/MAPK kinase (MEK)/MAPK pathway, we stimulated adult feline cardiomyocytes with 12-O-tetradecanoylphorbol-13-acetate (TPA), insulin, or forskolin to activate PKC, phosphatidylinositol-3-OH kinase, or protein kinase A (PKA), respectively. These treatments resulted in S6K1 activation with Thr-389 phosphorylation as well as mammalian target of rapamycin (mTOR) and S6 protein phosphorylation. Thr-421/Ser-424 phosphorylation of S6K1 was observed predominantly in TPA-treated cells. Dominant negative c-Raf expression or a MEK1/2 inhibitor (U0126) treatment showed a profound blocking effect only on the TPA-stimulated phosphorylation of S6K1 and mTOR. Whereas p38 MAPK inhibitors exhibited only partial effect, MAPK-phosphatase-3 expression significantly blocked the TPA-stimulated S6K1 and mTOR phosphorylation. Inhibition of mTOR with rapamycin blocked the Thr-389 but not the Thr-421/Ser-424 phosphorylation of S6K1. Therefore, during PKC activation, the c-Raf/MEK/extracellular signal-regulated kinase-1/2 (ERK1/2) pathway mediates both the Thr-421/Ser-424 and the Thr-389 phosphorylation in an mTOR-independent and -dependent manner, respectively. Together, our in vivo and in vitro studies indicate that the PKC/c-Raf/MEK/ERK pathway plays a major role in the S6K1 activation in hypertrophic cardiac growth. C1 Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, Div Cardiol, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC 29425 USA. RP Kuppuswamy, D (reprint author), Med Univ S Carolina, Gazes Cardiac Res Inst, Dept Med, Div Cardiol, 114 Doughty St, Charleston, SC 29425 USA. OI Willey, Christopher/0000-0001-9953-0279 FU NHLBI NIH HHS [HL-48788]; NIGMS NIH HHS [GM08716] NR 76 TC 107 Z9 110 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 JUN 21 PY 2002 VL 277 IS 25 BP 23065 EP 23075 DI 10.1074/jbc.M200328200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564KM UT WOS:000176313600122 PM 11940578 ER PT J AU Gabriel, SB Schaffner, SF Nguyen, H Moore, JM Roy, J Blumenstiel, B Higgins, J DeFelice, M Lochner, A Faggart, M Liu-Cordero, SN Rotimi, C Adeyemo, A Cooper, R Ward, R Lander, ES Daly, MJ Altshuler, D AF Gabriel, SB Schaffner, SF Nguyen, H Moore, JM Roy, J Blumenstiel, B Higgins, J DeFelice, M Lochner, A Faggart, M Liu-Cordero, SN Rotimi, C Adeyemo, A Cooper, R Ward, R Lander, ES Daly, MJ Altshuler, D TI The structure of haplotype blocks in the human genome SO SCIENCE LA English DT Article ID HUMAN LIPOPROTEIN-LIPASE; MODERN HUMAN ORIGINS; LINKAGE DISEQUILIBRIUM; SEQUENCE VARIATION; CROHNS-DISEASE; GENE; SUSCEPTIBILITY; COMPLEX; IDENTIFICATION; MUTATION AB Haplotype-based methods offer a powerful approach to disease gene mapping, based on the association between causal mutations and the ancestral haplotypes on which they arose. As part of The SNP Consortium Allele Frequency Projects, we characterized haplotype patterns across 51 autosomal regions (spanning 13 megabases of the human genome) in samples from Africa, Europe, and Asia. We show that the human genome can be parsed objectively into haplotype blocks: sizable regions over which there is little evidence for historical recombination and within which only a few common haplotypes are observed. The boundaries of blocks and specific haplotypes they contain are highly correlated across populations. We demonstrate that such haplotype frameworks provide substantial statistical power in association studies of common genetic variation across each region. Our results provide a foundation for the construction of a haplotype map of the human genome, facilitating comprehensive genetic association studies of human disease. C1 Whitehead MIT Ctr Genome Res, Cambridge, MA 02139 USA. MIT, Dept Biol, Cambridge, MA 02142 USA. Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. Univ Ibadan, Coll Med, Dept Pediat, Ibadan, Nigeria. Loyola Univ, Sch Med, Dept Prevent Med & Epidemiol, Maywood, IL 60143 USA. Univ Oxford, Inst Biol Anthropol, Oxford OX2 6QS, England. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. RP Altshuler, D (reprint author), Whitehead MIT Ctr Genome Res, Cambridge, MA 02139 USA. RI Altshuler, David/A-4476-2009; Schaffner, Stephen/D-1189-2011; OI Altshuler, David/0000-0002-7250-4107; Adeyemo, Adebowale/0000-0002-3105-3231 NR 32 TC 3653 Z9 3773 U1 17 U2 168 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 21 PY 2002 VL 296 IS 5576 BP 2225 EP 2229 DI 10.1126/science.1069424 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565PQ UT WOS:000176379000060 PM 12029063 ER PT J AU Dunah, AW Jeong, H Griffin, A Kim, YM Standaert, DG Hersch, SM Mouradian, MM Young, AB Tanese, N Krainc, D AF Dunah, AW Jeong, H Griffin, A Kim, YM Standaert, DG Hersch, SM Mouradian, MM Young, AB Tanese, N Krainc, D TI Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease SO SCIENCE LA English DT Article ID MEDIATED TRANSCRIPTION; GLUTAMINE REPEATS; GENE-EXPRESSION; TRANSGENIC MICE; MAMMALIAN-CELLS; BINDING PROTEIN; NERVOUS-SYSTEM; RECEPTOR GENE; TFIID SUBUNIT; HUMAN BRAIN AB Huntington's disease (HD) is an inherited neurodegenerative disease caused by expansion of a polyglutamine tract in the huntingtin protein. Transcriptional dysregulation has been implicated in HD pathogenesis. Here, we report that huntingtin interacts with the transcriptional activator Sp1 and coactivator TAFII130. Coexpression of Sp1 and TAFII130 in cultured striatal cells from wild-type and HD transgenic mice reverses the transcriptional inhibition of the dopamine D2 receptor gene caused by mutant huntingtin, as well as protects neurons from huntingtin-induced cellular toxicity. Furthermore, soluble mutant huntingtin inhibits Sp1 binding to DNA in postmortem brain tissues of both presymptomatic and affected HD patients. Understanding these early molecular events in HD may provide an opportunity to interfere with the effects of mutant huntingtin before the development of disease symptoms. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Ctr Aging Genet & Neurodegenerat, Charlestown, MA 02129 USA. NINCDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. NYU, Sch Med, Dept Microbiol MSB258, New York, NY 10016 USA. RP Krainc, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Neurol,Ctr Aging Genet & Neurodegenerat, Charlestown, MA 02129 USA. OI Tanese, Naoko/0000-0002-1946-3211; Mouradian, M. Maral/0000-0002-9937-412X; Standaert, David/0000-0003-2921-8348 FU NCCIH NIH HHS [AT00613]; NIA NIH HHS [5R37AG13617]; NINDS NIH HHS [NS02174, NS34361, NS35255] NR 42 TC 448 Z9 458 U1 2 U2 15 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 21 PY 2002 VL 296 IS 5576 BP 2238 EP 2243 DI 10.1126/science.1072613 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565PQ UT WOS:000176379000064 PM 11988536 ER PT J AU John, M Bridges, EA Miller, AO Calderwood, SB Ryan, ET AF John, M Bridges, EA Miller, AO Calderwood, SB Ryan, ET TI Comparison of mucosal and systemic humoral immune responses after transcutaneous and oral immunization strategies SO VACCINE LA English DT Article DE transcutaneous; oral; immunization ID SHIGELLA-SONNEI LIPOPOLYSACCHARIDE; ADP-RIBOSYLATING EXOTOXINS; ATTENUATED VACCINE STRAINS; VIBRIO-CHOLERAE VACCINE; FREE MOUSE MODEL; VECTOR STRAINS; B-SUBUNIT; HETEROLOGOUS ANTIGENS; PROTECTIVE IMMUNITY; ANTIBODY-RESPONSES AB In order to compare the ability of transcutaneous and oral immunization strategies to induce mucosal and systemic immune responses, we inoculated mice transcutaneously with cholera toxin (CT) or the non-toxic B subunit of cholera toxin (CtxB), or orally with Peru2(pETR1), an attenuated vaccine strain of Vibrio cholerae expressing CtxB. In addition, we also evaluated dual immunization regimens (oral inoculation with transcutaneous boosting, and transcutaneous immunization with oral boosting) in an attempt to optimize induction of both mucosal and systemic immune responses. We found that transcutaneous immunization with purified CtxB or CT induces much more prominent systemic IgG anti-CtxB responses than does oral inoculation with a vaccine vector strain of V cholerae expressing CtxB. In comparison, anti-CtxB I.-A in serum, stool and bile were comparable in mice either transcutaneously or orally immunized. Overall, the most prominent systemic and mucosal anti-CtxB responses occurred in mice that were orally primed with Peru2(pETR1) and transcutaneously boosted with CT. Our results suggest that combination oral and transcutaneous immunization strategies may most prominently induce both mucosal and systemic humoral responses. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Div Infect Dis, Trop & Geog Med Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Harvard Univ, Med Sch, Dept Med, Boston, MA 02115 USA. RP Ryan, ET (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Trop & Geog Med Ctr, 55 Fruit St,Jackson 504, Boston, MA 02114 USA. FU NIAID NIH HHS [K08 AI 01332, R01 AI040725, AI 40725]; NICHD NIH HHS [HD 39165, U01 HD039165] NR 33 TC 23 Z9 24 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 JUN 21 PY 2002 VL 20 IS 21-22 BP 2720 EP 2726 AR PII S0264-410X(02)00208-6 DI 10.1016/S0264-410X(02)00208-6 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 568JL UT WOS:000176538600012 PM 12034098 ER PT J AU Mahon, MJ Donowitz, M Yun, CC Segre, GV AF Mahon, MJ Donowitz, M Yun, CC Segre, GV TI Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling SO NATURE LA English DT Article ID OK CELLS; PROTEIN-BINDING; PHOSPHOLIPASE-C; PEPTIDE; DOMAIN; PDZ; INHIBITION; TRANSPORT; CALCIUM; PTH C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Gastroenterol, Baltimore, MD 21205 USA. RP Segre, GV (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. FU NIDDK NIH HHS [P01 DK044484, R01 DK061418] NR 31 TC 208 Z9 211 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 20 PY 2002 VL 417 IS 6891 BP 858 EP 861 DI 10.1038/nature00816 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563YM UT WOS:000176285600049 PM 12075354 ER PT J AU Delmonico, FL Arnold, R Scheper-Hughes, N Siminoff, LA Kahn, J Youngner, SJ AF Delmonico, FL Arnold, R Scheper-Hughes, N Siminoff, LA Kahn, J Youngner, SJ TI Sounding board - Ethical incentives - Not payment - For organ donation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PRESUMED CONSENT; KIDNEY C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15213 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. Univ Minnesota, Minneapolis, MN 55455 USA. RP Delmonico, FL (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Siminoff, Laura /H-6277-2012 NR 36 TC 121 Z9 123 U1 2 U2 12 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 20 PY 2002 VL 346 IS 25 BP 2002 EP 2005 DI 10.1056/NEJMsb013216 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 563QC UT WOS:000176266200012 PM 12075064 ER PT J AU Hasegawa, M Nelson, HH Peters, E Ringstrom, E Posner, M Kelsey, KT AF Hasegawa, M Nelson, HH Peters, E Ringstrom, E Posner, M Kelsey, KT TI Patterns of gene promoter methylation in squamous cell cancer of the head and neck SO ONCOGENE LA English DT Article DE p16(INK4a); DAP-kinase; RASSF1A; E-Cadherin; hypermethylation; oral cancer; head and neck cancer ID TUMOR-SUPPRESSOR GENE; E-CADHERIN EXPRESSION; CPG ISLAND; EPIGENETIC INACTIVATION; LUNG-CANCER; DNA HYPERMETHYLATION; BREAST CANCERS; HIGH-FREQUENCY; CARCINOMAS; RASSF1A AB Promoter methylation is an important pathway in transcriptional silencing of known and candidate tumor suppressor genes in Head and Neck Squamous Cell Carcinoma (HNSCC). In order to study the association of tumor suppressor gene promoter methylation in HNSCC with patient clinical characteristics, especially alcohol consumption and tobacco smoking, we examined promoter methylation of the p16(INK4a), DAP-kinase, E-Cadherin, and RASSF1A genes using methylation-specific PCR (MSP) in 80 patients. The prevalence of p16(INK4a), DAP-kinase, E-Cadherin, and RASSF1A promoter methylation was 26/80 (32.5%), 19/80 (23.8%), 29/80 (36.3%), 6/80 (7.5%) respectively. In 48 cases (60%), at least one of these promoters was methylated. There was a significant association of methylation of any of these genes and ever smoking (P=0.006). p16(INK4a), gene promoter methylation was associated with a younger age of smoking initiation (P<0.03); E-Cadherin promoter methylation was associated with an increased number of pack years smoked (P<0.03). We also found an association of methylation of any gene and T status (OR=2.7, P<0.05). Tumors with p16(INK4a) methylation were significantly less likely to show lymph node metastasis (P<0.001). DAP-kinase promoter methylation was significantly associated with lymph node metastasis and this relationship was dependent upon p16(INK4a) promoter methylation status. Our results suggest that, in HNSCC, promoter methylation of these four genes accumulates with increasing tumor size. This may reflect distinct pathways of somatic inactivation leading to cancer; additional larger studies are needed to further investigate this possibility. Tobacco smoking may play an important role in both the occurrence of promoter methylation as well as delineating the precise pathway that eventually results in a tumorigenic phenotype. C1 Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm Epidemiol Program, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Dent & Oral Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Adult Oncol, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. RP Kelsey, KT (reprint author), Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, Boston, MA 02115 USA. RI Kelsey, Karl/I-1252-2014; OI /0000-0003-4928-6532 FU NCI NIH HHS [CA78609]; NIDCR NIH HHS [1P01-DE12467-05]; NIEHS NIH HHS [ES00002, ES08357] NR 41 TC 136 Z9 143 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 20 PY 2002 VL 21 IS 27 BP 4231 EP 4236 DI 10.1038/sj.onc.1205528 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 562AA UT WOS:000176174200005 PM 12082610 ER PT J AU Johnson, BA Blackwell, TK AF Johnson, BA Blackwell, TK TI Multiple tristetraprolin sequence domains required to induce apoptosis and modulate responses to TNF alpha through distinct pathways SO ONCOGENE LA English DT Article DE tristetraprolin; TNF alpha; immediate-early; apoptosis; zinc finger ID NECROSIS-FACTOR-ALPHA; AU-RICH ELEMENTS; ACTIVATED PROTEIN-KINASE; ZINC-FINGER PROTEINS; MESSENGER-RNA DEGRADATION; NF-KAPPA-B; C-ELEGANS; TRANSCRIPTION FACTOR; CAENORHABDITIS-ELEGANS; CELL-DEATH AB Expression of the immediate early protein tristetraprolin (TTP) is induced by numerous stimuli, including tumor necrosis factor-alpha (TNFalpha). Evidence indicates that TTP limits production of TNFalpha and other cytokines by directly binding and destabilizing their mRNAs. This effect seems to require only the conserved TTP zinc finger region, and is characteristic of the related proteins TIS11b and TIS11d. TTP, TIS11b, and TIS11d each also induce apoptosis through the mitochondrial pathway analogously to certain oncogenes, suggesting that they influence growth or survival signals. Among TTP/TIS11 proteins, TTP alone also promotes apoptosis synergistically with TNFalpha. Here we show that other regions of TTP along with the zinc fingers are required for TTP to induce apoptosis. We also demonstrate that TTP acts through an additional pathway to sensitize cells to the pro-apoptotic stimulus of TNFalpha. This modulation of TNFalpha responses specifically requires the TTP N-terminal region, which is not conserved in TIS11b or TIS11d. We conclude that the physiological functions of TTP depend upon multiple regions of the TTP protein, that TTP has diverged functionally from TIS11b and TIS11d, and that modulation of TNFa responses may be a unique and important aspect of TTP function. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Blackwell, TK (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [1R01 CA84418] NR 58 TC 39 Z9 39 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 20 PY 2002 VL 21 IS 27 BP 4237 EP 4246 DI 10.1038/sj.onc.1205526 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 562AA UT WOS:000176174200006 PM 12082611 ER PT J AU Davis, HE Morgan, JR Yarmush, ML AF Davis, HE Morgan, JR Yarmush, ML TI Polybrene increases retrovirus gene transfer efficiency by enhancing receptor-independent virus adsorption on target cell membranes SO BIOPHYSICAL CHEMISTRY LA English DT Article DE recombinant retroviruses; gene therapy; retrovirus adsorption; polybrene ID MURINE LEUKEMIA; INFECTION; THERAPY; VECTOR; BINDING; TRANSDUCTION; ENVELOPE; SURFACE; IDENTIFICATION; ENHANCEMENT AB Cationic polymers, such as polybrene and protamine sulfate, are typically used to increase the efficiency of retrovirus-mediated gene transfer, however, the mechanism of their enhancement of transduction has remained unclear. As retrovirus transduction is fundamentally limited by the slow diffusion of virus to the target cell surface, we investigated the ability of polybrene to modulate this initial transport step. We compared the ability of both envelope (gp70) and capsid (p30) protein based assays to quantitate virus adsorption and found that p30 based assays were more reliable due to their ability to distinguish virus binding from free gp70 binding. Using the p30 based assay, we established that polybrene concentrations, which yielded 10-fold increases in transduction also, yielded a significant increase in virus adsorption rates on murine fibroblasts. Surprisingly, this enhancement, and adsorption in general, were receptor and envelope independent, as adsorption occurred equivalently on receptor positive and negative Chinese hamster ovary cells, as well as with envelope positive and negative virus particles. These findings suggest that the currently accepted physical model for early steps in retrovirus transduction may need to be reformulated to accommodate an initial adsorption step whose driving force does not include the retrovirus concentration, and the reclassification of currently designated `receptor' molecules as fusion triggers. The implication of these findings with respect to the development of targeted retrovirus-mediated gene therapy protocols is discussed. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Surg Serv,Ctr Engn Med, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA 02114 USA. Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. RP Yarmush, ML (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Surg Serv,Ctr Engn Med, Boston, MA 02114 USA. OI Morgan, Jeffrey/0000-0002-7546-3443 FU NICHD NIH HHS [P01HD 28528-07] NR 41 TC 69 Z9 73 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD JUN 19 PY 2002 VL 97 IS 2-3 BP 159 EP 172 AR PII S0301-4622(02)00057-1 DI 10.1016/S0301-4622(02)00057-1 PG 14 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 564AY UT WOS:000176292700006 PM 12050007 ER PT J AU Hlatky, L Hahnfeldt, P Folkman, J AF Hlatky, L Hahnfeldt, P Folkman, J TI Clinical application of antiangiogenic therapy: Microvessel density, what it does and doesn't tell us SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CANCER; BLOOD-VESSEL MATURATION; TUMOR ANGIOGENESIS; PROGNOSTIC-SIGNIFICANCE; MULTIPLE-MYELOMA; PROSTATE-CANCER; COLORECTAL-CANCER; BREAST-CANCER; BONE-MARROW C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02115 USA. Childrens Hosp, Dept Surg, Surg Res Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dept Surg, Cambridge, MA 02138 USA. RP Hlatky, L (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 136 TC 514 Z9 544 U1 1 U2 25 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 19 PY 2002 VL 94 IS 12 BP 883 EP 893 PG 11 WC Oncology SC Oncology GA 564PW UT WOS:000176323600006 PM 12072542 ER PT J AU Reis, SE Olson, MB Fried, L Reeser, V Mankad, S Pepine, CJ Kerensky, R Merz, CNB Sharaf, BL Sopko, G Rogers, WJ Holubkov, R AF Reis, SE Olson, MB Fried, L Reeser, V Mankad, S Pepine, CJ Kerensky, R Merz, CNB Sharaf, BL Sopko, G Rogers, WJ Holubkov, R TI Mild renal insufficiency is associated with angiographic coronary artery disease in women SO CIRCULATION LA English DT Article DE coronary artery disease; renal insufficiency; women ID SYNDROME EVALUATION WISE; FAILURE; INTERLEUKIN-6; MORTALITY; RISK AB Background-Mild renal insufficiency is associated with an increased risk for cardiovascular events in women with coronary artery disease (CAD). However, the relationship between mild renal insufficiency and atherosclerotic CAD in women is not known. Methods and Results-Women with chest pain who were referred for coronary angiography in the NHLBI Women's Ischemia Syndrome Evaluation (WISE) study underwent quantitative coronary angiography, blood measurements of creatinine, lipids, and homocysteine, and assessment of CAD risk factors. Fifty-six women had mild renal insufficiency (serum creatinine 1.2 to 1.9 mg/dL), and 728 had normal renal function (creatinine < 1.2 mg/dL). Creatinine correlated with angiographic CAD severity score (r=0.11, P<0.004) and maximum coronary artery stenosis (r=0.11, P<0.003). Compared with women with normal renal function, those with mild renal insufficiency were more likely to have significant angiographic CAD (greater than or equal to50% diameter stenosis in greater than or equal to1 coronary artery) (61% versus 37%; P<0.001) and CAD in multiple vessels (P<0.001 for association) and had greater maximum percent diameter coronary stenosis (59+/-35% versus 38+/-36%; P<0.001). Mild renal insufficiency was associated with significant angiographic CAD independent of age and risk factors (OR=1.9, 95%CI=1.1 to 3.5). After controlling for homocysteine in 509 women, mild renal insufficiency remained predictive of CAD (OR=3.2, 95%CI=1.4 to 7.2). Conclusions-In women with chest pain, mild renal insufficiency is an independent predictor of significant angiographic CAD. Mildly increased serum creatinine is probably a marker for unmeasured proatherogenic factors. C1 Univ Alabama, Div Cardiol, Birmingham, AL USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Rhode Isl Hosp, Div Cardiol, Providence, RI USA. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. Univ Florida, Div Cardiol, Gainesville, FL USA. W Penn Allegheny Hlth Syst, MCP Hahnemann Sch Med, Div Cardiol, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, VA Pittsburgh Healthcare Syst, Dept Med, Pittsburgh, PA 15213 USA. RP Reis, SE (reprint author), Univ Pittsburgh, Med Ctr, Cardiovasc Inst, 200 Lothrop St, Pittsburgh, PA 15213 USA. RI Reis, Steven/J-3957-2014 FU NHLBI NIH HHS [U01-HL64829-01, U01-HL64914-01, N01-HV-68164, N01-HV-68163, N01-HV-68161, N01-HV-68162, U01-HL64924-01] NR 14 TC 83 Z9 86 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 JUN 18 PY 2002 VL 105 IS 24 BP 2826 EP 2829 DI 10.1161/01.CIR.0000021597.63026.65 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 573FH UT WOS:000176818300008 PM 12070108 ER PT J AU Sinnaeve, P Chiche, JD Gillijins, H Van Pelt, N Wirthlin, D Van de Werf, F Collen, D Bloch, KD Janssens, S AF Sinnaeve, P Chiche, JD Gillijins, H Van Pelt, N Wirthlin, D Van de Werf, F Collen, D Bloch, KD Janssens, S TI Overexpression of a constitutively active protein kinase G mutant reduces neointima formation and in-stent restenosis SO CIRCULATION LA English DT Article DE kinases; nitric oxide; apoptosis; restenosis ID SMOOTH-MUSCLE CELLS; ADENOVIRUS-MEDIATED TRANSFER; SOLUBLE GUANYLYL CYCLASE; OXIDE SYNTHASE GENE; BALLOON INJURY; GMP; EXPRESSION; CGMP; PROLIFERATION; INCREASES AB Background-Neointima formation after arterial injury is associated with reduced vascular cyclic guanosine monophosphate (cGMP) and cGMP-dependent protein kinase (PKG), a major cGMP effector in vascular smooth muscle. We tested the effect of PKG overexpression on the neointimal response to vascular injury. Methods and Results Infection of cultured rat aortic smooth muscle cells (RASMCs) with an adenoviral vector specifying a cGMP-independent, constitutively active PKG mutant (AdPKGcat) reduced serum-induced migration by 33% and increased serum-deprivation-induced apoptosis 2-fold (P<0.05 for both). Infection with wild-type PKG (AdPKG), in the absence of cGMP, did not affect migration or apoptosis. Two weeks after balloon-injured rat carotid arteries were infected with 1 x 10(10) pfu AdPKGcat (n=12), AdPKG (n=8), or a control adenovirus (n=8), intima-to-media ratio was less in AdPKGcat-infected arteries than in AdPKG- or control adenovirus-infected vessels (0.26+/-0.06 versus 0.61+/-0.12 and 0.70+/-0.12, respectively, P<0.05 for both). Two weeks after intramural administration of 1.75 x 10(10) pfu AdPKGcat (n=8) or a control adenovirus (n=8) into porcine coronary arteries with in-stent restenosis, luminal diameter was greater in AdPKGcat-infected arteries than in control adenovirus-infected vessels (2.32+/-0.16 versus 1.81+/-0.13 mm, P=0.028), associated with reduced neointimal area (3.30+/-0.24 versus 4.15+/-0.13 mm(2), P=0.008), neointima-to-vessel area ratio (0.42+/-0.05 versus 0.58+/-0.04, P<0.05), and percent stenosis (45+/-6% versus 70+/-4%, P<0.05). Conclusions-Expression of a constitutively active PKG reduces neointima formation after balloon injury in rats and reduces coronary in-stent restenosis in pigs. PKGcat gene transfer may be a promising strategy for vasculoproliferative disorders. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. Katholieke Univ Leuven, Univ Hosp Gasthuisberg, Cardiac Unit, Louvain, Belgium. Flanders Interuniv Inst Biotechnol, Ctr Transgene Technol & Gene Therapy, Louvain, Belgium. RP Janssens, S (reprint author), Katholieke Univ Leuven, Cardiac Unit, Campus Gasthuisberg,Herestr 49, B-3000 Louvain, Belgium. OI Van de Werf, Frans/0000-0001-9479-7767 FU NHLBI NIH HHS [HL-57172] NR 24 TC 43 Z9 49 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 18 PY 2002 VL 105 IS 24 BP 2911 EP 2916 DI 10.1161/01.CIR.0000018169.59205.CA PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 573FH UT WOS:000176818300022 PM 12070122 ER PT J AU Goldrath, AW Sivakumar, PV Glaccum, M Kennedy, MK Bevan, MJ Benoist, C Mathis, D Butz, EA AF Goldrath, AW Sivakumar, PV Glaccum, M Kennedy, MK Bevan, MJ Benoist, C Mathis, D Butz, EA TI Cytokine requirements for acute and basal homeostatic proliferation of naive and memory CD8(+) T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE homeostasis; IL-7; IL-15; T cell numbers; memory ID IN-VIVO; INTERLEUKIN-7 RECEPTOR; DEFICIENT MICE; IL-7; SURVIVAL; LYMPHOCYTES; PHENOTYPE; ACTIVATION; EXPANSION; APOPTOSIS AB Both naive arid memory T cells undergo antigen-independent proliferation after transfer into a T cell-depleted environment (acute homeostatic proliferation), whereas only memory T cells slowly divide in a full T cell compartment (basal proliferation). We show, first, that naive and memory CD8(+) T cells have different cytokine requirements for acute homeostatic proliferation, Interleukin (IL)-7 receptor(R)alpha-mediated signals were obligatory for proliferation of naive T cells in lymphopenic hosts, whereas IL-15 did not influence their division. Memory T cells. on the other hand, could use either IL-7Ralpha- or IL-15-mediated signals for acute homeostatic proliferation: their proliferation was delayed when either IL-7Ralpha was blocked or IL-15 removed, but only, when both signals were absent was proliferation ablated. Second, the cytokine requirements for basal and acute homeostatic proliferation of CD8(+) memory T cells differ. as basal division of memory T cells was blocked completely in IL-15-deficient hosts. These data suggest a possible mechanism for the dearth of memory CD8(+) T cells in IL-15- arid IL-15Ralpha-deficient mice is their impaired basal proliferation. Our results show that naive and memory T lymphocytes differ in their cytokine dependence for acute homeostatic proliferation and that memory T lymphocytes have distinct requirements for proliferation in full versus empty compartments. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Sect Immunol & Immunogenet,Joslin Diabet Ctr, Boston, MA 02215 USA. Immunex Res & Dev Corp, Seattle, WA 98101 USA. Univ Washington, Dept Immunol, Seattle, WA 98195 USA. Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Goldrath, AW (reprint author), Joslin Diabet Ctr, Sect Immunol & Immunogenet, 1 Joslin Pl, Boston, MA 02215 USA. FU NIAID NIH HHS [AI51530-01, R01 AI051530, R37 AI051530] NR 32 TC 378 Z9 386 U1 0 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 17 PY 2002 VL 195 IS 12 BP 1515 EP 1522 DI 10.1084/jem.20020033 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 565DR UT WOS:000176354100002 PM 12070279 ER PT J AU Panigada, M Porcellini, S Barbier, E Hoeflinger, S Cazenave, PA Gu, H Band, H von Boehmer, H Grassi, F AF Panigada, M Porcellini, S Barbier, E Hoeflinger, S Cazenave, PA Gu, H Band, H von Boehmer, H Grassi, F TI Constitutive endocytosis and degradation of the pre-T cell receptor SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE c-Cbl; pre-TCR; T cell development; thymocyte; ubiquitin ID SYK TYROSINE KINASE; PHOSPHOTYROSINE-BINDING DOMAIN; CBL PROTOONCOGENE PRODUCT; GROWTH-FACTOR RECEPTOR; TCR ALPHA-CHAIN; GAMMA-DELTA; C-CBL; IMMATURE THYMOCYTES; NEGATIVE REGULATOR; ALLELIC EXCLUSION AB The pre-T cell receptor (TCR) signals constitutively in the absence of putative ligands on thymic stroma and signal transduction correlates with translocation of the pre-TCR, into glycolipid-enriched microdomains (rafts) in the plasma membrane. Here, we show that the pre-TCR, is constitutively routed to lysosomes after reaching the cell surface. The cell-autonomous down-regulation of the pre-TCR requires activation of the src-like kinase p56(lck) actin polymerization, and dynamin. Constitutive signaling and degradation represents a feature of the pre-TCR because the gammadeltaTCR expressed in the same cell line does not exhibit these features. This is also evident by the observation that the protein adaptor/ubiquitin ligase c-Cbl is phosphorylated and selectively translocated into rafts in pre-TCR- but riot gammadeltaTCR-expressing cells. A role of c-Cbl-mediated ubiquitination in pre-TCR, degradation is supported by the reduction of degradation through pharmacological inhibition of the proteasome and through a dominant-negative c-Cbl ubiquitin ligase as well as by increased pre-TCR surface expression on immature thymocytes in c-Cbl-deficient mice. The pre-TCR internalization contributes significantly to the low surface level of the receptor on developing T cells, and may in fact be a requirement for optimal pre-TCR function. C1 Univ Milan, Dipartimento Biol & Genet Sci Med, I-20133 Milan, Italy. Inst Pasteur, Dept Immunol, F-75724 Paris 15, France. Univ Paris 06, F-75005 Paris, France. Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Lymphocyte Biol Sect,Div Rheumatol Immunol & Alle, Boston, MA 02115 USA. NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA. RP Grassi, F (reprint author), Dana Farber Canc Inst, Dept Pathol, 1 Jimmy Fund Way, Boston, MA 02115 USA. NR 84 TC 50 Z9 50 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 17 PY 2002 VL 195 IS 12 BP 1585 EP 1597 DI 10.1084/jem.20020047 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 565DR UT WOS:000176354100009 PM 12070286 ER PT J AU Tantisira, KG Systrom, DM Ginns, LC AF Tantisira, KG Systrom, DM Ginns, LC TI An elevated breathing reserve index at the lactate threshold is a predictor of mortality in patients with cystic fibrosis awaiting lung transplantation SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE cystic fibrosis; lung transplantation; exercise; anaerobic threshold; mortality ID PRIMARY PULMONARY-HYPERTENSION; EXERCISE PERFORMANCE; SKELETAL-MUSCLE; ANAEROBIC THRESHOLD; CARBON-DIOXIDE; HEART-FAILURE; GAS-EXCHANGE; VENTILATION; PROGNOSIS; SURVIVAL AB The proportion of cystic fibrosis (CF) patients dying while on the lung transplant wait list remains high; identification of such patients remains difficult. The breathing reserve index (BRI = minute ventilation/maximal voluntary ventilation) at the lactate threshold (LT) is a predictor of a pulmonary mechanical limit to incremental exercise. We hypothesized that an elevated BRI at the LT in patients with CF awaiting lung transplantation would be a predictor of wait list mortality. Forty-five consecutive patients with CIF completed cardiopulmonary exercise testing as part of their pretransplant assessment. We evaluated BRI at LT, baseline demographic characteristics, pulmonary function, and other exercise parameters via Cox proportional hazards modeling. Fifteen patients died while awaiting transplant. Twenty one were transplanted, and nine still awaited transplantation. Relative risks from the multivariate model included (95% confidence interval in parentheses) BRI at LT, 17.52 (2.45-123.97); resting Pa-CO2, 1.29 (1.10-1.49); resting Pa-O2, 0.97 (0.90-1.05); and forced expiratory volume at one second as a percent of predicted, 1.19 (1.05-1.34). BRI at LT not only provided the highest point estimate of risk for wait list mortality but also identified a physiologically significant threshold value (0.70 or more) for those at risk. This measurement may allow improved timing of listing for transplantation, including consideration for living donor transplantation. C1 Massachusetts Gen Hosp, Lung Transplantat Program, Pulm & Crit Care Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Gen Med Serv, Pulm & Crit Care Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ginns, LC (reprint author), Massachusetts Gen Hosp, Lung Transplantat Program, Pulm & Crit Care Unit, Bigelow 808, Boston, MA 02114 USA. OI Systrom, David/0000-0002-9610-6330 FU NHLBI NIH HHS [K24: HL04022-02] NR 53 TC 28 Z9 29 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUN 15 PY 2002 VL 165 IS 12 BP 1629 EP 1633 DI 10.1164/rccm.2105090 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 566AB UT WOS:000176402200012 PM 12070064 ER PT J AU Tsuchiya, T Chida, K Suda, T Schneeberger, EE Nakamura, H AF Tsuchiya, T Chida, K Suda, T Schneeberger, EE Nakamura, H TI Dendritic cell involvement in pulmonary granuloma formation elicited by bacillus Calmette-Guerin in rats SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE dendritic cells; granuloma; BCG ID NAIVE B-CELLS; IN-VIVO; EXPRESSION; LYMPHOCYTES; ANTIGEN; COSTIMULATOR; TOLERANCE; IMMUNITY; INTEGRIN; OX-62 AB Dendritic cells (DCs) are the most potent antigen-presenting cells that play a central role in initiating the primary immune response. However, their role in granulomatous inflammation has not been well studied. The aim of the present study was to elucidate the role of DCs in granuloma formation, Using a rat model of bacillus Calmette-Guerin (BCG)-elicited pulmonary granulomas, we investigated the distribution of DCs in the granulomas by immunohistochemistry with a rat-DC-specific monoclonal antibody, OX62. We found numerous large, pleiomorphic OX62(+) cells accumulating at the borders of the pulmonary granulomas. The OX62(+) cells isolated from the granulomatous lung showed intense surface expression of major histocompatibility complex class II, B7-1 and B7-2, and a lack of T cell- and monocyte/macrophacle-specific markers. Their ultrastructural morphology was characteristic of DCs. Functionally, they had potent capacity to stimulate allogeneic T cells as well as purified protein derivative-specific syngeneic T cells in the absence of exogenous peptides. Based on these findings, the OX62+ cells infiltrating the granulomas were considered to be DCs expressing BCG-derived peptides. These results indicate that DCs contribute to pulmonary granuloma formation elicited by BCG by means of their potent antigen-presenting function, providing a novel insight into DC function in T cell-mediated granulomatous immune responses. C1 Hamamatsu Univ Sch Med, Dept Internal Med, Div 2, Hamamatsu, Shizuoka 4313192, Japan. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. RP Suda, T (reprint author), Hamamatsu Univ Sch Med, Dept Internal Med, Div 2, 3600 Handa Cho, Hamamatsu, Shizuoka 4313192, Japan. EM suda@hama-med.ac.jp FU NHLBI NIH HHS [HL36781] NR 28 TC 24 Z9 25 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUN 15 PY 2002 VL 165 IS 12 BP 1640 EP 1646 DI 10.1164/rccm.2110086 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 566AB UT WOS:000176402200014 PM 12070066 ER PT J AU Skodol, AE Gunderson, JG Pfohl, B Widiger, TA Livesley, WJ Siever, LJ AF Skodol, AE Gunderson, JG Pfohl, B Widiger, TA Livesley, WJ Siever, LJ TI The borderline diagnosis I: Psychopathology comorbidity, and personaltity structure SO BIOLOGICAL PSYCHIATRY LA English DT Article DE borderline; personality disorder; personality structure; diagnosis; psychopathology; comorbidity ID DSM-III-R; TEST-RETEST RELIABILITY; SUBSTANCE USE DISORDERS; ASSESSING AXIS II; EATING DISORDERS; CLINICAL INTERVIEW; ALCOHOLIC PATIENTS; SCID-II; CLASSIFICATION; DEPRESSION AB Borderline personality disorder (BPD) is a complex and serious mental disorder associated with severe functional impairment, substantial treatment utilization, and a high rate of mortality by suicide. Recently, BPD has become a focus of intensifying study. In Part I of this three-part article meant to provide a foundation to researchers on the current status of the borderline diagnosis and prospects for its future development, we examine the psychopathology, comorbidity, and personality structure of BPD. Although the descriptive characteristics of BPD are well-represented by DSM-IV diagnostic criteria, other important aspects of BPD psychopathology are not included. The descriptive criteria in conjunction with semistructured interviews have, however, increased the ability of investigators to diagnose BPD as reliably as many Axis I disorders. Frequent comorbidity of BPD with Axis I disorders necessitates a broad assessment of psychopathology to help account for clinical heterogeneity. Because of the absence of evidence of the validity of the diagnostic threshold for a categorical diagnosis of BPD, and because of the heterogeneity within the diagnosis, investigators should also supplement their DSM-IV diagnoses with assessments of underlying personality trait structures. Although there are a number of competing models of personality structure, they have remarkable convergence on a set of three to five basic personality dimensions. Biol Psychiatry 2002;51:936-950(C) 2002 Society of Biological Psychiatry. C1 New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02178 USA. McLean Hosp, Belmont, MA 02178 USA. Univ Iowa, Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. Univ Kentucky, Dept Psychol, Lexington, KY 40506 USA. Mt Sinai Sch Med, Dept Psychiat, Bronx, NY USA. Bronx Vet Adm Med Ctr, Bronx, NY USA. RP Skodol, AE (reprint author), New York State Psychiat Inst & Hosp, Box 121,1051 Riverside Dr, New York, NY 10032 USA. FU NIMH NIH HHS [MH 50839] NR 146 TC 365 Z9 373 U1 9 U2 42 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2002 VL 51 IS 12 BP 936 EP 950 AR PII S0006-3223(02)01324-0 DI 10.1016/S0006-3223(02)01324-0 PG 15 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 561WF UT WOS:000176165500002 PM 12062877 ER PT J AU Skodol, AE Siever, LJ Livesley, WJ Gunderson, JG Pfohl, B Widiger, TA AF Skodol, AE Siever, LJ Livesley, WJ Gunderson, JG Pfohl, B Widiger, TA TI The borderline diagnosis II: Biology, genetics, and clinical course SO BIOLOGICAL PSYCHIATRY LA English DT Article DE borderline; personality disorder; impulsive aggression; affective instability; genetics; course ID POSITRON-EMISSION-TOMOGRAPHY; NONVIOLENT MALE PAROLEES; TERM FOLLOW-UP; PERSONALITY-DISORDER; NOVELTY SEEKING; AXIS-II; PSYCHOMETRIC MEASUREMENTS; FAMILIAL TRANSMISSION; PSYCHIATRIC-DISORDERS; IMPULSIVE-AGGRESSION AB In Part I of this three-part article, consideration of the core features of BPD psychopathology, of comorbidity with Axis I disorders, and of underlying personality trait structure suggested that the borderline diagnosis might be productively studied from the perspective of dimensions of trait expression, in addition to that of the category itself In Part II, we review the biology, genetics, and clinical course of borderline personality disorder (BPD), continuing to attend to the utility of a focus on fundamental dimensions of psychopathology. Biological approaches to the study of personality can identify individual differences with both genetic and environmental influences. The aspects of personality disorder that are likely to have biologic correlates are those involving regulation of affects, impulse/action patterns, cognitive organization and anxiety/inhibition. For BPD, key psychobiological domains include impulsive aggression, associated with reduced serotonergic activity in the brain, and affective instability, associated with increased responsivity of cholinergic systems. There may be a strong genetic component for the development of BPD, but it seems clear, at least, that there are strong genetic influences on traits that underlie it, such as neuroticism, impulsivity, anxiousness, affective lability and insecure attachment. The course of BPD suggests a heterogenous disorder. Predictors of poor prognosis include history of childhood sexual abuse, early age at first psychiatric contact, chronicity of symptoms, affective instability, aggression, substance abuse, and increased comorbidity. For research purposes, at least, biological, genetic, and prognostic studies all continue to suggest the need to supplement categorical diagnoses of BPD with assessments of key underlying personality trait dimensions and with historical and clinical observations apart from those needed to make the borderline diagnosis itself Biol Psychiatry 2002;51:951-963 (C) 2002 Society of Biological Psychiatry. C1 New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Bronx Vet Adm Med Ctr, Dept Psychiat, New York, NY USA. Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02178 USA. McLean Hosp, Belmont, MA 02178 USA. Univ Iowa, Coll Med, Dept Psychiat, Iowa City, IA 52242 USA. Univ Kentucky, Dept Psychol, Lexington, KY 40506 USA. RP Skodol, AE (reprint author), New York State Psychiat Inst & Hosp, Box 121,1051 Riverside Dr, New York, NY 10032 USA. FU NIMH NIH HHS [MH 50839] NR 120 TC 192 Z9 194 U1 7 U2 28 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2002 VL 51 IS 12 BP 951 EP 963 AR PII S0006-3223(02)01325-2 DI 10.1016/S0006-3223(02)01325-2 PG 13 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 561WF UT WOS:000176165500003 PM 12062878 ER PT J AU Siever, LJ Torgersen, S Gunderson, JG Livesley, WJ Kendler, KS AF Siever, LJ Torgersen, S Gunderson, JG Livesley, WJ Kendler, KS TI The borderline diagnosis III: Identifying endophenotypes for genetic studies SO BIOLOGICAL PSYCHIATRY LA English DT Article DE borderline; endophenotype; genetic; familial ID PERSONALITY-DISORDER; FAMILIAL TRANSMISSION; SEROTONIN TRANSPORTER; IMPULSIVE-AGGRESSION; SCHIZOPHRENIA; RELATIVES; TWIN; SCHIZOTYPAL; ATTENTION; BEHAVIOR AB Although it is generally acknowledged that borderline personality disorder (BPD) has a complex, multifactorial etiology with interacting genetic and environmental substrates, the specific genetic underpinnings of this disorder have not been extensively investigated. Family aggregation studies suggest the heritability for BPD as a diagnosis, but the genetic basis for this disorder may be stronger for dimensions such as impulsivity/aggression and affective instability than for the diagnostic criteria itself. Family, adoptive, and twin studies also converge to support an underlying genetic component to the disorder. An endophenotypic approach to defining the genetics of this complex disorder may be called for. Twin studies in an epidemiologic, non-clinically ascertained sample using both diagnostic measures and laboratory measures that can be operationalized, including neuropsychologic, psychophysiologic, and operationalized behavioral tests, may be useful. Large-scale family studies of clinically ascertained samples with careful diagnostic demarcation and measurement of endophenotypes in probands and relatives may also prove to be a promising approach. The use of laboratory paradigms for measures of aggression and affective instability are discussed in the context of such endophenotypic approaches. Biol Psychiatry 2002;51: 964-968 (C) 2002 Society of Biological Psychiatry. C1 CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Univ Oslo, Dept Psychol, Ctr Res Clin Psychol, Oslo, Norway. McLean Hosp, Belmont, MA 02178 USA. Univ British Columbia, Dept Psychiat, Vancouver, BC, Canada. Virginia Commonwealth Univ, Med Coll Virginia, Dept Psychiat, Richmond, VA 23298 USA. RP Siever, LJ (reprint author), Bronx Vet Affairs Med Ctr, Dept Psychiat, 116A,130 W Kingsbridge Rd,Room 3B-20, Bronx, NY 10468 USA. NR 51 TC 125 Z9 126 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2002 VL 51 IS 12 BP 964 EP 968 AR PII S0006-3223(02)01326-4 DI 10.1016/S0006-3223(02)01326-4 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 561WF UT WOS:000176165500004 PM 12062879 ER PT J AU Green, MF Marder, SR Glynn, SM McGurk, SR Wirshing, WC Wirshing, DA Liberman, RP Mintz, J AF Green, MF Marder, SR Glynn, SM McGurk, SR Wirshing, WC Wirshing, DA Liberman, RP Mintz, J TI The neurocognitive effects of low-dose haloperidol: A two-year comparison with risperidone SO BIOLOGICAL PSYCHIATRY LA English DT Article DE cognitive deficits; schizophrenia; antipsychotic medications; risperidone; haloperidol; neurocognition ID SCHIZOPHRENIA; PERFORMANCE AB Background: Neurocognitive deficits are core features of schizophrenia that are linked to functional outcome for the disorder. Recent studies and reviews have concluded that newer antipsychotic medications are better for neurocognitive deficits than conventional antipsychotic medications; however, one difficulty in interpreting this literature is that the comparisons have mainly been with high doses of conventional medications. This study examined the neurocognitive effects of low-dose haloperidol compared with risperidone over a 2-year period. Methods: Sixty-two patients were randomly assigned to medication (starting at 6 mg of each medication) and administered neurocognitive batteries six times over the course of follow-up. At 6 months, the mean dose of haloperidol was 5.0 mg, and the mean dose of risperidone was 6.0 mg. Neurocognitive data were reduced into cluster scores and a global summary score. Results: We found no significant overall differences in treatment effects on the cluster scores or the global score. The global score revealed a significant group by time interaction, reflecting the fact that the haloperidol group tended to improve initially and then stay stable, whereas the risperidone group improved more gradually over the follow-up period. Conclusions: This study did not provide support for neurocognitive advantages of a newer antipsychotic medication over a low-dose conventional medication. We speculate that conventional medications May have neurocognitive benefits at low doses that are neutralized or reversed at higher doses. Biol Psychiatry 2002;51: 972-978 (C) 2002 Society of Biological Psychiatry. C1 Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Univ Calif Los Angeles, Vet Affairs VISN Mental Illness Res Educ & Clin C, Los Angeles, CA 90024 USA. RP Green, MF (reprint author), Univ Calif Los Angeles, Inst Neuropsychiat, 760 Westwood Plaza,C9-420, Los Angeles, CA 90024 USA. FU NIMH NIH HHS [MH41573] NR 27 TC 149 Z9 155 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2002 VL 51 IS 12 BP 972 EP 978 AR PII S0006-3223(02)01370-7 DI 10.1016/S0006-3223(02)01370-7 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 561WF UT WOS:000176165500006 PM 12062881 ER PT J AU Bagley, J Tian, CR Sachs, DH Iacomini, J AF Bagley, J Tian, CR Sachs, DH Iacomini, J TI Induction of T-cell tolerance to an MHC class I alloantigen by gene therapy SO BLOOD LA English DT Article ID BONE-MARROW; RETROVIRAL TRANSDUCTION; B-LYMPHOCYTES; STEM-CELLS; EXPRESSION; ALLOGRAFTS; ANTIGEN; MICE; PROLONGATION; MAINTENANCE AB Induction of immunologic tolerance to alloantigens is a major goal in the field of transplantation. Here, we demonstrate that efficient transduction and expression of a retrovirally transduced major histocompatibility complex (MHC) class I gene (H-2K(b)) in bone marrow (BM)-derived cells, resulting in a permanent state of hematopoletic molecular chimerism, induces stable tolerance to the transduced gene product. Reconstitution of lethally irradiated syngeneic recipients with BM transduced with virus encoding H-2K(b) resulted in life-long expression of the retroviral gene product on the surface of SM-derived hematopoletic lineages including Sca-1(+), lineage negative, hematopoietic progenitors. T cells from mice receiving MHC-transduced BM were unable to kill targets expressing H-2K(b) but were able to respond to third-party controls. Mice reconstituted with H-2K(b) transduced BM exhibited long-term acceptance of H-2K(b) mismatched skin grafts but were able to rapidly reject third-party control grafts. Thus, gene therapy approaches may be used to Induce T-cell tolerance. (C) 2002 by The American Society of Hematology. C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Iacomini, J (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, 149-5210 13th St, Boston, MA 02129 USA. FU NIAID NIH HHS [T32 AI07529, R01 AI43619] NR 26 TC 61 Z9 64 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 JUN 15 PY 2002 VL 99 IS 12 BP 4394 EP 4399 DI 10.1182/blood.V99.12.4394 PG 6 WC Hematology SC Hematology GA 559WA UT WOS:000176047800018 PM 12036867 ER PT J AU Burns, S Arcasoy, MO Li, L Kurian, E Selander, K Emanuel, PD Harris, KW AF Burns, S Arcasoy, MO Li, L Kurian, E Selander, K Emanuel, PD Harris, KW TI Purification and characterization of the yeast-expressed erythropoietin mutant Epo (R103A), a specific inhibitor of human primary hematopoietic cell erythropoiesis SO BLOOD LA English DT Article ID ERYTHROID PROGENITOR CELLS; FAMILIAL ERYTHROCYTOSIS; EXTRACELLULAR DOMAIN; RECEPTOR ACTIVATION; BIOLOGICAL-ACTIVITY; HIGH-AFFINITY; SICKLE; DIMERIZATION; PROTEINS; GROWTH AB A drug that specifically inhibits erythropoiesis would be clinically useful. The erythropoietin (Epo) mutant Epo (R103A) could potentially be used for this purpose. Epo (R103A) has a single amino acid substitution of alanine for arginine at position 103. Because of this mutation, Epo (R103A) is only able to bind to one of the 2 subunits of the erythropoietin receptor (EpoR) homodimer and is thus a competitive inhibitor of Epo activity. To produce large quantities of Epo (R103A) to test in animal models of thalassemia and sickle cell disease, we expressed and purified recombinant Epo (R103A) from the yeast Pichia pastoris. Using this method milligram quantities of highly purified Epo (R103A) are obtained. The yeast-expressed Epo (R103A) is properly processed and glycosylated and specifically inhibits Epo-dependent cell growth and I-125-Epo binding. Epo (R103A) does not, however, directly induce apoptosis in 32D cells expressing EpoR. Epo (R103A) inhibits erythropoiesis of human CD34(+) hematopoietic cells and completely blocks erythroid burst-forming unit formation in normal human bone marrow colony assays. Yeast-expressed Epo (R103A) is a specific inhibitor of primary erythropoiesis suitable for testing in animal models. (C) 2002 by The American Society of Hematology. C1 Univ Alabama, Wallace Tumor Inst, Div Hematol Oncol, Dept Med, Birmingham, AL 35294 USA. S Texas Vet Hlth Care Syst, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, Div Hematol, Dept Med, San Antonio, TX USA. Duke Univ, Med Ctr, Div Hematol Oncol, Dept Med, Durham, NC USA. Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Harris, KW (reprint author), Univ Alabama, Wallace Tumor Inst, Div Hematol Oncol, Dept Med, 520-D,1530 3rd Ave S, Birmingham, AL 35294 USA. OI Emanuel, Peter/0000-0002-9764-2434 FU NIDDK NIH HHS [DK-02566] NR 29 TC 6 Z9 6 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 JUN 15 PY 2002 VL 99 IS 12 BP 4400 EP 4405 DI 10.1182/blood.V99.12.4400 PG 6 WC Hematology SC Hematology GA 559WA UT WOS:000176047800019 PM 12036868 ER PT J AU Zhang, P Nelson, E Radomska, HS Iwasaki-Arai, J Akashi, K Friedman, AD Tenen, DG AF Zhang, P Nelson, E Radomska, HS Iwasaki-Arai, J Akashi, K Friedman, AD Tenen, DG TI Induction of granulocytic differentiation by 2 pathways SO BLOOD LA English DT Article ID ENHANCER-BINDING-PROTEIN; HEMATOPOIETIC STEM-CELLS; STIMULATING FACTOR RECEPTORS; ALPHA C/EBP-ALPHA; MYELOID PROGENITORS; KNOCKOUT MICE; RAR-ALPHA; IN-VIVO; LEUKEMIA; PU.1 AB The CCAAT enhancer binding protein alpha (C/EBPalpha) transcription factor plays a critical role in granulocytopoiesis. Mice with a disruption of the C/EBPalpha gene demonstrate an early block in granulocytic differentiation, and disruption of C/EBPalpha function is a common theme in many types of human acute myelogenous leukemia, which is characterized by a block in myeloid development. To characterize further the nature of this block, we derived ell lines from the fetal liver of C/EBPalpha-deficient animals. These lines resembled morphologically the immature myeloid blasts observed in C/EBPalpha(-/-) fetal livers and did not express messenger RNA encoding early myeloid genes such as myeloperoxidase. Similarly, granulocytic markers such as Mac-1 and Gr-1 were not expressed; nor were erythroid and lymphoid surface antigens. Introduction of an inducible C/EBPalpha gene into the line revealed that conditional expression of C/EBPalpha induced the C/EBP family members C/EBPbeta and C/EBPepsilon and subsequent granulocyte differentiation. Similar results were obtained when C/EBPalpha(-/-) cells were stimulated with the cytokines interleukin-3 and granulocyte-macrophage colony-stimulating factor, but not with all-trans retinoic acid, supporting a model of at least 2 pathways leading to the differentiation of myeloid progenitors to granulocytes and implicating induction of other C/EBP family members in granulopoiesis. (C) 2002 by The American Society of Hematology. C1 Harvard Univ, Sch Med, Inst Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Johns Hopkins Univ, Baltimore, MD USA. RP Tenen, DG (reprint author), Harvard Univ, Sch Med, Inst Med, Rm 954,77 Ave Louis Pasteur, Boston, MA 02115 USA. FU NCI NIH HHS [CA72009]; NHLBI NIH HHS [HL56745] NR 44 TC 56 Z9 61 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 JUN 15 PY 2002 VL 99 IS 12 BP 4406 EP 4412 DI 10.1182/blood.V99.12.4406 PG 7 WC Hematology SC Hematology GA 559WA UT WOS:000176047800020 PM 12036869 ER PT J AU Peyton, KJ Reyna, SV Chapman, GB Ensenat, D Liu, XM Wang, H Schafer, AI Durante, W AF Peyton, KJ Reyna, SV Chapman, GB Ensenat, D Liu, XM Wang, H Schafer, AI Durante, W TI Heme oxygenase-1-derived carbon monoxide is an autocrine inhibitor of vascular smooth muscle cell growth SO BLOOD LA English DT Article ID OXIDATIVE STRESS; GENE-EXPRESSION; OXYGENASE; INJURY; INDUCTION; PROTEIN; RATS AB Vascular smooth muscle cells (SMCs) generate carbon monoxide (CO) via the catabolism of heme by the enzyme heme oxygenase (HO). In the present study, we found that serum stimulated a time- and concentration-dependent increase in the levels of HO-1 messenger RNA (mRNA) and protein in vascular SMCs. The induction of HO-1 expression by serum was inhibited by actinomycin D or cycloheximide. In addition, serum stimulated HO activity, as reflected by an increase in the concentration of bilirubin in the culture media. Treatment of vascular SMCs with serum stimulated DNA synthesis and this was potentiated by the HO inhibitors, zinc and tin protoporphyrin-IX as well as by the CO scavenger, hemoglobin. The iron chelator desferrioxamine had no effect on DNA synthesis. However, exposure of vascular SMCs to exogenous CO inhibited serum-stimulated SMC proliferation and the phosphorylation of retinoblastoma protein. In addition, CO arrested SMCs at the Gills transition phase of the cell cycle and selectively blocked the serum-stimulated expression of cyclin A mRNA and protein without affecting the expression of cyclin D1 and E. CO also inhibited the serum-stimulated activation of cyclin A-associated kinase activity and cyclin-dependent kinase 2 activity. These results demonstrate that serum stimulates HO-1 gene expression and CO synthesis. Furthermore, they show that CO acts in a negative feedback fashion to inhibit vascular SMC growth by regulating specific components of the cell cycle machinery. The capacity of vascular mitogens to induce CO synthesis may provide a novel mechanism by which these agents modulate cell growth. (C) 2002 by The American Society of Hematology. C1 Houston VA Med Ctr, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Dept Pharmacol, Houston, TX 77030 USA. RP Durante, W (reprint author), Houston VA Med Ctr, Bldg 109,Rm 130,2002 Holcombe Blvd, Houston, TX 77030 USA. FU NHLBI NIH HHS [HL36045, HL59976, HL62467] NR 33 TC 127 Z9 142 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2002 VL 99 IS 12 BP 4443 EP 4448 DI 10.1182/blood.V99.12.4443 PG 6 WC Hematology SC Hematology GA 559WA UT WOS:000176047800025 PM 12036874 ER PT J AU Mitsiades, N Mitsiades, CS Poulaki, V Chauhan, D Richardson, PG Hideshima, T Munshi, NC Treon, SP Anderson, KC AF Mitsiades, N Mitsiades, CS Poulaki, V Chauhan, D Richardson, PG Hideshima, T Munshi, NC Treon, SP Anderson, KC TI Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications SO BLOOD LA English DT Article ID NF-KAPPA-B; DEXAMETHASONE-INDUCED APOPTOSIS; OVERCOMES DRUG-RESISTANCE; GROWTH-FACTOR-I; INHIBITOR; ACTIVATION; DEATH; TRAIL/APO2L; MODULATION; INDUCTION AB Thalidomide (Thai) achieves responses even in the setting of refractory multiple myeloma (MM). Although increased angiogenesis in MM bone marrow and the antiangiogenic effect of Thai formed the empiric basis for its use in MM, we have shown that Thal and its immunomodulatory analogs (IMIDs) directly induce apoptosis or growth arrest of MM cells, alter adhesion of MM cells to bone marrow stromal cells, inhibit the production of cytokines (interleukin-6 and vascular endothelial growth factor in bone marrow, and stimulate natural killer cell anti-MM immunity. In the present study, we demonstrate that the IMIDs trigger activation of caspase-8, enhance MM cell sensitivity to Fas-induced apoptosis, and down-regulate nuclear factor (NF)-kappaB activity as well as expression of cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein. IMiDs also block the stimulatory effect of insulinlike growth factor-1 on NF-kappaB activity and potentiate the activity of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), dexamethasone, and proteasome inhibitor (PS-341) therapy. These studies both delineate the mechanism of action of IMIDs against MM cells in vitro and form the basis for clinical trials of these agents, alone and coupled with conventional and other novel therapies, to improve outcome in MM. (C) 2002 by The American Society of Hematology. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Res Lab, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU PHS HHS [P0-1 78378] NR 35 TC 452 Z9 469 U1 2 U2 14 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2002 VL 99 IS 12 BP 4525 EP 4530 DI 10.1182/blood.V99.12.4525 PG 6 WC Hematology SC Hematology GA 559WA UT WOS:000176047800035 PM 12036884 ER PT J AU Million, RP Aster, J Gilliland, DG Van Etten, RA AF Million, RP Aster, J Gilliland, DG Van Etten, RA TI The Tel-Abl (ETV6-Abl) tyrosine kinase, product of complex (9;12) translocations in human leukemia, induces distinct myeloproliferative disease in mice SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOMONOCYTIC LEUKEMIA; HEMATOPOIETIC-CELL LINES; BCR-ABL; ETV6/ABL FUSION; SIGNALING PATHWAYS; BONE-MARROW; INDUCTION AB Several patients with clinical features of chronic myeloid leukemia (CML) have fusion of the TEL (ETV6) gene on 12p13 with ABL on 9q34 and express a chimeric Tel-Abl protein that contains the same portion of the Abl tyrosine kinase fused to Tel, an Ets family transcription factor, rather than Bcr. In a murine retroviral bone marrow transcduction-transplantation model, a Tel (exon 1-5)-Abl fusion protein induced 2 distinct illnesses: a CIVIL-like myeloproliferative disease very similar to that induced by Bcr-Abl but with increased latency and a novel syndrome characterized by small-bowel myeloid cell infiltration and necrosis, increased circulating endotoxin and tumor necrosis factor a levels, and fulminant hepatic and renal failure. Induction of both diseases required the Tel pointed homology oligomerization domain and Abl tyrosine kinase activity. Myeloid cells from mice with both diseases expressed Tel-Abl protein. CML-like disease induced by Tel-Abl and Bcr-Abl was polyclonal and originated from cells with multilineage (myeloid, erythroid, and B- and T-lymphoid) repopulating ability and the capacity to generate day-12 spleen colonies In secondary transplantations. In contrast to findings with Bcr-Abl, however, neither Tel-Abl-induced disease could be adoptively transferred to Irradiated secondary recipient syngeneic mice. These results show that Tel-Abl has leukemogenic properties from distinct from those of Bcr-Abl and may act in a different bone marrow progenitor. (C) 2002 by The American Society of Hematology. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Genet, Boston, MA 02115 USA. Harvard Inst Med, Boston, MA USA. Harvard Univ, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Van Etten, RA (reprint author), Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA09595, CA66996, CA90576]; NIDDK NIH HHS [DK50654] NR 33 TC 33 Z9 35 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 JUN 15 PY 2002 VL 99 IS 12 BP 4568 EP 4577 DI 10.1182/blood-2001-12-0244 PG 10 WC Hematology SC Hematology GA 559WA UT WOS:000176047800041 PM 12036890 ER PT J AU Li, SL Valente, AJ Qiang, M Schlegel, W Gamez, M Clark, RA AF Li, SL Valente, AJ Qiang, M Schlegel, W Gamez, M Clark, RA TI Multiple PU.1 sites cooperate in the regulation of p40(phox) transcription during granulocytic differentiation of myeloid cells SO BLOOD LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; PHAGOCYTE NADPH OXIDASE; RESPIRATORY BURST OXIDASE; PERIPHERAL-BLOOD PROGENITORS; SEQUENCE-BINDING PROTEIN; CYTOSOLIC COMPONENT; HL-60 CELLS; SH3 DOMAIN; GP91(PHOX) EXPRESSION; MICROBICIDAL OXIDASE AB The p40(phox) protein, a regulatory component of the phagocyte NADPH oxidase, is preferentially expressed in cells of myeloid lineage. We investigated transcriptional regulation of the p40(phox) gene in HL-60 myeloid cells. Deletion analysis of approximately 6 kb of the 5'-flanking sequence of the gene demonstrated that the proximal 106 base pair of the promoter exhibited maximum reporter activity. This region contains 3 potential binding sites for PU.1, a myeloid-restricted member of the ets family of transcription factors. Mutation or deletion of each PU.1 site decreased promoter activity and the level of activity mediated by each site correlated with its binding avidity for PU.1, site determined by gel shift competition assays. Mutation of all 3 sites abolished promoter activity in myeloid cells. PU.1 dependent expression was also observed in the Raji B-cell line, whereas the moderate level of promoter reporter activity in the nonmyeloid HeLa cell line was independent of PU.1. Chromatin immuno-precipitation assay demonstrated occupation of the PU.1 sites by PU.1 in vivo in HL-60 cells, Cotransfection of the pGL3-p40-106 reporter construct with a dominant-negative PU.1 mutant dramatically reduced promoter activity, whereas the overexpression of PU.1 increased promoter activity. Promoter activity and transcript levels of p40(phox) increased in HL-60 cells during dimethyl sulfoxide-induced differentiation toward the granulocyte phenotype, and this was associated with increased cellular levels of PU.1 protein. Our findings demonstrate that PU.1 binding at multiple sites is required for p40(phox) gene transcription In myeloid cells and that granulocytic differentiation is associated with the coordinated up-regulation of PU.1 and P40(phox) expression. (C) 2002 by The American Society of Hematology. C1 Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. Univ Geneva, Fdn Rech Med, Geneva, Switzerland. RP Clark, RA (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NIAID NIH HHS [R01 AI020866, AI20866, R37 AI020866] NR 70 TC 25 Z9 25 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 JUN 15 PY 2002 VL 99 IS 12 BP 4578 EP 4587 DI 10.1182/blood.V99.12.4578 PG 10 WC Hematology SC Hematology GA 559WA UT WOS:000176047800042 PM 12036891 ER PT J AU Bellucci, R Alyea, EP Weller, E Chillemi, A Hochberg, E Wu, CJ Canning, C Schlossman, R Soiffer, RJ Anderson, KC Ritz, J AF Bellucci, R Alyea, EP Weller, E Chillemi, A Hochberg, E Wu, CJ Canning, C Schlossman, R Soiffer, RJ Anderson, KC Ritz, J TI Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; GRAFT-VERSUS-LEUKEMIA; T-CELL REPERTOIRE; POLYMERASE CHAIN-REACTION; BONE-MARROW; IMMUNE RECONSTITUTION; LEUKOCYTE INFUSIONS; B-CELL; HEMATOPOIETIC CHIMERISM; THYMIC EMIGRANTS AB Reconstitution of T-cell immunity after bone marrow transplantation (BMT) is often delayed, resulting in a prolonged period of immunodeficiency. Donor lymphocyte infusion (DLI) has been used to enhance graft-versus-leukemia activity after BMT, but the effects of DLI on immune reconstitution have not been established. We studied 9 patients with multiple myeloma who received myeloalblative therapy and T-cell-depleted allogeneic BMT followed 6 months later by infusion of lymphocytes from the same donor. DLI consisted of 3 X 10(7) CD4(+) donor T cells per kilogram obtained after in vitro depletion of CD8(+) cells. Cell surface phenotype of peripheral lymphocytes, T-cell receptor (TCR) Vbeta repertoire, TCR rearrangement excision circles (TRECs), and hematopoietic chimerism were studied in the first 6 months after BMT and for I year after DLI. These studies were also performed in 7 patients who received similar myeloablative therapy and BMT but without DLI. Phenotypic reconstitution of T and natural killer cells was similar in both groups, but patients who received CD4(+) DLI developed increased numbers of CD20(+) B cells. TCR Vbeta repertoire complexity was decreased at 3 and 6 months after BMT but Improved more rapidly in patients who received DLI (P = .01). CD4(+) DLI was also associated with increased numbers of TRECs In CD3(+) T cells (P < .001) and with conversion to complete donor hematopoiesis (P = .05). These results provide evidence that prophylactic infusion of CD4(+) donor lymphocytes 6 months after BMT enhances reconstitution of donor T cells and conversion to donor hematopoiesis as well as promoting antitumor Immunity. (C) 2002 by The American Society of Hematology. C1 Dana Farber Canc Inst, Ctr Hematol Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Ritz, J (reprint author), Dana Farber Canc Inst, Ctr Hematol Oncol, 44 Binney St,M530, Boston, MA 02115 USA. RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 FU NCI NIH HHS [CA78378]; NHLBI NIH HHS [HL04293]; NIAID NIH HHS [AI29530] NR 44 TC 52 Z9 56 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 JUN 15 PY 2002 VL 99 IS 12 BP 4610 EP 4617 DI 10.1182/blood.V99.12.4610 PG 8 WC Hematology SC Hematology GA 559WA UT WOS:000176047800046 PM 12036895 ER PT J AU Testa, U Torelli, GF Riccioni, R Muta, AO Militi, S Annino, L Mariani, G Guarini, A Chiaretti, S Ritz, J Mandell, F Peschle, C Foa, R AF Testa, U Torelli, GF Riccioni, R Muta, AO Militi, S Annino, L Mariani, G Guarini, A Chiaretti, S Ritz, J Mandell, F Peschle, C Foa, R TI Human acute stem cell leukemia with multilineage differentiation potential via cascade activation of growth factor receptors SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; FLOW-CYTOMETRY; B-LINEAGE; EXPRESSION; DIAGNOSIS; IMMUNOPHENOTYPE; PROGENITORS; RELAPSE; ADULT AB The morphologic, immunophenotypic, genotypic, genomic, and functional features of an undifferentiated acute leukemia with stem cell features are reported. At light and electron microscopy, the leukemic population was represented by primitive progenitor cells with no evidence of differentiation. The blasts were CD34(+), AC133(+), CD71(-), HLA-DR-, CD38(-/dim+), CD90(+), CD117(dim+), flt3(+); did not express B, T, or myeloid-associated antigens; and showed a germline configuration of the immunoglobulin and T-cell receptor. Genomic profiling documented the expression of early stem cell and myeloid-associated genes. Receptors for early-acting hemopoietic growth factors (HGFs) were detected, while receptors for unilineage HGF were not expressed. Incubation with the flt3 or Kit ligand induced the expression of unilineage HGF receptors, allowing these cells to respond to their respective ligands. Growth without differentiation was sustained only In the presence of early-acting HGF, namely flt3 ligand, while early and unilineage HGF gave rise to all types of hemopoietic colonies. (C) 2002 by The American Society of Hematology. C1 Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, I-00161 Rome, Italy. Ist Super Sanita, Dept Hematol Oncol, I-00161 Rome, Italy. Univ Roma La Sapienza, Dept Expt Med & Pathol, I-00161 Rome, Italy. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Thomas Jefferson Univ, Kimmel Canc Inst, Philadelphia, PA 19107 USA. RP Foa, R (reprint author), Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, Via Benevento 6, I-00161 Rome, Italy. RI Ritz, Jerome/C-7929-2009; Testa, ugo/J-6472-2016 OI Ritz, Jerome/0000-0001-5526-4669; Testa, ugo/0000-0001-7900-8942 NR 23 TC 10 Z9 11 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 JUN 15 PY 2002 VL 99 IS 12 BP 4634 EP 4637 DI 10.1182/blood.V99.12.4634 PG 4 WC Hematology SC Hematology GA 559WA UT WOS:000176047800051 PM 12036900 ER PT J AU Fuchs, CS Clark, JW Ryan, DP Kulke, MH Kim, H Earle, CC Vincitore, M Mayer, RJ Stuart, KE AF Fuchs, CS Clark, JW Ryan, DP Kulke, MH Kim, H Earle, CC Vincitore, M Mayer, RJ Stuart, KE TI A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma SO CANCER LA English DT Article DE hepatocellular carcinoma; gemcitabine; chemotherapy; Phase II trial ID THERAPY; EXPRESSION; HEPATOMA AB BACKGROUND. There is no effective systemic therapy for patients with hepatocellular carcinoma. A recent trial reported a moderate antitumor activity for gemcitabine among Asian patients with advanced hepatocellular carcinoma. This led to our examination of the efficacy and tolerability of the drug in a population of U.S. patients. METHODS. Thirty patients with measurable, unresectable, or metastatic hepatocellular carcinoma who had received at least one previous form of systemic therapy were enrolled. All patients were required to have adequate major organ function 4 and performance status. Patients received gemcitabine (1000 mg/m(2) intravenously over 30 minutes weekly) for 3 consecutive weeks followed by a 1-week rest. Patients were assessed radiographically every 8 weeks. RESULTS. All 30 patients were evaluable for response and toxicity. Ninety cycles of 2 therapy were administered (median 2, range 1-8). No complete or partial responses were observed. Nine patients (30%) had stable disease (median duration 7.4 months, range 2-17). Median survival for all 30 patients was 6.9 months (95% confidence interval, 4.5-13.5) and the 1-year survival rate was 40%. Mild hematologic toxicity occurred. Two patients (7%) developed Grade 4 neutropenia and one patient (3%) experienced Grade 3 thrombocytopenia. There were no episodes of febrile neutropenia. One patient who had previously undergone orthotopic liver transplantation developed hemolytic-uremic syndrome that resolved with discontinuation of chemotherapy and plasmapheresis. CONCLUSIONS. Although generally well tolerated, gemcitabine had minimal effect in patients with advanced hepatocellular carcinoma. (C) 2002 American Cancer Society. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA 02215 USA. RP Fuchs, CS (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 23 TC 59 Z9 60 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 15 PY 2002 VL 94 IS 12 BP 3186 EP 3191 DI 10.1002/cncr.10607 PG 6 WC Oncology SC Oncology GA 564GA UT WOS:000176305600015 PM 12115351 ER PT J AU Wahlberg, SS Schmeits, J Thomas, G Loda, M Garber, H Syngal, S Kolodner, RD Fox, E AF Wahlberg, SS Schmeits, J Thomas, G Loda, M Garber, H Syngal, S Kolodner, RD Fox, E TI Evaluation of microsatellite instability and inummohistochemistry for the prediction of germ-line MSH2 and MLH1 mutations in hereditary nonpolyposis colon cancer families SO CANCER RESEARCH LA English DT Article ID DNA-MISMATCH-REPAIR; COLORECTAL-CANCER; CELL-LINES; BETHESDA GUIDELINES; HMLH1; HMSH2; EXPRESSION; TUMORS; GENES; IMMUNOHISTOCHEMISTRY AB Forty-eight hereditary nonpolyposis colorectal carcinoma (HNPCC) families for which a tumor sample was available were evaluated for the presence of germ-line mutations in MSH2 and MLH1, tumor microsatellite instability (MSI), and where possible, expression of MSH2 and MLH1 in tumors by immunohistochemistry. Fourteen of 48 of the families had a germ-line mutation in either MSH2 or MLH1 that could be detected by genomic DNA sequencing, and 28 of 48 of the families had MSI-H tumors. Four additional families showed loss of expression of MSH2, and one additional family showed loss of expression of MLH1 but did not have germ-line mutations in MSH2 or MLH1 that could be detected by DNA sequencing. MSI-H, as defined using the National Cancer Institute recommended five-microsatellite panel, had a 100% sensitivity for identifying samples having MSH2 or MLH1 mutations or loss of expression. In contrast, loss of MSH2 and MLH1 expression did not identify all samples having germ-line mutations in MSH2 or MLH1, because in 5 five cases, a mutant protein product was expressed that could be detected by 1HC. A combination of the Bethesda criteria for HNPCC and an MSI-H phenotype defined the smallest number of cases having all of the germ-line MSH2 and MLH1 mutations that could be detected by DNA sequencing. C1 Univ Calif San Diego, Ludwig Inst Canc Res, Sch Med, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Ctr Canc, Sch Med, La Jolla, CA 92093 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kolodner, RD (reprint author), Univ Calif San Diego, Ludwig Inst Canc Res, Sch Med, Dept Med, CMME3080,9500 Gilman Dr, La Jolla, CA 92093 USA. NR 46 TC 141 Z9 144 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 15 PY 2002 VL 62 IS 12 BP 3485 EP 3492 PG 8 WC Oncology SC Oncology GA 562NB UT WOS:000176203500025 PM 12067992 ER PT J AU Wigen, CL Goetz, MB AF Wigen, CL Goetz, MB TI Serotonin syndrome and linezolid SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material AB We present a case of serotonin syndrome in a patient who initiated linezolid therapy shortly after discontinuation of therapy with a selective serotonin reuptake inhibitor (paroxetine). C1 VA Greater Los Angeles Healthcare Syst, Dept Med, Infect Dis Sect, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. RP Goetz, MB (reprint author), VA Greater Los Angeles Healthcare Syst, Dept Med, Infect Dis Sect, 111-F,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. OI Goetz, Matthew/0000-0003-4542-992X NR 9 TC 50 Z9 51 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 15 PY 2002 VL 34 IS 12 BP 1651 EP 1652 DI 10.1086/340710 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 559CC UT WOS:000176006400018 PM 12032904 ER PT J AU Kaelin, WG AF Kaelin, WG TI How oxygen makes its presence felt SO GENES & DEVELOPMENT LA English DT Editorial Material ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; HIPPEL-LINDAU PROTEIN; MITOCHONDRIAL RESPIRATORY-CHAIN; PROLYL 4-HYDROXYLASE; TRANSCRIPTIONAL ACTIVITY; STRUCTURAL BASIS; HIF-ALPHA; IN-VITRO; VHL; HYDROXYLATION C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Kaelin, WG (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst, 44 Binney St, Boston, MA 02115 USA. EM william_kaelin@dfci.harvard.edu NR 41 TC 116 Z9 127 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 15 PY 2002 VL 16 IS 12 BP 1441 EP 1445 DI 10.1101/gad.1003602 PG 5 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 566XJ UT WOS:000176453300001 PM 12080083 ER PT J AU Fingar, DC Salama, S Tsou, C Harlow, E Blenis, J AF Fingar, DC Salama, S Tsou, C Harlow, E Blenis, J TI Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E SO GENES & DEVELOPMENT LA English DT Article DE mTOR; S6K1; eIF4E; 4EBP1; size; growth ID MESSENGER-RNA TRANSLATION; PHOSPHOINOSITIDE 3-KINASE; SIGNALING PATHWAY; CONSERVED SERINE; GENE-EXPRESSION; ORGAN GROWTH; IN-VIVO; RAPAMYCIN; DROSOPHILA; KINASE AB The coordinated action of cell cycle progression and cell growth (an increase in cell size and cell mass) is critical for sustained cellular proliferation, yet the biochemical signals that control cell growth are poorly defined, particularly in mammalian systems. We find that cell growth and cell cycle progression are separable processes in mammalian cells and that growth to appropriate cell size requires mTOR- and PI3K-dependent signals. Expression of a rapamycin-resistant mutant of mTOR rescues the reduced cell size phenotype induced by rapamycin in a kinase-dependent manner, showing the evolutionarily conserved role of mTOR in control of cell growth. Expression of S6K1 mutants that possess partial rap amycin-resistant activity or overexpression of eIF4E individually and additively partially rescues the rapamycin-induced decrease in cell size. In the absence of rapamycin, overexpression of S6K1 or eIF4E increases cell size, and, when coexpressed, they cooperate to increase cell size further. Expression of a phosphorylation site-defective mutant of 4EBP1 that constitutively binds the eIF4E-Cap complex to inhibit translation initiation reduces cell size and blocks eIF4E effects on cell size. These data show that mTOR signals downstream to at least two independent targets, S6K1 and 4EBP1/eIF4E, that function in translational control to regulate mammalian cell size. C1 Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Blenis, J (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. FU NCI NIH HHS [CA69808, F32 CA069808] NR 67 TC 612 Z9 644 U1 3 U2 38 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 15 PY 2002 VL 16 IS 12 BP 1472 EP 1487 DI 10.1101/gad.995802 PG 16 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 566XJ UT WOS:000176453300004 PM 12080086 ER PT J AU Cross, CK Shultz, D Malkowicz, SB Huang, WC Whittington, R Tomaszewski, JE Renshaw, AA Richie, JP D'Amico, AV AF Cross, CK Shultz, D Malkowicz, SB Huang, WC Whittington, R Tomaszewski, JE Renshaw, AA Richie, JP D'Amico, AV TI Impact of race on prostate-specific antigen outcome after radical prostatectomy for clinically localized adenocarcinoma of the prostate SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POSITIVE SURGICAL MARGINS; ANDROGEN RECEPTOR GENE; SERUM TESTOSTERONE LEVELS; BEAM RADIATION-THERAPY; AFRICAN-AMERICAN MEN; WHITE MEN; MULTIVARIATE-ANALYSIS; RACIAL-DIFFERENCES; CAG REPEAT; INTRAEPITHELIAL NEOPLASIA AB Purpose : To compare prostate-specific antigen (PSA) outcome after radical prostatectomy (RP) for prostate cancer in African-American and white men using previously established risk groups. Patients and Methods: Between 1989 and 2000, 2,036 men (n = 162 African-American men, n = 1,874 white men) underwent RP for clinically localized prostate cancer. Using pretreatment PSA, Gleason score, clinical T stage, and percentage of positive biopsy specimens, patients were stratified into low- and high-risk groups. For each risk group, PSA outcome was estimated using the actuarial method of Kaplan and Meier. Comparisons of PSA outcome between African-American and white men were made using the log-rank test. Results: The median age and PSA level for African-American and white men were 60 and 62 years old and 8.8 and 7.0 ng/mL, respectively. African-Americans had a statistically significant increase in PSA (P =.002), Gleason score (P =.003), clinical T stage (P =.004), and percentage of positive biopsy specimens (P =.04) at presentation. However, there was no statistical difference in the distribution of PSA, clinical T stage, or Gleason score between racial groups in the low- and high-risk groups. The 5-year estimate of PSA outcome was 87% in the low-risk group for all patients (P =.70) and 28% versus 32% in African-American and white patients in the high-risk group (P =.28), respectively. Longer follow-up is required to confirm if these results are maintained at 10 years. Conclusion: Even though African-American men presented at a younger age and with more advanced disease compared with white men with prostate cancer, PSA outcome after RP when controlled for known clinical predictive factors was not statistically different. This study supports earlier screening in African-American men. (C) 2002 by American Society of Clinical Oncology. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Urol, Boston, MA 02215 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Millersville Univ Pennsylvania, Dept Math, Millersville, PA 17551 USA. Hosp Univ Penn, Dept Urol, Philadelphia, PA 19104 USA. Hosp Univ Penn, Dept Radiat Oncol, Philadelphia, PA 19104 USA. Hosp Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. RP Cross, CK (reprint author), Brigham & Womens Hosp, Dept Radiat Oncol, 75 Francis St,L-2 Level, Boston, MA 02215 USA. OI Huang, William/0000-0001-5261-0650 NR 45 TC 34 Z9 35 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 15 PY 2002 VL 20 IS 12 BP 2863 EP 2868 DI 10.1200/JCO.2002.11.054 PG 6 WC Oncology SC Oncology GA 563ZU UT WOS:000176289200014 PM 12065563 ER PT J AU Onami, TM Harrington, LE Williams, MA Galvan, M Larsen, CP Pearson, TC Manjunath, N Baum, LG Pearce, BD Ahmed, R AF Onami, TM Harrington, LE Williams, MA Galvan, M Larsen, CP Pearson, TC Manjunath, N Baum, LG Pearce, BD Ahmed, R TI Dynamic regulation of T cell immunity by CD43 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID WISKOTT-ALDRICH-SYNDROME; VIRAL-INFECTION; IMMUNOLOGICAL SYNAPSE; NEGATIVE REGULATION; CUTTING EDGE; LYMPHOCYTE-ACTIVATION; BYSTANDER ACTIVATION; ALTERED EXPRESSION; CBL-B; MICE AB During a viral response, Ag-specific effector T cells show dramatically increased binding by the mAb 1B11 and the lectin peanut agglutinin (PNA). We investigated the contribution of CD43 expression to 1B11 and PNA binding as well as its role in generation and maintenance of a CD8 T cell response. Analysis of CD43(-/-) mice revealed no increased 1B11 binding and reduced PNA binding on virus-specific CD8 T cells from -/- mice compared with +/+ mice. Furthermore, we examined the role of CD43 in the kinetics of an immune response. We show that CD43 expression modestly effects generation of a primary virus-specific CD8 T cell response in vivo but plays a more significant role in trafficking of CD8 T cells to tissues such as the brain. More interestingly, CD43 plays a role in the contraction of the immune response, with CD43(-/-) mice showing increased numbers of Ag-specific CD8 T cells following initial expansion. Following the peak of expansion, Ag-specific CD8 T cells from -/- mice show similar proliferation but demonstrate increased Bcl-2 levels and decreased apoptosis of Ag-specific effector CD8 T cells in vitro. Consistent with a delay in the down-modulation of the immune response, following chronic viral infection CD43(-/-) mice show increased morbidity. These data suggest a dynamic role of CD43 during an immune response: a positive regulatory role in costimulation and trafficking of T cells to the CNS and a negative regulatory role in the down-modulation of an immune response. C1 Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Carlos & Marguerite Mason Transplantat Res Ctr, Dept Surg, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA 30322 USA. Univ Calif Los Angeles, Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Ahmed, R (reprint author), Emory Univ, Sch Med, Emory Vaccine Ctr, 1510 Clifton Rd,Room G211, Atlanta, GA 30322 USA. RI Larsen, Christian/B-6906-2012 OI Larsen, Christian/0000-0001-6573-2649 FU NIAID NIH HHS [AI30048, AI44644] NR 51 TC 72 Z9 74 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2002 VL 168 IS 12 BP 6022 EP 6031 PG 10 WC Immunology SC Immunology GA 561MT UT WOS:000176145300009 PM 12055210 ER PT J AU Mold, C Rodic-Polic, B Du Clos, TW AF Mold, C Rodic-Polic, B Du Clos, TW TI Protection from Streptococcus pneumoniae infection by C-reactive protein and natural antibody requires complement but not Fc gamma receptors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MEDIATED PROTECTION; TRANSGENIC MICE; DEFICIENT MICE; CELL-WALL; IN-VIVO; MOUSE; BINDING; PHAGOCYTOSIS; CLEARANCE; PHOSPHORYLCHOLINE AB Streptococcus pneumoniae is an important human pathogen and the most common cause of community-acquired pneumonia. Both adaptive and innate immune mechanisms provide protection from infection. Innate immunity to S. pneumoniae in mice is mediated by naturally occurring anti-phosphocholine (PC) Abs and complement. The human acute-phase reactant C-reactive protein (CRP) also protects mice from lethal S. pneumoniae infection. CRP and anti-PC Ab share the ability to bind to PC on the cell wall C-polysaccharide of S. pneumoniae and to activate complement. CRP and IgG anti-PC also bind to FcgammaR. In this study, FcgammaR- and complement-deficient mice were used to compare the mechanisms of protection conferred by CRP and anti-PC Ab. Injection of CRP protected wild-type, FcRgamma-chain-, FcgammaRIIb-, and FcgammaRIII-deficient mice from infection. Complement was required for the protective effect of CRP as cobra venom factor treatment eliminated the effect of CRP in both gamma-chain-deficient and wild-type mice, and CRP failed to protect C3- or C4-deficient mice from infection. Unexpectedly, gamma-chain-deficient mice were extremely sensitive to pneumococcal infection. This sensitivity was associated with low levels of natural anti-PC Ab. gamma-chain-deficient mice immunized with nonencapsulated S. pneumoniae produced both IgM- and IgG PC-specific Abs, were protected from infection, and were able to clear the bacteria from the bloodstream. The protection provided by immunization was eliminated by complement depletion. The results show that in this model of systemic infection with highly virulent S. pneumoniae, protection from lethality by CRP and anti-PC Abs requires complement, but not FcgammaR. C1 US Dept Vet Affairs, Med Ctr, Res Serv 151, Albuquerque, NM 87108 USA. Univ New Mexico, Sch Med, Dept Microbiol & Mol Genet, Albuquerque, NM 87131 USA. Univ New Mexico, Sch Med, Dept Internal Med, Albuquerque, NM 87131 USA. RP Du Clos, TW (reprint author), US Dept Vet Affairs, Med Ctr, Res Serv 151, 1501 San Pedro SE, Albuquerque, NM 87108 USA. FU NIAID NIH HHS [AI28358] NR 46 TC 82 Z9 86 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2002 VL 168 IS 12 BP 6375 EP 6381 PG 7 WC Immunology SC Immunology GA 561MT UT WOS:000176145300054 PM 12055255 ER PT J AU Bhattacharyya, A Watson, FL Pomeroy, SL Zhang, YZZ Stiles, CD Segal, RA AF Bhattacharyya, A Watson, FL Pomeroy, SL Zhang, YZZ Stiles, CD Segal, RA TI High-resolution imaging demonstrates dynein-based vesicular transport of activated Trk receptors SO JOURNAL OF NEUROBIOLOGY LA English DT Article DE neurotrophin; signal transduction; dynein; retrograde transport; vesicle; Trk ID NERVE GROWTH-FACTOR; RETROGRADE AXONAL-TRANSPORT; RAT SYMPATHETIC NEURONS; CYTOPLASMIC DYNEIN; ULTRASTRUCTURAL-LOCALIZATION; INTERNALIZED NEUROTROPHINS; SIGNALING ENDOSOMES; SYSTEM; ORGANELLE; COMPLEX AB Target-derived neurotrophins signal from nerve endings to the cell body to influence cellular and nuclear responses. The retrograde signal is conveyed by neurotrophin receptors (Trks) themselves. To accomplish this, activated Trks may physically relocalize from nerve endings to the cell bodies. However, alternative signaling mechanisms may also be used. To identify the vehicle wherein the activated Trks are located and transported, and to identify associated motor proteins that would facilitate transport. we use actination-state specific antibodies in concert with immuno-electron microscopy and deconvolution microscopy.. We show that the activated Trks within rat sciatic nerve axons are preferentially localized to coated and uncoated vesicles. These vesicles are moving in a retrograde direction and so accumulate distal to a ligation site. The P-Trk containing vesicles, in turn, colocalize with dynein components, and not with kinesins. Collectively, these results indicate activated Trk within axons travel in vesicles and dynein is the motor that drives these vesicles towards the cell bodies. (C) 2002 Wiley Periodicals Inc. J Neurobiol 51: 302-312, 2002. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Childrens Hosp, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. RP Segal, RA (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. FU NINDS NIH HHS [NS 35148, NS35701] NR 42 TC 71 Z9 71 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-3034 J9 J NEUROBIOL JI J. Neurobiol. PD JUN 15 PY 2002 VL 51 IS 4 BP 302 EP 312 DI 10.1002/neu.10062 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 556DQ UT WOS:000175834400004 PM 12150505 ER PT J AU Georges, F Aston-Jones, G AF Georges, F Aston-Jones, G TI Activation of ventral tegmental area cells by the bed nucleus of the stria terminalis: A novel excitatory amino acid input to midbrain dopamine neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine neurons; ventral tegmental area; bed nucleus of the stria terminalis; NMDA receptors; non-NMDA receptors; extracellular recording ID METHYL-D-ASPARTATE; GLUTAMATE-RECEPTOR SUBTYPES; DUAL-PROBE MICRODIALYSIS; LOCUS-COERULEUS NEURONS; RAT SUBSTANTIA NIGRA; PREFRONTAL CORTEX; NMDA RECEPTORS; BEHAVIORAL SENSITIZATION; AFFERENT-PROJECTIONS; SUBTHALAMIC NUCLEUS AB We examined the role of excitatory amino acids (EAAs) in the activation of midbrain dopaminergic (DA) neurons evoked by stimulation of the ventromedial and ventrolateral (subcommissural) bed nucleus of the stria terminalis (vBNST). Using anesthetized rats and extracellular recording techniques, we found that 84.8% of ventral tegmental area (VTA) DA neurons were activated synaptically by single-pulse electrical stimulation of the vBNST. In contrast, similar stimulation did not affect the activity of presumed GABA neurons in the VTA. Three characteristic responses were observed in VTA DA neurons: short latency activation (<25 msec; 55.1% of cells), long latency activation (>65 msec; 56% of cells), and inhibition (61.8% of cells, usually followed by long latency excitation). Microinfusion of antagonists of EAA receptors (3 mM kynurenic acid, 100 muM AP-5, or 50 muM CNQX) from a micropipette adjacent to the recording electrode significantly reduced both short and long latency activations evoked in DA neurons by vBNST stimulation. Specific responses were attenuated similarly by AP-5 alone, CNQX alone, or a cocktail of AP-5+CNQX, indicating that joint activation of NMDA plus non-NMDA receptors was required. Stimulation of the vBNST by local microinfusion of glutamate increased the firing and bursting activity of VTA DA neurons. Similar microinfusion of GABA decreased bursting of VTA DA neurons without altering their firing rate. Retrograde and anterograde labeling and antidromic activation of vBNST neurons by VTA stimulation confirmed a direct projection from the vBNST to the VTA. These results reveal that inputs from the vBNST exert a strong excitatory influence on VTA DA neurons mediated by both NMDA and non-NMDA receptors. C1 Vet Affairs Med Ctr, Dept Psychiat, Lab Neuromodulat & Behav, Philadelphia, PA 19104 USA. RP Aston-Jones, G (reprint author), Vet Affairs Med Ctr, Dept Psychiat, Lab Neuromodulat & Behav, Mail Box 151,Univ & Woodland Ave, Philadelphia, PA 19104 USA. FU NIDA NIH HHS [DA06214] NR 62 TC 187 Z9 188 U1 2 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 JUN 15 PY 2002 VL 22 IS 12 BP 5173 EP 5187 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 564KE UT WOS:000176312900043 PM 12077212 ER PT J AU Solomon, V Madihally, S Mitchell, RN Yarmush, M Toner, M AF Solomon, V Madihally, S Mitchell, RN Yarmush, M Toner, M TI Antiproteolytic action of insulin in burn-injured rats SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE burn injury; insulin; protein synthesis; protein degradation; muscle wasting ID MUSCLE PROTEIN-SYNTHESIS; SKELETAL-MUSCLE; THERMAL-INJURY; GLUCOSE-UTILIZATION; TURNOVER; DEGRADATION; CELLS; HYPERINSULINEMIA; STIMULATION; RESISTANCE AB Background. Negative nitrogen balance is a typical metabolic response to burn injury resulting in decreased muscle mass and activity. Since insulin is an anabolic hormone, using insulin as a prophylactic agent in burned patients has received some attention. The present study was carried out to investigate the systemic effect of insulin on burn injury-induced muscle wasting. Patients and methods. A 15-20% total body surface area (TBSA) scald burn injury was inflicted on the shaved dorsum of rats. Rats were treated with a daily subcutaneous insulin injection for 3 days (0.25-1.0 U/day). After the treatment, a variety of insulin-dependent physiological parameters were monitored. Overall body protein degradation rates were determined by measuring the urinary tyrosine. Also, protein degradations were measured in diaphragm muscles, splenocytes, and peripheral blood mononuclear cells to directly confirm the antiproteolytic activity of insulin. Results. Administration of insulin to burn-injured rats restored body weight primarily by reducing accelerated protein degradation and regaining the intracellular protein content in individual skeletal muscle. The measured physiological parameters showed no possible side effects. Protein degradation in immune cells was also suppressed after the therapy. Conclusion. Results indicate that lower dose insulin particularly suppresses protein degradation without causing secondary effects. It may be a useful approach to preventing burn injury-induced muscle wasting and also has a potential to improve immune response. (C) 2002 Elsevier Science (USA). C1 Shriners Burn Hosp, Surg Serv, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Solomon, V (reprint author), Shriners Burn Hosp, Surg Serv, Boston, MA 02114 USA. RI Madihally, Sundararajan/D-9285-2012 OI Madihally, Sundararajan/0000-0001-7498-5760 NR 40 TC 15 Z9 24 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0022-4804 J9 J SURG RES JI J. Surg. Res. PD JUN 15 PY 2002 VL 105 IS 2 BP 234 EP 242 DI 10.1006/jsre.2002.6355 PG 9 WC Surgery SC Surgery GA 573BB UT WOS:000176808500023 PM 12121712 ER PT J AU Spektor, BS Miller, DW Hollingsworth, ZR Kaneko, YA Solano, SM Johnson, JM Penney, JB Young, AB Luthi-Carter, R AF Spektor, BS Miller, DW Hollingsworth, ZR Kaneko, YA Solano, SM Johnson, JM Penney, JB Young, AB Luthi-Carter, R TI Differential D-1 and D-2 receptor-mediated effects on immediate early gene induction in a transgenic mouse model of Huntington's disease SO MOLECULAR BRAIN RESEARCH LA English DT Article DE cAMP; striatum; Huntingtin; SKF-38393 ID MESSENGER-RNA LEVELS; D1 DOPAMINE-RECEPTOR; METABOTROPIC GLUTAMATE RECEPTORS; RAT STRIATUM; C-FOS; TRANSCRIPTION FACTOR; BASAL GANGLIA; INSITU HYBRIDIZATION; PROJECTION NEURONS; AGONIST SKF-82958 AB The diminished expression of D-1 and D-2 dopamine receptors is a well-documented hallmark of Huntington's disease (HD), but relatively little is known about how these changes in receptor populations affect the dopaminergic responses of striatal neurons. Using transgenic mice expressing an N-terminal portion of mutant huntingtin (R6/2 mice). we have examined immediate early gene (IEG) expression as an index of dopaminergic signal transduction. c-fos, jun B, zif268. and N10 mRNA levels and expression patterns were analyzed using quantitative in situ hybridization histochemistry following intraperitoneal administration of selective D-1 and D-2 family pharmacological agents (SKF-82958 and eticlopride). Basal IEG levels were generally lower in the dorsal subregion of R6/2 striata relative to wild-type control striata at 10-11 weeks of age, a finding in accord with previously reported decreases in D-1 and adenosine A(2A) receptors, D-antagonist-stimulated IEG expression was significantly reduced in the striata of transgenic animals, In contrast, D-1-agonist-induced striatal R6/2 IEG mRNA levels were either equivalent or significantly enhanced relative to control levels, an unexpected result given the reduced level of D, receptors in R6/2 animals. Understanding the functional bases for these effects may further elucidate the complex pathophysiology of Huntington's disease. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Ctr Aging Genet & Neurodegenerat Neurol, Charlestown, MA 02129 USA. RP Luthi-Carter, R (reprint author), Massachusetts Gen Hosp, Dept Neurol, 114 16th St, Charlestown, MA 02129 USA. NR 82 TC 26 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD JUN 15 PY 2002 VL 102 IS 1-2 BP 118 EP 128 AR PII S0169-328X(02)00216-4 DI 10.1016/S0169-328X(02)00216-4 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 570FQ UT WOS:000176648600015 ER PT J AU Kawai, T Cosimi, AB Wee, SL Houser, S Andrews, D Sogawa, H Phelan, J Boskovic, S Nadazdin, O Abrahamian, G Colvin, RB Sach, DH Madsen, JC AF Kawai, T Cosimi, AB Wee, SL Houser, S Andrews, D Sogawa, H Phelan, J Boskovic, S Nadazdin, O Abrahamian, G Colvin, RB Sach, DH Madsen, JC TI Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys SO TRANSPLANTATION LA English DT Article ID MINIATURE SWINE; TRANSPLANTATION TOLERANCE; RENAL-ALLOGRAFT; LONG-TERM; CLASS-I; KIDNEY-TRANSPLANTATION; INTERNATIONAL-SOCIETY; ALLOGENEIC CHIMERISM; DONOR; VASCULOPATHY AB Background We have previously reported the successful induction of mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates after nonmyeloablative conditioning and donor bone marrow transplantation. In this study, we extended our regimen to cardiac allotransplantation and compared the immunological responses of heart and kidney allograft recipients. Methods. Five cynomolgus monkeys were conditioned with low-dose total body irradiation (1.5 Gy on days -6 and -5), supplemental thymic irradiation (7 Gy on day -1), antithymocyte globulin (50 mg/kg on days -2, -1, and 0), splenectomy (day 0), donor bone marrow transplantation (day 0), and a 4-week posttransplant course of cyclosporine. Heart allografts from MHC-mismatched donors were transplanted heterotopically on day 0. Results. Two monkeys failed to develop multilineage chimerism and rejected their allografts soon after cyclosporine was stopped (postoperative days [PODS] 43 and 56). Three monkeys developed multilineage chimerism, which persisted 20 to 43 days posttransplant by flow cytometric analysis and to POD 124 by polymerase chain reaction analysis. Allograft survival in these recipients was prolonged to 138, 428, and 509 days, and in vitro mixed leukocyte reaction and cell-mediated lympholysis (CML) assays demonstrated donor-specific hyporesponsiveness. However, in contrast to kidney allograft recipients, long-term heart allograft recipients eventually developed humoral and cellular immunity against the donor and rejected the grafts. At the time of rejection, 1.3% to 9.5% of donor coronary arteries exhibited intimal proliferation. Conclusions. The induction of transient mixed hematopoietic chimerism leads to long-term heart allograft survival in MHC disparate monkeys without chronic immunosuppression. However, unlike kidney allografts, full tolerance to cardiac allografts was not achieved. Organ-specific modifications of the preparative regimen may be necessary to prevent the chronic cellular and humoral immune responses elicited by cardiac allografts. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiac Surg,Transplantat Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Kawai, T (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiac Surg,Transplantat Unit, White 510,55 Fruit St, Boston, MA 02114 USA. FU NHLBI NIH HHS [P01 HL 18646]; NIAID NIH HHS [R21 AI037692, R01 AI 37692-05, R01 AI037692, R01 AI037692-09, R21 AI037692-06] NR 29 TC 64 Z9 68 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUN 15 PY 2002 VL 73 IS 11 BP 1757 EP 1764 AR UNSP 0041-1337/02/7311-1757/0 DI 10.1097/00007890-200206150-00011 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 565BJ UT WOS:000176348000011 PM 12084998 ER PT J AU Huang, JS Mulkern, RV Grinspoon, S AF Huang, JS Mulkern, RV Grinspoon, S TI Reduced intravertebral bone marrow fat in HIV-infected men SO AIDS LA English DT Article DE bone density; bone marrow fat; HIV; lipodystrophy ID PROTEASE INHIBITORS; LIPODYSTROPHY; DIFFERENTIATION; THERAPY AB Objective: To measure intravertebral bone marrow fat in HIV-infected men. Design: A cross-sectional study of HIV-positive men, subcategorized by lipodystrophy and antiretroviral status, and healthy age- and body mass index (BMI)-matched HIV-negative controls. Setting: A tertiary care academic medical institution. Patients: Fifteen HIV-infected men and nine age- and BMI-matched healthy control subjects were recruited for bone density, intravertebral bone marrow fat, and body composition measurements. Methods: Magnetic resonance spectroscopy was used to measure intravertebral marrow fat. Quantitative computed tomography was used to quantify visceral and subcutaneous fat. Dual energy X-ray absorptiometry was used to determine lumbar spine bone density. Statistical comparisons were performed according to HIV, lipodystrophy, and protease inhibitor (PI) exposure status. Results: Intravertebral marrow fat was reduced in HIV-infected men (N = 15) compared with healthy HIV-negative controls (N = 9) (28.5 +/- 8.0 versus 37.3 +/- 12.5%, P = 0.04). Intravertebral bone marrow fat was most severely reduced in HIV-infected men with lipodystrophy compared with healthy HIV-negative controls (25.6 +/- 8.8% versus 37.3 +/- 12.5%, P = 0.04). Furthermore, nelfinavir (P = 0.02) was associated with decreased intravertebral marrow fat and indinavir (P < 0.05) was associated with increased intravertebral marrow fat in HIV-infected subjects. Conclusion: We demonstrated reduced intravertebral marrow fat in HIV-infected men using magnetic resonance spectroscopy. Notably, reduced marrow fat occurred in the setting of reduced bone density and may be affected by specific P1 and lipodystrophy status. Further studies are necessary to determine the relationship between marrow fat and osteopenia and the effect of antiretroviral therapy on marrow fat in this population. (C) 2002 Lippincott Williams Wilkins. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Combined Program Pediat Gastroenterol & Nutr, Boston, MA 02114 USA. Childrens Hosp, Dept Radiol, Boston, MA 02115 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, BUL457B,55 Fruit St, Boston, MA 02114 USA. FU NCRR NIH HHS [M01 RR00088]; NIAID NIH HHS [K23 AI051947, AI51947, K23 AI051947-02, P30-AI42851]; NIDDK NIH HHS [DK 07477, R 01 DK 59535] NR 23 TC 20 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUN 14 PY 2002 VL 16 IS 9 BP 1265 EP 1269 DI 10.1097/00002030-200206140-00009 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 565KR UT WOS:000176369600011 PM 12045492 ER PT J AU McGill, GG Horstmann, M Widlund, HR Du, JY Motyckova, G Nishimura, EK Lin, YL Ramaswamy, S Avery, W Ding, HF Jordan, SA Jackson, IJ Korsmeyer, SJ Golub, TR Fisher, DE AF McGill, GG Horstmann, M Widlund, HR Du, JY Motyckova, G Nishimura, EK Lin, YL Ramaswamy, S Avery, W Ding, HF Jordan, SA Jackson, IJ Korsmeyer, SJ Golub, TR Fisher, DE TI Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability SO CELL LA English DT Article ID MICROPHTHALMIA TRANSCRIPTION FACTOR; ELEMENT-BINDING PROTEIN; MALIGNANT-MELANOMA; GROWTH-FACTOR; BCL-2-DEFICIENT MICE; POLYCYSTIC KIDNEY; FAMILY MEMBERS; NEURAL CREST; EXPRESSION; GENE AB Kit/SCF signaling and Mitf-dependent transcription are both essential for melanocyte development and pigmentation. To identify Mitf-dependent Kit transcriptional targets in primary melanocytes, microarray studies were undertaken. Among identified targets was BCL2, whose germline deletion produces melanocyte loss and which exhibited phenotypic synergy with Mitf in mice. BCL2's regulation by Mitf was verified in melanocytes and melanoma cells and by chromatin immunoprecipitation of the BCL2 promoter. Mitf also regulates BCL2 in osteoclasts, and both Mitf(mi/mi) and Bcl2(-/-) mice exhibit severe osteopetrosis. Disruption of Mitf in melanocytes or melanoma triggered profound apoptosis susceptible to rescue by BCL2 overexpression. Clinically, primary human melanoma expression microarrays revealed tight nearest neighbor linkage for MITF and BCL2. This linkage helps explain the vital roles of both Mitf and Bcl2 in the melanocyte lineage and the well-known treatment resistance of melanoma. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Whitehead MIT Ctr Genome Res, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA. Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. RP Fisher, DE (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. FU NCI NIH HHS [CA50239]; NIAMS NIH HHS [AR45662, AR43369] NR 57 TC 441 Z9 450 U1 3 U2 18 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 14 PY 2002 VL 109 IS 6 BP 707 EP 718 DI 10.1016/S0092-8674(02)00762-6 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 563PW UT WOS:000176265600002 PM 12086670 ER PT J AU Macian, F Garcia-Cozar, F Im, SH Horton, HF Byrne, MC Rao, A AF Macian, F Garcia-Cozar, F Im, SH Horton, HF Byrne, MC Rao, A TI Transcriptional mechanisms underlying lymphocyte tolerance SO CELL LA English DT Article ID CD4(+) T-CELLS; NEGATIVE REGULATION; GENE-EXPRESSION; SELF-TOLERANCE; FACTOR NFAT1; ACTIVATION; RECEPTOR; PROTEIN; CLEAVAGE; SIGNALS AB In lymphocytes, integration of Call and other signaling pathways results in productive activation, while unopposed Call signaling leads to tolerance or anergy. We show that the Ca2+-regulated transcription factor NFAT has an integral role in both aspects of lymphocyte function. Ca2+/calcineurin signaling induces a limited set of anergy-associated genes, distinct from genes induced in the productive immune response; these genes are upregulated in vivo in tolerant T cells and are largely NFAT dependent. T cells lacking NFAT1 are resistant to anergy induction; conversely, NFAT1 induces T cell anergy if prevented from interacting with its transcriptional partner AP-1 (Fos/Jun). Thus, in the absence of AP-1, NFAT imposes a genetic program of lymphocyte anergy that counters the program of productive activation mediated by the cooperative NFAT:AP-1 complex. C1 Harvard Univ, Sch Med, Ctr Blood Res, Dept Pathol, Boston, MA 02115 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Dept Pathol, 200 Longwood Ave, Boston, MA 02115 USA. RI Garcia-Cozar, Francisco/A-6212-2013; Im, Sin-Hyeog/E-6811-2013 OI Garcia-Cozar, Francisco/0000-0003-3720-259X; Im, Sin-Hyeog/0000-0002-3173-1856 FU NCI NIH HHS [CA42471]; NIAID NIH HHS [AI48213] NR 61 TC 412 Z9 423 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 14 PY 2002 VL 109 IS 6 BP 719 EP 731 DI 10.1016/S0092-8674(02)00767-5 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 563PW UT WOS:000176265600003 PM 12086671 ER PT J AU Sakaguchi, T Gu, XB Golden, HM Suh, ER Rhoads, DB Reinecker, HC AF Sakaguchi, T Gu, XB Golden, HM Suh, ER Rhoads, DB Reinecker, HC TI Cloning of the human claudin-2 5 '-flanking region revealed a TATA-less promoter with conserved binding sites in mouse and human for caudal-related homeodomain proteins and hepatocyte nuclear factor-1 alpha SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTESTINE-SPECIFIC TRANSCRIPTION; PHLORHIZIN HYDROLASE GENE; SUCRASE-ISOMALTASE GENE; TIGHT JUNCTION STRANDS; EPITHELIAL-CELL LINE; NF-KAPPA-B; HOMEOBOX GENE; FACTOR-I; EXPRESSION; HNF-1-ALPHA AB Claudin-2 is a structural component of tight junctions in the kidneys, liver, and intestine, but the mechanisms regulating its expression have not been defined. The 5'-flanking region of the claudin-2 gene contains binding sites for intestine-specific Cdx homeodomain proteins and hepatocyte nuclear factor (HNF)-1, which are conserved in human and mouse. Both Cdx1 and Cdx2 activated the claudin-2 promoter in the human intestinal epithelial cell line Caco-2. HNF-1alpha augmented the Cdx2-induced but not Cdx1-induced transcriptional activation of the human claudin-2 promoter. In mice, HNF-1alpha was required for claudin-2 expression in the villus epithelium of the ileum and within the liver but not in the kidneys, indicating an organ-specific function of HNF-1alpha in the regulation of claudin-2 gene expression. Tight junction structural components, which determine epithelial polarization and intestinal barrier function, can be regulated by homeodomain proteins that control the differentiation of the intestinal epithelium. C1 Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pediat, Pediat Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Penn, Sch Med, Dept Internal Med, Philadelphia, PA 19104 USA. RP Reinecker, HC (reprint author), Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Dept Med, Gastrointestinal Unit, 32 Fruit St, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK33506, DK51003, DK54399, DK54427] NR 55 TC 119 Z9 126 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 JUN 14 PY 2002 VL 277 IS 24 BP 21361 EP 21370 DI 10.1074/jbc.M110261200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 563YR UT WOS:000176286000033 PM 11934881 ER PT J AU Kemp, DM Ubeda, M Habener, JF AF Kemp, DM Ubeda, M Habener, JF TI Identification and functional characterization of inelatonin Mel 1a receptors in pancreatic beta cells: potential role in incretin-mediated cell function by sensitization of cAMP signaling SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE melatonin 1a receptor; glucagon-like peptide-1; insulin; pancreatic beta cell ID GLUCAGON-LIKE PEPTIDE-1; PARS TUBERALIS CELLS; MELATONIN RECEPTOR; INSULIN-SECRETION; ADENYLATE-CYCLASE; CIRCADIAN-RHYTHM; MT2 RECEPTORS; PINEAL-GLAND; RAT; GLUCOSE AB Melatonin receptors are expressed within the pancreatic islets of Langerhans, and melatonin induces a direct effect oil insulin secretion ex-vivo. Here, we report the endogenous expression of the melatonin Mel la receptor in the INS-1 pancreatic cell line. Pharmacological characterization of the receptor using a CRE-luciferase reporter gene demonstrated its functional activity in INS-1 cells, displaying the characteristic signaling properties of the G(i/o) coupled receptor. Acute melatonin treatment of INS-1 cells in the presence of either forskolin or the incretin hormone glucagon-like peptide 1 (GLP-1) caused an attenuation of the responses in insulin secretion, insulin promoter activity, and CRE mediated gene expression, consistent with its effects in inhibiting cAMP mediated signal transduction. However, prolonged exposure (12 h) of INS-1 cells to melatonin treatment resulted in a sensitization of cAMP mediated responses to forskolin and GLP-1. Insulin secretion, insulin promoter activity and CRE mediated gene expression levels were augmented compared with responses without melatonin pre-treatment in INS-1 cells. In isolated rat islets, insulin secretion was enhanced following melatonin pre-treatment both in the absence and presence of GLP-1 or forskolin. This phenomenon reflects observations reported in other cell types expressing the melatonin Mel la receptor, and may represent the first evidence of a specific physiological role for melatonin-induced sensitization. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Howard Hughes Med Inst,Lab Mol Endocrinol, Boston, MA 02114 USA. RP Habener, JF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Howard Hughes Med Inst,Lab Mol Endocrinol, 55 Fruit St WEL320, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK-30834] NR 40 TC 69 Z9 71 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD JUN 14 PY 2002 VL 191 IS 2 BP 157 EP 166 AR PII S0303-7207(02)00064-3 DI 10.1016/S0303-7207(02)00064-3 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 568FY UT WOS:000176532800004 PM 12062899 ER PT J AU Cannon, SC AF Cannon, SC TI Sodium channel gating: No margin for error SO NEURON LA English DT Editorial Material ID GENERALIZED EPILEPSY; FEBRILE SEIZURES; MUTATION; SCN1A AB Voltage-gated Na+ channels are the workhorses of spike generation and propagation in excitable cells. Mutations in Na+ channel genes have been identified in disorders causing episodic dysfunction of heart, skeletal muscle, and brain. Lossin and colleagues from Al George's lab report in this issue of Neuron that three missense mutations of SCN1A found in a dominant epilepsy syndrome disrupt inactivation, thereby producing small persistent inward Na+ currents that may result in hyperexcitability and seizures. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Dept Neurobiol, Boston, MA 02114 USA. RP Cannon, SC (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Dept Neurobiol, Wellman 423, Boston, MA 02114 USA. NR 10 TC 7 Z9 8 U1 1 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUN 13 PY 2002 VL 34 IS 6 BP 853 EP 854 DI 10.1016/S0896-6273(02)00735-3 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 563HF UT WOS:000176249700001 PM 12086630 ER PT J AU Harthorne, JW Palacios, I AF Harthorne, JW Palacios, I TI A medical mystery SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Harthorne, JW (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 13 PY 2002 VL 346 IS 24 BP 1878 EP 1878 DI 10.1056/NEJMicm020134 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 561NA UT WOS:000176146100006 ER PT J AU Kradin, RL Mark, EJ Belley, G Norris, PJ Ton, F AF Kradin, RL Mark, EJ Belley, G Norris, PJ Ton, F TI A 48-year-old man with a cough and bloody sputum - Wegener's granulomatosis, with microabscesses, capillaritis, granulomatous vasculitis, diffuse granulomatous tissue, and palisading granuloma. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; OPEN LUNG BIOPSIES; PULMONARY HEMORRHAGE; LYMPHOMATOID GRANULOMATOSIS; PATHERGIC GRANULOMATOSIS; NATURAL-HISTORY; DISEASE; ANGIITIS C1 Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Kradin, RL (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 27 TC 8 Z9 8 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 13 PY 2002 VL 346 IS 24 BP 1892 EP 1899 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 561NA UT WOS:000176146100008 PM 12063374 ER PT J AU Goldman, J O'Brien, SG Russell, N Fischer, T Ottmann, O Cony-Makhoul, P Facon, T Stone, R Miller, C Tallman, M Brown, R Schuster, M Loughran, T Gratwohl, A Mandelli, F Saglio, G Lazzarino, M Russo, D Baccarani, M Morra, E AF Goldman, J O'Brien, SG Russell, N Fischer, T Ottmann, O Cony-Makhoul, P Facon, T Stone, R Miller, C Tallman, M Brown, R Schuster, M Loughran, T Gratwohl, A Mandelli, F Saglio, G Lazzarino, M Russo, D Baccarani, M Morra, E TI Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia (vol 346, pg 645, 2002) SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Correction C1 Hammersmith Hosp, Imperial Coll Sch Med, London, England. Univ Newcastle Upon Tyne, Royal Victoria Infirm, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. City Hosp Nottingham, Nottingham, England. Univ Mainz, D-6500 Mainz, Germany. Univ Frankfurt, D-6000 Frankfurt, Germany. Univ Victor Segalen, Bordeaux, France. Ctr Hosp Reg & Univ Lille, Hop Claude Huriez, F-59037 Lille, France. Dana Farber Canc Inst, Boston, MA 02115 USA. Johns Hopkins Oncol Ctr, Baltimore, MD USA. Northwestern Univ, Sch Med, Chicago, IL USA. Washington Univ, Sch Med, St Louis, MO USA. Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, New York, NY USA. Univ S Florida, Tampa, FL USA. Kantonsspital, CH-4031 Basel, Switzerland. Univ Roma La Sapienza, Rome, Italy. Univ Turin, Orbassano, Italy. Policlin San Matteo, Ist Ricovero & Cura Carattere Sci, I-27100 Pavia, Italy. Udine Univ Hosp, Udine, Italy. Univ Bologna, Bologna, Italy. Azienda Osped Niguarda Ca Granda, Milan, Italy. RP Goldman, J (reprint author), Hammersmith Hosp, Imperial Coll Sch Med, London, England. RI Russo, Domenico/C-3947-2011; FACON, THIERRY/M-9736-2014; Ottmann, Oliver/D-5007-2016 OI FACON, THIERRY/0000-0001-7705-8460; Ottmann, Oliver/0000-0001-9559-1330 NR 1 TC 0 Z9 0 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 13 PY 2002 VL 346 IS 24 BP 1923 EP 1923 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 561NA UT WOS:000176146100035 ER PT J AU Gounari, F Signoretti, S Bronson, R Klein, L Sellers, WR Kum, J Siermann, A Taketo, MM von Boehmer, H Khazaie, K AF Gounari, F Signoretti, S Bronson, R Klein, L Sellers, WR Kum, J Siermann, A Taketo, MM von Boehmer, H Khazaie, K TI Stabilization of beta-catenin induces lesions reminiscent of prostatic intraepithelial neoplasia, but terminal squamous transdifferentiation of other secretory epithelia SO ONCOGENE LA English DT Article DE beta-catenin; prostate; neoplasia; metaplasia ID COLORECTAL-CANCER; APC GENE; MAMMARY-GLAND; MICE; CELLS; EXPRESSION; MUTATIONS; POLYPOSIS; ACTIVATION; CARCINOMA AB The present study documents that stabilization of beta-catenin is sufficient to induce lesions reminiscent of prostate intraepithelial neoplasia (PIN). Such lesions were present in all compound mutant mice and all prostate acini expressing stabilized beta-catenin. High grade PIN-like lesions resembling early human prostate cancer were detected as early as 10 weeks of age. Surprisingly, stabilization of beta-catenin in other secretory epithelia including salivary, preputial, harderian, and mammary glands induced extensive squamous metaplasia and keratinization associated with terminal differentiation of the target cells, but failed to cause neoplastic transformation. Epidermal hyperplasia, hair follicle cysts, and odontomas were also observed. The prostatic lesions exhibited upregulation of c-myc, increased rate of cellular proliferation, loss of the Na-K-Cl co-transporter NKCC1, and expression of androgen receptor. Basal cell markers such as p63 and keratin 5 were not expressed by the masses of PIN-like lesions, but were present in small foci of proliferating beta-catenin expressing basal cells. Our observations indicate that beta-catenin stabilization is a crucial event for the initiation of PIN-like lesions, but induces squamous metaplasia rather than tumorigenesis in secretory epithelia other than the prostate. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pathol, Boston, MA 02115 USA. Kyoto Univ, Grad Sch Med, Dept Pharmacol, Sakyo Ku, Kyoto 6068501, Japan. RP Khazaie, K (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. RI Klein, Ludger/G-8785-2011 NR 47 TC 74 Z9 77 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUN 13 PY 2002 VL 21 IS 26 BP 4099 EP 4107 DI 10.1038/sj.onc.1205562 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 562FD UT WOS:000176186000004 PM 12037666 ER PT J AU Kelicen, P Cantuti-Castelvetri, I Pekiner, C Paulson, KE AF Kelicen, P Cantuti-Castelvetri, I Pekiner, C Paulson, KE TI The spin trapping agent PBN stimulates H2O2-induced Erk and Src kinase activity in human neuroblastoma cells SO NEUROREPORT LA English DT Article DE extracellular signal regulated kinases (Erk); human neuroblastoma cell type SH-SY5Y; hydrogen peroxide (H2O2); mitogen-activated protein kinases (MAPK); alpha-phenyl-N-tert-butylnitrone (PBN); reactive oxygen species (ROS); voltage sensitive Ca2+ channels (VSCCs) ID BUTYL-ALPHA-PHENYLNITRONE; ACTIVATED PROTEIN-KINASE; OXIDATIVE STRESS; C-SRC; SIGNAL-TRANSDUCTION; CALCIUM CHANNELS; FOCAL ISCHEMIA; IN-VITRO; PHOSPHORYLATION; RATS AB The spin-trap, alpha-phenyl-N-tert-butylnitrone (PBN) has been shown to have neuroprotective properties and may prevent oxidative injury in vivo and in cultured cells. Although PBN quenches reactive oxygen species, the direct mechanism of neuroprotective action is unknown. In the present study, we examined the effects of PBN on the regulation of the mitogen activated kinase Erk and as well as Src family tyrosine kinases, enzymes known to be activated by oxygen species such as H2O2. In SH-SYSY human neuroblastoma cells, H2O2 induced activation of Erk and Src kinases was markedly potentiated by treatment with PBN. The potentiation by PBN of the Erk and Src kinase activation by H2O2 required extracellular Ca2+ and appeared dependent on voltage sensitive Ca2+ channels. In contrast, PBN did not affect depolarization-dependent or growth factor-dependent Erk and Src kinase phosphorylation. Our results suggest that PBN might have a protective effect on cells by potentiating the anti-apoptotic Erk and Src kinase pathways responding to H2O2, an effect apparently distinct from its ability to trap oxygen free radicals. C1 Univ Hacettepe, Fac Pharm, Dept Pharmacol, TR-06100 Ankara, Turkey. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA USA. Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. Tufts Univ, HNRC, Genet Lab, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Kelicen, P (reprint author), Karolinska Inst, Div Mol Toxicol, Inst Environm Med, S-17177 Stockholm, Sweden. NR 27 TC 15 Z9 15 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUN 12 PY 2002 VL 13 IS 8 BP 1057 EP 1061 DI 10.1097/00001756-200206120-00016 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 573HN UT WOS:000176823600023 PM 12060808 ER PT J AU Hallen, S Mareninova, O Branden, M Sachs, G AF Hallen, S Mareninova, O Branden, M Sachs, G TI Organization of the membrane domain of the human liver sodium/bile acid cotransporter SO BIOCHEMISTRY LA English DT Article ID GLUTAMATE TRANSPORTER GLT-1; TRANSMEMBRANE HELICES; TOPOLOGY PREDICTION; EXPRESSION CLONING; TOPOGENIC SIGNALS; REENTRANT LOOP; PROTEINS; INSERTION; IDENTIFICATION; TRANSLATION AB Mammalian sodium/bile acid cotransporters (SBATs) are glycoproteins with an exoplasmic N-terminus, an odd number of transmembrane regions, and a cytoplasmic C-terminus. Various algorithms predict eight or nine membrane-embedded regions derived from nine hydrophobic stretches of the protein (H1-H9). Three methods were used to define which of these were transmembrane or membrane-associated segments in the liver bile acid transporter. The first was in vitro translation/insertion scanning using either single hydrophobic sequences between the N-terminal domain of the alpha-subunit of the gastric H,K-ATPase and the C-terminal domain of the beta-subunit that contains five N-linked glycosylation exoplasmic flags or using constructs beginning with the N-terminus of the transporter of various lengths and again ending in the C-terminus of the H,K-ATPase beta-subunit. Seven of the predicted segments, but not the amphipathic H3 and H8 sequences, insert as both individual signal anchor and stop transfer sequences in the reporter constructs. These sequences, H3 and H8, are contained within two postulated long exoplasmic loops in the classical seven-transmembrane segment model. The H3 segment acts as a partial stop transfer signal when expressed downstream of the endogenous H2. In a similar manner, the other amphipathic segment, H8, inserts as a signal anchor sequence when translated in the context with the upstream transporter sequence in two different glycosylation constructs. Alanine insertion scanning identified regions of the transporter requiring precise alignment of sequence to form competent secondary structures. The transport activity of these mutants was evaluated either in native protein or in a yellow fluorescent protein (YFP) fusion protein construct. All alanine insertions in H3 and H8 abolished taurocholate uptake, suggesting that both these regions have structures with critical intramolecular interactions. Moreover, these insertions also prevented trafficking to the plasma membrane as assessed by confocal microscopy with a polyclonal antibody against either the C-terminus of the transporter or the YFP signal of the YFP-transporter fusion protein. Two glycosylation signals inserted in the first postulated loop region and four of five such signals in the second postulated loop region were not recognized by the oligosaccharide transferase, and the L256N mutation exhibited 10% glycosylation and was inactive. These findings support a topography with nine membrane-spanning or membrane-associated segments. C1 Univ Calif Los Angeles, Los Angeles, CA 90073 USA. Wadsworth Vet Adm Hosp, Los Angeles, CA 90073 USA. RP Sachs, G (reprint author), W Los Angeles Vet Affairs Med Ctr, Membrane Biol Lab, 11301 Wilshire Blvd,Bldg 113,Rm 324, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK53462, DK17294, DK41301, DK46917] NR 29 TC 24 Z9 25 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 11 PY 2002 VL 41 IS 23 BP 7253 EP 7266 DI 10.1021/bi012152s PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 559ZU UT WOS:000176057300009 PM 12044156 ER PT J AU Carabello, BA AF Carabello, BA TI Evolution of the study of left ventricular function - Everything old is new again SO CIRCULATION LA English DT Editorial Material ID SYSTOLIC WALL STRESS; AORTIC-VALVE REPLACEMENT; PRESSURE-VOLUME RELATION; MITRAL REGURGITATION; PRELOAD; CONTRACTILITY; HYPERTROPHY; PREDICTORS; AFTERLOAD; MECHANICS C1 Baylor Coll Med, Dept Med, Houston, TX USA. Houston Vet Affairs Med Ctr, Houston, TX USA. RP Carabello, BA (reprint author), 2002 Holcombe Blvd 111 MCL, Houston, TX 77030 USA. NR 26 TC 71 Z9 73 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 JUN 11 PY 2002 VL 105 IS 23 BP 2701 EP 2703 DI 10.1161/01.CIR.0000021240.86593.9D PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 562GT UT WOS:000176189600011 PM 12057980 ER PT J AU Chen, JQ Tung, CH Mahmood, U Ntziachristos, V Gyurko, R Fishman, MC Huang, PL Weissleder, R AF Chen, JQ Tung, CH Mahmood, U Ntziachristos, V Gyurko, R Fishman, MC Huang, PL Weissleder, R TI In vivo imaging of proteolytic activity in atherosclerosis SO CIRCULATION LA English DT Article DE atherosclerosis; enzymes; cathepsin B; imaging ID AORTIC-ANEURYSMS; DEFICIENT MICE; HUMAN ATHEROMA; EXPRESSION; LESIONS; PLAQUE; SPECTROSCOPY; ASSOCIATION; RUPTURE; DENSITY AB Background-Atherosclerotic plaque rupture, the most important cause of acute cardiovascular incidents, has been strongly associated with vascular inflammation. On the basis of the hypothesis that the inflammatory response and proteolysis lead to plaque rupture, we have examined the role of cathepsin B as a model proteolytic enzyme. Methods and Results-Using western-type diet-fed apoE and apoE/endothelial NO synthase double knockout mice as models of atherosclerosis, we show (1) that cathepsin B is upregulated in atherosclerotic lesions characterized by high degrees of inflammation compared with normal aorta or silent lesions, (2) that intravenously injectable novel cathepsin B imaging beacons are highly activated within active atherosclerotic lesions and colocalize with cathepsin B immunoreactivity, and (3) that cathepsin B activity in atherosclerotic lesions can be imaged in whole animals by using a novel near-infrared tomographic imaging system. Conclusions-These studies indicate that cathepsin B, and potentially other proteases, may serve as a biomarker for vulnerable plaques when probed with beacons. The tomographic in vivo imaging method as well as catheter-based optical sensing methods could be readily adapted to screening and potentially to the molecular profiling of a number of proteases in vulnerable plaque in vivo. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA 02129 USA. RP Weissleder, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Mol Imaging Res, Bldg 149,13th St,Room 5406, Charlestown, MA 02129 USA. OI Gyurko, Robert/0000-0003-1457-6812; Tung, Ching-Hsuan/0000-0001-6648-6195 NR 35 TC 245 Z9 254 U1 1 U2 18 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 11 PY 2002 VL 105 IS 23 BP 2766 EP 2771 DI 10.1161/01.CIR.0000017860.20619.23 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 562GT UT WOS:000176189600023 PM 12057992 ER PT J AU Greenberg, SM AF Greenberg, SM TI Cerebral amyloid angiopathy and dementia - Two amyloids are worse than one SO NEUROLOGY LA English DT Editorial Material ID ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; PRECURSOR PROTEIN; DUTCH TYPE; HEMORRHAGE; INFARCTION; RISK C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Greenberg, SM (reprint author), Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St,WABG ACC 836, Boston, MA 02114 USA. NR 15 TC 9 Z9 10 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 JUN 11 PY 2002 VL 58 IS 11 BP 1587 EP 1588 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 561CN UT WOS:000176119500003 PM 12058082 ER PT J AU Bassing, CH Chua, KF Sekiguchi, J Suh, H Whitlow, SR Fleming, JC Monroe, BC Ciccone, DN Yan, C Vlasakova, K Livingston, DM Ferguson, DO Scully, R Alt, FW AF Bassing, CH Chua, KF Sekiguchi, J Suh, H Whitlow, SR Fleming, JC Monroe, BC Ciccone, DN Yan, C Vlasakova, K Livingston, DM Ferguson, DO Scully, R Alt, FW TI Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-DAMAGE; MAMMALIAN-CELLS; CRE RECOMBINASE; REPAIR; ATM; PHOSPHORYLATION; STABILITY; GROWTH; 53BP1 AB In mammalian cells, DNA double-strand breaks (DSBs) cause rapid phosphorylation of the H2AX core histone variant (to form gamma-H2AX) in megabase chromatin domains flanking sites of DNA damage. To investigate the role of H2AX in mammalian cells, we generated H2AX-deficient (H2AX(Delta/Delta)) mouse embryonic stem (ES) cells. H2AX(Delta/Delta) ES cells are viable. However, they are highly sensitive to ionizing radiation (IR) and exhibit elevated levels of spontaneous and IR-induced genomic instability. Notably, H2AX is not required for NHEJ per se because H2AX(Delta/Delta) ES cells support normal levels and fidelity of V(D)J recombination in transient assays and also support lymphocyte development in vivo. However, H2AX(Delta/Delta) ES cells exhibit altered IR-induced BRCA1 focus formation. Our findings indicate that H2AX function is essential for mammalian DNA repair and genomic stability. C1 Harvard Univ, Sch Med, Childrens Hosp, Howard Hughes Med,Inst Dept Genet, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Hematol & Oncol,Canc Biol Program, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Howard Hughes Med,Inst Dept Genet, Boston, MA 02115 USA. RI Scully, Ralph/F-5008-2013; OI Sekiguchi, JoAnn/0000-0002-7178-4258 FU NCI NIH HHS [CA 92625, K01 CA079576, P01 CA092625]; NIAID NIH HHS [AI 35714, P01 AI035714] NR 41 TC 381 Z9 395 U1 0 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 11 PY 2002 VL 99 IS 12 BP 8173 EP 8178 DI 10.1073/pnas.122228699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 562UQ UT WOS:000176217700068 PM 12034884 ER PT J AU Artandi, SE Alson, S Tietze, MK Sharpless, NE Ye, S Greenberg, RA Castrillon, DH Horner, JW Weiler, SR Carrasco, RD DePinho, RA AF Artandi, SE Alson, S Tietze, MK Sharpless, NE Ye, S Greenberg, RA Castrillon, DH Horner, JW Weiler, SR Carrasco, RD DePinho, RA TI Constitutive telomerase expression promotes mammary carcinomas in aging mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN TUMOR-CELLS; MURINE T-CELLS; HUMAN FIBROBLASTS; IMMORTAL CELLS; CANCER; TUMORIGENESIS; DYSFUNCTION; INHIBITION; MOUSE; RNA AB Telomerase is up-regulated in the vast majority of human cancers and serves to halt the progressive telomere shortening that ultimately blocks would-be cancer cells from achieving a full malignant phenotype. In contrast to humans, the laboratory mouse possesses long telomeres and, even in early generation telomerase-deficient mice, the level of telomere reserve is sufficient to avert telomere-based checkpoint responses and to permit full malignant progression. These features in the mouse provide an opportunity to determine whether enforced high-level telomerase activity can serve functions that extend beyond its ability to sustain telomere length and function. Here, we report the generation and characterization of transgenic mice that express the catalytic subunit of telomerase (mTERT) at high levels in a broad variety of tissues. Expression of mTERT conferred increased telomerase enzymatic activity in several tissues, including mammary gland, splenocytes, and cultured mouse embryonic fibroblasts. In mouse embryonic fibroblasts, mTERT overexpression extended telomere lengths but did not prevent culture-induced replicative arrest, thus reinforcing the view that this phenomenon is not related to occult telomere shortening. Robust telomerase activity, however, was associated with the spontaneous development of mammary intra-epithelial neoplasia and invasive mammary carcinomas in a significant proportion of aged females. These data indicate that enforced mTERT expression can promote the development of spontaneous cancers even in the setting of ample telomere reserve. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Stanford Univ, Canc Biol Program, Dept Hematol, Stanford, CA 94305 USA. RP DePinho, RA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St M413, Boston, MA 02115 USA. FU NCI NIH HHS [K08 CA 84044, K08 CA082176, K08 CA084044, KO8 CA 82176, R01 CA 84628, R01 CA084628, U01 CA 84313, U01 CA084313]; NIA NIH HHS [K08 AG 0103] NR 37 TC 211 Z9 222 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 11 PY 2002 VL 99 IS 12 BP 8191 EP 8196 DI 10.1073/pnas.112515399 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 562UQ UT WOS:000176217700071 PM 12034875 ER PT J AU Hofmann-Lehmann, R Williams, AL Swenerton, RK Li, PL Rasmussen, RA Chenine, AL McClure, HM Ruprecht, RM AF Hofmann-Lehmann, R Williams, AL Swenerton, RK Li, PL Rasmussen, RA Chenine, AL McClure, HM Ruprecht, RM TI Quantitation of simian cytokine and beta-chemokine mRNAs, using real-time reverse transcriptase-polymerase chain reaction: Variations in expression during chronic primate lentivirus infection SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MESSENGER-RNA EXPRESSION; ACUTE SIVMAC251 INFECTION; BLOOD MONONUCLEAR-CELLS; HIV-INFECTION; PERIPHERAL-BLOOD; RHESUS-MONKEYS; LYMPH-NODES; ANTIRETROVIRAL THERAPY; PLASMODIUM-COATNEYI AB Cytokines and beta-chemokines are important mediators of the immune system and are expressed in many infectious diseases. To study cytokine and beta-chemokine profiles during pathogenesis of lentiviral infection and progression to AIDS in rhesus macaques, we established new quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays based on TaqMan chemistry. Using synthetic RNA standards, we quantified mRNAs of IL-2, IL-4, IL-6, IL-10, IL-12 p40, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), RANTES, macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-1beta in unstimulated peripheral blood mononuclear cells (PBMCs) and lymph nodes from macaques chronically infected with SIV or SHIV. Viremic monkeys with decreased CD4(+) T cell counts (<500 cells/μl) had significantly higher IL-10 mRNA expression than uninfected controls, which parallels the findings in HIV-1-infected humans. In addition, MIP-1α, MIP-1β, and RANTES mRNA expression increased in viremic monkeys with decreased CD4(+) T cell counts; gene expression was inversely correlated with CD4(+) T cell counts, but not viral load. The newly established quantitative real-time RT-PCR assays will allow the determination of cytokine and β-chemokine patterns in rhesus macaques in studies of microbial pathogenesis or vaccine development. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Emory Univ, Yerkes Reg Primate Res Ctr, Atlanta, GA 30322 USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, 44 Binney St,JFB809, Boston, MA 02115 USA. RI Hofmann-Lehmann, Regina/C-6528-2009 FU NCIRD CDC HHS [IP30 28691]; NCRR NIH HHS [RR-00165, RR14180]; NIAID NIH HHS [R01 AI34266, P01 AI48280]; NIDCR NIH HHS [DE12937] NR 84 TC 30 Z9 34 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUN 10 PY 2002 VL 18 IS 9 BP 627 EP 639 DI 10.1089/088922202760019329 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 560WP UT WOS:000176104600003 PM 12079558 ER PT J AU Back, AL Starks, H Hsu, C Gordon, JR Bharucha, A Pearlman, RA AF Back, AL Starks, H Hsu, C Gordon, JR Bharucha, A Pearlman, RA TI Clinician-patient interactions' about requests for physician-assisted suicide - A patient and family view SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID TERMINALLY ILL PATIENTS; OF-LIFE DISCUSSIONS; SUPREME-COURT; PALLIATIVE CARE; UNITED-STATES; EUTHANASIA; DEATH; ATTITUDES; DESIRE; COMMUNICATION AB Background: Responding effectively to a patient request for physician-assisted suicide (PAS) is an important clinical skill that involves careful evaluation. Clinician responses to PAS requests, however, have only been described using data obtained from clinicians. Objective: To describe qualities of clinician-patient interactions about requests for PAS that were valued by patients and their family members. Participants and Methods: Intensive qualitative case study involving multiple longitudinal interviews conducted prospectively with patients pursuing PAS and with their family members and retrospectively with family members of deceased patients who seriously pursued PAS. The study setting was community based. Participants were recruited through patient advocacy organizations, hospices, and grief counselors. A total of 35 cases were studied: 12 were prospective and 23 were retrospective. Study procedures involved semistructured interviews that were audiotaped, transcribed, reviewed, and analyzed by a multidisciplinary research team. Results: Three themes were identified that describe qualities of clinician-patient interactions that were valued by patients and family members: (1) openness to discussions about PAS; (2) clinician expertise in dealing with the dying process; and (3) maintenance of a therapeutic clinician-patient relationship, even when clinician and patient disagree about PAS. Conclusions: These patient and family accounts reveal missed opportunities for clinicians to engage in therapeutic relationships, including discussions about PAS, dying, and end-of-life care. Clinicians responding to patients requesting PAS need communication skills enabling them to discuss PAS and dying openly, as well as expertise in setting reasonable expectations, individualizing pain control, and providing accurate information about the lethal potential of medications. C1 Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Med Hist & Eth, Seattle, WA 98195 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Univ Washington, Dept Anthropol, Seattle, WA 98195 USA. Univ Washington, Dept Psychol, Seattle, WA 98195 USA. Seattle Inst Biomed & Clin Res, Seattle, WA USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Vet Hlth Adm, Natl Ctr Eth, Washington, DC USA. RP Back, AL (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way S-111, Seattle, WA 98108 USA. NR 46 TC 27 Z9 27 U1 2 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUN 10 PY 2002 VL 162 IS 11 BP 1257 EP 1265 DI 10.1001/archinte.162.11.1257 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 559GB UT WOS:000176017100007 PM 12038944 ER PT J AU Halm, EA Fine, MJ Kapoor, WN Singer, DE Marrie, TJ Siu, AL AF Halm, EA Fine, MJ Kapoor, WN Singer, DE Marrie, TJ Siu, AL TI Instability on hospital discharge and the risk of adverse outcomes in patients with pneumonia SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 23rd Annual Meeting of the Society-for-General-Internal-Medicine CY MAY 02-06, 2000 CL BOSTON, MASSACHUSETTS SP Soc Gen Internal Med ID COMMUNITY-ACQUIRED PNEUMONIA; PROSPECTIVE PAYMENT SYSTEM; MEDICAL OUTCOMES; ELDERLY PATIENTS; CARE; QUALITY; COHORT AB Background: Investigating claims that patients are being sent home from the hospital "quicker and sicker" requires a way of objectively measuring appropriateness of hospital discharge. Objective: To define and validate a simple, usable measure of clinical stability on discharge for patients with community-acquired pneumonia. Methods: Information on daily vital signs and clinical status was collected in a prospective, multicenter, observational cohort study. Unstable factors in the 24 hours prior to discharge were temperature greater than 37.8degreesC, heart rate greater than 100/min, respiratory rate greater than 24/min, systolic blood pressure lower than 90 mm Hg, oxygen saturation lower than 90%, inability to maintain oral intake, and abnormal mental status. Outcomes were deaths, readmissions, and failure to return to usual activities within 30 days of discharge. Results: Of the 680 patients, 19.1% left the hospital with 1 or more instabilities. Overall, 10.5% of patients with no instabilities on discharge died or were readmitted compared with 13.7% of those with 1 instability and 46.2% of those with 2 or more instabilities (P<.003). Instability on discharge (greater than or equal to1 unstable factor) was associated with higher risk-adjusted rates of death or readmission (odds ratio [OR], 1.6; 95% confidence interval [0], 1.0-2.8) and failure to return to usual activities (OR, 1.5; 95% CI, 1.0-2.4). Patients with 2 or more instabilities had a 5-fold greater risk-adjusted odds of death or readmission (OR, 5.4; 93% CI, 1.6-18.4). Conclusions: Instability on discharge is associated with adverse clinical outcomes. Pneumonia guidelines and pathways should include objective criteria for judging stability on discharge to ensure that efforts to shorten length of stay do not jeopardize patient safety. C1 CUNY Mt Sinai Sch Med, Dept Hlth Policy, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Div Gen Internal Med, New York, NY 10029 USA. Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA USA. Univ Pittsburgh, Ctr Res Hth Care, Pittsburgh, PA USA. Va Pittsburgh Ctr Hlth Serv Res, VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Alberta, Dept Med, Edmonton, AB, Canada. RP Halm, EA (reprint author), CUNY Mt Sinai Sch Med, Dept Hlth Policy, Box 1077,1 Gustave L Levy Pl, New York, NY 10029 USA. FU AHRQ HHS [HS06468, HS09973] NR 21 TC 98 Z9 102 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD JUN 10 PY 2002 VL 162 IS 11 BP 1278 EP 1284 DI 10.1001/archinte.162.11.1278 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 559GB UT WOS:000176017100009 PM 12038946 ER PT J AU Fitzek, MM Dahlberg, WK Nagasawa, H Mukai, S Munzenrider, JE Little, JB AF Fitzek, MM Dahlberg, WK Nagasawa, H Mukai, S Munzenrider, JE Little, JB TI Unexpected sensitivity to radiation of fibroblasts from unaffected parents of children with hereditary retinoblastoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE ionizing radiation; retinoblastoma; G(1) arrest; radiation sensitivity; fibroblast ID ONCOGENIC POINT MUTATIONS; GERM-LINE MUTATIONS; X-IRRADIATION; CHROMOSOMAL-ABERRATIONS; ATAXIA TELANGIECTASIA; INCOMPLETE PENETRANCE; DIPLOID FIBROBLASTS; GENE; RB1; CANCER AB The response to ionizing radiation was examined in diploid skin fibroblasts derived from 5 patients with hereditary type retinoblastoma as well as their parents. Unexpected sensitivity to cell killing, as measured by clonogenic survival, as well as enhanced radiation-induced G 1 arrest were observed in at least I parental fibroblast strain in all 5 families. In all cases, parental strains were equally or more radiosensitive than the probands. The mutation of the retinoblastoma gene (RB) determined in 4 of 5 probands was either absent from the parental cells, as expected from the negative family histories, or identical, in I father who was a known carrier. In the fifth family, the family history was negative for retinoblastoma. We hypothesize that the increased parental cell sensitivity to radiation suggests the presence of an as yet unrecognized genetic event occurring in I or both parents of children with retinoblastoma. Whether it increases mutability of the RB locus or other loci or interacts with RB is conjectural. (C) 2002 Wiley-Liss, Inc. C1 Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, Boston, MA 02116 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA USA. Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. RP Little, JB (reprint author), Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, 665 Huntigton Ave, Boston, MA 02116 USA. FU NCI NIH HHS [CA-47542]; NIEHS NIH HHS [ES-00002] NR 29 TC 11 Z9 11 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD JUN 10 PY 2002 VL 99 IS 5 BP 764 EP 768 DI 10.1002/ijc.10401 PG 5 WC Oncology SC Oncology GA 555YU UT WOS:000175821300022 PM 12115515 ER PT J AU Liu, SC Kiosses, WB Rose, DM Slepak, M Salgia, R Griffin, JD Turner, CE Schwartz, MA Ginsberg, MH AF Liu, SC Kiosses, WB Rose, DM Slepak, M Salgia, R Griffin, JD Turner, CE Schwartz, MA Ginsberg, MH TI A fragment of paxillin binds the alpha(4) integrin cytoplasmic domain (tail) and selectively inhibits alpha(4)-mediated cell migration SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FOCAL ADHESION KINASE; TYROSINE PHOSPHATASE-PEST; LD MOTIFS; PROTEIN; ASSOCIATION; LOCALIZATION; MODULATION; MOLECULES; AFFINITY; SRC AB The alpha(4) integrins play important roles in embryogenesis, hematopoiesis, cardiac development, and the immune responses. The alpha(4) integrin subunit is indispensable for these biological processes, possibly because the alpha(4) subunit regulates cellular functions differently from other integrin a subunits. We have previously reported that the alpha(4) cytoplasmic domain directly and tightly binds paxillin, an intracellular signaling adaptor molecule, and this interaction accounts for some of the unusual functional responses to alpha(4) integrin-mediated cell adhesion. We also have identified a conserved 9-amino acid region (Glu(983)-Tyr(991)) in the alpha(4) cytoplasmic domain that is sufficient for paxillin binding, and an alanine substitution at either Glu(983) or Tyr(991) within this regrion disrupted the alpha(4)-paxillin interaction and reversed the effects of the alpha(4) cytoplasmic domain on cell spreading and migration. In the current study, we have mapped the alpha(4)-binding site within paxillin using mutational analysis, and examined its effects on the alpha(4) tail-mediated functional responses. Here we report that sequences between residues Ala(176) and Asp(275) of paxillin are sufficient for binding to the alpha(4) tail. We found that the alpha(4) tail, paxillin, and FAT, the focal adhesion targeting domain of pp125(FAK), could form a ternary complex and that the alpha(4)-binding paxillin fragment, P(Ala(176)-Asp(275)), specifically blocked paxillin binding to the alpha(4) tail more efficiently than it blocked binding to FAT. Furthermore, when expressed in cells, this alpha(4)-binding paxillin fragment specifically inhibited the alpha(4) tail-stimulated cell migration. Thus, paxillin binding to the alpha(4) tail leads to enhanced cell migration and inhibition of the alpha(4)-paxillin interaction selectively blocks the alpha(4)-dependent cellular responses. C1 Scripps Res Inst, Dept Vasc Biol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. SUNY Upstate Med Univ, Dept Cell & Dev Biol, Syracuse, NY 13210 USA. RP Liu, SC (reprint author), Millennium Pharmaceut Inc, Cardiovasc Res, 256 E Grand Ave, San Francisco, CA 94080 USA. FU NHLBI NIH HHS [HL31950, HL48728]; NIAMS NIH HHS [AR27214]; NIGMS NIH HHS [GM47607] NR 33 TC 40 Z9 42 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 JUN 7 PY 2002 VL 277 IS 23 BP 20887 EP 20894 DI 10.1074/jbc.M110928200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562NJ UT WOS:000176204500101 PM 11919182 ER PT J AU von Andrian, UH AF von Andrian, UH TI Immunology: T cell-activation in six dimensions SO SCIENCE LA English DT Editorial Material ID HIGH ENDOTHELIAL VENULES; LYMPH-NODES; FLUORESCENCE MICROSCOPY; DENDRITIC CELLS; CHEMOKINES C1 Harvard Univ, Sch Med, Dept Pathol, Ctr Blood Res, Boston, MA 02115 USA. RP von Andrian, UH (reprint author), Harvard Univ, Sch Med, Dept Pathol, Ctr Blood Res, Boston, MA 02115 USA. EM uva@cbr.med.harvard.edu RI von Andrian, Ulrich/A-5775-2008 NR 20 TC 26 Z9 26 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 7 PY 2002 VL 296 IS 5574 BP 1815 EP 1817 DI 10.1126/science.296.5574.1815 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 559YP UT WOS:000176054300030 PM 12052942 ER PT J AU Padera, TP Kadambi, A di Tomaso, E Carreira, CM Brown, EB Boucher, Y Choi, NC Mathisen, D Wain, J Mark, EJ Munn, LL Jain, RK AF Padera, TP Kadambi, A di Tomaso, E Carreira, CM Brown, EB Boucher, Y Choi, NC Mathisen, D Wain, J Mark, EJ Munn, LL Jain, RK TI Lymphatic metastasis in the absence of functional intratumor lymphatics SO SCIENCE LA English DT Article ID GROWTH-FACTOR-C; TUMOR LYMPHANGIOGENESIS; VESSELS; SYSTEM; RECRUITMENT; INDUCTION; LYVE-1; CANCER AB Lymphatic metastasis contributes to mortality from solid tumors. Whether metastasizing cancer cells reach lymph nodes via intratumor lymphatic vessels is unknown. Here, we examine functional lymphatics associated with mouse tumors expressing normal or elevated levels of vascular endothelial growth factor-C (VEGF-C), a molecule that stimulates lymphangiogenesis. Although VEGF-C overexpression increased lymphatic surface area in the tumor margin and lymphatic metastasis, these tumors contained no functional lymphatics, as assessed by four independent functional assays and immunohistochemical staining. These findings suggest that the functional lymphatics in the tumor margin alone are sufficient for lymphatic metastasis and should be targeted therapeutically. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,EL Steele Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Jain, RK (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiat Oncol,EL Steele Lab, 100 Blossom St, Boston, MA 02114 USA. RI Munn, Lance/L-3950-2016; OI Munn, Lance/0000-0003-0698-7232; Padera, Timothy/0000-0002-3453-9384 FU NCI NIH HHS [R24-CA85140] NR 26 TC 593 Z9 665 U1 4 U2 35 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 7 PY 2002 VL 296 IS 5574 BP 1883 EP 1886 DI 10.1126/science.1071420 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 559YP UT WOS:000176054300053 PM 11976409 ER PT J AU Min, JH Yang, HF Ivan, M Gertler, F Kaelin, WG Pavletich, NP AF Min, JH Yang, HF Ivan, M Gertler, F Kaelin, WG Pavletich, NP TI Structure of an HIF-1 alpha-pVHL complex: Hydroxyproline recognition in signaling SO SCIENCE LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; HIPPEL-LINDAU PROTEIN; PROLYL HYDROXYLATION; PROLINE HYDROXYLATION; UBIQUITIN LIGASE; HIF-ALPHA; VHL; HYPOXIA; FAMILY; GENE AB The ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) plays a central role in the cellular response to changes in oxygen availability. pVHL binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. The 1.85 angstrom structure of a 20-residue HIF-1alpha peptide-pVHL-ElonginB-ElonginC complex shows that HIF-1alpha binds to pVHL in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the pVHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling. C1 Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10021 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. RP Pavletich, NP (reprint author), Mem Sloan Kettering Canc Ctr, Cellular Biochem & Biophys Program, 1275 York Ave, New York, NY 10021 USA. RI Ivan, Mircea/A-8109-2012 NR 27 TC 388 Z9 431 U1 3 U2 26 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JUN 7 PY 2002 VL 296 IS 5574 BP 1886 EP 1889 DI 10.1126/science.1073440 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 559YP UT WOS:000176054300054 PM 12004076 ER PT J AU Merrell, DS Butler, SM Qadri, F Dolganov, NA Alam, A Cohen, MB Calderwood, SB Schoolnik, GK Camilli, A AF Merrell, DS Butler, SM Qadri, F Dolganov, NA Alam, A Cohen, MB Calderwood, SB Schoolnik, GK Camilli, A TI Host-induced epidemic spread of the cholera bacterium SO NATURE LA English DT Article ID VIBRIO-CHOLERAE; GENE-EXPRESSION; DNA MICROARRAY; TOXR REGULON; VIRULENCE; INFECTION; MOTILITY AB The factors that enhance the transmission of pathogens during epidemic spread are ill defined. Water-borne spread of the diarrhoeal disease cholera occurs rapidly in nature, whereas infection of human volunteers with bacteria grown in vitro is difficult in the absence of stomach acid buffering(1). It is unclear, however, whether stomach acidity is a principal factor contributing to epidemic spread(2). Here we report that characterization of Vibrio cholerae from human stools supports a model whereby human colonization creates a hyperinfectious bacterial state that is maintained after dissemination and that may contribute to epidemic spread of cholera. Transcriptional profiling of V. cholerae from stool samples revealed a unique physiological and behavioural state characterized by high expression levels of genes required for nutrient acquisition and motility, and low expression levels of genes required for bacterial chemotaxis. C1 Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. Int Ctr Diarrhoeal Dis Res, Dhaka 1212, Bangladesh. Stanford Univ, Sch Med, Beckman Ctr, Stanford, CA 94305 USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Camilli, A (reprint author), Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. OI Cohen, Mitchell/0000-0002-4412-350X FU Howard Hughes Medical Institute; NIAID NIH HHS [R01 AI045746, R01 AI045746-02] NR 19 TC 298 Z9 321 U1 4 U2 24 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUN 6 PY 2002 VL 417 IS 6889 BP 642 EP 645 DI 10.1038/nature00778 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 559AE UT WOS:000176001200046 PM 12050664 ER PT J AU Colleoni, M Litman, HJ Castiglione-Gertsch, M Sauerbrei, W Gelber, RD Bonetti, M Coates, AS Schumacher, M Bastert, G Rudenstam, CM Schmoor, C Lindtner, J Collins, J Thurlimann, B Holmberg, SB Crivellari, D Beyerle, C Neumann, RLA Goldhirsch, A AF Colleoni, M Litman, HJ Castiglione-Gertsch, M Sauerbrei, W Gelber, RD Bonetti, M Coates, AS Schumacher, M Bastert, G Rudenstam, CM Schmoor, C Lindtner, J Collins, J Thurlimann, B Holmberg, SB Crivellari, D Beyerle, C Neumann, RLA Goldhirsch, A CA Int Breast Canc Study Grp German Breast Canc Study Grp TI Duration of adjuvant chemotherapy for breast cancer: a joint analysis of two randomised trials investigating three versus six courses of CMF SO BRITISH JOURNAL OF CANCER LA English DT Article DE breast cancer; chemotherapy duration; cyclophosphamide; methotrexate and fluorouracil (CMF); predictive factors ID EVALUATING HORMONAL TREATMENT; THERAPY; CYCLOPHOSPHAMIDE; FLUOROURACIL; METHOTREXATE; DOXORUBICIN; IMPACT; WOMEN; LIFE AB Cyclophosphamide, methotrexate and fluorouracil adjuvant combination chemotherapy for breast cancer is currently used for the duration of six monthly courses. We performed a joint analysis of two studies on the duration of adjuvant cyclophosphamide, methotrexate and fluorouracil in patients with node-positive breast cancer to investigate whether three courses of cyclophosphamide, methotrexate and fluorouracil might suffice. The International Breast Cancer Study Group Trial VI randomly assigned 735 pre- and perimenopausal patients to receive 'classical' cyclophosphamide, methotrexate and fluorouracil for three consecutive cycles, or the same chemotherapy for six consecutive cycles. The German Breast Cancer Study Group randomised 289 patients to receive either three or six cycles of i.v. cyclophosphamide, methotrexate and fluorouracil day 1, 8. Treatment effects were estimated using Cox regression analysis stratified by clinical trial without further adjustment for covariates. The 5-year disease-free survival per cents (+/-s.e.) were 54+/-2% for three cycles and 55+/-2% for six cycles (n=1024; risk ratio (risk ratio: CMF x 3/CMF x 6), 1.00; 95% confidence interval, 0.85 to 1.18; P=0.99). Use of three rather than six cycles was demonstrated to be adequate in both studies for patients at least 40-years-old with oestrogen-receptor-positive tumours (n=594; risk ratio, 0.86; 95% confidence interval, 0.68 to 1.08; P=0.19). In fact, results slightly favoured three cycles over six for this subgroup, and the 95% confidence interval excluded an adverse effect of more than 2% with respect to absolute 5-year survival. In contrast, three cycles appeared to be possibly inferior to six cycles for women less than 40-years-old (n=190; risk ratio, 1.25; 95% confidence interval, 0.87 to 1.80; P=0.22) and for women with oestrogen-receptor-negative tumours (n=302; risk ratio, 1.15; 95% confidence interval, 0.85 to 1.57; P=0.37). Thus, three initial cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil chemotherapy were as effective as six cycles for older patients (40-years-old) with oestrogen-receptor-positive tumours, while six cycles of adjuvant cyclophosphamide, methotrexate and fluorouracil might still be required for other cohorts. Because endocrine therapy with tamoxifen and GnRH analogues is now available for younger women with oestrogen-receptor-positive tumours, the need for six cycles of cyclophosphamide, methotrexate and fluorouracil is unclear and requires further investigation. (C) 2002 Cancer Research UK. C1 European Inst Oncol, Dept Med, Div Med Oncol, I-20141 Milan, Italy. Dana Farber Canc Inst, IBCSG, Ctr Stat, Boston, MA USA. Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. IBCSG, Coordinat Ctr, Bern, Switzerland. Univ Hosp Freiburg, Inst Med Biometry & Med Informat, Freiburg, Germany. Canc Council Australia, Sydney, NSW, Australia. Univ Sydney, Sydney, NSW 2006, Australia. Marien Hosp, Dept Gynaecol, Essen, Germany. Univ Heidelberg Hosp, Dept Gynaecol, Heidelberg, Germany. Sahlgrenska Univ Hosp, Western Sweden Breast Canc Study Grp, Gothenburg, Sweden. Inst Oncol, Ljubljana, Slovenia. Anti Canc Council Victoria, Melbourne, Vic, Australia. Kantonsspital, St Gallen, Switzerland. Ctr Riferimento Oncol, I-33081 Aviano, Italy. Kreiskrankenhaus Kronach, Dept Gynaecol, Kronach, Germany. Oncol Inst So Switzerland, Lugano, Switzerland. RP Colleoni, M (reprint author), European Inst Oncol, Dept Med, Div Med Oncol, Via Ripamonti 435, I-20141 Milan, Italy. OI Bonetti, Marco/0000-0003-2304-4180 FU NCI NIH HHS [CA-75362, U24 CA075362] NR 32 TC 43 Z9 43 U1 0 U2 2 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 JUN 5 PY 2002 VL 86 IS 11 BP 1705 EP 1714 DI 10.1038/sj.bjc.6600334 PG 10 WC Oncology SC Oncology GA 568BH UT WOS:000176522200008 PM 12087454 ER PT J AU Jain, RK Padera, TP AF Jain, RK Padera, TP TI Prevention and treatment of lymphatic metastasis by antilymphangiogenic therapy SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID ENDOTHELIAL-GROWTH-FACTOR; MICROVESSEL DENSITY; BREAST-CANCER; FACTOR-C; FACTOR RECEPTOR-3; CERVICAL-CANCER; NODE METASTASIS; GASTRIC-CANCER; LYMPHANGIOGENESIS; VEGF C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, EL Steele Lab,Dept Radiat Oncol, Boston, MA 02114 USA. RP Jain, RK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, EL Steele Lab,Dept Radiat Oncol, 100 Blossom St, Boston, MA 02114 USA. NR 30 TC 31 Z9 36 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 5 PY 2002 VL 94 IS 11 BP 785 EP 787 PG 3 WC Oncology SC Oncology GA 558UG UT WOS:000175984600001 PM 12048260 ER PT J AU Euhus, DM Smith, KC Robinson, L Stucky, A Olopade, OI Cummings, S Garber, JE Chittenden, A Mills, GB Rieger, P Esserman, L Crawford, B Hughes, KS Roche, CA Ganz, PA Seldon, J Fabian, CJ Klemp, J Tomlinson, G AF Euhus, DM Smith, KC Robinson, L Stucky, A Olopade, OI Cummings, S Garber, JE Chittenden, A Mills, GB Rieger, P Esserman, L Crawford, B Hughes, KS Roche, CA Ganz, PA Seldon, J Fabian, CJ Klemp, J Tomlinson, G TI Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID OVARIAN-CANCER FAMILIES; BREAST-CANCER; ASHKENAZI JEWS; WOMEN; CARRIERS; PENETRANCE; PROBABILITY; MASTECTOMY; FREQUENCY; HISTORY AB Background: Because BRCA gene mutation testing is costly, occasionally uninformative, and frequently associated with ethical and legal issues, careful patient selection is required prior to testing. Estimation of BRCA gene mutation probability is an important component of pretest counseling, but the accuracy of these estimates is currently unknown. We measured the performance of eight cancer risk counselors and of a computer model, BRCAPRO, at identifying families likely to carry a BRCA gene mutation. Methods: Eight cancer risk counselors and the computer model BRCAPRO estimated BRCA gene mutation probabilities for 148 pedigrees selected from an initial sample of 272 pedigrees. The final sample was limited to pedigrees with a proband affected by breast or ovarian cancer and BRCA1 and BRCA2 gene sequencing results unequivocally reported as negative or positive for a deleterious mutation. Sensitivity, specificity, negative predictive value, positive predictive value, and areas under receiver operator characteristics (ROC) curves were calculated for each risk counselor and for BRCAPRO. All statistical tests were two sided. Results: Using a greater-than-10% BRCA gene mutation probability threshold, the median sensitivity for identifying mutation carriers was 94% (range = 81% to 98%) for the eight risk counselors and 92% (range = 91% to 92%) for BRCAPRO. Median specificity at this threshold was 16% (range = 6% to 34%) for the risk counselors and 32% (range = 30% to 34%) for BRCAPRO (P =.04). Median area under the ROC curves was 0.671 for the risk counselors (range = 0.620 to 0.717) and 0.712 (range = 0.706 to 0.720) for BRCAPRO (P =.04). There was a slight, but not statistically significant, improvement in all counselor performance measures when BRCAPRO-assigned gene mutation probability information was included with the pedigrees. Conclusions: Sensitivity for identifying BRCA gene mutation carriers is similar for experienced risk counselors and the computer model BRCAPRO. Because the computer model consistently demonstrated superior specificity, overall discrimination between BRCA gene mutation carriers and BRCA gene mutation noncarriers was slightly better for BRCAPRO. C1 Univ Texas, SW Med Ctr, Div Surg Oncol, Dallas, TX 75390 USA. Univ Chicago, Chicago, IL 60637 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Calif San Francisco, Med Ctr, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. RP Euhus, DM (reprint author), Univ Texas, SW Med Ctr, Div Surg Oncol, 5323 Harry Hines Blvd,E6-222, Dallas, TX 75390 USA. OI Hughes, Kevin/0000-0003-4084-6484 NR 30 TC 99 Z9 101 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 JUN 5 PY 2002 VL 94 IS 11 BP 844 EP 851 PG 8 WC Oncology SC Oncology GA 558UG UT WOS:000175984600012 PM 12048272 ER PT J AU Chaiyakunapruk, N Veenstra, DL Lipsky, BA Saint, S AF Chaiyakunapruk, N Veenstra, DL Lipsky, BA Saint, S TI Chlorhexidine compared with povidone-iodine solution for vascular catheter-site care: A meta-analysis SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CENTRAL VENOUS CATHETERS; BLOOD-STREAM INFECTION; PROSPECTIVE RANDOMIZED TRIAL; CRITICALLY ILL PATIENTS; PREVENTION; MORTALITY; CONSEQUENCES; DISINFECTION; ANAPHYLAXIS; GLUCONATE AB Purpose: Bloodstream infections related to use of catheters, particularly central-line catheters, are an important cause of patient morbidity, mortality, and increased health care costs. This study evaluated the efficacy of skin disinfection with chlorhexidine gluconate compared with povidone-iodine solution in preventing catheter-related bloodstream infection. Data Sources: Multiple computerized databases (1966 to 2001), reference lists of identified articles, and queries of principal investigators and antiseptic manufacturers. Study Selection: Randomized, controlled trials comparing chlorhexidine gluconate with povidone-iodine solutions for catheter-site care. Data Extraction: Using a standardized form, two reviewers abstracted data on study design, patient population, intervention, and incidence of catheter-related bloodstream infection from all included studies. Data Synthesis: Eight studies involving a total of 4143 catheters met the inclusion criteria. All studies were concluded in a hospital setting, and various catheter types were used. The summary risk ratio for catheter-related bloodstream infection was 0.49 (95% CI, 0.28 to 0.88) in patients whose catheter sites were disinfected with chlorhexidine gluconate Instead of povidone-iodine. Among patients with a central vascular catheter, chlorhexidine gluconate reduced the risk for catheter-related bloodstream infection by 49% (risk ratio, 0.51 [CI 0.27 to 0.97]). Conclusions: These results suggest that incidence of bloodstream infections is significantly reduced In patients with central vascular lines who receive chlorhexidine gluconate versus povidone-iodine for insertion-site skin disinfection. Use of chlorhexidine gluconate is a simple and effective means of reducing vascular catheter-related infections. C1 Naresuan Univ, Pitsanuloak, Thailand. Vet Affairs Puget Sound Healthcare Syst, Seattle, WA USA. Univ Michigan, Ann Arbor, MI 48109 USA. Ann Arbor Vet Adm Med Ctr, Ann Arbor, MI USA. RP Veenstra, DL (reprint author), Univ Washington, Pharmaceut Outcomes Res & Policy Program, Box 357630, Seattle, WA 98195 USA. OI Lipsky, Benjamin A./0000-0001-9886-5114 NR 41 TC 282 Z9 295 U1 0 U2 18 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 4 PY 2002 VL 136 IS 11 BP 792 EP 801 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 558KG UT WOS:000175964500002 PM 12044127 ER PT J AU Dowd, CS Leavitt, S Babcock, G Godillot, AP Van Ryk, D Canziani, GA Sodroski, J Freire, E Chaiken, IM AF Dowd, CS Leavitt, S Babcock, G Godillot, AP Van Ryk, D Canziani, GA Sodroski, J Freire, E Chaiken, IM TI beta-turn Phe in HIV-1 env binding site of CD4 and CD4 mimetic miniprotein enhances env binding affinity but is not required for activation of co-receptor/17b site SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN; CONFORMATIONAL-CHANGES; CHEMOKINE RECEPTORS; GP120 BINDING; CHARYBDOTOXIN; ANTIBODY; INFECTION; EPITOPES; DISEASE AB HIV-1 enters a host cell after an initial interaction between viral envelope glycoprotein gp 120 and cell surface receptor CD4, followed by a second interaction between gp 120 and a cell surface chemokine receptor. CD4 residue Phe43 makes a significant contribution to the high-affinity interaction between CD4 and env. We and others have used scorpion toxin scaffolds to display and examine CD4 epitopes used for gp120 recognition. These peptides, which have a beta-turn Phe that acts as a Phe43 surrogate, compete with CD4 for gp120 binding and enhance the binding of cpl20 to 17b, an antibody that binds near the co-receptor-binding site. In the current study, a scyllatoxin-scaffolded peptide, identified via phage epitope randomization and lacking a U-turn Phe (indeed, containing no aromatic residues), was shown to behave in a distinctly CD4-like manner. This peptide, denoted [(20)EGLV(23)]ST, not only competed with CD4 for gp120 binding, but also enhanced the binding of gp120 to 17b. Quantitatively, an [(20)EGLV(23)]ST-gp120 complex exhibited the same 17b binding on-rate as a complex of gp120 with [(20)AGSF(23)]ST, a scyllatoxin-based CD4 mimetic peptide containing a U-turn Phe. In view of this result, we examined the role of Phe43 in CD4 itself by comparing F43V D1D2 sCD4 versus D1D2 sCD4. Like the peptides, a close similarity was observed for both Phe43 and Phe43-less D1D2 sCD4s in enhancing gp120 binding to 17b. Further, when examined for their ability to enhance binding of gp120 to CCR5(+) cells, [(20)EGLV(23)]ST and [(20)AGSF(23)]ST were found to have the same efficacy, after correcting for the difference in their gp120 affinities. These results show that, although Phe43 is important in maintaining high affinity in gp120 ligands, the aromatic residue is not necessary for triggering the conforinational isomerization in gp120 that results in formation or exposure of the binding sites for the 17b antibody and the CCR5 receptor. C1 Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Aids, Boston, MA 02115 USA. RP Chaiken, IM (reprint author), Univ Penn, Dept Med, Philadelphia, PA 19104 USA. NR 32 TC 24 Z9 27 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUN 4 PY 2002 VL 41 IS 22 BP 7038 EP 7046 DI 10.1021/bi012168i PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 558LC UT WOS:000175966900019 PM 12033937 ER PT J AU Albert, CM Ma, J Rifai, N Stampfer, MJ Ridker, PM AF Albert, CM Ma, J Rifai, N Stampfer, MJ Ridker, PM TI Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death SO CIRCULATION LA English DT Article DE death, sudden; inflammation; lipids; risk factors ID CORONARY HEART-DISEASE; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; RISK-FACTORS; ATHEROSCLEROSIS; HOMOCYST(E)INE; INFLAMMATION; PHYSICIANS; WOMEN; MEN AB Back-ground-Sudden cardiac death (SCD) is an important cause of mortality even among apparently healthy populations. However, our ability to identify those at risk for SCD in the general population is poor, and more specific markers are needed. Methods and Results-To compare and contrast the relative importance of C-reactive protein (CRP), homocysteine, and lipids as long-term predictors of SCD, we performed a prospective, nested, case-control analysis involving 97 cases of SCD among apparently healthy men enrolled in the Physician's Health Study. Of these plasma markers measured, only baseline CRP levels were significantly associated with the risk of SCD over the ensuing 17 years of follow-up (P for trend=0.001). The increase in risk associated with CRP levels was primarily seen among men in the highest quartile, who were at a 2.78-fold increased risk of SCD (95% CI 1.35 to 5.72) compared with men in the lowest quartile. These results were not significantly altered in analyses that (in addition to the matching variables of age and smoking status) controlled for lipid parameters, homocysteine, and multiple cardiac risk factors (relative risk for highest versus lowest quartile 2.65, 95% CI 0.79 to 8.83; P for trend=0.03). In contrast to the positive relationship observed for CRP, neither homocysteine nor lipid levels were significantly associated with risk of SCD. Conclusions-These prospective data suggest that CRP levels may be useful in identifying apparently healthy men who are at an increased long-term risk of SCD. C1 Brigham & Womens Hosp, Div Prevent Med, Dept Med,Leducq Ctr Mol & Genet Epidemiol, Ctr Cardiovasc Dis Prevent, Boston, MA 02215 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Med, Div Cardiovasc, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Med Ctr, Dept Lab Med, Boston, MA USA. Harvard Univ, Sch Med, Childrens Med Ctr, Dept Pathol, Boston, MA USA. RP Albert, CM (reprint author), Brigham & Womens Hosp, Div Prevent Med, Dept Med,Leducq Ctr Mol & Genet Epidemiol, Ctr Cardiovasc Dis Prevent, 900 Commonwealth Ave E, Boston, MA 02215 USA. FU NHLBI NIH HHS [HL-58755, 1-K08-HL-03783, HL-63293] NR 28 TC 286 Z9 308 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUN 4 PY 2002 VL 105 IS 22 BP 2595 EP 2599 DI 10.1161/01.CIR.0000017493.03108.1C PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 559UE UT WOS:000176043100009 PM 12045163 ER PT J AU Boxem, M van den Heuvel, S AF Boxem, M van den Heuvel, S TI C-elegans class B synthetic multivulva genes act in G(1) regulation SO CURRENT BIOLOGY LA English DT Article ID CELL-CYCLE PROGRESSION; CAENORHABDITIS-ELEGANS; DEVELOPMENTAL REGULATION; VULVAL DEVELOPMENT; LIN-35 RB; ANTAGONIZE; LINEAGES; PATHWAY; PROTEIN; NEMATODE AB The single C. elegans member of the retinoblastoma gene family, lin-35 Rb, was originally identified as a synthetic Multivulva (synMuv) gene [1]. These genes form two redundant classes, A and B, that repress ectopic vulval cell fate induction [2, 3]. Recently, we demonstrated that lin-35 Rb also acts as a negative regulator of G(1) progression and likely is the major target of cyd-1 Cyclin D and cdk-4 CDK4/6 [4]. Here,we describe G(1) control functions for several other class B synMuv genes. We found that efl-1 E2F negatively regulates cell cycle entry, while dpl-1 DP appeared to act both as a positive and negative regulator. In addition, we identified a negative G(1) regulatory function for lin-9 ALY, as well as lin-15B and lin-36, which encode novel proteins. Inactivation of lin-35 Rb, efl-1, or lin-36 allowed S phase entry in the absence of cyd-1/cdk-4 and increased ectopic cell division when combined with cki-1 Cip/Kip RNAi. These data are consistent with lin-35 Rb, efl-1, and lin-36 acting in a common pathway or complex that negatively regulates G(1) progression. In contrast, lin-15B appeared to act in parallel to lin-35. Our results demonstrate the potential for genetic identification of novel G(1) regulators in C. elegans. C1 Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP van den Heuvel, S (reprint author), Massachusetts Gen Hosp, Ctr Canc, Bldg 149,13th St, Charlestown, MA 02129 USA. RI Boxem, Mike/B-8857-2011; van den Heuvel, Sander/B-8892-2011 OI Boxem, Mike/0000-0003-3966-4173; NR 19 TC 69 Z9 93 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 4 PY 2002 VL 12 IS 11 BP 906 EP 911 AR PII S0960-9822(02)00844-8 DI 10.1016/S0960-9822(02)00844-8 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 560MH UT WOS:000176085500019 PM 12062054 ER PT J AU Yu, CN Cantor, AB Yang, H Browne, C Wells, RA Fujiwara, Y Orkin, SH AF Yu, CN Cantor, AB Yang, H Browne, C Wells, RA Fujiwara, Y Orkin, SH TI Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE eosinophil; GATA-1; gene targeting; hematopoiesis; transcription ID TRANSCRIPTION FACTOR GATA-1; TRANSGENIC MICE; IN-VIVO; GENE; EXPRESSION; CELLS; MOUSE; COMMITMENT; UPSTREAM; EMBRYOS AB Transcription factor GATA-1 reprograms immature myeloid cells to three different hematopoietic lineages-erythroid cells, megakaryocytes, and eosinophils. GATA-1 is essential for maturation of erythroid and megakaryocytic precursors, as revealed by gene targeting in mice. Here we demonstrate that deletion of a high-affinity GATA-binding site in the GATA-1 promoter, an element presumed to mediate positive autoregulation of GATA-1 expression, leads to selective loss of the eosinophil lineage. These findings suggest that GATA-1 is required for specification of this lineage during hematopoietic development. Mice lacking the ability to produce eosinophils should prove useful in ascertaining the role of eosinophils in a variety of inflammatory or allergic disorders. C1 Harvard Univ, Sch Med, Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Div Hematol Oncol, 300 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA-82175-03] NR 24 TC 313 Z9 318 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 3 PY 2002 VL 195 IS 11 BP 1387 EP 1395 DI 10.1084/jem.20020656 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 561DE UT WOS:000176121800003 PM 12045237 ER PT J AU Sasada, T Touma, M Chang, HC Clayton, LK Wang, JH Reinherz, EL AF Sasada, T Touma, M Chang, HC Clayton, LK Wang, JH Reinherz, EL TI Involvement of the TCR C beta FG loop in thymic selection and T cell function SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE negative selection; thymocyte development; TCR structure; Ig superfamily; transgenic mice ID MAJOR HISTOCOMPATIBILITY COMPLEX; THYMOCYTE POSITIVE SELECTION; ANTIGEN RECEPTOR TCR; ALPHA-BETA; SIGNAL-TRANSDUCTION; CD3-EPSILON SUBUNITS; ACTIVATION MOTIFS; TCR/CD3 COMPLEX; CHAIN LACKING; ZETA-CHAIN AB The asymmetric disposition of T cell receptor (TCR) Cbeta and Calpha ectodomains creates a cavity with a side-wall formed by the rigid Cbeta FG loop. To investigate the significance of this conserved structure, we generated loop deletion (betaDeltaFG) and betawt transgenic (tg) mice using the TCR P subunit of the N15 CTL. N15betawt and N15betaDeltaFG H-2(b) animals have comparable numbers of thymocytes in S phase and manifest developmental progression through the CD4(-)CD8(-) double-negative (DN) compartment. N15betaDeltaFG facilitates transition from DN to CD4(+)8(+) double-positive (DP) thymocytes in recombinase activating gene (RAG)-2(-/-) mice, showing that pre-TCR function remains. N15betaDeltaFG animals possess similar totwofold more CD8(+) single-positive (SP) thymocytes and lymph node T cells, consistent with enhanced positive selection. As an altered Vet repertoire observed in N15betaDeltaFG mice may confound the deletion's effect, we crossed N15alphabeta TCR tg RAG-2(-/-) with N15betaDeltaFG tg RAG-2(-/-) H-2(b) mice to generate N15alphabeta RAG-2(-/-) and N15alphabeta.betaDeltaFG RAG-2(-/-) littermates. N15alphabeta.betaDeltaFG RAG-2(-/-) mice show an 8-10-fold increase in DP thymocytes due to reduced negative selection, as evidenced by diminished constitutive and cognate peptide-induced apoptosis. Compared with N15alphabeta, N15alphabeta.betaDeltaFG T cells respond poorly to cognate antigens and weak agonists. Thus, the Cbeta FG loop facilitates negative selection of thymocytes and activation of T cells. C1 Dana Farber Canc Inst, Immunobiol Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Reinherz, EL (reprint author), Dana Farber Canc Inst, Immunobiol Lab, 44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [R01 AI019807, R56 AI019807, AI 19807, AI 39098, R37 AI019807]; NIGMS NIH HHS [GM 56008] NR 62 TC 18 Z9 19 U1 1 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUN 3 PY 2002 VL 195 IS 11 BP 1419 EP 1431 DI 10.1084/jem.20020119 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 561DE UT WOS:000176121800006 PM 12045240 ER PT J AU Mahmood, U Weissleder, R AF Mahmood, U Weissleder, R TI Some tools for molecular imaging SO ACADEMIC RADIOLOGY LA English DT Editorial Material ID EXPRESSION; CANCER C1 Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, Boston, MA 02125 USA. RP Weissleder, R (reprint author), Massachusetts Gen Hosp, Dept Radiol, Ctr Mol Imaging Res, CNY149-5408,5403 13th St,Bldg 149, Boston, MA 02125 USA. NR 12 TC 11 Z9 11 U1 2 U2 3 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD JUN PY 2002 VL 9 IS 6 BP 629 EP 631 DI 10.1016/S1076-6332(03)80306-9 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 557PH UT WOS:000175916600001 PM 12061735 ER PT J AU Cody, V Galitsky, N Luft, JR Pangborn, W Rosowsky, A Queener, SF AF Cody, V Galitsky, N Luft, JR Pangborn, W Rosowsky, A Queener, SF TI Structure-based enzyme inhibitor design: modeling studies and crystal structure analysis of Pneumocystis carinii dihydrofolate reductase ternary complex with PT653 and NADPH SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID MICROBATCH MACROMOLECULAR CRYSTALLIZATION; TOXOPLASMA-GONDII; OPPORTUNISTIC INFECTIONS; BIOLOGICAL-ACTIVITIES; ANTITUMOR AGENTS; CLASSICAL ANTITUMOR; ESCHERICHIA-COLI; DRUG DESIGN; ANALOGS; TRIMETHOPRIM AB Structural data are reported for N-(2,4-diaminopteridin-6-yl)methyldibenz[b,f]azepine (PT653), an example of structure-based inhibitor design with 21-fold selectivity for Pneumocystis carinii dihydrofolate reductase (pcDHFR) relative to rat liver dihydrofolate reductase (r1DHFR). These data test the hypothesis that 2,4-diaminopteridines with a bulky N,N-diarylaminomethyl side chain at the 6-position could fit better into the larger active site of pcDHFR than into that of mammalian DHFR. The crystal structure of the ternary complex of NADPH, PT653 and pcDHFR, refined to 2.4 Angstrom resolution, reveals that PT653 binds in a different orientation than predicted from modeling studies reported previously [Rosowsky et al. (1999), J. Med. Chem. 42, 4853-4860]. These crystal data show that the pteridine-ring plane is tilted compared with that observed in the crystal structure of the pcDHFR methotrexate (MTX) NADPH ternary complex used as a template to model PT653 binding. Also, as a result of this tilt, the dibenzoazepine ring is bound deeper into the p-aminobenzoyl folate binding pocket of pcDHFR, thereby relieving close intermolecular contacts predicted from the modeling data. By far the most significant structural change, but more subtle in magnitude, is the ligand-induced conformational shift of 1.2 Angstrom away from the inhibitor of residues 61-66 in helix C. The other major effect is the unwinding of the short helical segment involving loop 47 which has a different conformation to that observed in other pcDHFR complexes [Cody et al. (1999), Biochemistry, 38, 4303-4312]. The favorable pcDHFR selectivity of PT653 could be a result of ligand-induced fit of the large hydrophobic dibenzazepine ring which occupies regions of the enzyme active site not probed by other antifolates and which take advantage of sequence and conformational differences between the structures of human and pcDHFR. These data suggest that such hydrophobic analogs could be used as lead compounds in the design of more pcDHFR-selective antifolates. Enzyme inhibition data also show that PT653 is 102-fold selective for Toxoplasma gondii (tg) DHFR relative to r1DHFR. Homology-modeling studies of the tgDHFR structure suggest that differences in ligand-binding orientation and enzyme sequence could influence the enhanced selectivity of PT653 for tgDHFR. C1 Hauptman Woodward Med Res Inst Inc, Buffalo, NY 14203 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. Indiana Univ, Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA. RP Cody, V (reprint author), Hauptman Woodward Med Res Inst Inc, 73 High St, Buffalo, NY 14203 USA. EM cody@hwi.buffalo.edu FU NIAID NIH HHS [AI-29904, N01-AI-35171]; NIGMS NIH HHS [GM-51670] NR 51 TC 19 Z9 20 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUN PY 2002 VL 58 SI 2 BP 946 EP 954 DI 10.1107/S090744490200505X PN 6 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 563TG UT WOS:000176271200004 PM 12037296 ER PT J AU Roy, AK Oh, T Rivera, O Mubiru, J Song, CS Chatterjee, B AF Roy, AK Oh, T Rivera, O Mubiru, J Song, CS Chatterjee, B TI Impacts of transcriptional regulation on aging and senescence SO AGEING RESEARCH REVIEWS LA English DT Review DE transcription factors; aging; gene regulation; senescence phenotype; reactive oxygen species ID NF-KAPPA-B; ANDROGEN RECEPTOR GENE; DNA-BINDING PROTEIN; HEAT-SHOCK PROTEINS; C/EBP-ALPHA; POSTTRANSCRIPTIONAL REGULATION; GLUCOCORTICOID RECEPTOR; DEPENDENT REGULATION; MOLECULAR-BIOLOGY; MMTV PROMOTER AB The genetic makeup of the organism appears to dictate the species-specific rate of aging and the maximum life-span potential. The genotype is converted to phenotype through transcriptional and translational regulation. A group of gene regulatory proteins (transcription factors) play critical roles in controlling the rates of transcription of specific genes by directly interacting with regulatory sequences at gene promoters. Here, we review the basic mechanism of transcriptional control and the role of a number of transcription factors whose level and/or activity alter with age. Among these age-dependent transcription factors, many are involved in the regulation of stress and inflammatory responses and are subjected to functional alterations by reactive oxygen species (ROSs). A progressive rise of oxidative stress, impaired ability to cope with stressful stimuli and prolongation of the inflammatory response are some of the hallmarks of the senescent phenotype. Results published to date are supportive of the concept that a species-specific program of the temporal regulation of genes with additional modulation by a number of epigenetic factors, mediates the age-dependent deterioration of physiological functions and development of the senescent phenotype. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Roy, AK (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NIA NIH HHS [R37AG-10486, T32AG-00165]; NIDDK NIH HHS [R01DK-14744] NR 79 TC 42 Z9 44 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1568-1637 J9 AGEING RES REV JI Ageing Res. Rev. PD JUN PY 2002 VL 1 IS 3 BP 367 EP 380 AR PII S1568-1637(02)00006-5 DI 10.1016/S1568-1637(02)00006-5 PG 14 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 603AP UT WOS:000178536900005 PM 12067592 ER PT J AU McGlinchey-Berroth, R Fortier, CB Cermak, LS Disterhoft, JF AF McGlinchey-Berroth, R Fortier, CB Cermak, LS Disterhoft, JF TI Temporal discrimination learning in abstinent chronic alcoholics SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcohol; eyeblink classical conditioning; timing; discrimination ID CONDITIONED NICTITATING-MEMBRANE; MAGNETIC-RESONANCE SPECTROSCOPY; EYELID RESPONSES; QUANTITATIVE-ANALYSIS; CEREBELLAR LESIONS; MAMMILLARY BODY; BRAIN-DAMAGE; NEUROPATHOLOGY; AMNESIA; DELAY AB Background: Converging evidence from varied experimental paradigms has demonstrated that the cerebellum is involved in the timing of learned behavior. Given the documented neurological changes secondary to chronic alcoholism, particularly cerebellar degeneration, the ability of recovered chronic alcoholics to learn a temporal discrimination was assessed by using delayed eyeblink classical conditioning. Methods: Twelve abstinent alcoholic participants and 12 matched control participants were randomly presented 2 clearly discriminable tone conditioned stimuli that were individually paired with 2 different interstimulus intervals. Results: The data revealed a significant alteration in the abstinent alcoholics' peak latency measure at the long interstimulus intervals and an overall impairment in their level of acquisition of conditioned responses. No group differences in extinction were observed. Conclusions: It was speculated that cerebellar cortical atrophy caused by years of alcohol abuse resulted in the peak latency alteration and that atrophy extending into deep cerebellar nuclei caused the overall impairment in conditioned response acquisition. C1 VA Boston Healthcare Syst, Geriatr Res Educ & Clin Ctr RMB, Boston, MA 02130 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Boston Univ, Sch Med, Memory Disorders Res Ctr, Boston, MA 02118 USA. Northwestern Univ, Sch Med, Dept Cell & Mol Biol, Chicago, IL USA. RP McGlinchey-Berroth, R (reprint author), VA Boston Healthcare Syst, GRECC 182, Bldg 9,150 S Huntington Ave, Boston, MA 02130 USA. RI McGlinchey, Regina/R-1971-2016; OI Disterhoft, John/0000-0002-8817-7913 FU NIAAA NIH HHS [NIAAA 00187]; NIMH NIH HHS [MH47340]; NINDS NIH HHS [1P50NS26985] NR 47 TC 9 Z9 9 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD JUN PY 2002 VL 26 IS 6 BP 804 EP 811 DI 10.1097/00000374-200206000-00009 PG 8 WC Substance Abuse SC Substance Abuse GA 566HR UT WOS:000176421700008 PM 12068248 ER PT J AU El-Serag, HB Olden, K Bjorkman, D AF El-Serag, HB Olden, K Bjorkman, D TI Health-related quality of life among persons with irritable bowel syndrome: a systematic review SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Review ID OF-LIFE; GASTROINTESTINAL-DISEASE; IMPACT; CARE; GASTROENTEROLOGY; VALIDATION; SEVERITY; SYMPTOMS; WOMEN AB Aim: To perform a systematic review of the literature with three objectives: (1) to compare the health related quality of life (HRQoL) of patients with irritable bowel syndrome with that of healthy controls; (2) to compare the HRQoL of irritable bowel syndrome patients to those with other diseases; and (3) to examine therapy-associated changes in HRQoL of irritable bowel syndrome patients. Methods: Searches of all English and non-English articles from 1980 to 2001 were performed in Medline and Embase, and two investigators performed independent data abstraction. Results: Seventeen articles met our selection criteria. 13 studies addressed objective no. 1; 11 showed a significant reduction in HRQoL among irritable bowel syndrome patients. Of these, only one study was considered of high quality. Four studies addressed objective no. 2, none of which was considered to be high quality in addressing this objective. Four trials (three of high quality) addressed objective no. 3. One showed that symptomatic improvement with Leupron compared to placebo was accompanied an improvement only in the comparative health domain of the HRQoL. The second study reported significant positive changes in HRQoL after 12 weeks of cognitive behavioural therapy. The third report of two placebo-controlled studies indicated significant improvement with alosetron on most domains of Irritable Bowel Syndrome Quality of Life Questionnaire. Conclusions: (i) There is reasonable evidence for a decrease in HRQoL in patients with moderate to severe irritable bowel syndrome; however, the data are conflicting regarding the impact of irritable bowel syndrome on HRQoL in population-based studies of nonconsulters. (ii) HRQoL in irritable bowel syndrome patients is impaired to a degree comparable to other chronic disorders such as GERD and depression. (iii) A therapeutic response in irritable bowel syndrome-related pain has a corresponding improvement in HRQoL. (iv) Limitations of the literature include focusing on moderate-severe irritable bowel syndrome in referral centres, and lack of appropriate controls. C1 Houston Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX 77030 USA. Houston Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. Mayo Clin Scottsdale, Dept Med, Scottsdale, AZ 85251 USA. Mayo Clin Scottsdale, Dept Psychiat, Scottsdale, AZ 85251 USA. Univ Utah, Sch Med, Div Gastroenterol, Salt Lake City, UT 84112 USA. RP El-Serag, HB (reprint author), Houston Vet Affairs Med Ctr, Gastroenterol Sect, 152,2002 Holcombe Blvd, Houston, TX 77030 USA. NR 34 TC 130 Z9 136 U1 2 U2 11 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-2813 J9 ALIMENT PHARM THERAP JI Aliment. Pharmacol. Ther. PD JUN PY 2002 VL 16 IS 6 BP 1171 EP 1185 DI 10.1046/j.1365-2036.2002.01290.x PG 15 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 556FG UT WOS:000175838300018 PM 12030961 ER PT J AU Sabatine, MS McCabe, CH Morrow, DA Giugliano, RP de Lemos, JA Cohen, M Antman, EM Braunwald, E AF Sabatine, MS McCabe, CH Morrow, DA Giugliano, RP de Lemos, JA Cohen, M Antman, EM Braunwald, E TI Identification of patients at high risk for death and cardiac ischemic events after hospital discharge SO AMERICAN HEART JOURNAL LA English DT Article ID WAVE MYOCARDIAL-INFARCTION; MOLECULAR-WEIGHT HEPARIN; CORONARY-ARTERY DISEASE; UNFRACTIONATED HEPARIN; UNSTABLE ANGINA; ENOXAPARIN AB Background Patients with unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI) remain at risk for death and cardiac ischemic events after being discharged from the hospital. Methods We examined whether the Thrombolysis In Myocardial Infarction (TIMI) risk score for UA/NSTEMI, ascertained at presentation in patients enrolled in the TIMI 11 B and Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI (ESSENCE) trials, could be used to identify patients at high risk for major cardiac events after hospital discharge. Results There were a total of 1218 major cardiac events, defined as death, nonfatal myocardial infarction, or urgent revascularization, by day 43. Of these events, 336 (28%) occurred in patients after they were discharged from the hospital. Use of the TIMI risk score for UA/NSTEMI revealed a progressive, statistically significant increase in the rate of events after leaving the hospital as the patients' baseline level of risk increased (P < .001 for chi(2) test for trend). For patients with a risk score of 5 to 7, treatment with enoxaparin during the acute phase was associated with an odds ratio of 0.51 (95% Cl 0.29-0.91) for the occurrence of death and cardiac ischemic events after hospital discharge. Conclusions More than one fourth of the major cardiac events that will occur in the first 6 weeks occur after discharge from the hospital. Stratification at presentation on the basis of the TIMI risk score for UA/NSTEMl can be used to identify patients at high risk for these events. Among patients at high-risk, acute-phase treatment with enoxaparin significantly reduces the risk of major cardiac events after leaving the hospital. C1 Brigham & Womens Hosp, Dept Med, Div Cardiovasc, TIMI Study Grp, Boston, MA 02115 USA. Univ Texas, SW Med Ctr, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX USA. Med Coll Penn & Hahnemann Univ, Sch Med, Dept Med, Div Cardiol, Philadelphia, PA 19102 USA. RP Sabatine, MS (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. NR 12 TC 20 Z9 24 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUN PY 2002 VL 143 IS 6 BP 966 EP 970 DI 10.1067/mhj.2002.122870 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 568CT UT WOS:000176525400010 PM 12075250 ER PT J AU Myers, J Oesterle, SN Jones, J Burkhoff, D AF Myers, J Oesterle, SN Jones, J Burkhoff, D TI Do transmyocardial and percutaneous laser revascularization induce silent ischemia? An assessment by exercise testing SO AMERICAN HEART JOURNAL LA English DT Article ID CORONARY-ARTERY DISEASE; REFRACTORY ANGINA; MYOCARDIAL REVASCULARIZATION; CANINE MYOCARDIUM; RANDOMIZED TRIAL; MEDICAL THERAPY; BLOOD-FLOW; ANGIOGENESIS; PECTORIS; CHANNELS AB Background Transmyocardial and percutaneous laser revascularization (TMR, PTMR) may reduce angina and increase exercise tolerance in otherwise untreatable angina patients, although the mechanism is unknown and the placebo effect may be significant. One other proposed mechanism is cardiac denervation leading to silent ischemia. Methods Electrocardiograms obtained during symptom-limited exercise (ETT, modified Bruce protocol) at baseline and 12 months were analyzed (blinded core laboratory) from 182 patients randomized to TMR (n = 92) or medical therapy alone (MEDTMR, n = 90) and 219 patients randomized to PTMR (n = 109) or medical therapy alone (MEDPTMR, n = 110). Results Exercise duration increased 1 year after TMR or PTMR relative to medically treated patients (6.8 +/- 3.4 min vs 8.6 +/- 3.5 min for TMR; 7.3 +/- 3.1 min vs 9.1 +/- 3.6 min for PTMR, P < .05). At baseline, 20% of TMR and MEDTMR subjects had ST depression >1.0 mm, >80% had angina during exercise, but only 3% had ST changes without chest pain (silent ischemia). This did not change after TMR. In the PTMR group, more subjects exercised to >1.0 mm ST depression (from 17% to 34%, P < .05), with no change in MEDPTMR, but the proportion with silent ischemia did not change in either group. Conclusion Exercise tolerance improved after TMR and after PTMR. Relative to PTMR, TMR more effectively suppressed pain during exercise and ischemic ST depression, However, neither TMR nor PTMR induced significant silent ischemia. These results suggest that denervation may not be a significant factor contributing to angina relief after these procedures. The contribution of the placebo effect was not determined by these results. C1 Stanford Univ, Palo Alto VA Hlth Care Syst, Div Cardiol, Palo Alto, CA 94304 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Missouri, Columbia, MO 65212 USA. Columbia Univ, New York, NY 10032 USA. RP Myers, J (reprint author), Stanford Univ, Palo Alto VA Hlth Care Syst, Div Cardiol, 111C,3801 Miranda Ave, Palo Alto, CA 94304 USA. RI Burkhoff, Daniel/D-7674-2011 NR 28 TC 17 Z9 17 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD JUN PY 2002 VL 143 IS 6 BP 1052 EP 1057 DI 10.1067/mhj.2002.122287 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 568CT UT WOS:000176525400023 PM 12075263 ER PT J AU Bednar, MM Harrigan, EP Ruskin, JN AF Bednar, MM Harrigan, EP Ruskin, JN TI Torsades do Pointes associated with nonantiarrhythmic drugs and observations on gender and QTc SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID INTERVAL PROLONGATION; SEX; DIFFERENCE; CYCLE; AGE AB The reported occurrence of torsades de pointes in association with nonantiarrhythmic drugs (n = 189) suggests that >90% of events occur in association with QTc values greater than or equal to500 ms and that women accounted for approximately two thirds of all reported cases. Both observations are extremely similar to the findings reported in a large database (n = 332) for antiarrhythmic agents, suggesting a fundamental biologic response that transcends both drug class and population studied. C1 Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. Pfizer Global Res & Dev, Groton, CT USA. RP Ruskin, JN (reprint author), Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. NR 19 TC 61 Z9 64 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 1 PY 2002 VL 89 IS 11 BP 1316 EP + DI 10.1016/S0002-9149(02)02337-8 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 558UN UT WOS:000175985300019 PM 12031739 ER PT J AU Aranda, JM Krause-Steinrauf, HJ Greenberg, BH Heng, MK Kosolcharoen, PK Renlund, DG Thaneemit-Chen, S White, M Cintron, GB AF Aranda, JM Krause-Steinrauf, HJ Greenberg, BH Heng, MK Kosolcharoen, PK Renlund, DG Thaneemit-Chen, S White, M Cintron, GB CA BEST Investigators TI Comparison of the beta blocker bucindolol in younger versus older patients with heart failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ADRENERGIC-RECEPTOR BLOCKADE; AGE AB The elderly population in the Beta-Blocker Evaluation of Survival Trial is a sicker cohort of patients characterized by increased duration of heart failure, more coronary artery disease, and higher mortality. Compared with younger patients, older patients with heart failure safely tolerate the beta blocker bucindolol with similar physiologic effects; advanced age should not be the sole reason for avoiding beta blockers in elderly patients with heart failure. C1 Univ Florida, Coll Med, Gainesville, FL 32610 USA. Gainesville Vet Adm Med Ctr, Gainesville, FL USA. NHLBI, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Sepulveda Vet Adm Med Ctr, Sepulveda, CA USA. William S Middleton Mem Vet Adm Med Ctr, Madison, WI USA. Latter Day St Hosp, Salt Lake City, UT 84143 USA. Dept Vet Affairs Palo Alto Hlth Care Syst, CSPCC, Palo Alto, CA USA. Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Tampa Vet Adm Med Ctr, Tampa, FL USA. RP Aranda, JM (reprint author), Univ Florida, Coll Med, 1600 SW Archer Rd,Room 10-539, Gainesville, FL 32610 USA. NR 11 TC 11 Z9 11 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 1 PY 2002 VL 89 IS 11 BP 1322 EP + DI 10.1016/S0002-9149(02)02339-1 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 558UN UT WOS:000175985300021 PM 12031741 ER PT J AU Freed, LA Levy, D Levine, RA Evans, JC Larson, MG Fuller, DL Lehman, B Benjamin, EJ AF Freed, LA Levy, D Levine, RA Evans, JC Larson, MG Fuller, DL Lehman, B Benjamin, EJ TI Mitral valve prolapse and atrial septal aneurysm: An evaluation in the Framingham heart study SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TWO-DIMENSIONAL ECHOCARDIOGRAPHY; PATENT FORAMEN OVALE; TRANSESOPHAGEAL ECHOCARDIOGRAPHY; CEREBROVASCULAR EVENTS; DIAGNOSIS; PREVALENCE; EMBOLISM; MEMBRANE; ADULT AB Mitral valve prolapse and atrial septal aneurysms have been linked in previous studies. The results of this study demonstrate that atrial septal aneurysms, examined for the first time in a community-based sample, the Framingham Heart Study, occur with similar frequency in subjects with and without mitral valve prolapse. C1 NHLBI, Framington Heart Study, Framingham, MA USA. Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Div Cardiol, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Clin Epidemiol, Boston, MA 02215 USA. Boston Univ, Sch Med, Div Cardiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Div Epidemiol & Prevent Med, Boston, MA 02118 USA. RP Benjamin, EJ (reprint author), Boston Univ, Sch Med, Framington Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. OI Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [R01-HL-38176, K24-HL-67434, N01 HC-38038, R01-HL-53702]; NINDS NIH HHS [5-R01-NS-17950-16] NR 20 TC 6 Z9 6 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 1 PY 2002 VL 89 IS 11 BP 1326 EP + DI 10.1016/S0002-9149(02)02340-8 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 558UN UT WOS:000175985300022 PM 12031742 ER PT J AU Breathnach, OS Kasturi, V Kaye, F Herscher, L Georgiadis, MS Edison, M Schuler, BS Pizzella, P Steinberg, SM O'Neil, K Johnson, BE AF Breathnach, OS Kasturi, V Kaye, F Herscher, L Georgiadis, MS Edison, M Schuler, BS Pizzella, P Steinberg, SM O'Neil, K Johnson, BE TI Phase II neoadjuvant trial of paclitaxel by 96-hour continuous infusion (CIVI) in combination with cisplatin followed by chest radiotherapy for patients with stage III non-small-cell lung cancer SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE lung neoplasm; carcinoma; non-small-cell lung cancer; clinical trial; phase II; neoadjuvant ID THERAPY ONCOLOGY GROUP; HYPERFRACTIONATED RADIATION-THERAPY; RANDOMIZED TRIAL; CONCURRENT CHEMOTHERAPY; BREAST-CANCER; I/II TRIAL; CARCINOMA; PATTERNS; SURVIVAL; FAILURE AB Sixteen patients with untreated locally advanced (n = 15) or recurrent (n = 1) non-small-cell lung cancer (NSCLC) were enrolled in this study between July 1996 and March 1999. Eight patients had stage IIIA NSCLC, seven had stage = disease, and one had recurrent disease after prior resection of stage I disease. Patients were treated with paclitaxel 30 mg/rm(2) /d for 4 days by continuous intravenous infusion followed by cisplatin 80 mg/m(2) on day 5. Therapy was administered every 3 weeks until disease progression or a maximum of four cycles. Thoracic radiation was started within 3 to 4 weeks of day I of the last cycle of paclitaxel and cisplatin. Fourteen patients (87.5%) received all four cycles of chemotherapy and subsequent radiation therapy. Forty-four percent of patients achieved a partial response, and 1 patient complete response (overall response rate, 50%). The median progression-free survival was 8.8 months. At a median potential follow-up of 3.7 years, the median survival for all 16 enrolled patients was 13.2 months and the actuarial 1-, 2-, and 3-year survivals were 62.5%: 43.8%, and 21.9%. In contrast to predictions from in vitro cytotoxicity models, the sequential use of prolonged infusional paclitaxel and bolus cisplatin followed by thoracic radiation does not appear to have a greater impact over shorter chemotherapy infusion schedules. C1 Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. NCI, Natl Naval Med Ctr, Med Branch, Bethesda, MD 20892 USA. NCI, Natl Naval Med Ctr, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Natl Naval Med Ctr, Radiat Oncol Branch, Bethesda, MD 20892 USA. Natl Naval Med Res Inst, Dept Radiol, Bethesda, MD USA. Natl Naval Med Res Inst, Dept Pulm Med, Bethesda, MD USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Suite 1234,44 Binney St, Boston, MA 02115 USA. RI kaye, frederic/E-2437-2011 NR 25 TC 2 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD JUN PY 2002 VL 25 IS 3 BP 269 EP 273 DI 10.1097/00000421-200206000-00013 PG 5 WC Oncology SC Oncology GA 559VG UT WOS:000176045900013 PM 12040286 ER PT J AU Hodi, FS Soiffer, RJ Clark, J Finkelstein, DM Haluska, FG AF Hodi, FS Soiffer, RJ Clark, J Finkelstein, DM Haluska, FG TI Phase II study of paclitaxel and carboplatin for malignant melanoma SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE malignant melanoma; ccarboplatin; paclitaxel ID CELL LUNG-CANCER; COMBINATION CHEMOTHERAPY; METASTATIC MELANOMA; IN-VITRO; CISPLATIN; TAXOL; TRIAL AB Conventional chemotherapy in the treatment of malignant melanoma has been disappointingly ineffective. Although the most active single agent is dacarbazine, numerous trials support the activity of platinum analogs against melanoma. Several recent trials also demonstrate the single-agent activity of paclitaxel, and support the administration of these agents together in the treatment of a number of solid tumors. We conducted a phase II study treating patients with metastatic melanoma with paclitaxel as a 3-hour infusion of 175 mg/m(2), and carboplatin dosed to yield an area under the curve of 7.5 administered during 30 minutes. Patients were previously untreated or treated once with a regimen not including a platinum or taxane agent and had a performance status of 0 or 1. Seventeen patients (8 males; 9 females; average age 51) were enrolled. Thirty-three percent of patients had disease involving the skin, 40% lungs, 33% lymph nodes, 26% liver, and 13% other visceral organs. Anaphylactic reactions developed in two patients associated with paclitaxel infusion, and the patients were subsequently taken off the study. Of the 15 remaining patients, 3 (20%) had partial responses, 7 (47%) had stable disease, and 5 (33%) showed evidence of progressive disease. Eleven patients experienced grade III or IV hematologic toxicity. All treatment-related toxicities were reversible. There were no treatment-related deaths. The combination of paclitaxel and carboplatin has moderate activity against malignant melanoma, with expected reversible hematologic toxicities. Although not prospectively compared with single agents, the combination of paclitaxel and carboplatin may be a treatment option for some patients. Comparisons with other treatment regimens and the search for additional active compounds against melanoma are needed. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Ctr Canc, Biostat Grp, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. RP Haluska, FG (reprint author), Melanoma Program, Jackson Bldg,GRJ 1021,55 Fruit St, Boston, MA 02114 USA. NR 22 TC 60 Z9 61 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD JUN PY 2002 VL 25 IS 3 BP 283 EP 286 DI 10.1097/00000421-200206000-00016 PG 4 WC Oncology SC Oncology GA 559VG UT WOS:000176045900016 PM 12040289 ER PT J AU Mick, E Biederman, J Faraone, S AF Mick, E Biederman, J Faraone, S TI Risk of attention-deficit/hyperactivity disorder associated with low birth weight and maternal substance use during pregnancy. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUN 1 PY 2002 VL 155 IS 11 SU S MA 352 BP s88 EP s88 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558FK UT WOS:000175955500347 ER PT J AU Sepulveda, AR Peterson, LE Shelton, J Gutierrez, O Graham, DY AF Sepulveda, AR Peterson, LE Shelton, J Gutierrez, O Graham, DY TI Histological patterns of gastritis in H-pylori-infected individuals with a family history of gastric cancer SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID HELICOBACTER-PYLORI; RISK; POPULATION; CARCINOMA; LESIONS; STOMACH; JAPAN AB OBJECTIVE: Different types of chronic gastritis, including antral predominant, corpus predominant, and multifocal pangastritis, are associated with Helicobacter pylori infection. Specific patterns of H. pylori gastritis that might characterize individuals with family histories of noncardia gastric cancer (GC) were investigated. METHODS: Histopathological changes associated with H. pylori gastritis were assessed in 111 individuals with family histories of GC and in 77 without from a region with high prevalence of H. pylori infection and GC. Gastric biopsies were taken from 12 sites (antrum, five; corpus, six; and cardia, one). RESULTS: Individuals (age < 36 yr) with family histories of GC developed pangastritis and had higher H. pylori bacterial scores (p < 0.05) in the gastric corpus, whereas those without family histories of GC typically had antral predominant gastritis. The correlation between density of polymorphonuclear leukocytes and density of H. pylori at each biopsy site was statistically significant (p < 0.01). Pangastritis was associated with a higher density of lymphoid aggregates and follicles (p < 0.05) in the corpus of younger individuals (age < 36) and in the antrum of older individuals (age &GE; 48) with positive family histories of GC. CONCLUSIONS: Pangastritis and high lymphoid follicle density associated with H. pylori infection were found in patients with family histories of GC. Because a family history of gastric carcinoma is associated with increased risk of gastric cancer development, characterization of histological patterns of gastritis may be applicable to gastric cancer screening and surveillance, especially in relatively young at-risk populations. C1 Univ Pittsburgh, Med Ctr, Dept Pathol, Pittsburgh, PA 15213 USA. VA Med Ctr, Dept Med, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Nacl Colombia, Bogota, Colombia. RP Sepulveda, AR (reprint author), Univ Pittsburgh, Med Ctr, Dept Pathol, PUH-A610,200 Lothrop St, Pittsburgh, PA 15213 USA. OI Peterson, Leif/0000-0002-1187-0883 FU NCI NIH HHS [CA78199-03] NR 27 TC 25 Z9 27 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JUN PY 2002 VL 97 IS 6 BP 1365 EP 1370 AR PII S0002-9270(02)04023-6 DI 10.1016/S0002-9270(02)04023-6 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 566AJ UT WOS:000176403300014 PM 12094851 ER PT J AU Grant, RW Cagliero, E Murphy-Sheehy, P Singer, DE Nathan, DM Meigs, JB AF Grant, RW Cagliero, E Murphy-Sheehy, P Singer, DE Nathan, DM Meigs, JB TI Comparison of hyperglycemia, hypertension, and hypercholesterolemia management in patients with type 2 diabetes SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID CORONARY HEART-DISEASE; DENSITY-LIPOPROTEIN CHOLESTEROL; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; GLYCEMIC CONTROL; MORTALITY; EVENTS; POPULATION; PHYSICIANS; THERAPY AB PURPOSE: Cardiovascular disease is the leading cause of death in patients with type 2 diabetes. We compared hyperglycemia management with the management of the cardiovascular disease risk factors hypertension and hypercholesterolemia in a cohort of type 2 diabetes patients. SUBJECTS AND METHODS: We randomly selected 601 patients with type 2 diabetes seen at the outpatient practices of all academic medical center and assessed the care they received during an 18-month period. we compared proportions of patients who had hemoglobin A(1c) (HbA(1c)) levels, blood pressure, or total cholesterol levels measured; who had been prescribed any drug therapy if HbA(1c) levels, systolic blood pressure, or low-density lipoprotein (LDL) cholesterol levels exceeded recommended treatment goals; and who had been prescribed greater-than-starting-close therapy if these values were above those of treatment goals. Results: Patients were less likely to have cholesterol levels (76%, n = 455) measured than HbA(1c) (92%, n = 552) levels or blood pressure (99%, n = 595; P <0.0001 for either comparison). The proportion of patients that received any drug therapy was greater for above-goal HbA(1c) (92%, n = 348) than for above-goal systolic blood pressure (78%, n = 274) or LDL cholesterol (38%, n = 82; P <0.0001 for each comparison). Similarly, patients whose HbA(1c) levels were above the treatment goal (80%, n = 302) were more likely to receive greater-than-starting-dose therapy, compared with those who had above-goal systolic blood pressure (62%, n = 218) and LDL cholesterol levels (13%, n = 28, P <0.0001). CONCLUSION: In this cohort, hypercholesterolemia and hypertension were managed less aggressively than was hyperglycemia. Given the prevalence of cardiovascular disease in patients with Type 2 diabetes, increased screening for hypercholesterolemia and more aggressive drug therapy for hypercholesterolemia and hypertension are needed. C1 Massachusetts Gen Hosp, Gen Med Div, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Div Gen Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Clin Res Program, Boston, MA USA. Harvard Univ, Sch Med, Dept Med, Diabet Unit, Boston, MA USA. RP Grant, RW (reprint author), Massachusetts Gen Hosp, Gen Med Div, 50 Staniford St,9th Floor, Boston, MA 02114 USA. OI Grant, Richard/0000-0002-6164-8025 FU NCRR NIH HHS [RR01066]; PHS HHS [2-T3211001-14] NR 48 TC 66 Z9 68 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUN 1 PY 2002 VL 112 IS 8 BP 603 EP 609 AR PII S0002-9343(02)01103-8 DI 10.1016/S0002-9343(02)01103-8 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 557PV UT WOS:000175917700001 PM 12034408 ER PT J AU Hamberg, LM Hunter, GJ Maynard, KI Owen, C Morris, PP Putman, CM Ogilvy, C Gonzalez, RG AF Hamberg, LM Hunter, GJ Maynard, KI Owen, C Morris, PP Putman, CM Ogilvy, C Gonzalez, RG TI Functional CT perfusion Imaging in predicting the extent of cerebral infarction from a 3-hour middle cerebral arterial occlusion in a primate stroke model SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID ANESTHETIZED BABOONS; BLOOD-FLOW; ISCHEMIA; INJURY; REPERFUSION; THRESHOLDS; ANTIBODY; MONKEYS; RAT AB BACKGROUND AND PURPOSE. Our purpose was to determine whether cerebral perfusion functional CT (fCT), performed after endovascular middle cerebral artery (MCA) occlusion, can be used to predict final cerebral infarction extent in a primate model. METHODS: fCT with bolus tracking was performed before and 30 and 150 minutes after 3-hour digital subtraction angiography (DSA)-guided endovascular MCA occlusion in five baboons. Parametric cerebral blood now (CBF), cerebral blood volume (CBV) and mean transit time (MTT) maps were constructed by voxel-by-voxel gamma variate fitting and used to determine lesion sizes. Animals were sacrificed 48 hours after the occlusion, and ex vivo MR imaging was performed. Lesion sizes on fCT and MR images were compared. RESULTS: Hypoperfusion was clearly identified on all images obtained after MCA occlusion. Thirty and 150 minutes after occlusion onset, respectively, mean lesion sizes were 737 mm(2) +/- 33 and 737 mm(2) +/- 44 for CBF, 722 mm(2) +/- 32 and 730 mm(2) +/- 43 for CBV, and 819mm(2) +/- 14 and 847 mm(2) +/- 11 for MTT. Mean outcome infarct size on MR images was 733 mm(2) +/- 30. Measurements based on CBV and CBF (R-2 = 0.97 and 0.96, P <.001), but not MTT (R-2 = 0.40, P >.5), were highly correlated with final lesion size. CONCLUSION. An endovascular approach to MCA occlusion provides a minimally invasive, reproducible animal model for controlled studies of cerebral ischemia and infarction. Derived cerebral perfusion maps closely predict the 48-hour infarct size after 3-hour MCA occlusion. C1 Massachusetts Gen Hosp, MGH Perfus & Physiol Anal Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neuroradiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Hamberg, LM (reprint author), Massachusetts Gen Hosp, MGH Perfus & Physiol Anal Lab, Gray B238,55 Fruit St, Boston, MA 02114 USA. NR 24 TC 30 Z9 37 U1 0 U2 1 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JUN-JUL PY 2002 VL 23 IS 6 BP 1013 EP 1021 PG 9 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 563UM UT WOS:000176275000026 PM 12063235 ER PT J AU Yamada, K Gonzalez, RG Ostergaard, L Komili, S Weisskoff, RM Rosen, BR Koroshetz, WJ Nishimura, T Sorensen, AG AF Yamada, K Gonzalez, RG Ostergaard, L Komili, S Weisskoff, RM Rosen, BR Koroshetz, WJ Nishimura, T Sorensen, AG TI Iron-induced susceptibility effect at the globus pallidus causes underestimation of flow and volume on dynamic susceptibility contrast-enhanced MR perfusion images SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; HIGH-RESOLUTION MEASUREMENT; TRACER BOLUS PASSAGES; BRAIN IRON; BASAL GANGLIA; TRANSHEMISPHERIC DIASCHISIS; OXYGEN UTILIZATION; HYPERACUTE STROKE; 1.5 T AB BACKGROUND AND PURPOSE: Age-related iron accumulation in extrapyramidal nuclei causes T2 shortening, which may result in decreased signal intensity in these areas on MR images. Because the dynamic susceptibility contrast-enhanced technique uses heavily T2*- or T2-weighted images, the iron-induced susceptibility may have direct impact on perfusion imaging. The purpose of this study was to assess the effect of iron-induced susceptibility on the calculated perfusion parameters. The difference of this effect between gradient-echo and spin-echo sequences was also assessed. METHODS: Dynamic susceptibility contrast-enhanced MR perfusion imaging data of 12 patients were used for this study. Perfusion images were obtained using a single shot spin-echo echo-planar imaging sequence in seven patients and a gradient-echo echo-planar imaging sequence in five patients. Region of interest measurements of relative cerebral blood flow, relative cerebral blood volume, and mean transit time were obtained at various parts of the gray matter, including the globus pallidus, putamen, caudate nucleus, thalamus, and cerebral cortex of temporal, frontal, and occipital lobes. The baseline signal intensity on the source images and the magnitude of signal change (DeltaR2* or DeltaR2) were also assessed. RESULTS: The globus pallidus had statistically significantly lower values of relative cerebral blood flow, relative cerebral blood volume, baseline signal intensity, and magnitude of signal change compared with other parts of the gray matter for both gradient-echo and spin-echo sequences (P <.05). Underestimations of these values were more prominent for the gradient-echo than for the spin-echo sequence. Little variance in the measured mean transit time was noted. CONCLUSION. Iron-induced susceptibility effect may lead to underestimation of relative cerebral blood flow and relative cerebral blood volume in the basal ganglia. C1 Kyoto Prefectural Univ Med, Dept Radiol, Kamigyo Ku, Kyoto 6028566, Japan. Harvard Univ, Massachusetts Gen Hosp, Sch Med, NMR Ctr, Boston, MA USA. Aarhus Univ Hosp, Dept Neuroradiol, DK-8000 Aarhus, Denmark. RP Yamada, K (reprint author), Kyoto Prefectural Univ Med, Dept Radiol, Kamigyo Ku, Kyoto 6028566, Japan. RI Bonefeld, Birgit/B-7936-2010; Ostergaard, Leif/A-9281-2008 OI Ostergaard, Leif/0000-0003-2930-6997 FU NCRR NIH HHS [P41-RR14075]; NHLBI NIH HHS [R01-HL39810]; NINDS NIH HHS [R01NS8477] NR 47 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD JUN-JUL PY 2002 VL 23 IS 6 BP 1022 EP 1029 PG 8 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 563UM UT WOS:000176275000027 PM 12063236 ER PT J AU Montesinos, MC Desai, A Chen, JF Yee, H Schwarzschild, MA Fink, JS Cronstein, BN AF Montesinos, MC Desai, A Chen, JF Yee, H Schwarzschild, MA Fink, JS Cronstein, BN TI Adenosine promotes wound healing and mediates angiogenesis in response to tissue injury via occupancy of A(2A) receptors SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; SUPEROXIDE ANION GENERATION; OXYGEN-INDUCED RETINOPATHY; PROTEIN-KINASE-C; ADENINE-NUCLEOTIDES; HUMAN-NEUTROPHILS; POLYMORPHONUCLEAR LEUKOCYTES; ANTIINFLAMMATORY MECHANISM; CELL-PROLIFERATION; INFLAMED SITES AB Recent evidence indicates that topical application of adenosine A(2A) receptor agonists, unlike growth factors, increases the rate at which wounds close in normal animals and promotes wound healing in diabetic animals as well as growth factors, yet neither the specific adenosine receptor involved nor the mechanism(s) by which adenosine receptor occupancy promotes wound healing have been fully established. To determine which adenosine receptor is involved and whether adenosine receptor-mediated stimulation of angiogenesis plays a role in promotion of wound closure we compared the effect of topical application of the adenosine receptor agonist CGS-21680 (2-p-[2-carboxyethyl]phenethyl-amino-5'-N-ethylcarboxamido-adenosine) on wound closure and angiogenesis in adenosine A(2A) receptor knockout mice and their wild-type littermates. There was no change in the rate of wound closure in the A(2A) receptor knockout mice compared to their wild-type littermates although granulation tissue formation was nonhomogeneous; and there seemed to be greater inflammation at the base of the wound. Topical application of CGS-21680 increased the rate of wound closure and increased the number of microvessels in the wounds of wild-type mice but did not affect the rate of wound closure in A(2A) receptor knockout mice. Similarly, in a model of internal trauma and repair (murine air pouch model), endogenously produced adenosine released into areas of internal tissue injury stimulates angiogenesis because there was a marked reduction in blood vessels in the wafts of healing air pouches of A(2A) receptor knockout mice compared to their wild-type controls. Inflammatory vascular leakage and leukocyte accumulation in the inflamed air pouch were similarly reduced in the A(2A) receptor knockout mice reflecting the reduced vascularity. Thus, targeting the adenosine A(2A) receptor is a novel approach to promoting wound healing and angiogenesis in normal individuals and those suffering from chronic wounds. C1 NYU, Med Ctr, Dept Med, New York, NY 10016 USA. Massachusetts Gen Hosp, Dept Neurol, Mol Neurobiol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Cronstein, BN (reprint author), NYU, Med Ctr, Dept Med, 550 First Ave, New York, NY 10016 USA. RI Montesinos, M. Carmen/G-8852-2015 OI Montesinos, M. Carmen/0000-0003-1801-311X FU NCRR NIH HHS [M01 RR000096, M01RR00096]; NIAMS NIH HHS [R01 AR041911, AR41911]; NIGMS NIH HHS [GM56268, R01 GM056268] NR 52 TC 115 Z9 122 U1 1 U2 4 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2002 VL 160 IS 6 BP 2009 EP 2018 DI 10.1016/S0002-9440(10)61151-0 PG 10 WC Pathology SC Pathology GA 559ZQ UT WOS:000176056900013 PM 12057906 ER PT J AU Leibovich, SJ Chen, JF Pinhal-Enfield, G Belem, PC Elson, G Rosania, A Ramanathan, M Montesinos, C Jacobson, M Schwarzschild, MA Fink, JS Cronstein, B AF Leibovich, SJ Chen, JF Pinhal-Enfield, G Belem, PC Elson, G Rosania, A Ramanathan, M Montesinos, C Jacobson, M Schwarzschild, MA Fink, JS Cronstein, B TI Synergistic up-regulation of vascular endothelial growth factor expression in murine macrophages by adenosine A(2A) receptor agonists and endotoxin SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; SMOOTH-MUSCLE CELLS; FACTOR GENE; TRANSCRIPTIONAL REGULATION; PERITONEAL-MACROPHAGES; MOLECULAR-CLONING; RAT-BRAIN; HYPOXIA; ANGIOGENESIS; INDUCTION AB Under normoxic conditions, macrophages from C57BL mice produce low levels of vascular endothelial growth factor (VEGF). Hypoxia stimulates VEGF expression by similar to500%; interferon-gamma (IFN-gamma) with endotoxin [lipopolysaccharide (LPS)] also stimulates VEGF expression by similar to50 to 150% in an inducible nitric oxide synthase (iNOS)-dependent manner. Treatment of normoxic macrophages with 5'-N-ethyl-carboxamido-adenosine (NECA), a nonselective adenosine A, receptor agonist, or with 2-[p-(2-carboxyethyl)-phenylethyl amino]-5'-N-ethyl-carboxamido-adenosine (CGS21680), a specific adenosine A(2A) receptor agonist, modestly increases VEGF expression, whereas 2-chloro-N-6-cyclopentyl adenosine (CCPA), an adenosine A(1) agonist, does not. Treatment with LPS (0 to 1000 ng/ml), or with IFN-gamma (0 to 300 U/ml), does not affect VEGF expression. In the presence of LPS (EC50 < 10 ng/ml), but not of IFN-gamma, both NECA and CGS21680 synergistically up-regulate VEGF expression by as much as 10-fold. This VEGF is biologically active in vivo in the rat corneal bioassay of angiogenesis. Inhibitors of iNOS do not affect this synergistic induction of VEGF, and macrophages from iNOS-/- mice produce similar levels of VEGF as wildtype mice, indicating that NO does not play a role in this induction. Under hypoxic conditions, VEGF expression is slightly increased by adenosine receptor agonists but adenosine A(2) or A(1) receptor antagonists 3,7-dimethyl-1-propargyl xanthine (DMPX), ZM241385, and 8-cyclopentyl-1,3-dipropylxanthine (DCPCX) do not modulate VEGF expression. VEGF expression is also not reduced in hypoxic macrophages from A(3)-/- and A(2A)-/- mice. Thus, VEGF expression by hypoxic macrophages does not seem to depend on endogenously released or exogenous adenosine. VEGF expression is strongly up-regulated by LPS/NECA in macrophages from A(3)-/- but not A(2A)-/- mice, confirming the role of adenosine A(2A) receptors in this pathway. LPS with NECA strongly up-regulates VEGF expression by macrophages from C3H/HeN mice (with intact Tlr4 receptors), but not by macrophages; from C3H/HeJ mice (with mutated, functionally inactive Tlr4 receptors), implicating signaling through the Tlr4 pathway in this synergistic up-regulation. Finally, Western blot analysis of adenosine A,A receptor expression indicated that the synergistic interaction of LPS with A(2A) receptor agonists does not involve up-regulation of A(2A) receptors by LPS. These results indicate that in murine macrophages there is a novel pathway regulating VEGF production, that involves the synergistic interaction of adenosine A(2A) receptor agonists through A(2A) receptors with LPS through the Tlr4 pathway, resulting in the strong up-regulation of VEGF expression by macrophages in a hypoxia- and NO-independent manner. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA. Massachusetts Gen Hosp, Mol Neurobiol Lab, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NYU, Sch Med, Dept Med, New York, NY USA. NYU, Sch Med, Div Clin Pharmacol, New York, NY USA. Merck & Co Inc, W Point, PA USA. RP Leibovich, SJ (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Cell Biol & Mol Med, 185 S Orange Ave, Newark, NJ 07103 USA. RI Montesinos, M. Carmen/G-8852-2015 OI Montesinos, M. Carmen/0000-0003-1801-311X FU NIAMS NIH HHS [AR41911, R01 AR041911]; NIGMS NIH HHS [GM56268, R01 GM056268, R01-GM57982] NR 65 TC 118 Z9 123 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2002 VL 160 IS 6 BP 2231 EP 2244 DI 10.1016/S0002-9440(10)61170-4 PG 14 WC Pathology SC Pathology GA 559ZQ UT WOS:000176056900032 PM 12057925 ER PT J AU Mathurin, P Xiong, SG Kharbanda, KK Veal, N Miyahara, T Motomura, K Rippe, RA Bachem, MG Tsukamoto, H AF Mathurin, P Xiong, SG Kharbanda, KK Veal, N Miyahara, T Motomura, K Rippe, RA Bachem, MG Tsukamoto, H TI IL-10 receptor and coreceptor expression in quiescent and activated hepatic stellate cells SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE interleukin-10; cytokine receptor family 2-4; procollagen-alpha(1)(I); matrix metalloprotease-2; matrix metalloprotease-13; monocyte-chemoattracting protein-1; liver fibrosis ID GALACTOSAMINE-SENSITIZED MICE; HUMAN INTERLEUKIN-10 RECEPTOR; SINUSOIDAL ENDOTHELIAL-CELLS; NECROSIS-FACTOR-ALPHA; KUPFFER CELLS; GENE-EXPRESSION; LIVER FIBROSIS; I COLLAGEN; INJURY; RNA AB Interleukin (IL)-10 expression is induced in activated hepatic stellate cells (HSC) in vitro and in vivo. We analyzed expression of IL-10 receptor (IL-10R) and coreceptor cytokine receptor family (CRF2-4) in HSC. We aimed to clone and sequence partial cDNA for rat IL-10R and CRF2-4, determine their expression in activated rat HSC in vivo and in vitro, and examine the biological responsiveness of HSC to exogenous IL-10. PCR cloning and sequencing of partial rat IL-10R and CRF2-4 cDNAs revealed 86% homology with corresponding mouse sequences. In hepatic macrophages, Northern blot with cloned IL-10R cDNA detected an expected 3.5-kb transcript, and IL-10R and CRF2-4 mRNAs showed steady constitutive expression after in vitro lipopolysaccharide treatment or cholestatic liver injury. IL-10R mRNA expression, as confirmed by immunohistochemistry, was induced 20.1- and 8.6-fold in HSC from cholestatic livers and 7-day culture-activated HSC, respectively but CRF2-4 mRNA levels were unchanged. Under serum-free conditions, IL-10 had minimal effects on collagen production but reduced DNA synthesis, matrix metalloprotease-2 mRNA levels, and activity in HSC. With serum, IL-10 inhibited both collagen production and DNA synthesis but had no effect on procollagen-alpha(1)(I) mRNA levels. This shows concomitant induction of IL-10R but not CRF2-4 to that of IL-10 by activated HSC in vitro and in vivo and associated acquisition of the responsiveness to IL-10, entailing complex effects on HSC. C1 Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90089 USA. Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90089 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Sepulveda, CA 91343 USA. Dept Vet Affairs Med Ctr, Omaha, NE 68198 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. Univ Ulm, Inst Clin Chem, D-89070 Ulm, Germany. RP Tsukamoto, H (reprint author), Univ So Calif, Keck Sch Med, Dept Pathol, 1333 San Pablo St,MMR-412, Los Angeles, CA 90089 USA. FU NIAAA NIH HHS [R37-AA-06603, R24-AA-12885, R01-AA-10459, P50-AA-11999]; NIDDK NIH HHS [P30-DK-48522]; PHS HHS [R01-DR-34987] NR 44 TC 23 Z9 23 U1 1 U2 1 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 JUN PY 2002 VL 282 IS 6 BP G981 EP G990 DI 10.1152/ajpgi.00293.2001 PG 10 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 552KT UT WOS:000175620100009 PM 12016123 ER PT J AU Dai, GH Tsukurov, O Chen, M Gertler, JP Kamm, RD AF Dai, GH Tsukurov, O Chen, M Gertler, JP Kamm, RD TI Endothelial nitric oxide production during in vitro simulation of external limb compression SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE deep vein thrombosis; hemodynamics; nitric oxide synthase ID INTERMITTENT PNEUMATIC COMPRESSION; DISTANT SKELETAL-MUSCLE; TOTAL HIP-REPLACEMENT; DEEP-VEIN THROMBOSIS; VENOUS-BLOOD FLOW; SHEAR-STRESS; CALF COMPRESSION; IN-VITRO; SYNTHASE; CELLS AB External pneumatic compression (EPC) is effective in preventing deep vein thrombosis (DVT) and is thought to alter endothelial thromboresistant properties. We investigated the effect of EPC on changes in nitric oxide (NO), a critical mediator in the regulation of vasomotor and platelet function. An in vitro cell culture system was developed to simulate flow and vessel collapse conditions under EPC. Human umbilical vein endothelial cells were cultured and subjected to tube compression (C), pulsatile flow (F), or a combination of the two (FC). NO production and endothelial nitric oxide synthase (eNOS) mRNA expression were measured. The data demonstrate that in the F and FC groups, there is a rapid release of NO followed by a sustained increase. NO production levels in the F and FC groups were almost identical, whereas the C group produced the same low amount of NO as the control group. Conditions F and FC also upregulate eNOS mRNA expression by a factor of 2.08 +/- 0.25 and 2.11 +/- 0.21, respectively, at 6 h. Experiments with different modes of EPC show that NO production and eNOS mRNA expression respond to different time cycles of compression. These results implicate enhanced NO release as a potentially important factor in the prevention of DVT. C1 MIT, Div Biol Engn, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Div Vasc Surg, Vasc Surg Res Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Kamm, RD (reprint author), MIT, Div Biol Engn, Rm 3-260, Cambridge, MA 02139 USA. OI Dai, Guohao/0000-0001-7346-2685 NR 45 TC 19 Z9 19 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN PY 2002 VL 282 IS 6 BP H2066 EP H2075 DI 10.1152/ajpheart.00288.2001 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 550YC UT WOS:000175531800017 PM 12003813 ER PT J AU Nemoto, S Vallejo, JG Knuefermann, P Misra, A Defreitas, G Carabello, BA Mann, DL AF Nemoto, S Vallejo, JG Knuefermann, P Misra, A Defreitas, G Carabello, BA Mann, DL TI Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE innate immunity; endotoxic shock; proinflammatory cytokine; myocardial depression ID NECROSIS-FACTOR-ALPHA; CELL WALL COMPONENTS; SEPTIC SHOCK; NITRIC-OXIDE; EXPRESSION; ENDOTOXIN; GENE; MICE; TLR4; RECOGNITION AB The precise molecular mechanisms responsible for sepsis-induced myocardial dysfunction remain undefined. Toll-like receptor-4 (TLR-4) engages lipopolysaccharide (LPS) and activates signaling pathways leading to the expression of proinflammatory cytokines implicated in myocardial dysfunction. We determined whether TLR-4 was necessary for LPS-induced myocardial dysfunction in vivo. The effects of LPS on left ventricular (LV) function were studied in mice with defective TLR-4 signaling (C3H/HeJ, TLR-4 deficient) and wild-type mice (C3HeB/FeJ). Mice (n=5/group) were injected with LPS or diluent, and LV function was examined by using two-dimensional echocardiography and conductance catheters. LPS significantly decreased all indexes of LV function in wild-type mice when compared with controls; LV function was not depressed in the LPS-treated TLR-4-deficient mice relative to controls. LPS increased myocardial nitric oxide synthase-2 expression and cGMP only in wild-type mice. This study suggests that TLR-4 mediates the LV dysfunction that occurs in LPS-induced shock. Therefore, TLR-4 might be a therapeutic target for attenuating the effects of LPS on the heart. C1 Baylor Coll Med, Houston Vet Affairs Med Ctr, Dept Med, Houston, TX 77030 USA. Baylor Coll Med, Winters Ctr Heart Failure Res, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Infect Dis Sect, Houston, TX 77030 USA. RP Mann, DL (reprint author), Baylor Coll Med, Houston Vet Affairs Med Ctr, Dept Med, 2002 Holcombe Blvd, Houston, TX 77030 USA. FU NHLBI NIH HHS [HL-42250-10/10, P50 HL-O6H, R01 HL-58081-01, R01 HL-61543-01]; NIGMS NIH HHS [R01 GM-62474-01] NR 25 TC 109 Z9 118 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN PY 2002 VL 282 IS 6 BP H2316 EP H2323 DI 10.1152/ajpheart.00763.2001 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 550YC UT WOS:000175531800046 PM 12003842 ER PT J AU Stroud, JD Baicu, CF Barnes, MA Spinale, FG Zile, MR AF Stroud, JD Baicu, CF Barnes, MA Spinale, FG Zile, MR TI Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE matrix metalloproteinases; muscle; stiffness; viscosity ID MATRIX-METALLOPROTEINASE INHIBITION; AORTIC-VALVE DISEASE; DIASTOLIC FUNCTION; HEART-FAILURE; RAT HEARTS; COLLAGEN MATRIX; SUPRAVENTRICULAR TACHYCARDIA; EXTRACELLULAR-MATRIX; FIBRILLAR COLLAGEN; PAPILLARY-MUSCLE AB To determine whether and to what extent one component of the extracellular matrix, fibrillar collagen, contributes causally to abnormalities in viscoelasticity, collagen was acutely degraded by activation of endogenous matrix metalloproteinases (MMPs) with the serine protease plasmin. Papillary muscles were isolated from normal cats and cats with right ventricular pressure overload hypertrophy (POH) induced by pulmonary artery banding. Plasmin treatment caused MMP activation, collagen degradation, decreased the elastic stiffness constant, and decreased the viscosity constant in both normal and POH muscles. Thus, whereas many mechanisms may contribute to the abnormalities in myocardial viscoelasticity in the POH myocardium, changes in fibrillar collagen appear to play a predominant role. C1 Med Univ S Carolina, Div Cardiol, Dept Med, Gazes Cardiac Res Inst, Charleston, SC 29425 USA. Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC 29401 USA. Med Univ S Carolina, Dept Surg, Div Cardiothorac Surg, Charleston, SC 29425 USA. RP Zile, MR (reprint author), Med Univ S Carolina, Div Cardiol, Dept Med, Gazes Cardiac Res Inst, 96 Jonathan Lucas St,Suite 816,POB 250623, Charleston, SC 29425 USA. FU NHLBI NIH HHS [P01-HL-48788, R01-HL-55444-03] NR 49 TC 36 Z9 40 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD JUN PY 2002 VL 282 IS 6 BP H2324 EP H2335 DI 10.1152/ajpheart.00711.2001 PG 12 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 550YC UT WOS:000175531800047 PM 12003843 ER PT J AU Sun, TX Van Hoek, A Huang, Y Bouley, R McLaughlin, M Brown, D AF Sun, TX Van Hoek, A Huang, Y Bouley, R McLaughlin, M Brown, D TI Aquaporin-2 localization in clathrin-coated pits: inhibition of endocytosis by dominant-negative dynamin SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE kidney epithelial cells; immunofluorescence; water channels; vasopressin stimulation; immunocytochemistry ID NEPHROGENIC DIABETES-INSIPIDUS; INTEGRAL MEMBRANE-PROTEINS; KIDNEY COLLECTING DUCT; WATER CHANNELS; RAT-KIDNEY; ANTIDIURETIC-HORMONE; MEDIATED ENDOCYTOSIS; PLASMA-MEMBRANE; ELECTRON-MICROSCOPY; GLUT4 ENDOCYTOSIS AB Before the identification of aquaporin (AQP) proteins, vasopressin-regulated "water channels" were identified by freeze-fracture electron microscopy as aggregates or clusters of intramembraneous particles (IMPs) on hormonally stimulated target cell membranes. In the kidney collecting duct, these IMP clusters were subsequently identified as possible sites of clathrin-coated pit formation on the plasma membrane, and a clathrin-mediated mechanism for internalization of vasopressin-sensitive water channels was suggested. Using an antibody raised against the extracellular C loop of AQP2, we now provide direct evidence that AQP2 is concentrated in clathrin-coated pits on the apical surface of collecting duct principal cells. Furthermore, by using a fracture-label technique applied to LLC-PK(1) cells expressing an AQP2-c-myc construct, we show that AQP2 is located in IMP aggregates and is concentrated in shallow membrane invaginations on the surface of forskolin-stimulated cells. We also studied the functional role of clathrin-coated pits in AQP2 trafficking by using a GTPase-deficient dynamin mutation (K44A) to inhibit clathrin-mediated endocytosis. Immunofluorescence labeling and freeze-fracture electron microscopy showed that dominant-negative dynamin 1 and dynamin 2 mutants prevent the release of clathrin-coated pits from the plasma membrane and induce an accumulation of AQP2 on the plasma membrane of AQP2-transfected cells. These data provide the first direct evidence that AQP2 is located in clathrin-coated pits and show that AQP2 recycles between the plasma membrane and intracellular vesicles via a dynamin-dependent endocytotic pathway. We propose that the IMP clusters previously associated with vasopressin action represent sites of dynamin-dependent, clathrin-mediated endocytosis in which AQP2 is concentrated before internalization. C1 Massachusetts Gen Hosp, Program Membrane Biol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Renal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Brown, D (reprint author), Massachusetts Gen Hosp E, Program Membrane Biol, 149 13th St, Charlestown, MA 02129 USA. EM brown@receptor.mgh.harvard.edu RI chen, xuanlan/H-4158-2011 FU NIDDK NIH HHS [DK-38452, DK-55864] NR 64 TC 76 Z9 79 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD JUN PY 2002 VL 282 IS 6 BP F998 EP F1011 DI 10.1152/ajprenal.00257.2001 PG 14 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 549JN UT WOS:000175440900005 PM 11997316 ER PT J AU Iyonaga, K McCarthy, KM Schneeberger, EE AF Iyonaga, K McCarthy, KM Schneeberger, EE TI Dendritic cells and the regulation of a granulomatous immune response in the lung SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article ID MHC CLASS-II; INTRATRACHEAL INSTILLATION; CONDUCTING AIRWAYS; IL-12 PRODUCTION; DOWN-REGULATION; LYMPH-NODES; IFN-GAMMA; ANTIGEN; INFECTION; TRANSPORT AB To investigate the contribution of dendritic cells (DC) in a pulmonary granulomatous immune response, C57BL/16 mice, nonimmunized or immunized with purified protein derivative (PPD) of Mycobacterium bovis, were intravenously injected with PPD-coated Sepharose-4B beads. One and three days later lungs were harvested, granuloma size was measured, and immunolabeled cells in granulomas were counted. On Day 1, granulomas in immunized mice were 3-fold larger and contained more major histocompatibility complex class 11(+), CD11c(+) DCs than nonimmunized mice. By Day 3, these differences had diminished. In all granulomas MHC class 11(+), CD11c(+) DCs were in contact with the beads. By in situ hybridization these DCs expressed interleukin (IL)-12 p40 mRNA. MOMA2(+) macrophages were present throughout the granulomas, whereas CD4(+) and CD8alpha(+) T cells were localized at the granuloma periphery. DCs isolated from granulomatous lungs at Day 1, and from thoracic lymph nodes (LNs) at Days I and 3, stimulated PPD-specific T cell proliferation without exogenously added antigen, indicating that they had acquired bead-bound antigen. By Day 3, however, granuloma DCs presented little antigen, suggesting that newly immigrated DC lacked access to antigen or that antigen uptake/processing was inhibited. RNase protection assays of whole-lung mRNA showed increased interferon-gamma, IL-1beta, IL-1 receptor antagonist, IL-6, and macrophage inhibitory factor, but no IL-10 mRNA on Days I and 3. These observations support the premise that DCs are key in initiating granulomatous cell-mediated immunity. However, factors generated within the granuloma downregulate the antigen presenting function of DC by Day 3 in this experimental model. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Schneeberger, EE (reprint author), Massachusetts Gen Hosp E, Mol Pathol Unit, 149 13th St, Charlestown, MA 02129 USA. FU NHLBI NIH HHS [HL36781] NR 35 TC 17 Z9 17 U1 0 U2 1 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 JUN PY 2002 VL 26 IS 6 BP 671 EP 679 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 559YW UT WOS:000176054900006 PM 12034565 ER PT J AU Kircher, MF Rhea, JT Kihiczak, D Novelline, RA AF Kircher, MF Rhea, JT Kihiczak, D Novelline, RA TI Frequency, sensitivity, and specificity of individual signs of diverticulitis on thin-section helical CT with colonic contrast material: Experience with 312 cases SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article; Proceedings Paper CT 101st Annual Meeting of the American-Roentgen-Ray-Society CY APR 29-MAY 04, 2001 CL SEATTLE, WASHINGTON SP Amer Roentgen Ray Soc ID COMPUTED-TOMOGRAPHY; SIGMOID DIVERTICULITIS; BARIUM ENEMA; DIAGNOSIS; US AB OBJECTIVE. The aim of our study was to determine the frequency, sensitivity, and specificity of the individual signs of diverticulitis using helical CT with colonic contrast material. MATERIALS AND METHODS. Between March 1997 and September 1999, 312 patients with suspected diverticulitis were examined on helical CT using rectally administered colonic contrast material. CT scans that were positive for diverticulitis or indeterminate were rereviewed by two radiologists; CT interpretations were correlated with patients' clinical courses and surgical findings. RESULTS. One hundred fourteen (37%) of the 312 CT scans were interpreted as positive for diverticulitis; 192 scans (61%), as negative; six scans (2%), as indeterminate. Of the 114 scans that were positive for diverticulitis, 109 (96%; sensitivity 96%, specificity 91%) showed bowel wall thickening; 108 (95%; sensitivity 96%, specificity 90%.), fat stranding; 104 (91%; sensitivity 91%, specificity 67%), diverticula; 57 (50%; sensitivity 50%, specificity 100%), fascial thickening; 51 (45%; sensitivity 45%, specificity 97%), free fluid; 49 (43%; sensitivity 43%, specificity 100%), inflamed diverticula; 34 (30% sensitivity 30%, specificity 100%), free air; 18 (16%; sensitivity 16%, specificity 100%), "arrowhead" signs; nine (8%; sensitivity 8%, specificity 99%), abscesses; four (4%; sensitivity 4%, specificity 100%,), phlegmons; five (4%; sensitivity 4%, specificity 99%), intramural air; two (2%; sensitivity 2%, specificity 100%), intramural sinus tracts. Overall CT interpretation had a sensitivity of 99%, a specificity of 99%, a positive predictive value of 99%, a negative predictive value of 99%, and an overall accuracy of 99%. CONCLUSION. The two most frequent signs of diverticulitis were bowel wall thickening (96%) and fat stranding (95%). Less frequent but highly specific signs were fascial thickening (50%), free fluid (45%), and inflamed diverticula (43%). C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res,Dept Radiol, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. RP Kircher, MF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res,Dept Radiol, CNY 149,13th St,R-5406, Charlestown, MA 02129 USA. NR 23 TC 65 Z9 69 U1 0 U2 3 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 JUN PY 2002 VL 178 IS 6 AR UNSP 0361-803X/02/1786-1313 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 557VT UT WOS:000175929800002 PM 12034590 ER PT J AU Titton, RL Gervais, DA Boland, GW Mueller, PR AF Titton, RL Gervais, DA Boland, GW Mueller, PR TI Interventional radiology case conferences of Massachusetts General Hospital. Renal trauma: Radiologic evaluation and percutaneous treatment of nonvascular injuries. SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article ID COMPUTED-TOMOGRAPHY; ABDOMINAL-TRAUMA; MANAGEMENT; DIAGNOSIS C1 Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Radiol, Boston, MA 02114 USA. RP Mueller, PR (reprint author), Massachusetts Gen Hosp, Div Abdominal Imaging & Intervent, Dept Radiol, 55 Fruit St,White Bldg 270, Boston, MA 02114 USA. NR 24 TC 7 Z9 8 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 JUN PY 2002 VL 178 IS 6 AR UNSP 0361-803X/02/1786-1507 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 557VT UT WOS:000175929800036 PM 12034629 ER PT J AU Farren, CK O'Malley, S AF Farren, CK O'Malley, S TI A pilot double blind placebo controlled trial of sertraline with naltrexone in the treatment of opiate dependence SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID OPIOID ADDICTS; FLUOXETINE; ALCOHOLISM; PROGRAM AB Naltrexone has been used for thirty years as an aid to maintenance of opiate abstinence with limited success. One reason is that naltrexone does not appear to reduce craving in opiate addiction, unlike in alcoholism. The authors conducted this trial of naltrexone in combination with the SSRI sertraline to assess treatment retention with combination pharmacotherapy. They used a double-blind placebo controlled trial of naltrexone 50 mg qd with placebo versus naltrexone 50 mg plus sertraline 50 mg, qd in 13 recently nondepressed abstinent opiate addicts followed over a 12 week period. Both groups had a similar side effect profile and while there was an initial trend in increased retention in the combination therapy group, there was no difference in retention by the end of the study. There was a fall in the Beck Depression Inventory scores in both groups over time, and there was a significant negative correlation between BDI scores and duration in treatment in the combination therapy group. There was a fall in opiate craving, as measured by an opiate craving questionnaire, over time in both groups. The authors conclude that combination pharmacotherapy appeared to be well tolerated and was initially successful in increasing treatment retention relative to naltrexone alone, but this effect tended to diminish over time. C1 Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Farren, CK (reprint author), Bronx Vet Adm Med Ctr, 130 W Kingsbridge Rd, Bronx, NY 10468 USA. NR 14 TC 12 Z9 12 U1 0 U2 0 PU BRUNNER-ROUTLEDGE PI PHILADELPHIA PA 325 CHESTNUT ST, 8TH FL, PHILADELPHIA, PA 19106 USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SUM PY 2002 VL 11 IS 3 BP 228 EP 234 DI 10.1080/10550490290088009 PG 7 WC Substance Abuse SC Substance Abuse GA 583GV UT WOS:000177399700006 PM 12202015 ER PT J AU Mojsilovic, A Rogowitz, B Gomes, J Deisboeck, TS AF Mojsilovic, A Rogowitz, B Gomes, J Deisboeck, TS TI Analysis and 3D reconstruction of heterogeneity in malignant brain tumors - An interdisciplinary case study using a novel computational visualization approach SO ANALYTICAL AND QUANTITATIVE CYTOLOGY AND HISTOLOGY LA English DT Article DE brain cancer; image analysis; computer-assisted; 3D reconstruction ID LASER CAPTURE MICRODISSECTION; MULTICELLULAR SPHEROIDS; GROWTH DYNAMICS; MODEL; CELLS; PROLIFERATION; INVASION AB OBJECTIVE: To explore how a multidisciplinary approach, combining modern visualization and image processing techniques with innovative experimental studies, can augment the understanding of tumor development. STUDY DESIGN: We analyzed histologic sections of a microscopic brain tumor and reconstructed these slices into a 3D representation. We processed these slices to: (1) identify tumor boundaries, (2) isolate proliferating tumor cells, and (3) segment the tumor into regions based on the density of proliferating cells. We then reconstructed the 3D shape of the tumor using a constrained deformable surface approach, RESULTS: This novel method allows the analyst to (1) see specific properties of histologic slices in the 3D environment with animation, (2) switch 2D "views" dynamically, and (3) see relationships between the 3D structure and structure on a plane. C1 IBM TJ Watson Res Ctr, Visual Anal Grp, Hawthorne, NY 10532 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp,Mol Neurooncol Lab, Harvard MIT Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. Harvard Univ, Sch Med,Massachusetts Gen Hosp, Complex Biosyst Modeling Lab, Harvard MIT Athinoula A Martinos Ctr Biomed Imagi, Charlestown, MA USA. FU NCI NIH HHS [CA69246, CA84509] NR 23 TC 8 Z9 8 U1 0 U2 1 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0884-6812 J9 ANAL QUANT CYTOL JI Anal. Quant. Cytol. Histol. PD JUN PY 2002 VL 24 IS 3 BP 125 EP 133 PG 9 WC Cell Biology SC Cell Biology GA 566WU UT WOS:000176451900001 PM 12102123 ER PT J AU Kimmel, SE Sekeres, M Berlin, JA Ellison, N AF Kimmel, SE Sekeres, M Berlin, JA Ellison, N TI Mortality and adverse events after protamine administration in patients undergoing cardiopulmonary bypass SO ANESTHESIA AND ANALGESIA LA English DT Article ID OPEN-HEART-SURGERY; NEW-YORK-STATE; OPERATIVE MORTALITY; GRAFT-SURGERY; RISK-FACTORS; SULFATE AB We designed this study to determine whether adverse hemodynamic events after a protamine administration increase the risk of in-hospital mortality. Using a retrospective cohort study design, medical and anesthesia records of patients undergoing cardiopulmonary bypass (CPB) at the Hospital of the University of Pennsylvania, Philadelphia, between 1990 and 1994 were reviewed. Adverse events after a protamine administration were determined using strict, predefined criteria, and in-hospital mortality was assessed without knowledge of exposure status. Mortality was more frequent among the 53 patients with adverse events (13.2%) than the 223 patients without events (2.7%; crude odds ratio 5.50; 95% confidence interval, 1.49-20.6). After adjusting for confounders, the odds ratio was 6.98 (95% confidence interval, 1.36-35.9; P = 0.017). Those suffering severe events had the highest mortality (23.5%, compared with 8.3% among those with less severe events versus 2.7% among those without any event, P = 0.001 for trend). In addition, the odds ratio was largest when using the strictest definition for Protamine-related events. In conclusion, patients undergoing CPB who experience adverse events after a protamine administration have an increased risk of in-hospital mortality. Further studies to confirm these findings and development and testing of protamine alternatives or prophylactic therapies are required to determine if mortality can be reduced. C1 Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA USA. Hosp Univ Penn, Div Cardiovasc, Dept Med & Anesthesia, Philadelphia, PA USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. RP Kimmel, SE (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, 717 Blockey Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. FU NHLBI NIH HHS [K08 HL 03021] NR 25 TC 31 Z9 32 U1 1 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 JUN PY 2002 VL 94 IS 6 BP 1402 EP 1408 DI 10.1097/00000539-200206000-00005 PG 7 WC Anesthesiology SC Anesthesiology GA 557CZ UT WOS:000175890900005 PM 12031996 ER PT J AU Hurford, WE Bigatello, LM AF Hurford, WE Bigatello, LM TI NO-body's perfect SO ANESTHESIOLOGY LA English DT Editorial Material ID INHALED NITRIC-OXIDE; RESPIRATORY-DISTRESS SYNDROME; PERSISTENT PULMONARY-HYPERTENSION; AWAKE LAMBS; VASODILATOR; SILDENAFIL; NEWBORN; VENTILATION; INCREASE; SURVIVAL C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Resp Acute Care Unit, Boston, MA 02114 USA. RP Hurford, WE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RI Hurford, William/G-6386-2013 OI Hurford, William/0000-0003-1201-0313 NR 32 TC 2 Z9 3 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 JUN PY 2002 VL 96 IS 6 BP 1285 EP 1287 DI 10.1097/00000542-200206000-00003 PG 3 WC Anesthesiology SC Anesthesiology GA 558KQ UT WOS:000175965500002 PM 12170036 ER PT J AU Franco, RA Zeitels, SM Farinelli, WA Anderson, RR AF Franco, RA Zeitels, SM Farinelli, WA Anderson, RR TI 585-nm pulsed dye laser treatment of glottal papillomatosis SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article; Proceedings Paper CT Meeting of the American-Broncho-Esophagological-Association CY MAY 14-16, 2001 CL PALM DESERT, CALIFORNIA SP Amer Broncho Esophagol Assoc DE glottal papillomatosis; glottis; pulsed dye laser treatment; recurrent respiratory papillomatosis; vocal cord; vocal fold ID RECURRENT RESPIRATORY PAPILLOMATOSIS; JUVENILE LARYNGEAL PAPILLOMATOSIS; PHOTODYNAMIC THERAPY; 5-AMINOLEVULINIC ACID; TUNABLE DYE; MICROSURGERY; COMMISSURE; MANAGEMENT; VERRUCAE; EXPOSURE AB Treatment of recurrent respiratory papillomatosis of the glottis is often challenging. The surgeon and patient must cooperatively balance decisions regarding air-way safety, effects of multiple general anesthesias, employment disturbance, and vocal dysfunction. A pilot study was done in 41 adult cases (23 patients; 78 vocal folds) without complication to evaluate the effectiveness of a 585-nm pulsed dye laser (PDL; 450-mus pulse width; fluence of 38 to 255 J/cm(2); 1- to 2-mm spot size) in the treatment of this disorder. Thirty-seven of the 41 cases (90%) were bilateral disease. Twenty-six of the 41 cases (63%; including 20 cases with involvement of the anterior commissure) were treated by bilateral photocoagulation of the lesions' microcirculation without microflap resection of tissue. Clinical observation revealed that irradiated but unresected disease involuted without development of an anterior commissure web. In the initial 13 of the 41 cases (32%), PDL treatment was followed by cold instrument microflap, resection. The PDL enhanced the epithelial excision by improving hemostasis and by creating an optimal dissection plane between the basement membrane and the underlying superficial lamina propria. The PDL at 585 nm was less effective in the management of exophytic lesions because of its limited depth of penetration (approximately 2 mm). In this initial trial, the PDL was a relatively safe and efficacious treatment for glottal recurrent respiratory papillomatosis. Since the lesions involute without complete resection of the diseased epithelium, the anterior commissure can be treated to minimize the number of procedures. To study patterns of recurrence will require longer follow-up. C1 Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. RP Franco, RA (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Div Laryngol, 243 Charles St, Boston, MA 02114 USA. NR 39 TC 40 Z9 41 U1 0 U2 4 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 JUN PY 2002 VL 111 IS 6 BP 486 EP 492 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 560CU UT WOS:000176065000003 PM 12090703 ER PT J AU Grillo, HC AF Grillo, HC TI Tracheal replacement: A critical review SO ANNALS OF THORACIC SURGERY LA English DT Review ID ALLOGRAFT REPLACEMENT; PERICARDIAL PATCH; RECONSTRUCTION; TRANSPLANTATION; TRACHEOPLASTY; STENOSIS; DOGS; REVASCULARIZATION; PROSTHESIS; ALLOTRANSPLANTATION AB This review discusses the need for tracheal replacement, distinct from resection with primary anastomosis, the requirements for replacement, and the many efforts over the past century to accomplish this goal experimentally and clinically. Approaches have included use of foreign materials, nonviable tissue, autogenous tissue, tissue engineering, and transplantation. Biological problems in each category are noted. C1 Massachusetts Gen Hosp, Div Gen Thorac Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. RP Grillo, HC (reprint author), Massachusetts Gen Hosp, Div Gen Thorac Surg, Blake 1570,55 Fruit St, Boston, MA 02114 USA. NR 81 TC 204 Z9 242 U1 0 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD JUN PY 2002 VL 73 IS 6 BP 1995 EP 2004 AR PII S0003-4975(02)03564-6 DI 10.1016/S0003-4975(02)03564-6 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 558YJ UT WOS:000175995300081 PM 12078821 ER PT J AU Andes, D Craig, WA AF Andes, D Craig, WA TI Pharmacodynamics of the new fluoroquinolone gatifloxacin in murine thigh and lung infection models SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID STREPTOCOCCUS-PNEUMONIAE; PHARMACOKINETICS; CIPROFLOXACIN; PARAMETERS; AM-1155 AB Gatifloxacin is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of gatifloxacin and determine which pharmacokinetic (PK)-pharmacodynamic (PD) parameter best correlated with efficacy. The thighs of mice were infected with 10(6.5), to 10(7.4) CFU of strains of Staphylococcus aureus, Streptococcus pneumoniae, or Escherichia coli, and the mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg of body weight per day, with the dose fractionated for dosing every 3, 6, 12, and 24 h. Levels in serum were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were calculated from serial values of the log(10) numbers of CFU per thigh 2 to 4 h after the administration of doses of 8 and 32 mg/kg. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the numbers of CFU per thigh at 24 h. Pharmacokinetic studies revealed peak/dose values of 0.23 to 0.32, area under the concentration-time curve (AUC)/dose values of 0.47 to 0.62, and half-lives of 0.6 to 1.1 h. Gatifloxacin produced in vivo PAEs of 0.2 to 3.1 h for S. pneumoniae and 0.4 to 2.3 h for S. aureus. The 24-h AUC/MIC was the PK-PD parameter that best correlated with efficacy (R-2 = 90 to 94% for the three organisms, whereas R-2 = 70 to 81% for peak level/MIC and R-2 = 48 to 73% for the time that the concentration in serum was greater than the MIC). There was some reduced activity when dosing every 24 h was used due to the short half-life of gatifloxacin in mice. In subsequent studies we used the neutropenic and nonneutropenic murine thigh and lung infection models to determine if the magnitude of the AUC/MIC needed for the efficacy of gatifloxacin varied among pathogens (including resistant strains) and infection sites. The mice were infected with 106.5 to 107.4 CFU of four isolates of S. aureus (one methicillin resistant) per thigh, nine isolates of S. pneumoniae (two penicillin intermediate, four penicillin resistant, and two ciprofloxacin resistant) per thigh, four isolates of the family Enterobacteriaceae per thigh, a single isolate of Pseudomonas aeruginosa per thigh, and 10(8.3) CFU of Klebsiella pneumoniae per lung. The mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg every 6 or 12 h. A sigmoid dose-response model was used to estimate the dose (in milligrams per kilogram per 24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.015 to 8 mug/ml. The 24-h AUC/MICs for each static dose (1.7 to 592) varied from 16 to 72. Mean +/- standard deviation 24-h AUC/MICs for isolates of the family Enterobacteriaceae, S. pneumoniae, and S. aureus were 41 +/- 21, 52 +/- 20, and 36 9, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC required for efficacy. The 24-h AUC/MICs required to achieve bacteriostatic effects against K. pneumoniae were quite similar in the thigh and lung (70 versus 56 in neutropenic mice and 32 versus 43 in nonneutropenic mice, respectively). The magnitude of the 24-h AUC/MIC of gatifloxacin required for efficacy against multiple pathogens varied only fourfold and was not significantly altered by drug resistance or site of infection. C1 Univ Wisconsin, Sch Med, Dept Med, Infect Dis Sect, Madison, WI 53792 USA. William S Middleton Mem Vet Adm Med Ctr, Dept Med, Madison, WI USA. RP Andes, D (reprint author), Univ Wisconsin, Sch Med, Dept Med, Infect Dis Sect, Room H4-570,600 Highland Ave, Madison, WI 53792 USA. NR 17 TC 85 Z9 90 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUN PY 2002 VL 46 IS 6 BP 1665 EP 1670 DI 10.1128/AAC.46.6.1665-1670.2002 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 553EM UT WOS:000175662800008 PM 12019073 ER PT J AU Perea, S Lopez-Ribot, JL Wickes, BL Kirkpatrick, WR Dib, OP Bachmann, SP Keller, SM Martinez, M Patterson, TF AF Perea, S Lopez-Ribot, JL Wickes, BL Kirkpatrick, WR Dib, OP Bachmann, SP Keller, SM Martinez, M Patterson, TF TI Molecular mechanisms of fluconazole resistance in Candida dubliniensis isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID AZOLE ANTIFUNGAL AGENTS; LANOSTEROL 14-ALPHA-DEMETHYLASE; ANTIRETROVIRAL THERAPY; MULTIDRUG TRANSPORTERS; NORTH-AMERICA; UNITED-STATES; IN-VITRO; ALBICANS; IDENTIFICATION; AIDS AB Candida dubliniensis is a newly identified species of Candida that is phenotypically similar to but genetically distinct from C. albicans. This organism has been recovered with increasing frequency from the oral cavities of human immunodeficiency virus (HIV)-infected and AIDS patients and has been implicated as a causative agent of oral candidiasis and systemic disease. In the present study we characterized the molecular mechanisms of resistance to fluconazole (FLC) in C. dubliniensis clinical isolates from two different HIV-infected patients with oropharyngeal candidiasis. Isolates were identified to the species level by phenotypic and genotypic tests. DNA-typing techniques were used to assess strain identity. Antifungal susceptibility testing was performed by NCCLS techniques. Northern blotting analysis was used to monitor the expression of genes encoding lanosterol demethylase (ERG11) and efflux transporters (CDR and MDR1) in matched sets of C. dubliniensis-susceptible and -resistant isolates by using probes generated from their homologous C. albicans sequences. In addition, ERG11 genes were amplified by PCR, and their nucleotide sequences were determined in order to detect point mutations with a possible effect in the affinity for azoles. Decreasing susceptibilities to FLC were detected in C. dubliniensis isolates recovered from both patients during the course of treatment. FLC-resistant C. dubliniensis isolates from one patient demonstrated combined upregulation of the MDR1, CDR1, and ERG11 genes. Among the isolates from the second patient, all isolates showing decreased susceptibility to FLC demonstrated upregulation of MDR1, whereas the levels of mRNA for the ERG11 genes remained constant and the expression of CDR genes was negligible. Fourteen point mutations were found in the ERG11 genes of the isolates with decreased susceptibility to FLC. These data demonstrate that the development of azole resistance in C. dublinensis clinical isolates from HIV-infected patients treated with FLC is mediated by multiple molecular mechanisms of resistance, similar to the observations found in the case of C albicans. C1 Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis,S Texas Ctr Biol, San Antonio, TX 78245 USA. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78245 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Lopez-Ribot, JL (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis,S Texas Ctr Biol, 15355 Lambda Dr, San Antonio, TX 78245 USA. RI Lopez-Ribot, Jose/D-2048-2010 FU NCRR NIH HHS [M01 RR001346, M01-RR-01346]; NIAID NIH HHS [R29 AI42401]; NIDCR NIH HHS [5R01 DE11381-04A2, R01 DE011381] NR 47 TC 46 Z9 54 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUN PY 2002 VL 46 IS 6 BP 1695 EP 1703 DI 10.1128/AAC.46.6.1695-1703.2002 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 553EM UT WOS:000175662800013 PM 12019078 ER PT J AU Chlichlia, K Los, M Schulze-Osthoff, L Gazzolo, L Schirrmacher, V Khazaie, K AF Chlichlia, K Los, M Schulze-Osthoff, L Gazzolo, L Schirrmacher, V Khazaie, K TI Redox events in HTLV-1 tax-induced apoptotic T-cell death SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID VIRUS TYPE-I; NF-KAPPA-B; LEUKEMIA-VIRUS; HUMAN THIOREDOXIN; GENE-EXPRESSION; TRANSCRIPTION FACTORS; SIGNALING PATHWAY; OXIDATIVE STRESS; PROOXIDANT STATE; DNA-REPAIR AB A number of studies implicate reactive oxygen intermediates in the induction of DNA damage and apoptosis. Recent studies suggest that the human T-cell leukemia virus type I (HTLV-1) Tax protein induces oxidative stress and apoptotic T-cell death. Activation of the T-cell receptor/CD3 pathway enhances the Tax-mediated oxidative and apoptotic effects. Tax-mediated apoptosis and oxidative stress as well as activation of nuclear factor-kappaB can be potently suppressed by antioxidants. This review focuses on Tax-dependent changes in the intracellular redox status and their role in Tax-mediated DNA damage and apoptosis. The relevance of these observations to HTLV-1 virus-mediated T-cell transformation and leukemogenesis are discussed. C1 German Canc Res Ctr, Div Cellular Immunol G0100, Tumor Immunol Program, D-69120 Heidelberg, Germany. Univ Munster, Dept Immunol & Cell Biol, D-48149 Munster, Germany. Ecole Normale Super Lyon, INSERM U412, F-69367 Lyon 07, France. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP German Canc Res Ctr, Div Cellular Immunol G0100, Tumor Immunol Program, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM katerina.chlichlia@urz.uni-heidelberg.de RI Schulze-Osthoff, Klaus/N-9025-2013; OI Schulze-Osthoff, Klaus/0000-0003-1443-2720; Los, Marek/0000-0001-9518-1411 NR 75 TC 13 Z9 13 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD JUN PY 2002 VL 4 IS 3 BP 471 EP 477 DI 10.1089/15230860260196263 PG 7 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 569ZP UT WOS:000176633600012 PM 12215214 ER PT J AU Lin, YSE Vidic, RD Stout, JE Yu, VL AF Lin, YSE Vidic, RD Stout, JE Yu, VL TI Negative effect of high pH on biocidal efficacy of copper and silver ions in controlling Legionella pneumophila SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID WATER DISTRIBUTION-SYSTEMS; IONIZATION; INACTIVATION AB Copper-silver (Cu-Ag) ionization has effectively controlled Legionella spp. in the hot water systems of numerous hospitals. However, it was ineffective at controlling Legionella in one Ohio hospital despite the confirmation of adequate total concentrations of copper and silver ions. The pH of the water at this hospital was found to be 8.5 to 9.0. The purpose of this study was to investigate the impact of pH and other water quality parameters, including alkalinity (HCO3-), hardness (Ca2+ and Mg2+), and amount of dissolved organic carbon (DOC), on the control of Legionella by Cu-Ag ionization. Initial concentrations of Legionella and copper and silver ions used in batch experiments were 3 x 10(6) CFU/ml and 0.4 and 0.08 mg/liter, respectively. Changes in bicarbonate ion concentration (50, 100, and 150 mg/liter), water hardness (Ca2+ at 50 and 100 mg/liter; Mg2+ at 40 and 80 mg/liter), and level of DOC (0.5 and 2 mg/liter) had no significant impact on the efficacy of copper and silver ions in killing Legionella at a neutral pH. When the pH was elevated to 9 in these experiments, copper ions achieved only a 10-fold reduction in the number of Legionella organisms in 24 h, compared to a millionfold decrease at pH 7.0. Silver ions were able to achieve a millionfold reduction in 24 h at all ranges of water quality parameters tested. Precipitation of insoluble copper complexes was observed at a pH above 6.0. These results suggest that pH may be an important factor in the efficacy of copper-silver ionization in controlling Legionella in water systems. C1 Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. Natl Kaohsiung Normal Univ, Grad Inst Environm Educ, Kaohsiung, Taiwan. Univ Pittsburgh, Dept Civil & Environm Engn, Pittsburgh, PA 15261 USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15240 USA. RP Yu, VL (reprint author), Vet Adm Med Ctr, Infect Dis Sect, Univ Dr C, Pittsburgh, PA 15240 USA. OI Vidic, Radisav/0000-0001-7969-6845 NR 14 TC 47 Z9 49 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD JUN PY 2002 VL 68 IS 6 BP 2711 EP 2715 DI 10.1128/AEM.68.6.2711-2715.2002 PG 5 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 559MN UT WOS:000176030100012 PM 12039724 ER PT J AU Tsao, H Millman, P Linette, GP Hodi, FS Sober, AJ Goldberg, MA Haluska, FG AF Tsao, H Millman, P Linette, GP Hodi, FS Sober, AJ Goldberg, MA Haluska, FG TI Hypopigmentation associated with an adenovirus-mediated gp100/MART-1-transduced dendritic cell vaccine for metastatic melanoma SO ARCHIVES OF DERMATOLOGY LA English DT Article ID MALIGNANT-MELANOMA; T-LYMPHOCYTES; IN-VITRO; PHASE-I; VITILIGO; IMMUNOTHERAPY; DESTRUCTION AB Background: Reports of vitiligo associated with metastases and rare cases of spontaneous regression of disease have fueled enthusiasm for immunologic approaches to the treatment of advanced melanoma. More recent strategies have focused on using antigen-presenting dendritic cells as vaccines. Observations: We observed 3 cases of leukoderma associated with a novel adenovirus-mediated gp 100/MART1-transduced dendritic cell (MART indicates mela-nomaantigen recognized by T cells). All 3 patients had advanced metastatic melanoma. Despite the development of this leukodermic response, all patients experienced disease progression while under treatment. Conclusion: We provide the initial evidence for effective induction of a leukodermic response with a gp 100/ MART-1-transduced dendritic cell vaccine. C1 Massachusetts Gen Hosp, Dept Dermatol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Wellman Labs Photomed, Boston, MA 02114 USA. Massachusetts Gen Hosp, Melanoma Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Oncol, Boston, MA 02114 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Albert Einstein Coll Med, Dept Pediat, New York, NY USA. Washington Univ, Dept Med, St Louis, MO USA. Genzyme Mol Oncol, Framingham, MA USA. RP Tsao, H (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Bartlett 622,48 Blossom St, Boston, MA 02114 USA. NR 20 TC 27 Z9 29 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUN PY 2002 VL 138 IS 6 BP 799 EP 802 DI 10.1001/archderm.138.6.799 PG 4 WC Dermatology SC Dermatology GA 563ZG UT WOS:000176287700011 PM 12056962 ER PT J AU Chen, SC Yeung, JS Chren, MM AF Chen, SC Yeung, JS Chren, MM TI Scalpdex - A quality-of-life instrument for scalp dermatitis SO ARCHIVES OF DERMATOLOGY LA English DT Article ID SEBORRHEIC DERMATITIS; PSORIASIS; RESPONSIVENESS; SKINDEX AB Objective: To develop a scalp dermatitis-specific quality-of-life instrument. Methods: Based on the results of directed focus sessions with 8 patients with scalp psoriasis or seborrheic dermatitis, we conceptualized 3 major constructs that explain the way scalp dermatoses affect patient quality of life: symptoms, functioning. and emotions. We constructed a 23-item instrument, Scalpdex, and tested its reliability, responsiveness, and validity. Results: Fifty-two dermatology patients completed the study. We demonstrated construct validity by confirming that the factors derived by principal axes factor analyses with orthogonal rotation correlated to our hypothesized scales (r=0.76-0.84) and that differences in symptom, functioning, and emotion scores differed among the varying levels of self-reported scalp severity more than would be expected by chance (P<.05 by analysis of variance). The instrument demonstrated reliability with internal consistency (Cronbach alpha, 0.62-0.80) and reproducibility (intraclass correlation coefficient, 0.90-0.97). The quality-of-life scores changed in the expected direction in our test for responsiveness (Pless than or equal to.05, by paired t test for functioning and emotion for those who improved). We ascertained the discriminant capability of Scalpdex compared with a dermatological generic quality-of-life tool, Skindex, by demonstrating superior responsiveness (Pless than or equal to.005 by paired t test in functioning and emotion) and improved overall sensitivity in individual items. Conclusions: Scalpclex is, to our knowledge, the first quality-of-life instrument specifically for patients with scalp dermatitis that is reliable, valid, and responsive. Clinicians can use the instrument to determine which aspect of the disease most bothers the patient and to evaluate quality of life as one variable of responsiveness to the therapeutic intervention. C1 Emory Univ, Sch Med, Dept Dermatol, Atlanta, GA 30033 USA. Emory Univ, Sch Med, Emory Ctr Outcomes Res, Atlanta, GA 30033 USA. Atlanta Vet Adm Med Ctr, Dept Hlth Serv Res, Atlanta, GA USA. Atlanta Vet Adm Med Ctr, Dept Dev Med, Atlanta, GA USA. Atlanta Vet Adm Med Ctr, Div Dermatol, Atlanta, GA USA. McMaster Univ, Hamilton, ON, Canada. Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. San Francisco Vet Affairs Med Ctr, Dermatol Serv, San Francisco, CA USA. RP Chen, SC (reprint author), Emory Univ, Sch Med, Dept Dermatol, 1639 Pierce Dr,5001 Woodruff Mem Bldg, Atlanta, GA 30033 USA. NR 10 TC 45 Z9 48 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD JUN PY 2002 VL 138 IS 6 BP 803 EP 807 DI 10.1001/archderm.138.6.803 PG 5 WC Dermatology SC Dermatology GA 563ZG UT WOS:000176287700012 PM 12056963 ER PT J AU Howanitz, PJ Steindel, SJ Heard, NV AF Howanitz, PJ Steindel, SJ Heard, NV TI Laboratory critical values policies and procedures - A College of American Pathologists Q-probes study in 623 institutions SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID CRITICAL LIMITS; IONIZED CALCIUM; NOTIFICATION; MANAGEMENT AB Context.-Critical values lists have been used for many years to decide when to notify physicians and other caregivers of potentially life-threatening situations; however, these lists have not been studied widely. Objectives.-To investigate critical values lists in institutions participating in the College of American Pathologists Q-Probes program and to provide suggestions for improvement. Setting.-A total of 623 institutions voluntarily participating in the Q-Probes program. Design.-A multipart study in which participants responded to information from preprinted lists, collected information about current practices, completed a questionnaire, monitored critical values calls, reviewed patients' medical records, and surveyed nursing supervisors and physicians about critical values. Main Outcome Measures.-Defining critical values systems, including lists, personnel, costs, processes, usefulness, and related medical outcomes. Results.-Critical values lists were determined for routine chemistry and hematology analytes and were found to vary widely among participants. In contrast, more than 95% of participants reported positive blood cultures, cerebrospinal fluid cultures, and toxic therapeutic drug levels as critical values. Based on more than 13000 critical values, participants' data showed that most critical values reports (92.8%) were made by the person who performed the test, and that 65% of reports for inpatients were received by nurses. For outpatients, physicians' office staff received the largest percentage (40%) of reports. The majority of participants (71.4%) had no policy on how repeat critical calls should be handled. On average, completion of notification required about 6 minutes for inpatients and 14 minutes for outpatients. Slightly greater than 5% of critical value telephone calls were abandoned, with the largest percentage abandoned for outpatients. More than 45% of critical values were unexpected, and 65% resulted in a change in therapy. Although only 20.8% of 2301 nursing supervisors thought critical values lists were helpful, 94.9% of 514 physicians found critical values lists valuable. Conclusions.-Critical values systems were medically important, highly variable, but also costly practices for participants. We propose a number of recommendations for improvement, including that the critical values list should be approved by the medical staff, each laboratory should develop a written policy for handling initial and repeat critical values reports, a foolproof policy should be established to report results from calls abandoned, and efforts at automating the process should become widespread. C1 Suny Downstate Med Ctr, Dept Pathol, Brooklyn, NY 11203 USA. Ctr Dis Control & Prevent, Div Lab Syst, Publ Hlth Practice Program Off, Atlanta, GA USA. W Los Angeles Vet Adm Med Ctr, Dept Lab Med, Los Angeles, CA USA. RP Howanitz, PJ (reprint author), Suny Downstate Med Ctr, Dept Pathol, Box 25,450 Clarkson Ave, Brooklyn, NY 11203 USA. NR 24 TC 82 Z9 91 U1 0 U2 3 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 JUN PY 2002 VL 126 IS 6 BP 663 EP 669 PG 7 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 559ZK UT WOS:000176056400005 PM 12033953 ER PT J AU Ferris, TG Chang, YC Perrin, JM Blumenthal, D Pearson, SD AF Ferris, TG Chang, YC Perrin, JM Blumenthal, D Pearson, SD TI Effects of removing gatekeeping on specialist utilization by children in a health maintenance organization SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID MEDICAID-ENROLLED CHILDREN; MANAGED CARE; EXPENDITURES; PHYSICIANS; PATTERNS; SERVICES AB Background: The "gatekeeping" model of access to specialty care has been an essential managed care tool, intended to control costs of care and promote coordination between generalists and specialists. Objective: To investigate the impact of removing gatekeeping on specialist utilization. Methods: A capitated multispecialty group discontinued a gatekeeping system on April 1, 1998. We assessed the overall number and distribution of patient visits to primary care physicians and specialists and initial patient visits to specialists before and after the removal of gatekeeping. We performed focused analyses for specific specialties, children with chronic conditions, and children with specific diagnoses. Results: Elimination of gatekeeping was not associated with changes in the mean number of visits to specialists (0.28 visits per 6 months before and after gatekeeping was removed) or the percentage of all child visits to specialists (11.6% vs 12.1%; 95% confidence interval, 11.3%-11.9% vs 11.8%-12.4%). The proportion of all specialist visits that were initial consultations increased after gatekeeping was removed, from 30.6% (95% CI, 29.4%-31.8%) to 34.8% (95% CI, 33.6%-36.1%). Visits to any specialist by children with chronic conditions increased from 18.6% (95% Cl, 17.7%-19.1%) to 19.8% (95% CI, 19.0%-20.7%). New patient visits to specialists by children with chronic conditions as a proportion of all specialist visits increased from 28.1% (95% Cl, 25.9%-30.2%) to 32.3% (95% CI, 30.1%-34.5%). Conclusions: Replacing a gatekeeping system with open access to all specialty physicians in a managed care organization resulted in minimal changes on the utilization of specialists. Visits to specialists by children with chronic conditions increased after the removal of gatekeeping. C1 Massachusetts Gen Hosp, Inst Hlth Policy, Div Gen Internal Med, Partners Healthcare Syst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Med Practices Evaluat Ctr, Boston, MA 02114 USA. MassGen Hosp Children, Ctr Child & Adolescent Hlth Policy, Div Gen Pediat, Boston, MA 02114 USA. Harvard Pilgrim Hlth Care, Dept Ambulatory Care & Prevent, Boston, MA USA. RP Ferris, TG (reprint author), Massachusetts Gen Hosp, Partners Inst Hlth Policy, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU NICHD NIH HHS [K12-HD00850] NR 22 TC 14 Z9 14 U1 2 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD JUN PY 2002 VL 156 IS 6 BP 574 EP 579 PG 6 WC Pediatrics SC Pediatrics GA 559ZE UT WOS:000176055900010 PM 12038890 ER PT J AU Casey, DE AF Casey, DE TI Atypical antipsychotics: Enhancing healthy outcomes SO ARCHIVES OF PSYCHIATRIC NURSING LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; WEIGHT-GAIN; DIABETES-MELLITUS; MYOCARDIAL-INFARCTION; LIPID ABNORMALITIES; SMOKING CESSATION; RISK FACTOR; SCHIZOPHRENIA; MORTALITY; PREVALENCE C1 Portland VA Med Ctr, Mental Illness Res Educ & Clin, Mental Hlth Div P3MIRECC, MIRECC VISN 20, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Psychiat, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Neurol, Portland, OR 97201 USA. RP Casey, DE (reprint author), Portland VA Med Ctr, Mental Illness Res Educ & Clin, Mental Hlth Div P3MIRECC, MIRECC VISN 20, 3710 SW US Vet Hosp Rd, Portland, OR 97201 USA. NR 32 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0883-9417 J9 ARCH PSYCHIAT NURS JI Arch. Psychiatr. Nurs. PD JUN PY 2002 VL 16 IS 3 SU 1 BP S12 EP S19 DI 10.1053/apnu.2002.33695 PG 8 WC Nursing; Psychiatry SC Nursing; Psychiatry GA 568CK UT WOS:000176524700003 PM 12046020 ER PT J AU Monnard, PA Apel, CL Kanavarioti, A Deamer, DW AF Monnard, PA Apel, CL Kanavarioti, A Deamer, DW TI Influence of ionic inorganic solutes on self-assembly and polymerization processes related to early forms of life: Implications for a prebiotic aqueous medium SO ASTROBIOLOGY LA English DT Article DE ionic inorganic solutes; self-assembly; monoribonucleotide polymerization; ocean; fresh water; proto-cells ID TEMPLATE-DIRECTED SYNTHESIS; MEMBRANES; VESICLES; LIPOSOMES; ORIGIN; ACIDS; EARTH AB A commonly accepted view is that life began in a marine environment, which would imply the presence of inorganic ions such as Na+, Cl-, Mg2+, Ca2+, and Fe2+. We have investigated two processes relevant to the origin of life-membrane self-assembly and RNA polymerization-and established that both are adversely affected by ionic solute concentrations much lower than those of contemporary oceans. In particular, monocarboxylic acid vesicles, which are plausible models of primitive membrane systems, are completely disrupted by low concentrations of divalent cations, such as magnesium and calcium, and by high sodium chloride concentrations as well. Similarly, a nonenzymatic, nontemplated polymerization of activated RNA monomers in ice/eutectic phases (in a solution of low initial ionic strength) yields oligomers with >80% of the original monomers incorporated, but polymerization in initially higher ionic strength aqueous solutions is markedly inhibited. These observations suggest that cellular life may not have begun in a marine environment because the abundance of ionic inorganic solutes would have significantly inhibited the chemical and physical processes that lead to self-assembly of more complex molecular systems. C1 Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA. RP Monnard, PA (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Wellman 9,55 Fruit St, Boston, MA 02114 USA. NR 33 TC 92 Z9 99 U1 2 U2 29 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1531-1074 J9 ASTROBIOLOGY JI Astrobiology PD SUM PY 2002 VL 2 IS 2 BP 139 EP 152 DI 10.1089/15311070260192237 PG 14 WC Astronomy & Astrophysics; Biology; Geosciences, Multidisciplinary SC Astronomy & Astrophysics; Life Sciences & Biomedicine - Other Topics; Geology GA 671KJ UT WOS:000182463700001 PM 12469365 ER PT J AU Blair, HC Zaidi, M Schlesinger, PH AF Blair, HC Zaidi, M Schlesinger, PH TI Mechanisms balancing skeletal matrix synthesis and degradation SO BIOCHEMICAL JOURNAL LA English DT Review DE apoptosis; macrophage; mesenchymal stem cell; osteoblast; osteoclas; t ID NF-KAPPA-B; OSTEOBLAST-LIKE CELLS; OSTEOCLASTIC BONE-RESORPTION; COLONY-STIMULATING FACTOR; GROWTH-FACTOR-BETA; HORMONE-RELATED PROTEIN; NITRIC-OXIDE PRODUCTION; TNF FAMILY MEMBER; PARATHYROID-HORMONE; RECEPTOR ACTIVATOR AB Bone is regulated by evolutionarily conserved signals that balance continuous differentiation of bone matrix-producing cells against apoptosis and matrix removal. This is continued from embryogenesis, where the skeleton differentiates as a solid mass and is shaped into separate bones by cell death and proteolysis. The two major tissues of the skeleton are avascular cartilage, with an extracellular matrix based on type II collagen and hydrophilic proteoglycans, and bone, a stronger and lighter material based on oriented type I collagen and hydroxyapatite. Both differentiate from the same mesenchymal stem cells. This differentiation is regulated by a family of related signals centred on bone morphogenic proteins. Fibroblast growth factors, Indian hedgehog and parathyroid hormone-related protein are important in determining the type of matrix and the relation of skeletal and nonskeletal structures. Removal of mineralized matrix involves apoptosis of matrix cells and differentiation of acid-secreting cells (osteoclasts) from macrophage precursors. Key regulators of matrix removal are signals in the tumour-necrosis-factor family. Osteoclasts dissolve bone by isolating a region of the matrix and secreting HCl and proteinases at that site. Successive cycles of removal and replacement allow growth, repair and remodelling. The signals for bone turnover are predominantly cell-membrane-associated, allowing very specific spatial regulation. In addition to its support function, bone is a reservoir of Ca2+, PO43- and OH-. Secondary modulation of mineral secretion and bone degradation are mediated by humoral signals, including parathyroid hormone and vitamin D, as well as the cytokines that also regulate the underlying cell differentiation. C1 Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Physiol & Cell Biol, Pittsburgh, PA USA. Vet Affairs Hlth Syst, Pittsburgh, PA USA. Mt Sinai Sch Med, Dept Med, New York, NY USA. Mt Sinai Sch Med, Dept Geriatr, New York, NY USA. Mt Sinai Sch Med, Dept Physiol & Biophys, New York, NY USA. Bronx Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, New York, NY USA. Washington Univ, Sch Med, Dept Physiol & Cell Biol, St Louis, MO USA. RP Blair, HC (reprint author), Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. RI Schlesinger, Paul/C-6049-2012 FU NIA NIH HHS [AG14917, AG12951]; NIAMS NIH HHS [AR46539, AR47700] NR 148 TC 93 Z9 97 U1 2 U2 12 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD JUN 1 PY 2002 VL 364 BP 329 EP 341 DI 10.1042/BJ20020165 PN 2 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 562CT UT WOS:000176180400001 PM 12023876 ER PT J AU Pastor-Soler, L Isnard-Bagnis, C Herak-Kramberger, C Sabolic, I Van Hoek, A Brown, D Breton, S AF Pastor-Soler, L Isnard-Bagnis, C Herak-Kramberger, C Sabolic, I Van Hoek, A Brown, D Breton, S TI Expression of aquaporin 9 in the adult rat epididymal epithelium is modulated by androgens SO BIOLOGY OF REPRODUCTION LA English DT Article DE AQP9; castrated rats; epididymis; flutamide; orchiectomy ID MALE REPRODUCTIVE-TRACT; NEUTRAL SOLUTE CHANNEL; CHIP28 WATER CHANNEL; CAUDA-EPIDIDYMIDIS; EFFERENT DUCTS; MOLECULAR CHARACTERIZATION; NONSTEROIDAL ANTIANDROGEN; TESTIS; CELLS; TRANSPORT AB Reabsorption of fluid and solutes across the epithelium lining the male excurrent duct is important for adequate sperm maturation, concentration, and storage. Water channels contribute to water movement across epithelia in many tissues. Aquaporin 9 (AQP9) is abundantly expressed in the apical membrane of principal cells that line the epididymis, and in reabsorptive and secretory epithelial cells of the male reproductive tract. In this study we show that the nonsteroidal antiandrogen flutamide, given to adult rats at a dose of 50 mg kg(-1) day(-1) for 2 wk via osmotic minipumps significantly decreased the amount of AQP9 in the epididymis. This down-regulation was observed by immunofluorescence of cryostat tissue sections and by Western blotting of epididymal brush border membrane preparations. In addition, castrated adult rats showed lower levels of epididymal AQP9 compared with adult controls, whereas systemic testosterone treatment of castrated adult rats induced a recovery of the expression of AQP9 to control levels. These data indicate that the expression of AQP9, a likely candidate for apical transepithelial fluid and solute transport in several regions of the male reproductive tract, is modulated by androgens in the adult rat epididymis. C1 Massachusetts Gen Hosp East, Renal Unit, Program Membrane Biol, Dept Med, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Inst Med Res & Occupat Hlth, Unit Mol Toxicol, Zagreb 10001, Croatia. RP Breton, S (reprint author), Massachusetts Gen Hosp East, Renal Unit, Program Membrane Biol, Dept Med, 149 13th St,8th Floor, Charlestown, MA 02129 USA. NR 64 TC 6 Z9 6 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD JUN PY 2002 VL 66 IS 6 BP 1716 EP 1722 PG 7 WC Reproductive Biology SC Reproductive Biology GA 554WP UT WOS:000175760400020 ER PT J AU Li, Y Ryan, L AF Li, Y Ryan, L TI Modeling spatial survival data using semiparametric frailty models SO BIOMETRICS LA English DT Article DE Cholesky decomposition; Cox models; frailty models; identifiability; Laplace approximation; Monte Carlo simulation; rank likelihood; spatial covariance; survival data ID PROPORTIONAL HAZARDS MODEL; ASYMPTOTIC THEORY; LIKELIHOOD; INFERENCE AB We propose a new class of semiparametric frailty models for spatially correlated survival data. Specifically, we extend the ordinary frailty models by allowing random effects accommodating spatial correlations to enter into the baseline hazard function multiplicatively. We prove identifiability of the models and give sufficient regularity conditions. We propose drawing inference based on a marginal rank likelihood. No parametric forms of the baseline hazard need to be assumed in this semiparametric approach. Monte Carlo simulations and the Laplace approach are used to tackle the intractable integral in the likelihood function. Different spatial covariance structures are explored in simulations and the proposed methods are applied to the East Boston Asthma Study to detect prognostic factors leading to childhood asthma. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Li, Y (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RI Ryan, Louise/A-4562-2009 OI Ryan, Louise/0000-0001-5957-2490 FU NCI NIH HHS [CA48061, CA57253] NR 24 TC 37 Z9 38 U1 1 U2 5 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2002 VL 58 IS 2 BP 287 EP 297 DI 10.1111/j.0006-341X.2002.00287.x PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 561RT UT WOS:000176157000004 PM 12071401 ER PT J AU Finkelstein, DM Goggins, WB Schoenfeld, DA AF Finkelstein, DM Goggins, WB Schoenfeld, DA TI Analysis of failure time data with dependent interval censoring SO BIOMETRICS LA English DT Article DE cytomegalovirus; EM algorithm; HIV; missing data; screening; survival ID PROPORTIONAL HAZARDS MODEL AB This article develops a method for the analysis of screening data for which the chance of being screened is dependent on the event of interest (informative censoring). Because not all subjects make all screening visits, the data on the failure of interest is interval censored. We propose a model that will properly adjust for the dependence to obtain an unbiased estimate of the nonparametric failure time function, and we provide an extension for applying the method for estimation of the regression parameters from a (discrete time) proportional hazards regression model. The method is applied on a data set from an observational study of cytomegalovirus shedding in a population of HIV-infected subjects who participated in a trial conducted by the AIDS Clinical Trials Group. C1 Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Hong Kong Baptist Univ, Dept Math, Kowloon, Hong Kong, Peoples R China. RP Finkelstein, DM (reprint author), Massachusetts Gen Hosp, Ctr Biostat, 50 Staniford St,Suite 560, Boston, MA 02114 USA. FU NCI NIH HHS [CA 74302]; NIAID NIH HHS [N0-AI38855] NR 12 TC 19 Z9 19 U1 0 U2 1 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2002 VL 58 IS 2 BP 298 EP 304 DI 10.1111/j.0006-341X.2002.00298.x PG 7 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 561RT UT WOS:000176157000005 PM 12071402 ER PT J AU Xu, RH Adak, S AF Xu, RH Adak, S TI Survival analysis with time-varying regression effects using a tree-based approach SO BIOMETRICS LA English DT Article DE change paint; classification and regression tree; maximized score test; nonproportional hazards; time-varying regression effect ID PROPORTIONAL HAZARDS MODEL; NUISANCE PARAMETER; PARTIAL LIKELIHOOD; COX MODEL; RESIDUALS; SPLINES AB Nonproportional hazards often arise in survival analysis, as is evident in the data from the International Non-Hodgkin's Lymphoma Prognostic Factors Project. A tree-based method to handle such survival data is developed for the assessment and estimation of time-dependent regression effects under a Cox-type model. The tree method approximates the time-varying regression effects as piecewise constants and is designed to estimate change points in the regression parameters. A fast algorithm that relies on maximized score statistics is used in recursive segmentation of the time axis. Following the segmentation, a pruning algorithm with optimal properties similar to those of classification and regression trees (CART) is used to determine a sparse segmentation. Bootstrap resampling is used in correcting for overoptimism due to split point optimization. The piecewise constant model is often more suitable for clinical interpretation of the regression parameters than the more flexible spline models. The utility of the algorithm is shown oil the lymploma data, where. we further develop the, published International Risk Index into a time-varying risk index for non-Hodgkin's lymphoma. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Indian Inst Technol, Bioinformat Grp, IBM India Res Lab, New Delhi 110016, India. RP Xu, RH (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. NR 41 TC 13 Z9 13 U1 1 U2 4 PU INTERNATIONAL BIOMETRIC SOC PI WASHINGTON PA 1441 I ST, NW, SUITE 700, WASHINGTON, DC 20005-2210 USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD JUN PY 2002 VL 58 IS 2 BP 305 EP 315 DI 10.1111/j.0006-341X.2002.00305.x PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 561RT UT WOS:000176157000006 PM 12071403 ER PT J AU Forsch, RA Wright, JE Rosowsky, A AF Forsch, RA Wright, JE Rosowsky, A TI Synthesis and in vitro antitumor activity of thiophene analogues of 5-chloro-5,8-dideazafolic acid and 2-methyl-2-desamino-5-chloro-5,8-dideazafolic acid SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID THYMIDYLATE SYNTHASE INHIBITORS; BENZOYL RING MODIFICATIONS; FOLIC-ACID; FOLYLPOLYGLUTAMATE SYNTHETASE; 5,8-DIDEAZAISOFOLIC ACID; QUINAZOLINE INHIBITOR; BIOLOGICAL EVALUATION; INVITRO; SUBSTITUENTS; CB3717 AB N-[5-[N-2-Amino-5-chloro-3,4-dihydro-4-oxoquinazolin-6-yl)methylamino]-2-thenoyl]-L-glutamic acid (6) and N-[5-[N-(5-chloro-3,4-dihydro-2-methyl-4-oxoquinazolin-6-yl)methylamino]-2-thenoyl]-L-glutamic acid (7), the first reported thiophene analogues of 5-chloro-5,8-dideazafolic acid, were synthesized and tested as inhibitors of tumor cell growth in culture. 4-Chloro-5-methylisatin (10) was converted stepwise to methyl 2-amino-5-methyl-6-chlorobenzoate (22) and 2-amino-5-chloro-3,4-dihydro-6-methyl-4-oxoquinazoline (19). Pivaloylation of the 2-amino group. followed by NBS bromination. condensation with di-tert-butyl N-(5-amino-2-thenoyl)-L-glutamate (28), and stepwise cleavage of the protecting groups with ammonia and TFA yielded 6. Treatment of 9 with acetic anhydride afforded 2,6-dimethyl-5-chlorobenzy[1,3-d]oxazin-4-one (31), which on reaction with ammonia, NaOH was converted to 2,6-dimethyl-5-chloro-3,4-dihydroquinazolin-4-one (33). Bromination of 33, followed by condensation with 28 and ester cleavage with TFA, yielded 7. The IC50 of 6 and 7 against CCRF-CEM human leukemic lymphoblasts was 1.8 +/- 0.1 and 2.1 +/- 0.8 muM, respectively. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Rosowsky, A (reprint author), 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [R01-CA63064, R01-CA70349] NR 33 TC 12 Z9 14 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUN PY 2002 VL 10 IS 6 BP 2067 EP 2076 AR PII S0968-0896(02)00018-4 DI 10.1016/S0968-0896(02)00018-4 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 540YY UT WOS:000174959500043 PM 11937365 ER PT J AU Xu, W Zhang, Y Yeh, LY Ruprecht, CR Wong-Staal, F McFadden, BA Reddy, TR Ruprecht, RM AF Xu, W Zhang, Y Yeh, LY Ruprecht, CR Wong-Staal, F McFadden, BA Reddy, TR Ruprecht, RM TI One-step, highly efficient site-directed mutagenesis by toxic protein selection SO BIOTECHNIQUES LA English DT Article ID F-PLASMID; DNA; SAM68; MUTATIONS; MUTANTS; DOMAIN AB A fast and efficient site-directed mutagenesis method has been developed, using the newly constructed plasmid pTPS19, which expresses the toxic CcdB protein originally encoded by the E. coli F plasmid. Once the target gene is cloned into pTPS19, desired mutations can be introduced with two primers. The first contains the desired mutation, and the second is designed to create a +1 frame shift in the ccdB gene to inactivate the CcdB protein. The mutants can be directly selected on LB plates containing IPTG, through which the toxic CcdB protein is induced, thereby eliminating cells carrying wild-type parental plasmids. Based on stringent selection through the toxic CcdB protein, mutagenesis efficiency of 90%-100% was reached even after one round of transformation. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Washington State Univ, Pullman, WA 99164 USA. Wayne State Univ, Detroit, MI 48202 USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, 44 Brinney St, Boston, MA 02115 USA. FU NIAID NIH HHS [P01AI48240, AI46240]; NIGMS NIH HHS [GM56089]; PHS HHS [19972] NR 16 TC 6 Z9 6 U1 0 U2 1 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUN PY 2002 VL 32 IS 6 BP 1266 EP + PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 561ND UT WOS:000176146400010 PM 12074156 ER PT J AU Mitsiades, N Mitsiades, CS Poulaki, V Chauhan, D Richardson, PG Hideshima, T Munshi, N Treon, SP Anderson, KC AF Mitsiades, N Mitsiades, CS Poulaki, V Chauhan, D Richardson, PG Hideshima, T Munshi, N Treon, SP Anderson, KC TI Biologic sequelae of nuclear factor-kappa B blockade in multiple myeloma: therapeutic applications SO BLOOD LA English DT Article ID ALPHA-INDUCED APOPTOSIS; NECROSIS-FACTOR-ALPHA; OVERCOMES DRUG-RESISTANCE; ACTIVATED PROTEIN-KINASE; TNF-ALPHA; CONSTITUTIVE ACTIVATION; MEDIATED APOPTOSIS; CYTOCHROME-C; RAT STRIATUM; CELLS AB The transcription factor nuclear factor-kappaB (NF-kappaB) confers significant survival potential In a variety of tumors, Several established or novel anti-multiple myeloma (anti-MM) agents, such as dexamethasone, thalidomide, and proteasome inhibitors (PS-341), inhibit NF-kappaB activity as part of their diverse actions. However, studies to date have not delineated the effects of specific Inhibition of NF-kappaB activity in MM. We therefore Investigated the effect of SN50, a cell-permeable specific inhibitor of NF-kappaB nuclear translocation and activity, on MM cells. SN50 induced apoptosis in MM cell lines and patient cells; down-regulated expression of Bcl-2, A1, X-chromosome-linked inhibitor-of-apoptosis protein (XIAP), cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, and survivin; up-regulated Bax; increased mitochondrial cytochrome c release into the cytoplasm; and activated caspase-9 and caspase-3, but not caspase-8. We have previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) is present locally in the bone marrow microenvironment and induces NF-kappaB-dependent up-regulation of adhesion molecules on both MM cells and bone marrow stromal cells, with resultant increased adhesion. In this study, TNF-alpha alone induced NF-kappaB nuclear translocation, cIAP-1 and cIAP-2 up-regulation, and MM cell proliferation; in contrast, SN50 pretreatment sensitized MM cells to TNF-alpha-induced apoptosis and cleavage of caspase-8 and caspase-3, similar to our previous finding of SN50-induced sensitization to apoptosis induced by the TNF-alpha family member TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. Moreover, SN50 inhibited TNF-alpha-induced expression of another NF-kappaB target gene, intercellular adhesion molecule-1. Although the p38 inhibitor PD169316 did not directly kill MM cells, it potentiated the apoptotic effect of SN50, suggesting an interaction between the p38 and NF-kappaB pathways. Our results therefore demonstrate that NF-kappaB activity in MM cells promotes tumor-cell survival and protects against apoptotic stimuli. These studies provide the framework for targeting NF-kappaB activity in novel biologically based therapies for MM. (C) 2002 by The American Society of Hematology. C1 Harvard Univ, Dept Adult Oncol, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Retina Res Lab, Boston, MA USA. RP Anderson, KC (reprint author), Harvard Univ, Dept Adult Oncol, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 60 TC 297 Z9 316 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 JUN 1 PY 2002 VL 99 IS 11 BP 4079 EP 4086 DI 10.1182/blood.V99.11.4079 PG 8 WC Hematology SC Hematology GA 555QL UT WOS:000175804700029 PM 12010810 ER PT J AU Mazo, IB Quackenbush, EJ Lowe, JB von Andrian, UH AF Mazo, IB Quackenbush, EJ Lowe, JB von Andrian, UH TI Total body irradiation causes profound changes in endothelial traffic molecules for hematopoietic progenitor cell recruitment to bone marrow SO BLOOD LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; STEM-CELLS; ADHESION MOLECULE-1; MOUSE EMBRYO; FETAL LIVER; VASCULAR ENDOTHELIUM; CD34(+) CELLS; NOD/SCID MICE; NORMAL TISSUE; SHEAR-FLOW AB Nonirradiated bone marrow (BM) venules and sinusoids in murine skull support hematopoletic progenitor cell (HPC) rolling through constitutively expressed endothelial (P- and E-) selectins and VCAM-1. Using intravital microscopy, we tested whether host conditioning with total body irradiation (TBI) changes the molecular mechanisms by which murine HPCs from fetal livers (FL) interact with BM endothelial cells. Although a high dose of TBI did not affect the overall frequency of HPC rolling in BM microvessels, the underlying molecular mechanisms differed from those in nonirradiated BM. TBI induced VCAM-1 up-regulation in BM microvessels, whereas P-selectin expression was reduced and the low baseline level of E-selectin remained unchanged. Only the administration of anti-VCAM-1, but not anti-P- or -E-selectin monoclonal antibodies, decreased FL HPC rolling. Rolling was frequently followed by firm arrest (sticking), even in nonirradiated BM microvessels in which sticking was entirely pertussis toxin-insensitive-that is, G(alphai)-coupled signaling events (eg, through chemokines) were apparently not required. TBI increased the frequency of sticking FL HPC. This irradiation-induced additional sticking was reversed when FL HPCs were pretreated with pertussis toxin, suggesting that TBI induced elevated expression of a G(alphai)-protein-coupled chemotactic signal In the BM. This chemoattractant was probably distinct from SDF-1alpha because, unlike adult HPCs, FL HPCs (day 11 of gestation) responded poorly to SDF-1alpha in vitro. These results demonstrate that TBI induces profound changes in the expression of endothelial traffic molecules in the BM, and they indicate that FL HPCs can home to the BM in the absence of SDF-1alpha and other G(alphai)-protein-coupled signals. (C) 2002 by The American Society of Hematology. C1 Harvard Univ, Sch Med, Childrens Hosp, Ctr Blood Res, Boston, MA USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Pathol, Boston, MA USA. Harvard Univ, Sch Med, Childrens Hosp, Div Clin Genet, Boston, MA USA. Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. RP von Andrian, UH (reprint author), Ctr Blood Res, Dept Pathol, 200 Longwood Ave, Boston, MA 02115 USA. RI von Andrian, Ulrich/A-5775-2008 FU NHLBI NIH HHS [HL15157, HL56949, T 32 HL66987] NR 60 TC 59 Z9 61 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2002 VL 99 IS 11 BP 4182 EP 4191 DI 10.1182/blood.V99.11.4182 PG 10 WC Hematology SC Hematology GA 555QL UT WOS:000175804700043 PM 12010824 ER PT J AU Yang, YG Qi, J Wang, MG Sykes, M AF Yang, YG Qi, J Wang, MG Sykes, M TI Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells SO BLOOD LA English DT Article ID BONE-MARROW TRANSPLANTATION; NATURAL-KILLER-CELLS; MURINE RENAL-CANCER; RISK ACUTE-LEUKEMIA; IFN-GAMMA; AUTOIMMUNE ENCEPHALOMYELITIS; BIOCHEMICAL-CHARACTERIZATION; HEMATOLOGIC MALIGNANCIES; UNRELATED DONORS; NITRIC-OXIDE AB The graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD)-inducing activity of CD8 T cells was compared in murine recipients of wild-type (WT) or interferon gamma (IFN-gamma)-deficient (GKO) allogeneic donor cells. CD8 T cells (or CD4-depleted splenocytes) from GKO donor mice induced more severe GVHD in lethally irradiated allogeneic recipients compared to the same cell populations from WT donors. Consistent with GVHD severity, donor CD8 T-cell expansion in allogeneic recipients was augmented in the absence of IFN-gamma. These results demonstrate that IFN-gamma does not stimulate but instead down-modulates GVHD induced by donor CD8 T cells. Remarkably, anti-host lymphohematopoietic reactions, including GVL effects against host leukemia/lymphoma cells, of CD8 T cells correlated inversely with their GVHD-inducing activity, and those of GKO donors were markedly weaker than those mediated by WT donor CD8 T cells. These data show for the first time that GVHD-inducing activity and GVL effects of allogeneic CD8 T cells can be separated by a single cytokine, IFN-gamma. (C) 2002 by The American Society of Hematology. C1 Harvard Univ, Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr, Massachusetts Gen Hosp,Sch Med,Surg Serv, Boston, MA 02129 USA. RP Yang, YG (reprint author), Harvard Univ, Bone Marrow Transplantat Sect, Transplantat Biol Res Ctr, Massachusetts Gen Hosp,Sch Med,Surg Serv, MGH East,Bldg 149-5102,13th St, Boston, MA 02129 USA. FU NCI NIH HHS [R01 CA79989] NR 78 TC 63 Z9 67 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 JUN 1 PY 2002 VL 99 IS 11 BP 4207 EP 4215 DI 10.1182/blood.V99.11.4207 PG 9 WC Hematology SC Hematology GA 555QL UT WOS:000175804700046 PM 12010827 ER PT J AU Kramer, JL Baltathakis, I Alcantara, OSF Boldt, DH AF Kramer, JL Baltathakis, I Alcantara, OSF Boldt, DH TI Differentiation of functional dendritic cells and macrophages from human peripheral blood monocyte precursors is dependent on expression of p21 (WAF1/CIP1) and requires iron SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE iron; haematopoiesis; p21(WAF1/CIP1); dendritic cells; macrophages ID HUMAN LYMPHOCYTES-T; CYCLE PROGRESSION; DEFICIENCY; MECHANISMS; GENES AB Iron is required for monocyte/macrophage differentiation of HL-60 leukaemia cells. Differentiation requires induction of the cyclin-dependent kinase inhibitor p21 (WAF1/CIP1), and cell cycle arrest at the G1/S checkpoint. With iron depletion, p21 induction and differentiation are blocked. To establish the roles of iron and p21 in normal monocyte/macrophage differentiation, we examined generation of dendritic cells (DCs) and macrophages from peripheral monocytes. Monocytes were cultured with interleukin 4 and granulocyte-macrophage colony-stimulating factor (GM-CSF), then treated with lipopolysaccharide to produce DCs or with M-CSF to produce macrophages. Iron deprivation was induced by desferrioxamine (DF). Monocyte-derived DCs had characteristic phenotype and morphology, and stimulated proliferation of naive allogeneic T lymphocytes. In contrast, DCs generated under iron deprivation were phenotypically undifferentiated and did not stimulate T cells. Similarly, macrophages expressed a characteristic phenotype and morphology, and phagocytosed latex beads, but macrophages generated under iron deprivation failed to develop a mature phenotype and had impaired phagocytosis. Iron deprivation blocked induction of p21 (WAF1/CIP1) expression in both DC and macrophage cultures. Furthermore, p21 antisense oligonucleotides, but not sense oligonucleotides, inhibited both DC and macrophage differentiation. These data indicate that a key role of iron in haematopoiesis is to support induction of p21 which, in turn, is required for DC and macrophage differentiation. C1 Univ Texas, Hlth Sci Ctr, Dept Med Hematol, San Antonio, TX USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Boldt, DH (reprint author), Mail Code 7880,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NIDDK NIH HHS [R01 DK 5042] NR 22 TC 35 Z9 35 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2002 VL 117 IS 3 BP 727 EP 734 DI 10.1046/j.1365-2141.2002.03498.x PG 8 WC Hematology SC Hematology GA 553LL UT WOS:000175676600038 PM 12028050 ER PT J AU Friedberg, JW Neuberg, D Gribben, JG Fisher, DC Canning, C Koval, M Poor, CM Green, LM Daley, J Soiffer, R Ritz, J Freedman, AS AF Friedberg, JW Neuberg, D Gribben, JG Fisher, DC Canning, C Koval, M Poor, CM Green, LM Daley, J Soiffer, R Ritz, J Freedman, AS TI Combination immunotherapy with rituximab and interleukin 2 in patients with relapsed or refractory follicular non-Hodgkin's lymphoma SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE IL-2; Rituxan; follicular non-Hodgkin's lymphoma; cytokines; ADCC ID ANTI-CD20 MONOCLONAL-ANTIBODY; ACTIVATED KILLER-CELLS; DOSE RECOMBINANT INTERLEUKIN-2; BONE-MARROW TRANSPLANTATION; LOW-GRADE; ADVANCED CANCER; PHASE-II; IN-VIVO; CONTINUOUS-INFUSION; B-CELLS AB Rituximab has significant activity as a single agent in the treatment of follicular non-Hodgkin's lymphoma (NHL). Interleukin 2 (IL-2) is a lymphokine that increases effector cell number. In an effort to augment antibody-dependent cell-mediated cytotoxicity (ADCC) associated with rituximab therapy, low-dose IL-2 was added to a standard rituximab regimen and patients were evaluated for safety and efficacy. Twenty patients with relapsed or refractory follicular NHL were treated with IL-2 (1.2 MIU/m(2) /d for 56 d subcutaneously) as outpatients. Rituximab (375 mg/m(2) ) was given on d 15, 22, 29 and 36. The regimen was well tolerated and only three patients required dose adjustments in IL-2. Infusional toxicity associated with rituximab was not exacerbated by IL-2. Peripheral blood immunophenotyping demonstrated significant increases in circulating CD8(+) and CD56(+) lymphocytes in all evaluable patients (P = 0.0002). Increases in total eosinophil number were observed in all patients. Eleven patients responded to therapy, for an overall response rate of 55%. Four additional patients had stable disease. For these 15 patients, the median time to progression exceeded 13 months. We conclude concomitant cytokine therapy to enhance ADCC with monoclonal antibody therapy was well tolerated and did not exacerbate antibody-related infusional toxicity. Further studies of this rational combination are warranted and ongoing. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Friedberg, JW (reprint author), James P Wilmot Canc Ctr, 601 Elmwood Ave,Box 704, Rochester, NY 14642 USA. RI Ritz, Jerome/C-7929-2009 OI Ritz, Jerome/0000-0001-5526-4669 FU NCI NIH HHS [CA 66996] NR 46 TC 101 Z9 103 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2002 VL 117 IS 4 BP 828 EP 834 DI 10.1046/j.1365-2141.2002.03535.x PG 7 WC Hematology SC Hematology GA 561FT UT WOS:000176130100008 PM 12060117 ER PT J AU Feldmann, J Le Deist, F Ouachee-Chardin, M Certain, S Alexander, S Quartier, P Haddad, E Wulffraat, N Casanova, JL Blanche, S Fischer, A de Saint Basile, G AF Feldmann, J Le Deist, F Ouachee-Chardin, M Certain, S Alexander, S Quartier, P Haddad, E Wulffraat, N Casanova, JL Blanche, S Fischer, A de Saint Basile, G TI Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE familial haemophagocytic lymphohistiocytosis; perforin; genotype/phenotype; cytotoxicity; haemophagocytic syndromes ID BONE-MARROW TRANSPLANTATION; CYTOTOXIC T-LYMPHOCYTES; NATURAL-KILLER-CELLS; HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; ERYTHROPHAGOCYTIC LYMPHOHISTIOCYTOSIS; DEFICIENT MICE; INFECTION; HETEROGENEITY; CHEMOTHERAPY; APOPTOSIS AB Familial haemophagocytic lymphohistiocytosis (FHL), an inherited form of haemophagocytic lymphohistiocytosis (HLH) syndrome, is characterized by the overwhelming activation of T lymphocytes and macrophages invariably leading to death in the absence of treatment. FHL is a heterogeneous autosomal recessive disorder, with one known causative gene which codes for perforin, a cytotoxic effector protein. In this study, we have characterized the genotype and phenotype of 14 unrelated families with perforin deficiency. Four new missense mutations of the perforin gene were identified. In every case, perforin gene mutations led to undetectable intracellular perforin expression within cytotoxic cells, while some residual T-cell cytotoxic activity could be associated with certain missense mutations. Clinical and biological analyses did not differentiate between patients with nonsense or missense mutations, although age at diagnosis, which tended to be similar within members of the same family, was delayed in patients from two families belonging to the second group. In one case, consequences of perforin deficiency, diagnosed at birth, could be assessed prior to onset of clinical manifestations. No evidence for T-cell activation could be shown, suggesting that an exogenous event is required to trigger the disease manifestation. Control assessment of perforin expression and cytotoxic assays by lymphocytes from young children led to the conclusion that perforin content of natural killer cells could be a reliable diagnostic test at any age. Altogether, these data enabled a better characterization of perforin deficiency and its consequences, and defined reliable diagnostic tools. C1 Hop Necker Enfants Malad, INSERM, U429, Unite Rech Dev Normal & Pathol Syst Immunitaire, F-75743 Paris 15, France. Hop Necker Enfants Malad, Unite Immunohematol Pediat, F-75743 Paris, France. Dana Farber Canc Inst, Boston, MA 02115 USA. Wilhelmina Childrens Hosp, Dept Pediat Immunol, Utrecht, Netherlands. RP de Saint Basile, G (reprint author), Hop Necker Enfants Malad, INSERM, U429, Unite Rech Dev Normal & Pathol Syst Immunitaire, 149 Rue Sevres, F-75743 Paris 15, France. OI Haddad, Elie/0000-0003-2446-6879 NR 33 TC 98 Z9 101 U1 0 U2 5 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2002 VL 117 IS 4 BP 965 EP 972 DI 10.1046/j.1365-2141.2002.03534.x PG 8 WC Hematology SC Hematology GA 561FT UT WOS:000176130100030 PM 12060139 ER PT J AU Becker, AE Burwell, RA Gilman, SE Herzog, DB Hamburg, P AF Becker, AE Burwell, RA Gilman, SE Herzog, DB Hamburg, P TI Eating behaviours and attitudes following prolonged exposure to television among ethnic Fijian adolescent girls SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID BODY-IMAGE; MEDIA; WOMEN; SELF; DISORDERS; THINNESS; BULIMIA AB Background There are no published studies evaluating the impact of introduction of television on disordered eating in media-naive populations. Aims To assess the impact of novel, prolonged exposure to television on disordered eating attitudes and behaviours among ethnic Fijian adolescent girls. Method A prospective, multi-wave cross-sectional design was used to compare two samples of Fijian schoolgirls before and after prolonged regional television exposure with a modified 26-item eating attitudes test, supplemented with a semi-structured interview to confirm self-reported symptoms. Narrative data from a subset of respondents from the exposed sample were analysed for content relating television exposure to body image concerns. Results Key indicators of disordered eating were significantly more prevalent following exposure. Narrative data revealed subjects' interest in weight loss as a means of modelling themselves after television characters. Conclusions This naturalistic experiment suggests a negative impact of television upon disordered eating attitudes and behaviours in a media-naive population. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Social Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. RP Becker, AE (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St,WAC 812, Boston, MA 02114 USA. RI Gilman, Stephen/E-7632-2010 OI Gilman, Stephen/0000-0002-8331-6419 NR 22 TC 198 Z9 206 U1 9 U2 46 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD JUN PY 2002 VL 180 BP 509 EP 514 DI 10.1192/bjp.180.6.509 PG 6 WC Psychiatry SC Psychiatry GA 560AF UT WOS:000176058500009 PM 12042229 ER PT J AU Viguera, AC Cohen, LS Baldessarini, RJ Nonacs, R AF Viguera, AC Cohen, LS Baldessarini, RJ Nonacs, R TI Managing bipolar disorder during pregnancy: Weighing the risks and benefits SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Review DE bipolar disorder; women; lithium; anticonvulsants; pregnancy; postpartum; psychosis; teratogenic risk ID DISCONTINUING LITHIUM MAINTENANCE; PSYCHOTROPIC-DRUG USE; IN-UTERO EXPOSURE; ANTIEPILEPTIC DRUGS; CONGENITAL-MALFORMATIONS; ATYPICAL ANTIPSYCHOTICS; GRADUAL DISCONTINUATION; PROPHYLACTIC LITHIUM; POSTPARTUM PSYCHOSES; PUERPERAL PSYCHOSIS AB Background: Challenges for the clinical management of bipolar disorder (BD) during pregnancy are multiple and complex and include competing risks to mother and offspring. Method: We reviewed recent research findings on the course of BD during pregnancy and postpartum, as well as reproductive safety data on the major mood stabilizers. Results: Pregnancy, and especially the postpartum period, are associated with a high risk for recurrence of BD. This risk appears to be limited by mood-stabilizing treatments and markedly increased by the abrupt discontinuation of such treatments, However, drugs used to treat or protect against recurrences of BD vary markedly in teratogenic potential: there are low risks with typical neuroleptics. moderate risks with lithium, higher risks with older anticonvulsants such as valproic acid and carbainazepine, and virtually unknown risks with other newer-generation anticonvulsants and a typical antipsychotics (ATPs). Conclusions: Clinical management of BD through pregnancy and postpartum calls for balanced assessments of maternal and fetal risks and benefits. C1 Massachusetts Gen Hosp, Perinatal & Reprod Psychiat Program, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Bipolar & Psychot Disorders & Psychopharmacol Pro, Lab Psychiat Res, Boston, MA 02114 USA. Massachusetts Gen Hosp, McLean Div, Int Consortium Bipolat Disorder Res, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Boston, MA USA. RP Viguera, AC (reprint author), Massachusetts Gen Hosp, Perinatal & Reprod Psychiat Program, Dept Psychiat, WACC 812, Boston, MA 02114 USA. EM aviguera@partners.org FU NIMH NIH HHS [K23 MH01609] NR 116 TC 59 Z9 62 U1 1 U2 5 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 141 LAURIER AVENUE WEST, STE 701, OTTAWA, ONTARIO K1P 5J3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD JUN PY 2002 VL 47 IS 5 BP 426 EP 436 PG 11 WC Psychiatry SC Psychiatry GA 565JE UT WOS:000176365600003 PM 12085677 ER PT J AU Gilliland, DG Tallman, MS AF Gilliland, DG Tallman, MS TI Focus on acute leukemias SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE PROMYELOCYTIC LEUKEMIA; BONE-MARROW TRANSPLANTATION; HIGH-DOSE CYTARABINE; TRANSGENIC MICE; FIRST REMISSION; FUSION GENE; CHEMOTHERAPY; THERAPY; ADULTS C1 Brigham & Womens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Harvard Inst Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Northwestern Univ, Sch Med, Robert H Lurie Comprehens Canc Ctr, Div Hematol Oncol, Chicago, IL 60611 USA. RP Gilliland, DG (reprint author), Brigham & Womens Hosp, Howard Hughes Med Inst, 4 Blackton Circle,Room 418, Boston, MA 02115 USA. NR 33 TC 121 Z9 125 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUN PY 2002 VL 1 IS 5 BP 417 EP 420 DI 10.1016/S1535-6108(02)00081-8 PG 4 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599TY UT WOS:000178352300006 PM 12124171 ER PT J AU Kelly, LM Yu, JC Boulton, CL Apatira, M Li, J Sullivan, CM Williams, I Amaral, SM Curley, DP Duclos, N Neuberg, D Scarborough, RM Pandey, A Hollenbach, S Abe, K Lokker, NA Gilliland, DG Giese, NA AF Kelly, LM Yu, JC Boulton, CL Apatira, M Li, J Sullivan, CM Williams, I Amaral, SM Curley, DP Duclos, N Neuberg, D Scarborough, RM Pandey, A Hollenbach, S Abe, K Lokker, NA Gilliland, DG Giese, NA TI CT53518, a novel selective FLT3 antagonist for the treatment of acute myelogenous leukemia (AML) SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; TYROSINE KINASE INHIBITOR; INTERNAL TANDEM DUPLICATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; ABL-POSITIVE CELLS; BCR-ABL; GROWTH-FACTOR; CONSTITUTIVE ACTIVATION; SIGNAL-TRANSDUCTION; HEMATOLOGIC MALIGNANCIES AB Up to 30% of acute myelogenous leukemia (AML) patients harbor an activating internal tandem duplication (ITD) within the juxtamembrane domain of the FLT3 receptor, suggesting that it may be a target for kinase inhibitor therapy. For this purpose we have developed CT53518, a potent antagonist that inhibits FLT3, platelet-derived growth factor receptor (PDGFR), and c-Kit (IC50 similar to200 nM), while other tyrosine or serine/threonine kinases were not significantly inhibited. In Ba/F3 cells expressing different FLT3-ITD mutants, CT53518 inhibited IL-3-independent cell growth and FLT3-ITD autophosphorylation with an IC50 of 10-100 nM. In human FLT3-ITD-positive AML cell lines, CT53518 induced apoptosis and inhibited FLT3-ITD phosphorylation, cellular proliferation, and signaling through the MAP kinase and PI3 kinase pathways. Therapeutic efficacy of CT53518 was demonstrated both in a nude mouse model and in a murine bone marrow transplant model of FLT3-ITD-induced disease. C1 Brigham & Womens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Millennium Pharmaceut Inc, San Francisco, CA 94080 USA. RP Gilliland, DG (reprint author), Brigham & Womens Hosp, Div Hematol Oncol, 75 Francis St, Boston, MA 02115 USA. RI Williams, Ifor/D-3648-2011 OI Williams, Ifor/0000-0002-8810-2911 FU NCI NIH HHS [CA66996]; NIDDK NIH HHS [DK50654] NR 52 TC 225 Z9 237 U1 4 U2 11 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUN PY 2002 VL 1 IS 5 BP 421 EP 432 DI 10.1016/S1535-6108(02)00070-3 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599TY UT WOS:000178352300007 PM 12124172 ER PT J AU Weisberg, E Boulton, C Kelly, LM Manley, P Fabbro, D Meyer, T Gilliland, DG Griffin, JD AF Weisberg, E Boulton, C Kelly, LM Manley, P Fabbro, D Meyer, T Gilliland, DG Griffin, JD TI Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412 SO CANCER CELL LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; CHRONIC MYELOGENOUS LEUKEMIA; HEMATOPOIETIC-CELL; CONSTITUTIVE ACTIVATION; SIGNAL-TRANSDUCTION; GENE; TRANSFORMATION; LINES; PROTEIN AB Constitutively activating FLT3 receptor mutations have been found in 35% of patients with acute myeloblastic leukemia (AML). Here we report the identification of a small molecule Fill tyrosine kinase inhibitor PKC412, which selectively induced G1 arrest and apoptosis of Ba/F3 cell lines expressing mutant FLT3 (IC50 < 10 nM) by directly inhibiting the tyrosine kinase. Ba/F3-FLT3 cell lines made resistant to PKC412 demonstrated overexpression of mutant FLT3, confirming that FLT3 is the target of this drug. Finally, progressive leukemia was prevented in PKC412-treated Balb/c mice transplanted with marrow transduced with a FLT3-ITD-expressing retrovirus. PKC412 is a potent inhibitor of mutant Ill and is a candidate for testing as an antileukemia agent in AML patients with mutant FLT3 receptors. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Novartis Pharma AG, Basel, Switzerland. RP Griffin, JD (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. FU NCI NIH HHS [P01 CA66996]; NIDDK NIH HHS [P01 DK50654] NR 36 TC 336 Z9 342 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUN PY 2002 VL 1 IS 5 BP 433 EP 443 DI 10.1016/S1535-6108(02)00069-7 PG 11 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599TY UT WOS:000178352300008 PM 12124173 ER PT J AU Sattler, M Mohi, MG Pride, YB Quinnan, LR Malouf, NA Podar, K Gesbert, F Iwasaki, H Li, SG Van Etten, RA Gu, HH Griffin, JD Neel, BG AF Sattler, M Mohi, MG Pride, YB Quinnan, LR Malouf, NA Podar, K Gesbert, F Iwasaki, H Li, SG Van Etten, RA Gu, HH Griffin, JD Neel, BG TI Critical role for Gab2 in transformation by BCR/ABL SO CANCER CELL LA English DT Article ID BCR-ABL ONCOGENE; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; HEMATOPOIETIC-CELLS; PHILADELPHIA-CHROMOSOME; TYROSINE KINASE; T-CELL; C-ABL; SIGNALING PATHWAY; FUSED TRANSCRIPT AB The BCR/ABL oncogene causes chronic myelogenous leukemia (CML) in humans and a CML-like disease, as well as lymphoid leukemia, in mice. p210 BCR/ABL is an activated tyrosine kinase that phosphorylates itself and several cellular signaling proteins. The autophosphorylation site tyrosine 177 binds the adaptor Grb2 and helps determine the lineage and severity of BCR/ABL disease: Tyr177 mutation (BCR/ABL-Y177F) dramatically impairs myeloid leukemogenesis, while diminishing lymphoid leukemogenesis. The critical signal(s) from Tyr177 has remained unclear. We report that Tyr177 recruits the scaffolding adaptor Gab2 via a Grb2/Gab2 complex. Compared to BCR/ABL-expressing Ba/F3 cells, BCR/ABL-Y177F cells exhibit markedly reduced Gab2 tyrosine phosphoryllation and association of phosphatidylinositol-3 kinase (PI3K) and Shp2 with Gab2 and BCR/ABL, and decreased PI3K/Akt and Ras/Erk activation, cell proliferation, and spontaneous migration. Remarkably, bone marrow myeloid progenitors from Gab2 (-/-) mice are resistant to transformation by BCR/ABL, whereas lymphoid transformation is diminished as a consequence of markedly increased apoptosis. BCR/ABL-evoked PI3K/Akt and Ras/Erk activation also are impaired in Gab2 (-/-) primary myeloid and lymphoid cells. Our results identify Gab2 and its associated proteins as key determinants of the lineage and severity of BCR/ABL transformation. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Inst Med, Beth Israel Deaconess Med Ctr, Dept Med, Canc Biol Program, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Genet, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Immunol & AIDS, Boston, MA 02115 USA. RP Gu, HH (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA66996, R01 CA90576]; NIDDK NIH HHS [P01 DK50654] NR 64 TC 225 Z9 228 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD JUN PY 2002 VL 1 IS 5 BP 479 EP 492 DI 10.1016/S1535-6108(02)00074-0 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 599TY UT WOS:000178352300012 PM 12124177 ER PT J AU Garner, EIO Stokes, EE Berkowitz, RS Mok, SC Cramer, DW AF Garner, EIO Stokes, EE Berkowitz, RS Mok, SC Cramer, DW TI Polymorphisms of the estrogen-metabolizing genes CYP17 and catechol-O-methyltransferase and risk of epithelial ovarian cancer SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER; ASSOCIATION; ALLELE; WOMEN AB Because some studies have linked polymorphic variants of the estrogen-metabolizing genes CYP17 and catechol O-methyl transferase (COMT) with risk for hormonally related cancers, we sought to determine whether selected polymorphisms of these genes differed between women with and without ovarian cancer. From a population-based study of ovarian cancer, we analyzed DNA from a total of 480 cases and controls. PCR amplification was performed using primers that amplify restriction sites for MspAI (A2 polymorphism-CYP17) and NlaIII (Val/Met polymorphism-COMT). Digestion of the PCR products was performed. Genotypes identified by gel electrophoresis were assigned as homozygous wild type (WW), heterozygous variant (Wv), and homozygous variant (vv). Frequencies were compared using chi(2) or Fisher's exact tests. Logistic regression was used to calculate crude and adjusted relative risks (RRs) for ovarian cancer associated with possession of any variant allele overall, and within demographic, weight, and smoking history categories, and by histological subtype of ovarian cancer. A portion (68.9%) of cases either carried or was homozygous for the A,2 variant of CYP17 compared with 53.9% of controls, for a RR (and 95% confidence interval) of 1.86 (1.26, 2.75; P = 0.003), adjusted for age, parity, oral contraceptive use, site of study, and family history of breast or ovarian cancer. The increased risk was most apparent for women >50 and women with invasive serous cancers. A portion (71.9%) of cases either carried or was homozygous for the Van, let variant of COMT, compared with 76.9% of controls (P = 0.27). Although the inverse association of ovarian cancer with possession of a Val/Met variant was not significant overall, it was for mucinous tumors of the ovary, with an adjusted RR of 0.28 (0.13, 0.61; P = 0.0012). Possession of the A2 variant of CYP17 appears to increase risk for ovarian cancer, whereas possession of the Val/Met variant of COMT decreases the risk for mucinous tumors. Confirmation in other populations and further exploration of potential pathogenetic mechanisms will be necessary. C1 Harvard Univ, Sch Med,Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Div Gynecol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ob Gyn Epidemiol Ctr, Boston, MA 02115 USA. RP Garner, EIO (reprint author), Harvard Univ, Sch Med,Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Div Gynecol Oncol, 75 Francis St, Boston, MA 02115 USA. NR 21 TC 47 Z9 47 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUN 1 PY 2002 VL 62 IS 11 BP 3058 EP 3062 PG 5 WC Oncology SC Oncology GA 559RE UT WOS:000176038500013 PM 12036914 ER PT J AU Kakkar, AK Levine, MN Prandoni, P Lee, AY Rasmussen, MS Kuter, D AF Kakkar, AK Levine, MN Prandoni, P Lee, AY Rasmussen, MS Kuter, D TI What is the role for antithrombotics in cancer care? Interactive session with panel discussion SO CANCER TREATMENT REVIEWS LA English DT Editorial Material C1 Univ London Imperial Coll Sci Technol & Med, London, England. McMaster Univ, Hamilton, ON L8S 4L8, Canada. Univ Padua, I-35100 Padua, Italy. Bispebjerg Hosp, DK-2400 Copenhagen, Denmark. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kakkar, AK (reprint author), Univ London Imperial Coll Sci Technol & Med, Hamanoumachi Hosp, Fac Med, Dept Surg Oncol & Technol, London W12 0NN, England. NR 2 TC 2 Z9 2 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0305-7372 J9 CANCER TREAT REV JI Cancer Treat. Rev. PD JUN PY 2002 VL 28 IS 3 BP 157 EP 159 DI 10.1016/S0305-7372(02)00045-2 PG 3 WC Oncology SC Oncology GA 602GA UT WOS:000178496500007 PM 12234568 ER PT J AU Terracciano, CMN Hajjar, RJ Harding, SE AF Terracciano, CMN Hajjar, RJ Harding, SE TI Overexpression of SERCA2a accelerates repolarisation in rabbit ventricular myocytes SO CELL CALCIUM LA English DT Article ID INDUCED HEART-FAILURE; SARCOPLASMIC-RETICULUM; GUINEA-PIG; CALCIUM CONTENT; PROTEINS; HYPERTROPHY; MECHANISMS; DECREASES AB Overexpression of the sarcoplasmic reticulum Ca ATPase (SERCA2a) produces positive inotropism and it has been proposed as a promising strategy to counteract defective excitation-contraction coupling in the failing heart. However, the effects of overexpressing SERCA2a on action potential duration (APD), which can affect diastolic parameters in the heart, is unknown. We, therefore, investigated the relationship between SERCA2a overexpression and APD in adult rabbit ventricular myocytes which were cultured for 48 h. Overexpression of SERCA2a was achieved by infection with an adenovirus carrying both SERCA2a and GFP independently driven by CMV promoters, Ad.SERCA2a. Myocytes infected with Ad.GFP only and/or non-infected myocytes were used as controls. Electrophysiological measurements were taken using switch clamping with 15-25 MOmega resistance microelectrodes. In Ad.SERCA2a infected myocytes, APD was significantly reduced compared with both groups of control cells at 0.5 Hz (APD50 (ms) non-infected: 481 +/- 98, n = 12; Ad.GFP: 464 +/- 85, n = 11; Ad.SERCA2a: 285 69, n = 13 (mean +/- S.E.M.) and at 1 Hz (APD50 (ms) non-infected: 375 +/- 64, n = 22; Ad.GFP: 363 +/- 47, n = 18; Ad.SERCA2a: 231 +/- 54, n = 24). Using AP voltage-clamping, we recorded a 0.2 mM Cd-sensitive current which can be ascribed to Ca current flowing during the AR The integral of this current was reduced in Ad.SERCA2a myocytes compared with control (non-infected charge (pC): 27.5 +/- 4.2, n = 8; Ad.SERCA2a: 15.5 +/- 4.1, n = 11; P < 0.01). Using AP clamping during the loading protocol, to take into account changes in APD, SR Ca content (assessed by integrating a 20 mM caffeine-induced inward current) was significantly larger in Ad.SERCA2a compared with both controls (SR Ca content (μM/l non-mitochondrial volume): non-infected: 25.5 +/- 7, n = 8; Ad.GFP: 25.7 +/- 11, n = 6; Ad.SERCA2a: 80.5 +/- 19, n = 8). In conclusion, this study shows that SR Ca content is increased despite decreased Ca entry after overexpression of SERCA2a, and this can lead to positive inotropism. This effect coupled with shorter APD may be a useful therapeutic modality in heart failure. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ London Imperial Coll Sci Technol & Med, Heart Sci Ctr, Fac Med, Natl Heart & Lung Inst,Harefield Hosp, Harefield UB9 6JH, Middx, England. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ London Imperial Coll Sci Technol & Med, Fac Med, London SW3 6LY, England. RP Terracciano, CMN (reprint author), Univ London Imperial Coll Sci Technol & Med, Heart Sci Ctr, Fac Med, Natl Heart & Lung Inst,Harefield Hosp, Harefield UB9 6JH, Middx, England. NR 18 TC 15 Z9 17 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD JUN PY 2002 VL 31 IS 6 BP 299 EP 305 DI 10.1016/S0143-4160(02)00058-1 PG 7 WC Cell Biology SC Cell Biology GA 580ML UT WOS:000177238300005 PM 12098219 ER PT J AU Sakaguchi, T Kohler, H Gu, XB McCormick, BA Reinecker, HC AF Sakaguchi, T Kohler, H Gu, XB McCormick, BA Reinecker, HC TI Shigella flexneri regulates tight junction-associated proteins in human intestinal epithelial cells SO CELLULAR MICROBIOLOGY LA English DT Article ID BRONCHISEPTICA DERMONECROTIZING TOXIN; ACTIN STRESS FIBERS; POSSIBLE INVOLVEMENT; MEMBRANE-PROTEINS; BARRIER FUNCTION; E-CADHERIN; KINASE-C; OCCLUDIN; BINDING; ZO-1 AB Shigella spp. are a group of Gram-negative enteric bacilli that cause acute dysentery in humans. We demonstrate that Shigella flexneri has evolved the ability to regulate functional components of tight junctions after interaction at the apical and basolateral pole of model intestinal epithelia. In the regulation of tight junctional protein assemblies, S. flexneri can engage serotype-specific mechanisms, which targets not only expression, but also cellular distri-bution and membrane association of components of tight junctions. Distinct mechanisms resulting in the regulation of tight junction-associated proteins are initiated after either apical or basolateral interactions. S. flexneri serotype 2a has the ability to remove claudin-1 from Triton X-insoluble protein fractions upon apical exposure to T-84 cell monolayers. S. flexneri serotype 2a and 5, but not the non-invasive Escherichia coli strain F-18, share the ability to regulate expression of ZO-1, ZO-2, E-cadherin and to dephosphorylate occludin. The disruption of tight junctions is dependent on direct interaction of living Shigella with intestinal epithelial cells and is supported by heat-stable secreted bacterial products. Intestinal epithelial cells have the ability to compensate in part for S. flexneri induced regulation of tight junction-associated proteins. C1 Massachusetts Gen Hosp, Dept Med, Ctr Study Inflammatory Bowel Dis, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Combined Program Pediat Gastroenterol & Nutr, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Reinecker, HC (reprint author), Massachusetts Gen Hosp, Dept Med, Ctr Study Inflammatory Bowel Dis, Gastrointestinal Unit, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK 54427, DK 5674, DK 33506, DK 51003] NR 51 TC 81 Z9 83 U1 2 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD JUN PY 2002 VL 4 IS 6 BP 367 EP 381 DI 10.1046/j.1462-5822.2002.00197.x PG 15 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 562TB UT WOS:000176214100005 PM 12067320 ER PT J AU Mitsikostas, DD del Rio, MS Waeber, C AF Mitsikostas, DD del Rio, MS Waeber, C TI 5-Hydroxytryptamine(1B/1D) and 5-hydroxytryptamine(1F) receptors inhibit capsaicin-induced c-fos immunoreactivity within mouse trigeminal nucleus caudalis SO CEPHALALGIA LA English DT Article DE 5-HT1B/1D receptors; 5-HT1F receptors; c-fos; trigeminal pain; migraine ID NEUROGENIC DURAL INFLAMMATION; NOXIOUS FACIAL STIMULATION; BOVINE CEREBRAL-ARTERIES; SUPERIOR SAGITTAL SINUS; BLOOD-VESSELS; CHEMICAL-STIMULATION; PLASMA EXTRAVASATION; ANTIMIGRAINE DRUGS; 5-HT1F RECEPTORS; CORONARY-ARTERY AB In order to investigate the c-fos response within the trigeminal nucleus caudalis (Sp5C) after noxious meningeal stimulation, capsaicin (0.25, 0.5, 1 and 5 nmol) was administered intracisternally in urethane (1 g/kg) and alpha-chloralose (20 mg/kg) anaesthetized male mice. Capsaicin induced a robust and dose-dependent c-fos -like immunoreactivity (c-fos LI) within Sp5C. C-fos LI was observed within laminae I and II of the entire brain stem from the area postrema to C2 level, being maximum at the decussatio pyramidum level. The area postrema, solitary tract, medullary and lateral reticular nuclei were also labelled. The 5-hydroxytryptamine(1B/1D/1F) receptor agonist sumatriptan (0.01, 0.1, 1 and 10 mg/kg), administered intraperitoneally 15 min before capsaicin stimulation (1 nmol), decreased the c-fos response within Sp5C, but not within solitary tract. The novel specific 5-hydroxytryptamine(1F) agonist LY 344864 (0.1 and 1 mg/kg, i.p.) significantly decreased the c-fos LI within the Sp5C as well. These findings suggest that intracisternally administered capsaicin activates the trigeminovascular system and that the pain neurotransmission can be modulated by 5-hydroxytryptamine(1B/1D/1F) receptors in mice. Thus, the availability of this model in mice, taken together with the possibility of altering the expression of specific genes in this species, may help to investigate further the importance of distinct proteins in the neurotransmission of cephalic pain. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab, Charlestown, MA USA. RP Mitsikostas, DD (reprint author), Athens Naval Hosp, Dept Neurol, Headache Clin, 70 Dinokratous Str, Athens 11521, Greece. RI Waeber, Christian/A-8333-2009 OI Waeber, Christian/0000-0001-6078-0027 FU NINDS NIH HHS [NS35611] NR 48 TC 13 Z9 16 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0333-1024 J9 CEPHALALGIA JI Cephalalgia PD JUN PY 2002 VL 22 IS 5 BP 384 EP 394 DI 10.1046/j.1468-2982.2002.00382.x PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 571XP UT WOS:000176744700008 PM 12110114 ER PT J AU Pollen, DA Przybyszewski, AW Rubin, MA Foote, W AF Pollen, DA Przybyszewski, AW Rubin, MA Foote, W TI Spatial receptive field organization of macaque V4 neurons SO CEREBRAL CORTEX LA English DT Article ID VISUAL CORTICAL AREAS; CAT STRIATE CORTEX; FREQUENCY-SELECTIVITY; CARTESIAN GRATINGS; SINGLE NEURONS; FORM VISION; RESPONSES; MONKEY; ORIENTATION; CELLS AB Subfield analysis of the receptive fields (RFs) of parafoveal V4 complex cells demonstrates directly that most Rfs are tiled by overlapping second-order excitatory inputs that for any given V4 cell are predominantly selective to the same preferred values of spatial frequency and orientation. These results extend hierarchical principles of RF organization in the spatial, orientation and spatial frequency domains, first recognized in V1, to an intermediate extrastriate cortex. Spatial interaction studies across subfields demonstrate that the responses of V4 neurons to paired stimuli may either decrease or increase as a function of inter-stimulus distance across the width axis. These intra-RF suppressions and facilitations vary independently in magnitude and spatial extent from cell to cell. These results taken together with the relatively large RF sizes of V4 neurons - as compared with RF sizes of their afferent inputs - lead us to hypothesize a novel property, namely that classes of stimulus configurations that enhance areal summation while reducing suppressive interactions between excitatory inputs will evoke especially robust responses. We tested, and found support for, this hypothesis by presenting stimuli consisting of optimally tuned sine-wave gratings visible only within an annular region and found that such stimuli vigorously activate V4 neurons at firing rates far higher than those evoked by comparable stimuli to either the full-field or central core. On the basis of these results we propose a framework for a new class of neural network models for the spatial RF organizations of prototypic V4 neurons. C1 Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. Boston Univ, Dept Cognit & Neural Syst, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Pollen, DA (reprint author), Univ Massachusetts, Sch Med, Dept Neurol, 55 Lake Ave N, Worcester, MA 01655 USA. NR 42 TC 45 Z9 45 U1 4 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JUN PY 2002 VL 12 IS 6 BP 601 EP 616 DI 10.1093/cercor/12.6.601 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 553BK UT WOS:000175655500005 PM 12003860 ER PT J AU Vanduffel, W Tootell, RBH Schoups, AA Orban, GA AF Vanduffel, W Tootell, RBH Schoups, AA Orban, GA TI The organization of orientation selectivity throughout macaque visual cortex SO CEREBRAL CORTEX LA English DT Article ID MONKEY STRIATE CORTEX; RECEPTIVE-FIELD PROPERTIES; AREA MT; FUNCTIONAL-ANATOMY; CORTICAL CONNECTIONS; EXTRASTRIATE CORTEX; METABOLIC-ACTIVITY; SPATIAL-FREQUENCY; OCULAR-DOMINANCE; NEURONS AB A double-label deoxyglucose technique was used to study orientation columns throughout visual cortex in awake behaving macaques. Four macaques were trained to fixate while contrast-reversing, stationary gratings or one-dimensional noise of a single orientation or an orthogonal orientation were presented, during uptake of [C-14]deoxyglucose ([C-14]DG) or [H-3]DG, respectively. The two orthogonal stimulus orientations produced DG-labeled columns that were maximally separated in the two isotope maps (Interdigitated) in four areas: V1, V2, V3 and VP The topographic change from interdigitated to overlapping columns occurred abruptly rather than gradually, at corresponding cortical area borders (e.g. VP and V4v, respectively). In addition, the data suggest that orientation column topography systematically changes with retinotopic eccentricity. In V1, the orientation columns systematically avoided the cytochrome oxidase blobs in the parafoveal representation, but converged closer to the blobs in the foveal representation. A control experiment indicated that this was unlikely to reflect eccentricity-dependent differences in cortical spatial frequency sensitivity. A similar eccentricity-dependent change in the topography of orientation columns occurred in V2. In parafoveal but not foveal visual field representations of V2, the orientation columns were centered on the thick cytochrome oxidase stripes, extended into the adjacent interstripe region, but were virtually absent in the thin stripes. C1 Katholieke Univ Leuven, Fac Geneeskunde, Neuro & Psychofysiol Lab, B-3000 Louvain, Belgium. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Boston, MA 02129 USA. RP Vanduffel, W (reprint author), Katholieke Univ Leuven, Fac Geneeskunde, Neuro & Psychofysiol Lab, Campus Gasthuisberg,Herestr 49, B-3000 Louvain, Belgium. NR 69 TC 79 Z9 79 U1 0 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JUN PY 2002 VL 12 IS 6 BP 647 EP 662 DI 10.1093/cercor/12.6.647 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 553BK UT WOS:000175655500009 PM 12003864 ER PT J AU Littner, M AF Littner, M TI Obstructive sleep apnea - Asleep in our consciousness no more SO CHEST LA English DT Editorial Material C1 VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. RP Littner, M (reprint author), Sepulveda VAMC, 16111 Plummer St, Sepulveda, CA 91343 USA. NR 4 TC 3 Z9 4 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUN PY 2002 VL 121 IS 6 BP 1729 EP 1730 DI 10.1378/chest.121.6.1729 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 563TN UT WOS:000176271800001 PM 12065327 ER PT J AU Edmonds, ML Camargo, CA Brenner, BE Rowe, BH AF Edmonds, ML Camargo, CA Brenner, BE Rowe, BH TI Replacement of oral corticosteroids with inhaled corticosteroids in the treatment of acute asthma following emergency department discharge - A meta-analysis SO CHEST LA English DT Article; Proceedings Paper CT Annual Meeting of the Canadian-Association-of-Emergency-Physicians CY JUN, 2000 CL ST JOHN, CANADA SP Canadian Assoc Emergency Physicians DE asthma; corticosteroids; emergency department; inhaled corticosteroids; prevention; relapse ID FLUTICASONE PROPIONATE; ACUTE EXACERBATIONS; CLINICAL-TRIALS; PEAK FLOW; THERAPY; PREDNISOLONE; PUBLICATION; BUDESONIDE; CHILDREN; ADULTS AB Objectives: Oral corticosteroids (CS) are standard treatment for patients discharged from the emergency department (ED) after treatment for acute asthma. Several recent, relatively small trials have investigated the replacement of CS with inhaled corticosteroids (ICS), with varied results and conclusions. This systematic review examined the effect of using ICS in place of CS on outcomes in this setting. Methods: Only randomized controlled trials were eligible for inclusion. Studies in which patients were treated for acute asthma in the ED or its equivalent, and on discharge compared ICS therapy to standard CS therapy, were eligible for inclusion. Trials were identified using the Coehrane Airways Review Group register, searching abstracts and bibliographies, and contacting primary authors and pharmaceutical companies. Data were extracted and methodologic quality assessed independently by two reviewers, and missing data were obtained from authors. Results: Seven trials, involving a total of 1,204 patients, compared high-dose ICS therapy vs CS therapy after ED discharge. There were no significant differences demonstrated between the treatments for relapse rates (odds ratio, 1.00; 95% confidence interval, 0.66 to 1.52) or in the secondary outcomes of beta-agonist use, symptoms, or adverse events. However, the sample size was not adequate to prove equivalence between the treatments, and severe asthmatics were excluded from these trials. Conclusions: There is some evidence that high-dose ICS therapy alone may be as effective as CS therapy when used in mild asthmatics on ED discharge; however, there is a significant possibility of a type II error in drawing this conclusion. C1 Univ Alberta, Walter Mackenzie Ctr, Fac Med & Dent, Div Emergency Med, Edmonton, AB T6G 2B7, Canada. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Arkansas, Dept Emergency Med, Little Rock, AR 72204 USA. RP Rowe, BH (reprint author), Univ Alberta, Walter Mackenzie Ctr, Fac Med & Dent, Div Emergency Med, 1G1-63,9440 112th St, Edmonton, AB T6G 2B7, Canada. FU NHLBI NIH HHS [HL-03533] NR 32 TC 29 Z9 29 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUN PY 2002 VL 121 IS 6 BP 1798 EP 1805 DI 10.1378/chest.121.6.1798 PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 563TN UT WOS:000176271800015 PM 12065341 ER PT J AU Hoo, GWS Park, L AF Hoo, GWS Park, L TI Variations in the measurement of weaning parameters - A survey of respiratory therapists SO CHEST LA English DT Article DE mechanical ventilation; respiratory; therapists; weaning parameters ID MECHANICALLY VENTILATED PATIENTS; OBSTRUCTIVE PULMONARY-DISEASE; MAXIMAL INSPIRATORY PRESSURE; SUPPORT VENTILATION; OCCLUSION PRESSURE; ENDOTRACHEAL-TUBE; BREATHING INDEX; VOLUME RATIO; WORK; AIRWAY AB Objectives: Respiratory therapists differ in the methods used to obtain weaning parameters. A questionnaire survey was conducted to better characterize those differences. Design: A questionnaire survey was conducted among respiratory therapists from nine hospitals in the Los Angeles area. The four-page, 32-question instrument was self-administered and anonymous. Responses were tabulated for analysis. Setting: Respondents from nine hospitals, three hospitals with residency. training programs and six community hospitals without training programs in the Los Angeles area. Participants: One hundred two respiratory therapists. Results: There was no universally acknowledged group of weaning parameters, although four parameters were named by > 90%. There was wide variation in methods used to obtaining weaning parameters. Almost all (91%) obtained measurements with the patients breathing their current fraction of inspired oxygen, but there was great variability in the ventilator mode used to collect these parameters (T-tube, continuous positive airway pressure, pressure support), with an equally wide range of pressures added to each mode (0 to 10 cm H2O). There was great variation in the time (< 1 to > 15 min) before recording weaning parameters. Measurement of parameters was done either with bedside instruments or read from the ventilator display. The maximal inspiratory pressure had great variation in the duration of airway occlusion (< 1 to 20 s), with the most frequent time frame being 2 to 4 s. Differences were noted between therapists from the same hospital as well as between hospitals. Conclusions: There is great variation among respiratory therapists when obtaining weaning parameters. This calls for further standardization of the measurement of weaning parameters. C1 W Los Angeles VAMC, Pulm & Crit Care Sect, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Sch Med, Los Angeles, CA 90024 USA. RP Hoo, GWS (reprint author), W Los Angeles VAMC, Pulm & Crit Care Sect, 11301 Wilshire Blvd,111Q, Los Angeles, CA 90073 USA. NR 32 TC 15 Z9 17 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD JUN PY 2002 VL 121 IS 6 BP 1947 EP 1955 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 563TN UT WOS:000176271800036 ER PT J AU Bernal, RM Sharma, S Gardner, BK Douglas, JT Bergelson, JM Dubinett, SM Batra, RK AF Bernal, RM Sharma, S Gardner, BK Douglas, JT Bergelson, JM Dubinett, SM Batra, RK TI Soluble coxsackievirus adenovirus receptor is a putative inhibitor of adenoviral gene transfer in the tumor milieu SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; EPITHELIAL-CELLS; APICAL SURFACE; TYPE-5 FIBER; PROTEIN; INFECTION; INTEGRIN; VECTORS; IDENTIFICATION; SPECIFICITIES AB Purpose: Several barriers that collectively restrict gene delivery by viral vectors in vivo have been described. Previously, we identified soluble chondroitin sulfate-proteoglycans/glycosaminoglycans in malignant pleural effusions (MPEs) as inhibitors of retroviral vector transduction. Soluble components of MPE also inhibited adentiviral (Ad) gene transfer, and the factors were characteristically filterable, titrable, stable at 56degreesC, and blocked the binding of Ad to target cells. Depleting immunoglobulin from MPE, partially reversed the block to Ad transduction, instigating a search for additional factors that bound Ad in MPE. Experimental design: Vector-protein interactions were identified after the resolution of MPE-components by SDS-PAGE. Viral overlays and immunoblots delineated significant interactions, and the potential relevance of those interactions was tested in transduction efficiency bioassays. Results: Immunoglobulin is the predominant factor inhibiting Ad gene transfer in MPE. Albumin also interacted with Ad, although at predicted serum concentrations, it did not effect Ad transduction efficiency in vitro. Soluble cox-sackievirus-Ad receptor (sCAR) was then identified in MPE. In a survey of 18 MPE, the mean concentration of sCAR was variable and estimated to be 3.51 +/- 5.02 ng/ml by ELISA. The impact of sCAR on transduction efficiency in this milieu was next assessed. Whereas immunodepletion of sCAR from MPE by affinity chromatography resulted in enhanced gene transfer within MPE, the inhibition of adenoviral gene transfer was not evident when the predicted concentrations of recombinant sCAR were added into the transduction medium. Conclusions: These studies indicate that, in addition to anti-Ad antibodies, other specific and nonspecific factors interact with viral vectors and may impair gene transfer in the tumor milieu. The presence of sCAR in MPE puts forward the notion that in certain contexts (e.g., within the extracellular matrix of solid tumors) the concentrations of secreted (or shed) CAR may be high enough to effectively compete with Ad gene delivery. C1 Univ Calif Los Angeles, Sch Med, Div Pulm & Crit Care Med, Vet Adm Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90073 USA. Univ Alabama, Div Human Gene Therapy, Dept Med, Birmingham, AL 35222 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35222 USA. Univ Alabama, Dept Surg, Birmingham, AL 35222 USA. Univ Alabama, Gene Therapy Ctr, Birmingham, AL 35222 USA. Childrens Hosp Philadelphia, Div Infect Dis & Immunol, Philadelphia, PA 19104 USA. Univ Calif Los Angeles, Wadsworth Pulm Immunol & Gene Med Lab, Los Angeles, CA 90073 USA. RP Batra, RK (reprint author), Univ Calif Los Angeles, Sch Med, Div Pulm & Crit Care Med, Vet Adm Greater Los Angeles Hlth Care Syst, 111Q,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NCI NIH HHS [R01 CA 78654, R01 CA078654-02]; NHLBI NIH HHS [HL 54734]; PHS HHS [1P50 90388] NR 52 TC 23 Z9 23 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUN PY 2002 VL 8 IS 6 BP 1915 EP 1923 PG 9 WC Oncology SC Oncology GA 561LJ UT WOS:000176141900033 PM 12060636 ER PT J AU Chun, KY Lewandrowski, K McWhorter, B Ng, K Lewandrowski, EL AF Chun, KY Lewandrowski, K McWhorter, B Ng, K Lewandrowski, EL TI Performance evaluation of the Roche URISYS 2400 (R): A fully automated urine test strip analyzer. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Roche Diagnost Corp, Indianapolis, IN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA D85 BP A139 EP A139 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000449 ER PT J AU Khoury, RH Sluss, PM VanKrieken, L Abdulmasih, B AF Khoury, RH Sluss, PM VanKrieken, L Abdulmasih, B TI Biochemical markers measured in Syrian population for phenotyping PCOS. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Endocrine Reference Lab, Eaton, PA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Diagnost Prod Corp, Los Angeles, CA USA. MOassa Univ Hosp, Damascus, Syria. RI van Krieken, Joannes/D-4138-2009 OI van Krieken, Joannes/0000-0001-6544-1040 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA D76 BP A135 EP A136 PN 2 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000440 ER PT J AU Khoury, RH VanKrieken, L Abdulmasih, Y Sluss, PM AF Khoury, RH VanKrieken, L Abdulmasih, Y Sluss, PM TI Evaluation of the Immulite analyzer for the measurement of urinary LH and FSH. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Endocrine Reference Lab, Easton, PA USA. Diagnost Prod Corp, Los Angeles, CA USA. Totown Pediat, Totowa, NJ USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI van Krieken, Joannes/D-4138-2009 OI van Krieken, Joannes/0000-0001-6544-1040 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA D75 BP A135 EP A135 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000439 ER PT J AU Sluss, P Moy, J AF Sluss, P Moy, J TI Performance and reference range evaluation of the Abbott AxSYM assays for estradiol, LH, and FSH in men and women. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD JUN PY 2002 VL 48 IS 6 SU S MA D44 BP A126 EP A126 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 559QZ UT WOS:000176038000408 ER PT J AU Baecher-Allan, C Freeman, G Hafler, D AF Baecher-Allan, C Freeman, G Hafler, D TI Dissecting the mechanism of action of human CD4+CD25+high regulatory T cells. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Lab Mol Immunol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 208 BP S69 EP S69 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600209 ER PT J AU Baecher-Allan, C Freeman, G Hafler, D AF Baecher-Allan, C Freeman, G Hafler, D TI Dissecting the mechanism of action of human CD4+CD25+high regulatory T cells. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Lab Mol Immunol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 172 BP S57 EP S57 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600173 ER PT J AU Das, S Dasgupta, JD Husain, Z Alper, C Dubey, D AF Das, S Dasgupta, JD Husain, Z Alper, C Dubey, D TI An in vitro model to analyze CD8+T cell memory development in humans. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. InvenioTech Inc, Southborough, MA 01772 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 157 BP S51 EP S52 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600158 ER PT J AU Karni, A Abraham, M Cai, GF Freeman, G Hafler, D Khoury, S Weiner, H AF Karni, A Abraham, M Cai, GF Freeman, G Hafler, D Khoury, S Weiner, H TI Dendritic cells are activated in secondary progressive multiple sclerosis. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 360 BP S118 EP S119 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600359 ER PT J AU Kraynov, VS Broyles, DL Hill, TM Lofaro, LR Chang, JCC Kalams, SA Kuus-Reichel, K Kumar, A AF Kraynov, VS Broyles, DL Hill, TM Lofaro, LR Chang, JCC Kalams, SA Kuus-Reichel, K Kumar, A TI Improved method of antigen-specific T cell enumeration: Mutated MHC class I tetramers show reduced CD8 binding and retain efficient detection of antigen-specific T cell. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Beckman Coulter Inc, Immuno Operat, San Diego, CA 92121 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 395 BP S130 EP S130 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600394 ER PT J AU Kurtz, J Lie, A Griffith, M Turka, L Sykes, M AF Kurtz, J Lie, A Griffith, M Turka, L Sykes, M TI Requirement for passive cell death, but not activation-induced cell death (AICD), for the establishment of CD4 T cell tolerance via-bone marrow transplantation with anti-CD40L. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, TBRC, BMT Sect, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Univ Penn, Philadelphia, PA 19104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 130 BP S43 EP S43 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600131 ER PT J AU Kurtz, J Shaffer, J Anasova, N Benichou, G Sykes, M AF Kurtz, J Shaffer, J Anasova, N Benichou, G Sykes, M TI Lack of evidence for regulatory mechanisms or infectious tolerance in donor-specific CD4 T cell tolerance in mixed hematopoietic chimeras prepared with anti-CD40L. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, TBRC, BMT Sect, Boston, MA 02114 USA. Harvard Univ, Sch Med, Schepens Eye Res Inst, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 127 BP S41 EP S42 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600128 ER PT J AU Levinson, RD Park, MS Rikkers, SM Reed, EF Smith, JR Martin, TM Rosenbaum, JT Foster, CS Sherman, MD Holland, GN AF Levinson, RD Park, MS Rikkers, SM Reed, EF Smith, JR Martin, TM Rosenbaum, JT Foster, CS Sherman, MD Holland, GN TI Association of HLA-DQ and HLA-DR Alleles with the tubulointerstitial nephritis and uveitis syndrome. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Oregon Hlth Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. Univ Calif Los Angeles, Dept Pathol, Immunogenet Ctr, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Jules Stein Eye Inst, Inflammatory Dis Ctr, Los Angeles, CA 90024 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 415 BP S136 EP S136 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600414 ER PT J AU Nikolic, B Leykin, I Smith, RN Sykes, M AF Nikolic, B Leykin, I Smith, RN Sykes, M TI Mixed bone marrow chimerism induced with a non-myeloablative conditioning regimen leads to tolerance of recipient T cells to donor islet grafts and cure of autoimmune diabetes. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 249 BP S81 EP S82 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600250 ER PT J AU O'Connor, KC Chitnis, T Bar-Or, A Griffin, D Piyasirisilp, S Khoury, S Wucherpfennig, K Hafler, D AF O'Connor, KC Chitnis, T Bar-Or, A Griffin, D Piyasirisilp, S Khoury, S Wucherpfennig, K Hafler, D TI Myelin reactive autoantibodies in multiple sclerosis (MS); immunochemical characterization reveals autoantibodies capable of recognizing MBP and MOG in solution are absent in MS serum and CSF. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Johns Hopkins Univ, Baltimore, MD USA. McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Lab Mol Immunol, Boston, MA USA. RI Bar-Or, Amit/C-4213-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 405 BP S133 EP S133 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600404 ER PT J AU Razzaque, MS Foster, CS Ahmed, AR AF Razzaque, MS Foster, CS Ahmed, AR TI Role of conjunctival fibroblast-secreted m-CSF in the pathogenesis of ocular cicatricial pemphigoid. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Dent Med, Dept Oral Med & Diagnost Sci, Boston, MA 02115 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Immunol & Uveitis Serv, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 21 BP S7 EP S8 PN 2 PG 2 WC Immunology SC Immunology GA 566QK UT WOS:000176439600022 ER PT J AU Reddy, J Bettelli, E Nicholson, L Waldner, H Wucherpfennig, K Kuchroo, V AF Reddy, J Bettelli, E Nicholson, L Waldner, H Wucherpfennig, K Kuchroo, V TI Enumeration of proteolipid protein 139-151-reactive T cells using MHC II (I-As) tetramers in marine experimental autoimmune encephatomyelitis. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RI Reddy, Jay/K-7200-2014 OI Reddy, Jay/0000-0003-4082-9254 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 202 BP S67 EP S67 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600203 ER PT J AU Ryu, S Kodama, S Ryu, K Schoenfeld, D Faustman, D AF Ryu, S Kodama, S Ryu, K Schoenfeld, D Faustman, D TI Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Fukuoka Univ, Fukuoka 81401, Japan. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 261 BP S85 EP S85 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600262 ER PT J AU Uko, GP Dorney, K Larson, CE Cleary, M Alper, CA AF Uko, GP Dorney, K Larson, CE Cleary, M Alper, CA TI Monozygotic twins show concordant antibody titer and lymphoproliferative responses in vitro but discrepant TCRBV utilization to hepatitis B vaccine. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 159 BP S52 EP S52 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600160 ER PT J AU Xue, L Chu, F Cheng, Y Sun, X Borthakur, A Ramarao, M Pandey, P Wu, M Schlossman, SF Prasad, KVS AF Xue, L Chu, F Cheng, Y Sun, X Borthakur, A Ramarao, M Pandey, P Wu, M Schlossman, SF Prasad, KVS TI Siva-1 binds to and inhibits BCL-X-L mediated protection against UV radiation induced apoptosis. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Illinois, Chicago, IL 60612 USA. Baylor Coll Med, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 48 BP S16 EP S16 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600049 ER PT J AU Zhang, M Gadjeva, M Moore, F Carroll, M AF Zhang, M Gadjeva, M Moore, F Carroll, M TI Natural antibody in endotoxin shock. SO CLINICAL IMMUNOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Ctr Blood Res, Cambridge, MA 02138 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUN PY 2002 VL 103 IS 3 SU S MA 228 BP S75 EP S75 PN 2 PG 1 WC Immunology SC Immunology GA 566QK UT WOS:000176439600229 ER PT J AU Nucci, M Akiti, T Barreiros, G Silveira, F Revankar, SG Wickes, BL Sutton, DA Patterson, TF AF Nucci, M Akiti, T Barreiros, G Silveira, F Revankar, SG Wickes, BL Sutton, DA Patterson, TF TI Nosocomial outbreak of Exophiala jeanselmei fungemia associated with contamination of hospital water SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID BLOOD-STREAM INFECTIONS; INTENSIVE-CARE UNIT; INVASIVE ASPERGILLOSIS; FUNGI; DISEASE AB From December 1996 through September 1997, we diagnosed 19 cases of fungemia due to Exophiala jeanselmei. We conducted a matched case-control study in which we cultured specimens of blood products, intravenous solutions, and water from a hospital water system. Isolates from environmental cultures were compared to those recovered from patients by random amplification of polymorphic DNA (RAPD). Multivariate analysis showed that neutropenia, longer duration of hospitalization, and use of corticosteroids were risk factors for infection. Environmental cultures yielded E. jeanselmei from 3 of 85 sources: deionized water from the hospital pharmacy, 1 water tank, and water from a sink in a non-patient care area. Use of deionized pharmacy water to prepare antiseptic solutions was discontinued, and no additional cases of infection occurred. RAPD typing showed that isolates from case patients and isolates from the pharmacy water were highly related, whereas the patterns of isolates recovered from the 2 other sources of water were distinct. C1 Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Mycol Lab, BR-21941590 Rio De Janeiro, Brazil. Univ Texas, Hlth Sci Ctr, Dept Microbiol, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. RP Nucci, M (reprint author), Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Mycol Lab, Av Brigadeiro Trompovsky S-N, BR-21941590 Rio De Janeiro, Brazil. RI Nucci, Marcio/G-4515-2012; Silveira, Fernanda/K-4465-2012 OI Nucci, Marcio/0000-0003-4867-0014; NR 20 TC 34 Z9 35 U1 1 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2002 VL 34 IS 11 BP 1475 EP 1480 DI 10.1086/340344 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552LB UT WOS:000175620900008 PM 12015694 ER PT J AU Grimes, RM Otiniano, ME Rodriguez-Barradas, MC Lai, DJ AF Grimes, RM Otiniano, ME Rodriguez-Barradas, MC Lai, DJ TI Clinical experience with human immunodeficiency virus-infected older patients in the era of effective antiretroviral therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID TYPE-1 INFECTION; AIDS; AGE; HIV; SURVIVAL; PROGRESSION AB New therapies for human immunodeficiency virus (HIV)-infected patients suggest the need to examine whether these therapies are as effective in older patients as in younger patients. Fifty-two patients aged greater than or equal to50 years were compared with 52 patients aged <50 years for changes in CD4(+) counts, viral loads, opportunistic disease, hospitalizations, drug side effects, and death. No differences were found, except for higher rates of candidiasis in younger patients. Antiretroviral therapy seems to be equally effective in older and younger patients. C1 Univ Texas, Houston Hlth Sci Ctr, Sch Publ Hlth, Dept Management & Policy Sci, Houston, TX 77225 USA. Univ Texas, Houston Hlth Sci Ctr, Sch Publ Hlth, Dept Biometry, Houston, TX 77225 USA. Houston Vet Adm Med Ctr, HIV Clin, Houston, TX USA. Baylor Coll Med, Dept Med, Houston, TX USA. Univ Texas, Med Branch, Dept Internal Med, Galveston, TX 77550 USA. RP Grimes, RM (reprint author), Univ Texas, Houston Hlth Sci Ctr, Sch Publ Hlth, Dept Management & Policy Sci, RAS 319,POB 20186,1200 Herman Pressler, Houston, TX 77225 USA. NR 15 TC 33 Z9 33 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2002 VL 34 IS 11 BP 1530 EP 1533 DI 10.1086/340404 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552LB UT WOS:000175620900015 PM 12015701 ER PT J AU Barza, M Gorbach, S Bailar, J Fedorka-Cray, PJ McEwen, S O'Brien, TF Summers, AO Swartz, M Vidaver, A Levy, SB Travers, K Young, KT DeVincent, SJ AF Barza, M Gorbach, S Bailar, J Fedorka-Cray, PJ McEwen, S O'Brien, TF Summers, AO Swartz, M Vidaver, A Levy, SB Travers, K Young, KT DeVincent, SJ CA FAAIR Sci Advisory Panel TI Policy recommendations SO CLINICAL INFECTIOUS DISEASES LA English DT Article C1 Alliance Prudent Use Antibiot, Ecol Program, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Carney Hosp, Boston, MA USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. ARS, Antimicrobial Resistance Res Unit, USDA, Richard B Russell Agr Res Ctr, Athens, GA USA. Univ Guelph, Dept Populat Med, Guelph, ON N1G 2W1, Canada. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Georgia, Dept Microbiol, Athens, GA 30602 USA. Massachusetts Gen Hosp, Med Serv, Jackson Firm, Boston, MA USA. Univ Nebraska, Dept Plant Pathol, Lincoln, NE 68583 USA. RP DeVincent, SJ (reprint author), Alliance Prudent Use Antibiot, Ecol Program, 75 Kneeland St, Boston, MA 02111 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2002 VL 34 SU 3 BP S76 EP S77 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552LD UT WOS:000175621100003 ER PT J AU Barza, M Gorbach, S Bailar, J Fedorka-Cray, PJ McEwen, S O'Brien, TF Summers, AO Swartz, M Vidaver, A Levy, SB Travers, K Young, KT DeVincent, SJ AF Barza, M Gorbach, S Bailar, J Fedorka-Cray, PJ McEwen, S O'Brien, TF Summers, AO Swartz, M Vidaver, A Levy, SB Travers, K Young, KT DeVincent, SJ CA FAAIR Sci Advisory Panel TI Select findings and conclusions SO CLINICAL INFECTIOUS DISEASES LA English DT Article C1 Alliance Prudent Use Antibiot, Ecol Program, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Carney Hosp, Boston, MA USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. ARS, Antimicrobial Resistance Res Unit, USDA, Richard B Russell Agr Res Ctr, Athens, GA USA. Univ Guelph, Dept Populat Med, Guelph, ON N1G 2W1, Canada. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Georgia, Dept Microbiol, Athens, GA 30602 USA. Massachusetts Gen Hosp, Med Serv, Jackson Firm, Boston, MA 02114 USA. Univ Nebraska, Dept Plant Pathol, Lincoln, NE 68583 USA. RP DeVincent, SJ (reprint author), Alliance Prudent Use Antibiot, Ecol Program, 75 Kneeland St, Boston, MA 02111 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2002 VL 34 SU 3 BP S73 EP S75 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552LD UT WOS:000175621100002 ER PT J AU Swartz, MN AF Swartz, MN TI Human diseases caused by foodborne pathogens of animal origin SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID VANCOMYCIN-RESISTANT ENTEROCOCCI; UNITED-STATES; FOOD-ANIMALS; ANTIMICROBIAL RESISTANCE; GLYCOPEPTIDE RESISTANCE; SALMONELLA INFECTION; TYPHIMURIUM DT104; ESCHERICHIA-COLI; FAECIUM; SPREAD AB Many lines of evidence link antimicrobial-resistant human infections to foodborne pathogens of animal origin. Types of evidence reviewed include: (1) direct epidemiologic studies; (2) temporal evidence; (3) additional circumstantial evidence; (4) trends in antimicrobial resistance among Salmonella isolates; and (5) trends in antimicrobial resistance among other pathogens, such as Campylobacter jejuni. Commensal microorganisms in animals and humans may contribute to antimicrobial resistance among pathogens that cause disease among humans. For instance, enterococci of food-animal origin, particularly strains that are vancomycin resistant, have been linked to strains found in the human gastrointestinal tract. The latent period between the introduction of a given antimicrobial and emergence of resistance varies considerably, but once the prevalence in a population reaches a certain level, control becomes extremely difficult. C1 Massachusetts Gen Hosp, Med Serv, Boston, MA 02114 USA. RP Swartz, MN (reprint author), Massachusetts Gen Hosp, Med Serv, Bullfinch Room 25,55 Fruit St, Boston, MA 02114 USA. NR 72 TC 71 Z9 73 U1 1 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUN 1 PY 2002 VL 34 SU 3 BP S111 EP S122 DI 10.1086/340248 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 552LD UT WOS:000175621100008 PM 11988881 ER PT J AU Koesch, S Mulder, J AF Koesch, S Mulder, J TI Electric brain responses to inappropriate harmonies during listening to expressive music SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE auditory processing; music; electroencephalogram; early right anterior negativity; right anterior-temporal negativity; P3; N5; late positive component ID MISMATCH NEGATIVITY; EXPECTANCY; CONTEXT; LANGUAGE; CHORDS; REPRESENTATIONS; ORGANIZATION; COMPONENTS; PERCEPTION; FREQUENCY AB Objectives: Recent studies with event-related brain potentials (ERPs) investigating music processing found (early) negativities with right-hemispheric predominance as a response to inappropriate harmonies within sequences of chords. The stimuli used in those studies were fairly artificial in order to control the experimental factors (e.g. variations in tempo and loudness were eliminated). This raises the question of whether these ERPs can also be elicited during listening to more naturalistic stimuli. Methods: Excerpts from classical piano sonatas were taken from commercial CDs and presented to the participants while recording the continuous electroencephalogram. Expected chords and unexpected (transposed) chords were presented at the end of chord-sequences. Results: Unexpected chords elicited a negativity which was maximal around 250 ins, visible over both hemispheres, and preponderant over right temporal leads. Conclusions: The found negativity is strongly reminiscent to both early right anterior negativity and right anterior-temporal negativity, suggesting that cognitive processes underlying these ERP components are not only elicited with fairly artificial experimental stimuli but also when listening to expressive music. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Dept Neurol, BIDMC, Boston, MA 02215 USA. Univ Groningen, Groningen, Netherlands. RP Koesch, S (reprint author), Harvard Univ, Sch Med, Dept Neurol, BIDMC, Dana 779,330 Brookline Ave, Boston, MA 02215 USA. NR 43 TC 41 Z9 41 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD JUN PY 2002 VL 113 IS 6 BP 862 EP 869 AR PII S1388-2457(02)00050-0 DI 10.1016/S1388-2457(02)00050-0 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 567UD UT WOS:000176503000009 PM 12048045 ER PT J AU Tang, P Hornicek, FJ Gebhardt, MC Cates, J Mankin, HJ AF Tang, P Hornicek, FJ Gebhardt, MC Cates, J Mankin, HJ TI Surgical treatment of hemangiomas of soft tissue SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article AB Hemangioma is one of the most common soft tissue tumors comprising 7% of all benign tumors. The etiology is unclear. Many treatment modalities for the symptomatic deep subdermal or intramuscular hemangioma have been used, but surgical excision is the preferred treatment. During the past 20 years, 89 patients with soft tissue hemangiomas were treated by surgical excision at the authors' institution. This study was done to define the clinical characteristics of pathologically proven hemangiomas and to evaluate the outcome of the operative procedures. Intralesional or marginal excision for symptomatic hemangiomas yields satisfactory results for pain relief, functional recovery, and avoidance of recurrence. According to the data a hemangioma of the soft tissues is a benign lesion in which more aggressive surgery (wide or radical excision) or other modalities such as radiation usually are not warranted. C1 Massachusetts Gen Hosp, Orthopaed Serv Gray 604, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA 02115 USA. RP Mankin, HJ (reprint author), Massachusetts Gen Hosp, Orthopaed Serv Gray 604, Boston, MA 02114 USA. OI Cates, Justin/0000-0002-7336-5196 NR 19 TC 24 Z9 25 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD JUN PY 2002 IS 399 BP 205 EP 210 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 578MU UT WOS:000177122400025 PM 12011711 ER PT J AU Blagys, MD Hilsenroth, MJ AF Blagys, MD Hilsenroth, MJ TI Distinctive activities of cognitive-behavioral therapy - A review of the comparative psychotherapy process literature SO CLINICAL PSYCHOLOGY REVIEW LA English DT Article DE cognitive-behavioral; therapist activity; distinctive features ID INTERPERSONAL THERAPY; DEPRESSION; ADHERENCE; SESSIONS; FOCUS; INTERVENTIONS AB The present review examined the comparative psychotherapy process literature in order to identify the distinctive activities of cognitive-behavioral (CB) treatment. Six techniques and interventions were found to distinguish CB from psychodynamic-interpersonal (PI) therapy: (1) use of homework and outside-of-session activities; (2) direction of session activity; (3) teaching of skills used by patients to cope with symptoms; (4) emphasis on patients' future experiences; (5) providing patients with information about their treatment, disorder, or symptoms; and (6) an intrapersonal/cognitive (C) focus. Identifying the distinctive features of CB therapy can improve the measurement of process-outcome correlations by more accurately specifying and operationalizing the treatment-specific processes of CB treatment, help researchers differentiate between common and treatment-specific factors, and aid in development of more psychometrically sound instruments assessing adherence and competence in CB therapy. In addition, this review can improve training of CB therapists by providing a guide for clinical practice. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. Adelphi Univ, Derner Inst Adv Psychol Studies, Garden City, NY 11530 USA. RP Blagys, MD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, 15 Parkman St,WAC 805, Boston, MA 02114 USA. NR 77 TC 100 Z9 101 U1 3 U2 29 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0272-7358 J9 CLIN PSYCHOL REV JI Clin. Psychol. Rev. PD JUN PY 2002 VL 22 IS 5 BP 671 EP 706 AR PII S0272-7358(01)00117-9 DI 10.1016/S0272-7358(01)00117-9 PG 36 WC Psychology, Clinical SC Psychology GA 567TL UT WOS:000176501200003 PM 12113201 ER PT J AU Van Cott, EM Soderberg, BL Laposata, M AF Van Cott, EM Soderberg, BL Laposata, M TI Hypercoagulability test strategies in the protein C and protein S pathway SO CLINICS IN LABORATORY MEDICINE LA English DT Article ID FACTOR-V-LEIDEN; COAGULATION-FACTOR-V; VENOUS THROMBOSIS; RESISTANCE ASSAY; APC RESISTANCE; PLASMA-LEVELS; MUTATION; GENE; DEFICIENCY; RISK AB The protein C/protein S pathway is critical in controlling normal clot formation to provide a balance between thrombosis and hemorrhage. Abnormalities have been described in which the pathway is altered because factor V cannot be degraded by activated protein C, producing activated protein C resistance. It has been shown that protein C or protein S deficiencies can result in impaired inhibition of clot formation resulting in increased risk for thrombosis. This article describes the testing strategies associated with the diagnosis of activated protein C resistance, protein C deficiency, and protein S deficiency. Laboratory testing algorithms also are provided. C1 Massachusetts Gen Hosp, Dept Pathol, Div Lab Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Laposata, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, Div Lab Med, Room 235 Gray Bldg,55 Fruit St, Boston, MA 02114 USA. NR 32 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-2712 J9 CLIN LAB MED JI Clin. Lab. Med. PD JUN PY 2002 VL 22 IS 2 BP 391 EP + AR PII S0272-2712(01)00011-7 DI 10.1016/S0272-2712(01)00011-7 PG 14 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 579TX UT WOS:000177194900004 PM 12134467 ER PT J AU Winkelman, JW Tanasijevic, MJ AF Winkelman, JW Tanasijevic, MJ TI Noninvasive testing in the clinical laboratory SO CLINICS IN LABORATORY MEDICINE LA English DT Article ID PULSE OXIMETRY; MICROCIRCULATION AB Clinical laboratory testing over the recent decades has been characterized by a remarkable increase in the variety and volume of information made available to assist physicians in the practice of medicine. The authors have chosen to provide a brief review of only three of the numerous existing, emerging or future applications of novel technologies that provide noninvasive testing. Among current trends that facilitate prompt delivery of results, noninvasive testing holds great promise. Technologies that already exist or that have not yet been developed may extend the opportunities to exploit this approach. Noninvasive testing has other obvious attractive features; safety, painlessness, and adaptability to special care situations. Our profession may well enjoy additional vitalization from the further evolution of this fascinating and important field. C1 Brigham & Womens Hosp, Clin Labs, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Clin Labs, Boston, MA 02115 USA. RP Winkelman, JW (reprint author), Brigham & Womens Hosp, Clin Labs, 75 Francis St, Boston, MA 02115 USA. NR 13 TC 0 Z9 1 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-2712 J9 CLIN LAB MED JI Clin. Lab. Med. PD JUN PY 2002 VL 22 IS 2 BP 547 EP + AR PII S0272-2712(01)00013-0 DI 10.1016/S0272-2712(01)00013-0 PG 13 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 579TX UT WOS:000177194900014 PM 12134477 ER PT J AU Orsillo, SM Batten, SV AF Orsillo, SM Batten, SV TI ACT as treatment of a disorder of excessive control: Anorexia SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article ID EATING-DISORDERS; NERVOSA; WEIGHT AB Acceptance and Commitment Therapy (ACT) is a conceptually driven approach to treatment that is directed at undermining the experiential avoidance and cognitive fusion that are assumed to produce restrictive and damaging behavioral patterns. ACT has recently been applied to the treatment Of a number of behavioral problems. The current paper explores how an ACT perspective might guide the treatment of disordered eating based on the presentation of an adolescent female. Particularly, methods focused on addressing the treatment-resistant nature of anorexia, working with the complex control issues related to both eating and private events, facilitating the differentiation of the patient's sense of self from her private events and physical being, and assisting the client in refocusing on her valued directions are described. An ACT approach to treating anorexia seems strongly indicated, and further research is needed to assess the efficacy of ACT for this difficult problem. C1 Boston VA Healthcare Syst, Natl Ctr, PTSD Womens Hlth Sci Div 116B3, Boston, MA 02130 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Orsillo, SM (reprint author), Boston VA Healthcare Syst, Natl Ctr, PTSD Womens Hlth Sci Div 116B3, 150 S Huntington Ave, Boston, MA 02130 USA. EM susan.orsillo@med.va.gov NR 19 TC 13 Z9 15 U1 3 U2 12 PU ASSOC ADV BEHAVIOR THERAPY PI NEW YORK PA 305 7TH AVE #16A, NEW YORK, NY 10001-6008 USA SN 1077-7229 J9 COGN BEHAV PRACT JI Cogn. Behav. Pract. PD SUM PY 2002 VL 9 IS 3 BP 253 EP 259 DI 10.1016/S1077-7229(02)80057-8 PG 7 WC Psychology, Clinical SC Psychology GA 918NS UT WOS:000228550400010 ER PT J AU Vlasak, J Vlasakova, K AF Vlasak, J Vlasakova, K TI Records of cerambycidae (Coleoptera) in Massachusetts with notes on larval hosts SO COLEOPTERISTS BULLETIN LA English DT Article AB A summary of Massachusetts's records of Cerambycidae reported in the literature is presented, including our own records of 132 species from years 1999 to 2001. Altogether it represents a total of 198 species, from which 27 species collected during our study are noted from Massachusetts for the first time. Host plants for 106 species are presented, including 60 new host plant records. Host plant and biology of Hesperophanes pubescens (Haldeman) is discussed for the first time. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Vlasak, J (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 55 TC 12 Z9 12 U1 0 U2 2 PU COLEOPTERISTS SOC PI NATCHEZ PA PO BOX 767, NATCHEZ, MS 39121 USA SN 0010-065X J9 COLEOPTS BULL JI Coleopt. Bull. PD JUN PY 2002 VL 56 IS 2 BP 203 EP 219 DI 10.1649/0010-065X(2002)056[0203:ROCCIM]2.0.CO;2 PG 17 WC Entomology SC Entomology GA 570ND UT WOS:000176663600004 ER PT J AU Alston, TA AF Alston, TA TI Pulmonary catheter fear factor SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE confidence; construct validity; face validity; psychometrics; pulmonary artery catheter; questionnaire ID INTRAOPERATIVE TRANSESOPHAGEAL ECHOCARDIOGRAPHY C1 Harvard Univ, Sch Med,Massachusetts Gen Hosp, Cardiac Anesthesia Grp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Alston, TA (reprint author), Harvard Univ, Sch Med,Massachusetts Gen Hosp, Cardiac Anesthesia Grp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. NR 15 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUN PY 2002 VL 30 IS 6 BP 1383 EP 1384 DI 10.1097/00003246-200206000-00044 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 564AN UT WOS:000176291600034 PM 12072699 ER PT J AU Bigatello, LM George, E Hurford, WE AF Bigatello, LM George, E Hurford, WE TI The alveolus and the capillary SO CRITICAL CARE MEDICINE LA English DT Editorial Material ID RESPIRATORY-DISTRESS-SYNDROME; INHALED NITRIC-OXIDE; PULMONARY VASOCONSTRICTION; GAS-EXCHANGE; BLOOD-FLOW; DISTRIBUTIONS; ALMITRINE C1 Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Bigatello, LM (reprint author), Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, Massachusetts Gen Hosp, Boston, MA 02115 USA. RI Hurford, William/G-6386-2013 OI Hurford, William/0000-0003-1201-0313 NR 11 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUN PY 2002 VL 30 IS 6 BP 1394 EP 1395 DI 10.1097/00003246-200206000-00052 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 564AN UT WOS:000176291600042 PM 12072707 ER PT J AU Pisegna, JR AF Pisegna, JR TI Pharmacology of acid suppression in the hospital setting: Focus on proton pump inhibition SO CRITICAL CARE MEDICINE LA English DT Article DE gastric acid secretion; acid suppression; drugs; mechanism of action; severe Intravenous; nasogastric; proton pump inhibitors; histamine-2-receptor antagonists; severe gastroesophageal reflux disease; Zollinger-Ellison syndrome ID GASTROESOPHAGEAL REFLUX DISEASE; ZOLLINGER-ELLISON-SYNDROME; CALCIUM-SENSING RECEPTOR; CRITICALLY ILL PATIENTS; INTRAGASTRIC ACIDITY; I RECEPTOR; OMEPRAZOLE; SECRETION; LANSOPRAZOLE; PANTOPRAZOLE AB The more potent and longer-lasting inhibition of gastric acid secretion provided by proton pump inhibitors (PPIs) as compared with histamine-2-receptor antagonists is caused In large part by differences in their mechanism of action. PPIs block histamine-2-, gastrin-, and cholinergic-mediated sources of acid production and inhibit gastric secretion at the final common pathway of the H+/K+ adenosine triphosphatase proton pump. In contrast, histamine-2-receptor antagonists cannot block receptor sites other than those mediated by histamine. It seems that the rapid loss of acid suppression activity by the histamine-2-receptor antagonists may be attributed to tolerance. Such tolerance has not occurred in patients receiving PPIs because these agents are irreversible inhibitors of the H+/K+ adenosine triphosphatase proton pump. For these reasons, patients who have acid-related disorders that require high levels of acid suppression do not respond well to intravenous histamine-2-receptor antagonists and would be excellent candidates for intravenous PPI therapy. Candidates for Intravenous PPIs also include patients who cannot receive oral PPIs and those who may need the higher acid suppression therapy provided by the Intravenous rather than the oral route. Clinical studies have demonstrated the efficacy of Intravenous pantoprazole In maintaining adequate control of gastric acid output during the switch from oral to Intravenous therapy In patients with severe gastroesophageal rerflux disease or the Zollinger-Ellison syndrome. Intragastric administration of solutions prepared from oral PPIs has been used as an alternative to the Intravenous route in critical care settings. However, decreased bioavailability may limit the value of Intragastric delivery of PPIs because of the high frequency of gastric emptying problems In critically ill patients. C1 Greater Los Angeles Vet Adm, Los Angeles, CA USA. RP Pisegna, JR (reprint author), Greater Los Angeles Vet Adm Healthcare Syst, Div Gastroenterol & Hepatol, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 47 TC 21 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD JUN PY 2002 VL 30 IS 6 SU S BP S356 EP S361 DI 10.1097/00003246-200206001-00003 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 566AM UT WOS:000176403600003 PM 12072661 ER PT J AU Mujagic, H Chabner, BA Mujagic, Z AF Mujagic, H Chabner, BA Mujagic, Z TI Mechanisms of action and potential therapeutic uses of thalidomide SO CROATIAN MEDICAL JOURNAL LA English DT Review DE angiogenesis inhibitors; myelodysplastic syndromes; multiple myeloma; pharmacokinetics; neoplasms; thalidomide ID NECROSIS-FACTOR-ALPHA; VERSUS-HOST DISEASE; ENDOTHELIAL GROWTH-FACTOR; REFRACTORY MULTIPLE-MYELOMA; BONE-MARROW TRANSPLANTATION; HIV-INFECTED PATIENTS; TUMOR ANGIOGENESIS; PHASE-II; MYELODYSPLASTIC SYNDROMES; BREAST-CARCINOMA AB Thalidomide was first introduced to the market in Germany under the brand name of Contergan in 1956, as a "non-barbiturate hypnotic", advocated to ensure a good night's sleep and to prevent morning sickness in pregnancy. It was advertised for its prompt action, lack of hangover, and apparent safety. It has been banned from the market si lice 1963 after it caused the worldwide teratogenic disaster: babies exposed to thalidomide in Utero during the first 34-50 days of pregnancy were born with severe life-threatening birth defects. Despite its unfortunate history, thalidomide has attracted scientific interest again because of its recently discovered action against inflammatory diseases and cancer. Its broad range of biological activities stems from its ability to moderate cytokine action in, cancer and inflammatory diseases. Early studies examined its anxiolytic, mild hypnotic, antiemetic, and adjuvant analgesic properties. subsequently, thalidomide was found to be highly effective in managing the cutaneous manifestations of leprosy, being superior to Aspirin in controlling leprosy-associated fever. Recent research has shown promising results with thalidomide in patients with myeloma, myelodysplastic syndrome, a variety of infectious diseases, autoimmune diseases, cancer, and progressive body weight loss related to advanced cancer and AIDS. Here we review the history of its development, pharmacokinetics, metabolism, biologic effects, and the results of clinical trials conducted thus far. Further research in this field should be directed towards better understanding of thalidomide metabolism, its mechanism of action, and the development of less toxic and more active analogs. C1 Tuzla Univ, Sch Med, Dept Oncol, Tuzla 75000, Bosnia & Herceg. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. Tuzla Univ, Sch Med, Dept Biochem, Tuzla, Bosnia & Herceg. RP Mujagic, H (reprint author), Tuzla Univ, Sch Med, Dept Oncol, Univerzitetska 1, Tuzla 75000, Bosnia & Herceg. NR 107 TC 15 Z9 16 U1 2 U2 7 PU MEDICINSKA NAKLADA PI ZAGREB PA VLASKA 69, HR-10000 ZAGREB, CROATIA SN 0353-9504 J9 CROAT MED J JI Croat. Med. J. PD JUN PY 2002 VL 43 IS 3 BP 274 EP 285 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 564PK UT WOS:000176322600004 PM 12035132 ER PT J AU Erdag, G Eroglu, A Morgan, JR Toner, M AF Erdag, G Eroglu, A Morgan, JR Toner, M TI Cryopreservation of fetal skin is improved by extracellular trehalose SO CRYOBIOLOGY LA English DT Article DE trehalose; fetus; skin; cryopreservation; transplantation ID MOUSE; TRANSPLANTATION; CRYOPROTECTANTS; STABILIZATION; VIABILITY; STORAGE; CELLS AB In this study, we tested a non-permeating cryoprotectant, trehalose, in combination with dimethyl sulfoxide (Me2SO) in the cryopreservation of human fetal skin and compared it to Me2SO and glycerol, protocols that are routinely used by skin banks. The viability of fetal skin from four groups (fresh, and cryopreserved with glycerol, Me2SO, or trehalose/Me2SO) were evaluated using an in vitro membrane integrity assay and by transplantation to immunodeficient mice. The membrane integrity assay showed a 90% integrity in fresh, unfrozen fetal skin. The number of intact cells dropped to 23 and 44% in fetal skin cryopreserved with glycerol and Me2SO, respectively. When trehalose was added to the cryopreservation medium containing Me2SO, the membrane integrity rose to 65%. When transplanted to immunodeficient mice, fetal skin cryopreserved with trehalose/Me2SO showed a graft performance indistinguishable from fresh unfrozen fetal skin and strikingly better graft take than that of fetal skin cryopreserved with Me2SO or glycerol only. These results suggest that cryopreservation protocols routinely used the skin banks can be improved by combining sugars such as trehalose with a permeating cryoprotectant. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Shriners Burns Hosp, Boston, MA 02114 USA. RP Toner, M (reprint author), Massachusetts Gen Hosp, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. OI Morgan, Jeffrey/0000-0002-7546-3443 NR 37 TC 47 Z9 52 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0011-2240 J9 CRYOBIOLOGY JI Cryobiology PD JUN PY 2002 VL 44 IS 3 BP 218 EP 228 AR PII S0011-2240(02)00023-8 DI 10.1016/S0011-2240(02)00023-8 PG 11 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA 601YG UT WOS:000178476400004 PM 12237087 ER PT J AU Chen, T Bhowmick, S Sputtek, A Fowler, A Toner, M AF Chen, T Bhowmick, S Sputtek, A Fowler, A Toner, M TI The glass transition temperature of mixtures of trehalose and hydroxyethyl starch SO CRYOBIOLOGY LA English DT Article DE trehalose; HES; hydroxyethyl starch; water; binary mixture; supplemented phase diagram; glass transition; anhydrobiosis; freeze-drying; cryoprotectant; lyophilization; DSC ID RED-BLOOD-CELLS; VITRIFICATION AB Although mixtures of HES and sugars are used to preserve cells during freezing or drying, little is known about the glass transition of HES, or how mixtures of HES and sugars vitrify. These difficulties may be due to the polydispersity between HES samples or differences in preparation techniques, as well as problems in measuring the glass transition temperature (T-g) using differential scanning calorimetry (DSC). In this report, we examine the T-g of mixtures of HES and trehalose sugar with <1% moisture content using DSC measurements. By extrapolating these measurements to pure HES using the Gordon-Taylor and Fox equations, we were able to estimate the T-g of our HES sample at 44degreesC. These results were additionally confirmed by using mixtures of glucose-HES which yielded a similar extrapolated T-g value. Our approach to estimating the glass transition temperature of HES may be useful in other cases where glass transitions are not easily identified. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. Shriners Hosp Children, Boston, MA 02114 USA. Univ Hamburg, Klinikum Eppendorf, Abt F Transfusionsmed, Hamburg, Germany. Univ Massachusetts, Dept Mech Engn, Dartmouth, MA 02747 USA. RP Toner, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Engn Med & Surg Serv, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK46270] NR 17 TC 20 Z9 22 U1 1 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0011-2240 J9 CRYOBIOLOGY JI Cryobiology PD JUN PY 2002 VL 44 IS 3 BP 301 EP 306 AR PII S0011-2240(02)00025-1 DI 10.1016/S0011-2240(02)00025-1 PG 6 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA 601YG UT WOS:000178476400012 PM 12237095 ER PT J AU Hinton, D Nathan, M Bird, B Park, L AF Hinton, D Nathan, M Bird, B Park, L TI Panic probes and the identification of panic: A historical and cross-cultural perspective SO CULTURE MEDICINE AND PSYCHIATRY LA English DT Article DE agoraphobia; Cambodian; cross-cultural; panic attack; panic disorder ID ATTACKS; DISORDER; REFUGEES; CUES AB This article reviews the historical development of the category of panic disorder in the United States, particularly the shifting perspectives on both what causes panic and how the presence of panic should be determined. The notion that panic attacks of a panic-disorder type must be "out of the blue'' and "unexpected,'' except in the case of triggering by a particular place (i.e., agoraphobia), is critiqued. The authors illustrate that a meaningful epidemiological determination of panic rates in other cultural groups must be preceded by a detailed ethnography that ascertains the catastrophic cognitions, core symptoms, and typical cues of panic attacks in that particular context. C1 Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. RP Hinton, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. NR 41 TC 4 Z9 4 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-005X J9 CULT MED PSYCHIAT JI Cult. Med. Psychiatr. PD JUN PY 2002 VL 26 IS 2 BP 137 EP 153 DI 10.1023/A:1016359531483 PG 17 WC Anthropology; Psychiatry; Social Sciences, Biomedical SC Anthropology; Psychiatry; Biomedical Social Sciences GA 574BK UT WOS:000176868400002 PM 12211322 ER PT J AU Hinton, D Hinton, S AF Hinton, D Hinton, S TI Panic disorder, somatization, and the new cross-cultural psychiatry: The seven bodies of a medical anthropology of panic SO CULTURE MEDICINE AND PSYCHIATRY LA English DT Article DE Cambodian refugees; cross-cultural psychiatry; dizziness; panic disorder; Vietnamese refugees ID REFUGEES; CONSTRUCTION; PREVALENCE; SYMPTOMS; SUBTYPES; ATTACKS; NERVIOS AB This article aims to adduce a framework that will allow for the cross-cultural study of panic disorder. The authors take sensation as the key unit of analysis, aiming to contribute to a medical anthropology of sensation. The seven analytic perspectives that are suggested in the article are the following: the full spectrum of panic attack sensations (the sensation body), the biological generation of panic sensations (the biological body), sensation as invoking an ethnophysiology (the ethnophysiological body), sensation as metaphor (the metaphoric body), sensation as invoking the landscape (the landscape body), sensation as invoking catastrophic cognitions (the catastrophic cognitions body), and sensation as invoking memory (the memory-associational body). C1 Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. RP Hinton, D (reprint author), Harvard Univ, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02115 USA. NR 76 TC 27 Z9 27 U1 2 U2 9 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-005X J9 CULT MED PSYCHIAT JI Cult. Med. Psychiatr. PD JUN PY 2002 VL 26 IS 2 BP 155 EP 178 DI 10.1023/A:1016374801153 PG 24 WC Anthropology; Psychiatry; Social Sciences, Biomedical SC Anthropology; Psychiatry; Biomedical Social Sciences GA 574BK UT WOS:000176868400003 PM 12211323 ER PT J AU Park, L Hinton, D AF Park, L Hinton, D TI Dizziness and panic in China: Associated sensations of zang fu organ disequilibrium SO CULTURE MEDICINE AND PSYCHIATRY LA English DT Article DE China; dizziness; general anxiety; panic disorder; somatization ID MENTAL-DISORDERS; CLASSIFICATION AB In China, distress is commonly experienced as dizziness that can develop into acute episodes resembling Western panic attacks. These distressing sensations occur in a unique cultural context with a distinctive set of associated symptoms, beliefs and purported etiologies. The experience of illness is informed by traditional Chinese medicine (TCM), an indigenous theory that elaborates a system of organ functioning called zang fu. Depending on the implicated zang fu organ disequilibrium, dizziness and panic present with a specific constellation of associated physical and mental symptoms. This paper presents a clinical survey of psychiatric disorders that demonstrates dizziness to be characteristic of Chinese anxiety states, most particularly panic. Three specific cases of dizziness-focused panic ascribed to different states of zang fu disequilibrium are described. In a typical pattern, initial dizziness and associated symptoms intensify until they generalize into panic attacks. The degree of dizziness and panic corresponds to the state of disequilibrium of the zang fu organ system as well as instability of the social, interpersonal and environmental context of the patient. This paper elucidates the dynamic interpretants of dizziness in the Chinese context to contribute to a medical anthropology of this sensation. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. RP Park, L (reprint author), Massachusetts Gen Hosp, Dept Psychiat, Warren 6,55 Fruit St, Boston, MA 02114 USA. NR 29 TC 21 Z9 21 U1 0 U2 4 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0165-005X J9 CULT MED PSYCHIAT JI Cult. Med. Psychiatr. PD JUN PY 2002 VL 26 IS 2 BP 225 EP 257 DI 10.1023/A:1016341425842 PG 33 WC Anthropology; Psychiatry; Social Sciences, Biomedical SC Anthropology; Psychiatry; Biomedical Social Sciences GA 574BK UT WOS:000176868400006 PM 12211326 ER PT J AU Slaugenhaupt, SA Gusella, JF AF Slaugenhaupt, SA Gusella, JF TI Familial dysautonomia SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID POLYMERASE-II ELONGATOR; MOUSE IKBKAP GENE; IKAP GENE; COMPLEX; RNA; LOCALIZATION; HOLOENZYME; EXPRESSION; COMPONENT; ISRAEL AB Familial dysautonomia is a developmental disorder of the sensory and autonomic nervous system. Recent studies have shown that two mutations in the gene IKBKAP are responsible for the disease. IKAP, the IKBKAP-encoded protein, is a member of the recently identified human Elongator complex. The major FD mutation is a splice mutation that results in aberrant tissue-specific mRNA splicing. C1 Harvard Univ, Sch Med, Harvard Inst Human Genet, Boston, MA 02115 USA. Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA 02129 USA. RP Slaugenhaupt, SA (reprint author), Harvard Univ, Sch Med, Harvard Inst Human Genet, Boston, MA 02115 USA. EM slaugenh@helix.mgh.harvard.edu; gusella@helix.mgh.harvard.edu FU NINDS NIH HHS [NS39995] NR 23 TC 47 Z9 47 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD JUN PY 2002 VL 12 IS 3 BP 307 EP 311 DI 10.1016/S0959-437X(02)00303-9 PG 5 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 548JB UT WOS:000175383900008 PM 12076674 ER PT J AU Sauvageot, CM Stiles, CD AF Sauvageot, CM Stiles, CD TI Molecular mechanisms controlling cortical gliogenesis SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; BONE MORPHOGENETIC PROTEINS; NEURAL PROGENITOR CELLS; LOOP-HELIX GENES; SUBVENTRICULAR ZONE; SONIC HEDGEHOG; OLIGODENDROCYTE DIFFERENTIATION; NEURONAL DIFFERENTIATION; VENTRICULAR ZONE; CEREBRAL-CORTEX AB The sequential appearance of neurons and glia in the vertebrate central nervous system may be governed by competition between growth factor signaling pathways and downstream transcription factors. In cortical progenitor cell cultures, the proneural basic helix-loop-helix transcription factor Ngn1 suppresses formation of astrocytes by sequestering coactivator proteins that are required by signal transducers and activators of transcription for the expression of astrocyte-specific genes. In the developing neural tube, combinatorial interactions between the proneural transcription factor Ngn2 and the basic helix-loop-helix transcription factor Olig2 specify the formation of motor neurons or oligodendrocytes. C1 Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Sauvageot, CM (reprint author), Harvard Univ, Sch Med, Dept Neurobiol, 220 Longwood Ave, Boston, MA 02115 USA. FU NICHD NIH HHS [HD24296]; PHS HHS [N54051] NR 45 TC 203 Z9 209 U1 5 U2 11 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD JUN PY 2002 VL 12 IS 3 BP 244 EP 249 DI 10.1016/S0959-4388(02)00322-7 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 562CX UT WOS:000176180800002 PM 12049929 ER PT J AU Ginty, DD Segal, RA AF Ginty, DD Segal, RA TI Retrograde neurotrophin signaling: Trk-ing along the axon SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID NERVE GROWTH-FACTOR; SYMPATHETIC NEURONS; INDUCED DIFFERENTIATION; TYROSINE KINASE; TRANSPORT; NGF; SURVIVAL; PATHWAY; RAS; PHOSPHORYLATION AB Target-derived neurotrophins are required for the growth and survival of innervating neurons. When released by postsynaptic targets, neurotrophins bind receptors (Trks) on nerve terminals. Activated Trks signal locally within distal axons and retrogradely through long axons to distant cell bodies in order to promote gene expression and survival. Although the mechanism of retrograde neurotrophin signaling is not fully elucidated, considerable evidence supports a model in which the vesicular transport of neurotrophin-Trk complexes transmits a survival signal that involves PI3K and Erk5. Other, non-vesicular modes of retrograde signaling are likely to function in parallel. Recent studies highlight the importance of the location of stimulation as a determinant of Trk signaling. Defects in signaling from distal axons to cell bodies may be causally related to neurodegenerative disorders. C1 Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Ginty, DD (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. EM dginty@jhmi.edu; rosalind_segal@dfci.harvard.edu FU NINDS NIH HHS [NS34814, NS35148] NR 42 TC 199 Z9 207 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD JUN PY 2002 VL 12 IS 3 BP 268 EP 274 DI 10.1016/S0959-4388(02)00326-4 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 562CX UT WOS:000176180800005 PM 12049932 ER PT J AU Welt, CK AF Welt, CK TI The physiology and pathophysiology of inhibin, activin and follistatin in female reproduction SO CURRENT OPINION IN OBSTETRICS & GYNECOLOGY LA English DT Article ID FOLLICLE-STIMULATING-HORMONE; POLYCYSTIC-OVARY-SYNDROME; RAT GRANULOSA-CELLS; SERUM INHIBIN; MENSTRUAL-CYCLE; BINDING PROTEIN; ALPHA-SUBUNIT; LUTEAL CELLS; DIFFERENTIAL REGULATION; ASSISTED REPRODUCTION AB In the last 2 years, major advances have been made in the understanding of inhibin physiology. Discovery of an inhibin receptor and binding protein has expanded our knowledge of the mechanism whereby inhibin antagonizes activin action. Controlled experimental studies have clarified the regulation and physiology of inhibin A and inhibin B, providing evidence for their use as markers of ovarian function. Clinical studies continue to uphold the use of inhibin as a marker for ovarian cancer, but have not generally supported its use over standard prognostic markers in assisted reproductive technologies. Finally, ongoing work suggests alterations in inhibin and follistatin that may be linked to the pathophysiology of polycystic ovary syndrome. Thus, the mechanism of inhibin action and its role in normal and abnormal ovarian function continues to emerge. C1 Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Sci Ctr, Reprod Endocrine Unit,BHX 511, Boston, MA 02114 USA. RP Welt, CK (reprint author), Massachusetts Gen Hosp, Dept Med, Reprod Endocrine Sci Ctr, Reprod Endocrine Unit,BHX 511, 55 Fruit St, Boston, MA 02114 USA. OI Welt, Corrine/0000-0002-8219-5504 FU NCRR NIH HHS [M01-RR-01066]; NICHD NIH HHS [U54-HD-29164] NR 74 TC 37 Z9 39 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-872X J9 CURR OPIN OBSTET GYN JI Curr. Opin. Obstet. Gynecol. PD JUN PY 2002 VL 14 IS 3 BP 317 EP 323 DI 10.1097/00001703-200206000-00012 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 557FX UT WOS:000175899000012 PM 12032389 ER PT J AU Song, H Lim, H Paria, BC Matsumoto, H Swift, LL Morrow, J Bonventre, JV Dey, SK AF Song, H Lim, H Paria, BC Matsumoto, H Swift, LL Morrow, J Bonventre, JV Dey, SK TI Cytosolic phospholipase A(2)alpha deficiency is crucial for 'on-time' embryo implantation that directs subsequent development SO DEVELOPMENT LA English DT Article DE cPLA(2)alpha; implantation; uterus; embryo; pregnancy ID LEUKEMIA INHIBITORY FACTOR; MOUSE UTERUS; REDUCED FERTILITY; GROWTH-FACTORS; EGF-RECEPTOR; MICE LACKING; MAST-CELLS; A(2); BLASTOCYST; GENE AB Cytosolic phospholipase A(2)alpha. (cPLA(2)alpha) is a major provider of arachidonic acid (AA) for the cyclooxygenase (COX) system for the biosynthesis of prostaglandins (PGs). Female mice with the null mutation for Pla2g4a (cPLA(2)alpha) produce small litters and often exhibit pregnancy failures, although the cause(s) of these defects remains elusive. We show that the initiation of implantation is temporarily deferred in Pla2g4a(-/-) mice, shifting the normal 'window' of implantation and leading to retarded feto-placental development without apparent defects in decidual growth. Furthermore, cPLA(2)alpha deficiency results in aberrant uterine spacing of embryos. The deferred implantation and deranged gestational development in Pla2g4a(-/-) mice were significantly improved by exogenous PG administration. The results provide evidence that cPLA(2)alpha-derived AA is important for PG synthesis required for on-time implantation. This study in Pla2g4a(-/-) mice, together with the results of differential blastocyst transfers in wild-type mice provides the first evidence for a novel concept that a short delay in the initial attachment reaction creates a ripple effect propagating developmental anomalies during the subsequent course of pregnancy. C1 Univ Kansas, Med Ctr, Dept Mol Physiol, Kansas City, KS 66160 USA. Univ Kansas, Med Ctr, Dept Integrat Physiol, Kansas City, KS 66160 USA. Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Cell Biol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Physiol, St Louis, MO 63110 USA. Univ Kansas, Ctr Med, Dept Pediat, Kansas City, KS 66160 USA. Vanderbilt Univ, Sch Med, Dept Med & Pharmacol, Nashville, TN 37232 USA. Harvard Univ, Sch Med, Dept Med, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Dey, SK (reprint author), Univ Kansas, Med Ctr, Dept Mol Physiol, Kansas City, KS 66160 USA. RI Lim, Hyunjung/D-5343-2011 OI Lim, Hyunjung/0000-0003-2191-666X FU NCI NIH HHS [CA77839]; NICHD NIH HHS [HD12304, HD29968, HD37394, HD40193]; NIDDK NIH HHS [DK38452, DK39773, DK48831]; NIGMS NIH HHS [GM15431] NR 47 TC 157 Z9 172 U1 1 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2002 VL 129 IS 12 BP 2879 EP 2889 AR UNSP DEV3654 PG 11 WC Developmental Biology SC Developmental Biology GA 572JB UT WOS:000176769800008 PM 12050136 ER PT J AU Kobayashi, T Chung, UI Schipani, E Starbuck, M Karsenty, G Katagiri, T Goad, DL Lanske, B Kronenberg, HM AF Kobayashi, T Chung, UI Schipani, E Starbuck, M Karsenty, G Katagiri, T Goad, DL Lanske, B Kronenberg, HM TI PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps SO DEVELOPMENT LA English DT Article DE PTHrP; PTH/PTHrP receptor; Inidian hedgeghog; growth plate; chondrocyte differentiation; Cre-loxP; mouse ID HORMONE-RELATED PEPTIDE; ENDOCHONDRAL BONE-DEVELOPMENT; PARATHYROID-HORMONE; PTH/PTHRP RECEPTOR; EXPRESSION; GENE; MICE; RECOMBINATION; MORPHOGENESIS; SERIES AB In developing murine growth plates, chondrocytes near the articular surface (periarticular chondrocytes) proliferate, differentiate into flat column-forming proliferating cells (columnar chondrocytes), stop dividing and finally differentiate into hypertrophic cells. Indian hedgehog (Ihh), which is predominantly expressed in prehypertrophic cells, stimulates expression of parathyroid hormone (PTH)-related peptide (PTHrP) which negatively regulates terminal chondrocyte differentiation through the PTH/PTHrP receptor (PPR). However, the roles of PTHrP and Ihh in regulating earlier steps in chondrocyte differentiation are unclear. We present novel mouse models with PPR abnormalities that help clarify these roles. In mice with chondrocyte-specific PPR ablation and mice with reduced PPR expression, chondrocyte differentiation was accelerated not only at the terminal step but also at an earlier step: periarticular to columnar differentiation. In these models, upregulation of Ihh action in the periarticular region was also observed. In the third model in which the PPR was disrupted in about 30% of columnar chondrocytes, Ihh action in the periarticular chondrocytes was upregulated because of ectopically differentiated hypertrophic chondrocytes that had lost PPR. Acceleration of periarticular to columnar differentiation was also noted in this mouse, while most of periarticular chondrocytes retained PPR signaling. These data suggest that Ihh positively controls differentiation of periarticular chondrocytes independently of PTHrP. Thus, chondrocyte differentiation is controlled at multiple steps by PTHrP and Ihh through the mutual regulation of their activities. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Baylor Coll Med, Dept Human & Mol Genet, Houston, TX 77030 USA. RP Kronenberg, HM (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. NR 26 TC 161 Z9 169 U1 0 U2 7 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2002 VL 129 IS 12 BP 2977 EP 2986 AR UNSP DEV3634 PG 10 WC Developmental Biology SC Developmental Biology GA 572JB UT WOS:000176769800016 PM 12050144 ER PT J AU Roman, BL Pham, V Lawson, ND Kulik, M Childs, S Lekven, AC Garrity, DM Moon, RT Fishman, MC Lechleider, RJ Weinstein, BM AF Roman, BL Pham, V Lawson, ND Kulik, M Childs, S Lekven, AC Garrity, DM Moon, RT Fishman, MC Lechleider, RJ Weinstein, BM TI Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels SO DEVELOPMENT LA English DT Article DE Acvrl1; hereditary hemorrhagic telangiectasia; endothelium; angiogenesis; zebrafish; violet beauregard ID HEREDITARY HEMORRHAGIC TELANGIECTASIA; SERINE/THREONINE KINASE RECEPTOR; DORSOVENTRAL PATTERN-FORMATION; TGF-BETA; I RECEPTOR; ARTERIOVENOUS-MALFORMATIONS; SIGNAL-TRANSDUCTION; DEFICIENT MICE; GENE; ANGIOGENESIS AB The zebrafish mutant violet beauregarde (vbg) can be identified at two days post-fertilization by an abnormal circulation pattern in which most blood cells flow through a limited number of dilated cranial vessels and fail to perfuse the trunk and tail. This phenotype cannot be explained by caudal vessel abnormalities or by a defect in cranial vessel patterning, but instead stems from an increase in endothelial cell number in specific cranial vessels. We show that vbg encodes activin receptor-like kinase 1 (Acvr11; also known as Alk1), a TGFbeta type I receptor that is expressed predominantly in the endothelium of the vessels that become dilated in vbg mutants. Thus, vbg provides a model for the human autosomal dominant disorder, hereditary hemorrhagic telangiectasia type 2, in which disruption of ACVRL1 causes vessel malformations that may result in hemorrhage or stroke. C1 NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. Massachusetts Gen Hosp East, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. Univ Washington, Sch Med, Howard Hughes Med Inst, Seattle, WA 98185 USA. Univ Washington, Sch Med, Dept Pharmacol, Seattle, WA 98185 USA. RP Weinstein, BM (reprint author), NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RI Moon, Randall/B-1743-2014 OI Moon, Randall/0000-0002-9352-1408 FU NHLBI NIH HHS [HL65681]; NICHD NIH HHS [Z01-HD-01011] NR 59 TC 186 Z9 191 U1 1 U2 6 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUN PY 2002 VL 129 IS 12 BP 3009 EP 3019 AR UNSP DEV14536 PG 11 WC Developmental Biology SC Developmental Biology GA 572JB UT WOS:000176769800019 PM 12050147 ER PT J AU Rogus, JJ Warram, JH Krolewski, AS AF Rogus, JJ Warram, JH Krolewski, AS TI Genetic studies of late diabetic complications - The overlooked importance of diabetes duration before complication onset SO DIABETES LA English DT Article ID SEGREGATION ANALYSIS; NEPHROPATHY; RISK; POLYMORPHISM; ASSOCIATION; DISEQUILIBRIUM; RETINOPATHY; FAMILIES; HISTORY; DISEASE AB Genes play a role in many processes underlying late diabetic complications, but efforts to identify genetic variants have produced disappointing and contradictory results. Here, we evaluate Whether the study designs and analytic methods commonly being used are optimal for finding susceptibility genes for diabetic complications. We do so by generating plausible genetic models and assessing the performance of case-control and family-based trio study designs. What emerges as a key determinant of success is duration of diabetes. This perspective focuses on duration of diabetes before complication onset and its influence on the ability to detect major and minor gene effects. It does not delve into the distinct effect of duration after complication onset, which can enrich case subjects with genotypes conferring survival advantage. We use clinically diagnosed nephropathy in type I diabetes to show how ignoring duration can result in considerable power loss in both case-control and family-based trio designs. We further show how, under certain circumstances, disregard for duration information can paradoxically lead to implicating nonrisk alleles as causative. Our results indicate that problems can be minimized by selecting case subjects with short diabetes duration and, to a lesser extent, control subjects with long duration or, perhaps, by adjusting for duration during analysis. C1 Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Rogus, JJ (reprint author), Joslin Diabet Ctr, Sect Genet & Epidemiol, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [R01-DK41526, R01-DK53534] NR 22 TC 42 Z9 42 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2002 VL 51 IS 6 BP 1655 EP 1662 DI 10.2337/diabetes.51.6.1655 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 557YM UT WOS:000175936700001 PM 12031950 ER PT J AU Laybutt, DR Weir, GC Kaneto, H Lebet, J Palmiter, RD Sharma, A Bonner-Weir, S AF Laybutt, DR Weir, GC Kaneto, H Lebet, J Palmiter, RD Sharma, A Bonner-Weir, S TI Overexpression of c-Myc in beta-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes SO DIABETES LA English DT Article ID PANCREATIC-ISLETS; MALIGNANT INSULINOMA; TRANSCRIPTION FACTOR; FATTY RAT; IN-VIVO; PROTEIN; GROWTH; DIFFERENTIATION; HYPERGLYCEMIA; GLUCAGON AB To test the hypothesis that c-Myc plays an important role in beta-cell growth and differentiation, we generated transgenic mice overexpressing c-Myc in beta-cells under control of the rat insulin II promoter. F-1 transgenic mice from two founders developed neonatal diabetes (associated with reduced plasma insulin levels) and died of hyperglycemia 3 days after birth. In pancreata of transgenic mice, marked hyperplasia of cells with an altered phenotype and amorphous islet organization was displayed: islet volume was increased threefold versus wild-type littermates. Apoptotic nuclei were increased fourfold in transgenic versus wild-type mice, suggesting an increased turnover of beta-cells. Very few cells immunostained for insulin; pancreatic insulin mRNA and content were markedly reduced. GLUT2 mRNA was decreased, but other beta-cell-associated genes (IAPP [islet amyloid pancreatic polypeptide], PDX-1 [pancreatic and duodenal homeobox-1], and BETA2/NeuroD) were expressed at near-normal levels. Immunostaining for both GLUT2 and Nkx6.1 was mainly cytoplasmic. The defect in beta-cell phenotype in transgenic embryos (embryonic days 17-18) and neonates (days 1-2) was similar and, therefore, was not secondary to overt hyperglycemia. When pancreata were transplanted under the kidney capsules of athymic mice to analyze the long-term effects of c-Myc activation, beta-cell depletion was found, suggesting that, ultimately, apoptosis predominates over proliferation. In conclusion, these studies demonstrate that activation of c-Myc in beta-cells leads to 1) increased proliferation and apoptosis, 2) initial hyperplasia with amorphous islet organization, and 3) selective downregulation of insulin gene expression and the development of overt diabetes. C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Boston, MA 02215 USA. Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. RP Bonner-Weir, S (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK36836, DK35449] NR 53 TC 84 Z9 86 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2002 VL 51 IS 6 BP 1793 EP 1804 DI 10.2337/diabetes.51.6.1793 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 557YM UT WOS:000175936700018 PM 12031967 ER PT J AU Meigs, JB D'Agostino, RB Nathan, DM Rifai, N Wilson, PWF AF Meigs, JB D'Agostino, RB Nathan, DM Rifai, N Wilson, PWF TI Longitudinal association of glycemia and microalbuminuria - The Framingham Offspring Study SO DIABETES CARE LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Heart-Association-Council-on-Cardiovascular-Disease-Epidemiolog y-and-Prevention CY MAR 03, 2000 CL SANB DIEGO, CALIFORNIA SP Amer Heart Assoc Council Cardiovascular Disease Epidemiol Prevent ID DEPENDENT DIABETES-MELLITUS; URINARY ALBUMIN EXCRETION; CORONARY HEART-DISEASE; CARDIOVASCULAR RISK-FACTORS; IMPAIRED GLUCOSE-TOLERANCE; PIMA-INDIANS; INSULIN-RESISTANCE; TYPE-2; NIDDM; PROGRESSION AB OBJECTIVE - To assess current and long-term associations of glycemia with microalbuminuria, a marker of generalized endothelial injury. RESEARCH DESIGN AND METHODS - We measured clinical characteristics, fasting plasma glucose, and the urinary albumin-to-creatinine ratio (UACR) in 1,311 men and 1,518 women attending the sixth examination cycle (1995-1998) of the Framingham Offspring Study. After excluding participants with diabetes or cardiovascular disease (CVD) at the baseline examination (1971-1974), we used fasting glucose measured at baseline, examination 6, and at least two additional examinations from 1974 to 1995 in regression models to predict risk for microalbuminuria (UACR greater than or equal to30 mg/g) associated with baseline, current, and 24-year time-integrated glycemia. RESULTS - Microalbuminuria was present in 9.5% of men and 13.4% of women. Among men, age-adjusted odds ratios (95% Cl) for microalbuminuria associated with each 0.28 mmol/l (5 mg/dl) increase in baseline, current, and time-integrated glucose levels were 1.12 (1.00-1.16), 1.08 (1.05-1.10), and 1.16 (1.11-1.21), respectively. These effects persisted after adjustment for systolic blood pressure and other confounders. Higher glucose levels also predicted incident diabetes and CVD. Mean time-integrated glucose levels were highest among men who developed both CVD and microalbuminuria (SE 6.82 +/- 0.16 mmol/l), intermediate among men with either condition (6.03 +/- 0.65 mmol/l), and lowest among men with neither condition (5.49 +/- 0.02 mmol/l; P < 0.001 for all pairwise comparisons). We observed similar associations in women. CONCLUSIONS - Long-term hyperglycemia and subdiabetic glycemia increase risk for type 2 diabetes, and CVD seem to arise together over the microalbuminuria, Microalbuminuria, course of decades, consistent with the hypothesis that they share a common antecedent. C1 Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Boston Univ, Dept Math, Stat & Consulting Unit, Boston, MA 02215 USA. Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Childrens Hosp, Med Ctr, Boston, MA 02115 USA. Boston Univ, Sch Med, Framingham Heart Study, Framingham, MA USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU NHLBI NIH HHS [N01-HC-38083] NR 44 TC 56 Z9 57 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2002 VL 25 IS 6 BP 977 EP 983 DI 10.2337/diacare.25.6.977 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 724TY UT WOS:000185503800006 PM 12032102 ER PT J AU Caselli, A Pham, H Giurini, JM Armstrong, DG Veves, A AF Caselli, A Pham, H Giurini, JM Armstrong, DG Veves, A TI The forefoot-to-rearfoot plantar pressure ratio is increased in severe diabetic neuropathy and can predict foot ulceration SO DIABETES CARE LA English DT Article ID HIGH-RISK; BIOMECHANICAL CONSEQUENCES; MELLITUS AB OBJECTIVE - We have previously demonstrated that high plantar pressures can predict foot ulceration in diabetic patients. The aim of the present study was to evaluate both the relationship between forefoot and rearfoot plantar pressure in diabetic patients with different degrees of peripheral neuropathy and their role in ulcer development. RESEARCH DESIGN AND METHODS - Diabetic patients of a 30-month prospective study were classified according to the neuropathy disability score: scores of 0, 1-5, 6-16, and 17-28 are defined as absent (n = 20), mild (n = 66), moderate n = 95), and severe (n = 57) neuropathy, respectively. The F-Scan mat system was used to measure dynamic plantar pressures. The peak pressures under the forefoot and the rearfoot were selectively measured for each foot, and the fore foot-to-rearfoot ratio (FIR ratio) was calculated. RESULTS - Foot ulcers developed in 73 (19%) feet. The peak pressures were increased in the forefoot of the severe and moderate neuropathic groups compared with the mild neuropathic and nonneuropathic groups (6.2 +/- 4.5 and 3.8 +/- 2.7 vs. 3.0 +/- 2.1 and 3.3 +/- 2.1 kg/cm(2) [mean +/- SD], respectively; P < 0.0001). The rearfoot pressures were also higher in the severe and moderate neuropathic groups compared with the mild neuropathic and nonneuropathic groups (3.2 +/- 2.0 and 3.2 +/- 1.9 vs. 2.5 +/- 1.3 and 2.3 +/- 1.0, respectively; P < 0.0001). The F/R ratio was increased only in the severe group compared with the moderate and mild neuropathic and nonneuropathic groups (2.3 +/- 2.4 vs. 1.5 +/- 1.2, 1.3 +/- 0.9, and 1.6 +/- 1.0, respectively; P < 0.0001). In a logistic regression analysis, both forefoot pressure (odds ratio 1.19 [95% CI 1.11-1.28], P< 0.0001) and the F/R ratio (1.37 [1.16-1.61], P< 0.0001) were related to risk of foot ulceration, whereas rearfoot pressure was not. CONCLUSIONS - Both the rearfoot and forefoot pressures are increased in the diabetic neuropathic. foot,, whereas the F/R ratio is increased only in severe diabetic neuropathy, indicating an imbalance in pressure distribution with increasing degrees of neuropathy. This may lend further evidence toward the concept that equinus develops in the latest stages of peripheral neuropathy and may play an important role in the etiology of diabetic foot ulceration. C1 Harvard Univ, Sch Med, Dept Surg, Joslin Beth Israel Deaconess Foot Ctr, Boston, MA 02215 USA. So Arizona Vet Affairs Med Ctr, Tucson, AZ USA. RP Veves, A (reprint author), Harvard Univ, Sch Med, Dept Surg, Joslin Beth Israel Deaconess Foot Ctr, 1 Deaconess Rd, Boston, MA 02215 USA. OI Pham, Hau/0000-0003-4583-9873 NR 28 TC 111 Z9 120 U1 0 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD JUN PY 2002 VL 25 IS 6 BP 1066 EP 1071 DI 10.2337/diacare.25.6.1066 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 724TY UT WOS:000185503800020 PM 12032116 ER PT J AU Linehan, MM Dimeff, LA Reynolds, SK Comtois, KA Welch, SS Heagerty, P Kivlahan, DR AF Linehan, MM Dimeff, LA Reynolds, SK Comtois, KA Welch, SS Heagerty, P Kivlahan, DR TI Dialectical behavior therapy versus comprehensive validation therapy plus 12-step for the treatment of opioid dependent women meeting criteria for borderline personality disorder SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE dialectical behavior therapy; borderline personality disorder; heroin; co-morbidity; psychotherapy; women ID SUBSTANCE USE DISORDERS; METHADONE-MAINTENANCE; OPIATE ADDICTS; FOLLOW-UP; SUICIDE ATTEMPTS; DRUG-ADDICTS; PSYCHOTHERAPY; COMORBIDITY; ABUSE; BUPRENORPHINE AB We conducted a randomized controlled trial to evaluate whether dialectical behavior therapy (DBT). a treatment that synthesizes behavioral change with radical acceptance strategies, would be more effective for heroin-dependent women with borderline personality disorder (N = 23) than Comprehensive Validation Therapy with 12-Step (CVT + 12S), a manualized approach that provided the major acceptance-based strategies used in DBT in combination with participation in 12-Step programs. In addition to psychosocial treatment, subjects also received concurrent opiate agonist therapy with adequate doses of LAAM (thrice weekly: modal dose 90/90/130 mg). Treatment lasted for 12 months. Drug use outcomes were measured via thrice-weekly urinalyses and self-report. Three major findings emerged. First. results of urinalyses indicated that both treatment conditions were effective in reducing opiate use relative to baseline. At 16 months post-randomization (4 months post-treatment). all participants had a low proportion of opiate-positive Urinalyses (27%, in DBT: 33% in CVT + 12S). With regard to between-condition differences, participants assigned to DBT maintained reductions in mean opiate use through 12 months of active treatment while those assigned to CVT+12S significantly increased opiate use during the last 4 months of treatment. Second. CVT + 12S retained all 12 participants for the entire year of treatment, compared to a 64%, retention rate in DBT. Third. at both post-treatment and at the 16-month follow-up assessment, subjects in both treatment conditions showed significant overall reductions in level of psychopathology relative to baseline. A noteworthy secondary finding was that DBT participants were significantly more accurate in their self-report of opiate use than were those assigned to CVT + 12S. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Univ Washington, Dept Psychol, Behav Res & Therapy Clin, Seattle, WA 98195 USA. Behav Technol Transfer Grp, Seattle, WA 98105 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, VA Puget Sound Hlth Care Syst, Dept Psychiat & Behav Sci, Ctr Excellence Substance Abuse Treatment & Educat, Seattle, WA 98108 USA. RP Linehan, MM (reprint author), Univ Washington, Dept Psychol, Behav Res & Therapy Clin, Box 351525, Seattle, WA 98195 USA. FU NIDA NIH HHS [DA08674] NR 62 TC 257 Z9 264 U1 5 U2 33 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUN 1 PY 2002 VL 67 IS 1 BP 13 EP 26 AR PII S0376-8716(02)00011-X DI 10.1016/S0376-8716(02)00011-X PG 14 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 569RX UT WOS:000176617000002 PM 12062776 ER PT J AU Kensinger, EA Brierley, B Medford, N Growdon, JH Corkin, S AF Kensinger, Elizabeth A. Brierley, Barbara Medford, Nick Growdon, John H. Corkin, Suzanne TI Effects of Normal Aging and Alzheimer's Disease on Emotional Memory SO EMOTION LA English DT Article AB Recall is typically better for emotional than for neutral stimuli. This enhancement is believed to rely on limbic regions. Memory is also better for neutral stimuli embedded in an emotional context. The neural substrate supporting this effect has not been thoroughly investigated but may include frontal lobe, as well as limbic circuits. Alzheimer's disease (AD) results in atrophy of limbic structures, whereas normal aging relatively spares limbic regions but affects prefrontal areas. The authors hypothesized that AD would reduce all enhancement effects, whereas aging would disproportionately affect enhancement based on emotional context. The results confirmed the authors' hypotheses: Young and older adults, but not AD patients, showed better memory for emotional versus neutral pictures and words. Older adults and AD patients showed no benefit from emotional context, whereas young adults remembered more items embedded in an emotional versus neutral context. C1 [Kensinger, Elizabeth A.; Growdon, John H.; Corkin, Suzanne] MIT, Dept Brain & Cognit Sci, Clin Res Ctr, Cambridge, MA 02139 USA. [Growdon, John H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Brierley, Barbara; Medford, Nick] Kings Coll Hosp, Dept Psychol Med, Inst Psychiat, London, England. [Brierley, Barbara; Medford, Nick] Kings Coll Hosp, GKT Sch Med, London, England. RP Kensinger, EA (reprint author), MIT, Dept Brain & Cognit Sci, Clin Res Ctr, Bldg E18-470,77 Massachusetts Ave, Cambridge, MA 02139 USA. EM ekensing@mit.edu FU NCRR NIH HHS [RR00088]; NIA NIH HHS [AG05134, AG06605, AG08812] NR 68 TC 192 Z9 199 U1 1 U2 16 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1528-3542 J9 EMOTION JI Emotion PD JUN PY 2002 VL 2 IS 2 BP 118 EP 134 DI 10.1037//1528-3542.2.2.118 PG 17 WC Psychology, Experimental SC Psychology GA V21RK UT WOS:000208224500003 PM 12899186 ER PT J AU Seminara, SB Crowley, WF AF Seminara, SB Crowley, WF TI Genetic approaches to unraveling reproductive disorders: Examples of bedside to bench research in the genomic era SO ENDOCRINE REVIEWS LA English DT Review ID POLYCYSTIC-OVARY-SYNDROME; FOLLICLE-STIMULATING-HORMONE; ADRENAL HYPOPLASIA CONGENITA; INSULIN-RECEPTOR GENE; SINGLE-NUCLEOTIDE POLYMORPHISMS; GONADOTROPIN-RELEASING HORMONE; DEPENDENT DIABETES-MELLITUS; LIMITED PRECOCIOUS PUBERTY; MALE PATTERN BALDNESS; HYPOGONADOTROPIC HYPOGONADISM AB Despite the rapid advances in medical genetics, many clinicians and investigators remain unaware of the general approaches that can be used to map genes. Although there are specific challenges to using genetic approaches in reproductive medicine, the following report summarizes mapping efforts for three diseases: adrenal hypoplasia congenita, hypergonadotropic ovarian failure, and polycystic ovary syndrome. The themes of rare and novel phenotypes, genetically homogenous populations, and genotype/phenotype correlations are emphasized. C1 Massachusetts Gen Hosp, Reprod Endocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Harvard Wide Reprod Endocrine Sci Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Natl Ctr Infertil Res, Boston, MA 02114 USA. RP Seminara, SB (reprint author), Reprod Endocrine Unit, Bartlett Hall Extens 505 Fruit St, Boston, MA 02114 USA. FU NICHD NIH HHS [U54 HD028138, P30 HD028138, R01 HD015788, U54 HD029164] NR 109 TC 10 Z9 10 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0163-769X J9 ENDOCR REV JI Endocr. Rev. PD JUN PY 2002 VL 23 IS 3 BP 382 EP 392 DI 10.1210/er.23.3.382 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 562HX UT WOS:000176192300007 PM 12050127 ER PT J AU Kahn, SE AF Kahn, SE TI Insulin resistance and beta cell dysfunction: A dual therapeutic approach - Foreword SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Editorial Material ID TYPE-2 C1 VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98108 USA. RP Kahn, SE (reprint author), VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, 1660 S Columbian Way, Seattle, WA 98108 USA. OI Kahn, Steven/0000-0001-7307-9002 NR 4 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD JUN PY 2002 VL 32 SU 3 BP 1 EP 2 DI 10.1046/j.1365-2362.32.s3.1.x PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 553MZ UT WOS:000175681200001 PM 12028369 ER PT J AU Rhodes, CJ White, MF AF Rhodes, CJ White, MF TI Molecular insights into insulin action and secretion SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Review DE diabetes mellitus, noninsulin-dependent; glucose/metabolism; insulin resistance; insulin/secretion; signal transduction ID PANCREATIC BETA-CELLS; PROTEIN-KINASE-C; HOMOZYGOUS NONSENSE MUTATION; RECEPTOR SUBSTRATE FAMILY; INDUCED GLUCOSE-TRANSPORT; SIGNAL-TRANSDUCTION; GROWTH-FACTOR; MICE LACKING; PROINSULIN BIOSYNTHESIS; DIABETES-MELLITUS AB Tightly co-ordinated control of both insulin action and secretion is required in order to maintain glucose homeostasis. Gene knockout experiments have helped to define key signalling molecules that affect insulin action, including insulin and insulin-like growth factor-1 (IGF-1) receptors, insulin receptor substrate (IRS) proteins and various downstream effector proteins. beta-cell function is also a tightly regulated process, with numerous factors (including certain signalling molecules) having an impact on insulin production, insulin secretion and beta-cell mass. While signalling molecules play important roles in insulin action and secretion under normal circumstances, abnormal insulin signalling in muscle, adipose tissue, liver and pancreas leads to insulin resistance and beta-cell dysfunction. In particular, the signalling protein IRS-2 may have a central role in linking these abnormalities, although other factors are likely to be involved. C1 Univ Washington, Pacific NW Res Inst, Seattle, WA 98122 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98122 USA. Harvard Univ, Sch Med, Dept Biochem, Joslin Diabet Ctr,Howard Hughes Med Inst, Boston, MA 02215 USA. RP Rhodes, CJ (reprint author), Univ Washington, Pacific NW Res Inst, 720 Broadway, Seattle, WA 98122 USA. NR 111 TC 95 Z9 98 U1 1 U2 16 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD JUN PY 2002 VL 32 SU 3 BP 3 EP 13 DI 10.1046/j.1365-2362.32.s3.2.x PG 11 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 553MZ UT WOS:000175681200002 PM 12028370 ER PT J AU Bergman, RN Finegood, DT Kahn, SE AF Bergman, RN Finegood, DT Kahn, SE TI The evolution of beta-cell dysfunction and insulin resistance in type 2 diabetes SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Review DE biological models; disease progression; insulin resistance; islets of Langerhans/physiopathology; noninsulin-dependent diabetes mellitus ID HOMEOSTASIS MODEL ASSESSMENT; POLYCYSTIC-OVARY-SYNDROME; IMPAIRED GLUCOSE-TOLERANCE; ISLET AMYLOID POLYPEPTIDE; MELLITUS GENETICS FUSION; PLACEBO-CONTROLLED TRIAL; AUTOSOMAL GENOME SCAN; C-PEPTIDE KINETICS; FREE FATTY-ACIDS; MINIMAL-MODEL AB Insulin resistance and beta-cell dysfunction have important roles in the pathogenesis and evolution of type 2 diabetes. The development of precise methods to measure these factors has helped us to define the relationship between them and evidence is reviewed that changes in insulin sensitivity are compensated by inverse changes in beta-cell responsiveness such that the product of insulin sensitivity and insulin secretion (the disposition index) remains constant. While the disposition index promises to be a useful tool to predict individuals at high risk of developing type 2 diabetes, other factors that contribute to beta-cell dysfunction and mark disease onset and progression include impairments in proinsulin processing and insulin secretion, decreased beta-cell mass and islet amyloid deposition. Emerging data indicate that anti-diabetic agents, such as the thiazolidinediones that simultaneously target insulin resistance and beta-cell dysfunction, may have a beneficial impact on disease onset and progression. Several landmark clinical studies are underway to investigate if their initial promise is supported by data from large-scale trials. C1 Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Diabet Res Ctr, Los Angeles, CA 90089 USA. Simon Fraser Univ, Sch Kinesiol, Diabet Res Lab, Burnaby, BC V5A 1S6, Canada. Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA 98195 USA. RP Bergman, RN (reprint author), Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Diabet Res Ctr, 1333 San Pablo St, Los Angeles, CA 90089 USA. NR 117 TC 166 Z9 175 U1 1 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD JUN PY 2002 VL 32 SU 3 BP 35 EP 45 DI 10.1046/j.1365-2362.32.s3.5.x PG 11 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 553MZ UT WOS:000175681200005 PM 12028373 ER PT J AU Davids, E Hevers, W Damgen, K Zhang, K Tarazi, FI Luddens, H AF Davids, E Hevers, W Damgen, K Zhang, K Tarazi, FI Luddens, H TI Organotypic rat cerebellar slice culture as a model to analyze the molecular pharmacology of GABA(A) receptors SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Article DE organotypic culture; rat; cerebellum; GABA(A) receptor ID SUBUNIT MESSENGER-RNAS; POSTNATAL-DEVELOPMENT; ALPHA-6 SUBUNIT; NERVOUS-TISSUE; GRANULE CELLS; BINDING-SITES; IN-VITRO; SUBTYPES; NEURONS; EXPRESSION AB The preservation of the neuronal circuitry in rat cerebellar slice cultures provides an advantage in monitoring the development and characterizing the pharmacology of GABA A receptor subtypes. Sprague-Dawley rats, 8-11 days of age, were decapitated. their cerebella were cut into 400-mum slices and transferred into culture dishes. Cell viability and organotypic cerebellar organization of the culture remained well preserved up to 3 weeks. Autoradiographic Procedures were introduced in these advanced culture technique and employed [H-3]Ro 15-4513 in the absence and presence of 10 muM diazepam to visualize all benzodiazepine (BZD) and diazepam-insensitive (DIS) binding sites, respectively. Since expression of the alpha6 subunit variant of the GABA(A)/BZD receptor is restricted to the cerebellar granule cells and the BZD receptor agonist diazepam has very low affinity for this subunit, changes in DIS [H-3]Ro 15-4513 binding sites during cultivation time can be attributed to changes in alpha6 subunit expression. A time-dependent development of total and DIS [H-3]Ro 15-4513 binding sites were observed in the culture with a trend towards an increase in GABA, receptor alpha6 subunit levels during the first week. These findings suggest that explant preparations can be used to examine morphological changes in rat cerebellar slices, In addition, these preparations can be utilized to study the pharmacological effects of GABA(A)/BZD selective drugs on postnatal development of GABA(A) receptors in rat cerebellum. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Mainz, Clin Res Grp, Dept Psychiat, D-6500 Mainz, Germany. Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Consolidated Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Davids, E (reprint author), Univ Essen Gesamthsch, Dept Psychiat & Psychotherapy, Virchowstr 174, D-45147 Essen, Germany. NR 47 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD JUN PY 2002 VL 12 IS 3 BP 201 EP 208 AR PII S0924-977X(02)00024-X DI 10.1016/S0924-977X(02)00024-X PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 558VK UT WOS:000175987300004 PM 12007671 ER PT J AU Barnes, GR Schmid, AM AF Barnes, GR Schmid, AM TI Sequence learning in human ocular smooth pursuit SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article ID SLOW OCULOMOTOR CONTROL; EYE-MOVEMENTS; TARGET DISPLACEMENTS; PREDICTION; SYSTEM; MOTION; EXPECTATIONS; RESPONSES; MODEL; INITIATION AB It has been established that repeated presentation of a transient target motion stimulus such as a constant-velocity ramp leads to the build up of steady state (SS), anticipatory smooth pursuit eye movements after two or three presentations. Each SS response is then composed of the anticipatory component of nonvisual origin, a visual component associated with the stimulus presentation and another nonvisual component that represents the decay of the response after extinction of the stimulus. Here we investigated the interactions that occur when each motion stimulus was itself a sequence containing more than one ramp component. Ramp components had a velocity of 15degrees/s or 30degrees/s to left or right and were separated by gaps of 200 ms duration. In an initial experiment, responses to 2-ramp stimuli were examined and compared with responses to the single-ramp stimuli from which they were constituted. We present evidence that the anticipatory, nonvisual components of the double-ramp response result from the linear summation of the nonvisual components of the responses to the constituent single-ramp components. In a 2nd experiment, we examined responses to a wide variety of 4-ramp sequences and again found evidence that, in the SS, the responses were formed from the linear summation of the constituent single-ramp components. Regression analysis performed on the velocity at onset of each ramp component indicated that this nonvisual part of the response was predictive of the upcoming ramp component. To confirrn this, unexpected changes were introduced into single ramp components of the 4-ramp sequence after at least five prior presentations of the sequence had allowed a SS response to be established. Subjects continued to initiate a response to the modified component that was appropriate in velocity and direction for the corresponding part of the previous sequence and inappropriate for the newly modified stimulus. This preprogrammed response persisted unmodified for more than 170 ms after onset of the modified ramp component. In contrast, in the second presentation of the new sequence, the anticipatory component of the response was highly correlated with the SS response of the new sequence. but not with that of the prior sequence, showing that the preprogrammed response had been modified very rapidly. Similar behaviour was observed whichever of the 4-ramp components was modified, indicating that the velocity and direction of the anticipatory response to each component had been preprogrammed. The results suggest that velocity information related to at least four elements of a sequence can be temporarily stored and subsequently released with appropriate temporal order to form an anticipatory response throughout the whole sequence. C1 Univ Manchester, Inst Sci & Technol, Dept Optometry & Neurosci, Manchester M60 1QD, Lancs, England. Massachusetts Gen Hosp, NMR Ctr, Charlestown, MA 02129 USA. RP Barnes, GR (reprint author), Univ Manchester, Inst Sci & Technol, Dept Optometry & Neurosci, POB 88, Manchester M60 1QD, Lancs, England. NR 38 TC 34 Z9 34 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD JUN PY 2002 VL 144 IS 3 BP 322 EP 335 DI 10.1007/s00221-002-1050-8 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 562KW UT WOS:000176196800005 PM 12021814 ER PT J AU Veiga, P Sallan, S Nadler, L Cardoso, A AF Veiga, P Sallan, S Nadler, L Cardoso, A TI Development of human leukemia in murine models is associated with de novo angiogenesis: Relevance for the design of novel anti-leukemia therapies SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 138 BP 71 EP 71 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000136 ER PT J AU Carlesso, N Choral, A Cruz, E Cristinal, F Goumnerov, B Rahme, L Aster, J Cardoso, A Scadden, D AF Carlesso, N Choral, A Cruz, E Cristinal, F Goumnerov, B Rahme, L Aster, J Cardoso, A Scadden, D TI TNF-alpha modulates Jagged2 and Notch expression in the bone marrow microenvironment SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 157 BP 76 EP 76 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000155 ER PT J AU Barata, J Cardoso, A Brandao, J Nadler, L Boussiotis, V AF Barata, J Cardoso, A Brandao, J Nadler, L Boussiotis, V TI PI-3K/Akt(PKB) pathway is critical for interieukin-7-mediated survival, activation and cell cycle progression of T-cell acute lymphoblastic leukemia cells SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Univ Lisbon, P-1699 Lisbon, Portugal. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 234 BP 95 EP 95 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000232 ER PT J AU Orkin, S AF Orkin, S TI Control of hematopoietic lineage: Molecular mechanisms and implications SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 SU 1 MA 429 BP 144 EP 144 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 562FP UT WOS:000176187000424 ER PT J AU Ladetto, M Omede, P Sametti, S Donovan, JW Astolfi, M Drandi, D Volpato, F Giaccone, L Giaretta, F Palumbo, A Bruno, B Pileri, A Gribben, JG Boccadoro, M AF Ladetto, M Omede, P Sametti, S Donovan, JW Astolfi, M Drandi, D Volpato, F Giaccone, L Giaretta, F Palumbo, A Bruno, B Pileri, A Gribben, JG Boccadoro, M TI Real-time polymerase chain reaction in multiple myeloma: Quantitative analysis of tumor contamination of stem cell harvests SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID MINIMAL RESIDUAL DISEASE; HIGH-DOSE CHEMOTHERAPY; ACUTE LYMPHOBLASTIC-LEUKEMIA; BONE-MARROW TRANSPLANTATION; MONOCLONAL PLASMA-CELLS; PERIPHERAL-BLOOD; FOLLICULAR LYMPHOMA; IDIOTYPE VACCINATION; PROGENITOR CELLS; MALIGNANT-CELLS AB Objective. Autologous transplantation of bone marrow (BM) and peripheral blood progenitor cells (PBPC) is commonly used for treatment of multiple myeloma (MM). Although both stem cell sources harbor residual clonal cells, a quantitative evaluation of their level of tumor contamination (LTC) still needs to be performed through highly accurate and reproducible approaches. In this study, we used a validated real-time polymerase chain reaction (PCR) strategy to evaluate LTC of BM and PBPC samples obtained from MM patients. Materials and Methods. The patients underwent two different mobilization courses (defined as early or late course) following two cycles of cyclophosphamide 5 g/m(2). LTC was evaluated by measuring the number of clonal immunoglobulin heavy-chain rearrangements followed by normalization of samples using the GAPDH gene. Results. Overall, 26 PBPC and 12 BM samples were analyzed. Main results are as follows. 1) PBPC harvests are less contaminated than BM samples taken immediately after each mobilization course (median difference 2.68 logs; range 1.7 to 4.6) (p < 0.0001). 2) LTC of PBPC harvests has only minimal variation among different leukaphereses performed during the same mobilization course (median difference 0.45 logs; range 0.22 to 1.2). 3) No difference was observed among PBPC and BM samples obtained after the late mobilization course as compared to the early mobilization course (median reduction 0.21 logs; range -0.39 to 1.3) (p = 0.84). 4) In PBPC but not in BM samples, there is a clear overestimation of the percentage of plasma cells when flow cytometric evaluation of CD38(bright) cells is compared to real-time PCR results. This suggests that in PBPC, most CD38(bright) cells do not belong to the neoplastic clone. Conclusions. Real-time PCR using the IgH rearrangement proved an effective tool for monitoring LTC in stem cell harvests from MM patients. The smaller LTC of PBPC harvests supports the role of PBPC as stem cell rescue for MM patients compared to BM cells. (C) 2002 International Society for Experimental Hematology. Published by Elsevier Science Inc. C1 Univ Turin, Azienda Osped S Giovanni Battista, Div Ematol, Turin, Italy. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Ladetto, M (reprint author), Cattedra Ematol, Via Genova 3, I-10126 Turin, Italy. RI drandi, daniela/Q-6504-2016; OI LADETTO, Marco/0000-0002-8283-2681 NR 50 TC 14 Z9 14 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUN PY 2002 VL 30 IS 6 BP 529 EP 536 AR PII S0301-472X(02)00794-4 DI 10.1016/S0301-472X(02)00794-4 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 559QP UT WOS:000176037100003 PM 12063019 ER PT J AU Ourednik, V Ourednik, J Herlenius, E Zou, Z Snyder, EY AF Ourednik, V Ourednik, J Herlenius, E Zou, Z Snyder, EY TI Tracing of multisynaptic fiber tracts originating from grafted neural stem cells - A study using plant lectins. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, BIDMC, Dept Neurol, Boston, MA 02115 USA. Karolinska Inst, Astrid Lindgrens Childrens Hosp, Dept Women & Child Hlth, S-10521 Stockholm, Sweden. Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Neurobiol, Boston, MA 02115 USA. RI Herlenius, Eric/B-7260-2008 OI Herlenius, Eric/0000-0002-6859-0620 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 418 EP 418 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600022 ER PT J AU Chen, YI Sanchez-Pernaute, R Bjorklund, L Isacson, O Jenkins, BG AF Chen, YI Sanchez-Pernaute, R Bjorklund, L Isacson, O Jenkins, BG TI In vivo assessment of ES cells restoration of dopamine function using amphetamine and fMRL. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Harvard Univ, McLean Hosp, Sch Med,Neuroregenerat Labs, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. Massachusetts Gen Hosp, Dept Radiol, NMR Ctr, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 422 EP 423 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600039 ER PT J AU Ourednik, J Ourednik, V Redmond, DE Kosaras, B Wagle, N Hack, N Sidman, RL Snyder, EY AF Ourednik, J Ourednik, V Redmond, DE Kosaras, B Wagle, N Hack, N Sidman, RL Snyder, EY TI A primate model for cerebellar atrophy using selective lesioning of Purkinje cells by onconase. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, BIDMC, Dept Neurol, Boston, MA 02115 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT 06520 USA. NR 0 TC 1 Z9 1 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 423 EP 423 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600040 ER PT J AU Teng, YD Onario, R Marconi, M Snyder, EY AF Teng, YD Onario, R Marconi, M Snyder, EY TI The effects of engrafted human neural stem cells on somatomotor function and life longevity of SOD1 mouse, an animal model of amyotrophic lateral sclerosis (ALS). SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, BIDMC, Boston, MA USA. VA Healthcare Syst, SCI Ctr, W Roxbuy, MA USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD JUN PY 2002 VL 175 IS 2 BP 443 EP 443 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 562NU UT WOS:000176205600113 ER PT J AU Perez, MC Bodine, PVN Leiva, MC Isaacson, KB Komm, BS AF Perez, MC Bodine, PVN Leiva, MC Isaacson, KB Komm, BS TI Signal transduction pathways involved in macrophage migration induced by peritoneal fluid chemotactic factors in stages I and II endometriosis SO FERTILITY AND STERILITY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 03-09, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Reproduct Med DE chemotaxis; endometriosis; macrophages; peritoneal fluid; signal transduction ID INFLAMMATORY CYTOKINES; INFERTILE WOMEN; CELL-LINE; RECEPTOR; INTERLEUKIN-1; PATHOGENESIS; CHEMOKINES; EXPRESSION; PROTEINS; DISEASE AB Objective: To explore the role of G-protein coupled signaling pathways in activation of macrophage migration in endometriosis stages I and II. Design: Case controlled study. Setting: University hospital. Patient(s): Fifteen patients undergoing laparoscopy for elective sterilization (n = 5) or for diagnosis of endometriosis stages I and 11 associated with infertility (n = 10). Intervention(s): Peritoneal fluid samples were collected during laparoscopy. Main Outcome Measure(s): Macrophage migration induced by peritoneal fluid from patients with endometriosis stages I and II (PF SI-II) and potential G-protein coupled receptors and second messengers involved in macrophage activation. Result(s): Potential G-protein coupled receptors and second messengers involved in macrophage activation were evaluated after incubation of U-937 cells differentiated into macrophages with inhibitors of phospholipase A and C, adenylate cyclase, and protein kinase A and C. Macrophage chemotactic activity induced by PF SI-II was inhibited in the presence of a phospholipase C and A(2) inhibitor (IC50= 30 muM) and after treatment with myristoylated protein kinase C peptide inhibitor (50 nM). An increase in inositol phosphate (IP3) was also observed in macrophages exposed to PF SI-II. Activation of multiple G-proteins in macrophages was examined after exposure of cells to PF SI-II in the presence and absence of Bordettela pertussis and cholera toxins. No effect on macrophage migration was observed. Conclusion(s): Macrophage chemotaxis induced by PF SI-II appears to involve activation of pertussis toxin-insensitive G-protein coupled receptors in macrophages. Our data suggest that these events lead to subsequent activation of phospholipases followed by generation of IP3 and potential mobilization of intracellular Ca2+. Subsequent phosphorylation of target proteins by protein kinase C may regulate the chemotactic responses. The adenylate cyclase pathway does not appear to play a role in this process. (C) 2002 by American Society for Reproductive Medicine. C1 Wyeth Pharmaceut, Womens Hlth Res Inst, Dept Endocrinol, Collegeville, PA 19426 USA. Wyeth Pharmaceut, Womens Hlth Res Inst, Dept Cell Biol, Collegeville, PA 19426 USA. Penn Hosp, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. Massachusetts Gen Hosp, Dept Obstet & Gynecol, Boston, MA 02114 USA. RP Perez, MC (reprint author), Wyeth Pharmaceut, Womens Hlth Res Inst, Dept Endocrinol, 500 Arcola Rd,N2107A, Collegeville, PA 19426 USA. NR 32 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2002 VL 77 IS 6 BP 1261 EP 1268 AR PII S0015-0282(02)03130-8 DI 10.1016/S0015-0282(02)03130-8 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 562AV UT WOS:000176176000027 PM 12057738 ER PT J AU El-Serag, HB Everhart, JE AF El-Serag, HB Everhart, JE TI Diabetes increases the risk of acute hepatic failure SO GASTROENTEROLOGY LA English DT Article ID FATTY LIVER-DISEASE; OF-VETERANS-AFFAIRS; NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; UNITED-STATES; MELLITUS; TROGLITAZONE; MITOCHONDRIA; CIRRHOSIS; ETIOLOGY AB Background & Aims: It Is unclear whether patients with diabetes are at an Increased risk of developing acute liver failure (ALF). We performed a large cohort study to examine the occurrence of ALF by using the databases of the Department of Veterans Affairs. Methods: We identified all patients with a hospital discharge diagnosis of diabetes (ICD-9 codes: 250 [1-9][0-4]) from 1985 to :1990 and randomly assigned patients without diabetes for comparison (3:1 ratio). We excluded patients with concomitant liver disease as far back as 1980. After excluding the first year of follow-up, the remaining patients were observed through 2000 for the occurrence of ALF (ICD-9 570). The cumulative risk and the relative risk of ALF were determined by Kaplan-Meier and Cox Proportional Hazard survival analysis, respectively. Results: We included :173,643 patients with diabetes and 650,620 patients without diabetes. Patients with diabetes were significantly older (62 vs. 54 years) and were less likely to be white (28% vs. 24%). The cumulative risk of ALF was significantly higher among patients with diabetes (incidence rate, 2.31 per 10,000 vs. 1.44 per 10,000 person-years; P < 0.0001). In the Cox proportional hazard model, diabetes was associated with a relative risk of :1.44 (95% Cl, 1.26-1.63; P < 0.0001) for ALF while controlling for comorbidity index, age, sex, ethnicity, and period of service. This risk remained significantly Increased after excluding patients with liver disease or viral hepatitis recorded during follow-up or those with ALF recorded after the introduction of troglitazone (relative risk = 1.40; P < 0.0001). Conclusions: Diabetes Increases the risk of ALF. The Increase In ALF is Independent of recognized underlying chronic liver disease or viral hepatitis. C1 Houston Dept Vet Affairs Med Ctr, Serv Gastroenterol, Houston, TX USA. Houston Dept Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. NIDDKD, Bethesda, MD 20892 USA. RP El-Serag, HB (reprint author), Houston Vet Affairs Med Ctr 152, 2002 Holcombe Blvd, Houston, TX 77030 USA. NR 28 TC 81 Z9 87 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUN PY 2002 VL 122 IS 7 BP 1822 EP 1828 DI 10.1053/gast.2002.33650 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 563WQ UT WOS:000176280300017 PM 12055590 ER PT J AU El-Serag, HB AF El-Serag, HB TI The epidemic of esophageal adenocarcinoma SO GASTROENTEROLOGY CLINICS OF NORTH AMERICA LA English DT Article ID HELICOBACTER-PYLORI INFECTION; GASTROESOPHAGEAL-REFLUX DISEASE; SQUAMOUS-CELL CARCINOMA; GASTRIC CARDIA CANCER; BARRETTS-ESOPHAGUS; DUODENAL-ULCER; INTESTINAL METAPLASIA; RISING INCIDENCE; ACID-SECRETION; UNITED-STATES AB The incidence and mortality related to esophageal adenocarcinoma (EAC) have been increasing in the United States, several European countries, and Oceania for the past 2 to 3 decades. Survival remains dismal, with little improvement during the same time period. Variations in the coding, classification, and detection of gastroesophageal malignancy may have contributed partially to the observed trends. Remarkable differences related to gender, ethnicity, and geography characterize the epidemiology of EAC. Gastroesophageal reflux disease (GERD) is the main risk factor for Barrett's esophagus, which is the only known precursor lesion for EAC. Several risk factors that promote the development of GERD and/or Barrett's esophagus have been proposed to explain these rising trends; these factors include the declining rates of Helicobactcr pylori infection, obesity, dietary factors, and certain drugs. C1 Houston Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX 77030 USA. Houston Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. RP El-Serag, HB (reprint author), Houston Vet Affairs Med Ctr, Gastroenterol Sect, 2002 Holcombe Blvd 152, Houston, TX 77030 USA. EM hasheme@bcm.tme.edu NR 81 TC 75 Z9 76 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 0889-8553 J9 GASTROENTEROL CLIN N JI Gastroenterol. Clin. North Am. PD JUN PY 2002 VL 31 IS 2 BP 421 EP + DI 10.1016/S0889-8553(02)00016-X PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 572VE UT WOS:000176795000005 PM 12134611 ER PT J AU Whitcomb, DC Pogue-Geile, K AF Whitcomb, DC Pogue-Geile, K TI Pancreatitis as a risk for pancreatic cancer SO GASTROENTEROLOGY CLINICS OF NORTH AMERICA LA English DT Review ID COMPARATIVE GENOMIC HYBRIDIZATION; CATIONIC TRYPSINOGEN GENE; RAS ONCOGENE MUTATIONS; HEREDITARY PANCREATITIS; CYSTIC-FIBROSIS; INTRAEPITHELIAL NEOPLASIA; DUCTAL HYPERPLASIA; EXOCRINE PANCREAS; SOMATIC MUTATIONS; MEDICAL HISTORY AB Pancreatic cancer remains one of the most recalcitrant of all cancers. As current treatment regimens for pancreatic cancer are inadequate, a major focus of research is to understand the pathways important for pancreatic cancer development, and to identify factors that can be modified to retard the development of pancreatic cancer. Smoking is the strongest risk factor amenable to modification. Other major risk factors include chronic pancreatitis and germ line genetic mutations. Epidemiologic studies of patients with chronic pancreatitis, cystic fibrosis, tropical pancreatitis, and hereditary pancreatitis prove that all forms of pancreatitis increase the risk of pancreatic cancer. Recent studies also demonstrate gene-gene and gene-environmental interactions that increase the risk of pancreatic cancer in the setting of chronic pancreatitis. Finally, the article outlines new guidelines that address the problem of whether or not patients with chronic pancreatitis should be screened for pancreatic cancer. C1 Univ Pittsburgh, Dept Med, UPMC Presbyterian, Pittsburgh, PA 15213 USA. Univ Pittsburgh, UPMC Presbyterian, Dept Cell Biol & Physiol & Human Genet, Pittsburgh, PA 15213 USA. VA Pittsburgh Hlth Care Syst, Pittsburgh, PA 15240 USA. RP Whitcomb, DC (reprint author), Univ Pittsburgh, Dept Med, UPMC Presbyterian, Mezzanine Level,C Wing,200 Lothrop St, Pittsburgh, PA 15213 USA. FU NIDDK NIH HHS [DK54709] NR 101 TC 44 Z9 49 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8553 J9 GASTROENTEROL CLIN N JI Gastroenterol. Clin. North Am. PD JUN PY 2002 VL 31 IS 2 BP 663 EP + AR PII S0889-8553(02)00004-3 DI 10.1016/S0889-8553(02)00004-3 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 572VE UT WOS:000176795000017 PM 12134623 ER PT J AU Olipitz, W Hopfinger, G Aguiar, RCT Gunsilius, E Girschikofsky, M Bodner, C Hiden, K Linkesch, W Hoefler, G Sill, H AF Olipitz, W Hopfinger, G Aguiar, RCT Gunsilius, E Girschikofsky, M Bodner, C Hiden, K Linkesch, W Hoefler, G Sill, H TI Defective DNA-mismatch repair: A potential mediator of leukemogenic susceptibility in therapy-related myelodysplasia and leukemia SO GENES CHROMOSOMES & CANCER LA English DT Article ID MICROSATELLITE MUTATOR PHENOTYPE; REPLICATION ERROR PHENOTYPE; CANCER-INSTITUTE WORKSHOP; CHRONIC MYELOID-LEUKEMIA; COLORECTAL-CANCER; GASTROINTESTINAL TUMORS; FAMILIAL PREDISPOSITION; INTERNATIONAL CRITERIA; FRAMESHIFT MUTATIONS; INSTABILITY AB We investigated the potential role of defective DNA-mismatch repair (MMR) as a mediator of leukemogenic susceptibility in patients with therapy-related myelodysplasia (t-MDS) and leukemia (t-leuk). Thirty-seven individuals with t-MDS/t-leuk were analyzed for microsatellite instability (MSI), the hallmark of defective DNA-MMR. Using standardized international criteria, 5137 (14%) patients displayed high MSI, whereas 3 other patients had low MSI (8%). To determine the stage at which MSI had developed, we analyzed the primary tumors of 12 patients. Three of 4 patients with high MSI t-MDS/t-leuk also had microsatellite unstable primary tumors. Conversely, MSI was not detected in any primary malignancy of patients with low MSI or microsatellite stable t-MDS/t-leuk (P = 0.0182). In the high MSI group, we further investigated genes targeted by defective DNA-MMR (BAX, TGFBRII, IGFIIR, Caspase-5, APC, PTEN, E2F4, MBD4, MSH6, and MSH3) in both primary tumor and t-MDS/t-leuk. However, no mutation was found in any gene. The significant association of MSI in t-MDS/t-leuk and corresponding primary tumors suggests that defective DNA-MMR confers leukemogenic susceptibility to this cohort of patients. (C) 2002 Wiley-Liss, Inc. C1 Karl Franzens Univ Graz, Div Hematol, Dept Med, A-8036 Graz, Austria. Hanusch Hosp, Dept Med 3, Vienna, Austria. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Innsbruck, Div Hematol & Oncol, A-6020 Innsbruck, Austria. Elisabethinen Hosp, Linz, Austria. Karl Franzens Univ Graz, Inst Pathol, A-8036 Graz, Austria. RP Sill, H (reprint author), Karl Franzens Univ Graz, Div Hematol, Dept Med, Auenbruggerpl 38, A-8036 Graz, Austria. EM heinz.sill@kfunigraz.ac.at RI Hoefler, Gerald/B-7006-2008; Hopfinger, Georg/E-7602-2016; Hoefler, Gerald/H-1796-2016; OI Hoefler, Gerald/0000-0002-9056-3063; Sill, Heinz/0000-0003-0993-4371 NR 29 TC 29 Z9 31 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUN PY 2002 VL 34 IS 2 BP 243 EP 248 DI 10.1002/gcc.10059 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 543KU UT WOS:000175101800011 PM 11979558 ER PT J AU Naar, AM Taatjes, DJ Zhai, WG Nogales, E Tjian, R AF Naar, AM Taatjes, DJ Zhai, WG Nogales, E Tjian, R TI Human CRSP interacts with RNA polymerase IICTD and adopts a specific CTD-bound conformation SO GENES & DEVELOPMENT LA English DT Article DE CRSP; mediator; CTD; structure; transcription ID CARBOXY-TERMINAL DOMAIN; PRE-MESSENGER-RNA; TRANSCRIPTIONAL REGULATION; 3-DIMENSIONAL RECONSTRUCTION; COACTIVATOR COMPLEX; NUCLEAR RECEPTORS; MEDIATOR COMPLEX; COFACTOR COMPLEX; II HOLOENZYME; PROTEIN AB Activation of gene transcription in mammalian cells requires several classes of coactivators that participate in different steps of the activation cascade. Using conventional and affinity chromatography, we have isolated a human coactivator complex that interacts directly with the C-terminal domain (CTD) of RNA polymerase II (Pol II). The CTD-binding complex is structurally and functionally indistinguishable from our previously isolated CRSP coactivator complex. The closely related, but transcriptionally inactive, ARC-L complex failed to interact with the CTD, indicating a significant biochemical difference between CRSP and ARC-L that may, in part, explain their functional divergence. Electron microscopy and three-dimensional single-particle reconstruction reveals a conformation for CTD-CRSP that is structurally distinct from unliganded CRSP or CRSP bound to SREBP-la, but highly similar to CRSP bound to the VP16 activator. Together, our findings suggest that the human CRSP coactivator functions, at least in part, by mediating activator-dependent recruitment of RNA Pol II via the CTD. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Ctr Dept Cell Biol, Charlestown, MA 02129 USA. Howard Hughes Med Inst, Berkeley, CA 94720 USA. Lawrence Berkeley Lab, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. RP Tjian, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Ctr Dept Cell Biol, Charlestown, MA 02129 USA. RI Taatjes, Dylan/G-2027-2011 NR 39 TC 94 Z9 98 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD JUN 1 PY 2002 VL 16 IS 11 BP 1339 EP 1344 DI 10.1101/gad.987602 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 561BZ UT WOS:000176117800004 PM 12050112 ER PT J AU Skinner, CS Schildkraut, JM Berry, D Calingaert, B Marcom, PK Sugarman, J Winer, EP Iglehart, JD Futreal, PA Rimer, BK AF Skinner, CS Schildkraut, JM Berry, D Calingaert, B Marcom, PK Sugarman, J Winer, EP Iglehart, JD Futreal, PA Rimer, BK TI Pre-counseling education materials for BRCA testing: Does tailoring make a difference? SO GENETIC TESTING LA English DT Article ID BREAST-CANCER SUSCEPTIBILITY; LATE-ONSET DISORDERS; OVARIAN-CANCER; PSYCHOLOGICAL DISTRESS; DECISION-MAKING; FAMILY HISTORY; PROPHYLACTIC MASTECTOMY; GENERAL-POPULATION; HEREDITARY BREAST; MUTATION CARRIERS AB Although tailored print materials (TPMs) have been assessed for a variety of behavioral targets, their effectiveness as decision aids for genetic testing had not been evaluated at the time this study began. We compared TPMs and non-tailored print material (NPMs) that included similar content about genetic testing for breast and ovarian cancer susceptibility. TPMs were prepared especially for an individual based on information from and about her. We mailed baseline surveys to 461 women referred by physicians or identified through a tumor registry. All had personal and family histories of breast and/or ovarian cancer and, on the basis of these histories, an estimated greater than or equal to10% probability of carrying a mutation in the breast/ovarian cancer genes BRCA1 or BRCA2. The 325 (70%) who responded were randomly assigned to receive TPM or NPM. Followup surveys, mailed 2 weeks following receipt of print materials, were returned by 262 women (81% of baseline responders). Participants were predominately white (94%) and well-educated (50% college graduates). The mean age was 49 years. At follow-up, TPM recipients exhibited significantly greater improvement in percent of correct responses for the 13-item, true/false measure of knowledge (24% increase for TPM vs. 16% for NPM; p < 0.0001) and significantly less over-estimation of risk of being a mutation carrier (40% TPM group overestimated vs. 70% NPM; p < 0.0001). Anxiety did not differ significantly between groups. Reactions to materials differed on two items: "seemed to be prepared just for me" (76% TPM vs. 52% NPM; p < 0.001) and "told me what I wanted to know about BRCA1 and 2 testing" (98% TPM vs. 91% NPM; p < 0.05). TPMs showed an advantage in increasing knowledge and enhancing accuracy of perceived risk. Both are critical components of informed decision making. C1 Duke Univ, Med Ctr, Dept Community & Family Med, Durham, NC 27710 USA. Duke Comprehens Canc Ctr, Durham, NC 27710 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Duke Univ, Med Ctr, Dept Med, Div Oncol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Ctr Study Med Eth & Humanities, Durham, NC 27710 USA. Dana Farber Canc Inst, Breast & Gynecol Canc Ctr, Boston, MA 02115 USA. Sanger Inst, Cambridge, England. RP Skinner, CS (reprint author), Duke Univ, Med Ctr, Dept Community & Family Med, Hanes House,Box 2949, Durham, NC 27710 USA. RI 谢, 飞/C-7706-2009 FU NCI NIH HHS [2P50CA68438] NR 60 TC 46 Z9 46 U1 2 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1090-6576 J9 GENET TEST JI Genet. Test. PD SUM PY 2002 VL 6 IS 2 BP 93 EP 105 DI 10.1089/10906570260199348 PG 13 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 584WP UT WOS:000177492000005 PM 12215248 ER PT J AU Parker, MW Bellis, JM Bishop, P Harper, M Allman, RM Moore, C Thompson, P AF Parker, MW Bellis, JM Bishop, P Harper, M Allman, RM Moore, C Thompson, P TI A Multidisciplinary model of health promotion incorporating spirituality into a successful aging intervention with African American and white elderly groups SO GERONTOLOGIST LA English DT Article DE faith-based communities; health promotion; successful aging ID OLDER ADULTS; CHURCH; EDUCATION; PROGRAM; BLACKS AB Purpose: A community and faith-based on with elderly persons and their adult children involving religious, medical, and academic communities is described. Design and Methods: Lifestyle changes and individual and corporate forms of spirituality were affirmed using an expanded Rowe and Kahn model of successful aging. Faculty from academic, medical, state, and religious Institutions presented a variety of workshops at a multichurch-sponsored conference that hosted over 500 seniors. Results: Postconference surveys suggested extremely favorable satisfaction rates across all groups represented. The African American religious community provided critical leadership in achieving an excellent African American participation rate. Implications: The model described has the capacity to generate collaborations across denominational, racial, and class barriers, and has the potential of helping to unify the religious community around the important task of promoting successful aging. C1 Univ Alabama, Sch Social Work, Tuscaloosa, AL 35487 USA. Univ Alabama, Div Gerontol & Geriatr Med, Birmingham, AL USA. Univ Alabama, Sch Publ Hlth, Dept Hlth Behav, Birmingham, AL USA. Univ Alabama, Dept Educ, Tuscaloosa, AL USA. Univ Alabama, Div Gerontol & Geriatr Med, Ctr Aging, Birmingham, AL USA. Birmingham VA Med Ctr, Birmingham Atlanta VA Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. Univ Montevallo, Montevallo, AL 35115 USA. Samford Univ, McWhorter Sch Pharm, Birmingham, AL USA. RP Parker, MW (reprint author), Univ Alabama, Sch Social Work, Little Hall,Box 870314, Tuscaloosa, AL 35487 USA. NR 42 TC 24 Z9 25 U1 1 U2 3 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 0016-9013 J9 GERONTOLOGIST JI Gerontologist PD JUN PY 2002 VL 42 IS 3 BP 406 EP 415 PG 10 WC Gerontology SC Geriatrics & Gerontology GA 557UQ UT WOS:000175926900016 PM 12040144 ER PT J AU Duska, LR Garrett, A Eltabbakh, GH Oliva, E Penson, R Fuller, AF AF Duska, LR Garrett, A Eltabbakh, GH Oliva, E Penson, R Fuller, AF TI Paclitaxel and platinum chemotherapy for malignant mixed mullerian tumors of the ovary SO GYNECOLOGIC ONCOLOGY LA English DT Article ID GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-II TRIAL; MESODERMAL TUMORS; COMBINATION CHEMOTHERAPY; EXPERIENCE; IFOSFAMIDE; CARCINOMA; CANCER; MESNA AB Objective. Malignant mixed mullerian tumor (MMMT) of the ovary is a rare tumor with a dismal prognosis. The most effective therapy is unknown. The current study was undertaken to characterize a group of patients treated as if they had aggressive epithelial ovarian tumors, with cytoreductive surgery and combination paclitaxel/platinum chemotherapy. Methods. Retrospective analysis of data obtained from tumor registry and hospital records of cases of malignant mixed mullerian tumor between January 1, 1992 and January 1, 2000 treated at the Massachusetts General Hospital, Brigham and Women's Hospital, and University of Vermont was performed. Only patients treated with combination paclitaxel and platinum therapy were included in the analysis. Data were collected regarding cytoreduction, response to chemotherapy, disease-free interval, and survival. Results. Fifty-five patients were identified with MMMT. Twenty-eight patients with a clearly ovarian primary had received treatment with combination paclitaxel and platinum. Paclitaxel and carboplatin was given as second-line therapy in 2 patients who had chemoresponsive but incurable disease; the remaining patients were treated with paclitaxel and platinum therapy as first-line therapy. These 28 patients had a median (range) age of 66 (46 - 84 years) and stage was 1 in 2 patients, II in 3, III in 18, and IV in 5. Treatment was generally well tolerated. Sixteen patients of 26 treated with paclitaxel and platinum as first-line therapy achieved a complete clinical response (55%) and 6 patients achieved partial response for a total response rate of 72%. Optimal cytoreduction was associated with increased time to recurrence (P = 0.001) but not with survival. Overall median survival for the 28 patients is 27.1 months. Conclusion. Although treatment fails many patients, a minority of patients with MMMT in this highly selected population do unexpectedly well. An aggressive approach with surgery and combination paclitaxel-platinum chemotherapy appears to offer very effective therapy. (C) 2002 Elsevier Science (USA). C1 Massachusetts Gen Hosp, Vincent Gynecol Serv, Div Gynecol Oncol, Boston, MA 02114 USA. Brigham & Womens Hosp, Div Gynecol Oncol, Boston, MA 02115 USA. Univ Vermont, Div Gynecol Oncol, Burlington, VT 05405 USA. Massachusetts Gen Hosp, Div Med Oncol, Boston, MA 02114 USA. RP Duska, LR (reprint author), Massachusetts Gen Hosp, Vincent Gynecol Serv, Div Gynecol Oncol, Boston, MA 02114 USA. NR 14 TC 52 Z9 53 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 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUN PY 2002 VL 85 IS 3 BP 459 EP 463 DI 10.1006/gyno.2002.6645 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 560PV UT WOS:000176091200011 PM 12051874 ER PT J AU Bailey, HH Levy, D Harris, LS Schink, JC Foss, F Beatty, P Wadler, S AF Bailey, HH Levy, D Harris, LS Schink, JC Foss, F Beatty, P Wadler, S TI A phase II trial of daily perillyl alcohol in patients with advanced ovarian cancer: Eastern Cooperative Oncology Group study E2E96 SO GYNECOLOGIC ONCOLOGY LA English DT Article AB Objective. This was a phase 11 study of perillyl alcohol in the treatment of advanced ovarian cancer. The primary endpoint was to evaluate the 6-month progression-free rate of perillyl alcohol as compared with historic controls. Secondary objectives were to evaluate the objective response rate, time to progression and survival, dropout rate, and number of cycles administered; define the qualitative nature of acute and chronic toxicities; and evaluate the effect of perillyl alcohol on triglycerides and total, HDL, and LDL cholesterol levels. Methods. Women who had received prior platinum-based therapy and had residual or recurrent disease were eligible. Perillyl alcohol was administered orally, four times daily, at a dose of 1200 Mg/m(2). This was repeated until disease progression or unacceptable toxicity was experienced. Results. The 6-month progression-free rate was 17%. None of the patients achieved a complete or partial response. The median progression-free survival was 1.7 months. The median overall survival was 9.1 months. Compliance was greater than 90% but gastrointestinal toxicity (grade 1-2 nausea, satiety, eructation in 70%) and fatigue (grade 1-2 in 40%) were common and limited the ability to escalate the dose from 1200 to 1500 Mg/m(2). Conclusion. Perillyl alcohol administered at this dose and formulation did not exhibit signs of extending the time-to-progression in patients with advanced ovarian carcinoma. (C) 2002 Elsevier Science (USA). C1 Univ Wisconsin, Madison, WI 53792 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Meriter Hosp, Madison, WI 53715 USA. Albert Einstein Coll Med, Bronx, NY 10461 USA. RP Bailey, HH (reprint author), Univ Wisconsin, K4-3 CSC 600 Highland Ave, Madison, WI 53792 USA. FU NCI NIH HHS [CA14958, CA21115, CA23318, CA66636] NR 12 TC 27 Z9 30 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD JUN PY 2002 VL 85 IS 3 BP 464 EP 468 DI 10.1006/gyno.2002.6647 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 560PV UT WOS:000176091200012 PM 12051875 ER PT J AU Rogers, SN Gwanne, S Lowe, D Stat, C Humphris, G Yueh, B Weymuller, EA AF Rogers, SN Gwanne, S Lowe, D Stat, C Humphris, G Yueh, B Weymuller, EA TI The addition of mood and anxiety domains to the University of Washington quality of life scale SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Article DE health-related quality of life; head and neck cancer; mood; anxiety; UW-QOL ID NECK-CANCER PATIENTS; OF-LIFE; PRIMARY SURGERY; ORAL-CANCER; OROPHARYNGEAL CANCER; HEAD; DEPRESSION; INSTRUMENT; PERFORMANCE; ILL AB \Background. There are numerous head and neck specific quality of life questionnaires, each having its own merits and disadvantages. The University of Washington questionnaire has been widely used and is notable by the inclusion of a shoulder dysfunction domain, domain importance ratings, and patient free text. It is short, simple to process, and provides clinically relevant information. However, it has lacked any psychological dimension of quality of life. The aim of this study was to report the inclusion of two psychological domains (mood, anxiety) to the most recent refinement of the questionnaire (version 3). Method. A cross-sectional survey was performed in April 2000. Questionnaires were sent to 183 patients alive and disease free after surgery for oral and oro-pharyngeal malignancy. Replies were received from 145 patients (79% response rate). Results. The new domains (mood and anxiety) correlated significantly with the emotional functioning domains from the EORTC C30 and with the pain and appearance domains of UW-QOL. There were also significant correlations between the "global quality of life" item and the two new domains. Mood (p = .005) and anxiety (p < .001) scores were associated with patient age but with no other clinicodemographic variable. Conclusion. The addition of mood and anxiety domains makes the UW-QOL version 4 a single broad measure suitable for effective health-related quality of life evaluation in the routine clinical setting. (C) 2002 Wiley Periodicals, Inc. C1 Univ Hosp Aintree, Reg Maxillofacial Unit, Liverpool L9 1AL, Merseyside, England. Univ Liverpool, Liverpool L69 3BX, Merseyside, England. Univ Manchester, Dept Clin Psychol, Sch Psychiat & Behav Sci, Manchester M13 9PL, Lancs, England. Univ Washington, Sch Med, Dept Otolaryngol Head & Neck Surg, Seattle, WA USA. Vet Affairs Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Serv, Seattle, WA USA. RP Rogers, SN (reprint author), Univ Hosp Aintree, Reg Maxillofacial Unit, Liverpool L9 1AL, Merseyside, England. OI Yueh, Bevan/0000-0003-1380-1053; Rogers, Simon n/0000-0002-5989-6142 NR 27 TC 159 Z9 163 U1 1 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1043-3074 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD JUN PY 2002 VL 24 IS 6 BP 521 EP 529 DI 10.1002/hed.10106 PG 9 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 561CE UT WOS:000176118400002 PM 12112548 ER PT J AU Clark, DE Ryan, LM AF Clark, DE Ryan, LM TI Concurrent prediction of hospital mortality and length of stay from risk factors on admission SO HEALTH SERVICES RESEARCH LA English DT Article DE mortality; length of stay; prediction; injury; trauma; piecewise exponential models; Poisson regression ID TRAUMA PATIENTS; HIP FRACTURE; INJURY AB Objective. To develop a method for predicting concurrently both hospital survival and length of stay (LOS) for seriously ill or injured patients, with particular attention to the competing risks of death or discharge alive as determinants of LOS. Data Sources. Previously collected 1995-1996 registry data on 2,646 cases of injured patients from three trauma centers in Maine. Study Design. Time intervals were determined for which the rates of discharge or death were relatively constant. Poisson regression was used to develop a model for each type of terminal event, with risk factors on admission contributing proportionately to the subsequent rates for each outcome in each interval. Mean LOS and cumulative survival were calculated from a combination of the resulting piecewise exponential models. Principal Findings. Age, Glasgow Coma Scale, Abbreviated Injury Scores, and specific mechanisms of injury were significant predictors of the rates of death and discharge, with effects that were variable in different time intervals. Predicted probability of survival and mean LOS from the model were similar to actual values for categorized patient groups. Conclusions. Piecewise exponential models may be useful in predicting LOS, especially if determinants of mortality are separated from determinants of discharge alive. C1 Maine Med Ctr, Dept Surg, Portland, ME 04102 USA. Harvard Injury Control Res Ctr, Boston, MA USA. Bavarian Publ Hlth Res Ctr, Munich, Germany. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Ctr, Dept Biostat, Boston, MA USA. RP Clark, DE (reprint author), Maine Med Ctr, Dept Surg, 887 Congress St, Portland, ME 04102 USA. RI Ryan, Louise/A-4562-2009 OI Ryan, Louise/0000-0001-5957-2490 NR 17 TC 30 Z9 31 U1 0 U2 4 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0017-9124 J9 HEALTH SERV RES JI Health Serv. Res. PD JUN PY 2002 VL 37 IS 3 BP 631 EP 645 DI 10.1111/1475-6773.00041 PG 15 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 569TC UT WOS:000176617500006 PM 12132598 ER PT J AU Trcka, J Moroi, Y Clynes, RA Goldberg, SM Bergtold, A Perales, MA Ma, MH Ferrone, CR Carroll, MC Ravetch, JV Houghton, AN AF Trcka, J Moroi, Y Clynes, RA Goldberg, SM Bergtold, A Perales, MA Ma, MH Ferrone, CR Carroll, MC Ravetch, JV Houghton, AN TI Redundant and alternative roles for activating Fc receptors and complement in an anti body-dependent model of autoimmune vitiligo SO IMMUNITY LA English DT Article ID REVERSE ARTHUS REACTION; TUMOR-NECROSIS-FACTOR; BROWN LOCUS PROTEIN; DEFICIENT MICE; INFLAMMATORY RESPONSES; TARGETED DISRUPTION; ULTRAVIOLET-LIGHT; IMMUNE-RESPONSE; C5A RECEPTOR; IN-VIVO AB Complement and Fc receptor (FcR)-positive cells mediate effector functions of antibodies. Antibody-dependent immunity against the melanosome membrane glycoprotein gp75/tyrosinase-related protein-1 (TYRP-1) of melanocytes leads to autoimmune hypopigmentation (vitiligo) in mice. Hypopigmentation occurred in mice deficient in activating FcR containing the common gamma subunit (FcgammaR gamma(-/-)) and in mice deficient in the C3 complement component. Mice doubly deficient in both FcgammaRgamma and C3 did not develop hypopigmentation, suggesting that complement and FcgammaR formed redundant mechanisms. Following passive immunization with antibody, no further adaptive immune responses were required. Chimeric FcgammaR gamma(-/-),C3(-/-) mice reconstituted with bone marrow from either FcgammaR gamma(-/-) or C3-/- mice or adoptively transferred with FcgammaR gamma(+/-) macrophages did develop antibody-mediated hypopigmentation. Thus, either complement or macrophages expressing activating FcgammaR can independently and alternatively mediate disease in a model of autoimmune vitiligo. C1 Mem Sloan Kettering Canc Ctr, Swim Amer Lab, New York, NY 10021 USA. Cornell Univ, Weill Grad Sch, New York, NY 10021 USA. Columbia Univ Coll Phys & Surg, Dept Med & Microbiol, New York, NY 10032 USA. Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10021 USA. RP Houghton, AN (reprint author), Mem Sloan Kettering Canc Ctr, Swim Amer Lab, 1275 York Ave, New York, NY 10021 USA. FU NCI NIH HHS [CA09512, CA09501, CA56821] NR 40 TC 47 Z9 47 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN PY 2002 VL 16 IS 6 BP 861 EP 868 DI 10.1016/S1074-7613(02)00327-8 PG 8 WC Immunology SC Immunology GA 568GL UT WOS:000176534000011 PM 12121667 ER PT J AU Venkatesan, MM Hartman, AB Newland, JW Ivanova, VS Hale, TL McDonough, M Butterton, J AF Venkatesan, MM Hartman, AB Newland, JW Ivanova, VS Hale, TL McDonough, M Butterton, J TI Construction, characterization, and animal testing of WRSd1, a Shigella dysenteriae 1 vaccine SO INFECTION AND IMMUNITY LA English DT Article ID ESCHERICHIA-COLI; B-SUBUNIT; TOXIN-II; FLEXNERI; STRAINS; TYPE-1; SHIGELLA-DYSENTERIAE-1; GENES; POLYSACCHARIDE; IMMUNOGENICITY AB WRSd1 is a Shigella dysenteriae I vaccine containing deletions of the virG(icsA) gene required for intercellular spreading and a 20-kb chromosomal region encompassing the Shiga toxin genes (stxAB). WRSd1 was constructed from S. dysenteriae 1 strain 1617 that was originally isolated during the 1968 to 1969 epidemic of Shiga dysentery in Guatemala. The virG(icsA) deletion was constructed from a streptomycin-resistant (Str(r)) mutant of 1617 by a filter mating procedures using a virG(icsA) deletion derivative, pDeltavirG2. A colony that was invasive for HeLa cells and negative for the virG(icsA) gene by Southern blotting was grown anaerobically on plates containing chlorate for selection of resistant colonies that had lost the entire Shiga toxin gene. A virG(icsA) stxAB Str(r) mutant selected from the chlorate plates was designated WRSd1. This candidate vaccine was evaluated for safety, immunogenicity, and protective efficacy using the guinea pig keratoconjunctivitis model. WRSd1 was Sereny negative, and two applications of this strain to the cornea elicited a significant protective immune response against the S. dysenteriae 1 O antigen. Vaccination with WRSd1 conferred protection against challenge with each of three virulent S. dysenteriae 1 strains. Since a vaccine protecting against multiple Shigella species is required for most areas where Shigella is endemic, protection studies using a combination vaccine of Shigella sonnei vaccine strain WRSS1, Shigella flexneri 2a vaccine strain SC602, and WRSd1 were also performed. Guinea pigs vaccinated with a mixture of equal amounts of the three vaccine strains were protected against challenge with each of the homologous virulent strains. Unlike WRSS1 and SC602, however, the level of protection afforded by WRSd1 in a combination vaccine was lower than the protection elicited by, a pure culture. A current Good Manufacturing Practice product of WRSd1 given intragastrically to rhesus monkeys proved safe and immunogenic. C1 Walter Reed Army Inst Res, Dept Enter Infect, Div Communicable Dis & Immunol, Silver Spring, MD 20910 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Venkatesan, MM (reprint author), Walter Reed Army Inst Res, Dept Enter Infect, Div Communicable Dis & Immunol, 503,Forney Dr,Room 3S12, Silver Spring, MD 20910 USA. NR 34 TC 29 Z9 35 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD JUN PY 2002 VL 70 IS 6 BP 2950 EP 2958 DI 10.1128/IAI.70.6.2950-2958.2002 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 554XA UT WOS:000175761400027 PM 12010984 ER PT J AU Krieger, JN Riley, DE AF Krieger, JN Riley, DE TI Prostatitis: what is the role of infection SO INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS LA English DT Article; Proceedings Paper CT 22nd International Congress of Chemotherapy CY JUN 30-JUL 03, 2001 CL AMSTERDAM, NETHERLANDS DE chronic prostatitis/chronic pelvic pain syndrome; inflammation; bacteria; mycoplasmas; ribosomal DNA; polymerase chain reaction ID POLYMERASE-CHAIN-REACTION; CHRONIC ABACTERIAL PROSTATITIS; CHRONIC IDIOPATHIC PROSTATITIS; DNA-SEQUENCES; UREAPLASMA-UREALYTICUM; CHLAMYDIA-TRACHOMATIS; MEN; CLASSIFICATION; DIAGNOSIS; TISSUE AB Although bacterial prostatitis is a common diagnosis, well documented infections of the prostate are uncommon. Culture studies of prostate tissue led our group to hypothesize that bacterial colonization/invasion of the prostate gland might occur more commonly than is appreciated by standard microbiological techniques. Specific polymerase chain reaction (PCR) assays were used for each of the pathogens previously implicated in chronic prostatitis as well as broad-spectrum PCR assays to identify tetracycline resistance genes and bacterial ribosomal-encoding genes (16S rDNAs), followed by cloning and sequencing of the PCR products. Only ten (8%) of the 135 patients with chronic prostatitis had positive specific PCR assays including: Mycoplasma genitalium in four men, Chlamydia trachomatis in three and Trichomonas vaginalis in two, as well as one man positive for both M. genitalium and C. trachomatis. In contrast to the specific probes, the broad-spectrum PCR assays had a substantial proportion of positives. We found evidence of tetracycline resistance in 25% of patients. 16S rDNA-encoding sequences in 77% of the subjects. The tetracycline resistance positives were a subset of the 16S rDNA positive patients. Patients with 16S rDNA-encoding sequences were significantly more likely to have expressed prostatic secretion leukocytes. Many patients with chronic prostatitis/chronic pelvic pain syndrome have a wide variety of bacterial DNA-encoding sequences despite extensive negative microbiological investigations. Understanding the precise role of infection in this syndrome may well lead to better methods to elucidate the microbiology of the prostate in health and disease. (C) 2002 Elsevier Science B.V. and International Society of Chemotherapy All rights reserved. C1 Univ Washington, Sch Med, Dept Urol, VA Puget Sound Hlth Care Syst, Seattle, WA 98109 USA. RP Krieger, JN (reprint author), Univ Washington, Sch Med, Dept Urol, VA Puget Sound Hlth Care Syst, 112-UR,1660 S Columbian Way, Seattle, WA 98109 USA. NR 35 TC 28 Z9 33 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-8579 J9 INT J ANTIMICROB AG JI Int. J. Antimicrob. Agents PD JUN PY 2002 VL 19 IS 6 SI SI BP 475 EP 479 AR PII S0924-8579(02)00086-9 DI 10.1016/S0924-8579(02)00086-9 PG 5 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 587CA UT WOS:000177621900009 PM 12135836 ER PT J AU Cheng, T Scadden, DT AF Cheng, T Scadden, DT TI Cell cycle entry of hematopoietic stem and progenitor cells controlled by distinct cyclin-dependent kinase inhibitors SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Article DE hematopoietic stem cells; cell cycle; p21; p27; TGF-beta 1 ID GROWTH-FACTOR-BETA; EX-VIVO EXPANSION; BONE-MARROW TRANSPLANTATION; COLONY-STIMULATING FACTOR; STAGE-SPECIFIC REGULATION; IN-VIVO; CDK-INHIBITORS; TRANSFORMING GROWTH-FACTOR-BETA-1; NONHUMAN-PRIMATES; CD34(+) CELLS AB The therapeutic promise of hematopoietic stem cells in medicine has been expanded as broader differentiation potential of the cells has gained experimental support. However, hurdles for stem cell manipulation in vitro and tissue regeneration in vivo remain because of lack of the molecular biology of the stem cells. In particular, elucidating the molecular control of cell cycle entry is necessary for rational stem cell expansion strategies. Understanding how the stem and progenitor cell populations are controlled by negative regulators of cell cycle entry may provide one basis for manipulating these cells. In this mini-review, we focus on the rationale of targeting the cyclin-dependent kinase inhibitors (CKIs) in stem cell biology. Two CKI members, p21(Cip1/Waf1) (p21) and p27(kip1) (p27), have been shown to govern the pool sizes of hematopoietic stem and progenitor cells, respectively. Of note, their inhibitory roles in primitive hematopoietic cells are distinct from the action of the inhibitory cytokine, transforming growth factor-beta1 (TGF-beta1). Therefore, the distinct roles of p21, p27, and TGF-beta1 in hematopoietic cells offer attractive targets for specific manipulation of the stem or progenitor cell populations in therapeutic strategies. (C) 2002 The Japanese Society of Hematology. C1 Univ Pittsburgh, Canc Inst, Sch Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Radiat Oncol, Sch Med, Pittsburgh, PA 15213 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, AIDS Res Ctr, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA USA. RP Cheng, T (reprint author), Univ Pittsburgh, Canc Inst, Sch Med, 200 Lothrop St BST-W942, Pittsburgh, PA 15213 USA. FU NHLBI NIH HHS [HL70561, HL65909]; NIDDK NIH HHS [DK02761, DK50234] NR 84 TC 23 Z9 30 U1 1 U2 3 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD JUN PY 2002 VL 75 IS 5 BP 460 EP 465 DI 10.1007/BF02982107 PG 6 WC Hematology SC Hematology GA 566NG UT WOS:000176434200002 PM 12095144 ER PT J AU Faraone, SV Short, EJ Biederman, J Findling, RL Roe, C Manos, MJ AF Faraone, SV Short, EJ Biederman, J Findling, RL Roe, C Manos, MJ TI Efficacy of Adderall and methylphenidate in attention deficit hyperactivity disorder: a drug-placebo and drug-drug response curve analysis of a naturalistic study SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Article DE Adderall; ADHD; clinical trial; methylphenidate; placebo ID DSM-III-R; DEFICIT/HYPERACTIVITY DISORDER; AUTISTIC DISORDER; CHILDREN; METHODOLOGY; REANALYSIS; TRIALS; ADHD AB Stimulant medication has, for many years, been the pharmacological treatment of choice for children and adults with attention deficit hyperactivity disorder (ADHD). Recently, several studies have documented the efficacy of a new stimulant, Adderall. Although these initial studies provide useful information for clinicians treating ADHD children, their method of data presentation has provided limited information about the clinical significance of drug effects. Thus, to address the issue of clinical significance, we completed drug-placebo response curve analyses of a blinded, placebo-controlled study of Adderall and methylphenidate (MPH). Our results show that the efficacy of Adderall and MPH to improve functioning is seen throughout the full range of improvement scores. Both drugs prevent worsening and, for a majority of patients, lead to improvements that are well into the normal range. The analyses also highlight an important subgroup of placebo responders, which suggests that future research should focus on how to predict robust placebo response in ADHD patients. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Child Psychiat Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Mental Hlth Ctr, Boston, MA 02115 USA. Harvard Univ, Inst Psychiat Epidemiol & Genet, Boston, MA 02115 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. RP Faraone, SV (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Child Psychiat Serv, ACC 725,15 Parkman St, Boston, MA 02114 USA. OI Faraone, Stephen/0000-0002-9217-3982 NR 19 TC 16 Z9 17 U1 0 U2 12 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4221 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD JUN PY 2002 VL 5 IS 2 BP 121 EP 129 DI 10.1017/S1461145702002845 PG 9 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 570KK UT WOS:000176657300003 PM 12135536 ER PT J AU Levy, RM Giannobile, WV Feres, M Haffajee, AD Smith, C Socransky, SS AF Levy, RM Giannobile, WV Feres, M Haffajee, AD Smith, C Socransky, SS TI The effect of apically repositioned flap surgery on clinical parameters and the composition of the subgingival microbiota: 12-month data SO INTERNATIONAL JOURNAL OF PERIODONTICS & RESTORATIVE DENTISTRY LA English DT Article ID RAPIDLY PROGRESSIVE PERIODONTITIS; MICROBIOLOGICAL PARAMETERS; PORPHYROMONAS-GINGIVALIS; CIGARETTE-SMOKING; THERAPY; PLAQUE; BACTERIA; MICROORGANISMS; RESPONSES; DISEASES AB The purpose of this investigation was to examine the clinical and microbiologic effects of apically repositioned flap surgery. Eighteen patients with chronic periodontitis received initial preparation (IP) including scaling and root planing, followed at 3 months by apically repositioned flap surgery at sites with pocket depth > 4 mm. Subjects were monitored clinically and microbiologically at baseline, 3 months after IP and at 3, 6, 9, and 12 months postsurgery, Clinical assessments of plaque accumulation, gingival redness, suppuration, bleeding on probing, pocket depth, and attachment level were made at six sites per tooth. Subgingival plaque samples were taken from the mesial aspect of each tooth, and the presence and levels of 40 subgingival taxa were determined using checkerboard DNA-DNA hybridization. Significant reductions were seen in mean pocket depth and percentage of sites exhibiting gingival redness and bleeding on probing in both sites that received IP only and in sites receiving IP followed by surgery. Mean attachment level increased significantly for both sets of sites, but the increase was greater at the surgically treated sites. The total DNA probe counts were significantly reduced at sites in both treatment groups. At surgically treated sites, 19 of 40 taxa were significantly reduced posttherapy. At sites receiving IP only, 16 species were significantly reduced over time. While there were some reductions in mean counts after IP in this site group, the major reductions occurred after the surgical phase in these patients, even though these particular sites did not receive surgical therapy. The reduction in pocket depth by surgical means and the associated decrease in reservoirs of periodontal pathogens may be important in achieving sustained periodontal stability. C1 Forsyth Inst, Dept Periodontol, Boston, MA 02115 USA. Univ Michigan, Sch Dent, Dept Periodont Prevent Geriatr, Ann Arbor, MI 48109 USA. Univ Guarulhos, Dept Periodontol, Dent Res Div, Sao Paulo, Brazil. RP Socransky, SS (reprint author), Forsyth Inst, Dept Periodontol, 140 Fenway, Boston, MA 02115 USA. RI Feres, Magda/H-7964-2012; OI Giannobile, William/0000-0002-7102-9746 FU NIDCR NIH HHS [DE-12108, DE-10977, R01 DE012108, R01 DE012108-02, R37 DE010977, R37 DE010977-05] NR 30 TC 17 Z9 18 U1 0 U2 0 PU QUINTESSENCE PUBL CO INC PI CAROL STREAM PA 551 NORTH KIMBERLY DR, CAROL STREAM, IL 60188-1881 USA SN 0198-7569 J9 INT J PERIODONT REST JI Int. J. Periodontics Restor. Dent. PD JUN PY 2002 VL 22 IS 3 BP 209 EP 219 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 582WW UT WOS:000177375000002 PM 12186343 ER PT J AU Jeter, MD Janne, PA Brooks, S Burstein, HJ Wen, P Fuchs, CS Loeffler, JS Devlin, PM Salgia, R AF Jeter, MD Janne, PA Brooks, S Burstein, HJ Wen, P Fuchs, CS Loeffler, JS Devlin, PM Salgia, R TI Gemcitabine-induced radiation recall SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article ID IMMUNE-DEFICIENCY-SYNDROME; COLON-CARCINOMA CELLS; MUCOCUTANEOUS REACTIONS; BREAST-CANCER; DERMATITIS; PATIENT; CHEMOTHERAPY; PACLITAXEL; ADRIAMYCIN; RADIOSENSITIZATION AB Purpose: To study and report 6 patients with radiation recall in unique sites, secondary to gemcitabine chemotherapy. Methods and Materials: The clinical presentations and outcomes of 6 patients with radiation recall secondary to gemcitabine chemotherapy were retrospectively analyzed over the course of a 1-year period. Results: Radiation recall reactions were seen in the central nervous system, skin, gastrointestinal tract, and in the lymphatic and musculoskeletal systems. The time between initiation of radiation and recall of the radiation phenomenon ranged from 3 weeds to 8 months from the time gemcitabine was initiated. The usual dosage of gemcitabine in these cases was 1000 mg/m(2) given on a weekly basis. No radiation therapy was given concomitantly with gemcitabine. Treatment of the recall reaction consisted of discontinuing gemcitabine and initiating steroid therapy, supportive therapy, and/or nonsteroidal anti-inflammatory agents. Minimal improvement was seen in 3 out of 6 patients, and resolution of the radiation recall was seen in 3 out of 6 patients. A comprehensive review of the literature revealed that radiation recall with gemcitabine has been related to skin reactions only, no previous cases of radiation recall occurring in the central nervous system have been reported with any chemotherapy agent. Conclusion: Radiation recall from gemcitabine chemotherapy is rare, but can potentially arise in any site that has been previously irradiated. Treating physicians must be aware of this potential toxicity from gemcitabine and radiation and discontinue the gemcitabine if radiation recall is observed. (C) 2002 Elsevier Science Inc. C1 Dana Farber Canc Inst, Dept Adult Oncol & Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Joint Ctr Radiat Therapy, Boston, MA USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Salgia, R (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, D1234B,44 Binney St, Boston, MA 02115 USA. NR 55 TC 76 Z9 79 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUN 1 PY 2002 VL 53 IS 2 BP 394 EP 400 AR PII S0360-3016(02)02773-6 DI 10.1016/S0360-3016(02)02773-6 PG 7 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 557TC UT WOS:000175923400017 PM 12023144 ER PT J AU Paganetti, H Niemierko, A Ancukiewicz, M Gerweck, LE Goitein, M Loeffler, JS Suit, HD AF Paganetti, H Niemierko, A Ancukiewicz, M Gerweck, LE Goitein, M Loeffler, JS Suit, HD TI Relative biological effectiveness (RBE) values for proton beam therapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE protons; RBE; relative biological effectiveness; normal tissues ID LOW-ENERGY PROTONS; CHINESE-HAMSTER CELLS; HUMAN-TUMOR-CELLS; GAMMA-RAYS; V79 CELLS; X-RAYS; CONFORMAL RADIOTHERAPY; RADIATION RESPONSE; MAMMALIAN-CELLS; NORMAL TISSUE AB Purpose: Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of 1.0 or 1.1, since the available evidence has been interpreted as indicating that the magnitude of RBE variation with treatment parameters is small relative to our abilities to determine RBEs. As substantial clinical experience and additional experimental determinations of RBE have accumulated and the number of proton radiation therapy centers is projected to increase, it is appropriate to reassess the rationale for the continued use of a generic RBE and for that RBE to be 1.0-1.1. Methods and Materials: Results of experimental determinations of RBE of in vitro and in vivo systems are examined, and then several of the considerations critical to a decision to move from a generic to tissue-, dose/fraction-, and LET-specific RBE values are assessed. The impact of an error in the value assigned to RBE on normal tissue complication probability (NTCP) is discussed. The incidence of major morbidity in proton-treated patients at Massachusetts General Hospital (NIGH) for malignant tumors of the skull base and of the prostate is reviewed. This is followed by an analysis of the magnitude of the experimental effort to exclude an error in RBE of greater than or equal to10% using in vivo systems. Results: The published RBE values, using colony formation as the measure of cell survival, from in vitro studies indicate a substantial spread between the diverse cell lines. The average value at mid SOBP (Spread Out Bragg Peak) over all dose levels is approximate to1.2, ranging from 0.9 to 2.1. The average RBE value at mid SOBP in vivo is approximate to1.1, ranging from 0.7 to 1.6. Overall, both in vitro and in vivo data indicate a statistically significant increase in RBE for lower doses per fraction, which is much smaller for in vivo systems. There is agreement that there is a measurable increase in RBE over the terminal few millimeters of the SOBP, which results in an extension of the bioeffective range of the beam in the range of 1-2 mm. There is no published report to indicate that the RBE of 1.1 is low. However, a substantial proportion of patients treated at approximate to2 cobalt Gray equivalent (CGE)/fraction 5 or more years ago were treated by a combination of both proton and photon beams. Were the RBE to be erroneously underestimated by approximate to10%, the increase in complication frequency would be quite serious were the complication incidence for the reference treatment greater than or equal to3% and the slope of the dose response curves steep, e.g., a gamma(50) approximate to 4. To exclude greater than or equal to1.2 as the correct RBE for a specific condition or tissue at the 95% confidence limit would require relatively large and multiple assays. Conclusions: At present, there is too much uncertainty in the RBE value for any human tissue to propose RBE values specific for tissue, dose/fraction, proton energy, etc. The experimental in vivo and clinical data indicate that continued employment of a generic RBE value and for that value to be 1.1 is reasonable. However, there is a local "hot region" over the terminal few millimeters of the SOBP and an extension of the biologically effective range. This needs to be considered in treatment planning, particularly for single field plans or for an end of range in or close to a critical structure. There is a clear need for prospective assessments of normal tissue reactions in proton irradiated patients and determinations of RBE values for several late responding tissues in laboratory animal systems, especially as a function of dose/fraction in the range of 1-4 Gy. (C) 2002 Elsevier Science Inc. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Paganetti, H (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. EM hpaganetti@partners.org FU NCI NIH HHS [CA 50628, CA21239] NR 72 TC 299 Z9 304 U1 6 U2 44 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUN 1 PY 2002 VL 53 IS 2 BP 407 EP 421 AR PII S0360-3016(02)02754-2 DI 10.1016/S0360-3016(02)02754-2 PG 15 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 557TC UT WOS:000175923400019 PM 12023146 ER PT J AU Pawlyk, BS Li, TS Scimeca, MS Sandberg, MA Berson, EL AF Pawlyk, BS Li, TS Scimeca, MS Sandberg, MA Berson, EL TI Absence of photoreceptor rescue with D-cis-diltiazem in the rd mouse SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CALCIUM-CHANNEL BLOCKER; ROD OUTER SEGMENT; RETINITIS-PIGMENTOSA; CYCLIC-GMP; BETA-SUBUNIT; RETINAL DEGENERATION; PLASMA-MEMBRANE; PHOSPHODIESTERASE; CONDUCTANCE; DISEASE AB PURPOSE. Because of a previous report suggesting that D-cis-diltiazem slows retinal degeneration in rd mice, this study, was undertaken to examine the effect of D-cis-diltiazem on photoreceptor structure and function in this line of mice. METHODS. Mice were randomly assigned to daily intraperitoneal injections of D-cis-diltiazem or saline between postnatal days 9 and 24. On postnatal day 26 or 27, retinal function was assessed by recording dark-adapted bright-flash ERGs in all animals. Retinal morphology was examined in fixed sections and in immunolabeled frozen sections. Examiners were masked to the treatment group assignment. RESULTS. On postnatal days 26 and 27, diltiazem- and saline-treated mice had only one row of remaining photoreceptor cells throughout most of the central retina. Cone cells in the periphery had remnants of inner segments. Total cell counts and separate counts of rod and cone photoreceptor cells by immunostaining were similar in the diltiazem- versus saline-treated mice. Both groups of mice had, on average, comparable subnormal ERG amplitudes. CONCLUSIONS. D-cis-Diltiazem had no detectable effect oil preservation of photoreceptor structure and function in rd mice. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. RP Berson, EL (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY10309, EY00169] NR 20 TC 43 Z9 45 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2002 VL 43 IS 6 BP 1912 EP 1915 PG 4 WC Ophthalmology SC Ophthalmology GA 557VA UT WOS:000175927800033 PM 12036998 ER PT J AU Sharon, D Yamamoto, H McGee, TL Rabe, V Szerencsei, RT Winkfein, R Prinsen, CFM Barnes, CS Andreasson, S Fishman, GA Schnetkamp, PPM Berson, EL Dryja, TP AF Sharon, D Yamamoto, H McGee, TL Rabe, V Szerencsei, RT Winkfein, R Prinsen, CFM Barnes, CS Andreasson, S Fishman, GA Schnetkamp, PPM Berson, EL Dryja, TP TI Mutated alleles of the rod and cone Na-Ca+K-exchanger genes in patients with retinal diseases SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID SODIUM-CALCIUM EXCHANGER; RETINITIS-PIGMENTOSA; MOLECULAR-CLONING; EXPRESSION; MUTATIONS; SEQUENCE; SUBUNIT; CHANNEL AB PURPOSE. To study the possible involvement of the rod (SLC24A1) and cone (SLC24A2) Na-Ca+K exchanger (NCKX) genes in retinal diseases. METHODS. DNA was collected from unrelated patients with retinal disease, mainly from North America. A human genomic library was screened with the cone NCKX cDNA, and hybridizing clones were sequenced to determine the genomic organization of the SLC24A2 gene. The single-strand conformation polymorphism (SSCP) technique and direct sequencing were used to screen the patients' DNA for mutations in SLC24A1 and SLC24A2. The effect of selected missense changes on protein function was tested by measuring potassium-dependent Na-Ca exchange of the mutant proteins expressed in insect cells. RESULTS. Twenty-seven novel sequence changes were found in the rod NCKX gene, 21 of which are unlikely to be pathogenic, because they did not cosegregate with the disease or did not affect conserved regions of the protein. Of the remaining six, two were frameshift mutations found in one patient each. If translated, these alleles would encode nonfunctional proteins. Three of the six possibly pathogenic mutations were missense changes located in conserved regions, and their protein functions were assayed. Only one (Ile992Thr) had a significantly low level of exchanger function, but it was found in two unrelated patients who were heterozygotes with different retinal diseases, and this mutation could not be unequivocally associated with either disease. The last of the six changes is likely to create a new splice acceptor site. The genomic organization of the cone NCKX gene was determined, and it contained 11 exons with a few splice variants. Fifteen novel sequence changes were identified in the cone exchanger gene in patients with a cone dysfunction or degeneration. Only three of these sequence changes, all missense changes found in heterozygous patients, were considered possibly pathogenic. Functional analysis showed only a slight reduction in the activity of the corresponding mutant proteins. CONCLUSIONS. Although variant alleles of the rod and cone NCKX genes were found, none could be definitively associated with a specific retinal disease. The human phenotype associated with mutant exchanger alleles remains unknown. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Med Genet Inst, Boston, MA 02114 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman gund Lab study Retinal Degenerat, Boston, MA 02114 USA. Univ Calgary, Fac Med, Dept Physiol & Biophys, Calgary, AB T2N 1N4, Canada. Univ Illinois, Dept Ophthalmol & Visual Sci, Chicago, IL USA. Lund Univ, Dept Ophthalmol, Lund, Sweden. RP Dryja, TP (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Med Genet Inst, 243 Charels St, Boston, MA 02114 USA. RI Sharon, Dror/P-4539-2015 OI Sharon, Dror/0000-0002-1789-5811 FU NEI NIH HHS [EY00169, EY08683] NR 17 TC 18 Z9 19 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD JUN PY 2002 VL 43 IS 6 BP 1971 EP 1979 PG 9 WC Ophthalmology SC Ophthalmology GA 557VA UT WOS:000175927800042 PM 12037007 ER PT J AU Kidd, G Arbogast, TL Mason, CR Walsh, M AF Kidd, G Arbogast, TL Mason, CR Walsh, M TI Informational masking in listeners with sensorineural hearing loss SO JARO LA English DT Article ID AUDITORY FILTER SHAPES; MULTICOMPONENT MASKERS; IMPAIRED LISTENERS; FREQUENCY-RESOLUTION; TONAL PATTERNS; NOISE; DISCRIMINATION; LEVEL; UNCERTAINTY; THRESHOLD AB Measures of energetic and informational masking were obtained from 46 listeners with sensorineural hearing loss. The task was to detect the presence of a sequence of eight contiguous 60-ms bursts of a pure tone embedded in masker bursts that were played synchronously with the signal. The masker was either a sequence of Gaussian noise bursts (energetic masker) or a sequence of random-frequency 2-tone bursts (informational masker). The 2-tone maskers were of two types: one type that normally tends to produce large amounts of informational masking and a second type that normally tends to produce very little informational masking. The two informational maskers are called "multiple-bursts same" (MBS), because the same frequency components are present in each burst of a sequence, and "multiple-bursts different" (MBD), because different frequency components are presented in each burst of a sequence. The difference in masking observed for these two maskers is thought to occur because the signal perceptually segregates from the masker in the MBD condition but fuses with the masker in MBS. In the present study, the effectiveness of the MBD masker, measured as the signal-to-masker ratio at masked threshold, increased with increasing hearing loss. In contrast, the signal-to-masker ratio at masked threshold for the MBS masker changed much less as a function of hearing loss. These results suggest that sensorineural hearing loss interferes with the ability of the listener to perceptually segregate individual components of complex sounds. The results from the energetic masking condition, which included critical ratio estimates for all listeners and auditory filter characteristics for a subset of the listeners, indicated that increasing hearing loss also reduced frequency selectivity at the signal frequency. Overall, these results suggest that the increased susceptibility to masking observed in listeners with sensorineural hearing loss is a consequence of both peripheral and central processes. C1 Boston Univ, Dept Commun Disorders, Boston, MA 02215 USA. Boston Univ, Hearing Res Ctr, Boston, MA 02215 USA. VA Boston Healthcare Syst, Audiol Speech Pathol Serv, Boston, MA 02130 USA. RP Kidd, G (reprint author), Boston Univ, Dept Commun Disorders, 635 Commonwealth Ave, Boston, MA 02215 USA. FU NIDCD NIH HHS [DC04545, DC00100, R01 DC004545] NR 32 TC 24 Z9 25 U1 0 U2 4 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1525-3961 J9 JARO JI JARO PD JUN PY 2002 VL 3 IS 2 BP 107 EP 119 DI 10.1007/s1016200210095 PG 13 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 566TB UT WOS:000176443400001 PM 12162362 ER PT J AU Chen, ZY Corey, DP AF Chen, ZY Corey, DP TI An inner ear gene expression database SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE cochlea; utricle; microarray; genomic; Wnt ID ARREST-SPECIFIC GENE; CANDIDATE GENES; HUMAN-GENOME; PROTEIN; GROWTH; CELLS; IDENTIFICATION; SEQUENCE; HEARING; CANCER AB Microarray technology has provided an unprecedented opportunity to study gene expression profiles at a whole-genome level. As a first step toward a comprehensive understanding of inner ear gene expression, mouse cochleas were examined at two developmental stages (P2 and P32) using GeneChip oligonucleotide arrays. A large number of genes and ESTs (>10,000) were found to be expressed in the cochlea. Expression profiles derived from duplicate samples at the same developmental stages showed general agreement and indicated the reproducibility of the assay. The expression of many known hair-cell genes was detected in the whole-cochlea samples, demonstrating the relatively high sensitivity of the assay. Genes highly expressed only at P2 or P32 were also identified and their expression patterns correlate with their functions in the cochlea. A web-based database with external links was set up for public access, which should facilitate the discovery of genes important in the development and function of the inner car and Should aid the identification of additional deafness genes. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02114 USA. Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Chen, ZY (reprint author), Massachusetts Gen Hosp, Dept Neurol, WEL415, Boston, MA 02114 USA. EM zhengyi@helix.mgh.harvard.edu OI Corey, David/0000-0003-4497-6016 FU NIDCD NIH HHS [R01-DC02281]; NIMHD NIH HHS [263MD008288] NR 36 TC 36 Z9 40 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 J9 JARO-J ASSOC RES OTO JI JARO PD JUN PY 2002 VL 3 IS 2 BP 140 EP 148 DI 10.1007/s101620020029 PG 9 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 566TB UT WOS:000176443400003 PM 12162364 ER PT J AU Hamblin, MR O'Donnell, DA Murthy, N Rajagopalan, K Michaud, N Sherwood, ME Hasan, T AF Hamblin, MR O'Donnell, DA Murthy, N Rajagopalan, K Michaud, N Sherwood, ME Hasan, T TI Polycationic photosensitizer conjugates: effects of chain length and Gram classification on the photodynamic inactivation of bacteria SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE photodynamic therapy; polylysine; Escherichia coli; Staphylococcus aureus; electron microscopy ID MESOSUBSTITUTED CATIONIC PORPHYRINS; LIPID-SOLUBLE PHTHALOCYANINES; OUTER-MEMBRANE PERMEABILITY; PURE SINGLET OXYGEN; ESCHERICHIA-COLI; NEGATIVE BACTERIA; POSITIVE BACTERIA; EFFICIENT PHOTOSENSITIZERS; STAPHYLOCOCCUS-AUREUS; SUPEROXIDE-DISMUTASE AB Objectives: We have shown previously that a polycationic conjugate between poly-l-lysine and the photosensitizer chlorin(e6) was effective in photodynamic inactivation (PDI) of both Gram-positive and Gram-negative bacteria. In this report we explore the relationship between the size of the polylysine chain and its effectiveness for mediating the killing of Gram-negative and Gram-positive bacteria. Methods: Conjugates were prepared by attaching precisely one chlorin(e6) molecule to the alpha-amino group of poly-(epsilon-benzyloxycarbonyl)lysines of average length eight and 37 lysine residues, followed by deprotection of the epsilon-amino groups, and were characterized by iso-electric focusing. The uptake of these conjugates and free chlorin(e6) by Gram-positive Staphylococcus aureus (ATCC 27659) and Gram-negative Escherichia coli (ATCC 29181) after washing was measured as a function of photosensitizer concentration (0-4 muM chlorin(e6) equivalent) and incubation time. After incubation the bacteria were exposed to low fluences (10-40 J/cm(2)) of 660 nm light delivered from a diode laser, and viability was assessed after serial dilutions by a colony-forming assay. Results: S. aureus and E. coli took up comparable amounts of the two conjugates, but free chlorin(e6) was only taken up by S. aureus. After illumination S. aureus was killed in a fluence-dependent fashion when loaded with the 8-lysine conjugate and free chlorin(e6) but somewhat less so with the 37-lysine conjugate. In contrast, PDI of E. coli was only effective with the 37-lysine conjugate at concentrations up to 4 muM. PDI using the 8-lysine conjugate and free chlorin(e6) on E. coli was observed at a concentration of 100 muM. Transmission electron micrographs showed internal electron-lucent areas consistent with chromosomal damage. Conclusion: These results can be explained by the necessity of a large polycation to penetrate the impermeable outer membrane of Gram-negative E. coli, while Gram-positive S. aureus is more easily penetrated by small molecules. However, because S. aureus is more sensitive overall than E. coli the 37-lysine conjugate can effectively kill both bacteria. C1 Massachusetts Gen Hosp, Dept Dermatol, Wellman Labs Photomed, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02114 USA. RP Hamblin, MR (reprint author), Massachusetts Gen Hosp, Dept Dermatol, Wellman Labs Photomed, 50 Blossom St,WEL 224, Boston, MA 02114 USA. EM hamblin@helix.mgh.harvard.edu OI Hamblin, Michael/0000-0001-6431-4605 NR 56 TC 163 Z9 169 U1 1 U2 25 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD JUN PY 2002 VL 49 IS 6 BP 941 EP 951 DI 10.1093/jac/dkf053 PG 11 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 557MD UT WOS:000175911600009 PM 12039886 ER PT J AU Haddad, FS Duncan, CP Berry, DJ Lewallen, DG Gross, AE Chandler, HP AF Haddad, FS Duncan, CP Berry, DJ Lewallen, DG Gross, AE Chandler, HP TI Periprosthetic femoral fractures around well-fixed implants: Use of cortical onlay allografts with or without a plate SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID TOTAL HIP-ARTHROPLASTY; MENNEN PLATE; FEMUR; FIXATION; SHAFT; KNEE AB Background: Periprosthetic femoral fractures around hip replacements are increasingly common. When the femoral component is stable, open reduction and internal fixation is recommended in all but exceptional cases. The purpose of this study was to evaluate the outcome of treatment of fractures around stable implants with cortical onlay strut allografts with or without a plate. Methods: A survey of our four centers identified forty patients with a fracture around a well-fixed femoral stem treated with cortical onlay strut allografts without revision of the femoral component. There were fourteen men and twenty-six women, with an average age of sixty-nine years. Nineteen patients were treated with cortical onlay strut allografts alone, and twenty-one were managed with a plate and one or two cortical struts. All of the patients were followed until fracture union or until a reoperation was done. The mean duration of follow-up was twenty-eight months for thirty-nine patients. One patient, who was noncompliant with treatment recommendations, had a failure at two months because of a fracture of the plate and graft. The primary end point of the evaluation was fracture union; secondary endpoints included strut-to-host bone union, the amount of final bone stock, and postoperative function. Results: Thirty-nine (98%) of the forty fractures united, and strut-to-host bone union was typically seen within the first year. There were four malunions, all of which had <10degrees of malalignment, and one deep infection. There was no evidence of femoral loosening in any patient. All but one of the surviving patients returned to their preoperative functional level within one year. Conclusions: Cortical onlay strut allografts act as biological bone plates, serving both a mechanical and a biological function. The use of cortical struts, either alone or in conjunction with a plate, led to a very high rate of fracture union, satisfactory alignment, and an increase in femoral bone stock at the time of short-term follow-up. Although this study did not address the potential for later allograft remodeling, our findings suggest that cortical strut grafts should be used routinely to augment fixation and healing of a periprosthetic femoral fracture. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Toronto, Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. Mayo Clin, Rochester, MN 55905 USA. Vancouver Gen Hosp, Vancouver, BC V5Z 4E3, Canada. RP Haddad, FS (reprint author), 46B Hanover Gate Mans,Pk Rd, London NW1 4SN, England. NR 27 TC 110 Z9 124 U1 1 U2 2 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 JUN PY 2002 VL 84A IS 6 BP 945 EP 950 PG 6 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 561ZZ UT WOS:000176174100008 PM 12063328 ER PT J AU DiGiovanni, CW Kuo, R Tejwani, N Price, R Hansen, ST Cziernecki, J Sangeorzan, BJ AF DiGiovanni, CW Kuo, R Tejwani, N Price, R Hansen, ST Cziernecki, J Sangeorzan, BJ TI Isolated gastrocnemius tightness SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID LIMITED JOINT MOBILITY; DIABETIC-PATIENTS; EQUINUS DEFORMITY; ACHILLES-TENDON; FOOT ULCERATION; CEREBRAL-PALSY; ANKLE EQUINUS; TIBIAL NERVE; CHILDREN; NEUROPATHY AB Background: Contracture of the gastrocnemius-soleus complex has well-documented deleterious effects on lower-limb function in spastic or neurologically impaired individuals. There is scarce literature, however, on the existence of isolated gastrocnemius contracture or its impact in otherwise normal patients. We hypothesized that an inability to dorsiflex the ankle due to equinus contracture leads to increased pain in the forefoot and/or midfoot and therefore a population with such pain will have less maximum ankle dorsiflexion than controls. We further postulated that the difference would be present whether the knee was extended or flexed. Methods: This investigation was a prospective comparison of maximal ankle dorsiflexion, as a proxy for gastrocnemius tension, in response to a load applied to the undersurface of the foot in two healthy age, weight, and sex-matched groups. The patient group comprised thirty-four consecutive patients with a diagnosis of metatarsalgia or related midfoot and/or forefoot symptoms. The control group consisted of thirty-four individuals without foot or ankle symptoms. The participants were clinically examined for gastrocnemius and soleus contracture and were subsequently assessed for tightness with use of a specially designed electrogoniometer. Measurements were made both with the knee extended (the gastrocnemius under tension) and with the knee flexed (the gastrocnemius relaxed). Results: With the knee fully extended, the average maximal ankle dorsiflexion was 4.5degrees the patient group and 13.1degrees in the control group (p < 0.001). With the knee flexed 90, the average was 17.9degrees in the patient group and 22.3degrees in the control population (p = 0.09). When gastrocnemius contracture was defined as dorsiflexion of less than or equal to5degrees during knee extension, it was identified in 65% of the patients compared with 24% of the control population. However, when gastrocnemius contracture was defined as dorsiflexion of 510, it was present in 88% and 44%, respectively. When gastrocnemius-soleus contracture was defined as dorsiflexion of less than or equal to10degrees with the knee in 90degrees of flexion, it was identified in 29% of the patient group and 15% of the control group. Conclusions: On the average, patients with forefoot and/or midfoot symptoms had less maximum ankle dorsiflexion with the knee extended than did a control population without foot or ankle symptoms. When the knee was flexed 90 to relax the gastrocnemius, this difference was no longer present. Clinical Relevance: These findings support the existence of isolated gastrocnemius contracture in the development of forefoot and/or midfoot pathology in otherwise healthy people. These data may have implications for preventative and therapeutic care of patients with chronic foot problems. C1 Brown Univ, Sch Med, Dept Orthopaed, Univ Orthopaed Inc, Providence, RI 02904 USA. NYU, Sch Med, Dept Orthopaed, Edgewater, NJ 07020 USA. Univ Washington, Dept Rehabil Med, RR&D Ctr, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Harborview Med Ctr, Dept Orthopaed, Seattle, WA 98104 USA. Seattle Vet Affairs Med Ctr, Seattle, WA USA. RP DiGiovanni, CW (reprint author), Brown Univ, Sch Med, Dept Orthopaed, Univ Orthopaed Inc, 1287 N Main St, Providence, RI 02904 USA. NR 53 TC 152 Z9 157 U1 0 U2 2 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 JUN PY 2002 VL 84A IS 6 BP 962 EP 970 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 561ZZ UT WOS:000176174100010 PM 12063330 ER PT J AU Wells, MJ Wilkie, DJ Brown, MA Corless, IB Farber, SJ Judge, MKM Shannon, SE AF Wells, MJ Wilkie, DJ Brown, MA Corless, IB Farber, SJ Judge, MKM Shannon, SE TI Technology available in nursing programs: Implications for developing virtual end-of-life educational tools SO JOURNAL OF CANCER EDUCATION LA English DT Article ID PALLIATIVE CARE; MULTIMEDIA; CLASSROOM; FUTURE; NURSES AB Background. To overcome insufficient attention to end-of-life (EOL) care in nursing education, the authors are developing the "Toolkit for Nursing Excellence at End-of-Life Transition" (TNEEL). Method. An evidence-based design process was used to create a computerized (CD-ROM) multimedia toolkit of instructional aides. An online survey of all U.S. undergraduate nursing programs was conducted to identify their current technologic infrastructures available for innovative teaching aides. Expert review process guided pedagogic decisions. Results. Survey findings enabled TNEEL development to be responsive to nurse educators' needs and preferences. Conclusion. Educators can use TNEEL to actively engage students in meaningful learning about EOL care. C1 Univ Washington, Sch Nursing, Seattle, WA 98195 USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. Massachusetts Gen Hosp, MGH Inst Hlth Profess, Boston, MA 02114 USA. RP Wilkie, DJ (reprint author), Univ Washington, Sch Nursing, Box 367266, Seattle, WA 98195 USA. OI Corless, Inge/0000-0003-0438-2037 NR 49 TC 2 Z9 2 U1 4 U2 7 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 0885-8195 J9 J CANCER EDUC JI J. Cancer Educ. PD SUM PY 2002 VL 17 IS 2 BP 92 EP 96 PG 5 WC Oncology; Education, Scientific Disciplines; Public, Environmental & Occupational Health SC Oncology; Education & Educational Research; Public, Environmental & Occupational Health GA 567NY UT WOS:000176491900008 PM 12092860 ER PT J AU Teerlink, JR AF Teerlink, JR TI Recent heart failure trials of neurohormonal modulation (OVERTURE and ENABLE): Approaching the asymptote of efficacy? SO JOURNAL OF CARDIAC FAILURE LA English DT Article ID RANDOMIZED TRIAL; CLINICAL-TRIALS; UPDATE; MERIT C1 San Francisco VA Med Ctr, Cardiol Sect, San Francisco, CA 94121 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. RP Teerlink, JR (reprint author), San Francisco VA Med Ctr, Cardiol Sect, 4150 Clement St, San Francisco, CA 94121 USA. RI Teerlink, John/D-2986-2012 NR 6 TC 45 Z9 45 U1 0 U2 0 PU CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS PI PHILADELPHIA PA CURTIS CENTER, INDEPENDENCE SQUARE WEST, PHILADELPHIA, PA 19106-3399 USA SN 1071-9164 J9 J CARD FAIL JI J. Card. Fail. PD JUN PY 2002 VL 8 IS 3 BP 124 EP 127 DI 10.1054/jcaf.2002.126486 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 579NH UT WOS:000177184400003 PM 12140803 ER PT J AU Wozniak, J Biederman, J Monuteaux, MC Richards, J Faraone, SV AF Wozniak, J Biederman, J Monuteaux, MC Richards, J Faraone, SV TI Parsing the comorbidity between bipolar disorder and anxiety disorders: A familial risk analysis SO JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; PANIC DISORDER; CHILDREN; MANIA; RELIABILITY; SUBTYPE; INTERVIEW; FEATURES AB Background: A growing literature suggests that anxiety disorders (ANX) co-occur with bipolar disorder (BPD), but the nature of this overlap is unknown. Thus, we investigated the familial association between BPD and ANX among the first-degree relatives of children with BPD with and without comorbid ANX. Methods: We compared relatives of four proband groups defined by the presence or absence of BPD and ANX in the proband: (1) BPD + ANX (n=23 probands, 74 relatives), (2) BPD without ANX (n=11 probands, 38 relatives), (3) ANX without BPD (n=48 probands,167 relatives), and (4) controls without BPD or ANX (n=118 probands, 385 relatives). All subjects were evaluated with structured diagnostic interviews. Diagnoses of relatives were made blind to the diagnoses of probands. Results: The results show high rates of both BPD and ANX in relatives of children with BPD + ANX. Moreover, BPD and ANX cosegregated among the relatives of children with BPD + ANX. Although relatives of both ANX proband groups (with and without BPD) had high rates of ANX, and relatives of both BPD proband groups (with and without ANX) had high rates of BPD, the combined condition BPD + ANX was the predominant form of BPD among relatives of probands with BPD + ANX. Conclusions: These family-genetic findings suggest that the comorbid condition BPD+ANX may be a distinct clinical entity. More work is needed to evaluate whether the presence of comorbid ANX may be a marker of very early onset BPD. C1 Harvard Univ, Child Psychiat Serv, Pediat Psychopharmacol Unit, Med Sch,Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wozniak, J (reprint author), Harvard Univ, Child Psychiat Serv, Pediat Psychopharmacol Unit, Med Sch,Massachusetts Gen Hosp, ACC 725,MGH Fruit St, Boston, MA 02114 USA. OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [R01 MH50657-05] NR 35 TC 64 Z9 64 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1044-5463 J9 J CHILD ADOL PSYCHOP JI J. Child Adolesc. Psychopharmacol. PD SUM PY 2002 VL 12 IS 2 BP 101 EP 111 DI 10.1089/104454602760219144 PG 11 WC Pediatrics; Pharmacology & Pharmacy; Psychiatry SC Pediatrics; Pharmacology & Pharmacy; Psychiatry GA 576HM UT WOS:000176997900004 PM 12188979 ER PT J AU Felbinger, TW Reuter, DA Eltzschig, HK Moerstedt, K Goedje, O Goetz, AE AF Felbinger, TW Reuter, DA Eltzschig, HK Moerstedt, K Goedje, O Goetz, AE TI Comparison of pulmonary arterial thermodilution and arterial pulse contour analysis: Evaluation of a new algorithm SO JOURNAL OF CLINICAL ANESTHESIA LA English DT Article DE cardiac index; cardiac output; pulse contour analysis; thermodilution ID CONTINUOUS CARDIAC-OUTPUT; CRITICALLY ILL PATIENTS; PRESSURE WAVE-FORM; INTENSIVE-CARE; MODEL; CATHETER; SURGERY AB Study Objective: To compare cardiac index (CI) measurement by arterial pulse contour analysis using two different algorithms (CIPC, CIPCnew) with pulmonary arterial thermodilution values (CIPA) so as to evaluate the difference between the conventional algorithm, CIPC, and a new algorithm, CIPCnew, that accounts for patients' individual aortic compliance. Design: Prospective clinical study Setting: Intensive care unit of a university hospital. Patients: 20 ASA physical status II and III patients following elective cardiac surgery. Measurements and Main Results: 360 parallel triplicate determinations of CI (CIPA, CIPC, CIPCnew) were performed within a 90-minute period during the immediate postoperative period. Prior to the start of the study period, CIPC as well as CIPCnew were calibrated by triplicate femoral arterial thermodilution measurements. Regression analysis of CIPA and CIPC, as well as CIPA and CIPCnew revealed r = 0.89, p < 0.001, and r = 0.93, p < 0.001, respectively. Bland-Altman analysis was used for determining the accuracy and precision of CIPC and CIPCnew compared with CIPA. The mean differences (m) and standard deviation (SD) between CIPA and CIPC, as well as CIPA and CIPCnew resulted in m = -0.312 L/min/m(2), SD = 0.456 L/min/m(2), and m = -0.140 L/min/m(2), SD = 0.328 L/min/m(2), respectively. Conclusion: Arterial pulse contour analysis measurement of CI using either algorithm correlates well with CI values derived by pulmonary arterial thermodilution. However, the algorithm introduced in this study proved to be a more accurate predictor of values as derived by pulmonary artery catheter. (C) 2002 by Elsevier Science Inc. C1 Univ Munich, Grosshadern Med Ctr, D-80539 Munich, Germany. RP Felbinger, TW (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. NR 22 TC 35 Z9 36 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0952-8180 J9 J CLIN ANESTH JI J. Clin. Anesth. PD JUN PY 2002 VL 14 IS 4 BP 296 EP 301 AR PII S0952-8180(02)00363-X DI 10.1016/S0952-8180(02)00363-X PG 6 WC Anesthesiology SC Anesthesiology GA 569CU UT WOS:000176583500012 PM 12088815 ER PT J AU Miller, KK Biller, BMK Hier, J Arena, E Klibanski, A AF Miller, KK Biller, BMK Hier, J Arena, E Klibanski, A TI Androgens and bone density in women with hypopituitarism SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID X-RAY ABSORPTIOMETRY; HUMAN THECAL CELLS; GROWTH-FACTOR-I; MINERAL DENSITY; ANOREXIA-NERVOSA; SEX STEROIDS; POSTMENOPAUSAL WOMEN; GH DEFICIENCY; IGF-I; MEN AB Hypopituitarism is associated with osteopenia and a reduction in lean body mass. We have recently demonstrated markedly reduced serum androgen levels in women with hypopituitarism. We hypothesized that serum androgen levels and lean body mass are important determinants of bone mineral density (BMD) in women with hypopituitarism. In addition, because IGF-I may stimulate androgen secretion in women, we investigated whether GH administration results in an increase in serum androgen levels. Sixteen women with a history of pituitary disease of adult-onset and serum GH levels less than 5 ng/ml on stimulation testing underwent BMD and body composition testing by dual-energy x-ray absorptiometry. Univariate regression analysis revealed strong correlations between androgen levels and BMD [lateral spine BMD and dehydroepiandrosterone sulfate (DHEAS) (r = 0.68, P = 0.03), total hip BMD and free T (r = 0.60, P = 0.01), Ward's triangle BMD and DHEAS (r = 0.68, P = 0.004), Ward's triangle BMD and free T (r = 0.54, P = 0.03), femoral neck BMD and free T (r = 0.52, P = 0.04), and femoral neck BMD and DHEAS (r = 0.51, P = 0.04)]. When adjusted for age using Z scores, correlations at the femoral neck no longer reach significance. Correlations between androgens and BMD at other sites, including anterior-posterior spine and total body, were not significant, and neither total T nor androstenedione correlated with BMD at any site. Lean body mass strongly correlated with BMD [total hip (r = 0.80, P = 0.0002), total body (r = 0.78, P = 0.0003), trochanter (r = 0.74, P = 0.001), Ward's triangle (r = 0.56, P = 0.02), femoral neck (r = 0.53, P = 0.04), and anterior-posterior spine (r = 0.52, P = 0.04)]. In stepwise regression models, DHEAS determined 47% of the variation in Ward's triangle BMD (R(2) = 0.47, P = 0.004) and 46% of lateral spine BMD (R(2) = 0.46, P 0.03). Lean body mass determined 64% of the variation in total hip BMD (R(2) = 0.64, P = 0.0002), 62% of total body (R(2) = 0.62, P = 0.0003), and 55% of trochanter BMD (R(2) = 0.55, P = 0.001). Subjects were then randomized to receive GH at a dose of 12.5 mug/kg per day or placebo for 12 months in a double-blind protocol. Serum androgen levels were obtained at baseline, 1, 3, 6, 9, and 12 months after initiation of GH. Androgen levels did not increase in the women receiving GH for 12 months, compared with those receiving placebo. Stimulation of androgen secretion is therefore unlikely to be a mechanism underlying the improvement in BMD, body composition, or quality of life observed with GH administration. In conclusion, androgen levels and lean body mass may be important determinants of BMD in women with hypopituitarism. It remains to be determined whether androgen replacement therapy itself or an increase in lean body mass achieved as a result of androgen administration will result in an improvement in BMD in this population. C1 Massachusetts Gen Hosp, Neuroendocrinol Unit, Dept Med, Clin Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Miller, KK (reprint author), Massachusetts Gen Hosp, Neuroendocrinol Unit, Dept Med, Clin Res Ctr, Bulfinch 457B,, Boston, MA 02114 USA. EM kkmiller@partners.org FU NCRR NIH HHS [M01 RR 01066] NR 32 TC 20 Z9 21 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 JUN PY 2002 VL 87 IS 6 BP 2770 EP 2776 DI 10.1210/jc.87.6.2770 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 563DW UT WOS:000176241000053 PM 12050248 ER PT J AU Grinspoon, S Thomas, L Miller, K Herzog, D Klibanski, A AF Grinspoon, S Thomas, L Miller, K Herzog, D Klibanski, A TI Effects of recombinant human IGF-1 and oral contraceptive administration on bone density in anorexia nervosa SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID GROWTH-FACTOR-I; BINDING PROTEIN; MINERAL DENSITY; WOMEN; OSTEOPOROSIS; HORMONE; TURNOVER; ESTROGEN; PREVALENCE; OSTEOPENIA AB Over 90% of women with anorexia nervosa demonstrate osteopenia, and almost 40% demonstrate osteoporosis at one or more skeletal sites. In addition to estrogen deficiency causing an increase in bone resorption, nutritional effects on the GH-IGI-I axis may contribute to the severe bone loss in this population by decreasing bone formation. We tested the hypothesis that recombinant human IGF-I (rhIGF-I) would increase bone density in women with anorexia nervosa and furthermore assessed the effects of combined rhIGF-I and oral contraceptive administration (OCP) in this population. Sixty osteopenic women with Diagnosis and Statistical Manual of Mental Disorders IV Revised confirmed anorexia nervosa [age (25.2 +/- 0.7 yr, range 18-38 yr), body mass index (17.8 +/- 0.3 kg/m(2)), spinal bone mineral density T score (-2.1 +/- 0.1 SD) were randomized to one of four treatment groups [rhIGF-I (30 mug/kg sc twice daily) and a daily oral contraceptive (Ovcon 35, 35 mug ethinyl estradiol and 0.4 mg norethindrone], rhIGF-I alone (30 mug/kg sc twice daily), oral contraceptive alone, or neither treatment for 9 months. All subjects received calcium 1500 mg/d and a standard multivitamin containing 400 IU of vitamin D. Administration of rhIGF-I was placebo controlled and blinded to subjects. The rhIGF-I was titrated to maintain IGF-I levels within the age-adjusted normal range for each patient and was well tolerated. The effects of rhIGF-I and OCP were analyzed simultaneously among all subjects in a factorial analysis and in an analysis of the four individual treatment groups. Anteroposterior spinal bone density increased significantly in response to rhIGF-I (1.1% +/- 0.5% vs. -0.6% +/- 0.8%, P = 0.05, all rhIGF-I vs. all placebo treated, respectively, by analysis of covariance). In contrast, OCP did not result in increased bone density (0.8% +/- 0.6% vs. -0.4% +/- 0.8%, P = 0.21, all OCP vs. all non-OCP treated, respectively, by analysis of covariance). However, bone density increased to the greatest extent in the combined treatment group (rhIGF-I and OCP), compared with control patients receiving no active therapy (1.8%, +/- 0.8% vs. 0.3% +/- 0.6% vs. - 0.2% +/- 0.8% vs. - 1.0% +/- 1.3%, rhIGF-I and OCP vs. rhIGF-I alone vs. OCP alone vs. no active therapy, P < 0.05 for rhIGF-I and OCP vs. no active therapy). These data demonstrate that osteopenic women with anorexia nervosa treated with rhIGF-I showed more beneficial changes in bone density, compared with patients not treated with rhIGF-I. Antiresorptive therapy with OCP is not sufficient to improve bone density in undernourished patients, but such therapy may augment the effects of rhIGF-I in a combined treatment strategy. Further long-term studies are needed to investigate the effects of rhIGF-I and combined anabolic/antiresorptive strategies on bone in women with anorexia nervosa. C1 Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Adolescent Eating Disorders, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Neuroendocrine Unit, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NIDDK NIH HHS [P30 DK040561, P30 DK040561-08, R01 DK 52625] NR 27 TC 180 Z9 183 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 JUN PY 2002 VL 87 IS 6 BP 2883 EP 2891 DI 10.1210/jc.87.6.2883 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 563DW UT WOS:000176241000069 PM 12050268 ER PT J AU Ichinose, F Ullrich, R Sapirstein, A Jones, RC Bonventre, JV Serhan, CN Bloch, KD Zapol, WM AF Ichinose, F Ullrich, R Sapirstein, A Jones, RC Bonventre, JV Serhan, CN Bloch, KD Zapol, WM TI Cytosolic phospholipase A(2) in hypoxic pulmonary vasoconstriction SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NADPH-OXIDASE; ARACHIDONIC-ACID; BLOOD-FLOW; MICE; HYPERTENSION; INJURY; CELLS; GENERATION; BRAIN; LUNGS AB Cytosolic phospholipase A(2) (cPLA(2)) releases arachidonic acid (AA) from phospholipids in cell membranes. To assess the role of cPLA2 in hypoxic pulmonary vasoconstriction. (HPV), we measured the increase in left lung pulmonary vascular resistance (LPVR) before and during hypoxia produced by left main stem bronchus occlusion (LMBO) in mice with and without a targeted deletion of the PLA2g4a gene that encodes cPLA(2alpha.) LMBO increased LPVR in cPLA(2alpha)(+/+) mice but not in cPLA(2alpha)(-/-) mice. cPLA(2alpha)(+/+) mice were better able to maintain systemic oxygenation during LMBO than were cPLA(2alpha)(-/-) mice. Administration of a cPLA(2alpha)(-/-) inhibitor, arachidonyl trifluoromethyl ketone, blocked the LMBO-induced increase in LPVR in wild-type mice, while exogenous AA restored HPV in cPLA(2alpha)(-/-) mice. Intravenous angiotensin II infusion increased PVR similarly in cPLA(2alpha)(+/+) and cPLA(2alpha)(-/-) mice. Inhibitors of cyclooxygenase or nitric oxide synthase restored HPV in cPLA(2alpha)(-/-) mice. Breathing 10% oxygen for 3 weeks produced less right ventricular hypertrophy in cPLA(2alpha)(-/-) than in cPLA(2alpha)(+/+) mice, but restored HPV in cPLA(2alpha)(-/-) mice despite the continued absence of cPLA(2) activity. These results indicate that cPLA2 contributes to the murine pulmonary vasoconstrictor response to hypoxia. Augmenting pulmonary vascular tone restores HPV in the absence of cPLA, activity. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Renal Div, Boston, MA 02114 USA. RP Ichinose, F (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL-42397, HL-57172, R01 HL042397]; NIDCR NIH HHS [P01 DE013499, P01-DE-13499]; NIDDK NIH HHS [DK-02493, DK-50305, P01 DK050305] NR 33 TC 44 Z9 46 U1 0 U2 1 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 JUN PY 2002 VL 109 IS 11 BP 1493 EP 1500 DI 10.1172/JCI200214294 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 559FN UT WOS:000176015300013 PM 12045263 ER PT J AU Nakorn, TN Traver, D Weissman, IL Akashi, K AF Nakorn, TN Traver, D Weissman, IL Akashi, K TI Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU-S SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID HEMATOPOIETIC STEM-CELLS; COLONY-FORMING CELLS; BONE-MARROW; MEGAKARYOCYTE COLONIES; PAIRED PROGENITORS; FORMATION INVITRO; DIFFERENTIATION; IDENTIFICATION; TRANSPLANTATION; CULTURE AB Whole-body irradiation at the minimal lethal dose causes bone marrow failure and death within 12-18 days. To identify the principal components of the hematopoietic system that are radioprotective, we transplanted lethally irradiated mice with purified progenitors: common myeloid progenitors (CMPs), megakaryocyte/erythrocyte-restricted progenitors (MEPs), or granulocyte/monocyte-restricted progenitors (GMPs). Transplanted CMPs gave rise to cells both of the granulocyte/monocyte (GM) series and the megakaryocyte/erythrocyte series, whereas GMPs or MEPs showed reconstitution of only GM or ME cells, respectively. CMPs and MEPs but not GMPs protected mice in a dose-dependent manner, suggesting that erythrocytes, platelets, or both are the critical effectors of radioprotection. Accordingly, CMPs and MEPs formed robust colonies in recipient bone marrow and spleen, whereas GMPs formed small colonies that rapidly disappeared. Direct comparisons of spleen CFU (CFU-S) potentials among each progenitor subset showed that MEPs contain the vast majority of day 8 CFU-S activity, suggesting that day 8 CFU-S are the precursors of radioprotective cell subsets. All animals radioprotected for 30 days subsequently survived for at least 6 months post-transplant, and showed only host-derived hematopoiesis after 30 days. These findings suggest that rare hematopoietic stem cells survive myeloablation that can eventually repopulate irradiated hosts if myeloerythroid-restricted progenitors transiently rescue ablated animals through the critical window of bone marrow failure. C1 Stanford Univ, Sch Med, Dept Pathol, Beckman Ctr, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. RP Nakorn, TN (reprint author), Stanford Univ, Sch Med, Dept Pathol, Beckman Ctr, 279 Campus Dr,Rm B261, Stanford, CA 94305 USA. NR 40 TC 82 Z9 84 U1 0 U2 1 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 JUN PY 2002 VL 109 IS 12 BP 1579 EP 1585 DI 10.1172/JCI200215272 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 564MR UT WOS:000176318600011 ER PT J AU Fridkis-Hareli, M Santambrogio, L Stern, JNH Fugger, L Brosnan, C Strominger, JL AF Fridkis-Hareli, M Santambrogio, L Stern, JNH Fugger, L Brosnan, C Strominger, JL TI Novel synthetic amino acid copolymers that inhibit autoantigen-specific T cell responses and suppress experimental autoimmune encephalomyelitis SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID MYELIN BASIC-PROTEIN; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; REMITTING MULTIPLE-SCLEROSIS; ANTIGEN-PRESENTING CELLS; HISTOCOMPATIBILITY COMPLEX-MOLECULES; TUMOR-NECROSIS-FACTOR; GLATIRAMER ACETATE; PROTEOLIPID PROTEIN; ENCEPHALITOGENIC DETERMINANT; RECEPTOR ANTAGONISM AB Copolymer 1 (Cop 1, Copaxone [Teva Marion Partners, Kansas City, Missouri, USA]), a random amino acid copolymer of tyrosine (Y), glutamic acid (E), alanine (A), and lysine (K), reduces the frequency of relapses by 30% in relapsing-remitting multiple sclerosis (MS) patients. In the present study, novel random four-amino acid copolymers, whose design was based on the nature of the anchor residues of the immunodominant epitope of myelin basic protein (MBP) 85-99 and of the binding pockets of MS-associated HLA-DR2 (DRB1*1501), have been synthesized by solid-phase chemistry. Poly (Y, F, A, K) (YFAK) inhibited binding of the biotinylated MBP 86-100 epitope to HLA-DR2 molecules more efficiently than did either unlabeled MBP 85-99 or any other copolymer including Cop 1. Moreover, YFAK and poly (F, A, K) (FAK) were much more effective than Cop 1 in inhibition of MBP 85-99-specific HLA-DR2-restricted T cell clones. Most importantly, these novel copolymers suppressed experimental autoimmune encephalomyelitis, induced in the susceptible SJL/J(H-2s) strain of mice with the encephalitogenic epitope PLP 139-151, more efficiently than did Cop 1. Thus, random synthetic copolymers designed according to the binding motif of the human immunodominant epitope MBP 85-99 and the binding pockets of HLA-DR2 might be more beneficial than Cop 1 in treatment of MS. C1 Harvard Univ, Dept Mol & Cell Biol, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Aarhus Univ Hosp, Skejby Sygehus, Dept Clin Immunol, Aarhus N, Denmark. Albert Einstein Coll Med, Dept Pathol, Bronx, NY 10467 USA. RP Strominger, JL (reprint author), Harvard Univ, Dept Mol & Cell Biol, 7 Divin Ave, Cambridge, MA 02138 USA. FU NCI NIH HHS [5R35-CA47554]; NIAID NIH HHS [AI49524, R01 AI049524] NR 55 TC 27 Z9 32 U1 0 U2 5 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 JUN PY 2002 VL 109 IS 12 BP 1635 EP 1643 DI 10.1172/JCI200215402 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 564MR UT WOS:000176318600017 PM 12070311 ER PT J AU Demeter, LM Bosch, RJ Coombs, RW Fiscus, S Bremer, J Johnson, VA Erice, A Jackson, JB Spector, SA Squires, KM Fischl, MA Hughes, MD Hammer, SM AF Demeter, LM Bosch, RJ Coombs, RW Fiscus, S Bremer, J Johnson, VA Erice, A Jackson, JB Spector, SA Squires, KM Fischl, MA Hughes, MD Hammer, SM TI Detection of replication-competent human immunodeficiency virus type 1 (HIV-1) in cultures from patients with levels of HIV-1 RNA in plasma suppressed to less than 500 or 50 copies per milliliter SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID COMBINATION ANTIRETROVIRAL THERAPY; CLINICAL-TRIALS GROUP; PLUS INDINAVIR; INFECTION; ZIDOVUDINE; LAMIVUDINE; BLOOD; LYMPHOCYTES; MULTICENTER; RESERVOIR AB We determined the frequency with which human immunodeficiency virus (HIV) peripheral blood mononuclear cell cultures convert from positive to negative in subjects enrolled in a substudy of AIDS Clinical Trials Group (ACTG) 320, which compared the efficacy of treatment with a combination of indinavir, zidovudine, and lamivudine (indinavir arm) to that of a combination of zidovudine and lamivudine (dual-nucleoside arm). All subjects included for study had positive baseline HIV cultures. Cultures were performed in real time with 107 fresh patient peripheral blood mononuclear cells, using the ACTG consensus method. We found lower rates of positive HIV cultures in the indinavir treatment arm than in the dual-nucleoside treatment arm (64 versus 96% at week 24, P < 0.001). Within the indinavir arm of the study, we found that positive cultures were less likely to occur in samples with a plasma HIV type 1 (HIV-1) RNA level of <500 copies/ml than in those with a level of greater than or equal to500 copies/ml (44 versus 90%, P < 0.001). In addition, HIV cultures from samples with HIV-1 RNA levels of greater than or equal to500 copies/ml turned positive 8.5 days earlier, on average, than those from samples with levels of <500 copies/ml (P < 0.001). However, 38% of samples with plasma RNA levels of <50 copies/ml still were positive for HIV by culture. Thus, the rates of HIV isolation by standard culture procedures decrease as the plasma viral load decreases below 1,000 copies/ml; however, HIV isolates were still obtained from a substantial proportion of subjects with RNA levels of <50 copies/ml. The delay in the time required for HIV cultures to turn positive should be considered when attempting to obtain an HIV isolate from patients with suppression of plasma viral load. C1 Univ Rochester, Infect Dis Unit, Sch Med & Dent, Rochester, NY 14642 USA. Columbia Univ, New York, NY 10027 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Washington, Seattle, WA 98195 USA. Univ N Carolina, Chapel Hill, NC USA. Rush Med Coll, Chicago, IL 60612 USA. Univ Alabama, Sch Med, Birmingham, AL USA. Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. Univ Minnesota, Minneapolis, MN USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Calif San Diego, San Diego, CA 92103 USA. Univ Miami, Sch Med, Miami, FL USA. RP Demeter, LM (reprint author), Univ Rochester, Infect Dis Unit, Sch Med & Dent, 601 Elmwood Ave,Box 689, Rochester, NY 14642 USA. FU NCRR NIH HHS [M01 RR000044, RR-00044]; NIAID NIH HHS [AI-40876, U01 AI027664, U01 AI038858, U01 AI038855, U01 AI027658, AI-30731, AI-27664, AI-27658, AI-38855, AI-38858, P01 AI030731] NR 18 TC 10 Z9 10 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD JUN PY 2002 VL 40 IS 6 BP 2089 EP 2094 DI 10.1128/JCM.40.6.2089-2094.2002 PG 6 WC Microbiology SC Microbiology GA 561TR UT WOS:000176159200032 PM 12037070 ER PT J AU Paster, BJ Falkler, WA Enwonwu, CO Idigbe, EO Savage, KO Levanos, VA Tamer, MA Ericson, RL Lau, CN Dewhirst, FE AF Paster, BJ Falkler, WA Enwonwu, CO Idigbe, EO Savage, KO Levanos, VA Tamer, MA Ericson, RL Lau, CN Dewhirst, FE TI Prevalent bacterial species and novel phylotypes in advanced noma lesions SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID INFECTIVE ENDOCARDITIS; SUBGINGIVAL PLAQUE; CANCRUM ORIS; IDENTIFICATION; DIVERSITY; CHILDREN AB The purpose of this study was to determine the bacterial diversity in advanced noma lesions using culture-independent molecular methods. 16S ribosomal DNA bacterial genes from DNA isolated from advanced noma lesions of four Nigerian children were PCR amplified with universally conserved primers and spirochetal selective primers and cloned into Escherichia coli. Partial 16S rRNA sequences of approximately 500 bases from 212 cloned inserts were used initially to determine species identity or closest relatives by comparison with sequences of known species or phylotypes. Nearly complete sequences of approximately 1,500 bases were obtained for most of the potentially novel species. A total of 67 bacterial species or phylotypes were detected, 25 of which have not yet been grown in vitro. Nineteen of the species or phylotypes, including Propionibacterium acnes, Staphylococcus spp., and the opportunistic pathogens Stenotrophomonas maltophilia and Ochrobactrum anthropi were detected in more than one subject. Other known species that were detected included Achromobacter spp., Afipia spp., Brevundimonas diminuta, Capnocytophaga spp., Cardiobacterium sp., Eikenella corrodens, Fusobacterium spp., Gemella haemoylsans, and Neisseria spp. Phylotypes that were unique to noma infections included those in the genera Eubacterium, Flavobacterium, Kocuria, Microbacterium, and Porphyromonas and the related Streptococcus salivarius and genera Sphingomonas and Treponema. Since advanced noma lesions are infections open to the environment, it was not surprising to detect species not commonly associated with the oral cavity, e.g., from soil. Several species previously implicated as putative pathogens of noma, such as spirochetes and Fusobacterium spp., were detected in at least one subject. However, due to the limited number of available noma subjects, it was not possible at this time to associate specific species with the disease. C1 Forsyth Inst, Dept Mol Genet, Boston, MA 02115 USA. Harvard Univ, Sch Dent Med, Dept Oral Biol, Boston, MA 02115 USA. Univ Maryland, Sch Dent, Dept Oral & Craniofacial Biol Sci, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Biochem, Baltimore, MD 21201 USA. Nigerian Inst Med Res, Lagos, Nigeria. RP Paster, BJ (reprint author), Forsyth Inst, Dept Mol Genet, 140 Fenway, Boston, MA 02115 USA. FU FIC NIH HHS [D43 TW000907]; NIDCR NIH HHS [DE11443, R01 DE010374, R01 DE011443, DE10374] NR 34 TC 89 Z9 96 U1 0 U2 7 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 JUN PY 2002 VL 40 IS 6 BP 2187 EP 2191 DI 10.1128/JCM.40.6.2187-2191.2002 PG 5 WC Microbiology SC Microbiology GA 561TR UT WOS:000176159200047 PM 12037085 ER PT J AU Sepucha, KR Belkora, JK Mutchnick, S Esserman, LJ AF Sepucha, KR Belkora, JK Mutchnick, S Esserman, LJ TI Consultation planning to help breast cancer patients prepare for medical consultations: Effect on communication and satisfaction for patients and physicians SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DECISION-MAKING; MASTECTOMY; OUTCOMES; CHOICE; MODEL; CARE AB Purpose: To measure the prevalence of communication barriers between breast cancer patients and their physicians and to present the results of a study evaluating the impact of two visit preparation techniques on communication and satisfaction for breast cancer patients and their physicians. Patients and Methods: We recruited 132 breast cancer patients from two outpatient cancer centers in a sequential, controlled trial. Ninety-four consented and completed the trial. Patients were assigned to one of two visit preparation interventions before their appointment with either a surgeon or a medical oncologist. in the control intervention, called Productive Listening, a researcher listened to and prompted patients to reflect on their experiences communicating with physicians. In the experimental intervention, called Consultation Planning, a researcher elicited questions and concerns, generated a printed agenda for the upcoming consultation, and engaged patients in techniques to improve communication with their physicians. Valid and reliable surveys measured communication barriers, satisfaction with the intervention, and patients' and physicians' satisfaction with the consultation. Results: Sixty-four percent of the patients reported three or more communication barriers. Patients reported a significant reduction in communication barriers after both the intervention and the control session. Patients reported significantly higher satisfaction after the Consultation Planning sessions. Physicians reported significantly higher satisfaction with those patients who had participated in a Consultation Planning session. Conclusion: Visit preparation sessions help patients prepare for medical consultations and reduce barriers to communication. Consultation Planning sessions, in which a researcher solicited the patient's agenda, were more satisfying to patients and physicians than the Productive Listening sessions. (C) 2002 by American Society of Clinical Oncology. C1 Harvard Univ, Sch Med, Boston, MA USA. Stanford Univ, Palo Alto, CA 94304 USA. Community Breast Hlth Project, Palo Alto, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Sepucha, KR (reprint author), Massachusetts Gen Hosp, Hlth Div, Res Unit, 50 Staniford St,9th Floor, Boston, MA 02114 USA. NR 26 TC 71 Z9 71 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 1 PY 2002 VL 20 IS 11 BP 2695 EP 2700 DI 10.1200/JCO.2002.10.068 PG 6 WC Oncology SC Oncology GA 557CP UT WOS:000175890000013 PM 12039932 ER PT J AU Berry, DA Iversen, ES Gudbjartsson, DF Hiller, EH Garber, JE Peshkin, BN Lerman, C Watson, P Lynch, HT Hilsenbeck, SG Rubinstein, WS Hughes, KS Parmigiani, G AF Berry, DA Iversen, ES Gudbjartsson, DF Hiller, EH Garber, JE Peshkin, BN Lerman, C Watson, P Lynch, HT Hilsenbeck, SG Rubinstein, WS Hughes, KS Parmigiani, G TI BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID OVARIAN-CANCER; FAMILY HISTORY; SEQUENCE-ANALYSIS; ASHKENAZI JEWS; RISK; MUTATIONS; WOMEN; JEWISH; PROBABILITIES; FREQUENCY AB Purpose: To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. Patients and Methods: Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. Results: Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. Conclusion: BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA I and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance. (C) 2002 by American Society of Clinical Oncology. C1 Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Baylor Coll Med, Breast Ctr, Houston, TX 77030 USA. Duke Univ, Inst Stat & Decis Sci, Durham, NC USA. Harvard Univ, Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Surg Oncol, Boston, MA 02114 USA. Lahey Clin Fdn, Burlington, MA USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC USA. Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. Creighton Univ, Omaha, NE 68178 USA. Evanston Northwestern Healthcare, Ctr Med Genet, Evanston, IL USA. Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. Johns Hopkins Univ, Dept Biostat, Baltimore, MD USA. RP Berry, DA (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Biostat, 1515 Holcombe Blvd,Box 447, Houston, TX 77030 USA. OI Hughes, Kevin/0000-0003-4084-6484 FU NCI NIH HHS [P50 CA68438] NR 34 TC 263 Z9 268 U1 3 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUN 1 PY 2002 VL 20 IS 11 BP 2701 EP 2712 DI 10.1200/JCO.2002.05.121 PG 12 WC Oncology SC Oncology GA 557CP UT WOS:000175890000014 PM 12039933 ER PT J AU Marder, SR AF Marder, SR TI Schizophrenia revealed: From neurons to social interactions SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Book Review C1 Univ Calif Los Angeles, VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90024 USA. RP Marder, SR (reprint author), Univ Calif Los Angeles, VA Greater Los Angeles Hlth Care Syst, Los Angeles, CA 90024 USA. NR 1 TC 0 Z9 0 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 JUN PY 2002 VL 63 IS 6 BP 542 EP 542 PG 1 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 566GZ UT WOS:000176419700025 ER PT J AU Parzen, M Lipsitz, S Ibrahim, J Klar, N AF Parzen, M Lipsitz, S Ibrahim, J Klar, N TI An estimate of the odds ratio that always exists SO JOURNAL OF COMPUTATIONAL AND GRAPHICAL STATISTICS LA English DT Article DE median unbiased estimators; phase II clinical trials; small samples ID SAMPLES AB This article proposes an estimate of the odds ratio in a (2 x 2) table obtained from studies in which the row totals are fixed by design, such as a phase II clinical trial. Our estimate, based on the median unbiased estimate of the probabilities of success in the (2 x 2) table, will always be in the interval (0,infinity). Another estimate of the odds ratio which has such properties is obtained when adding .5 to each cell of the table. Using simulations, we compared our proposed estimate to that obtained by adding .5 to every cell, and found that our estimate had smaller finite sample bias, and larger mean square error. We also propose the use of the bootstrap to form a confidence interval for the odds ratio based on our proposed estimate. Instead of a Monte Carlo bootstrap, one can easily calculate the "exact" bootstrap distribution of our estimate of the odds ratio. and use this distribution to calculate confidence intervals. C1 Univ Chicago, Grad Sch Business, Chicago, IL 60637 USA. Med Univ S Carolina, Dept Biometry & Epidemiol, Charleston, SC 29425 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Parzen, M (reprint author), Univ Chicago, Grad Sch Business, 101 E 58th St, Chicago, IL 60637 USA. NR 19 TC 21 Z9 21 U1 1 U2 2 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 1061-8600 J9 J COMPUT GRAPH STAT JI J. Comput. Graph. Stat. PD JUN PY 2002 VL 11 IS 2 BP 420 EP 436 DI 10.1198/106186002760180590 PG 17 WC Statistics & Probability SC Mathematics GA 561RX UT WOS:000176157400010 ER PT J AU Greene, RW Beszterczey, SK Katzenstein, T Park, K Goring, J AF Greene, RW Beszterczey, SK Katzenstein, T Park, K Goring, J TI Are students with ADHD more stressful to teach? Patterns of teacher stress in an elementary school sample SO JOURNAL OF EMOTIONAL AND BEHAVIORAL DISORDERS LA English DT Article ID ATTENTION-DEFICIT-HYPERACTIVITY; PARENTING STRESS; CONDUCT DISORDER; SOCIAL DISABILITY; RESPONSE COST; CHILDREN; BOYS; COMPATIBILITY; PERFORMANCE; VALIDATION AB The inattentive and/or hyperactive-impulsive behaviors that typify attention-deficit/hyperactivity disorder (ADHD) have been associated with increased stress in parents of children who are so diagnosed and are known to adversely affect the quality of parent-child interactions. Far less is known, however, about the effects of ADHD on interactions between students with the disorder and their teachers and on levels of teacher stress. Using the Index of Teaching Stress, an instrument assessing a teacher's subjective level of stress and frustration in response to teaching and interacting with a particular student,we found that general education elementary school teachers rated students with ADHD as significantly more stressful to teach than their classmates without ADHD. However, we found that the stress reported by teachers was highly individualized. Students with ADHD who evidenced oppositional/aggressive behavior or severe social impairment were rated as significantly more stressful to teach than students with ADHD who did not evidence these associated difficulties. C1 Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. Univ Massachusetts, Doctoral Program Clin Psychol, Boston, MA 02125 USA. Univ Calif Berkeley, Doctoral Program Clin Psychol, Berkeley, CA 94720 USA. RP Greene, RW (reprint author), Massachusetts Gen Hosp, Clin & Res Program Pediat Psychopharmacol, ACC725, Boston, MA 02114 USA. NR 54 TC 61 Z9 61 U1 3 U2 20 PU PRO-ED INC PI AUSTIN PA 8700 SHOAL CREEK BLVD, AUSTIN, TX 78757-6897 USA SN 1063-4266 J9 J EMOT BEHAV DISORD JI J. Emot. Behav. Disord. PD SUM PY 2002 VL 10 IS 2 BP 79 EP 89 DI 10.1177/10634266020100020201 PG 11 WC Education, Special; Psychology, Educational; Psychology, Multidisciplinary SC Education & Educational Research; Psychology GA 553FJ UT WOS:000175664900002 ER PT J AU Moonga, BS Adebanjo, OA Wang, HJ Li, S Wu, XB Troen, B Inzerillo, A Abe, E Minkin, C Huang, CLH Zaidi, M AF Moonga, BS Adebanjo, OA Wang, HJ Li, S Wu, XB Troen, B Inzerillo, A Abe, E Minkin, C Huang, CLH Zaidi, M TI Differential effects of interleukin-6 receptor activation on intracellular signaling and bone resorption by isolated rat osteoclasts SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID LEUKEMIA INHIBITORY FACTOR; INOSITOL TRISPHOSPHATE; OSTEOBLASTIC CELLS; EMERGING INSIGHTS; MECHANISMS; INVITRO; IL-6; TRANSDUCTION; STIMULATION; EXPRESSION AB The effects of the related cytokines interleukin-6 (IL-6), leukemia inhibitory factor (LIF) and oncostatin-M on bone resorption and cytosolic Ca2+ signaling were compared in isolated rat osteoclasts. In the traditional disaggregated osteoclast (pit) assay, IL-6 and LIF, but not oncostatin-M, conserved the bone resorption otherwise inhibited by high extracellular [Ca2+] (15 mM). It produced a paradoxical, concentration-dependent stimulation of resorption by elevated extracellular Ca2+. In the micro isolated single osteoclast resorption assay, IL-6, high [Ca2+] or IL-6 plus high [Ca2+] all increased pit formation. In contrast, the IL-6 receptor (IL-6R)-specific agonist antibody MT-18 inhibited bone resorption in a concentration-dependent manner (1:500 to 1:500 000). MT-18 triggered cytosolic Ca2+ signals in fura 2-loaded osteoclasts within similar to 10 min of application. Each cytosolic Ca2+ transient began with a peak deflection that persisted in Ca2+-free, EGTA-containing extracellular medium, consistent with a release of intracellularly stored Ca2+. This was followed by a sustained elevation of cytosolic [Ca2+] that was abolished in Ca2+-free medium, as expected from an entry of extracellular Ca2+, and by the Ca2+ channel antagonist Ni2+. The inclusion of either IL-6 or soluble human (sh) IL-6R specifically reversed both the above effects of MT-18, confirming that both effects were specific for the IL-6R. The findings suggest that IL-6R activation by IL-6 stimulates osteoclastic bone resorption either by reversing the inhibitory effect of high extracellular Ca2+ in stromal-containing systems or itself stimulating bone resorption along with Ca2+ by micro-isolated osteoclasts. In contrast, activation of the IL-6R by an agonist antibody produces an inhibition of bone resorption and an associated triggering of the cytosolic Ca2+ signals previously associated with regulation of bone resorptive function in other situations. C1 Univ Cambridge, Physiol Lab, Cambridge CB2 3EG, England. Mt Sinai Sch Med, Mt Sinai Bone Program, New York, NY 10029 USA. Mt Sinai Sch Med, Div Endocrinol Diabet & Bone Dis, New York, NY 10029 USA. Bronx Vet Affairs Med Ctr, Div Endocrinol, New York, NY 10029 USA. Bronx Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, New York, NY 10029 USA. Univ So Calif, Sch Dent, Los Angeles, CA 90089 USA. RP Huang, CLH (reprint author), Univ Cambridge, Physiol Lab, Downing St, Cambridge CB2 3EG, England. RI Huang, Christopher/A-6248-2008 FU NIA NIH HHS [R01 AG 14917-02]; NIDCR NIH HHS [R01 DE 09965] NR 38 TC 10 Z9 10 U1 0 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD JUN PY 2002 VL 173 IS 3 AR UNSP 0022-0795/02/0173-395 DI 10.1677/joe.0.1730395 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 568LB UT WOS:000176542300002 PM 12065229 ER PT J AU Kroll, NEA Yonelinas, AP Dobbins, IG Frederick, CM AF Kroll, NEA Yonelinas, AP Dobbins, IG Frederick, CM TI Separating sensitivity from response bias: Implications of comparisons of yes-no and forced-choice tests for models and measures of recognition memory SO JOURNAL OF EXPERIMENTAL PSYCHOLOGY-GENERAL LA English DT Article ID RECEIVER-OPERATING CHARACTERISTICS; DUAL-PROCESS MODEL; RECOLLECTIVE EXPERIENCE; SIGNAL-DETECTION; AMNESIC PATIENTS; EPISODIC MEMORY; REMEMBER-KNOW; ROC CURVES; FAMILIARITY; HIPPOCAMPAL AB A fundamental challenge to psychological research is the measurement of cognitive processes uncontaminated by response strategies resulting from different testing procedures. Test-free estimates of ability are vital when comparing the performance of different groups or different conditions. The current study applied several sets of measurement models to both forced-choice and yes-no recognition memory tests and concluded that the traditional signal-detection model resulted in distorted estimates of accuracy. Two-factor models were necessary to separate memory sensitivity from response bias. These models indicated that (a) memory accuracy did not differ across the tests and (b) the tests relied on the same underlying memory processes. The results illustrate the pitfalls of using a single-component model to measure accuracy in tasks that reflect 2 or more underlying processes. C1 Univ Calif Davis, Dept Psychol, Davis, CA 95616 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Cambridge, MA 02138 USA. Univ Calif Berkeley, Dept Psychol, Berkeley, CA 94720 USA. RP Kroll, NEA (reprint author), Univ Calif Davis, Dept Psychol, 1 Shields Ave, Davis, CA 95616 USA. FU NIMH NIH HHS [MH59352-01] NR 47 TC 27 Z9 27 U1 0 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0096-3445 J9 J EXP PSYCHOL GEN JI J. Exp. Psychol.-Gen. PD JUN PY 2002 VL 131 IS 2 BP 241 EP 254 DI 10.1037//0096-3445.131.2.241 PG 14 WC Psychology, Experimental SC Psychology GA 554KR UT WOS:000175735000006 PM 12049242 ER PT J AU Maxwell, RA Sweet, RA Mulsant, BH Rosen, J Kirshner, MA Kastango, KB Pollock, BG AF Maxwell, RA Sweet, RA Mulsant, BH Rosen, J Kirshner, MA Kastango, KB Pollock, BG TI Risperidone and 9-hydroxyrisperidone concentrations are not dependent on age or creatinine clearance among elderly subjects SO JOURNAL OF GERIATRIC PSYCHIATRY AND NEUROLOGY LA English DT Article ID BEHAVIORAL SYMPTOMS; DOUBLE-BLIND; DEMENTIA; PHARMACOKINETICS; PLACEBO; DISEASE; TRIAL; ANTIPSYCHOTICS; PSYCHOSIS AB Risperidone is extensively metabolized to an active metabolite, 9-hydroxyrisperidone (9-OH), which is dependent on renal clearance. Risperidone and 9-OH clearances are reduced in the elderly when compared to young subjects. The objective of this study was to determine whether among elderly subjects, risperidone and 9-OH clearance would further decline with increasing age and decreasing creatinine clearance (CrCl). Twenty geriatric inpatients were evaluated in a naturalistic setting with regard to total daily risperidone dose and dosing interval. Creatinine clearance was determined using an 8-hour urine collection. Risperidone and 9-OH concentrations were determined by radioimmunoassay. Spearman's correlation coefficients were used to examine the impact of age and CrCl on concentrations of risperidone, 9-OH, their sum, and the quotient of 9-OH/risperidone. Mean age was 76.4 +/- 9 years (range 56-91). Mean CrCl was 55.4 +/- 32.8 mL/min/1.73 m(2) (range 17-142 mL/min/1.73 m(2)). Mean risperidone daily dose was 1.3 +/- 0.7 mg. Steady-state risperidone and 9-OH concentrations were 4.1 +/- 5.3 ng/mL and 9.1 +/- 6.2 ng/mL, respectively. Mean 9-OH/risperidone was 6.2 +/- 6.1. Concentrations of risperidone, 9-OH, their sum, and 9-OH/risperidone were not significantly correlated with age or CrCl. These results were unchanged when concentrations were corrected for total daily risperidone dose. Among elderly subjects, risperidone and 9-OH clearance do not decline with increasing age or declining CrCl. C1 Western Psychiat Inst & Clin, Dept Pharm, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Psychiat,Div Geriatr & Neuropsychiat, Geriatr Psychopharmacol Program, Pittsburgh, PA USA. VA Pittsburgh Hlth Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Sweet, RA (reprint author), Western Psychiat Inst & Clin, Dept Pharm, 3811 OHara St, Pittsburgh, PA 15213 USA. FU NIMH NIH HHS [MH01153, MH01509, MH01613, MH52247, MH59666] NR 22 TC 3 Z9 4 U1 1 U2 1 PU B C DECKER INC PI HAMILTON PA 20 HUGHSON ST SOUTH, PO BOX 620, L C D 1, HAMILTON, ONTARIO L8N 3K7, CANADA SN 0891-9887 J9 J GERIATR PSYCH NEUR JI J. Geriatr. Psychiatry Neurol. PD SUM PY 2002 VL 15 IS 2 BP 77 EP 81 DI 10.1177/089198870201500205 PG 5 WC Geriatrics & Gerontology; Clinical Neurology; Psychiatry SC Geriatrics & Gerontology; Neurosciences & Neurology; Psychiatry GA 560AA UT WOS:000176057900004 PM 12083597 ER PT J AU Chen, TC Yuen, SJA Sangalang, MA Fernando, RE Leuenberger, EU AF Chen, TC Yuen, SJA Sangalang, MA Fernando, RE Leuenberger, EU TI Retrobulbar chlorpromazine injections for the management of blind and seeing painful eyes SO JOURNAL OF GLAUCOMA LA English DT Article DE blind; chlorpromazine; painful; retrobulbar AB Purpose: To report the efficacy of primary retrobulbar chlorpromazine injections for the management of blind and seeing painful eves. Patients and Methods: Retrospective case series from three university hospitals was done, Twenty eyes of 20 patients with at least 3 months of follow-up are reported. Ten of these 20 eyes did not receive any other ophthalmic medications either 2 weeks before chlorpromazine injection or at any time point after injection. Treatment was considered successful if pain control lasted for at least 3 months, without the need for reinjection or enucleation. Results: Sixteen of 20 (80.0%) eyes achieved successful pain control. There were no permanent complications in any patient. Conclusions: Retrobulbar chlorpromazine appears to be safe and effective for the management of pain in blind eyes. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Glaucoma Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. Univ E RMMMC, Dept Ophthalmol, Manila, Philippines. St Martin Porres Char Hosp, Dept Ophthalmol, Manila, Philippines. Rockwell Ctr, Asian Eye Inst, Dept Ophthalmol, Glaucoma Serv, Makati, Philippines. RP Chen, TC (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Glaucoma Serv, 243 Charles St, Boston, MA 02114 USA. NR 20 TC 11 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1057-0829 J9 J GLAUCOMA JI J. Glaucoma PD JUN PY 2002 VL 11 IS 3 BP 209 EP 213 DI 10.1097/00061198-200206000-00008 PG 5 WC Ophthalmology SC Ophthalmology GA 562PC UT WOS:000176207000008 PM 12140397 ER PT J AU Tuck, ML AF Tuck, ML TI Does aldosterone modulate central control of blood pressure? SO JOURNAL OF HYPERTENSION LA English DT Editorial Material ID MINERALOCORTICOID HYPERTENSION; RECEPTORS; INFUSION; TERTIARY; BRAIN C1 Vet Adm Med Ctr, VA Greater Los Angeles Hlth Care Syst, Div Endocrinol & Metab, Dept Med, Sepulveda, CA 91343 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. RP Tuck, ML (reprint author), Vet Adm Med Ctr, VA Greater Los Angeles Hlth Care Syst, Div Endocrinol & Metab, Dept Med, 111 E 16111 Plummer St, Sepulveda, CA 91343 USA. EM mtuck@ucla.edu NR 13 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2002 VL 20 IS 6 BP 1079 EP 1080 DI 10.1097/00004872-200206000-00015 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 559LL UT WOS:000176027600015 PM 12023673 ER PT J AU Stojiljkovic, MP Lopes, HF Zhang, D Morrow, JD Goodfriend, TL Egan, BM AF Stojiljkovic, MP Lopes, HF Zhang, D Morrow, JD Goodfriend, TL Egan, BM TI Increasing plasma fatty acids elevates F2-isoprostanes in humans: implications for the cardiovascular risk factor cluster SO JOURNAL OF HYPERTENSION LA English DT Article DE insulin resistance; fatty acids; F2-isoprostanes; oxidative stress; blood pressure ID SMOOTH-MUSCLE CELLS; PROTEIN-KINASE-C; OXIDATIVE STRESS; ANGIOTENSIN-II; HYPERTENSION; GLUCOSE; EXPRESSION; ACTIVATION; MECHANISM; INSULIN AB Objective To determine whether raised concentrations of non-esterified fatty acids (NEFAs) may contribute to the cardiovascular risk factor cluster by increasing oxidative stress in vivo. Design and Methods Plasma and urine F2-isoprostanes, biomarkers of oxidative stress, were measured after an overnight fast and during a 4 h infusion of Intralipid and heparin to increase NEFAs in 10 obese hypertensive patients with and 12 healthy normotensive individuals without evidence of insulin resistance. A time-control group of nine healthy normotensive individuals received saline and heparin. Results Plasma F2-isoprostanes increased more in obese hypertensive individuals than in lean normotensive individuals after 2 h (14.9 +/- 2.8 ng/ml compared with 4.6 +/- 2.8 ng/ml; P < 0.05) but not after 4 h (10.3 +/- 2.5 ng/ml compared with 8.1 +/- 4.1 ng/ml; NS) of the Intralipid and heparin infusion, When obese and lean individuals were combined, plasma (+9.1 +/- 2.5 ng/ml; P < 0.05) and urine (+0.7 +/- 0.3 ng/mg creatinine; P < 0.05) F2-isoprostanes increased by about 20% after 4 h of Intralipid and heparin, whereas plasma F2-isoprostanes decreased by approximately 20% (-9.7 +/- 4.5 ng/ml; P < 0.05) after 4 h of saline and heparin. When individuals from both infusions were combined, the correlation between changes in plasma NEFAs and F2-isoprostanes after 4 h persisted after controlling for changes in triglyceride concentrations (partial r = 0.49; P < 0.01), whereas the correlation between changes in triglycerides and F2-isoprostanes did not persist after controlling for changes in NEFA concentrations (partial r = 0.33, NS). Conclusions The findings indicate that an acute increase in plasma lipids increases the concentration of F2-isoprostanes, biomarkers of oxidative stress, especially in obese hypertensive individuals. The observations raise the possibility that increased concentrations of NEFAs contribute to the cardiovascular risk factor cluster through oxidative-stress-sensitive mechanisms. (C) 2002 Lippincott Williams Wilkins. C1 Med Univ S Carolina, Div Clin Pharmacol, Dept Pharmacol, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. Univ Wisconsin, William S Middleton Mem Vet Adm Hosp, Madison, WI 53706 USA. RP Egan, BM (reprint author), Med Univ S Carolina, Div Clin Pharmacol, Dept Pharmacol, 96 Jonathan Lucas St,Suite 826,POB 250623, Charleston, SC 29425 USA. FU NCI NIH HHS [CA77839]; NCRR NIH HHS [RR-01070]; NHLBI NIH HHS [HL04290, HL55782, HL58794]; NIDDK NIH HHS [DK26657, DK48831]; NIGMS NIH HHS [GM42056] NR 31 TC 49 Z9 50 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2002 VL 20 IS 6 BP 1215 EP 1221 DI 10.1097/00004872-200206000-00036 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 559LL UT WOS:000176027600036 PM 12023694 ER PT J AU Haupert, GT Randall, JD Gullans, SR AF Haupert, GT Randall, JD Gullans, SR TI Gene expression in biosynthetic pathway of endogenous ouabain in Milan strain hypertensive rat hypothalamus SO JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Meeting of the International-Society-for-Hypertension/12th European-Society-of-Hypertension Meeting CY JUN 23-27, 2002 CL PRAGUE, CZECH REPUBLIC SP Int Soc Hypertens, European Soc Hypertens C1 Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Renal, 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 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD JUN PY 2002 VL 20 SU 4 MA P509 BP S126 EP S126 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 600JF UT WOS:000178386300586 ER PT J AU Fuhlbrigge, RC King, SL Dimitroff, CJ Kupper, TS Sackstein, R AF Fuhlbrigge, RC King, SL Dimitroff, CJ Kupper, TS Sackstein, R TI Direct real-time observation of E- and P-selectin-mediated rolling on cutaneous lymphocyte-associated antigen immobilized on Western blots SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HOMING T-CELLS; GLYCOPROTEIN LIGAND-1; LEUKOCYTE ADHESION; DIFFERENTIAL EXPRESSION; FUCOSYL-TRANSFERASE; COUNTER-RECEPTOR; FUCT-VII; SKIN; BINDING; MOLECULE AB Human memory T cells associated with cutaneous inflammatory responses are characterized by their expression of cutaneous lymphocyte-associated Ag (CLA), a carbohydrate determinant differentially expressed on P-selectin glycoprotein ligand-1 (PSGL1). Although expression of the CLA epitope on PSGL-1 (CLA(+) PSGL-1) by memory T cells is associated with acquisition of E-selectin ligand activity, it is not known whether CLA(+) PSGL-1, itself, is a ligand for E-selectin on human T cells or whether other glycoproteins, with or without CLA modification, support E-selectin-dependent rolling in shear flow. To address this issue, we developed a method for real-time analysis of functional adhesive interactions between selectin-bearing cells in shear flow with leukocyte ligands resolved by SDS-PAGE and immobilized on standard Western blots. The results of these studies provide direct evidence that CLA(+) PSGL-1 is a functional ligand for both E- and P-selectin, confirm that the P-selectin ligand activity of PSGL-1 is independent of CLA modification, and identify a distinct, non-PSGL-1 E-selectin ligand on CLA-positive human memory T cells. C1 Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Skin Dis Res Ctr, Boston, MA 02115 USA. RP Sackstein, R (reprint author), Harvard Inst Med, 77 Ave Louis Pasteur, Boston, MA 02115 USA. FU NCI NIH HHS [CA84156]; NHLBI NIH HHS [HL60528]; NIAMS NIH HHS [AR02115] NR 33 TC 57 Z9 57 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2002 VL 168 IS 11 BP 5645 EP 5651 PG 7 WC Immunology SC Immunology GA 555WA UT WOS:000175815200034 PM 12023362 ER PT J AU Scardino, A Gross, DA Alves, P Schultze, JL Graff-Dubois, S Faure, O Tourdot, S Chouaib, S Nadler, LM Lemonnier, FA Vonderheide, RH Cardoso, AA Kosmatopoulos, K AF Scardino, A Gross, DA Alves, P Schultze, JL Graff-Dubois, S Faure, O Tourdot, S Chouaib, S Nadler, LM Lemonnier, FA Vonderheide, RH Cardoso, AA Kosmatopoulos, K TI HER-2/neu and hTERT cryptic epitopes as novel targets for broad spectrum tumor immunotherapy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; TELOMERASE CATALYTIC SUBUNIT; ADOPTIVE IMMUNOTHERAPY; SELF-TOLERANCE; OVARIAN-CANCER; BREAST-CANCER; CELL RESPONSE; NEU ONCOGENE; HIGH-AVIDITY; RENAL-CELL AB Tolerance to tumor-nonmutated self proteins represents a major obstacle for successful cancer immunotherapy. Since this tolerance primarily concerns dominant epitopes, we hypothesized that targeting cryptic epitopes that have a low affinity for HLA could be an efficient strategy to breach the tolerance to tumor Ags. Using the P1Y heteroclitic peptide approach, we identified low affinity cryptic HLA-A*0201-restricted epitopes derived from two widely expressed tumor Ags, HER-2/neu and hTERT. The P1Y variants of four HER-2/neu (neu(391,) neu(402), neu(466), neu(650))- and two hTERT (hTERT(572) and hTERT(988))-derived low affinity peptides exhibited strong affinity for HLA-A*0201 and stimulated specific CTL from healthy donor PBMCs. These CTL specifically recognized HER-2/neu- and hTERT-expressing tumor cells of various histological origins. In vivo studies showed that HLA-A*0201 transgenic HHD mice vaccinated with the P1Y variant peptides generated CTL that specifically lysed Ag-expressing tumor cells, thus recognizing the cognate endogenous Ags. These results suggest that heteroclitic variants of low affinity, cryptic epitopes of widely expressed tumor Ags may serve as valid tools for tumor immunotherapy. C1 Inst Gustave Roussy, INSERM, U487, F-94800 Villejuif, France. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Inst Pasteur, Dept Sida Retrovirus, Unite Immunite Cellulaire Antivirale, Paris, France. RP Kosmatopoulos, K (reprint author), Inst Gustave Roussy, INSERM, U487, 39 Rue Camille Desmoulins, F-94800 Villejuif, France. RI Schultze, Joachim/D-7794-2011; Chouaib, Salem/F-7939-2016 OI Schultze, Joachim/0000-0003-2812-9853; NR 42 TC 100 Z9 106 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2002 VL 168 IS 11 BP 5900 EP 5906 PG 7 WC Immunology SC Immunology GA 555WA UT WOS:000175815200067 PM 12023395 ER PT J AU Levy, HL Vargas, JE Waisbren, SE Kurczynski, TW Roeder, ER Schwartz, RS Rosengren, S Prasad, C Greenberg, CR Gilfix, BM MacGregor, D Shih, VE Bao, L Kraus, JP AF Levy, HL Vargas, JE Waisbren, SE Kurczynski, TW Roeder, ER Schwartz, RS Rosengren, S Prasad, C Greenberg, CR Gilfix, BM MacGregor, D Shih, VE Bao, L Kraus, JP TI Reproductive fitness in maternal homocystinuria due to cystathionine beta-synthase deficiency SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID NEURAL-TUBE DEFECTS; HOMOCYSTEINE METABOLISM; CLINICAL PHENOTYPE; FOLIC-ACID; PREGNANCY; PLASMA; HYPERHOMOCYSTEINEMIA; PREECLAMPSIA; HISTORY; HEART AB Early diagnosis and improved treatment are leading to the potential for increased reproductive capability in homocystinuria due to cystathionine beta-synthase (CbetaS) deficiency, but information about reproductive outcome and risk of thromboembolism in pregnancy is limited. To provide further information, clinical and biochemical information was obtained on women with maternal homocystinuria, on their pregnancies and on the offspring. This information included blood sulphur amino acids and total homocysteine, CbetaS gene mutations and developmental and cognitive scores in the offspring. The study involved 15 pregnancies in 11 women, of whom 5 were pyridoxine-nonresponsive and 6 were pyridoxine-responsive. Complications of pregnancy included pre-eclampsia at term in two pregnancies and superficial venous thrombosis of the leg in a third pregnancy. One pregnancy was terminated and two pregnancies resulted in first-trimester spontaneous abortions. The remaining 12 pregnancies produced live-born infants with normal or above-normal birth measurements. One offspring has multiple congenital anomalies that include colobomas of the iris and choroid, neural tube defect and undescended testes. He is also mentally retarded and autistic. A second offspring has Beckwith-Wiedemann syndrome. The remaining 10 offspring were normal at birth and have remained normal. There was no relationship between the severity of the biochemical abnormalities or the therapies during pregnancy to either the pregnancy complications or the offspring outcomes. The infrequent occurrences of pregnancy complications, offspring abnormalities and maternal thromboembolic events in this series suggest that pregnancy and outcome in maternal homocystinuria are usually normal. Nevertheless, a cautious approach would include careful monitoring of these pregnancies with attention to metabolic therapy and possibly anticoagulation. C1 Childrens Hosp, Div Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Med Coll Ohio, Dept Pediat, Toledo, OH 43699 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43699 USA. Med Coll Ohio, Dept Obstet & Gynecol, Toledo, OH 43699 USA. Med Coll Ohio, Dept Med, Toledo, OH 43699 USA. UCSF, Valley Childrens Hosp, Madera, CA USA. Univ Connecticut, Ctr Hlth, Div Human Genet, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Dept Pediat, Farmington, CT USA. Connecticut Childrens Med Ctr, Hartford, CT USA. Univ Manitoba, Dept Pediat, Sect Genet & Metab, Winnipeg, MB R3T 2N2, Canada. Univ Manitoba, Dept Child Hlth, Winnipeg, MB, Canada. Univ Manitoba, Dept Biochem, Winnipeg, MB, Canada. Univ Manitoba, Dept Med Genet, Winnipeg, MB, Canada. MUHC Royal Victoria Hosp, Div Med Genet, Montreal, PQ, Canada. Mem Univ Newfoundland, St Johns, NF A1C 5S7, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Univ Colorado, Sch Med, Dept Pediat, Denver, CO USA. RP Levy, HL (reprint author), Childrens Hosp, Div Genet, 300 Longwood Ave,IC-106, Boston, MA 02115 USA. FU NICHD NIH HHS [N01-HD-2-3149] NR 36 TC 12 Z9 12 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD JUN PY 2002 VL 25 IS 4 BP 299 EP 314 DI 10.1023/A:1016502408305 PG 16 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 578TC UT WOS:000177134200006 PM 12227460 ER PT J AU Hofmann-Lehmann, R Vlasak, J Rasmussen, RA Jiang, S Li, PL Baba, TW Montefiori, DC Bernacky, BJ Rizvi, TA Schmidt, R Hill, LR Keeling, ME Katinger, H Stiegler, G Cavacini, LA Posner, MR Ruprecht, RM AF Hofmann-Lehmann, R Vlasak, J Rasmussen, RA Jiang, S Li, PL Baba, TW Montefiori, DC Bernacky, BJ Rizvi, TA Schmidt, R Hill, LR Keeling, ME Katinger, H Stiegler, G Cavacini, LA Posner, MR Ruprecht, RM TI Postnatal pre- and postexposure passive immunization strategies: protection of neonatal macaques against oral simian-human immunodeficiency virus challenge SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Article DE mother-to-child transmission; primate model; synergistic neutralizing human anti-HIV-1; monoclonal antibodies ID HUMAN MONOCLONAL-ANTIBODIES; COMPLEMENT-MEDIATED LYSIS; POLYMERASE CHAIN-REACTION; HIV-1/SIV CHIMERIC VIRUS; RHESUS MACAQUES; NEUTRALIZING ANTIBODIES; SYNERGISTIC NEUTRALIZATION; ENVELOPE GLYCOPROTEIN; IN-VIVO; INFECTION AB Simian-human immunodeficiency viruses (SHIV) allow the evaluation of antiviral strategies that target the envelope glycoproteins of the human immunodeficiency virus 1 (HIV-1) in macaques. We previously protected neonates from oral challenge with cell-free SHIV-vpu(+) by passive immunization with synergistic human neutralizing monoclonal antibodies (mAbs) (Baba et al., Nat Med 6:200-206, 2000). mAbs were administered prenatally to pregnant dams and postnatally to the neonates. Here, we used solely postnatal or postexposure mAb treatment, thus significantly reducing the amount of mAbs necessary. All neonatal monkeys were also protected with these abbreviated mAb regimens. Our results are directly relevant for humans because we used mAbs that target HIV-1 envelope glycoproteins. Thus, the large-scale use of passive immunization with neutralizing mAbs may be feasible in human neonates, The mAbs, being natural human proteins, can be expected to have low toxicity. Passive immunization has promise to prevent intrapartum as well as milk-borne virus transmission from HIV-1-infected women to their infants. C1 Dana Farber Canc Inst, Dept Canc Immmunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Tufts Univ, Sch Med, Div Newborn Med, Boston, MA 02111 USA. Duke Univ, Med Ctr, Dept Surg, AIDS Res Ctr, Durham, NC 27710 USA. Univ Texas, MD Anderson Canc Ctr, Dept Vet Sci, Bastrop, TX USA. Agr Univ Vienna, Inst Appl Microbiol, A-1180 Vienna, Austria. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Ruprecht, RM (reprint author), Dana Farber Canc Inst, Dept Canc Immmunol & AIDS, 44 Binney St,JFB809, Boston, MA 02115 USA. RI Hofmann-Lehmann, Regina/C-6528-2009 FU NCIRD CDC HHS [IP3028691]; NIAID NIH HHS [R21 AI46177, R01 AI34266, R01 AI26926, P01 AI48240]; OAPP OPHS HHS [PG-50864-23]; PHS HHS [5 KO8-A101327] NR 48 TC 33 Z9 34 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD JUN PY 2002 VL 31 IS 3 BP 109 EP 119 DI 10.1034/j.1600-0684.2002.01014.x PG 11 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 570UK UT WOS:000176676500001 PM 12190851 ER PT J AU Kassiri, Z Hajjar, R Backx, PH AF Kassiri, Z Hajjar, R Backx, PH TI Molecular components of transient outward potassium current in cultured neonatal rat ventricular myocytes SO JOURNAL OF MOLECULAR MEDICINE-JMM LA English DT Article DE neonatal myocytes; transient outward K+ current; Kv1.4; Kv4.2 ID INDUCED HEART-FAILURE; K+ CHANNEL SUBUNITS; CURRENT I-TO; DIFFERENTIAL EXPRESSION; CARDIAC MYOCYTES; ALPHA-SUBUNIT; MESSENGER-RNA; LONG-QT; GENE; KV1.4 AB We have previously reported that K-v1.4, K-v4.2, and K-v4,K-3 mRNAs are present in adult and neonatal rat ventricular myocytes, and that transient outward potassium current (I-to) recovers from inactivation with a slow (I-to,I-s) and a fast (I-to,I-f) time course. This study was designed to determine the molecular correlates of I-to,I-s and I-to,I-f in cultured neonatal rat ventricular myocytes (NRVM) employing dominant-negative adenoviral infections to manipulate the function of endogenous I-to-encoding K+ channels. Western blot data from cultured NRVM showed that K-v1,K-4, K-v4,K-2, and K-v4,K-3 channel proteins are present in these myocytes. The biphasic recovery from inactivation of I-to in control GFP-infected myocytes demonstrated equal contribution of and I-to,I-f in NRVM. Infection of cultured NRVM with adenoviruses expressing full-length K-v1,K-4 or K-v4,K-2 genes generated currents with recovery from inactivation kinetics similar to native I-to,I-s and I-to,I-f in GFP-infected myocytes, respectively. Overexpression of dominant-negative truncated K-v1,K-4 transgene (Kv1,4N) caused a 51% reduction in I-to, selectively removing the slowly recovering I-to,I-s. Overexpression of dominant-negative Kv4,2N reduced I-to by 53% and eliminated the fast-recovering I-to,I-f. Our results establish that, in neonatal rat ventricular myocytes, the shaker K-v1 family (probably K-v1,K-4 and/or K-v1,K-7) underlies I-to,I-s, and that the shal K-v4 family (probably K-v4,K-2 and K-v4,K-3) is responsible for I-to,I-f.. C1 Univ Toronto, Dept Physiol & Med Heart & Stroke, Richard Lewar Ctr, Toronto, ON M5G 3E2, Canada. Univ Toronto, Div Cardiol, Univ Hlth Network, Toronto, ON M5G 3E2, Canada. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. RP Backx, PH (reprint author), Univ Toronto, Dept Physiol & Med Heart & Stroke, Richard Lewar Ctr, 150 Coll St, Toronto, ON M5G 3E2, Canada. NR 38 TC 9 Z9 10 U1 1 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0946-2716 J9 J MOL MED-JMM JI J. Mol. Med. PD JUN PY 2002 VL 80 IS 6 BP 351 EP 358 DI 10.1007/s00109-002-0325-7 PG 8 WC Genetics & Heredity; Medicine, Research & Experimental SC Genetics & Heredity; Research & Experimental Medicine GA 575PU UT WOS:000176957300005 PM 12072910 ER PT J AU Yao, JK Leonard, S Reddy, RD AF Yao, JK Leonard, S Reddy, RD TI Reduced glutathione redox state in schizophrenia SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract C1 VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA 15213 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2002 VL 81 SU 1 BP 22 EP 22 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 573KU UT WOS:000176829500075 ER PT J AU Yao, JK Cheng, P AF Yao, JK Cheng, P TI A simple and sensitive HPLC-method for simultaneous monitoring of oxidative stress indices and monoamine metabolites SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract C1 Univ Pittsburgh, Med Ctr, VA Pittsburgh Healthcare Syst, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Med Ctr, Dept Psychiat, Pittsburgh, PA 15206 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2002 VL 81 SU 1 BP 30 EP 30 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 573KU UT WOS:000176829500097 ER PT J AU Stiles, CD Lu, QR Sun, T Rowitch, DH AF Stiles, CD Lu, QR Sun, T Rowitch, DH TI The oligodendrocyte lineage genes Olig1 and Olig2 in CNS development SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2002 VL 81 SU 1 BP 75 EP 75 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 573KU UT WOS:000176829500236 ER PT J AU Chen, DX Cao, GD Hastings, T Feng, YQ Pei, W O'Horo, C Chen, J AF Chen, DX Cao, GD Hastings, T Feng, YQ Pei, W O'Horo, C Chen, J TI Age-dependent decline of DNA repair activity for oxidative lesions in rat brain mitochondria SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE 8-hydroxyl-2 '-deoxyguanosine; aging; DNA damage; mitochondrial dysfunction; oxidative stress ID FOCAL CEREBRAL-ISCHEMIA; SUPEROXIDE-DISMUTASE; PARKINSONS-DISEASE; LYASE ACTIVITY; ABASIC SITES; OGG1 GENE; DAMAGE; CELLS; NUCLEAR; MICE AB Endogenous oxidative damage to brain mitochondrial DNA and mitochondrial dysfunction are contributing factors in aging and in the pathogenesis of a number of neurodegenerative diseases. In this study, we characterized the regulation of base-excision-repair (BER) activity, the predominant repair mechanism for oxidative DNA lesions, in brain mitochondria as the function of age. Mitochondrial protein extracts were prepared from rat cerebral cortices at the ages of embryonic day 17 (E17) or postnatal 1-, 2-, and 3-weeks, or 5- and 30-months. The total BER activity and the activity of essential BER enzymes were examined in mitochondria using in vitro DNA repair assay employing specific repair substrates. Mitochondrial BER activity showed marked age-dependent declines in the brain. The levels of overall BER activity were highest at E17, gradually decreased thereafter, and reached to the lowest at the age of 30-month (similar to80% reduction). The decline of overall BER activity with age was attributed to the decreased expression of repair enzymes such as 8-OHdG glycosylase and DNA polymerase-gamma and, consequently, the reduced activity at the steps of lesion-base incision, DNA repair synthesis and DNA ligation in the BER pathway. These results strongly suggest that the decline in BER activity may be an important mechanism contributing to the age-dependent accumulation of oxidative DNA lesions in brain mitochondria. C1 Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Pittsburgh Inst Neurodegenerat Disorders, Pittsburgh, PA 15213 USA. Vet Affairs Pittsburgh Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Chen, J (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, S-507,Biomed Sci Tower, Pittsburgh, PA 15213 USA. FU NINDS NIH HHS [NS36736, NS38560, NS35965] NR 53 TC 101 Z9 102 U1 1 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2002 VL 81 IS 6 BP 1273 EP 1284 DI 10.1046/j.1471-4159.2002.00916.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 559ZN UT WOS:000176056700013 PM 12068075 ER PT J AU Okada, Y Nishikawa, R Matsutani, M Louis, DN AF Okada, Y Nishikawa, R Matsutani, M Louis, DN TI Hypomethylated X chromosome gain and rare isochromosome 12p in diverse intracranial germ cell tumors SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE brain tumor; chromosome 12; germ cell tumor; methylation; p16; X chromosome ID IN-SITU HYBRIDIZATION; KLINEFELTERS-SYNDROME; CYTOGENETIC ANALYSIS; GENE AMPLIFICATION; MOLECULAR ANALYSIS; RB ALTERATIONS; ABNORMALITIES; ASTROCYTOMAS; EXPRESSION; DELETIONS AB Twenty-five primary intracranial germ cell tumors (11 germinomas, 5 teratomas, 5 mixed teratomas-germinomas, 1 mixed choriocarcinoma-teratoma, 1 yolk sac tumor, 1 mixed yolk sac tumor-teratoma, and I embryonal carcinoma; from 24 males and 1 female) were studied by fluorescence in situ hybridization with probes to the X and Y chromosomes, chromosome 12p, the CDKN2A/p16 gene, and chromosome 13q-loci previously noted to be altered in either intracranial or systemic germ cell tumors. An increased number of X chromosomes, typically I extra copy, was observed in 23 of 25 cases (92%), with methylation-sensitive PCR demonstrating that the additional X chromosomes were hypomethylated in 13 of 16 (81%) studied tumors. Five cases (20%) had increased copy numbers of 12p (including tumors with isochromosome 12p), and 3 (12%) had 13q loss. No tumors had CDKN2A/p16 deletion or mutation, and 16 of 25 (64%) were positive for p16 expression by immunohistochemistry. Genetic alterations such as isochromosome 12p, 13q loss and CDKN2A/p16 are therefore not common in intracranial germ cell tumors. However, gains of hypomethylated, active X chromosomes occur in nearly all intracranial germ cell tumors, regardless of histological subtype. Along with the observed male predominance of intracranial germ cell tumors and the predisposition in Klinefelter syndrome patients for these lesions, the data argue strongly that sex chromosome aberrations, rather than isochromosome 12p, are integral to intracranial germ cell tumorigenesis. C1 Massachusetts Gen Hosp, Dept Pathol, Mol Neurooncol Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Mol Pathol Lab, Boston, MA 02114 USA. Massachusetts Gen Hosp, Neurosurg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Saitama Med Sch, Dept Neurosurg, Saitama, Japan. RP Louis, DN (reprint author), Massachusetts Gen Hosp, Mol Pathol Lab, CNY7,149 13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [CA57683] NR 49 TC 26 Z9 27 U1 0 U2 0 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2002 VL 61 IS 6 BP 531 EP 538 PG 8 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 561MC UT WOS:000176143700004 PM 12071636 ER PT J AU Augustinack, JC Sanders, JL Tsai, LH Hyman, BT AF Augustinack, JC Sanders, JL Tsai, LH Hyman, BT TI Colocalization and fluorescence resonance energy transfer between cdk5 and AT8 suggests a close association in pre-neurofibrillary tangles and neurofibrillary tangles SO JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY LA English DT Article DE cdk5; fluorescence resonance energy transfer (FRET); hippocampus; tau ID PAIRED HELICAL FILAMENTS; GLYCOGEN-SYNTHASE KINASE-3-BETA; ALZHEIMER-LIKE STATE; TAU-PROTEIN; LEWY BODIES; MAP KINASE; DISEASE; PHOSPHORYLATION; LOCALIZATION; MICROTUBULES AB Cyclin-dependent kinase 5 (cdk5) is a serine/threonine kinase that, when activated, induces neurite outgrowth. Recent in vitro studies have shown that cdk5 phosphorylates tau at serine 199, serine 202, and threonine 205 and that p25, an activator of cdk5, is increased in Alzheimer disease (AD). Since tau is hyperphosphorylated at these sites in neurofibrillary tangles, we examined brain tissue from patients with AD and normal elderly control cases to determine whether cdk5 and these phosphoepitopes colocalize in neurofibrillary tangles. Adjacent temporal lobe sections were double immunostained with a polyclonal anti-cdk5 and monoclonal AT8 (which recognizes phosphorylated serine 199, serine 202, and threonine 205 in tau) antibodies. A subset of AT8 phosphotau-positive neurons was immunoreactive for cdk5 in entorhinal (area 28) and perirhinal (area 35) cortices and CA1 of the hippocampus. We assessed the ratio of cdk5-positive cells to AT8-positive cells and found that there is a higher degree of colocalization in pre-neurofibrillary tangles as opposed to intraneuronal and extraneuronal neurofibrillary tangles. We further examined colocalization using fluorescence resonance energy transfer. This suggests a close, stable intermolecular association between cdk5 and phosphorylated tau, consistent with phosphorylation of tau by cdk5 in AD brain. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. RP Hyman, BT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Alzheimers Res Unit, Charlestown, MA 02129 USA. FU NIA NIH HHS [AG08487]; NINDS NIH HHS [NS 07484-01] NR 37 TC 43 Z9 53 U1 0 U2 1 PU AMER ASSN NEUROPATHOLOGISTS INC PI LAWRENCE PA 1041 NEW HAMPSHIRE ST, LAWRENCE, KS 66044 USA SN 0022-3069 J9 J NEUROPATH EXP NEUR JI J. Neuropathol. Exp. Neurol. PD JUN PY 2002 VL 61 IS 6 BP 557 EP 564 PG 8 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 561MC UT WOS:000176143700007 PM 12071639 ER PT J AU Hurley, RA Saxena, S Rauch, SL Hoehn-Saric, R Taber, KH AF Hurley, RA Saxena, S Rauch, SL Hoehn-Saric, R Taber, KH TI Predicting treatment response in obsessive-compulsive disorder SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID CEREBRAL GLUCOSE-METABOLISM; PHARMACOTHERAPY; SYMPTOM C1 Baylor Coll Med, Dept Radiol, Houston, TX 77030 USA. Baylor Coll Med, Dept Psychiat, Houston, TX 77030 USA. Baylor Coll Med, Dept Behav Sci, Houston, TX 77030 USA. Baylor Coll Med, Herbert J Frensley Ctr Imaging Res, Houston, TX 77030 USA. Houston Vet Affairs Med Ctr, Houston, TX USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Massachusetts Gen Hosp, Dept Psychiat, Charlestown, MA USA. Massachusetts Gen Hosp, Dept Radiol, Charlestown, MA USA. Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. RP Taber, KH (reprint author), Baylor Coll Med, Dept Radiol, 1 Baylor Plaza, Houston, TX 77030 USA. NR 24 TC 9 Z9 9 U1 1 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SUM PY 2002 VL 14 IS 3 BP 249 EP 253 DI 10.1176/appi.neuropsych.14.3.249 PG 5 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 579NP UT WOS:000177185000001 PM 12154147 ER PT J AU Sultzer, DL Chen, ST Brown, CV Mahler, ME Cummings, JL Hinkin, CH Mandelkern, MA AF Sultzer, DL Chen, ST Brown, CV Mahler, ME Cummings, JL Hinkin, CH Mandelkern, MA TI Subcortical hyperintensities in Alzheimer's disease: Associated clinical and metabolic findings SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID POSITRON EMISSION TOMOGRAPHY; WHITE-MATTER LESIONS; ELDERLY SUBJECTS; RATING-SCALE; FRONTAL-LOBE; DEMENTIA; DEPRESSION; MRI; ABNORMALITIES; DIASCHISIS AB The authors measured subcortical hyperintensities (SH) on magnetic resonance images (MRI) in 18 patients with probable Alzheimer's disease and examined the relationships of SH severity with cortical metabolic function and clinical symptoms. Severity of SH was not correlated with absolute metabolic rates in cortical lobes. However, anterior SH severity was inversely correlated with frontal/parietal metabolic ratios after covarying for cognitive impairment. SH severity in some areas was associated with the severity of global neuropsychiatric symptoms, but marked effects on individual symptoms were not apparent. The small sample size and multiple variables limit conclusions that can be drawn. These preliminary findings indicate that subcortical MRI hyperintensities may play a role in the pathophysiology and clinical expression of Alzheimer's disease. C1 Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Dept Psychiat, Los Angeles, CA USA. Vet Affairs Greater Los Angeles Healthcare Syst, Dept Psychol, Los Angeles, CA USA. Vet Affairs Greater Los Angeles Healthcare Syst, Dept Nucl Med Serv, Los Angeles, CA USA. RP Sultzer, DL (reprint author), W Los Angeles VA Healthcare Ctr, 3South,116AF,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIA NIH HHS [AG10123]; NIMH NIH HHS [MH56031, MH00910] NR 50 TC 9 Z9 9 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SUM PY 2002 VL 14 IS 3 BP 262 EP 269 DI 10.1176/appi.neuropsych.14.3.262 PG 8 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 579NP UT WOS:000177185000003 PM 12154149 ER PT J AU Filley, CM Arciniegas, DB Wood, GV Anderson, CA Cheney, E Dygert, CR Summerall, L Goos, RB AF Filley, CM Arciniegas, DB Wood, GV Anderson, CA Cheney, E Dygert, CR Summerall, L Goos, RB TI Geriatric Treatment Center: A contemporary model for collaboration between psychiatry and neurology SO JOURNAL OF NEUROPSYCHIATRY AND CLINICAL NEUROSCIENCES LA English DT Article ID CARE; MANAGEMENT; DIAGNOSIS; DEMENTIA; BEHAVIOR; DISEASE; UNIT AB The diagnosis and treatment of individuals with problems involving both psychiatry and neurology have become more sophisticated in recent years, but these, advances may be difficult to implement in the modern health care environment. For 16 years, an inpatient Geriatric Treatment Center within a state mental hospital has been used to diagnose and treat older persons with complex neuropsychiatric disorders. Eight illustrative cases are presented of patients with major behavioral dysfunction that could not be managed effectively in other health care facilities. After neuropsychiatric evaluation and behavioral neurology consultation, all had neurologic diagnoses established as the cause of their presentation. Seven improved with appropriate treatment, of whom one could return to independent living, and the eighth died and had are autopsy diagnosis of his disease at a nearby arademic medical center. This series-highlights the value of collaboration between psychiatry and neurology for evaluation and treatment of older patients with neuropsychiatric problems not easily accommodated by many existing health care settings. C1 Univ Colorado, Sch Med, Hlth Sci Ctr, Behav Neurol Sect,Dept Neurol, Denver, CO 80262 USA. Univ Colorado, Sch Med, Dept Psychiat, Denver, CO 80262 USA. Colorado Mental Hlth Inst Pueblo, Denver, CO USA. Denver Vet Affairs Med Ctr, Denver, CO USA. RP Filley, CM (reprint author), Univ Colorado, Sch Med, Hlth Sci Ctr, Behav Neurol Sect,Dept Neurol, B-183,4200 E 9th Ave, Denver, CO 80262 USA. RI Arciniegas, David/A-3792-2009 NR 15 TC 2 Z9 2 U1 0 U2 0 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0895-0172 J9 J NEUROPSYCH CLIN N JI J. Neuropsychiatr. Clin. Neurosci. PD SUM PY 2002 VL 14 IS 3 BP 344 EP 350 DI 10.1176/appi.neuropsych.14.3.344 PG 7 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 579NP UT WOS:000177185000015 PM 12154161 ER PT J AU Rehm, HL Zhang, DS Brown, MC Burgess, B Halpin, C Berger, W Morton, CC Corey, DP Chen, ZY AF Rehm, HL Zhang, DS Brown, MC Burgess, B Halpin, C Berger, W Morton, CC Corey, DP Chen, ZY TI Vascular defects and sensorineural deafness in a mouse model of Norrie disease SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Norrie disease; mouse model; deafness; blindness; retina; cochlea; stria vascularis; marginal cells; vascular; angiogenesis; norrin ID FAMILIAL EXUDATIVE VITREORETINOPATHY; MISSENSE MUTATIONS; CANDIDATE GENE; MICE; IDENTIFICATION; DOMAIN; BRAIN AB Norrie disease is an X-linked recessive syndrome of blindness, deafness, and mental retardation. A knock-out mouse model with an Ndp gene disruption was studied. We examined the hearing phenotype, including audiological, histological, and vascular evaluations. As is seen in humans, the mice had progressive hearing loss leading to profound deafness. The primary lesion was localized to the stria vascularis, which houses the main vasculature of the cochlea. Fluorescent dyes showed an abnormal vasculature in this region and eventual loss of two-thirds of the vessels. We propose that one of the principal functions of norrin in the ear is to regulate the interaction of the cochlea with its vasculature. C1 Massachusetts Gen Hosp, Dept Neurol, Neurosurg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Dept Otol & Laryngol, Boston, MA 02114 USA. Max Planck Inst Mol Genet, D-14195 Berlin, Germany. Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. RP Chen, ZY (reprint author), Massachusetts Gen Hosp, Dept Neurol, Neurosurg Serv, WEL425,55 Fruit St, Boston, MA 02114 USA. OI Corey, David/0000-0003-4497-6016 FU NIDCD NIH HHS [DC02281, DC03402, DC04546] NR 31 TC 77 Z9 81 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 JUN 1 PY 2002 VL 22 IS 11 BP 4286 EP 4292 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 557GL UT WOS:000175900700007 PM 12040033 ER PT J AU Lee, EJ Chen, HY Wu, TS Chen, TY Ayoub, IA Maynard, KI AF Lee, EJ Chen, HY Wu, TS Chen, TY Ayoub, IA Maynard, KI TI Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE stroke; focal cerebral ischemia; neuroprotection; Ginkgo biloba extract; EGb 761 ID PLATELET-ACTIVATING-FACTOR; ARTERY OCCLUSION; OXIDATIVE STRESS; ENERGY-METABOLISM; BRAIN ISCHEMIA; STROKE THERAPY; NEURONAL CELLS; INFARCT VOLUME; WISTAR RATS; EGB-761 AB We examined the neuroprotective action of a standardized extract of Ginkgo biloba leaves (EGb 761) in permanent and transient middle cerebral artery (MCA) occlusion models in Sprague-Dawley rats. Forty-four animals were given either EGb 761 (50-200 mg/kg) or vehicle intraperitoneally, 1 hr before permanent MCA occlusion, to evaluate the dose-response effects. An additional 58 animals received EGb 761 (200 mg/kg) or vehicle, 0.5-4 hr after permanent MCA occlusion, for establishing the therapeutic window. Delayed treatment was also employed in 110 animals treated with either EGb 761 (100 200 mg/kg) or vehicle at 2-3 hr following transient focal cerebral ischemia induced by MCA occlusion for 2 hr. Neurobehavioral scores were determined 22-24 hr after permanent MCA occlusion and either 3 or 7 days after transient MCA occlusion, and brain infarction volumes were measured upon sacrifice. Local cortical blood flow (LCBF) was serially measured in a subset of animals receiving EGb 761 (100-200 mg/kg) or vehicle, 0.5 hr and 2 hr after permanent and transient MCA occlusion, respectively. Relative to vehicle-treated controls, rats pretreated with EGb761 (100 and 200 mg/kg) had significantly reduced infarct volumes, by 36% and 49%, respectively, and improved sensory behavior (P < 0.05). Delayed treatment with EGb 761 also significantly reduced brain infarction, by 20-29% and 31 %, when given up to 2 and 3 hr following transient and permanent MCA occlusion, respectively, whereas improved neurobehavioral scores were noted up to 2 hr after the onset of MCA occlusion (P < 0.05). LCBF was significantly improved in the ipsilateral cortex following the EGb 761 treatment, whereas a higher dose showed a more sustained effect. In conclusion, EGb 761 protected against transient and permanent focal cerebral ischemia and was effective after a prolonged reperfusion period even when therapy is delayed up to 2 hr. This neuroprotection may be at least partially attributed to the beneficial effects of selectively improved LCBF in the area at risk of infarction. (C) 2002 Wiley-Liss, Inc. C1 Natl Cheng Kung Univ, Neurosurg Serv, Dept Surg, Med Ctr,Neuophysiol Lab, Tainan 70428, Taiwan. Natl Cheng Kung Univ, Neurosurg Serv, Dept Surg, Sch Med, Tainan 70428, Taiwan. Natl Cheng Kung Univ, Inst Chem, Tainan 70428, Taiwan. Massachusetts Gen Hosp, Neurosurg Serv, Neurophysiol Lab, Boston, MA 02114 USA. Natl Cheng Kung Univ, Dept Anesthesiol, Med Ctr, Tainan 70428, Taiwan. Natl Cheng Kung Univ, Dept Anesthesiol, Sch Med, Tainan 70428, Taiwan. RP Lee, EJ (reprint author), Natl Cheng Kung Univ, Neurosurg Serv, Dept Surg, Med Ctr,Neuophysiol Lab, 138 Sheng Li Rd, Tainan 70428, Taiwan. NR 53 TC 77 Z9 86 U1 1 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN 1 PY 2002 VL 68 IS 5 BP 636 EP 645 DI 10.1002/jnr.10251 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 557QY UT WOS:000175920300015 PM 12111854 ER PT J AU Tzika, AA Cheng, LL Goumnerova, L Madsen, JR Zurakowski, D Astrakas, LG Zarifi, MK Scott, RM Anthony, DC Gonzalez, RG Black, PM AF Tzika, AA Cheng, LL Goumnerova, L Madsen, JR Zurakowski, D Astrakas, LG Zarifi, MK Scott, RM Anthony, DC Gonzalez, RG Black, PM TI Biochemical characterization of pediatric brain tumors by using in vivo and ex vivo magnetic resonance spectroscopy SO JOURNAL OF NEUROSURGERY LA English DT Article DE brain neoplasm; biopsy; magnetic resonance spectroscopy; children ID IN-VITRO; GLIOBLASTOMA-MULTIFORME; PROTON SPECTROSCOPY; MR SPECTROSCOPY; RESOLUTION; APOPTOSIS; PHOSPHOCHOLINE; SPECIMENS; GLIOMA; CELLS AB Object. Magnetic resonance (MR) spectroscopy provides biochemical information about tumors. The authors sought to determine the relationship between in vivo and ex vivo biochemical characterization of pediatric brain tumors by using MR spectroscopy. Their hypothesis was that ex vivo MR spectroscopy provides a link between in vivo MR spectroscopy and neuropathological analysis. Methods. In vivo proton MR spectroscopy was performed before surgery in I I patients with neuroepithelial tumors. During resection, a total of 40 tumor biopsy samples were obtained from within the volume of interest identified on in vivo MR spectroscopy and were frozen immediately in liquid nitrogen. High-Resolution Magic Angle Spinning (HRMAS) was used to perform ex vivo MR spectroscopy in these 40 tumor biopsy samples. Neuropathological analysis was performed using the same biopsy samples, and the tumors were classified as ependymoma, choroid plexus carcinoma, pineoblastoma (one each), and pilocytic astrocytoma, medullobastoma, low-grade glioma, and glioblastoma multiforme (two each). Ex vivo HRMAS MR spectroscopy improved line widths and line shapes in the spectra, compared with in vivo MR spectroscopy. Choline (Cho) detected in vivo corresponded to three different peaks ex vivo (glycerophosphocholine, phosphocholine [PCho], and Cho). Metabolite ratios from in vivo spectra correlated with ratios from ex vivo spectra (Pearson correlation coefficient range r = 0.72-0.91; p less than or equal to 0.01). Metabolite ratios from ex vivo spectra, such as PCho/total creatine (tCr) and lipid/tCr, correlated with the percentage of cancerous tissue and percentage of tumor necrosis, respectively (r = 0.84; p < 0.001). Conclusions. Agreement between in vivo and ex vivo MR spectroscopy indicates that ex vivo HRMAS MR spectroscopy can improve resolution of this modality and provide a link between in vivo MR spectroscopy and neuropathological analysis. C1 Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Childrens Hosp, Dept Radiol, Boston, MA 02115 USA. Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Childrens Hosp, Dept Biostat, Boston, MA 02115 USA. RP Tzika, AA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Nucl Magnet Resonance Surg Lab, 51 Blossom St,Room 261, Boston, MA 02114 USA. RI Astrakas, Loukas/F-5918-2011; OI Anthony, Douglas/0000-0002-3815-2240 FU NCI NIH HHS [CA77727] NR 26 TC 79 Z9 81 U1 1 U2 7 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD JUN PY 2002 VL 96 IS 6 BP 1023 EP 1031 DI 10.3171/jns.2002.96.6.1023 PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 559LD UT WOS:000176026900016 PM 12066902 ER PT J AU Hodge, MB Asch, SM Olson, VA Kravitz, RL Sauve, MJ AF Hodge, MB Asch, SM Olson, VA Kravitz, RL Sauve, MJ TI Developing indicators of nursing quality to evaluate nurse staffing ratios SO JOURNAL OF NURSING ADMINISTRATION LA English DT Article C1 Univ Calif Davis, Med Ctr, Ctr Nursing Res, Sacramento, CA 95817 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. Univ Calif Davis, Ctr Hlth Serv Res Primary Care, Sacramento, CA 95817 USA. RP Hodge, MB (reprint author), Univ Calif Davis, Med Ctr, Ctr Nursing Res, 2315 Stockton Blvd,Rm 4205, Sacramento, CA 95817 USA. OI Kravitz, Richard/0000-0001-5575-529X NR 11 TC 8 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-0443 J9 J NURS ADMIN JI J. Nurs. Adm. PD JUN PY 2002 VL 32 IS 6 BP 338 EP 345 DI 10.1097/00005110-200206000-00010 PG 8 WC Nursing SC Nursing GA 578VU UT WOS:000177142400009 PM 12055490 ER PT J AU Davids, E Zhang, KH Kula, NS Tarazi, FI Baldessarini, RJ AF Davids, E Zhang, KH Kula, NS Tarazi, FI Baldessarini, RJ TI Effects of norepinephrine and serotonin transporter inhibitors on hyperactivity induced by neonatal 6-hydroxydopamine lesioning in rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; CENTRAL-NERVOUS-SYSTEM; DOPAMINE NEURONS; D-AMPHETAMINE; BRAIN; METHYLPHENIDATE; MECHANISMS; ADHD; DENERVATION; STIMULANTS AB Consistent with their clinical effects in attention deficit-hyperactivity disorder (ADHD), the stimulants methylphenidate and amphetamine reduce motor hyperactivity in juvenile male rats with neonatal 6-hydroxydopamine (6-OHDA) lesions of the forebrain dopamine (DA) system. Since stimulants act on several aminergic neurotransmission systems, we investigated underlying mechanisms involved by comparing behavioral actions of d-methylphenidate, selective inhibitors of the neuronal transport of DA[GBR-12909 (1-[2-[bis(4-fluorophenyl) methoxy] ethyl] 4-[ 3-phenylpropyl] piperazine dihydrochloride), amfonelic acid], serotonin [5-hydroxytryptamine (5-HT), citalopram, fluvoxamine], and norepinephrine (NE; desipramine, nisoxetine) in 6-OHDA lesioned rats. Selective dopamine lesions were made using 6-OHDA (100 mug, intracisternal) on postnatal day (PD) 5 after desipramine pretreatment (25 mg/kg, s.c.) to protect noradrenergic neurons. Rats were given test agents or vehicle, intraperitoneally, before recording motor activity for 90 min at PD 25 in a novel environment. d-Methylphenidate stimulated motor activity in sham controls and antagonized hyperactivity in lesioned rats. Selective DA transport inhibitors GBR-12909 and amfonelic acid greatly stimulated motor activity in sham control subjects, too, but did not antagonize hyperactivity in lesioned rats. In contrast, all selective 5-HT and NE transporter antagonists tested greatly reduced motor hyperactivity in 6-OHDA lesioned rats but did not alter motor activity in sham controls. The findings indicate that behavioral effects of stimulants in young rats with neonatal 6-OHDA lesions may be mediated by release of NE or 5-HT and support interest in using drugs that increase activity of norepinephrine or serotonin to treat ADHD. C1 Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA USA. RP Baldessarini, RJ (reprint author), McLean Hosp, Mailman Res Ctr, 115 Mill St, Belmont, MA 02478 USA. FU NIMH NIH HHS [MH-34006, MH-47370] NR 42 TC 58 Z9 59 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2002 VL 301 IS 3 BP 1097 EP 1102 AR UNSP 4718/987472 DI 10.1124/jpet.301.3.1097 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 554LK UT WOS:000175736800039 PM 12023542 ER PT J AU Smith, SR Reddy, LA AF Smith, SR Reddy, LA TI The concurrent validity of the Devereux Scales of Mental Disorders SO JOURNAL OF PSYCHOEDUCATIONAL ASSESSMENT LA English DT Article ID CHILD-BEHAVIOR CHECKLIST; ADHD AB The present study was designed as an initial investigation of the concurrent validity of the Devereux Scales of Mental Disorders (DSMD; Naglieri, LeBuffe, & Pfeiffer, 1994) in relation to the Behavior Assessment System for Children (BASC) and the Child Behavior Checklist (CBCL) in two clinically referred samples of children and adolescents. The DSMD is a recently published multidimensional behavior rating scale comprised of empirically and conceptually derived scales designed to aid the diagnostic decision-making process for youth with severe psychiatric and educational classifications. To date, no published study has examined the concurrent validity of the DSMD. The first of the present studies compared the DSMD and BASC with 64 children and adolescents in an inpatient hospital setting; the second study compared the DSMD and CBCL with 74 children and adolescents classified as having serious emotional disturbance (SED) in residential care. Concurrent validity was assessed through correlations and squared semipartial correlation coefficients between the DSMD scale scores and the BASC and CBCL, scale scores. Paired t tests (p <.001) were also computed across scales of similar constructs. In comparison to the BASC and CBCL, the DSMD demonstrated strong concurrent validity between conceptually similar scales, providing some evidence for the concurrent validity of the DSMD. Specifically, relative to the other measures, the DSMD appears to have some unique scales designed to detect more acute or serious pathology, whereas the BASC and CBCL may be better equipped to assess specific types of externalizing symptoms. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Fairleigh Dickinson Univ, Rutherford, NJ 07070 USA. RP Smith, SR (reprint author), Massachusetts Gen Hosp, Dept Psychiat, 15 Parkman St,WACC 812, Boston, MA 02114 USA. NR 24 TC 5 Z9 5 U1 0 U2 0 PU PSYCHOEDUCATIONAL CORP PI CORDOVA PA 173 LEIF COVE, CORDOVA, TN 38018 USA SN 0734-2829 J9 J PSYCHOEDUC ASSESS JI J. Psychoeduc. Assess. PD JUN PY 2002 VL 20 IS 2 BP 112 EP 127 DI 10.1177/073428290202000201 PG 16 WC Psychology, Educational SC Psychology GA 583LD UT WOS:000177408600001 ER PT J AU Elman, I Karlsgodt, KH Gastfriend, DR Chabris, CF Breiter, HC AF Elman, I Karlsgodt, KH Gastfriend, DR Chabris, CF Breiter, HC TI Cocaine-primed craving and its relationship to depressive symptomatology in individuals with cocaine dependence SO JOURNAL OF PSYCHOPHARMACOLOGY LA English DT Article DE Addiction Severity Index; cocaine infusion; euphoria; Hamilton Rating Scale for Depression; high; multidimensional craving questionnaire; non-treatment seekers ID SELF-MEDICATION HYPOTHESIS; ABUSERS; PHARMACOTHERAPY; ABSTINENCE; ADDICTION; REWARD; PSYCHOTHERAPY; PREDICTION; DISORDERS; SYMPTOMS AB Several lines of evidence suggest a link between cocaine-primed craving and depressive symptomatology. The purpose of this study was to directly relate these two clinical phenomena. Thirty-three cocaine-dependent subjects were rated on the Hamilton Rating Scale for Depression (HRSD) at baseline and then administered an i.v. bolus of cocaine (0.2 mg/kg). Multiple regression analysis revealed that only the HRSD score was an independent predictor of cocaine-primed craving (F = 4.09; d.f. = 10,22; r = 0.81, p < 0.003) when baseline spontaneous craving during early withdrawal, age, gender, frequency of use, time since last use, monetary expenditure on cocaine and the Addiction Severity. Index Drug Composite Scores were considered. These data support the hypothesis that depressive symptomatology affects cocaine-primed craving and that this relationship is relatively specific to symptoms defined by the HRSD and is not seen with a number of other clinical and demographic variables. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, MENC, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychol, Boston, MA 02114 USA. RP Elman, I (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, 15 Parkman St WACC-812, Boston, MA 02114 USA. RI Karlsgodt, Katherine/H-2964-2013 OI Karlsgodt, Katherine/0000-0003-3332-4231 FU NCRR NIH HHS [M01 RR01066]; NIDA NIH HHS [DA00265, DA09467] NR 41 TC 31 Z9 31 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 6 BONHILL STREET, LONDON EC2A 4PU, ENGLAND SN 0269-8811 J9 J PSYCHOPHARMACOL JI J. Psychopharmacol. PD JUN PY 2002 VL 16 IS 2 BP 163 EP 167 PG 5 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 562NL UT WOS:000176204700007 PM 12095075 ER PT J AU Choi, HK Seeger, JD Kuntz, KM AF Choi, HK Seeger, JD Kuntz, KM TI A cost effectiveness analysis of treatment options for methotrexate-naive rheumatoid arthritis SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE rheumatoid arthritis; methotrexate-naive; cost effectiveness ID TRIAL; LEFLUNOMIDE; IMPROVEMENT; ETANERCEPT; PLACEBO; THERAPY; INFLIXIMAB; EFFICACY; SAFETY; MODEL AB Objective. New treatment options for patients with methotrexate (MTX)-naive rheumatoid arthritis (RA) have become available. Given wide variability in efficacy and cost among different treatment options, we sought to determine their relative cost effectiveness to help guide policy in different cost constrained settings. Methods. We performed a cost effectiveness analysis comparing 5 monotherapy options for patients with MTX-naive RA: (1) etanercept, (2) leflunomide, (3) MTX (up to 15 mg weekly), (4) sulfasalazine (SSZ), and (5) no second line agent. A decision analysis model was used with a time horizon of 6 months. We employed 2 measures of effectiveness based on published clinical trial data: American College of Rheumatology (ACR) 20% response proportion (ACR 20) and a weighted average of proportions achieving ACR 70, ACR 50, and ACR 20 (ACR 70 weighted response, ACR 70WR). Incremental cost effectiveness ratios were calculated as additional cost per patient achieving either outcome, compared with the next most expensive option. Results. In both base case analyses employing ACR 20 and ACR 70WR as effectiveness measures, MTX and SSZ both cost less and were more effective (i.e., cost saving) than no second line agent, Leflunomide cost more and was less efficacious than SSZ (dominated) in analyses using either outcome. The most efficacious option, etanercept, cost US $41,900 per ACR 20 and $40,800 per ACR 70 WR compared with SSZ and MTX, respectively. When we included only direct costs in analyses, the least expensive non-dominated option was SSZ with incremental cost effectiveness ratios of US $900 per ACR 20 and $1500 per ACR 70WR compared with no second line agent. Overall, relative cost effectiveness between MTX and SSZ was sensitive to variation in relevant variables in sensitivity analyses. Otherwise, our extensive sensitivity analyses did not substantially affect the base case results. Conclusion. MTX is cost effective (cost saving vs the no second line agent option) for MTX-naive RA in achieving ACR 20 or ACR 70WR over a 6 month period. Based on available data, the relative cost effectiveness between SSZ and MTX cannot be determined with reasonable certainty and SSZ therapy appears to be as cost effective as MTX (cost saving) in achieving ACR outcomes over a 6 month period. The most efficacious option, etanercept, incurs much higher incremental costs per ACR 20 or ACR 70WR than other options analyzed. Whether etanercept compared with MTX is cost effective depends on whether > $40,000 per ACR 20 or ACR 70WR over a 6 month period is considered acceptable. C1 Massachusetts Gen Hosp, Arthrit Unit, Harvard Med Sch, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Boston, MA 02115 USA. RP Choi, HK (reprint author), Massachusetts Gen Hosp, Arthrit Unit, Harvard Med Sch, Bulfinch 165,Fruit St, Boston, MA 02114 USA. NR 23 TC 45 Z9 48 U1 0 U2 5 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 JUN PY 2002 VL 29 IS 6 BP 1156 EP 1165 PG 10 WC Rheumatology SC Rheumatology GA 559PA UT WOS:000176033500008 PM 12064828 ER PT J AU Takayanagi, S Dirks, DD Moshfegh, A AF Takayanagi, S Dirks, DD Moshfegh, A TI Lexical and talker effects on word recognition among native and non-native listeners with normal and impaired hearing SO JOURNAL OF SPEECH LANGUAGE AND HEARING RESEARCH LA English DT Article; Proceedings Paper CT 140th Annual Meeting of the Acoustical-Society-of-America CY DEC 03-08, 2000 CL NEWPORT BEACH, CA SP Acoust Soc Amer DE spoken-word recognition; talker and lexical effects; hearing impairment; non-native listeners; structural equation modeling ID SPEECH-PERCEPTION; SPOKEN WORDS; VARIABILITY; ENGLISH; MODEL AB Evidence suggests that word recognition depends on numerous talker-, listener-, and stimulus-related characteristics. The current study examined the effects of talker variability and lexical difficulty on spoken-word recognition among four groups of listeners: native listeners with normal hearing or hearing impairment (moderate sensorineural hearing loss) and non-native listeners with normal hearing or hearing impairment. The ability of listeners to accommodate trial-to-trial variations in talkers' voice was assessed by comparing recognition scores for a single-talker condition to those obtained in a multiple-talker condition. Lexical difficulty was assessed by comparing word-recognition performance between lexically "easy" and "hard" words as determined by frequency of occurrence in language and the structural characteristics of similarity neighborhoods formalized in the Neighborhood Activation Model. An up-down adaptive procedure was used to determine the sound pressure level for 50% performance. Non-native listeners in both normal-hearing and hearing-impaired groups required greater intensity for equal intelligibility than the native normal-hearing and hearing-impaired listeners. Results, however, showed significant effects of talker variability and lexical difficulty for the four groups. Structural equation modeling demonstrated that an audibility factor accounts for 2-3 times more variance in performance than does a linguistic-familiarity factor. However, the linguistic-familiarity factor is also essential to the model fit. The results demonstrated effects of talker variability and lexical difficulty on word recognition for both native and non-native listeners with normal or impaired hearing. The results indicate that linguistic and indexical factors should be considered in the development of speech-recognition tests. C1 Natl Ctr Rehabil Auditory Res Vet Adm Med Ctr, Portland, OR USA. Vet Adm Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. RP Takayanagi, S (reprint author), House Ear Res Inst, Dept Commun Neurosci, 2100 W 3rd St, Los Angeles, CA 90057 USA. EM stakayanagi@mailhouse.hei.org NR 27 TC 26 Z9 27 U1 2 U2 4 PU AMER SPEECH-LANGUAGE-HEARING ASSOC PI ROCKVILLE PA 10801 ROCKVILLE PIKE, ROCKVILLE, MD 20852-3279 USA SN 1092-4388 J9 J SPEECH LANG HEAR R JI J. Speech Lang. Hear. Res. PD JUN PY 2002 VL 45 IS 3 BP 585 EP 597 DI 10.1044/1092-4388(2002/047) PG 13 WC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation SC Audiology & Speech-Language Pathology; Linguistics; Rehabilitation GA 561MH UT WOS:000176144200016 PM 12069010 ER PT J AU Tanabe, KK AF Tanabe, KK TI Palliative liver resections SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Editorial Material ID COLORECTAL METASTASES; ADJUVANT THERAPY; BREAST-CANCER; CARCINOMA; SURVIVAL C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Boston, MA 02114 USA. RP Tanabe, KK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Surg Oncol, Cox Bldg 626, Boston, MA 02114 USA. NR 11 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD JUN PY 2002 VL 80 IS 2 BP 69 EP 71 DI 10.1002/jso.10108 PG 3 WC Oncology; Surgery SC Oncology; Surgery GA 557KV UT WOS:000175908500001 PM 12173382 ER PT J AU Estourgie, SH Nielsen, GP Ott, MJ AF Estourgie, SH Nielsen, GP Ott, MJ TI Metastatic patterns of extremity myxoid liposarcoma and their outcome SO JOURNAL OF SURGICAL ONCOLOGY LA English DT Article DE retroperitoneal; abdominal; paraspinal; liposarcoma ID SOFT-TISSUE SARCOMAS; PROGNOSTIC FACTORS; RECURRENCE; SURVIVAL AB Background and Objectives: Extremity myxoid liposarcomas have a unique extrapulmonary metastatic potential. We studied the metastatic pattern of extremity liposarcomas to determine what types of post-treatment imaging may be of value in the follow-up these patients. Methods: Twenty-two patients from a total of 128 patients with primary extremity liposarcoma were treated at a tertiary care institution for subsequent metastases from January 1981 to January 2000. Median follow-up was 45 months (range: 6-270 months). Data on these patients was prospectively collected and then retrospectively analyzed for effect of metastatic pattern and treatment on outcome. Results: Of these 22 patients, extrapulmonary metastases developed in 10, combined pulmonary and extrapulmonary metastases developed in 6, and isolated pulmonary metastases developed in 6. Of the 16 patients with extrapulmonary metastases, 13 were of the myxoid subtype. Of the 49 patients with extremity myxoid liposarcomas, metastases developed in 14 (29%). The most common sites of metastases among these 14 patients include: the retroperitoneum, 10 patients (71)%; intra-abdominal extrahepatic, 7 patients (50%); spinal/paraspinal, 6 patients (43%). Only 3 of the patients are alive and disease free and all 3 of these patients are from the subgroup of 10 patients with only extra-pulmonary metastases (2 intra-abdominal and I retroperitoneal). Conclusions: Extremity myxoid liposarcomas have an unusually high C predilection for extra-pulmonary metastases, frequently without any pulmonary metastases. After treatment of the primary tumor, these patients should be followed with periodic chest X-ray and abdominal/pelvic computed tomography (CT) scans. Any back or neurologic complaints should prompt additional imaging of the appropriate spinal area. Consideration should be given to surgical and adjuvant treatment of Z metastatic disease when appropriate. (C) 2002 Wiley-Liss, Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Surg Oncol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. Univ Utrecht, Sch Med, Utrecht, Netherlands. RP Ott, MJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Surg Oncol, Cox 626,100 Blossom St, Boston, MA 02114 USA. NR 18 TC 34 Z9 43 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0022-4790 J9 J SURG ONCOL JI J. Surg. Oncol. PD JUN PY 2002 VL 80 IS 2 BP 89 EP 93 DI 10.1002/jso.10093 PG 5 WC Oncology; Surgery SC Oncology; Surgery GA 557KV UT WOS:000175908500004 PM 12173385 ER PT J AU Mehta, KM Yaffe, K Covinsky, KE AF Mehta, KM Yaffe, K Covinsky, KE TI Cognitive impairment, depressive symptoms, and functional decline in older people SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE physical functioning; functional decline; activities of daily living; cognitive impairment; depressive symptoms ID PHYSICAL-DISABILITY; RISK-FACTORS; HEALTH; ADULTS; PREDICTION; DEPENDENCE; MACARTHUR; OUTCOMES; PROXY; WOMEN AB OBJECTIVES: Although cognitive impairment and depressive symptoms are associated with functional decline, it is not understood how these risk factors act together to affect the risk of functional decline. The purpose of this study is to determine the relative contributions of cognitive impairment and depressive symptoms on decline in activity of daily living (ADL) function over 2 years in an older cohort. DESIGN: Prospective cohort study. SETTING: A U.S. national prospective cohort study of older people, Asset and Health Dynamics in the Oldest Old. PARTICIPANTS: Five thousand six hundred ninety-seven participants (mean age 77, 64% women, 86% white) followed from 1993 to 1995 MEASUREMENTS: Cognitive impairment and depressive symptoms were defined as the poorest scores: 1.5 standard deviations below the mean on a cognitive scale or 1.5 standard deviations above the mean on validated depression scales. Risk of functional decline in participants with depressive symptoms, cognitive impairment, and both, compared with neither risk factor, were calculated and stratified by baseline dependence. Analyses were adjusted for demographics and comorbidity. RESULTS: Eight percent (n = 450) of subjects declined in ADL function. In participants who were independent in all ADLs at baseline, the relative risk (RR) of 2-year functional decline was 2.3 (95% confidence interval (CI) = 1.7-3.1) for participants with cognitive impairment, 1.9 (95% Cl = 1.3-2.6) for participants with depressive symptoms, and 2.4 (95% Cl = 1.4-3.7) for participants with cognitive impairment and depressive symptoms. In participants who were dependent in one or more ADLs at baseline, RR of 2-year functional decline was 1.9 (95% CI = 1.2-2.8) for participants with cognitive impairment, 0.6 (95% CI = 0.3-1.3) for participants with depressive symptoms, and 1.5 (95% Cl = 0.8-2.6) for participants with cognitive impairment and depressive symptoms. CONCLUSIONS: In participants with no ADL dependence at baseline, cognitive impairment and depressive symptoms are risk factors for decline, but that, in participants with dependence in ADL at baseline, cognitive impairment, but not depressive symptoms, is a risk factor for additional decline. C1 Univ Calif San Francisco, Dept Internal Med, Div Geriatr, San Francisco, CA 94121 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. RP Mehta, KM (reprint author), Univ Calif San Francisco, Dept Internal Med, Div Geriatr, 4150 Clement St,Box 181G, San Francisco, CA 94121 USA. FU AHRQ HHS [K02 HS 00006-01, K02 HS000006]; NIA NIH HHS [P30 AG015272-07S1, K23 AG 00888, K23 AG000888, P30 AG015272, R01 AG 19827-01, R01 AG019827, T32 AG 00212-08, T32 AG000212] NR 29 TC 98 Z9 105 U1 2 U2 15 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2002 VL 50 IS 6 BP 1045 EP 1050 DI 10.1046/j.1532-5415.2002.50259.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 565EA UT WOS:000176354900009 PM 12110064 ER PT J AU Ferrell, B Casarett, D Epplin, J Fine, P Gloth, FM Herr, K Katz, P Keefe, F Koo, PJS O'Grady, M Szwabo, P Vallerand, AH Weiner, D AF Ferrell, B Casarett, D Epplin, J Fine, P Gloth, FM Herr, K Katz, P Keefe, F Koo, PJS O'Grady, M Szwabo, P Vallerand, AH Weiner, D CA AGS Panel Persistent Pain Older TI The management of persistent pain in older persons SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Review ID RANDOMIZED CONTROLLED TRIAL; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; OSTEOARTHRITIC KNEE PAIN; CONTROLLED-RELEASE OXYCODONE; PLACEBO-CONTROLLED TRIAL; CORONARY HEART-DISEASE; QUALITY-OF-LIFE; MIDDLE-AGED MEN; PHYSICAL-ACTIVITY; NURSING-HOME C1 Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Philadelphia VA Med Ctr, Ctr Hlth Equity Res & Promot, Philadelphia, PA USA. Litchfield Family Practice Ctr, Litchfield, IL USA. Univ Utah, Pain Management Ctr, Salt Lake City, UT USA. Victory Springs Senior Hlth Associates, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Univ Iowa, Iowa City, IA USA. Univ Rochester, Sch Med, Rochester, NY USA. Duke Med Ctr, Durham, NC USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Emory Univ, Sch Med, Atlanta, GA USA. St Louis Univ, St Louis, MO 63103 USA. Wayne State Univ, Detroit, MI USA. Univ Pittsburgh, Sch Med, Pain Evaluat & Treatment Inst, Pittsburgh, PA USA. RP Ferrell, B (reprint author), Amer Geriatr Soc, Profess Educ & Special Projects, 350 5th Ave,Suite 801, New York, NY 10118 USA. RI Vallerand, April/I-8150-2012 NR 128 TC 18 Z9 22 U1 3 U2 7 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2002 VL 50 SU 6 BP S205 EP S224 PG 20 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 563TP UT WOS:000176271900001 ER PT J AU Obrador, GT Ojo, A Thadhani, R AF Obrador, GT Ojo, A Thadhani, R TI End-stage renal disease in patients with Fabry disease SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID REPLACEMENT THERAPY; TRANSPLANTATION; INVOLVEMENT; EXPERIENCE; ALLOGRAFT; FAILURE C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02114 USA. Tufts Univ New England Med Ctr, Div Nephrol, Boston, MA 02111 USA. Panamer Univ, Sch Med, Mexico City, DF, Mexico. Univ Michigan, Dept Nephrol, Ann Arbor, MI USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Renal Unit, Boston, MA 02114 USA. RP Thadhani, R (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Founders 036,55 Fruit St, Boston, MA 02114 USA. NR 11 TC 14 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2002 VL 13 IS 6 SU 2 BP S144 EP S146 AR UNSP 1046-6673/1300-0144 DI 10.1097/01.ASN.0000015237.87719.DC PG 3 WC Urology & Nephrology SC Urology & Nephrology GA 558YZ UT WOS:000175997000006 PM 12068027 ER PT J AU Thadhani, R AF Thadhani, R TI Anderson-Fabry disease: A nephrology perspective - Introduction SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Editorial Material C1 Massachusetts Gen Hosp, Med & Renal Unit, Boston, MA 02114 USA. RP Thadhani, R (reprint author), Massachusetts Gen Hosp, Med & Renal Unit, 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 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2002 VL 13 IS 6 SU 2 BP S125 EP S125 DI 10.1097/01.ASN.0000017940.40617.41 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 558YZ UT WOS:000175997000001 ER PT J AU Reisdorff, J En-nia, A Stefanidis, I Floege, J Lovett, DH Mertens, PR AF Reisdorff, J En-nia, A Stefanidis, I Floege, J Lovett, DH Mertens, PR TI Transcription factor Ets-1 regulates gelatinase A gene expression in mesangial cells SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MATRIX METALLOPROTEINASE-2; IV COLLAGENASE; ENDOTHELIAL-CELLS; DNA-BINDING; PROLIFERATION; PROMOTER; FAMILY; RAT; GLOMERULONEPHRITIS; COMPLEX AB Ets transcription factors are involved in cell growth and angiogenesis. Ets-1 targets include members of the matrix metalloproteinase superfamily. In inflammatory glomerular diseases, the patterns and regulation of Ets expression have not been fully characterized. In the present study. nuclear binding activities to the consensus Ets-1/PEA3 motif were detected in mesangial cells (MC), and the Ets-1 protein was positively identified by Western blotting. reverse transcription PCR (RTPCR), and DNA-binding studies. The 5' flanking regions of the human and rat gelatinase A genes contain clusters of potential Ets-1 binding motifs, one of which is evolutionarily conserved. Using a series of 5' deletion reporter constructs of the rat gelatinase A gene and an Ets-1 expression plasmid. a concentration-dependent threefold trans-activation of gene expression mapped to the conserved Ets-1 binding motif at -1004/-1053 bps, designated responsive element-2 (RE-2). The RE-2 was operative within the context of the homologous gelatinase A promoter but not with a heterologous simian virus 40 promoter. Specific Ets-1 binding to this sequence was demonstrated by DNA-binding studies. Transient expression of an Ets-1 expression plasmid increased gelatinase A protein expression. Our findings identify an additional matrix metalloproteinase family member. gelatinase A. as an Ets-1 responsive gene in MC that may play a role in the high level expression of this enzyme in inflammatory glomerular diseases. C1 Rhein Westfal TH Aachen, Dept Nephrol & Immunol, D-52057 Aachen, Germany. Univ Calif San Francisco, San Francisco VAMC, Dept Med, San Francisco, CA USA. RP Mertens, PR (reprint author), Rhein Westfal TH Aachen, Dept Nephrol & Immunol, Pauwelsstr 30, D-52057 Aachen, Germany. FU NIDDK NIH HHS [DK39776] NR 38 TC 28 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2002 VL 13 IS 6 AR UNSP 1046-6673/1306-1568 DI 10.1097/01.ASN.0000015617.39974.FB PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 557PW UT WOS:000175917800017 PM 12039986 ER PT J AU Angeja, BG Kermgard, S Chen, MS McKay, M Murphy, SA Antman, EM Cannon, CP Braunwald, E Gibson, CM AF Angeja, BG Kermgard, S Chen, MS McKay, M Murphy, SA Antman, EM Cannon, CP Braunwald, E Gibson, CM TI The smoker's paradox: Insights from the angiographic substudies of the TIMI trials SO JOURNAL OF THROMBOSIS AND THROMBOLYSIS LA English DT Article DE acute myocardial infarction; thrombolysis; tobacco smoking; coronary flow ID ACUTE MYOCARDIAL-INFARCTION; TISSUE-PLASMINOGEN-ACTIVATOR; RECEIVING THROMBOLYTIC THERAPY; ST-SEGMENT ELEVATION; BLOOD-FLOW; CLINICAL OUTCOMES; CIGARETTE-SMOKING; MORTALITY; REPERFUSION; ANGIOPLASTY AB Background: Despite increased risk for coronary artery disease and acute myocardial infarction (AMI), smokers have a paradoxically lower mortality after thrombolysis for AMI than non-smokers. We determined the clinical risk profiles and coronary flow characteristics of patients in the TIMI trials according to smoking status, focusing on microvascular flow. Methods: Among 2,573 patients in the TIMI 4, 10A, 10B and TIMI 14 trials, epicardial flow post-thrombolysis was measured using angiographic TIMI flow grades and the corrected TIMI frame count (CTFC). Microvascular flow was measured by TIMI Myocardial Perfusion Grade (TMPG) and, in TIMI 14, the percentage of ST segment resolution. Results: Clinically, the mean age (54 vs. 62 years), the prevalence of diabetes mellitus (11% vs. 16%) and hypertension (26% vs. 40%), and the 30-day mortality (2.6% vs. 6.2%) were lower among smokers than nonsmokers (all p less than or equal to 0.001). Angiographically, single-vessel disease (48% vs. 40%) and non-left anterior descending infarct arteries (65.4% vs. 60.8%) were more common among smokers (both p less than or equal to 0.01). Epicardial TIMI grade 3 flow was achieved more often in smokers than nonsmokers (61% vs. 56%) and the CTFC was faster (34 vs. 37 frames/sec, both p less than or equal to 0.01), especially in LAD lesions. However, the frequency of normal microvascular flow (TMPG 3) was similar among smokers and non-smokers (24% vs. 29%, p = 0.16), as was the frequency of complete ST segment resolution (50% vs. 46%, p = 0.29). Conclusions: Smokers have lower mortality after AMI than non-smokers, due in large part to lower clinical risk profiles and faster epicardial flow. Differences in tissue-level perfusion do not appear to contribute to lower mortality in smokers. C1 TIMI Study Grp, Boston, MA 02115 USA. Univ Calif San Francisco, Dept Med, Div Cardiovasc, San Francisco, CA USA. RP Gibson, CM (reprint author), TIMI Study Grp, 333 Longwood Ave, Boston, MA 02115 USA. NR 30 TC 28 Z9 33 U1 0 U2 0 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0929-5305 J9 J THROMB THROMBOLYS JI J. Thromb. Thrombolysis PD JUN PY 2002 VL 13 IS 3 BP 133 EP 139 DI 10.1023/A:1020470721977 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 599RM UT WOS:000178349000002 PM 12355029 ER PT J AU Orcutt, HK Erickson, DJ Wolfe, J AF Orcutt, HK Erickson, DJ Wolfe, J TI A prospective analysis of trauma exposure: The mediating role of PTSD symptomatology SO JOURNAL OF TRAUMATIC STRESS LA English DT Article DE PTSD; Gulf War veterans; trauma exposure; retraumatization ID POSTTRAUMATIC-STRESS-DISORDER; GULF-WAR VETERANS; RISK-FACTORS; REVICTIMIZATION; ASSAULT; SAMPLE; WOMEN; VICTIMIZATION; EXPERIENCES; EVENTS AB Trauma exposure has been associated with increased risk of exposure to additional traumatic events. Reactions to trauma exposure, specifically PTSD symptomatology, may mediate the link between trauma exposure and later traumatic events. Data from a longitudinal sample of Gulf War veterans (N = 2,949) were analyzed using a series of regression models. Higher levels of combat exposure were related to increased reports of PTSD symptomatology immediately upon return as well as increased reports of traumatic events in the 2 years following the Gulf War. PTSD symptomatology partially mediated the link between combat exposure and later trauma. Symptom clusters were also analyzed separately as potential mediators. Implications for the treatment of PTSD and prevention of exposure to multiple traumas are discussed. C1 Vet Adm Boston Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, Womens Hlth Sci Div, Boston, MA USA. Boston Univ, Sch Med, Dept Psychol, Boston, MA 02118 USA. RP Orcutt, HK (reprint author), No Illinois Univ, Dept Psychol, De Kalb, IL 60115 USA. NR 33 TC 52 Z9 53 U1 1 U2 4 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD JUN PY 2002 VL 15 IS 3 BP 259 EP 267 AR UNSP 0894-9867/02/0600-0259/1 DI 10.1023/A:1015215630493 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 549QR UT WOS:000175456300012 PM 12092919 ER PT J AU O'Toole, TP Gibbon, JL Seltzer, D Hanusa, BH Fine, MJ AF O'Toole, TP Gibbon, JL Seltzer, D Hanusa, BH Fine, MJ TI Urban homelessness and poverty during economic prosperity and welfare reform: Changes in self-reported comorbidities, insurance, and sources for usual care, 1995-1997 SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Article DE health access; homeless; Medicaid managed care; welfare reform ID HOUSED POOR; MEDICAL-CARE; LOS-ANGELES; ADULTS; SERVICES AB Little is known of how homeless and other urban poor populations have fared during the robust economy and within structural changes in health care delivery and entitlement programs of the 1990s. This is important in determining the need for population-specific services during a vigorous economy with low unemployment and increasing Medicaid managed-care penetration. This study compared health insurance status and availability of a source for usual medical care, psychiatric and substance abuse comorbidities, and perceived causes of homelessness in homeless adults surveyed in 1995 and 1997. Cross-sectional, community-based surveys were conducted in 1995 and 1997 at sites frequented by urban homeless adults residing in Pittsburgh, Pennsylvania. Self-reported medical, mental health, and substance abuse comorbidities, health insurance, and source for usual care were measured. Compared to the 388 individuals surveyed in 1995, the 267 homeless adults surveyed in 1997 had more medical comorbidity (56.6% vs. 30.2%, P < .001) and mental health comorbidity (44.9% vs. 36.9%, P = .04) and required more chronic medication (52.1% vs. 30.3%, P < .001). More respondents in 1997 than 1995 reported having no health insurance (41.4% vs. 29.4%, P < .001). While there was no difference in the overall proportion reporting a source for usual care (78.3% in 1997 vs. 80.2% in 1995, P = .55), fewer persons reported use of the emergency department and more persons reported using a shelter-based clinic for usual care in 1997 compared with 1995. These findings suggest more need for medical care among homeless and urban poor persons in 1997 compared with 1995 and support the continued need for outreach and support services despite a vigorous economy. C1 Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. VA Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Ctr Res Hlth Care, Pittsburgh, PA 15260 USA. RP O'Toole, TP (reprint author), Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, 2024 E Monument St,Suite 2-500, Baltimore, MD 21205 USA. NR 23 TC 17 Z9 17 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD JUN PY 2002 VL 79 IS 2 BP 200 EP 210 DI 10.1093/jurban/79.2.200 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 557QC UT WOS:000175918400006 PM 12023495 ER PT J AU Cambria, RP Brewster, DC Lauterbach, SR Kaufman, JL Geller, S Fan, CM Greenfield, A Hilgenberg, A Clouse, WD AF Cambria, RP Brewster, DC Lauterbach, SR Kaufman, JL Geller, S Fan, CM Greenfield, A Hilgenberg, A Clouse, WD TI Evolving experience with thoracic aortic stent graft repair SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the New-England-Society-for-Vascular-Surgery CY SEP 19-21, 2001 CL PROVIDENCE, RHODE ISLAND SP New England Soc Vasc Surg ID ANEURYSM REPAIR; ENDOVASCULAR REPAIR; PLACEMENT; DISSECTION AB Purpose: We reviewed our initial thoracic aorta (TA) stent graft experience in 28 patients from the perspective of treatment with homemade devices (Dacron over Gianturco Z stents; 14 cases) and a commercial device (Excluder; W.L. Gore Co, Flagstaff, Ariz; 14 cases). Methods: From November 1996 to August 2001, 28 patients with a spectrum of disease (degenerative aneurysm, n = 18; chronic dissection, n = 4; pseudoaneurysm, n = 3, with 1 trauma and 2 anastomotic; intramural hematoma, n = 2; and coarctation, n = 1) underwent TA stent grafting. Clinical parameters included a mean age of 71 years, 12 female (43%) and 16 male (57%) patients, 14 of 28 patients (50%) with major comorbidities that prohibited open repair, and nine of 28 patients (32%) with urgent or ruptured conditions. Seven patients (25%) needed open surgical access to the aorta or iliac artery for either concomitant abdominal aortic aneurysm repair (n = 3) or device deployment (n = 4), and six of 28 patients (21%) needed left subclavian-carotid transposition to provide for an adequate proximal fixation site. Focal (< 15 cm) grafts were used in 19 patients, and the remaining patients had at least two thirds of their descending aorta excluded. Results: The procedural mortality rate was 3.5% (1/28 patients); three additional deaths, (1 device-related) occurred during the mean follow-up period of 17 months. Access artery complications occurred in six of 28 patients (21%), with one fatal. No immediate or late open conversions were performed. One patient needed urgent dilation and stenting of a collapsed stent graft 3 weeks after deployment. Serious systemic complications included temporary dialysis (n = 1), congestive heart failure (n = 1), and unstable angina (n = 1). Complete exclusion of the TA lesion was noted in 27 of 28 cases (96%). No cases of spinal cord ischemia were noted. Ease and accuracy of deployment was superior for the second generation (commercial) device. Conclusion: TA stent graft repair, although in evolution, appears to be a safe and effective alternative to open repair for many patients with a spectrum of TA disease. Prospective trials for individual diseases will be necessary to define its ultimate role. C1 Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Radiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Vasc Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Vasc Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. RP Cambria, RP (reprint author), 15 Parkman St,WAC 458, Boston, MA 02114 USA. NR 20 TC 110 Z9 113 U1 1 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2002 VL 35 IS 6 BP 1129 EP 1135 DI 10.1067/mva.2002.123323 PG 7 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 562BX UT WOS:000176178500016 PM 12042714 ER PT J AU Dattilo, JB Brewster, DC Fan, CM Geller, SC Cambria, RP LaMuraglia, GM Greenfield, AJ Lauterbach, SR Abbott, WM AF Dattilo, JB Brewster, DC Fan, CM Geller, SC Cambria, RP LaMuraglia, GM Greenfield, AJ Lauterbach, SR Abbott, WM TI Clinical failures of endovascular abdominal aortic aneurysm repair: Incidence, causes, and management SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the New-England-Society-for-Vascular-Surgery CY SEP 19-21, 2001 CL PROVIDENCE, RHODE ISLAND SP New England Soc Vasc Surg ID LIFE-TABLE ANALYSIS; ENDOLUMINAL REPAIR; STENT-GRAFT; 2ND-GENERATION PROSTHESES; INITIAL EXPERIENCE; MULTICENTER; COMPLICATIONS; MIDTERM; CONVERSION; ENDOGRAFT AB Objective: Despite well-documented good early results and benefits of endoluminal stent graft repair of abdominal aortic aneurysm (J Vasc Surg 2002;35:1137-44.)(AAA), the long-term outcome of this method of treatment remains uncertain. In particular, concern exists that late effectiveness and durability are inferior to that of open repair. To determine the incidence and causes of clinical failures of endovascular AAA repair, a 7-year experience with 362 primary AAA endografts was reviewed. Methods: Clinical failures were defined as deaths within 30 days of the procedure, conversions (early and late) to open AAA repair, AAA rupture after endoluminal treatment, or AAA sac growth of more than 5 mm in maximal diameter despite endograft repair. Endoleak status per se was not considered unless it resulted in an adverse event. If clinical problems arose but could be corrected with catheter-based therapies or limited surgical procedures, thereby maintaining the integrity of successful stent graft treatment of the AAA, such cases were considered as primary assisted success and not classified as clinical failures. Results: The average follow-up period was 1.5 years. Six deaths (1.6%) occurred after the procedure, all in elderly patients or patients at high risk. Five patients (1.4%) needed early conversion (immediate, 2 days) to open repair for access problems or technical difficulties with deployment, resulting in an implantation success rate of 98.6%. Eight patients (2.2%) underwent late conversion for a variety of problems, including AAA expansion (n = 4), endograft thrombosis (n = 1), secondary graft infection (n = 2), and rupture at 3 years (n = 1). Rupture occurred in an additional two patients for a total incidence rate of 0.8%. AAA sac growth of greater than 5 mm was observed in 20 patients (5.6%), four of whom have undergone successful catheter-based treatments to date. Overall, 39 patients (10.7%) needed catheter-based (n = 45) or limited surgical (n = 4) reinterventions for a variety of late problems that were successful in 92%. Conclusion: In our 7-year experience, one or more clinical failures of endovascular AAA repair were observed in 31 patients (8.3%). Reinterventions were necessitated in a total of 10.7% of patients but were usually successful in maintaining AAA exclusion and limiting AAA growth. These results emphasize that endovascular repair provides good results and many benefits for most properly selected patients but is not as durable as standard open repair. C1 Massachusetts Gen Hosp, Div Vasc Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Vasc Intervent Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Brewster, DC (reprint author), Massachusetts Gen Hosp, Div Vasc Surg, 1 Hawthorne Pl,Ste 111, Boston, MA 02114 USA. NR 46 TC 96 Z9 99 U1 0 U2 3 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2002 VL 35 IS 6 BP 1137 EP 1144 DI 10.1067/mva.2002.124627 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 562BX UT WOS:000176178500018 PM 12042723 ER PT J AU Bernhard, VM Mitchell, RS Matsumura, JS Brewster, DC Decker, M Lamparello, P Raithel, D Collin, J AF Bernhard, VM Mitchell, RS Matsumura, JS Brewster, DC Decker, M Lamparello, P Raithel, D Collin, J TI Ruptured abdominal aortic aneurysm after endovascular repair SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID ENDOLUMINAL REPAIR; RISK-FACTORS; GRAFT; EXPERIENCE; ENDOPROSTHESIS; CONVERSION AB Objective: The purpose of this study was to present the experience with aneurysm rupture after deployment of Guidant/EVT (Guidant) endografts and review previously reported cases with other devices. Methods: Records from Guidant/EVT clinical trials and postmarket approval databases from February 1993 to August 2000 were analyzed to identify patients with rupture and to extract pertinent data. Previously reported cases were obtained with a Medline search. Results: Seven ruptures were found with Guidant/EVT devices. Five of these occurred among the 686 patients in US Food and Drug Administration protocols (group I) who were followed for a mean of 41.8 +/- 21.9 months and limited to the subgroup of 93 first generation tube endografts. Two ruptures occurred in group II (3260 patients after market approval with limited follow-up), specifically in the subgroup of 166 patients who underwent treatment with second generation tube grafts. No ruptures were found in patients with bifurcation or unilateral iliac implants followed for a mean of 37.5 months. All ruptures were caused by distal aortic type I endoleaks on the basis of attachment system fractures (first generation devices only), aortic neck dilatations, persistent primary endoleaks, migration, overlooked imaging abnormalities, refused reintervention, and poor patient selection. The mortality rate was 57% (4/7) overall and was 50% for surgical repair (3/6). A literature search identified 40 additional ruptures related to other devices, for a total of 47. All 44 that were documented with adequate data were caused by endoleaks (26 type I, 2 type II, II type III, and 5 source not reported). Other contributing factors were graft module separation and graft wall deterioration. The overall mortality rate for the combined series was 50%, with an operative mortality rate of 41%. Conclusion: Postendograft AAA rupture is infrequent, although the true incidence rate is unclear because of inadequate follow-up of individual device designs. Tube endografts should be limited to the rare patient with ideal anatomy, no other alternatives, and at high risk for standard open repair. Prevention of aneurysm rupture requires long-term surveillance with attention to subtle imaging abnormalities and the establishment of reliable follow-up protocols for specific devices. The outcome of postendograft aneurysm rupture is similar to that of rupture without prior endograft therapy. C1 Univ Chicago, Dept Surg, Sch Med, Chicago, IL 60637 USA. Stanford Univ, Sch Med, Stanford, CA USA. Northwestern Univ, Sch Med, Chicago, IL 60611 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. NYU, Med Ctr, New York, NY USA. Klinikum Sud Nurnberg, Nurnberg, Germany. John Radcliffe Hosp, Oxford OX3 9DU, England. Guidant Corp, Indianapolis, IN 46244 USA. RP Bernhard, VM (reprint author), Univ Chicago, Dept Surg, Sch Med, SBRI J555,MC5028,5841 S Maryland Ave, Chicago, IL 60637 USA. NR 22 TC 103 Z9 109 U1 1 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2002 VL 35 IS 6 BP 1155 EP 1162 DI 10.1067/mva.2002.123758 PG 8 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 562BX UT WOS:000176178500021 PM 12042725 ER PT J AU Marone, L Nigri, G LaMuraglia, GM AF Marone, L Nigri, G LaMuraglia, GM TI A novel technique of upper extremity revascularization: The retrohumeral approach SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the New-England-Society-for-Vascular-Surgery CY SEP 19-21, 2001 CL PROVIDENCE, RHODE ISLAND SP New England Soc Vasc Surg ID BRACHIAL-ARTERY; BYPASS AB Although the standard approach for inflow to the brachial artery is directly from the subclavian or the carotid artery, unusual scenarios exist when this direct route is not accessible. We present a case of a patient after right radical mastectomy and radiation therapy for breast cancer with severe ischemic symptoms of the dominant right upper extremity. Angiography revealed an occluded right subclavian artery with a paucity of distal collaterals across the right shoulder. A reversed vein graft was constructed from the right common carotid artery to the right brachial artery and was tunneled with a retrohumeral approach to avoid the previously operated and irradiated field. The patient has remained asymptomatic with a patent graft at 2 years. C1 Massachusetts Gen Hosp, Dept Surg, Div Vasc Surg, Boston, MA 02114 USA. RP LaMuraglia, GM (reprint author), 15 Parkman St,WAC 464, Boston, MA 02114 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2002 VL 35 IS 6 BP 1277 EP 1279 DI 10.1067/mva.2002.124626 PG 3 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 562BX UT WOS:000176178500040 PM 12042742 ER PT J AU Cambria, RP AF Cambria, RP TI Regarding "Analysis of predictive factors for progression of type B aortic intramural hematoma with computed tomography" SO JOURNAL OF VASCULAR SURGERY LA English DT Editorial Material ID DISSECTION C1 Massachusetts Gen Hosp, Thorac Aort Ctr, Boston, MA 02114 USA. RP Cambria, RP (reprint author), Massachusetts Gen Hosp, Thorac Aort Ctr, 15 Parkman St,WAC 458, Boston, MA 02114 USA. NR 3 TC 8 Z9 8 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2002 VL 35 IS 6 BP 1295 EP 1296 DI 10.1067/mva.2002.123982 PG 2 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 562BX UT WOS:000176178500046 PM 12042746 ER PT J AU Strack, B Calistri, A Gottlinger, HG AF Strack, B Calistri, A Gottlinger, HG TI Late assembly domain function can exhibit context dependence and involves ubiquitin residues implicated in endocytosis SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; VESICULAR STOMATITIS-VIRUS; MURINE LEUKEMIA-VIRUS; ROUS-SARCOMA VIRUS; PROLINE-RICH MOTIF; GAG POLYPROTEIN; MULTIUBIQUITIN CHAIN; PARTICLE-PRODUCTION; MATRIX PROTEIN; VIRION RELEASE AB Retroviral Gag polyproteins contain regions that promote the separation of virus particles from the plasma membrane and from each other. These Gag regions are often referred to as late assembly (L) domains. The L domain of human immunodeficiency virus type 1 (HIV-1) is in the C-terminal p6(gag) domain and harbors an essential P(T/S)APP motif, whereas the L domains of oncoretroviruses are in the N-terminal half of the Gag precursor and have a PPXY core motif. We recently observed that L domains induce the ubiquitination of a minimal HIV-1 Gag construct and that point mutations which abolish L domain activity prevent Gag ubiquitination. In that study, a peptide from the Ebola virus L domain with overlapping P(T/S)APP and PPXY motifs showed exceptional activity in promoting Gag ubiquitination and the release of virus-like particles. We now show that a substitution which disrupts the PPXY motif but leaves the P(T/S)APP motif intact abolishes L domain activity in the minimal Gag context, but not in the context of a near full-length HIV-1 Gag precursor. Our results reveal that the P(T/S)APP motif does not function autonomously and indicate that the HIV-1 nucleocapsid-p1 region, which is proximal to p6(gag), can cooperate with the conserved L domain core motif. We have also examined the effects of ubiquitin mutants on virus-like particle production, and the results indicate that residues required for the endocytosis function of ubiquitin are also involved in virus budding. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Gottlinger, HG (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [P30 AI028691, AI29873, AI50466, R37 AI029873, R01 AI050466, R01 AI029873, AI28691] NR 41 TC 65 Z9 65 U1 0 U2 0 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 JUN PY 2002 VL 76 IS 11 BP 5472 EP 5479 DI 10.1128/JVI.76.11.5472-5479.2002 PG 8 WC Virology SC Virology GA 551EF UT WOS:000175546000018 PM 11991975 ER PT J AU Bosch, I Xhaja, K Estevez, L Raines, G Melichar, H Warke, RV Fournier, MV Ennis, FA Rothman, AL AF Bosch, I Xhaja, K Estevez, L Raines, G Melichar, H Warke, RV Fournier, MV Ennis, FA Rothman, AL TI Increased production of interleukin-8 in primary human monocytes and in human epithelial and endothelial cell lines after dengue virus challenge SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; KAPPA-B ACTIVATION; HISTONE ACETYLATION; COMPLEMENT ACTIVATION; HEMORRHAGIC-FEVER; DISEASE SEVERITY; GENE-EXPRESSION; IN-VITRO; IL-8; INFECTION AB The more severe form of dengue virus infection, dengue hemorrhagic fever, is characterized by plasma leakage and derangements in hemostasis. As elevated interleukin-8 (IL-8) levels have been observed in sera from patients with more severe disease manifestations, a study was initiated to look at the effect of dengue virus infection in vitro on proinflammatory cytokine secretion and expression. A significant increase in IL-8 levels in the culture supernatant of primary human monocytes infected with dengue 2 virus (D2V) New Guinea C (NGC) was found by enzyme-linked immunosorbent assay. Additionally, by reverse transcriptase PCR, the mRNA was also augmented. Among the proinflammatory cytokines and their mRNAs measured (IL-6, IL-1beta, IL-8, and tumor necrosis factor alpha), IL-8 showed the greatest change following D2V infection. Similarly, two cell lines, 293T (a human epithelial cell line) and ECV304 (an endothelial cell line), were permissive to D2V NGC and responded to the infection by increasing the synthesis of IL-8. Nuclear factor kappa B (NF-kappaB) and nuclear factor IL-6 (NFIL-6) are primary mediators of IL-8 expression. We studied the transcriptional regulation of IL-8 in the ECV304 and 293T cell lines and found that the induction of IL-8 gene expression involved the activation of NF-kappaB (P = 0.001) and, to a lesser extent, the activation of NFIL-6 in ECV304 cells only. We next observed by the chromatin immunoprecipitation procedure in vivo acetylation of core histones bound to the IL-8 promoter after D2V infection. IL-8 produced by infected monocytes and also IL-8 that may be produced by endothelial or other epithelial cells is associated with the hyperacetylation of histones bound to the IL-8 promoter in addition to the activation of transcription by NF-kappaB. We hypothesize that the overall increase in IL-8 synthesis observed in this in vitro study may play a role in the pathogenesis of the plasma leakage seen in dengue hemorrhagic fever and dengue shock syndrome. C1 Univ Massachusetts, Sch Med, Ctr Infect Dis & Vaccine Res, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Dept Med, Worcester, MA 01655 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Bosch, I (reprint author), Univ Massachusetts, Sch Med, Ctr Infect Dis & Vaccine Res, 55 Lake Ave N,Room S5-326, Worcester, MA 01655 USA. FU NIAID NIH HHS [R01 AI30624] NR 35 TC 99 Z9 106 U1 0 U2 7 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 JUN PY 2002 VL 76 IS 11 BP 5588 EP 5597 DI 10.1128/JVI.76.11.5588-5597.2002 PG 10 WC Virology SC Virology GA 551EF UT WOS:000175546000030 PM 11991987 ER PT J AU Lauer, GM Ouchi, K Chung, RT Nguyen, TN Day, CL Purkis, DR Reiser, M Kim, AY Lucas, M Klenerman, P Walker, BD AF Lauer, GM Ouchi, K Chung, RT Nguyen, TN Day, CL Purkis, DR Reiser, M Kim, AY Lucas, M Klenerman, P Walker, BD TI Comprehensive analysis of CD8+-T-cell responses against hepatitis C virus reveals multiple unpredicted specificities SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; PERIPHERAL-BLOOD; VIRAL CLEARANCE; QUANTITATIVE-ANALYSIS; IMMUNE-RESPONSES; CELL EPITOPES; INFECTION; PEPTIDES; HCV; NUCLEOPROTEIN AB The hepatitis C virus (HCV)-specific CD8(+)-T-cell response is thought to play a critical role in HCV infection. Studies of these responses have largely relied on the analysis of a small number of previously described or predicted HCV epitopes, mostly restricted by HLA A2. In order to determine the actual breadth and magnitude of CD8(+)-T-cell responses in the context of diverse HLA class I alleles, we performed a comprehensive analysis of responses to all expressed HCV proteins. By using a panel of 301 overlapping peptides, we analyzed peripheral blood mononuclear cells (PBMC) from a cohort of 14 anti-HCV-positive, HLA A2-positive individuals in an enzyme-linked immunospot assay. Only four subjects had detectable HLA A2-restricted responses in PBMC, and only 3 of 19 predicted A2 epitopes were targeted, all of which were confirmed by tetramer analysis. In contrast, 9 of 14 persons showed responses with more comprehensive analyses, with many responses directed against previously unreported epitopes. These results indicate that circulating HCV-specific CD8(+)-T-cell responses can be detected in PBMC in the majority of infected persons and that these responses are heterogeneous with no immunodominant epitopes consistently recognized. Since responses to epitopes restricted by single HLA alleles such as HLA A2 do not predict the overall response in an individual, more comprehensive approaches, as shown here, should facilitate definition of the role of the CD8(+)-T-cell response in HCV infection. Moreover, the low level or absence of responses to many predicted epitopes provides a rationale for immunotherapeutic interventions to broaden cytotoxic-T-lymphocyte recognition. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Ruhr Univ Bochum, Med Klin, D-44892 Bochum, Germany. Univ Oxford, Nuffield Dept Clin Med, Oxford OX1 3SY, England. RP Walker, BD (reprint author), Massachusetts Gen Hosp E, Partners AIDS Res Ctr, 149 13th St, Charlestown, MA 02129 USA. RI Yang, Chen/G-1379-2010; Day, Cheryl/J-9844-2012 NR 42 TC 152 Z9 155 U1 1 U2 2 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 JUN PY 2002 VL 76 IS 12 BP 6104 EP 6113 DI 10.1128/JVI.76.12.6104-6113.2002 PG 10 WC Virology SC Virology GA 557MK UT WOS:000175912200027 PM 12021343 ER PT J AU Dick, FA Dyson, NJ AF Dick, FA Dyson, NJ TI Three regions of the pRB pocket domain affect its inactivation by human papillomavirus E7 proteins SO JOURNAL OF VIROLOGY LA English DT Article ID RETINOBLASTOMA TUMOR-SUPPRESSOR; UBIQUITIN-PROTEASOME PATHWAY; CERVICAL-CARCINOMA CELLS; LARGE T-ANTIGEN; TYPE-16 E7; GENE-PRODUCT; ADENOVIRUS E1A; GROWTH ARREST; HOMOLOGOUS SEQUENCES; TRANSCRIPTION FACTOR AB A critical event in papillomavirus transformation of human cells is the inactivation of pRB by the E7 protein. E7, like many other viral oncoproteins, possesses a well-characterized LXCXE peptide motif that interacts with the pocket domain of pRB. Disruption of the LXCXE-binding cleft on pRB renders it resistant to E7 binding and inactivation. Such binding cleft mutants of pRB are capable of inducing a G(1) arrest in the human papillomavirus 18-transformed HeLa cell line. We show here that the efficient inactivation of pRB in HeLa cells does not simply depend on the integrity of the LXCXE-binding cleft. Multiple site-directed mutants that alter conserved surfaces of the pRB pocket domain cause HeLa cells to accumulate in G(1). We divide these mutants into two classes: those that can be bound by E7 and those that cannot. The E7 interacting mutants include changes in conserved residues that lie in a groove between the A and B halves of the pocket. Surprisingly, none of these mutants show a clear defect in any of the known mechanisms for pRB inactivation by E7. Analysis of mutants that are compromised for E7 binding reveals that this interaction depends on both the LXCXE-binding cleft and on a conserved group of lysines adjacent to the cleft. These basic amino acids on pRB define a discrete interaction point with E7. These residues most likely form ionic interactions with conserved acidic amino acids on E7 since a stable pRB/E7 interaction was restored when the lysine residues on pRB and the acidic residues on E7 were interchanged. C1 Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. RP Dyson, NJ (reprint author), Massachusetts Gen Hosp, Ctr Canc, 149 13th St, Charlestown, MA 02129 USA. NR 50 TC 44 Z9 45 U1 0 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 JUN PY 2002 VL 76 IS 12 BP 6224 EP 6234 DI 10.1128/JVI.76.12.6224-6234.2002 PG 11 WC Virology SC Virology GA 557MK UT WOS:000175912200040 PM 12021356 ER PT J AU Gorry, PR Taylor, J Holm, GH Mehle, A Morgan, T Cayabyab, M Farzan, M Wang, H Bell, JE Kunstman, K Moore, JP Wolinsky, SM Gabuzda, D AF Gorry, PR Taylor, J Holm, GH Mehle, A Morgan, T Cayabyab, M Farzan, M Wang, H Bell, JE Kunstman, K Moore, JP Wolinsky, SM Gabuzda, D TI Increased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent primary human immunodeficiency virus type 1 isolate SO JOURNAL OF VIROLOGY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; HUMAN MONOCLONAL-ANTIBODIES; CHEMOKINE RECEPTORS CCR3; HIV TYPE-1; NEUTRALIZATION SENSITIVITY; IN-VITRO; FUNCTIONAL CORECEPTOR; ALVEOLAR MACROPHAGES; NEURONAL APOPTOSIS; DIFFERENT REGIONS AB Most human immunodeficiency virus type 1 (HIV-1) viruses in the brain use CCR5 as the principal coreceptor for entry into a cell. However, additional phenotypic characteristics are necessary for HIV-1 neurotropism. Furthermore, neurotropic strains are not necessarily neurovirulent. To better understand the determinants of HIV-1 neurovirulence, we isolated viruses from brain tissue samples from three AIDS patients with dementia and HIV-1 encephalitis and analyzed their ability to induce syncytia in monocyte-derived macrophages (MDM) and neuronal apoptosis in primary brain cultures. Two R5X4 viruses (MACS1-br and MACS1-spln) were highly fusogenic in MDM and induced neuronal apoptosis. The R5 viruses UK1-br and MACS2-br are both neurotropic. However, only UK1-br induced high levels of fusion in MDM and neuronal apoptosis. Full-length Env clones from UK1-br required lower CCR5 and CD4 levels than Env clones from MACS2-br to function efficiently in cell-to-cell fusion and single-round infection assays. UK1-br Envs also had a greater affinity for CCR5 than MACS2-br Envs in binding assays. Relatively high levels of UK1-br and MACS2-br Envs bound to CCR5 in the absence of soluble CD4. However, these Envs could not mediate CD4-independent infection, and MACS2-br Envs were unable to mediate fusion or infection in cells expressing low levels of CD4. The UK1-br virus was more resistant than MACS2-br to inhibition by the CCR5-targeted inhibitors TAK-779 and Sch-C. UK1-br was more sensitive than MACS2-br to neutralization by monoclonal antibodies (2175 and immunoglobulin G1b12 [IgG1b12]) and CD4-IgG2. These results predict the presence of HIV-1 variants with increased CCR5 affinity and reduced dependence on CCR5 and CD4 in the brains of some AIDS patients with central nervous system disease and suggest that R5 variants with increased CCR5 affinity may represent a pathogenic viral phenotype contributing to the neurodegenerative manifestations of AIDS. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. Cornell Univ, Weill Med Coll, New York, NY USA. Univ Edinburgh, Dept Pathol, Edinburgh EH8 9YL, Midlothian, Scotland. RP Gabuzda, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St,JF816, Boston, MA 02115 USA. RI Holm, Geoffrey/C-3188-2009; Wolinsky, Steven/B-2893-2012; OI Wolinsky, Steven/0000-0002-9625-6697 FU NCI NIH HHS [CA79458]; NIAID NIH HHS [AI28691, AI41420, P30 AI028691, R01 AI041420, U01 AI035039, U01 AI35039]; NIDA NIH HHS [DA13127]; NINDS NIH HHS [NS35734, NS37277, R01 NS035734, R01 NS037277] NR 98 TC 159 Z9 161 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2002 VL 76 IS 12 BP 6277 EP 6292 DI 10.1128/JVI.76.12.6277-6292.2002 PG 16 WC Virology SC Virology GA 557MK UT WOS:000175912200045 PM 12021361 ER PT J AU Gallivan, KH Gallivan, GJ AF Gallivan, KH Gallivan, GJ TI Bilateral mixed laryngoceles: Simultaneous strobovideolaryngoscopy and external video examination SO JOURNAL OF VOICE LA English DT Article; Proceedings Paper CT 29th Annual Symposium: Care of the Professional Voice CY JUN, 2000 CL PHILADELPHIA, PENNSYLVANIA DE laryngeal music performers; strobovideolaryngoscopy (SVL); external video examination; laryngoceles ID SACCULAR CYSTS; ASSOCIATION; LARYNX AB A music medicine practice affords a unique opportunity to diagnose and treat laryngeal music performers. Strobovideolaryngoscopic (SVL) and external video examination of the voice professional or brass instrument player may focus on the vocal folds, yet abnormalities of the supraglottis, neck, and thorax should be appreciated and documented. Laryngoceles are uncommon laryngeal disorders but may occur in up to 5% of benign laryngeal lesions. While many laryngoceles are asymptomatic, they may cause a cough, hoarseness, stridor, sore throat, pain, snoring, or globus sensation. In particular, musicians who play brass instruments are at high risk for laryngocele development. We highlight two patients with symptomatic laryngoceles to present anatomical, historical, classification, epidemiological, diagnostic, and management considerations. C1 Winchester Hosp, Winchester, Hants, England. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. Mercy Hosp, Springfield, MA USA. Wing Mem Hosp, Palmer, MA USA. Massachusetts Med Sch, Worcester, MA USA. RP Gallivan, GJ (reprint author), 299 Carew St,Suite 404, Springfield, MA 01104 USA. NR 19 TC 15 Z9 15 U1 0 U2 0 PU SINGULAR PUBLISHING GROUP INC PI CLIFTON PARK PA 5 MAXWELL DR, CLIFTON PARK, NY 12065 USA SN 0892-1997 J9 J VOICE JI J. Voice PD JUN PY 2002 VL 16 IS 2 BP 258 EP 266 DI 10.1016/S0892-1997(02)00095-4 PG 9 WC Otorhinolaryngology SC Otorhinolaryngology GA 651XC UT WOS:000181346800010 PM 12150378 ER PT J AU Kestenbaum, B Gillen, DL Sherrard, DJ Seliger, S Ball, A Stehman-Breen, C AF Kestenbaum, B Gillen, DL Sherrard, DJ Seliger, S Ball, A Stehman-Breen, C TI Calcium channel blocker use and mortality among patients with end-stage renal disease SO KIDNEY INTERNATIONAL LA English DT Article DE calcium channel blocker; dialysis; mortality; cardiovascular disease; hypertension; dihydropyridines; USRDS DMMS II ID LEFT-VENTRICULAR HYPERTROPHY; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED TRIAL; SYSTOLIC HYPERTENSION; DIALYSIS PATIENTS; DOUBLE-BLIND; NIFEDIPINE; DILTIAZEM; VERAPAMIL; FAILURE AB Background. Patients on dialysis suffer from alarming rates of cardiovascular disease. While calcium channel blockers (CCBs) are prescribed widely to patients with end-stage renal disease (ESRD) for the treatment of hypertension, the long-term outcomes associated with the use of these medications are not known. We sought to determine the association between CCB use and mortality among a cohort of ESRD patients. Methods. Data were utilized from the United States Renal Data System Dialysis Morbidity and Mortality Wave II, a randomly selected prospective cohort of 4065 ESRD patients who began dialysis in 1996. Clinical data, including medication information, were collected 60 days after the start of dialysis. Subsequent survival status and cause of death were ascertained. The Cox proportional hazards model was used to estimate the relative risk of death associated with CCB use. Results. Data from 3716 patients (91.4%) were available for analysis. Fifty-one percent of the study patients were prescribed a CCB. The use of a CCB was associated with a 21% lower risk of total mortality (RR 0.79, CI 0.69 to 0.90) and a 26% lower risk of cardiovascular specific mortality (RR 0.74, CI 0.60 to 0.91). For patients with pre-existing cardiovascular disease, CCB use was associated with a 23% (RR 0.77, CI 0.65 to 0.91) and 32% (RR 0.68, CI 0.53 to 0.87) lower risk of total and cardiovascular mortality, respectively. Conclusion. After controlling for known risk factors and potential confounders, CCBs were found to be associated with a lower risk of mortality among ESRD patients. C1 Puget Sound Hlth Care Syst, Div Nephrol, Seattle, WA USA. Univ Washington, Sch Publ Hlth & Community Med, Div Nephrol, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Kestenbaum, B (reprint author), Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way,Mailstop 111A, Seattle, WA 98108 USA. FU NIDDK NIH HHS [DK07721-6] NR 34 TC 70 Z9 71 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUN PY 2002 VL 61 IS 6 BP 2157 EP 2164 DI 10.1046/j.1523-1755.2002.00355.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 553FX UT WOS:000175666100024 PM 12028456 ER PT J AU Denton, MD Magee, CC Ovuworie, C Mauiyyedi, S Pascual, M Colvin, RB Cosimi, AB Tolkoff-Rubin, N AF Denton, MD Magee, CC Ovuworie, C Mauiyyedi, S Pascual, M Colvin, RB Cosimi, AB Tolkoff-Rubin, N TI Prevalence of renal cell carcinoma in patients with ESRD pre-transplantation: A pathologic analysis SO KIDNEY INTERNATIONAL LA English DT Article DE acquired cystic disease; kidney cancer; transplantation; end-stage renal disease; renal tumors; selective screening population study ID ACQUIRED CYSTIC-DISEASE; LONG-TERM DIALYSIS; KIDNEY-DISEASE; COMPUTED-TOMOGRAPHY; HEMODIALYSIS; TUMORS; ULTRASONOGRAPHY; PERITONEAL; PAPILLARY AB Background. Acquired renal cystic disease (ARCD), renal adenoma (AD), and renal cell carcinoma (RCC) are more common in patients with end-stage renal disease (ESRD). However, the prevalence of these conditions in patients undergoing transplantation, and the clinical characteristics associated with their occurrence are unclear. Methods. At our institution, the majority of patients undergo an ipsilateral native nephrectomy at the time of transplantation, providing a unique opportunity to study the prevalence and pathology of ARCD, AD and RCC in ESRD. We retrospectively reviewed all consecutive nephrectomy pathology reports over a six year period. Demographic and clinical characteristics associated with these lesions were identified. Results. Two hundred and sixty nephrectomy reports were reviewed: ARCD, AD, RCC and oncocytoma were found in 33%, 14%, 4.2% and 0.6% of cases, respectively. On multivariable analysis, ARCD was positively associated with male sex and longer dialysis duration and negatively associated with peritoneal dialysis. Similarly, AD was positively associated with male sex, longer dialysis duration and greater age. There was a trend for RCC cases to share similar associations although the small total number of cases precluded findings of statistical significance. Conclusion. By pathologic analysis, renal tumors are more common in the pre-transplant ESRD population than previously reported (using radiologic methods). Our study also identifies risk factors for their occurrence. This may prove useful in designing screening studies for renal tumors in this patient population. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med,Lab Transplantat & Immunogenet, Dept Med,Div Renal, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Nephrol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg, Boston, MA USA. RP Denton, MD (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med,Lab Transplantat & Immunogenet, Dept Med,Div Renal, 75 Francis St, Boston, MA 02115 USA. NR 34 TC 105 Z9 107 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUN PY 2002 VL 61 IS 6 BP 2201 EP 2209 DI 10.1046/j.1523-1755.2002.00374.x PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 553FX UT WOS:000175666100029 PM 12028461 ER PT J AU Shimizu, A Yamada, K Sachs, DH Colvin, RB AF Shimizu, A Yamada, K Sachs, DH Colvin, RB TI Mechanisms of chronic renal allograft rejection. II. Progressive allograft glomerulopathy in miniature swine SO LABORATORY INVESTIGATION LA English DT Article ID CELL-MEDIATED CYTOTOXICITY; SEGMENTAL GLOMERULOSCLEROSIS; TRANSPLANTATION TOLERANCE; DNA FRAGMENTATION; CAPILLARY REPAIR; STABLE INDUCTION; GLOMERULONEPHRITIS; APOPTOSIS; ANTIBODY; DEATH AB we have reported that in thymectomized miniature swine treated with a 12-day course of cyclosporin A that major histocompatibility complex class I-mismatched renal allografts either progress to chronic rejection (progression group; n = 4) or tolerance after acute rejection (recovery group; n = 4). Two types of glomerulopathies, termed acute and chronic allograft glomerulopathy, occur in allografts in this model. Morphological and immunohistochemical studies were performed on serial renal biopsies from both groups to examine the pathogenic mechanisms of acute and chronic allograft glomerulopathy. In acute rejection, acute allograft glomerulopathy developed in both groups by Day 18, with antibody deposition and T cell and macrophage infiltration. In situ DNA nick end-labeling (TUNEL)+ injured glomerular endothelial cells appeared from the early phase, followed by destruction of the glomerular capillary network with segmental mesangiolysis. Thereafter, in the progression group, acute allograft glomerulopathy progressed to chronic allograft glomerulopathy during the development of chronic rejection. This process was associated with persistent T cell and macrophage infiltration, antibody deposition, and TUNEL+ glomerular endothelial injury in the glomeruli. Impaired capillary repair, mesangial cell proliferation, and activation were still noted at Day 100, together with accumulation of mesangial matrix and duplication of glomerular basement membrane. In contrast, in the recovery group, acute allograft glomerulopathy recovered by Day 100, associated with the resolution of cellular infiltration and reduction of antibody deposition. We conclude that the acute and persistent cell- and antibody-mediated rejection against glomerular endothelial cells is the key pathogenic determinant of acute allograft glomerulopathy and progression toward chronic allograft glomerulopathy. Impaired capillary repair and phenotypic change of endothelial and mesangial cells also contribute to the development of chronic allograft glomerulopathy. With the development of tolerance, substantial recovery of acute allograft glomerulopathy can occur after the resolution of glomerular inflammation. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Nippon Med Coll, Dept Pathol, Tokyo 113, Japan. RP Colvin, RB (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, 55 Fruit St,WRN 225, Boston, MA 02114 USA. FU NHLBI NIH HHS [P01-HL 18646]; NIAID NIH HHS [R01-AI 31046]; PHS HHS [P01-H218646] NR 46 TC 31 Z9 33 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD JUN PY 2002 VL 82 IS 6 BP 673 EP 685 DI 10.1097/01.LAB.0000017370.74529.89 PG 13 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 564MF UT WOS:000176317600001 PM 12065677 ER PT J AU Pui, CH Gaynon, PS Boyett, JM Chessells, JM Baruchel, A Kamps, W Silverman, LB Biondi, A Harms, DO Vilmer, E Schrappe, M Camitta, B AF Pui, CH Gaynon, PS Boyett, JM Chessells, JM Baruchel, A Kamps, W Silverman, LB Biondi, A Harms, DO Vilmer, E Schrappe, M Camitta, B TI Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region SO LANCET LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MLL-GENE REARRANGEMENTS; CHILDRENS CANCER GROUP; INFANT ACUTE-LEUKEMIA; POOR-PROGNOSIS; CLINICAL CHARACTERISTICS; TRANSPLANTATION; CHEMOTHERAPY; FEATURES; AGE AB Background The prognosis and optimum treatment of childhood acute lymphoblastic leukaemia (ALL) with abnormalities of chromosomal band 11q23 are controversial. We aimed to identify prognostic factors that might help in planning future therapy, and to assess the effectiveness of haemopoietic stem-cell transplantation in patients with the t(4;11) translocation, which is associated with a particularly poor outcome. Methods We reviewed data on 497 children and young adults who had ALL with various 11q23 abnormalities, including the translocations t(4;11), t(9;11), and t(11;19). All patients were treated with intensive chemotherapy, with or without haemopoietic stem-cell transplantation in first complete remission, by 11 study groups and single institutions from 1983 to 1995. Findings Age was the most important prognostic factor. In a Cox's proportional-hazard model stratified by 11q23 abnormalities, infants younger than 1 year fared significantly worse than patients 1 year of age or older (hazard ratio for event-free survival 1.84 [95% CI 1.38-2.47], p=0.0001). Among infants, any category of 11q23 abnormality conferred a dismal outcome, whereas in older patients, t(4;11) and t(9;11) were associated with a worse outcome than were other 11q23 changes. In the largest subgroup-256 patients with t(4;11)-any type of transplantation was associated with significantly worse disease-free survival (1.61 [1.10-2.35], p=0.014) and overall survival (1.76 [1.08-2.45], p=0.004) compared with chemotherapy only. Even transplantation with stem cells from HLA-matched related or HLA-matched unrelated donors tended to be associated with a worse outcome than chemotherapy alone. Interpretation The prognosis of acute lymphoblastic leukaemia with an 11q23 abnormality is particularly dismal in infants. Allogeneic transplantation with haemopoietic stem cells from an HLA-matched related donor does not seem to improve the clinical outcome in patients with t(4:11)-positive leukaemia. C1 St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Univ Tennessee, Coll Med, Memphis, TN 38163 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Univ So Calif, Los Angeles, CA USA. Inst Child Hlth, Mol Haematol Unit, London, England. Hop St Louis, Serv Pediat Hematol, Paris, France. Dutch Childhood Leukemia Study Grp, The Hague, Netherlands. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Med Sch, Boston, MA USA. Univ Milano Bicocca, Dept Pediat, Monza, Italy. Osped San Gerardo, Monza, Italy. Univ Hamburg, Dept Pediat Hematol & Oncol, Hamburg, Germany. Hop Robert Debre, Serv Hematoimmunol, F-75019 Paris, France. Hannover Med Sch, Dept Pediat Hematol Oncol, Childrens Univ Hosp, Hannover, Germany. Med Coll Wisconsin, Dept Pediat, Midwest Childrens Canc Ctr, Milwaukee, WI 53226 USA. RP Pui, CH (reprint author), St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA. EM ching-hon.pui@stjude.org RI Schrappe, Martin/A-8109-2010 FU NCI NIH HHS [CA37379, CA 31566, CA21765, CA29139, CA51001, CA78224] NR 35 TC 218 Z9 228 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD JUN 1 PY 2002 VL 359 IS 9321 BP 1909 EP 1915 DI 10.1016/S0140-6736(02)08782-2 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 558PL UT WOS:000175975700011 PM 12057554 ER PT J AU Mankarious, LA Adams, AB Pires, VL AF Mankarious, LA Adams, AB Pires, VL TI Patterns of cartilage structural protein loss in human tracheal stenosis SO LARYNGOSCOPE LA English DT Article DE tracheal stenosis; subglottic stenosis; collagen I; collagen II; aggrecan; cartilage regeneration ID GROWTH; MATRIX AB Objectives: The study sought to identify which of the major structural proteins in tracheal cartilage are lost in the inflammatory process, and to determine whether damaged cartilage shows signs of regeneration and whether this is an age-dependent phenomenon. Study Design: Immunohistochemical analysis. Methods. Archival human tracheal and subglottic stenosis segments removed for the treatment of airway compromise were investigated by means of immunohistochemical analysis for differential loss of collagen type I or type 11 or aggrecan. Results: Specimens were found to have preferentially lost collagen I and aggrecan in areas of severe disruption of the cartilage ring. Collagen 11 was preserved. In addition, areas of apparent cartilage regeneration were identified based on increased collagen II and aggrecan relative to baseline levels in uninjured sections of the rings. Regenerative capacity was present in most of the specimens investigated and was not age specific. Conclusions: Collagen I and aggrecan are lost in areas of severe ring compromise, indicating that at least one of these two molecules is responsible for structural integrity. The remaining cartilage has some regenerative capacity, but it is small relative to the degree of cartilage damage. No new collagen I was identified in the cartilage ring, indicating that, although an intense inflammatory reaction occurred, fibroblasts did not deposit new collagen I as seen in other sear tissues. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, Boston, MA 02114 USA. RP Mankarious, LA (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Otol & Laryngol, 243 Charles St, Boston, MA 02114 USA. NR 9 TC 10 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD JUN PY 2002 VL 112 IS 6 BP 1025 EP 1030 DI 10.1097/00005537-200206000-00017 PG 6 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 575DN UT WOS:000176931500017 PM 12160268 ER PT J AU Appleman, LJ Tzachanis, D Grader-Beck, T Van Puijenbroek, AAFL Boussiotis, VA AF Appleman, LJ Tzachanis, D Grader-Beck, T Van Puijenbroek, AAFL Boussiotis, VA TI Induction of immunologic tolerance for allogeneic hematopoietic cell transplantation SO LEUKEMIA & LYMPHOMA LA English DT Review DE immunologic tolerance; allogeneic hematopoietic cell transplantation; chemotherapy; immunosuppression ID VERSUS-HOST DISEASE; BONE-MARROW TRANSPLANTATION; CD4(+) T-CELLS; KINASE INHIBITOR P27; ALLOGRAFT-REJECTION; TARGETED DISRUPTION; DOWN-REGULATION; CLONAL ANERGY; IN-VIVO; GRAFT AB The ability to achieve complete hematopoietic engraftment in the allogeneic setting without intensive myeloablative chemotherapy will have a profound effect on the practice of allogeneic hematopoietic cell transplantation (HCT). Novel methods to induce antigen-specific T-cell tolerance provide promise to ensure engraftment and reduce GVHD without producing generalized and other toxicities caused by myeloablative conditioning regimens. Compelling experimental evidence indicates that the antigen receptors on T-lymphocytes have dual potential to transmit crucial activation signals for initiating immune responses and to discharge equally potent inactivating signals to abort or inhibit immune responses. Many events impact on this fundamental decision-making process and one of the great challenges for modem immunology is to decipher the molecular wiring that integrates and converts the extrinsic and intrinsic variables into positive or negative cellular responses termed immunity and anergy, respectively. Our currently expanding understanding of the biochemical and molecular basis of T-cell anergy provides great promise to improve our ability to design novel clinical therapeutic approaches in order to induce antigen-specific tolerance in vivo. Importantly, strategies now exist to segregate graft versus tumor (GVT) effects from GVHD. Therefore, achievement of limited and specific tolerance to host alloantigens by selectively inactivating the indicated subsets of alloantigen-specific T-lymphocytes will prevent GVHD but retain the GVT effect of the graft. Such treatment approaches will expand the donor pool, because they will allow transplantation between individuals with increasing human leukocyte antigen (HLA) disparity, enable reduction of the need for non-specific immunosuppression, and reduce the risk of opportunistic infections and relapse of leukemia. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Boussiotis, VA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Mayer 547,44 Binney St, Boston, MA 02115 USA. OI Appleman, Leonard/0000-0003-4951-7388 FU NIAID NIH HHS [AI46548, AI41584, AI43552] NR 72 TC 5 Z9 5 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUN PY 2002 VL 43 IS 6 BP 1159 EP 1167 DI 10.1080/10428190290026213 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 559EL UT WOS:000176012600001 PM 12152983 ER PT J AU Duarte, RF Frank, DA AF Duarte, RF Frank, DA TI The synergy between stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF): Molecular basis and clinical relevance SO LEUKEMIA & LYMPHOMA LA English DT Review DE stem cell factor; granulocyte colony stimulating factor; STAT3 phosphorylation; p27kip1; signal transduction ID BLOOD PROGENITOR CELLS; EX-VIVO EXPANSION; C-KIT LIGAND; BREAST-CANCER PATIENTS; NON-HODGKINS-LYMPHOMA; BONE-MARROW CELLS; PERIPHERAL-BLOOD; IN-VIVO; SERINE PHOSPHORYLATION; PROTEIN-KINASE AB Stem cell factor (SCF), an essential growth factor in normal hematopoiesis. exerts potent effects when combined with cytokines. In particular, its synergy with granulocyte colony-stimulating factor (G-CSF) results in important biologic responses. These include enhancement of ex vivo long-term expansion of human primitive hematopoietic cells and increased mobilization of peripheral blood progenitor cells (PBPC) for transplantation. Despite the clinical importance of the interaction between SCF and G-CSF, the absence of a model system in which it could be studied at the cellular level had impaired the ability to understand the basis of their co-operation. To overcome this impediment, a system was recently generated which recapitulates the biologic synergy between SCF and G-CSF. MO7e-G cells have allowed the identification of key events in the synergistic actions of these cytokines on proliferation and gene expression. Among the biochemical and molecular events mediated by these cytokines are the down-regulation of p27(kip1) and the independent phosphorylation of STAT3 on tyrosine and serine residues, Recent work has provided increasing evidence for the clinical importance of the combination of SCIF and G-CSF. The elucidation of the intracellular events triggered by their receptors is now shedding light on key mediators of their synergistic effects. The identification of these pathways is of considerable importance for understanding fundamental aspects of hematopoiesis, and as potential targets for therapeutic intervention. C1 Anthony Nolan Res Inst, London NW3 2QG, England. RP Frank, DA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA79547] NR 101 TC 28 Z9 37 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD JUN PY 2002 VL 43 IS 6 BP 1179 EP 1187 DI 10.1080/10428190290026231 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 559EL UT WOS:000176012600003 PM 12152985 ER PT J AU Lin, CW Manshouri, T Jilani, I Neuberg, D Patel, K Kantarjian, H Andreeff, M Estrov, Z Beran, M Keating, M Estey, E Albitar, M AF Lin, CW Manshouri, T Jilani, I Neuberg, D Patel, K Kantarjian, H Andreeff, M Estrov, Z Beran, M Keating, M Estey, E Albitar, M TI Proliferation and apoptosis in acute and chronic leukemias and myelodysplastic syndrome SO LEUKEMIA RESEARCH LA English DT Article DE caspase; PCNA; annexin V; BrdU; apoptosis; proliferation; leukemia; MDS; CMML; AML; ALL; CML; CLL ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; COLONY-STIMULATING FACTOR; ACUTE MYELOID-LEUKEMIA; CELL-CYCLE; BONE-MARROW; ANNEXIN-V; HEMATOLOGIC MALIGNANCIES; HEMATOPOIETIC-CELLS; PROTEIN EXPRESSION AB Clonal expansion of leukemic cells is thought to be due to proliferation in excess of apoptosis. To define and compare proliferation and apoptosis between various leukemias and myelodysplastic syndrome (MDS), we measured proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) incorporation as surrogate markers for proliferation and caspase 3 activity and annexin V surface binding as surrogate markers for activation of the apoptotic cascade in patients with MDS, chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). We found high proliferation in bone marrow cells from MDS and CMML as measured by PCNA and BrdU incorporation. The lowest level of proliferation was found in CLL. Apoptosis was also highest in MDS and CMML as measured by annexin V and caspase 3 activity. Unexpectedly, we found no significant difference in proliferation in bone marrow CD34+ cells from various leukemias or MDS. Apoptosis was significantly higher in bone marrow CD34+ cells from MDS and CML in chronic phase as compared to CD34+ cells from AML patients. Our results illustrate differences in proliferation and apoptosis between acute and chronic leukemias and MDS. These differences may have diagnostic and therapeutic implications. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Univ Texas, MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. RP Albitar, M (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Hematopathol, 1515 Holcombe Blvd,POB 72, Houston, TX 77030 USA. OI LIN, CHUNG-WU/0000-0001-5042-0503 NR 41 TC 29 Z9 31 U1 1 U2 1 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 JUN PY 2002 VL 26 IS 6 BP 551 EP 559 AR PII S0145-2126(01)00170-9 DI 10.1016/S0145-2126(01)00170-9 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 558ND UT WOS:000175972700006 PM 12007503 ER PT J AU Chen, MH Ibrahim, JG Lipsitz, SR AF Chen, MH Ibrahim, JG Lipsitz, SR TI Bayesian methods for missing covariates in cure rate models SO LIFETIME DATA ANALYSIS LA English DT Article DE exponential model; Gibbs sampling; historical data; latent variables; posterior distribution; semi-parametric model ID SURVIVAL-DATA AB We propose methods for Bayesian inference for missing covariate data with a novel class of semi-parametric survival models with a cure fraction. We allow the missing covariates to be either categorical or continuous and specify a parametric distribution for the covariates that is written as a sequence of one dimensional conditional distributions. We assume that the missing covariates are missing at random (MAR) throughout. We propose an informative class of joint prior distributions for the regression coefficients and the parameters arising from the covariate distributions. The proposed class of priors are shown to be useful in recovering information on the missing covariates especially in situations where the missing data fraction is large. Properties of the proposed prior and resulting posterior distributions are examined. Also, model checking techniques are proposed for sensitivity analyses and for checking the goodness of fit of a particular model. Specifically, we extend the Conditional Predictive Ordinate (CPO) statistic to assess goodness of fit in the presence of missing covariate data. Computational techniques using the Gibbs sampler are implemented. A real data set involving a melanoma cancer clinical trial is examined to demonstrate the methodology. C1 Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Med Univ S Carolina, Dept Biometry & Epidemiol, Charleston, SC 29425 USA. RP Chen, MH (reprint author), Univ Connecticut, Dept Stat, Storrs, CT 06269 USA. FU NCI NIH HHS [CA 74015-01] NR 21 TC 16 Z9 17 U1 0 U2 2 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1380-7870 J9 LIFETIME DATA ANAL JI Lifetime Data Anal. PD JUN PY 2002 VL 8 IS 2 BP 117 EP 146 DI 10.1023/A:1014835522957 PG 30 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 534UN UT WOS:000174606200002 PM 12048863 ER PT J AU Porter, D Lahti-Domenici, J Torres-Arzayus, M Chin, L Polyak, K AF Porter, D Lahti-Domenici, J Torres-Arzayus, M Chin, L Polyak, K TI Expression of high in normal-1 (HIN-1) and uteroglobin related protein-1 (UGRP-1) in adult and developing tissues SO MECHANISMS OF DEVELOPMENT LA English DT Article DE high in normal-1 (HIN-1); uteroglobin related protein-1 (URGP-1) uteroglobin; secretoglobin; C/EBP-delta; development; differentiation; epithelium; mammary gland; lung; Drosophila; trachea; retinoic acid ID GENE-EXPRESSION; CELL AB We analyzed the expression of high in normal-1 (HIN-1), a putative breast tumor suppressor gene, and uteroglobin related protein-1 (UGRP-1), a homologue of HIN-1, in adult and developing mouse tissues. Highest HIN-1 and UGRP-1 expression is detected in the lung, while lower level HIN-1 expression is also detected in the stomach, heart, small intestine, uterine and mammary glands. The expression of both genes was detected only at E17.5-18.5 and the HIN-1 messenger RNA was localized to the epithelia of the trachea, bronchi, and uterine glands. The expression of HIN-1 is up-regulated during retinoic acid induced differentiation of bronchial epithelial cells. We also identified two putative Drosophila HIN-1 homologues, The expression of HIN-1 is restricted to terminally differentiated airway epithelial cells in vivo and in vitro implicating HIN-1 in the acquisition or maintenance of terminally differentiated epithelial phenotype. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Polyak, K (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NR 7 TC 26 Z9 27 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4773 J9 MECH DEVELOP JI Mech. Dev. PD JUN PY 2002 VL 114 IS 1-2 BP 201 EP 204 AR PII S0925-4773(02)00056-4 DI 10.1016/S0925-4773(02)00056-4 PG 4 WC Developmental Biology SC Developmental Biology GA 558VM UT WOS:000175987500028 PM 12175512 ER PT J AU Perrin, EB AF Perrin, EB TI Some thoughts on outcomes research, quality improvement, and performance measurement SO MEDICAL CARE LA English DT Article AB Outcomes research, quality improvement, and performance measurement are important activities in the cancer research community. They are, indeed, closely related activities because indicators of quality and performance can logically be regarded as the outcomes of interest in outcomes research. Considerable progress has been made in the past decade in broadening the definition and strengthening the measurement of the important outcomes of health care in general, and cancer care specifically. The real value of studying outcomes, according to the Donabedian paradigm, lies in understanding their relation to the structure and processes (eg, the health care) that have produced them, because it is these latter factors which we can control. Therefore, the methods that we have available to us by which we can infer this relation of causality become very important. Because the systems that we study in health care research are usually complex, we will need to invest more of our resources in the future in the development of methods of inference beyond what we have available now if we are to realize the full potential of health outcomes research. This presents a unique opportunity for leadership by the cancer outcomes research program. C1 Univ Washington, Dept Hlth Serv, Seattle, WA USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Perrin, EB (reprint author), 4900 NE 39th St, Seattle, WA 98105 USA. NR 10 TC 5 Z9 5 U1 0 U2 0 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 JUN PY 2002 VL 40 IS 6 SU S BP 89 EP 91 PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 556YG UT WOS:000175876700013 ER PT J AU Ang, DC Ibrahim, SA Burant, CJ Siminoff, LA Kwoh, CK AF Ang, DC Ibrahim, SA Burant, CJ Siminoff, LA Kwoh, CK TI Ethnic differences in the perception of prayer and consideration of joint arthroplasty SO MEDICAL CARE LA English DT Article DE health disparities; osteoarthritis; joint arthroplasty; prayer ID TOTAL HIP-ARTHROPLASTY; RACIAL-DIFFERENCES; OSTEO-ARTHRITIS; RENAL-TRANSPLANTATION; KNEE REPLACEMENT; HEALTH-CARE; VALIDATION; ACCESS; SPIRITUALITY; PREFERENCES AB CONTEXT. Ethnic differences in utilization of arthroplasty may reflect differences in health-related attitudes and beliefs. OBJECTIVE. To examine ethnic differences in the perception and use of prayer in the treatment of arthritis and its role in patients' decision making toward surgery. DESIGN. A cross-sectional survey. SETTING. VA Primary Care Clinics. PATIENTS. Patients older than 50 years with chronic moderate-to-severe knee pain, hip pain, or both. MEASURES. The "helpfulness of prayer" in the treatment of arthritis and patients' attitude toward joint arthroplasty. RESULTS. Five hundred ninety-six veterans; 44% black patients, 56% white patients. Groups were comparable with respect to age (65 +/- 9.5 vs. 66 +/- 9), disease severity as assessed by WOMAC (47 +/- 17 vs. 45 +/- 17). Black patients scored higher than white patients on the religiosity scale (77 +/- 17 vs. 70 +/- 21). In multivariate analysis, black patients were more likely than white patients to perceive prayer as helpful in the management of their arthritis (OR, 2.1; 95% Cl, 1.19, 3.72). Black patients were also less likely than white patients to consider surgery for severe hip/knee pain (OR, 0.58, 95% Cl 0.34, 0.99); this relationship between ethnicity and consideration of surgery is mediated by perceptions of "helpfulness of prayer." The odds ratio for this relationship changes to 0.70 (P = 0.215). CONCLUSION. In this sample, black patients were more likely than white patients to perceive prayer as helpful and to have actually used prayer for their arthritis. Perception of helpfulness of prayer may be an important explanatory variable in the relationship between ethnicity and patients' decision in considering arthroplasty. C1 Louis Stokes Dept Vet Affairs Med Ctr, Cleveland, OH USA. Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Dept Med, Pittsburgh, PA USA. RP Kwoh, CK (reprint author), Univ Pittsburgh, Div Clin Immunol & Rheumatol, 3500 Terrace St,S702 BST, Pittsburgh, PA 15261 USA. RI Siminoff, Laura /H-6277-2012 NR 40 TC 51 Z9 51 U1 1 U2 3 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 JUN PY 2002 VL 40 IS 6 BP 471 EP 476 DI 10.1097/00005650-200206000-00004 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 555WX UT WOS:000175817200004 PM 12021673 ER PT J AU Maciejewski, ML Diehr, P Smith, MA Hebert, P AF Maciejewski, ML Diehr, P Smith, MA Hebert, P TI Common methodological terms in health services research and their symptoms SO MEDICAL CARE LA English DT Article DE research methods; terminology; statistics; study design ID PANEL-DATA; SELECTION BIAS; VARIABLES; MODELS; CARE AB OBJECTIVE. Health services researchers use methods and terminology from a variety of disciplines to understand individual and organizational behavior related to health, health care, and health insurance. Although this diversity benefits the process of research, the resulting differences in terminology can occasionally lead to confusion among even the most experienced researchers. The purpose of this paper is to clarify different methodological terms used to represent common study designs and statistical concepts in health services research. METHOD. Faculty from the departments of Health Services, Biostatistics and Epidemiology at the University of Washington were asked to provide a list of terms commonly used in health services research that had one or more methodological terms with the same or similar meaning. Consistent with the Delphi method, the initial list was then circulated to internal and external methodologists and additional terms were added for completeness. Terms related to study designs, equation specification, and estimation problems with synonymous terminology were included. RESULTS. A "methodological thesaurus" is developed and described in this paper. Many terms were found which described essentially identical concepts. In other cases, terms had slight but important differences in meaning across disciplines, leading to potential confusion in their use. CONCLUSION. In light of these differences in terminology, it is not surprising that health services researchers with a particular disciplinary orientation currently find literature within their own discipline entirely readable and literature from another discipline considerably less accessible. The "methodological thesaurus" presented in this paper should be of value to health services researchers who are interested in exploring the full array of methods developed to address a particular problem. Teachers and students of health services research should also find this article of use in relating similar concepts across disciplines in quantitative health services research publications. C1 VA Puget Sound Hlth Care Syst, NW Ctr Outcomes Res Older Adults, Seattle, WA 98108 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Wisconsin, Dept Prevent Med, Madison, WI 53706 USA. CUNY Mt Sinai Sch Med, Dept Hlth Policy, New York, NY 10029 USA. RP Maciejewski, ML (reprint author), VA Puget Sound Hlth Care Syst, NW Ctr Outcomes Res Older Adults, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 32 TC 7 Z9 7 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD JUN PY 2002 VL 40 IS 6 BP 477 EP 484 DI 10.1097/00005650-200206000-00005 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 555WX UT WOS:000175817200005 PM 12021674 ER PT J AU Gonzalez, GM Tijerina, R Najvar, L Rinaldi, M Yeh, IT Graybill, JR AF Gonzalez, GM Tijerina, R Najvar, L Rinaldi, M Yeh, IT Graybill, JR TI Experimental murine model of disseminated Pseudallescheria infection SO MEDICAL MYCOLOGY LA English DT Article DE experimental infection; murine model; Pseudallescheria; pseudallescheriosis ID CENTRAL-NERVOUS-SYSTEM; SCEDOSPORIUM-APIOSPERMUM; PETRIELLIDIUM-BOYDII; BRAIN-ABSCESS; ENDOPHTHALMITIS; TRANSPLANTATION; ENDOCARDITIS; PATIENT; THERAPY; VALVE AB Pseudallescheria boydii is found in soil and has a worldwide distribution. This fungus was initially identified as a pathogen targeting a variety of tissues. There are fragmentary data in the literature on the in vitro susceptibility of P. boydii to different antifungal compounds. P. boydii is highly refractory to antifungal treatments. In this study, a murine model of disseminated Pseudallescheria infection was developed to evaluate efficacy of different treatment regimens. A clinical strain of P. boydii was studied in normal and neutropenic outbred ICR mice. Several inocula were tested over a range from 1 x 10(3) to 5 x 10(6) cfu. Groups of eight mice were injected with a intravenous dose of one inoculum. Mortality correlated with the dose of the inoculum, and with immunosuppression. Quantitative cultures of various tissues showed initial dissemination of disease in immune competent mice. This was followed by reduction of tissue burden, except in the brain. In contrast, disseminated infection persisted in most organs in immunosuppressed animals (p < 0.0001). This model should be appropriate for in vivo evaluation of antifungal chemotherapy. C1 Univ Autonoma Nuevo Leon, Fac Med, Dept Microbiol, Colonia Mitras Ctr, Monterrey 64460, Nuevo Leon, Mexico. Univ Texas, Hlth Sci Ctr, Dept Med, Div Infect Dis 7881, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Aldie L Murphy Div, San Antonio, TX 78229 USA. RP Gonzalez, GM (reprint author), Univ Autonoma Nuevo Leon, Fac Med, Dept Microbiol, Colonia Mitras Ctr, Madero & Dr Eduardo A Pequeno SN, Monterrey 64460, Nuevo Leon, Mexico. NR 28 TC 10 Z9 10 U1 0 U2 0 PU B I O S SCIENTIFIC PUBLISHERS LTD PI OXFORD PA 9 NEWTEC PLACE, MAGDALEN RD, OXFORD OX4 1RE, ENGLAND SN 1369-3786 J9 MED MYCOL JI Med. Mycol. PD JUN PY 2002 VL 40 IS 3 BP 243 EP 248 DI 10.1080/714031108 PG 6 WC Infectious Diseases; Mycology; Veterinary Sciences SC Infectious Diseases; Mycology; Veterinary Sciences GA 577UL UT WOS:000177080400002 PM 12146753 ER PT J AU Rivinius, C Mauceri, T AF Rivinius, C Mauceri, T TI An adapter to substitute 192Ir for 137Cs in existing gynecological applicators SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1222 EP 1222 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400159 ER PT J AU Li, JS Ma, CM Jiang, SB Deng, J Price, RA McNeeley, SW Chen, L Ding, M Fourkal, E AF Li, JS Ma, CM Jiang, SB Deng, J Price, RA McNeeley, SW Chen, L Ding, M Fourkal, E TI Source modeling and beam commissioning for photon beams from a Siemens accelerator SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Yale Univ, New Haven, CT USA. NR 0 TC 3 Z9 3 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1230 EP 1230 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400197 ER PT J AU Gerweck, L El-Ghamry, M Biggs, P AF Gerweck, L El-Ghamry, M Biggs, P TI A filter and blocking arrangement for irradiation of the mouse spinal cord SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1235 EP 1235 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400223 ER PT J AU Biggs, P AF Biggs, P TI Primary beam widths in ceiling shielding SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1236 EP 1236 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400227 ER PT J AU Biggs, P AF Biggs, P TI Does the dose outside a primary barrier follow the inverse square law? SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1236 EP 1236 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400228 ER PT J AU Bortfeld, T Kufer, KH Monz, M Scherrer, A Thieke, C Trinkaus, H AF Bortfeld, T Kufer, KH Monz, M Scherrer, A Thieke, C Trinkaus, H TI Radiation therapy planning - A multicriteria approach SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Fraunhofer ITWM, Kaiserslautern, Germany. Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1258 EP 1258 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400334 ER PT J AU Gierga, D Jiang, S AF Gierga, D Jiang, S TI A Monte Carlo study on the interplay effect between MLC leaf motion and respiration-induced tumor motion in lung IMRT delivery SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 1 U2 1 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 JUN PY 2002 VL 29 IS 6 BP 1266 EP 1266 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400376 ER PT J AU Harris, T Doppke, K Jiang, S AF Harris, T Doppke, K Jiang, S TI Effect of source-to-detector distance on the measurement of in-air output factors for very small field sizes in IMRT commissioning SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1272 EP 1272 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400404 ER PT J AU Thieke, C Bortfeld, T Niemierko, A AF Thieke, C Bortfeld, T Niemierko, A TI Direct consideration of EUD constraints in IMRT optimization SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 1 Z9 1 U1 1 U2 3 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 JUN PY 2002 VL 29 IS 6 BP 1283 EP 1283 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400447 ER PT J AU Neicu, T Shirato, H Seppenwold, Y Jiang, SB AF Neicu, T Shirato, H Seppenwold, Y Jiang, SB TI Gated Motion Adaptive Therapy (GMAT): Average tumor trajectory for lung patients SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Antoni Van Leeuwenhoek Huis, Netherlands Canc Inst, Amsterdam, Netherlands. Hokkaido Univ, Sch Med, Sapporo, Hokkaido 060, Japan. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Shirato, Hiroki/A-7068-2010 NR 0 TC 0 Z9 0 U1 1 U2 1 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 JUN PY 2002 VL 29 IS 6 BP 1309 EP 1310 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400560 ER PT J AU Zygmanski, P Jiang, SB Kung, JH AF Zygmanski, P Jiang, SB Kung, JH TI How to evaluate dose errors in IMRT from random leaf-positional errors SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1320 EP 1320 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400610 ER PT J AU Paganetti, H Flanz, J Newhauser, W Rosenthal, S Titt, U Wagner, M Kooy, H AF Paganetti, H Flanz, J Newhauser, W Rosenthal, S Titt, U Wagner, M Kooy, H TI Monte Carlo studies for commissioning and beam characterization of the northeast proton therapy center SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Cyclotron Lab, Cambridge, MA 02138 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1326 EP 1327 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400640 ER PT J AU Basilion, J AF Basilion, J TI MR imaging of gene expression SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1328 EP 1329 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400648 ER PT J AU Paganetti, H Gottschalk, B AF Paganetti, H Gottschalk, B TI Test of Monte Carlo nuclear interaction models for polyethylene (CH2) using a multi-layer faraday cup SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Cyclotron Lab, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 JUN PY 2002 VL 29 IS 6 BP 1328 EP 1328 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400645 ER PT J AU Bortfeld, T Jokivarsi, K Goitein, M Jiang, S AF Bortfeld, T Jokivarsi, K Goitein, M Jiang, S TI Effects of intra-fraction motion on IMRT delivery with MLC, compensators, and scanning SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1347 EP 1347 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400727 ER PT J AU Jiang, S Zygmanski, P Kung, J Chen, G AF Jiang, S Zygmanski, P Kung, J Chen, G TI Gated Motion Adaptive Therapy (GMAT): Modification of IMRT MLC leaf sequence to compensate for tumor motion SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 6 Z9 6 U1 0 U2 2 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 JUN PY 2002 VL 29 IS 6 BP 1347 EP 1348 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400729 ER PT J AU Jiang, S Rivinius, C Al Jarrah, K Kung, J Bortfeld, T Chen, G AF Jiang, S Rivinius, C Al Jarrah, K Kung, J Bortfeld, T Chen, G TI An experimental investigation on interplay effect between DMLC leaf motion and respiration-induced tumor motion in lung IMRT treatment SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NR 0 TC 6 Z9 6 U1 0 U2 2 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 JUN PY 2002 VL 29 IS 6 BP 1347 EP 1347 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400725 ER PT J AU Mauceri, T Chen, G Gierga, D Munro, J Rivinius, C AF Mauceri, T Chen, G Gierga, D Munro, J Rivinius, C TI Dosimetric characteristics of a uniform and differentially loaded 90Y plaque for irradiation of sarcomas of the spine SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Implant Serv, Wakefield, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1349 EP 1349 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400737 ER PT J AU Hacker, F Zygmanski, P Ramakrishna, N AF Hacker, F Zygmanski, P Ramakrishna, N TI A comparison of forward planned IMRT to inverse planned IMRT for stereotactic radiotherapy SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Dana Farber Brigham & Womens Canc Ctr, Boston, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1367 EP 1367 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400813 ER PT J AU Biggs, P AF Biggs, P TI X-ray spectra characteristics of the new PRS source SO MEDICAL PHYSICS LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 JUN PY 2002 VL 29 IS 6 BP 1368 EP 1368 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 565ME UT WOS:000176373400816 ER PT J AU Nakatani, Y Masudo, K Miyagi, Y Inayama, Y Kawano, N Tanaka, Y Kato, K Ito, T Kitamura, H Nagashima, Y Yamanaka, S Nakamura, N Sano, J Ogawa, N Ishiwa, N Notohara, K Resl, M Mark, EJ AF Nakatani, Y Masudo, K Miyagi, Y Inayama, Y Kawano, N Tanaka, Y Kato, K Ito, T Kitamura, H Nagashima, Y Yamanaka, S Nakamura, N Sano, J Ogawa, N Ishiwa, N Notohara, K Resl, M Mark, EJ TI Aberrant nuclear localization and gene mutation of beta-catenin in low-grade adenocarcinoma of fetal lung type: Up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors that form morules SO MODERN PATHOLOGY LA English DT Article; Proceedings Paper CT 90th General Meeting of the Japanese-Society-of-Pathology CY APR 05-07, 2001 CL TOKYO, JAPAN SP Japanese Soc Pathol DE adenocarcinoma of the fetal lung type; APC gene; beta-catenin mutation; biotin-rich optically clear nucleus; cribriform-morular variant of papillary thyroid carcinoma; Wnt signaling pathway ID FAMILIAL ADENOMATOUS POLYPOSIS; OPTICALLY CLEAR NUCLEI; THYROID-CARCINOMA; PAPILLARY CARCINOMA; OVARIAN CARCINOMAS; PULMONARY BLASTOMA; COLORECTAL-CANCER; APC GENE; EXPRESSION; BIOTIN AB The salient histopathologic features of low-grade adenocarcinoma. of the fetal lung type (L-FLAC)/well-differentiated fetal adenocarcinoma (WDFA) include complex glandular structures and morules with biotin-rich optically clear nuclei. Interestingly, these characteristic features are shared by the cribriform-morular variant of papillary thyroid carcinoma, whose morphology is identical to that of familial adenomatous polyposis (FAP)-associated thyroid carcinoma. Furthermore, the single reported case of lung cancer associated with FAP was L-FLAC/WDFA. These observations lead us to hypothesize that up-regulation of the Writ signaling pathway underlies the development of L-FLAC/WDFA. To verify this hypothesis, 11 cases of L-FLAC/WDFA, including the one FAP-associated case, eight cases of high-grade adenocarcinoma. of the fetal lung type (H-FIAC), 24 cases of conventional pulmonary adenocarcinoma (CAC), and 13 fetal lungs were immunostained for beta-catenin. All cases of L-FLAC/WDFA showed predominantly aberrant nuclear/cytoplasmic expression, especially in budding glands and morules, whereas six of eight cases (75%) of H-FLAC and all but one case (96%) of CAC showed predominantly membranous expression. Fetal lungs showed nuclear/cytoplasmic expression restricted to the distal branching airway epithelium. Mutational analysis of exon 3 of the beta-catenin gene in five sporadic cases of L-FLAC/WDFA showed a point mutation at codon 34 and codon 37 in two cases, respectively. The present study indicates that up-regulating disturbances in the Wnt signaling pathway, including mutation of the beta-catenin gene, underlie tumorigenesis of L-FLAC/WDFA. The expression pattern of beta-catenin in L-FLAC/WDFA resembles that of the developing fetal lung airway. With the expression pattern of beta-catenin as a marker, most cases of H-FLAC as well as CAC appear to have different oncogenic pathways from cases of L-FLAC/WDFA. The present study together with other available data also suggests that abnormal up-regulation of the Writ signaling pathway may be a common denominator for the development of tumors with morular formation from a variety of anatomic sites. C1 Yokohama City Univ, Med Ctr, Sch Med, Dept Pathol,Minami Ku, Yokohama, Kanagawa 2320024, Japan. Hosp Yokohama City Univ, Div Anat & Surg Pathol, Yokohama, Kanagawa, Japan. Kanagawa Prefectural Canc Ctr, Clin Res Lab, Yokohama, Kanagawa, Japan. Kanagawa Prefectural Childrens Med Ctr, Dept Pathol, Yokohama, Kanagawa, Japan. Yokohama Citizens Hosp, Dept Pathol, Yokohama, Kanagawa, Japan. Kanagawa Prefectural Cardiovasc & Resp Ctr, Dept Surg, Yokohama, Kanagawa, Japan. Okayama Univ, Grad Sch Med & Dent, Dept Pathol Res, Okayama, Japan. Charles Univ, Sch Med, Dept Pathol, Hradec Kralove, Czech Republic. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Nakatani, Y (reprint author), Yokohama City Univ, Med Ctr, Sch Med, Dept Pathol,Minami Ku, 4-57 Urafume, Yokohama, Kanagawa 2320024, Japan. NR 44 TC 58 Z9 63 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD JUN PY 2002 VL 15 IS 6 BP 617 EP 624 DI 10.1038/modpathol.3880575 PG 8 WC Pathology SC Pathology GA 564YR UT WOS:000176341600006 PM 12065775 ER PT J AU Aoyagi, S Narlikar, G Zheng, CY Sif, S Kingston, RE Hayes, JJ AF Aoyagi, S Narlikar, G Zheng, CY Sif, S Kingston, RE Hayes, JJ TI Nucleosome remodeling by the human SWI/SNF complex requires transient global disruption of histone-DNA interactions SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID N-TERMINAL TAIL; YEAST SWI/SNF; TRANSCRIPTIONAL REGULATION; CHROMATIN; BINDING; ACTIVATOR; CORE; RSC; MECHANISM; PROTEIN AB We utilized a site-specific cross-linking technique to investigate the mechanism of nucleosome remodeling by hSWI/SNF. We found that a single cross-link between H2B and DNA virtually eliminates the accumulation of stably remodeled species as measured by restriction enzyme accessibility assays. However, cross-linking the histone octamer to nucleosomal DNA does not inhibit remodeling as monitored by DNase I digestion assays. Importantly, we found that the restriction enzyme-accessible species can be efficiently cross-linked after remodeling and that the accessible state does not require continued ATP hydrolysis. These results imply that the generation of stable remodeled states requires at least transient disruption of histone-DNA interactions throughout the nucleosome, while hSWI/SNF-catalyzed disruption of just local histone-DNA interactions yields less-stable remodeled states that still display an altered DNase I cleavage pattern. The implications of these results for models of the mechanism of SWI/SNF-catalyzed nucleosome remodeling are discussed. C1 Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14642 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Hayes, JJ (reprint author), Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14642 USA. FU NIGMS NIH HHS [R01 GM052426, R01GM52426] NR 42 TC 35 Z9 35 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2002 VL 22 IS 11 BP 3653 EP 3662 DI 10.1128/MB.22.11.3653-3662.2002 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 551JP UT WOS:000175557600009 PM 11997502 ER PT J AU Carr, AN Schmidt, AG Suzuki, Y del Monte, F Sato, Y Lanner, C Breeden, K Jing, SL Allen, PB Greengard, P Yatani, A Hoit, BD Grupp, IL Hajjar, RJ DePaoli-Roach, AA Kranias, EG AF Carr, AN Schmidt, AG Suzuki, Y del Monte, F Sato, Y Lanner, C Breeden, K Jing, SL Allen, PB Greengard, P Yatani, A Hoit, BD Grupp, IL Hajjar, RJ DePaoli-Roach, AA Kranias, EG TI Type 1 phosphatase, a negative regulator of cardiac function SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FAILING HUMAN HEARTS; RABBIT SKELETAL-MUSCLE; PROTEIN PHOSPHATASE; SARCOPLASMIC-RETICULUM; DILATED CARDIOMYOPATHY; PHOSPHOLAMBAN PHOSPHORYLATION; CONTRACTILE FUNCTION; TRANSGENIC MICE; GENE-TRANSFER; TROPONIN-I AB Increases in type 1 phosphatase (PP1) activity have been observed in end stage human heart failure, but the role of this enzyme in cardiac function is unknown. To elucidate the functional significance of increased PP1 activity, we generated models with (i) overexpression of the catalytic subunit of PP1 in murine hearts and (ii) ablation of the PP1-specific inhibitor. Overexpression of PP1 (threefold) was associated with depressed cardiac function, dilated cardiomyopathy, and premature mortality, consistent with heart failure. Ablation of the inhibitor was associated with moderate increases in PP1 activity (23%) and impaired beta-adrenergic contractile responses. Extension of these findings to human heart failure indicated that the increased PP1 activity may be partially due to dephosphorylation or inactivation of its inhibitor. Indeed, expression of a constitutively active inhibitor was associated with rescue of beta-adrenergic responsiveness in failing human myocytes. Thus, PP1 is an important regulator of cardiac function, and inhibition of its activity may represent a novel therapeutic target in heart failure. C1 Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Krannert Inst Cardiol, Indianapolis, IN 46202 USA. Harvard Univ, Div Cardiol, Sch Med, Boston, MA 02129 USA. Massachusetts Gen Hosp, Boston, MA 02129 USA. Natl Inst Hlth Sci, Tokyo 1588501, Japan. Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA. Case Western Reserve Univ, Div Cardiol, Cleveland, OH 44106 USA. RP Kranias, EG (reprint author), Univ Cincinnati, Coll Med, Dept Pharmacol & Cell Biophys, 231 Albert B Sabin Way,POB 670575, Cincinnati, OH 45267 USA. FU NCRR NIH HHS [P40RR12358]; NHLBI NIH HHS [R01 HL026057, P50 HL052318, HL06308, R01 HL064018, HL26057, HL07382, R37 HL026057, HL52318, HL64018, T32 HL007382]; NIDA NIH HHS [DA10044, P01 DA010044]; NIDDK NIH HHS [R01 DK036569, DK36569]; NIMH NIH HHS [P01 MH040899, MH40899] NR 53 TC 160 Z9 164 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2002 VL 22 IS 12 BP 4124 EP 4135 DI 10.1128/MCB.22.12.4124-4135.2002 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 556UB UT WOS:000175866400017 PM 12024026 ER PT J AU Cantor, AB Katz, SG Orkin, SH AF Cantor, AB Katz, SG Orkin, SH TI Distinct domains of the GATA-1 cofactor FOG-1 differentially influence erythroid versus megakaryocytic maturation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; HEART TUBE FORMATION; ZINC-FINGER PROTEIN; HEMATOPOIETIC-CELLS; VENTRAL MORPHOGENESIS; BINDING PROTEINS; MAMMALIAN-CELLS; GENE; DROSOPHILA; PRECURSORS AB FOG family zinc finger proteins play essential roles in development through physical interaction with GATA factors. FOG-1, like its interacting partner GATA-1, is required for normal differentiation of erythroid and megakaryocytic cells. Here, we have developed a functional assay for FOG-1 based on its ability to rescue erythroid and megakaryocytic maturation of a genetically engineered FOG-1(-/-) cell line. We demonstrate that interaction through only one of FOG-1's four GATA-binding zinc fingers is sufficient for rescue, providing evidence against a model in which FOG-1 acts to bridge multiple GATA-binding DNA elements. Importantly, we find that distinct regions of FOG-1 differentially influence erythroid versus megakaryocyte maturation. As such, we propose that FOG-1 may modulate the fate of a bipotential erythroid/megakaryocytic precursor cell. C1 Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat, Boston, MA 02115 USA. Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Childrens Hosp, Div Hematol, 320 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [5K08CA82175] NR 43 TC 73 Z9 73 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2002 VL 22 IS 12 BP 4268 EP 4279 DI 10.1128/MCB.22.12.4268-4279.2002 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 556UB UT WOS:000175866400029 PM 12024038 ER PT J AU Raina, D Mishra, N Kumar, S Kharbanda, S Saxena, S Kufe, D AF Raina, D Mishra, N Kumar, S Kharbanda, S Saxena, S Kufe, D TI Inhibition of c-Abl with STI571 attenuates stress-activated protein kinase activation and apoptosis in the cellular response to 1-beta-D-arabinofuranosylcytosine SO MOLECULAR PHARMACOLOGY LA English DT Article ID MYELOID-LEUKEMIA CELLS; DNA-DAMAGING AGENTS; P56/P53(LYN) TYROSINE KINASE; JUN GENE-EXPRESSION; IONIZING-RADIATION; BCR-ABL; PATHWAY; GROWTH; TRANSCRIPTION; MITOCHONDRIA AB The response of myeloid leukemia cells to treatment with 1-beta-D-arabinofuranosylcytosine (ara-C) includes activation of the c-Abl protein tyrosine kinase and the stress-activated protein kinase (SAPK). The present studies demonstrate that treatment of human U-937 leukemia cells with ara-C is associated with translocation of SAPK to mitochondria. STI571 (imatinib mesylate), an inhibitor of c-Abl, blocked both activation and mitochondrial targeting of SAPK in the ara-C response. In concert with these effects of STI571, similar findings were obtained in c-Abl-deficient cells. The results further show that STI571 inhibits ara-C-induced loss of mitochondrial transmembrane potential, caspase-3 activation, and apoptosis. These findings demonstrate that STI571 down-regulates c-Abl-mediated signals that target the mitochondria in the apoptotic response to ara-C. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Lovelace Resp Res Inst, Albuquerque, NM USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St 830, Boston, MA 02115 USA. FU NCI NIH HHS [CA29431] NR 42 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD JUN PY 2002 VL 61 IS 6 BP 1489 EP 1495 AR UNSP 0/986409 DI 10.1124/mol.61.6.1489 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 554LH UT WOS:000175736600025 PM 12021410 ER PT J AU Deeks, SG Wagner, B Anton, PA Mitsuyasu, RT Scadden, DT Haung, C Macken, C Richman, DD Christopherson, C June, CH Lazar, R Broad, DF Jalali, S Hege, KM AF Deeks, SG Wagner, B Anton, PA Mitsuyasu, RT Scadden, DT Haung, C Macken, C Richman, DD Christopherson, C June, CH Lazar, R Broad, DF Jalali, S Hege, KM TI A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy SO MOLECULAR THERAPY LA English DT Article DE gene therapy; adoptive immunotherapy; HIV infection; HIV reservoirs; highly active antiretroviral therapy ID EPSTEIN-BARR-VIRUS; DISEASE PROGRESSION; VIRAL REPLICATION; INFECTED SUBJECTS; ADOPTIVE TRANSFER; CD4(+); LYMPHOCYTES; PERSISTENCE; RESPONSES; IDENTIFICATION AB Highly active antiretroviral therapy (HAART) can suppress HIV replication to undetectable levels in plasma, but it is unlikely to eradicate cellular reservoirs of virus. Immunotherapies that are cytolytic may be useful adjuncts to drug therapies that target HIV replication. We have generated HIV-specific CD4(+) and CD8(+) T cells bearing a chimeric T-cell receptor (CD4zeta) composed of the extracellular and transmembrane domain of human CD4 (which binds HIVgp120) linked to the intracellular-zeta signaling chain of the CD3 T-cell receptor. CD4zeta-modified T cells can inhibit viral replication, kill HIV-infected cells in vitro, and survive for prolonged periods in vivo. We report the results of a phase II randomized trial of CD4zeta gene-modified versus unmodified T cells in 40 HIV-infected subjects on HAART with plasma viral loads <50 copies/ml. Serial analyses of residual blood and tissue HIV reservoirs were done for 6 months postinfusion. No significant between-group differences were noted in viral reservoirs following therapy. However, infusion of gene-modified, but not unmodified, T cells was associated with a decrease from baseline in HIV burden in two of four reservoir assays and a trend toward fewer patients with recurrent viremia. Both groups experienced a treatment-related increase in CD4(+) T-cell counts. C1 Cell Genesys Inc, Foster City, CA 94404 USA. Univ Calif San Francisco, San Francisco, CA 94110 USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. ViRx Inc, San Francisco, CA 94109 USA. Univ Calif Los Angeles, Ctr Hlth Sci, MRL 2734, Los Angeles, CA 90095 USA. Massachusetts Gen Hosp, Charlestown, MA 02129 USA. Adv Res Associates, Mt View, CA 94940 USA. Los Alamos Natl Lab, Div Theoret, Los Alamos, NM 87545 USA. San Diego Vet Adm Hlth Care Syst, San Diego, CA USA. Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. Roche Mol Syst, Alameda, CA 94501 USA. Univ Penn, Abramson Inst, Philadelphia, PA 19104 USA. RP Hege, KM (reprint author), Cell Genesys Inc, 342 Lakeside Dr, Foster City, CA 94404 USA. FU NCRR NIH HHS [RR-00865, 5-M01-RR00083-37]; NIAID NIH HHS [AI28697] NR 38 TC 103 Z9 110 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD JUN PY 2002 VL 5 IS 6 BP 788 EP 797 DI 10.1006/mthe.2002.0611 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 560LC UT WOS:000176082700020 PM 12027564 ER PT J AU Wing, JP Schreader, BA Yokokura, T Wang, UQ Andrews, PS Huseinovic, N Dong, CK Ogdahl, JL Schwartz, LM White, K Nambu, JR AF Wing, JP Schreader, BA Yokokura, T Wang, UQ Andrews, PS Huseinovic, N Dong, CK Ogdahl, JL Schwartz, LM White, K Nambu, JR TI Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis SO NATURE CELL BIOLOGY LA English DT Article ID PROGRAMMED CELL-DEATH; LIGASE ACTIVITY; UBIQUITIN; PROTEASOMES; DEGRADATION; INHIBITOR; CASPASE-3; PATHWAY; CYCLE C1 Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. Univ Massachusetts, Mol & Cellular Biol Program, Amherst, MA 01003 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. RP Nambu, JR (reprint author), Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. RI White, Kristin/D-7936-2013; Tang, Amy/L-3226-2016 OI Tang, Amy/0000-0002-5772-2878 FU NIA NIH HHS [AG55118]; NIGMS NIH HHS [GM55568] NR 33 TC 100 Z9 101 U1 0 U2 1 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 JUN PY 2002 VL 4 IS 6 BP 451 EP 456 DI 10.1038/ncb800 PG 6 WC Cell Biology SC Cell Biology GA 558NN UT WOS:000175973600016 PM 12021772 ER PT J AU Springer, TA AF Springer, TA TI Cesar Milstein, the father of modern immunology - In memoriam SO NATURE IMMUNOLOGY LA English DT Biographical-Item C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. NR 1 TC 7 Z9 7 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2002 VL 3 IS 6 BP 501 EP 503 DI 10.1038/ni0602-501 PG 3 WC Immunology SC Immunology GA 556XR UT WOS:000175874700004 PM 12032559 ER PT J AU Ezekowitz, RA AF Ezekowitz, RA TI Local opsonization for apoptosis? SO NATURE IMMUNOLOGY LA English DT Editorial Material ID PROGRAMMED CELL-DEATH; MACROPHAGES; CLEARANCE; FUTURE; GROWTH AB Classical opsonins are serum proteins that coat microorganisms and particles so as to enhance uptake by macrophages. A recent Nature paper has identified a macrophage-derived opsonin for apoptotic cells. C1 Harvard Univ, Sch Med, MassGen Hosp Children, Lab Dev Immunol, Boston, MA 02114 USA. RP Ezekowitz, RA (reprint author), Harvard Univ, Sch Med, MassGen Hosp Children, Lab Dev Immunol, Boston, MA 02114 USA. NR 13 TC 14 Z9 14 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2002 VL 3 IS 6 BP 510 EP 512 DI 10.1038/ni0602-513 PG 4 WC Immunology SC Immunology GA 556XR UT WOS:000175874700008 PM 12032563 ER PT J AU Obici, S Feng, ZH Karkanias, G Baskin, DG Rossetti, L AF Obici, S Feng, ZH Karkanias, G Baskin, DG Rossetti, L TI Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats SO NATURE NEUROSCIENCE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; Y MESSENGER-RNA; GENE-EXPRESSION; FOOD-INTAKE; VISCERAL ADIPOSITY; ARCUATE NUCLEUS; DIABETIC RATS; BODY-WEIGHT; LEPTIN; BRAIN AB We investigated the role of hypothalamic insulin signaling in the regulation of energy balance and insulin action in rats through selective decreases in insulin receptor expression in discrete hypothalamic nuclei. We generated an antisense oligodeoxynucleotide directed against the insulin receptor precursor protein and administered this directly into the third cerebral ventricle. Immunostaining of rat brains after 7-day administration of the oligodeoxynucleotide showed a selective decrease of insulin receptor protein within cells in the medial portion of the arcuate nucleus (decreased by similar to80% as compared to rats treated with a control oligodeoxynucleotide). Insulin receptors in other hypothalamic and extra-hypothalamic areas were not affected. This selective decrease in hypothalamic insulin receptor protein was accompanied by rapid onset of hyperphagia and increased fat mass. During insulin-clamp studies, physiological hyperinsulinemia decreased glucose production by 55% in rats treated with control oligodeoxynucleotides but by only 25% in rats treated with insulin receptor antisense oligodeoxynucleotides. Thus, insulin receptors in discrete areas of the hypothalamus have a physiological role in the control of food intake, fat mass and hepatic action of insulin. C1 Yeshiva Univ Albert Einstein Coll Med, Bronx, NY 10461 USA. VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Seattle, WA 98108 USA. RP Rossetti, L (reprint author), Yeshiva Univ Albert Einstein Coll Med, 1300 Morris Pk Ave, Bronx, NY 10461 USA. FU NIDDK NIH HHS [DK 48321, DK 20541, DK 17047, DK 45024] NR 36 TC 390 Z9 403 U1 1 U2 7 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD JUN PY 2002 VL 5 IS 6 BP 566 EP 572 DI 10.1038/nn861 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 556XQ UT WOS:000175874600017 PM 12021765 ER PT J AU Barbieri, R Frank, LM Quirk, MC Solo, V Wilson, MA Brown, EN AF Barbieri, R Frank, LM Quirk, MC Solo, V Wilson, MA Brown, EN TI Construction and analysis of non-Gaussian spatial models of neural spiking activity SO NEUROCOMPUTING LA English DT Article; Proceedings Paper CT 10th Computational Neuroscience Meeting (CSN 01) CY JUL, 2001 CL MONTEREY, CALIFORNIA DE hippocampal place cells; interspike interval distribution; inhomogeneous Poisson process; Zernike polynomials ID RAT AB The spiking activity of rat CA1 hippocampal place cells during open field foraging can be described with stimulus-response models based on an inhomogeneous Poisson (IP) interspike interval probability model. The spatial structure of this model has been previously represented as a simple Gaussian surface. We analyze four new spatial models. two extensions of the Gaussian surface, a surface based on a logistic transformation, and a surface constructed by using Zernike polynomials. Goodness-of-fit analysis based on the Bayesian information criterion (BIC) shows that the Zernike polynomial surfaces give the most accurate description of the spatial place cell spiking activity under this experimental paradigm. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Dept Anesthesia & Crit Care, Neursci Stat Res Lab, Div Hlth Sci & Technol,MIT,Massachusetts Gen Hosp, Boston, MA 02114 USA. MIT, Ctr Learning & Memory, RIKEN MIT Neurosci Res Ctr, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Univ New S Wales, Sch Elect & Telecommun, Sydney, NSW, Australia. RP Barbieri, R (reprint author), Harvard Univ, Dept Anesthesia & Crit Care, Neursci Stat Res Lab, Div Hlth Sci & Technol,MIT,Massachusetts Gen Hosp, Clin 3,55 Fruit St, Boston, MA 02114 USA. OI Barbieri, Riccardo/0000-0001-9381-3833; Frank, Loren/0000-0002-1752-5677 NR 6 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-2312 J9 NEUROCOMPUTING JI Neurocomputing PD JUN PY 2002 VL 44 BP 309 EP 314 AR PII S0925-2312(02)00365-X DI 10.1016/S0925-2312(02)00365-X PG 6 WC Computer Science, Artificial Intelligence SC Computer Science GA 573PC UT WOS:000176839200047 ER PT J AU Leite, FP Tsao, D Vanduffel, W Fize, D Sasaki, Y Wald, LL Dale, AM Kwong, KK Orban, GA Rosen, BR Tootell, RBH Mandeville, JB AF Leite, FP Tsao, D Vanduffel, W Fize, D Sasaki, Y Wald, LL Dale, AM Kwong, KK Orban, GA Rosen, BR Tootell, RBH Mandeville, JB TI Repeated fMRI using iron oxide contrast agent in awake, behaving macaques at 3 Tesla SO NEUROIMAGE LA English DT Article ID RAT FOREPAW STIMULATION; CEREBRAL BLOOD-VOLUME; FUNCTIONAL MRI; HUMAN V1; BOLD; BRAIN; CORTEX; SEPARATION; MONKEYS; SIGNAL AB Iron oxide contrast agents have been employed extensively in anesthetized rodents to enhance fMRI sensitivity and to study the physiology of cerebral blood volume (CBV) in relation to blood oxygen level-dependent (BOLD) signal following neuronal activation. This study quantified the advantages of exogenous agent for repeated neuroimaging in awake, nonhuman primates using a clinical 3 Tesla scanner. A monocrystalline iron oxide nanoparticle (MION) solution was injected at iron doses of 8 to 10 mg/kg in two macaque monkeys. Adverse behavioral effects due to contrast agent were not observed in either monkey using cumulative doses in excess of 60 mg/kg. Relative to BOLD imaging at 3 Tesla, MION increased functional sensitivity by an average factor of 3 across the brain for a stimulus of long duration. Rapid stimulus presentation attenuated MION signal changes more than BOLD signal changes, due to the slower time constant of the blood volume response relative to BOLD signal. Overall, the contrast agent produced a dramatic improvement in functional brain imaging results in the awake, behaving primate at this field strength. (C) 2002 Elsevier Science (USA). C1 MIT, Dept Nucl Engn, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Catholic Univ Louvain, Neuro & Psychofysiol Lab, B-3000 Louvain, Belgium. Massachusetts Gen Hosp, Charlestown, MA 02129 USA. Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Leite, FP (reprint author), MIT, Dept Nucl Engn, Cambridge, MA 02139 USA. RI Dale, Anders/A-5180-2010; Fize, Denis/F-4525-2011; Wald, Lawrence/D-4151-2009; OI Leite, Francisca/0000-0003-2550-2616 FU NCRR NIH HHS [P41-RR14075, R01-RR13609, R01-RR14543A02]; NINDS NIH HHS [R01-NS39581] NR 39 TC 140 Z9 142 U1 2 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 JUN PY 2002 VL 16 IS 2 BP 283 EP 294 DI 10.1006/nimg.2002.1110 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 561CM UT WOS:000176119300001 PM 12030817 ER PT J AU Hoh, BL Carter, BS Ogilvy, CS AF Hoh, BL Carter, BS Ogilvy, CS TI Risk of hemorrhage from unsecured, unruptured aneurysms during and after hypertensive hypervolemic therapy SO NEUROSURGERY LA English DT Article DE hypertension; multiple aneurysms; rebleed; subarachnoid hemorrhage; unruptured; vasospasm ID SUBARACHNOID HEMORRHAGE; CEREBRAL VASOSPASM; ARTERIAL-HYPERTENSION; BALLOON ANGIOPLASTY; VOLUME EXPANSION; PAPAVERINE; MANAGEMENT; EFFICACY AB OBJECTIVE: Hypertensive hypervolemic therapy for vasospasm is widely practiced. It is not clear, however, whether the use of hypertension and hypervolemia as a treatment for vasospasm risks hemorrhage from an unsecured, unruptured aneurysm. METHODS: From 1991 to 2000 the neurovascular unit at the Massachusetts General Hospital treated 1908 aneurysms, of which 966 were ruptured. Forty patients with ruptured aneurysms had unsecured, unruptured aneurysms and underwent hypertensive hypervolemic therapy for vasospasm. Hypertension was induced by intravenously administered phenylephrine, norepinephrine, and/or dopamine, and hypervolemia was achieved by intravenously administered crystalloid and colloid solutions. The 24-hour mean arterial systolic blood pressure (SBP) and the 24-hour mean central venous pressure were calculated on the basis of hourly measurements during hypertensive hypervolemic treatment. RESULTS: The 40 study patients harbored 124 aneurysms, of which 51 aneurysms were treated (clipping, 37; coiling, 14) by the time hypertensive hypervolemic therapy began, leaving 73 unsecured aneurysms at risk. The mean size of the unsecured aneurysms was 4.45 mm. Nineteen patients were treated with mild hypertension (SBP, 140-180 mm Hg), 12 patients were treated with moderate hypertension (SBP, 180-200 mm Hg), and 9 patients were treated with severe hypertension (SBP, >200 mm Hg). The 24-hour mean SBP readings were 166.81 +/- 8.19, 187.57 +/- 5.79, and 204.01 +/- 3.75 mm Hg for the mild, moderate, and severe hypertension groups, respectively. The mean central venous pressure was 10.43 +/- 3.89 mm Hg. The mean course of hypertensive hypervolemic therapy was 7.25 days, and therapy began on mean post-subarachnoid hemorrhage Day 6.73. Twenty-eight aneurysms were eventually treated in later procedures (clipping, 25; coiling, 3). The mean interval to treatment was 6.93 months. In a treatment and follow-up period of 121.75 aneurysm-years of risk, there was no instance of hemorrhage. CONCLUSION: Hypertension and hypervolemia do not seem to increase the risk of hemorrhage from unsecured, unruptured aneurysms in the acute setting or in their short-term natural history. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Brain Aneurysm AVM Ctr,Neurosurg Serv, Boston, MA 02114 USA. RP Ogilvy, CS (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Brain Aneurysm AVM Ctr,Neurosurg Serv, VBK-710,55 Fruit St, Boston, MA 02114 USA. NR 15 TC 21 Z9 23 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 JUN PY 2002 VL 50 IS 6 BP 1207 EP 1211 DI 10.1097/00006123-200206000-00006 PG 5 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 560XE UT WOS:000176106000008 PM 12015837 ER PT J AU Greene, MF AF Greene, MF TI Vaginal breech delivery is no longer justified SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material ID CESAREAN-SECTION; UNITED-STATES; TRIAL; TERM; BIRTH C1 Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, Boston, MA 02114 USA. RP Greene, MF (reprint author), Massachusetts Gen Hosp, Vincent Obstet & Gynecol Serv, 32 Fruit St,Founders Bldg,Room 445, Boston, MA 02114 USA. NR 14 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD JUN PY 2002 VL 99 IS 6 BP 1113 EP 1115 AR PII S0029-7844(02)02032-X DI 10.1016/S0029-7844(02)02032-X PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 558QF UT WOS:000175977500027 PM 12052607 ER PT J AU Hoobyar, AR Ferrucci, S Anderson, SF Townsend, JC AF Hoobyar, AR Ferrucci, S Anderson, SF Townsend, JC TI Juxtapapillary capillary hemangioblastoma SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE capillary hemangioblastoma; hemangioma; juxtapapillary; von Hippel-Lindau disease ID HIPPEL-LINDAU-DISEASE; CLINICAL-FEATURES; RETINAL ANGIOMATOSIS; HEMANGIOMA; MUTATION; GENE AB Background. Juxtapapillary capillary hemangioblastomas are vascular lesions that occur on the optic nerve head or immediately adjacent to the optic disc. Although juxtapapillary capillary hemangioblastomas may appear as an isolated clinical finding, they are more likely to be a precursor to the diagnosis of von Hippel-Lindau (VHL) disease. When associated with VHL, the ocular complications from hemangioblastoma are generally greater, and subsequently the prognosis is poorer than for isolated entities. Case Report. A 67-year-old white male presented to our clinic complaining of decreased vision in both eyes at distance and near. A dilated fundus examination revealed a swollen left optic nerve. Visual field testing revealed an inferior arcuate defect in the left eye. Laboratory and radiological testing were normal. Fluorescein angiography showed filling during the retinal arterial phase with late diffuse leakage. Based on these results, a diagnosis of juxtapapillary capillary hemangioblastoma was made. This was later confirmed when fundus photographs taken 7 years earlier were obtained, revealing a stable appearance to the nerve. Conclusion. Potential ocular complications of juxtapapillary capillary hemangioblastomas include vision loss secondary to subretinal and intraretinal fluid, as well as epi-retinal membrane formation and, rarely, exudative retinal detachment. Management ranges from observation to surgical intervention, although definitive treatment guidelines have yet to be established. In addition, it is important for the eye care practitioner to be aware of the association with VHL disease, so that patients may be appropriately referred and managed for other possible systemic complications of the disease. C1 VA Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr & Nursing Home, Sepulveda, CA USA. VA Greater Los Angeles Healthcare Syst, Santa Barbara Outpatient Clin, Santa Barbara, CA USA. So Calif Coll Optometry, Fullerton, CA USA. RP Ferrucci, S (reprint author), Sepulveda VA Ambulatory Care Ctr, 16111 Plummer St 112E, Sepulveda, CA 91343 USA. NR 27 TC 3 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD JUN PY 2002 VL 79 IS 6 BP 346 EP 352 AR UNSP 1040-5488/02/7906-0346/0 DI 10.1097/00006324-200206000-00007 PG 7 WC Ophthalmology SC Ophthalmology GA 564HX UT WOS:000176309900002 PM 12086300 ER PT J AU Lyons-Wait, VA Anderson, SF Townsend, JC De Land, P AF Lyons-Wait, VA Anderson, SF Townsend, JC De Land, P TI Ocular and systemic findings and their correlation with hemodynamically significant carotid artery stenosis: A retrospective study SO OPTOMETRY AND VISION SCIENCE LA English DT Article DE amaurosis fugax; carotid artery disease; cerebrovascular accident; guidelines; hemodynamically significant carotid artery stenosis; ocular; peripheral retinal hemorrhages; retinal emboli; risk factors; stroke; systemic ID PERIPHERAL VASCULAR-DISEASE; RETINAL ISCHEMIC SYNDROMES; LOW-TENSION GLAUCOMA; RISK-FACTORS; CIGARETTE-SMOKING; ASYMPTOMATIC PATIENTS; VEIN OBSTRUCTION; OPTIC NEUROPATHY; ELDERLY PATIENTS; SURGERY PATIENTS AB Background. Optometrists often encounter patients with ocular signs and/or symptoms suggestive of carotid artery disease, but criteria for eye care practitioners concerning when to order carotid studies are not well established. A retrospective study in an optometry clinic was performed to determine if certain ocular findings and associated systemic risk factors were associated with hemodynamically significant carotid artery stenosis (HSCAS). Methods. A retrospective analysis was performed on all patients examined in the optometry clinic at the Sepulveda Ambulatory Care Center from January 1, 1998 through December 31, 1999 to identify all patients who had carotid studies ordered. Charts were then reviewed to determine the ocular finding that prompted the carotid study. Statistical analysis using an odds-ratio was performed to determine whether any ocular sign/symptom or systemic risk factor was associated with HSCAS. Results. Of 3822 patients, 48 (1.26%) had carotid studies ordered. Eight (17%) had HSCAS of >50% and symptomatic patients were 1.6 times more likely to have HSCAS than asymptomatic patients. Patients with HSCAS were 1.8 times more likely to have retinal vascular occlusions, 1.9 times more likely to have normotensive glaucoma, 2.4 times more likely to have peripheral retinal hemorrhages, and 2.6 times more likely to be smokers, although none of these factors were found to be a statistically significant indicator of HSCAS. However, the number of systemic diseases tended to be greater for the HSCAS patients compared with the non-HSCAS patients (HSCAS median = 3.5 and the non-HSCAS median = 2, p = 0.049). Conclusion. Although no single ocular or systemic risk factor was found to be a statistically significant indicator of HSCAS, the number of systemic disease risk factors tended to be greater for the HSCAS patients compared with the non-HSCAS patients (p = 0.049). An extensive literature review was also performed to help establish guidelines for when to order carotid studies on the basis of ocular signs and/or symptoms as well as the presence of additive associated systemic risk factors. C1 VA Greater Los Angeles Healthcare Syst, Sepulveda Ambulatory Care Ctr & Nursing Home, Sepulveda, CA USA. So Calif Coll Optometry, Fullerton, CA USA. VA Greater Los Angeles Healthcare Syst, Santa Barbara Community Based Outpatient Clin, Santa Barbara, CA USA. Calif State Univ Fullerton, Dept Math, Fullerton, CA USA. RP Anderson, SF (reprint author), Baltimore VAMC, 10 N Greene St,BT 112-OPT, Baltimore, MD 21201 USA. NR 82 TC 9 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-5488 J9 OPTOMETRY VISION SCI JI Optom. Vis. Sci. PD JUN PY 2002 VL 79 IS 6 BP 353 EP 362 AR UNSP 1040-5488/02/7906-0353/0 DI 10.1097/00006324-200206000-00008 PG 10 WC Ophthalmology SC Ophthalmology GA 564HX UT WOS:000176309900003 PM 12086301 ER PT J AU Mao, JR AF Mao, JR TI Translational pain research: bridging the gap between basic and clinical research SO PAIN LA English DT Review ID TOTAL ABDOMINAL HYSTERECTOMY; NMDA RECEPTOR; NEUROPATHIC PAIN; PERIPHERAL MONONEUROPATHY; ORAL DEXTROMETHORPHAN; CENTRAL SENSITIZATION; HYPERALGESIA; KETAMINE; ACTIVATION; ANTAGONIST C1 Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, MGH Pain Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Mao, JR (reprint author), Harvard Univ, Sch Med, Dept Anesthesia & Crit Care, MGH Pain Ctr,Massachusetts Gen Hosp, Boston, MA 02114 USA. FU NIDA NIH HHS [R01 DA08835] NR 29 TC 25 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUN PY 2002 VL 97 IS 3 BP 183 EP 187 AR PII S0304-3959(02)00109-4 DI 10.1016/S0304-3959(02)00109-4 PG 5 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 571LW UT WOS:000176719700001 PM 12044614 ER PT J AU Geller, AC Colditz, G Oliveria, S Emmons, K Jorgensen, C Aweh, GN Frazier, AL AF Geller, AC Colditz, G Oliveria, S Emmons, K Jorgensen, C Aweh, GN Frazier, AL TI Use of sunscreen, sunburning rates, and tanning bed use among more than 10 000 US children and adolescents SO PEDIATRICS LA English DT Article DE melanoma; skin cancer prevention; children; epidemiology ID SKIN-CANCER PREVENTION; SUN-PROTECTION; SUNLIGHT EXPOSURE; MELANOMA RISK; ULTRAVIOLET-RADIATION; CELL CARCINOMA; CHILDHOOD; PROGRAM; POPULATION; ATTITUDES AB Objectives. To describe the association of sunscreen use, sunburning, and tanning bed use by age, sex, residence, and psychosocial variables associated with tan-seeking behaviors, and to compare these findings with sun protection recommendations from federal agencies and cancer organizations. Methods. A cross-sectional study, from all 50 states, of 10 079 boys and girls 12 to 18 years of age in 1999. Data were collected from self-report questionnaires with the children of the participants from the Nurses Health Study (Growing Up Today Study). Results. The prevalence of sunscreen use was 34.4% with girls more likely to use sunscreen than boys (40.0 vs 26.4, odds ratio: 1.86; 95% confidence interval: 1.70-2.03). Eighty-three percent of respondents had at least 1 sunburn during the previous summer, and 36% had 3 or more sunburns. Nearly 10% of respondents used a tanning bed during the previous year. Girls were far more likely than boys to report tanning bed use (14.4 vs 2.4), and older girls (ages 15-18) were far more likely than younger girls (ages 12-14) to report tanning bed use (24.6% vs 4.7). Tanning bed use increased from 7% among 14-year-old girls to 16% by age 15, and more than doubled again by age 17 (35%; N=244). Multivariate analysis demonstrated that attitudes associated with tanning, such as the preference for tanned skin, having many friends who were tanned, and belief in the worth of burning to get a tan, were generally associated with sporadic sunscreen use, more frequent sunburns, and increased use of tanning beds. Conclusions. Our findings suggest that many children are at subsequent risk of skin cancer because of suboptimal sunscreen use, high rates of sunburning, and tanning bed use. Recommendations in the United States for improved sun protection and avoidance of tanning beds and sunburning, which began in the early 1990s, have been primarily unheeded. Nationally coordinated campaigns with strong policy components must be developed and sustained to prevent skin cancer in a new generation of children and adolescents. C1 Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Canc Prevent & Control Ctr, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Harvard Sch Med,Brigham & Womens Hosp, Dept Med,Channing Lab, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, Dept Med, Serv Dermatol, New York, NY 10021 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Geller, AC (reprint author), Boston Univ, Sch Med, Dept Dermatol, 720 Harrison Ave,DOB 801A, Boston, MA 02118 USA. RI Colditz, Graham/A-3963-2009 OI Colditz, Graham/0000-0002-7307-0291 FU NHLBI NIH HHS [HL03533]; NIDDK NIH HHS [DK46834] NR 44 TC 211 Z9 214 U1 2 U2 26 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 JUN PY 2002 VL 109 IS 6 BP 1009 EP 1014 DI 10.1542/peds.109.6.1009 PG 6 WC Pediatrics SC Pediatrics GA 557KE UT WOS:000175907100017 PM 12042536 ER PT J AU Lyamin, OI Shpak, OV Nazarenko, EA Mukhametov, LM AF Lyamin, OI Shpak, OV Nazarenko, EA Mukhametov, LM TI Muscle jerks during behavioral sleep in a beluga whale (Delphinapterus leucas L.) SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE sleep; paradoxical sleep; REM sleep; jerks; beluga whale; white whale; cetaceans AB We conducted video recording of the behavior of one captive adult male beluga (or white) whale over eight nights aiming to quantify muscle jerks and to evaluate their relationship to the sleep-waking cycle. Presumably, the whale was asleep during a significant portion of the time it spent lying on the bottom of the pool. Individual sleep episodes lasted between 20 and 492 s and on average occupied 66.7 +/- 2.6% of the nighttime (n = 8). Muscle jerks were quantified in the last three nights, during which an average of 144 +/- 24 jerks were documented per night. Forty-six percent of all jerks occurred within 10 s of each other. Series of jerks lasted 2-21 s (on average 4.8 +/- 0.5 s, n = 97) and in total occupied 0.3-0.7% of the rest time (0.2-0.5% of total nighttime). Jerks occurred more frequently at the end of rest episodes. A significant portion of rest episodes with jerks (62%) followed each other. These series of episodes with jerks alternated with periods when jerks were not recorded over 8-37 min. We conclude that some jerks meet the behavioral criteria of paradoxical [or rapid eye movement (REM)] sleep (PS). On the other hand, definitive conclusions about the presence and duration of this sleep stage in cetaceans cannot be reached without further combined electropolygraphic studies and visual observations. (C) 2002 Elsevier Science Inc. All rights reserved. C1 VA Greater Los Angeles Health Syst, Ctr Sleep Res 151A3, North Hills, CA 91343 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat, Los Angeles, CA 90024 USA. Severtsov Inst Ecol & Evolut, Moscow 117071, Russia. RP Lyamin, OI (reprint author), VA Greater Los Angeles Health Syst, Ctr Sleep Res 151A3, 16111 Plummer St, North Hills, CA 91343 USA. NR 29 TC 14 Z9 14 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD JUN 1 PY 2002 VL 76 IS 2 BP 265 EP 270 AR PII S0031-9384(02)00722-9 DI 10.1016/S0031-9384(02)00722-9 PG 6 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 569FY UT WOS:000176591400012 PM 12044599 ER PT J AU Cheng, SH Willmann, MR Chen, HC Sheen, J AF Cheng, SH Willmann, MR Chen, HC Sheen, J TI Calcium signaling through protein kinases. The Arabidopsis calcium-dependent protein kinase gene family SO PLANT PHYSIOLOGY LA English DT Review ID CALMODULIN-LIKE DOMAIN; MEMBRANE H+-ATPASE; SUCROSE-PHOSPHATE SYNTHASE; REGULATORY PHOSPHORYLATION SITE; PHENYLALANINE AMMONIA-LYASE; SPINACEA-OLERACEA LEAVES; LEAF NITRATE REDUCTASE; PLASMA-MEMBRANE; HIGHER-PLANTS; NADPH OXIDASE AB In plants, numerous Ca(2+)-stimulated protein kinase activities occur through calcium-dependent protein kinases (CDPKs). These novel calcium sensors are likely to be crucial mediators of responses to diverse endogenous and environmental cues. However, the precise biological function(s) of most CDPKs remains elusive. The Arabidopsis genome is predicted to encode 34 different CDPKs. In this Update, we analyze the Arabidopsis CDPK gene family and review the expression, regulation, and possible functions of plant CDPKs. By combining emerging cellular and genomic technologies with genetic and biochemical approaches, the characterization of Arabiclopsis CDPKs provides a valuable opportunity to understand the plant calcium-signaling network. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Clemson Univ, Dept Biochem & Genet, Clemson, SC 29634 USA. RP Sheen, J (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. EM sheen@molbio.mgh.harvard.edu OI Willmann, Matthew R./0000-0002-4146-8158 NR 154 TC 389 Z9 488 U1 9 U2 55 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 0032-0889 J9 PLANT PHYSIOL JI Plant Physiol. PD JUN PY 2002 VL 129 IS 2 BP 469 EP 485 DI 10.1104/pp.005645 PG 17 WC Plant Sciences SC Plant Sciences GA 565HL UT WOS:000176363800009 PM 12068094 ER PT J AU Hwang, D Chen, HC Sheen, J AF Hwang, D Chen, HC Sheen, J TI Two-component signal transduction pathways in Arabidopsis SO PLANT PHYSIOLOGY LA English DT Article ID TO-ASP PHOSPHORELAY; PSEUDO-RESPONSE REGULATORS; RECEPTOR GENE FAMILY; HISTIDINE KINASE; DIFFERENTIAL EXPRESSION; APRR1/TOC1 QUINTET; ETHYLENE RECEPTOR; PROTEIN-KINASES; TRANSCRIPTION FACTOR; CIRCADIAN-RHYTHMS AB The two-component system, consisting of a histidine (His) protein kinase that senses a signal input and a response regulator that mediates the Output, is an ancient and evolutionarily conserved signaling mechanism in prokaryotes and eukaryotes. The identification of 54 His protein kinases, His-containing phosphotransfer proteins, response regulators, and related proteins in Arabidopsis suggests an important role of two-component phosphorelay in plant signal transduction. Recent studies indicate that two-component elements are involved in plant hormone, stress, and light signaling. In this review, we present a genome analysis of the Arabidopsis two-component elements and summarize the major advances in our understanding of Arabidopsis two-component signaling. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Sheen, J (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. EM sheen@molbio.mgh.harvard FU NIGMS NIH HHS [R01 GM060493, GM 60493] NR 76 TC 54 Z9 61 U1 1 U2 12 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 0032-0889 J9 PLANT PHYSIOL JI Plant Physiol. PD JUN PY 2002 VL 129 IS 2 BP 500 EP 515 DI 10.1104/pp.005504 PG 16 WC Plant Sciences SC Plant Sciences GA 565HL UT WOS:000176363800011 PM 12068096 ER PT J AU Cui, JP Jander, G Racki, LR Kim, PD Pierce, NE Ausubel, FM AF Cui, JP Jander, G Racki, LR Kim, PD Pierce, NE Ausubel, FM TI Signals involved in Arabidopsis resistance to Trichoplusia ni caterpillars induced by virulent and avirulent strains of the phytopathogen Pseudomonas syringae SO PLANT PHYSIOLOGY LA English DT Review ID SYSTEMIC ACQUIRED-RESISTANCE; PLANT DEFENSE RESPONSES; ENHANCED DISEASE SUSCEPTIBILITY; NUCLEOTIDE-BINDING SITE; SALICYLIC-ACID; JASMONIC ACID; GENE-EXPRESSION; WOUND RESPONSE; CELL-DEATH; HYPERSENSITIVE RESPONSE AB Plants have evolved different but interconnected strategies to defend themselves against herbivorous insects and microbial pathogens. We used an Arabidopsis/Pseudomonas syringae pathosystem to investigate the impact of pathogen-induced defense responses on cabbage looper (Trichoplusia ni) larval feeding. Arabidopsis mutants [npr1, pad4, eds5, and sid2(eds16)] or transgenic plants (nahG) that are more susceptible to microbial pathogens and are compromised in salicylic acid (SA)-dependent defense responses exhibited reduced levels of feeding by T. ni compared with wild-type plants. Consistent with these results, Arabidopsis mutants that are more resistant to microbial pathogens and have elevated levels of SA (cpr1 and cpr6) exhibited enhanced levels of T. ni feeding. These experiments suggested an inverse relationship between an active SA defense pathway and insect feeding. In contrast to these results, there was increased resistance to T. ni in wild-type Arabidopsis ecotype Columbia plants that were infected with P. syringae pv. maculicola strain ES4326 (Psm ES4326) expressing the avirulence genes avrRpt2 or avrB, which elicit a hypersensitive response, high levels of SA accumulation, and systemic acquired resistance to bacterial infection. Similar results were obtained with other ecotypes, including Landsberg erecta, Cape Verdi Islands, and Shakdara. When infected with Psm ES4326(avrRpt2) or Psm ES4326(avrB), nahG transgenic and npr1 mutant plants (which are more susceptible to virulent and avirulent P. syringae strains) failed to show the increased insect resistance exhibited by wild-type plants. It was surprising that wild-type plants, as well as nahG and npr1 plants, infected with Psm ES4326 not expressing avrRpt2 or avrB, which elicits disease, became more susceptible to T. ni. Our results suggest two potentially novel systemic signaling pathways: a systemic response elicited by HR that leads to enhanced T. ni resistance and overrides the SA-mediated increase in T. ni susceptibility, and a SA-independent systemic response induced by virulent pathogens that leads to enhanced susceptibility to T. ni. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. RP Ausubel, FM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. EM ausubel@molbio.mgh.harvard RI Marion-Poll, Frederic/D-8882-2011 OI Marion-Poll, Frederic/0000-0001-6824-0180 FU NIGMS NIH HHS [GM 48707, R01 GM048707, R37 GM048707] NR 104 TC 72 Z9 72 U1 5 U2 22 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 0032-0889 J9 PLANT PHYSIOL JI Plant Physiol. PD JUN PY 2002 VL 129 IS 2 BP 551 EP 564 DI 10.1104/pp.010815 PG 14 WC Plant Sciences SC Plant Sciences GA 565HL UT WOS:000176363800015 PM 12068100 ER PT J AU Corey, E Quinn, JE Bladou, F Brown, LG Roudier, MP Brown, JM Buhler, KR Vessella, RL AF Corey, E Quinn, JE Bladou, F Brown, LG Roudier, MP Brown, JM Buhler, KR Vessella, RL TI Establishment and characterization of osseous prostate cancer models: Intra tibial injection of human prostate cancer cells SO PROSTATE LA English DT Article DE prostate cancer; bone metastasis; osteoblastic response; osteolytic response; animal model ID HORMONE-RELATED PROTEIN; PYRIDINIUM CROSS-LINKS; METASTATIC PATTERNS; BONE METASTASES; LNCAP MODEL; SCID MICE; ANTIGEN; CARCINOMA; EXPRESSION; OSTEOPROTEGERIN AB BACKGROUND. To improve the therapy of advanced prostate cancer (CaP), it is critical to develop animal models that mimic Cap bone metastases. Unlike the human disease, CaP xenograft models rarely metastasize spontaneously to bone from the orthotopic site of primary tumor growth. METHODS. Single-cell suspensions of LNCaP, PC-3, LuCaP 35, and LuCaP 23.1 CaP cells were injected directly into tibia of SCID mice. Immunohistochemistry and bone histomorphometrical analyses were performed to characterize these osseous-CaP models. RESULTS. LuCaP 23.1 Yields an osteoblastic response, LNCaP Yields mixed lesions, and LuCaP 35 and PC-3 result in osteolytic responses. We have detected osteoprotegerin, RANK ligand, parathyroid hormone-related protein, and endothelin-1, proteins associated with bone growth and remodeling, in the CaP cells grown in the bone. CONCLUSIONS. These animal models can be used to study biological interactions, pathways, and potential therapeutic targets, and also to evaluate new agents for treatment and prevention of CaP bone metastasis. (C) 2002 Wiley-Liss, Inc. C1 Univ Washington, Dept Urol, Seattle, WA 98195 USA. Hop Salvator, Marseille, France. VA Puget Sound Hlth Care Syst, Seattle, WA USA. RP Corey, E (reprint author), Univ Washington, Dept Urol, Mail Stop 356510,1959 NE Pacific St, Seattle, WA 98195 USA. FU NIDDK NIH HHS [2 P50 DK47656-07] NR 47 TC 118 Z9 121 U1 1 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0270-4137 J9 PROSTATE JI Prostate PD JUN 1 PY 2002 VL 52 IS 1 BP 20 EP 33 DI 10.1002/pros.10091 PG 14 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 556HK UT WOS:000175843200003 PM 11992617 ER PT J AU Orr, SP Metzger, LJ Pitman, RK AF Orr, SP Metzger, LJ Pitman, RK TI Psychophysiology of post-traumatic stress disorder SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Review ID EVENT-RELATED POTENTIALS; HEART-RATE-VARIABILITY; VIETNAM COMBAT VETERANS; GULF-WAR VETERANS; PHYSIOLOGICAL-RESPONSES; ANXIETY DISORDERS; LOUD TONES; CARDIOVASCULAR ACTIVITY; TRAUMATIC STIMULI; EMOTIONAL IMAGERY AB Clinical observations supporting an association between exposure to life-threatening events and altered physiologic arousal, especially overactivity or over-reactivity of the sympathetic nervous system, has made post-traumatic stress disorder (PTSD) an obvious target for psychophysiologic research. A variety of physiologic and cognitive symptoms and features of PTSD have lent themselves especially well to this type of investigation. These have included heightened responsiveness to reminders of a traumatic event, exaggerated startle, elevated autonomic arousal, hypervigilance, and concentration difficulties. Psychophysiologic and electrophysiologic findings addressing these and related issues in PTSD are reviewed. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. Dept Vet Affairs Med Ctr, Res Serv, Manchester, NH USA. RP Orr, SP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. EM scott_orr@hms.harvard.edu NR 112 TC 97 Z9 103 U1 3 U2 14 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD JUN PY 2002 VL 25 IS 2 BP 271 EP + AR PII S0193-953X(01)00007-7 DI 10.1016/S0193-953X(01)00007-7 PG 25 WC Psychiatry SC Psychiatry GA 573XJ UT WOS:000176857500003 PM 12136501 ER PT J AU Grossman, R Buchsbaum, MS Yehuda, R AF Grossman, R Buchsbaum, MS Yehuda, R TI Neuroimaging studies in post-traumatic stress disorder SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL BLOOD-FLOW; HIPPOCAMPAL PYRAMIDAL NEURONS; IMPAIRED DECLARATIVE MEMORY; SUBSTANCE-ABUSE HISTORIES; LONG-TERM POTENTIATION; CHILDHOOD SEXUAL ABUSE; SCRIPT-DRIVEN IMAGERY; HUMAN AMYGDALA; PHYSIOLOGICAL-RESPONSES AB The authors review some of the advances that have been made in understanding the structural, biochemical, and functional neuroanatomy of post-traumatic stress disorder (PTSD). First, the authors review the primary brain regions that had been hypothesized a priori, from the phenomenology and neurobiology of PTSD, to be implicated in the pathophysiology. Next, they review findings from neuroimaging studies of these brain regions in PTSD and explain the various experimental methods and imaging technologies used in these studies. A broader perspective, including a discussion of additional brain areas that may be involved in PTSD, is synthesized. The authors conclude with a rationale and approach for studies testing sharply defined hypotheses and those using multidisciplinary strategies that integrate neuroimaging data with other cognitive, biologic, and genetic tools to study this complex disorder. C1 CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. Bronx Vet Adm Med Ctr, Dept Psychiat, New York, NY 10029 USA. RP Grossman, R (reprint author), CUNY Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. FU NIMH NIH HHS [KO8 MH01653-01] NR 107 TC 28 Z9 30 U1 1 U2 10 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD JUN PY 2002 VL 25 IS 2 BP 317 EP + AR PII S0193-953X(01)00011-9 DI 10.1016/S0193-953X(01)00011-9 PG 25 WC Psychiatry SC Psychiatry GA 573XJ UT WOS:000176857500005 PM 12136503 ER PT J AU Rabois, D Batten, SV Keane, TM AF Rabois, D Batten, SV Keane, TM TI Implications of biological findings for psychological treatments of post-traumatic stress disorder SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article ID CHILDHOOD SEXUAL ABUSE; COMBAT-RELATED PTSD; HIPPOCAMPAL VOLUME; BEHAVIORAL TREATMENT; VIETNAM VETERANS; ASSAULT VICTIMS; EXPOSURE THERAPY; PROGRAM; SLEEP; PREVENTION AB The goal of this article is to initiate dialogue among those conducting research on the biological aspects of post-traumatic stress disorder (PTSD) and clinicians and researchers concerned with developing effective psychological treatments for PTSD. Important biological findings in PTSD are reviewed, paying special attention to the clinical implications of these findings. A discussion of the psychological treatments effective for PTSD follows, focusing on how these empirically supported treatments may address some of the issues raised by the biological findings. Finally, suggestions are made for future directions for psychological treatment development for this disabling condition, examining how these innovative treatment approaches may be relevant to the reviewed biological findings. C1 VA Boston Healthcare Syst, Natl Ctr PTSD, Boston, MA 02130 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Keane, TM (reprint author), VA Boston Healthcare Syst, Natl Ctr PTSD, 150 S Huntington Ave, Boston, MA 02130 USA. NR 80 TC 8 Z9 9 U1 2 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD JUN PY 2002 VL 25 IS 2 BP 443 EP + AR PII S0193-953X(01)00002-8 DI 10.1016/S0193-953X(01)00002-8 PG 21 WC Psychiatry SC Psychiatry GA 573XJ UT WOS:000176857500011 PM 12136509 ER PT J AU Belkin, GS AF Belkin, GS TI Emergency psychiatry - Self-restraint, self-examination: A historical perspective on restraints and ethics in psychiatry SO PSYCHIATRIC SERVICES LA English DT Editorial Material C1 Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Belkin, GS (reprint author), Erich Lindemann Mental Hlth Ctr, Off Med Director, 25 Staniford St, Boston, MA 02114 USA. NR 7 TC 7 Z9 7 U1 0 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD JUN PY 2002 VL 53 IS 6 BP 663 EP 664 DI 10.1176/appi.ps.53.6.663 PG 2 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 557UT UT WOS:000175927100002 PM 12045300 ER PT J AU Simon, NM Otto, MW Korbly, NB Peters, PM Nicolaou, DC Pollack, MH AF Simon, NM Otto, MW Korbly, NB Peters, PM Nicolaou, DC Pollack, MH TI Quality of life in social anxiety disorder compared with panic disorder and the general population SO PSYCHIATRIC SERVICES LA English DT Article ID OF-LIFE; FUNCTIONAL IMPAIRMENT; MEDICAL OUTCOMES; PHOBIA; DISABILITY; COMORBIDITY; MORBIDITY AB Objective: Quality of life in a treatment-seeking cohort of patients with social anxiety disorder was compared with that of patients with panic disorder who were matched for age, comorbid illnesses, and gender and with population-based norms. Methods: The study participants were 33 patients with social anxiety disorder and 33 patients with panic disorder who had participated in clinical trials and who had completed the Medical Outcomes Study Short-Form-36 (SF-36) as part of a baseline evaluation. The patients did not have significant comorbid psychiatric disorders. Paired t tests were used to compare baseline scores on subscales of the SF-36 between the two cohorts. One-sample t tests were used to compare scores on subscales of the SF-36 with expectation scores based on 2,474 persons from the general population. Results: Compared with the general population, the patients with social anxiety disorder had significantly, greater impairment as measured by the SF-36 social functioning and mental health subscales. Subscale scores also indicated poorer emotional role functioning, but the difference was not significant. However, they were significantly less impaired than the patients with panic disorder in terms of physical functioning, physical role, and mental health. Conclusions: Patients with social anxiety disorder who do not have significant comorbid depression or anxiety, are substantially impaired in quality, of life, but to a lesser extent than patients with panic disorder, who suffer from both mental and physical impairments in quality, of life. C1 Massachusetts Gen Hosp, Anxiety Disorders Program, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Simon, NM (reprint author), Massachusetts Gen Hosp, Anxiety Disorders Program, 15 Parkman St,WAC 815, Boston, MA 02114 USA. FU NIMH NIH HHS [K23-MH-01831-02] NR 35 TC 51 Z9 54 U1 0 U2 4 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 1075-2730 J9 PSYCHIATR SERV JI Psychiatr. Serv. PD JUN PY 2002 VL 53 IS 6 BP 714 EP 718 DI 10.1176/appi.ps.53.6.714 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 557UT UT WOS:000175927100010 PM 12045308 ER PT J AU Liberman, RP Glynn, S Blair, KE Ross, D Marder, SR AF Liberman, RP Glynn, S Blair, KE Ross, D Marder, SR TI In vivo amplified skills training: Promoting generalization of independent living skills for clients with schizophrenia SO PSYCHIATRY-INTERPERSONAL AND BIOLOGICAL PROCESSES LA English DT Article ID SEVERE MENTAL-ILLNESS; PSYCHOSOCIAL TREATMENT; COMMUNITY; INDIVIDUALS; MANAGEMENT; TRIAL; MODEL AB In Vivo Amplified Skills Training, IVAST, functions to bridge the gap between clinic-based skills training and use of social and independent living skills in everyday life for persons with schizophrenia and other serious and persistent mental illness. IVAST utilizes a specialist case manager who provides individualized, community-based teaching using behavioral techniques to promote clients' use of skills that were learned in classroom group sessions. The IVAST trainer also liaises with the client's psychiatrist and other clinic-based staff, family members, and community agencies to create opportunities, encouragement and reinforcement for the client's independent use of skills in the community. The aim of IVAST is to accelerate autonomous functioning of persons with mental disabilities in the community and thereby reduce their dependency on case managers and other therapists. To the extent that IVAST can empower clients to solve their own problems and attain their personal goals, enduring improvements in social role functioning and quality of life should ensue. A controlled study of IVAST has documented improvements in social adjustment when behavioral learning techniques are employed in the community settings of the clients. An IVAST case study is presented to illustrate the community-based use of medication management, symptom management, and social problem solving in the attainment of personally relevant goals. Obstacles to success of IVAST may derive from deficits in personal motivation, family involvement, community support, financial resources, premorbid functioning, and medication compliance. C1 VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Psych REHAB Program, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. RP Liberman, RP (reprint author), Univ Calif Los Angeles, Psych REHAB Program, Dept Psychiat & Biobehav Sci, 300 UCLA Med Plaza,Ste 2263, Los Angeles, CA 90095 USA. NR 49 TC 29 Z9 31 U1 1 U2 3 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0033-2747 J9 PSYCHIATRY JI Psychiatry-Interpers. Biol. Process. PD SUM PY 2002 VL 65 IS 2 BP 137 EP 155 DI 10.1521/psyc.65.2.137.19931 PG 19 WC Psychiatry SC Psychiatry GA 567TD UT WOS:000176500400005 PM 12108138 ER PT J AU Letko, E Zafirakis, P Baltatzis, S Voudouri, A Livir-Rallatos, C Foster, CS AF Letko, E Zafirakis, P Baltatzis, S Voudouri, A Livir-Rallatos, C Foster, CS TI Relapsing polychondritis: A clinical review SO SEMINARS IN ARTHRITIS AND RHEUMATISM LA English DT Review DE cartilage; relapsing polychondritis; scleritis ID COLLAGEN-INDUCED ARTHRITIS; II COLLAGEN; MYELODYSPLASTIC SYNDROMES; INFLAMED CARTILAGE; PASSIVE TRANSFER; GENITAL ULCERS; MAGIC SYNDROME; DISEASE; MANIFESTATIONS; INVOLVEMENT AB Objective: This study comprehensively reviews the literature related to relapsing polychondritis (RP). Methods: A detailed search via MEDLINE (PubMed) was performed using relapsing polychondritis as the key term. Relevant articles were analyzed with a focus on history, epidemiology, etiology, pathogenesis, clinical manifestations, diagnosis, treatment, and prognosis of RP. Results: RP is a rare episodic and progressive inflammatory disease of presumed autoimmune etiology first described in 1923, RP affects cartilage in multiple organs, such as the ear, nose, larynx, trachea, bronchi, and joints. In addition, it can affect proteoglycan-rich tissues, such as the eyes, aorta, heart, and skin. The diagnosis of RP is based on the presence of clinical criteria. A standardized therapeutic protocol for RP has not been established. Nonsteroidal anti-inflammatory drugs, dapsone and/or colchicine, may control disease activity in some patients. In other patients, immunosuppressive drugs and prednisone have been effective, RP is a potentially lethal disease; pulmonary infection, systemic vasculitis, airway collapse, and renal failure are the most common causes of death. Earlier studies indicate survival rates between 70% at 4 years and 55% at 10 years. In a recent study, a survival rate of 94% at 8 years may be due to improved medical and surgical management. Conclusions: RP is a rare, multisystemic, and potentially fatal disease. The pathogenesis and optimal therapeutic approach to patients with RP is poorly understood. C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Uveitis & Immunol Serv, Boston, MA 02114 USA. Gen Hosp Athens, Athens Med Sch, Dept Ophthalmol, Athens, Greece. RP Foster, CS (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Uveitis & Immunol Serv, 243 Charles St, Boston, MA 02114 USA. NR 91 TC 101 Z9 114 U1 2 U2 10 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0049-0172 J9 SEMIN ARTHRITIS RHEU JI Semin. Arthritis Rheum. PD JUN PY 2002 VL 31 IS 6 BP 384 EP 395 DI 10.1053/sarh.2002.32586 PG 12 WC Rheumatology SC Rheumatology GA 569EK UT WOS:000176587500005 PM 12077711 ER PT J AU Campos, S AF Campos, S TI The impact of anemia and its treatment on patients with gynecologic malignancies SO SEMINARS IN ONCOLOGY LA English DT Article; Proceedings Paper CT International Symposium on Evolving Issues in Oncology - What is the Optimal Hemoglobin CY 2000 CL SEVILLE, SPAIN ID EPITHELIAL OVARIAN-CANCER; QUALITY-OF-LIFE; PHASE-II TRIAL; ONCOLOGY-GROUP; STAGE-III; CHEMOTHERAPY PATIENTS; COMMUNITY ONCOLOGY; 2ND-LINE TREATMENT; RANDOMIZED TRIAL; EPOETIN-ALPHA C1 Dana Farber Canc Ctr, Dept Med Oncol, Boston, MA 02115 USA. RP Campos, S (reprint author), Dana Farber Canc Ctr, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. NR 33 TC 12 Z9 14 U1 1 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 2002 VL 29 IS 3 SU 8 BP 7 EP 12 DI 10.1053/sonc.2002.33526 PG 6 WC Oncology SC Oncology GA 568TW UT WOS:000176561000003 PM 12082647 ER PT J AU Schneider, JW Chang, AY Garratt, A AF Schneider, JW Chang, AY Garratt, A TI Trastuzumab cardiotoxicity: Speculations regarding pathophysiology and targets for further study SO SEMINARS IN ONCOLOGY LA English DT Review ID NEUREGULIN RECEPTOR; CARDIAC DEVELOPMENT; BREAST-CANCER; ERBB4; ONCOPROTEIN; EXPRESSION; ANTIBODIES; KINASES C1 VA Boston Healthcare Syst, Dept Med, Div Cardiol, W Roxbury, MA 02132 USA. Harvard Univ, Sch Med, W Roxbury, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Gen Internal Med, Boston, MA 02115 USA. Max Delbruck Ctr Mol Med, Dept Med Genet, Berlin, Germany. RP Schneider, JW (reprint author), VA Boston Healthcare Syst, Dept Med, Div Cardiol, 1400 VFW Pkwy, W Roxbury, MA 02132 USA. RI Garratt, Alistair/D-9893-2013 OI Garratt, Alistair/0000-0001-9631-3041 NR 17 TC 36 Z9 37 U1 0 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 2002 VL 29 IS 3 SU 11 BP 22 EP 28 DI 10.1053/sonc.2002.34051 PG 7 WC Oncology SC Oncology GA 578AT UT WOS:000177095800004 PM 12138394 ER PT J AU Ligibel, JA Winer, EP AF Ligibel, JA Winer, EP TI Trastuzumab/chemotherapy combinations in metastatic breast cancer SO SEMINARS IN ONCOLOGY LA English DT Review ID FIRST-LINE CHEMOTHERAPY; PROSPECTIVE RANDOMIZED TRIAL; MONOCLONAL-ANTIBODY; PHASE-II; ADJUVANT THERAPY; OVARIAN-CANCER; VINORELBINE; DOXORUBICIN; RECEPTOR; WOMEN C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Winer, EP (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 48 TC 50 Z9 53 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD JUN PY 2002 VL 29 IS 3 SU 11 BP 38 EP 43 DI 10.1053/sonc.2002.34054 PG 6 WC Oncology SC Oncology GA 578AT UT WOS:000177095800006 PM 12138396 ER PT J AU Bauer, KA AF Bauer, KA TI Selective inhibition of coagulation factors: Advances in antithrombotic therapy SO SEMINARS IN THROMBOSIS AND HEMOSTASIS LA English DT Article DE anticoagulants; fondaparinux; heparin; pentasaccharide; thrombosis ID MOLECULAR-WEIGHT HEPARIN; TISSUE FACTOR PATHWAY; TICK ANTICOAGULANT PEPTIDE; FACTOR-XA INHIBITOR; AMERICAN-HEART-ASSOCIATION; HEALTH-CARE PROFESSIONALS; TOTAL HIP-REPLACEMENT; DEEP-VEIN THROMBOSIS; BLOCKED FACTOR-IXA; BLOOD-COAGULATION AB Heparin and coumarin derivatives have long been used for the prophylaxis and treatment of venous thromboembolism (VTE). Although they have demonstrated efficacy and safety, they act at multiple targets within the coagulation cascade and their efficacy is influenced by many patient variables. Because of the need to improve the benefit-to-risk ratio of antithrombotic drugs, newer agents that target single coagulation factors have been developed. These include selective factor Xa inhibitors, direct thrombin inhibitors (DTIs), and inhibitors of factor IXa and the factor VII-tissue factor complex. Three DTIs-hirudin, bivalirudin, and argatroban-have been approved for clinical use. Fondaparinux, a novel pentasaccharide and the first selective factor Xa inhibitor to be approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products, is indicated for the prevention of VTE after major orthopedic surgery. Fondaparinux has predictable pharmacokinetics, is almost 100% bioavailable, and has a half-life that allows once-daily dosing in all indications. In addition, the routine monitoring of standard indicators of hemostasis is not required. The availability of these agents and the continued development of investigational selective coagulation inhibitors have the potential to improve efficacy and decrease adverse events in patients at risk for VTE. C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. VA Boston Healthcare Syst, Boston, MA USA. RP Bauer, KA (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. NR 81 TC 21 Z9 21 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0094-6176 J9 SEMIN THROMB HEMOST JI Semin. Thromb. Hemost. PD JUN PY 2002 VL 28 SU 2 BP 15 EP 24 DI 10.1055/s-2002-32313 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 566QQ UT WOS:000176440100003 PM 12073176 ER PT J AU Hau, MA Kim, JI Kattapuram, S Hornicek, FJ Rosenberg, AE Gebhardt, MC Mankin, HJ AF Hau, MA Kim, JI Kattapuram, S Hornicek, FJ Rosenberg, AE Gebhardt, MC Mankin, HJ TI Accuracy of CT-guided biopsies in 359 patients with musculoskeletal lesions SO SKELETAL RADIOLOGY LA English DT Article DE biopsy; needle; bone; soft tissue; tumor; accuracy ID PERCUTANEOUS NEEDLE-BIOPSY; SOFT-TISSUE TUMORS; COMPUTED-TOMOGRAPHY; VERTEBRAL BIOPSY; PRIMARY BONE; SPINE; ASPIRATION; DIAGNOSIS; NEOPLASMS AB The study was undertaken to assess the diagnostic accuracy and clinical usefulness of computed tomography (CT)-guided biopsies and fine needle aspirates of musculoskeletal lesions. The analysis compared the accuracy according to anatomical location, size, type of lesion, and histology. On the basis of the information obtained by reviewing the report of the CT biopsy and comparing it with the final diagnosis for 359 cases, the overall accuracy was determined to be 71%. The accuracy for 101 fine needle aspirations was 63% and for 258 CT-guided core biopsies was 74%. It is of note that the biopsies of 81 pelvic lesions had higher rates of diagnostic accuracy (81%) than those of 278 non-pelvic sites (68%), and especially 94 lesions of the spine (61%). The lowest success rates occurred in 26 patients with infectious diseases (50%). We conclude that these procedures remain the logical and safe choice for diagnostic studies of patients with lesions of the musculoskeletal system. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Oncol Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02114 USA. RP Mankin, HJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed Surg,Oncol Serv, Boston, MA 02114 USA. NR 34 TC 68 Z9 74 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD JUN PY 2002 VL 31 IS 6 BP 349 EP 353 DI 10.1007/s00256-002-0474-3 PG 5 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 568AF UT WOS:000176519700004 PM 12073119 ER PT J AU Catlin, DH Leder, BZ Ahrens, BD Hatton, CK Finkelstein, JS AF Catlin, DH Leder, BZ Ahrens, BD Hatton, CK Finkelstein, JS TI Effects of androstenedione administration on epitestosterone metabolism in men SO STEROIDS LA English DT Article DE androstenedione; epitestosterone; steroids; metabolism; doping; testosterone/epitestosterone ratio ID HUMAN TESTIS; STEROIDS; DEHYDROEPIANDROSTERONE; SECRETION; EXCRETION AB Androstenedione is a steroid hormone sold over-the-counter to individuals who expect that it will enhance strength and athletic performance. Endogenous androstenedione is the immediate precursor of testosterone. To evaluate the metabolism of oral androstenedione, we randomly assigned 37 healthy men to receive 0 (group 1), 100 mg (group 2), or 300 mg (group 3) of androstenedione in a single daily dose for 7 days. Eight-hour urines were collected I day before the start of androstenedione, and on days 1 and 7. Using gas chromatography-mass spectrometry, we measured excretion rates of glucuronide-conjugated epitestosterone, its putative precursor (E-precursor), and metabolites (EM-1 and EM-2), and we evaluated possible markers of androstenedione administration. Day I and 7 rates were not different: the means were averaged. The means (mug/h) for groups 1, 2, and 3, respectively were, for epitestosterone 2.27, 7.74, and 18.0; for E-precursor, 2.9, 2.0, and 1.5; for EM-1/E-precursor 0.31, 1.25, and 2.88; for EM-2/E-precursor 0.14, 0.15, and 1.15; for testosterone/epitestosterone (T/E) 1.1, 3.5, and 3.2. Epitestosterone, EM-1, and EM-2 excretion was greater in groups 2 and 3 versus group 1 (0.0001 < P < 0.03), as were EM-1/E-precursor, EM-2/E-precursor, and T/E. E-precursor excretion was lower in groups 2 (P = 0.08) and 3 (P = 0.047) versus group 1. Androstenedione increases excretion of epitestosterone and its two metabolites, while decreasing that of its precursor. Elevated ratios of EM-1- and EM-2/E-precursor, and the presence of 6alpha-hydroxyandrostenedione are androstenedione administration markers. (C) 2002 Elsevier Science Inc. All rights reserved. C1 Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Olymp Analyt Lab, Los Angeles, CA 90025 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90025 USA. Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. RP Catlin, DH (reprint author), Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Olymp Analyt Lab, Los Angeles, CA 90025 USA. FU NCRR NIH HHS [RR-1066]; NIDDK NIH HHS [K24 DK02759] NR 30 TC 15 Z9 18 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD JUN PY 2002 VL 67 IS 7 BP 559 EP 564 AR PII S0039-128X(02)00005-3 DI 10.1016/S0039-128X(02)00005-3 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 564UE UT WOS:000176331300003 PM 11996927 ER PT J AU Willers, H Romanova, L Krivacek, C Dahm-Daphi, J Powell, S Xia, F AF Willers, H Romanova, L Krivacek, C Dahm-Daphi, J Powell, S Xia, F TI Regulation of homologous DNA recombination by the tumor suppressor gene p53: analysis of mechanisms SO STRAHLENTHERAPIE UND ONKOLOGIE LA English DT Meeting Abstract CT 8th Meeting of the Deutschen-Gesellschaft-fur-Radioonkologie CY JUN 29-JUL 02, 2002 CL BERLIN, GERMANY SP Deutsch Gesell Radioonkol C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Hamburg, Krankenhaus Eppendorf, Abt Radioonkol, D-20246 Hamburg, Germany. NR 0 TC 0 Z9 0 U1 1 U2 1 PU URBAN & VOGEL PI MUNICH PA NEUMARKTER STRASSE 43, D-81673 MUNICH, GERMANY SN 0179-7158 J9 STRAHLENTHER ONKOL JI Strahlenther. Onkol. PD JUN PY 2002 VL 178 SU 1 BP 17 EP 17 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 570LK UT WOS:000176659600069 ER PT J AU Sarr, MG Warshaw, AL AF Sarr, MG Warshaw, AL TI Editorial: Industry-sponsored studies - What are our responsibilities as investigators and as editors? SO SURGERY LA English DT Editorial Material C1 Mayo Clin & Mayo Fdn, Div Gastroenterol & Gen Surg, GI Res Unit, Rochester, MN 55905 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Sarr, MG (reprint author), Mayo Clin & Mayo Fdn, Div Gastroenterol & Gen Surg, GI Res Unit, 200 1st St SW,AL 2-435, Rochester, MN 55905 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD JUN PY 2002 VL 131 IS 6 BP 594 EP 594 DI 10.1067/msy.2002.125348 PG 1 WC Surgery SC Surgery GA 569LE UT WOS:000176603200002 ER PT J AU Walsh, DS AF Walsh, DS TI Perspectives of a woman resident SO SURGERY LA English DT Article ID SURGICAL RESIDENTS; TRAINING-PROGRAM; ATTRITION C1 Massachusetts Gen Hosp, Surg HST, Boston, MA 02114 USA. RP Walsh, DS (reprint author), Massachusetts Gen Hosp, Surg HST, 55 Fruit St, Boston, MA 02114 USA. NR 10 TC 0 Z9 0 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0039-6060 J9 SURGERY JI Surgery PD JUN PY 2002 VL 131 IS 6 BP 666 EP 669 DI 10.1067/msy.2002.124881 PG 4 WC Surgery SC Surgery GA 569LE UT WOS:000176603200013 PM 12075181 ER PT J AU Stock, UA Vacanti, JP Mayer, JE Wahlers, T AF Stock, UA Vacanti, JP Mayer, JE Wahlers, T TI Tissue engineering of heart valves - Current aspects SO THORACIC AND CARDIOVASCULAR SURGEON LA English DT Review DE tissue engineering; heart valves; scaffold; autologous cells ID MICROVASCULAR ENDOTHELIAL-CELLS; SMALL-INTESTINAL SUBMUCOSA; PULMONARY-ARTERY; VASCULAR GRAFTS; GROWTH-FACTOR; LONG-TERM; IN-VITRO; IDENTIFICATION; PROLIFERATION; POLYMERS AB Tissue engineering of heart valves is an evolving research field. Driven by the shortcomings of the heart valve substitutes currently available, such as need for anticoagulation, susceptibility to infections, inability to grow and autorepair, the multidisciplinary approach for designing and growing viable heart valves identical to the native heart valves has begun. The following will give an update of the recent developments, current limitations and potential future applications of tissue-engineered heart valves. C1 Univ Jena, Dept Thorac & Cardiovasc Surg, D-07743 Jena, Germany. Harvard Univ, Sch Med, Childrens Hosp, Dept Cardiovasc Surg, Boston, MA USA. Harvard Univ, Sch Med, Ctr Integrat Med & Innovat Technol, Boston, MA USA. Harvard Univ, Sch Med, Dept Surg, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Stock, UA (reprint author), Univ Jena, Dept Thorac & Cardiovasc Surg, D-07743 Jena, Germany. NR 76 TC 34 Z9 40 U1 1 U2 3 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0171-6425 J9 THORAC CARDIOV SURG JI Thorac. Cardiovasc. Surg. PD JUN PY 2002 VL 50 IS 3 BP 184 EP 193 DI 10.1055/s-2002-32406 PG 10 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 571CH UT WOS:000176696900014 PM 12077696 ER PT J AU Spector, M AF Spector, M TI Novel cell-scaffold interactions encountered in tissue engineering: Contractile behavior of musculoskeletal connective tissue cells SO TISSUE ENGINEERING LA English DT Review ID SMOOTH-MUSCLE ACTIN; ANTERIOR CRUCIATE LIGAMENT; COLLAGEN-GAG MATRICES; HUMAN ARTICULAR CHONDROCYTES; IN-VITRO; WOUND CONTRACTION; GLYCOSAMINOGLYCAN SCAFFOLDS; FIBROBLAST CONTRACTION; BIOSYNTHETIC ACTIVITY; EXTRACELLULAR-MATRIX AB Methods employed in the course of tissue engineering often offer unique opportunities to observe cell-matrix interactions that cannot otherwise be viewed. These observations may provide insights into cell behavior than can contribute important new knowledge about cell biology. One such set of observations led to the discoveries that musculoskeletal connective tissue cells express a contractile muscle actin isoform, a-smooth muscle actin, and can contract. This knowledge may help to explain how these cells generate forces required for certain physiological and pathological functions, and this information may inform future approaches to regulate this function to advance tissue engineering. Tissue engineering science is thus emerging as an importance force that can both contribute to cell and molecular biology and add to the fund of knowledge supporting the production of tissue in vitro or in vivo to improve the management of a wide variety of disorders. C1 Harvard Univ, Brigham & Womens Hosp, Dept Orthoped Surg, Sch Med, Boston, MA 02115 USA. Va Boston Healthcare Syst, W Roxbury, MA USA. RP Spector, M (reprint author), Harvard Univ, Brigham & Womens Hosp, Dept Orthoped Surg, Sch Med, MRB 106,75 Francis St, Boston, MA 02115 USA. NR 58 TC 21 Z9 20 U1 0 U2 4 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD JUN PY 2002 VL 8 IS 3 BP 351 EP 357 DI 10.1089/107632702760184628 PG 7 WC Cell & Tissue Engineering SC Cell Biology GA 570UW UT WOS:000176677800001 PM 12167222 ER PT J AU Balis, UJ Yarmush, ML Toner, M AF Balis, UJ Yarmush, ML Toner, M TI Bioartificial liver process monitoring and control systems with integrated systems capability SO TISSUE ENGINEERING LA English DT Article ID CONTINUOUS FERMENTATION PROCESS; ADAPTIVE PREDICTIVE CONTROL; SANDWICH CONFIGURATION; OXYGEN; HEPATOCYTES; CELLS AB Monitoring and control of a bioartificial liver (BAL) support system have the potential to allow for maximization of device bioactivity and protection of both patient and device from untoward consequences of a complex hemoperfused fluidic process, such as coagulation, leakage, or decreased metabolic output. In this work, an integrated embedded systems controller and associated experimental platform were developed to allow for simultaneous monitoring and control of the physical environment of the BAL support system to ensure optimal and sustained hepatic metabolic function and to allow for simplified recording of experimental data. The user interface and core embedded system kernel were developed with rapid prototyping software tools and allowed for operation of easily modified user interface panels. BAL environment monitoring consisted of real-time recording of ambient and reactor temperatures, reactor inlet pressure, the presence of bubbles in the prereactor inlet tubing, and aqueous oxygen tension. Environmental parameters under direct real-time control included reactor inlet flow rate, ambient temperature, and adaptive control of flow rate in response to changes in either inlet pressure or outlet oxygen tension. Use of embedded system integration techniques will facilitate subsequent BAL studies that are dependent on scale-up of reactor size and number, fluidic complexity, and the degree of parallelism such as large animal studies and, ultimately, human clinical studies. In addition, further studies of the effects of flow rate, shear, oxygenation and metabolic substrate on real-time cellular respiration can be pursued with the use of real-time ruthenium oxymetry, as described in this article. C1 Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Surg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Shriners Hosp Children, Boston, MA USA. RP Toner, M (reprint author), Massachusetts Gen Hosp, Ctr Engn Med, Bigelow 1401,55 Fruit St, Boston, MA 02114 USA. NR 19 TC 3 Z9 3 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD JUN PY 2002 VL 8 IS 3 BP 483 EP 498 DI 10.1089/107632702760184736 PG 16 WC Cell & Tissue Engineering SC Cell Biology GA 570UW UT WOS:000176677800012 PM 12167233 ER PT J AU Rigotti, NA Regan, S Majchrzak, NE Knight, JR Wechsler, H AF Rigotti, NA Regan, S Majchrzak, NE Knight, JR Wechsler, H TI Tobacco use by Massachusetts public college students: long term effect of the Massachusetts Tobacco Control Program SO TOBACCO CONTROL LA English DT Article ID CIGARETTE USE AB Objective: To assess tobacco use among Massachusetts public college students and compare students who attended high school in Massachusetts and were exposed to the Massachusetts Tobacco Control Program (MTCP) with students who attended high school outside Massachusetts and were unexposed to the programme. Design: Analysis of the 1999 Massachusetts College Alcohol Survey. Setting: Four year public colleges and universities in Massachusetts (n = 11). Subjects: 1252 randomly selected students (response rate 56%). Main outcome measures: Self report of current (post 30 day), post year, and lifetime use of cigarettes, cigars, and smokeless tobacco. Results: One third of students had used a tobacco product in the past month and 46.4% had used tobacco in the post year. Cigarettes accounted for most of this tobacco use. Total tobacco use was higher among males than females but cigarette smoking did not differ by sex. Tobacco use was lower among athletes and higher among students who used alcohol or marijuana. Current tobacco use was lower among public college students who had attended high school in Massachusetts compared with those who attended high school in another state (31.5% v 42.6%, p = 0,006) This difference persisted after adjustment for age, sex, race, parental education, and students' college residence (adjusted odds ratio (OR) 0.67, 95% confidence interval (CI) 0.46 to 0.97, p = 0.034). Conclusion: Tobacco use is common among Massachusetts public college students. Students who, were exposed to the MTCP during high school are less likely to use tobacco than their peers who were not exposed to this programme. The MTCP may have reduced tobacco use among this group of young adults. C1 Massachusetts Gen Hosp, Div Gen Med, Tobacco Res & Treatment Ctr, Boston, MA 02114 USA. RP Rigotti, NA (reprint author), Massachusetts Gen Hosp, Div Gen Med, Tobacco Res & Treatment Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. NR 14 TC 0 Z9 0 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD JUN PY 2002 VL 11 SU 2 BP II20 EP II24 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 564JT UT WOS:000176311800005 PM 12034976 ER PT J AU Todd, R Margolin, DH AF Todd, R Margolin, DH TI Challenges of single-cell diagnostics: analysis of gene expression SO TRENDS IN MOLECULAR MEDICINE LA English DT Editorial Material ID LASER-CAPTURE MICRODISSECTION; AMPLIFICATION; PCR; TISSUE; CDNA; SAGE AB Analysis of single-cell gene expression promises a more precise understanding of human disease pathogenesis and important diagnostic applications. Here, we review the rationale for the study of gene expression at the single-cell level, practical methods to isolate homogeneous or single-cell samples, and current approaches to the analysis of single-cell gene expression. Finally, we highlight applications of laser microdissection-based gene expression analysis to the study of human disease and clinical diagnosis. C1 Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. RP Todd, R (reprint author), Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, 188 Longwood Ave, Boston, MA 02115 USA. FU NIAID NIH HHS [AI-01587, AI-45370]; NIDCR NIH HHS [K02 DE 00456, R29 DE 11983] NR 25 TC 24 Z9 25 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD JUN PY 2002 VL 8 IS 6 BP 254 EP 257 AR PII S1471-4914(02)02350-X DI 10.1016/S1471-4914(02)02350-X PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 557VB UT WOS:000175928000004 PM 12067605 ER PT J AU Platz, EA Smit, E Curhan, GC Nyberg, LM Giovannucci, E AF Platz, EA Smit, E Curhan, GC Nyberg, LM Giovannucci, E TI Prevalence of and racial/ethnic variation in lower urinary tract symptoms and noncancer prostate surgery in US men SO UROLOGY LA English DT Article ID HIGH-RISK GROUP; HYPERPLASIA; HYPERTROPHY; ETHNICITY; LIFE AB Objectives. To estimate the proportion of U.S. men affected by specific lower urinary tract symptoms (LUTS) and to assess whether the prevalence of LUTS varies by race/ethnicity. Methods. Included were 30+-year-old men who took part in the Third National Health and Nutrition Examination Survey. Men were asked whether they experienced nocturia, incomplete emptying, or hesitancy. Men 60+ years old were also asked whether they had a decreased urinary stream or had ever undergone noncancer prostate surgery. To obtain the estimated prevalences for the U.S. population, we applied sampling fraction weights, We calculated age-adjusted odds ratios (ORs) of 3+ symptoms or surgery by race/ethnicity using logistic regression analysis. Results. Only nocturia was common in 30 to 59-year-old men. Among men who had not had prostate surgery, 59.9% of men 60 to 69 years old and 75.1% of men 70+ years old had at least one symptom. All four symptoms were reported by 3.0% of men 60 to 69 years and 5.6% of men 70+ years old. Of the men 60 to 69 years old and men 70+ years old, 8.0% and 22.4%, respectively, reported having undergone surgery. In men 60+ years old, the age-adjusted OR for either having 3+ symptoms or surgery was 0.8 for non-Hispanic black men compared with non-Hispanic white men. The odds of having 3+ symptoms (OR = 1.6), but not surgery (OR = 1.1), appeared greater for Mexican-American men than for non-Hispanic white men. Conclusions. Specific LUTS are common in older U.S. men, Older black men were not more likely to have LUTS than were older white men. The apparent modestly higher prevalence of LUTS in older Mexican-American men requires additional study, (C) 2002, Elsevier Science Inc. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. SUNY Buffalo, Sch Med, Dept Social & Prevent Med, Buffalo, NY 14260 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NIDDKD, Div Kidney Urol & Hematol Dis, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Channing Lab, Dept Med, Boston, MA USA. Brigham & Womens Hosp, Boston, MA USA. RP Platz, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St,Room E6143, Baltimore, MD 21205 USA. NR 25 TC 86 Z9 88 U1 1 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 JUN PY 2002 VL 59 IS 6 BP 877 EP 883 DI 10.1016/S0090-4295(01)01673-9 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 554UG UT WOS:000175755100018 PM 12031373 ER PT J AU Hathaway, JE Willis, G Zimmer, B AF Hathaway, JE Willis, G Zimmer, B TI Listening to survivors' voices - Addressing partner abuse in the health care setting SO VIOLENCE AGAINST WOMEN LA English DT Article ID DOMESTIC VIOLENCE; WOMENS EXPERIENCES; MEDICAL-CARE; PANDORA BOX; PHYSICIANS; ATTITUDES; INTERVENTION; CLINICIAN; VICTIMS AB To understand how providers can address partner abuse more effectively, the authors conducted semistructured interviews with 49 clients of a hospital-based domestic violence (DV) program. Due to the potentially grave consequences survivors face for disclosing abuse, it often took the right combination of circumstances in their lives and/or the presence of an understanding and caring provider for them to disclose. Following disclosure, survivors frequently found referral to the in-house DV program most helpful, along with other emotional and practical support. Findings from this study reveal additional ways in which health care providers call respond more effectively to this pervasive problem. C1 Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. Massachusetts Gen Hosp, HAVEN, Boston, MA 02114 USA. RP Hathaway, JE (reprint author), Massachusetts Gen Hosp, Inst Hlth Policy, Boston, MA 02114 USA. NR 24 TC 42 Z9 42 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1077-8012 J9 VIOLENCE AGAINST WOM JI Violence Against Women PD JUN PY 2002 VL 8 IS 6 SI SI BP 687 EP 719 DI 10.1177/10778010222183242 PG 33 WC Women's Studies SC Women's Studies GA 553HJ UT WOS:000175669400005 ER PT J AU Dong, LQ Ramos, FJ Wick, MJ Lim, MA Guo, ZM Strong, R Richardson, A Liu, F AF Dong, LQ Ramos, FJ Wick, MJ Lim, MA Guo, ZM Strong, R Richardson, A Liu, F TI Cloning and characterization of a testis and brain-specific isoform of mouse 3 '-phosphoinositide-dependent protein kinase-1, mPDK-1 beta SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID AGE-1 PI3 KINASE; INSULIN-RECEPTOR; TYROSINE PHOSPHORYLATION; CAENORHABDITIS-ELEGANS; NERVOUS-SYSTEM; EXPRESSION; IDENTIFICATION; TRANSCRIPTS; ACTIVATION; PATHWAYS AB 3'-Phosphoinositide-dependent protein kinase-1 (PDK-1) phosphorylates and activates members of the protein kinase AGC family and plays a key role in receptor tyrosine kinase signaling. Here we report the cloning and characterization of a splice variant of mouse PDK-1, mPDK-1beta. The cDNA encoding mPDK-1beta contains two alternative start codons and translation from these start codons generates proteins that are, respectively, 27 or 51 amino acid residues shorter at the amino-terminus than the previously identified PDK-1 isolated from mouse liver (now renamed mPDK-1alpha) [J. Biol. Chem. 274 (1999) 8117]. Analysis of mouse tissues shows that mPDK-1beta is highly expressed in the testis and various functional regions of the brain. Expression of this isoform is increased in the brain of aged mice. Both mPDK-1alpha and mPDK-1beta are autophosphorylated at both serine and threonine residues in vitro and showed similar levels of tyrosine phosphorylation when co-expressed with either constitutively active Src or Fyn tyrosine kinases in cells. However, the mPDK-1 isoforms showed significant differences in their response to pervanadate- or insulin plus vanadate-stimulated tyrosine phosphorylation. Taken together, our findings suggest that the two PDK-1 isoforms may be differentially regulated in cells. The specific expression of mPDK-1beta in mouse testis and brains of aged mice also suggests potential involvement of this kinase in regulating animal spermatogenesis and aging. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Audie L Murphy Div, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78229 USA. RP Dong, LQ (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NIA NIH HHS [P03 AG13319]; NIDDK NIH HHS [DK56166, DK52543] NR 32 TC 9 Z9 9 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 31 PY 2002 VL 294 IS 1 BP 136 EP 144 AR PII S0006-291X(02)00449-7 DI 10.1016/S0006-291X(02)00449-7 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 563BU UT WOS:000176234500023 PM 12054753 ER PT J AU Terai, H Hannouche, D Ochoa, E Yamano, Y Vacanti, JP AF Terai, H Hannouche, D Ochoa, E Yamano, Y Vacanti, JP TI In vitro engineering of bone using a rotational oxygen-permeable bioreactor system SO MATERIALS SCIENCE & ENGINEERING C-BIOMIMETIC AND SUPRAMOLECULAR SYSTEMS LA English DT Article; Proceedings Paper CT International Conference on Materials for Advanced Technologies (ICMAT2001) CY JUL 01-06, 2001 CL SINGAPORE, SINGAPORE DE bioreactor; tissue engineering; bone; in vitro; partial gas pressure ID BIODEGRADABLE POLYMER; IN-VITRO; SCAFFOLDS; CULTURE AB Tissue engineering of bone may supersede the need in the future of autograft procedures to treat bone defects resulting from trauma or developmental diseases. A Rotational Oxygen-Permeable Bioreactor System (ROBS) has recently been developed in our laboratory to reproduce dynamic and gas-permeable culture conditions that would supply optimal oxygen and continuous loading to cell/polymer constructs in culture. The cell culture media in ROBS were examined at 1, 24 and 48 h to evaluate the kinetics of pO(2), pCO(2) and pH without culturing cells. The results were compared to the kinetics in 100 mm diameter cell culture dishes (Control I: static, gas permeable) and 50 ml centrifuge tubes (Control II: dynamic, non-gas permeable). The results showed the same kinetics in ROBS and Control I, whereas Control II failed to maintain the gas conditions of the media. Next, osteoblasts derived from mesenchymal stromal cells (MSCs) of neonatal rats were cultured in three-dimensional poly(DL-lactide-co-glycolide) (PLGA) foams using ROBS to study the effectiveness of this bioreactor system to support cell growth and differentiation. Mineralization was observed within 2 weeks of culture and was shown throughout the polymer at 7 weeks with embedded osteocytic cells. This study demonstrates the usefulness of ROBS for in vitro bone tissue engineering. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Dept Surg, Lab Tissue Engn & Organ Fabricat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Ctr Integrat Med & Innovat Technol, Boston, MA 02114 USA. RP Vacanti, JP (reprint author), Massachusetts Gen Hosp, Dept Surg, Lab Tissue Engn & Organ Fabricat, Boston, MA 02114 USA. NR 14 TC 55 Z9 58 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0928-4931 J9 MAT SCI ENG C-BIO S JI Mater. Sci. Eng. C-Biomimetic Supramol. Syst. PD MAY 31 PY 2002 VL 20 IS 1-2 SI SI BP 3 EP 8 AR PII S0928-4931(02)00006-1 DI 10.1016/S0928-4931(02)00006-1 PG 6 WC Materials Science, Multidisciplinary SC Materials Science GA 560NM UT WOS:000176088200002 ER PT J AU Wang, LX Saint-Pierre, DH Tache, Y AF Wang, LX Saint-Pierre, DH Tache, Y TI Peripheral ghrelin selectively increases Fos expression in neuropeptide Y - synthesizing neurons in mouse hypothalamic arcuate nucleus SO NEUROSCIENCE LETTERS LA English DT Article DE ghrelin; neuropeptide Y expression; Fos; arcuate nucleus; food intake; mouse ID HORMONE SECRETAGOGUE RECEPTOR; ACYLATED PEPTIDE; FOOD-INTAKE; LEAN MICE; RATS; STOMACH; HUMANS; INJECTION; LEPTIN; BRAIN AB Ghrelin, a peptide isolated from the rat stomach, is the endogenous ligand of the growth hormone-secretagogue receptor and also known to have orexigenic effect. We examined the influence of intraperitoneal (i.p.) injection of ghrelin on food intake and brain neuronal activity in freely fed mice. Ghrelin (3, 10 or 30 mug/mouse) dose-dependently increased food intake by 0.8-,1.6-and 2.6-fold, respectively, at 30 min post injection. Ghrelin (10 mug/mouse) induces Fos expression selectively in the ventromedial part of the hypothalamic arcuate nucleus (Arc). No change in Fos expression was observed in other hypothalamic and hindbrain nuclei. About 90% of the Fos-positive neurons in the Arc expressed neuropeptide Y (NPY) messenger RNA. These data indicate that NPY neurons in the Arc are likely the primary target mediating i.p. ghrelin induced orexigenic effect. (C) 2002 Published by Elsevier Science Ireland Ltd. C1 Univ Calif Los Angeles, CURE, Digest Dis Res Ctr,Dept Med, VA Greater Los Angeles Healthcare Syst,Digest Dis, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90073 USA. Univ Montreal, Fac Med Vet, St Hyacinthe, PQ J2S 2M2, Canada. RP Wang, LX (reprint author), Univ Calif Los Angeles, CURE, Digest Dis Res Ctr,Dept Med, VA Greater Los Angeles Healthcare Syst,Digest Dis, Bldg 115,Room 203,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK41301, R01 DK 30110] NR 23 TC 227 Z9 232 U1 0 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAY 31 PY 2002 VL 325 IS 1 BP 47 EP 51 AR PII S0304-3940(02)00241-0 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 559HX UT WOS:000176021700012 PM 12023064 ER PT J AU Morita, M Ho, M Hosler, BA McKenna-Yasek, D Brown, RH AF Morita, M Ho, M Hosler, BA McKenna-Yasek, D Brown, RH TI A novel mutation in the spastin gene in a family with spastic paraplegia SO NEUROSCIENCE LETTERS LA English DT Article DE hereditary spastic paraplegia; SPG4; spastin; mutation; cryptic acceptor site ID CHROMOSOME 2P; SPG4 GENE; LOCUS; INSERTION; SPECTRUM; LINKAGE; FORM AB Hereditary spastic paraplegia (HSP) is a degenerative neuromuscular disease characterized by progressive lower extremity weakness, spasticity and hyperreflexia. Inheritance of HSP is commonly autosomal dominant, spastin was identified as the defective gene in chromosome 2p-linked autosomal dominant hereditary spastic paraplegia (AD-HSP). In a large American family with AD-HSP, we have identified a novel spastin mutation at a splice-acceptor site in intron 6 (1130-1 g --> a) and detected a corresponding aberrant transcript generated from a cryptic splice site. This is predicted to cause a frameshift and premature truncation of the abnormal spastin protein. Our data are the first to confirm that a mutation in an acceptor site in the spastin gene results in activation of a cryptic acceptor site and a translational frameshift. The clinical phenotype of this pedigree is also discussed. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved. C1 Jichi Med Sch, Dept Neurol, Minami Kawachi, Tochigi 3290498, Japan. Massachusetts Gen Hosp East, Cecil B Day Lab Neuromuscular Res, Charlestown, MA 02129 USA. RP Morita, M (reprint author), Jichi Med Sch, Dept Neurol, 3311-1 Yakushiji, Minami Kawachi, Tochigi 3290498, Japan. FU NIA NIH HHS [1P01AG12992]; NINDS NIH HHS [R01NS37912] NR 20 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAY 31 PY 2002 VL 325 IS 1 BP 57 EP 61 AR PII S0304-3940(02)00239-2 DI 10.1016/S0304-3940(02)00239-2 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 559HX UT WOS:000176021700014 PM 12023066 ER PT J AU Sheen, J AF Sheen, J TI Phosphorelay and transcription control in cytokinin signal transduction SO SCIENCE LA English DT Editorial Material ID HISTIDINE KINASE; ARABIDOPSIS-THALIANA; RESPONSE REGULATORS; ASP PHOSPHORELAY; PLANTS; GENES; EXPRESSION; MOLECULE; RECEPTOR; FAMILY AB The past decade has seen substantial advances in knowledge of molecular mechanisms and actions of plant hormones, but only in the past few years has research on cytokinins begun to hit its stride. Cytokinins are master regulators of a large number of processes in plant development, which is known to be unusually plastic and adaptive, as well as resilient and perpetual. These characteristics allow plants to respond sensitively and quickly to their environments. Recent studies have demonstrated that cytokinin signaling involves a multistep two-component signaling pathway, resulting in the development of a canonical model of cytokinin signaling that is likely representative in plants. This Viewpoint outlines this genera[ model, focusing on the specific example of Arabidopsis, and introduces the STKE Connections Maps for both the canonical module and the specific Arabidopsis Cytokinin Signaling Pathway. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Sheen, J (reprint author), Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. EM sheen@molbio.mgh.harvard.edu NR 31 TC 61 Z9 63 U1 1 U2 6 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 MAY 31 PY 2002 VL 296 IS 5573 BP 1650 EP 1652 DI 10.1126/science.1071883 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 558PR UT WOS:000175976200046 PM 12040183 ER PT J AU Ziefer, P Leung, J Razzano, T Shalish, C LeDoux, MS Lorden, JF Ozelius, L Breakefield, XO Standaert, DG Augood, SJ AF Ziefer, P Leung, J Razzano, T Shalish, C LeDoux, MS Lorden, JF Ozelius, L Breakefield, XO Standaert, DG Augood, SJ TI Molecular cloning and expression of rat torsinA in the normal and genetically dystonic (dt) rat SO MOLECULAR BRAIN RESEARCH LA English DT Article DE dystonia; TorsinA; cDNA clone ID MESSENGER-RNAS; HUMAN BRAIN; GENE DYT1; PREDICTION; FORMS; CELLS AB Deletions within the TOR I A gene cause early-on set (DYT1) torsion dystonia. We have cloned and sequenced the rat cDNA homologue of TOR1A and found a 91% identity with the human sequence. Northern blot analysis detects a single transcript of approximately 1.5 kb. In situ hybridization reveals a widespread distribution of torsinA mRNA within brain. No mutations were identified in the coding region of the gene in the genetically dystonic (dt) rat. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Univ Freiburg, Dept Neurol, D-79106 Freiburg, Germany. Massachusetts Gen Hosp, Mol Neurogenet Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Univ Tennessee, Ctr Hlth Sci, Dept Neurol, Memphis, TN 38163 USA. Univ Alabama, Dept Psychol, Birmingham, AL 35294 USA. RP Ziefer, P (reprint author), Univ Freiburg, Dept Neurol, Neurozentrum Breisacher str 64, D-79106 Freiburg, Germany. EM ziefer@ukl.uni-freiburg.de OI Standaert, David/0000-0003-2921-8348 NR 23 TC 9 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD MAY 30 PY 2002 VL 101 IS 1-2 BP 132 EP 135 AR PII S0169-328X(02)00176-6 DI 10.1016/S0169-328X(02)00176-6 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 560NN UT WOS:000176088300016 ER PT J AU Ge, K Guermah, M Yuan, CX Ito, M Wallberg, AE Spiegelman, BM Roeder, RG AF Ge, K Guermah, M Yuan, CX Ito, M Wallberg, AE Spiegelman, BM Roeder, RG TI Transcription coactivator TRAP220 is required for PPAR gamma 2-stimulated adipogenesis SO NATURE LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTOR; PPAR-GAMMA; NUCLEAR RECEPTORS; COMPLEX; PROTEIN; MEDIATOR; DIFFERENTIATION; COMPONENT; TRAP/SMCC; REGULATOR AB The TRAP (thyroid hormone receptor-associated proteins) transcription coactivator complex (also known as Mediator) was first isolated as a group of proteins that facilitate the function of the thyroid hormone receptor(1). This complex interacts physically with several nuclear receptors through the TRAP220 subunit, and with diverse activators through other subunits(2). TRAP220 has been reported to show ligand-enhanced interaction with peroxisome proliferator-activated receptor gamma(2) (PPARgamma2)(3,4),a nuclear receptor essential for adipogenesis(5-8). Here we show that Trap220(-/-) fibroblasts are refractory to PPARgamma(2-)stimulated adipogenesis, but not to MyoD-stimulated myogenesis, and do not express adipogenesis markers or PPARgamma2 target genes. These defects can be restored by expression of exogenous TRAP220. Further indicative of a direct role for TRAP220 in PPARgamma2 function via the TRAP complex, TRAP functions directly as a transcriptional coactivator for PPARgamma2 in a purified in vitro system and interacts with PPARgamma2 in a ligand- and TRAP220-dependent manner. These data indicate that TRAP220 acts, via the TRAP complex, as a PPARgamma2-selective coactivator and, accordingly, that it is specific for one fibroblast differentiation pathway (adipogenesis) relative to another (myogenesis). C1 Rockefeller Univ, Biochem & Mol Biol Lab, New York, NY 10021 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Roeder, RG (reprint author), Rockefeller Univ, Biochem & Mol Biol Lab, 1230 York Ave, New York, NY 10021 USA. NR 30 TC 216 Z9 230 U1 3 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 30 PY 2002 VL 417 IS 6888 BP 563 EP 567 DI 10.1038/417563a PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 556QK UT WOS:000175860300046 PM 12037571 ER PT J AU Hajjar, RJ Kradin, RL Januzzi, JL Mark, EJ AF Hajjar, RJ Kradin, RL Januzzi, JL Mark, EJ TI A 55-year-old man with second-degree atrioventricular block and chest pain - Lymphocytic myocarditis due to Borrelia burgdorferi infection (Lyme disease). SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID CARDIAC INVOLVEMENT; CORONARY-ARTERIES; AV BLOCK; PREVALENCE; DIAGNOSIS; HEART; HEMOCHROMATOSIS; ABNORMALITIES; MRI C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Hajjar, RJ (reprint author), Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NR 36 TC 18 Z9 18 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 30 PY 2002 VL 346 IS 22 BP 1732 EP 1738 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 556DM UT WOS:000175834100009 PM 12037154 ER PT J AU Mukamal, KJ Maclure, M Muller, JE Sherwood, JB Mittleman, MA AF Mukamal, KJ Maclure, M Muller, JE Sherwood, JB Mittleman, MA TI Tea consumption and myocardial mortality after acute infarction SO CIRCULATION LA English DT Article; Proceedings Paper CT 24th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 02-05, 2001 CL SAN DIEGO, CALIFORNIA SP Soc Gen Internal Med DE mortality; myocardial infarction; nutrition ID CORONARY-HEART-DISEASE; LOW-DENSITY-LIPOPROTEIN; PLATELET-AGGREGATION; ARTERY DISEASE; FOLLOW-UP; RISK; FLAVONOIDS; COFFEE; ANTIOXIDANT; ATHEROGENESIS AB Background-Some studies have suggested that tea consumption may be associated with lower mortality among individuals with cardiovascular disease, but the effects of tea consumption on mortality after acute myocardial infarction are unknown. Methods and Results-As part of the Determinants of Myocardial Infarction Onset Study, we performed a prospective cohort study of 1900 patients hospitalized with a confirmed acute myocardial infarction between 1989 and 1994, with a median follow-up of 3.8 years. Trained interviewers assessed self-reported usual weekly caffeinated tea consumption during the year before infarction with a standardized questionnaire. We compared long-term mortality according to tea consumption using Cox proportional hazards regression. Of the 1900 patients, 10 19 consumed no tea (nondrinkers), 615 consumed < 14 cups per week (moderate tea drinkers), and 266 consumed 14 or more cups per week (heavy tea drinkers). Compared with nondrinkers, age- and sex-adjusted mortality was lower among moderate tea drinkers (hazard ratio, 0.69; 95% Cl, 0.53 to 0.89) and heavy tea drinkers (hazard ratio, 0.61; 95% Cl, 0.42 to 0.86). Additional adjustment for clinical and sociodemographic characteristics did not appreciably alter this association (hazard ratio, 0.72; 95% Cl, 0.55 to 0.94 for moderate tea drinkers; hazard ratio, 0.56; 95%, Cl, 0.37 to 0.84 for heavy tea drinkers). The association of tea and mortality was similar for total and cardiovascular mortality. Conclusions-Self-reported tea consumption in the year before acute myocardial infarction is associated with lower mortality after infarction. C1 Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. RP Mukamal, KJ (reprint author), Beth Israel Deaconess Med Ctr, Div Gen Med & Primary Care, 330 Brookline Ave,LY-303, Boston, MA 02215 USA. FU NHLBI NIH HHS [R01HL41016]; NIAAA NIH HHS [K23AA00299] NR 32 TC 108 Z9 119 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 28 PY 2002 VL 105 IS 21 BP 2476 EP 2481 DI 10.1161/01.CIR.0000017201.88994.F7 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 557UX UT WOS:000175927500013 PM 12034652 ER PT J AU Packer, RJ Gutmann, DH Rubenstein, A Viskochil, D Zimmerman, RA Vezina, G Small, J Korf, B AF Packer, RJ Gutmann, DH Rubenstein, A Viskochil, D Zimmerman, RA Vezina, G Small, J Korf, B TI Plexiform neurofibromas in NF1 - Toward bliologic-based therapy SO NEUROLOGY LA English DT Article ID NERVE SHEATH TUMORS; CELL NUCLEAR ANTIGEN; SCHWANN-CELLS; MALIGNANT-TRANSFORMATION; EXPRESSION; TYPE-1; GENE; BENIGN; MODEL; P53 AB Neurofibromatosis type 1 (NF1) is one of the most common neurogenetic diseases affecting adults and children. Neurofibromas are one of the most common of the protean manifestations of NF1. Plexiform neurofibromas, which will frequently cause cosmetic abnormalities, pain, and neurologic deficits, are composed of "neoplastic" Schwann cells accompanied by other participating cellular and noncellular components. There is increasing evidence that loss of NF1 expression in neoplastic Schwann cells is associated with elevated levels of activated RAS, supporting the notion that the NF1 gene product, neurofibromin, acts as a growth regulator by inhibiting ras growth-promoting activity. In addition, there is increasing evidence that other cooperating events, which may be under cytokine modulation, are important for neurofibroma development and growth. Treatment of plexiform neurofibromas has been empiric, with surgery being the primary option for those with progressive lesions causing a major degree of morbidity. The efficacy of alternative treatment approaches, including the use of antihistamines, maturation agents, and antiangiogenic drugs, has been questionable. More recently, biologic-based therapeutic approaches, using drugs that target the molecular genetic underpinnings of plexiform neurofibromas or cytokines believed important in tumor growth, have been initiated. Evaluation of such trials is hindered by the unpredictable natural history of plexiform neurofibromas and difficulties in determining objective response in tumors that are notoriously large and irregular in shape. Innovative neuroimaging techniques and the incorporation of quality-of-life scales may be helpful in evaluation of therapeutic interventions. The ability to design more rational therapies for NF1-associated neurofibromas is heavily predicated on an improved understanding of the molecular and cellular biology of the cells involved in neurofibroma formation and growth. C1 George Washington Univ, Childrens Natl Med Ctr, Ctr Neurosci & Behav Med, Dept Neurol, Washington, DC 20010 USA. George Washington Univ, Childrens Natl Med Ctr, Dept Radiol Neuroradiol, Washington, DC 20010 USA. Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63178 USA. St Louis Childrens Hosp, Neurofibromatosis Program, St Louis, MO 63178 USA. Mt Sinai Sch Med, Dept Neurol, New York, NY USA. Natl Neurofibromatosis Fdn, New York, NY USA. Univ Utah, Dept Pediat, Salt Lake City, UT USA. Childrens Hosp, Dept Radiol Neuroradiol, Philadelphia, PA 19104 USA. Univ Penn, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Harvard Partners Ctr Genet & Genom, Boston, MA 02114 USA. RP Packer, RJ (reprint author), George Washington Univ, Childrens Natl Med Ctr, Ctr Neurosci & Behav Med, Dept Neurol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM rpacker@cnmc.org NR 54 TC 91 Z9 92 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD MAY 28 PY 2002 VL 58 IS 10 BP 1461 EP 1470 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 555LC UT WOS:000175794700004 PM 12041525 ER PT J AU Delgado, JC Tsai, EY Thim, S Baena, A Boussiotis, VA Reynes, JM Sath, S Grosjean, P Yunis, EJ Goldfeld, AE AF Delgado, JC Tsai, EY Thim, S Baena, A Boussiotis, VA Reynes, JM Sath, S Grosjean, P Yunis, EJ Goldfeld, AE TI Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SKIN-TEST ANTIGENS; T-CELL ANERGY; OLIGONUCLEOTIDE HYBRIDIZATION; EXOGENOUS REINFECTION; HIV-INFECTION; HLA; SUSCEPTIBILITY; ASSOCIATION; PREVALENCE; RESPONSES AB Purified protein derivative (PPD) skin testing is used to identify persons infected with Mycobacterium tuberculosis (Mtb) and to assess cell-mediated immune responses to Mtb. However, lack of skin induration to intradermal injection of PPD or PPD anergy is observed in a subset of patients with active tuberculosis (TB). To investigate the sensitivity and persistence of PPD reactivity and its in vitro correlates during active TB disease and after successful chemotherapy, we evaluated the distribution of skin size induration after intradermal injection of PPD among 364 pulmonary TB patients in Cambodia. A subset of 25 pulmonary TB patients who had a positive skin reaction to mumps and/or candida antigens showed persistent anergy to PPD after successful completion of TB therapy. Strikingly, in vitro stimulation of T cells from persistently anergic TB patients with mumps but not PPD resulted in T cell proliferation, and lower levels of IL-2 and IFN-gamma and higher levels of IL-10 were detected in PPD-stimulated cellular cultures from PPD-anergic as compared with PPD-reactive pulmonary TB patients. These results show that anergy to PPD is antigen-specific and persistent in a subset of immunocompetent pulmonary TB patients and is characterized by antigen-specific impaired T cell proliferative responses and a distinct pattern of cytokine production including reduced levels of IL-2. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Stanford Med Ctr, Palo Alto, CA 94303 USA. Cambodian Hlth Comm, Phnom Penh, Cambodia. Inst Pasteur Cambodge Phnom Penh, Phnom Penh, Cambodia. Dana Farber Canc Inst, Div Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Div Canc Immunol, Boston, MA 02115 USA. Inst Pasteur Madagascar, Antananarivo, Malagasy Republ. RP Goldfeld, AE (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RI Reynes, Jean-Marc/M-6108-2014 FU NHLBI NIH HHS [HL-59838, R01 HL059838] NR 33 TC 73 Z9 73 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 28 PY 2002 VL 99 IS 11 BP 7576 EP 7581 DI 10.1073/pnas.062056099 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 557KW UT WOS:000175908600047 PM 12032325 ER PT J AU Cretin, N Iacomini, J AF Cretin, N Iacomini, J TI Immunoglobulin heavy chain transgenic mice expressing Gal alpha(1,3)Gal-reactive antibodies SO TRANSPLANTATION LA English DT Article ID ANTI-GAL ANTIBODY; RETROVIRAL GENE-THERAPY; B-CELL TOLERANCE; NATURAL ANTIBODIES; MIXED CHIMERISM; LYMPHOID-CELLS; KNOCKOUT MOUSE; HUMAN SERUM; REJECTION; PIG AB Background. Natural antibodies that bind the carbohydrate antigen Galalpha1-3Galbeta1-4GlcNAc-R (alphaGal) mediate rigorous rejection of porcine xenografts and represent a major immunological hurdle to successful discordant xenotransplantation. However, little is known about how production of antibodies specific for alphaGal is regulated. Methods. Transgenic mice expressing an IgM heavy chain isolated from a B-cell hybridoma that produces antibodies specific for alphaGal were constructed. These mice were bred to mutant mice that lack the alphaGal epitope (GT(0) mice) or wild-type (GT(+)) mice to generate animals in which the transgene is expressed in the presence or absence of alphaGal as a "self"-antigen. Development of transgene-expressing B cells and production of alphaGal-specific serum antibodies were then analyzed in transgenic mice on GT(0) and GT(+) backgrounds. Results. B cells expressing the transgenic heavy chain and transgene-encoded serum antibodies specific for aGal were readily detected in mice on the GT(0) background. Most alphaGal-reactive antibodies in GT(0) mice used the transgene rather than endogenous Ig heavy chains. In contrast, transgene-encoded serum antibodies specific for alphaGal were not detected in GT(+) mice. In transgenic mice on the GT(+) background, B cells expressing the transgene underwent deletion as a result of encountering alphaGal during their development, indicating that expression of alphaGal as part of self-mediated efficient negative selection of B cells expressing transgene-encoded alphaGal-specific antibodies. Conclusions. The development of transgenic mice expressing a B cell receptor specific for alphaGal provides a novel system to study developmental regulation of B cells making carbohydrate-specific antibodies. In addition, these mice may be useful for examining methods to prevent production of alphaGal-reactive antibodies. C1 Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Iacomini, J (reprint author), Massachusetts Gen Hosp, Transplantat Biol Res Ctr, 149 13th St, Boston, MA 02129 USA. FU NIAID NIH HHS [R01 AI44268] NR 35 TC 2 Z9 2 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 MAY 27 PY 2002 VL 73 IS 10 BP 1558 EP 1564 AR UNSP 0041-1337/02/7310-1558/0 DI 10.1097/00007890-200205270-00007 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 560WN UT WOS:000176104500007 PM 12042640 ER PT J AU Lee, H Cusick, RA Browne, F Kim, TH Ma, PX Utsunomiya, H Langer, R Vacanti, JP AF Lee, H Cusick, RA Browne, F Kim, TH Ma, PX Utsunomiya, H Langer, R Vacanti, JP TI Local delivery of basic fibroblast growth factor increases both angiogenesis and engraftment of hepatocytes in tissue-engineered polymer devices SO TRANSPLANTATION LA English DT Article ID TRANSPLANTATION AB Background. We investigated heterotopic hepatocyte transplantation on biodegradable polymers as a potential treatment for end-stage liver disease. The primary problem has been insufficient engraftment of transplanted cells partly because of insufficient vascularization. Increasing vascularization through locally delivered angiogenic factors may increase angiogenesis and hepatocyte engraftment. Methods. We studied the effect of local delivery of basic fibroblast growth factor (bFGF) on angiogenesis and hepatocyte engraftment within tissue-engineered liver constructs. Poly-L-lactic acid discs were fabricated and coated with either a mixture of saline, sucralfate, and Hydron (control group) or bFGF, sucralfate, and Hydron (bFGF group). bFGF release from polymers in vitro was tested using an ELISA. Hepatocytes were isolated from Lewis rats, seeded on control (n=9) or bFGF (n=11) polymers, and implanted into the small bowel mesentery of syngeneic animals. Specimens were harvested after 2 weeks and analyzed for hepatocyte engraftment. Microvascular density was compared between control (n=6) and bFGF groups (n=5). Results. Three hundred twenty-three thousandths of a microgram of bFGF were incorporated per polymer. Greater than 99% of the bFGF was released into solution by 72 hr in vitro. Two weeks after implantation, microvascular density, as measured by capillaries per high-powered field (c/hpf), was significantly greater in the bFGF group (43.8 c/hpf), compared with the control group (30.5 c/hpf, P<0.005). Specimens from the bFGF group (mean engraftment, 61,355 mum(2)) showed a 2.5-fold increase in hepatocyte engraftment as compared with control (24,197 mum(2); P<0.002). Conclusions. The angiogenic growth factor bFGF can be incorporated into degradable polymers used as delivery devices for hepatocyte transplantation. Implantation of these devices increases angiogenesis into the device and increases hepatocyte engraftment. C1 Univ Calif San Francisco, Fetal Treatment Ctr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. Childrens Hosp, Dept Surg Res, Boston, MA USA. MIT, Dept Chem Engn, Cambridge, MA USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. RP Lee, H (reprint author), Univ Calif San Francisco, Fetal Treatment Ctr, 513 Parnassus Suite HSW 1601, San Francisco, CA 94143 USA. RI Ma, Peter/E-4895-2011 NR 17 TC 92 Z9 97 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAY 27 PY 2002 VL 73 IS 10 BP 1589 EP 1593 AR UNSP 0041-1337/02/7310-1589/0 DI 10.1097/00007890-200205270-00011 PG 5 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 560WN UT WOS:000176104500011 PM 12042644 ER PT J AU Gorry, PR Zhang, CS Wu, S Kunstman, K Trachtenberg, E Phair, J Wolinsky, S Gabuzda, D AF Gorry, PR Zhang, CS Wu, S Kunstman, K Trachtenberg, E Phair, J Wolinsky, S Gabuzda, D TI Persistence of dual-tropic HIV-1 in an individual homozygous for the CCR5 Delta 32 allele SO LANCET LA English DT Article ID INFECTION AB Entry of HIV-1 into a cell happens only after viral envelope glycoproteins have bound to CD4 and a chemokine receptor. Generally, macrophage-tropic strains use CCR5, and T cell-line-tropic strains use CXCR4 as coreceptors for virus entry. Dual-tropic viruses can use both CCR5 and CXCR4. About 1% of white people are homozygous for a non-functional CCR5 allele, containing a 32 base pair deletion (CCR5Delta32). We studied the persistence of dual-tropic HIV-1. In an individual homozygous for this deletion. Our results suggest that structural features of the HIV-1 envelope linked to CCR5 tropism could confer a selective advantage in vivo. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. RP Gabuzda, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. RI Wolinsky, Steven/B-2893-2012 FU NCI NIH HHS [CA79458]; NIAID NIH HHS [P30 AI28691, UO1 AI35039]; NINDS NIH HHS [R01 NS37277] NR 5 TC 47 Z9 48 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 25 PY 2002 VL 359 IS 9320 BP 1832 EP 1834 DI 10.1016/S0140-6736(02)08681-6 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 555CK UT WOS:000175775500015 PM 12044382 ER PT J AU Hecht, FM Busch, MP Rawal, B Webb, M Rosenberg, E Swanson, M Chesney, M Anderson, J Levy, J Kahn, JO AF Hecht, FM Busch, MP Rawal, B Webb, M Rosenberg, E Swanson, M Chesney, M Anderson, J Levy, J Kahn, JO TI Use of laboratory tests and clinical symptoms for identification of primary HIV infection SO AIDS LA English DT Article DE acute infection; HIV diagnostic tests; HIV-1 RNA assays; p24 antigen; primary HIV symptoms ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEALTH-CARE WORKERS; SEXUAL TRANSMISSION; RISK-FACTORS; VIRAL LOAD; TYPE-1; BLOOD AB Objective: To determine the sensitivity and specificity of symptoms, three HIV-1 RNA assays, a p24 antigen EIA and a third-generation enzyme immunoassay (EIA) antibody test for diagnosis of primary HIV infection (PHI). Design: Prospective cohort in a university research program. Participants: Of 258 eligible persons screened for PHI, 40 had primary/early infection (22 preseroconversion, 18 within 6 months of seroconversion) and 218 did not. Seven participants with preseroconversion HIV-1 from a second center were added for evaluating laboratory tests. Main outcome measure: PHI, defined as a negative or indeterminate antibody test with subsequent conversion. Symptom analysis also included persons with antibody conversion of less than 6 months' duration. Results: The symptoms most strongly associated with PHI in multivariate analysis were fever odds ratio (OR) 3.2; 95% confidence interval (0) 2.3-11.71 and rash (OR 4.8; 95% Cl 2.4-9.8). The sensitivity and specificity, respectively, for detecting preseroconversion HIV infection were: p24 antigen, 79% and 99%; third-generation EIA, 79% and 97%; HIV-1 RNA by branched chain DNA 100% and 95%; HIV-1 RNA by polymerase chain reaction 100% and 97%; HIV-1 RNA by transcription-mediated amplification testing, 100% and 98%. False-positive HIV-1 RNA tests were not reproducible and had values < 3000 copies/ml, while only one person with confirmed PHI was in this range. Conclusions: Rash and fever indicated the highest risk of PHI. HIV-1 RNA tests are very sensitive for PHI but false-positive results occur. False-positive results can be reduced through duplicate testing and considering tests < 5000 copies/ml as indeterminate results requiring additional testing. p24 antigen was more specific than HIV-1 RNA testing but less sensitive. (C) 2002 Lippincott Williams Wilkins. C1 Univ Calif San Francisco, San Francisco Gen Hosp, HIV Sect, Posit Hlth Program, San Francisco, CA 94110 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94110 USA. Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94110 USA. Univ Calif San Francisco, Inst Canc Res, San Francisco, CA 94110 USA. Blood Ctr Pacific, San Francisco, CA 94110 USA. Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Hecht, FM (reprint author), UCSF, Posit Hlth Program, 995 Potrero Ave,Ward 84, San Francisco, CA 94110 USA. FU NIAID NIH HHS [AI41531]; NIMH NIH HHS [P30 MH59037]; ODCDC CDC HHS [UC64/CCU91394] NR 28 TC 155 Z9 162 U1 3 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 24 PY 2002 VL 16 IS 8 BP 1119 EP 1129 DI 10.1097/00002030-200205240-00005 PG 11 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 554WR UT WOS:000175760600005 PM 12004270 ER PT J AU de Caestecker, MP Bottomley, M Bhattacharyya, S Payne, TL Roberts, AB Yelick, PC AF de Caestecker, MP Bottomley, M Bhattacharyya, S Payne, TL Roberts, AB Yelick, PC TI The novel type I serine-threonine kinase receptor Alk8 binds TGF-beta in the presence of TGF-beta RII SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE activin-like kinase receptor (Alk); serine-threonine kinases; transforming growth factor-beta (TGF-beta); cell signaling pathways ID GROWTH-FACTOR-BETA; FUNCTIONAL-CHARACTERIZATION; ACTIVIN; ZEBRAFISH; ACTIVATION; IDENTIFICATION; SPECIFICITY; SIGNALS AB The TGF-beta superfamily consists of an array of ligands including BMP, TGF-beta, activin, and nodal subfamilies. The extensive range of biological effects elicited by TGF-beta family signaling is due in part to the large numbers and promiscuity of types I and II TGF-beta family member receptors. Alk8 is a novel type I TGF-beta family member receptor first identified in zebrafish [Dev. Dyn. 211 (4) (1998) 352], which participates in BMP signaling pathways [Development 128 (6) (2001) 849; Development 128 (6) (2001) 859 Mech. Dev. 100 (2) (2001) 275; J. Dent. Res. 80 (11) (2001) 1968]. Here we report that Alk8 also forms active signaling complexes with TGF-beta in the presence of TGF-betaRII These results expand the signaling repertoire of zAlk8 by demonstrating an ability to participate in two distinct TGF-beta subfamily signaling pathways. (C) 2002 Elsevier Science (USA). All rights reserved. C1 Forsyth Inst, Dept Oral Biol, Dept Cytokine Biol & Harvard Forsyth, Boston, MA 02115 USA. Vanderbilt Univ, Sch Med, Div Nephrol, Nashville, TN 37232 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Yelick, PC (reprint author), Forsyth Inst, Dept Oral Biol, Dept Cytokine Biol & Harvard Forsyth, 140 The Fenway, Boston, MA 02115 USA. NR 29 TC 7 Z9 7 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 24 PY 2002 VL 293 IS 5 BP 1556 EP 1565 AR PII S0006-291X(02)00424-2 DI 10.1016/S0006-291X(02)00424-2 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 560YA UT WOS:000176107900040 PM 12054694 ER PT J AU Aikawa, R Huggins, GS Snyder, RO AF Aikawa, R Huggins, GS Snyder, RO TI Cardiomyocyte-specific gene expression following recombinant adeno-associated viral vector transduction SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADENOASSOCIATED VIRUS VECTORS; HEAVY-CHAIN GENE; SARCOPLASMIC-RETICULUM CA2+-ATPASE; REPLICATION-DEFECTIVE ADENOVIRUS; LEFT-VENTRICULAR FUNCTION; COAGULATION-FACTOR-IX; IMMUNE-RESPONSE; IN-VIVO; GROWTH-HORMONE; DILATED CARDIOMYOPATHY AB Recombinant adeno-associated viral (rAAV) vectors hold promise for delivering genes for heart diseases, but cardiac-specific expression by the use of rAAV has not been demonstrated. To achieve this goal rAAV vectors were generated expressing marker or potentially therapeutic genes under the control of the cardiac muscle-specific alpha myosin heavy chain (MHC) gene promoter. The rAAV-MHC vectors expressed in primary cardiomyocytes with similar kinetics to rAAV-CMV; however, expression by the rAAV-MHC vectors was restricted to cardiomyocytes. rAAV vectors have low cytotoxicity, and it is demonstrated here that rAAV fails to induce apoptosis in cardiomyocytes compared with a recombinant adenoviral vector. rAAV-MHC or rAAV-CMV vectors were administered to mice to determine the specificity of expression in vivo. The rAAV-MHC vectors expressed specifically in cardiomyocytes, whereas the control rAAV-CMV vector expressed in heart, skeletal muscle, and brain. rAAV-MHC transduction resulted in long term (16 weeks) expression of human growth hormone following intracardiac, yet not intramuscular, injection. Finally, we defined the minimal MHC enhancer/promoter sequences required for specific and robust in vivo expression in the context of a rAAV vector. For the first time we describe a panel of rAAV vectors capable of long term cardiac specific expression of intracellular and secreted proteins. C1 Harvard Univ, Sch Publ Hlth, Cardiovasc Biol Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Massachusetts Gen Hosp, Cardiac Unit, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Huggins, GS (reprint author), Harvard Univ, Sch Publ Hlth, Cardiovasc Biol Lab, 677 Huntington Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [R01 HL54592-06, R01 HL054592] NR 58 TC 34 Z9 37 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 24 PY 2002 VL 277 IS 21 BP 18979 EP 18985 DI 10.1074/jbc.M201257200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 558PM UT WOS:000175975800096 PM 11889137 ER PT J AU Fu, X Tan, PZ Kula, NS Baldessarini, R Tamagnan, G Innis, RB Baldwin, RM AF Fu, X Tan, PZ Kula, NS Baldessarini, R Tamagnan, G Innis, RB Baldwin, RM TI Synthesis, receptor potency, and selectivity of halogenated diphenylpiperidines as serotonin 5-HT2A ligands for PET or SPECT brain imaging SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RAT-BRAIN; BINDING; ALTANSERIN; DOPAMINE; F-18 AB A series of 4'-substituted phenyl-4-piperidinylmethanol and benzoyl-4-piperidine derivatives was synthesized as potential novel serotonin 5-HT2A receptor ligands that can be radiolabeled for in vivo brain imaging. Compounds were. prepared by alkylation of 4-substituted benzoyl-4-piperidine with an iodo- or fluoro-substituted phenylalkyl halide followed by reduction with sodium borohydride. Potency of novel compounds was determined by in vitro radioreceptor affinity assays selective for serotonin 5-HT2A receptors. Potent compounds were further evaluated for selectivity at serotonin-2A versus 2C, 6, and 7, as well as dopamine D-2 and adrenergic alpha(1) and alpha(2) receptors. The novel compound (4-fluorophenyl)-(1-[2-(4-fluorophenyl)ethyl] piperidin-4-yl])methanol was particularly promising with high 5-HT2A potency (K-i = 1.63 nM) and >300-fold selectivity over other 5-HT receptor types. C1 Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. VA Connecticut Hlth Care Serv, West Haven, CT 06516 USA. Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02478 USA. Harvard Univ, Sch Med, Program Neurosci, Belmont, MA 02478 USA. Massachusetts Gen Hosp, McLean Div, McLean Res Ctr, Labs Psychiat Res, Belmont, MA 02478 USA. RP Baldwin, RM (reprint author), Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. FU NIMH NIH HHS [MH-58620, MH-47370, MH-34006] NR 20 TC 8 Z9 9 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 23 PY 2002 VL 45 IS 11 BP 2319 EP 2324 DI 10.1021/jm0200411 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 554AY UT WOS:000175711700022 PM 12014970 ER PT J AU Rebbeck, TR Lynch, HT Neuhausen, SL Narod, SA van't Veer, L Garber, JE Evans, G Isaacs, C Daly, MB Matloff, E Olopade, OI Weber, BL AF Rebbeck, TR Lynch, HT Neuhausen, SL Narod, SA van't Veer, L Garber, JE Evans, G Isaacs, C Daly, MB Matloff, E Olopade, OI Weber, BL CA Prevention Observation Surg End Po TI Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PRIMARY PERITONEAL CARCINOMA; PAPILLARY SEROUS CARCINOMA; BREAST-CANCER RISK; OVARIAN-CANCER; ORAL-CONTRACEPTIVES; WOMEN AB Background: Data concerning the efficacy of bilateral prophylactic oophorectomy for reducing the risk of gynecologic cancer in women with BRCA1 or BRCA2 mutations are limited. We investigated whether this procedure reduces the risk of cancers of the coelomic epithelium and breast in women who carry such mutations. Methods: A total of 551 women with disease-associated germ-line BRCA1 or BRCA2 mutations were identified from registries and studied for the occurrence of ovarian and breast cancer. We determined the incidence of ovarian cancer in 259 women who had undergone bilateral prophylactic oophorectomy and in 292 matched controls who had not undergone the procedure. In a subgroup of 241 women with no history of breast cancer or prophylactic mastectomy, the incidence of breast cancer was determined in 99 women who had undergone bilateral prophylactic oophorectomy and in 142 matched controls. The length of postoperative follow-up for both groups was at least eight years. Results: Six women who underwent prophylactic oophorectomy (2.3 percent) received a diagnosis of stage I ovarian cancer at the time of the procedure; two women (0.8 percent) received a diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9 percent) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. With the exclusion of the six women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial cancer (hazard ratio, 0.04; 95 percent confidence interval, 0.01 to 0.16). Of 99 women who underwent bilateral prophylactic oophorectomy and who were studied to determine the risk of breast cancer, breast cancer developed in 21 (21.2 percent), as compared with 60 (42.3 percent) in the control group (hazard ratio, 0.47; 95 percent confidence interval, 0.29 to 0.77). Conclusions: Bilateral prophylactic oophorectomy reduces the risk of coelomic epithelial cancer and breast cancer in women with BRCA1 or BRCA2 mutations. (N Engl J Med 2002;346:1616-22.) Copyright (C) 2002 Massachusetts Medical Society. C1 Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Canc, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Abramson Family Canc Inst, Philadelphia, PA 19104 USA. Creighton Univ, Omaha, NE 68178 USA. Univ Utah, Div Genet Epidemiol, Salt Lake City, UT USA. Womens Coll Hosp, Toronto, ON M5S 1B2, Canada. Netherlands Canc Inst, Amsterdam, Netherlands. Dana Farber Canc Inst, Boston, MA 02115 USA. St Marys Hosp, Manchester M13 0JH, Lancs, England. Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Yale Univ, New Haven, CT USA. Univ Chicago, Chicago, IL 60637 USA. RP Rebbeck, TR (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, 904 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA57601, CA74415, N01-CN-6700, R01-CA83855] NR 20 TC 817 Z9 836 U1 3 U2 28 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 23 PY 2002 VL 346 IS 21 BP 1616 EP 1622 DI 10.1056/NEJMoa012158 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 554GZ UT WOS:000175728600003 PM 12023993 ER PT J AU Cummings, DE Weigle, DS Frayo, RS Breen, PA Ma, MK Dellinger, EP Purnell, JQ AF Cummings, DE Weigle, DS Frayo, RS Breen, PA Ma, MK Dellinger, EP Purnell, JQ TI Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VERTICAL BANDED GASTROPLASTY; QUALITY-OF-LIFE; MORBID-OBESITY; FOOD-INTAKE; ACYLATED PEPTIDE; HORMONE; BEHAVIOR; PERSPECTIVE; RESPONSES; EXERCISE AB Background: Weight loss causes changes in appetite and energy expenditure that promote weight regain. Ghrelin is a hormone that increases food intake in rodents and humans. If circulating ghrelin participates in the adaptive response to weight loss, its levels should rise with dieting. Because ghrelin is produced primarily by the stomach, weight loss after gastric bypass surgery may be accompanied by impaired ghrelin secretion. Methods: We determined the 24-hour plasma ghrelin profiles, body composition, insulin levels, leptin levels, and insulin sensitivity in 13 obese subjects before and after a six-month dietary program for weight loss. The 24-hour ghrelin profiles were also determined in 5 subjects who had lost weight after gastric bypass and 10 normal-weight controls; 5 of the 13 obese subjects who participated in the dietary program were matched to the subjects in the gastric-bypass group and served as obese controls. Results: Plasma ghrelin levels rose sharply shortly before and fell shortly after every meal. A diet-induced weight loss of 17 percent of initial body weight was associated with a 24 percent increase in the area under the curve for the 24-hour ghrelin profile (P=0.006). In contrast, despite a 36 percent weight loss after gastric bypass, the area under the curve for the ghrelin profile in the gastric-bypass group was 77 percent lower than in normal-weight controls (P<0.001) and 72 percent lower than in matched obese controls (P=0.01). The normal, meal-related fluctuations and diurnal rhythm of the ghrelin level were absent after gastric bypass. Conclusions: The increase in the plasma ghrelin level with diet-induced weight loss is consistent with the hypothesis that ghrelin has a role in the long-term regulation of body weight. Gastric bypass is associated with markedly suppressed ghrelin levels, possibly contributing to the weight-reducing effect of the procedure. (N Engl J Med 2002;346:1623-30.) Copyright (C) 2002 Massachusetts Medical Society. C1 Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Surg, Seattle, WA 98195 USA. Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. Univ Hosp, Seattle, WA 98104 USA. Oregon Hlth Sci Univ, Dept Med, Portland, OR 97201 USA. RP Cummings, DE (reprint author), Vet Affairs Puget Sound Hlth Care Syst, Seattle Div, 1660 S Columbian Way,S-111-Endo, Seattle, WA 98108 USA. FU NCRR NIH HHS [M01RR00037]; NIDDK NIH HHS [K23 DK02689, K24 DK02860, R01 DK55460]; NIH HHS [P3ODK17047] NR 43 TC 1378 Z9 1424 U1 5 U2 66 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 23 PY 2002 VL 346 IS 21 BP 1623 EP 1630 DI 10.1056/NEJMoa012908 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 554GZ UT WOS:000175728600004 PM 12023994 ER PT J AU Haber, D AF Haber, D TI Prophylactic oophorectomy to reduce the risk of ovarian and breast cancer in carriers of BRCA mutations SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID SURGICAL-ADJUVANT-BREAST; PREVENTION; TAMOXIFEN C1 Massachusetts Gen Hosp, Charlestown, MA 02129 USA. RP Haber, D (reprint author), Massachusetts Gen Hosp, Charlestown, MA 02129 USA. NR 9 TC 41 Z9 42 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 23 PY 2002 VL 346 IS 21 BP 1660 EP 1662 DI 10.1056/NEJMed020044 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 554GZ UT WOS:000175728600010 PM 12024000 ER PT J AU Flier, JS Maratos-Flier, E AF Flier, JS Maratos-Flier, E TI The stomach speaks - Ghrelin and weight regulation SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID OBESITY; PEPTIDE C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Joslin Diabet Ctr, Boston, MA 02215 USA. RP Flier, JS (reprint author), Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NR 10 TC 24 Z9 25 U1 1 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 23 PY 2002 VL 346 IS 21 BP 1662 EP 1663 DI 10.1056/NEJM200205233462112 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 554GZ UT WOS:000175728600011 PM 12024001 ER PT J AU Ganzini, L Block, S AF Ganzini, L Block, S TI Physician-assisted death - A last resort? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID TERMINALLY ILL PATIENTS; SUICIDE; EUTHANASIA; ATTITUDES; DESIRE; CARE; EXPERIENCES; OREGON C1 Dept Vet Affairs Med Ctr, Portland, OR 97201 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ganzini, L (reprint author), Dept Vet Affairs Med Ctr, Portland, OR 97201 USA. NR 15 TC 25 Z9 25 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 23 PY 2002 VL 346 IS 21 BP 1663 EP 1665 DI 10.1056/NEJM200205233462113 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 554GZ UT WOS:000175728600012 PM 12024002 ER PT J AU Bent, S Nallamothu, BK Simel, DL Fihn, SD Saint, S AF Bent, S Nallamothu, BK Simel, DL Fihn, SD Saint, S TI Does this woman have an acute uncomplicated urinary tract infection? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID CLINICAL-PRACTICE GUIDELINE; RISK-FACTORS; YOUNG-WOMEN; ASYMPTOMATIC BACTERIURIA; MANAGEMENT; DIAGNOSIS; ADULTS; ASSOCIATION; SYMPTOMS; PATIENT AB Context Symptoms suggestive of acute urinary tract infection (UTI) constitute one of the most common reasons for women to visit clinicians. Although the clinical en typically involves taking a history and performing a physical examination, the diagnostic accuracy of the clinical assessment for UTI remains uncertain. Objective To review the accuracy and precision of history taking and physical examination for the diagnosis of UTI in women. Data Sources We conducted a MEDLINE search for articles published from 1966 through September 2001 and manually reviewed bibliographies, 3 commonly used clinical skills textbooks, and contacted experts in the field. Study Selection Studies were included if they contained original data on the accuracy or precision of history or physical examination for diagnosing acute uncomplicated UTI in women. One author initially screened titles and abstracts found by our search. Nine of 464 identified studies met inclusion criteria. Data Extraction Two authors independently abstracted data from the included studies. Disagreements were resolved by discussion and consensus with a third author. Data Synthesis Four symptoms and 1 sign significantly increased the probability of UTI: dysuria (summary positive likelihood ratio [LR], 1.5; 95% confidence interval [CI], 1.2-2.0), frequency (LR, 1,8; 95% CI, 1.1-3.0), hematuria (LR, 2.0; 95% CI, 1.3-2.9), back pain (LR, 1.6; 95% CI, 1.2-2.1), and costovertebral angle tenderness (LR, 1.7; 95% CI, 1.1-2.5). Four symptoms and 1 sign significantly decreased the probability of UTI: absence of dysuria (summary negative LR, 0.5; 95% CI, 0.3-0.7), absence of back pain (LR, 0.8; 95% CI, 0.7-0.9), history of vaginal discharge (LR, 0.3; 95% CI, 0.1-0.9), history of vaginal irritation (LR, 0.2; 95% CI, 0.1-0.9), and vaginal discharge on examination (LR, 0.7; 95% CI, 0.5-0.9). Of all individual diagnostic signs and symptoms, the 2 most powerful were history of vaginal discharge and history of vaginal irritation, which significantly decreased the likelihood of UTI when present (LRs, 0.3 and 0.2, respectively). One study examined combinations of symptoms, and the resulting LRs were more powerful (24.6 for the combination of dysuria and frequency but no vaginal discharge or irritation). One study of patients with recurrent UTI found that self-diagnosis significantly increased the probability of UTI (LR, 4.0). Conclusions In women who present with 1 or more symptoms of UTI, the probability of infection is approximately 50%. Specific combinations of symptoms (eg, dysuria and frequency without vaginal discharge or irritation) raise the probability of UTI to more than 90%, effectively ruling in the diagnosis based on history alone. In contrast, history taking, physical examination, and dipstick urinalysis are not able to reliably lower the posttest probability of disease to a level where a UTI can be ruled out when a patient presents with 1 or more symptoms. C1 San Francisco VAMC, Gen Internal Med Sect, San Francisco, CA 94121 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Michigan, Sch Med, Dept Med, Ann Arbor, MI 48104 USA. Durham VA Med Ctr, Dept Med, Durham, NC USA. Duke Univ, Sch Med, Durham, NC USA. VA Puget Sound Hlth Care Syst, Hlth Serv Res & Dev Ctr Excellence, Seattle, WA USA. Ann Arbor VA Med Ctr, Dept Med, Ann Arbor, MI USA. Univ Michigan Hlth Syst, Patient Safety Enhancement Program, Ann Arbor, MI USA. RP Bent, S (reprint author), San Francisco VAMC, Gen Internal Med Sect, 111-A1,4150 Clement St, San Francisco, CA 94121 USA. NR 53 TC 166 Z9 171 U1 1 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 22 PY 2002 VL 287 IS 20 BP 2701 EP 2710 DI 10.1001/jama.287.20.2701 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 554JQ UT WOS:000175732400030 PM 12020306 ER PT J AU Postel, EH Abramczyk, BA Gursky, SK Xu, YW AF Postel, EH Abramczyk, BA Gursky, SK Xu, YW TI Structure-based mutational and functional analysis identify human NM23-H2 as a multifunctional enzyme SO BIOCHEMISTRY LA English DT Article ID NUCLEOSIDE-DIPHOSPHATE KINASE; NUCLEASE-HYPERSENSITIVE ELEMENT; ACTIVE-SITE; HEXAMERIC ENZYME; DNA-BINDING; GENE; REPAIR; DIFFERENTIATION; INITIATION; STABILITY AB The human NM23-H2 protein is a transcriptional regulator (PuF) that binds and cleaves DNA via covalent bond formation, and also catalyzes phosphoryl transfer (NDP kinase). Our previous work has identified two separate DNA-binding, regions on NM23-H2/PuF: a sequence-dependent DNA-binding surface involving, residues Ar34, Asn69, and Lys134 on the equator of the hexameric protein and a covalent DNA-binding site involving Lys12 located in the nucleotide-binding site, the site of the NDP kinase reaction. To understand the role of the nucleotide-binding site in the DNA cleavage reaction and to establish a connection between the nuclease and the NDP kinase activities, we used the known crystal structure of NM23-H2 complexed with GDP as the basis for site-directed mutagenesis. We thus identified Arg88 and Arg105 as residues that are, in addition to Lys12, critical for covalent DNA binding and DNA cleavage, as well as for the NDP kinase reaction. Another residue, Gln17, was required only for DNA cleavage, and Tyr52, Asn115, and His118 were found to be essential only for the NDP kinase activity. Six of these seven functionally important amino acids associated with the nucleotide-binding site are evolutionarily conserved, underscoring their biological importance. We also show that nucleoside triphosphates but not nucleoside diphosphates inhibited the covalent DNA binding and DNA cleavage reactions, independent of phosphoryl transfer and the NDP kinase reaction. These findings collectively suggest that the binding modes of mononucleotides and duplex DNA oligonucleotides in the nucleotide-binding site differ, and that NM23-H2 possesses multiple biochemical activities. A model consistent with these observations is presented. C1 Princeton Univ, Lewis Thomas Lab, Dept Mol Biol, Princeton, NJ 08546 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. RP Postel, EH (reprint author), Princeton Univ, Lewis Thomas Lab, Dept Mol Biol, Washington Rd, Princeton, NJ 08546 USA. FU NCI NIH HHS [CA76496] NR 31 TC 38 Z9 38 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 21 PY 2002 VL 41 IS 20 BP 6330 EP 6337 DI 10.1021/bi025606+ PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 552ZX UT WOS:000175651400014 PM 12009894 ER PT J AU Januzzi, JL Snapinn, SM DiBattiste, PM Jang, IK Theroux, P AF Januzzi, JL Snapinn, SM DiBattiste, PM Jang, IK Theroux, P TI Benefits and safety of tirofiban among acute coronary syndrome patients with mild to moderate renal insufficiency - Results from the platelet receptor inhibition in ischemic syndrome management in patients limited by unstable signs and symptoms (PRISM-PLUS) trial SO CIRCULATION LA English DT Article DE kidney; myocardial infarction; platelets ID GLYCOPROTEIN-IIB-IIIA; ACUTE MYOCARDIAL-INFARCTION; ARTERY DISEASE; FAILURE; REVASCULARIZATION; HEMODIALYSIS; AGGREGATION; SURVIVAL; DIALYSIS AB Background-The role of glycoprotein IIb/IIIa receptor antagonists for the treatment of patients with acute coronary syndrome and renal insufficiency remains undefined. Methods and Results-Patients from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial were stratified by creatinine clearance (CrCl) and assessed with respect to treatment assignment to tirofiban/heparin versus heparin alone for the risk of adverse outcomes and bleeding. Patients with severe renal insufficiency (defined as a serum creatinine greater than or equal to2.5 mg/dL) were excluded from PRISM-PLUS as a whole. Patients with the lowest CrCl (<30 mL/min) were more likely to present with high-risk clinical features. Decreasing renal function was strongly associated with adverse outcome, increasing the risk for ischemic complications at all time points examined (all P<0.002). Irrespective of CrCl. therapy with tirofiban reduced the odds of the composite end point of death, myocardial infarction, or refractory ischemia at 48 hours (odds ratio [OR], 0.68 95% confidence interval [CI], 0.46 to 1,0 P=0.05), 7 days (OR, 0.6& 95% CI, 0.52 to 0.88 P=0.003), 30 days (OR, 0.78 95% Cl, 0.63 to 0.98: P=0.03), and 6 months (OR, 0.81; 95% CI, 0.68 to 0.98 P=0.03). The risk of myocardial infarction/death was also significantly decreased to a similar magnitude at all time points examined. There was no evidence of treatment-by-CrCl interaction, The presence of declining renal function independently increased the risk for bleeding (OR. 1.57; P<0.001 for trend across categories), as did therapy with tirofiban, but no unexpected incremental risk of bleeding due to tirofiban was observed among lowest CrCl categories. Conclusions-Arnong patients with mild-to-nioderate renal insufficiency in PRISM-PLUS, tirofiban was well tolerated and effective in reducing ischemic acute coronary syndrome complications. C1 Montreal Heart Inst, Res Ctr, Cardiol Div, Montreal, PQ H1T 1C8, Canada. Massachusetts Gen Hosp, Cardiol Div, Boston, MA USA. Merck Res Labs, W Point, PA USA. RP Theroux, P (reprint author), Montreal Heart Inst, Res Ctr, Div Cardiol, 5000 E Belanger St, Montreal, PQ H1T 1C8, Canada. NR 22 TC 61 Z9 67 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 MAY 21 PY 2002 VL 105 IS 20 BP 2361 EP 2366 DI 10.1161/01.CIR.0000016359.94919.16 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 556MM UT WOS:000175853600008 PM 12021221 ER PT J AU Kratz, A Laposata, M AF Kratz, A Laposata, M TI Enhanced clinical consulting - moving toward the core competencies of laboratory professionals SO CLINICA CHIMICA ACTA LA English DT Article; Proceedings Paper CT 8th International Conference on Laboratory Medicine CY OCT 23, 2001 CL PADUA, ITALY DE laboratory tests; laboratory medicine; clinical pathology; value added services; clinical consulting ID PRIMARY-CARE PHYSICIANS; OF-MEDICINE REPORT; INFORMATION NEEDS; CONSULTATION; ERRORS; MET AB The large menu of laboratory assays available today makes it increasingly difficult for the non-specialist to order all necessary tests, avoid medical errors, and still contain cost. Curbside consultations, "intelligent" laboratory information systems, and medical information from the Internet cannot fully fill the need for expert advice on test selection and interpretation of laboratory results. In this communication, we show the need for a more actin. e role for laboratory physicians to select and interpret tests, demonstrate that existing attempts to deal with this issue are insufficient, and describe the model system which we have instituted at our institution. We combine reflexive testing algorithms with narrative interpretations provided by medical laboratory professionals and thereby enable physicians to obtain relevant laboratory results and to arrive at a definitive diagnosis without having to order individual tests. In our experience, such an arrangement can significantly improve the quality of care and reduce the cost per case by decreasing the time to diagnosis, the number of tests ordered, and the number of patient visits. In addition, interpretations provide a new source of professional revenue for the expert laboratory physician. This leads to a new role for laboratory professionals, in which their expertise in the selection and interpretation of laboratory tests is fully utilized. (C) 2002 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Dept Pathol, Div Lab Med, Clin Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Laposata, M (reprint author), Massachusetts Gen Hosp, Dept Pathol, Div Lab Med, Clin Labs, Room 235 Gray Bldg,55 Fruit St, Boston, MA 02114 USA. NR 27 TC 14 Z9 14 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD MAY 21 PY 2002 VL 319 IS 2 BP 117 EP 125 AR PII S0009-8981(02)00032-3 DI 10.1016/S0009-8981(02)00032-3 PG 9 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 552NV UT WOS:000175627200006 PM 11955488 ER PT J AU Tylaska, LA Boring, L Weng, W Aiello, R Charo, IF Rollins, BJ Gladue, RP AF Tylaska, LA Boring, L Weng, W Aiello, R Charo, IF Rollins, BJ Gladue, RP TI CCR2 regulates the level of MCP-1/CCL2 in vitro and at inflammatory sites and controls T cell activation in response to alloantigen SO CYTOKINE LA English DT Article DE CCL2; MCP-1; CCR2; alloantigen ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; RHEUMATOID-ARTHRITIS; TRANSGENIC MICE; EXPRESSION; IL-12; ATHEROSCLEROSIS; SUSCEPTIBILITY; RECRUITMENT; CHEMOKINES; MIGRATION AB CCR2, and its principle ligand MCP-1/CCL2, have been well documented for their ability to induce monocyte infiltration and promote the pathogenesis of rheumatoid arthritis and atherosclerosis. In order to assess additional roles for CCR2, we inserted allogeneic implants into CCR2-/- and MCP-1-/- mice and characterized T cell responses and the regulatory role of CCR2 on MCP-1 expression. The results demonstrate a marked decrease in lymphocyte infiltration in both CCR2-/- and MCP-1-/- animals. In contrast, IL-12 and CTL function were only suppressed in CCR2-/- animals. Further, whereas MCP-1 was only transiently elevated in the inflammatory fluid of WT animals, levels were sustained within the implants (5000 pg/ml; >8 days) and serum (243 pg/ml) of CCR2-/- mice. Higher levels of MCP-1 were also observed in the culture supernatants of CCR2-/- macrophages as compared to WT cells despite no difference in mRNA levels. Evidence that MCP-1 levels are regulated by receptor binding and internalization was suggested by its rapid decline when added to WT macrophages at 37degreesC but not 4degreesC. These studies indicate that CCR2 plays an important role in regulating T cell responses and controlling the level of MCP-1 at inflammatory sites. (C) 2002 Elsevier Science Ltd. All rights reserved. C1 Pfizer Inc, Dept Immunol, Global Res & Dev, Groton, CT 06340 USA. Gladstone Inst Cardiovasc Dis, San Francisco, CA 94141 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Gladue, RP (reprint author), Pfizer Inc, Dept Immunol, Global Res & Dev, Eastern Point Rd, Groton, CT 06340 USA. NR 24 TC 44 Z9 47 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD MAY 21 PY 2002 VL 18 IS 4 BP 184 EP 190 DI 10.1006/cyto.2002.1031 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 586EK UT WOS:000177571500002 PM 12126640 ER PT J AU Davies, CD Berk, DA Pluen, A Jain, RK AF Davies, CD Berk, DA Pluen, A Jain, RK TI Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE diffusion; extracellular matrix; tumours; spheroids; stromal cells ID SOLID TUMORS; MACROMOLECULES; PRESSURE AB The tumour extracellular matrix acts as a barrier to the delivery of therapeutic agents. To test the hypothesis that extracellular matrix composition governs the penetration rate of macromolecules in tumour tissue, we measured the diffusion coefficient of nonspecific IgG in three rhabdomyosarcoma subclones growing as multicellular spheroids in vitro or as subcutaneous tumours in dorsal windows in vivo. In subcutaneous tumours, the diffusion coefficient decreased with increasing content of collagen and sulphated glycosaminoglycans. When grown as multicellular spheroids, no differences in either extracellular matrix composition or diffusion coefficient were found. Comparison of in vitro vs in vivo results suggests an over riding role of host stromal cells in extracellular matrix production subjected to modulation by tumour cells, Penetration of therapeutic macromolecules through tumour extracellular matrix might thus be largely determined by the host organ. Hence, caution must be exercised in extrapolating drug penetrability from spheroids and multilayer cellular sandwiches consisting of only tumour cells to tumours in vivo. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02110 USA. Harvard Univ, Sch Med, Boston, MA 02110 USA. RP Jain, RK (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02110 USA. RI Berk, David/A-4863-2012; Pluen, Alain/F-5300-2015 OI Berk, David/0000-0002-3855-6886; Pluen, Alain/0000-0002-5953-8011 NR 29 TC 52 Z9 53 U1 0 U2 4 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 MAY 20 PY 2002 VL 86 IS 10 BP 1639 EP 1644 DI 10.1038/sj/bjc/6600270 PG 6 WC Oncology SC Oncology GA 561PF UT WOS:000176149500018 ER PT J AU Lassen, MR Bauer, KA Eriksson, BI Turpie, AGG AF Lassen, MR Bauer, KA Eriksson, BI Turpie, AGG CA European Pentasaccharide Hip Elec TI Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison SO LANCET LA English DT Article ID DEEP-VEIN THROMBOSIS; MOLECULAR-WEIGHT HEPARIN; SYNTHETIC PENTASACCHARIDE; RECOMBINANT HIRUDIN; PULMONARY-EMBOLISM; FACTOR XA; INHIBITION; GENERATION; TRIALS; RISK AB Background Despite use of thromboprophylaxis, elective hip-replacement surgery carries a high risk of venous thromboembolic complications. We aimed to assess the ability of the pentasaccharide fondaparinux, the first of a new class of synthetic antithrombotic agents, to further reduce this risk. Methods In a double-blind study, we randomly assigned 2309 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to once daily, subcutaneous injections of either 2.5 mg fondaparinux, starting postoperatively, or 40 mg enoxaparin, starting preoperatively. The primary efficacy outcome was venous thromboembolism up to day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The main safety outcomes were bleeding and death. The duration of follow-up was 6 weeks. Analysis was per protocol. Findings We assessed the primary efficacy outcome in 1827 (79%) of 2309 patients. By day 11, venous thromboembolisms were recorded in 37 (4%) of 908 patients assigned to fondaparinux and in 85 (9%) of 919 assigned to enoxaparin (difference -5.2% [95% Cl -8.1 to -2.7], p<0.0001). The relative reduction in risk was 55.9% (95% CI 33.1-72.8). The two groups did not differ in frequency of death or clinically relevant bleeding. Interpretation Drugs that act through specific inhibition of factor Xa, such as fondaparinux, could be more effective than low molecular weight heparins in prevention of venous thromboembolism in patients undergoing hip-replacement surgery. C1 Copenhagen Univ Hosp, Dept Orthopaed, DK-3400 Hillerod, Denmark. VA Boston Healthcare Syst, Dept Med, Boston, MA USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Sahlgrenska Univ Hosp Ostra, Dept Orthopaed, Gothenburg, Sweden. Hamilton Hlth Sci Corp, Dept Med, Gen Div, Hamilton, ON, Canada. RP Lassen, MR (reprint author), Copenhagen Univ Hosp, Dept Orthopaed, DK-3400 Hillerod, Denmark. NR 27 TC 327 Z9 340 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 18 PY 2002 VL 359 IS 9319 BP 1715 EP 1720 DI 10.1016/S0140-6736(02)08652-X PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 554MV UT WOS:000175740500006 PM 12049858 ER PT J AU Turpie, AGG Bauer, KA Eriksson, BI Lassen, MR AF Turpie, AGG Bauer, KA Eriksson, BI Lassen, MR CA PENTATHLON 2000 Study Steering TI Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial SO LANCET LA English DT Article ID MOLECULAR-WEIGHT HEPARIN; DEEP-VEIN THROMBOSIS; SYNTHETIC PENTASACCHARIDE; RECOMBINANT HIRUDIN; KNEE ARTHROPLASTY; FACTOR XA; PROPHYLAXIS; INHIBITION; GENERATION AB Background Elective hip-replacement surgery carries significant risk of venous thromboembolism, despite use of thromboprophylaxis. We aimed to see whether the pentasaccharide fondaparinux, the first drug of a new class of synthetic antithrombotic agents, could reduce this risk to a greater extent than other available treatments. Methods In a double-blind study, we randomly assigned 2275 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to receive postoperative subcutaneous injections of either 2.5 mg fondaparinux once daily or 30 mg enoxaparin twice daily. The primary efficacy outcome was venous thromboembolism to day 11. The main safety outcomes were bleeding and death. Patients were followed up for 6 weeks. Findings We assessed venous thromboembolism to day 11 in 1584 (70%) of 2275 patients. By day 11, venous thromboembolisms were recorded in 48 (6%) of 787 patients on fondaparinux and in 66 (8%) of 797 patients on enoxaparin. The relative reduction in risk was 26.3% (95% Cl -10.8 to 52.8, p=0.099). The two groups did not differ in the number of patients who died or in the number who had clinically relevant bleeding. Interpretation In patients undergoing elective hip-replacement surgery, 2.5 mg fondaparinux once daily was not significantly more effective than 30 mg enoxaparin twice daily in reducing risk of venous thromboembolism. However, the lower risk recorded with fondaparinux than enoxaparin was clinically important, with no increase in clinically relevant bleeding. C1 Hamilton Hlth Sci Corp, Dept Med, Gen Div, Hamilton, ON, Canada. Vet Affairs, Dept Med, Boston, MA USA. Healthcare Syst & Boston Israel Deaconess Med Ctr, Boston, MA USA. Sahlgrens Univ Hosp, S-41345 Gothenburg, Sweden. Univ Hosp Copenhagen Hillerod, Dept Orthopaed, Hillerod, Denmark. RP Turpie, AGG (reprint author), Gen Hosp, Hamilton Hlth Sci Gen, 237 Barton St E, Hamilton, ON L8L 2X2, Canada. NR 22 TC 324 Z9 337 U1 0 U2 2 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 18 PY 2002 VL 359 IS 9319 BP 1721 EP 1726 DI 10.1016/S0140-6736(02)08648-8 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 554MV UT WOS:000175740500008 PM 12049860 ER PT J AU Kirchhausen, T AF Kirchhausen, T TI Clathrin adaptors really adapt SO CELL LA English DT Review ID SORTING SIGNALS; COATED VESICLES; RECOGNITION; MEMBRANE; PROTEINS AB The clathrin pathway is the principal route for receptor-mediated endocytosis and growth factor downregulation. Heterotetrameric clathrin adaptors directly link the clathrin coat with cargo transmembrane proteins that are sorted into coated pits and vesicles. A paper in this issue of Call (Collins et al., 2002) describes the atomic structure of the adaptor-protein 2 (AP-2) core, the portion that makes contacts with the membrane and cytosolic tails of cargo proteins. C1 Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. RP Kirchhausen, T (reprint author), Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. NR 20 TC 78 Z9 80 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE,, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAY 17 PY 2002 VL 109 IS 4 BP 413 EP 416 DI 10.1016/S0092-8674(02)00751-1 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 553VM UT WOS:000175696800002 PM 12086597 ER PT J AU Taniguchi, T Garcia-Higuera, I Xu, B Andreassen, PR Gregory, RC Kim, ST Lane, WS Kastan, MB D'Andrea, AD AF Taniguchi, T Garcia-Higuera, I Xu, B Andreassen, PR Gregory, RC Kim, ST Lane, WS Kastan, MB D'Andrea, AD TI Convergence of the Fanconi anemia and ataxia telangiectasia signaling pathways SO CELL LA English DT Article ID NIJMEGEN-BREAKAGE-SYNDROME; DNA-DAMAGE RESPONSE; ATM-DEPENDENT PHOSPHORYLATION; TARGETED DISRUPTION; CHECKPOINT PATHWAY; IONIZING-RADIATION; X-IRRADIATION; NUCLEAR-COMPLEX; MAMMALIAN-CELLS; S-PHASE AB Fanconi anemia (FA) and ataxia telangiectasia (AT) are clinically distinct autosomal recessive disorders characterized by spontaneous chromosome breakage and hematological cancers. FA cells are hypersensitive to mitomycin C (MMC), while AT cells are hypersensitive to ionizing radiation (IR). Here, we identify the Fanconi anemia protein, FANCD2, as a link between the FA and ATM damage response pathways. ATM phosphorylates FANCD2 on serine 222 in vitro. This site is also phosphorylated in vivo in an ATM-dependent manner following IR. Phosphorylation of FANCD2 is required for activation of an S phase checkpoint. The ATM-dependent phosphorylation of FANCD2 on S222 and the FA pathway-dependent monoubiquitination of FANCD2 on K561 are independent posttranslational modifications regulating discrete cellular signaling pathways. Biallelic disruption of FANCD2 results in both MMC and IR hypersensitivity. C1 Harvard Univ, Childrens Hosp, Sch Med, Dana Farber Canc Inst,Dept Pediat Oncol, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Pediat, Boston, MA 02115 USA. St Jude Childrens Res Hosp, Dept Hematol Oncol, Memphis, TN 38105 USA. Harvard Univ, Harvard Microchem & Proteom Anal Facil, Cambridge, MA 02138 USA. RP D'Andrea, AD (reprint author), Harvard Univ, Childrens Hosp, Sch Med, Dana Farber Canc Inst,Dept Pediat Oncol, Boston, MA 02115 USA. EM alan_dandrea@dfci.harvard.edu RI Kim, Seong-Tae/A-9917-2013; Garcia-Higuera, Irene/L-5004-2014 FU NCI NIH HHS [CA21765, CA71387]; NHLBI NIH HHS [P01HL54785, R01HL52725]; NIDDK NIH HHS [R01DK43889] NR 62 TC 304 Z9 309 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 17 PY 2002 VL 109 IS 4 BP 459 EP 472 DI 10.1016/S0092-8674(02)00747-X PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 553VM UT WOS:000175696800008 PM 12086603 ER PT J AU Dhe-Paganon, S Werner, ED Chi, YI Shoelson, SE AF Dhe-Paganon, S Werner, ED Chi, YI Shoelson, SE TI Structure of the globular tail of nuclear lamin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DREIFUSS MUSCULAR-DYSTROPHY; FAMILIAL PARTIAL LIPODYSTROPHY; CAUSE AUTOSOMAL-DOMINANT; A/C GENE; DILATED CARDIOMYOPATHY; IMMUNOGLOBULIN FOLD; MISSENSE MUTATIONS; SEQUENCE-ANALYSIS; PROTEIN; DOMAIN AB The nuclear lamins form a two-dimensional matrix that provides integrity to the cell nucleus and participates in nuclear activities. Mutations in the region of human LMNA encoding the carboxyl-terminal tail Lamin A/C are associated with forms of muscular dystrophy and familial partial lipodystrophy (FPLD). To help discriminate tissue-specific phenotypes, we have solved at 1.4-Angstrom resolution the three-dimensional crystal structure of the lamin A/C globular tail. The domain adopts a novel, all beta-mmunoglobulin-like fold. FPLD-associated mutations cluster within a small surface, whereas muscular dystrophy-associated mutations are distributed throughout the protein core and on its surface. These findings distinguish myopathy- and lipodystrophy-associated mutations and provide a structural framework for further testing hypotheses concerning lamin function. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Shoelson, SE (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK09393, R01 DK43123] NR 33 TC 161 Z9 169 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 17 PY 2002 VL 277 IS 20 BP 17381 EP 17384 DI 10.1074/jbc.C200038200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 553PR UT WOS:000175685100002 PM 11901143 ER PT J AU Zhou, NM Luo, ZW Luo, JS Fan, XJ Cayabyab, M Hiraoka, M Liu, DX Han, XB Pesavento, J Dong, CZ Wang, YL An, J Kaji, H Sodroski, JG Huang, ZW AF Zhou, NM Luo, ZW Luo, JS Fan, XJ Cayabyab, M Hiraoka, M Liu, DX Han, XB Pesavento, J Dong, CZ Wang, YL An, J Kaji, H Sodroski, JG Huang, ZW TI Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with D-peptides derived from chemokines SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RECEPTOR CXCR4; SMALL-MOLECULE; CORECEPTOR ACTIVITY; BIOLOGICAL FUNCTION; MEMBRANE-FUSION; CELL-ADHESION; TROPIC HIV-1; FACTOR-I; VMIP-II AB Chemokine receptor CXCR4 plays an important role in the immune system and the cellular entry of human immunodeficiency virus type 1 (HIV-1). To probe the stereospecificity of the CXCR4-ligand interface, D-amino acid peptides derived from natural chemokines, viral macrophage inflammatory protein II (vMIP-II) and stromal cell-derived factor-1alpha (SDF-1alpha), were synthesized and found to compete with I-125-SDF-1alpha and monoclonal antibody 12G5 binding to CXCR4 with potency and selectivity comparable with or higher than their L-peptide counterparts. This was surprising because of the profoundly different side chain topologies between D- and L-enantiomers, which circular dichroism spectroscopy showed adopt mirror image conformations. Further direct binding experiments using D-peptide labeled with fluorescein (designated as FAM-DV1) demonstrated that D- and L-peptides shared similar or at least overlapping binding site(s) on the CXCR4 receptor. Structure-activity analyses of related peptide analogs of mixed chiralities or containing alanine replacements revealed specific residues at the N-terminal half of the peptides as key binding determinants. Acting as CXCR4 antagonists and with much higher biological stability than L-counterparts, the D-peptides showed significant activity in inhibiting the replication of CXCR4-dependent HIV-1 strains. These results show the remarkable stereochemical flexibility of the CXCR4-peptide interface. Further studies to understand the mechanism of this unusual feature of the CXCR4 binding surface might aid the development of novel CXCR4-binding molecules like the D-peptides that have high affinity and stability. C1 Univ Illinois, Dept Biochem, Sch Mol & Cellular Biol, Urbana, IL 61801 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Mol Pharmacol & Biochem, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Huang, ZW (reprint author), Univ Illinois, Dept Biochem, Sch Mol & Cellular Biol, 302 Burrill Hall,MC-119,407 S Goodwin Ave, Urbana, IL 61801 USA. FU NIAID NIH HHS [AI42848, AI24755, AI41851, AI45414]; NIGMS NIH HHS [GM57761] NR 56 TC 78 Z9 81 U1 1 U2 8 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 MAY 17 PY 2002 VL 277 IS 20 BP 17476 EP 17485 DI 10.1074/jbc.M202063200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 553PR UT WOS:000175685100013 PM 11880384 ER PT J AU Ren, J Li, YQ Kufe, D AF Ren, J Li, YQ Kufe, D TI Protein kinase C beta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR RECEPTOR; MEDIATED CELL-ADHESION; TRANSCRIPTION FACTOR LEF-1; TUMOR-SUPPRESSOR PROTEIN; E-CADHERIN; TYROSINE PHOSPHORYLATION; PROTEOLYTIC ACTIVATION; CYTOPLASMIC DOMAIN; GENETIC-DEFECTS; MAMMARY-GLAND AB The DF3/MUC1 mucin-like glycoprotein is aberrantly overexpressed in most human carcinomas. The MUC1 cytoplasmic domain interacts directly with beta-catenin, a component of the adherens junction of mammalian epithelial cells. The present results demonstrate that MUC1 associates with protein kinase Cdelta (PKCdelta). A TDR sequence adjacent to the beta-catenin binding motif in the MUC1 cytoplasmic domain functions as a site for PKCdelta phosphorylation. We show that phosphorylation of MUC1 by PKCdelta increases binding of MUC1 and beta-catenin in vitro and in vivo. The functional significance of the MUC1-PKCdelta interaction is further supported by the demonstration that mutation of the PKCdelta phosphorylation site abrogates MUC1-mediated decreases in binding of beta-catenin to E-cadherin. We also show that the stimulatory effects of MUC1 on anchorage-independent growth are abrogated by mutation of the PKCdelta phosphorylation site. These findings support a novel role for PKCdelta in regulating the interaction between MUC1 and the beta-catenin signaling pathway. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kufe, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA87421] NR 44 TC 108 Z9 115 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 17 PY 2002 VL 277 IS 20 BP 17616 EP 17622 DI 10.1074/jbc.M200436200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 553PR UT WOS:000175685100030 PM 11877440 ER PT J AU Johnson, BA Stehn, JR Yaffe, MB Blackwell, TK AF Johnson, BA Stehn, JR Yaffe, MB Blackwell, TK TI Cytoplasmic localization of tristetraprolin involves 14-3-3-dependent and -independent mechanisms SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AU-RICH ELEMENTS; ACTIVATED PROTEIN-KINASE; ALPHA MESSENGER-RNA; FINGER TRANSCRIPTION FACTOR; EARLY RESPONSE GENES; TNF-ALPHA; C-ELEGANS; NUCLEOCYTOPLASMIC TRANSPORT; DEFICIENCY SYNDROME; P38 MAPK AB The immediate early gene tristetraprolin (TTP) is induced transiently in many cell types by numerous extracellular stimuli TTP encodes a zinc finger protein that can bind and destabilize mRNAs that encode tumor necrosis factor-alpha (TNFalpha) and other cytokines. We hypothesize that TTP also has a broader role in growth factor-responsive pathways. In support of this model, we have previously determined that TTP induces apoptosis through the mitochondrial pathway, analogously to certain oncogenes and other immediate-early genes, and that TTP sensitizes cells to the pro-apoptotic signals of TNFa. In this study, we show that TTP and the related proteins TIS11b and TIS11d bind specifically to 14-3-3 proteins and that individual 14-3-3 isoforms preferentially bind to different phosphorylated TTP species. 14-3-3 binding does not appear to inhibit or promote induction of apoptosis by TTP but is one of multiple mechanisms that localize TTP to the cytoplasm. Our results provide the first example of 14-3-3 interacting functionally with an RNA binding protein and binding in vivo to a Type 11 14-3-3 binding site. They also suggest that 14-3-3 binding is part of a complex network of stimuli and interactions that regulate TTP function. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. MIT, Ctr Canc Res, Dept Biol, Cambridge, MA 02139 USA. RP Harvard Univ, Sch Med, Ctr Blood Res, 200 Longwood Ave, Boston, MA 02115 USA. EM blackwell@cbr.med.harvard.edu RI Stehn, Justine/G-5115-2013 OI Stehn, Justine/0000-0002-2136-5450 FU NCI NIH HHS [CA84418]; NIGMS NIH HHS [GM60594] NR 49 TC 91 Z9 92 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 17 PY 2002 VL 277 IS 20 BP 18029 EP 18036 DI 10.1074/jbc.M110465200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 553PR UT WOS:000175685100081 PM 11886850 ER PT J AU Huang, DS Cheung, AT Parsons, JT Bryer-Ash, M AF Huang, DS Cheung, AT Parsons, JT Bryer-Ash, M TI Focal adhesion kinase (FAK) regulates insulin-stimulated glycogen synthesis in hepatocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED GLUCOSE-TRANSPORT; RAT SKELETAL-MUSCLE; PHOSPHATIDYLINOSITOL 3-KINASE; GROWTH-FACTOR; TYROSINE PHOSPHORYLATION; SYNTHASE KINASE-3; RECEPTOR SUBSTRATE-1; 3T3-L1 ADIPOCYTES; GLUCOSE-TRANSPORTER-4 TRANSLOCATION; DIFFERENTIAL REGULATION AB Experimental data support a role for FAK, an important component of the integrin signaling pathway, in insulin action. To test the hypothesis that FAK plays a regulatory role in hepatic insulin action, we overexpressed wild type (WT), a kinase inactive (KR), or a COOH-terminal focal adhesion targeting (FAT) sequence-truncated mutant of FAK in HepG2 hepatoma cells. In control untransfected (NON) and vector (CMV2)- and WT-transfected cells, insulin stimulated an expected 54 +/- 13, 37 +/- 4, and 47 +/- 12 increase in [U-C-14]glucose incorporation into glycogen, respectively. This was entirely abolished in the presence of either KR (-1 +/- 7%) or FAT mutants (0 +/- 8%, n = 5, p < 0.05 for KR or FAT versus other groups), and this was associated with a significant attenuation of incremental insulin-stimulated glycogen synthase (GS) activity. Insulin-stimulated serine phosphorylation of Akt/protein kinase B was significantly impaired in mutant-transfected cells. Moreover, the ability of insulin to inactivate GS kinase-3β (GSK-3β), the regulatory enzyme immediately upstream of GS, by serine phosphorylation (308 &PLUSMN; 16, 321 &PLUSMN; 41, and 458 &PLUSMN; 34 optical densitometric units (odu) in NON, CMV2, and WT, respectively, p < 0.02 for WT versus CMV2) was attenuated in the presence of either FAT (205 +/- 14, p < 0.01) or KR (189 &PLUSMN; 4, p < 0.005) mutants. FAK co-immunoprecipitated with GSK-3beta, but only in cells overexpressing the KR (374 +/- 254 odu) and FAT (555 +/- 308) mutants was this association stimulated by insulin compared with NON (-209 +/- 92), CMV2 (-47 +/- 70), and WT (-39 +/- 31 odu). This suggests that FAK and GSK-3beta form both a constitutive association and a transient complex upon insulin stimulation, the dissociation of which requires normal function and localization of FAK. We conclude that FAK regulates the activity of Akt/protein kinase B and GSK-3beta and the association of GSK-3beta with FAK to influence insulin-stimulated glycogen synthesis in hepatocytes. Insulin action may be subject to regulation by the integrin signaling pathway, ensuring that these growth and differentiation-promoting pathways act in a coordinated and/or complementary manner. C1 Univ Calif Los Angeles, Sch Med, Div Endocrinol Diabet & Hypertens, Gonda Goldschmied Diabet Ctr, Los Angeles, CA 90095 USA. W Los Angeles Vet Adm Med Ctr, Res Serv, Los Angeles, CA 90095 USA. Univ Tennessee, Hlth Sci Ctr, Memphis, TN 38103 USA. Vet Adm Med Ctr, Res Serv, Memphis, TN 38103 USA. Univ Virginia, Charlottesville, VA 22908 USA. RP Bryer-Ash, M (reprint author), Univ Calif Los Angeles, Sch Med, Div Endocrinol Diabet & Hypertens, Gonda Goldschmied Diabet Ctr, 900 Vet Ave,Warren Hall 24-130, Los Angeles, CA 90095 USA. FU NCRR NIH HHS [RR00211] NR 69 TC 26 Z9 26 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 17 PY 2002 VL 277 IS 20 BP 18151 EP 18160 DI 10.1074/jbc.M104252200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 553PR UT WOS:000175685100097 PM 11809746 ER PT J AU Hasty, P Vijg, J AF Hasty, P Vijg, J TI Aging - Genomic priorities in aging SO SCIENCE LA English DT Editorial Material ID REPAIR GENE XPA; MICE; DEFICIENT C1 Univ Texas, Hlth Sci Ctr, Dept Mol Med, San Antonio, TX 78245 USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78245 USA. Univ Texas, Hlth Sci Ctr, Barshop Ctr Longev & Aging Studies, San Antonio, TX 78245 USA. S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78229 USA. RP Hasty, P (reprint author), Univ Texas, Hlth Sci Ctr, Dept Mol Med, San Antonio, TX 78245 USA. NR 11 TC 25 Z9 29 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAY 17 PY 2002 VL 296 IS 5571 BP 1250 EP 1251 DI 10.1126/science.1071808 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554BL UT WOS:000175713000033 PM 11951000 ER PT J AU Springer, TA AF Springer, TA TI Retrospective - Cesar Milstein (1927-2002) SO SCIENCE LA English DT Biographical-Item C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RP Springer, TA (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 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 MAY 17 PY 2002 VL 296 IS 5571 BP 1253 EP 1253 DI 10.1126/science.1073325 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 554BL UT WOS:000175713000035 PM 12016298 ER PT J AU Yu, N Kruskall, MS Yunis, JJ Knoll, JHM Uhl, L Alosco, S Ohashi, M Clavijo, O Husain, Z Yunis, EJ Yunis, JJ Yunis, EJ AF Yu, N Kruskall, MS Yunis, JJ Knoll, JHM Uhl, L Alosco, S Ohashi, M Clavijo, O Husain, Z Yunis, EJ Yunis, JJ Yunis, EJ TI Disputed maternity leading to identification of tetragametic chimerism SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SEQUENCE-SPECIFIC PRIMERS; TANDEM REPEAT LOCI; TRUE HERMAPHRODITE; CAUCASIAN-MESTIZOS; HUMAN CHROMOSOMES; POPULATION-DATA; HLA-B; FERTILIZATION; 46,XX/46,XY; COLOMBIA C1 Beth Israel Deaconess Med Ctr, Div Lab & Transfus Med, Boston, MA 02215 USA. Amer Red Cross, Blood Serv, New England Reg, Dedham, MA USA. Harvard Univ, Sch Med, Boston, MA USA. Serv Medicos Yunis Turbay, Bogota, Colombia. Univ Nacl Colombia, Fac Med & Inst Genet, Dept Patol, Bogota, Colombia. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kruskall, MS (reprint author), Beth Israel Deaconess Med Ctr, Div Lab & Transfus Med, Yamins 309,330 Brookline Ave, Boston, MA 02215 USA. EM mkruskal@caregroup.harvard.edu FU NHLBI NIH HHS [HL-29583, HL-59838] NR 41 TC 55 Z9 59 U1 3 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 16 PY 2002 VL 346 IS 20 BP 1545 EP 1552 DI 10.1056/NEJMoa013452 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 551LV UT WOS:000175563900006 PM 12015394 ER PT J AU Kinlay, S Timms, T Clark, M Karam, C Bilodeau, T Ridker, PM Rifai, N Carlson, W Lloyd-Jones, DM Johnstone, M Rubenstein, J Alexander, S Orav, J Stone, PH AF Kinlay, S Timms, T Clark, M Karam, C Bilodeau, T Ridker, PM Rifai, N Carlson, W Lloyd-Jones, DM Johnstone, M Rubenstein, J Alexander, S Orav, J Stone, PH CA Vascular Basis Study Grp TI Comparison of effect of intensive lipid lowering with atorvastatin to less intensive lowering with lovastatin on C-reactive protein in patients with stable angina pectoris and inducible myocardial ischemia SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY EVENTS; UNSTABLE ANGINA; STATIN THERAPY; PRAVASTATIN AB The effect of intensive lowering of low-density lipoprotein cholesterol with atorvastatin was compared with low-dose lovastatin in I 10 patients with stable angina pectoris and inducible myocardial ischemia. Over 12 months, low-density lipoprotein cholesterol and C-reactive protein decreased significantly with atorvastatin, with half of the long-term change occurring within 4 weeks. C1 Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. Newton Wellesley Hosp, Div Cardiol, Boston, MA USA. Lahey Clin Med Ctr, Cardiol Sect, Burlington, MA 01803 USA. RP Kinlay, S (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. RI Lloyd-Jones, Donald/C-5899-2009 FU NHLBI NIH HHS [R01-HL38780] NR 8 TC 55 Z9 60 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2002 VL 89 IS 10 BP 1205 EP + AR PII S0002-9149(02)02306-8 DI 10.1016/S0002-9149(02)02306-8 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 552QK UT WOS:000175630900012 PM 12008177 ER PT J AU Moore, AG Eagle, KA Bruckman, D Moon, BS Malouf, JF Fattori, R Evangelista, A Isselbacher, EM Suzuki, T Nienaber, CA Gilon, D Oh, JK AF Moore, AG Eagle, KA Bruckman, D Moon, BS Malouf, JF Fattori, R Evangelista, A Isselbacher, EM Suzuki, T Nienaber, CA Gilon, D Oh, JK TI Choice of computed tomography, transesophageal echocardiography, magnetic resonance imaging, and aortography in acute aortic dissection: International Registry of Acute Aortic Dissection (IRAD) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DIAGNOSIS; ANEURYSM AB To assess the current status of diagnostic imaging in acute aortic dissection, we reviewed the records of 628 patients from 13 international centers enrolled in the International Registry of Acute Aortic Dissection. Multiple imaging studies were performed in 66% of patients, with those at non-U.S. sites having a higher mean number of images per patient than those at U.S. sites. Computed tomography was the initial imaging modality in 63% of patients, followed by transesophageal echocardiography (32%), aortography (4%), and magnetic resonance imaging (1%); overall sensitivity for all modalities was similar (93.1%, 88.1%, 87.5%, and 100%, respectively). C1 Mayo Clin, Div Cardiovasc Dis & Internal Med, Rochester, MN 55905 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Bologna, S Orsola M Malpighi Hosp, Bologna, Italy. Univ Barcelona, Hosp Gen Valle Hebron, Barcelona, Spain. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Tokyo, Tokyo, Japan. Hadassah Univ Hosp, IL-91120 Jerusalem, Israel. Univ Hamburg, Hosp Eppendorf, D-20246 Hamburg, Germany. RP Moore, AG (reprint author), Mayo Clin, Div Cardiovasc Dis & Internal Med, 200 1st St SW, Rochester, MN 55905 USA. NR 16 TC 107 Z9 115 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2002 VL 89 IS 10 BP 1235 EP + AR PII S0002-9149(02)02316-0 DI 10.1016/S0002-9149(02)02316-0 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 552QK UT WOS:000175630900022 PM 12008187 ER PT J AU Barr, RG Herbstman, J Speizer, FE Camargo, CA AF Barr, RG Herbstman, J Speizer, FE Camargo, CA TI Validation of self-reported chronic obstructive pulmonary disease in a cohort study of nurses SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE airway obstruction; cohort studies; epidemiologic methods; lung diseases, obstructive; pulmonary disease, chronic obstructive; questionnaires ID RISK-FACTORS; LUNG-DISEASE; MISCLASSIFICATION; ASTHMA; HEALTH; BIAS AB Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death, and its prevalence is increasing; however, few strategies are available for disease prevention or modification besides smoking interventions. To facilitate examination of modifiable risk factors for COPD in the Nurses' Health Study, the authors validated a questionnaire-based definition of COPD in a subset of this US cohort. Participants were surveyed biennially about lifestyle factors, including smoking, since 1976 and physician diagnosis of COPD since 1988. Self-reported cases were defined as reporting COPD on both the original (1988-1996) and supplemental (1998) questionnaires. The authors requested medical records for a 10% random sample of 2,790 cases and reviewed these records in a systematic, blinded fashion. Validated cases required obstructive spirometry, emphysema on chest radiograph or computed tomography, or physician diagnosis. COPD was confirmed for 78% of 273 cases. Spirometry or radiographic results were available for 84%; when available, mean forced expiratory volume in 1 second was 51% predicted (standard deviation, 19). Applying these results to a hypothetical cohort, the authors estimated the degree to which disease misclassification biases relative risks toward the null value, confirming that questionnaire-based COPD research should focus on minimizing false positives rather than false negatives. In conclusion, COPD can be studied in large, questionnaire-based cohorts of health professionals. C1 Channing Labs, Boston, MA 02115 USA. Harvard Univ, Boston, MA 02115 USA. Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Gen Med Div, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. RP Camargo, CA (reprint author), Channing Labs, 181 Longwood Ave, Boston, MA 02115 USA. FU BHP HRSA HHS [PE-11001]; NCI NIH HHS [CA-87969]; NHLBI NIH HHS [HL-03533, HL-07427] NR 23 TC 74 Z9 75 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2002 VL 155 IS 10 BP 965 EP 971 DI 10.1093/aje/155.10.965 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 552PM UT WOS:000175628800012 PM 11994237 ER PT J AU Lang, K Menzin, J Earle, CC Mallick, R AF Lang, K Menzin, J Earle, CC Mallick, R TI Outcomes in patients treated with gemtuzumab ozogamicin for relapsed acute myelogenous leukemia SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article DE antineoplastic agents; combined therapy; cytarabine; drug comparisons; gemtuzumab ozogamicin; hospitals; leukemia; mitoxantrone; mortality; outcomes ID ACUTE MYELOID-LEUKEMIA; COLONY-STIMULATING FACTOR; REMISSION INDUCTION CHEMOTHERAPY; ADULT PATIENTS GREATER-THAN-55; BONE-MARROW TRANSPLANTATION; HIGH-DOSE CHEMOTHERAPY; CONTROLLED PHASE-III; G-CSF; CYTOSINE-ARABINOSIDE; NEUTROPENIC PATIENTS AB The outcomes of treatment with gemtuzumab ozogamicin compared with those of conventional chemotherapy for relapse of acute myelogenous leukemia (AML) were studied. The gemtuzumab ozogamicin group consisted of 104 patients treated in 15 U.S. and 25 European centers for first relapse of AML between May 1997 and December 1998. Conventional chemotherapy recipients consisted of 22 historical control patients who received treatment for their first occurrence of AML at a Boston teaching hospital between January 1991 and December 1994 and who subsequently underwent conventional inpatient reinduction chemotherapy for relapse. Patients in the gemtuzumab ozogamicin group received a two-hour i.v. infusion of 9 mg/m(2) for up to three doses with at least two weeks between doses, while the historical controls received conventional chemotherapy, usually consisting of continuousinfusion cytarabine (days 1-7) plus mitoxantrone. Outcomes evaluated included differences in survival and hospitalization (occurrence and duration) for up to six weeks. Both stratified and multivariate regression methods were used in making comparisons. Adjusting for baseline differences, six-week survival rates were similar in the two groups (95% for the historical control group versus 89% for the gemtuzumab ozogamicin group). However, gemtuzumab ozogamicin recipients had significantly fewer total hospital days (adjusted mean, 19 days, versus 35 days), which was consistent with the higher prevalence of outpatient chemotherapy in this group (43% versus 0% among the historical controls). The difference in the number of hospital days was consistent across various baseline and demographic factors. Gemtuzumab ozogamicin appeared to be associated with equivalent survival and fewer total days of hospitalization than conventional chemotherapy in adults with relapsed AML. C1 Boston Hlth Econ Inc, Waltham, MA 02451 USA. Harvard Med Sch, Boston, MA USA. Dana Farber Canc Inst, Dept Adult Onocl, Ctr Outcomes & Policy Res, Boston, MA 02115 USA. Wyeth Ayerst Res, Global Hlth Outcome Assessment, Collegeville, PA USA. RP Menzin, J (reprint author), Boston Hlth Econ Inc, 20 Fox Rd, Waltham, MA 02451 USA. NR 58 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD MAY 15 PY 2002 VL 59 IS 10 BP 941 EP 948 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 553RL UT WOS:000175689200010 PM 12040733 ER PT J AU Manoach, DS Lindgren, KA Cherkasova, MV Goff, DC Halpern, EF Intriligator, J Barton, JJS AF Manoach, DS Lindgren, KA Cherkasova, MV Goff, DC Halpern, EF Intriligator, J Barton, JJS TI Schizophrenic subjects show deficient inhibition but intact task switching on saccadic tasks SO BIOLOGICAL PSYCHIATRY LA English DT Article DE antisaccades; schizophrenia; prefrontal cortex; executive function; task switching; inhibition ID CARD SORTING TEST; ANTERIOR CINGULATE CORTEX; PREFRONTAL CORTEX; COGNITIVE CONTROL; SET; MEMORY; COSTS AB Background: Schizophrenic patients have executive function deficits, presumably on the basis of prefrontal cortex dysfunction. Although they consistently show impaired inhibition, the evidence of a task switching deficit is less consistent and is often based on performance of neuropsychological tests that require several cognitive processes (e.g., the Wisconsin Card Sort Test [WCST]). We investigated inhibition and task switching using saccadic tasks to determine whether schizophrenic patients have selective impairments of these executive functions. Methods: Sixteen normal and 21 schizophrenic subjects performed blocks of randomly mixed prosaccade and antisaccade trials. This gave rise to four trial types: prosaccades and antisaccades that were either repeated or switched. Response accuracy and latency were measured. Schizophrenic subjects also performed the WCST. Results: Schizophrenic subjects showed abnormal antisaccade and WCST performance. In contrast, task switching was normal and unrelated to either antisaccade or WCST performance. Conclusions: The finding of intact task switching performance that is unrelated to other measures of executive function demonstrates selective rather than general impairments of executive functions in schizophrenia. The findings also suggest that abnormal WCST performance is unlikely to be a consequence of deficient task switching. We hypothesize that inhibition and task switching are mediated by distinct neural networks, only one of which is dysfunctional in schizophrenia. (C) 2002 Society of Biological Psychiatry. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Neurol Human Vis & Eye Movement Lab, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02215 USA. RP Manoach, DS (reprint author), Massachusetts Gen Hosp E, MGH NMR Ctr, Room 9121,149 13th St, Charlestown, MA 02129 USA. RI Barton, Jason/A-6362-2012 FU NIMH NIH HHS [K23 MH 01829] NR 41 TC 66 Z9 66 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2002 VL 51 IS 10 BP 816 EP 826 AR PII S0006-3223(01)01356-7 DI 10.1016/S0006-3223(01)01356-7 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 550LF UT WOS:000175504000006 PM 12007456 ER PT J AU Sawyers, CL Hochhaus, A Feldman, E Goldman, JM Miller, CB Ottmann, OG Schiffer, CA Talpaz, M Guilhot, F Deininger, MWN Fischer, T O'Brien, SG Stone, RM Gambacorti-Passerini, CB Russell, NH Reiffers, JJ Shea, TC Chapuis, B Coutre, S Tura, S Morra, E Larson, RA Saven, A Peschel, C Gratwohl, A Mandelli, F Ben-Am, M Gathmann, I Capdeville, R Paquette, RL Druker, BJ AF Sawyers, CL Hochhaus, A Feldman, E Goldman, JM Miller, CB Ottmann, OG Schiffer, CA Talpaz, M Guilhot, F Deininger, MWN Fischer, T O'Brien, SG Stone, RM Gambacorti-Passerini, CB Russell, NH Reiffers, JJ Shea, TC Chapuis, B Coutre, S Tura, S Morra, E Larson, RA Saven, A Peschel, C Gratwohl, A Mandelli, F Ben-Am, M Gathmann, I Capdeville, R Paquette, RL Druker, BJ TI Imatinib induces hematologic and cytogenetic responses in patients with chronic myelogenous leukemia in myeloid blast crisis: results of a phase II study SO BLOOD LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-Society-of-Hematology CY DEC 07-11, 2001 CL ORLANDO, FL SP Amer Soc Hematol ID TYROSINE KINASE INHIBITOR; BONE-MARROW-TRANSPLANTATION; CHRONIC GRANULOCYTIC-LEUKEMIA; ABL-POSITIVE CELLS; BCR-ABL; PHILADELPHIA-CHROMOSOME; ACCELERATED PHASE; DOSE CYTARABINE; TERMINAL-PHASE; THERAPY AB Blast crisis Is the most advanced stage of chronic myelogenous leukemia (CML) and Is highly refractory to therapy. CML is caused by expression of the chimeric BCR-ABL tyrosine kinase oncogene, the product of the t(9;22) Philadelphia translocation. Imatinib (Glivec, formerly STI571) is a rationally developed, orally administered inhibitor of the Bcr-Abl tyrosine kinase. A total of 260 patients with CML were enrolled in a phase 11 trial, of whom 229 had a confirmed diagnosis of CML in blast crisis. Patients were treated with imatinib in daily oral doses of 400 mg or 600 mg. Imatinib induced hematologic responses in 52% of patients and sustained hematologic responses lasting at least 4 weeks in 31% of patients, including complete hematologic responses in 8%. For patients with a sustained response, the estimated median response duration was 10 months. Imatinib Induced major cytogenetic responses in 16% of patients, with 7% of the responses being complete. Median survival time was 6.9 months. Nonhematologic adverse reactions were frequent but generally mild or moderate. Episodes of severe cytopenia were also frequent and were attributable to the underlying condition and treatment with Imatinib. Drug-related adverse events led to discontinuation of therapy in 5% of patients, most often because of cytopenia, skin disorders, or gastrointestinal reactions. These results demonstrate that imatinib has substantial activity and a favorable safety profile when used as a single agent in patients with CML in blast crisis. Additional clinical studies are warranted to explore the efficacy and feasibility of imatinib used in combination with other antileukemic drugs. (C) 2002 by The American Society of Hematology. C1 Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. Univ Heidelberg, Med Klin Mannheim 3, D-6800 Mannheim, Germany. Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, New York, NY USA. Hammersmith Hosp, ICSM, Dept Haematol, London, England. Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21205 USA. Goethe Univ Frankfurt, Med Klin 3, D-6000 Frankfurt, Germany. Wayne State Univ, Barbara Ann Karmanos Canc Inst, Detroit, MI USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. CHU Poitiers, Dept Oncol Hematol & Cell Therapy, Poitiers, France. Univ Leipzig, Abt Haematol Onkol, Leipzig, Germany. Univ Mainz Klinikum, Med Klin & Poliklin 3, Mainz, Germany. Newcastle Univ, Royal Victoria Infirm, Dept Haematol, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. Dana Farber Canc Inst, Boston, MA 02115 USA. Osped San Gerardo, Hematol Sect, Monza, Italy. Natl Canc Inst, Dept Expt Oncol, I-20133 Milan, Italy. City Hosp Nottingham, Dept Haematol, Nottingham, England. Univ Victor Segalen, Lab Gregge Moelle, Bordeaux, France. Univ N Carolina, Div Hematol Oncol, Chapel Hill, NC USA. Hop Cantonal Univ Geneva, Div Hematol, Geneva, Switzerland. Stanford Univ, Sch Med, Div Hematol, Stanford, CA 94305 USA. Osped Policlin Sant Orsola Malpighi, Inst Ematol, Bologna, Italy. Azienda Osped Niguarda Ca Granda, Div Ematol, Milan, Italy. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Scripps Res Inst, Ida & Cecil Green Canc Ctr, La Jolla, CA USA. Tech Univ Munich, Med Klin & Poliklin 3, Munich, Germany. Univ Klin Kantonspital, Div Hematol, Basel, Switzerland. Univ Roma La Sapienza, Azienda Policlin Umberto I, Dipartimento Biotechnol Cedulari & Ematol, Rome, Italy. Novartis Pharmaceut, Basel, Switzerland. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Oregon Hlth & Sci Univ, Div Hematol, Portland, OR 97201 USA. RP Sawyers, CL (reprint author), Univ Calif Los Angeles, Dept Med, 11-934 Factor Bldg,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM csawyers@mednet.ucla.edu RI Ottmann, Oliver/D-5007-2016; Sawyers, Charles/G-5327-2016; OI Ottmann, Oliver/0000-0001-9559-1330; GAMBACORTI PASSERINI, CARLO/0000-0001-6058-515X; Larson, Richard/0000-0001-9168-3203; Hochhaus, Andreas/0000-0003-0626-0834 NR 49 TC 829 Z9 883 U1 2 U2 26 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 MAY 15 PY 2002 VL 99 IS 10 BP 3530 EP 3539 DI 10.1182/blood.V99.10.3530 PG 10 WC Hematology SC Hematology GA 550GY UT WOS:000175496300010 PM 11986204 ER PT J AU Fonseca, R Blood, EA Oken, MM Kyle, RA Dewald, GW Bailey, RJ Van Wier, SA Henderson, KJ Hoyer, JD Harrington, D Kay, NE Van Ness, B Greipp, PR AF Fonseca, R Blood, EA Oken, MM Kyle, RA Dewald, GW Bailey, RJ Van Wier, SA Henderson, KJ Hoyer, JD Harrington, D Kay, NE Van Ness, B Greipp, PR TI Myeloma and the t(11;14)(q13;q32); evidence for a biologically defined unique subset of patients SO BLOOD LA English DT Article ID IN-SITU HYBRIDIZATION; MANTLE CELL LYMPHOMA; CYCLIN D1 PROTEIN; MULTIPLE-MYELOMA; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; CLINICAL-SIGNIFICANCE; SWITCH REGIONS; TRANSLOCATIONS; EXPRESSION AB The t(11;14)(q13;q32) results In up-regulation of cyclin D1 and is the most common translocation detected in multiple myeloma, where it is also associated with a lymphoplasmacytic morphology. We performed an interphase fluorescent in situ hybridization (FISH) study to determine the clinical and biologic significance of the abnormality when testing a large cohort of myeloma patients. Bone marrow slides from multiple myeloma patients entered into the Eastern Cooperative Oncology Group phase III clinical trial E9486 and associated laboratory correlative study E9487 were analyzed using interphase FISH combined with immune-fluorescent (cytoplasmic immunoglobulin-FISH) detection of clonal plasma cells. We used FISH probes that hybridize to the 14q32 and 11q13 chromosomal loci. The t(11;14)(q13;q32) was correlated with known biologic and prognostic factors. Of 336 evaluable patients, 53 (16%) had abnormal FISH patterns compatible with the t(11;14)(q13;q32). These patients appeared to be more likely to have a serum monoclonal protein of less than 10 g/L (11 g/dL) (28% vs 15%, P = .029) and a lower plasma cell labeling index (P = .09). More strikingly, patients were less likely to be hyperdiploid by DNA content analysis (n = 251, 14% vs 62%, P < .001). Patients with the t(11;14)(q13;q32) appeared to have better survival and response to treatment, although this did not reach statistical significance. Multiple myeloma with the t(11;1 4)(q13;q32) is a unique subset of patients, not only characterized by cyclin D1 up-regulation and a lymphoplasmacytic morphology, but is also more frequently associated with small serum monoclonal proteins and is much less likely to be hyperdiploid. These patients do not have a worsened prognosis as previously thought. (C) 2002 by The American Society of Hematology. C1 Mayo Clin, Dana Farber Canc Inst, Div Hematol & Internal Med, Dept Pathol & Lab Med, Rochester, MN 55905 USA. Dana Farber Canc Inst, ECOG Stat Ctr, Boston, MA 02115 USA. Virginia Piper Canc Inst, Minneapolis, MN USA. Univ Minnesota, Minneapolis, MN USA. RP Fonseca, R (reprint author), Mayo Clin, Dana Farber Canc Inst, Div Hematol & Internal Med, Dept Pathol & Lab Med, Mayo Bldg W10B, Rochester, MN 55905 USA. OI Fonseca, Rafael/0000-0002-5938-3769 FU NCI NIH HHS [CA21115-25C, CA62242, R01 CA83724-01] NR 44 TC 171 Z9 179 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 MAY 15 PY 2002 VL 99 IS 10 BP 3735 EP 3741 DI 10.1182/blood.V99.10.3735 PG 7 WC Hematology SC Hematology GA 550GY UT WOS:000175496300036 PM 11986230 ER PT J AU Abe, M Qi, J Sykes, M Yang, YG AF Abe, M Qi, J Sykes, M Yang, YG TI Mixed chimerism induces donor-specific T-cell tolerance across a highly disparate xenogeneic barrier SO BLOOD LA English DT Article ID BONE-MARROW CHIMERAS; SKIN ALLOGRAFT TOLERANCE; CLASS II+ CELLS; XENOGRAFT REJECTION; TRANSPLANTATION TOLERANCE; MULTIPLE DEFECTS; GRAFT-REJECTION; SCID MICE; B-CELLS; INDUCTION AB Induction of tolerance is likely to be essential for successful xenotransplantation because immune responses across xenogeneic barriers are vigorous. Although mixed hematopoietic chimerism leads to stable donor-specific tolerance in allogeneic and closely related xenogeneic (eg, rat-to-mouse) combinations, the ability of this approach to induce tolerance across a highly disparate xenogeneic barrier has not yet been demonstrated. In this study, we investigated the immune responses of murine T cells that developed in mice with pre-established porcine hematopoietic chimerism. Our results show for the first time that induction of porcine hematopoietic chimerism can eliminate the development of antiporcine donor responses in a highly disparate xenogeneic species. Porcine hematopoietic chimeras showed donor-specific nonresponsiveness in the mixed lymphocyte reaction, lack of antidonor IgG antibody production, and acceptance of donor skin grafts. Thus, mixed chimerism is capable of inducing tolerance in a highly disparate xenogeneic combination and may have clinical potential to prevent xenograft rejection. (C) 2002 by The American Society of Hematology. C1 Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Surg Serv,Med Sch, Boston, MA 02129 USA. RP Yang, YG (reprint author), Harvard Univ, Transplantat Biol Res Ctr, Massachusetts Gen Hosp, Surg Serv,Med Sch, MGH E,Bldg 149-5202,13th St, Boston, MA 02129 USA. NR 42 TC 34 Z9 37 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 MAY 15 PY 2002 VL 99 IS 10 BP 3823 EP 3829 DI 10.1182/blood.V99.10.3823 PG 7 WC Hematology SC Hematology GA 550GY UT WOS:000175496300048 PM 11986242 ER PT J AU Fitzek, MM Thornton, AF Varvares, M Ancukiewicz, M Mcintyre, J Adams, J Rosenthal, S Joseph, M Amrein, P AF Fitzek, MM Thornton, AF Varvares, M Ancukiewicz, M Mcintyre, J Adams, J Rosenthal, S Joseph, M Amrein, P TI Neuroendocrine tumors of the sinonasal tract - Results of a prospective study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy SO CANCER LA English DT Article DE esthesioneuroblastoma; sinonasal tract; chemotherapy; radiotherapy; proton therapy; surgery ID OF-VIRGINIA EXPERIENCE; OLFACTORY NEUROBLASTOMA; RADIATION-THERAPY; NASAL CAVITY; ESTHESIONEUROBLASTOMA; CARCINOMA AB BACKGROUND. The authors report the results of a prospective study of patients with malignant neuroendocrine tumors of the sinonasal tract who received multimodality treatment incorporating high-dose proton-photon radiotherapy. METHODS. Nineteen patients with olfactory neuroblastoma (ONB) or neuroendocrine carcinoma (NEC) were treated between 1992 and 1998 on a prospective study. Four patients had Kadish Stage B disease, and 15 patients had Kadish Stage C disease. The median patient age was 44 years. Patients received chemotherapy with 2 courses of cisplatin and etoposide followed by high-dose proton-photon radiotherapy to 69.2 cobalt-Gray equivalents (CGE) using 1.6-1.8 CGE per fraction twice daily in a concomitant boost schedule. Two further courses of chemotherapy were given to responders. RESULTS. Of 19 patients, 15 patients were alive at the time of this report with a median follow-up of 45 months (range, 20-92 months). Four patients died from disseminated disease 8-47 months after their original diagnosis. The 5-year survival rate was 74%. There were two local recurrences, and both patients underwent salvage surgery. The 5-year local control rate of initial treatment was 88%. Acute toxicity of chemotherapy was tolerable, with no patient sustaining more than Grade 3 hematologic toxicity. Thirteen patients showed a partial or complete response to chemotherapy. One patient developed unilateral visual loss after the first course of chemotherapy; otherwise, visual preservation was achieved in all patients. Four patients who were clinically intact developed radiation-induced damage to the frontal or temporal lobe by magnetic resonance imaging criteria. Two patients showed soft tissue and/or bone necrosis, and one of these patients required surgical repair of a cerebrospinal fluid leak. CONCLUSIONS. Neoadjuvant chemotherapy and high-dose proton-photon radiotherapy is a successful treatment approach for patients with ONB and NEC. Radical surgery is reserved for nonresponders. Due to the precision of delivery of radiation with stereotactic setup and protons, no radiation-induced visual loss was observed. (C) 2002 American Cancer Society. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiat Oncol, Boston, MA USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ear Nose & Throat Surg, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Hematol & Oncol, Boston, MA USA. RP Fitzek, MM (reprint author), Univ Essen Gesamthsch, Dept Radiat Therapy, Hufeldandstr 55, D-45122 Essen, Germany. FU NCI NIH HHS [P01 CA 21239] NR 30 TC 68 Z9 75 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2002 VL 94 IS 10 BP 2623 EP 2634 DI 10.1002/cncr.10537 PG 12 WC Oncology SC Oncology GA 548JA UT WOS:000175383800015 PM 12173330 ER PT J AU Chang, SM Barker, FG Schmidt, MH Sloan, AE Kasper, R Phillips, L Shih, K Hariharan, S Berger, MS AF Chang, SM Barker, FG Schmidt, MH Sloan, AE Kasper, R Phillips, L Shih, K Hariharan, S Berger, MS CA Glioma Outcomes Investigators TI Clinical trial participation among patients enrolled in the Glioma Outcomes Project SO CANCER LA English DT Article; Proceedings Paper CT 5th Annual Meeting of the Society-of-Neuro-Oncology CY NOV 09-13, 2000 CL CHICAGO, ILLINOIS SP Soc Neuro Oncol DE glioblastoma multiforme; glioma; clinical trials participation; outcomes ID CANCER-TREATMENT TRIALS; AFRICAN-AMERICANS; RADIATION-THERAPY; MALIGNANT GLIOMAS; ELDERLY PATIENTS; ONCOLOGY-GROUP; MANAGED CARE; GLIOBLASTOMA-MULTIFORME; MINORITY POPULATIONS; ATTITUDES AB BACKGROUND. Patient participation in well-designed and conducted clinical trials enables researchers to test new therapies. An understanding of the variables that possibly influence patient enrollment may help in patient recruitment for future trials. The authors evaluated factors that influenced patient enrollment in clinical trials using a prospective, large, multi-institutional registry of patients with malignant glioma. METHODS. Data were examined from 708 patients who underwent first or second surgery for a malignant glioma who were enrolled in the Glioma Outcomes Project, which is a prospective observational data base that captures clinical practice patterns. The frequency of clinical trial participation and the variables that may have been associated with trial participation were evaluated, These variables included age, gender, race, household income, educational level, first versus second craniotomy, histology, and whether the patient was treated at an academic institution. RESULTS. One hundred fifty-one of 708 patients (21.3%) participated in a clinical trial, which was higher than the participation reported typically for patients with other types of primary malignancies. In univariate analysis, race, histology, and first craniotomy were significant between (lie two groups, with Caucasian patients and patients with glioblastoma histology showing higher participation rates. In a multivariate logistic regression model, significant predictors included young age and glioblastoma multiforme histology. CONCLUSIONS. The authors present information on factors that may influence clinical trial participation among patients with malignant glioma and compare their data with information described previously on patients with other types of malignant disease, The percent of participation among the patients in the current study was greater than among patients with other primary tumor sites. Strategies should be implemented to improve recruitment to neuro-oncology trials, especially in elderly and minority populations. (C) 2002 American Cancer Society. C1 Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Brain Tumor Ctr, Boston, MA 02114 USA. Wayne State Univ, Dept Neurosurg, Detroit, MI USA. Univ Massachusetts, Sch Med, Glioma Outcomes Project, Worcester, MA USA. Univ Washington, Harborview Med Ctr, Dept Neurol, Seattle, WA 98104 USA. John F Kennedy Neurosci Inst, Edison, NJ USA. RP Chang, SM (reprint author), Univ Calif San Francisco, Dept Neurol Surg, 400 Parnassus Ave,A808, San Francisco, CA 94143 USA. NR 91 TC 27 Z9 27 U1 3 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2002 VL 94 IS 10 BP 2681 EP 2687 DI 10.1002/cncr.10536 PG 7 WC Oncology SC Oncology GA 548JA UT WOS:000175383800022 PM 12173337 ER PT J AU Bell, DW Erban, J Sgroi, DC Haber, DA AF Bell, DW Erban, J Sgroi, DC Haber, DA TI Selective loss of heterozygosity in multiple breast cancers from a carrier of mutations in both BRCA1 and BRCA2 SO CANCER RESEARCH LA English DT Article ID OVARIAN-CANCER; GENES AB Carriers of one mutant allele of either BRCA1 or BRCA2 are at risk for somatic loss of the second wild-type allele, leading to the initiation of breast tumorigenesis. We identified a patient of Ashkenazi Jewish heritage with germ-line heterozygous mutations in both BRCA1 (5382insC) and BRCA2 (6174delT), who had developed three independent breast cancers by age 47. Two breast cancers demonstrated inactivation of both BRCA2 alleles but retention of the wild-type BRCA1 allele, and the third showed loss of heterozygosity for BRCA1 but not BRCA2. The observation that breast tumors arising in a double heterozygote show biallelic inactivation of either BRCA1 or BRCA2, but not both, suggests that these genetic events are functionally equivalent in initiating tumorigenesis. The distinct histopathological features of these tumors may reflect the acquisition of subsequent genetic events. C1 Massachusetts Gen Hosp, Ctr Canc Risk Anal, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Mol Pathol Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Tufts Univ New England Med Ctr, Div Hematol Oncol, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Erban, J (reprint author), Massachusetts Gen Hosp, Ctr Canc, CNY 7,Bldg 149,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [CA 87691, U10 CA 07190] NR 11 TC 20 Z9 20 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2002 VL 62 IS 10 BP 2741 EP 2743 PG 3 WC Oncology SC Oncology GA 552ZR UT WOS:000175650900003 PM 12019146 ER PT J AU Sharpless, NE Alson, S Chan, S Silver, DP Castrillon, DH DePinho, RA AF Sharpless, NE Alson, S Chan, S Silver, DP Castrillon, DH DePinho, RA TI p16(INK4a) and p53 deficiency cooperate in tumorigenesis SO CANCER RESEARCH LA English DT Article ID MAMMARY TUMORIGENESIS; MICE; SENESCENCE; P19(ARF); GROWTH; INACTIVATION; INSTABILITY; METHYLATION; RADIATION; CELLS AB The combined impact of mutations in p16(INK4a) and p53 was examined in cellular growth, transformation, and tumor formation. In cultured cells, p16(INK4a) loss enhanced growth at high density and conferred susceptibility to oncogene-induced transformation. In vivo, mice doubly deficient for p16(INK4a) and p53 showed an increased rate of tumor formation with particular susceptibility to aggressive angiosarcomas. Furthermore, p16(INK4a) silencing by promoter methylation was detected in tumors derived from P16(INK4a+/-) and (+/+) mice, independent of p53 status. These data suggest at least one general feature of malignancy, resistance to density-mediated growth arrest depends on p16(INK4a) rather than p53. This cooperation between p16(INK4a) and p53 loss in tumorigenesis is consistent with the view that these genes function in distinct anticancer pathways. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. RP DePinho, RA (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St M413, Boston, MA 02115 USA. NR 25 TC 51 Z9 52 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2002 VL 62 IS 10 BP 2761 EP 2765 PG 5 WC Oncology SC Oncology GA 552ZR UT WOS:000175650900008 PM 12019151 ER PT J AU Miller, DP Liu, G De Vivo, I Lynch, TJ Wain, JC Su, L Christiani, DC AF Miller, DP Liu, G De Vivo, I Lynch, TJ Wain, JC Su, L Christiani, DC TI Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk SO CANCER RESEARCH LA English DT Article ID GLUTATHIONE-S-TRANSFERASE; GENE-ENVIRONMENT INTERACTIONS; SAMPLE-SIZE CALCULATIONS; GLOBAL GENOMIC REPAIR; CODON-72 POLYMORPHISM; CIGARETTE-SMOKING; AFRICAN-AMERICANS; HUMAN-CELLS; DNA-DAMAGE; SUSCEPTIBILITY AB GSTP1 and GSTM1 are genes involved in Phase 11 metabolism, whereas p53 is a tumor suppressor gene. Individually, functional polymorphisms of these genes have been studied as risk factors for lung cancer. Small sample sizes have hindered the detection of possible increases in risk associated with having two or more "at risk" polymorphisms of these three genes. In a large Caucasian population, we examined the association of combined variant genotypes [or double-variants (DVs)] of these three genes and lung cancer risk, compared with their corresponding "double-wild-type" genotypes. Because these DVs may promote lung carcinogenesis at an earlier age, a subgroup of individuals aged 55 years or younger was examined separately. Using a case-control design, individuals were genotyped for GSTM1, GSTP1, and p53 codon 72 using PCR-RFLP techniques. All of the analyses used multiple logistic regression. Indicator variables were created to evaluate the risk for individuals with the following DVs: GSTP1 G,G + GSTM1-null and GSTP1 GG + p53 Arg/Pro or Pro/Pro. A total of 1694 cases and controls were evaluated. In the whole population, those with the double variants have a higher risk of lung cancer when compared with those with the double- wild-type genotypes, supporting our original hypothesis. Individuals with the GSTP1 and GSTM1, DV (P1-M1 DV) had a marginally significant higher risk of lung cancer compared with their double-wild-type counterparts [adjusted odds ratio (AOR), 1.60; 95% confidence interval (CI), 0.95-2.70]. A significantly higher risk was found for the GSTP1, p53 DV (P1-p53 DV; AOR, 1.99; 95% CI, 1.12-3.53). Among individuals aged 55 or younger, these risks were even higher: for the P1-M1 DV the AOR was 4.03 (95% CI, 1.47-11.1); for the P1-p53 DV the AOR was 5.10 (95% CI, 1.42-18.30). Specific DVs of GSTM1, GSTP1, and p53 codon 72 are associated with a higher lung cancer risk. This susceptibility is highest among younger individuals. C1 Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Environm Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Sch Med, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Sch Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hematol Oncol Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Thorac Surg Unit, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Pulm & Crit Care Unit, Boston, MA 02114 USA. RP Christiani, DC (reprint author), Harvard Univ, Sch Publ Hlth, Occupat Hlth Program, Dept Environm Hlth, 665 Huntington Ave,Bldg 1 Room 1407, Boston, MA 02115 USA. RI Liu, Geoffrey/N-4421-2016 FU NCI NIH HHS [CA 74386]; NIEHS NIH HHS [ES/CA 06409, ES 00002] NR 41 TC 97 Z9 110 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2002 VL 62 IS 10 BP 2819 EP 2823 PG 5 WC Oncology SC Oncology GA 552ZR UT WOS:000175650900016 PM 12019159 ER PT J AU Batchu, RB Shammas, MA Wang, JY Freeman, J Rosen, N Munshi, NC AF Batchu, RB Shammas, MA Wang, JY Freeman, J Rosen, N Munshi, NC TI Adeno-associated virus protects the retinoblastoma family of proteins from adenoviral-induced functional inactivation SO CANCER RESEARCH LA English DT Article ID REP-GENE; TRANSCRIPTION FACTOR; GROWTH-INHIBITION; HUMAN-CELLS; WILD-TYPE; PRODUCT; TRANSFORMATION; REPLICATION; GENOME AB Adeno-associated virus type 2 (AAV) is known to inhibit virally mediated oncogenic transformation. One of the early events of adenovirus (Ad) infection is the functional inactivation of cell cycle regulatory retinoblastoma (RB) family of proteins, which consists of retinoblastoma protein (pRB), p107. and p130. In an effort to understand the molecular basis of anti-oncogenic properties of AAV, we studied the effects of AAV expression on these proteins in cells infected with Ad. Western blot analysis showed that AAV interferes with the adenoviral-induced degradation and hyperphosphorylation of the pRB family of proteins in normal human fibroblasts as well as in HeLa and 293 cell lines. RNase protection assay showed enhanced expression of pocket protein gene by AAV expression. We also demonstrate that Rep proteins, the major AAV regulatory proteins, bind to E1A, the immediate early gene of Ad responsible for hyperphosphorylation and dissociation of pRB-E2F complex. This binding of AAV Rep proteins to E1A leads to decreased association between E1A and pRB leading to protection of pocket proteins from degradation, decreased expression of S phase genes and inhibition of cell cycle progression. These results suggest that the antiproliferative activity of AAV against Ad is mediated, at least in part, by effects of AAV Rep proteins on the Rb family of proteins. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Arkansas Med Sci, Myeloma & Transplantat Res Ctr, Little Rock, AR 72205 USA. Univ Arkansas Med Sci, Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA. RP Munshi, NC (reprint author), Dana Farber Canc Inst, 44 Binney St,M557, Boston, MA 02115 USA. FU NCI NIH HHS [CA 71092] NR 25 TC 9 Z9 11 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2002 VL 62 IS 10 BP 2982 EP 2985 PG 4 WC Oncology SC Oncology GA 552ZR UT WOS:000175650900039 PM 12019182 ER PT J AU Mylonakis, E Kallas, WM Fishman, JA AF Mylonakis, E Kallas, WM Fishman, JA TI Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID STEM-CELL TRANSPLANTATION; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; MUTATIONS; RETINITIS; EMERGENCE; STRAINS; DISEASE; ASSAY; UL97 AB The resistance of cytomegalovirus (CMV) to ganciclovir is a factor in therapeutic failure and disease progression. The clinical significance of such resistance in solid-organ transplantation has not been completely established. Six patients who developed persistent infection due to ganciclovir-resistant CMV were treated with a combination of ganciclovir (50% of the therapeutic dose) and a daily dose of intravenous foscarnet that gradually increased to a maximum of 125 mg/kg. All patients responded clinically within 72-96 hours. Magnesium depletion occurred in all patients. No clinical or laboratory relapses have been observed in 6-30 months of follow-up. Gradually increasing doses of foscarnet combined with half-dose regimens of ganciclovir are safe and can be beneficial in organ transplant recipients with ganciclovir-resistant CMV infection. Larger studies are needed to identify the patients who are most likely to benefit from this regimen. C1 Harvard Univ, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Dept Microbiol, Boston, MA 02114 USA. RP Fishman, JA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Div Infect Dis, GRJ-504,55 Fruit St, Boston, MA 02114 USA. FU NIAID NIH HHS [P01-AI45897] NR 24 TC 59 Z9 68 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAY 15 PY 2002 VL 34 IS 10 BP 1337 EP 1341 DI 10.1086/340101 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 546XF UT WOS:000175301100007 PM 11981729 ER PT J AU Qian, Y Shirasawa, S Chen, CL Cheng, LP Ma, QF AF Qian, Y Shirasawa, S Chen, CL Cheng, LP Ma, QF TI Proper development of relay somatic sensory neurons and D2/D4 interneurons requires homeobox genes Rnx/Tlx-3 and Tlx-1 SO GENES & DEVELOPMENT LA English DT Article DE Rnx; Tlx-1; MASH 1; DRG11; trkA; somatic sensory; D2; D4 interneurons ID MOUSE SPINAL-CORD; NERVOUS-SYSTEM DEVELOPMENT; SEMAPHORIN-III; COMMISSURAL INTERNEURONS; EXPRESSION PATTERNS; VERTEBRATE SLIT; AXON GUIDANCE; HOX11 GENE; PROTEIN; CNS AB Trigeminal nuclei and the dorsal spinal cord are first-order relay stations for processing somatic sensory information such as touch, pain, and temperature. The origins and development of these neurons are poorly understood. Here we show that relay somatic sensory neurons and D2/D4 dorsal interneurons likely derive from Mash1-positive neural precursors, and depend on two related homeobox genes, Rnx and Tlx-1, for proper formation. Rnx and Tlx-1 maintain expression of Drg11, a homeobox gene critical for the development of pain circuitry, and are essential for the ingrowth of trkA+ nociceptive/thermoceptive sensory afferents to their central targets. We showed previously that Rnx is necessary for proper formation of the nucleus of solitary tract, the target for visceral sensory afferents. Together, our studies demonstrate a central role for Rnx and Tlx-1 in the development of two major classes of relay sensory neurons, somatic and visceral. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02115 USA. Int Med Ctr Japan, Dept Pathol, Tokyo 1628655, Japan. RP Ma, QF (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. FU NIDCR NIH HHS [R01 DE013843, 1 R01 DE13843-01] NR 62 TC 86 Z9 88 U1 1 U2 3 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAY 15 PY 2002 VL 16 IS 10 BP 1220 EP 1233 DI 10.1101/gad.982802 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 555UJ UT WOS:000175811400006 PM 12023301 ER PT J AU Rivolta, C Sharon, D DeAngelis, MM Dryja, TP AF Rivolta, C Sharon, D DeAngelis, MM Dryja, TP TI Retinitis pigmentosa and allied diseases: numerous diseases, genes, and inheritance patterns SO HUMAN MOLECULAR GENETICS LA English DT Review ID BARDET-BIEDL-SYNDROME; BLUE CONE MONOCHROMACY; KEARNS-SAYRE SYNDROME; GREEN COLOR-VISION; MOLECULAR-GENETICS; MACULAR DEGENERATION; RETINAL DYSTROPHY; GYRATE ATROPHY; BIMODAL EXPRESSIVITY; FUNDUS-ALBIPUNCTATUS AB Retinitis pigmentosa (RP) and allied diseases are heterogeneous clinically and genetically. Here we summarize the retinal cell types involved in these diseases, the large number of genes that cause them, and the variety of inheritance patterns that the affected families display. Special consideration is given to unusual inheritance patterns. The aggregate carrier frequency for recessive RP alleles may be as high as 10%. C1 Harvard Univ, Sch Med, Ocular Mol Genet Inst, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Dryja, TP (reprint author), Harvard Univ, Sch Med, Ocular Mol Genet Inst, 243 Charles St, Boston, MA 02114 USA. RI DeAngelis, e/J-7863-2015; Sharon, Dror/P-4539-2015 OI Sharon, Dror/0000-0002-1789-5811 FU NEI NIH HHS [EY08683, EY11655] NR 106 TC 165 Z9 184 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2002 VL 11 IS 10 SI SI BP 1219 EP 1227 DI 10.1093/hmg/11.10.1219 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 556NT UT WOS:000175856400009 PM 12015282 ER PT J AU Ganesh, S Delgado-Escueta, AV Sakamoto, T Avila, MR Machado-Salas, J Hoshii, Y Akagi, T Gomi, H Suzuki, T Amano, K Agarwala, KL Hasegawa, Y Bai, DS Ishihara, T Hashikawa, T Itohara, S Cornford, EM Niki, H Yamakawa, K AF Ganesh, S Delgado-Escueta, AV Sakamoto, T Avila, MR Machado-Salas, J Hoshii, Y Akagi, T Gomi, H Suzuki, T Amano, K Agarwala, KL Hasegawa, Y Bai, DS Ishihara, T Hashikawa, T Itohara, S Cornford, EM Niki, H Yamakawa, K TI Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID GLYCATION END-PRODUCTS; ALZHEIMERS-DISEASE; MAILLARD REACTION; BODY DISEASE; UBIQUITIN; PROTEINS; SYSTEM; STRESS; MODEL AB Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid-Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the central nervous system. To study the pathology of LD and the functions of laforin, we disrupted the Epm2a gene in mice. At two months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibit swelling in the endoplasmic reticulum, Golgi networks and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies become more prominent at 4-12 months, organelles and nuclei are disrupted. The Lafora bodies, present both in neuronal and non-neural tissues, are positive for ubiquitin and advanced glycation end-products only in neurons, suggesting different pathological consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity. Our results suggest that LD is a primary neurodegenerative disorder that may utilize a non-apoptotic mechanism of cell death. C1 RIKEN, Brain Sci Inst, Lab Neurobiol Emot, Wako, Saitama 3510198, Japan. RIKEN, Brain Sci Inst, Lab Neural Architecture, Wako, Saitama 3510198, Japan. RIKEN, Brain Sci Inst, Lab Behav Genet, Wako, Saitama 3510198, Japan. Univ Nacl Autonoma Mexico, Dept Neurociencias, Mexico City 04510, DF, Mexico. Yamaguchi Univ, Sch Med, Dept Pathol 1, Yamaguchi, Japan. VA GLAHS W Los Angeles Med Ctr, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Comprehens Epilepsy Program, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Med, Epilepsy Genet Genom Labs, Los Angeles, CA USA. RIKEN, Brain Sci Inst, Neurogenet Lab, Wako, Saitama 3510198, Japan. RP Delgado-Escueta, AV (reprint author), RIKEN, Brain Sci Inst, Neurogenet Lab, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. RI Ganesh, Subramniam/B-4131-2009; Itohara, Shigeyoshi/I-8769-2012; Yamakawa, Kazuhiro/N-5050-2015 OI Itohara, Shigeyoshi/0000-0002-2410-9989; NR 37 TC 106 Z9 107 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAY 15 PY 2002 VL 11 IS 11 BP 1251 EP 1262 DI 10.1093/hmg/11.11.1251 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 556NQ UT WOS:000175856200001 PM 12019206 ER PT J AU Reiber, GE Smith, DG Wallace, C Sullivan, K Hayes, S Vath, C Maciejewski, ML Yu, OC Heagerty, PJ LeMaster, J AF Reiber, GE Smith, DG Wallace, C Sullivan, K Hayes, S Vath, C Maciejewski, ML Yu, OC Heagerty, PJ LeMaster, J TI Effect of therapeutic footwear on foot reulceration in patients with diabetes - A randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NEUROPATHY; PREVALENCE; POPULATION; PREVENTION; ULCERS; AMPUTATION; PATHWAYS; LESIONS; DISEASE AB Context Many people with diabetes experience lower-limb ulcers. Footwear has been implicated as a primary cause of foot ulcers, yet research is limited on the efficacy of shoe and insert combinations to prevent reulceration. Objective To determine whether extra-depth and -width therapeutic shoes used with 2 types of inserts reduce reulceration in diabetic individuals with a history of foot ulcer. Design, Setting, and Participants Randomized clinical trial of 400 diabetes patients with history of foot ulcer in 2 Washington State health care organizations who did not require custom shoes for foot deformity and were enrolled between August 1997 and December 1998 and followed up for 2 years. Data collected at regular intervals documented physical, foot, and diabetes characteristics; footwear use; foot lesions; and ulcers. Interventions Participants were randomly assigned to receive 3 pairs of therapeutic shoes and 3 pairs of customized medium-density cork inserts with a neoprene closed-cell cover (n=121); to receive 3 pairs of therapeutic shoes and 3 pairs of prefabricated, tapered polyurethane inserts with a brushed nylon cover (n = 119); or to wear their usual footwear (controls; n = 160). Main Outcome Measure Foot reulceration, compared among the 3 groups. Results Two-year cumulative reulceration incidence across the 3 groups was low: 15% in the cork-insert group, 14% in the prefabricated-insert group, and 17% in controls. In the intent-to-treat analysis, patients assigned to therapeutic shoes did not have a significantly lower risk of reulceration compared with controls (risk ratio [RR] for the cork-insert group, 0.88; 95% confidence interval [CI], 0,51-1.52 and RR the for prefabricated-insert group, 0.85; 95% CI, 0.48-1.48). All ulcer episodes in patients assigned to therapeutic shoes and 88% wearing nonstudy shoes occurred in patients with foot insensitivity. Conclusions This study of persons without severe foot deformity does not provide evidence to support widespread dispensing of therapeutic shoes and inserts to diabetic patents with a history of foot ulcer. Study shoes and custom cork or preformed polyurethane inserts conferred no significant ulcer reduction compared with control footwear. This study suggests that careful attention to foot care by health care professionals may be more important than therapeutic footwear but does not negate the possibility that special footwear is beneficial in persons with diabetes who do not receive such close attention to foot care by their health care providers or in individuals with severe foot deformities. C1 Dept Vet Affairs, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Orthopaed Surg, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Dept Family Med, Seattle, WA 98195 USA. Swedish Med Ctr, Joslin Diabet Ctr, Seattle, WA USA. RP Reiber, GE (reprint author), Dept Vet Affairs, VA Puget Sound Hlth Care Syst, 152,1660 Columbian Way, Seattle, WA 98108 USA. NR 32 TC 100 Z9 102 U1 3 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 15 PY 2002 VL 287 IS 19 BP 2552 EP 2558 DI 10.1001/jama.287.19.2552 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 551MV UT WOS:000175566200024 PM 12020336 ER PT J AU Silverman, LR Demakos, EP Peterson, BL Kornblith, AB Holland, JC Odchimar-Reissig, R Stone, RM Nelson, D Powell, BL DeCastro, CM Ellerton, J Larson, RA Schiffer, CA Holland, JF AF Silverman, LR Demakos, EP Peterson, BL Kornblith, AB Holland, JC Odchimar-Reissig, R Stone, RM Nelson, D Powell, BL DeCastro, CM Ellerton, J Larson, RA Schiffer, CA Holland, JF TI Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; RECOMBINANT-HUMAN-ERYTHROPOIETIN; BONE-MARROW TRANSPLANTATION; STEM-CELL TRANSPLANTATION; DOSE CYTOSINE-ARABINOSIDE; 13-CIS RETINOIC ACID; CHRONIC MYELOMONOCYTIC LEUKEMIA; FETAL HEMOGLOBIN PRODUCTION; ACUTE MYELOID-LEUKEMIA; PHASE-II TRIAL AB Purpose: Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza C) was active in patients with high-risk MDS. Patients and Methods: A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m(2)/d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C. Results: Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P < .001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P = .007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P = .001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P = .03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C. Conclusion: Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study. (C) 2002 by American Society of Clinical Oncology. C1 Mt Sinai Sch Med, New York, NY USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. SUNY Syracuse, Sch Med, Syracuse, NY USA. Duke Univ, Med Ctr, Canc & Leukemia Grp B, Ctr Stat, Durham, NC 27706 USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Med Ctr S Nevada, Community Clin Oncol Program, Las Vegas, NV USA. Univ Chicago, Chicago, IL 60637 USA. Wayne State Univ, Detroit, MI USA. RP Silverman, LR (reprint author), CUNY, Mt Sinai Med Ctr, Div Med Oncol, Box 1129,1 Gustave L Levy Pl, New York, NY 10029 USA. OI Larson, Richard/0000-0001-9168-3203 FU NCI NIH HHS [CA 31946, CA 33601] NR 88 TC 985 Z9 1007 U1 2 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 15 PY 2002 VL 20 IS 10 BP 2429 EP 2440 DI 10.1200/JCO.2002.04.117 PG 12 WC Oncology SC Oncology GA 552ET UT WOS:000175606900004 PM 12011120 ER PT J AU Kornblith, AB Herndon, JE Silverman, LR Demakos, EP Odchimar-Reissig, R Holland, JF Powell, BL DeCastro, C Ellerton, J Larson, RA Schiffer, CA Holland, JC AF Kornblith, AB Herndon, JE Silverman, LR Demakos, EP Odchimar-Reissig, R Holland, JF Powell, BL DeCastro, C Ellerton, J Larson, RA Schiffer, CA Holland, JC TI Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: A cancer and leukemia group B study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID MIXTURE-MODELS; QLQ-C30; SCORES AB Purpose: The impact of azacyticline (Aza C) on the quality of life of 191 patients with myelodysplastic syndrome was assessed in a phase III Cancer and Leukemia Group B trial (9221). Patients and Methods: One hundred ninety-one-patients (mean age, 67.5 years; 69% male) were randomized to receive either Aza C (75 mg/m(2) subcutaneous for 7 days every 4 weeks) or supportive care, with supportive care patients crossing over to Aza C upon disease progression. Quality of life was assessed by centrally conducted telephone interviews at baseline and days 50, 106, and 182. Overall quality of life, psychological state, and social functioning were assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and the Mental Health Inventory (MHI). Results: Patients on the Aza C arm experienced significantly greater improvement in fatigue (EORTC, P = .001), dyspnea (EORTC, P = .0014), physical functioning (EORTC, P = .0002), positive affect (MHI, P = .0077), and psychological distress (MHI, P = .015) over the course of the study period than those in the supportive care arm. Particularly striking were improvements in fatigue and psychological state (MHI) in patients treated with Aza C compared with those receiving supportive care for patients who remained on study through at least day 106, corresponding to four cycles of Aza C. Significant differences between the two groups in quality of life were maintained even after controlling for the number of RBC transfusions. Conclusion: Improved quality of life for patients treated with Aza C coupled with significantly greater treatment response and delayed time to transformation to acute myeloid leukemia or death compared with patients on supportive care (P < .001) establishes Aza C as an important treatment option for myelodysplastic syndrome. (C) 2002 by American Society of Clinical Oncology. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Womens Canc Program, Boston, MA 02115 USA. Duke Univ, Med Ctr, Canc & Leukemia Grp B, Ctr Stat, Durham, NC 27706 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY 10021 USA. Mt Sinai Sch Med, New York, NY USA. Univ Nevada, Med Ctr, S Nevada Community Clin Oncol Program, Las Vegas, NV 89154 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Wayne State Univ, Sch Med, Barbara Ann Karmanos Canc Inst, Detroit, MI USA. RP Kornblith, AB (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Womens Canc Program, 44 Binney St,Rm D1210, Boston, MA 02115 USA. OI Larson, Richard/0000-0001-9168-3203 FU NCI NIH HHS [CA 31946] NR 18 TC 207 Z9 211 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 15 PY 2002 VL 20 IS 10 BP 2441 EP 2452 DI 10.1200/JCO.2002.04.044 PG 12 WC Oncology SC Oncology GA 552ET UT WOS:000175606900005 PM 12011121 ER PT J AU Betensky, RA Louis, DN Cairncross, JG AF Betensky, RA Louis, DN Cairncross, JG TI Influence of unrecognized molecular heterogeneity on randomized clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID REGRESSION-MODELS; SURVIVAL-DATA; COX MODEL; COVARIATE; TESTS; AGE AB Purpose: In solid tumor oncology, decisions regarding treatment and eligibility for trials are governed by histologic diagnosis. Despite this reliance on histology and the assumption that histology defines the disease, underlying molecular heterogeneity likely differentiates among patients' outcomes. Patients and Methods: To illustrate how unrecognized molecular heterogeneity might obscure a truly effective new therapy for cancer, we analyzed the planning assumptions and results of a hypothetical randomized controlled trial of chemoradiotherapy for a cancer found to be drug sensitive in preliminary phase 11 studies. Results: Randomized controlled trials of effective cancer therapies can be falsely negative if therapeutic benefit is overestimated during study design because of enrichment of phase 11 trials for treatment-sensitive subtypes, a beneficial effect in responding patients is diluted by large numbers of nonresponding patients, or a beneficial effect in responders is reversed by a negative effect in nonresponders. Conclusion: Molecular heterogeneity, if it confers different risks to patients and is unaccounted for in the design of a randomized study, can result in a clinical trial that is underpowered and fails to detect a truly effective new therapy for cancer. (C) 2002 by American Society of Clinical Oncology. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol & Neurosurg Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Western Ontario, Dept Oncol, London, ON N6A 3K7, Canada. London Reg Canc Ctr, London, ON N6A 4L6, Canada. RP Betensky, RA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA 57683, R29 CA 75971] NR 18 TC 117 Z9 119 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAY 15 PY 2002 VL 20 IS 10 BP 2495 EP 2499 DI 10.1200/JCO.2002.06.140 PG 5 WC Oncology SC Oncology GA 552ET UT WOS:000175606900011 PM 12011127 ER PT J AU Trimble, LA Prince, KA Pestano, GA Daley, J Cantor, H AF Trimble, LA Prince, KA Pestano, GA Daley, J Cantor, H TI Fas-dependent elimination of nonselected CD8 cells and lpr disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID AUTOREACTIVE T-CELLS; COMPLEX CLASS-I; NEGATIVE SELECTION; POSITIVE SELECTION; LPR/LPR MICE; B-CELLS; SYSTEMIC AUTOIMMUNITY; DEVELOPING THYMOCYTES; IPR/IPR MICE; CUTTING EDGE AB MHC/self peptide interactions with cognate coreceptor/TCR complexes are central to homeostasis of the T cell repertoire. Recent reports have also underlined the critical role of IL-15/IL-2 cytokines in regulating this homeostatic process. In this study, we investigate mechanisms that regulate potentially autoreactive CD8 cells that have escaped intrathymic selection. These cells, upon exit from the thymus, express high levels of CD44, B220, and the IL-15R/IL-2R, and undergo fas-dependent apoptosis. Defects in fas signaling allow increased IL-15/IL-2-dependent survival of these CD44/B220(+) CD8(+) as well as the double-negative T cells, characteristic of lpr disease. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Cantor, H (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. FU NIAID NIH HHS [AI 45172, AI 13600, F32 AI 10468] NR 57 TC 10 Z9 12 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2002 VL 168 IS 10 BP 4960 EP 4967 PG 8 WC Immunology SC Immunology GA 550AF UT WOS:000175480100018 PM 11994447 ER PT J AU Medoff, BD Sauty, A Tager, AM Maclean, JA Smith, RN Mathew, A Dufour, JH Luster, AD AF Medoff, BD Sauty, A Tager, AM Maclean, JA Smith, RN Mathew, A Dufour, JH Luster, AD TI IFN-gamma-inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ALLERGEN-SPECIFIC TH1; CHEMOKINE RECEPTOR EXPRESSION; T-CELLS; MURINE MODEL; CYTOKINE EXPRESSION; IP-10 CHEMOKINE; IN-VIVO; MICE; LYMPHOCYTES; HYPERRESPONSIVENESS AB Allergic asthma is an inflammatory disease of the airways characterized by cosinophilic inflammation and airway hyper-reactivity. Cytokines and chemokines specific for Th2-type inflammation predominate in asthma and in animal models of this disease. The role of Th1-type inflammatory mediators in asthma remains controversial. IFN-gamma-inducible protein 10 (IP-10; CXCL10) is an EFN-gamma-inducible chemokine that preferentially attracts activated Th1 lymphocytes. IP-10 is up-regulated in the airways of asthmatics, but its function in asthma is unclear. To investigate the role of IP-10 in allergic airway disease, we examined the expression of IEP-10 in a murine model of asthma and the effects of overexpression and deletion of IP-10 in this model using IP-10-transgenic and IP-10-deficient mice. Our experiments demonstrate that IP-10 is up-regulated in the lung after allergen challenge. Mice that overexpress TP-10 in the lung exhibited significantly increased airway hyperreactivity, eosinophilia, IL-4 levels, and CD8(+) lmphocyte recruitment compared with wild-type controls. In addition, there was an increase in the percentage of IL-4-secreting T lymphocytes in the lungs of IP-10-transgenic mice. In contrast, mice deficient in IP-10 demonstrated the opposite results compared with wild-type controls, with a significant reduction in these measures of Th2-type allergic airway inflammation. Our results demonstrate that IP-10, a Th1-type chemokine, is up-regulated in allergic pulmonary inflammation and that this contributes to the airway hyperreactivity and Th2-type inflammation seen in this model of asthma. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Pulm & Crit Care Unit, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Charlestown, MA 02129 USA. CHU Vaudois, Div Allergol & Clin Immunol, CH-1011 Lausanne, Switzerland. RP Luster, AD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis,Div Rheumatol Alle, Bldg 149-8301,13th St, Charlestown, MA 02129 USA. FU NCI NIH HHS [F32 CA 88721, R01 CA 69212]; NHLBI NIH HHS [F32 HL 10375, K08 HL 04087]; NIAID NIH HHS [F32 AI 50399, R01 AI 40618] NR 39 TC 141 Z9 147 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2002 VL 168 IS 10 BP 5278 EP 5286 PG 9 WC Immunology SC Immunology GA 550AF UT WOS:000175480100056 PM 11994485 ER PT J AU Johnson, JR Kuskowski, MA O'Bryan, TT Maslow, JN AF Johnson, JR Kuskowski, MA O'Bryan, TT Maslow, JN TI Epidemiological correlates of virulence genotype and phylogenetic background among Escherichia coli blood isolates from adults with diverse-source bacteremia SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID URINARY-TRACT INFECTIONS; PATHOGENICITY ISLAND; EXTRAINTESTINAL INFECTIONS; CAPSULAR POLYSACCHARIDE; CLONAL RELATIONSHIPS; HOST COMPROMISE; SEVERE SEPSIS; PAPA ALLELES; STRAINS; IDENTIFICATION AB Associations of virulence genotype and phylogenetic background with epidemiological factors (primary source of bacteremia, host compromise status, and hospital versus community origin) were assessed among 182 Escherichia coli blood isolates from adults with diverse-source bacteremia in comparison with fecal controls from the E. coli Reference collection. A continuum of virulence was found, from urinary and pulmonary source bacteremia isolates (high virulence), through "other" or unknown source bacteremia isolates (intermediate virulence), to fecal isolates (low virulence), with a corresponding graded phylogenetic distribution from predominantly group B2 to predominantly groups A and B1. Associations of bacterial traits with clinical factors varied considerably, depending on subgroup and statistical method. However, certain putative virulence genes (including several "nontraditional" markers, such as pathogenicity island-associated malX) repeatedly emerged as significant epidemiological predictors, which provided evidence of their possible relevance in host-pathogen interactions and hence as potential targets for preventive interventions against extraintestinal infections due to E. coli. C1 Minneapolis Vet Affairs Med Ctr, Med Serv, Minneapolis, MN 55417 USA. Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Philadelphia Vet Affairs Med Ctr, Med Serv, Philadelphia, PA 19104 USA. RP Johnson, JR (reprint author), Minneapolis Vet Affairs Med Ctr, Med Serv, 111F,Rm 3B-101,1 Vet Dr, Minneapolis, MN 55417 USA. FU NIDDK NIH HHS [DK-47504] NR 65 TC 63 Z9 63 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAY 15 PY 2002 VL 185 IS 10 BP 1439 EP 1447 DI 10.1086/340506 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 547CE UT WOS:000175314700009 PM 11992279 ER PT J AU Goyal, A Samaha, FF Boden, WE Wade, MJ Kimmel, SE AF Goyal, A Samaha, FF Boden, WE Wade, MJ Kimmel, SE TI Stress test criteria used in the conservative arm of the FRISC-II trial underdetects surgical coronary artery disease when applied to patients in the VANQWISH trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID PRACTICE GUIDELINES COMMITTEE; ASSOCIATION TASK-FORCE; MYOCARDIAL-INFARCTION; ACC/AHA GUIDELINES; STRATEGY; MANAGEMENT AB OBJECTIVES We sought to determine whether the stringent stress test criteria for crossover to cardiac catheterization in the conservative arm of the Fast Revascularization During Instability in Coronary Artery, Disease (FRISC-II) trial subjected this strategy., to a disadvantage by failing to identify patients with surgical coronary artery disease (CAD). BACKGROUND In FRISC-II, an invasive strategy provided superior outcomes compared with a conservative strategy for patients with acute coronary syndromes. However, compared with the stress test criteria for crossover to catheterization in the Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) trial, the FRISC-II criteria were more restrictive and did not use nuclear imaging or pharmacologic stress testing. METHODS We analyzed the conservative arm of VANQWISH to identify the prevalence of surgical CAD in those patients who met the VANQWISH, but not FRISC-II, criteria for catheterization. RESULTS Of 385 VANQWISH patients, 90 (23%) met the FRISC-II criteria for catheterization. Another 98 patients (25%) met only VANQWISH stress test criteria (60 patients by exercise and 38 by pharmacologic nuclear stress testing). Among subjects who underwent pre discharge angiography, those meeting only VANQWISH stress test criteria had a high prevalence of surgical CAD (51%), comparable to patients who met FRISC-II criteria (54%, p = 0.805). CONCLUSIONS The overly stringent risk stratification protocol for conservative-arm patients in FRISC-II could have failed to identify almost as many patients with surgical CAD as it identified. A lower threshold for catheterization in the FRISC-II conservative patients might have improved their outcomes and therefore diminished the putative benefit of an invasive strategy. (J Am Coll Cardiol 2002;39:1601-7) (C) 2002 by the American College of Cardiology Foundation. C1 Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Dept Med, Philadelphia, PA 19104 USA. Div Cardiovasc, Philadelphia, PA USA. Vet Affairs Med Ctr, Philadelphia, PA USA. Hartford Hosp, Hartford, CT 06115 USA. Vet Affairs Med Ctr, Syracuse, NY USA. Ctr Clin Epidemiol & Biostat, Philadelphia, PA USA. RP Kimmel, SE (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Dept Med, 717 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. NR 13 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 15 PY 2002 VL 39 IS 10 BP 1601 EP 1607 AR PII S0735-1097(02)01841-7 DI 10.1016/S0735-1097(02)01841-7 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 551QB UT WOS:000175571500006 PM 12020486 ER PT J AU Otsuji, Y Kumanohoso, T Yoshifuku, S Matsukida, K Koriyama, C Kisanuki, A Minagoe, S Levine, RA Tei, C AF Otsuji, Y Kumanohoso, T Yoshifuku, S Matsukida, K Koriyama, C Kisanuki, A Minagoe, S Levine, RA Tei, C TI Isolated annular dilation does not usually cause important functional mitral regurgitation - Comparison between patients with lone atrial fibrillation and those with idiopathic or ischemic cardiomyopathy SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID PAPILLARY-MUSCLE DYSFUNCTION; LEFT-VENTRICULAR DYSFUNCTION; MYOCARDIAL-INFARCTION; 3-DIMENSIONAL ECHOCARDIOGRAPHY; HEART-FAILURE; ORIFICE AREA; MECHANISM; FLOW; SEVERITY; INSIGHTS AB OBJECTIVES We sought to test whether isolated mitral annular (MA.) dilation can cause important functional mitral regurgitation (mR). BACKGROUND Mitral annular dilation has been considered a primary, cause of functional MR. Patients,with functional AIR, however, usually have both MA dilation and left ventricular (LV) dilation and dysfunction. Lone atrial fibrillation (AF) can potentially cause isolated MA dilation, offering a unique opportunity to relate MA dilation to leaflet function. METHODS Mid-systolic MA area, MR fraction, LV volumes and papillary muscle (PM) leaflet tethering length were compared by echocardiography among 18 control subjects, 25 patients with lone AF and 24 patients with idiopathic or ischemic cardiomyopathy (ICM). RESULTS Patients with lone AF had a normal LV size and function, but MA dilation (isolated MA dilation) significant and comparable to that of patients with ICM (MA area: 8.0 +/- 1,2 vs, 11.6 +/- 2.3 vs. 12.5 +/- 2.9 cm(2) [control vs. lone AF vs. ICM]; p < 0.001 for both lone AF and ICM). However, patients with lone AF had only modest MR, compared with that of patients with ICM (MR fraction: -3 +/- 8% vs. 3 +/- 9% vs. 36 +/- 25%; p < 0.001 for patients with ICM). Multivariate analysis identified PM tethering length, not MA dilation, as an independent primary contributor to MR. CONCLUSIONS Isolated annular dilation does not usually cause moderate or severe MR. Important functional MR also depends on LV dilation and dysfunction, leading to an altered force balance on the leaflets, which impairs coaptation. (J Am Coll Cardiol 2002;39:1651-6) (C) 2002 by the American College of Cardiology Foundation. C1 Kagoshima Univ, Sch Med, Dept Internal Med 1, Kagoshima 8908520, Japan. Kagoshima Univ, Sch Med, Dept Publ Hlth, Kagoshima 8908520, Japan. Massachusetts Gen Hosp, Cardiac Ultrasound Lab, Boston, MA 02114 USA. RP Otsuji, Y (reprint author), Kagoshima Univ, Sch Med, Dept Internal Med 1, 8-35-1 Sakuragaoka, Kagoshima 8908520, Japan. NR 39 TC 126 Z9 128 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 15 PY 2002 VL 39 IS 10 BP 1651 EP 1656 AR PII S0735-1097(02)01838-7 DI 10.1016/S0735-1097(02)01838-7 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 551QB UT WOS:000175571500013 PM 12020493 ER PT J AU Kachnic, LA Powell, SN AF Kachnic, LA Powell, SN TI Can ICAM modulation prevent lung injury from ionizing radiation? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID BREAST-CANCER; GROWTH-FACTOR; IRRADIATION; RADIOTHERAPY; CHEMOTHERAPY; PNEUMONITIS; FIBROSIS; TISSUE; MICE C1 Boston Med Ctr, Dept Radiat Oncol, Boston, MA 02118 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Kachnic, LA (reprint author), Boston Med Ctr, Dept Radiat Oncol, 88 E Newton St,EB 11, Boston, MA 02118 USA. NR 16 TC 2 Z9 2 U1 0 U2 0 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 MAY 15 PY 2002 VL 94 IS 10 BP 704 EP 705 PG 2 WC Oncology SC Oncology GA 552MD UT WOS:000175623400001 PM 12011211 ER PT J AU Malone, T Catalano, PJ O'Dwyer, PJ Giantonio, B AF Malone, T Catalano, PJ O'Dwyer, PJ Giantonio, B TI High rate of consent to bank biologic samples for future research: The Eastern Cooperative Oncology Group experience SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article AB The Eastern Cooperative Oncology Group (ECOG) requires patient consent for the storage and future use of samples left over from its therapeutic cancer clinical trials. The ECOG consent instrument evolved from a simple statement requiring a signature to a more detailed three-question format. Between February 1998 and October 2000, more than 7000 patients were accrued to studies using one of the two consent forms. We analyzed our consent response data by consent type, demographic information, disease site, and institution type to determine the assent rates for future storage and research on biologic samples and to identify possible factors predicting patient refusal. The assent rate for the original banking consent statement was 89.4%, whereas that for the more detailed consent form was 93.7%. Higher assent rates were statistically significant for the detailed consent form versus the original consent form (P =.001), for community-based practices versus academic centers (P<.001), and for patients aged at least 65 years versus those younger (P =.002). The results show that increased patient protection does not result in decreased availability of biologic samples for future research purposes. C1 Eastern Cooperat Oncol Grp, Boston, MA 02215 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Penn, Philadelphia, PA 19104 USA. RP Malone, T (reprint author), Eastern Cooperat Oncol Grp, 900 Commonwealth Ave,2nd Floor, Boston, MA 02215 USA. FU NCI NIH HHS [CA66636, CA15488, CA21115, CA37403] NR 5 TC 55 Z9 58 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 MAY 15 PY 2002 VL 94 IS 10 BP 769 EP 771 PG 3 WC Oncology SC Oncology GA 552MD UT WOS:000175623400014 PM 12011228 ER EF