FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Sarraf, D Payne, AM Kitchen, ND Sehmi, KS Downes, SM Bird, AC AF Sarraf, D Payne, AM Kitchen, ND Sehmi, KS Downes, SM Bird, AC TI Familial cavernous hemangioma - An expanding ocular spectrum SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID CENTRAL NERVOUS-SYSTEM; RETINA; MALFORMATIONS; MANIFESTATIONS; INVOLVEMENT AB Objective: To describe the clinical and genetic findings in a family with multiple cases of cavernous hemangiomas. Design: Investigational clinical and genetic study in which 3 generations of a family consisting of 12 members were screened with magnetic resonance brain imaging, dilated ophthalmoscopic examination, and cutaneous survey coupled with linkage analysis to determined affected individuals and to better define manifestations of this neuro-oculo-cutaneous syndrome. Results: The proband had multiple cerebral cavernous hemangiomas and a choroidal hemangioma. Her son was found to harbor a retinal cavernous hemangioma. The proband's sister manifested a cerebral cavernous hemangioma cutaneous hemangiomas, and a presumed choroidal hemangioma; her daughter demonstrated radiological findings suggestive of a cerebral cavernous hemangioma. The father of the proband demonstrated multiple, cutaneous hemangiomas. The remaining family members were free of lesions. The 7q locus could not be excluded as harboring the causative gene. Conclusions: This family may have a dominantly inherited neuro-oculo-cutaneous condition of cavernous hemangiomas with variable expressivity. The presence of choroidal hemangiomas in this phacomatosis has not been described previously to our knowledge. Clinical Relevance: The presence of either retinal cavernous or choroidal hemangioma should alert the physician to search for features suggestive of systemic and familial involvement; either lesion may constitute the ocular component of the neuro-oculo-cutaneous phacomatosis, sometimes referred to as cavernoma multiplex. C1 Univ Calif Los Angeles, Jules Stein Eye Inst, Sch Med, Los Angeles, CA 90095 USA. Univ Halle Wittenberg, Med Ctr, D-4010 Halle, Germany. Greater Los Angeles Vet Adm Healthcare Ctr, Dept Ophthalmol, Los Angeles, CA USA. Inst Ophthalmol, London, England. Moorfields Eye Hosp, London, England. Inst Neurol, London, England. RP Sarraf, D (reprint author), Univ Calif Los Angeles, Jules Stein Eye Inst, Sch Med, 100 Stein Plaza, Los Angeles, CA 90095 USA. NR 25 TC 20 Z9 20 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUL PY 2000 VL 118 IS 7 BP 969 EP 973 PG 5 WC Ophthalmology SC Ophthalmology GA 334CZ UT WOS:000088169100015 PM 10900112 ER PT J AU Grant, CA Rubin, PAD AF Grant, CA Rubin, PAD TI An infratemporal fossa foreign body presents as an infraorbital mass SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID MR C1 Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol Ophthalm Plast Orbital & Cosmet S, Boston, MA 02114 USA. RP Grant, CA (reprint author), Harvard Univ, Sch Med, Massachusetts Eye & Ear Infirm, Dept Ophthalmol Ophthalm Plast Orbital & Cosmet S, 243 Charles St, Boston, MA 02114 USA. NR 3 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUL PY 2000 VL 118 IS 7 BP 993 EP 995 PG 3 WC Ophthalmology SC Ophthalmology GA 334CZ UT WOS:000088169100022 PM 10900119 ER PT J AU Hammond, MEH Fitzgibbons, PL Compton, CC Grignon, DJ Page, DL Fielding, LP Bostwick, D Pajak, T AF Hammond, MEH Fitzgibbons, PL Compton, CC Grignon, DJ Page, DL Fielding, LP Bostwick, D Pajak, T CA Cancer Comm & Conference Partic TI College of American Pathologists Conference XXXV: Solid tumor prognostic factors - Which, how and so what? Summary document and recommendations for implementation SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT XXXVth Conference of the College-of-American-Pathologists CY JUN 10-13, 1999 CL CHICAGO, ILLINOIS SP Coll Amer Pathologists ID CANCER WORKING GROUP; CLINICAL RELEVANCE; CONFERENCE XXVI; MARKERS AB The College of American Pathologists convened a prognostic factor conference in tune 1999 to consider prognostic and predictive factors in breast, colon, and prostate cancer, and to stratify these factors into categories reflecting the strength of published evidence. Because so little progress in prognostic factor clinical utility has been made in the last 5 years, the conference participants focused their attention on decreasing variation in methods, interpretation, and reporting of these factors so that greater clarity of value could be achieved. The conference was organized to promote discussion, broad input, and future planning. An initial plenary session provided an overview of the status of tumor marker research, the impact of variation in medicine and pathology, and statistical issues related to prognostic factor research. In working group sessions for each cancer type, participants interactively evaluated and refined the documents created by the expert panels. A second plenary session dealt with issues common to all 3 groups, including the problem of micrometastases in lymph nodes in these sites; statistical issues that arose during the breakout discussions; and issues of variation in methods, interpretation, and reporting of immunohistochemical assays. A faculty session brainstormed strategies that could be used to implement the changes recommended. This session included invited representatives of the Food and Drug Administration, Health Care Financing Administration, Centers for Disease Control and Prevention, National Cancer Institute, American Joint Committee on Cancer, and International Union Against Cancer. Cancer site and general recommendations were presented and discussed during a final session to achieve consensus of the conference participants and to address feasibility of implementation of these recommendations. A final discussion focused on future initiatives that might lead to implementation of the changes proposed in the conference by the various organizations represented. This report summarizes the general conference recommendations, cancer working group recommendations, and plans for implementation of the recommendations. C1 Latter Day St Hosp, Salt Lake City, UT 84143 USA. Univ Utah, Sch Med, Salt Lake City, UT USA. Good Samaritan Hosp, Los Angeles, CA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Wayne State Univ, Detroit, MI USA. Vanderbilt Univ, Memphis, TN USA. York Hosp, York, PA USA. Bostwick Labs, Richmond, VA USA. Amer Coll Radiol, Philadelphia, PA USA. RP Hammond, MEH (reprint author), Care of Schramm J, Coll Amer Pathologists, 325 Waukegan Rd, Northfield, IL 60093 USA. OI Fitzgibbons, Patrick/0000-0002-2998-6913 NR 14 TC 80 Z9 83 U1 0 U2 0 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 JUL PY 2000 VL 124 IS 7 BP 958 EP 965 PG 8 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 334HK UT WOS:000088180900006 PM 10888771 ER PT J AU Compton, CC Fielding, LP Burgart, LJ Conley, B Cooper, HS Hamilton, SR Hammond, MEH Henson, DE Hutter, RVP Nagle, RB Nielsen, ML Sargent, DJ Taylor, CR Welton, M Willett, C AF Compton, CC Fielding, LP Burgart, LJ Conley, B Cooper, HS Hamilton, SR Hammond, MEH Henson, DE Hutter, RVP Nagle, RB Nielsen, ML Sargent, DJ Taylor, CR Welton, M Willett, C TI Prognostic factors in colorectal cancer - College of American Pathologists Consensus Statement 1999 SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT XXXVth Conference of the College-of-American-Pathologists CY JUN 10-13, 1999 CL CHICAGO, ILLINOIS SP Coll Amer Pathologists ID CELL NUCLEAR ANTIGEN; NUCLEOLAR ORGANIZER REGIONS; LYMPH-NODE METASTASIS; NEGATIVE COLON-CANCER; K-RAS MUTATION; LONG-TERM PROGNOSIS; DNA FLOW-CYTOMETRY; LARGE BOWEL-CANCER; RECTAL-CANCER; MULTIVARIATE-ANALYSIS AB Background.-Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive factors (factors predicting response to therapy) in colorectal carcinoma was evaluated. A multidisciplinary group of clinical (including the disciplines of medical oncology, surgical oncology, and radiation oncology), pathologic, and statistical experts in colorectal cancer reviewed all relevant medical literature and stratified the reported prognostic factors into categories that reflected the strength of the published evidence demonstrating their prognostic value. Accordingly, the following categories of prognostic factors were defined. Category I includes factors definitively proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management. Category IIA includes factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value for outcome and/or predictive value for therapy that is of sufficient import to be included in the pathology report but that remains to be validated in statistically robust studies. Category IIB includes factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA. Category III includes factors not yet sufficiently studied to determine their prognostic value. Category IV includes factors well studied and shown to have no prognostic significance. Materials and Methods,-The medical literature was critically reviewed, and the analysis revealed specific points of variability in approach that prevented direct comparisons among published studies and compromised the quality of the collective data. Categories of variability recognized included the following: (1) methods of analysis, (2) interpretation of findings, (3) reporting of data, and (4) statistical evaluation. Additional points of variability within these categories were defined from the collective experience of the group. Reasons for the assignment of an individual prognostic factor to category I, II, III, or IV (categories defined by the level of scientific validation) were outlined with reference to the specific types of variability associated with the supportive data. For each factor and category of variability related to that factor, detailed recommendations for improvement were made. The recommendations were based on the following aims: (1) to increase the uniformity and completeness of pathologic evaluation of tumor specimens, (2) to enhance the quality of the data needed for definitive evaluation of the prognostic value of individual prognostic factors, and (3) ultimately, to improve patient care. Results and Conclusions-Factors that were determined to merit inclusion in category I were as follows: the local extent of tumor assessed pathologically (the pT category of the TNM staging system of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer [AJCC/UICC]); regional lymph node metastasis (the pN category of the TNM staging system); blood or lymphatic vessel invasion; residual tumor following surgery with curative intent (the R classification of the AJCC/UICC staging system), especially as it relates to positive surgical margins; and preoperative elevation of carcinoembryonic antigen elevation (a factor established by laboratory medicine methods rather than anatomic pathology). Factors in category IIA included the following: tumor grade, radial margin status (for resection specimens with nonperitonealized surfaces), and residual tumor in the resection specimen following neoadjuvant therapy (the ypTNM category of the TNM staging system of the AJCC/UICC). Factors in category IIB included the following: histologic type, histologic features associated with microsatellite instability (MSI) (ie, host lymphoid response to tumor and medullary or mucinous histologic type), high degree of MSI (MSI-H), loss of heterozygosity at 18q (DCC gene allelic loss), and tumor border configuration (infiltrating vs pushing border). Factors grouped in category III included the following: DNA content, all other molecular markers except loss of heterozygosity 18q/DCC and MSI-H, perineural invasion, microvessel density, tumor cell-associated proteins or carbohydrates, peritumoral fibrosis, peritumoral inflammatory response, focal neuroendocrine differentiation, nuclear organizing regions, and proliferation indices. Category IV factors included tumor size and gross tumor configuration. This report records findings and recommendations of the consensus conference group, organized according to structural guidelines defined herein. C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. York Hosp, York, PA USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. NCI, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Latter Day St Hosp, Salt Lake City, UT 84143 USA. St Barnabas Med Ctr, Livingston, NJ USA. Univ Arizona, Tucson, AZ USA. Kansas Pathol Consultants, Wichita, KS USA. Univ So Calif, Los Angeles, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Compton, CC (reprint author), Massachusetts Gen Hosp, Dept Pathol, Warren Bldg,Room 256,55 Fruit St, Boston, MA 02114 USA. OI Sargent, Daniel/0000-0002-2684-4741 NR 213 TC 640 Z9 676 U1 0 U2 22 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 JUL PY 2000 VL 124 IS 7 BP 979 EP 994 PG 16 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 334HK UT WOS:000088180900008 PM 10888773 ER PT J AU Compton, CC AF Compton, CC TI Updated protocol for the examination of specimens from patients with carcinomas of the colon and rectum, excluding carcinoid tumors, lymphomas, sarcomas, and tumors of the vermiform appendix - A basis for checklists SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID LARGE BOWEL-CANCER; MALIGNANT COLORECTAL POLYPS; MULTIVARIATE-ANALYSIS; ENDOSCOPIC POLYPECTOMY; SURGICAL PATHOLOGY; INVASIVE-CARCINOMA; PROGNOSTIC FACTORS; CURATIVE RESECTION; LOCAL RECURRENCE; VESSEL INVASION C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Compton, CC (reprint author), Care Of Schramm J, Coll Amer Pathologists, 325 Waukegan Rd, Northfield, IL 60093 USA. NR 80 TC 93 Z9 98 U1 0 U2 0 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 JUL PY 2000 VL 124 IS 7 BP 1016 EP 1025 PG 10 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 334HK UT WOS:000088180900013 PM 10888778 ER PT J AU Munakata, Y Iwata, S Dobers, J Ishii, T Nori, M Tanaka, H Morimoto, C AF Munakata, Y Iwata, S Dobers, J Ishii, T Nori, M Tanaka, H Morimoto, C TI Novel in vitro effects of bucillamine - Inhibitory effects on proinflammatory cytokine production and transendothelial migration of T cells SO ARTHRITIS AND RHEUMATISM LA English DT Article ID RHEUMATOID-ARTHRITIS; ACTIVATION; DISEASE; ANTIGEN; TH1; LYMPHOCYTES; EXPRESSION; SYNOVITIS; MECHANISM; RECEPTOR AB Objective, To investigate the novel antiinflammatory mechanism of a disease-modifying antirheumatic drug, bucillamine, on activated T cells, specifically its effect on T cell proliferation, cytokine production, and migration of T cells, Methods. T cells were cultured in wells coated with anti-CD3 monoclonal antibodies (mAb) plus anti-CD26 mAb or anti-CD3 plus anti-CD28 mAb, with or without bucillamine. Proliferative responses and the production of interleukin-2 (IL-2), interferon-gamma (IFN gamma), tumor necrosis factor alpha (TNF alpha), IL-6, IL-4, and IL-5 were measured under these costimulatory conditions. Phytohemagglutinin (PHA)-activated T cells were cultured on human umbilical vein endothelial cell-coated transwells in the presence or absence of bucillamine, and T cells migrating through the endothelial cell layer were counted. Immunofluorescence analysis was also performed to analyze the effect of bucillamine on the surface expression of adhesion molecules on T cells. Results. Bucillamine (64 mu M) significantly inhibited T cell proliferation and the production of IL-2, IFN gamma, TNF alpha, and IL-6, whereas it had no inhibitory effects on the production of IL-1 and IL-5 in the cultures with anti-CD3 plus anti-CD26 mAb, In contrast, bucillamine had no effects on T cell proliferation or any cytokine production in the cultures with anti-CD3 plus anti-CD28 mAb, Furthermore, the same concentration of bucillamine inhibited transendothelial migration of PHA-activated T cells, and reduced the expression level of CD44 on T cells, Conclusion. This study demonstrated the novel effects of bucillamine in vitro, showing inhibition of type 1 T helper-type cytokine production and proinflammatory cytokine production induced by certain costimulatory conditions, and inhibition of transendothelial migration of T cells, The inhibition of T cell migration appeared to be mediated partly through the reduced expression of CD44, an adhesion molecule on the T cell surface. C1 Dana Farber Canc Inst, Div Tumor Immunol, Boston, MA 02115 USA. Univ Tokyo, Tokyo, Japan. RP Morimoto, C (reprint author), Dana Farber Canc Inst, Div Tumor Immunol, 44 Binney St, Boston, MA 02115 USA. RI Iwata, Satoshi/A-8819-2011 FU NIAID NIH HHS [AI-29530]; NIAMS NIH HHS [AR-33713] NR 30 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUL PY 2000 VL 43 IS 7 BP 1616 EP 1623 PG 8 WC Rheumatology SC Rheumatology GA 332LX UT WOS:000088076700027 PM 10902767 ER PT J AU Wright, JE Vaidya, CM Chen, YN Rosowsky, A AF Wright, JE Vaidya, CM Chen, YN Rosowsky, A TI Efficient utilization of the reduced folate carrier in CCRF-CEM human leukemic lymphoblasts by the potent antifolate N-alpha-(4-amino-4-deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (PT523) and its B-ring analogues SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE N-alpha-(4-amino-4 deoxypteroyl)-N-delta-hemiphthaloyl-L-ornithine (PT523) analogues; reduced folate carrier; dihydrofolate reductase ID DIHYDROFOLATE-REDUCTASE; BIOLOGICAL-ACTIVITY; METHOTREXATE TRANSPORT; MEDIATED TRANSPORT; MEMBRANE-VESICLES; L1210 CELLS; FOLIC-ACID; SIDE-CHAIN; AMINOPTERIN; RECEPTOR AB The potent nonpolyglutamatable dihydrofolate reductase inhibitor N-alpha-(4-amino-4-deoxypteroyl) N-delta-hemiphthaloyl-L-ornithine (PT523) and six of its B-ring (5-deaza, 8-deaza, and 5,8-dideaza) analogues were compared in terms of their ability to: (a) inhibit the growth of CCRF-CEM human leukemic lymphoblasts, and (b) utilize the reduced folate carrier (RFC) in these cells as measured in a competition assay of [H-3]methotrexate ([H-3]MTX) influx. The Ic(50) values of the hemiphthaloylornithine derivatives against CCRF-CEM cells after 72 hr of drug exposure varied from 0.64 to 1.3 nM as compared with 14 nM for MTX and 4.4 nM for aminopterin (AMT). The K-i Values of these compounds in the [3H]MTX influx assay were in the 0.3 to 0.7 mu M range as compared with a K-i of 5.4 mu M for AMT and a K-t of 7.1 mu M for MTX. As a group, the affinities of these compounds for the RFC were approximately 10-fold greater than those of their respective glutamate analogues. These results indicate that, in addition to their previously reported tight binding to dihydrofolate reductase, a property contributing to the high potency of PT523 and its B-ring analogs as inhibitors of tumor cell growth is their strong affinity for the RFC. BIOCHEM PHARMACOL 60;1:41-46, 2000. (C) 2000 Elsevier Science Inc. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Rosowsky, A (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA25934, CA70349] NR 27 TC 22 Z9 22 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUL 1 PY 2000 VL 60 IS 1 BP 41 EP 46 DI 10.1016/S0006-2952(00)00294-X PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 315UL UT WOS:000087131300005 PM 10807943 ER PT J AU Faraone, SV Biederman, J Spencer, T Wilens, T Seidman, LJ Mick, E Doyle, AE AF Faraone, SV Biederman, J Spencer, T Wilens, T Seidman, LJ Mick, E Doyle, AE TI Attention-deficit/hyperactivity disorder in adults: An overview SO BIOLOGICAL PSYCHIATRY LA English DT Review DE attention-deficit/hyperactivity disorder; diagnostic validity; developmental psychopathology ID DEFICIT-HYPERACTIVITY-DISORDER; MINIMAL BRAIN-DYSFUNCTION; CEREBRAL GLUCOSE-METABOLISM; OF-ONSET CRITERION; IV FIELD TRIALS; COLLEGE-STUDENTS; DOUBLE-BLIND; FOLLOW-UP; NEUROPSYCHOLOGICAL PERFORMANCE; PSYCHIATRIC COMORBIDITY AB To assess the validity of adult attention-deficit/hyperactivity disorder (ADHD), we reviewed clinical, family, psychopharmacologic, neurobiological, and outcome studies. We found multiple reports describing adults with clinical features highly reminiscent of the childhood ADHD. These adults, who are impulsive, inattentive, and restless, have the clinical "look and feel" of ADHD children. As with their childhood counterparts, many adults with ADHD suffer from antisocial, depressive, and anxiety disorders. They also show clinically significant impairments-histories of school failure, occupational problems, and traffic accidents. Studies of biological features show correspondences between child and adult cases of ADHD, Both show familial aggregation and a characteristic profile of neuropsychologic deficits; an emerging neuroimaging literature suggests that abnormalities in the same brain regions underlie both the child and adult forms of the disorder, Although these converging lines of evidence support the validity of ADHD in adults, follow-up studies of ADHD children have yielded ambiguous results, This ambiguity is in part due to differences in how researchers define the persistence of ADHD, a problem that suggests future research focus on how best to diagnose ADHD in adulthood (C) 2000 Society of Biological Psychiatry. C1 Harvard Univ, Sch Med, Pediat Psychopharmacol Unit, Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Mental Hlth Ctr, Dept Psychiat, Boston, MA USA. RP Faraone, SV (reprint author), Harvard Univ, Sch Med, Pediat Psychopharmacol Unit, Massachusetts Gen Hosp, ACC 725,15 Parkman St, Boston, MA 02114 USA. OI Mick, Eric/0000-0001-8505-8145; Faraone, Stephen/0000-0002-9217-3982 FU NICHD NIH HHS [R01HD37999, R01HD37694]; NIMH NIH HHS [R01MH57934] NR 93 TC 364 Z9 376 U1 8 U2 52 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 1 PY 2000 VL 48 IS 1 BP 9 EP 20 DI 10.1016/S0006-3223(00)00889-1 PG 12 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 331ZF UT WOS:000088048000002 PM 10913503 ER PT J AU Faraone, SV Biederman, J Monuteaux, MC AF Faraone, SV Biederman, J Monuteaux, MC TI Attention-deficit disorder and conduct disorder in girls: Evidence for a familial subtype SO BIOLOGICAL PSYCHIATRY LA English DT Article DE ADHD; conduct disorder; oppositional defiant disorder; family-genetic; risk factors ID OPPOSITIONAL DEFIANT DISORDER; LA-TOURETTES SYNDROME; HYPERACTIVITY DISORDER; CHILD PSYCHOPATHOLOGY; GENETIC-RELATIONSHIP; MULTIPLE THRESHOLDS; COMORBIDITY; ISSUES; ADHD; BOYS AB Background: The frequent comorbidity between attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) raises the possibility that ADHD+CD is a distinct and sepal-ate condition. Methods: We tested hypotheses about patterns of familial association between ADHD, CD, oppositional defiant disorder (ODD) and adult antisocial personality disorder (ASPD), Using family study methodology in a sample of girls, we found II children with diagnoses of ADHD+CD, 39 with ADHD+ODD, and 90 with ADHD only. These were compared with 122 non-ADHD, non-CD control probands, Familial risk analysis was utilized Results: Relatives of each ADHD proband subgroup were at significantly greater risk for ADHD, and the relatives of ADHD-only subjects were at a greater risk of ODD than relatives of control subjects. Also, rates of CD were elevated among relatives of ADHD+CD probands only, and the coaggregation of ADHD and the antisocial disorders could not be accounted for by marriages between ADHD and antisocial spouses. Both ADHD and antisocial disorders occurred in the same relatives more often than expected by chance, Conclusions: These findings suggest that ADHD with and without. antisocial disorders may be etiologically distinct disorders and provide evidence for the nosologic validity of ICD-10 hyperkinetic conduct disorder. (C) 2000 Society of Biological Psychiatry. C1 Harvard Univ, Sch Med, Pediat Psychopharmacol Unit, Massachusetts Gen Hosp,Psychiat Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brockton W Roxbury Vet Affairs Med Ctr, Dept Psychiat,Harvard Inst Psychiat Epidemiol & G, Boston, MA USA. Massachusetts Mental Hlth Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Faraone, SV (reprint author), Harvard Univ, Sch Med, Pediat Psychopharmacol Unit, Massachusetts Gen Hosp,Psychiat Serv, ACC 725,Fruit St, Boston, MA 02114 USA. OI Faraone, Stephen/0000-0002-9217-3982 FU NIMH NIH HHS [R01 MH41314-07, R01MH57934-0] NR 56 TC 70 Z9 71 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 1 PY 2000 VL 48 IS 1 BP 21 EP 29 DI 10.1016/S0006-3223(00)00230-4 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 331ZF UT WOS:000088048000003 PM 10913504 ER PT J AU Shin, LM Dougherty, DD Orr, SP Pitman, RK Lasko, M Macklin, ML Alpert, NM Fischman, AJ Rauch, SL AF Shin, LM Dougherty, DD Orr, SP Pitman, RK Lasko, M Macklin, ML Alpert, NM Fischman, AJ Rauch, SL TI Activation of anterior paralimbic structures during guilt-related script-driven imagery SO BIOLOGICAL PSYCHIATRY LA English DT Article DE PET; emotion; anterior cingulate; insula; paralimbic; guilt ID POSTTRAUMATIC-STRESS-DISORDER; POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL BLOOD-FLOW; OLD-WORLD MONKEY; OBSESSIVE-COMPULSIVE DISORDER; CHILDHOOD SEXUAL ABUSE; CINGULATE CORTEX; SYMPTOM PROVOCATION; FACIAL EXPRESSIONS; HUMAN AMYGDALA AB Background: Several recent neuroimaging studies have examined the neuroanatomical correlates of normal emotional states, such as happiness, sadness, fear, anger anxiety, and disgust; however, no previous study has examined the emotional state of guilt. Methods: In the current study, we used positron emission tomography and the script-driven imagery paradigm to study regional cerebral blood flow (rCBF) during the transient emotional experience of guilt in, eight healthy male participants. In the Guilt condition, participants recalled and imagined participating in a personal event involving the most guilt they had ever experienced. In the Neutral condition, participants recalled and imagined participating in an emotionally neutral personal event. Results: In the Guilt versus Neutral comparison, rCBF increases occurred in anterior paralimbic regions of the brain: bilateral anterior temporal poles, anterior cingulate gyrus, and left anterior insular cortex/inferior frontal gyrus. Conclusions: These results, along with those of previous studies, are consistent with the notion that anterior paralimbic regions of the brain mediate negative emotional states in healthy individuals. (C) 2000 Society of Biological Psychiatry. C1 Tufts Univ, Dept Psychol, Medford, MA 02155 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. VA Res Serv, Manchester, NH USA. RP Shin, LM (reprint author), Tufts Univ, Dept Psychol, 490 Boston Ave, Medford, MA 02155 USA. FU NIMH NIH HHS [MH01215] NR 65 TC 131 Z9 136 U1 6 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 1 PY 2000 VL 48 IS 1 BP 43 EP 50 DI 10.1016/S0006-3223(00)00251-1 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 331ZF UT WOS:000088048000005 PM 10913506 ER PT J AU Goldstein, G Fava, M Culler, M Fisher, A Rickels, K Lydiard, RB Rosenbaum, J AF Goldstein, G Fava, M Culler, M Fisher, A Rickels, K Lydiard, RB Rosenbaum, J TI Elevated plasma thymopoietin associated with therapeutic nonresponsiveness in major depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE major depression; plasma thymopoietin; plasma arginine vasopressin; pulsatile secretion; therapeutic response; stress ID CORTICOTROPIN-RELEASING FACTOR; ARGININE-VASOPRESSIN; FLUOXETINE TREATMENT; ADRENOCORTICOTROPIN; POLYPEPTIDE-2; THYMOPENTIN; DISORDERS; SECRETION; HORMONE; STRESS AB Background: Stress predisposes to major depression, and hyperactivity of the stress-activated hypothalamic-pituitary-adrenal (HPA) axis occurs in this disease. Thymopentin, an active fragment of thymopoietin (TP), reduces endocrine and behavioral responses to experimental stress, possibly by lowering plasma TP (pTP) levels. Methods: Plasma TP and the HPA hormones arginine vasopressin (pAVP), adrenocorticotropic hormone (pACTH), and plasma cortisol (pCORT) were measured in 21 untreated depressed patients and 21 matched control subjects. Clinical responses to antidepressants were evaluated in 17 depressed patients, Results: Plasma TP was elevated in depression (p < .002), with in 8 our of 21 (38%) depressed patients having significant elevations (p <,03), For 17 patients whose antidepressant responses were evaluated nonresponsiveness occurred in 6 out of 7 (86%) with elevated pTP (> 7.5 pg/mL) versus 3 our of 10 (30%) with normal pTP (p < .05), Conclusions: The significant association of elevated pTP with nonresponsiveness to antidepressant drugs may signify a distinct pathogenesis for the depression of patients with elevated pTP, (C) 2000 Society of Biological Psychiatry. C1 Thymon LLC, Short Hills, NJ USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Biomeasure Inc, Milford, MA 01757 USA. RW Johnson Pharmaceut Res Inst, Raritan, NJ 08864 USA. Univ Penn, Psychopharmacol Unit, Philadelphia, PA 19104 USA. Med Univ S Carolina, Psychopharmacol Unit, Charleston, SC 29425 USA. RP Goldstein, G (reprint author), Thymon LLC, 30 Dorison Dr, Short Hills, NJ USA. NR 27 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUL 1 PY 2000 VL 48 IS 1 BP 65 EP 69 DI 10.1016/S0006-3223(00)00246-8 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 331ZF UT WOS:000088048000008 PM 10913509 ER PT J AU Avigan, D Wu, Z Joyce, R Elias, A Richardson, P McDermott, D Levine, J Kennedy, L Giallombardo, N Hurley, D Gong, J Kufe, D AF Avigan, D Wu, Z Joyce, R Elias, A Richardson, P McDermott, D Levine, J Kennedy, L Giallombardo, N Hurley, D Gong, J Kufe, D TI Immune reconstitution following high-dose chemotherapy with stem cell rescue in patients with advanced breast cancer SO BONE MARROW TRANSPLANTATION LA English DT Article DE stem cell transplantation; breast cancer; cellular and humoral immune reconstitution; dendritic cells ID BONE-MARROW TRANSPLANTATION; PULSED DENDRITIC CELLS; THERAPEUTIC ANTITUMOR IMMUNITY; IN-VITRO; BLOOD; SUPPORT; INTERLEUKIN-2; PROLIFERATION; VACCINATION; LYMPHOCYTES AB The present study examines the nature of humoral and cellular immune reconstitution in 28 patients with advanced breast cancer following high-dose chemotherapy with stem cell rescue, patients underwent testing of T, B, NK and dendritic cell function at serial time points until 1 year post transplant or until the time of disease progression. Abnormalities in T cell phenotype and function were observed following high-dose chemotherapy that persisted for at least 6-12 months. The vast majority of patients experienced an inversion of the CD4/CD8 ratio and demonstrated an anergic response to candida antigen. Mean T cell proliferation in response to PHA and to co-culture with allogeneic monocytes was significantly compromised. In contrast, mean Ige and IgA levels were normal 6 months post transplant and NK cell yields and function were transiently elevated following high-dose chemotherapy. Dendritic cells generated from peripheral blood progenitors displayed a characteristic phenotype and were potent inducers of allogeneic T cell proliferation in the post-transplant period. The study demonstrates that patients undergoing autologous transplantation for breast cancer experience a prolonged period of T cell dysfunction, In contrast, B, NK, and DC recover more rapidly. These findings carry significant implications for the design of post-transplant immunotherapy. C1 Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Avigan, D (reprint author), 330 Brookline Ave, Boston, MA 02215 USA. NR 37 TC 28 Z9 34 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JUL PY 2000 VL 26 IS 2 BP 169 EP 176 DI 10.1038/sj.bmt.1702474 PG 8 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 340DH UT WOS:000088517500008 PM 10918427 ER PT J AU Spitzer, TR Friedman, CJ Bushnell, W Frankel, SR Raschko, J AF Spitzer, TR Friedman, CJ Bushnell, W Frankel, SR Raschko, J TI Double-blind, randomized, parallel-group study on the efficacy and safety of oral granisetron and oral ondansetron in the prophylaxis of nausea and vomiting in patients receiving hyperfractionated total body irradiation SO BONE MARROW TRANSPLANTATION LA English DT Article DE granisetron; ondansetron; nausea; vomiting; total body irradiation; bone marrow transplant ID HIGH-DOSE METOCLOPRAMIDE; STEM-CELL TRANSPLANTATION; CISPLATIN-INDUCED EMESIS; SEROTONIN-ANTAGONIST; ANTIEMETIC EFFICACY; RECEPTOR ANTAGONIST; CANCER-PATIENTS; PREVENTION; CHEMOTHERAPY; DEXAMETHASONE AB The efficacy and safety of granisetron and ondansetron for the prophylaxis of nausea and vomiting resulting from hyperfractionated total body irradiation (TBI) were assessed. Thirty-four patients randomly received double-blind, oral granisetron (2 mg, lh before first daily fraction of radiation) or ondansetron (8 mg, 1.5 h prior to each fraction of TBI), Ninety patients who received the same TBI regimen prior to hone marrow transplantation (BMT), but Ilo 5-HT3-receptor antagonist, were identified and comprised the historical control group. By design, this study was only powered to show a difference between each of the active treatment groups and the historical control group. Significantly more patients given granisetron (33.3%) or ondansetron (26.7%) had zero emetic episodes over 4 days, the primary efficacy end point, than those in the historical control group (0%) (P < 0.01; intent-to-treat), Secondary efficacy end points were also evaluated. During the first 24 h, significantly more patients taking granisetron (61.1%) or ondansetron (46.7%) had zero emetic episodes than patients in the historical control group (6.7%) (P < 0.01). Complete emetic control (no emesis or rescue antiemetic) over 4 days was more frequent in patients taking granisetron (27.8%) or ondansetron (26.7%) compared with the historical control group (0%) (P<0.01), Significantly fewer patients taking granisetron (18/18), but not those taking ondansetron (12/15), experienced more than five emetic episodes during the 4 days of the study compared with the historical control group (40/90; P < 0.01), Oral granisetron and ondansetron are safe and effective for the prevention of nausea and vomiting resulting from TBI. C1 Massachusetts Gen Hosp, Bone Marrow Transplant Program, Boston, MA 02114 USA. SmithKline Beecham Pharmaceut, Collegeville, PA USA. Greenebaum Canc Ctr, Baltimore, MD USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. RP Spitzer, TR (reprint author), Massachusetts Gen Hosp, Bone Marrow Transplant Program, Cox 640,55 Fruit St, Boston, MA 02114 USA. NR 34 TC 28 Z9 28 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD JUL PY 2000 VL 26 IS 2 BP 203 EP 210 DI 10.1038/sj.bmt.1702479 PG 8 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 340DH UT WOS:000088517500013 PM 10918432 ER PT J AU Kohn, SE Melvold, J AF Kohn, SE Melvold, J TI Effects of morphological complexity on phonological output deficits in fluent and nonfluent aphasia SO BRAIN AND LANGUAGE LA English DT Article ID DISORDERS; DISSOCIATION; LANGUAGE; SYSTEM; ACCESS; WORDS AB This study examined the effects of morphological complexity on aphasic speakers with lexical-phonological output deficits. Subjects were two fluent and two nonfluent aphasic speakers who repeated morphologically simple words at the same level of accuracy and whose errors were virtually all phonological in nature. They were asked to repeat a variety of morphologically complex (i.e., affixed) words. Results were interpreted within our two-stage model of lexical-phonological production (Kohn & Smith, 1994, 1995), which we expand to include a distinction between derivational and inflectional morphology. When comparing overall performance levels between morphologically simple and complex words, only three subjects exhibited more difficulty repeating the morphologically complex targets. Nevertheless, when comparing repetition accuracy between different types of morphologically complex words (e.g., derived vs. inflected), all four subjects displayed similar pat terns. These findings suggested that while morphological complexity has different effects on the two stages within the lexical-phonological output system, the relative effects of different morphological structures are constant. At the level of error analysis, patterns of affix errors distinguished the nonfluent from the fluent subjects in ways that are reminiscent of the affix errors associated with agrammatic and para-grammatic speech. This finding raised questions concerning the relationship between morphosyntactic and morphophonological deficits. (C) 2000 Academic Press. C1 Moss Rehabil Res Inst, Philadelphia, PA USA. Temple Univ, Sch Med, Philadelphia, PA 19122 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kohn, SE (reprint author), 1411 Westwood Lane, Wynnewood, PA 19096 USA. FU NIDCD NIH HHS [1 R01 DC 02517-02] NR 33 TC 11 Z9 11 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD JUL PY 2000 VL 73 IS 3 BP 323 EP 346 DI 10.1006/brln.2000.2179 PG 24 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 331HZ UT WOS:000088014300001 PM 10860560 ER PT J AU Korsmeyer, SJ AF Korsmeyer, SJ TI Integrating the cell death pathway SO BRITISH JOURNAL OF CANCER 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 CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD JUL PY 2000 VL 83 SU 1 MA S18 BP 7 EP 7 PG 1 WC Oncology SC Oncology GA 334BX UT WOS:000088166200026 ER PT J AU Bostwick, DG Alexander, EE Singh, R Shan, A Qian, JQ Santella, RM Oberley, LW Yan, T Zhong, WX Jiang, XH Oberley, TD AF Bostwick, DG Alexander, EE Singh, R Shan, A Qian, JQ Santella, RM Oberley, LW Yan, T Zhong, WX Jiang, XH Oberley, TD TI Antioxidant enzyme expression and reactive oxygen species damage in prostatic intraepithelial neoplasia and cancer SO CANCER LA English DT Article DE prostatic intraepithelial neoplasia; superoxide dismutase; catalase; reactive oxygen species; antioxidant enzymes; prostatic neoplasms; prostate carcinoma ID GLUTATHIONE-S-TRANSFERASE; SUPEROXIDE-DISMUTASE ACTIVITY; IN-SITU HYBRIDIZATION; CARCINOMA-CELLS; CHROMOSOMAL-ANOMALIES; INDEPENDENT ORIGIN; OXIDATIVE STRESS; CONTROLLED TRIAL; ADENOCARCINOMA; DNA AB BACKGROUND. Oxidative stress results in damage to cellular structures and has been linked to many diseases, including cancer. The authors sought to determine whether the expression of three major antioxidant enzymes, copper-zinc superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), and catalase, was altered in human prostate carcinoma and its likely precursor, high grade prostatic intraepithelial neoplasia (PIN). The level of reactive oxygen species damage was evaluated by measuring the expression of the DNA adduct 8-hydroxydeoxyguanosine. METHODS. The authors evaluated the tissue expression of the antioxidant enzymes in prostate carcinoma by immunohistochemistry, immunogold electron microscopy, and enzymatic assay. The polymerase chain reaction was used to amplify and screen tissue specimens for the genes of SOD1, SOD2, and extracellular SOD (SOD3). Matched paraffin embedded tissue sections were evaluated by RNA in situ hybridization for expression of SOD1 and immunohistochemically for the DNA adduct 8-hydroxydeoxyguanosine. RESULTS. All prostatic tissues, including cancer, displayed immunoreactivity for the three antioxidant enzymes in epithelial cells, with no staining of the stroma, inflammatory cells, or endothelial cells. The number of immunoreactive cells was greater in benign epithelium than in PIN and cancer for each enzyme. The mean percentage rand intensity of immunoreactive cells was greatest for SOD2, intermediate for SODI, and lower for catalase. Staining in cancer was heterogeneous. Immunogold ultrasound studies revealed strong mitochondrial labeling for SOD2, which was greater in benign epithelium than in cancer; SOD1 labeling was invariably weaker, with nuclear labeling in benign epithelium and cytoplasmic labeling in cancer cells. There was no difference in enzyme activity for the three antioxidant enzymes between benign epithelium and cancer. No mutations were found in the 5 exons of SOD1, 5 exons of SOD2, and 3 exons of SOD3, except for 3 of 20 cases with polymorphisms for exon 3 of SOD1. Intense nuclear immunoreactivity for 8-hydroxydeoxyguanosine was present in fewer than 3% of epithelial cells, with no apparent differences among benign epithelium, PIN, and cancer. CONCLUSIONS. SOD1, SOD2, and catalase had lower expression in PIN and prostate carcinoma than in benign epithelium. The number of immunoreactive cells in PIN was similar to cancer, indicating that these are closely related. Enzyme activities were variable, with no difference between benign epithelial cells and cancer, although this lack of change in enzyme activity could have been due to the presence of contaminating benign cells within the cancer specimens. The results of reactive oxygen species damage were found only in the epithelium and not in the stroma. Expression of the DNA adduct 8-hydroxydeoxyguanosine was present in fewer than 3% of cells, with no apparent differences among benign epithelium, PIN, and cancer. These findings suggest that oxidative stress is an early event in carcinogenesis. (C) 2000 American Cancer Society. C1 Bostwick Labs, Richmond, VA 23294 USA. Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA. Mayo Clin & Mayo Fdn, Dept Urol, Rochester, MN 55905 USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. Univ Iowa, Coll Med, Radiat Res Lab, Iowa City, IA USA. William S Middleton Mem Vet Hosp, Pathol & Lab Med Serv, Madison, WI 53705 USA. RP Bostwick, DG (reprint author), Bostwick Labs, 9351 W Broad St, Richmond, VA 23294 USA. NR 53 TC 174 Z9 187 U1 0 U2 6 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 1 PY 2000 VL 89 IS 1 BP 123 EP 134 DI 10.1002/1097-0142(20000701)89:1<123::AID-CNCR17>3.0.CO;2-9 PG 12 WC Oncology SC Oncology GA 331KJ UT WOS:000088017800018 PM 10897009 ER PT J AU Mohr, L Rainov, NG Mohr, UG Wands, JR AF Mohr, L Rainov, NG Mohr, UG Wands, JR TI Rabbit cytochrome P4504B1: A novel prodrug activating gene for pharmacogene therapy of hepatocellular carcinoma SO CANCER GENE THERAPY LA English DT Article DE tumor gene therapy; cytochrome P450; suicide gene; 4-ipomeanol; hepatoma ID TARGET ORGAN ALKYLATION; VIRUS THYMIDINE KINASE; MULTIDRUG-RESISTANCE; CYTOSINE DEAMINASE; P-GLYCOPROTEIN; DOSE SCHEDULE; LUNG-CANCER; P53 GENE; IN-VIVO; PHASE-I AB Gene therapy using vector-mediated transfer of prodrug activating genes Is a promising treatment approach for malignant tumors. As demonstrated recently, the novel prodrug activating gene coding for rabbit cytochrome P450 4B1 (CYP4B1) is able to induce tumor cell death at low micromolar concentrations in glioblastoma cells after treatment with the prodrug 4-ipomeanol (4-IM) in vitro and in vivo. The rabbit CYP4B1 converts this prodrug and other furane analogs and aromatic amines, such as 2-aminoanthracene, to highly toxic alkylating metabolites, whereas the human isoenzyme exhibits only minimal enzymatic activity. In the present study, the cDNA encoding rabbit CYP4B1 was used for pharmacogene therapy of hepatocellular carcinoma (HCC). Cell clones derived from the human HCC cell lines Hep3B, HuH-7, and HepG2 and stably expressing the chimeric protein CYP4B1-EGFP (the CYP4B1 coding sequence fused to the enhanced green fluorescent protein (EGFP) gene) were selected. HCC clones expressing EGFP served as controls. 4-IM rapidly induced tumor cell death in CYP4B1 -EGFP-expressing clones at low concentrations (a 50% lethal dose of between 0.5 and 2 mu g/mL). No signs of toxicity were found in control cells expressing EGFP even at high prodrug concentrations (20 mu g/mL). Cell death occurred by apoptosis and was independent of functional p53. A pronounced direct bystander effect was observed in Hep3B cells, whereas bystander HepG2 and HuH-7 cells were highly resistant to toxic 4-IM metabolites. These results demonstrate that the CYP4B1/4-IM system efficiently and rapidly induces cell death in HCC cells, and that a cell line-specific mechanism may exist that limits the extent of the bystander effect of this novel prodrug activating system. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Canc Ctr,Mol Hepatol Lab, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mol Neurogenet Lab, Charlestown, MA 02129 USA. Univ Halle Wittenberg, Fac Med, Dept Neurosurg, Mol Neurooncol Lab, Halle, Germany. Liver Res Ctr, Providence, RI 02903 USA. RP Mohr, L (reprint author), Univ Klin Freiburg, Abt Med 2, Lab B3, Hugstetterstr 55, D-79106 Freiburg, Germany. FU NIAAA NIH HHS [AA-02666] NR 38 TC 28 Z9 29 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD JUL PY 2000 VL 7 IS 7 BP 1008 EP 1014 DI 10.1038/sj.cgt.7700190 PG 7 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 335QP UT WOS:000088256100005 PM 10917203 ER PT J AU Spear, MA Sun, F Eling, DJ Gilpin, E Kipps, TJ Chiocca, EA Bouvet, M AF Spear, MA Sun, F Eling, DJ Gilpin, E Kipps, TJ Chiocca, EA Bouvet, M TI Cytotoxicity, apoptosis, and viral replication in tumor cells treated with oncolytic ribonucleotide reductase-defective herpes simplex type 1 virus (hrR3) combined with ionizing radiation SO CANCER GENE THERAPY LA English DT Article; Proceedings Paper CT 90th Annual Meeting of the American-Association-for-Cancer-Research CY APR 10-14, 1999 CL PHILADELPHIA, PENNSYLVANIA SP Amer Assoc Canc Res DE pancreatic cancer; glioma; gene therapy; ionizing radiation; herpes simplex virus type-1; ribonucleotide reductase ID MALIGNANT GLIOMAS; CARCINOMA CELLS; FLOW-CYTOMETRY; IN-VITRO; MUTANT; GENE; RADIOSENSITIZATION; ENHANCEMENT; GANCICLOVIR; VIVO AB The viral ribonucleotide reductase (rR)-defective herpes simplex type-1 (HSV-1) virus (hrR3) has been shown previously to preferentially replicate in and kill tumor cells. This selectivity is associated with tumor cell up-regulation of mammalian rR. Ionizing radiation (IR) is currently used in the therapy of many malignancies, including glioblastoma, cervical carcinoma, and pancreatic carcinoma. IR has been shown to up-regulate mammalian rR in tumor cells and appears to increase the efficacy of at least one non-rR-deleted HSV-1 strain in an in vivo tumor model. Here, we test the hypothesis that a single therapeutic radiation fraction will increase the replication and toxicity of hrR3 for malignant cell lines in vitro. PANC-1 pancreatic carcinoma, U-87 glioblastoma, and CaSki cervical carcinoma cell lines were treated with varying doses of IR and subsequently infected with hrR3 or KOS (wild-type HSV-1 strain). Cell survival was then measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and trypan blue exclusion cytometry. At 72 hours posttreatment, irradiation with 2 Gy reduced survival from 100% to 76% in noninfected cells, from 61% to 48% in KOS-infected cells, and from 39% to 27% in hrR3-infected PANC-1 cells. As such, analysis of variance indicated that the toxicity of the two modalities was additive. Similar additivity was seen in U-87 MG and CaSki cells. Absolute survival of hrR3-infected or KOS-infected PANC-1 cells decreased as a function of time after treatment (24-72 hours) and multiplicity of infection (MOI) (0.05-5.0). However, the relative decrease in survival with the addition of IR to hrR3 or KOS in PANC-1 cells was not markedly affected by altering MOI (0.05-5.0), time (24-72 hours), radiation dose (2-20 Gy), or cell culture conditions (confluent/growth arrested). We used fluorescence-activated cell sorter analysis with the cationic lipophilic dye DiOC(6) to quantify a reduction in mitochondrial membrane potential that is associated with apoptosis. Fluorescence-activated cell sorter analysis indicated increased apoptosis in both hrR3- and IR-treated cells at 48-72 hours, with hrR3 alone producing the most induction. Viral yields from PANC-1 cells after irradiation and infection were examined. No significant differences were seen between irradiated and nonirradiated cells in viral replication, with hrR3 producing single-step titers of 3.1 +/- 0.9 x 10(5) and 4.0 +/- 1.2 x 10(5) plaque-forming units/mL in nonirradiated and irradiated cells. Thus, complementary toxicity was seen between IR and hrR3 or KOS, regardless of cell type, time, MOI, IR dose, or culture conditions, without evidence of augmented apoptosis or viral replication. C1 Univ Calif San Diego, Med Ctr, Dept Radiat Oncol, San Diego, CA 92103 USA. Univ Calif San Diego, Dept Surg, San Diego, CA 92103 USA. Univ Calif San Diego, Translat Canc Res Program, Dept Hematol Oncol, Gene Therapy Program, San Diego, CA 92103 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Mol Neurooncol Labs,Neurosurg Serv, Charlestown, MA 02129 USA. Univ Calif San Diego, Ctr Canc, San Diego, CA 92103 USA. RP Spear, MA (reprint author), Univ Calif San Diego, Med Ctr, Dept Radiat Oncol, 220 W Arbor Dr,MC 8757, San Diego, CA 92103 USA. NR 24 TC 36 Z9 42 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD JUL PY 2000 VL 7 IS 7 BP 1051 EP 1059 DI 10.1038/sj.cgt.7700208 PG 9 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 335QP UT WOS:000088256100010 PM 10917208 ER PT J AU Babbitt, JT Kharazi, AI Taylor, JMG Bonds, CB Mirell, SG Frumkin, E Zhuang, DL Hahn, TJ AF Babbitt, JT Kharazi, AI Taylor, JMG Bonds, CB Mirell, SG Frumkin, E Zhuang, DL Hahn, TJ TI Hematopoietic neoplasia in C57BL/6 mice exposed to split-dose ionizing radiation and circularly polarized 60 Hz magnetic fields SO CARCINOGENESIS LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ELECTRIC UTILITY WORKERS; ELECTROMAGNETIC-FIELDS; CHILDHOOD LEUKEMIA; BRAIN-TUMORS; OCCUPATIONAL EXPOSURE; CANCER; MORTALITY; RATS; CARCINOGENICITY AB This study assessed the effect of chronic exposure to a 60 Hz circularly polarized magnetic field on the occurrence of ionizing radiation-induced lymphoma and other hematopoietic neoplasia in mice. Female C57BL/6 mice received lifetime exposure to either a magnetic field flux density of 1.42 mT for 18 h/day, or an ambient magnetic field of 0.13 mu T Beginning- on the first day of magnetic field exposure, 1710 mice were treated with one of three levels of split-dose Cobalt-60 gamma-radiation (cumulative 3.0, 4.0 or 5.1 Cy), The remaining 570 mice received sham irradiation treatment, Sections from 10 lymphoid tissues were evaluated histopathologically for hematopoietic neoplasia, The primary statistical analysis used the Poly3 method to compare lymphoma incidences in magnetic field (MF)-exposed and control mice. Secondary analyses used the Cox proportional hazards model to analyze incidence rates for mortality and development of specific types of neoplasia, The mortality incidence rate was increased by ionizing radiation treatment, and all neoplasms were observed sooner in irradiated mice. However, the lifetime incidence of hematopoietic neoplasia was similar in all experimental groups, including those that were not exposed to ionizing radiation. Chronic exposure to MFs did not affect the mortality incidence rates and did not change the relative incidences of hematopoietic neoplasia in mice that received the same ionizing radiation treatment, with the exception of a marginally significant reduced relative risk of 0.97 (P = 0.05) for lymphoblastic lymphoma in mice exposed to a magnetic field and treated with 5.1 Cy, Lymphomas and histiocytic sarcomas were first observed similar to 50 days sooner in mice that were exposed to magnetic fields but not ionizing radiation, although this comparison was not statistically significant and the incidence of hematopoietic neoplasia in these mice was not different from that of mice in the 0 T/0 Gy group. C1 Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Radiol, Los Angeles, CA 90095 USA. St Vincents Med Ctr, Immunotherapy Lab, Los Angeles, CA 90057 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Merle Norman Cosmet, El Segundo, CA USA. VA Greater Los Angeles Healthcare Syst W Los Ange, Educ & Clin Ctr, Los Angeles, CA 90073 USA. Scirex Corp, Horsham, PA 19044 USA. RP Babbitt, JT (reprint author), Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. NR 53 TC 18 Z9 18 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2000 VL 21 IS 7 BP 1379 EP 1389 DI 10.1093/carcin/21.7.1379 PG 11 WC Oncology SC Oncology GA 336QD UT WOS:000088313700015 PM 10874017 ER PT J AU Suratt, BT Welsh, CH AF Suratt, BT Welsh, CH TI A 48-year-old smoker with cough and weight loss SO CHEST LA English DT Article ID ACTINOMYCOSIS C1 Denver Vet Affairs Med Ctr, Denver, CO USA. RP Suratt, BT (reprint author), Univ Colorado, Hlth Sci Ctr, Div Pulm Sci & Crit Care Med, Box C272,4200 E 9th Ave, Denver, CO 80231 USA. FU NHLBI NIH HHS [T32 HL007085] NR 6 TC 3 Z9 3 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 JUL PY 2000 VL 118 IS 1 BP 239 EP 241 DI 10.1378/chest.118.1.239 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 336CR UT WOS:000088284800042 PM 10893386 ER PT J AU Wilens, TE Spencer, TJ AF Wilens, TE Spencer, TJ TI The stimulants revisited SO CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Review ID ATTENTION-DEFICIT-HYPERACTIVITY; MINIMAL BRAIN-DYSFUNCTION; MOTHER-CHILD INTERACTIONS; SUSTAINED-RELEASE METHYLPHENIDATE; SEROTONIN REUPTAKE INHIBITORS; CONDUCT DISORDER; CONTROLLED TRIAL; DEFICIT/HYPERACTIVITY DISORDER; TIC DISORDER; PHARMACOLOGICAL TREATMENT AB Stimulants are the most often prescribed psychotropics in children and adolescents, used generally for the treatment of attention deficit/hyperactivity disorder (ADHD). In this article the authors summarize the literature on prevalence of usage, neurobiology, and pharmacology of the stimulants. Recent studies on the use of stimulants in special ADHD populations including preschoolers and adults, and co-occuring neurologic, psychiatric, and substance use disorders are cited. Clinical guidelines for the management of individuals receiving the stimulants are offered, and treatment strategies delineated for ADHD subjects with comorbidity and medication-induced adverse effects are discussed. C1 Massachusetts Gen Hosp, Clin Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, Child Psychiat Serv, ACC 725, Boston, MA 02114 USA. NR 177 TC 116 Z9 120 U1 10 U2 17 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1056-4993 J9 CHILD ADOL PSYCH CL JI Child Adolesc. Psychiatr. N. Am. PD JUL PY 2000 VL 9 IS 3 BP 573 EP + PG 32 WC Psychiatry SC Psychiatry GA 382YG UT WOS:000165854500010 PM 10944658 ER PT J AU Weinberg, A Zhang, L Brown, D Erice, A Polsky, B Hirsch, MS Owens, S Lamb, K AF Weinberg, A Zhang, L Brown, D Erice, A Polsky, B Hirsch, MS Owens, S Lamb, K TI Viability and functional activity of cryopreserved mononuclear cells SO CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY LA English DT Article ID INHIBITOR; RITONAVIR; PROTEASE AB Factors that influence viability and function of cryopreserved peripheral blood mononuclear cells (PBMC) were identified on 54 samples from 27 AIDS Clinical Trial Units. PBMC viability ranged from I to 96% with a median of 70%, was higher in laboratories with experienced staff, and was not significantly associated with CD4 cell number. Function of cryopreserved PBMC, measured by lymphocyte proliferation, was associated with viability. Preparations with viability greater than or equal to 70% had consistent proliferative responses and,were suitable For functional analyses. C1 Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA. Univ Minnesota, Minneapolis, MN USA. St Lukes Roosevelt Hosp Ctr, New York, NY USA. Harvard Univ, Sch Publ Hlth, Massachusetts Gen Hosp, Boston, MA 02115 USA. Frontier Sci & Technol Res Fdn, Washington, DC USA. Adult AIDS Clin Trials Grp Operat Ctr, Washington, DC USA. RP Weinberg, A (reprint author), Univ Colorado, Hlth Sci Ctr, Campus Box C227,4200 E 9th Ave, Denver, CO 80262 USA. NR 9 TC 57 Z9 59 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1071-412X J9 CLIN DIAGN LAB IMMUN JI Clin. Diagn. Lab. Immunol. PD JUL PY 2000 VL 7 IS 4 BP 714 EP 716 DI 10.1128/CDLI.7.4.714-716.2000 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 332AT UT WOS:000088051400036 PM 10882680 ER PT J AU Chandrasekar, B Melby, PC Troyer, DA Freeman, GL AF Chandrasekar, B Melby, PC Troyer, DA Freeman, GL TI Differential regulation of nitric oxide synthase isoforms in experimental acute Chagasic cardiomyopathy SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE Chagas' disease; Trypanosoma cruzi; cardiomyopathy; nitric oxide synthase; peroxynitrite ID TUMOR-NECROSIS-FACTOR; TRYPANOSOMA-CRUZI INFECTION; PROINFLAMMATORY CYTOKINE; EXPRESSION; INDUCTION; DISEASE; SUPEROXIDE; MICE; PEROXYNITRITE; RECEPTOR AB We have previously demonstrated induction and high level expression of IL-1 beta, IL-6 and tumour necrosis factor-alpha in the myocardium during the acute stage of experimental Trypanosoma cruzi infection (Chagas' disease). The myocardial depressive effects of these cytokines are mediated in part by the induction of nitric oxide synthase (NOS), production of nitric oxide (NO) and formation of peroxynitrite. In this study we investigated the expression, activity and localization of NOS isoforms, and the levels of NO, malondialdehyde (a measure of oxidative stress), and peroxynitrite in rats at 1.5, 5, 10 and 15 days after infection with T. cruzi trypomastigotes. The myocardial inflammatory infiltrate and number of amastigote nests increased over the course of infection. A significant increase in tissue nitrate + nitrite levels, NOS2 mRNA, and NOS2 enzyme activity was observed at all time points in the infected compared with uninfected animals. The enzyme activity of constitutive NOS, tissue malondialdehyde levels, and NOS3 mRNA levels was only transiently increased after infection. The protein levels of the NOS isoforms paralleled their mRNA expression. While no positive nitrotyrosine immunoreactivity was detected in control myocardium, its levels increased in infected animals over time. Thus, by 1.5 days post-infection, when no parasite or immune cell infiltration could be detected, the myocardium expressed high levels of NOS and NO metabolites. Nevertheless, the early production of NO in the myocardium was not sufficient to clear the parasites. C1 Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. Dept Vet Affairs Med Ctr, Med Serv, San Antonio, TX USA. RP Freeman, GL (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med Cardiol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. NR 33 TC 29 Z9 29 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD JUL PY 2000 VL 121 IS 1 BP 112 EP 119 DI 10.1046/j.1365-2249.2000.01258.x PG 8 WC Immunology SC Immunology GA 328NH UT WOS:000087856600017 PM 10886247 ER PT J AU Breathnach, OS Georgiadis, MS Schuler, BS Pizzella, P Llorens, V Kasturi, V Steinberg, SM O'Neil, K Takimoto, CH Johnson, BE AF Breathnach, OS Georgiadis, MS Schuler, BS Pizzella, P Llorens, V Kasturi, V Steinberg, SM O'Neil, K Takimoto, CH Johnson, BE TI Phase II trial of paclitaxel by 96-hour continuous infusion in combination with cisplatin for patients with advanced non-small cell lung cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID COLORECTAL-CANCER; CLINICAL-TRIALS; 3-HOUR INFUSION; BREAST-CANCER; LINES; TAXOL; CARBOPLATIN; TOXICITY; EXPOSURE; SCHEDULE AB Our purpose was to determine the antitumor efficacy and safety profile of the combination of paclitaxel administered by 96-h continuous i,v, infusion followed by bolus cisplatin in patients with untreated advanced non-small cell lung cancer (NSCLC), Fifty-eight patients with untreated advanced or recurrent NSCLC were enrolled between October 1995 and December 1998, The median patient age was 60 years (age range, 34-75 years). Twenty-four patients were female. The majority of patients (n = 52) had an Eastern Cooperative Oncology Group performance status of 0/1, Twelve patients had stage IIIB NSCLC, 43 had stage IV disease, and 3 had recurrent disease after prior resection, Seven patients had received cranial irradiation for brain metastases, and 5 patients had received bone irradiation before enrollment. Patients,were treated with paclitaxel (120 mg/m(2)/96 h) by continuous i,v, infusion followed by cisplatin (80 mg/m(2)) on day 5, Therapy was administered every 3 weeks as tolerated until disease progression or a maximum of six cycles. A total of 264 cycles of therapy were administered. Twenty-nine patients received all six cycles, Forty-six patients had measurable disease, with 20 patients achieving a partial response, and no complete responses were seen (overall response rate, 43%; 95% confidence interval, 29-60%), The median progression-free survival was 5.5 months. At a median potential follow-up of 27.2 months, the median survival for all 58 enrolled patients was 8.5 months, and the actuarial 1-year survival was 37% (95% confidence interval, 25.9-50.5%). This is the most extensive evaluation of prolonged continuous infusional paclitaxel in patients,vith advanced-stage cancer. In contrast to predictions from in vitro cytotoxicity models, the regimen does not appear to be obviously superior to shorter infusion times in the clinical setting. Additional trials of this regimen in patients with NSCLC are therefore of low priority. C1 Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Boston, MA 02115 USA. NCI, Natl Naval Med Ctr, Med Branch, Bethesda, MD 20889 USA. NCI, Natl Naval Med Ctr, Biostat & Data Management Sect, Bethesda, MD 20889 USA. NCI, Natl Naval Med Ctr, Div Clin Sci, Bethesda, MD 20889 USA. Natl Naval Med Ctr, Dept Radiol, Bethesda, MD 20889 USA. Natl Naval Med Ctr, Dept Pulm Med, Bethesda, MD 20889 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Dept Adult Oncol, Dana 1234,44 Binney St, Boston, MA 02115 USA. NR 37 TC 9 Z9 10 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 JUL PY 2000 VL 6 IS 7 BP 2670 EP 2676 PG 7 WC Oncology SC Oncology GA 333TU UT WOS:000088147500011 PM 10914708 ER PT J AU Norman, DC AF Norman, DC TI Fever in the elderly SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID NURSING-HOME RESIDENTS; UNKNOWN ORIGIN; INFECTIVE ENDOCARDITIS; CLINICAL-SIGNIFICANCE; BACTEREMIA; AGE; TEMPERATURE; PROGNOSIS; FEATURES; PYREXIA AB Infections in the elderly, similar to other acute illnesses in this age group, may present in atypical, nonclassical fashions. Fever, the cardinal sign of infection, may be absent or blunted 20%-30% of the time. An absent or blunted fever response may in turn contribute to diagnostic delays in this population, which is already at risk for increased morbidity and mortality due to infection. On the other hand, the presence of a fever in the geriatric patient is more likely to be associated with a serious viral or bacterial infection than is fever in a younger patient. Finally, a diagnosis can be made in the majority of cases of fever of unknown origin (FUO) in the elderly. FUO is often associated with treatable conditions in this age group. C1 Univ Calif Los Angeles, Dept Med, Div Geriatr, Sch Med, Los Angeles, CA 90024 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. RP Norman, DC (reprint author), Vet Affairs Med Ctr W Los Angeles, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 42 TC 85 Z9 91 U1 3 U2 8 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 BP 148 EP 151 DI 10.1086/313896 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900028 PM 10913413 ER PT J AU Warren, JR Farmer, JJ Dewhirst, F Zembower, TR Peterson, LR Bhattacharya, M AF Warren, JR Farmer, JJ Dewhirst, F Zembower, TR Peterson, LR Bhattacharya, M TI Outbreak of nosocomial infections due to extended spectrum beta-lactamase-producing enteric group 137: A new Enterobacteriaceae SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Ctr Dis Control & Prevent, Atlanta, GA USA. Northwestern Univ, Sch Med, Chicago, IL USA. Forsyth Inst, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 7 BP 213 EP 213 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900057 ER PT J AU Sutton, PR Harley, JD Jacobson, AF Lipsky, BA AF Sutton, PR Harley, JD Jacobson, AF Lipsky, BA TI Diagnosing osteomyelitis with percutaneous bone biopsy in patients with diabetes and foot ulceration. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 VA Puget Sound Hlth Care Syst, Seattle, WA USA. Univ Washington, Seattle, WA 98195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 30 BP 218 EP 218 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900080 ER PT J AU Hamill, RJ Pappas, PG Rex, JH Lee, JY Horowitz, H Kauffman, CA Hyslop, N Larsen, RA Stein, DK Graviss, EA Thomas, CJ AF Hamill, RJ Pappas, PG Rex, JH Lee, JY Horowitz, H Kauffman, CA Hyslop, N Larsen, RA Stein, DK Graviss, EA Thomas, CJ CA Mycoses Study Grp TI Multicenter surveillance of non-albicans candidemia SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Univ Michigan, Ann Arbor VA Med Ctr, Ann Arbor, MI 48109 USA. Baylor Coll Med, Houston VA Med Ctr, Houston, TX 77030 USA. NIAID, Jacobi Med Ctr, Bethesda, MD 20892 USA. Tulane Univ, New Orleans, LA 70118 USA. Univ Alabama, Birmingham, AL USA. Univ So Calif, Los Angeles, CA USA. Univ Texas, Houston, TX USA. Westchester Cty Hosp, Valhalla, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 36 BP 219 EP 219 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900086 ER PT J AU Omer, I Perfect, JR Warren, RM Hamill, RJ Kauffman, CA Pappas, PG AF Omer, I Perfect, JR Warren, RM Hamill, RJ Kauffman, CA Pappas, PG TI Cryptococcosis without central nervous system or pulmonary involvement in HIV-negative patients SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Univ Michigan, Ann Arbor VA Med Ctr, Ann Arbor, MI 48109 USA. Duke Univ, Med Ctr, Durham, NC USA. Baylor Coll Med, Houston VA Med Ctr, Houston, TX 77030 USA. Univ Alabama, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 39 BP 219 EP 219 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900089 ER PT J AU Musher, DM Phan, HM Mediwala, R Baughn, RE AF Musher, DM Phan, HM Mediwala, R Baughn, RE TI Human IgG to Pneumolysin (PLY) is protective in vivo against infection by Streptococcus pneumoniae (Spn) SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 VA Med Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 117 BP 233 EP 233 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900167 ER PT J AU Ballard, JE Jernigan, DB O'Connor, S Strausbaugh, LJ Liedtke, LA Ashford, DA AF Ballard, JE Jernigan, DB O'Connor, S Strausbaugh, LJ Liedtke, LA Ashford, DA CA IDSA Emerging Infections Network TI Crohn's disease and possible infectious etiologies: Infectious disease consultants' views SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Ctr Dis Control & Prevent, Atlanta, GA USA. Infect Dis Soc Amer, Portland, OR USA. Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 154 BP 239 EP 239 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900204 ER PT J AU Darouiche, RO Hull, RA Donovan, WH AF Darouiche, RO Hull, RA Donovan, WH TI Bacterial interference for prevention of urinary tract infection (UTI). SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Baylor Coll Med, VA Med Ctr, Houston, TX 77030 USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 180 BP 244 EP 244 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900230 ER PT J AU Mylonakis, EE Calderwood, SB Paliou, MN Hohmann, EL Wing, EJ AF Mylonakis, EE Calderwood, SB Paliou, MN Hohmann, EL Wing, EJ TI Perinatal Listeriosis in Massachusetts and Rhode island 1980-1999. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Brown Univ, Providence, RI 02912 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Miriam Hosp, Providence, RI 02906 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 212 BP 249 EP 249 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900262 ER PT J AU Walensky, RP Freedberg, KA Losina, E Goldie, SJ AF Walensky, RP Freedberg, KA Losina, E Goldie, SJ TI Testing primary HIV-1 infection: Modeling clinical outcomes SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Med Ctr, Boston, MA USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 322 BP 268 EP 268 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900372 ER PT J AU Hanna, HA Alakech, B Chatzinikolaou, I Darouiche, RO Rolston, KV Whimbey, EE Hachem, RY Raad, II AF Hanna, HA Alakech, B Chatzinikolaou, I Darouiche, RO Rolston, KV Whimbey, EE Hachem, RY Raad, II TI Predictors of catheter-related bloodstream infections (CRBSI) in cancer patients with bacteremia or fungemia SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Baylor Coll Med, VA Med Ctr, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 414 BP 284 EP 284 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900464 ER PT J AU Strausbaugh, LJ Jernigan, DB Liedtke, LA Young, JC Khan, AS Ksiazek, TG AF Strausbaugh, LJ Jernigan, DB Liedtke, LA Young, JC Khan, AS Ksiazek, TG CA IDSA Emerging Infections Network TI Hantavirus pulmonary syndrome in the United States: Experience of infectious diseases consultants SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Ctr Dis Control & Prevent, Atlanta, GA USA. Portland VA Med Ctr, Portland, OR USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 495 BP 298 EP 298 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900545 ER PT J AU Restrepo, MI Bohorquez, M Restrepo, A Jorgensen, JH Anzueto, A Melby, PC AF Restrepo, MI Bohorquez, M Restrepo, A Jorgensen, JH Anzueto, A Melby, PC TI Antimicrobial susceptibility to Mycobacterial szulgai: 25-year experience SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Vet Adm Med Ctr, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 573 BP 312 EP 312 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900623 ER PT J AU Murphy, MD Rosen, HR Chou, SW AF Murphy, MD Rosen, HR Chou, SW TI Hepatitis C virus NSSA sequence configuration does not predict response to interferon. SO CLINICAL INFECTIOUS DISEASES LA English DT Meeting Abstract C1 Portland VA Med Ctr, Portland, OR USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD JUL PY 2000 VL 31 IS 1 MA 617 BP 319 EP 319 PG 1 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 347VY UT WOS:000088950900667 ER PT J AU Cao, H Walker, BD AF Cao, H Walker, BD TI Immunopathogenesis of HIV-1 infection SO CLINICS IN DERMATOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; CYTOTOXIC T-LYMPHOCYTES; LONG-TERM NONPROGRESSORS; PRIMARY IMMUNE-RESPONSE; LOW VIRAL LOAD; TYPE-1 INFECTION; MONOCLONAL-ANTIBODY; CHEMOKINE RECEPTOR; CELL RESPONSES; IN-VIVO C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Boston, MA 02114 USA. RP Cao, H (reprint author), Massachusetts Gen Hosp, AIDS Res Ctr, 149 13th St,Room 5212, Charlestown, MA 02129 USA. NR 133 TC 2 Z9 2 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0738-081X J9 CLIN DERMATOL JI Clin. Dermatol. PD JUL-AUG PY 2000 VL 18 IS 4 BP 401 EP 410 DI 10.1016/S0738-081X(99)00135-2 PG 10 WC Dermatology SC Dermatology GA 361RK UT WOS:000089736900004 PM 11024307 ER PT J AU Zachary, KC AF Zachary, KC TI Systemic manifestations of HIV infection SO CLINICS IN DERMATOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIRETROVIRAL THERAPY; AIDS; TUBERCULOSIS C1 Massachusetts Gen Hosp, Dept Med, Infect Dis Unit, Boston, MA 02114 USA. RP Zachary, KC (reprint author), Massachusetts Gen Hosp, Dept Med, Infect Dis Unit, 55 Fruit St, Boston, MA 02114 USA. NR 25 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0738-081X J9 CLIN DERMATOL JI Clin. Dermatol. PD JUL-AUG PY 2000 VL 18 IS 4 BP 441 EP 446 DI 10.1016/S0738-081X(99)00139-X PG 6 WC Dermatology SC Dermatology GA 361RK UT WOS:000089736900008 PM 11024311 ER PT J AU Whelan, P Scadden, DT AF Whelan, P Scadden, DT TI New developments in the etiopathogenesis and treatment of HIV-related Kaposi's sarcoma SO CLINICS IN DERMATOLOGY LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; IMMUNODEFICIENCY-VIRUS INFECTION; PEGYLATED-LIPOSOMAL DOXORUBICIN; INTERFERON REGULATORY FACTOR; BLOOD MONONUCLEAR-CELLS; SPINDLE CELLS; HUMAN-HERPESVIRUS-8 INFECTION; ANTIRETROVIRAL THERAPY; SEXUAL TRANSMISSION; PROTEASE INHIBITORS C1 Massachusetts Gen Hosp, AIDS Res Ctr, Charlestown, MA 02129 USA. RP Scadden, DT (reprint author), Massachusetts Gen Hosp, AIDS Res Ctr, 149 Bldg,13 Str, Charlestown, MA 02129 USA. NR 79 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0738-081X J9 CLIN DERMATOL JI Clin. Dermatol. PD JUL-AUG PY 2000 VL 18 IS 4 BP 469 EP 477 DI 10.1016/S0738-081X(99)00142-X PG 9 WC Dermatology SC Dermatology GA 361RK UT WOS:000089736900011 PM 11024314 ER PT J AU Podolsky, DK AF Podolsky, DK TI Editorial commentary - Pride and prejudice: inflammatory bowel disease models and drug development SO CURRENT OPINION IN GASTROENTEROLOGY LA English DT Editorial Material C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02114 USA. RP Podolsky, DK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, 55 Fruix St, Boston, MA 02114 USA. NR 0 TC 7 Z9 7 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0267-1379 J9 CURR OPIN GASTROEN JI Curr. Opin. Gastroenterol. PD JUL PY 2000 VL 16 IS 4 BP 295 EP 296 DI 10.1097/00001574-200007000-00001 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 324YL UT WOS:000087649500001 PM 17031091 ER PT J AU Sjak-Shie, NN Vescio, RA Berenson, JR AF Sjak-Shie, NN Vescio, RA Berenson, JR TI Recent advances in multiple myeloma SO CURRENT OPINION IN HEMATOLOGY LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW TRANSPLANTATION; SARCOMA-ASSOCIATED HERPESVIRUS; IN-SITU HYBRIDIZATION; TUMOR-NECROSIS-FACTOR; HEPATOCYTE GROWTH-FACTOR; KAPOSIS-SARCOMA; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; DENDRITIC CELLS AB Multiple myeloma is the second most common hematologic malignancy, with approximately 15,000 new cases each year in the United States. Our understanding of the pathophysiology underlying myeloma continues to expand, but the cause of this plasma cell dyscrasia remains unclear, Though controversy remains regarding a possible viral cause of myeloma, evidence suggesting a role for the human herpesvirus-8 is mounting, The roles of cytogenetic abnormalities as well as aberrant angiogenesis and cytokine expression in the etiology of myeloma continue to be explored and may lead to future therapeutic strategies. Transplantation in myeloma is rarely curative but offers clinical benefit not only for young but possibly for older myeloma patients as well. Newer bisphosphonates may offer greater ease of administration, improved efficacy, and possibly even enhanced antitumor effect. Finally, thalidomide offers significant clinical benefit to patients with myeloma previously refractory to multiple agents, and its role in early stages of the disease is under investigation. (C) 2000 Lippincott Williams & Wilkins, Inc. C1 W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. RP Berenson, JR (reprint author), W Los Angeles Vet Affairs Med Ctr, 111 H,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 75 TC 8 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1065-6251 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD JUL PY 2000 VL 7 IS 4 BP 241 EP 246 DI 10.1097/00062752-200007000-00007 PG 6 WC Hematology SC Hematology GA 379YW UT WOS:000165671600007 PM 10882180 ER PT J AU Chung, UI Kronenberg, HM AF Chung, UI Kronenberg, HM TI Parathyroid hormone-related peptide and Indian hedgehog SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review ID ENDOCHONDRAL BONE-FORMATION; CUBITUS-INTERRUPTUS; SONIC-HEDGEHOG; BLOMSTRAND-CHONDRODYSPLASIA; METAPHYSEAL CHONDRODYSPLASIA; TRANSCRIPTIONAL ACTIVATOR; INACTIVATING MUTATION; POLARIZING ACTIVITY; BINDING PROTEIN; RECEPTOR AB Normal endochondral bone development requires temporal and spatial coordination of various cell types. Parathyroid hormone-related peptide and Indian hedgehog interact with each other and form a feedback loop that plays a major role in this coordination. Defects in the signalling of either of the two molecules cause severe bone malformations. Curr Opin Nephrol Hypertens 9:357-362, (C) 2000 Lippincott Williams & Wilkins. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Chung, UI (reprint author), Massachusetts Gen Hosp, Endocrine Unit, 50 Blossom St,Wellman 5, Boston, MA 02114 USA. NR 54 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JUL PY 2000 VL 9 IS 4 BP 357 EP 362 DI 10.1097/00041552-200007000-00006 PG 6 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 331RP UT WOS:000088032700006 PM 10926171 ER PT J AU Sheridan, AM Bonventre, JV AF Sheridan, AM Bonventre, JV TI Cell biology and molecular mechanisms of injury in ischemic acute renal failure SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review ID ENDOTHELIN-RECEPTOR ANTAGONIST; PLATELET-ACTIVATING-FACTOR; TUBULAR EPITHELIAL-CELLS; HORMONE-RELATED PROTEIN; RAT-KIDNEY; REPERFUSION INJURY; NEUTRAL ENDOPEPTIDASE; POSTISCHEMIC INJURY; PHOSPHOLIPASE A(2); PROXIMAL TUBULES AB The pathogenesis of acute renal failure has been attributed to persistent vasoconstriction and leukocyte-endothelial interactions, resulting in inflammation and compromise of local blood flow to the outer medulla, the loss of tubular epithelial cell polarity with multiple functional sequelae, necrosis or apoptosis of epithelial cells, and the de-differentiation, migration and proliferation of surviving cells, In this paper, the authors present their views of pathophysiology of ischemic acute renal failure. Curr Opin Nephrol Hypertens 9:427-434. (C) 2000 Lippincott Williams & Wilkins. C1 Harvard Univ, Sch Med, Dept Med, Charlestown, MA 02129 USA. Harvard MIT Div Hlth Sci & Technol, Charlestown, MA 02129 USA. RP Bonventre, JV (reprint author), Massachusetts Gen Hosp, Med Serv, 149-4002 13th St, Charlestown, MA 02129 USA. NR 95 TC 194 Z9 206 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD JUL PY 2000 VL 9 IS 4 BP 427 EP 434 DI 10.1097/00041552-200007000-00015 PG 8 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 331RP UT WOS:000088032700015 PM 10926180 ER PT J AU Freytes, CO AF Freytes, CO TI Indications and complications of intravenous devices for chemotherapy SO CURRENT OPINION IN ONCOLOGY LA English DT Review ID CENTRAL VENOUS CATHETERS; BLOOD-STREAM INFECTIONS; CANCER-PATIENTS; RANDOMIZED TRIAL; ACCESS DEVICES; PREVENTION; CULTURES; SYSTEMS; AGENTS AB Vascular access devices (VADs) are frequently used in patients with cancer. Vascular access devices can be divided into external catheters and subcutaneous venous access ports. Each type of device has its advantages and disadvantages, but the indications and optimal use of specific VADs remain to be defined. There are multiple complications of VADs but, with the exception of catheter-related bloodstream infections and thrombosis, most complications are rare. The use of VADs impregnated with antibiotic reduces the rates of catheter colonization and catheter-related bloodstream infections as compared with the use of unimpregnated catheters for short-term use. Thrombosis remains a major complication of VADs, and prospective, controlled studies are needed to clearly define the risk factors, natural history, and optimal treatment of this complication. Curr Opin Oncol 2000, 12:303-307 (C) 2000 Lippincott Williams & Wilkins, Inc. C1 Univ Texas, Hlth Sci Ctr, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. RP Freytes, CO (reprint author), Univ Texas, Hlth Sci Ctr, Mail Code 7880,7703 Floyd Curl Dr, San Antonio, TX 78229 USA. NR 16 TC 17 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD JUL PY 2000 VL 12 IS 4 BP 303 EP 307 DI 10.1097/00001622-200007000-00005 PG 5 WC Oncology SC Oncology GA 357BU UT WOS:000089479300005 PM 10888414 ER PT J AU Ryan, DP Mayor, RJ AF Ryan, DP Mayor, RJ TI Anal carcinoma: histology, staging, epidemiology, treatment SO CURRENT OPINION IN ONCOLOGY LA English DT Review ID SQUAMOUS-CELL CARCINOMA; ACQUIRED IMMUNODEFICIENCY SYNDROME; HUMAN PAPILLOMAVIRUS INFECTION; PRIMARY RADIATION-THERAPY; COOPERATIVE-ONCOLOGY-GROUP; COMBINED-MODALITY THERAPY; HIV-POSITIVE PATIENTS; EPIDERMOID CARCINOMA; CANAL CARCINOMA; CANCER INCIDENCE AB Our understanding of the pathogenesis and management of squamous cell carcinoma of the anal canal has undergone profound change over the last 30 years. Epidemiologic studies have demonstrated that infection with human papillomavirus is most likely responsible for the majority of cases. Primary treatment with concomitant chemotherapy and radiation cures the majority of patients without the need for an abdominoperineal resection. Recent series have demonstrated that approximately one half of patients with a local recurrence after chemoradiation will be cured with salvage surgery. The incorporation of cisplatin into the primary chemoradiation treatment of patients with carcinoma of the anal canal is the focus of current studies. Curr Opin Oncol 2000, 12:345-352 (C) 2000 Lippincott Williams & Wilkins, Inc. C1 Massachusetts Gen Hosp, Div Hematol Oncol, Gastrointestinal Canc Ctr, Boston, MA 02114 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ryan, DP (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Gastrointestinal Canc Ctr, 44 Binney St, Boston, MA 02114 USA. NR 93 TC 34 Z9 37 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8746 J9 CURR OPIN ONCOL JI Curr. Opin. Oncol. PD JUL PY 2000 VL 12 IS 4 BP 345 EP 352 DI 10.1097/00001622-200007000-00011 PG 8 WC Oncology SC Oncology GA 357BU UT WOS:000089479300011 PM 10888420 ER PT J AU Inman, RD Whittum-Hudson, JA Schumacher, HR Hudson, AP AF Inman, RD Whittum-Hudson, JA Schumacher, HR Hudson, AP TI Chlamydia and associated arthritis SO CURRENT OPINION IN RHEUMATOLOGY LA English DT Review ID INDUCED REACTIVE ARTHRITIS; POLYMERASE-CHAIN-REACTION; REITERS-SYNDROME; SYNOVIAL TISSUE; TRACHOMATIS INFECTION; GENE-EXPRESSION; YERSINIA ANTIGENS; NUCLEIC-ACIDS; BACTERIAL-DNA; CELLS AB An inflammatory arthritis is known to follow urogenital infection with the intracellular bacterium Chlamydia trachomatis in some individuals, and recent research results have elucidated important aspects of the characteristics of this Chlamydia-associated joint disease. Although the several extra-articular features of Chlamydia-induced arthritis have been defined clinically, their detailed causes remain largely unexplained. Current data indicate that the clinical characteristics of joint disease associated with C, trachomatis infection and those associated with postenteric arthritis are not easily distinguishable, although the response of each to antibiotic therapy does differ. The biologic characteristics of Chlamydia and enteric organisms in the joint show profound differences, and these are probably responsible for the variable responses to drug treatment. Molecular analyses of synovial C. trachomatis have demonstrated that long-term infection of the joint occurs primarily in synovial tissue and that the organism exhibits highly unusual biologic properties in its synovial context. These unusual molecular, biochemical, and other characteristics provide explanations for the frequent culture negativity of joint materials for C. trachomatis and for several other aspects of the arthritogenic process. Much remains to be learned concerning the behavior of this organism in the joint and concerning its interaction with its synovial host cells. (C) 2000 Lippincott Williams & Wilkins, Inc. C1 Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. Univ Toronto, Dept Med, Toronto, ON, Canada. Univ Toronto, Dept Immunol, Toronto, ON, Canada. Wayne State Univ, Sch Med, Div Rheumatol, Dept Internal Med, Detroit, MI USA. Univ Penn, Sch Med, Div Rheumatol, Dept Med, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Arthritis & Immunol Ctr, Philadelphia, PA 19104 USA. RP Hudson, AP (reprint author), Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Gordon H Scott Hall,540 E Canfield Ave, Detroit, MI 48201 USA. FU NIAID NIH HHS [AI-44493]; NIAMS NIH HHS [AR-42541] NR 81 TC 54 Z9 58 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-8711 J9 CURR OPIN RHEUMATOL JI CURR. OPIN. RHEUMATOL. PD JUL PY 2000 VL 12 IS 4 BP 254 EP 262 DI 10.1097/00002281-200007000-00004 PG 9 WC Rheumatology SC Rheumatology GA 329LT UT WOS:000087909000004 PM 10910176 ER PT J AU Li, JZ Sabath, DF Kuter, DJ AF Li, JZ Sabath, DF Kuter, DJ TI Cloning and functional characterization of a novel c-mpl variant expressed in human CD34 cells and platelets SO CYTOKINE LA English DT Article DE CD34 cells; c-mpl; megakaryocyte; platelet; thrombopoietin ID HUMAN BLOOD-PLATELETS; IMMORTALIZES HEMATOPOIETIC PROGENITORS; PROTEIN-TYROSINE PHOSPHORYLATION; TRUNCATED CYTOKINE RECEPTOR; THROMBOPOIETIN RECEPTOR; MEGAKARYOCYTE GROWTH; V-MPL; LIGAND; MICE; PROLIFERATION AB The thrombopoietin receptor, c-mpl, is a crucial element not only in thrombopoietin (TPO)-initiated signaling pathways but also in the regulation of the circulating amount of TPO, We have identified a new c-mpl isoform, called c-mpl-del, that lacks 72 bp (24 amino acids) in the extracellular region of c-mpl and arises as a consequence of alternative RNA splicing between exons 8 and 9, c-mpl-del is expressed along with c-mpl-wt in blood mononuclear cells, CD34(+) cells, megakaryocytes, and platelets prepared from either normal donors or ET patients, although its relative expression appears to increase with megakaryocyte differentiation. The c-mpl-del-transfected cells expressed greater amounts of c-mpl-del RNA and protein than the comparable c-mpl-wt-transfected cells, however flow cytometry analysis could not detect any c-mpl receptor on the surface of the c-mpl-del-transfected cells. Further evidence for the absence of surface c-mpl-del was that in contrast to cells transfected with c-mpl-wt, those transfected with c-mpl-del did not grow in response to TPO, failed to undergo tyrosine phosphorylation of TPO-specific signal molecules, and did not bind I-125-rHuTPO. Taken together, these results demonstrate that c-mpl-del, a naturally occurring variant of c-mpl, fails to be incorporated into the cell membrane but might serve as a mechanism to decrease the overall expression of functional c-mpl late in megakaryocyte differentiation. (C) 2000 Academic Press. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hematol Oncol Unit, Boston, MA 02114 USA. Univ Washington, Dept Med, Seattle, WA USA. RP Kuter, DJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Hematol Oncol Unit, 100 Blossom St, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL61222, HL54838]; NIDDK NIH HHS [DK02448] NR 41 TC 15 Z9 16 U1 1 U2 6 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2000 VL 12 IS 7 BP 835 EP 844 DI 10.1006/cyto.1999.0654 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 335AY UT WOS:000088220900001 PM 10880227 ER PT J AU Zweiman, B Parrott, CM Graif, Y David, M Lessin, SR AF Zweiman, B Parrott, CM Graif, Y David, M Lessin, SR TI Quantitative comparison of cytokine mRNA and inflammatory responses in cutaneous late phase allergic reactions SO CYTOKINE LA English DT Article DE cutaneous late phase reactions; cytokine; IL-5; mRNA ID MESSENGER-RNA EXPRESSION; ADHESION MOLECULES; ATOPIC SUBJECTS; SKIN; IGE; EOSINOPHILS; IL-5; LYMPHOCYTES; CHALLENGE; CELLS AB The aim of this study was to quantitatively compare expression of mRNA for IL-5 and IFN-gamma with the frequency of mRNA-positive cells, total and activated eosinophils, neutrophils, lymphocytes, and vessels expressing adhesion molecules. Replicate biopsies of skin LPR to pollen antigens (Ag) and control injection sites (B) at 6 and 24 h were assessed for: (1) mRNA for IL-5 and IFN-gamma by quantitative RT-PCR (QC-RT/PCR); (2) frequency of cells expressing mRNA for IL-5 and IFN-gamma by in situ hybridization (ISH); (3) inflammatory cells and adhesion molecule expression. More mRNA for IL-5 was found in Ag- than in B-injected sites at 6 and 24 h by both QC-RT/PCR and ISH. Small amounts of mRNA for IFN-gamma were detected in Ag sites by QC-RT/PCR at 6 and 24 h, but mere not significantly different than at B sites. The frequency of IFN-gamma mRNA(+) cells was higher in Ag than in B sites at 6h, There was no correlation between the amount if IL-5 detected by QC-RT/PCR and frequency of IL-5 mRNA(+) cells by ISH, These findings also did not correlate with the degree of inflammatory responses. In conclusion: (1) greater IL-5 than IFN-gamma deposition in Ag sites suggests Th-2 predominance in LPR; (2) lack of correlation between QC-RT/PCR and ISH findings may reflect varying mRNA content of inflammatory cells. (C) 2000 Academic Press. C1 Univ Penn, Med Ctr, Dept Dermatol, Div Allergy & Immunol, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Dept Internal Med, Div Allergy & Immunol, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. RP Zweiman, B (reprint author), Univ Penn, Sch Med, Dept Allergy & Immunol, 512 Johnson Pavil, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA-55017]; NIAID NIH HHS [R01 AI-14332] NR 28 TC 2 Z9 2 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 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2000 VL 12 IS 7 BP 1065 EP 1075 DI 10.1006/cyto.2000.0671 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 335AY UT WOS:000088220900027 PM 10880253 ER PT J AU Bradley, RL Kokkotou, EG Maratos-Flier, E Cheatham, B AF Bradley, RL Kokkotou, EG Maratos-Flier, E Cheatham, B TI Melanin-concentrating hormone regulates leptin synthesis and secretion in rat adipocytes SO DIABETES LA English DT Article ID PROTEIN-COUPLED RECEPTORS; OBESE GENE-PRODUCT; BODY-WEIGHT; MESSENGER-RNA; OB/OB MICE; EXPRESSION; IDENTIFICATION; PEPTIDE; LIGAND; SLC-1 AB Obesity is a common problem in Western society and is associated with significant morbidity and mortality. Energy homeostasis is regulated by a complex system involving both peripheral signals such as leptin and a number of orexigenic and anorectic neuropeptides. Obesity can result from dysregulation of the peripheral and/or central signals. Melanin-concentrating hormone (MCH) is a hypothalamic peptide that is important in the regulation of feeding behavior, primarily via uncharacterized signaling pathways in the central nervous system. Leptin, expressed in adipose tissue, mediates some of its actions through several hypothalamic neuropeptides, notably agouti-related peptide, proopiomelanocortin, and neuropeptide Y. Expression of leptin is regulated by dietary status, insulin, and glucocorticoids. Furthermore, certain neuropeptides may act on adipocytes. However, the potential effect of MCH has not been investigated. We report that MCH stimulates leptin mRNA expression and leptin secretion. MCH stimulated a 2-fold increase in leptin secretion by isolated rat adipocytes after 4 h of treatment. This increase in secreted leptin was preceded by a rapid and transient increase in ob mRNA levels; MCH stimulated a 2.5-fold increase in ob mRNA within 1 h of treatment, followed by a decline to basal levels within 4 h. In addition, we demonstrate that the MCH receptor SLC-1 is expressed in adipocytes, suggesting that fat cells may be targets of MCH or an MCH-like peptide under physiological conditions. Finally, using a radioimmunoassay, MCH/MCH-like peptide was detected in rat plasma. This study establishes a novel in vitro mammalian system for examining MCH signaling pathways. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Cheatham, B (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [R01 DK-53978, DK-09745, R01 DK-51668] NR 35 TC 69 Z9 70 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2000 VL 49 IS 7 BP 1073 EP 1077 DI 10.2337/diabetes.49.7.1073 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 329EH UT WOS:000087893400001 PM 10909960 ER PT J AU Skoglund, G Hussain, MA Holz, GG AF Skoglund, G Hussain, MA Holz, GG TI Glucagon-like peptide 1 stimulates insulin gene promoter activity by protein kinase A - Independent activation of the rat insulin I gene cAMP response element SO DIABETES LA English DT Article ID PANCREATIC BETA-CELLS; CYCLIC-AMP; TRANSCRIPTION FACTOR; GLUCOSE STIMULATION; LEPTIN SUPPRESSION; BINDING PROTEIN; BETA-TC-1 CELLS; MESSENGER-RNA; C-FOS; EXPRESSION AB Glucagon-like peptide 1 (GLP-1), a hormonal activator of adenyl cyclase, stimulates insulin gene transcription, an effect mediated by the cAMP response element (CRE) of the rat insulin I gene promoter (RIP1). Here we demonstrate that the signaling mechanism underlying stimulatory effects of GLP-1 on insulin gene transcription results from protein kinase A (PKA)-independent activation of the RIP1 CRE. Although GLP-1 stimulates cAMP production in rat INS-1 insulinoma cells, we And accompanying activation of a -410-bp RIP1 luciferase construct (-410RIP1-LUC) to exist independently of this second messenger. GLP-1 produced a dose-dependent stimulation of -410RIP1-LUC (EC50 0.43 nmol/l), an effect reproduced by the GLP-1 receptor agonist exendin-4 and abolished by the antagonist exendin(9-39). Activation of RIP1 by GLP-1 was not affected by cotransfection with dominant-negative G(s) alpha, was not blocked by cAMP antagonist Rp-cAMPS, and was insensitive to PKA antagonist H-89. Truncation of -410RIP1-LUC to generate -307-, -206-, and -166-bp constructs revealed 2 segments of RIP1 targeted by GLP-1. The first segment, not regulated by forskolin, was located between -410 and -307 bp of the promoter. The second segment, regulated by both GLP-1 and forskolin, included the CRE and was located between -206 and -166 bp. Consistent with these observations, stimulatory effects of GLP-1 at RIP1 were reduced after introduction of Delta-182 and Delta-183/180 inactivating deletions at the CRE. The action of GLP-1 at -410RIP1-LUC was also reduced by cotransfection with A-CREB, a genetically engineered isoform of the CRE binding protein CREB, which dimerizes with and prevents binding of basic-region-leucine-zipper (bZIP) transcription factors to the CRE. In contrast, the action of GLP-1 at the CRE was not blocked by cotransfection with M1-CREB, an isoform that lacks a consensus serine residue serving as substrate for PKA-mediated phosphorylation. On the basis of these studies, it is proposed that PKA-independent stimulatory actions of GLP-1 at RIP1 are mediated by bZIP transcription factors related in structure but not identical to CREB. C1 NYU, Med Ctr, Sch Med, Dept Physiol & Neurosci, New York, NY 10016 USA. Massachusetts Gen Hosp, Mol Endocrinol Lab, Boston, MA 02114 USA. Fac Med Pitie Salpetriere, INSERM, CJF, Physiol Lab, Paris, France. RP Holz, GG (reprint author), NYU, Med Ctr, Sch Med, Dept Physiol & Neurosci, Med Sci Bldg,Rm 442,550 1st Ave, New York, NY 10016 USA. RI Holz, George/A-3386-2012 FU NIDDK NIH HHS [R01DK52166, R01 DK052166-04, R01 DK052166, R01 DK045817-14, R01 DK045817, R01DK45817] NR 59 TC 84 Z9 89 U1 1 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2000 VL 49 IS 7 BP 1156 EP 1164 DI 10.2337/diabetes.49.7.1156 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 329EH UT WOS:000087893400014 PM 10909973 ER PT J AU Park, JY Takahara, N Gabriele, A Chou, E Naruse, K Suzuma, K Yamauchi, T Ha, SW Meier, M Rhodes, CJ King, GL AF Park, JY Takahara, N Gabriele, A Chou, E Naruse, K Suzuma, K Yamauchi, T Ha, SW Meier, M Rhodes, CJ King, GL TI Induction of endothelin-1 expression by glucose - An effect of protein kinase C activation SO DIABETES LA English DT Article ID RETINAL BLOOD-FLOW; SMOOTH-MUSCLE CELLS; DIABETIC RATS; RECOMBINANT ADENOVIRUS; INSULIN; ISOFORMS; BETA; INHIBITION; MECHANISM; RELEASE AB Enhanced actions or levels of endothelin-1 (ET-1), a potent vasoconstrictor, have been associated with decreased blood flow in the retina and peripheral nerves of diabetic animals and may be related to the development of pathologies in these tissues. Hyperglycemia has been postulated to increase ET-1 secretion in endothelial cells. We have characterized the mechanism by which elevation of glucose is increasing ET-1 mRNA expression in capillary bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRPC). Elevation of glucose, but not mannitol, from 5.5 to 25 mmol/l for 3 days increased membranous protein kinase C (PKC) activities and ET-1 mRNA in parallel levels by 2-fold in BREC and BRPC. These effects were reversed by decreasing glucose levels to 5.5 mmol/l for an additional 2 days. Glucose-induced ET-1 overexpression was inhibited by a general PKC inhibitor, GF109203X, and a mitogen-activated protein kinase kinase inhibitor, PD98059, but not by wortmannin, a phosphatidylinositol 3-kinase inhibitor By immunoblot analysis, PKC-beta 2 and -delta isoforms in BREC were significantly increased relative to other isoforms in the membranous fractions when glucose level was increased. Overexpression of PKC-beta 1 and -delta isoforms but not PKC-zeta isoform by adenovirus vectors containing the respective cDNA enhanced in parallel PKC activities, proteins, and basal and glucose-induced ET-1 mRNA expression by at least 2-fold. These results showed that enhanced ET-1 expression induced by hyperglycemia in diabetes is partly due to activation of PKC-beta and -delta isoforms, suggesting that inhibition of these PKC isoforms may prevent early changes in diabetic retinopathy and neuropathy. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Res Div,Sect Vasc Cell Biol, Boston, MA 02215 USA. RP Harvard Univ, Sch Med, Joslin Diabet Ctr, Res Div,Sect Vasc Cell Biol, 1 Joslin Pl, Boston, MA 02215 USA. EM george.king@joslin.harvard.edu FU NEI NIH HHS [EY 9178]; NIDDK NIH HHS [DK36836] NR 55 TC 170 Z9 189 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 EI 1939-327X J9 DIABETES JI Diabetes PD JUL PY 2000 VL 49 IS 7 BP 1239 EP 1248 DI 10.2337/diabetes.49.7.1239 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 329EH UT WOS:000087893400025 PM 10909984 ER PT J AU Jones, HE Johnson, RE Fudala, PJ Henningfield, JE Heishman, SJ AF Jones, HE Johnson, RE Fudala, PJ Henningfield, JE Heishman, SJ TI Nalmefene: blockade of intravenous morphine challenge effects in opioid abusing humans SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE nalmefene; morphine; subjective effects; blockade; pharmacology ID BRAIN MEMBRANES; ORAL NALMEFENE; NALOXONE; DURATION; NALTREXONE; DISPOSITION; ANTAGONIST; DEPENDENCE; SEDATION; BINDING AB No studies have assessed the dose-effect or duration of opioid blockade in opioid abusers produced by oral nalmefene: a mu-opioid antagonist. The present study examined the profile and time course of oral nalmefene blockade of subjective and physiological effects produced by intravenous morphine. To assess these effects, seven opioid abusers received oral nalmefene (0, 50 and 100 mg) followed by intravenous morphine (0, 10 and 20 mg) challenges every 24 h for 96 h using a Latin square randomized cross-over design. The duration of blockade varied by measure and dose. Both 50 and 100 mg nalmefene blocked morphine's effects up to 48 h. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Ctr Addict & Pregnancy, Baltimore, MD 21224 USA. Univ Penn, Sch Med, Dept Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Pinney Associates, Bethesda, MD USA. RP Heishman, SJ (reprint author), NIDA, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sheish@intra.nida.nih.gov NR 35 TC 2 Z9 4 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 EI 1879-0046 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD JUL 1 PY 2000 VL 60 IS 1 BP 29 EP 37 DI 10.1016/S0376-8716(99)00138-6 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 320XC UT WOS:000087425300004 ER PT J AU St-Arnaud, R Arabian, A Travers, R Barletta, F Raval-Pandya, M Chapin, K Depovere, J Mathieu, C Christakos, S Demay, MB Glorieux, FH AF St-Arnaud, R Arabian, A Travers, R Barletta, F Raval-Pandya, M Chapin, K Depovere, J Mathieu, C Christakos, S Demay, MB Glorieux, FH TI Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylase-ablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D SO ENDOCRINOLOGY LA English DT Article ID RECEPTOR-ABLATED MICE; ALPHA-HYDROXYLASE; ION HOMEOSTASIS; TIBIAL FRACTURE; UP-REGULATION; METABOLISM; RICKETS; MATRIX; RAT; CLONING AB The 25-hydroxyvitamin D-24-hydroxylase enzyme (24-OHase) is responsible for the catabolic breakdown of 1,25-dihydroxyvitamin D [1,25(OH)(2)D], the active form of vitamin D. The 24-OHase enzyme can also act on the 25-hydroxyvitamin D substrate to generate 24,25-dihydroxyvitamin D, a metabolite whose physiological importance remains unclear. We report that mice with a targeted inactivating mutation of the 24-OHase gene had impaired 1,25(OH)(2)D catabolism. Surprisingly, complete absence of 24-OHase activity during development leads to impaired intramembranous bone mineralization. This phenotype was rescued by crossing the 24-OHase mutant mice to mice harboring a targeted mutation in the vitamin D receptor gene, confirming that the elevated 1,25(OH)(2)D levels, acting through the vitamin D receptor, were responsible for the observed accumulation of osteoid. Our results confirm the physiological importance of the 24-OHase enzyme for maintaining vitamin D homeostasis, and they reveal that 24,25-dihydroxyvitamin D is a dispensable metabolite during bone development. C1 Shriners Hosp Crippled Children, Genet Unit, Montreal, PQ H3G 1A6, Canada. McGill Univ, Dept Surg, Montreal, PQ H3A 1B1, Canada. McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. Univ Med & Dent New Jersey, Dept Biochem & Mol Biol, Newark, NJ 07103 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Catholic Univ Louvain, Lab Expt Geneeskunde Endocrinol, B-3000 Louvain, Belgium. RP St-Arnaud, R (reprint author), Shriners Hosp Crippled Children, Genet Unit, 1529 Cedar Ave, Montreal, PQ H3G 1A6, Canada. EM rst-arnaud@shriners.mcgill.ca NR 43 TC 155 Z9 157 U1 3 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUL PY 2000 VL 141 IS 7 BP 2658 EP 2666 DI 10.1210/en.141.7.2658 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 337WN UT WOS:000088386200046 PM 10875271 ER PT J AU Morales, KH Ryan, L Kuo, TL Wu, MM Chen, CJ AF Morales, KH Ryan, L Kuo, TL Wu, MM Chen, CJ TI Risk of internal cancers from arsenic in drinking water SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE bladder cancer; generalized linear model; lifetime death risk; lung cancer; margin of exposure; multistage-Weibull ID WELL WATER; MORTALITY; BLADDER; LUNG AB The U.S. Environmental Protection Agency is under a congressional mandate to revise its current standard for arsenic in drinking water. We present a risk assessment for cancers of the bladder, liver, and lung from exposure to arsenic in water, based on data from 42 villages in an arseniasis-endemic region of Taiwan. We calculate excess lifetime risk estimates for several variations of the generalized linear model and for the multistage-Weibull model. Risk estimates are sensitive to the model choice, to whether or not a comparison population is used to define the unexposed disease mortality rates, and to whether the comparison population is all of Taiwan or just the southwestern region. Some factors that may affect risk could not be evaluated quantitatively: the ecologic nature of the data, the nutritional status of the study population, and the dietary intake of arsenic. Despite all of these sources of uncertainty, however, our analysis suggests that the current standard of 50 mu g/L is associated with a substantial increased risk of cancer and is not sufficiently protective of public health. C1 Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Natl Taiwan Univ, Coll Med, Dept Forens Med, Taipei, Taiwan. Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. Natl Taiwan Univ, Grad Inst Epidemiol, Taipei 10764, Taiwan. RP Ryan, L (reprint author), Dana Farber Canc Inst, Dept Biostat, 44 Binney St, Boston, MA 02115 USA. RI Chen, Chien-Jen/C-6976-2008; Ryan, Louise/A-4562-2009 OI Ryan, Louise/0000-0001-5957-2490 FU NCI NIH HHS [CA48061]; NIEHS NIH HHS [ES0002]; NIGMS NIH HHS [5F31GM18906] NR 29 TC 272 Z9 283 U1 4 U2 41 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD JUL PY 2000 VL 108 IS 7 BP 655 EP 661 DI 10.1289/ehp.00108655 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 340JQ UT WOS:000088529700038 PM 10903620 ER PT J AU Tanzi, RE AF Tanzi, RE TI Alzheimer's disease and related dementias: the road to intervention SO EXPERIMENTAL GERONTOLOGY LA English DT Editorial Material ID GENE C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Res Unit, Charlestown, MA 02129 USA. RP Tanzi, RE (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Res Unit, Bldg 149,13th St, Charlestown, MA 02129 USA. NR 7 TC 3 Z9 3 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUL PY 2000 VL 35 IS 4 BP 433 EP 437 DI 10.1016/S0531-5565(00)00109-1 PG 5 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 356GL UT WOS:000089435500001 PM 10959030 ER PT J AU Lynch, T Cherny, RA Bush, AI AF Lynch, T Cherny, RA Bush, AI TI Oxidative processes in Alzheimer's disease: the role of A beta-metal interactions SO EXPERIMENTAL GERONTOLOGY LA English DT Review DE amyloid beta; metals; oxidative stress; hydrogen peroxide; neurodegeneration; antioxidants; superoxide dismutase ID FREE-RADICALS; HYDROGEN-PEROXIDE; END-PRODUCTS; AGGREGATION; TOXICITY; DAMAGE; PEPTIDE; STRESS; PROTECTION; ZINC AB Alzheimer's disease is characterized by signs of a major oxidative stress in the neocortex and the concomitant deposition of Amyloid beta (A beta). A beta is a metalloprotein that binds copper. and is electrochemically active. A beta converts molecular oxygen into hydrogen peroxide by reducing copper or iron, and this may lead to Fenton chemistry. Hydrogen peroxide is a freely permeable prooxidant that may be responsible for many of the oxidative adducts that form in the Alzheimer-affected brain. The electrochemical activity of various A beta species correlates with the peptides' neurotoxicity in cell culture, and participation in the neuropathology of Alzheimer's disease. These reactions present a novel target for Alzheimer therapeutics. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. Mental Hlth Res Inst Victoria, Neuropathol Lab, Parkville, Vic 3052, Australia. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Unit,Lab Oxidat Biol, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Charlestown, MA 02129 USA. RP Bush, AI (reprint author), Univ Melbourne, Dept Pathol, Parkville, Vic 3052, Australia. RI Bush, Ashley/A-1186-2007 OI Bush, Ashley/0000-0001-8259-9069 NR 33 TC 112 Z9 121 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUL PY 2000 VL 35 IS 4 BP 445 EP 451 DI 10.1016/S0531-5565(00)00112-1 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 356GL UT WOS:000089435500003 PM 10959032 ER PT J AU Kovacs, DM AF Kovacs, DM TI alpha 2-macroglobulin in late-onset Alzheimer's disease SO EXPERIMENTAL GERONTOLOGY LA English DT Review DE alpha 2-microglobulin; Alzheimer's disease; beta-amyloid; low density lipoprotein receptor-related protein; polymorphism; protease inhibitor ID RECEPTOR-RELATED PROTEIN; BETA-AMYLOID PEPTIDE; GENETIC ASSOCIATION; DELETION POLYMORPHISM; FIBRIL FORMATION; ALPHA(2)-MACROGLOBULIN; CELLS; INTERLEUKIN-6; DEGRADATION; EXPRESSION AB alpha 2-macroglobulin (alpha(2)M) is an abundant plasma protein similar in structure and function to a group of proteins called alpha-macroglobulins. alpha(2)M is also produced in the brain where it binds multiple extracellular ligands and is internalized by neurons and astrocytes. In the brain of Alzheimer's disease (AD) patients, alpha(2)M has been localized to diffuse amyloid plaques. alpha(2)M also binds soluble beta-amyloid, of which it mediates degradation. However, an excess of alpha(2)M can also have neurotoxic effects. Based on genetic evidence, is now recognized as one of the two confirmed late onset AD genes. As for the three early onset genes (the amyloid beta-protein precursor and the two presenilins) and for the other late onset gene (ApoE), DNA polymorphisms in the A2M gene associated with AD result in significantly increased accumulation of amyloid plaques in AD brains. These data support an important role for A2M in AD etiopathology. (C) 2000 Published by Elsevier Science Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Unit, Charlestown, MA 02129 USA. RP Kovacs, DM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Genet & Aging Unit, Bldg 149,13th St, Charlestown, MA 02129 USA. NR 29 TC 58 Z9 59 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD JUL PY 2000 VL 35 IS 4 BP 473 EP 479 DI 10.1016/S0531-5565(00)00113-3 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 356GL UT WOS:000089435500006 PM 10959035 ER PT J AU Sackstein, R Dimitroff, CJ Fuhlbrigge, R AF Sackstein, R Dimitroff, CJ Fuhlbrigge, R TI A new method for identification of adhesive interactions under shear force conditions SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Skin Dis Res Ctr, Massachusetts Gen Hosp, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 13 BP 35 EP 35 DI 10.1016/S0301-472X(00)00198-3 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200014 ER PT J AU Wu, L Aster, J Griffin, JD AF Wu, L Aster, J Griffin, JD TI Notch receptor signal transduction SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 193 BP 92 EP 92 DI 10.1016/S0301-472X(00)00373-8 PG 1 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200188 ER PT J AU Sykes, M AF Sykes, M TI Progress on macrochimerism and tolerance SO EXPERIMENTAL HEMATOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 SU 1 MA 313 BP 130 EP 131 DI 10.1016/S0301-472X(00)00494-X PG 2 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 331EK UT WOS:000088004200304 ER PT J AU Yamane, T Kunisada, T Yamazaki, H Nakano, T Orkin, SH Hayashi, SI AF Yamane, T Kunisada, T Yamazaki, H Nakano, T Orkin, SH Hayashi, SI TI Sequential requirements for SCL/tal-1, GATA-2, macrophage colony-stimulating factor, and osteoclast differentiation factor/osteoprotegerin ligand in osteoclast development SO EXPERIMENTAL HEMATOLOGY LA English DT Article DE osteoclast; embryonic stem cells; SCL/tal-1; GATA-2; macrophage colony-stimulating factor; osteoclast differentiation factor/osteoprotegerin ligand ID TRANSCRIPTION FACTOR GATA-1; EMBRYONIC STEM-CELLS; MICE LACKING; C-KIT; HEMATOPOIETIC-CELLS; BONE-MARROW; TARGETED MUTATION; INHIBITORY FACTOR; KEY REGULATOR; STROMAL CELLS AB Objectives. Osteoclasts are of hematopoietic origin. The mechanism by which hematopoietic stem cells are specified to the osteoclast lineage is unclear. To understand the process of generation and differentiation of this lineage of cells, we performed in vitro studies on the differentiation of embryonic stem cells. Materials and Methods. We examined the potential of mutant embryonic stem cell lines harboring targeted deletions of the GATA-1, FOG, SCL/tal-1, or GATA-2 genes to differentiate into osteoclasts and determined when these molecules function in osteoclast development. Results. The lack of GATA-1 or FOG did not affect osteoclastogenesis. In contrast, SCL/tal-1-null embryonic stem cells generated no osteoclasts. In the case of the loss of GATA-2, a small number of osteoclasts were generated. GATA-2-null osteoclasts were morphologically normal and the terminal maturation was not disturbed, but a defect was observed in the generation of osteoclast progenitors. Experiments using specific inhibitors that block the signaling through macrophage colony-stimulating factor and osteoclast differentiation factor/osteoprotegerin ligand suggested that GATA-2 seems to act earlier in osteoclastogenesis than these cytokines. Interestingly, macrophage colony-forming units were not severely reduced by the loss of GATA-2 compared to osteoclast progenitors. Conclusion. These results indicate that osteoclasts need SCL/tal-1 at an early point in development, and that GATA-2 is required for generation of osteoclast progenitors but not for the later stages when macrophage colony-stimulating factor and osteoclast differentiation factor/osteoprotegerin ligand are needed. We also demonstrated that osteoclast progenitors behave as a different population than macrophage colony-forming units. (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc. C1 Tottori Univ, Fac Med, Sch Life Sci, Dept Immunol, Yonago, Tottori 6838503, Japan. Osaka Univ, Microbial Dis Res Inst, Dept Mol Cell Biol, Suita, Osaka 565, Japan. Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. RP Yamane, T (reprint author), Tottori Univ, Fac Med, Sch Life Sci, Dept Immunol, 86 Nishi Machi, Yonago, Tottori 6838503, Japan. OI Yamane, Toshiyuki/0000-0001-9906-4714 NR 51 TC 22 Z9 25 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD JUL PY 2000 VL 28 IS 7 BP 833 EP 840 DI 10.1016/S0301-472X(00)00175-2 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 329DY UT WOS:000087892300013 PM 10907645 ER PT J AU Costantini, LC Isacson, O AF Costantini, LC Isacson, O TI Immunophilin ligands and GDNF enhance neurite branching or elongation from developing dopamine neurons in culture SO EXPERIMENTAL NEUROLOGY LA English DT Article; Proceedings Paper CT 7th Intenational Symposium on Neural Transplantation and Repair (INT-7) CY AUG 26-30, 1999 CL ODENSE, DENMARK DE immunophilin; FKBP12; neurite; GDNF; calcineurin; dopamine cultures; FK506; rapamycin ID FK506 BINDING-PROTEIN; VENTRAL MESENCEPHALIC GRAFTS; CHANNEL RYANODINE RECEPTOR; FIBROBLAST GROWTH-FACTOR; RAT VISUAL-CORTEX; NEUROTROPHIC FACTOR; IMMUNOSUPPRESSANT FK506; CYCLOSPORINE-A; AXONAL REGENERATION; PROLYL ISOMERASE AB Neurotrophic effects of immunophilin ligands have been shown in animal models of peripheral and central nervous system insult. To investigate the specific growth-promoting effects of these compounds, we examined the effects of various immunophilin ligands on primary dopamine (DA) neurons in culture and compared these with a well-known DA trophic factor, glial cell line-derived neurotrophic factor (GDNF). In neuronal cultures from Embryonic Day 14 ventral mesencephalon, enhanced elongation of DA neurites was observed with immunophilin ligands, which inhibited the phosphatase activity of calcineurin (FK506 and cyclosporin A) when compared to vehicle-treated cultures. This elongation was also observed with GDNF, known to exert its trophic effects through phosphorylation-dependent pathways. In contrast, immunophilin ligands that do not inhibit calcineurin (rapamycin and V-10,367) increased branching of DA neurites, suggesting that elongation is dependent upon maintained phosphorylation while branching is not, In addition, both V-10,367 and rapamycin antagonized the elongation effects of FK506 and induced branching. The antagonism of elongation (and reappearance of branching) illustrates the intrinsic abilities of developing DA neurons to either elongate or branch, but not both, We show that the immunophilin FKBP12 (12-kDa FK506-binding protein) is expressed in ventral mesencephalic neuronal cultures and colocalizes with DA neurons, This work elucidates the specific growth-promoting effects by which GDNF and immunophilin ligands modify developmental growth processes of DA neurons, via their interactions with intracellular targets, (C) 2000 Academic Press. C1 Harvard Univ, Sch Med, McLean Hosp, Neuroregenerat Lab,Program Neurosci, Belmont, MA 02478 USA. Massachusetts Gen Hosp, Dept Neurol & Psychiat, Belmont, MA 02478 USA. McLean Hosp, Belmont, MA 02478 USA. RP Costantini, LC (reprint author), Harvard Univ, Sch Med, McLean Hosp, Neuroregenerat Lab,Program Neurosci, 115 Mill St, Belmont, MA 02478 USA. FU NINDS NIH HHS [(P50) NS 39793-01] NR 80 TC 63 Z9 66 U1 0 U2 0 PU ACADEMIC PRESS INC 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 JUL PY 2000 VL 164 IS 1 BP 60 EP 70 DI 10.1006/exnr.2000.7417 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 336XM UT WOS:000088328300008 PM 10877916 ER PT J AU Saubermann, LJ Beck, P De Jong, YP Pitman, RS Ryan, MS Kim, HS Exley, M Snapper, S Balk, SP Hagen, SJ Kanauchi, O Motoki, K Sakai, T Terhorst, C Koezuka, Y Podolsky, DK Blumberg, RS AF Saubermann, LJ Beck, P De Jong, YP Pitman, RS Ryan, MS Kim, HS Exley, M Snapper, S Balk, SP Hagen, SJ Kanauchi, O Motoki, K Sakai, T Terhorst, C Koezuka, Y Podolsky, DK Blumberg, RS TI Activation of natural killer T cells by alpha-galactosylceramide in the presence of CD1d provides protection against colitis in mice SO GASTROENTEROLOGY LA English DT Article ID DEXTRAN SULFATE SODIUM; INTESTINAL EPITHELIAL-CELLS; IMMUNOGLOBULIN-E PRODUCTION; IMMUNODEFICIENT MICE; CYTOPLASMIC TAIL; CUTTING EDGE; RECOGNITION; EXPRESSION; GAMMA; REQUIREMENTS AB Background & Aims: CD1d is a major histocompatibility complex class I-like molecule that presents glycolipid antigens to a subset of natural killer (NK)1.1(+) T cells. These NK T cells exhibit important immunoregulatory functions in several autoimmune disease models. Methods: To investigate whether CD1d and NK T cells have a similar role in intestinal inflammation, the effects of the glycolipid, alpha-galactosylceramide (alpha-GalCer), on dextran sodium sulfate (DSS)-induced colitis were examined. Wild-type (WT), CD1d(-/-), and RAG(-/-) mice were examined for their response to either alpha-GalCer or the control analogue, alpha-mannosylceramide (alpha-ManCer). Results: WT mice, but not CD1d(-/-) and RAG-/- mice, receiving alpha-GalCer had a significant improvement in DSS-induced colitis based on body weight, bleeding, diarrhea, and survival when compared with those receiving alpha-ManCer. Elimination of NK T cells through antibody-mediated depletion resulted in a reduction of the effect of alpha-GalCer. Furthermore, adoptive transfer of NK T cells preactivated by alpha-GalCer, but not alpha-ManCer, resulted in diminished colitis. Using a fluorescent-labeled analogue of alpha-GalCer, confocal microscopy localized alpha-GalCer to the colonic surface epithelium of WT but not CD1d(-/-) mice, indicating alpha-GalCer binds CD1d in the intestinal epithelium and may be functionally active at this site. Conclusions: These results show an important functional role for NK T cells, activated by alpha-GalCer in a CD1d-restricted manner, in regulating intestinal inflammation. C1 Brigham & Womens Hosp, Div Gastroenterol, Boston, MA 02115 USA. Brigham & Womens Hosp, Harvard Digest Dis Ctr, Boston, MA 02115 USA. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA USA. Beth Israel Deaconess Med Ctr, Div Immunol, Boston, MA USA. Beth Israel Deaconess Med Ctr, Div Hematol Oncol, Boston, MA USA. Kirin Brewery Co Ltd, Pharmaceut Res Lab, Takasaki, Gumma, Japan. RP Blumberg, RS (reprint author), Brigham & Womens Hosp, Div Gastroenterol, 75 Francis St, Boston, MA 02115 USA. FU NIAID NIH HHS [AI33911]; NIDDK NIH HHS [DK46906, DK02532] NR 42 TC 144 Z9 145 U1 0 U2 3 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 JUL PY 2000 VL 119 IS 1 BP 119 EP + DI 10.1053/gast.2000.9114 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 333BL UT WOS:000088108800018 PM 10889161 ER PT J AU Singh, P Velasco, M Given, R Varro, A Wang, TC AF Singh, P Velasco, M Given, R Varro, A Wang, TC TI Progastrin expression predisposes mice to colon carcinomas and adenomas in response to a chemical carcinogen SO GASTROENTEROLOGY LA English DT Article ID GASTRIN GENE-EXPRESSION; GLYCINE-EXTENDED GASTRIN; CANCER-CELLS; COLORECTAL-CANCER; TRANSGENIC MICE; ABERRANT CRYPTS; GROWTH-FACTOR; HYPERGASTRINEMIA; PROLIFERATION; RECEPTORS AB Background & Aims: Processing intermediates of preprogastrin (gly-gastrin and progastrin), termed nonamidated gastrins, are mitogenic for several cell types including colonic epithelial cells. However, presently it is not known if nonamidated gastrins play a role in colon carcinogenesis and if the effects are similar to those of amidated gastrins, Methods: Colon carcinogenesis in response to azoxymethane (AOM) was examined in transgenic mice overexpressing either progastrin (hGAS) or amidated gastrin (INS-GAS), compared with that in wild-type (WT) mice. Results: In AOM-treated groups, the total number of tumors per colon was significantly higher in hGAS (4.8 +/- 0.34) than INS-GAS (3.0 +/- 0.16) and WT (2.7 +/- 0.35) mice. Total numbers of adenocarcinomas and adenomas per animal colon were also significantly higher in hGAS than INS-GAS and WT mice. The size of the tumors was greater in hGAS mice, resulting in a significantly higher tumor burden per mouse in the hGAS mice than INS-GAS and WT mice. Although >90% of the tumors were located in the distal half of the colon in INS-GAS and WT mice, a significant number (42%) were present at the proximal end of the colon in hGAS mice. Conclusions: The results suggest that the risk for developing colon carcinomas and adenomas in response to AOM is significantly increased in mice expressing high levels of progastrin, but not amidated gastrins. C1 Univ Texas, Med Branch, Dept Anat & Neurosci, Galveston, TX 77555 USA. Vel Lab Res, Houston, TX USA. Univ Liverpool, Dept Digest Dis, Liverpool L69 3BX, Merseyside, England. Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. RP Singh, P (reprint author), Univ Texas, Med Branch, Dept Anat & Neurosci, 10-138 Med Res Bldg, Galveston, TX 77555 USA. RI Varro, Andras/M-2647-2016 OI Varro, Andras/0000-0003-0745-3603 FU NCI NIH HHS [CA60087, CA72992]; NIDDK NIH HHS [DK52778] NR 49 TC 89 Z9 91 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 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD JUL PY 2000 VL 119 IS 1 BP 162 EP 171 DI 10.1053/gast.2000.8527 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 333BL UT WOS:000088108800022 PM 10889165 ER PT J AU Hahn, M Fennerty, MB Corless, CL Magaret, N Lieberman, DA Faigel, DO AF Hahn, M Fennerty, MB Corless, CL Magaret, N Lieberman, DA Faigel, DO TI Noninvasive tests as a substitute for histology in the diagnosis of Helicobacter pylori infection SO GASTROINTESTINAL ENDOSCOPY LA English DT Article; Proceedings Paper CT Annual Digestive Disease Week/97th Annual Meeting of the American-Gastroenterological-Association CY MAY 17-20, 1998 CL NEW ORLEANS, LOUISIANA SP Amer Gastroenterol Assoc ID NONULCER DYSPEPSIA; GOLD STANDARD; GASTRITIS; ACCURACY; BIOPSIES; SEROLOGY; CULTURE; BLOOD; ELISA AB Background: Rapid urease tests for Helicobacter pylori have a sensitivity of 80% to 90%. Therefore histologic examination of gastric biopsies is recommended as a "backup" diagnostic test in rapid urease test-negative patients. However, noninvasive tests (urea breath test, serology whole blood antibody tests) may provide a more rapid diagnosis and be less expensive but offer similar accuracy. Methods: Sixty-seven patients (no prior treatment for H pylori, no proton pump inhibitors, antibiotics, or bismuth within 4 weeks) undergoing endoscopy for evaluation of dyspepsia symptoms and testing rapid urease test-negative by antral biopsy were enrolled. All had the following tests: gastric biopsies (2 antral, 1 fundus; H&E and Alcian Yellow stain) examined for gastritis and H pylori;C-13-UBT; capillary blood for whole blood rapid antibody tests: FlexSure HP, QuickVue, AccuStat, and Stat-Simple Pylori; serum for FlexSure HP; HM-CAP enzyme-linked immunoassay. H pylori infection was diagnosed (reference standard) if chronic gastritis was present on histology and at least 2 of the 3 following tests were positive: urea breath test, H pylori organisms unequivocally demonstrated in biopsies on special stain, and/or enzyme-linked immunoassay. The test and treatment costs per patient were calculated. Results: Of 67 patients with a negative rapid urease test, 4 were positive for H pylori. None had active peptic ulcer disease. Histology only identified 1 patient with organisms visible on special stain. Using chronic active gastritis (neutrophilic and mononuclear infiltrate) as a diagnostic criterion for H pylori, 6 patients would have been judged positive. However, only 2 of these were truly positive by the reference standard (positive predictive value 33%). Negative predictive value for presence of organisms and chronic active gastritis was 95% and 97%, respectively. All of the noninvasive tests identified all 4 truly positive patients correctly. Urea breath test and FlexSure whole blood assay yielded a substantial number of false-positive results (positive predictive value 31% and 36%, respectively); positive predictive value for the other tests ranged from 50% to 80%. All tests except histology had a negative predictive value of 100%. Histology was the most costly test (p < 0.001 compared with all other tests), followed by urea breath test and HM-CAP serology (p < 0.001 compared with all rapid antibody tests). Conclusions: Whole blood or serum antibody testing is a rapid, accurate, and cost-effective means for establishing H pylori status in rapid urease test-negative patients. Whole blood or serology rapid antibody testing should substitute for histology when the patient has not been previously treated for H pylori. C1 Portland VA Med Ctr, Div Gastroenterol, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. RP Faigel, DO (reprint author), Portland VA Med Ctr, Div Gastroenterol, P3GI,3710 SW US Vet Hosp Rd, Portland, OR 97201 USA. NR 25 TC 25 Z9 27 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0016-5107 J9 GASTROINTEST ENDOSC JI Gastrointest. Endosc. PD JUL PY 2000 VL 52 IS 1 BP 20 EP 26 DI 10.1067/mge.2000.106686 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 334PZ UT WOS:000088196000005 PM 10882957 ER PT J AU Rohlfs, EM Puget, N Graham, ML Weber, BL Garber, JE Skrzynia, C Halperin, JL Lenoir, GM Silverman, LM Mazoyer, S AF Rohlfs, EM Puget, N Graham, ML Weber, BL Garber, JE Skrzynia, C Halperin, JL Lenoir, GM Silverman, LM Mazoyer, S TI An Alu-mediated 7.1 kb deletion of BRCAI exons 8 and 9 in breast and ovarian cancer families that results in alternative splicing of exon 10 SO GENES CHROMOSOMES & CANCER LA English DT Article ID GENETIC-HETEROGENEITY; IDENTIFICATION; MUTATIONS; REARRANGEMENTS; DUPLICATION; SEQUENCES; CELLS; DNA AB Constitutive large deletions and duplications of BRCA I resulting from Alu-mediated recombination account for a significant proportion of disease-causing mutations in breast and/or ovarian cancer families, Using Southern blot analysis and a protein truncation test (PTT), we have identified a 7.1 kb germline deletion in two families with breast and ovarian cancer. This deletion, which includes exons 8 and 9 and leads to a frameshift at the mRNA level, appears to result from homologous recombination between closely related Alu repeats, one in intron 7 and one in intron 9. In addition to the transcript without exons 8 and 9, analysis of RNA by protein truncation test from individuals with the deletion also identified the presence of alternative splicing of exon 10 from the mutant allele, which results in a transcript that lacks exons 8, 9, and 10, Of interest is that the two American families who carry this deletion are of northern European ancestry and share a common haplotype, suggesting that this deletion may represent a founder mutation. (C) 2000 Wiley-Liss, Inc. C1 Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. Univ Lyon 1, CNRS, UMR 5461, Genet Lab, F-69365 Lyon, France. Univ Lyon 1, Int Agcy Res Canc, F-69365 Lyon, France. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. Dana Farber Canc Inst, Div Canc Epidemiol & Control, Boston, MA 02115 USA. Moses Cone Hlth Syst, Greensboro, NC USA. RP Rohlfs, EM (reprint author), Univ N Carolina, Dept Pathol & Lab Med, CB 7525, Chapel Hill, NC 27599 USA. NR 17 TC 61 Z9 61 U1 1 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD JUL PY 2000 VL 28 IS 3 BP 300 EP 307 DI 10.1002/1098-2264(200007)28:3<300::AID-GCC8>3.0.CO;2-1 PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 322DY UT WOS:000087496000008 PM 10862036 ER PT J AU Kim, RH Wang, D Tsang, M Martin, J Huff, C de Caestecker, MP Parks, WT Meng, XW Lechleider, RJ Wang, TW Roberts, AB AF Kim, RH Wang, D Tsang, M Martin, J Huff, C de Caestecker, MP Parks, WT Meng, XW Lechleider, RJ Wang, TW Roberts, AB TI A novel Smad nuclear interacting protein, SNIP1, suppresses p300-dependent TGF-beta signal transduction SO GENES & DEVELOPMENT LA English DT Article DE TGF-beta; Smad; CBP/p300; signal transduction; transcriptional suppression ID GROWTH-FACTOR-BETA; CREB BINDING-PROTEIN; TRANSCRIPTIONAL COACTIVATORS; RECEPTOR; P300; COOPERATION; SMAD4/DPC4; RESPONSES; CBP/P300; PATHWAYS AB Members of the transforming growth factor-beta superfamily play critical roles in controlling cell growth and differentiation. Effects of TGF-beta family ligands are mediated by Smad proteins. To understand the mechanism of Smad function, we sought to identify novel interactors of Smads by use of a yeast two-hybrid system. A 396-amino acid nuclear protein termed SNIP1 was cloned and shown to harbor a nuclear localization signal (NLS) and a Forkhead-associated (PHA) domain. The carboxyl terminus of SNIP1 interacts with Smad1 and Smad2 in yeast two-hybrid as well as in mammalian overexpression systems. However, the amino terminus of SNIP1 harbors binding sites for both Smad4 and the coactivator CBP/p300. Interaction between endogenous levels of SNIP1 and Smad4 or CBP/p300 is detected in NMuMg cells as well as in vitro. Overexpression of full-length SNIP1 or its amino terminus is sufficient to inhibit multiple gene responses to TGF-beta and CBP/p300, as well as the formation of a Smad4/p300 complex. Studies in Xenopus laevis further suggest that SNIP1 plays a role in regulating dorsomedial mesoderm formation by the TGF-beta family member nodal. Thus, SNIP1 is a nuclear inhibitor of CBP/p300 and its level of expression in specific cell types has important physiological consequences by setting a threshold for TGF-beta-induced transcriptional activation involving CBP/p300. C1 NICHHD, Mol Genet Lab, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Dept Genet, Boston, MA 02114 USA. RP Roberts, AB (reprint author), NICHHD, Mol Genet Lab, Bethesda, MD 20892 USA. RI TSANG, Michael/E-2758-2013; Tsang, Michael/I-9305-2014 OI TSANG, Michael/0000-0001-6384-2422; Tsang, Michael/0000-0001-7123-0063 NR 43 TC 89 Z9 99 U1 0 U2 1 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 JUL 1 PY 2000 VL 14 IS 13 BP 1605 EP 1616 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 333TC UT WOS:000088146000006 PM 10887155 ER PT J AU Karaivanova, VK Spiro, RG AF Karaivanova, VK Spiro, RG TI Effect of proteasome inhibitors on the release into the cytosol of free polymannose oligosaccharides from glycoproteins SO GLYCOBIOLOGY LA English DT Article DE proteasome inhibitors; polymannose oligosaccharide release; quality control of glycoproteins; T-lymphocytes; endoplasmic reticulum; cytosol ID MULTICATALYTIC PROTEINASE COMPLEX; NEWLY SYNTHESIZED PROTEINS; N-LINKED OLIGOSACCHARIDES; CLASS-I MOLECULES; RAT-LIVER GOLGI; ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; DEGRADATION; CALNEXIN; RECEPTOR AB Prompted by previous observations which suggested that the release of polymannose oligosaccharides shortly after the cotranslational N-glycosylation of proteins is a function of the ER-associated quality control system (Moore and Spiro (1994) J. Biol. Chem., 269, 12715-12721), we evaluated the effect which proteasome inhibitors have on the appearance of these free saccharide components. Employing as a model system castanospermine-treated BW5147 mouse T-lymphoma cells in which accelerated degradation of the T-cell receptor (TCR) alpha subunit takes place (Kearse et al. (1994) EMBO J., 13, 3678-3686), we noted that both lactacystin and N-acetyl-L-leucyl-L-leucyl-L-norleucinal, but not leupeptin, brought about a rapid and substantial reduction in the release of free polymannose oligosaccharides into the cytosol during pulse-chase studies, while the oligosaccharides in the intravesicular compartment remained unchanged, as measured by streptolysin O permeabilization. This inhibition was furthermore selective in that it affected solely the components terminating in a single N-acetylglucosamine residue (OS-GlcNAc(1)) and not the oligosaccharides terminating in a di-N-acetylchitobiose sequence (OS-GlcNAc(2)), which reside primarily in the intravesicular compartment, Despite the quantitative effect of the proteasome inhibitors on the cytosolic oligosaccharides, the molar distribution of the triglucosyl OS-GlcNAc(1) species was unaffected. The decrease in cytosolic oligosaccharides brought about by proteasome inhibition was reflected in a pronounced increase in the stability of the TCR alpha subunit, Our findings suggest that the N-deglycosylation and proteasome mediated degradation are coupled events. On the basis of our data and those of others we propose that the quality control mechanism involves proteasomes associated with the cytosolic side of the endoplasmic reticulum acting in concert with a membrane situated N-glycanase. Such a complex by removing the carbohydrate units could facilitate the retrograde ER to cytosol translocation of glycoproteins. C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Biol Chem, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK17477] NR 54 TC 21 Z9 22 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 EI 1460-2423 J9 GLYCOBIOLOGY JI Glycobiology PD JUL PY 2000 VL 10 IS 7 BP 727 EP 735 DI 10.1093/glycob/10.7.727 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 338QD UT WOS:000088430000010 PM 10910976 ER PT J AU Stoeckle, JD AF Stoeckle, JD TI A caring and teaching organization - The ethical lessons of the hospital SO HASTINGS CENTER REPORT LA English DT Article C1 Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Stoeckle, JD (reprint author), Harvard Univ, Sch Med, Boston, MA 02115 USA. NR 21 TC 1 Z9 1 U1 0 U2 2 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD JUL-AUG PY 2000 VL 30 IS 4 BP S33 EP S36 DI 10.2307/3527663 PG 4 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 345VG UT WOS:000088835400019 PM 10971903 ER PT J AU Saha, S Taggart, SH Komaromy, M Bindman, AB AF Saha, S Taggart, SH Komaromy, M Bindman, AB TI Do patients choose physicians of their own race? To provide the kind of care consumers want, medical schools might be able to justify using race as an admissions criterion. SO HEALTH AFFAIRS LA English DT Article ID HEALTH-CARE; MINORITY AB This study seeks to determine whether minority America ns tend to see physicians of their own race as a matter of choice or simply because minority physicians are more conveniently located within predominantly minority communities. Using data from the Commonwealth Fund 1994 National Comparative Survey of Minority Health Care, we found that black and Hispanic Americans sought care from physicians of their own race because of personal preference and language, not solely because of geographic accessibility. As minority populations continue to grow, the demand for minority physicians is likely to increase. Keeping up with this demand will require medical school admissions policies and physician workforce planning to include explicit strategies to increase the supply of underrepresented minority physicians. C1 Portland Vet Affairs Med Ctr, Portland, OR USA. Oregon Hlth Sci Univ, Portland, OR 97201 USA. Univ Washington, Ctr Reinventing Publ Educ, Seattle, WA 98195 USA. Univ Calif San Francisco, Primary Care Res Ctr, San Francisco, CA 94143 USA. San Francisco Gen Hosp, Div Gen Internal Med, San Francisco, CA USA. RP Saha, S (reprint author), Portland Vet Affairs Med Ctr, Portland, OR USA. NR 19 TC 172 Z9 172 U1 0 U2 2 PU PROJECT HOPE PI BETHESDA PA 7500 OLD GEORGETOWN RD, STE 600, BETHESDA, MD 20814-6133 USA SN 0278-2715 J9 HEALTH AFFAIR JI Health Aff. PD JUL-AUG PY 2000 VL 19 IS 4 BP 76 EP 83 DI 10.1377/hlthaff.19.4.76 PG 8 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 335KM UT WOS:000088242700008 PM 10916962 ER PT J AU Carey, K AF Carey, K TI A multilevel modelling approach to analysis of patient costs under managed care SO HEALTH ECONOMICS LA English DT Article DE patient costs; multilevel modelling; managed care ID HIERARCHICAL LINEAR-MODELS; STOCHASTIC FRONTIER; HEALTH ECONOMICS; EFFICIENCY AB The growth of the managed care model of health care delivery in the USA has led to broadened interest in the performance of health care providers. This paper uses multilevel modelling to analyse the effects of managed care penetration on patient level costs for a sample of 24 medical centres operated by the Veterans Health Administration (VHA). The appropriateness of a two level approach to this problem over ordinary least squares (OLS) is demonstrated. Results indicate a modicum of difference in institutions' performance after controlling for patient effects. Facilities more heavily penetrated by the managed care model may be more effective at controlling costs of their sicker patients. Published in 2000 by John Wiley & Sons, Ltd. C1 US Dept Vet Affairs, Management Sci Grp, Bedford, MA 01730 USA. Boston Univ, Sch Publ Hlth, Boston, MA USA. RP Carey, K (reprint author), US Dept Vet Affairs, Management Sci Grp, Bldg 12,200 Springs Rd, Bedford, MA 01730 USA. NR 28 TC 40 Z9 40 U1 0 U2 7 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1057-9230 J9 HEALTH ECON JI Health Econ. PD JUL PY 2000 VL 9 IS 5 BP 435 EP 446 DI 10.1002/1099-1050(200007)9:5<435::AID-HEC523>3.0.CO;2-Z PG 12 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 342UZ UT WOS:000088664700007 PM 10903543 ER PT J AU Herrlinger, U Jacobs, A Quinones, A Woiciechowsky, C Sena-Esteves, M Rainov, NG Fraefel, C Breakefield, XO AF Herrlinger, U Jacobs, A Quinones, A Woiciechowsky, C Sena-Esteves, M Rainov, NG Fraefel, C Breakefield, XO TI Helper virus-free herpes simplex virus type 1 amplicon vectors for granulocyte-macrophage colony-stimulating factor-enhanced vaccination therapy for experimental glioma SO HUMAN GENE THERAPY LA English DT Article ID EXPERIMENTAL BRAIN-TUMORS; MEDIATED GENE-TRANSFER; EXPRESSING GM-CSF; CELLS IN-VITRO; BETA-GALACTOSIDASE; ANTITUMOR IMMUNITY; IONIZING-RADIATION; NONDIVIDING CELLS; PLASMID VECTORS; MAMMALIAN-CELLS AB Subcutaneous vaccination therapy with glioma cells, which are retrovirally transduced to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF), has previously proven effective in C57BL/6 mice harboring intracerebral GL261 gliomas. However, clinical ex vivo gene therapy for human gliomas would be difficult, as transgene delivery via retroviral vectors occurs only in dividing cells and ex vivo glioma cells have a low growth fraction. To circumvent this problem, a helper virus-free herpes simplex virus type 1 (HSV-1) amplicon vector was used. When primary cultures of human glioblastoma cells were infected with HSV-1 amplicon vectors at an MOI of 1, more than 90% of both dividing and nondividing cells were transduced. When cells were infected with an amplicon vector, HSVGM, bearing the GM-CSF cDNA in the presence of Polybrene, GM-CSF secretion into the medium during the first 24 hr after infection was 1026 ng/10(6) cells, whereas mock-infected cells did not secrete detectable GM-CSF. Subcutaneous vaccination of C57BL/6 mice with 5 X 10(5) irradiated HSVGM-transduced GL261 cells 7 days prior to intracerebral implantation of 10(6) wild-type GL261 cells yielded 60% long-term survivors (> 80 days), similar to the 50% long-term survivors obtained by vaccination with retrovirally GM-CSF-transduced GL261 cells. In contrast, animals vaccinated with the same number of nontranduced GL261 cells or with GL261 cells infected with helper virus-free packaged HSV-1 amplicon vectors carrying no transgene showed only 10% long-term survivors. In conclusion, helper virus-free HSV-1 amplicon vectors appear to be effective for cytokine-enhanced vaccination therapy of glioma, with the advantages that both dividing and nondividing tumor cells can be infected, no viral proteins are expressed, and these vectors are safe and compatible with clinical use. C1 Massachusetts Gen Hosp, Mol Neurogenet Unit, Neurol Serv, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Univ Tubingen, Dept Neurol, D-72076 Tubingen, Germany. Univ Cologne, Dept Neurol, D-50931 Cologne, Germany. Univ Halle Wittenberg, Dept Neurosurg, D-06097 Halle, Germany. Massachusetts Gen Hosp, Mol Neurogenet Unit, Neurosurg Serv, Charlestown, MA 02129 USA. Humboldt Univ, Dept Neurosurg, D-1344 Berlin, Germany. Univ Zurich, Inst Virol, CH-8057 Zurich, Switzerland. RP Breakefield, XO (reprint author), Massachusetts Gen Hosp E, Dept Mol Neurogenet, 13th St,Bldg 149, Charlestown, MA 02129 USA. FU NCI NIH HHS [CA -69246] NR 41 TC 25 Z9 27 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD JUL PY 2000 VL 11 IS 10 BP 1429 EP 1438 DI 10.1089/10430340050057503 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 331FJ UT WOS:000088006600005 PM 10910140 ER PT J AU Chang, HT Yantiss, RK Nielsen, GP McKee, GT Mark, EJ AF Chang, HT Yantiss, RK Nielsen, GP McKee, GT Mark, EJ TI Lipid-rich diffuse malignant mesothelioma: A case report SO HUMAN PATHOLOGY LA English DT Article DE malignant mesothelioma; intracytoplasmic lipid ID DIFFERENTIATING EPITHELIAL MESOTHELIOMA; ADENOCARCINOMA AB An 80-year old man presented with shortness of breath and was found to have a large right pleural effusion. Cytology of the pleural fluid showed atypical papillary clusters of epithelioid cells. Multiple white-yellow nodules studding the pleural surfaces were seen at thoracoscopy, and biopsies showed solid and papillary clusters of large epithelioid cells with abundant cytoplasm filled with clear vacuoles. Special stains and electron microscopic findings indicated that the tumor was a diffuse malignant mesothelioma with numerous intracytoplasmic lipid vacuoles. Fat stain may be useful at time of frozen section for a pleural-based tumor with vacuolated cells, and the presence of lipid vacuoles in a pleural-based tumor does not exclude diffuse malignant mesothelioma. Copyright (C) 2000 by W.B. Saunders Company. C1 Harvard Univ, Dept Pathol, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Mark, EJ (reprint author), Harvard Univ, Dept Pathol, Massachusetts Gen Hosp, Sch Med, 55 FRuit St, Boston, MA 02114 USA. NR 10 TC 9 Z9 9 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 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD JUL PY 2000 VL 31 IS 7 BP 876 EP 879 DI 10.1053/hupa.2000.7628 PG 4 WC Pathology SC Pathology GA 336GG UT WOS:000088293100019 PM 10923929 ER PT J AU Cooper, RA Boninger, ML AF Cooper, RA Boninger, ML TI Encouraging students with disabilities to pursue careers in bioengineering SO IEEE ENGINEERING IN MEDICINE AND BIOLOGY MAGAZINE LA English DT Editorial Material C1 Univ Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr Hlth Syst, Dept Phys Med & Rehabil, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Med Ctr Hlth Syst, Dept Orthopaed Surg, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA 15260 USA. RP Cooper, RA (reprint author), VA Pittsburgh Healthcare Syst, Human Engn Res Labs 151 R1, 7180 Highland Dr, Pittsburgh, PA 15206 USA. OI Boninger, Michael/0000-0001-6966-919X NR 3 TC 0 Z9 0 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0739-5175 J9 IEEE ENG MED BIOL JI IEEE Eng. Med. Biol. Mag. PD JUL-AUG PY 2000 VL 19 IS 4 BP 9 EP 12 PG 4 WC Engineering, Biomedical; Medical Informatics SC Engineering; Medical Informatics GA 336WG UT WOS:000088325500003 PM 10916726 ER PT J AU Cooper, RA Jones, DK Fitzgerald, S Boninger, ML Albright, SJ AF Cooper, RA Jones, DK Fitzgerald, S Boninger, ML Albright, SJ TI Analysis of position and isometric joysticks for powered wheelchair driving SO IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING LA English DT Article DE Fitts' law; human-machine control; information processing; modeling; wheelchair ID FITTS LAW; MOVEMENTS; HAND AB The control interface is one of the most critical components of the electric-powered wheelchair (EPW). The control interface must accommodate the user's limitations and maximize the user's abilities. This study extended Fitts' Law for target-acquisition to a continuously updated target. The extended Fitts' Law was used to examine EPW driving with a standard position sensing joystick and a prototype isometric joystick (IJ). The extended Fitts' Law provides insight into the difficulty of performing target-acquisition tasks with an EPW. The test results showed significant differences (p < 0.05) among the two types of joysticks for selected measures of information processing capacity, movement time, root-mean-square-error, and average velocity while performing turning maneuvers. The mean values indicate that the IJ may provide superior turning performance. C1 Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Dept Phys Med & Rehabil, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15206 USA. Univ Pittsburgh, Dept Mech Engn, Pittsburgh, PA 15206 USA. VA Pittsburgh Healthcare Syst, Human Engn Res Labs, VA Rehabil Res & Dev Ctr, Pittsburgh, PA 15206 USA. Cent Michigan Univ, Ind & Engn Technol Dept, Mt Pleasant, MI 48859 USA. RP Cooper, RA (reprint author), Univ Pittsburgh, Dept Rehabil Sci & Technol, Pittsburgh, PA 15206 USA. OI Boninger, Michael/0000-0001-6966-919X NR 27 TC 34 Z9 34 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0018-9294 J9 IEEE T BIO-MED ENG JI IEEE Trans. Biomed. Eng. PD JUL PY 2000 VL 47 IS 7 BP 902 EP 910 DI 10.1109/10.846684 PG 9 WC Engineering, Biomedical SC Engineering GA 327KV UT WOS:000087793800009 PM 10916261 ER PT J AU Coyle, AJ Lehar, S Lloyd, C Tian, J Delaney, T Manning, S Nguyen, T Burwell, T Schneider, H Gonzalo, JA Gosselin, M Owen, LR Rudd, CE Gutierrez-Ramos, JC AF Coyle, AJ Lehar, S Lloyd, C Tian, J Delaney, T Manning, S Nguyen, T Burwell, T Schneider, H Gonzalo, JA Gosselin, M Owen, LR Rudd, CE Gutierrez-Ramos, JC TI The CD28-related molecule ICOS is required for effective T cell-dependent immune responses SO IMMUNITY LA English DT Article ID IN-VIVO; CUTTING EDGE; TNF-ALPHA; CTLA-4; ACTIVATION; INDUCTION; CD28; RECEPTORS; BLOCKADE; ANTIGEN AB While CD28 is critical for expansion of naive T cells, recent evidence suggests that the activation of effector T cells is largely independent of CD28/B7. We suggest that ICOS, the third member of the CD28/CTLA-4 family, plays an important role in production of IL-2, IL-4, IL-5, and lFN gamma from recently activated T cells and contributes to T cell-dependent B help in vivo. Inhibition of ICOS attenuates lung mucosal inflammation induced by Th2 but not Th1 effector populations. Our data indicate a critical function for the third member of the CD28 family in T cell-dependent immune responses. C1 Millennium Pharmaceut Inc, Dept Biol, Inflammat Div, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Coyle, AJ (reprint author), Millennium Pharmaceut Inc, Dept Biol, Inflammat Div, Cambridge, MA 02139 USA. FU Wellcome Trust [087618] NR 50 TC 348 Z9 374 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUL PY 2000 VL 13 IS 1 BP 95 EP 105 DI 10.1016/S1074-7613(00)00011-X PG 11 WC Immunology SC Immunology GA 339EA UT WOS:000088463600010 PM 10933398 ER PT J AU Patterson, JE Hardin, TC Kelly, CA Garcia, RC Jorgensen, JH AF Patterson, JE Hardin, TC Kelly, CA Garcia, RC Jorgensen, JH TI Association of antibiotic utilization measures and control of multiple-drug resistance in Klebsiella pneumoniae SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the Infectious-Diseases-Society-of-America CY NOV 12-15, 1998 CL DENVER, COLORADO SP Infect Dis Soc Amer ID SPECTRUM BETA-LACTAMASES; ENTEROBACTERIACEAE; ELECTROPHORESIS; RESTRICTION; OUTBREAK; PATTERNS AB OBJECTIVE: To study the association of antibiotic-utilization measures and control of multidrug-resistant (MDR) Klebsiella pneumoniae after emergence in two hospitals in our medical center. DESIGN AND SETTING: Rates of MDR K pneumoniae at two hospitals were compared before and after acute interventions, including emphasis on Contact Precautions and education in antibiotic utilization. Antipseudomonal beta-lactam antibiotic use was measured before and after the interventions at both hospitals. Pulsed-field gel electrophoresis of whole cell DNA was used as a marker of strain identity. RESULTS: Clonal strain dissemination was the major mechanism of emergence at hospital A ; emergence was polyclonal at hospital B. Antibiotic-utilization interventions at both institutions included physician education regarding the association of ceftazidime use and MDR K pneumoniae. At hospital a ceftazidime use decreased from 4,301g in the preintervention period, to 1,248 g in the postintervention period. Piperacillin-tazobactam increased from 12,455 g to 17,464 g. Ceftazidime resistance in K pneumoniae decreased from 110 (22%) of 503 isolates to 61 (15%) of 407 isolates (P<.05); piperacillin-tazobactam resistance decreased from 181 (36%) of 503 to 77 (19%) of 407 isolates (P<.05). At hospital B, ceftazidime use decreased from 6,533 g in the preintervention period to 4,792 g in the postintervention period. Piperacillin-tazobactam use increased from 58,691 g to 67,027 g. Ceftazidime resistance in K pneumoniae decreased from 42 (10%) of 415 isolates to 19 (5%) of 383 isolates (P<.05). Piperacillin-tazobactam resistance decreased from 91 (22%) of 415 isolates to 54 (14%) of 383 isolates (P<.05). Follow-up data showed continued decrease in piperacillin-tazobactam resistance despite increased use at both hospitals. CONCLUSIONS: Antibiotic-use measures may be particularly important for control of MDR K pneumoniae, whether emergence is clonal or polyclonal. C1 Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78284 USA. S Texas Vet Hlth Care Syst, San Antonio, TX USA. RP Patterson, JE (reprint author), Dept Med Infect Dis, 7703 Floyd Curl Dr,Mail Code 7881, San Antonio, TX 78229 USA. NR 13 TC 104 Z9 116 U1 0 U2 1 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUL PY 2000 VL 21 IS 7 BP 455 EP 458 DI 10.1086/501787 PG 4 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 335WG UT WOS:000088267300010 PM 10926395 ER PT J AU Pahlavani, MA Vargas, DA AF Pahlavani, MA Vargas, DA TI Activation-induced apoptosis in T cells from young and old Fischer 344 rats SO INTERNATIONAL ARCHIVES OF ALLERGY AND IMMUNOLOGY LA English DT Article DE T cell; apoptosis; CD95; CD95L; Bax; Bcl-2; rat; aging ID FAS ANTIGEN; DNA FRAGMENTATION; OXIDATIVE STRESS; PERIPHERAL-BLOOD; DEATH APOPTOSIS; EXPRESSION; AGE; RECEPTOR; MICE; ENDONUCLEASE AB Background: Activation-induced apoptosis is believed to limit cell proliferation and eliminate the high number of activated cells during an immune response. Methods: Activation-induced apoptosis was investigated in splenic T cells isolated from young (6 months) and old (24 months) male Fischer 344 rats. The cells were incubated with anti-CD3, concanavalin A or staphylococcal enterotoxin B (primary stimulus) for 72 h, followed by restimulation with anti-CDB or concanavalin A (secondary stimulus). Apoptosis was assessed by DNA fragmentation assay and DNA gel electrophoresis. The expression of the apoptotic marker CD95 was analyzed by flow cytometry and the relative levels of CD95 ligand, Bcl-2 and Bax protein were measured by immunoblotting. Results: It was shown that DNA fragmentation was very low in the unstimulated T cells from both young and old rats. However, the level of DNA fragmentation was 45-55% great er in the activated T cells from old rats than in the activated T cells from young rats. The increase in DNA fragmentation was paralleled by an increase in the proportion of cells expressing the CD95 molecule. The proportion of CD95+ cells was approximately 40% higher in T cells from old rats than in T cells from young rats. In addition, it was found that the expression of CD95 ligand and Bax increased and Bcl-2 decreased in the activated T cells from old rats compared to the activated T cells from young rats. Conclusion: Our data suggest that the increase in sensitivity of T cells to apoptosis with age may contribute to age-associated immune dysfunction and disorders. Copyright (C) 2000 S. Karger AG, Basel. C1 Audie L Murphy Mem Vet Adm Med Ctr, GRECC 182, S Texas Vet Hlth Care Syst, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78284 USA. RP Pahlavani, MA (reprint author), Audie L Murphy Mem Vet Adm Med Ctr, GRECC 182, S Texas Vet Hlth Care Syst, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. FU NIA NIH HHS [AG00677, AG14088] NR 52 TC 4 Z9 4 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1018-2438 J9 INT ARCH ALLERGY IMM JI Int. Arch. Allergy Immunol. PD JUL PY 2000 VL 122 IS 3 BP 182 EP 189 DI 10.1159/000024395 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 340LQ UT WOS:000088535000004 PM 10899761 ER PT J AU Herzog, DB Greenwood, DN Dorer, DJ Flores, AT Ekeblad, ER Richards, A Blais, MA Keller, MB AF Herzog, DB Greenwood, DN Dorer, DJ Flores, AT Ekeblad, ER Richards, A Blais, MA Keller, MB TI Mortality in eating disorders: A descriptive study SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE mortality; anorexia nervosa; bulimia nervosa ID ANOREXIA-NERVOSA; PSYCHIATRIC-PATIENTS; BULIMIA-NERVOSA; FOLLOW-UP; PREDICTORS; RECOVERY; COMORBIDITY; SUICIDE; RELAPSE AB Objective: We report rates and causes of death for a cohort of 246 eating disordered women and provide descriptive information on their eating disorder and comorbid diagnoses Method: Data on mortality were collected as part of a longitudinal study of anorexia nervosa and bulimia nervosa, now in its 11th year. Of her data sources included death certificates, autopsy reports, relative interviews, and a National Death Index search. Results: Seven deaths have occurred during the study, all among anorexic subjects with a history of binging and purging and with comorbid Axis I disorders. The crude mortality rate was 5.1%. The standardized mortality ratios for death (9.6) and suicide (58.1) were significantly elevated (p <.001). Conclusions: Anorexia nervosa is associated with a substantial risk of death and suicide. Features correlated with fatal outcome are longer duration of illness, binging and purging, comorbid substance abuse, and comorbid affective disorders. (C) 2000 by John Wiley & Sons, Inc. C1 Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Eating Disorders Ctr, Boston, MA 02115 USA. Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. RP Herzog, DB (reprint author), Massachusetts Gen Hosp, Dept Psychiat, ACC 725,15 Parkman St, Boston, MA 02114 USA. FU NIMH NIH HHS [R01 MH 38333-06A4] NR 21 TC 141 Z9 144 U1 2 U2 11 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0276-3478 J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD JUL PY 2000 VL 28 IS 1 BP 20 EP 26 DI 10.1002/(SICI)1098-108X(200007)28:1<20::AID-EAT3>3.0.CO;2-X PG 7 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 313GH UT WOS:000086991600003 PM 10800010 ER PT J AU Ulman, KH AF Ulman, KH TI An integrative model of stress management groups for women SO INTERNATIONAL JOURNAL OF GROUP PSYCHOTHERAPY LA English DT Article AB This article proposes an integrative model for stress management groups for women, representing a biopsychosocial point of view and drawing on theories of psychodynamic group psychotherapy, self-psychology, female development, and stress management. The basis of the model is an eight week traditional stress management group. The novel aspects of this integrative model are that it aims to increase the power of stress management groups for women by Providing an articulated frame, attending to group process, promoting curiosity regarding resistance to behavior changes, encouraging the elaboration of affect, and giving importance to the role of relationships in each member's quest for self care and healthy entitlement. C1 Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Ulman, KH (reprint author), 17 Elm St, Boxford, MA 01921 USA. NR 26 TC 6 Z9 7 U1 0 U2 1 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0020-7284 J9 INT J GROUP PSYCHOTH JI Int. J. Group Psychother. PD JUL PY 2000 VL 50 IS 3 BP 341 EP 362 PG 22 WC Psychology, Clinical SC Psychology GA 327WE UT WOS:000087816500004 PM 10883549 ER PT J AU Gans, JS Weber, RL AF Gans, JS Weber, RL TI The detection of shame in group psychotherapy: Uncovering the hidden emotion SO INTERNATIONAL JOURNAL OF GROUP PSYCHOTHERAPY LA English DT Article ID GROUP-THERAPY AB Shame, recently so extensively investigated in the individual and family therapy literature, has remained curiously underexplored in the group literature since Alonso and Rutan's noteworthy article on the subject in 1988. Shame is frequently bypassed because, as a result of its hidden nature, its presence is often not detected. This article strives to insure that shame does not go unaddressed. We catalogue and discuss six defenses that may suggest the subterranean workings of shame: (1) focusing on themes that stress similarities among members, (2) generating feelings of scorn and disdain, (3) avoiding here-and-now material, (4) inducing guilt, (5) transference reactions, and (6) preserving the illusion of the leader's infallibility. The best antidote for shame's neglect is a heightened readiness to detect it. Such detection is important because shame plays some role in many of our patients' complaints. C1 Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Cambridge Hosp, Core Psychol Fac, Dept Psychiat, Cambridge, MA 02139 USA. Grp Solut Network Inc, Cambridge, MA USA. RP Gans, JS (reprint author), 55 Cleveland Rd, Wellesley, MA 02181 USA. NR 32 TC 14 Z9 14 U1 0 U2 2 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0020-7284 J9 INT J GROUP PSYCHOTH JI Int. J. Group Psychother. PD JUL PY 2000 VL 50 IS 3 BP 381 EP 396 PG 16 WC Psychology, Clinical SC Psychology GA 327WE UT WOS:000087816500006 PM 10883551 ER PT J AU Gilks, CB Clement, PB Hart, WR Young, RH AF Gilks, CB Clement, PB Hart, WR Young, RH TI Uterine adenomyomas excluding atypical polypoid adenomyomas and adenomyomas of endocervical type: A clinicopathologic study of 30 cases of an underemphasized lesion that may cause diagnostic problems with brief consideration of adenomyomas of other female genital tract sites SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE uterine corpus; adenomyoma; adenosarcoma; polyp ID UTERUS-LIKE MASS; MULLERIAN ADENOSARCOMA; ENDOMETRIAL ADENOCARCINOMA; TAMOXIFEN THERAPY; DIFFERENTIATION; LEIOMYOMATOSIS; TUMORS; OVARY AB We report 30 uterine tumors composed of an admixture of endometrioid glands, endometrioid stroma, and smooth muscle that lacked the characteristic features of atypical polypoid adenomyoma. The patients ranged from 26 to 64 (median 47) years of age. The usual presenting symptom was abnormal vaginal bleeding, which was "massive" in two patients. Six patients were treated by polypectomy only, with hysterectomy performed in the remainder. Twenty-seven adenomyomas were in the corpus (22 submucosal, two mural, and three subserosal) and three in the cervix. The subserosal and submucosal examples were polypoid. The tumors were 0.3 to 17 cm in greatest dimension, and firm with cystic areas often present on sectioning. Focal hemorrhage was described in five cases. On microscopic examination, the tumors were composed of glands and cysts lined by endometrial-type epithelium separated by endometrial stroma and smooth muscle, with smooth muscle predominating. Minor foci of tubal-type epithelium (14 cases), mucinous endocervical-type epithelium (2 cases), and squamous epithelium (1 case) were present. The smooth muscle component was cellular in three cases and contained occasional bizarre nuclei in three cases. The epithelial cells were uniformly bland. No mitotic activity was observed in the epithelial or mesenchymal elements in 20 cases. In the remainder, up to 5 mitotic figures/10 high-power fields were observed in the epithelium (3 cases), the stroma and smooth muscle (3 cases), or both compartments (4 cases). Follow-up in 14 cases revealed no recurrence or extrauterine spread in any case. A diagnosis of adenocarcinoma or adenosarcoma was entertained by the submitting pathologist in five of 14 consultation cases. Adenomyomas are unusual benign uterine tumors that can be misdiagnosed, in part, because the lesion has not often received attention in the literature. The most realistic considerations in the differential diagnosis are atypical polypoid adenomyoma and adenosarcoma. The former, by definition, has epithelial atypia and the latter a malignant (usually low grade) stromal component with typically absent or inconspicuous smooth muscle. Distinction of adenomyoma from adenosarcoma may have significant therapeutic implications, particularly in young women. C1 Vancouver Hosp & Hlth Sci Ctr, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Cleveland Clin Fdn, Div Pathol & Lab Med, Cleveland, OH 44195 USA. Harvard Univ, Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Sch Med, Boston, MA 02115 USA. RP Gilks, CB (reprint author), UBC Hosp, Dept Pathol, 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada. NR 55 TC 54 Z9 55 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD JUL PY 2000 VL 19 IS 3 BP 195 EP 205 DI 10.1097/00004347-200007000-00001 PG 11 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA 330TU UT WOS:000087977900001 PM 10907166 ER PT J AU Paganetti, H Gerweck, LE Goitein, M AF Paganetti, H Gerweck, LE Goitein, M TI The general relation between tissue response to x-radiation (alpha/beta-values) and the relative biological effectiveness (RBE) of protons: Prediction by the Katz track-structure model SO INTERNATIONAL JOURNAL OF RADIATION BIOLOGY LA English DT Article ID CELLULAR RADIOSENSITIVITY PARAMETERS; INVITRO RADIOSENSITIVITY; LINES; CELLS; BEAM; SENSITIVITY; SURVIVAL; NEUTRONS; FRACTIONATION; THERAPY AB Purpose: Experimental data suggest that the relative biological effectiveness (RBE) of protons compared to x-rays may be determined by the alpha/beta-ratio of the x-ray survival curve. The data are referring to the centre of a spread-out Bragg peak (SOBP) formed to deliver a homogeneous dose to the tumour by modulating the proton energy. In an effort to explore the basis for this observation, calculations were performed to investigate the response of different biological targets through a range of proton energies and doses. Materials and methods: To describe the x-ray survival curve, the parameters of the linear-quadratic equation, alpha and beta, as well as those of the multi-target/single-hit equation, n and D-0, were considered. These parameters were varied to investigate the RBE using the Katz track-structure model. Known cell line characterizations, as well as different hypothetical cells assuming different alpha/beta-ratios but similar target size parameters in the framework of the track-structure theory, were considered. Results: The RBE was found to increase with increasing alpha/beta when the parameter n was varied, but to decrease with increasing alpha/beta when D-0 was varied. This held when all other radiosensitivity parameters were assumed to stay constant. Thus, the RBE cannot be predicted by the alpha/beta-ratio alone. Conclusions: Although there is no direct correlation between the proton RBE and the parameters describing the x-ray survival curve, the track-structure model predicts a tendency for late-responding tissues (low alpha/beta) to have higher RBE values than early-responding tissues(high alpha/beta) These calculations reinforce the experimental findings, but also strongly suggest that there are circumstances in which the tendency for RBE to increase with increasing alpha/beta does not occur, or even could be reversed. C1 Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Paganetti, H (reprint author), Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. FU NCI NIH HHS [CA21239] NR 43 TC 17 Z9 17 U1 0 U2 4 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 0955-3002 J9 INT J RADIAT BIOL JI Int. J. Radiat. Biol. PD JUL PY 2000 VL 76 IS 7 BP 985 EP 998 PG 14 WC Biology; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 335PG UT WOS:000088251400012 PM 10923623 ER PT J AU Lu, HM Cash, E Chen, MH Chin, L Manning, WJ Harris, J Bornstein, B AF Lu, HM Cash, E Chen, MH Chin, L Manning, WJ Harris, J Bornstein, B TI Reduction of cardiac volume in left-breast treatment fields by respiratory maneuvers: A CT study SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE respiratory maneuvers; breast cancer treatment; treatment planning ID RADIATION-THERAPY; CANCER PATIENTS; POSTOPERATIVE RADIOTHERAPY; ADJUVANT RADIOTHERAPY; MEDICAL PROGRESS; MORTALITY; TRIAL; SURGERY AB Purpose: A previous study of healthy female volunteers suggested that deep inspiratory breath holding can reduce the cardiac volume in the treatment portals for left-breast cancer treatment. The reduction of irradiated cardiac volume may be important considering the reported late cardiac morbidity and mortality and the frequent coexistent use of potentially cardiotoxic chemotherapy in breast cancer patients. In the present study, we evaluated the heart volume in the fields and, thus, the true benefit of this respiratory maneuver in breast cancer patients undergoing CT simulation, Materials and Methods: Fifteen patients (median age, 53) were studied. For each patient, CT scans were performed both when the patient breathed normally (quiet respiration) and when the patient held her breath after a deep inspiration. Tangential fields were planned using the same medial, lateral, superior, and inferior borders on skin for the normal breathing and the breath-holding configurations. The cardiac and left-lung volumes within the tangential fields were calculated for both breathing configurations. Multiple scan series were performed for the breath-holding configuration to provide a more accurate delineation of the cardiac tissue and to study the reproducibility of the patient's position between different cycles of deep inspiration. Results: None of the patients had difficulty holding her breath for 20 s. The cardiac volume in the field was reduced (-86 +/- 24%; p < 0.001) when patients held their breath after a deep inspiration compared to when breathing normally. For 7 patients (47%), deep inspiration moved the heart completely out of the radiation fields. The expansion of the lung tissue due to deep inspiration also increased the absolute lung volume in the tangential fields (183 cm(3) vs 97 cm(3), p < 0.001). However, the fractional volume of the left lung in the field was essentially unchanged. For all but 1 patient, the maximum difference between the external body contours from different breath holding cycles was 5 mm and occurred at the lateral aspect of the breast. At the medial aspect, as indicated by the position of the midline marker, the variations were well within the currently accepted tolerance for patient positioning during tangential treatment. Conclusions: Deep-inspiration breath holding substantially reduces cardiac volume in the tangential fields for left-sided breast cancer treatment. The variation between patient positions at different cycles of breath holding was found to be reasonably small, Therefore, it appears feasible to reduce cardiac radiation by treating patients with intratreatment minifractions lasting 10-15 s while patients hold their breath. (C) 2000 Elsevier Science Inc. C1 Harvard Univ, Sch Med, Joint Ctr Radiat Therapy, Boston, MA 02215 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Div Cardiovasc, Boston, MA 02215 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dana Farber Canc Inst,Dept Radiat Oncol, Boston, MA 02215 USA. RP Lu, HM (reprint author), Harvard Univ, Sch Med, Joint Ctr Radiat Therapy, 330 Brookline Ave, Boston, MA 02215 USA. NR 16 TC 69 Z9 69 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2000 VL 47 IS 4 BP 895 EP 904 DI 10.1016/S0360-3016(00)00512-5 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 328HV UT WOS:000087845500006 PM 10863057 ER PT J AU Thomas, MD Cormack, R Tempany, CM Kumar, S Manola, J Schneider, L Hurwitz, MD D'Amico, AV AF Thomas, MD Cormack, R Tempany, CM Kumar, S Manola, J Schneider, L Hurwitz, MD D'Amico, AV TI Identifying the predictors of acute urinary retention following magnetic-resonance-guided prostate brachytherapy SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE prostate cancer; radiation therapy; magnetic resonance imaging; implant; urinary retention ID CANCER AB Purpose: Larger prostate gland volumes have been associated with long-term urinary morbidity in prostate interstitial radiation therapy utilizing ultrasound image guidance technique. This study was performed to identify the clinical and technical predictors of acute urinary retention following magnetic-resonance (MR)-guided prostate interstitial brachytherapy. Methods and Materials: Fifty patients underwent MR-guided prostate brachytherapy between December 1997 and March 1999. Patient selection was limited to men with stage T1cNXM0 disease, PSA of less than 10 ng/mL, biopsy Gleason score not more than 3 + 4, and endorectal coil MR stage T2 disease. Dosimetry plans were developed in the operating room and (125)Iodine sources were implanted using MR real-time guidance. The peripheral zone (PZ) of the prostate gland was defined as the clinical target volume (CTV) and the minimum prescribed dose to the CTV was 137 Gy. The volumes of the PZ, transition zone (TZ), and total prostate gland volume were also determined by MR. Individual source strength ranged from 0.35 to 0.54 mu Gym(2)/h (NIST 99, median 0.46 mu Gym(2)/h) and the total implanted activity ranged from 17.0 to 43.1 mCi (median, 28.1 mCi) using 43-120 seeds (median, 79). The seeds were placed using MR-compatible biopsy needles (14-28, median, 19). Results: The ability of clinical (MR defined prostate, PZ, and TZ volumes) and technical (number of catheters, number of seeds implanted, and total activity) factors to predict AUR for 50 men undergoing MR-guided prostate interstitial brachytherapy were evaluated using univariable and logistic regression multivariable analyses. Six men (12%) experienced AUR within 24 h after removal of the Foley catheter subsequent to prostate brachytherapy. The total number of seeds (p = 0.05), MR determined prostate volume (p < 0.01), and the MR-determined TZ volume (p < 0.01) were significant predictors of AUR on univariable analysis. Utilizing a multivariable logistic regression analysis, the TZ volume was the only significant predictor of AUR (p < 0.01). The prostate volume is highly correlated to the TZ volume (Spearman correlation coefficient of 0.91) and was thus significant in the univariable analysis; however, the prostate volume did not add prognostic value in multivariable analysis. Conclusion: Benign prostatic hyperplasia (BPH) resulting in an enlarged TZ volume, is the most important predictor of AUR following MR-guided prostate interstitial radiation therapy. Although AUR was significant (60%) in men with moderate BPH (TZ volume greater than or equal to 50 cc), it was also self-limiting. (C) 2000 Elsevier Science Inc. C1 Brigham & Womens Hosp, Dept Radiat Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Urol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Radiat Oncol, Boston, MA 02115 USA. RP Thomas, MD (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Radiat Oncol, 330 Brookline Ave,5th Floor, Boston, MA 02215 USA. OI Cormack, Robert/0000-0001-5553-9984 NR 7 TC 39 Z9 43 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2000 VL 47 IS 4 BP 905 EP 908 DI 10.1016/S0360-3016(00)00541-1 PG 4 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 328HV UT WOS:000087845500007 PM 10863058 ER PT J AU Childs, HA Spencer, SA Raben, D Bonner, JA Newsome, J Robert, F AF Childs, HA Spencer, SA Raben, D Bonner, JA Newsome, J Robert, F TI A phase I study of combined uft plus leucovorin and radiotherapy for pancreatic cancer SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-Society-for-Therapeutic-Radiology-and-Oncology CY OCT 30-NOV 04, 1999 CL SAN ANTONIO, TEXAS SP Amer Soc Therapeut Radiol & Oncol DE pancreatic; UFT; leucovorin; radiation ID COOPERATIVE-ONCOLOGY-GROUP; RADIATION-THERAPY; COLORECTAL-CANCER; ORAL REGIMEN; 5-FLUOROURACIL; CARCINOMA; FLUOROURACIL; FTORAFUR; INFUSION; URACIL AB Purpose: This Phase I study combines tegafur and uracil (UFT) with leucovorin and conventional radiation for the treatment of pancreatic cancer. The design seeks to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of this regimen as well as to define a future Phase II dose level. Methods: Patients with locally advanced and unresectable pancreatic cancer were treated with 45 Gy of radiation therapy. The initial UFT dose was 150 mg/m(2)/day given with leucovorin 90 mg/day, both divided into 3 daily doses for 35 days concurrent with radiation. UFT doses were escalated at increments of 50 mg/m(2)/day. Dose-limiting toxicity (DLT) was defined as Grade 3 or greater nausea, vomiting or diarrhea despite medical intervention; or Grade 3 or greater neutropenia/thrombocytopenia; or Grade 3 or greater hepatic toxicity; or inability of the patient to take 75% or more of the planned UFT/leucovorin; or radiotherapy interruption of greater than 1 week. The MTD for UFT/leucovorin was exceeded by one dose level when a certain dose caused DLT in 2 or more patients of 6. Results: Five evaluable patients had Stage I resectable disease but had pathologic adenopathy. Seven had Stage II unresectable disease. Compliance with therapy was excellent. At a daily dose of 300 mg/m(2) of UFT, we noticed minimal diarrhea and hematologic toxicity with mild-moderate nausea, anorexia, and fatigue. Three patients had Grade 4 toxicity: 1 had neutropenia on Day 38, 1 had diarrhea on Day 55, and 1 had vomiting on Day 15. Conclusion: Oral UFT/leucovorin and radiation therapy offers patients a viable treatment option for pancreatic cancer. The major known toxicity of diarrhea was tolerable. The MTD was not reached in this study. Our current plan is to expand this into a Phase I/II trial beginning at a UFT dose of 300 mg/m(2) and correlate this with clinical pharmacologic parameters. The potential benefit of long bioavailability and oral delivery of UFT compares favorably with continuous infusion regimens without the added morbidity of a catheter and pump. (C) 2000 Elsevier Science Inc. C1 Univ Alabama, Birmingham Comprehens Canc Ctr, Birmingham, AL 35294 USA. Birmingham VA Med Ctr, Birmingham, AL USA. RP Robert, F (reprint author), Univ Alabama, Birmingham Comprehens Canc Ctr, 1824 6th Ave S,236 TI, Birmingham, AL 35294 USA. NR 25 TC 18 Z9 19 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2000 VL 47 IS 4 BP 939 EP 944 DI 10.1016/S0360-3016(00)00496-X PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 328HV UT WOS:000087845500012 PM 10863063 ER PT J AU Hug, EB Adams, J Fitzek, M De Vries, A Munzenrider, JE AF Hug, EB Adams, J Fitzek, M De Vries, A Munzenrider, JE TI Fractionated, three-dimensional, planning-assisted proton-radiation therapy for orbital rhabdomyosarcoma: A novel technique SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE protons; orbital rhabdomyosarcoma; particle therapy; conformal therapy; pediatric malignancies ID 2ND MALIGNANT NEOPLASMS; INTERGROUP RHABDOMYOSARCOMA; STUDY-II; CHILDREN; IRRADIATION AB Purpose: Most children with orbital rhabdomyosarcoma will survive their disease. However, conventional photon-radiation treatment, as part of multimodality therapy, results in varying degrees of long-term functional and cosmetic side effects. This report introduces external beam proton radiation therapy (PRT) as a conformal, three-dimensional planned radiation technique for this disease, analyzes normal tissue dosimetry, and describes the technique's application in the first 2 patients. Material and Methods: Between January 1995 and February 1996, 2 patients underwent PRT following biopsy and chemotherapy for orbital rhabdomyosarcoma. Fifty and 55 Cobalt Gray Equivalent (CGE) were delivered to the gross tumor volume and 40 CGE to clinical target volumes in both patients. A relative biologic effectiveness (RBE) of 1.1 was utilized to correlate proton dose calculations with CGE. To achieve dose conformity, a "patch technique" was utilized, where target regions were divided into segments, each treated by a separate proton field. Dose-volume histograms were obtained for target and nontarget regions, including lens, bony orbit, pituitary gland, optic chiasm, optic nerves, lacrimal gland, and ipsilateral frontal and temporal lobes. Results: At 3.4 and 2.5 years after PRT, both patients are clinically and radiographically free of disease. Visual acuity remains excellent, without signs of cataract formation; pituitary function is normal; cosmetically, only mild enophthalmos is noticeable. Doses to 90%, 50%, and 5% of lens volume were kept at less than 1%, less than 2%, and less than 8%, respectively. Fifty percent of lacrimal gland volume received less than 36% of the prescribed dose and 50% of the volume of the optic chiasm, pituitary gland, and hypothalamus were restricted to less than 2%. Proton conformity to orbital contents resulted in between 9% and 36% of the prescribed dose reaching the ipsilateral temporal and frontal lobes immediately adjacent to bony orbit (5% volume). Conclusion: PRT can offer excellent sparing of lens and selected intraorbital and ocular normal structures, while maintaining conformal target-dose coverage. The steep dose gradient beyond the orbit minimizes irradiation of normal brain parenchyma, with almost complete sparing of the pituitary gland. Reduction of integral irradiation exposure of the periorbital region will, hopefully, reduce the risk of second malignancy later in life, Reduced radiation dose to specific organs in close proximity to, but not part of the target region promises improved functional outcome and better cosmesis for childhood cancer survivors. (C) 2000 Elsevier Science Inc. C1 Loma Linda Univ, Med Ctr, Dept Radiat Med, Loma Linda, CA 92354 USA. Loma Linda Univ, Med Ctr, Dept Pediat, Loma Linda, CA 92354 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Cyclotron Lab, Cambridge, MA 02138 USA. RP Hug, EB (reprint author), Loma Linda Univ, Med Ctr, Dept Radiat Med, 11234 Anderson St,POB 2000, Loma Linda, CA 92354 USA. NR 22 TC 41 Z9 47 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 1 PY 2000 VL 47 IS 4 BP 979 EP 984 DI 10.1016/S0360-3016(00)00545-9 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 328HV UT WOS:000087845500017 PM 10863068 ER PT J AU Clement, PB Young, RH AF Clement, PB Young, RH TI Two previously unemphasized features of endometriosis: Micronodular stromal endometriosis and endometriosis with stromal elastosis SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE endometriosis; stromal endometriosis; elastosis ID PERITONEAL INCLUSION CYSTS AB This report draws attention to two unusual features of the stromal component of endometriosis that can create problems in diagnosis. One of these is the exclusive presence of endometriotic stroma, so-called stromal endometriosis, that can occasionally take the form of microscopic nodules of endometriotic stroma on the pelvic peritoneum and other locations. This finding, which we refer to as a micronodular stromal endometriosis, can be overlooked entirely or lead to confusion with peritoneal involvement by low-grade endometrial stromal sarcoma. The other finding we describe is the presence of a prominent elastotic stromal response to endometriosis that can occasionally obscure or even focally obliterate the typical endometriotic stroma. This finding, although nonspecific, can be a diagnostic clue to the presence of endometriosis, especially when accompanied by the presence of the typical endometriod glands of that lesion. C1 Vancouver Hosp & Hlth Sci Ctr, Dept Pathol, Vancouver, BC V5Z 4E3, Canada. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Med Sch, Dept Pathol, Boston, MA USA. RP Clement, PB (reprint author), Vancouver Hosp & Hlth Sci Ctr, Dept Pathol, 910 W 10th,Room 1302, Vancouver, BC V5Z 4E3, Canada. NR 11 TC 19 Z9 22 U1 0 U2 0 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 1066-8969 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD JUL PY 2000 VL 8 IS 3 BP 223 EP 227 DI 10.1177/106689690000800310 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA 357PC UT WOS:000089509200010 PM 11493993 ER PT J AU Scully, RE AF Scully, RE TI The prolonged gestation, birth, and early life of the sex cord tumor with annular tubules and how it joined a syndrome SO INTERNATIONAL JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE discovery; nomenclature; sex cord tumor with annular tubules; Sertoli cell tumor; Peutz-Jeghers syndrome; adenoma malignum of cervix ID PEUTZ-JEGHERS SYNDROME; ADENOMA MALIGNUM; OVARIAN; MARKER; CERVIX AB The sex cord tumor with annular tubules was discovered as a distinctive entity when its unusual-appearing microscopic pattern was encountered repetitively in a pathology consultation practice. The author was stimulated to describe the clinicopathological features of the tumor and assign it a specific name when a minority of the cases in his series were found to be associated with the rare Peutz-Jeghers syndrome. Both these tumors and those occurring in the absence of the syndrome have been shown to have distinctive clinicopathological features that differ from those of other tumors in the sex cord-stromal category. C1 Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Harvard Med Sch, Boston, MA USA. RP Scully, RE (reprint author), Massachusetts Gen Hosp, Dept Pathol, James Homer Wright Pathol Labs, 55 Fruit St,WRN 215, Boston, MA 02114 USA. NR 23 TC 5 Z9 5 U1 0 U2 3 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 1066-8969 J9 INT J SURG PATHOL JI Int. J. Surg. Pathol. PD JUL PY 2000 VL 8 IS 3 BP 233 EP 238 DI 10.1177/106689690000800312 PG 6 WC Pathology; Surgery SC Pathology; Surgery GA 357PC UT WOS:000089509200012 PM 11493995 ER PT J AU Goodyear, LJ AF Goodyear, LJ TI Signal transduction and glucose transport SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Cambridge, MA 02138 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD JUL PY 2000 VL 8 IS 3 BP 243 EP 243 PG 1 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 338XQ UT WOS:000088448900017 ER PT J AU Horton, ES AF Horton, ES TI Prevention and treatment of Type 2 diabetes with exercise SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD JUL PY 2000 VL 8 IS 3 BP 243 EP 244 PG 2 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 338XQ UT WOS:000088448900018 ER PT J AU Sweeney, HL Rosenthal, N Barton-Davis, ER AF Sweeney, HL Rosenthal, N Barton-Davis, ER TI Gene therapy for aging muscles SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Meeting Abstract C1 Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. RI Rosenthal, Nadia/O-7009-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD JUL PY 2000 VL 8 IS 3 BP 252 EP 252 PG 1 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 338XQ UT WOS:000088448900034 ER PT J AU Boppart, MD Hirshman, MF Fielding, RA Goodyear, LJ AF Boppart, MD Hirshman, MF Fielding, RA Goodyear, LJ TI Regulation of focal adhesion proteins following contraction in rat skeletal muscle SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Cambridge, MA 02138 USA. Boston Univ, Dept Hlth Sci, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD JUL PY 2000 VL 8 IS 3 BP 260 EP 261 PG 2 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 338XQ UT WOS:000088448900052 ER PT J AU Sakamoto, K Hirshman, MF Iguchi, T Goodyear, LJ AF Sakamoto, K Hirshman, MF Iguchi, T Goodyear, LJ TI Contraction-induced phosphorylation of ERK and its downstream substrate Elk-1 in rat skeletal muscle SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Meeting Abstract C1 Joslin Diabet Ctr, Boston, MA 02215 USA. Yokohama City Univ, Grad Sch Integrated Sci, Kanazawa Ku, Yokohama, Kanagawa, Japan. NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD JUL PY 2000 VL 8 IS 3 BP 261 EP 262 PG 2 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 338XQ UT WOS:000088448900054 ER PT J AU Higaki, Y Hirshman, MF Fujii, N Goodyear, LJ AF Higaki, Y Hirshman, MF Fujii, N Goodyear, LJ TI Nitric oxide increases glucose transport through a mechanism that is distinct from insulin and contraction pathways in rat skeletal muscle SO JOURNAL OF AGING AND PHYSICAL ACTIVITY LA English DT Meeting Abstract C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02115 USA. RI Fujii, Nobuharu/J-2724-2014 OI Fujii, Nobuharu/0000-0002-0974-3033 NR 0 TC 0 Z9 0 U1 0 U2 0 PU HUMAN KINETICS PUBL INC PI CHAMPAIGN PA 1607 N MARKET ST, CHAMPAIGN, IL 61820-2200 USA SN 1063-8652 J9 J AGING PHYS ACTIV JI J. Aging Phys. Act. PD JUL PY 2000 VL 8 IS 3 BP 267 EP 268 PG 2 WC Geriatrics & Gerontology; Gerontology; Sport Sciences SC Geriatrics & Gerontology; Sport Sciences GA 338XQ UT WOS:000088448900065 ER PT J AU Otto, MW Pollack, MH Gould, RA Worthington, JJ McArdle, ET Rosenbaum, JF AF Otto, MW Pollack, MH Gould, RA Worthington, JJ McArdle, ET Rosenbaum, JF TI A comparison of the efficacy of clonazepam and cognitive-behavioral group therapy for the treatment of social phobia SO JOURNAL OF ANXIETY DISORDERS LA English DT Article; Proceedings Paper CT 17th Annual Conference of the Anxiety-Disorders-Association-of-America CY MAR 20-23, 1997 CL NEW ORLEANS, LOUISIANA SP Anxiety Disorders Assoc Amer DE social phobia; cognitive-behavioral therapy; clonazepam; social anxiety disorder; benzodiazepine ID 2-YEAR FOLLOW-UP; DOUBLE-BLIND; PLACEBO; METAANALYSIS; PHARMACOTHERAPY; COMORBIDITY; PHENELZINE; ANXIETY; SCALE; TRIAL AB There is a growing body of evidence that social phobia may be treated effectively by either pharmacologic or cognitive-behavioral interventions, but few studies have examined the relative benefits of these treatments. In this study, we examined the relative efficacy of pharmacotherapy with clonazepam and cognitive-behavioral group therapy (CBGT) for treating social phobia. In addition, we examined potential predictors of differential treatment response. Outpatients meeting Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) criteria for social phobia were randomly assigned to treatment. Clinician-rated and patient-rated symptom severity was examined at baseline and after 4, 8, and 12 weeks of treatment. All clinician-rated assessments were completed by individuals blind to treatment condition. Patients in both conditions improved significantly, and differences between treatment conditions were absent, except for greater improvement on clonazepam on several measures at the 12-week assessment. Symptom severity was negatively associated with treatment success for both methods of treatment, and additional predictors-sex, comorbidity with other anxiety or mood disorders, fear of anxiety symptoms, and dysfunctional attitudes-failed to predict treatment outcome above and beyond severity measures. In summary, we found that patients randomized to clinical care with clonazepam or CBGT were equally likely to respond to acute treatment, and pretreatment measures of symptom severity provided no guidance for the selection of one treatment over another. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. RP Otto, MW (reprint author), Massachusetts Gen Hosp, WACC-815,15 Parkman St, Boston, MA 02114 USA. NR 42 TC 83 Z9 86 U1 2 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-6185 J9 J ANXIETY DISORD JI J. Anxiety Disord. PD JUL-AUG PY 2000 VL 14 IS 4 BP 345 EP 358 DI 10.1016/S0887-6185(00)00027-X PG 14 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 350AJ UT WOS:000089077800002 PM 11043885 ER PT J AU Jander, G Rahme, LG Ausubel, FM AF Jander, G Rahme, LG Ausubel, FM TI Positive correlation between virulence of Pseudomonas aeruginosa mutants in mice and insects SO JOURNAL OF BACTERIOLOGY LA English DT Article ID CAENORHABDITIS-ELEGANS; INNATE IMMUNITY; GALLERIA-MELLONELLA; MODEL; DROSOPHILA; PATHOGENESIS; BACTERIA AB Strain PA14, a human clinical isolate of Pseudomonas aeruginosa, is pathogenic in mice and insects (Galleria mellonella). Analysis of 32 different PA14 mutants in these two hosts showed a novel positive correlation in the virulence patterns. Thus, G. mellonella is a good model system for identifying mammalian virulence factors of P. aeruginosa. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Shriners Burns Inst, Boston, MA 02114 USA. RP Ausubel, FM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, 50 Blossom St, Boston, MA 02114 USA. FU NIGMS NIH HHS [GM18735, F32 GM018735] NR 23 TC 279 Z9 290 U1 0 U2 18 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUL PY 2000 VL 182 IS 13 BP 3843 EP 3845 DI 10.1128/JB.182.13.3843-3845.2000 PG 3 WC Microbiology SC Microbiology GA 324BX UT WOS:000087602900032 PM 10851003 ER PT J AU Fournier, B Hooper, DC AF Fournier, B Hooper, DC TI A new two-component regulatory system involved in adhesion autolysis, and extracellular proteolytic activity of Staphylococcus aureus SO JOURNAL OF BACTERIOLOGY LA English DT Article ID COAGULASE-NEGATIVE STAPHYLOCOCCI; BETA-N-ACETYLGLUCOSAMINIDASE; CELL-WALL TURNOVER; L-ALANINE AMIDASE; ESCHERICHIA-COLI; BACILLUS-SUBTILIS; MOLECULAR CHARACTERIZATION; NUCLEOTIDE-SEQUENCE; SIGNAL-TRANSDUCTION; PHOSPHATE REGULON AB A transposition mutant of Staphylococcus aureus was selected from the parent strain MT23142, a derivative of strain 8325. The site of transposition was near the 5' terminus of the gene arlS. ArlS exhibits strong similarities with histidine protein kinases. Sequence analysis suggested that arlS forms an operon with upstream gene arlR. The predicted product of arlR is a member of the OmpR-PhoB family of response regulators. The arlS mutant formed a biofilm on a polystyrene surface unlike the parent strain and the complemented mutant. Biofilm formation was associated with increased primary adherence to polystyrene, whereas cellular adhesion was only slightly decreased. In addition, the arlS mutant exhibited increased autolysis and altered peptidoglycan hydrolase activity compared to the parental strain and to the complemented mutant. As it has been shown for coagulase-negative staphylococci that some autolysins are able to bind polymer surfaces, these data suggest that the two-component regulatory system ArlS-ArlR may control attachment to polymer surfaces by affecting secreted peptidoglycan hydrolase activity. Finally, the arlS mutant showed a dramatic decrease of extracellular proteolytic activity, including serine protease activity, in comparison to the wild-type strain and the complemented mutant, and cells grown in the presence of phenylmethylsulfonyl fluoride (a serine protease inhibitor) showed an increased autolysin activity. Since the locus arlR-arlS strikingly modifies extracellular proteolytic activity, this locus might also be involved in the virulence of S. aureus. C1 Inst Pasteur, Unite Biochim Microbienne, CNRS URA 1300, F-75724 Paris 15, France. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Med Serv, Boston, MA 02114 USA. RP Fournier, B (reprint author), Inst Pasteur, Unite Biochim Microbienne, CNRS URA 1300, 25 Rue Dr Roux, F-75724 Paris 15, France. FU NIAID NIH HHS [AI23988, R01 AI023988, R37 AI023988] NR 58 TC 133 Z9 140 U1 2 U2 10 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUL PY 2000 VL 182 IS 14 BP 3955 EP 3964 DI 10.1128/JB.182.14.3955-3964.2000 PG 10 WC Microbiology SC Microbiology GA 329ZN UT WOS:000087938500011 PM 10869073 ER PT J AU Takeshita, H Kusuzaki, K Ashihara, T Gebhardt, MC Mankin, HJ Hirasawa, Y AF Takeshita, H Kusuzaki, K Ashihara, T Gebhardt, MC Mankin, HJ Hirasawa, Y TI Intrinsic resistance to chemotherapeutic agents in murine osteosarcoma cells SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID P-GLYCOPROTEIN; CANCER; DNA; EXPRESSION; CISPLATIN; LINE; DOXORUBICIN; ELECTROCHEMOTHERAPY; OVEREXPRESSION; ACCUMULATION AB Background: There are two general categories of drug resistance: acquired and intrinsic. The mechanisms involved in acquired drug resistance have been extensively studied, and several mechanisms have been described. However, the mechanisms responsible for intrinsic drug resistance have not been elucidated, to our knowledge. The purpose of the present study was to investigate the cytological and biochemical differences between acquired and intrinsic drug resistance in osteosarcoma cells. Methods: We previously isolated a clonal cell line (MOS/ADR1) to study acquired resistance in osteosarcoma by exposure of parental murine osteosarcoma cells (MOS) to doxorubicin. In the present study, we cloned a new intrinsically resistant cell line (MOS/IR1) by single-cell culture of MOS cells and we investigated the differences in cell phenotype and the mechanisms of resistance in both of these resistant clones. Results: The MOS/ADR1 and MOS/IR1 cells were sevenfold and fivefold more resistant to doxorubicin than the parental murine osteosarcoma cells. Morphologically, the MOS/ADR1 cell line was composed of polygonal cells, whereas the MOS/IR1 cell line consisted of plump spindle cells with long cytoplasmic processes. The MOS/IR1 cells showed a much lower level of alkaline phosphatase activity than did the MOS/ADR1 and MOS cells. There were no substantial differences in the cellular DNA content or the doubling time among these three lines. Overexpression of the P-glycoprotein involved in the function of an energy-dependent drug-efflux pump was detected in the MOS/ADR1 cells but not in the MOS/IR1 cells. After the cells were incubated with doxorubicin for one hour, the two resistant lines had less accumulation of the drug than did the parent line (p < 0.05). The addition of a P-glycoprotein antagonist, verapamil, or the depletion of cellular adenosine triphosphate resulted in a marked increase in the accumulation of doxorubicin in the MOS/ADR1 cells (p < 0.05) but not in the MOS/IR1 cells. The MOS/ADR1 cells were found to exhibit cross-resistance only to substrates for P-glycoprotein (such as doxorubicin, vincristine, and etoposide), whereas the MOS/IR1 cells were resistant to all of the drugs studied (including cisplatin and methotrexate). The degree of drug resistance in the MOS/IR1 cells was found to be associated,vith the molecular weight of the drugs (p < 0.05). Permeabilization of the plasma membrane by saponin increased both the accumulation of doxorubicin (p < 0.05) and the cytotoxic activity of this drug in all lines, but the effects were most pronounced in the MOS/IR1 cells. Conclusions: Taken together, this data suggests that reduced drug accumulation in the MOS/IR1 cells may be due to the effect of decreased permeability of the plasma membrane on the transport of drugs from the extracellular environment into the cytosol of the cell and that this may be the mechanism responsible for intrinsic resistance to multiple drugs in the MOS/IR1 cell line. Clinical Relevance: Current drug treatment for human osteosarcoma may include multiple chemotherapeutic agents, such as doxorubicin, cisplatin, and methotrexate. These drugs exhibit different cytotoxic actions and, thus, the mechanisms of resistance to individual drugs vary. Clinical resistance to multidrug chemotherapy may be observed in tumors that recur after repetitive chemotherapy and in previously untreated tumors. In the former group, a turner cell may express multidrug resistance by combining several different mechanisms due to its exposure to various drugs. In the latter group, however, this is not likely. Decreased intracellular drug accumulation due to reduced permeability of the plasma membrane, found in the MOS/IR1 cells, is one possible mechanism and may explain the intrinsic resistance to multidrug chemotherapy for the treatment of osteosarcoma. Further study regarding the resistance mechanism in the MOS/IR1 cells may help to overcome the intrinsic drug resistance in osteosarcoma. C1 Kyoto Prefectural Univ Med, Dept Orthopaed Surg, Kamikyo Ku, Kyoto 6020841, Japan. Kyoto Prefectural Univ Med, Dept Pathol, Kamikyo Ku, Kyoto 6020841, Japan. Massachusetts Gen Hosp, Dept Orthopaed Surg, Boston, MA 02114 USA. RP Takeshita, H (reprint author), Otsu Municipal Hosp, Dept Orthopaed Surg, 2 Chome, Otsu, Shiga 5200804, Japan. NR 29 TC 9 Z9 10 U1 0 U2 1 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD JUL PY 2000 VL 82A IS 7 BP 963 EP 969 PG 7 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 332NL UT WOS:000088080300008 PM 10901311 ER PT J AU Kuhn, LT Xu, YT Rey, C Gerstenfeld, LC Grynpas, MD Ackerman, JL Kim, HM Glimcher, MJ AF Kuhn, LT Xu, YT Rey, C Gerstenfeld, LC Grynpas, MD Ackerman, JL Kim, HM Glimcher, MJ TI Structure, composition, and maturation of newly deposited calcium-phosphate crystals in chicken osteoblast cell cultures SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE bone mineral; apatite; osteoblast; calcium phosphate; maturation ID TRANSFORM INFRARED-SPECTROSCOPY; NUCLEAR-MAGNETIC-RESONANCE; X-RAY-DIFFRACTION; SOLID-PHASE; PO4 DOMAIN; BONE; P-31; MINERALIZATION; ENVIRONMENT; ENAMEL AB Characterization of the very early calcium phosphate (CaP) crystals deposited in bone or in osteoblast cell cultures has been hampered by the overwhelming presence of organic matrix components and cells that obscure spectral analyses. We have overcome this problem using isolated protein-free crystals and have obtained new data including P-31 nuclear magnetic resonance (NMR) spectra for the first time from mineral crystals deposited during osteoblast calcification in culture. Crystals were isolated from cultures at two time points: (a) at first calcium accumulation (day 8-10) and (b) after 60 days of culture, to assess maturational changes. The analyses show that the chemical composition overall and short range order of the early and mature crystals are characteristic of the apatite crystals found in young embryonic chick bone in vivo. No mineral phase other than apatite was detected by any of the methods used. P-31 NMR spectroscopy identified the HPO4 groups as those present in bone apatite, Similar to bone apatites, no OH groups were detected by Fourier transform infrared (FTIR) spectroscopy. The temporal maturational changes in composition and structure of the mineral phase were difficult to assess because of the continuous deposition of crystals throughout culturing. The pathway of the maturational changes observed were similar to those occurring in chick bone in vivo and synthetic apatite crystals in vitro although to a much smaller extent. C1 Childrens Hosp, Lab Study Skeletal Disorders & Rehabil, Dept Orthoped Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Inst Natl Polytech Toulouse, Chim Phys Solide Lab, F-31077 Toulouse, France. Boston Univ, Sch Med, Boston, MA 02118 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Biomat Lab, Charlestown, MA USA. Seoul Natl Univ, Coll Dent, Dept Oral Anat, Seoul, South Korea. RP Glimcher, MJ (reprint author), Childrens Hosp, Lab Study Skeletal Disorders & Rehabil, Dept Orthoped Surg, 300 Longwood Ave, Boston, MA 02115 USA. RI Grynpas, Marc/E-4576-2013; Ackerman, Jerome/E-2646-2015; OI Ackerman, Jerome/0000-0001-5176-7496; /0000-0002-0477-1211 FU NIA NIH HHS [R01-AG14701]; NIAMS NIH HHS [R01-AR42258, T32-AR07112] NR 31 TC 35 Z9 35 U1 0 U2 5 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 1200 19TH ST, N W, STE 300, WASHINGTON, DC 20036-2422 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2000 VL 15 IS 7 BP 1301 EP 1309 DI 10.1359/jbmr.2000.15.7.1301 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 326YA UT WOS:000087763800007 PM 10893678 ER PT J AU Zmuda, JM Cauley, JA Glynn, NW Finkelstein, JS AF Zmuda, JM Cauley, JA Glynn, NW Finkelstein, JS TI Posterior-anterior and lateral dual-energy x-ray absorptiometry for the assessment of vertebral osteoporosis and bone loss among older men SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE osteoporosis; men; bone density; dual-energy X-ray absorptiometry ID QUANTITATIVE COMPUTED-TOMOGRAPHY; MINERAL DENSITY-MEASUREMENTS; LUMBAR SPINE; PHOTON-ABSORPTIOMETRY; POSTMENOPAUSAL WOMEN; ELDERLY MEN; PROXIMAL FEMUR; FRACTURE RISK; FEMORAL-NECK; AGE AB Lateral spine dual-energy x-ray absorptiometry (DXA) selectively measures the trabecular-rich vertebral bodies without the contributions of the cortical-rich posterior elements of the spine and is less affected by spinal degenerative disease than posterior-anterior DXA, We tested whether lateral DXA detects vertebral osteoporosis more often and is more sensitive to age-related bone loss than posterior-anterior DXA in 193 healthy, community-dwelling men aged 51-81 years (mean +/- SD; 67 +/- 8 years). All men had supine lateral, posterior-anterior, and proximal femur DXA scans on a Hologic QDR 2000 densitometer, A subset (n = 102) had repeat scans after 4 years to determine annualized rates of change in bone mineral density (BMD), Age was inversely and significantly associated with BMD in the midlateral (r = -0.27) and lateral (r = -0.24) but not posterior-anterior (r = 0.04) projections. Midlateral (-1.43 +/- 3.48% per year; p = 0.0001), lateral (-0.27 +/- 1.68% per year; p = 0.12), and hip (-0.19 +/- 1.02% per year; p = 0.06) BMD decreased, whereas posterior-anterior BMD increased (0.73 +/- 1.11% per year; p = 0.0001) during follow-up. When compared with normal values in 43 men aged 21-42 years, mean T scores were significantly lower with lateral (-1.47 +/- 1.32) and midlateral (-1.57 +/- 1.36) than posterior-anterior (-0.12 +/- 1.30; p < 0.0001) DXA. Only 2.6% of the older men were considered osteoporotic (T score less than or equal to -2.5) at the posterior-anterior spine, whereas 11.0% were osteoporotic at the femoral neck, 22.5% at the lateral spine, and 24.6% were osteoporotic at the midlateral spine. We conclude that supine lateral DXA identifies considerably more men as osteoporotic and is more sensitive to age-related bone loss than posterior-anterior DXA, Spinal osteoporosis may represent a substantially greater health problem among older men than previously recognized. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Family Med & Clin Epidemiol, Pittsburgh, PA USA. Massachusetts Gen Hosp, Dept Med, Endocrine Unit, Boston, MA 02114 USA. RP Zmuda, JM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, 130 DeSoto St, Pittsburgh, PA 15261 USA. RI Cauley, Jane/N-4836-2015; OI Cauley, Jane/0000-0003-0752-4408; Glynn, Nancy/0000-0003-2265-0162 FU NIAMS NIH HHS [1P60 AR44811, AR 35582]; NIDDK NIH HHS [DK 46204] NR 54 TC 40 Z9 46 U1 0 U2 2 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 1200 19TH ST, N W, STE 300, WASHINGTON, DC 20036-2422 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUL PY 2000 VL 15 IS 7 BP 1417 EP 1424 DI 10.1359/jbmr.2000.15.7.1417 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 326YA UT WOS:000087763800022 PM 10893693 ER PT J AU Chen, J Simon, RP Nagayama, T Zhu, R Loeffert, E Watkins, SC Graham, SH AF Chen, J Simon, RP Nagayama, T Zhu, R Loeffert, E Watkins, SC Graham, SH TI Suppression of endogenous bcl-2 expression by antisense treatment exacerbates ischemic neuronal death SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE cerebral ischemia; bcl-2; antisense ID PROGRAMMED CELL-DEATH; TRANSIENT FOREBRAIN ISCHEMIA; CEREBRAL-ARTERY OCCLUSION; DNA FRAGMENTATION; GLOBAL-ISCHEMIA; GENE; RAT; PROTEIN; BAX; HIPPOCAMPUS AB Previous studies have shown that overexpression of bcl-2 in transgenic mice or by viral vectors protects the brain against cerebral ischemia. However, it is not known whether bcl-2, which is endogenously expressed in response to ischemia, exerts a protective effect. To address this question, the authors blocked the endogenous expression of bcl-2 after ischemia using antisense oligodeoxynucleotides (ODN). Antisense, sense, scrambled ODN, or vehicles were infused in the lateral ventricle of the rat for 24 hours after 30 minutes of temporary middle cerebral artery occlusion. Twenty-four hours later the brains were removed and bcl-2 protein expression was assayed by Western blot. Antisense ODN, but not sense or scrambled ODN treatment, significantly inhibited bcl-2 protein expression after ischemia. Bcl-2 protein expression was also studied 24 hours after 60 minutes of temporary middle cerebral artery occlusion in vehicle and antisense ODN-treated rats. After 60 minutes of ischemia and vehicle treatment, bcl-2 was expressed in many neurons in the ventral cortical mantle and the medial striatum. After antisense ODN treatment there were few neurons in this region expressing bcl-2, instead most neurons TUNEL labeled. Treatment with the antisense ODN, but not sense ODN, increased infarction volume as determined by cresyl violet staining 72 hours after ischemia compared with vehicle controls. These results suggested that endogenously expressed bcl-2 promoted survival in ischemic neurons and was not simply an epiphenomenon in neurons already destined to live or die. C1 Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Ctr Biol Imaging, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Cell Biol & Physiol, Pittsburgh, PA 15213 USA. Vet Affairs Pittsburgh Hlth Ctr, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Graham, SH (reprint author), Univ Pittsburgh, Dept Neurol, 526 South BST, Pittsburgh, PA 15213 USA. FU NINDS NIH HHS [R01 NS24728, P01 NS35965] NR 31 TC 55 Z9 62 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUL PY 2000 VL 20 IS 7 BP 1033 EP 1039 PG 7 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 329NX UT WOS:000087914200002 PM 10908036 ER PT J AU Wenzel, R Wobst, P Heekeren, HH Kwong, KK Brandt, SA Kohl, M Obrig, H Dirnagl, U Villringer, A AF Wenzel, R Wobst, P Heekeren, HH Kwong, KK Brandt, SA Kohl, M Obrig, H Dirnagl, U Villringer, A TI Saccadic suppression induces focal hypooxygenation in the occipital cortex SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE neurovascular coupling; focal hypooxygenation; acoustically cued saccades; near-infrared spectroscopy; fMRI; BOLD-contrast ID NEAR-INFRARED SPECTROSCOPY; HUMAN BRAIN-FUNCTION; CEREBRAL BLOOD-FLOW; HUMAN VISUAL-CORTEX; EYE-MOVEMENTS; OPTICAL SPECTROSCOPY; ADULT HEAD; OXYGENATION; STIMULATION; TISSUE AB This study investigated how a decrease in neuronal activity affects cerebral blood oxygenation employing a paradigm of acoustically triggered saccades in complete darkness. Known from behavioral evidence as saccadic suppression, electrophysiologically it has been shown in monkeys that during saccades an attenuation of activity occurs in Visual cortex neurons (Duffy and Burchfiel, 1975). In study A, using blood oxygen level-dependent (BOLD) contrast functional magnetic resonance imaging (fMRI), the authors observed signal intensity decreases bilaterally at the occipital pole during the performance of saccades at 2 Hz. In study B.1, the authors directly measured changes in deoxyhemoglobin [deoxy-Hb] and oxyhemoglobin [oxy-Hb] concentration in the occipital cortex with near-infrared spectroscopy (NIRS). Whereas a rise in [deoxy-Hb] during the performance of saccades occurred, there was a drop in [oxy-Hb]. In a second NIRS study (B.2), subjects performed saccades at different rates (1.6, 2.0, and 2.3 Hz), Here the authors found the increase in deoxy-Kb and the decrease of oxy-Hb to be dependent on the frequency of the saccades. In summary, the authors observed a focal hypooxygenation in the human visual cortex dependent on the saccade-frequency in an acoustically triggered saccades paradigm. This could be interpreted as evidence that corresponding to the focal hyperoxygenation observed in functional brain activation, caused by an excessive increase in cerebral blood flow (CBF) over the increase in CMRO2 during decreased neuronal activity CBF, is more reduced than oxygen delivery. C1 Humboldt Univ, Charite, Dept Neurol, D-10098 Berlin, Germany. Massachusetts Gen Hosp, Magnet Resonance Ctr, Dept Radiol, Charlestown, MA USA. RP Wenzel, R (reprint author), Humboldt Univ, Charite, Dept Neurol, D-10098 Berlin, Germany. RI Ritter, Petra/B-6953-2008; Heekeren, Hauke/B-7739-2008; OI Ritter, Petra/0000-0002-4643-4782; Heekeren, Hauke/0000-0001-7912-6826; Dirnagl, Ulrich/0000-0003-0755-6119 NR 42 TC 53 Z9 53 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD JUL PY 2000 VL 20 IS 7 BP 1103 EP 1110 PG 8 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 329NX UT WOS:000087914200010 PM 10908044 ER PT J AU Laufs, U Endres, M Stagliano, N Amin-Hanjani, S Chui, DS Yang, SX Simoncini, T Yamada, M Rabkin, E Allen, PG Huang, PL Bohm, M Schoen, FJ Moskowitz, MA Liao, JK AF Laufs, U Endres, M Stagliano, N Amin-Hanjani, S Chui, DS Yang, SX Simoncini, T Yamada, M Rabkin, E Allen, PG Huang, PL Bohm, M Schoen, FJ Moskowitz, MA Liao, JK TI Neuroprotection mediated by changes in the endothelial actin cytoskeleton SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NITRIC-OXIDE SYNTHASE; BINDING PROTEIN-RHO; 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE INHIBITORS; SERINE-THREONINE KINASE; MESSENGER-RNA; FOCAL ADHESIONS; PUTATIVE TARGET; DOWN-REGULATION; STRESS FIBERS; SMOOTH-MUSCLE AB Cerebral blood flow is regulated by endothelium-derived nitric oxide (NO), and endothelial NO synthase-deficient (eNOS-deficient; eNOS(-/-)) mice develop larger cerebral infarctions following middle cerebral artery (MCA) occlusion. We report that disruption of Rho-mediated endothelial actin cytoskeleton leads to the upregulation of eNOS expression and reduces the severity of cerebral ischemia following MCA occlusion. Mice treated with the Rho inhibitor Clostridium botulinum C3 transferase (10 mu g/d) or the actin cytoskeleton disrupter cytochalasin D (1 mg/kg) showed a two- to fourfold increase in vascular eNOS expression and activity. This increase in eNOS expression was not due to increases in eNOS gene transcription, but to prolongation of eNOS mRNA half-life from 10 +/- 3 hours to 24 +/- 4 hours. Indeed, endothelial cells overexpressing a dominant-negative Rho mutant (N19RhoA) exhibited decreased actin stress fiber formation and increased eNOS expression. Inhibition of vascular Rho guano sine-5'-triphosphate binding activity by the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin increased cerebral blood flow to ischemic regions of the brain, and mice treated with simvastatin, C3 transferase, or cytochalasin D showed smaller cerebral infarctions following MCA occlusion. No neuroprotection was observed with these agents in eNOS(-/-) mice. These findings suggest that therapies which target the endothelial actin cytoskeleton may have beneficial effects in ischemic stroke. C1 Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Cologne, Innere Med Klin 3, Cologne, Germany. Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA USA. Massachusetts Gen Hosp, Stroke & Neurovasc Regulat Lab, Charlestown, MA USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Expt Med, Boston, MA 02115 USA. RP Liao, JK (reprint author), Brigham & Womens Hosp, Dept Med, Div Cardiovasc, LMRC-322,221 Longwood Ave, Boston, MA 02115 USA. RI Moskowitz, Michael/D-9916-2011; OI Simoncini, Tommaso/0000-0002-2971-0079 FU NHLBI NIH HHS [HL-26202, HL-52233, R01 HL052233]; NINDS NIH HHS [F32 NS010828, NS-10828, P01 NS010828, P50 NS010828] NR 43 TC 201 Z9 216 U1 1 U2 6 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2000 VL 106 IS 1 BP 15 EP 24 DI 10.1172/JCI9639 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 332ZF UT WOS:000088103700004 PM 10880044 ER PT J AU Kishimoto, K Dong, VM Issazadeh, S Fedoseyeva, EV Waaga, AM Yamada, A Sho, M Benichou, G Auchincloss, H Grusby, MJ Khoury, SJ Sayegh, MH AF Kishimoto, K Dong, VM Issazadeh, S Fedoseyeva, EV Waaga, AM Yamada, A Sho, M Benichou, G Auchincloss, H Grusby, MJ Khoury, SJ Sayegh, MH TI The role of CD154-CD40 versus CD28-B7 costimulatory pathways in regulating allogeneic Th1 and Th2 responses in vivo SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID T-CELL COSTIMULATION; RENAL-ALLOGRAFT REJECTION; PRIMARILY VASCULARIZED ALLOGRAFTS; CARDIAC ALLOGRAFTS; PERIPHERAL TOLERANCE; IN-VIVO; TRANSPLANT ARTERIOSCLEROSIS; SIGNAL TRANSDUCER; EFFECTOR-CELLS; INHIBITS TH1 AB We used signal transducer and activator of transcription 4 (STAT4) and STAT6 gene knockout (-/-) mice as recipients of fully mismatched cardiac allografts to study the role of T-cell costimulatory pathways in regulating allogeneic T-helper 1 (Th1) versus Th2 responses in vivo. STAT4(-/-) mice have impaired Th1 responses, whereas STAT6(-/-) mice do not generate normal Th2 responses. Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients. STAT4(-/-) and STAT6(-/-) mice rejected their grafts with the same tempo as untreated WT recipients. CD28-B7 blockade by a single injection of CTLA4Ig induced long-term engraftment and donor-specific tolerance in all three groups of recipients. CD 154 blockade by a single injection of MR1 was effective in prolonging allograft survival and inducing tolerance in STAT4(-/-) mice but was only marginally effective in STAT6(-/-) recipients and WT controls. In addition, a similar protocol of MR1 was ineffective in prolonging graft survival in CD28(-/-) BALB/c recipients, suggesting that the lack of efficacy seen in WT and STAT6(-/-) mice is not due to the presence of a functional CD28-B7 pathway. Furthermore, there was a similar differential effect of CD28-B7 versus CD154-CD40 blockade in inhibiting immune responses in animals immunized with ovalbumin and complete Freund's adjuvant. These novel data indicate that Th1 and Th2 cells are differentially regulated by CD28-B7 versus CD154-CD40 costimulation pathways in vivo and may have potential implications for the development of therapeutic strategies such as T-cell costimulatory blockade in humans. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Lab Immunogenet & Transplantat, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Schepens Eye Res Inst,Cellular & Mol Immunol Lab, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Transplantat Unit, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Harvard Univ, Childrens Hosp, Sch Med, Div Nephrol, Boston, MA 02115 USA. RP Sayegh, MH (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Lab Immunogenet & Transplantat, 75 Francis St, Boston, MA 02115 USA. OI khoury, samia/0000-0003-3198-6063 FU NIAID NIH HHS [R01 AI-34965, R01 AI034965, AI-43496, P01 AI041521, P01 AI-41521, R01 AI043496] NR 60 TC 108 Z9 114 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA ROOM 4570 KRESGE I, 200 ZINA PITCHER PLACE, ANN ARBOR, MI 48109-0560 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUL PY 2000 VL 106 IS 1 BP 63 EP 72 DI 10.1172/JCI9586 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 332ZF UT WOS:000088103700009 PM 10880049 ER PT J AU Fox, JG Chien, CC Dewhirst, FE Paster, BJ Shen, ZL Melito, PL Woodward, DL Rodgers, FG AF Fox, JG Chien, CC Dewhirst, FE Paster, BJ Shen, ZL Melito, PL Woodward, DL Rodgers, FG TI Helicobacter canadensis sp nov isolated from humans with diarrhea as an example of an emerging pathogen SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID PULLORUM; IDENTIFICATION; PHYLOGENY; MICE AB We recently analyzed 11 helicobacter isolates cultured from diarrhea patients in Canada. These isolates had been characterized biochemically by restriction fragment length polymorphism (RFLP; AluI, HhaI) analysis and by fatty-acid analysis as Helicobacter pullorum. However, four of the isolates differed biochemically from H. pullorum by their inability to hydrolyze indoxyl acetate and their resistance to nalidixic acid. Using complete 16S rRNA analysis, we determined that these four strains clustered near H. pullorum but had a sequence difference of 2% and therefore represent a novel helicobacter, Helicobacter canadensis. This novel helicobacter could also be distinguished from Ii pullorum by RFLP analysis using ApaLI. The number of novel Helicobacter spp, associated with gastrointestinal disease in humans and animals is rapidly increasing. There are now six Helicobacter spp, isolated from diarrheic humans, the other five being Ii. pullorum, Ii. canis, "H, rappini," Ii fennelliae, and Ii cinaedi. This finding highlights the importance of careful molecular analysis in addition to standard biochemical tests in identifying the increasing number of Helicobacter spp, isolated from humans and animals. C1 MIT, Div Comparat Med, Cambridge, MA 02139 USA. Natl Lab Enter Pathogens, Winnipeg, MB, Canada. Forsyth Inst, Boston, MA USA. RP Fox, JG (reprint author), MIT, Div Comparat Med, 77 Massachusetts Ave,Bldg 16,Rm 825C, Cambridge, MA 02139 USA. FU NCI NIH HHS [R01 CA067529, R01CA67529]; NCRR NIH HHS [RR-01046]; NIDDK NIH HHS [R01DK52413, R01 DK052413] NR 17 TC 77 Z9 80 U1 0 U2 2 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 JUL PY 2000 VL 38 IS 7 BP 2546 EP 2549 PG 4 WC Microbiology SC Microbiology GA 331WR UT WOS:000088042100016 PM 10878041 ER PT J AU Hanna, GJ Johnson, VA Kuritzkes, DR Richman, DD Martinez-Picado, J Sutton, L Hazelwood, JD D'Aquila, RT AF Hanna, GJ Johnson, VA Kuritzkes, DR Richman, DD Martinez-Picado, J Sutton, L Hazelwood, JD D'Aquila, RT TI Comparison of sequencing by hybridization and cycle sequencing for genotyping of human immunodeficiency virus type 1 reverse transcriptase SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID CONTROLLED TRIAL; IN-VIVO; RESISTANCE; HIV; THERAPY; GENE; POL; POLYMORPHISMS; PERFORMANCE; ZIDOVUDINE AB The performances of two methods of nucleotide sequencing were compared for the detection of drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase (RT) in viruses isolated from highly RT inhibitor-experienced individuals. Of 11,677 amino acids deduced from population PCR products by both cycle sequencing and sequencing by hybridization to high-density arrays of oligonucleotide probes, 97.4% were concordant by both methods, 0.8% were discordant, and 1.7% had an ambiguous determination by at least one method. A higher rate of discordance (3.9%) was observed among RT inhibitor resistance-associated codons, In 45% of the isolates, RT codon 67 was deduced as the wild-type Asp by hybridization sequencing but as the zidovudine resistance-associated Asn by cycle sequencing. In other resistance-associated codon discordances, cycle sequencing also more commonly called a known resistance-associated amino acid than hybridization sequencing did. The nucleotide sequence in the vicinity of several codons with discordant calls influenced population-based hybridization sequencing. For isolates evaluated by additional sequencing of molecular clones of PCR products by both methods, the discordance between methods was less frequent (0.4% of all 5,994 amino acids and 0 of 494 drug resistance-associated codons), At positions which were discordant or ambiguous in the population sequences, the results of sequencing of clones by both methods were usually in agreement with the population cycle sequencing result, In summary, most RT codons were highly concordant by both methods of population-based sequencing, with discordances due in large part to genetic mixtures within or adjacent to discordant codons. C1 Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA USA. Univ Alabama, Sch Med, Birmingham, AL USA. Vet Affairs Med Ctr, Birmingham, AL USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Vet Affairs Med Ctr, Denver, CO USA. Univ Calif San Diego, San Diego, CA 92103 USA. Vet Affairs Med Ctr, San Diego, CA 92161 USA. Fundacio IrsiCaixa, Barcelona, Spain. RP D'Aquila, RT (reprint author), Massachusetts Gen Hosp, Infect Dis Unit, 149 13th St, Charlestown, MA 02129 USA. RI Martinez-Picado, Javier/G-5507-2012 OI Martinez-Picado, Javier/0000-0002-4916-2129 FU NCRR NIH HHS [M01 RR000051]; NIAID NIH HHS [U01 AI032775, AI01696, AI07387, AI29193, P30 AI027767, P30 AI036214, R01 AI029193, R01 AI042567, R37 AI029164, T32 AI007387, U01 AI027659, U01 AI027670, U01 AI032770, U01 AI038858] NR 19 TC 18 Z9 19 U1 0 U2 1 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 JUL PY 2000 VL 38 IS 7 BP 2715 EP 2721 PG 7 WC Microbiology SC Microbiology GA 331WR UT WOS:000088042100044 PM 10878069 ER PT J AU Burstein, HJ AF Burstein, HJ TI Discussing complementary therapies with cancer patients: What should we be talking about? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID ALTERNATIVE MEDICINE; UNITED-STATES; PREVALENCE C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Burstein, HJ (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 19 TC 49 Z9 49 U1 2 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 JUL PY 2000 VL 18 IS 13 BP 2501 EP 2504 PG 4 WC Oncology SC Oncology GA 330AL UT WOS:000087940600001 PM 10893279 ER PT J AU Grupp, SA Stern, JW Bunin, N Nancarrow, C Ross, AA Mogul, M Adams, R Grier, HE Gorlin, JB Shamberger, R Marcus, K Neuberg, D Weinstein, HJ Diller, L AF Grupp, SA Stern, JW Bunin, N Nancarrow, C Ross, AA Mogul, M Adams, R Grier, HE Gorlin, JB Shamberger, R Marcus, K Neuberg, D Weinstein, HJ Diller, L TI Tandem high-dose therapy in rapid sequence for children with high-risk neuroblastoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID BONE-MARROW TRANSPLANTATION; STEM-CELL TRANSPLANTATION; PROGRESSION-FREE SURVIVAL; METASTATIC BREAST-CANCER; PEDIATRIC-PATIENTS; PROGENITOR CELLS; INTENSIVE CHEMOTHERAPY; VENOOCCLUSIVE DISEASE; SOLID TUMORS; LEUKAPHERESIS AB Purpose: Advances in chemotherapy and supportive care have slowly improved survival rates for patients with high-risk neuroblastoma. The focus of many of these chemotherapeutic advances has been dose intensification. In this phase II trial involving children with advanced neuroblastoma, we used a program of induction chemotherapy followed by tandem high-dose, myeloablative treatments (high-dose therapy) with stem-cell rescue (HDT/SCR) in rapid sequence. Patients and Methods: Patients underwent induction chemotherapy during which peripheral-blood stem and progenitor cells were collected and local control measures undertaken. Patients then received tandem courses of HDT/SCR, 4 to 6 weeks apart. Thirty-nine patients (age 1 to 12 years) were assessable, and 70 cycles of HDT/SCR were completed. Results: Pheresis wets possible in the case of all patients, despite their young ages, with an average of 7.2 x 10(6) CD34(+) cells/kg available to support each cycle. Engraftment was rapid; median time to neutrophil engraftment was 11 days. Four patients who completed the first HDT course did not complete the second, and there were three deaths due to toxicity. With a median follow-up of 22 months (from diagnosis), 26 of 39 patients remained event-free. The 3-year event-free survival rate for these patients was 58%. Conclusion: A tandem HDT/SCR regimen for highrisk neuroblastoma is a feasible treatment strategy for children and may improve disease-free survival. J Clin Oncol 18:2567-2575. (C) 2000 by American Society of Clinical Oncology. C1 Univ Penn, Childrens Hosp Philadelphia, Sch Med,Dept Pediat, Div Oncol, Philadelphia, PA 19104 USA. Nexell Therapeut Inc, Irvine, CA USA. Emory Univ, Atlanta, GA 30322 USA. Univ Utah, Hlth Sci Ctr, Primary Childrens Hosp, Salt Lake City, UT USA. Childrens Hosp, Dept Med, Boston, MA 02115 USA. Childrens Hosp, Dept Surg, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Div Pediat Hematol Oncol, Boston, MA 02114 USA. Univ Minnesota, Minneapolis, MN USA. Mem Blood Ctrs Minnesota, Minneapolis, MN USA. RP Grupp, SA (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med,Dept Pediat, Div Oncol, 324 S 34th St, Philadelphia, PA 19104 USA. NR 37 TC 72 Z9 72 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 JUL PY 2000 VL 18 IS 13 BP 2567 EP 2575 PG 9 WC Oncology SC Oncology GA 330AL UT WOS:000087940600010 PM 10893288 ER PT J AU Meyerson, M AF Meyerson, M TI Role of telomerase in normal and cancer cells SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID CATALYTIC SUBUNIT GENE; HUMAN EPITHELIAL-CELLS; HUMAN TUMOR-CELLS; REVERSE-TRANSCRIPTASE; MOUSE TELOMERASE; HUMAN FIBROBLASTS; HUMAN-CHROMOSOMES; RNA COMPONENT; LIFE-SPAN; BLADDER-CARCINOMA AB Shortening of the telomeric DNA at chromosome ends is postulated to limit the lifespan of human cells. In contrast, activation of telomerase, the enzyme that synthesizes telomeric DNA, is proposed to be an essential step in cancer cell immortalization and cancer progression. This review discusses the structure and function of telomeres and telomerase, the role of telomerase in cell immortalization, and the effects of telomerase inactivation on normal and cancer cells. Moreover, data on the experimental use of telomerase assays for cancer detection and diagnosis are reviewed. Finally, the review considers the evidence regarding whether telomerase inhibitors could be used to treat human cancers. J Clin Oncol 78:2626-2634. (C) 2000 by American Society of Clinical Oncology. 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 Pathol, Boston, MA 02115 USA. RP Meyerson, M (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Mayer Bldg 430,44 Binney St, Boston, MA 02115 USA. RI Meyerson, Matthew/E-7123-2012 NR 114 TC 131 Z9 148 U1 1 U2 6 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 JUL PY 2000 VL 18 IS 13 BP 2626 EP 2634 PG 9 WC Oncology SC Oncology GA 330AL UT WOS:000087940600018 PM 10893296 ER PT J AU Partridge, A Nasser, S Dzik, S AF Partridge, A Nasser, S Dzik, S TI Nonmalignant diagnoses in patients - Case 1. Mediastinal lymphadenopathy associated with congestive heart failure SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CT FINDINGS C1 Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dana Farber Canc Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Partridge, A (reprint author), Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. NR 5 TC 3 Z9 3 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 JUL PY 2000 VL 18 IS 13 BP 2635 EP 2636 PG 2 WC Oncology SC Oncology GA 330AL UT WOS:000087940600019 PM 10893297 ER PT J AU Partridge, A Mcmenamin, M Sugarbaker, D AF Partridge, A Mcmenamin, M Sugarbaker, D TI Nonmalignant diagnoses in patients - Case 2. Lung cancer with mediastinal lymphadenopathy due to amyloidosis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LYMPH-NODES; LESIONS C1 Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Partridge, A (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. NR 8 TC 4 Z9 4 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 JUL PY 2000 VL 18 IS 13 BP 2636 EP 2637 PG 2 WC Oncology SC Oncology GA 330AL UT WOS:000087940600020 PM 10893298 ER PT J AU Oh, WK Lee, BH Sweitzer, NK AF Oh, WK Lee, BH Sweitzer, NK TI Nonmalignant diagnoses in patients - Case 2. Right atrial thrombus associated with a central venous catheter in a patient with metastatic adrenocortical carcinoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CHILDREN; INFANTS C1 Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Oh, WK (reprint author), Brigham & Womens Hosp, Dana Farber Canc Inst, 75 Francis St, Boston, MA 02115 USA. RI Oh, William/B-9163-2012 OI Oh, William/0000-0001-5113-8147 NR 9 TC 0 Z9 0 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 JUL PY 2000 VL 18 IS 13 BP 2638 EP 2639 PG 2 WC Oncology SC Oncology GA 330AL UT WOS:000087940600021 PM 10893299 ER PT J AU Kulke, MH AF Kulke, MH TI The treatment of advanced gastric cancer: In search of the right combination SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PHASE-II; SUPPORTIVE CARE; CHEMOTHERAPY; DOXORUBICIN; CISPLATIN; 5-FLUOROURACIL; METHOTREXATE; FLUOROURACIL; CARCINOMA; ETOPOSIDE C1 Dana Farber Canc Inst, Boston, MA 02115 USA. RP Kulke, MH (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. NR 28 TC 9 Z9 10 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 JUL PY 2000 VL 18 IS 14 BP 2645 EP 2647 PG 3 WC Oncology SC Oncology GA 335UF UT WOS:000088262600001 PM 10894862 ER PT J AU Baidas, SM Winer, EP Fleming, GF Harris, L Pluda, JM Crawford, JG Yamauchi, H Isaacs, C Hanfelt, J Tefft, M Flockhart, D Johnson, MD Hawkins, MJ Lippman, ME Hayes, DF AF Baidas, SM Winer, EP Fleming, GF Harris, L Pluda, JM Crawford, JG Yamauchi, H Isaacs, C Hanfelt, J Tefft, M Flockhart, D Johnson, MD Hawkins, MJ Lippman, ME Hayes, DF TI Phase II evaluation of thalidomide in patients with metastatic breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; HUMAN-IMMUNODEFICIENCY-VIRUS; TUMOR ANGIOGENESIS; APHTHOUS ULCERS; CARCINOMA; PHARMACOKINETICS; DEGRADATION; RECURRENT; INHIBITOR; PLASMA AB Purpose: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. Patients and Methods: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg, Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. Results: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia, Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. Conclusion: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels. (C) 2000 by American Society of Clinical Oncology. C1 Georgetown Univ, Ctr Med, Vincent T Lombardi Canc Res Ctr, Breast Canc Program, Washington, DC 20007 USA. Georgetown Univ, Ctr Med, Vincent T Lombardi Canc Res Ctr, Dev Therapeut Program, Washington, DC 20007 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Duke Univ, Med Ctr, Durham, NC USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Baidas, SM (reprint author), Georgetown Univ, Ctr Med, Vincent T Lombardi Canc Res Ctr, Breast Canc Program, 3800 Reservoir Rd,NW, Washington, DC 20007 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 40 TC 92 Z9 93 U1 0 U2 1 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 JUL PY 2000 VL 18 IS 14 BP 2710 EP 2717 PG 8 WC Oncology SC Oncology GA 335UF UT WOS:000088262600009 PM 10894870 ER PT J AU Lu, KH Garber, JE Cramer, DW Welch, WR Niloff, J Schrag, D Berkowitz, RS Muto, MG AF Lu, KH Garber, JE Cramer, DW Welch, WR Niloff, J Schrag, D Berkowitz, RS Muto, MG TI Occult ovarian tumors in women with BRCA1 or BRCA2 mutations undergoing prophylactic oophorectomy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CANCER; BREAST; CARCINOMA; FAMILIES; CARRIERS; GENES; RISK AB Purpose: to review the findings at prophylactic oophorectomy of a series of women who presented to a familial breast and ovarian cancer clinic. Materials and Methods: Data from medical charts, operative notes, and pathology reports were collected on women who had undergone prophylactic oophorectomies because of the elevated risk of ovarian cancer. Because only a subset of patients underwent BRCA1 and BRCA2 testing, each patient's risk of hereditary predisposition was calculated using the Berry-Parmigiani model and family history data. Results: From June 1989 to December 1998, 50 women seen at our clinic underwent prophylactic oophorectomy, 33 of whom had a calculated risk of carrying a germline BRCA1 or BRCA2 mutation greater than 25%, Among this group, four incidental tumors were found (four of 33, or 12%); one tumor was noted at the time of surgery and three were noted only in the final pathology. Two patients had microscopic, poorly differentiated serous adenocarcinomas in multiple sites on both ovaries. A third patient had a bilateral serous borderline tumor with micropapillary features, The fourth patient had a microscopic serous borderline ovarian tumor. All four patients had germline BRCA1 or BRCA2 mutations, and three had unremarkable transvaginal ultrasonagraphy examinations within 6 months before prophylactic surgery. Conclusion: Foci of malignant tumor are not uncommon in prophylactic oophorectomies performed in women at very high risk for ovarian cancer and may not be detected on ultrasonograms. Surgeons should have a high suspicion of finding cancer in these women at the time of prophylactic surgery, and careful pathologic assessment of the specimens should be conducted. (C) 2000 by American Society of Clinical Oncology. C1 Dana Farber Canc Inst, Gillette Ctr Womens Canc, Div Canc Epidemiol & Control, Canc Risk & Prevent Program,Familial Ovarian Canc, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Obstet Gynecol & Reprod Biol, Div Gynecol Oncol, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctt, Div Gynecol Oncol, Boston, MA USA. RP Lu, KH (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, 1515 Holcombe Blvd,Box 67, Houston, TX 77030 USA. NR 15 TC 111 Z9 113 U1 0 U2 1 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 JUL PY 2000 VL 18 IS 14 BP 2728 EP 2732 PG 5 WC Oncology SC Oncology GA 335UF UT WOS:000088262600011 PM 10894872 ER PT J AU Cremieux, PY Barrett, B Anderson, K Slavin, MB AF Cremieux, PY Barrett, B Anderson, K Slavin, MB TI Cost of outpatient blood transfusion in cancer patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RECOMBINANT-HUMAN-ERYTHROPOIETIN; ANEMIA AB Purpose: To determine the cost of outpatient RBC transfusion from the provider's perspective at a major urban, academic cancer center. Patients and Methods: We retrospectively studied 517 cancer patients with hematologic or solid tumors who received blood during fiscal year 1995 to 1996, A process-flow diagram was developed, and cost and utilization data for 12 months were collected and analyzed. A structured interview process was used to identify all direct and indirect costs from within the inpatient unit, blood bank, and outpatient clinic. Average costs were computed for the entire sample and for specific subgroups. Results: In 1998 dollars, the average cost per RBC unit was $469 for adults and $568 for pediatric cancer patients. Adults and children generally received two and one RBC units per transfusion, respectively. Therefore, the average cost of a two-unit transfusion was $938 for adults. Patients with hematologic rumors required more RBC units (7.1 RBC units per year) at a higher average cost ($512 per RBC unit) than patients with solid tumors (4.7 RBC units per year, $474 per RBC unit). Further variations across tumor types were observed. Overhead, direct material, and direct labor represented 46%, 19%, and 35% of total costs respectively. Conclusion: The cost of outpatient RBC transfusions in cancer patients is higher than previously reported, in part because overhead costs and fixed costs might have been underestimated in previous studies. Furthermore, age, tumor type, and geographic variations in the cost of fixed assets and labor have a substantial impact on the cost of blood. The results indicate that the cost-effectiveness of alternatives to transfusions in the management of cancer patients may have been underestimated in the existing literature. (C) 2000 by American Society of Clinical Oncology. C1 Anal Grp Econ, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Quebec, Montreal, PQ H3C 3P8, Canada. Ortho Biotech Inc, Raritan, NJ USA. RP Cremieux, PY (reprint author), Anal Grp Econ, 1 Brattle Sq,5th Floor, Cambridge, MA 02138 USA. NR 5 TC 76 Z9 78 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 JUL PY 2000 VL 18 IS 14 BP 2755 EP 2761 PG 7 WC Oncology SC Oncology GA 335UF UT WOS:000088262600015 PM 10894876 ER PT J AU Tanner, ACR Kent, RL Maiden, MFJ Macuch, PJ Taubman, MA AF Tanner, ACR Kent, RL Maiden, MFJ Macuch, PJ Taubman, MA TI Serum IgG reactivity to subgingival bacteria in initial periodontitis, gingivitis and healthy subjects SO JOURNAL OF CLINICAL PERIODONTOLOGY LA English DT Article DE initial periodontitis; health; gingivitis; serum antibodies; periodontal disease; immunology; microbiology ID ATTACHMENT LOSS; ANTIBODY; DISEASES; GINGIVALIS; RECESSION; AVIDITY AB Background/aims: Established periodontal diseases may be associated with antibody responses to periodontal pathogens, but it is not known at which stage of disease this antibody response is initiated. This study aimed to characterize the host systemic response in initial periodontitis, gingivitis, and periodontal health, to evaluate whether elevated serum antibodies to subgingival species could be detected in initial periodontitis. Method: Human systemic immune response were evaluated to 40 subgingival bacterial species in 16 healthy, 21 gingivitis, 11 initial periodontitis and 5 progressing recession adults. Subjects had minimal periodontal attachment level (AL) loss at baseline. Disease categories were determined after 12 months monitoring at three-month intervals. Increased AL loss greater than or equal to 1.5 mm (disease activity) at interproximal sites defined initial periodontitis, recession was characterized by AL loss at buccal sites. Serum IgG antibodies were evaluated semi-quantitatively by immunoblot from blood taken at baseline, active and final visits. Results: No antibody was detected from 55% of reactions. When detected, levels were below those reported for advanced periodontitis subjects. There were no major differences in serum antibody levels between healthy, gingivitis and initial periodontitis subjects, despite differences in the subgingival microbiota. Serum antibodies for more species were detected in recession subjects, compared with the other study subjects. No changes in antibody levels were detected between baseline, active, and final visits. No systematic association between species colonization and presence of systemic antibody was observed. Conclusions: This study did not detect differential elevation of mean serum antibody levels in initial periodontitis subjects, suggesting that serum antibody levels are not sensitive risk markers for initial periodontitis. C1 Forsyth Inst, Boston, MA 02115 USA. RP Tanner, ACR (reprint author), Forsyth Inst, 140 Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE 03420, DE 09513] NR 24 TC 10 Z9 11 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0303-6979 J9 J CLIN PERIODONTOL JI J. Clin. Periodontol. PD JUL PY 2000 VL 27 IS 7 BP 473 EP 480 DI 10.1034/j.1600-051x.2000.027007473.x PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 329HE UT WOS:000087900900003 PM 10914887 ER PT J AU McGrath, PJ Stewart, JW Petkova, E Quitkin, FM Amsterdam, JD Fawcett, J Reimherr, FW Rosenbaum, JF Beasley, CM AF McGrath, PJ Stewart, JW Petkova, E Quitkin, FM Amsterdam, JD Fawcett, J Reimherr, FW Rosenbaum, JF Beasley, CM TI Predictors of relapse during fluoxetine continuation or maintenance treatment of major depression SO JOURNAL OF CLINICAL PSYCHIATRY LA English DT Article ID POPULATION-BASED SAMPLE; TRUE DRUG RESPONSE; PATTERN-ANALYSIS; ATYPICAL DEPRESSION; RECURRENT DEPRESSION; FEMALE TWINS; LONG; DISORDER; EFFICACY; THERAPY AB Background: The goal was to examine predictors of relapse during continuation/maintenance treatment of major depression that had remitted following 12 to 14 weeks of fluoxetine therapy. Method: The study utilizes data collected in a collaborative clinical trial including patients with DSM-III-R major depression at 5 university-affiliated outpatient psychiatry clinics. Three hundred ninety-five patients who remitted with fluoxetine therapy were randomly assigned to 1 of 4 treatments: fluoxetine for 14 weeks followed by placebo for 36 weeks, fluoxetine for 38 weeks followed by placebo for 12 weeks, fluoxetine for 50 weeks, or placebo for 50 weeks. Cox proportional hazard models were used to identify predictors of time to relapse. Results: In addition to the previously reported longitudinal pattern of response during acute treatment, neurovegetative symptom pattern was a predictor of fluoxetine benefit compared with placebo. Greater chronicity predicted poorer survival, which was not differential by treatment. The most robust advantage of fluoxetine was seen for patients with endogenous vegetative symptoms, chronic depression, and acute treatment response characterized by onset in the third week or later and persistence of response once attained. Conclusion: Both nonspecific pattern of response and neurovegetative symptoms characteristic of atypical depression were predictive of lack of fluoxerine efficacy in continuation/maintenance treatment. These findings have importance for both clinical management and analyses of future maintenance trials. C1 New York State Psychiat Inst, Unit 51, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10027 USA. Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Rush Med Ctr, Dept Psychiat, Chicago, IL USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Univ Utah, Dept Psychiat, Salt Lake City, UT USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP McGrath, PJ (reprint author), New York State Psychiat Inst, Unit 51, 1052 Riverside Dr, New York, NY 10032 USA. RI McGrath, Patrick/I-6410-2013; OI McGrath, Patrick/0000-0001-7217-7321; Beasley, Charles/0000-0001-8743-7691 NR 42 TC 50 Z9 52 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 JUL PY 2000 VL 61 IS 7 BP 518 EP 524 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 341KK UT WOS:000088589400010 PM 10937611 ER PT J AU Murray, RE Tancredi, DN Nadel, ES Brown, DFM Benzer, T Peak, D Finkel, M Legome, E Biddinger, P AF Murray, RE Tancredi, DN Nadel, ES Brown, DFM Benzer, T Peak, D Finkel, M Legome, E Biddinger, P TI Syncope in pregnancy SO JOURNAL OF EMERGENCY MEDICINE LA English DT Article ID PULMONARY ARTERIOVENOUS-MALFORMATIONS C1 Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Brigham & Womens Hosp, Dept Emergency Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Emergency Med, Harvard Affiliated Emergency Med Residency, Boston, MA USA. RP Brown, DFM (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, 55 Fruit St, Boston, MA 02114 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0736-4679 J9 J EMERG MED JI J. Emerg. Med. PD JUL PY 2000 VL 19 IS 1 BP 57 EP 61 DI 10.1016/S0736-4679(00)00191-8 PG 5 WC Emergency Medicine SC Emergency Medicine GA 324EV UT WOS:000087609600011 PM 10863120 ER PT J AU Fihn, SD Schleyer, AM Kelly-Hedrick, H Martin, DB AF Fihn, SD Schleyer, AM Kelly-Hedrick, H Martin, DB TI Effects of the revised HCFA evaluation and management guidelines on inpatient teaching SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 22nd Annual Meeting of the Society-of-General-Internal-Medicine CY APR 29-MAY 01, 1999 CL SAN FRANCISCO, CALIFORNIA SP Soc Gen Internal Med DE medical education; teaching; Medicare AB OBJECTIVE: In 1996, the Health Care Financing Administration (HCFA) introduced new evaluation and management (E&M) guidelines mandating more intensive supervision and documentation by attending physicians. We assessed the effects of the guidelines on inpatient teaching. DESIGN: Pretest-posttest, nonequivalent control group design. SETTING: A university hospital and an affiliated county hospital where the guidelines were implemented and an affiliated VA medical center where they were not. PARTICIPANTS: Sixty-one full-time faculty who had attended on the general medical wards for at least 1 month for 2 of 3 consecutive years prior to July 1996 and for at least 1 month during the 18 following months. MEASUREMENTS AND MAIN RESULTS: We evaluated standardized, confidential evaluations of attending physicians that are routinely completed by residents and students after clinical rotations at all three sites. Comparing 863 evaluations completed before July 1, 1996 and 497 completed after that date, there were no significant differences at any of the hospitals on any items assessed. There were also no differences between the university and county hospitals as compared with the VA. Eighty-seven percent of 39 university and county attending physicians returned a survey about their perceptions of inpatient teaching activities before and after July 1, 1996. They reported highly significant increases in time devoted to attending responsibilities but diminished time spent on teaching activities. CONCLUSIONS: Physicians reported a dramatic increase in overall time spent attending but a decrease in time spent teaching following implementation of the revised E&M guidelines. Yet, evaluations of their teaching effectiveness did not change. C1 VA Puget Sound Hlth Care Syst, Ctr Excellence 152, Seattle, WA 98108 USA. Univ Washington, Seattle, WA 98195 USA. RP Fihn, SD (reprint author), VA Puget Sound Hlth Care Syst, Ctr Excellence 152, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 9 TC 9 Z9 9 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2000 VL 15 IS 7 BP 451 EP 456 DI 10.1046/j.1525-1497.2000.07001.x PG 6 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 336LL UT WOS:000088302700002 PM 10940130 ER PT J AU Jablonover, RS Blackman, DJ Bass, EB Morrison, G Goroll, AH AF Jablonover, RS Blackman, DJ Bass, EB Morrison, G Goroll, AH TI Evaluation of a national curriculum reform effort for the medicine core clerkship SO JOURNAL OF GENERAL INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 22nd Annual Meeting of the Society-of-General-Internal-Medicine CY APR 29-MAY 01, 1999 CL SAN FRANCISCO, CALIFORNIA SP Soc Gen Internal Med DE evaluation; medical education; curriculum reform; medicine core clerkship ID INTERNAL-MEDICINE; UNITED-STATES; EDUCATION AB BACKGROUND: In 1995, the Society of General Internal Medicine (SGIM) and the Clerkship Directors in Internal Medicine (CDIM) developed and disseminated a new model curriculum for the medicine core clerkship that was designed to enhance learning of generalist competencies and increase interest in general internal medicine. OBJECTIVE: To evaluate the dissemination and use of the resulting SGIM/CDIM Core Medicine Clerkship Curriculum Guide. DESIGN: Survey of internal medicine clerkship directors at the 125 medical schools in the United States. MEASUREMENTS AND MAIN RESULTS: The questionnaire elicited information about the use and usefulness of the Guide and each of its components, barriers to effective use of the Guide, and outcomes associated with use of the Guide. Responses were received from 95 clerkship directors, representing 88 (70%) of the 125 medical schools. Eighty-seven (92%) of the 95 respondents were familiar with the Guide, and 80 respondents had used it. The 4 components used most frequently were the basic generalist competencies (used by 83% of those familiar with the Guide), learning objectives for these competencies (used by 83%), learning objectives for training problems (used by 70%), and specific training problems (used by 67%); 74% to 85% of those using these components found them moderately or very useful. The most frequently identified barriers to use of the Guide were insufficient faculty time, insufficient number of ambulatory care preceptors and training sites, and need for more faculty development. About 30% or more of those familiar with the Guide reported that use of the Guide was associated with improved ability to meet clerkship accreditation criteria, improved performance of students on the clerkship exam, and increased clerkship time devoted to ambulatory care. CONCLUSION: This federally supported initiative that engaged the collaborative efforts of the SGIM and the CDIM was successful in facilitating significant changes in the medicine core clerkship across the United States. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. RP Jablonover, RS (reprint author), MCP Ambulatory Med Grp, Associate Residency Program, 3300 Henry Ave,4th Floor, Philadelphia, PA 19129 USA. NR 33 TC 20 Z9 21 U1 1 U2 3 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0884-8734 J9 J GEN INTERN MED JI J. Gen. Intern. Med. PD JUL PY 2000 VL 15 IS 7 BP 484 EP 491 DI 10.1046/j.1525-1497.2000.06429.x PG 8 WC Health Care Sciences & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 336LL UT WOS:000088302700007 PM 10940135 ER PT J AU He, SQ Weston, MW Lemmon, J Jensen, M Levine, RA Yoganathan, AP AF He, SQ Weston, MW Lemmon, J Jensen, M Levine, RA Yoganathan, AP TI Geometric distribution of chordae tendineae: An important anatomic feature in mitral valve function SO JOURNAL OF HEART VALVE DISEASE LA English DT Article ID LEFT-VENTRICULAR SHAPE; SYSTOLIC ANTERIOR MOTION; HEART-FAILURE; DILATED CARDIOMYOPATHY; INTEGRATED MECHANISM; IN-VITRO; REGURGITATION; REPLACEMENT; ECHOCARDIOGRAPHY; PRESERVATION AB Background and aim of the study: This study examined the geometric distribution of chordae tendineae and their importance in compensating for papillary muscle (PM) displacement. Methods: Anatomic, chordal mechanics and hemodynamic measurements were performed with porcine mitral valves. For hemodynamic measurements, physiological pulsatile flow conditions were maintained, and PM positions varied. Leaflet coaptation was documented by 2-D echocardiography, and regurgitation measured directly. Results: Anatomic measurements showed the sum of marginal leaflet and marginal chordal lengths to exceed basal chordal length (1.8 +/- 0.4 versus 2.8 +/- 0.7 cm for anterior leaflets; 1.6 +/- 0.3 versus 2.5 +/- 0.6 cm for posterior leaflets). Triangular structures existed between basal chordae and marginal chordae with the marginal leaflet as the third side. Basal chordae resisted apical PM displacement in static experiments, while marginal chordae governed leaflet closure in hemodynamic experiments. Under pulsatile flow conditions, apical PM displacement decreased leaflet coaptation length and increased regurgitation (9.4 +/- 2.1 versus 4.0 +/- 1.6 mi). When marginal chordae were fused to the basal chordae, eliminating the role of the marginal chordae, severe regurgitation resulted (28.5 +/- 5.0 mi with apical PM displacement). Conclusion: Based on triangular structures involving the basal and marginal chordae, a compensatory mechanism was described which explains how the severity of mitral regurgitation can vary following PM displacement. Basal chordae provide a constant connection between the annulus and papillary muscles, while marginal chordae maintain marginal leaflet flexibility, governing proper valve closure. This study relates chordal distribution to normal valve function, and provides a better understanding of breakdown in valve function under pathophysiological conditions. C1 Georgia Inst Technol, Sch Biomed Engn, Atlanta, GA 30332 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA USA. RP Yoganathan, AP (reprint author), Georgia Inst Technol, Sch Biomed Engn, 315 Ferst Dr, Atlanta, GA 30332 USA. FU NHLBI NIH HHS [HL52009] NR 26 TC 31 Z9 33 U1 1 U2 3 PU I C R PUBLISHERS PI NORTHWOOD PA CRISPIN HOUSE, 12/A SOUTH APPROACH, MOOR PARK, NORTHWOOD, ENGLAND HA6 2ET SN 0966-8519 J9 J HEART VALVE DIS JI J. Heart Valve Dis. PD JUL PY 2000 VL 9 IS 4 BP 495 EP 501 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 337CL UT WOS:000088339800005 PM 10947041 ER PT J AU Rioux, KP Beck, PL Hoppin, AG Ezedi, I Kaplan, L Le, T Swain, MG AF Rioux, KP Beck, PL Hoppin, AG Ezedi, I Kaplan, L Le, T Swain, MG TI Differential leptin responses to acute and chronic biliary obstruction in rats SO JOURNAL OF HEPATOLOGY LA English DT Article DE cholestasis; cytokine; feeding behavior; leptin ID BODY-WEIGHT REGULATION; NEUROPEPTIDE-Y; OBESE GENE; ANOREXIA; EXPRESSION; MICE; ENDOTOXIN; CYTOKINES; PRODUCT AB Background/Aims: Recently leptin, a protein released from adipocytes, has been identified as a potent circulating satiety factor. We therefore undertook this series of experiments to examine leptin's role in the anorexia associated with biliary obstruction. Methods: Rats underwent either surgical bile duct resection (BDR) or sham resection (sham). Body weight, and food and water intake were measured during a baseline period and for 8 days after surgery. At 4, 8 and 16 h as well as on days 2, 4, 6, and 8 post-surgery, sham and BDR rats were sacrificed and sera collected for subsequent measurement of leptin hormone concentration by RIA. White adipose tissue was collected on days 2, 4, 6 and 8 for leptin mRNA determination by Northern blot. Results: Obstructive cholestasis in BDR rats caused significant anorexia for up to 7 days post-surgery, whereas in sham rats, a significant decrease in food intake was only observed in the first 24-h period following surgery. In both sham and BDR rats, water intake was significantly decreased during the first 24-h period after surgery, but had recovered to base-line levels by day 2 in both groups. Fat pad mass corrected to body weight was not significantly different between the two experimental groups. Serum leptin levels were significantly increased 4 and 8 h after surgery, had normalized by 16 h post-surgery, and were then decreased in BDR rats on days 2, 4, 6 and 8 compared with controls. Leptin mRNA levels in epididymal fat pads were decreased by approximately 2-fold in BDR rats compared with sham rats on days 2, 4, 6 and 8. Furthermore, day 5 BDR and sham rats demonstrated similar anorectic responses to centrally administered leptin. Conclusions: Leptin production is significantly increased early after biliary obstruction but is reduced after prolonged biliary obstruction. Increased circulating leptin levels may contribute to the profound anorexia observed early after biliary obstruction but appear not to mediate the anorexia observed during more chronic biliary obstruction. C1 Univ Calgary, Hlth Sci Ctr, Fac Med, Gastrointestinal Res Grp,Liver Unit, Calgary, AB T2N 4N1, Canada. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA USA. RP Swain, MG (reprint author), Univ Calgary, Hlth Sci Ctr, Fac Med, Gastrointestinal Res Grp,Liver Unit, 3330 Hosp Dr NW, Calgary, AB T2N 4N1, Canada. FU NIDDK NIH HHS [DKO 7191] NR 26 TC 4 Z9 5 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0168-8278 J9 J HEPATOL JI J. Hepatol. PD JUL PY 2000 VL 33 IS 1 BP 19 EP 25 DI 10.1016/S0168-8278(00)80154-3 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 329FN UT WOS:000087896400004 PM 10905581 ER PT J AU Rosowsky, A Fu, HN Queener, SF AF Rosowsky, A Fu, HN Queener, SF TI Synthesis of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4-diaminoquinazolines with bulky dibenz[b,f]azepine and dibenzo[a,d]-cycloheptene substituents at the 6-position as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium SO JOURNAL OF HETEROCYCLIC CHEMISTRY LA English DT Article ID SELECTIVE INHIBITORS; ANTIFOLATE ACTIVITY; FOLIC-ACID; SIDE-CHAIN; ANALOGS; METHOTREXATE; TRIMETREXATE; PIRITREXIM AB The synthesis of four previously undescribed 2,4-diaminopyrido[2,3-d]pyrimidines (3,4) and 2,4-diaminoquinazolines (5,6) with a bulky tricyclic aromatic group at the 6-position is described. Condensation of dibenz[b,f]azepine with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine(8) and 2,4-diamino-6-bromomethylqunazoline (17) in the presence of sodium hydride afforded N-[(2,4-diaminopyrido[2,3-d]-pyrimidin-6-yl)methyl]dibenz[bf]azepine (3) and N-[(2,4-diaminoquinazolin-6-yl)methyl]dibenz[b,f]-azepine (4), respectively. Condensation of 5-chlorodibenzo[a,d]cycloheptene (19) and 5-chloro-10,11-dihydrodibenzo[a,d]cycloheptene (20) with 2,4,6-triaminoquinazoline (13) afforded 5-[(2,4-diamino-quinazolin-6-yl)amino] 5H-dibenzo[a,d]cycloheptene (5) and the corresponding 10,11-dihydro derivative (6), respectively. The bromides 8 and 17, as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three-step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3-6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liver. Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC50 values in the 0.03-0.1 mu M range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was <10-fold, whereas the recently reported lead compound in this series, N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine (1) has >100-fold selectivity for the T. gondii and M. avium enzyme and 21-fold selectivity for the P. carinii enzyme. 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. Indiana Univ, Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA. RP Rosowsky, A (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. NR 23 TC 16 Z9 17 U1 0 U2 2 PU HETERO CORPORATION PI ODESSA PA PO BOX 993, ODESSA, FL 33556-0993 USA SN 0022-152X J9 J HETEROCYCLIC CHEM JI J. Heterocycl. Chem. PD JUL-AUG PY 2000 VL 37 IS 4 BP 921 EP 926 PG 6 WC Chemistry, Organic SC Chemistry GA 358KB UT WOS:000089556300040 ER PT J AU Feske, S Draeger, R Peter, HH Eichmann, K Rao, A AF Feske, S Draeger, R Peter, HH Eichmann, K Rao, A TI The duration of nuclear residence of NFAT determines the pattern of cytokine expression in human SCID T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR NFAT1; COMMON VARIABLE IMMUNODEFICIENCY; CYCLOSPORINE-SENSITIVE ELEMENT; ATP-DEFICIENT MICE; GENE-EXPRESSION; CLONAL ANERGY; DEFECTIVE TRANSCRIPTION; INTERLEUKIN-2 PROMOTER; PHOSPHATASE-ACTIVITY; PROTEIN PHOSPHATASE AB The expression of cytokine genes and other inducible genes is crucially dependent on the pattern and duration of signal transduction events that activate transcription factor binding to DNA, Two infant patients with SCID and a severe defect in T cell activation displayed an aberrant regulation of the transcription factor NFAT. Whereas the expression levels of the NFAT family members NFAT1, -2, and -4 were normal in the patients' T cells, dephosphorylation and nuclear translocation of these NFAT proteins occurred very transiently and incompletely upon stimulation. Only after inhibition of nuclear export with leptomycin B were we able to demonstrate a modest degree of nuclear translocation in the patients' T cells. This transient activation of NFAT was not sufficient to induce the expression of several cytokines, including IL-2, IL-3, IL-4, and IFN-gamma, whereas mRNA levels for macrophage inflammatory protein-1 alpha, GM-CSF, and IL-13 were only moderately reduced. By limiting the time of NFAT activation in normal control cells using the calcineurin inhibitor cyclosporin A, we were able to mimic the cytokine expression pattern in SCID T cells, suggesting that the expression of different cytokine genes is differentially regulated by the duration of NFAT residence in the nucleus. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Univ Freiburg, Dept Med, Div Clin Immunol & Rheumatol, D-7800 Freiburg, Germany. Max Planck Inst Immunbiol, D-7800 Freiburg, Germany. RP Rao, A (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. FU NCI NIH HHS [CA42471]; NIAID NIH HHS [AI40127] NR 64 TC 81 Z9 84 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 1 PY 2000 VL 165 IS 1 BP 297 EP 305 PG 9 WC Immunology SC Immunology GA 327WH UT WOS:000087816800040 PM 10861065 ER PT J AU Campton, K Ding, WH Yan, ZM Ozawa, H Seiffert, K Miranda, E Lonati, A Beissert, S Granstein, RD AF Campton, K Ding, WH Yan, ZM Ozawa, H Seiffert, K Miranda, E Lonati, A Beissert, S Granstein, RD TI Tumor antigen presentation by dermal antigen-presenting cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE antigen presentation; dendritic cells; immuno-therapy; tumor immunity ID EPIDERMAL LANGERHANS CELLS; DENDRITIC CELLS; MURINE DERMIS; SKIN; INDUCTION; RECIPIENTS; IMMUNITY AB Several phenotypes of antigen-presenting cells are present in the dermis, where they presumably function to present encountered antigens for immune responses. This study examined the ability of dermal antigen-presenting cells to present tumor-associated antigens for the induction of in vivo antitumor immunity. Total murine dermal cells were exposed either to medium alone or to medium containing tumor-associated antigens from S1509a tumor cells. Subsequently, dermal cells were injected subcutaneously at weekly intervals into naive mice for a total of three immunizations. One week following the final immunization, mice were challenged with living tumor cells. In these experiments, dermal cells pulsed with tumor-associated antigens induced protective immunity to tumor growth. Dermal cells exposed to tumor-associated antigens were also able to elicit delayed-type hypersensitivity after footpad injection into mice previously immunized against S1509a tumor cells. The ability to present tumor-associated antigens for both induction of antitumor immunity and elicitation of delayed-type hypersensitivity was dependent on I-A(+) cells and was genetically restricted. Finally, dermal cells tended towards eliciting a greater antitumor delayed-type hypersensitivity response than epidermal cells. These results show that the murine dermis contains antigen-presenting cells capable of processing S1509a tumor antigens for the generation of protective antitumor immunity in vivo. C1 Cornell Univ, Joan & Sanford I Weill Med Coll, Dept Dermatol, New York, NY 10021 USA. Massachusetts Gen Hosp, Dept Dermatol, MGH Harvard Cutaneous Biol Res Ctr, Charlestown, MA USA. RP Granstein, RD (reprint author), Cornell Univ, Joan & Sanford I Weill Med Coll, Dept Dermatol, 1300 York Ave,Room F-342, New York, NY 10021 USA. FU NIAMS NIH HHS [R01 AR44240] NR 20 TC 9 Z9 9 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2000 VL 115 IS 1 BP 57 EP 61 DI 10.1046/j.1523-1747.2000.00014.x PG 5 WC Dermatology SC Dermatology GA 336LN UT WOS:000088302900009 PM 10886508 ER PT J AU Gonzalez, S Zonios, G Nguyen, BC Gillies, R Kollias, N AF Gonzalez, S Zonios, G Nguyen, BC Gillies, R Kollias, N TI Endogenous skin fluorescence is a good marker for objective evaluation of comedolysis SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE acne; comedones; fluorescence spectroscopy; retinoids; rhino mouse ID TRANS-RETINOIC ACID; RHINO MOUSE SKIN; MODEL; ACNE AB Objective evaluation of comedone lesions, especially in vivo, remains a challenge. We have used the rhino mouse model in combination with topical application of all-trans retinoic acid as a comedolytic agent, to investigate the potential of fluorescence spectroscopy as a noninvasive technique in the assessment of noninflammatory acne. The results indicate that there is a strong correlation between the fluorescence excitation spectral features assessed in vivo, and the histologic changes identified, particularly the size of the utriculi as well as the dermal and epidermal thickness. We conclude that fluorescence excitation spectroscopy represents a promising novel and useful tool in the quantitative evaluation of the pseudocomedones and could also be used for the rapid and noninvasive assessment of comedolysis induced by the application of pharmacologic agents such as retinoids. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol,Wellman Labs Photomed, Boston, MA 02114 USA. RP Gonzalez, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Dermatol,Wellman Labs Photomed, 40 Blossom St, Boston, MA 02114 USA. NR 24 TC 8 Z9 8 U1 0 U2 4 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUL PY 2000 VL 115 IS 1 BP 100 EP 105 DI 10.1046/j.1523-1747.2000.00025.x PG 6 WC Dermatology SC Dermatology GA 336LN UT WOS:000088302900016 PM 10886515 ER PT J AU Reue, K Xu, P Wang, XP Slavin, BG AF Reue, K Xu, P Wang, XP Slavin, BG TI Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene SO JOURNAL OF LIPID RESEARCH LA English DT Article DE lipodystrophy; gene expression; insulin resistance; lipoproteins ID DENSITY-LIPOPROTEIN LEVELS; INSULIN-RESISTANCE; TRANSGENIC MICE; ADIPOCYTE DIFFERENTIATION; DIABETES-MELLITUS; RAT ADIPOCYTES; MESSENGER-RNA; MUTANT MOUSE; LIPASE; EXPRESSION AB The fatty liver dystrophy (fld) mutant mouse is characterized by neonatal fatty liver and hypertriglyceridemia that resolve at weaning, and neuropathy affecting peripheral nerve in adulthood. We now report additional significant manifestations of this single gene mutation, which include adipose tissue deficiency, glucose intolerance, and increased susceptibility to atherosclerosis. In adult fld/fld mice, both white and brown fat pads exhibit an 80% reduction in mass compared with wild-type controls, and consist of immature adipocytes as assessed by morphological and molecular criteria. The lack of Lipid accumulation in fld/fld adipose tissue could be attributed, in part, to a failure to induce expression of lipoprotein lipase and enzymes involved in fatty acid synthesis, such as fatty acid synthase and acetyl-CoA carboxylase. Related to the deficiency of adipose tissue, fld/fld mice were also found to exhibit profound glucose intolerance, modest hyperinsulinemia, and reduced tissue response to insulin. As insulin resistance is a important risk factor in vascular disease, we examined susceptibility of fld/fld mice to diet-induced atherosclerosis. Mutant mice fed an atherogenic diet developed 2-fold greater aortic lesions than their wild-type counterparts, despite having a less atherogenic lipoprotein cholesterol profile. The fld adipose-deficient phenotype has both similarities to and distinctions from the group of rare human diseases known as lipodystrophies. C1 Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. Univ So Calif, Dept Cell & Neurobiol, Los Angeles, CA 90033 USA. RP Reue, K (reprint author), Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. FU NHLBI NIH HHS [HL-28481] NR 61 TC 110 Z9 114 U1 1 U2 2 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD JUL PY 2000 VL 41 IS 7 BP 1067 EP 1076 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 335GZ UT WOS:000088236900005 PM 10884287 ER PT J AU Brousseau, ME Eberhart, GP Dupuis, J Asztalos, BF Goldkamp, AL Schaefer, EJ Freeman, MW AF Brousseau, ME Eberhart, GP Dupuis, J Asztalos, BF Goldkamp, AL Schaefer, EJ Freeman, MW TI Cellular cholesterol efflux in heterozygotes for Tangier disease is markedly reduced and correlates with high density lipoprotein cholesterol concentration and particle size SO JOURNAL OF LIPID RESEARCH LA English DT Article DE apolipoprotein; ATP-binding cassette 1; cholesterol; efflux; lipoproteins; Tangier disease ID APOLIPOPROTEIN-A-I; BINDING CASSETTE TRANSPORTER-1; FRACTIONAL CATABOLIC RATE; INTRACELLULAR CHOLESTEROL; CONTAINING SUBPOPULATIONS; INVIVO METABOLISM; PLASMA; FIBROBLASTS; GENE; MACROPHAGES AB Tangier disease (TD), caused by mutations in the ATP-binding cassette 1 (ABC-1) gene, is a rare genetic disorder characterized by severe deficiency of high density lipoproteins (HDL) in the plasma, hypercatabolism of HDL, and defective apolipoprotein (apo)-mediated cellular cholesterol efflux. In the present study, we assessed plasma lipid concentrations, HDL particle size and subspecies, and cellular cholesterol efflux in 9 TD heterozygotes from a kindred in which the proband was homozygous for an A-->C missense mutation at nucleotide 5338 of the ABC-1 transcript. Relative to age- and gender-matched controls from the Framing-ham Offspring Study (FOS), TD heterozygotes had significant reductions (P < 0.000) in HDL-C (-54% female; -40% male) and apoA-I (-33% female; -37% male) concentrations, as well as significantly less cholesterol (-68% female; -58% male) distributed in the largest HDL subclasses, H5 and H4. Consequently, HDL particle size (mm) was significantly smaller (P < 0.000) in TD heterozygotes (8.6 +/- 0.6 female; 8.7 +/- 0.1 male) relative to FOS controls (9.4 +/- 0.4 female; 9.0 +/- 0.3 male). Further studies demonstrated that apoA-I-mediated cellular cholesterol efflux in TD heterozygotes was essentially half that of controls (11 +/- 2 vs. 20 +/- 3% of total [H-3]cholesterol, P < 0.001), with strong correlations observed between cholesterol efflux and both HDL- C level (r = 0.600) and particle size (r = 0.680). In summary, our data demonstrate that apolipoprotein-mediated cholesterol efflux is aberrant in TD heterozygotes, as it is in homozygotes. This finding, along with the associations observed between HDL-C concentration, HDL particle size, and cholesterol efflux, supports the concept that plasma HDL-C levels are regulated, in part, by cholesterol efflux, which in turn influences HDL particle size and, ultimately, HDL apoA-I catabolism. C1 Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA 02114 USA. Genome Therapeut Corp, Dept Human Genet, Waltham, MA 02453 USA. Tufts Univ, JM USDA, Human Nutr Res Ctr Aging, Lipid Metab Lab, Boston, MA 02111 USA. New England Med Ctr, Dept Med, Boston, MA 02111 USA. RP Freeman, MW (reprint author), Massachusetts Gen Hosp, Lipid Metab Unit, Boston, MA 02114 USA. RI 应, 宁宁/G-9472-2011 FU NHLBI NIH HHS [HL-45098, HL-09319, R01 HL064738] NR 53 TC 60 Z9 63 U1 0 U2 1 PU LIPID RESEARCH INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD JUL PY 2000 VL 41 IS 7 BP 1125 EP 1135 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 335GZ UT WOS:000088236900013 PM 10884295 ER PT J AU Kubota, I Han, XQ Opel, DJ Zhao, YY Baliga, R Huang, P Fishman, MC Shannon, RP Michel, T Kelly, RA AF Kubota, I Han, XQ Opel, DJ Zhao, YY Baliga, R Huang, P Fishman, MC Shannon, RP Michel, T Kelly, RA TI Increased susceptibility to development of triggered activity in myocytes from mice with targeted disruption of endothelial nitric oxide synthase SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE nitric oxide synthase; digitalis glycoside; triggered arrhythmia; transient inward current; cGMP; calcium overload ID TRANSIENT INWARD CURRENT; CARDIAC PURKINJE-FIBERS; RAT VENTRICULAR MYOCYTES; DEPENDENT PROTEIN-KINASE; CA2+ CURRENT; CONTRACTILE RESPONSIVENESS; CHOLINERGIC MODULATION; NA+-CA2+ EXCHANGE; HEART; CALCIUM AB Nitric oxide generated by cardiac myocytes or delivered by drugs has been shown to regulate cardiac contractile function and has been implicated in suppressing some cardiac arrhythmias, although this remains controversial. We examined the ability of the soluble cardiac glycoside. ouabain, to trigger arrhythmic contractions in ventricular myocytes isolated from mice lacking a functional endothelial nitric oxide synthase gene (eNOS(null)), Arrhythmic activity, defined as aftercontractions, was induced with ouabain (50 mu mol/L) and recorded using a video-motion detector in isolated, electrically driven single ventricular myocytes from adult eNOS(null) or from their wild-type (WT) litermates. The rate of ouabain-induced arrhythmic contractions was significantly higher in eNOS(null) myocytes than in WT myocytes. Application of the NO donor S-nitroso-acetylcysteine (SNAC) significantly diminished the frequency of arrhythmic contractions in eNOS(null) myocytes, The antiarrhythmic effect of NO, whether generated by eNOS in WT cells or by SNAC, could be partially reversed by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), a specific soluble guanylyl cyclase inhibitor. Ouabain significantly increased intracellular cGMP in WT but not eNOS(null) hearts, and this cGMP response was blocked by ODQ. Since cardiac glycoside-induced aftercontractions are activated by the transient inward current (I-ti). the role of NO in ouabain (100 mu mol/L)induced I-ti was examined using the nystatin-perforated pat:ch-clamp technique. The frequency of ouabain-induced I-ti was significantly higher in eNOS(null) myocytes than in WT myocytes, and this could be suppressed by SNAG. These data demonstrate that NO derived from myocyte eNOS activation suppresses ouabain-induced arrhythmic contractions by a mechanism that might involve activation of guanylyl cyclase and elevation of cGMP. (C) 2000 Academic Press. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiovasc, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. RP Han, XQ (reprint author), Allegheny Gen Hosp, Dept Med, 320 North East Ave, Pittsburgh, PA 15212 USA. FU PHS HHS [H52320] NR 39 TC 27 Z9 30 U1 1 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUL PY 2000 VL 32 IS 7 BP 1239 EP 1248 DI 10.1006/jmcc.2000.1158 PG 10 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 330KY UT WOS:000087962300009 PM 10860766 ER PT J AU Moore, CI Stern, CE Corkin, S Fischl, B Gray, AC Rosen, BR Dale, AM AF Moore, CI Stern, CE Corkin, S Fischl, B Gray, AC Rosen, BR Dale, AM TI Segregation of somatosensory activation in the human rolandic cortex using fMRI SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; TACTILE DISCRIMINATION TASK; HUMAN CEREBRAL-CORTEX; HUMAN MOTOR CORTEX; MACAQUE MONKEYS; HAND AREA; POSTCENTRAL-GYRUS; CENTRAL SULCUS; SENSORIMOTOR CORTEX; RECEPTIVE-FIELD AB The segregation of sensory information into distinct cortical areas is an important organizational feature of mammalian sensory systems. Here, we provide functional magnetic resonance imaging (fMRI) evidence for the functional delineation of somatosensory representations in the human central sulcus region. Data were collected with a 3-Tesla scanner during two stimulation protocols, a punctate tactile condition without a kinesthetic/motor component, and a kinesthetic/motor condition without a punctate tactile component. With three-dimensional (3-D) anatomical reconstruction techniques, we analyzed data in individual subjects, using the pattern of activation and the anatomical position of specific cortical areas to guide the analysis. As a complimentary analysis, we used a brain averaging technique that emphasized the similarity of cortical features in the morphing of individual subjects and thereby minimized the distortion of the location of cortical activation sites across individuals. A primary finding of this study was differential activation of the cortex on the fundus of the central sulcus, the position of area 3a, during the two tasks. Punctate tactile stimulation of the palm, administered at 3 Hz with a 5.88(log10.mg) von Frey filament, activated discrete regions within the precentral (PreCG) and postcentral (PoCG) gyri, corresponding to areas 6, 3b, 1, and 2, but did not activate area 3a. Conversely, kinesthetic/motor stimulation, 3-Hz flexion and extension of the digits, activated area 3a, the PreCG (areas 6 and 4), and the PoCG (areas 3b, 1, and 2). These activation patterns were observed in individual subjects and in the averaged data, providing strong evidence for the existence of a distinct representation within area 3a in humans. The percentage signal changes in the PreCG and PoCG regions activated by tactile stimulation, and in the intervening gap region, support this functional dissociation. In addition to this distinction within the fundus of the central sulcus, the combination of high-resolution imaging and 3-D analysis techniques permitted localization of activation within areas 6, 4, 3a, 3b, 1, and 2 in the human. With the exception of area 4, which showed inconsistent activation during punctate tactile stimulation, activation in these areas in the human consistently paralleled the pattern of activity observed in previous studies of monkey cortex. C1 MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Charlestown, MA 02129 USA. Boston Univ, Dept Psychol, Boston, MA 02215 USA. RP Moore, CI (reprint author), MIT, Dept Brain & Cognit Sci, NE20-329, Cambridge, MA 02139 USA. RI Moore, Christopher/C-5588-2009; Dale, Anders/A-5180-2010 NR 122 TC 113 Z9 114 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUL PY 2000 VL 84 IS 1 BP 558 EP 569 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 334YU UT WOS:000088215000050 PM 10899227 ER PT J AU Bailey, GP Sewell, WF AF Bailey, GP Sewell, WF TI Calcitonin gene-related peptide suppresses hair cell responses to mechanical stimulation in the Xenopus lateral line organ SO JOURNAL OF NEUROSCIENCE LA English DT Article DE sensory; cochlea; neurotransmitter; efferent; vestibular; calcitonin gene-related peptide; acetylcholine ID EFFERENT VESTIBULAR SYSTEM; INNER-EAR; NERVE-FIBERS; GUINEA-PIG; CHOLINE-ACETYLTRANSFERASE; SYNAPTIC TRANSMISSION; ELECTRON-MICROSCOPY; CAT COCHLEA; RAT; AFFERENT AB The presence of calcitonin gene-related peptide (CGRP) in the efferent fibers of virtually every hair cell organ studied suggests it may serve some fundamental but heretofore unknown role in control of hair cell function. We examined the effects of CGRP on spontaneous and stimulus-evoked discharge patterns in an in vitro preparation of the lateral line organ of Xenopus laevis. Discharge patterns were determined by sinusoidally displacing the cupula with a glass micropipette driven with a piezoelectric device while recording afferent fiber activity. All afferent fibers had characteristic frequencies of 16-32 Hz. Responses synchronized to cupular displacements as small as 20 nm. CGRP suppressed responses of the lateral line organ to displacement while increasing spontaneous discharge rate. In the presence of CGRP, stimulus-response curves were shifted 10 dB toward higher displacement levels. The suppression of stimulus-evoked responses suggests a function for CGRP as an efferent neurotransmitter that is similar to that of cholinergic efferent transmission in other hair cell organs. The 10 dB shift toward larger displacements makes it comparable in magnitude with the effects of electrical stimulation of efferents in the mammalian cochlea. This suggests a significant role for CGRP in efferent modulation of the output of this mechanosensory organ. C1 Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. RP Sewell, WF (reprint author), Massachusetts Eye & Ear Infirm, Dept Otolaryngol, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. NR 41 TC 19 Z9 19 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 1 PY 2000 VL 20 IS 13 BP 5163 EP 5169 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 327WC UT WOS:000087816300042 PM 10864973 ER PT J AU August, M Tompach, P Chang, YC Kaban, L AF August, M Tompach, P Chang, YC Kaban, L TI Factors influencing the long-term outcome of mandibular reconstruction SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID STERNOCLEIDOMASTOID MYOCUTANEOUS FLAP AB Purpose: The aim of this study was to understand the association of 30 candidate variables with the outcome of mandibular reconstruction. Patients and Methods: Seventy cases of mandibular reconstruction performed between 1976 and 1991 were identified. Medical records were reviewed for all patients. Thirty variables, including patient factors, preoperative preparation, and intraoperative and postoperative findings were determined for each patient. Bone graft outcome was evaluated in 2 ways: 1) Fisher's exact tests and logistic regression models were used to determine the association between the clinical parameters and the success of the bone graft at 1 year and 2) proportional hazard regression models were then used to identify the predictors of bone graft survival time from the 30 chosen variables. Results: Multivariate analysis determined that greater blood loss during the procedure (P =.018) and the presence of postoperative recipient site complications (P =.010) were significantly associated with bone graft failure during the first year. The diagnosis of malignant disease (P =.006), the use of sternocleidomastoid muscle (SCM) flaps for soft tissue augmentation (P <.001), longer duration of suction drainage (P =.001), and the presence of postoperative recipient site complications (P =.013) were found to be significant predictors of graft survival time in the proportional hazard regression model. Conclusions: The analysis of parameters associated with bone graft outcome may aid in surgical decision making and help improve the likelihood of a successful result in the future. (C) 2000 American Association of Oral and Maxillofacial Surgeons. C1 Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. Harvard Univ, Sch Dent Med, Med Practices Evaluat Ctr, Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP August, M (reprint author), Harvard Univ, Sch Dent Med, Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, 55 Fruit St,WRN 1201, Boston, MA 02114 USA. NR 22 TC 26 Z9 28 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 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD JUL PY 2000 VL 58 IS 7 BP 731 EP 737 DI 10.1053/joms.2000.7255 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 329ZX UT WOS:000087939300008 PM 10883687 ER PT J AU McPartland, MD Krebs, DE Wall, C AF McPartland, MD Krebs, DE Wall, C TI Quantifying ataxia: Ideal trajectory analysis - A technical note SO JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT LA English DT Article DE ataxia; balance assessment; body sway; stability; vestibular subject ID SPACE-FLIGHT; LOWER-LIMB; STABILITY; WALKING; MASS; QUANTIFICATION; KINEMATICS; POSTURE AB We describe a quantitative method to assess repeated stair stepping stability. In both the mediolateral (ML) and anterioposterior (AP) directions, the trajectory of the subject's center of mass (COM) was compared to an ideal sinusoid. The two identified sinusoids were unique in each direction but coupled. Two dimensionless numbers-the mediolateral instability index (I-ML) and AP instability index (I-AP)-were calculated using the COM trajectory and ideal sinusoids for each subject with larger index values resulting from less stable performance. The COM trajectories of nine nonimpaired control and six patients diagnosed with unilateral or bilateral vestibular labyrinth hypofunction were analyzed. The average I-ML and I-AP values of labyrinth disorder patients were respectively 127% and 119% greater than those of controls (p<0.014 and 0.006, respectively), indicating that the ideal trajectory analysis distinguishes persons with labyrinth disorder from those without. The COM trajectories also identify movement inefficiencies attributable to vestibulopathy. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed,Biomot Lab, Boston, MA 02114 USA. MGH Inst Hlth Profess, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otolaryngol, Jenks Vestibural Lab, Boston, MA 02114 USA. Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP McPartland, MD (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Orthopaed,Biomot Lab, Boston, MA 02114 USA. NR 24 TC 6 Z9 6 U1 0 U2 0 PU JOURNAL REHAB RES & DEV PI BALTIMORE PA DEPT OF VETERANS AFFAIRS REHABIL RES & DEVELOP CTR 103 SOUTH GAY STREET, BALTIMORE, MD 21202-4051 USA SN 0748-7711 J9 J REHABIL RES DEV JI J. Rehabil. Res. Dev. PD JUL-AUG PY 2000 VL 37 IS 4 BP 445 EP 454 PG 10 WC Rehabilitation SC Rehabilitation GA 370YC UT WOS:000165150000009 PM 11028700 ER PT J AU Davidov, O Zelen, M AF Davidov, O Zelen, M TI Exact tests for exponential regression SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE exponential regression; conditional inference; exact tests ID VARIABLES; MODELS AB The exponential distribution is a fundamental model in parametric survival analysis. In this paper the exponential regression model with a canonical parameterization, lambda=beta(t)x, is explored. Large sample and exact significance tests are developed to test the relationship between survival and one covariate. The standard unconditional likelihood approach is compared with two new tests, which are based on the conditional distribution of the sufficient statistics. The various testing procedures are compared numerically. Finally, the relationship with the semiparametric proportional hazard model is investigated. (C) 2000 Elsevier Science B.V. All rights reserved. MSG: 62J05; 62J12. C1 Univ Haifa, Dept Stat, IL-31095 Haifa, Israel. Harvard Univ, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NR 19 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD JUL 1 PY 2000 VL 88 IS 1 BP 87 EP 97 DI 10.1016/S0378-3758(99)00202-5 PG 11 WC Statistics & Probability SC Mathematics GA 322LA UT WOS:000087510000008 ER PT J AU Kampman, KM Rukstalis, M Pettinati, H Muller, E Acosta, T Gariti, P Ehrman, R O'Brien, CP AF Kampman, KM Rukstalis, M Pettinati, H Muller, E Acosta, T Gariti, P Ehrman, R O'Brien, CP TI The combination of phentermine and fenfluramine reduced cocaine withdrawal symptoms in an open trial SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article ID PROGRESSIVE RATIO SCHEDULE; INTRAVENOUS COCAINE; DOUBLE-BLIND; BROMOCRIPTINE; AMANTADINE; DEPENDENCE; DECREASES; RECEPTORS; POINTS; DRUGS C1 Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. RP Kampman, KM (reprint author), Univ Penn, Sch Med, Dept Psychiat, 3900 Chestnut St, Philadelphia, PA 19104 USA. FU NIDA NIH HHS [K20 DA 00238, Y01 DA 30012] NR 24 TC 17 Z9 17 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD JUL PY 2000 VL 19 IS 1 BP 77 EP 79 DI 10.1016/S0740-5472(99)00076-8 PG 3 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 328HG UT WOS:000087844200011 PM 10867304 ER PT J AU Chang, LT Koutrakis, P Catalano, PJ Suh, HH AF Chang, LT Koutrakis, P Catalano, PJ Suh, HH TI Hourly personal exposures to fine particles and gaseous pollutants - Results from Baltimore, Maryland SO JOURNAL OF THE AIR & WASTE MANAGEMENT ASSOCIATION LA English DT Article; Proceedings Paper CT A&WMA Speciality Conference on Particulate Matter and Health - The Scientific Basis for Regularoty Decision-Making (PM2000) CY JAN 25-28, 2000 CL CHARLESTON, SOUTH CAROLINA SP Air & Waste Management Assoc ID CONGESTIVE-HEART-FAILURE; PARTICULATE AIR-POLLUTION; EMERGENCY ROOM VISITS; HOSPITAL ADMISSIONS; PULMONARY-FUNCTION; CARBON-MONOXIDE; OZONE EXPOSURE; CARDIOVASCULAR-DISEASE; RESPIRATORY ILLNESSES; AMBIENT OZONE AB A study to characterize 1-hr multi-pollutant exposures was performed in Baltimore, MD, during the summer of 1998 and the winter of 1999, and was conducted over a 15-day period in each of the two seasons. Personal exposures were measured by a trained field technician, who wore a newly developed Roll-Around System (RAS) to measure 1-hr PM2.5 and gaseous (CO, O-3, NO2, SO2, volatile organic compounds [VOCs]) exposures. One-hour O-3, NO2, and SO2 personal exposures were measured using samplers developed in our laboratory, while short-term PM2.5 CO, and VOCs exposures were measured using currently available monitors. All 1-hr multi-pollutant exposures were measured while the technician performed pre-determined activities, beginning at 7:00 a.m, and ending at 7:00 p.m. of the same day. Activities were scripted to simulate activities performed by older adults (65+ years of age). Corresponding 1-hr ambient pollutant concentrations were obtained from federal or state monitoring networks. In this paper, we discuss the results from our study and present our descriptive analysis of the 1-hr personal particulate and gaseous exposure data. Personal PM2.5, O-3, CO, and VOCs exposures showed substantial variability over the 12-hr sampling periods. Multiple pairwise comparison tests showed that 1-hr personal O-3 exposures were significantly lower in indoor microenvironments as compared with outdoor microenvironments. One-hour personal CO exposures measured in vehicles were significantly higher than those measured in other microenvironments. The associations between 1-hr personal exposures and corresponding ambient concentrations differed by pollutant and by microenvironment. For example, the correlation between personal PM2.5 exposures and ambient concentrations was lowest (r = 0.36, p < 0.05) in the winter for indoor non-residential microenvironments, and was highest (r = 0.90, p < 0.05) in the winter for in-vehicle microenvironments. For O-3, the correlation between personal exposures and ambient levels was weakest in the winter for residential microenvironments (r = 0.05, p > 0.05), and was strongest in the summer for outdoor near-roadway microenvironments (r(s) = 0.91, p < 0.05). C1 Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm Sci & Engn Program, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dana Farber Canc Inst, Dept Biostat, Boston, MA 02115 USA. RP Chang, LT (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Environm Sci & Engn Program, 665 Huntington Ave,Rm I-1308 B, Boston, MA 02115 USA. NR 46 TC 33 Z9 34 U1 8 U2 19 PU AIR & WASTE MANAGEMENT ASSOC PI PITTSBURGH PA ONE GATEWAY CENTER, THIRD FL, PITTSBURGH, PA 15222 USA SN 1047-3289 J9 J AIR WASTE MANAGE JI J. Air Waste Manage. Assoc. PD JUL PY 2000 VL 50 IS 7 BP 1223 EP 1235 PG 13 WC Engineering, Environmental; Environmental Sciences; Meteorology & Atmospheric Sciences SC Engineering; Environmental Sciences & Ecology; Meteorology & Atmospheric Sciences GA 339RP UT WOS:000088491900016 PM 10939215 ER PT J AU Aghassi, D Anderson, RR Gonzalez, S AF Aghassi, D Anderson, RR Gonzalez, S TI Time-sequence histologic imaging of laser-treated cherry angiomas with in vivo confocal microscopy SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID DYE-LASER; IN-VIVO; TELANGIECTASES AB Objective: To chronicle the pathophysiologic changes chat occur subsequent to laser treatment of vascular lesions, we used a confocal scanning laser microscope that yields high-resolution microscopic images of skin in vivo. Methods: Cherry angiomas were treated with the 585-nm flashlamp-pumped pulsed-dye laser (PDL) and the 568-nm continuous-wave krypton laser. Repeated confocal reflectance imaging was performed before and immediately after treatment, as well as after several hours, 1 day, 2 days, 1 week, 2 weeks, 3 weeks, and 4 weeks. Results: Before treatment, confocal images revealed dilated blood vessels ranging from 10 to 50 mu m in caliber, closely spaced at 5 to 50 mu m apart. After PDL treatment, amorphous cords of refractile material conformed to the shape of the original vessels, followed by dark nonrefractile spaces where the vessels once were. Inflammation and necrosis ensued, with eventual replacement after 3 weeks by normal-appearing skin. After krypton laser treatment, dark nonrefractile spaces appeared immediately with subsequent inflammation, necrosis, and eventual healing by 4 weeks. Conclusion: Confocal laser microscopic imaging elucidates the dynamic pathophysiologic events that occur after laser treatment of vascular lesions and has added insight into the different mechanisms of vessel damage induced by the PDL and krypton laser. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Dept Dermatol, Boston, MA 02114 USA. RP Gonzalez, S (reprint author), Massachusetts Gen Hosp, Wellman Labs Photomed, Dept Dermatol, 50 Blossom St, Boston, MA 02114 USA. NR 12 TC 48 Z9 50 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2000 VL 43 IS 1 BP 37 EP 41 DI 10.1067/mjd.2000.105560 PN 1 PG 5 WC Dermatology SC Dermatology GA 329RW UT WOS:000087922500005 PM 10863221 ER PT J AU Aghassi, D Anderson, RR Gonzalez, S AF Aghassi, D Anderson, RR Gonzalez, S TI Confocal laser microscopic imaging of actinic keratoses in vivo: A preliminary report SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID HUMAN SKIN AB Background: Real-time near-infrared confocal laser scanning microscopy (CM) offers an unprecedented method for confirming the clinical diagnosis of actinic keratosis (AK) without biopsy. Methods: Seven patients with clinically diagnosed AK underwent CM imaging over the lesion and over adjacent normal-appearing skin. Biopsy specimens were obtained From the presumed AKs in 4 patients. Results: CM detected lesional pathologic features of hyperkeratosis (71%), lower epidermal nuclear enlargement and pleomorphism (100%), and architectural disarray (57%). In contrast, cytologic atypia and architectural disarray were apparent in one patient (17%) over the adjacent, clinically normal skin. Three of 4 biopsy specimens confirmed the clinical diagnosis of AK, whereas one revealed invasive squamous cell carcinoma. Without optimizing CM for imaging hyperkeratotic skin lesions, the limited depth of penetration reached the stratum basale in only 3 lesions, precluding detection of dermal invasion in the others. Conclusion: Depth of penetration currently imposes a major limitation on CM in the diagnosis of AKs, especially in hypertrophic and hyperkeratotic lesions, which are more likely to be malignant. However, CM may become an alternative to biopsy, and its limitations may be overcome by future technologic advances in optical penetration or by simply removing the hyperkeratotic stratum corneum. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Dept Dermatol, Boston, MA 02114 USA. RP Gonzalez, S (reprint author), Massachusetts Gen Hosp, Wellman Labs Photomed, Dept Dermatol, BHX 630,55 Fruit St, Boston, MA 02114 USA. NR 11 TC 86 Z9 91 U1 0 U2 2 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2000 VL 43 IS 1 BP 42 EP 48 DI 10.1067/mjd.2000.105565 PN 1 PG 7 WC Dermatology SC Dermatology GA 329RW UT WOS:000087922500006 PM 10863222 ER PT J AU Aghassi, D Gonzalez, E Anderson, RR Rajadhyaksha, M Gonzalez, S AF Aghassi, D Gonzalez, E Anderson, RR Rajadhyaksha, M Gonzalez, S TI Elucidating the pulsed-dye laser treatment of sebaceous hyperplasia in vivo with real-time confocal scanning laser microscopy SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID GLAND HYPERPLASIA; IN-VIVO; HUMAN SKIN; ISOTRETINOIN AB Background: Several case reports document successful treatment of sebaceous hyperplasia with the pulsed-dye laser. Moreover, noninvasive real-time confocal laser scanning microscopy elucidates the vascular nature of these lesions and their pathophysiologic response to treatment mediated by vessel coagulation. Methods: Ten patients with 29 lesions of sebaceous hyperplasia were treated with 3 stacked 5-mm pulses of the 585-nm pulsed-dye laser at fluences of 7 or 7.5 J/cm(2). Confocal imaging was performed before and immediately after treatment, as well as at 2, 4, and 8 weeks of follow-up. Results: The great majority of lesions responded to one treatment, with complete disappearance in 28%, decrease in diameter in 66%, and flattening in 93%. Although 28% recrudesced after initial involution, only 7% recurred completely Three lesions became eroded or crusted, and 7 experienced cutaneous depressions before complete healing, but no scarring or pigmentary side effects were noted. Confocal imaging revealed a prominent "crown" of blood vessels surrounding the sebaceous duct and coagulation of these vessels with pulsed-dye laser treatment. However, the vessels reappeared during follow-up, and no noticeable morphologic changes in the sebaceous duct were noted. Conclusion: Vascular targeting of sebaceous hyperplasia can be monitored with real-time reflectance confocal microscopy. Most sebaceous hyperplasia regresses after one treatment with 3 stacked pulses of the 585-nm pulsed-dye laser. Whether this response is due to temporary ischemia induced by selective vessel destruction or nonspecific thermal diffusion beyond the vessels from pulse stacking has not been determined. C1 Massachusetts Gen Hosp, Wellman Labs Photomed, Dept Dermatol, Boston, MA 02114 USA. RP Gonzalez, S (reprint author), Massachusetts Gen Hosp, Wellman Labs Photomed, Dept Dermatol, BHX 630,55 Fruit St, Boston, MA 02114 USA. NR 18 TC 26 Z9 27 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2000 VL 43 IS 1 BP 49 EP 53 DI 10.1067/mjd.2000.105566 PN 1 PG 5 WC Dermatology SC Dermatology GA 329RW UT WOS:000087922500007 PM 10863223 ER PT J AU Behroozan, DS Christian, MM Moy, RL AF Behroozan, DS Christian, MM Moy, RL TI Short-pulse carbon dioxide laser resurfacing of the neck SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID PHOTOAGED FACIAL SKIN; RHYTIDES; CO2-LASER; SCARS AB Background: Carbon dioxide (CO2) laser resurfacing of the face has become an increasingly popular procedure. However, laser resurfacing of the neck has been largely avoided because of fears of scarring or pigmentation changes. Objective: Our purpose was to evaluate the efficacy of treatment and incidence of complications after short-pulse CO2 laser resurfacing of the neck. Methods: A total of 308 patients received concomitant face and neck CO2 laser resurfacing. A 90 -mu s pulse duration CO2 laser without a scanner was used in all cases for 2 passes on the neck (10.6-mu m wavelength, 500-mJ pulse energy, 90-mu s duration, 3-mm spot size) and a continuous CO2 laser with a computer-generated scanner (396-mu s dwell time, 18 W) was used for 3 passes over the face except for the perioral area, which received 4 passes. The incidence of scarring or permanent pigmentation changes was determined. Forty patients who had been treated at least 6 months but no longer than 18 months earlier were randomly surveyed by phone to assess the degree of improvement. Results: Of the 308 patients treated, there were no cases of scarring or permanent pigmentation changes. Surveyed patients reported a 39% improvement in rhytides and tightening on the neck. Conclusion: Resurfacing of the neck can be performed safely in conjunction with resurfacing of the face. Patients may be offered improvement in the neck with little chance of scarring or permanent pigmentary changes when resurfacing on the neck is performed by means of a short-pulse duration laser for a limited number of passes instead of the more aggressive laser parameters previously used such as continuous long-pulse duration treatments. C1 Univ Calif Los Angeles, Los Angeles, CA USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Moy, RL (reprint author), 100 UCLA Med Plaza,Suite 590, Los Angeles, CA 90024 USA. NR 18 TC 9 Z9 9 U1 0 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD JUL PY 2000 VL 43 IS 1 BP 72 EP 76 DI 10.1067/mjd.2000.104795 PN 1 PG 5 WC Dermatology SC Dermatology GA 329RW UT WOS:000087922500011 PM 10863227 ER PT J AU Grodstein, F Chen, J Pollen, DA Albert, MS Wilson, RS Folstein, MF Evans, DA AF Grodstein, F Chen, J Pollen, DA Albert, MS Wilson, RS Folstein, MF Evans, DA TI Postmenopausal hormone therapy and cognitive function in healthy older women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article ID ESTROGEN REPLACEMENT THERAPY; ALZHEIMERS-DISEASE; BASAL FOREBRAIN; FEMALE RATS; LONG-TERM; MEMORY; COMMUNITY; NEURONS; RISK; PERFORMANCE AB OBJECTIVE: Accumulating biologic evidence suggests that estrogen is related to cognitive function. Several epidemiologic investigations have reported that hormone therapy may reduce the risk of Alzheimer's disease. However, fewer studies have examined the relation of postmenopausal hormone use to general cognitive function in nondemented older women. Thus, we examined the association of hormone therapy to performance on four cognitive tests among healthy participants of the Nurses' Health Study. DESIGN: Cohort study. SETTING: The Nurses' Health Study, an ongoing prospective cohort study begun in 1976. PARTICIPANTS: From the Nurses' Health Study, 2138 women aged 70-78 years. MEASUREMENTS: From 1995-1999 we administered four cognitive tests (Telephone Interview for Cognitive Status (TICS), immediate and delayed recall of the East Boston Memory Test (EBMT), and verbal fluency) by telephone. Hormone use was ascertained from biennial questionnaires beginning in 1976. Linear and logistic regression models were used to calculate multivariate-adjusted differences in scores and relative risks of a low score for never users compared to current and past hormone users. RESULTS: After adjustment for confounders, neither current nor long-term hormone users demonstrated better performance on an overall measure of cognition (TICS), or on three tests of verbal memory (immediate and delayed recall of the EBMT, immediate recall of the TICS 10-word list) than never users. On the test of verbal fluency, current hormone users scored significantly better than never users (linear regression estimate of the difference in score = 0.78 points, 95% confidence interval (CI) 0.19-0.38, P =.01 for any current use; and 0.91 points, 95% CI 0.28-1.54, P =.005 for greater than or equal to 5 years current use). Current hormone users also had a 30% decrease (RR = 0.70, 95% CI 0.45-1.09) in their risk of a low score on the test of verbal fluency. These results were similar for women taking estrogen alone and estrogen combined with a progestin. CONCLUSIONS: Verbal fluency may be enhanced among women taking postmenopausal hormones, however, there is little support for better overall cognitive function in hormone users than nonusers. C1 Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA USA. Tufts Univ, New England Med Ctr, Sch Med, Dept Psychiat, Boston, MA 02111 USA. Rush Univ, Rush Presbyterian St Lukes Med Ctr, Rush Inst Hlth Aging, Chicago, IL 60612 USA. Rush Univ, Rush Presbyterian St Lukes Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA. RP Grodstein, F (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA40356]; NIA NIH HHS [AG13482, AG15424] NR 35 TC 80 Z9 81 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2000 VL 48 IS 7 BP 746 EP 752 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 333HK UT WOS:000088124700005 PM 10894312 ER PT J AU Iwao, S Iwao, N Muller, DC Elahi, D Shimokata, H Andres, R AF Iwao, S Iwao, N Muller, DC Elahi, D Shimokata, H Andres, R TI Effect of aging on the relationship between multiple risk factors and waist circumference SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE waist circumference; age; risk factors; coronary disease ID DENSITY-LIPOPROTEIN CHOLESTEROL; CARDIOVASCULAR RISK; FAT DISTRIBUTION; BODY-FAT; AGE; PLASMA; CLASSIFICATION; GLUCOSE; WOMEN AB OBJECTIVE: To examine the relationship between various coronary risk factors and the different levels of fat distribution in younger (<65 years) and older (greater than or equal to 65 years) men and women, using the classifications proposed by the National Heart, Lung and Blood Institute (NHLBI) and the World Health Organization (WHO). DESIGN: Cross-sectional study of subjects enrolled in the Baltimore Longitudinal Study of Aging. MEASUREMENTS: Systolic blood pressure, diastolic blood pressure, fasting glucose, 2-hour glucose, fasting insulin, homeostasis model assessment insulin resistance (HOMA(IR)), triglyceride, total cholesterol, high-density lipoprotein (HDL)-cholesterol, and low-density lipoprotein (LDL)cholesterol were measured as risk factors. The proportion of subjects with abnormal risk factor levels by waist circumference classifications was determined in the age and gender subgroups. RESULTS: There were significant adverse effects of age per se on all risk factors with the exception of fasting insulin and HOMA(IR) in both men and women, total cholesterol in men, and diastolic blood pressure in women. HDL-cholesterol was higher in older subjects. There were significant correlations between waist circumference and all of the risk factors in the younger group. Waist circumference did not have a significant correlation with total cholesterol in older men, or with total cholesterol and LDL-cholesterol in older women. The proportion of subjects with an abnormal risk factor level increased with increasing waist circumference for most risk factors in both younger and older subjects, but proportions of subjects in each individual waist group were higher in older than in younger groups for systolic blood pressure, diastolic blood pressure, fasting glucose, and 2-hour glucose in men, and for systolic blood pressure, fasting glucose, 2-hour glucose, total and LDL-cholesterol, and triglyceride in women. CONCLUSIONS: Our data indicate that the waist circumference cutpoints proposed by NHLBI and WHO standards are useful for the prediction of cardiovascular disease risk factors in older as well as in younger men and women. C1 NIA, NIH, Baltimore, MD 21224 USA. Massachusetts Gen Hosp, Geriatr Res Lab, Boston, MA 02114 USA. Natl Inst Longev Sci, Longitudinal Study Aging, Nagoya, Aichi, Japan. RP Andres, R (reprint author), NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 21 TC 25 Z9 25 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2000 VL 48 IS 7 BP 788 EP 794 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 333HK UT WOS:000088124700011 PM 10894318 ER PT J AU Hazzard, WR AF Hazzard, WR TI So you think you want to lead an academic geriatric program? SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article C1 Wake Forest Univ, Sch Med, J Paul Sticht Ctr Aging, Winston Salem, NC 27109 USA. RP Hazzard, WR (reprint author), VA Puget Sound Hlth Care Syst, S-182-GEC, Seattle, WA 98108 USA. NR 5 TC 2 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUL PY 2000 VL 48 IS 7 BP 835 EP 841 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 333HK UT WOS:000088124700019 PM 10894326 ER PT J AU Velmahos, GC Kern, J Chan, LS Oder, D Murray, JA Shekelle, P AF Velmahos, GC Kern, J Chan, LS Oder, D Murray, JA Shekelle, P TI Prevention of venous thromboembolism after injury: An evidence-based report - Part I: Analysis of risk fastors and evaluation of the role of vena caval filters SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article ID MOLECULAR-WEIGHT HEPARIN; SPINAL-CORD INJURY; DEEP-VEIN THROMBOSIS; LOW-DOSE HEPARIN; ORTHOPEDIC TRAUMA PATIENTS; COMPRESSION DEVICES; MULTIPLE TRAUMA; CLINICAL-TRIALS; MAJOR TRAUMA; PROPHYLAXIS AB Background: Trauma surgeons use a variety of methods to prevent venous thromboembolism (VT), The rationale for their use frequently is based on conclusions from research on nontrauma populations. Existing recommendations are based on expert opinion and consensus statements rather than systematic analysis of the existing literature and synthesis of available data. The objective is to produce an evidence-based report on the methods of prevention of VT after injury. Methods: A panel of 17 national authorities from the academic, private, and managed care sectors helped design and review the project. We searched three electronic databases (MEDLINE, EMBASE, and Cochrane Controlled Trial Register) to identify articles relevant to four key questions: methods of prophylaxis, methods of screening, risk factors for VT, and the role of vena caval filters. The initial 4,093 titles yielded 73 articles for meta-analysis, A random-effects model was used for all pooled results. Study quality was evaluated by previously published quality scores. In this article (part I), we report on the question ranked by the experts as the most important, i.e., Which is the best method to prevent VT?, and also on the incidence of deep venous thrombosis and pulmonary embolism in trauma patients. Results:The incidence of deep venous thrombosis and pulmonary embolism reported in different studies varies widely. The pooled rates are 11.8% for deep venous thrombosis and 1.5% for pulmonary embolism. Only a few randomized controlled trials have evaluated the methods of VT prophylaxis among trauma patients, and combining their data is difficult because of different designs and preventive methods used. The quality of most studies is low, Meta-analysis shows no evidence that low-dose heparin, mechanical prophylaxis, or low-molecular-weight heparin are more effective than no prophylaxis or each other. However, the 95% confidence intervals of many of the comparisons are wide; therefore, a clinically important difference may exist. Conclusion: The trauma literature on VT prophylaxis provides inconsistent data. There is no evidence that any existing method of VT prophylaxis is clearly superior to the other methods or even to no prophylaxis, Our results cast serious doubt on the existing policies on VT prophylaxis, and we call for a large, high-quality, multicenter trial that can provide definitive answers. C1 Univ So Calif, Los Angeles Cty Med Ctr, Div Res & Biostat, Los Angeles, CA 90033 USA. Univ So Calif, Dept Surg, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Clin Pharm, Los Angeles, CA 90033 USA. Univ So Calif, Sch Pharm, Los Angeles, CA 90033 USA. Greater Los Angeles VA Hlth Care Syst, Santa Monica, CA USA. RAND Corp, Santa Monica, CA USA. RP Velmahos, GC (reprint author), Univ So Calif, Los Angeles Cty Med Ctr, Div Res & Biostat, 1200 N State St,Room 9900, Los Angeles, CA 90033 USA. FU PHS HHS [290-97-0001] NR 41 TC 106 Z9 109 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-6061 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD JUL PY 2000 VL 49 IS 1 BP 132 EP 138 DI 10.1097/00005373-200007000-00020 PG 7 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 335LH UT WOS:000088244600029 PM 10912869 ER PT J AU Velmahos, GC Kern, J Chan, LS Oder, D Murray, JA Shekelle, P AF Velmahos, GC Kern, J Chan, LS Oder, D Murray, JA Shekelle, P TI Prevention of venous thromboembolism after injury: An evidence-based report - Part II: Analysis of risk factors and evaluation of the role of vena caval filters SO JOURNAL OF TRAUMA-INJURY INFECTION AND CRITICAL CARE LA English DT Article DE trauma; injury; venous thromboembolism; deep venous thrombosis; pulmonary embolism; risk factors; spinal injury; spinal cord injury; vena cava filters; vena cava interruption ID DEEP-VEIN THROMBOSIS; MOLECULAR-WEIGHT HEPARIN; MULTIPLE TRAUMA PATIENTS; PULMONARY-EMBOLISM; MAJOR TRAUMA; PROPHYLAXIS; EFFICACY; PLACEMENT; INSERTION AB Objective: In part II, we describe the results of the literature search and data analysis concerning risk factors for venous thromboembolism and the role of vena caval filters (VCF) in preventing pulmonary embolism. Methods: The methodology used in part I was used in part II. Results: Spinal fractures and spinal-cord injuries increase the risk for development of deep venous thrombosis (DVT) by twofold and threefold, respectively. Patients with DVT were an average of 9 years older than patients without DVT, No specific age cut-off point for increased risk could be established because data could not be combined across studies. Patients with prophylactically, inserted VCF bad a lower incidence of pulmonary embolism (0.2%) compared with concurrently managed patients without VCF (1.5%) or historical controls without VCF (5.8%). These results are reported on uncontrolled studies with observational design. Conclusion: spinal injuries, spinal cord injuries, and age are risk factors for development of DVT. Prophylactic placement of VCF in selected trauma patients may decrease the incidence of pulmonary embolism. Future research with well-designed studies is required to provide definitive answers. C1 Univ So Calif, Los Angeles Cty Med Ctr, Div Res & Biostat, Los Angeles, CA 90033 USA. Univ So Calif, Dept Surg, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Clin Pharmacol, Los Angeles, CA 90033 USA. Univ So Calif, Sch Pharm, Los Angeles, CA 90033 USA. Greater Los Angeles VA Hlth Care Syst, Santa Monica, CA USA. RAND Corp, Santa Monica, CA USA. RP Velmahos, GC (reprint author), Univ So Calif, Los Angeles Cty Med Ctr, Div Res & Biostat, 1200 N State St,Room 9900, Los Angeles, CA 90033 USA. FU PHS HHS [290-97-0001] NR 34 TC 74 Z9 77 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-6061 J9 J TRAUMA JI J. Trauma-Injury Infect. Crit. Care PD JUL PY 2000 VL 49 IS 1 BP 140 EP 144 DI 10.1097/00005373-200007000-00021 PG 5 WC Critical Care Medicine; Surgery SC General & Internal Medicine; Surgery GA 335LH UT WOS:000088244600031 PM 10912870 ER PT J AU Shipp, TD Chu, GC Benacerraf, B AF Shipp, TD Chu, GC Benacerraf, B TI Prenatal diagnosis of oral-facial-digital syndrome, type I SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article ID OROFACIODIGITAL SYNDROME; MOHR; MALFORMATIONS; DISEASE; FETUS; VI C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. RP Shipp, TD (reprint author), Diagnost Ultrasound Associates PC, 333 Longwood Ave,Suite 400, Boston, MA 02115 USA. NR 16 TC 4 Z9 4 U1 0 U2 0 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD JUL PY 2000 VL 19 IS 7 BP 491 EP 494 PG 4 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 415ZY UT WOS:000167754500009 PM 10898304 ER PT J AU de Virgilio, C Toosie, K Ephraim, L Elbassir, M Donayre, C Baker, JD Narahara, K Mishkin, F Lewis, RJ Chang, C White, R Mody, FV AF de Virgilio, C Toosie, K Ephraim, L Elbassir, M Donayre, C Baker, JD Narahara, K Mishkin, F Lewis, RJ Chang, C White, R Mody, FV TI Dipyridamole-thallium/sestamibi before vascular surgery: A prospective blinded study in moderate-risk patients SO JOURNAL OF VASCULAR SURGERY LA English DT Article; Proceedings Paper CT 14th Annual Meeting of the Western-Vascular-Society CY SEP 19-22, 1999 CL CALIFORNIA SP Western Vascular Soc ID ABDOMINAL AORTIC-SURGERY; CORONARY-ARTERY DISEASE; EMISSION COMPUTED-TOMOGRAPHY; CARDIAC RISK; MYOCARDIAL-INFARCTION; 2-METHOXYISOBUTYL ISONITRILE; THALLIUM SCANS; SCINTIGRAPHY; ANGIOGRAPHY; MORBIDITY AB Purpose: This study assessed in a prospective, blinded fashion whether a reversible defect on dipyridamole-thallium (DTHAL)/sestamibi (DMIBI) can predict adverse cardiac events after elective vascular surgery in patients with one or more clinical risk factors. Methods: Consecutive patients with one or more clinical risk factors underwent a preoperative blinded DTHAL/DMIBI. Patients with recent congestive heart failure (CHP) or myocardial infarction (MI) or severe or unstable angina were excluded. Results: Eighty patients (78% men; mean age, 65 years) completed the study. Diabetes mellitus was the most frequent clinical risk factor (73%), followed by age older than 70 years (41%), angina (29%), Q wave on electrocardiogram (26%), history of CHP (7%), and ventricular ectopy (3%). The results of DTHAL/DMIBI were normal in 36 patients (45%); a reversible plus or minus fixed defect was demonstrated in 28 patients (36%), and a fixed defect alone was demonstrated in 15 patients (19%). Nine adverse cardiac events (11%) occurred, including three cases of CHF, and one case each of unstable angina, Q wave MI, non-Q wave MI, and cardiac arrest (successfully resuscitated). Two cardiac deaths occurred (2% overall mortality), one after a Q wave MI and one after CHF and a non-Q wave MI. The cardiac event rate was 14% for reversible defect and 9.8% without reversible defect (P = .71). The cardiac event rate was 12.5% (one of eight cases) for two or more reversible defects, versus 11.1% (eight of 72 cases) for fewer than two reversible defects (P = 1.0). The sensitivity rate of two or more areas of redistribution was 11% (95% CI, 0.3%-48%), the specificity rate was 90%, and the positive and negative predictive values were 12.5% and 89%, respectively. Conclusion: Our study demonstrated no association between reversible defects on DTHAL/DMIBI and adverse cardiac events in moderate-risk patients undergoing elective vascular surgery. C1 Harbor UCLA Med Ctr, Div Vasc Surg, Dept Surg, Torrance, CA 90509 USA. W Los Angeles VA Med Ctr, Dept Surg, Div Vasc Surg, Torrance, CA USA. Harbor UCLA Med Ctr, Dept Med, Div Cardiol, Torrance, CA 90509 USA. W Los Angeles VA Med Ctr, Dept Med, Div Cardiol, Torrance, CA USA. Harbor UCLA Med Ctr, Dept Emergency Med, Torrance, CA 90509 USA. Harbor UCLA Med Ctr, Dept Radiol, Div Nucl Med, Torrance, CA 90509 USA. RP de Virgilio, C (reprint author), Harbor UCLA Med Ctr, Div Vasc Surg, Dept Surg, 1000 W Carson St, Torrance, CA 90509 USA. NR 24 TC 13 Z9 14 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 JUL PY 2000 VL 32 IS 1 BP 77 EP 86 DI 10.1067/mva.2000.107311 PG 10 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 334ED UT WOS:000088172500017 PM 10876209 ER PT J AU Grovit-Ferbas, K Hsu, JF Ferbas, J Gudeman, V Chen, ISY AF Grovit-Ferbas, K Hsu, JF Ferbas, J Gudeman, V Chen, ISY TI Enhanced binding of antibodies to neutralization epitopes following thermal and chemical inactivation of human immunodeficiency virus type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID T-LYMPHOCYTE RESPONSES; ENVELOPE GLYCOPROTEIN; LYMPHOTROPIC VIRUS; GP120 GLYCOPROTEIN; SIV VACCINE; SOLUBLE CD4; HIV; INFECTION; VIRIONS; CELLS AB Inactivation of viral particles is the basis for several vaccines currently in use. Initial attempts to use simian immunodeficiency virus to model a killed human immunodeficiency virus type 1 (HIV-1) vaccine were unsuccessful, and limited subsequent effort has been directed toward a systematic study of the requirements For a protective killed HIV-1 vaccine. Recent insights into BTV-l virion and glycoprotein structure and neutralization epitopes led us to revisit whether inactivated HIV-1 particles could serve as the basis for an HIV-I vaccine. Our results indicate that relatively simple processes involving thermal and chemical inactivation can inactivate HIV-1 by at least 7 logs. For some HIV-I strains, significant amounts of envelope glycoproteins are retained in high-molecular-weight fractions. Importantly, we demonstrate retention of each of three conformation-dependent neutralization epitopes, Moreover, reactivity of monoclonal antibodies directed toward these epitopes is increased following treatment, suggesting greater exposure of the epitopes, In contrast, treatment of free envelope under the same conditions leads only to decreased antibody recognition. These inactivated virions can also be presented by human dendritic cells to direct a cell-mediated immune response in vitro. These data indicate that a systematic study of HIV-1 inactivation, gp120 retention, and epitope reactivity with conformation-specific neutralizing antibodies can provide important insights for the development of an effective killed HIV-1 vaccine. C1 Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Microbiol & Immunol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, AIDS Inst, Los Angeles, CA 90095 USA. RP Chen, ISY (reprint author), Univ Calif Los Angeles, Sch Med, Dept Med, 11-934 Factor Bldg, Los Angeles, CA 90095 USA. FU NIAID NIH HHS [R15 AI082515, N0I-AI-82515, R21-AI42687, AI/MH28697] NR 47 TC 21 Z9 22 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 JUL PY 2000 VL 74 IS 13 BP 5802 EP 5809 DI 10.1128/JVI.74.13.5802-5809.2000 PG 8 WC Virology SC Virology GA 322GH UT WOS:000087501500008 PM 10846059 ER PT J AU Accola, MA Ohagen, A Gottlinger, HG AF Accola, MA Ohagen, A Gottlinger, HG TI Isolation of human immunodeficiency virus type 1 cores: Retention of Vpr in the absence of p6(gag) SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-CYCLE ARREST; PRIMATE LENTIVIRUSES; NUCLEAR IMPORT; GAG PRECURSOR; CYCLOPHILIN-A; HIV-1 VIRIONS; PROTEIN; ASSOCIATION; PARTICLE; DOMAIN AB Mature human immunodeficiency virus type 1 (HIV-1) virions contain a typically cone-shaped core that encases the viral genome. In this study, we established conditions which allowed the efficient isolation of morphologically intact HIV-1 cores from virions. The isolated cores consisted mostly of cones which appeared uniformly capped at both ends but were heterogeneous with respect to the shape of the broad cap as well as the dimensions and angle of the cone. Vpr, a nonstructural virion component implicated in the nuclear import of the viral genome, was recovered in core preparations of HIV-1 and simian immunodeficiency viruses from African green monkeys, Unexpectedly, p6(gag), a structural protein required for the incorporation of Vpr, was absent from HIV-1 core preparations. Taken together, our results indicate that the incorporation of Vpr into the virion core is a conserved feature of primate lentiviruses and that the interactions required for the uptake of Vpr into assembling particles differ from those which confine Vpr within the core. C1 Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Immunol, 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 NCI NIH HHS [T32 CA09141, T32 CA009141]; NIAID NIH HHS [AI28691, P30 AI028691, R01 AI029873, AI29873, R37 AI029873] NR 45 TC 51 Z9 52 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 JUL PY 2000 VL 74 IS 13 BP 6198 EP 6202 DI 10.1128/JVI.74.13.6198-6202.2000 PG 5 WC Virology SC Virology GA 322GH UT WOS:000087501500055 PM 10846106 ER PT J AU Severino, ME Sipsas, NV Nguyen, PT Kalams, SA Walker, BD Johnson, RP Yang, OO AF Severino, ME Sipsas, NV Nguyen, PT Kalams, SA Walker, BD Johnson, RP Yang, OO TI Inhibition of human immunodeficiency virus type 1 replication in primary CD4(+) T lymphocytes, monocytes, and dendritic cells by cytotoxic T lymphocytes SO JOURNAL OF VIROLOGY LA English DT Article ID LOW VIRAL LOAD; NONCYTOLYTIC MECHANISMS; HIV-1 INFECTION; CD8(+) CELLS; HUMAN BLOOD; IN-VIVO; PATHOGENESIS; RESPONSES; TISSUE; AIDS AB We demonstrate that human immunodeficiency virus type I (HIV-1)-specific CD8(+) cytotoxic T lymphocytes (CTL) suppress HIV-1 replication in primary lymphocytes, monocytes, and dendritic cells individually. Viral inhibition is significantly diminished in lymphocyte-dendritic cell dusters, suggesting that these clusters in vivo could be sites where viral replication is more difficult to control by CTL. C1 Massachusetts Gen Hosp, AIDS Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Southborough, MA 01772 USA. New England Reg Primate Res Ctr, Southborough, MA 01772 USA. RP Yang, OO (reprint author), Univ Calif Los Angeles, Med Ctr, Div Infect Dis, 37-121 CHS,10833 LeConte Ave, Los Angeles, CA 90095 USA. FU NIAID NIH HHS [F32 AI009270, R01 AI043202, R01 AI043203] NR 40 TC 12 Z9 13 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 JUL PY 2000 VL 74 IS 14 BP 6695 EP 6699 DI 10.1128/JVI.74.14.6695-6699.2000 PG 5 WC Virology SC Virology GA 327WU UT WOS:000087817900057 PM 10864688 ER PT J AU Cefalu, WT Terry, JG Thomas, MJ Morgan, TM Edwards, IJ Rudel, LL Kemnitz, JW Weindruch, R AF Cefalu, WT Terry, JG Thomas, MJ Morgan, TM Edwards, IJ Rudel, LL Kemnitz, JW Weindruch, R TI In vitro oxidation of low-density lipoprotein in two species of nonhuman primates subjected to caloric restriction SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID CORONARY-ARTERY ATHEROSCLEROSIS; AFRICAN-GREEN MONKEYS; RHESUS-MONKEYS; DIETARY RESTRICTION; PROTEIN OXIDATION; FATTY-ACIDS; ALPHA-TOCOPHEROL; SUSCEPTIBILITY; CHOLESTEROL; PLASMA AB Caloric restriction (CR), which increases longevity and retards age-associated diseases in laboratory rodents, is being evaluated in nonhuman primate trials. CR reduces oxidative stress in rodents and appears to improve risk factors for cardiovascular disease in nonhuman primates. We tested the hypothesis that low-density lipoprotein (LDL) oxidizability is reduced in two monkey species (rhesus and cynomolgus) subjected to chronic CR. In both species, no significant differences occurred between CR and control animals on total, LDL, or high-density lipoprotein (HDL) cholesterol. In rhesus monkeys, triglycerides were higher in controls than CR (139 +/- 23 vs 66 +/- 8 mg/dl, p < .01, respectively). LDL from CR rhesus monkeys was reduced in triglyceride content and molecular weight compared to controls, whereas LDL composition in cynomolgus monkeys was similar in CR and control animals. In keeping with minor deviations in lipids, antioxidants, and LDL composition, no consistent differences in in vitro LDL oxidizability were apparent between CR and controls in either species. C1 Univ Vermont, Coll Med, Endocrine Unit, Dept Med, Burlington, VT 05405 USA. Wake Forest Univ, Sch Med, Dept Med Comparat Med & Publ Hlth Sci, Winston Salem, NC 27109 USA. Wisconsin Reg Primate Ctr, Madison, WI USA. Univ Wisconsin, Dept Med, Madison, WI USA. William S Middleton Mem Vet Adm Med Ctr, GRECC, Madison, WI 53705 USA. RP Cefalu, WT (reprint author), Univ Vermont, Coll Med, Endocrine Unit, Dept Med, Given C331, Burlington, VT 05405 USA. FU NIA NIH HHS [R29AG10816, P01AG11915, K01AG00578] NR 35 TC 9 Z9 9 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2000 VL 55 IS 7 BP B355 EP B361 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 331XW UT WOS:000088044800005 PM 10898249 ER PT J AU Pine, ZM Gurland, B Chren, MM AF Pine, ZM Gurland, B Chren, MM TI Report of having slowed down: Evidence for the validity of a new way to inquire about mild disability in elders SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID SELF-RATED HEALTH; OLDER ADULTS; GERIATRIC ASSESSMENT; COMMUNITY; OUTCOMES; PEOPLE; LIFE AB Background. Mild disability in elderly persons may be detected by eliciting reports of modified task performance. even in the absence of reported difficulty. This study provides evidence for the validity of one type of task modification, namely, slowing, as a measure of mild walking disability. Methods. Community-dwelling elders (N = 287) were questioned about whether they were walking indoors as quickly as they had 1 year before and 10 years before. Construct validity was assessed by the degree to which responses to these two questions were logically consistent with a general decline in walking speed, and by determining whether reported slowing was associated with concurrent reports of difficulty walking and with measured gait speed. Predictive validity in subjects without reported difficulty walking was gauged by the association of reported slowing sith adverse walking outcomes at I-year follow-up. Results. Reports of slowing over 10- and 1-year periods were almost uniformly consistent with a general decline in speed. Reported slowing was significantly associated with reported difficulty walking and with slower gait speed. In the subgroup of riders initially reporting no difficulty walking, reported slowing significantly predicted incident difficulty walking at follow-up, as well as other adverse walking outcomes. For example, among elders who reported slowing, 7%. 10%, and 19% developed new difficulty walking indoors, new difficulty walking outdoors, or stopped walking for pleasure, compared with 0%, 0%, and 3% for those who had not reported slowing (p < .05). Conclusions. This study provides evidence for the construct and predictive validity of one type of task modification, namely, slowing in indoor walking. This work contributes to the development of new methods for measuring mild disability, which may in turn form the basis for clinical interventions based on the early identification of functional problems. C1 Univ Calif San Francisco, Mt Zion Ctr Aging, Div Geriatr, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Excellence Acad Geriatr, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. Columbia Univ, Stroud Ctr, New York, NY USA. San Francisco Vet Affairs Med Ctr, San Francisco, CA USA. RP Pine, ZM (reprint author), VA Med Ctr, Div Geriatr, Box 111G,4150 Clement St, San Francisco, CA 94121 USA. FU NCRR NIH HHS [RR00645]; NIA NIH HHS [R01 AG10489, P01 AG07232] NR 21 TC 9 Z9 9 U1 1 U2 2 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUL PY 2000 VL 55 IS 7 BP M378 EP M383 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 331XW UT WOS:000088044800010 PM 10898254 ER PT J AU Alem, AM Sherrard, DJ Gillen, DL Weiss, NS Beresford, SA Heckbert, SR Wong, C Stehman-Breen, C AF Alem, AM Sherrard, DJ Gillen, DL Weiss, NS Beresford, SA Heckbert, SR Wong, C Stehman-Breen, C TI Increased risk of hip fracture among patients with end-stage renal disease SO KIDNEY INTERNATIONAL LA English DT Article DE bone fracture and dialysis; dialysis; osteopenia; age and hip fracture; CAPD; peritoneal dialysis ID OSTEOPOROTIC FRACTURES; ELDERLY MEN; WOMEN; BONE; OSTEODYSTROPHY; EPIDEMIOLOGY; POPULATION; PREVALENCE; MORTALITY; THERAPY AB Background. Although patients with end-stage renal disease (ESRD) are at increased risk for bone loss, the risk of hip fracture in this population is not known. We compared the risk of hip Fracture among dialysis patients with the general population. Methods. We used data from the United States Renal Data System (USRDS) to identify all new Caucasian dialysis patients who began dialysis between January 1, 1989, and December 31, 1996. All hip fractures occurring during this time period were ascertained. The observed number of hip fractures was compared with the expected number based on the experience of residents of Olmstead County (MN, USA). Standardized incidence ratios were calculated as the ratio between observed and expected. The risk attributable to ESRD was calculated as the difference between the observed and expected rate of hip fracture per 1000 person-years. Results. The number of dialysis patients was 326,463 (55.9% male and 44.1% female). There were 6532 hip fractures observed during the follow-up period of 643,831 patient years. The overall incidence of hip fracture was 7.35 per 1000 person years for males and 13.63 per 1000 person years for females. The overall relative risk for hip fracture was 4.44 (95% CI, 4.16 to 3.75) for male dialysis patients and 4.40 (95% CI, 3.17 to 4.64) for female dialysis patients compared with people of the same sex in the general population. While the age-specific relative risk of hip fracture was highest in the youngest age groups, the added risks of fracture associated with dialysis rose steadily with increasing age. The relative risk of hip fracture increased as time since first dialysis increased. Conclusions. The overall risk of hip fracture among Caucasian patients with ESRD is considerably higher than in the general population, independent of age and gender. C1 VA Puget Sound Hlth Care Syst, Div Nephrol, Seattle, WA 98108 USA. Univ Washington, Div Nephrol, Seattle, WA 98195 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA. RP Stehman-Breen, C (reprint author), VA Puget Sound Hlth Care Syst, Div Nephrol, 1660 S Columbian Way,Mailstop 111A, Seattle, WA 98108 USA. NR 27 TC 337 Z9 346 U1 1 U2 10 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD JUL PY 2000 VL 58 IS 1 BP 396 EP 399 DI 10.1046/j.1523-1755.2000.00178.x PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 328VE UT WOS:000087870100044 PM 10886587 ER PT J AU Chang, M Raimondi, SC Ravindranath, Y Carroll, AJ Camitta, B Gresik, MV Steuber, CP Weinstein, H AF Chang, M Raimondi, SC Ravindranath, Y Carroll, AJ Camitta, B Gresik, MV Steuber, CP Weinstein, H TI Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POC) Study 8821 SO LEUKEMIA LA English DT Article DE childhood acute myeloid leukemia; prognostic factors; recursive partitioning analysis ID ACUTE LYMPHOBLASTIC-LEUKEMIA; BONE-MARROW TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; HIGH-DOSE CYTARABINE; CANCER GROUP; MYELODYSPLASTIC SYNDROME; THERAPY; CHEMOTHERAPY; CHILDHOOD; INDUCTION AB The purpose of the paper was to define clinical or biological features associated with the risk for treatment failure for children with acute myeloid leukemia. Data from 560 children and adolescents with newly diagnosed acute myeloid leukemia who entered the Pediatric Oncology Group Study 8821 from June 1988 to March 1993 were analyzed by univariate and recursive partitioning methods. Children with Down syndrome or acute promyelocytic leukemia were excluded from the study. Factors examined included age, number of leukocytes, sex, FAB morphologic subtype, cytogenetic findings, and extramedullary disease at the time of diagnosis. The overall event-free survival (EFS) rate at 4 years was 32.7% (s.e. = 2.2%). Age greater than or equal to 2 years, fewer than 50 x 10(9)/l leukocytes, and t(8;21) or inv(16), and normal chromosomes were associated with higher rates of EFS (P value = 0.003, 0.049, 0.0003, 0.031, respectively), whereas the M5 subtype of AML (P value = 0.0003) and chromosome abnormalities other than t(8;21) and inv(16) were associated with lower rates of EFS (P value = 0.0001). Recursive partitioning analysis defined three groups of patients with widely varied prognoses: female patients with t(8;21), inv(16), or a normal karyotype (n = 89) had the best prognosis (4-year EFS = 55.1%, s.e. = 5.7%); male patients with t(8;21), inv(16) or normal chromosomes (n = 106) had an intermediate prognosis (4-year EFS = 38.1%, s.e. = 5.3%); patients with chromosome abnormalities other than t(8;21) and inv(16) (n = 233) had the worst prognosis (4-year EFS = 27.0%, s.e. = 3.2%). One hundred and thirty-two patients (24%) could not be grouped because of missing cytogenetic data, mainly due to inadequate marrow samples. The results suggest that pediatric patients with acute myeloid leukemia can be categorized into three potential risk groups for prognosis and that differences in sex and chromosomal abnormalities are associated with differences in estimates of EFS. These results are tentative and must be confirmed by a large prospective clinical trial. C1 Univ Florida, Pediat Oncol Grp, Stat Off, Gainesville, FL 32611 USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Barbara Ann Karmanos Canc Inst, Detroit, MI USA. Wayne State Univ, Detroit, MI USA. Univ Alabama Birmingham, Dept Human Genet, Birmingham, AL USA. Midw Childrens Hosp, Milwaukee, WI USA. Baylor Coll Med, Houston, TX 77030 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Childrens Hosp Michigan, 3901 Beaubien Blvd, Detroit, MI 48201 USA. FU NCI NIH HHS [CA-30969, CA-29139, CA-31566] NR 30 TC 49 Z9 53 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD JUL PY 2000 VL 14 IS 7 BP 1201 EP 1207 DI 10.1038/sj.leu.2401832 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 332FM UT WOS:000088063600006 PM 10914543 ER PT J AU Stone, ME AF Stone, ME TI The complete directory for pediatric disorders. SO LIBRARY JOURNAL LA English DT Book Review C1 Massachusetts Gen Hosp Lib, Boston, MA USA. RP Stone, ME (reprint author), Massachusetts Gen Hosp Lib, Boston, MA USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU BOWKER MAGAZINE GROUP CAHNERS MAGAZINE DIVISION PI NEW YORK PA 249 W 17TH ST, NEW YORK, NY 10011 USA SN 0363-0277 J9 LIBR J JI Libr. J. PD JUL PY 2000 VL 125 IS 12 BP 72 EP + PG 2 WC Information Science & Library Science SC Information Science & Library Science GA 334UY UT WOS:000088205100035 ER PT J AU Armstrong, K Popik, S Guerra, C Ubel, PA AF Armstrong, K Popik, S Guerra, C Ubel, PA TI Beliefs about breast cancer risk and use of postmenopausal hormone replacement therapy SO MEDICAL DECISION MAKING LA English DT Article DE postmenopausal hormone replacement therapy; breast cancer risk perception ID WOMENS KNOWLEDGE; AFRICAN-AMERICAN; ATTITUDES; OSTEOPOROSIS; PERCEPTIONS; PREVENTION; ESTROGENS; MORTALITY; BENEFIT; AGE AB Background. Postmenopausal hormone replacement therapy (HRT) decreases the risks of coronary heart disease and osteoporosis, but increases the risk of breast cancer. Although only 20-30% of postmenopausal women in the United States take HRT, the relationship between breast cancer risk perception and use of HRT is not known. Objective. To assess the impact of belief that HRT increases breast cancer risk and high perceived risk of breast cancer on the use of HRT. Design. Cross-sectional mailed survey. Participants. 189 randomly selected postmenopausal women from a general internal medicine practice in the Philadelphia area. Main results. Of the 268 women (67%) who returned surveys, 189 were postmenopausal; 70 (37%) were currently using HRT and 21 (11%) had previously used HRT. Respondents' mean age was 59.6 years: 64% were Caucasian, and 33% had completed college. Fifty-nine women (33%) thought HRT increased the risk of breast cancer, 22 (12%) thought it did not, and 100 (55%) were unsure. Mean perceived lifetime risk of breast cancer was 31% (range 0%-100%). After multivariate adjustment, current use of HRT was inversely associated with age (OR 0.96 for each one-year increase, 95% CI 0.94-0.98), and positively associated with Caucasian race (OR 2.73, 95% CI 1.40-5.32). Use of HRT was not associated with belief that HRT increases the risk of breast cancer, breast cancer risk perception, or perceived severity of breast cancer. Conclusions. Belief that HRT increases the risk of breast cancer and high perceptions of breast cancer risk may not be important barriers to use of HRT. Efforts to improve decision making about HRT should focus on previously established barriers, such as perceptions of menopause and lack of physician discussion. rather than misconceptions about breast cancer risk. C1 Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. Univ Penn, Leonard Davis Inst Hlth Econ, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Philadelphia, PA USA. RP Armstrong, K (reprint author), 1233 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. NR 27 TC 14 Z9 14 U1 0 U2 1 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL-SEP PY 2000 VL 20 IS 3 BP 308 EP 313 DI 10.1177/0272989X0002000307 PG 6 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 333UM UT WOS:000088149200007 PM 10929853 ER PT J AU Halpern, EF Weinstein, MC Hunink, MGM Gazelle, GS AF Halpern, EF Weinstein, MC Hunink, MGM Gazelle, GS TI Representing both first- and second-order uncertainties by Monte Carlo simulation for groups of patients SO MEDICAL DECISION MAKING LA English DT Article DE simulation; probabilistic sensitivity analysis; Monte Carlo; confidence interval; cost-effectiveness; implementation ID COST-EFFECTIVENESS AB Actual implementation of probabilistic sensitivity analysis may lead to misleading or improper conclusions when it is applied to groups of patients rather than individual patients. The practice of combining first- and second-order simulations when modeling the outcome for a group of more than one patient yields an erroneous marginal distribution whenever the parameter values are randomly sampled for each patient while the results are presented as simulated means for the group of patients. This practice results in underrepresenting the second-order uncertainty. it may also distort the shape (especially the symmetry or extent of the tails) in the simulated distribution. As a result, it may lead to premature or incorrect conclusions of superiority. It may also result in inappropriate estimates of the value of further research to inform parameter values. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,DATA Grp, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth Policy & Management, Ctr Risk Anal, Boston, MA 02115 USA. Erasmus Univ, Med Ctr, Dept Epidemiol & Biostat, Program Assessment Radiol Technol, Rotterdam, Netherlands. Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands. RP Halpern, EF (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,DATA Grp, Zero Emerson Pl,Suite 2H, Boston, MA 02114 USA. NR 6 TC 77 Z9 78 U1 0 U2 0 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD JUL-SEP PY 2000 VL 20 IS 3 BP 314 EP 322 DI 10.1177/0272989X0002000308 PG 9 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 333UM UT WOS:000088149200008 PM 10929854 ER PT J AU Kung, JH Chen, GTY AF Kung, JH Chen, GTY TI Intensity modulated radiotherapy dose delivery error from radiation field offset inaccuracy SO MEDICAL PHYSICS LA English DT Article DE multileaf collimator (MLC); field edge; intensity modulation; dosimetry; quality assurance ID DYNAMIC MULTILEAF COLLIMATION; CONFORMAL RADIOTHERAPY; GENERATION; ALGORITHM; SYSTEM AB In Intensity Modulated Radiotherapy (IMRT), irradiation is delivered in a number of small aperture subfields. The fluences shaped by these small apertures are highly sensitive to inaccuracies in multileaf collimator (MLC) calibration. The Radiation Field Offset (RFO) is the difference between a radiation and a light field at the Source to Axis Distance (SAD) for a MLC. An Intensity Modulated Radiotherapy (IMRT) system must incorporate a RFO by closing in all leaf openings. In IMRT, RFO inaccuracy will result in a dose error to the interior of a target volume. We analyze dosimetric consequences of incorporating a wrong RFO into the CORVUS, 1 cm x 1 cm, step and shoot, IMRT system. The following method was employed. First an IMRT plan is generated for a target volume in a phantom, which produces a set of dynamic MLC (DMLC) files with the correct RFO value. To simulate delivery with a wrong RFO value, we wrote a computer code that reads in the DMLC file with the correct RFO value and produces another DMLC with an incorrect RFO specified by a user. Finally the phantom was irradiated with the correct and the incorrect RFO valued DMLC files, and the doses were measured with an ionization chamber. The method was applied to 9 fields, 6 MV, IMRT plans. We measured Dose Error Sensitivity Factor (DESF) for each plan, which ranged from (0-8)% mm(-1). The DESF(x) is defined as a fractional dose error to a point (x) in a target volume per mm of the RFO error, i.e., DESF(x) = \Delta D(x)/D(x)Delta RFO\. Therefore, we concluded that for CORVUS, 6 MV, 1 cm x 1 cm, step and shoot IMRT, RFO must be determined within an accuracy of 0.5 mm if a fractional dose error to a target volume is to be less than 4%. We propose an analytic framework to understand the measured DESF's. From the analysis we conclude that a large DESF was associated with an DMLC file with small average leaf openings. For 1 cm x 1 cm, step and shoot IMRT, the largest possible DESF is predicted to be 20% mm(-1). In addition, we wrote computer code that can calculate a DESF of a DMLC file. The code was written in Mathematica 3.0. The code can be used to screen patient IMRT plans that are highly sensitive to a RFO error. (C) 2000 American Association of Physicists in Medicine. [S0094-2405(00)01907-6]. C1 Massachusetts Gen Hosp, Boston, MA 02144 USA. Harvard Univ, Sch Med, Boston, MA USA. Harvard Univ, Cambridge, MA 02138 USA. RP Kung, JH (reprint author), Massachusetts Gen Hosp, Boston, MA 02144 USA. NR 15 TC 24 Z9 25 U1 1 U2 2 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUL PY 2000 VL 27 IS 7 BP 1617 EP 1622 DI 10.1118/1.599028 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 337QG UT WOS:000088372700015 PM 10947265 ER PT J AU Mylonakis, E Paliou, M Sax, PE Skolnik, PR Baron, MJ Rich, JD AF Mylonakis, E Paliou, M Sax, PE Skolnik, PR Baron, MJ Rich, JD TI Central nervous system aspergillosis in patients with human immunodeficiency virus infection - Report of 6 cases and review SO MEDICINE LA English DT Article ID ACQUIRED-IMMUNE-DEFICIENCY; BONE-MARROW TRANSPLANTATION; INVASIVE ASPERGILLOSIS; PULMONARY ASPERGILLOSIS; IMMUNOCOMPROMISED PATIENTS; HIV-INFECTION; BRAIN-ABSCESS; SYNDROME AIDS; SINUSITIS; MR C1 Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Boston, MA 02115 USA. Brown Univ, Sch Med, Miriam Hosp, Div Clin Immunol, Providence, RI 02912 USA. Tufts Univ, Sch Med, Dept Med, Div Geog Med & Infect Dis, Boston, MA 02111 USA. RP Mylonakis, E (reprint author), Massachusetts Gen Hosp, Div Infect Dis, 55 Fruit St, Boston, MA 02114 USA. FU NIAID NIH HHS [P30-AI-42853]; NIDA NIH HHS [DA00268] NR 50 TC 36 Z9 42 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7974 J9 MEDICINE JI Medicine (Baltimore) PD JUL PY 2000 VL 79 IS 4 BP 269 EP 280 DI 10.1097/00005792-200007000-00008 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 339VN UT WOS:000088498700008 PM 10941356 ER PT J AU Jayaraman, A Yarmush, ML Roth, CM AF Jayaraman, Arul Yarmush, Martin L. Roth, Charles M. TI Dynamics of Gene Expression in Rat Hepatocytes under Stress SO METABOLIC ENGINEERING LA English DT Article AB The response of cells to physical or biochemical stress involves concerted changes in the expression of a large number of genes encoding various functions. We have used a quantitative kinetic RTPCR technique to follow the dynamics of changes in transcription factor and acute-phase mRNA levels in cultured rat hepatocytes subjected to either elevated temperature (40 degrees C) or exposure to the inflammatory cytokine interleukin-6. The profiles of transcription factor gene expression displayed rapid and coordinate regulation, attainment of new steady-states, transitions in some instances from up-regulation to down-regulation (or vice versa), and, for elevated temperature, multiple spikes of up-regulation. Transcripts of acute-phase genes generally displayed relatively small changes during the first few hours followed by more significant changes over the course of tens of hours (elevated temperature) to days (IL-6 exposure). These observations are all consistent with the notion of genetic reprogramming due to a network of interacting transcription factor proteins and transcripts. We utilized a simple transcription/translation model incorporating autoregulation to describe the dynamics of transcription factor gene expression. This model successfully described key features of the transcription factor dynamics, most notably the multiple spikes observed after exposure to elevated temperature. The dynamics of gene expression are rich in information that, with considerably more study, may eventually be exploited to provide insights into the interplay of genetic networks in regulating a variety of cellular responses. (C) 2000 Academic Press C1 [Jayaraman, Arul] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med Surg Serv, Cambridge, MA 02138 USA. Shriners Burns Hosp, Galveston, TX USA. RP Jayaraman, A (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Engn Med Surg Serv, Cambridge, MA 02138 USA. OI Roth, Charles/0000-0002-4924-0721 FU Shriners Hospitals for Children [8570] FX This work was partially supported by funding from the Shriners Hospitals for Children (Grant 8570). NR 52 TC 16 Z9 16 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7176 J9 METAB ENG JI Metab. Eng. PD JUL PY 2000 VL 2 IS 3 BP 239 EP 251 DI 10.1006/mben.2000.0153 PG 13 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA V19NS UT WOS:000208079700009 PM 11056066 ER PT J AU Gerard, HC Schumacher, HR El-Gabalawy, H Goldbach-Mansky, R Hudson, AP AF Gerard, HC Schumacher, HR El-Gabalawy, H Goldbach-Mansky, R Hudson, AP TI Chlamydia pneumoniae present in the human synovium are viable and metabolically active SO MICROBIAL PATHOGENESIS LA English DT Article DE C. pneumoniae; reactive arthritis; bacterial pathogenesis; synovium ID REACTIVE ARTHRITIS; STRAIN TWAR; TRACHOMATIS DNA; GENE; IDENTIFICATION; INFECTION; TISSUE; FLUID AB We demonstrated that chromosomal DNA from Chlamydia pneumoniae is present in synovial tissue in at least some patients with reactive arthritis/Reiter's syndrome and other arthritides. Here, we provide initial molecular evidence that the bacterium is viable and metabolically active when present in the synovium. We used reverse transcription-polymerase chain reaction (RT-PCR) assays targeting primary transcripts from the chlamydial rRNA operons, and mRNA from several C, pneumoniae genes (hsp60, ompA, KDO transferase, Mr=76000 protein), to analyse RNA preparations from synovial tissue of 10 patients with various forms of arthritis; each patient was known to be PCR-positive for C. pneumoniae DNA in synovium prior to RT-PCR assays. Two PCR-negative patients served as controls for RT-PCR assays. in the in patients PCR-positive for C. pneumoniae DNA, RT-PCR assays targeting primary transcripts from the rRNA operons of the organism showed that these molecules were present in each sample, as were transcripts from the bacterial hsp60 gene. Assays targeting mRNAs from the Mr=76000 protein and the KDO transferase genes of C. pneumoniae gave positive results for 6/10 preparations. We were unable to identify mRNA from the chlamydial major outer membrane protein gene (ompA) in any preparation. RNA preparations from the two control patients were negative in all RT-PCR assays targeting C. pneumoniae transcripts. These results indicate that in patients infected with the organism, synovial C. pneumoniae are viable and metabolically active, as are C. trachomatis cells in the same context. Such viability is consistent with a role in long-term contribution to pathogenesis in joint disease. (C) 2000 Academic Press. C1 Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. Univ Penn, Sch Med, Dept Med, Div Rheumatol, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Med Res Serv, Philadelphia, PA 19104 USA. NIAMS, Arthrit & Rheumatism Branch, NIH, Bethesda, MD USA. RP Hudson, AP (reprint author), Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Gordon H Scott Hall,540 E Canfield Ave, Detroit, MI 48201 USA. FU NIAMS NIH HHS [AR42541] NR 24 TC 48 Z9 49 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0882-4010 J9 MICROB PATHOGENESIS JI Microb. Pathog. PD JUL PY 2000 VL 29 IS 1 BP 17 EP 24 DI 10.1006/mpat.2000.0360 PG 8 WC Immunology; Microbiology SC Immunology; Microbiology GA 333LX UT WOS:000088132500003 PM 10873487 ER PT J AU Haake, DA AF Haake, DA TI Spirochaetal lipoproteins and pathogenesis SO MICROBIOLOGY-UK LA English DT Review DE lipoprotein; bacterial outer membrane; pathogenesis ID OUTER SURFACE-PROTEIN; BORRELIA-BURGDORFERI LIPOPROTEINS; VIRULENT TREPONEMA-PALLIDUM; LYME-DISEASE SPIROCHETE; DECORIN-BINDING-PROTEIN; INTEGRAL MEMBRANE-PROTEINS; TOLL-LIKE RECEPTOR-2; MOLECULAR-CLONING; GLYCEROPHOSPHODIESTER PHOSPHODIESTERASE; SYPHILIS SPIROCHETE C1 Vet Affairs Greater Los Angeles Hlth Care Syst, Div Infect Dis, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Haake, DA (reprint author), Vet Affairs Greater Los Angeles Hlth Care Syst, Div Infect Dis, 111F, Los Angeles, CA 90073 USA. FU NIAID NIH HHS [AI34431, R01 AI034431, R21 AI034431, R29 AI034431, R29 AI034431-05] NR 110 TC 122 Z9 133 U1 0 U2 5 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AE, BERKS, ENGLAND SN 1350-0872 J9 MICROBIOL-UK JI Microbiology-(UK) PD JUL PY 2000 VL 146 BP 1491 EP 1504 PN 7 PG 14 WC Microbiology SC Microbiology GA 334ER UT WOS:000088174000001 PM 10878114 ER PT J AU Kinoshita, K Taupin, DR Itoh, H Podolsky, DK AF Kinoshita, K Taupin, DR Itoh, H Podolsky, DK TI Distinct pathways of cell migration and antiapoptotic response to epithelial injury: Structure-function analysis of human intestinal trefoil factor SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EPIDERMAL GROWTH-FACTOR; ACTIVATED PROTEIN-KINASE; PANCREATIC SPASMOLYTIC POLYPEPTIDE; URACIL DNA GLYCOSYLASE; FACTOR RECEPTORS; EGF RECEPTOR; FACTOR-BETA; INDUCED APOPTOSIS; PEPTIDE; EXPRESSION AB The trefoil peptide intestinal trefoil factor (ITF) plays a critical role in the protection of colonic mucosa and is essential to restitution after epithelial damage. These functional properties are accomplished through coordinated promotion of cell migration and inhibition of apoptosis. ITF contains a unique three-looped trefoil motif formed by intrachain disulfide bonds among six conserved cysteine residues, which is thought to contribute to its marked protease resistance. ITF also has a seventh cysteine residue, which permits homodimer formation. A series of cysteine-to-serine substitutions and a C-terminally truncated ITF were made by PCR site-directed mutagenesis. Any alteration of the trefoil motif or truncation resulted in loss of protease resistance. However, neither an intact trefoil domain nor dimerization was required to promote cell migration. This pro-restitution activity correlated with the ability of the ITF mutants to activate mitogen-activated protein (MAP) kinase independent of phosphorylation of the epidermal growth factor (EGF) receptor. In contrast, only intact ITF retained both phosphatidylinositol 3-kinase and the EGF receptor-dependent antiapoptotic effect in HCT116 and IEC-6 cells. The inability to block apoptosis correlated with a loss of trefoil peptide-induced transactivation of the EGF receptor or Akt kinase in HT-29 cells. In addition to defining structural requirements for the functional properties of ITF, these findings demonstrate that distinct intracellular signaling pathways mediate the effects of ITF on cell migration and apoptosis. C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Podolsky, DK (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,GRJ-719, Boston, MA 02114 USA. FU NIDDK NIH HHS [DK46906, DK43351, P30 DK043351, R01 DK046906] NR 59 TC 120 Z9 136 U1 3 U2 18 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2000 VL 20 IS 13 BP 4680 EP 4690 DI 10.1128/MCB.20.13.4680-4690.2000 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 323QL UT WOS:000087576400020 PM 10848594 ER PT J AU Vairo, G Soos, TJ Upton, TM Zalvide, J DeCaprio, JA Ewen, ME Koff, A Adams, JM AF Vairo, G Soos, TJ Upton, TM Zalvide, J DeCaprio, JA Ewen, ME Koff, A Adams, JM TI Bcl-2 retards cell cycle entry through p27(Kip1), pRB relative p130, and altered E2F regulation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID KINASE INHIBITOR; PROTEIN FAMILY; GROWTH-FACTOR; EXPRESSION; P107; DEATH; ACCUMULATION; PROGRESSION; APOPTOSIS; DISTINCT AB Independent of its antiapoptotic function, Bcl-2 can, through an undetermined mechanism, retard entry into the cell cycle. Cell cycle progression requires the phosphorylation by cyclin-dependent kinases (Cdks) of retinoblastoma protein (pRB) family members to free E2F transcription factors. We have explored whether retarded cycle entry is mediated by the Cdk inhibitor p27 or the pRB family. In quiescent fibroblasts, enforced Bcl-2 expression elevated levels of both p27 and the pRB relative p130. Bcl-2 still slowed G(1) progression in cells deficient in pRB but not in those lacking p27 or p130. Hence, pRB is not required, but both p27 and p130 are essential mediators. The ability of p130 to form repressive complexes with E2F4 is implicated, because the retardation by Bcl-2 was accentuated by coexpressed E2F4. A plausible relevant target of p130/E2F4 is the E2F1 gene, because Bcl-2 expression delayed E2F1 accumulation during G(1) progression and overexpression of E2F1 overrode the Bcl-2 inhibition. Hence, Bcl-2 appears to retard cell cycle entry by increasing p27 and p130 levels and maintaining repressive complexes of p130 with E2F4, perhaps to delay E2F1 expression. C1 Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Adams, JM (reprint author), Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3050, Australia. RI Adams, Jerry/E-1199-2013 FU NCI NIH HHS [R01 CA043540, CA80188, R01 CA080188, CA43540] NR 51 TC 108 Z9 111 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 JUL PY 2000 VL 20 IS 13 BP 4745 EP 4753 DI 10.1128/MCB.20.13.4745-4753.2000 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 323QL UT WOS:000087576400026 PM 10848600 ER PT J AU Fleming, JV Wang, TC AF Fleming, JV Wang, TC TI Amino- and carboxy-terminal PEST domains mediate gastrin stabilization of rat L-histidine decarboxylase isoforms SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NF-KAPPA-B; UBIQUITIN-PROTEASOME PATHWAY; ENTEROCHROMAFFIN-LIKE CELLS; INSULIN-DEGRADING ENZYME; STOMACH ECL CELLS; ORNITHINE DECARBOXYLASE; ENDOPLASMIC-RETICULUM; REGULATED DEGRADATION; ACID-SECRETION; MESSENGER-RNA AB Control of enzymatic function by peptide hormones can occur at a number of different levels and can involve diverse pathways that regulate cleavage, intracellular trafficking, and protein degradation. Gastrin is a peptide hormone that binds to the cholecystokinin B-gastrin receptor and regulates the activity of L-histidine decarboxylase (HDC), the enzyme that produces histamine. Here we show that gastrin can increase the steady-state levels of at least six HDC isoforms without affecting HDC mRNA levels. Pulse-chase experiments indicated that HDC isoforms are rapidly degraded and that gastrin-dependent increases are due to enhanced isoform stability. Deletion analysis identified two PEST domains (PEST1 and PEST2) and an intracellular targeting domain (ER2) which regulate HDC protein expression levels. Experiments with PEST domain fusion proteins demonstrated that PEST1 and PEST2 are strong and portable degradation-promoting elements which are positively regulated by both gastrin stimulation and proteasome inhibition. A chimeric protein containing the PEST domain of ornithine decarboxylase was similarly affected, indicating that gastrin can regulate the stability of other PEST domain-containing proteins and does so independently of antizyme/antizyme inhibitor regulation. At the same time, endoplasmic reticulum localization of a fluorescent chimera containing the ER2 domain of HDC was unaltered by gastrin stimulation. We conclude that gastrin stabilization of HDC isoforms is dependent upon two transferable and sequentially unrelated PEST domains that regulate degradation. These experiments revealed a novel regulatory mechanism by which a peptide hormone such as gastrin can disrupt the degradation function of multiple PEST-domain-containing proteins. C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02114 USA. RP Wang, TC (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 32 Fruit St, Boston, MA 02114 USA. FU NIDDK NIH HHS [R01 DK048077, R01 DK48077] NR 50 TC 34 Z9 34 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2000 VL 20 IS 13 BP 4932 EP 4947 DI 10.1128/MCB.20.13.4932-4947.2000 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 323QL UT WOS:000087576400044 PM 10848618 ER PT J AU Kharbanda, S Pandey, P Yamauchi, T Kumar, S Kaneki, M Kumar, V Bharti, A Yuan, ZM Ghanem, L Rana, A Weichselbaum, R Johnson, G Kufe, D AF Kharbanda, S Pandey, P Yamauchi, T Kumar, S Kaneki, M Kumar, V Bharti, A Yuan, ZM Ghanem, L Rana, A Weichselbaum, R Johnson, G Kufe, D TI Activation of MEK kinase 1 by the c-Abl protein tyrosine kinase in response to DNA damage SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MYELOID-LEUKEMIA CELLS; GERMINAL CENTER KINASE; IONIZING-RADIATION; INDUCED APOPTOSIS; MONOCYTIC DIFFERENTIATION; NUCLEAR-LOCALIZATION; NH2-TERMINAL KINASE; SIGNALING PATHWAY; GAMMA-RADIATION; STRESS-RESPONSE AB The c-Abl protein tyrosine kinase is activated by certain DNA-damaging agents and regulates induction of the stress-activated c-Jun N-terminal protein kinase (SAPK). Here we show that nuclear c-Abl associates with MEK kinase 1 (MEKK-1), an upstream effector of the SEK1-->SAPK pathway, in the response of cells to genotoxic stress. The results demonstrate that the nuclear c-Abl binds to MEKK-1 and that c-Abl phosphorylates MEKK-1 in vitro and in vivo. Transient-transfection studies with wild-type and kinase-inactive c-Abl demonstrate c-Abl kinase-dependent activation of MEKK-1. Moreover, c-Abl activates MEKK-1 in vitro and in response to DNA damage. The results also demonstrate that c-AbI induces MEKK-1-mediated phosphorylation and activation of SEK1-SAPK in coupled kinase assays. These findings indicate that c-Abl functions upstream of MEKK-1-dependent activation of SAPK in the response to genotoxic stress. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Mol Biol,Diabet Res Lab, Boston, MA 02114 USA. Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. Natl Jewish Ctr Immunol & Resp Med, Div Basic Sci, Denver, CO 80262 USA. RP Kharbanda, S (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. RI Ghanem, Louis/R-3733-2016 OI Ghanem, Louis/0000-0002-7723-5241 FU NCI NIH HHS [CA55241, CA75216] NR 80 TC 68 Z9 69 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2000 VL 20 IS 14 BP 4979 EP 4989 DI 10.1128/MCB.20.14.4979-4989.2000 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327XP UT WOS:000087820000003 PM 10866655 ER PT J AU Vazquez, F Ramaswamy, S Nakamura, N Sellers, WR AF Vazquez, F Ramaswamy, S Nakamura, N Sellers, WR TI Phosphorylation of the PTEN tail regulates protein stability and function SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID FORKHEAD TRANSCRIPTION FACTOR; TUMOR-SUPPRESSOR GENE; PHOSPHATASE-ACTIVITY; COWDEN-DISEASE; PHOSPHATIDYLINOSITOL 3-KINASE; GERMLINE MUTATIONS; FACTOR FKHR; CELL-DEATH; KINASE-B; AKT AB The PTEN gene is a tumor suppressor localized in the frequently altered chromosomal region 10q23. The tumor suppressor function of the PTEN protein (PTEN) has been linked to its ability to dephosphorylate the lipid second-messenger phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate and, by doing so, to antagonize the phosphoinositide 3-kinase pathway. The PTEN protein consists of an amino-terminal phosphatase domain, a lipid binding C2 domain, and a 50-amino-acid C-terminal domain (the ''tail") of unknown function. A number of studies have shown that the tail is dispensable for both phosphatase activity and blocking cell growth. Here, we show that the PTEN tail is necessary for maintaining protein stability and that it also acts to inhibit PTEN function. Thus, removing the tail results in a loss of stability but does not result in a loss of function because the resultant protein is more active. Furthermore, tail-dependent regulation of stability and activity is linked to the phosphorylation of three residues (S380, T382, and T383) within the tail. Therefore, the tail is likely to mediate the regulation of PTEN function through phosphorylation. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Sellers, WR (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [K11CA65594] NR 47 TC 479 Z9 492 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2000 VL 20 IS 14 BP 5010 EP 5018 DI 10.1128/MCB.20.14.5010-5018.2000 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327XP UT WOS:000087820000006 PM 10866658 ER PT J AU de Mora, JF Brown, M AF de Mora, JF Brown, M TI AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; BREAST-CANCER; NUCLEAR RECEPTORS; MAP KINASE; TRANSCRIPTIONAL COACTIVATOR; HISTONE ACETYLTRANSFERASE; BINDING DOMAIN; PATHWAYS; COMPLEX; CELLS AB Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Brown, M (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. EM myles_brown@dfci.harvard.edu RI Myles, Brown/B-6906-2008; OI Brown, Myles/0000-0002-8213-1658 NR 43 TC 298 Z9 301 U1 1 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 EI 1098-5549 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2000 VL 20 IS 14 BP 5041 EP 5047 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327XP UT WOS:000087820000009 ER PT J AU Yoon, JC Chickering, TW Rosen, ED Dussault, B Qin, YB Soukas, A Friedman, JM Holmes, WE Spiegelman, BM AF Yoon, JC Chickering, TW Rosen, ED Dussault, B Qin, YB Soukas, A Friedman, JM Holmes, WE Spiegelman, BM TI Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PPAR-GAMMA; 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2); EXPRESSION CLONING; INSULIN-RESISTANCE; TIE2 RECEPTOR; IN-VIVO; LIGAND; ALPHA; ANGIOGENESIS; REGULATOR AB The nuclear receptor peroxisome proliferator-activated receptor gamma regulates adipose differentiation and systemic insulin signaling via ligand-dependent transcriptional activation of target genes. However, the identities of the biologically relevant target genes are largely unknown. Here we describe the isolation and characterization of a novel target gene induced by PPAR gamma ligands, termed PGAR (for PPAR gamma angiopoietin related), which encodes a novel member of the angiopoietin family of secreted proteins. The transcriptional induction of PGAR follows a rapid time course typical of immediate-early genes and occurs in the absence of protein synthesis. The expression of PGAR is predominantly localized to adipose tissues and placenta and is consistently elevated in genetic models of obesity. Hormone-dependent adipocyte differentiation coincides with a dramatic early induction of the PGAR transcript. Alterations in nutrition and leptin administration are found to modulate the PGAR expression in vivo. Taken together, these data suggest a possible role for PGAR in the regulation of systemic lipid metabolism or glucose homeostasis. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Millennium Pharmaceut Inc, Cambridge, MA 02139 USA. Rockefeller Univ, Mol Genet Lab, New York, NY 10021 USA. RP Spiegelman, BM (reprint author), Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NIDDK NIH HHS [DK31405, R01 DK031405, R37 DK031405] NR 33 TC 240 Z9 254 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUL PY 2000 VL 20 IS 14 BP 5343 EP 5349 DI 10.1128/MCB.20.14.5343-5349.2000 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327XP UT WOS:000087820000038 PM 10866690 ER PT J AU Michael, MD Kulkarni, RN Postic, C Previs, SF Shulman, GI Magnuson, MA Kahn, CR AF Michael, MD Kulkarni, RN Postic, C Previs, SF Shulman, GI Magnuson, MA Kahn, CR TI Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction SO MOLECULAR CELL LA English DT Article ID DEPENDENT DIABETES-MELLITUS; MESSENGER-RNA STABILITY; PANCREATIC BETA-CELLS; GENE-EXPRESSION; FATTY-ACID; GLUCOSE OUTPUT; RECEPTOR SUBSTRATE-1; GLYCOGEN-SYNTHASE; RENAL METABOLISM; PRIMARY CULTURES AB The liver plays a central role in the control of glucose homeostasis and is subject to complex regulation by substrates, insulin, and other hormones. To investigate the effect of the loss of direct insulin action in liver, we have used the Cre-loxP system to inactivate the insulin receptor gene in hepatocytes. Liver-specific insulin receptor knockout (LIRKO) mice exhibit dramatic insulin resistance, severe glucose intolerance, and a failure of insulin to suppress hepatic glucose production and to regulate hepatic gene expression. These alterations are paralleled by marked hyperinsulinemia due to a combination of increased insulin secretion and decreased insulin clearance. With aging, the LIRKO liver exhibits morphological and functional changes, and the metabolic phenotype becomes less severe, Thus, insulin signaling in liver is critical in regulating glucose homeostasis and maintaining normal hepatic function. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06536 USA. RP Kahn, CR (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RI Magnuson, Mark/B-1335-2009 OI Magnuson, Mark/0000-0002-8824-6499 FU NIDDK NIH HHS [F32 DK09825, P01 DK42502, R01 DK040936, R01 DK31036] NR 73 TC 644 Z9 670 U1 3 U2 32 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell. PD JUL PY 2000 VL 6 IS 1 BP 87 EP 97 DI 10.1016/S1097-2765(00)00010-1 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 345DD UT WOS:000088799400009 PM 10949030 ER PT J AU Sena-Esteves, M Saeki, Y Fraefel, C Breakefield, XO AF Sena-Esteves, M Saeki, Y Fraefel, C Breakefield, XO TI HSV-1 amplicon vectors - Simplicity and versatility SO MOLECULAR THERAPY LA English DT Review ID SIMPLEX-VIRUS TYPE-1; EPSTEIN-BARR-VIRUS; BACTERIAL ARTIFICIAL CHROMOSOME; INDUCIBLE GENE-EXPRESSION; TYROSINE-HYDROXYLASE; HUMAN-CELLS; LONG-TERM; IN-VIVO; REPLICATION-COMPETENT; BETA-GALACTOSIDASE C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurogenet Unit, Charlestown, MA 02129 USA. Childrens Hosp Philadelphia, Metab & Biochem Genet Unit, Philadelphia, PA 19104 USA. Osaka Univ, Grad Sch Med, Div Gene Therapy Sci, Suita, Osaka, Japan. Univ Zurich, Inst Virol, Zurich, Switzerland. RP Breakefield, XO (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurogenet Unit, CNY 6205,Bldg 149,13th St, Charlestown, MA 02129 USA. NR 65 TC 71 Z9 72 U1 0 U2 1 PU ACADEMIC PRESS INC 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 JUL PY 2000 VL 2 IS 1 BP 9 EP 15 DI 10.1006/mthe.2000.0096 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 367EH UT WOS:000090048400005 PM 10899823 ER PT J AU Tarsy, D Bhattacharyya, N Borodic, G AF Tarsy, D Bhattacharyya, N Borodic, G TI Myasthenia gravis after botulinum toxin A for Meige syndrome SO MOVEMENT DISORDERS LA English DT Article ID INJECTIONS; DISTANT; DYSTONIA; PATIENT C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA USA. RP Tarsy, D (reprint author), Beth Israel Deaconess Med Ctr, 330 Brookline Ave, Boston, MA 02215 USA. NR 15 TC 11 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD JUL PY 2000 VL 15 IS 4 BP 736 EP 738 DI 10.1002/1531-8257(200007)15:4<736::AID-MDS1023>3.0.CO;2-9 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 333MA UT WOS:000088132800023 PM 10928589 ER PT J AU Poznansky, MC Evans, RH Foxall, RB Olszak, IT Piascik, AH Hartman, KE Brander, C Meyer, TH Pykett, MJ Chabner, KT Kalams, SA Rosenzweig, M Scadden, DT AF Poznansky, MC Evans, RH Foxall, RB Olszak, IT Piascik, AH Hartman, KE Brander, C Meyer, TH Pykett, MJ Chabner, KT Kalams, SA Rosenzweig, M Scadden, DT TI Efficient generation of human T cells from a tissue-engineered thymic organoid SO NATURE BIOTECHNOLOGY LA English DT Article DE T lymphocytes; stem cells; hematopoiesis; thymus ID FETAL LIVER; STEM-CELLS; BONE-MARROW; IN-VITRO; MICROENVIRONMENTS; DIFFERENTIATION; PRECURSORS; EXPRESSION; PRODUCTS; CULTURE AB Biocompatible inorganic matrices have been used to enhance bone repair by integrating with endogenous bone architecture. Hypothesizing that a three-dimensional framework might support reconstruction of other tissues as well, we assessed the capacity of a tantalum-coated carbon matrix to support reconstitution of functioning thymic tissue. We engineered a thymic organoid by seeding matrices with murine thymic stroma. Co-culture of human bone marrow-derived hematopoietic progenitor cells within this xenogeneic environment generated mature functional T cells within 14 days. The proportionate T-cell yield from this system was highly reproducible, generating over 70% CD3(+) T cells from either AC133(+) or CD34(+) progenitor cells. Cultured T cells expressed a high level of T-cell receptor excision circles (TREC), demonstrating de novo T lymphopoiesis, and function of fully mature T cells. This system not only facilitates analysis of the T-lymphopoietic potential of progenitor cell populations; it also permits ex vivo genesis of T cells for possible applications in treatment of immunodeficiency. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, AIDS Res Ctr,Div Infect Dis, Boston, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, MGH Canc Ctr, Boston, MA 02129 USA. Cytomatrix, Woburn, MA 01801 USA. RP Scadden, DT (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, AIDS Res Ctr,Div Infect Dis, Boston, MA 02129 USA. OI Foxall, Russell/0000-0001-9821-0708 NR 27 TC 78 Z9 80 U1 2 U2 11 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD JUL PY 2000 VL 18 IS 7 BP 729 EP 734 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 331YN UT WOS:000088046400020 PM 10888839 ER PT J AU Ohh, M Park, CW Ivan, N Hoffman, MA Kim, TY Huang, LE Pavletich, N Chau, V Kaelin, WG AF Ohh, M Park, CW Ivan, N Hoffman, MA Kim, TY Huang, LE Pavletich, N Chau, V Kaelin, WG TI Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein SO NATURE CELL BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR PROTEIN; FACTOR 1-ALPHA; PROTEASOME PATHWAY; ELONGIN-B; TRANSCRIPTION; COMPLEX; GENE; IDENTIFICATION; STABILIZATION; DISEASE AB von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome that is characterized by the development of multiple vascular tumors and is caused by inactivation of the von Hippel-Lindau protein (pVHL). Here we show that pVHL, through its beta-domain, binds directly to hypoxia-inducible factor (HIF), thereby targeting HIF for ubiquitination in an alpha-domain-dependent manner. This is the first function to be ascribed to the pVHL beta-domain. Furthermore, we provide the first direct evidence that pVHL has a function analogous to that of an F-box protein, namely, to recruit substrates to a ubiquitination machine. These results strengthen the link between overaccumulation of HIF and development of VHL disease. C1 Brigham & Womens Hosp, Dept Med, Boston, MA 02115 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. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Hematol, Boston, MA 02115 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Penn State Univ, Sch Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. RP Kaelin, WG (reprint author), Brigham & Womens Hosp, Dept Med, 75 Francis St, Boston, MA 02115 USA. RI Ivan, Mircea/A-8109-2012; Kim, Tae-You/J-2750-2012 NR 20 TC 953 Z9 974 U1 5 U2 35 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUL PY 2000 VL 2 IS 7 BP 423 EP 427 PG 5 WC Cell Biology SC Cell Biology GA 333MK UT WOS:000088133700018 PM 10878807 ER PT J AU Chen, M Ona, VO Li, MW Ferrante, RJ Fink, KB Zhu, S Bian, J Guo, L Farrell, LA Hersch, SM Hobbs, W Vonsattel, JP Cha, JHJ Friedlander, RM AF Chen, M Ona, VO Li, MW Ferrante, RJ Fink, KB Zhu, S Bian, J Guo, L Farrell, LA Hersch, SM Hobbs, W Vonsattel, JP Cha, JHJ Friedlander, RM TI Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease SO NATURE MEDICINE LA English DT Article ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; NEURONAL INTRANUCLEAR INCLUSIONS; POLYGLUTAMINE TRACT; MICE DEFICIENT; BRAIN; DYSFUNCTION; APOPTOSIS; PROTEASE; GENE; TETRACYCLINES AB Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg,Neurosurg Serv,Neuroapoptosis Lab, Boston, MA 02115 USA. Bedford VA Med Ctr, Ctr Geriatr Res Educ & Clin, Bedford, MA USA. Boston Univ, Sch Med, Bedford, MA 01730 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. Univ Bonn, Sch Med, Dept Pharmacol, D-5300 Bonn, Germany. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol, Boston, MA 02114 USA. Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neuropathol, Boston, MA 02114 USA. RP Friedlander, RM (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Surg,Neurosurg Serv,Neuroapoptosis Lab, Boston, MA 02115 USA. RI Friedlander, Robert/A-2845-2016 OI Friedlander, Robert/0000-0003-4423-9219 NR 31 TC 706 Z9 738 U1 2 U2 31 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUL PY 2000 VL 6 IS 7 BP 797 EP + PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 331VV UT WOS:000088040100037 PM 10888929 ER PT J AU Anderson, AJ Stoltzner, S Lai, F Su, J Nixon, RA AF Anderson, AJ Stoltzner, S Lai, F Su, J Nixon, RA TI Morphological and biochemical assessment of DNA damage and apoptosis in Down syndrome and Alzheimer disease, and effect of postmortem tissue archival on TUNEL SO NEUROBIOLOGY OF AGING LA English DT Article DE Alzheimer disease; apoptosis; cell death; DNA damage; high molecular weight DNA fragmentation; necrosis; neurodegeneration; postmortem tissue archival; TUNEL ID BETA-AMYLOID ACCUMULATION; CELL-DEATH; IN-SITU; CORTICAL-NEURONS; PLAQUE-FORMATION; INTERNUCLEOSOMAL FRAGMENTATION; NEUROFIBRILLARY TANGLES; AGED CANINE; BRAIN; NECROSIS AB We have previously shown that Alzheimer disease (AD) brain exhibits terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) for DNA damage and morphological evidence for apoptosis. Down syndrome (DS) is a neurodegenerative disorder that exhibits significant neuropathological parallels with AD. In accordance with these parallels and the need to clarify the mechanism of cell death in DS and AD, we investigated two principal issues in the present study. First, we investigated the hypothesis that TUNEL labeling for DNA damage and morphorogical evidence for apoptosis is also present in the DS brain. All DS cases employed had a neuropathological diagnosis of AD. Analysis of these cases showed that DS brain exhibits a significant increase in the number of TUNEL-labeled nuclei relative to controls matched for age, Postmortem Delay, and Archival Length, and that a subset of TUNEL-positive nuclei exhibits apoptotic morphologies. We also report that Archival Length in 10% formalin can significantly affect TUNEL labeling in postmortem human brain, and therefore, that Archival Length must be controlled for as a variable in this type of study. Second, we investigated whether biochemical evidence for the mechanism of cell death in DS and AD could be detected. To address this question we employed pulsed-field gel electrophoresis (PFGE) as a sensitive method to evaluate DNA integrity. Although apoptotic oligonucleosomal laddering has not previously been observed in AD, PFGE of DNA from control, DS and AD brain in the present study revealed evidence of high molecular weight DNA fragmentation indicative of apoptosis. This represents biochemical support for an apoptotic mechanism of cell death in DS and AD. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Univ Calif Irvine, Inst Brain Aging & Dementia, Irvine, CA 92697 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NYU, Nathan Klein Inst, Dept Psychiat, Orangeburg, NY 10962 USA. RP Anderson, AJ (reprint author), Univ Calif Irvine, Inst Brain Aging & Dementia, 1113 Gillespie NRF, Irvine, CA 92697 USA. RI Anderson, Aileen/H-5926-2012 FU NIA NIH HHS [AG10916]; PHS HHS [5T3219905] NR 68 TC 52 Z9 56 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUL-AUG PY 2000 VL 21 IS 4 BP 511 EP 524 DI 10.1016/S0197-4580(00)00126-3 PG 14 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 342VR UT WOS:000088666300003 PM 10924764 ER PT J AU Frank, LM Brown, EN Wilson, M AF Frank, LM Brown, EN Wilson, M TI Trajectory encoding in the hippocampus and entorhinal cortex SO NEURON LA English DT Article ID FREELY-MOVING RATS; SPATIAL FIRING PATTERNS; SINGLE UNIT-ACTIVITY; PLACE CELLS; NEURONAL-ACTIVITY; WORKING-MEMORY; DIRECTION; SYSTEM; SPACE; POSTSUBICULUM AB We recorded from single neurons in the hippocampus and entorhinal cortex (EC) of rats to investigate the role of these structures in navigation and memory representation. Our results revealed two novel phenomena: first, many cells in CA1 and the EC fired at significantly different rates when the animal was in the same position depending on where the animal had come from or where it was going. Second, cells in deep layers of the EC, the targets of hippocampal outputs, appeared to represent the similarities between locations on spatially distinct trajectories through the environment. Our findings suggest that the hippocampus represents the animal's position in the context of a trajectory through space and that the EC represents regularities across different trajectories that could allow for generalization across experiences. C1 MIT, Ctr Learning & Memory, RIKEN MIT Neurosci Res Ctr, Cambridge, MA 02139 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med,Dept Anesthesia & Crit Care, MIT Div Hlth Sci & Technol,Stat Res Lab, Boston, MA 02114 USA. RP Frank, LM (reprint author), MIT, Ctr Learning & Memory, RIKEN MIT Neurosci Res Ctr, 77 Massachusetts Ave, Cambridge, MA 02139 USA. OI Frank, Loren/0000-0002-1752-5677 FU NIMH NIH HHS [R01 MH059733, K02 MH061637, MH59733, MH61637] NR 34 TC 320 Z9 322 U1 3 U2 17 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL PY 2000 VL 27 IS 1 BP 169 EP 178 DI 10.1016/S0896-6273(00)00018-0 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 339XU UT WOS:000088503800019 PM 10939340 ER PT J AU Sauman, I Tsai, T Roca, AL Reppert, SM AF Sauman, I Tsai, T Roca, AL Reppert, SM TI Period protein is necessary for circadian control of egg hatching behavior in the silkmoth Antheraea pernyi (vol 17, pg 901, 1996) SO NEURON LA English DT Correction C1 Massachusetts Gen Hosp, Lab Dev Chronobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Sauman, I (reprint author), Acad Sci Czech Republ, Inst Entomol, Branisovska 31, CR-37005 Ceske Budejovice, Czech Republic. NR 1 TC 0 Z9 0 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL PY 2000 VL 27 IS 1 BP U12 EP U12 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 339XU UT WOS:000088503800021 ER PT J AU Allen, DN Goldstein, G Forman, SD Keshavan, MS van Kammen, DP Sanders, RD AF Allen, DN Goldstein, G Forman, SD Keshavan, MS van Kammen, DP Sanders, RD TI Neurologic examination abnormalities in schizophrenia with and without a history of alcoholism SO NEUROPSYCHIATRY NEUROPSYCHOLOGY AND BEHAVIORAL NEUROLOGY LA English DT Article ID SOFT SIGNS; SUBSTANCE-ABUSE; NEUROCOGNITIVE FUNCTION; DYSFUNCTION; PREVALENCE; DISORDERS AB Objective: The current investigation examines the impact of a past history of alcoholism on neurologic examination abnormalities in schizophrenia (SZ). Background: Individuals with SZ have a high rate of comorbid alcohol use disorders (AUDs), but relatively little is known about the potential adverse consequences of alcoholism for neuropsychological and neurologic functioning in SZ. Recent evidence suggests consistent but subtle neurocognitive differences between groups, with more prominent differences in neurologic examination abnormalities. Method: Thirty-three male patients with SZ or SZ/AUDs were evaluated using a modified Neurologic Evaluation Scale (NES) and ratings for positive and negative symptoms. Results: The SZ/AUD group exhibited a greater impairment in the Cognitive-Perceptual factor of the Neurologic Evaluation Scale. Greater impairment in the tandem-Romberg factor or in motor items was not found, nor were groups different based on positive or negative symptoms. Conclusions: A history of alcoholism in SZ is associated with greater overall neurologic impairment, particularly in the area of cognitive-perceptual dysfunction, an area often found to be impaired in patients with schizophrenia without alcoholism. C1 Univ Nevada, Dept Psychol, Las Vegas, NV 89154 USA. Vet Affairs Pittsburgh Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Robert Wood Johnson Pharmaceut Res Inst, Raritan, NJ USA. RP Sanders, RD (reprint author), 116 A-H,7180 Highland Dr, Pittsburgh, PA 15206 USA. FU NIMH NIH HHS [MH-44841] NR 30 TC 21 Z9 21 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-878X J9 NEUROPSY NEUROPSY BE JI Neuropsychiatr. Neuropsychol. Behav. Neurol. PD JUL PY 2000 VL 13 IS 3 BP 184 EP 187 PG 4 WC Clinical Neurology; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 332PH UT WOS:000088082300006 PM 10910089 ER PT J AU Jacobson, AF AF Jacobson, AF TI Association of prostate-specific antigen levels and patterns of benign and malignant uptake detected on bone scintigraphy in patients with newly diagnosed prostate carcinoma SO NUCLEAR MEDICINE COMMUNICATIONS LA English DT Article ID NO KNOWN METASTASES; CANCER-PATIENTS; SCAN; PHOSPHATASE; ABNORMALITIES AB The bone scan patterns of benign and malignant uptake in 432 patients with newly diagnosed prostate carcinoma were reviewed in relation to prostate-specific antigen (PSA) levels determined within 4 months of scintigraphy. Scan results were categorized in terms of likelihood of metastatic disease and anatomical locations of benign and malignant lesions were tabulated. At least one suspect focus was identified in 138 scans (32%), and metastatic bone disease was present in 38 (9%). Metastatic disease prevalence increased from 1% for PSA <20 ng.ml(-1) to 58% for PSA>100 ng.ml(-1). Among patients with PSA>20 ng.ml(-1) (n = 157), 70 (45%) had at least one bone scan finding of concern for metastases and 35 (22%) proved to have metastatic disease. Almost all scans with metastases had either limited disease (less than or equal to 5 suspicious lesions; n = 16; 42%) or extensive metastases (>20 abnormalities; n = 19; 50%). The majority of patients with Limited skeletal metastases had PSA < 100 ng.ml(-1) (11/16; 69%), while almost all patients with extensive skeletal involvement had PSA,100 ng.ml(-1) (17/19; 89%). Among those with Limited metastatic disease, most (13/16; 81%) had at least one lesion in the pelvis or sacrum; the next most common sites were in the thoracic and lumbar spine (six each; 38%). in scans with a low to moderate suspicion for bone metastases, the only anatomical site with a significantly higher prevalence of malignant than benign lesions was the pelvis. ((C) 2000 Lippincott Williams & Wilkins). C1 VA Puget Sound Hlth Care Syst, Seattle Div, Nucl Med Sect 115, Seattle, WA 98108 USA. RP Jacobson, AF (reprint author), VA Puget Sound Hlth Care Syst, Seattle Div, Nucl Med Sect 115, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 25 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0143-3636 J9 NUCL MED COMMUN JI Nucl. Med. Commun. PD JUL PY 2000 VL 21 IS 7 BP 617 EP 622 DI 10.1097/00006231-200007000-00003 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 341AE UT WOS:000088568200003 PM 10994663 ER PT J AU Alpert, JE Mischoulon, D Nierenberg, AA Fava, M AF Alpert, JE Mischoulon, D Nierenberg, AA Fava, M TI Nutrition and depression: Focus on folate SO NUTRITION LA English DT Article ID FOLIC-ACID; HOMOCYSTEINE CONCENTRATIONS; PSYCHIATRIC-DISORDERS; CELL FOLATE; DEFICIENCY; ILLNESS; SERUM; SUPPLEMENTS; INPATIENTS; THERAPY C1 Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA USA. RP Alpert, JE (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, WACC 812,15 Parkman St, Boston, MA 02114 USA. OI Alpert, Jonathan/0000-0002-4332-908X NR 47 TC 78 Z9 80 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0899-9007 J9 NUTRITION JI Nutrition PD JUL-AUG PY 2000 VL 16 IS 7-8 BP 544 EP 546 DI 10.1016/S0899-9007(00)00327-0 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 337RF UT WOS:000088374900027 PM 10906550 ER PT J AU Proctor, SP AF Proctor, SP TI Chemical sensitivity and Gulf War veterans' illnesses SO OCCUPATIONAL MEDICINE-STATE OF THE ART REVIEWS LA English DT Article ID SELF-REPORTED EXPOSURES; PERSIAN-GULF; HEALTH-STATUS; GENERAL-POPULATION; CHRONIC FATIGUE; SYMPTOMS; PREVALENCE; ASSOCIATION; DEFINITION; REGISTRY C1 VA Boston Healthcare Syst, Boston Environm Hazards Ctr 116B 4, Boston, MA 02130 USA. RP Proctor, SP (reprint author), VA Boston Healthcare Syst, Boston Environm Hazards Ctr 116B 4, 150 S Huntington Ave, Boston, MA 02130 USA. FU PHS HHS [U50/CCU114464-03] NR 71 TC 9 Z9 9 U1 1 U2 1 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 0885-114X J9 OCCUP MED JI Occup. Med.-State Art Rev. PD JUL-SEP PY 2000 VL 15 IS 3 BP 587 EP 599 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 353TM UT WOS:000089291600009 PM 10903552 ER PT J AU Cole, BJ Romeo, AA Warner, JJP AF Cole, BJ Romeo, AA Warner, JJP TI Arthroscopic Bankart repair with the Suretac device for traumatic anterior shoulder instability in athletes SO OPERATIVE TECHNIQUES IN SPORTS MEDICINE LA English DT Article DE patient selection; traumatic anterior instability; Bankart lesion; bioabsorbable implant ID INFERIOR GLENOHUMERAL LIGAMENT; STAPLE CAPSULORRHAPHY; CAPSULAR SHIFT; SUTURE REPAIR; DISLOCATION; STABILIZATION; RECONSTRUCTION AB Arthroscopic treatment of anterior shoulder instability in the athlete has evolved tremendously over the past decade. Currently, most techniques include the use of suture and suture anchors. However, the variety of arthroscopic instruments and techniques that are available shows the complexity of inh a-articular tissue fixation, which includes anchor placement, suture passing, and knot tying. Stabilization using the Suretac device (Acufex Microsurgical, Mansfield, MA) simplifies tissue fixation by eliminating the need for arthroscopic suture passing and intraarticular knot tying. However, a successful outcome is highly dependent on accurate patient selection. Preoperative evaluation, examination under anesthesia, and the pathoanatomy defined by a thorough arthroscopic examination suggest the most effective treatment strategy. The ideal candidate for shoulder stabilization using the Suretac device is an athlete with a relatively pure traumatic anterior instability pattern with detachment pathology (eg, a Bankart lesion) and minimal capsular deformation. C1 Rush Presbyterian St Lukes Med Ctr, Dept Orthopaed Surg, Shoulder Sect, Chicago, IL 60612 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Harvard Shoulder Serv, Boston, MA USA. RP Cole, BJ (reprint author), 1725 W Harrison,Suite 1063, Chicago, IL 60612 USA. OI Romeo, Anthony/0000-0003-4848-3411 NR 71 TC 0 Z9 0 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 1060-1872 J9 OPER TECHN SPORT MED JI Oper. Tech. Sports Med. PD JUL PY 2000 VL 8 IS 3 BP 197 EP 205 DI 10.1053/otsm.2000.9798 PG 9 WC Sport Sciences; Surgery SC Sport Sciences; Surgery GA 366DQ UT WOS:000089989900003 ER PT J AU Gragoudas, ES AF Gragoudas, ES TI Stereotactic radiosurgery of large uveal melanomas with the gamma-knife - Discussion SO OPHTHALMOLOGY LA English DT Editorial Material ID IRRADIATION C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02115 USA. RP Gragoudas, ES (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Boston, MA 02115 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD JUL PY 2000 VL 107 IS 7 BP 1387 EP 1388 DI 10.1016/S0161-6420(00)00151-2 PG 2 WC Ophthalmology SC Ophthalmology GA 331KV UT WOS:000088019000049 ER PT J AU Lin, CP Webb, RH AF Lin, CP Webb, RH TI Fiber-coupled multiplexed confocal microscope SO OPTICS LETTERS LA English DT Article ID OPTICAL MICROSCOPE AB We describe a new parallel scanning mechanism for confocal microscopy that is inherently fiber-optic compatible and that retains the simplicity of the line scanning confocal microscope. The method works by employing an incoherent fiber-optic bundle that maps a line illumination pattern back on itself on double passing, while separating the fibers that carry photons from out-of-focus sample planes. The transformation permits efficient rejection of out-of-focus photons by a slit aperture. (C) 2000 Optical Society of America. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed, Boston, MA 02114 USA. RP Lin, CP (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed, Boston, MA 02114 USA. NR 16 TC 13 Z9 14 U1 2 U2 5 PU OPTICAL SOC AMER PI WASHINGTON PA 2010 MASSACHUSETTS AVE NW, WASHINGTON, DC 20036 USA SN 0146-9592 J9 OPT LETT JI Opt. Lett. PD JUL 1 PY 2000 VL 25 IS 13 BP 954 EP 956 DI 10.1364/OL.25.000954 PG 3 WC Optics SC Optics GA 330CC UT WOS:000087944400006 PM 18064238 ER PT J AU Vacanti, CA Vacanti, JP AF Vacanti, CA Vacanti, JP TI The science of tissue engineering SO ORTHOPEDIC CLINICS OF NORTH AMERICA LA English DT Article ID INDUCED OSTEOGENESIS; ARTICULAR-CARTILAGE; BONE-FORMATION; CHONDROCYTES; REPAIR; TRANSPLANTATION; DEFECTS; CRANIOPLASTY; ALLOGRAFTS; SURFACES AB This article reviews the development of tissue engineering during the last decade. The science began to fully develop in association with efforts to combine viable cells with biocompatible material. The history and scope of this new field are presented. Basic principles of cell biology, materials, and technologies are discussed. Future challenges in the field are presented. C1 Univ Massachusetts, Sch Med, Dept Anesthesiol, Ctr Tissue Engn, Worcester, MA 01655 USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Vacanti, CA (reprint author), Univ Massachusetts, Sch Med, Dept Anesthesiol, Ctr Tissue Engn, 55 Lake Ave N, Worcester, MA 01655 USA. NR 41 TC 56 Z9 67 U1 0 U2 8 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0030-5898 J9 ORTHOP CLIN N AM JI Orthop. Clin. North Am. PD JUL PY 2000 VL 31 IS 3 BP 351 EP + DI 10.1016/S0030-5898(05)70155-3 PG 6 WC Orthopedics SC Orthopedics GA 340GJ UT WOS:000088524500002 PM 10882462 ER PT J AU Mao, JR Chen, LL AF Mao, JR Chen, LL TI Systemic lidocaine for neuropathic pain relief SO PAIN LA English DT Review DE lidocaine; ectopic discharge; neuropathic pain; sodium channel; mexiletine ID DORSAL-ROOT GANGLION; PERIPHERAL-NERVE INJURY; INTRAVENOUS LIDOCAINE; DIABETIC NEUROPATHY; LOCAL-ANESTHETICS; SENSORY NEURONS; SODIUM-CHANNELS; ADRENERGIC SENSITIVITY; POSTHERPETIC NEURALGIA; NOCICEPTIVE BEHAVIORS AB The effectiveness of systemic lidocaine in relieving acute and chronic pain has been recognized for over 35 years. In particular, systemic Lidocaine has been utilized both as a diagnostic and therapeutic tool for intractable neuropathic pain during the last decade. The introduction of oral lidocaine congeners such as mexiletine has significantly extended the usage of lidocaine therapy in chronic pain settings. However, a number of clinical issues remain to be addressed including (1) an effective, meaningful dose range for the clinical lidocaine test, (2) the predictive value of the lidocaine test for an oral trial of Lidocaine congeners, (3) identification of pain symptoms and signs relieved by systemic lidocaine, (4) comparisons of therapeutic effects between systemic lidocaine and its oral congeners, and (5) long-term outcomes of systemic lidocaine and its oral congeners. Mechanisms of neuropathic pain relief front lidocaine therapy are yet to be understood. Both central and peripheral mechanisms have been postulated. Systemic Lidocaine is thought to have its suppressive effects on spontaneous ectopic discharges of the injured nerve without blocking normal nerve conduction. However, there remain inconsistencies in the scientific basis underlying the clinical application of lidocaine therapy. Recent demonstration of change!; in tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels following nerve injury and their link to certain neuropathic pain symptoms may lead to the development of subtype-specific sodium channel blockers. The thoughtful use of lidocaine therapy and the potential application of subtype-specific sodium channel blockers could provide better management of distinctive neuropathic pain symptoms. (C) 2000 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Pain Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Beth Isareal & Deaconess Med Ctr, Arnold Pain Ctr, Boston, MA 02215 USA. RP Mao, JR (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, MGH Pain Ctr, 15 Parkman St,Suite WACC-324, Boston, MA 02114 USA. FU NIDA NIH HHS [DA08835] NR 65 TC 207 Z9 212 U1 6 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUL PY 2000 VL 87 IS 1 BP 7 EP 17 DI 10.1016/S0304-3959(00)00229-3 PG 11 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 333DA UT WOS:000088112400002 PM 10863041 ER PT J AU Juppner, H AF Juppner, H TI Role of parathyroid hormone-related peptide and Indian hedgehog in skeletal development SO PEDIATRIC NEPHROLOGY LA English DT Article DE parathyroid hormone-related peptide; Indian hedgehog; skeletal development ID MESSENGER RIBONUCLEIC-ACIDS; JANSENS METAPHYSEAL CHONDRODYSPLASIA; INHIBITS BONE-RESORPTION; PTH-PTHRP RECEPTOR; BLOMSTRAND-CHONDRODYSPLASIA; HUMORAL HYPERCALCEMIA; INACTIVATING MUTATION; PTH/PTHRP RECEPTOR; RENAL-FAILURE; HUMAN-TUMOR AB Parathyroid hormone-related peptide (PTHrP), which frequently causes the humoral hypercalcemia of malignancy syndrome, is an autocrine/paracrine regulator of chondrocyte proliferation and differentiation that acts through the PTH/PTHrP receptor (PTH1R). PTHrP is generated in response to Indian hedgehog (Ihh), which mediates its actions through the membrane receptor patched, but interacts also with hedgehog-interacting protein (Hip). Mice lacking PTHrP show accelerated chondrocyte differentiation, and thus premature ossification of those bones that are formed through an endochondral process, and similar but more-severe abnormalities are observed in PTH1R-ablated animals. The mirror image of these skeletal findings, i.e., a severe delay in chondrocyte differentiation and endochondral ossification, is observed in transgenic mice that overexpress PTHrP under the control of the alpha 1(II) procollagen promoter. Severe abnormalities in chondrocyte proliferation and differentiation are also observed in two genetic disorders in humans that are most likely caused by mutations in the PTH1R. Heterozygous PTH1R mutations that lead to constitutively activity were identified in Jansen metaphyseal chondrodysplasia, and homozygous or compound heterozygous mutations that lead to less-active or completely inactive receptors were identified in patients with Blomstrand lethal chondrodysplasia. Based on the growth plate abnormalities observed in these human disorders and in mice with abnormal expression of either PTHrP or the PTH1R, it appears plausible that impaired expression of PTHrP and/or its receptor contributes to the growth abnormalities in children with end-stage renal disease. In fact, mild-to-moderate renal failure leads in animals to a reduction in PTH1R expression in growth plates and impaired growth, but it remains uncertain whether this contributes to altered chondrocyte growth and differentiation. C1 Massachusetts Gen Hosp, Dept Pediat, Endocrine Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Juppner, H (reprint author), Massachusetts Gen Hosp, Dept Pediat, Endocrine Unit, Boston, MA 02114 USA. NR 57 TC 27 Z9 28 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JUL PY 2000 VL 14 IS 7 BP 606 EP + PG 102 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 342WQ UT WOS:000088668800015 PM 10912527 ER PT J AU Hickey, RW Kochanek, PM Ferimer, H Graham, SH Safar, P AF Hickey, RW Kochanek, PM Ferimer, H Graham, SH Safar, P TI Hypothermia and hyperthermia in children after resuscitation from cardiac arrest SO PEDIATRICS LA English DT Article DE cardiac arrest; temperature; fever; hypothermia ID CARDIOPULMONARY-RESUSCITATION; CEREBRAL-ISCHEMIA; NEURONAL DAMAGE; BRAIN; TEMPERATURE; STROKE AB Objective. In experimental models of ischemic-anoxic brain injury, changes in body temperature after the insult have a profound influence on neurologic outcome. Specifically, hypothermia ameliorates whereas hyperthermia exacerbates neurologic injury. Accordingly, we sought to determine the temperature changes occurring in children after resuscitation from cardiac arrest. Study Design. The clinical records of 13 children resuscitated from cardiac arrest were analyzed. Patients were identified through the emergency department and pediatric intensive care unit arrest logs. Only patients surviving for greater than or equal to 12 hours after resuscitation were considered for analysis. Charts were reviewed for body temperatures, warming or cooling interventions, antipyretic and antimicrobial administration, and evidence of infection. Results. Seven patients had a minimum temperature (T min) of less than or equal to 35 degrees C and 11 had a maximum temperature (T max) of greater than or equal to 38.1 degrees C. Hypothermia often preceded hyperthermia. All 7 patients with T min less than or equal to 35 degrees C were actively warmed with heating lamps and 5 of 7 responded to warming with a rebound of body temperatures greater than or equal to 38.1 degrees C. None of the 6 patients with T min >35 degrees C were actively warmed but all developed T max greater than or equal to 38.1 degrees C. Six patients received antipyretics and 11 received antibiotics. Fever was not associated with a positive culture in any case. Conclusion. Spontaneous hypothermia followed by hyperthermia is common after resuscitation from cardiac arrest. Temperature should be closely monitored after cardiac arrest and fever should be managed expectantly. C1 Childrens Hosp Pittsburgh, Dept Pediat, Div Pediat Emergency Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Anesthesia Crit Care Med, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Safar Ctr Resuscitat Res, Pittsburgh, PA 15260 USA. Mercy Hosp, Dept Pediat, Pittsburgh, PA 15219 USA. Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. VA Pittsburgh Hlth Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA USA. RP Hickey, RW (reprint author), Childrens Hosp Pittsburgh, Dept Pediat, Div Pediat Emergency Med, 3705 5th Ave, Pittsburgh, PA 15213 USA. RI Kochanek, Patrick/D-2371-2015 OI Kochanek, Patrick/0000-0002-2627-913X NR 21 TC 59 Z9 60 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUL PY 2000 VL 106 IS 1 BP 118 EP 122 DI 10.1542/peds.106.1.118 PG 5 WC Pediatrics SC Pediatrics GA 330YZ UT WOS:000087990400035 PM 10878160 ER PT J AU Jarvik, ME Madsen, DC Olmstead, RE Iwamoto-Schaap, PN Elins, JL Benowitz, NL AF Jarvik, ME Madsen, DC Olmstead, RE Iwamoto-Schaap, PN Elins, JL Benowitz, NL TI Nicotine blood levels and subjective craving for cigarettes SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE nicotine; craving; withdrawal; cigarette; abstinence ID SMOKING CESSATION; WITHDRAWAL SYMPTOMS; TOBACCO WITHDRAWAL; QUESTIONNAIRE; DOPAMINE; RELEASE AB This study examined cigarette craving and blood nicotine levels in 11 male heavy smokers who were observed during 16 h of tobacco abstinence. Subjects rated their urge to smoke on a new brief 10-item questionnaire, Urge to Smoke (UTS), Schuh and Stitzer's four-item Visual Analog Scale (SSI), and a Strength of Urge to Smoke (SUTS) item. Testing occurred: 1) after 16 h (1700 h the night before to 0900 h the next morning) of abstinence from smoking; 2) after an ad lib smoking period following the 16 h abstinence; 3) every hour during 6 hours of abstinence; 4) and finally, after the 6 h abstinence, another ad lib smoking period. Thus, subjects smoked twice in each session. Blood plasma nicotine levels were measured before, after, and every 2 h during the 6-h abstinence period for a total of six measures. Blood pressure and heart rate were measured prior to each blood draw. There was a significant negative correlation between blood nicotine levels and craving for cigarettes on all craving questionnaires (rs = -0.55 to -0.78; ps < 0.002). Carbon monoxide was shown to correlate highly with nicotine blood levels (rs = 0.83 to 0.98 across subjects. ps < 0.001). Results are consistent with the hypothesis that "urge to smoke" reflects nicotine seeking in continuing smokers. (C) 2000 Elsevier Science inc. C1 W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90073 USA. San Francisco Gen Hosp, Sch Med & Psychiat, San Francisco, CA 94110 USA. RP Jarvik, ME (reprint author), W Los Angeles Vet Affairs Med Ctr, 11301 Wilshire Blvd,T-350,619-B151D, Los Angeles, CA 90073 USA. FU NIDA NIH HHS [DA02277] NR 23 TC 125 Z9 127 U1 2 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD JUL PY 2000 VL 66 IS 3 BP 553 EP 558 DI 10.1016/S0091-3057(00)00261-6 PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 337HN UT WOS:000088351500013 PM 10899369 ER PT J AU Wyss, M Kaddurah-Daouk, R AF Wyss, M Kaddurah-Daouk, R TI Creatine and creatinine metabolism SO PHYSIOLOGICAL REVIEWS LA English DT Review ID MAGNETIC-RESONANCE SPECTROSCOPY; HIGH-ENERGY PHOSPHATE; BETA-GUANIDINOPROPIONIC ACID; ARGININE-GLYCINE AMIDINOTRANSFERASE; CHRONIC-RENAL-FAILURE; RAT GUANIDINOACETATE METHYLTRANSFERASE; LEFT-VENTRICULAR HYPERTROPHY; NITRIC-OXIDE SYNTHASE; TRANSGENIC MOUSE-LIVER; DUCHENNE MUSCULAR-DYSTROPHY AB The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis and degradation, species and tissue distribution of the enzymes and metabolites involved, and of the inherent implications for physiology and human pathology. Very recently, a series of new discoveries have been made that are bound to have distinguished implications for bioenergetics, physiology, human pathology, and clinical diagnosis and that suggest that deregulation of the creatine kinase (CK) system is associated with a variety of diseases. Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr and Or analogs such as cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage. Oral Cr ingestion is used in sports as an ergogenic aid, and some data suggest that Cr and creatinine may be precursors of food mutagens and uremic toxins. These findings are discussed in depth, the interrelationships are outlined, and all is put into a broader context to preside a more detailed understanding of the biological functions of Cr and of the CK system. C1 F Hoffmann La Roche & Co Ltd, Vitamins & Fine Chem Div, CH-4070 Basel, Switzerland. Avicena Grp, Cambridge, MA USA. Dana Farber Canc Inst, Div Canc Pharmacol, Boston, MA 02115 USA. RP Wyss, M (reprint author), F Hoffmann La Roche & Co Ltd, Vitamins & Fine Chem Div, Bldg 241-865, CH-4070 Basel, Switzerland. EM markus.wyss@roche.com NR 1162 TC 992 Z9 1033 U1 29 U2 173 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0031-9333 J9 PHYSIOL REV JI Physiol. Rev. PD JUL PY 2000 VL 80 IS 3 BP 1107 EP 1213 PG 107 WC Physiology SC Physiology GA 332TE UT WOS:000088088900009 PM 10893433 ER PT J AU O'Neill, J Halgren, E Marinkovic, K Siembieda, D Refai, D Fitten, LJ Perryman, K Fisher, A AF O'Neill, J Halgren, E Marinkovic, K Siembieda, D Refai, D Fitten, LJ Perryman, K Fisher, A TI Effects of muscarinic and adrenergic agonism on auditory P300 in the macaque SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE primates; evoked potentials; P300; muscarinic agonist; noradrenergic agonist; AF102B; guanfacine ID EVENT-RELATED POTENTIALS; ALZHEIMER-TYPE DEMENTIA; LONG-LATENCY; P300-LIKE POTENTIALS; ODDBALL PARADIGM; SQUIRREL-MONKEYS; BEHAVING MONKEY; AGED MONKEYS; SYSTEM; CLONIDINE AB Homologs of human endogenous evoked potentials are known in several species of nonhuman primates, but the neurotransmitter substrates of these potentials remain uncertain. In particular, the role of central cholinergic and adrenergic systems is not yet clearly defined. We recorded cognitive evoked potentials from the scalp in four adult bonnet macaque monkeys during a passive version of the auditory oddball paradigm with unique novel stimuli under saline control conditions. In two subjects each, cognitive evoked potentials were also recorded following intramuscular administration of the mi muscarinic agonist AF102B or of the alpha-2A noradrenergic agonist guanfacine. On saline, large positivities resembling the human P300 were recorded over midline sites in response to rare or novel auditory stimuli in all four monkeys. The amplitude of these positivities was sensitive to the delivery of fruit-juice reward in association with rare stimuli in three monkeys tested. At cognition-enhancing doses, AF102B enlarged the amplitude of P300-like positivities in both monkeys tested; guanfacine enlarged the amplitude of P300-like positivities in one of two monkeys tested. These results add to existing evidence of human-like endogenous late positivities in monkeys that are influenced by the cholinergic and adrenergic systems, and suggest a possible role of mi muscarinic and alpha-2A noradrenergic receptor subtypes. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Dept Vet Affairs W LA Med Ctr, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Brain Res Inst, Los Angeles, CA 90024 USA. Univ Utah, Dept Radiol, Salt Lake City, UT 84108 USA. Dept Vet Affairs Sepulveda Med Ctr, N Hills, CA 91343 USA. Eilan Inst Biol Res, IL-74100 Ness Ziona, Israel. RP O'Neill, J (reprint author), San Francisco VAMC, MRI Unit, 114M,4150 Clement St, San Francisco, CA 94121 USA. NR 47 TC 12 Z9 12 U1 1 U2 1 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 JUL 1 PY 2000 VL 70 IS 1-2 BP 163 EP 170 DI 10.1016/S0031-9384(00)00258-4 PG 8 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 356DM UT WOS:000089429100023 PM 10978492 ER PT J AU Tyan, ML AF Tyan, ML TI Effects of inositol, LiCl, and heparin on the antibody responses to SRBC by normal and immunodeficient XID mice SO PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article ID BRUTONS TYROSINE KINASE; TRISPHOSPHATE; RECEPTOR; CELLS; MYOINOSITOL; PATHWAYS; RELEASE; CA2+ AB Spleen cells from naive adult immunocompetent and immunodeficient XID mice were cultured on agar containing sheep red blood cells (SRBC) with and without myo-inositol, scyllo-inositol, lithium chloride, or heparin, and after 1 or 2 days the number of colonies of antiSRBC antibody-forming cells (PFC) were determined. It was found that myo-inositol and scyllo-inositol at one-tenth the concentration were equally effective in increasing the number of specific PFC, Myo-inositol, scyllo-inositol, and lithium chloride accelerated the appearance of direct foci in cultures of spleen cells from normal and XID mice, When heparin was added to cultures of XID spleen cells, PFC were found to be increased on Day 1; however, PFC and foci were not increased in cultures of spleen cells from competent mice until 1 day later, The addition of combinations of these agents to cultures of spleen cells had no positive or negative effect on the generation of fool or PFC, Normal mice given heparin intraperitoneally with SRBC had increased splenic PFC on Days 3 and 4 but not on Day 7, The results suggest that these agents modulate B-cell responses by increasing the rate of proliferation and/or secretion through a signaling pathway(s) distal to, or more likely, independent of Bruton's tyrosine Kinase (BTK), It is not clear that the mechanism is the same with each agent. C1 W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. RP Tyan, ML (reprint author), W Los Angeles Vet Affairs Med Ctr, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 18 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0037-9727 J9 P SOC EXP BIOL MED JI Proc. Soc. Exp. Biol. Med. PD JUL PY 2000 VL 224 IS 3 BP 187 EP 190 DI 10.1046/j.1525-1373.2000.22419.x PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 328RU UT WOS:000087864500010 PM 10865235 ER PT J AU Oberley, TD Zhong, WX Szweda, LI Oberley, LW AF Oberley, TD Zhong, WX Szweda, LI Oberley, LW TI Localization of antioxidant enzymes and oxidative damage products in normal and malignant prostate epithelium SO PROSTATE LA English DT Article DE prostate cancer; manganese superoxide dismutase; 4-hydroxy-2-nonenal; 8-hydroxy-2'-deoxyguanosine; nitrotyrosine ID MANGANESE SUPEROXIDE-DISMUTASE; GLUTATHIONE-S-TRANSFERASE; SYRIAN-HAMSTER TISSUES; CARCINOMA-CELLS; IMMUNOHISTOCHEMICAL LOCALIZATION; IMMUNOCHEMICAL DETECTION; IMMUNOGOLD ANALYSIS; KIDNEY DEVELOPMENT; HYDROGEN-PEROXIDE; PROTEIN ADDUCTS AB BACKGROUND. The risk for prostate cancer seems to be reduced by certain antioxidant compounds (vitamins E and A, and selenium). METHODS. Antioxidant enzymes and oxidative damage products were localized in normal prostatic epithelium and malignant glands in primary and metastatic prostatic adenocarcinomas, using well-characterized antibodies and immunoperoxidase techniques. RESULTS. Antioxidant enzymes and four markers of oxidative damage were compared in basal and secretory cells of normal prostatic epithelium and prostate adenocarcinoma cells, and each cell type had unique patterns of enzymes and oxidative damage products. One marker of oxidative damage, a fluorophore derived from 4-hydroxy-2-nonenal-lysine adduction, was found in secretory cells of normal but not malignant epithelium, demonstrating a different oxidative metabolism in normal vs. malignant prostate epithelium. Metastatic lesions from primary prostate cancer had higher levels of manganese superoxide dismutase and nuclear oxidative damage products than did primary tumors. CONCLUSIONS. Antioxidant enzymes and oxidative damage products are modulated in metastatic compared to primary prostate cancer. Prostate 44:144-155, 2000. (C) 2000 Wiley-Liss, Inc. C1 William S Middleton Mem Vet Hosp, Pathol & Lab Med Serv, Madison, WI 53705 USA. Univ Wisconsin, Sch Med, Dept Pathol & Lab Med, Madison, WI USA. Case Western Reserve Univ, Sch Med, Dept Physiol & Biophys, Cleveland, OH 44106 USA. Univ Iowa, Coll Med, Radiat Res Lab, Iowa City, IA USA. RP Oberley, TD (reprint author), William S Middleton Mem Vet Hosp, Pathol & Lab Med Serv, Room A-35,2500 Overlook Terrace, Madison, WI 53705 USA. NR 48 TC 79 Z9 79 U1 0 U2 2 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 JUL 1 PY 2000 VL 44 IS 2 BP 144 EP 155 DI 10.1002/1097-0045(20000701)44:2<144::AID-PROS7>3.0.CO;2-G PG 12 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 329AY UT WOS:000087885000007 PM 10881024 ER PT J AU Wiener, MC Verkman, AS Stroud, RM Van Hoek, AN AF Wiener, MC Verkman, AS Stroud, RM Van Hoek, AN TI Mesoscopic surfactant organization and membrane protein crystallization SO PROTEIN SCIENCE LA English DT Article DE aquaporin; bile salts; detergents; membrane protein crystallization; self-assembled system ID CHIP28 WATER CHANNELS; LIPIDIC CUBIC PHASES; X-RAY-ANALYSIS; 3-DIMENSIONAL CRYSTALS; ESCHERICHIA-COLI; BACTERIORHODOPSIN; PURIFICATION; ANGSTROM; COMPLEX; MICE AB The paucity of detailed X-ray crystallographic structures of integral membrane proteins arises from substantive technical obstacles in the overexpression of multimilligram quantities of protein, and in the crystallization of purified protein-detergent complexes (PDCs). With rare exception, crystal contacts within the lattice are mediated by protein-protein interaction, and the detergent surrounding the protein behaves as a disordered solvent. The addition and use of surfactants that display mesoscopic self-assembly behavior in membrane protein crystallization experiments presents a novel alternative strategy. Well-ordered crystals of the water channel human aquaporin-1 (hAQP1) that diffract to 4 Angstrom resolution have been obtained with this approach. C1 Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. Univ Calif San Francisco, Inst Cardiovasc Res, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. RP Wiener, MC (reprint author), Univ Virginia, Dept Mol Physiol & Biol Phys, POB 800736, Charlottesville, VA 22908 USA. FU NIGMS NIH HHS [GM24485, GM56251] NR 31 TC 5 Z9 5 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD JUL PY 2000 VL 9 IS 7 BP 1407 EP 1409 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 337RU UT WOS:000088376100019 PM 10933509 ER PT J AU Fuller, TR Oka, M Otsuka, K Yokoyama, N Liberman, RP Niwa, SI AF Fuller, TR Oka, M Otsuka, K Yokoyama, N Liberman, RP Niwa, SI TI A hybrid supported employment program for persons with schizophrenia in Japan SO PSYCHIATRIC SERVICES LA English DT Article C1 Univ Calif Los Angeles, Ctr Res Treatment & Rehabil Psychosis, Los Angeles, CA 90024 USA. Fukushima Med Coll, Fukushima, Japan. RP Liberman, RP (reprint author), W Los Angeles VA Med Ctr, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 6 TC 8 Z9 9 U1 1 U2 2 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 JUL PY 2000 VL 51 IS 7 BP 864 EP 866 DI 10.1176/appi.ps.51.7.864 PG 3 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 331HW UT WOS:000088013800005 PM 10875948 ER PT J AU Mares, A McGuire, J AF Mares, A McGuire, J TI Reducing psychiatric hospitalization among mentally ill veterans living in board-and-care homes SO PSYCHIATRIC SERVICES LA English DT Article; Proceedings Paper CT Va Health Services Research and Development National Meeting CY FEB 24-26, 1999 CL WASHINGTON, D.C. SP VA Hlth Serv Res & Dev Natl ID CASE-MANAGEMENT; COMMUNITY; NEEDS AB Objective: The effectiveness of a community-based case management program at the Veterans Affairs West Los Angeles Healthcare Center in reducing hospital readmission of mentally ill veterans living in privately operated board-and-care homes was evaluated. Methods: A retrospective cohort design was used, The sample consisted of 321 patients identified by hospital records as living in one of 24 board-and-care homes in the Los Angeles area that were approved by the community residential care program. A total of 214 subjects who received monthly home visits from case managers (program group) were compared with 107 subjects who did not receive monthly home visits (comparison group). The median number of psychiatric bed-days used was calculated for the two years before and after follow-up. The number of days from the start of follow-up to the first psychiatric hospitalization was also calculated. Results: Among subjects in the program group, the median number of psychiatric bed-days used decreased significantly, from 59 days to 50 days. No significant change in the median number was observed for comparison subjects. Comparison subjects were rehospitalized 1.7 times more often than program subjects, Overall, program subjects under age 62 (younger subjects) were rehospitalized 2.5 times more often than older subjects. In the program group, those who had received home visits for more than two years were hospitalized three times more often than those who had received visits for less than two years, and younger subjects were rehospitalized 1.8 times more often than older subjects. Conclusions:The findings suggest that home visits conducted by case managers in a community residential care program helped reduce psychiatric hospitalization among veteran patients living in privately operated board-and-care homes. C1 Univ Calif Los Angeles, Sch Publ Policy & Social Res, Sch Social Welf, Los Angeles, CA 90095 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Program Evaluat, Los Angeles, CA USA. RP Mares, A (reprint author), Univ Calif Los Angeles, Sch Publ Policy & Social Res, Sch Social Welf, 3250 Publ Policy Bldg,Box 951656, Los Angeles, CA 90095 USA. RI Mares, Alvin/I-8186-2012 NR 31 TC 8 Z9 8 U1 1 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 JUL PY 2000 VL 51 IS 7 BP 914 EP 921 DI 10.1176/appi.ps.51.7.914 PG 8 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 331HW UT WOS:000088013800013 PM 10875958 ER PT J AU Emilien, G Ponchon, M Caldas, C Isacson, O Maloteaux, JM AF Emilien, G Ponchon, M Caldas, C Isacson, O Maloteaux, JM TI Impact of genomics on drug discovery and clinical medicine SO QJM-AN INTERNATIONAL JOURNAL OF MEDICINE LA English DT Review ID LONG-QT SYNDROME; AMYOTROPHIC-LATERAL-SCLEROSIS; DEPENDENT DIABETES-MELLITUS; FAMILIAL ALZHEIMERS-DISEASE; THIOPURINE METHYLTRANSFERASE PHARMACOGENETICS; CARDIOVASCULAR RISK-FACTORS; CILIARY NEUROTROPHIC FACTOR; EPITHELIAL SODIUM-CHANNEL; GROWTH-FACTOR RECEPTOR; VECTOR PRODUCER CELLS AB Genomics, particularly high-throughput sequencing and characterization of expressed human genes, has created new opportunities for drug discovery. Knowledge of all the human genes and their functions may allow effective preventive measures, annd change drug research strategy and drug discovery development processes. Pharmacogenomics is the application of genomic technologies such as gene sequencing, statistical genetics, and gene expression analysis to drugs in clinical development and on the market. It applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism, or disease pathways. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to genetic and specific individual markers, selecting medications and dosages that are optimized for individual patients. The possibility of defining patient populations genetically may improve outcomes by predicting individual responses to drugs, and could improve safety and efficacy in therapeutic areas such as neuropsychiatry, cardiovascular medicine, endocrinology (diabetes and obesity) and oncology. Ethical questions need to be addressed and guidelines established for the use of genomics in clinical research and clinical medicine. Significant achievements are possible with an interdisciplinary approach that includes genetic, technological and therapeutic measures. C1 Catholic Univ Louvain, Pharmacol Lab, B-1200 Brussels, Belgium. Catholic Univ Louvain, Diabet & Nutr Unit, B-1200 Brussels, Belgium. Catholic Univ Louvain, Dept Neurol, B-1200 Brussels, Belgium. Univ Cambridge, Addenbrookes Hosp, Dept Oncol, Cambridge CB2 2QQ, England. Harvard Univ, Sch Med, Neuroregenerat Labs, Mclean, VA USA. Massachusetts Gen Hosp, Belmont, MA USA. RP 127 Rue Henri Prou, F-78340 Les Clayes Sous Bois, France. EM Gemillien@aol.com RI Caldas, Carlos/A-7543-2008 NR 255 TC 78 Z9 87 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1460-2725 EI 1460-2393 J9 QJM-INT J MED JI QJM-An Int. J. Med. PD JUL PY 2000 VL 93 IS 7 BP 391 EP 423 DI 10.1093/qjmed/93.7.391 PG 33 WC Medicine, General & Internal SC General & Internal Medicine GA 335BH UT WOS:000088221800001 PM 10874050 ER PT J AU Kopans, DB AF Kopans, DB TI Double reading SO RADIOLOGIC CLINICS OF NORTH AMERICA LA English DT Article ID SCREENING MAMMOGRAMS; BREAST-CANCER; MEDICAL AUDIT; RADIOLOGISTS; VARIABILITY; CARCINOMA; PROGRAM AB Whether looking for fractures, nodules on a chest radiograph, or cancers on a mammogram, all observers periodically fail to perceive significant findings. Since everyone can overlook different things, having two observers review the same study reduces the Likelihood of failing to detect a significant finding. Double reading of mammograms can reduce the oversight rate by 5 to 15%. in order to take advantage of double reading, without increasing the costs of screening, it must be done in a highly efficient manner. This article highlights ways to accomplish this. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Kopans, DB (reprint author), Massachusetts Gen Hosp, Dept Radiol, 32 Fruit St, Boston, MA 02114 USA. NR 18 TC 33 Z9 35 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 0033-8389 J9 RADIOL CLIN N AM JI Radiol. Clin. N. Am. PD JUL PY 2000 VL 38 IS 4 BP 719 EP + DI 10.1016/S0033-8389(05)70196-2 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 344FD UT WOS:000088747800007 PM 10943273 ER PT J AU Athanasoulis, CA Kaufman, JA Halpern, EF Waltman, AC Geller, SC Fan, CM AF Athanasoulis, CA Kaufman, JA Halpern, EF Waltman, AC Geller, SC Fan, CM TI Inferior vena caval filters: Review of a 26-year single-center clinical experience SO RADIOLOGY LA English DT Review DE embolism, pulmonary; interventional procedures, complications; venae cavae, filters; venae cavae, interventional procedures ID KIMRAY-GREENFIELD FILTER; PULMONARY-EMBOLISM; FOLLOW-UP; RENAL VEINS; PLACEMENT; PREVENTION; INSERTION; DISEASE AB PURPOSE: To review a 26-year single-center clinical experience with inferior vena caval filters. MATERIALS AND METHODS: During 1973-1998, 1,765 filters were implanted in 1,731 patients. Hospital files were reviewed, and data were collected about the indications, safety, effectiveness, numbers, and types of caval fillers. Fatal postfilter pulmonary embolism (PE) was considered the primary outcome. Morbidity and mortality were determined as secondary outcomes. Survival and morbidity-free survival curves were calculated. RESULTS: The prevalence of observed postfilter PE was 5.6%. It was fatal in 3.7% of patients. In most patients, fatal PE occurred soon after filter insertion (median, 4.0 days; 95% CI: 2.2, 5.8 days). Major complications occurred in 0.3% of procedures. The prevalence of observed postfilter caval thrombosis was 2.7%. The 30-day mortality rate was 17.0% overall, higher among patients with neoplasms (19.5%) as compared with those without neoplasms (14.3%; P = .004). Filter efficacy and associated morbidity were not different in 46 patients with suprarenal filters. The rate of filters placed for prophylaxis was 4.7% overall and increased to 16.4% in 1998. From 1980 to 1996, there was a fivefold increase in the number of caval filter implants. In recent years, more filters were implanted in younger patients. CONCLUSION: Inferior vena caval filters provide protection from life-threatening PE, with minimal morbidity. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Athanasoulis, CA (reprint author), Massachusetts Gen Hosp, Dept Radiol, 32 Fruit St,GRB 290A, Boston, MA 02114 USA. NR 36 TC 214 Z9 245 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2000 VL 216 IS 1 BP 54 EP 66 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 328BT UT WOS:000087829500009 PM 10887228 ER PT J AU Saini, S Seltzer, SE Bramson, RT Levine, LA Kelly, P Jordan, PF Chiango, BF Thrall, JH AF Saini, S Seltzer, SE Bramson, RT Levine, LA Kelly, P Jordan, PF Chiango, BF Thrall, JH TI Technical cost of radiologic examinations: Analysis across imaging modalities SO RADIOLOGY LA English DT Article; Proceedings Paper CT 83rd Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America CY NOV 30-DEC 05, 1997 CL CHICAGO, ILLINOIS SP Radiol Soc N Amer DE cost-effectiveness; computed tomography (CT), utilization; economics, medical; interventional procedures, utilization; magnetic resonance (MR), utilization; radiography; radionuclide imaging; ultrasound (US), utilization AB PURPOSE: To determine the individual technical costs of general diagnostic radiographic, ultrasonographic (US), computed tomographic (CT), magnetic resonance (MR) imaging, and scintigraphic examinations and interventional radiology. MATERIALS AND METHODS: The Radiology Cost and Productivity Benchmarking Study method of the University HealthSystem Consortium, a cooperative group of academic medical centers, was modified and extended to the six imaging modalities in a tertiary care academic setting. Hospital billing and cost records were analyzed for fiscal year 1996. Costs were divided into labor and nonlabor categories and were allocated to individual imaging modalities on the basis of resources consumed. Physician cost and hospital overhead were not included. Unit costs were analyzed per technical relative value unit (RVU) and per examination. RESULTS: The costs per technical RVU for diagnostic radiography, US, CT, MR imaging, scintigraphy, and interventional radiology were $65.06, $28.74, $20.95, $17.69, $42.19, and $89.03, respectively. The technical costs per examination for diagnostic radiography, US, CT, MR imaging, scintigraphy, and interventional radiology were $41.92, $50.28, $112.32, $266.96, $196.88, and $692.60, respectively. CONCLUSION: The method of unit cost analysis for individual imaging modalities was successfully tested in a tertiary care setting. The method should be adopted to allow cost comparison across many institutions, which will permit the promotion of best practices. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. RP Saini, S (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, 32 Fruit St, Boston, MA 02114 USA. NR 4 TC 30 Z9 30 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUL PY 2000 VL 216 IS 1 BP 269 EP 272 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 328BT UT WOS:000087829500039 PM 10887260 ER PT J AU Kraut, JA AF Kraut, JA TI Disturbances of acid-base balance and bone disease in end-stage renal disease SO SEMINARS IN DIALYSIS LA English DT Article ID CHRONIC METABOLIC-ACIDOSIS; HIGH BICARBONATE DIALYSATE; HEMODIALYSIS-PATIENTS; PARATHYROID-HORMONE; TUBULAR-ACIDOSIS; FAILURE; CALCIUM; RAT AB Bone disease in patients with chronic renal failure (CRF) is thought to he the consequence primarily of the interplay of several factors, including the serum levels of parathyroid hormone (PTH), vitamin D, calcium, and phosphorus, and exposure to hone toxins such as aluminum or amyloid. Recently the metabolic acidosis noted with CRF has been implicated as an additional factor contributing to the genesis of bone disease. Although metabolic acidosis might be the dominant factor in the cause of bone disease in some instances, more commonly this acid-base disturbance interacts with other factors contributing to the development of bone disease. The following article summarizes the data in support of an important role for metabolic acidosis in the genesis of bone disease in patients with CRF and presents our recommendations for treatment of uremic acidosis to prevent or treat the bone disease. C1 VA Greater Los Angeles Hlth Care Syst, Dialysis Unit 691 1111, Div Nephrol Med & Res Serv, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA. RP Kraut, JA (reprint author), VA Greater Los Angeles Hlth Care Syst, Dialysis Unit 691 1111, Div Nephrol Med & Res Serv, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 35 TC 30 Z9 30 U1 1 U2 2 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0894-0959 J9 SEMIN DIALYSIS JI Semin. Dial. PD JUL-AUG PY 2000 VL 13 IS 4 BP 261 EP 266 DI 10.1046/j.1525-139x.2000.00070.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 336QA UT WOS:000088313400011 PM 10923356 ER PT J AU Mitler, MM Harsh, J Hirshkowitz, M Guilleminault, C AF Mitler, Merrill M. Harsh, John Hirshkowitz, Max Guilleminault, Christian CA US Modafinil Narcolepsy Multictr TI Long-term efficacy and safety of modafinil (PROVIGIL (R)) for the treatment of excessive daytime sleepiness associated with narcolepsy SO SLEEP MEDICINE LA English DT Article DE Modafinil; Narcolepsy; Sleep disorders; Wakefulness; Quality of life; Disorders of excessive somnolence AB Objectives: To assess the long-term efficacy and safety of modafinil in patients with excessive daytime sleepiness (EDS) associated with narcolepsy. Background: Modafinil has been shown to be effective and well tolerated for treating EDS associated with narcolepsy in two large-scale, well-controlled, 9-week clinical trials. Methods: Four hundred and seventy eight adult patients with a diagnosis of narcolepsy who had completed one of two 9-week, double-blind, placebo-controlled, multicenter, clinical trials of modafinil were enrolled in two 40-week, open-label, extension studies. A flexible-dose regimen (i.e. 200, 300, or 400 mg daily) was followed in one study. In the second study, patients received 200 mg/day for 1 week, followed by 400 mg/day for 1 week. Investigators then prescribed either 200- or 400 mg doses for the duration of the study. Efficacy was evaluated using Clinical Global Impression of Change (CGI-C) scores, the Epworth Sleepiness Scale (ESS), and the 36-item Medical Outcomes Study health survey (SF-36). Adverse events were recorded. Data from the two studies were combined. Results: The majority of patients (similar to 75%) received 400 mg of modafinil daily. Disease severity improved in >80% of patients throughout the 40-week study. At weeks 2, 8, 24, and 40, disease severity was 'much improved' or 'very much improved' in 49, 58, 59, and 58% of patients, respectively. The mean (+/-SEM) ESS score improved significantly from 16.5 +/- 0.2 at open-label baseline to 12.4 +/- 0.2 at week 2 and remained at that level through week 40 (P<0.001). Quality of life scores at weeks 4, 8, 24, and 40 were significantly improved versus open-label baseline scores for six of the eight SF-36 domains (P<0.001). The most common treatment-related adverse events were headache (13%), nervousness (8%), and nausea (5%). Most adverse events were mild to moderate in nature. A total of 341 patients (71%) completed the studies. Forty-three patients (9.0%) discontinued treatment because of adverse events. Conclusions: Modafinil is effective for the long-term treatment of EDS associated with narcolepsy and significantly improves perceptions of general health. Modafinil is well tolerated, with no evidence of tolerance developing during 40 weeks of treatment. (C) 2000 Elsevier Science B. V. All rights reserved. C1 [Mitler, Merrill M.] Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA 92037 USA. [Harsh, John] Forrest Gen Hosp, Sleep Disorders Ctr, Hattiesburg, MS USA. [Hirshkowitz, Max] VA Med Ctr, Sleep Diagnost Ctr, Houston, TX USA. [Guilleminault, Christian] Stanford Sleep Disorders Clin, Stanford, CA USA. RP Mitler, MM (reprint author), Scripps Clin Res Fdn, Sleep Disorders Ctr, 9834 Genesee Ave,Suite 328, La Jolla, CA 92037 USA. EM mitler@scripps.edu FU Cephalon, Inc. FX The studies reported were funded by Cephalon, Inc. The authors thank the following investigators who participated in the studies: Amand Beck, Albuquerque, NM; Philip M. Becker, Dallas, TX; Jed Black, Stanford, CA; Richard K. Bogan, Columbia, SC; Ronald D. Chervin, Ann Arbor, MI; Bruce Corser, Cincinnati, OH; Dudley S. Dinner, Cleveland, OH; Helene Emsellem, Chevy Chase, MD; Charles W. Erwin, Durham, NC; Simon Farrow, Las Vegas, NV; Neil T. Feldman, St. Petersburg, FL; Paul A. Fredrickson, Jacksonville, FL; June M. Fry, Philadelphia, PA; Philip M. Green, Kalamazoo, MI; Paul T. Gross, Burlington, MA; Christian Guilleminault, Stanford, CA; John Harsh, Hattiesburg, MI; Roza Hayduk, La Jolla, CA; Carl A. Houch, Birmington, AL; Gila Hertz, Huntington, NY; Max Hirshkowitz, Houston, TX; Vasudeva Iyer, Louisville, KY; Mark M. Mahowald, Minneapolis, MN; Merrill M. Mitler, La Jolla, CA; Allan Pack, Philadelphia, PA; Ralph Pascualy, Seattle, WA; Ralph W. Richter, Tulsa, OK; Ruzica K. Ristanovic, Chicago, IL; Ann E. Rogers, Ann Arbor, MI; Russell Rosenberg, Atlanta, GA; Pradeep K. Sahota, Columbia, MO; R. Bart Sangal, Troy, MI; Helmut S. Schmidt, Dublin, OH; Wolfgang W. Schmidt-Nowara, Albuquerque, NM; Jonathan R. L. Schwartz, Oklahoma City, OK; Lawrence Scrima, Aurora, CO; Shashidar M. Shettar, Birmingham, AL; Calvin Stafford, MD, Upland, PA; Robert Tearse, Eugene, OR; Stephen G. Thein Jr, San Diego, CA; Boris A. Vern, Chicago, IL; Joyce A. Walsleben, New York, NY; Andrew Winokur, Farmington, CT. NR 29 TC 75 Z9 76 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1389-9457 J9 SLEEP MED JI Sleep Med. PD JUL 1 PY 2000 VL 1 IS 3 BP 231 EP 243 AR PII S1389-9457(00)00031-9 DI 10.1016/S1389-9457(00)00031-9 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA V22UQ UT WOS:000208300500008 ER PT J AU Hutcheson, K Kalafian, M Taylor, I Sagel, J Clyburn, B AF Hutcheson, K Kalafian, M Taylor, I Sagel, J Clyburn, B TI Neurocysticercosis SO SOUTHERN MEDICAL JOURNAL LA English DT Article C1 Med Univ S Carolina, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Sagel, J (reprint author), Dept Med, 96 Jonathan Lucas St,POB 250623, Charleston, SC 29425 USA. NR 5 TC 3 Z9 3 U1 0 U2 0 PU SOUTHERN MEDICAL ASSN PI BIRMINGHAM PA 35 LAKESHORE DR PO BOX 190088, BIRMINGHAM, AL 35219 USA SN 0038-4348 J9 SOUTHERN MED J JI South.Med.J. PD JUL PY 2000 VL 93 IS 7 BP 666 EP 668 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 337DR UT WOS:000088342600004 PM 10923951 ER PT J AU Ibrahim, JG Chen, MH Ryan, LM AF Ibrahim, JG Chen, MH Ryan, LM TI Bayesian variable selection for time series count data SO STATISTICA SINICA LA English DT Article DE correlated counts; Gibbs sampling; hierarchical centering; historical data; Poisson regression; posterior distribution ID POSTERIOR DENSITY-ESTIMATION; MODELS AB We consider a parametric model for time series of counts by constructing a likelihood-based generalization of a model considered by Zeger (1988). We consider a Bayesian approach and propose a class of informative prior distributions for the model parameters that are useful for variable subset selection. The prior specification is motivated from the notion of the existence of data from similar previous studies, called historical data, which is then quantified in a prior distribution for the current study. We derive theoretical and computational properties of the proposed priors and develop novel methods for computing posterior model probabilities. To compute the posterior model probabilities, me show that only posterior samples from the full model are needed to estimate the posterior probabilities for all of the possible subset models. We demonstrate our methodology with a simulated and a real data set. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Worcester Polytech Inst, Worcester, MA 01609 USA. RP Ibrahim, JG (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat, 44 Binney St, Boston, MA 02115 USA. RI Ryan, Louise/A-4562-2009 OI Ryan, Louise/0000-0001-5957-2490 NR 12 TC 11 Z9 11 U1 0 U2 0 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 J9 STAT SINICA JI Stat. Sin. PD JUL PY 2000 VL 10 IS 3 BP 971 EP 987 PG 17 WC Statistics & Probability SC Mathematics GA 340DB UT WOS:000088516900016 ER PT J AU Mokudai, T Ayoub, IA Sakakibara, Y Lee, EJ Ogilvy, CS Maynard, KI AF Mokudai, T Ayoub, IA Sakakibara, Y Lee, EJ Ogilvy, CS Maynard, KI TI Delayed treatment with nicotinamide (vitamin B-3) improves neurological outcome and reduces infarct volume after transient focal cerebral ischemia in Wistar rats SO STROKE LA English DT Article DE energy metabolism; middle cerebral artery occlusion neuroprotection; niacinamide; stroke; rats ID POLY(ADP-RIBOSE) POLYMERASE; ARTERY OCCLUSION; NITRIC-OXIDE; INHIBITORS; NEUROTOXICITY; SYNTHETASE; DEPLETION; DOPAMINE; STRIATUM; INJURY AB Background and Purpose-We have previously shown that nicotinamide (NAm) acutely reduces brain infarction induced by permanent middle cerebral artery occlusion (MCAo) in rats. In this study, we investigate whether NAm may protect against ischemia/reperfusion injury by improving sensory and motor behavior as well as brain infarction volumes in a model of transient focal cerebral ischemia. Methods-Forty-eight male Wistar rats were used, and transient focal cerebral ischemia was induced by MCAo for 2 hours, followed by reperfusion for either 3 or 7 days. Animals were treated with either intraperitoneal saline or NAm (500 mg/kg) 2 hours after the onset of MCAo (ie, on reperfusion). Sensory and motor behavior scores and body weight were obtained daily, and brain infarction volumes were measured on euthanasia. Results-Relative to treatment with saline, treatment with NAm (500 mg/kg IF) 2 hours after the onset of transient focal cerebral ischemia in Wistar rats significantly improved sensory (38%, P<0.005) and motor (42%, P<0.05) neurological behavior and weight gain (7%, P<0.05) up to 7 days after MCAo. The cerebral infarct volumes were also reduced 46% (P<0.05) at 3 days and 35% (P=0.09) at 7 days after MCAo. Conclusions-NAm is a robust neuroprotective agent against ischemia/reperfusion-induced brain injury in rats, even when administered up to 2 hours after the onset of stroke. Delayed NAm treatment improved both anatomic and functional indices of brain damage. Further studies are needed to clarify whether multiple doses of NAm will improve the extent and duration of this neuroprotective effect and to determine the mechanism(s) of action underlying the neuroprotection observed. Because NAm is already used clinically in large doses and has few side effects, these results are encouraging for the further examination of the possible use of NAm as a therapeutic neuroprotective agent in the clinical treatment of acute ischemic stroke. C1 Massachusetts Gen Hosp, Neurosurg Serv, Neurophysiol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Kochi Med Sch, Dept Neurosurg, Kochi, Japan. Natl Cheng Kung Univ, Med Ctr, Dept Surg, Div Neurosurg, Tainan 70101, Taiwan. Natl Cheng Kung Univ, Sch Med, Tainan 70101, Taiwan. RP Maynard, KI (reprint author), Massachusetts Gen Hosp, Neurosurg Serv, Neurophysiol Lab, 55 Fruit St,EDR 414, Boston, MA 02114 USA. FU NINDS NIH HHS [NS01732] NR 37 TC 75 Z9 78 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUL PY 2000 VL 31 IS 7 BP 1679 EP 1684 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 331LC UT WOS:000088019700034 PM 10884473 ER PT J AU Kubis, KC Danesh-Meyer, H Bilyk, JR AF Kubis, KC Danesh-Meyer, H Bilyk, JR TI Unilateral lid retraction during pregnancy SO SURVEY OF OPHTHALMOLOGY LA English DT Editorial Material DE atelectasis; chronic sinusitis; enophthalmos; lid retraction maxillary; orbit; silent sinus syndrome ID SILENT SINUS SYNDROME; SPONTANEOUS ENOPHTHALMOS; ATELECTASIS; REPAIR AB A 32-year-old woman noted left lid retraction during pregnancy. Examination revealed unilateral enophthalmos without symptoms of diplopia or sinus disease. Orbital imaging showed characteristic features of the silent sinus syndrome, which were confirmed intraoperatively. The clinical and imaging attributes of this syndrome are discussed, including possible mechanisms bf disease development. Management strategies are summarized. A brief discussion of the differential diagnosis of enophthalmos is also included. (Surv Ophthalmol 45:69-76, 2000. (C) 2000 by Elsevier Science Inc, All rights reserved.). C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. Thomas Jefferson Univ Hosp, Dept Otolaryngol Head & Neck Surg, Philadelphia, PA USA. RP Kubis, KC (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol, Boston, MA 02114 USA. NR 18 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0039-6257 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD JUL-AUG PY 2000 VL 45 IS 1 BP 69 EP 76 DI 10.1016/S0039-6257(00)00124-7 PG 8 WC Ophthalmology SC Ophthalmology GA 344EM UT WOS:000088744700005 PM 10946082 ER PT J AU Mitsiades, N Poulaki, V Tseleni-Balafouta, S Chrousos, GP Koutras, DA AF Mitsiades, N Poulaki, V Tseleni-Balafouta, S Chrousos, GP Koutras, DA TI Fas ligand expression in thyroid follicular cells from patients with thionamide-treated Graves' disease SO THYROID LA English DT Article ID HASHIMOTOS-THYROIDITIS; MOLECULAR-CLONING; ANTITHYROID DRUGS; INDUCED APOPTOSIS; PATHOGENESIS; MECHANISM; RECEPTOR; FAMILY; MEMBER AB Thionamides are used in the treatment of Graves' disease (GD) and act mainly by inhibiting the organification of iodide, but also lower We levels of thyroid autoantibodies, sometimes leading to long-term remission. Fas ligand (FasL) induces apoptosis of susceptible cells by cross-linking its own receptor, Fas. While Fas is present in a wide variety of normal tissues, Fast expression is limited mainly to cells of the immune system, where it acts as an effector molecule of cell-mediated cytotoxicity, and to the placenta, brain, eye, and testis where it presumably contributes to their immune-privileged status by eliminating infiltrating lymphocytes. We examined immunohistochemically the presence of Fast in thyroid tissue from 15 glands of thionamide-treated GD patients and in 8 normal thyroid control specimens. We also investigated We presence of Fast in thionamide-treated thyrocytes in vitro and their ability to induce Fas-mediated apoptosis in lymphocytes. We found that Fast expression was very weak to undetectable in normal thyroid tissue and cultured thyrocytes, whereas it was strong in thionamide-treated GD glands and cultured thyrocytes. Methimazole-treated thyrocytes induced Fast-dependent apoptosis in cocultured lymphocytes, whereas methimazole treatment of lymphocytes grown in the absence of thyrocytes had no such effect. We conclude that Fast is highly expressed in follicular cells of thyroid glands obtained from thionamide-treated Graves' patients and may contribute to the immunomodulatory effect of thionamides in this disease. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Evgenidion Hosp, Endocrine Unit, Athens, Greece. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Mitsiades, N (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Mayer Bldg,Room M557,44 Binney St, Boston, MA 02115 USA. NR 24 TC 31 Z9 37 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD JUL PY 2000 VL 10 IS 7 BP 527 EP 532 DI 10.1089/thy.2000.10.527 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 342LX UT WOS:000088647000002 PM 10958304 ER PT J AU Marino, M Andrews, D McCluskey, RT AF Marino, M Andrews, D McCluskey, RT TI Binding of rat thyroglobulin to heparan sulfate proteoglycans SO THYROID LA English DT Article ID RECEPTOR-RELATED PROTEIN; THYROID-FOLLICLE CELLS; LOW-DENSITY; LDL RECEPTOR; LIPOPROTEIN-LIPASE; ENDOCYTIC RECEPTOR; AFFINITY-BINDING; POTENTIAL ROLE; MEGALIN GP330; GENE FAMILY AB We previously showed that rat thyroglobulin (Tg) is a heparin-binding protein and that heparin inhibits Tg binding to megalin (gp330), an endocytic Tg receptor found on the apical surface of thyrocytes. Cooperation between cell surface receptors and heparin-like molecules, namely heparan sulfate proteoglycans (HSPGs), can facilitate cell surface binding of some heparin-binding proteins. Based on our previous findings indicating that heparin and megalin-binding sites of rat Tg are functionally related, here we investigated whether rat Tg binds to HSPGs, which are expressed by thyroid cells. We showed in solid phase assays that unlabeled rat Tg binds to a heparan sulfate (HS) preparation in a dose-dependent, saturable manner, with moderately high affinity (K-d similar to 19 nM, K-i similar to 25 nM). Binding was inhibited by heparin and by HS itself. We then studied the role of HSPGs in Tg binding to FRTL-5 cells, a differentiated Fisher rat thyroid cell line. As previously reported, after incubation of FRTL-5 cells with unlabeled rat Tg at 4 degrees C, heparin released virtually all the cell-bound Tg. Coincubation of Tg with HS or with a preparation of HSPGs resulted in a reduction of binding by 35%-40%. When FRTL-5, cells were preincubated with heparitinase or heparinase I, which released 20%-30% of cell surface HSPGs, Tg binding was reduced to a similar extent. An antibody against a Tg heparin-binding site functionally related to a major megalin-binding site virtually abolished Tg binding to HS and to FRTL-5 cells, supporting the hypothesis that combined interactions of Tg with HSPGs and with megalin are involved in Tg binding to rat thyroid cells. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Pathol Res Lab, Charlestown, MA USA. RP Marino, M (reprint author), Univ Pisa, Dept Endocrinol, Via Paradisa 2, I-56124 Pisa, Italy. FU PHS HHS [46301] NR 50 TC 12 Z9 12 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1050-7256 J9 THYROID JI Thyroid PD JUL PY 2000 VL 10 IS 7 BP 551 EP 559 DI 10.1089/thy.2000.10.551 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 342LX UT WOS:000088647000005 PM 10958307 ER PT J AU Vamvakas, EC Carven, JH AF Vamvakas, EC Carven, JH TI RBC transfusion and postoperative length of stay in the hospital or the intensive care unit among patients undergoing coronary artery bypass graft surgery: the effects of confounding factors SO TRANSFUSION LA English DT Article ID ALLOGENEIC BLOOD-TRANSFUSION; ELECTIVE COLORECTAL SURGERY; WHITE CELL-REDUCTION; COST-EFFECTIVENESS; BACTERIAL-INFECTION; LEUKOCYTE DEPLETION; CANCER; COMPLICATIONS; TRIAL; IMMUNOMODULATION AB BACKROUND: Data on the independent association between perioperative allogeneic blood transfusion (ABT) and postoperative length of stay at the hospital or in the intensive care unit (ICU) are sparse. STUDY DESIGN AND METHODS: The records of 421 consecutive patients undergoing coronary artery bypass graft (CABG) operations at the Massachusetts General Hospital were reviewed. The effect of perioperative ABT in explaining the variation in the postoperative length of stay (LOS) at the hospital or in the ICU was calculated after adjustment for the effects of 20 confounding factors that pertained to severity of illness, difficulty of operation, and risk of postoperative wound infection or pneumonia. RESULTS: Postoperative LOS averaged (mean +/- SE) 8.0 +/- 0.3 days in the hospital and 50.0 +/- 4.1 hours in the ICU. After adjustment for the effects of confounding factors, the postoperative length of hospitalization increased by 0.837 percent (95% CI, 0.249-1.425%) per RBC unit transfused (p<0.001), and the postoperative length of stay in the ICU increased by 0.873 percent (95% CI, -0.068-1.814%) per RBC unit transfused (p<0.10). CONCLUSION: Allogeneic blood transfusion was independently associated with longer postoperative stays in the hospital or the ICU, but the observed independent association is perhaps too small to be clinically relevant. This independent association may be due to a relationship between ABT and a higher incidence of septic complications of surgery, or it may reflect the function of blood transfusion as a surrogate marker for severity of illness. C1 NYU Med Ctr, Sch Med, Dept Pathol, Blood Bank, New York, NY 10016 USA. Massachusetts Gen Hosp, Blood Transfus Serv, Boston, MA 02114 USA. RP Vamvakas, EC (reprint author), NYU Med Ctr, Sch Med, Dept Pathol, Blood Bank, RRG-17,400 E 34th St, New York, NY 10016 USA. NR 42 TC 58 Z9 59 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD JUL PY 2000 VL 40 IS 7 BP 832 EP 839 DI 10.1046/j.1537-2995.2000.40070832.x PG 8 WC Hematology SC Hematology GA 341DC UT WOS:000088574900013 PM 10924612 ER PT J AU Baumgarten, G Knuefermann, P Mann, DL AF Baumgarten, G Knuefermann, P Mann, DL TI Cytokines as emerging targets in the treatment of heart failure SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Article ID TUMOR-NECROSIS-FACTOR; IDIOPATHIC DILATED CARDIOMYOPATHY; LEFT-VENTRICULAR DYSFUNCTION; FAILING HUMAN HEART; FACTOR-ALPHA GENE; CIRCULATING LEVELS; IMMUNE ACTIVATION; FACTOR RECEPTORS; NITRIC-OXIDE; EXPRESSION AB Recent studies have identified the importance of biologically active molecules such as neurohormones in disease progression in heart failure. More recently it has become apparent that in addition to neurohormones another portfolio of biologically active molecules termed cytokines are also expressed in the setting of heart failure. This article reviews recent clinical and experimental material which suggest that the cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6) may represent another class of biologically active molecules that are responsible for the development and progression of heart failure. In addition, we also review the early results from clinical trials that have utilized various targeted anti-cytokine strategies in patients with heart failure. (C) 2001, Elsevier Science Inc. C1 VA Med Ctr, Dept Med, Winters Ctr Heart Failure Res, Cardiol Sect, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Mann, DL (reprint author), VA Med Ctr, Dept Med, Winters Ctr Heart Failure Res, Cardiol Sect, 2002 Holcombe Blvd, Houston, TX 77030 USA. OI Mann, Douglas /0000-0002-2516-0145 FU NHLBI NIH HHS [R01 HL61543-01, HL-42250-10/10, P50 HL-O6H, R01 HL58081-01] NR 49 TC 42 Z9 44 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD JUL PY 2000 VL 10 IS 5 BP 216 EP 223 DI 10.1016/S1050-1738(00)00063-3 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 417PK UT WOS:000167843200007 PM 11282298 ER PT J AU Lein, M Koenig, F Misdraji, J McDougal, WS Jung, K Loening, SA Hasan, T Ortel, B AF Lein, M Koenig, F Misdraji, J McDougal, WS Jung, K Loening, SA Hasan, T Ortel, B TI Laser-induced hyperthermia in rat prostate cancer: Role of site of tumor implantation SO UROLOGY LA English DT Article ID NUDE-MICE; RADICAL PROSTATECTOMY; CARCINOMA-CELLS; METASTASIS; EXPRESSION; TISSUE; METALLOPROTEINASE-9; HYBRIDIZATION; BIOLOGY; GROWTH AB Objectives. To investigate the importance of the site of tumor implantation on the treatment response to laser-induced hyperthermia (LIH) of rat prostate cancer (PCa), because interventional manipulations of PCa have been reported to increase metastatic dissemination. Methods. Seven to nine days after either subcutaneous or orthotopic implantation of MatLyLu cells, LIH (46.5 degrees C) was induced using pulsed irradiations of a neodymium:yttrium-aluminum-garnet laser. Both local control and distant metastases were evaluated. Plasma metalloproteinase 9 (MMP-9) was tested as a possible marker of PCa progression and LIH response. Results. Twelve days after LIH treatment of subcutaneous tumors, the volumes were reduced by 64% after 8 minutes of irradiation, 73% after 10 minutes, 81% after 15 minutes, and 91.1% after 20 minutes. In the orthotopic model, the corresponding tumor reductions were 44% after 10 minutes, 61% after 20 minutes, and 65% after 30 minutes. Lung metastases were observed in only 1 animal with subcutaneous tumors. In contrast, 86% of the orthotopic tumor-bearing animals treated for 30 minutes had lung metastases compared with 23% of the untreated tumor-bearing rats. MMP-9 expression was detected in both orthotopic and subcutaneous tumor tissue and in the plasma of tumor-bearing rats. The prostate tissue of healthy rats and subcutaneous tumor-bearing rats was devoid of MMP-9. The plasma levels of MMP-9 showed a trend toward direct correlation with local tumor control but no correlation with the incidence of metastasis. Conclusions. These data emphasize the importance of the site of tumor implantation for evaluation of the efficacy of therapeutic interventions and may warrant further studies before widespread clinical application of LIH as monotherapy. UROLOGY 56: 167-172, 2000. (C) 2000, Elsevier Science Inc. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Urol, Boston, MA USA. Humboldt Univ, Univ Hosp Charite, Dept Urol, Berlin, Germany. RP Ortel, B (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Labs Photomed, WEL-224,55 Fruit St, Boston, MA 02114 USA. NR 29 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0090-4295 J9 UROLOGY JI UROLOGY PD JUL PY 2000 VL 56 IS 1 BP 167 EP 172 DI 10.1016/S0090-4295(00)00553-7 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 329HB UT WOS:000087900600045 PM 10869660 ER PT J AU Larsen, CE Xu, JH Lee, S Dubey, DP Uko, G Yunis, EJ Alper, CA AF Larsen, CE Xu, JH Lee, S Dubey, DP Uko, G Yunis, EJ Alper, CA TI Complex cytokine responses to hepatitis B surface antigen and tetanus toxoid in responders, nonresponders and subjects naive to hepatitis B surface antigen SO VACCINE LA English DT Article DE hepatitis B vaccine; tetanus toxoid; cytokines ID BLOOD MONONUCLEAR-CELLS; IMMUNE-RESPONSES; ANTIBODY-RESPONSE; T-CELLS; VACCINE; EFFICACY; HBSAG; STIMULATION; HUMANS; REVACCINATION AB Some human subjects vaccinated with hepatitis B surface antigen (HBsAg) do not produce antibodies to the vaccine (nonresponders). The mechanism for nonresponse is unknown. To understand the response and nonresponse to nominal antigens better, we determined the level and kinetics of cytokine secretion in response to HBsAg and tetanus toroid (TT) by peripheral blond mononuclear cells (PBMC) in vitro from HBsAg vaccine responders and nonresponders and from individuals naive to HBsAg, Proliferating PBMC secreted peak levels of interleukin-2 (IL-2) at 2 days and peak levels of tumor necrosis factor-beta (TNF-beta), interferon-gamma (IFN-gamma), IL-4 and IL-10 at 3-6 days post-stimulation. In contrast, nonproliferating PBMC (whether from nonresponders, naive subjects or weak responders) did not produce detectable levels of TNF-beta or IFN-gamma, nor was IL-4 or IL-10 produced significantly, and that produced had a different kinetic profile from that of proliferating PBMC. HBsAg-specific cytokine production by PBMC from strong responders broadly paralleled their cytokine responses to TT. Cellular cytokine mRNA levels measured by reverse transcriptase-polymerase chain reaction corroborated the secreted cytokine results. The anti-HBsAg- and anti-TT-specific T cell cytokine responses were mixed Th-1/2-like and donor-specific. An HBsAg-specific cytokine response, but not a TT-specific cytokine response, was completely missing in nonresponders. These data suggest that the T cell defect of HBsAg nonresponse is not due to a skewed cytokine profile. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Ctr Blood Res, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. RP Alper, CA (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NHLBI NIH HHS [HL-29583]; NIAID NIH HHS [AI-35630] NR 31 TC 19 Z9 21 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 JUL 1 PY 2000 VL 18 IS 26 BP 3021 EP 3030 DI 10.1016/S0264-410X(00)00084-0 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 329DC UT WOS:000087890000015 PM 10825606 ER PT J AU Gertler, JP Rehring, TF Davison, JK Laposata, M Cambria, RP AF Gertler, JP Rehring, TF Davison, JK Laposata, M Cambria, RP TI Correction of coagulation defect in thoracoabdominal aneurysm repair by mesenteric shunting SO VASCULAR SURGERY LA English DT Article ID AORTIC-ANEURYSM; NEUROLOGIC COMPLICATIONS; BYPASS; EXPERIENCE; OPERATIONS AB The authors have previously characterized laboratory coagulation abnormalities in patients undergoing thoracoabdominal aneurysm (TAA) repair as a reduction in clotting factor activity and an increase in the fibrinolysis that occurs after supraceliac clamping. A return to normal in these patients did not occur until the time of skin closure and was influenced by fresh frozen plasma (FFP) administration. To test the hypothesis that shortening the mesenteric ischemic time would mitigate the defect earlier in the operative course, the authors developed a technique of mesenteric shunting during TAA repair and studied coagulation response prospectively. Twelve consecutive elective patients had TAA repair carried out in standard fashion. No heparin was used. After completion of the proximal anastomosis, a coronary perfusion catheter was secured inside a previously sewn graft side arm and inserted into either the superior mesenteric artery or the celiac axis; the graft was clamped below the side arm. Blood levels of fibrinogen, F1.2, D-dimer, and Factors II, V, VII, VIII, IX, X, XI, and XII were analyzed at induction, immediately prior to mesenteric shunt insertion, at reimplantation of the visceral button and 30 minutes after visceral button reimplantation. Clamp times, volume and timing of blood products, and clinical outcomes were recorded prospectively. A two-sided, paired t test (pairwise/intersample) was applied for each factor studied. There was no coagulopathic bleeding. Indicators of fibrinolysis (fibrinogen, D-dimer) continued to rise throughout the procedure as had been true in our previous series. However, clotting factors returned to baseline shortly after mesenteric shunting and prior to administration of exogenous clotting factors. The return to baseline of the coagulation factors studied began at the time of the insertion of a mesenteric shunt. Visceral perfusion appears to have an impact on coagulation response. Earlier reperfusion may help extend the window of operative time by limiting coagulopathic bleeding that is occasionally seen during TAA repair. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Vasc Surg,Surg Serv,Div Lab Med, Boston, MA 02114 USA. RP Gertler, JP (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Vasc Surg,Surg Serv,Div Lab Med, 15 Parkman St,WAC 458, Boston, MA 02114 USA. NR 16 TC 0 Z9 0 U1 0 U2 0 PU WESTMINSTER PUBL INC PI GLEN HEAD PA 708 GLEN COVE AVE, GLEN HEAD, NY 11545 USA SN 0042-2835 J9 VASCULAR SURG JI Vasc. Surg. PD JUL-AUG PY 2000 VL 34 IS 4 BP 285 EP 290 DI 10.1177/153857440003400402 PG 6 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 334PL UT WOS:000088194800001 ER PT J AU Govardovskii, VI Fyhrquist, N Reuter, T Kuzmin, DG Donner, K AF Govardovskii, VI Fyhrquist, N Reuter, T Kuzmin, DG Donner, K TI In search of the visual pigment template SO VISUAL NEUROSCIENCE LA English DT Article DE retina; photoreceptors; rhodopsin; absorbance; spectral sensitivity ID MONKEY MACACA-FASCICULARIS; SPECTRAL SENSITIVITY; LINEAR DICHROISM; BULLFROG RETINA; CONES; GOLDFISH; RODS; RHODOPSIN; PHOTORECEPTORS; ULTRAVIOLET AB Absorbance spectra were recorded by microspectrophotometry from 39 different rod and cone types representing amphibians, reptiles, and fishes, with A1- or A2-based visual pigments and lambda(max) ranging from 357 to 620 nm. The purpose was to investigate accuracy limits of putative universal templates for visual pigment absorbance spectra, and if possible to amend the templates to overcome the limitations. it was found that (1) the absorbance spectrum of frog rhodopsin extract very precisely parallels that of rod outer segments from the same individual, with only a slight hypsochromic shift in lambda(max), hence templates based on extracts are valid for absorbance in situ (2) a template based on the bovine rhodopsin extract data of Partridge and De Grip (1991) describes the absorbance of amphibian rod outer segments excellently, contrary to recent electrophysiological results; (3) the lambda(max)/lambda invariance of spectral shape Fails fur A1 pigments with small lambda(max) and for A2 pigments with large lambda(max), but the deviations are systematic and can be readily incorporated into, for example, the Lamb (1995) template. We thus propose modified templates for the main "alpha-band" of A1 and A2 pigments and show that these describe both absorbance and spectral sensitivities of photoreceptors over the whole range of lambda(max). Subtraction of the alpha-band from the full absorbance spectrum leaves a "beta-band" described by a lambda(max)-dependent Gaussian. We conclude that the idea of universal templates (one for A1- and one for A2-based visual pigments) remains valid and useful at the present level of accuracy of data on photoreceptor absorbance and sensitivity. The sum of our expressions for the alpha- and beta-band gives a good description for visual pigment spectra with lambda(max) > 350 nm. C1 Russian Acad Sci, Inst Evolutionary Physiol & Biochem, St Petersburg 194223, Russia. Univ Helsinki, Dept Biosci, FIN-00014 Helsinki, Finland. Univ Helsinki, Dept Systemat & Ecol, FIN-00014 Helsinki, Finland. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Howe Labs, Boston, MA 02114 USA. RP Govardovskii, VI (reprint author), Russian Acad Sci, Inst Evolutionary Physiol & Biochem, Thorez Prospect 44, St Petersburg 194223, Russia. NR 72 TC 514 Z9 526 U1 4 U2 53 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0952-5238 J9 VISUAL NEUROSCI JI Visual Neurosci. PD JUL-AUG PY 2000 VL 17 IS 4 BP 509 EP 528 DI 10.1017/S0952523800174036 PG 20 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 353TP UT WOS:000089291800003 PM 11016572 ER PT J AU Pham, HT Rich, J Veves, A AF Pham, HT Rich, J Veves, A TI Wound healing in diabetic foot ulceration: A review and commentary SO WOUNDS-A COMPENDIUM OF CLINICAL RESEARCH AND PRACTICE LA English DT Article ID ULCERS C1 Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Joslin Foot Ctr,Dept Surg, Boston, MA 02215 USA. RP Pham, HT (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Joslin Foot Ctr,Dept Surg, Palmer Baker Span 315,W Campus,1 Deaconess Rd, Boston, MA 02215 USA. NR 11 TC 4 Z9 4 U1 0 U2 0 PU HEALTH MANAGEMENT PUBLICATIONSINC PI WAYNE PA 950 WEST VALLEY RD, STE 2800, WAYNE, PA 19087 USA SN 1044-7946 J9 WOUNDS JI Wounds-Compend. Clin. Res. Pract. PD JUL-AUG PY 2000 VL 12 IS 4 BP 79 EP 81 PG 3 WC Dermatology; Surgery SC Dermatology; Surgery GA 345DK UT WOS:000088800000003 ER PT J AU Cuajungco, MP Goldstein, LE Nunomura, A Smith, MA Lim, JT Atwood, CS Huang, XD Farrag, YW Perry, G Bush, AI AF Cuajungco, MP Goldstein, LE Nunomura, A Smith, MA Lim, JT Atwood, CS Huang, XD Farrag, YW Perry, G Bush, AI TI Evidence that the beta-amyloid plaques of Alzheimer's disease represent the redox-silencing and entombment of A beta by zinc SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SENILE PLAQUES; PROTEIN; AGGREGATION; DEPOSITION; ISOFORMS; PEPTIDE; NEURONS; DAMAGE; CORTEX; MICE AB A beta binds Zn2+, Cu2+ and Fe3+ in vitro, and these metals are markedly elevated in the neocortex and especially enriched in amyloid plaque deposits of individuals with Alzheimer's disease (AD). Zn2+ precipitates A beta in vitro, and Cu2+ interaction with A beta promotes its neurotoxicity, correlating with metal reduction and the cell-free generation of H2O2 (A beta 1-42 > A beta 1-40 > ratA beta 1-40). Because Zn2+ is redox-inert, we studied the possibility that it may play an inhibitory role in H2O2-mediated A beta toxicity. In competition to the cytotoxic potentiation caused by coincubation with Cu2+, Zn2+ rescued primary cortical and human embryonic kidney 293 cells that were exposed to A beta 1-42, correlating with the effect of Zn2+ in suppressing Cu2+-dependent H2O2 formation from A beta 1-42. Since plaques contain exceptionally high concentrations of Zn2+, we examined the relationship between oxidation (8-OH guanosine) levels in AD-affected tissue and histological amyloid burden and found a significant negative correlation. These data suggest a protective role for Zn2+ in AD, where plaques form as the result of a more robust Zn2+ antioxidant response to the underlying oxidative attack. C1 Massachusetts Gen Hosp, Lab Oxidat Biol, Genet Aging Unit, Charlestown, MA 02129 USA. Univ Auckland, Sch Med, Dept Psychiat & Behav Sci, Auckland, New Zealand. Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. Asahikawa Med Coll, Dept Psychiat & Neurol, Asahikawa, Hokkaido 0788510, Japan. RP Bush, AI (reprint author), Massachusetts Gen Hosp, Lab Oxidat Biol, Genet Aging Unit, Bldg 149,13th St, Charlestown, MA 02129 USA. RI Smith, Mark/A-9053-2009; Perry, George/A-8611-2009; Cuajungco, Math/B-2647-2008; Bush, Ashley/A-1186-2007 OI Perry, George/0000-0002-6547-0172; Cuajungco, Math/0000-0003-0749-9564; Bush, Ashley/0000-0001-8259-9069 FU NIA NIH HHS [R01-AG09287, R29 AG-12686] NR 30 TC 290 Z9 307 U1 1 U2 19 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 30 PY 2000 VL 275 IS 26 BP 19439 EP 19442 DI 10.1074/jbc.C000165200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 330AU UT WOS:000087941300002 PM 10801774 ER PT J AU Shimizu, M Carter, PH Gardella, TJ AF Shimizu, M Carter, PH Gardella, TJ TI Autoactivation of type-1 parathyroid hormone receptors containing a tethered ligand SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID (PTH)/PTH-RELATED PEPTIDE RECEPTOR; N-TERMINAL REGION; BIOLOGICAL-ACTIVITY; CROSS-LINKING; BINDING; RESIDUES; DETERMINANTS; MUTAGENESIS; ACTIVATION; PTH-(1-34) AB Interactions between the N-terminal residues of parathyroid hormone (PTH) and the region of the PTH receptor containing the extracellular loops and transmembrane domains are thought to be critical for receptor activation. We evaluated this hypothesis by replacing the large N-terminal extracellular domain of the human type 1 PTH receptor (hP1Rc-WT) with residues 1-9 of PTH (AVSEIQLMH) using a tetraglycine linker between His-9 of the ligand and Glu-182 of the receptor near the extracellular terminus of transmembrane domain-1. Expression of this construct, hP1Rc-Tether(1-9), in COS-7 cells resulted in basal cAMP levels that were 10-fold higher than those seen in control cells transfected with hP1Rc-WT, Extending the ligand sequence to include Asn-10 and the activity-enhancing substitution of Leu-11 --> Arg yielded hP1Rc-[Arg(11)]Tether(1-11), for which we observed basal cAMP levels that were 50-fold higher than those seen with P1Rc-WT, An alanine-scan analysis of hP1Rc-[Arg(11)]Tether(1-11) revealed that Gln-6 and His-9 were not critical for autoactivation, whereas Val-2, Ile-5, and Met-8 were. The data show that tethered PTH/PTH receptors can autoactivate. Analysis of the structure-activity relationships in these tethered receptor constructs can provide new information concerning how the N-terminal residues of PTH interact with the extracellular loops and transmembrane regions of the PTH-1 receptor, particularly in regard to receptor activation. C1 Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Gardella, TJ (reprint author), Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. NR 25 TC 35 Z9 36 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 30 PY 2000 VL 275 IS 26 BP 19456 EP 19460 DI 10.1074/jbc.M001596200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 330AU UT WOS:000087941300005 PM 10751403 ER PT J AU Harendza, S Lovett, DH Stahl, RAK AF Harendza, S Lovett, DH Stahl, RAK TI The hematopoietic transcription factor PU.1 represses gelatinase A transcription in glomerular mesangial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STIMULATING FACTOR-RECEPTOR; MURINE TISSUE MACROPHAGES; BETA-C GENE; MATRIX METALLOPROTEINASE-2; IV COLLAGENASE; DNA-BINDING; EXPRESSION; PROMOTER; RAT; ACTIVATION AB The matrix metalloproteinase gelatinase A plays a key role in the evolution of glomerular injury and is a major contributing factor to the development of glomerulosclerosis, Prior studies have focused on a potent cis-acting enhancer element located in the near 5'-flanking region of the rat and human gelatinase A genes (Harendza, S., Pollock, A. S., Mertens, P. R., and Lovett, D. H. (1995) J. Biol. Chem. 270, 18286-18796; Mertens, P. R., Alfonso-Jaume, M. A., Steinmann, K., and Lovett, D. H. (1999) J. Am. Soc. Nephrol. 10, 2480-2487). Given the combinatorial nature of transcriptional regulation, we examined additional regions of the 5'-flanking region of the rat gelatinase A gene to identify further regulatory elements. In this study the identification of a silencing element located between -1903 and -1847 base pairs of the 5'-flanking region of the rat gelatinase A gene is reported. Sequence analysis, electrophoretic mobility studies, and transfection experiments demonstrate that a specific binding sequence for the hematopoietic transcription factor PU.1 is present within the silencing sequence. PU.1 activity is absolutely required for the expression of silencing activity within the context of transfected glomerular mesangial cells. Western blots identify the PU.1 protein within nuclear extracts of mesangial cells, and cotransfection with a PU.1 expression vector directly augments silencing activity. These studies underscore the complex patterns of gelatinase A transcriptional regulation and also strongly suggest that glomerular mesangial cells are ultimately derived from bone marrow cells. C1 Univ Hamburg, Dept Med, Div Nephrol, D-20246 Hamburg, Germany. Univ Calif San Francisco, San Francisco Vet Affairs Med Ctr, Dept Med, San Francisco, CA 94121 USA. RP Harendza, S (reprint author), Univ Hamburg, Krankenhaus Eppendorf, Med Klin, Abt Nephrol & Osteol, Pavillon 61,Martinistr 52, D-20246 Hamburg, Germany. FU NIDDK NIH HHS [DK 39776] NR 43 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 30 PY 2000 VL 275 IS 26 BP 19552 EP 19559 DI 10.1074/jbc.M001322200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 330AU UT WOS:000087941300018 PM 10867017 ER PT J AU Koipally, J Georgopoulos, K AF Koipally, J Georgopoulos, K TI Ikaros interactions with CtBP reveal a repression mechanism that is independent of histone deacetylase activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TERMINAL BINDING-PROTEIN; MEDIATES TRANSCRIPTIONAL REPRESSION; ADENOVIRUS E1A; CO-REPRESSOR; CELLULAR PHOSPHOPROTEIN; LYMPHOCYTE DEVELOPMENT; NEGATIVE MODULATION; DROSOPHILA CTBP; N-COR; COREPRESSOR AB We have previously shown that Ikaros can repress transcription through the recruitment of histone deacetylase complexes. Here we provide evidence that Ikaros can also repress transcription through its interactions with the co-repressor, C-terminal binding protein (CtBP). CtBP interacts with Ikaros isoforms through a PEDLS motif present at the N terminus of these proteins but not with homologues like Aiolos which lack this motif. Mutations in Ikaros that prevent CtBP interactions reduce its ability to repress transcription, CtBP interacts with Sin3A but not with the Mi-2 co-repressor and it represses transcription in a manner that is independent of histone deacetylase activity. These data strongly suggest that CtBP contributes to a histone deacetylase activity independent mechanism of repression by Ikaros. Finally, we show that the viral oncoprotein E1A, which binds to CtBP, also shows a strong association with Ikaros. This Ikaros-E1A interaction may underlie Ikaros's decreased ability to repress transcription in E1A transformed cells. C1 Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Georgopoulos, K (reprint author), Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Bldg 149,13th St, Charlestown, MA 02129 USA. FU NIAID NIH HHS [R01 AI33062] NR 50 TC 143 Z9 144 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 30 PY 2000 VL 275 IS 26 BP 19594 EP 19602 DI 10.1074/jbc.M000254200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 330AU UT WOS:000087941300023 PM 10766745 ER PT J AU Abboud, S Haile, DJ AF Abboud, S Haile, DJ TI A novel mammalian iron-regulated protein involved in intracellular iron metabolism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSPORTER; NRAMP2; FERRITIN AB We have isolated and characterized a novel iron-regulated gene that is homologous to the divalent metal transporter 1 family of metal transporters. This gene, termed metal transporter protein (mtp1), is expressed in tissues involved in body iron homeostasis including the developing and mature reticuloendothelial system, the duodenum, and the pregnant uterus. MTP1 is also expressed in muscle and central nervous system cells in the embryo. At the subcellular level, MTP1 is localized to the basolateral membrane of the duodenal epithelial cell and a cytoplasmic compartment of reticuloendothelial system cells. Overexpression of MTP1 in tissue culture cells results in intracellular iron depletion. In the adult mouse, MTP1 expression in the liver and duodenum are reciprocally regulated. Iron deficiency induces MTP1 expression in the duodenum but down-regulates expression in the liver. These data indicate that MTP1 is an iron-regulated membrane-spanning protein that is involved in intracellular iron metabolism. C1 Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. Audie L Murphy Mem Vet Hosp, S Texas Vet Hlth Syst, San Antonio, TX 78284 USA. RP Haile, DJ (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pathol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. FU NIDDK NIH HHS [R01DK53079, R03DK96009] NR 14 TC 774 Z9 806 U1 4 U2 22 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 30 PY 2000 VL 275 IS 26 BP 19906 EP 19912 DI 10.1074/jbc.M000713200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 330AU UT WOS:000087941300065 PM 10747949 ER PT J AU Rimbach, G Park, YC Guo, Q Moini, H Qureshi, N Saliou, C Takayama, K Virgili, F Packer, L AF Rimbach, G Park, YC Guo, Q Moini, H Qureshi, N Saliou, C Takayama, K Virgili, F Packer, L TI Nitric oxide synthesis and TNF-alpha secretion in RAW 264.7 macrophages - Mode of action of a fermented papaya preparation SO LIFE SCIENCES LA English DT Article DE nitric oxide; tumor necrosis factor-alpha; RAW 264.7 macrophages; fermented papaya preparation; bionormalizer (TM) ID TUMOR-NECROSIS-FACTOR; BIO-NORMALIZER SUPPLEMENTATION; CELL-LINE RAW-264.7; KAPPA-B ACTIVATION; SUPEROXIDE-DISMUTASE; PERITONEAL-MACROPHAGES; ESCHERICHIA-COLI; INTERFERON-GAMMA; OXIDATIVE DAMAGE; MESANGIAL CELLS AB Macrophage inducible nitric oxide synthase is able to generate massive amounts of nitric oxide (NO) which contributes to the host immune defense against viruses and bacteria. Monocyte-macrophages stimulated with the bacterial wall component lipopolysaccharide (LPS) and cytokines such as interferon-gamma (IFN-gamma) express the inducible form of nitric oxide synthase (iNOS). Furthermore, tumor necrosis factor-alpha (TNF-alpha) is one of the central regulatory cytokines in macrophage antimicrobial activity and synergizes with IFN-gamma in the induction of NO synthesis. Because of its pivotal role in both antimicrobial and tumoricidal activities of macrophages, a significant effort has focused on developing therapeutic agents that regulate NO production. In the present study fermented papaya preparation (FPP) is shown to exert both immunomodulatory and antioxidant activity in the macrophage cell line RAW 264.7. Interestingly, a low and a high molecular weight fraction (LMF and HMF, respectively) of FPP exhibited different activity patterns. FPP fractions alone did not affect NO production, However in the presence of IFN-gamma, both LMF and HMF significantly increased iNOS activity and nitrite as well as nitrate accumulation. NO radical formation measured in real-time by electron paramagnetic resonance spectroscopy was higher in the presence of LMF and IFN-gamma. On the contrary, iNOS mRNA levels were enhanced further with HMF than with LMF Moreover, LMF displayed a stronger superoxide anion scavenging activity than HMF. In the presence of IFN-gamma, both FPP fractions stimulated TNF-alpha secretion. However in non-stimulated macrophages, TNF-alpha secretion was enhanced by HMF only. Since water-soluble FPP fractions contained no lipid A, present data indicate that FPP is a macrophage activator which augments nitric oxide synthesis and TNF-alpha secretion independently of lipopolysaccharides. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Univ Calif Berkeley, Dept Cell & Mol Biol, Berkeley, CA 94720 USA. William S Middleton Mem Vet Hosp, Mycobacteriol Res Lab, Madison, WI USA. Natl Inst Nutr, Rome, Italy. RP Packer, L (reprint author), Univ Calif Berkeley, Dept Cell & Mol Biol, 251 Life Sci Addit, Berkeley, CA 94720 USA. RI Rimbach, Gerald/A-7178-2011 OI Rimbach, Gerald/0000-0001-7888-4684 NR 51 TC 35 Z9 35 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD JUN 30 PY 2000 VL 67 IS 6 BP 679 EP 694 DI 10.1016/S0024-3205(00)00664-0 PG 16 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 332LZ UT WOS:000088076900009 PM 12659174 ER PT J AU Walhout, AJM Boulton, SJ Vidal, M AF Walhout, AJM Boulton, SJ Vidal, M TI Yeast two-hybrid systems and protein interaction mapping projects for yeast and worm SO YEAST LA English DT Review DE protein interaction mapping; yeast two-hybrid; co-immunoprecipitation; GST pull-down; two-hybrid matrix approach ID MASS-SPECTROMETRY; HUMAN-GENOME; IDENTIFICATION; MAP AB The availability of complete genome sequences necessitates the development of standardized functional assays to analyse the tens of thousands of predicted gene products in high-throughput experimental settings, Such approaches are collectively referred to as 'functional genomics', One approach to investigate the properties of a proteome of interest is by systematic analysis of protein-protein interactions. So far, the yeast two-hybrid system is the most commonly used method for large-scale, high-throughput identification of potential protein-protein interactions. Here, we discuss several technical features of variants of the two-hybrid systems in light of data recently obtained from different protein interaction mapping projects for the budding yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. OI Walhout, Marian/0000-0001-5587-3608 FU NCI NIH HHS [1 R21 CA81658 A 01]; NHGRI NIH HHS [1 RO1 HG01715-01] NR 29 TC 80 Z9 81 U1 3 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0749-503X EI 1097-0061 J9 YEAST JI Yeast PD JUN 30 PY 2000 VL 17 IS 2 BP 88 EP 94 DI 10.1002/1097-0061(20000630)17:2<88::AID-YEA20>3.0.CO;2-Y PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 337WA UT WOS:000088383600002 PM 10900455 ER PT J AU Chen, F Ma, L Parrini, MC Mao, X Lopez, M Wu, C Marks, PW Davidson, L Kwiatkowski, DJ Kirchhausen, T Orkin, SH Rosen, FS Mayer, BJ Kirschner, MW Alt, FW AF Chen, F Ma, L Parrini, MC Mao, X Lopez, M Wu, C Marks, PW Davidson, L Kwiatkowski, DJ Kirchhausen, T Orkin, SH Rosen, FS Mayer, BJ Kirschner, MW Alt, FW TI Cdc42 is required for PIP2-induced actin polymerization and early development but not for cell viability SO CURRENT BIOLOGY LA English DT Article ID WISKOTT-ALDRICH SYNDROME; GTPASE-BINDING DOMAIN; RHO-FAMILY GTPASE; ARP2/3 COMPLEX; PROTEIN CDC42; N-WASP; DEPOLYMERIZING PROTEIN; GENOMIC ORGANIZATION; RAS TRANSFORMATION; CYCLE PROGRESSION AB Background: Cdc42 and other Rho GTPases are conserved from yeast to humans and are thought to regulate multiple cellular functions by inducing coordinated changes in actin reorganization and by activating signaling pathways leading to specific gene expression. Direct evidence implicating upstream signals and components that regulate Cdc42 activity or for required roles of Cdc42 in activation of downstream protein kinase signaling cascades is minimal, however. Also, whereas genetic analyses have shown that Cdc42 is essential for cell viability in yeast, its potential roles in the growth and development of mammalian cells have not been directly assessed. Results: To elucidate potential functions of Cdc42 mammalian cells, we used gene-targeted mutation to inactivate Cdc42 in mouse embryonic stem (ES) cells and in the mouse germline. Surprisingly, Cdc42-deficient ES cells exhibited normal proliferation and phosphorylation of mitogen- and stress-activated protein kinases. Yet Cdc42 deficiency caused very early embryonic lethality in mice and led to aberrant actin cytoskeletal organization in ES cells, Moreover, extracts from Cdc42-deficient cells failed to support phosphatidylinositol 4,5-bisphosphate (PIP2)-induced actin polymerization. Conclusions: Our studies clearly demonstrate that Cdc42 mediates PIP2-induced actin assembly, and document a critical and unique role for Cdc42 in this process. Moreover, we conclude that, unexpectedly, Cdc42 is not necessary for viability or proliferation of mammalian early embryonic cells. Cdc42 is, however, absolutely required for early mammalian development. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Childrens Hosp, Mol Med Lab, Boston, MA 02115 USA. Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Genet Lab,Hematol Div, Boston, MA 02115 USA. RP Alt, FW (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RI Ma, Le/A-3733-2013; Parrini, Maria Carla/J-5390-2016 OI Parrini, Maria Carla/0000-0002-7082-9792 FU NHLBI NIH HHS [HL59561]; NIAID NIH HHS [AI2000047]; NIGMS NIH HHS [GM26875] NR 53 TC 139 Z9 140 U1 0 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD JUN 29 PY 2000 VL 10 IS 13 BP 758 EP 765 DI 10.1016/S0960-9822(00)00571-6 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 348HG UT WOS:000088979000016 PM 10898977 ER PT J AU Janne, PA Mayer, RJ AF Janne, PA Mayer, RJ TI Primary care: Chemoprevention of colorectal cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID FAMILIAL ADENOMATOUS POLYPOSIS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; HORMONE REPLACEMENT THERAPY; RANDOMIZED CONTROLLED TRIAL; EPITHELIAL-CELL PROLIFERATION; FATAL COLON-CANCER; METHIONINE SYNTHASE GENE; METHYLENETETRAHYDROFOLATE REDUCTASE; CYCLOOXYGENASE-2 LEVELS; BETA-CAROTENE C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA USA. RP Janne, PA (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 101 TC 310 Z9 321 U1 0 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 29 PY 2000 VL 342 IS 26 BP 1960 EP 1968 DI 10.1056/NEJM200006293422606 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 328TZ UT WOS:000087867400006 PM 10874065 ER PT J AU Jones, GB Wright, JM Hynd, G Wyatt, JK Yancisin, M Brown, MA AF Jones, GB Wright, JM Hynd, G Wyatt, JK Yancisin, M Brown, MA TI Protein-degrading enediynes: Library screening of Bergman cycloaromatization products SO ORGANIC LETTERS LA English DT Article ID ESTROGEN-RECEPTOR; PHOTOCLEAVAGE; SUPERFAMILY; STRATEGY; CLEAVAGE AB A screening method based on Bergman cycloaromatization products was applied to a compact library of estrogenic-enediyne hybrids, An enediyne candidate identified from the screen was subsequently synthesized, and it induced temperature- and concentration-dependent degradation of human estrogen receptor a upon cycloaromatization. C1 Northeastern Univ, Dept Chem, Bioorgan & Med Chem Labs, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Jones, GB (reprint author), Northeastern Univ, Dept Chem, Bioorgan & Med Chem Labs, 360 Huntington Ave,102HT, Boston, MA 02115 USA. OI Brown, Myles/0000-0002-8213-1658 FU NIGMS NIH HHS [R01GM57123] NR 25 TC 50 Z9 50 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD JUN 29 PY 2000 VL 2 IS 13 BP 1863 EP 1866 DI 10.1021/ol005926q PG 4 WC Chemistry, Organic SC Chemistry GA 327QR UT WOS:000087804700020 PM 10891177 ER PT J AU Fowler, FJ Collins, MM Albertsen, PC Zietman, A Elliott, DB Barry, MJ AF Fowler, FJ Collins, MM Albertsen, PC Zietman, A Elliott, DB Barry, MJ TI Comparison of recommendations by urologists and radiation oncologists for treatment of clinically localized prostate cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LONG-TERM SURVIVAL; RADICAL PROSTATECTOMY; THERAPY; PHYSICIANS; SEQUELAE; MEN AB Context Multiple treatment options are available for men with prostate cancer, but therapeutic recommendations may differ depending on the type of specialist they consult. Objective To define and contrast the distribution of management recommendations by urologists and radiation oncologists for a spectrum of men with prostate cancer. Design, Setting, and Participants Mail survey sent in 1998 to a random sample of physicians in the United States, who were listed as urologists (response rate 64%, n = 504) and radiation oncologists (response rate 76%, n=559) in the American Medical Association Registry of Physicians and practicing at least 20 hours per week. Main Outcome Measure Questionnaire addressing beliefs and practices regarding prostate cancer management. Results Forty-three percent of radiation oncologists vs 16% of urologists would recommend routine prostate-specific antigen testing for men aged 80 years and older. For men with moderately differentiated, clinically localized cancers, and a more than 10-year life expectancy, 93% of urologists chose radical prostatectomy as the preferred treatment option, while 72% of radiation oncologists believed surgery and external beam radiotherapy were equivalent treatments. For most tu mor grades and prostate-specific antigen levels, both specialty groups were significantly more likely to recommend the treatment in their specialty than the other treatment, Both groups reported giving patients similar estimates of the risks of complications due to surgery and radiation. Neither group favored watchful waiting In their treatment management except for a subset of men with life expectancies of less than 10 years and cancers with very favorable prognoses (Gleason score of 3 or 4 and prostate-specific antigen level less than or equal to 5 ng/mL), Conclusions Based on this study, while urologists and radiation oncologists do agree on a variety of issues regarding detection and treatment of prostate cancer, specialists overwhelmingly recommend the therapy that they themselves deliver. C1 Massachusetts Gen Hosp, Med Practices Evaluat Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Univ Massachusetts, Survey Res Ctr, Boston, MA 02125 USA. Univ Connecticut, Ctr Hlth, Div Urol, Farmington, CT USA. RP Barry, MJ (reprint author), Massachusetts Gen Hosp, Med Practices Evaluat Ctr, 50 Staniford St,9th Floor, Boston, MA 02114 USA. FU AHRQ HHS [HS 08397] NR 17 TC 243 Z9 246 U1 1 U2 3 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 28 PY 2000 VL 283 IS 24 BP 3217 EP 3222 DI 10.1001/jama.283.24.3217 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 326TY UT WOS:000087753900034 PM 10866869 ER PT J AU Chen, AM Zhou, Y Swenson, K Sachs, DH Sykes, M Yang, YG AF Chen, AM Zhou, Y Swenson, K Sachs, DH Sykes, M Yang, YG TI Porcine stem cell engraftment and seeding of murine thymus with class II+ cells in mice expressing porcine cytokines - toward tolerance induction across discordant xenogeneic barriers SO TRANSPLANTATION LA English DT Article ID IMMUNE-DEFICIENT MICE; LEUKOCYTE DIFFERENTIATION ANTIGENS; NONLETHAL PREPARATIVE REGIMEN; BONE-MARROW CHIMERAS; ONCOGENE C-KIT; MONOCLONAL-ANTIBODIES; IMMUNODEFICIENT MICE; HEMATOPOIETIC-CELLS; XENOGRAFT REJECTION; ALLOGRAFT TOLERANCE AB Background. Mixed hematopoietic chimerism is a reliable means of tolerance induction, but its utility has not been demonstrated in discordant xenogeneic combinations because of the difficulty in achieving lasting hematopoietic engraftment. Miniature swine are likely to be suitable organ donors for humans. To evaluate the ability of mixed chimerism to induce swine-specific tolerance in widely disparate xenogeneic recipients, this study aimed to achieve long-lasting chimerism in a pig to mouse combination. Methods. Immunodeficient transgenic mice were developed by crossing transgenic founders carrying porcine interleukin-3, granulocyte macrophage-colony stimulating factor, and stem cell factor genes with severe combined immunodeficient mice or non-obese diabetic /severe combined immunodeficient mice. Swine bone marrow transplantation was performed in these mice, and porcine chimerism was followed for 20 weeks. Results. Whereas swine cells became undetectable in all non-Tg littermates by 7 weeks, high levels of porcine hematopoietic chimerism, including the presence of porcine class II+ cells in the host thymus were maintained in Tg mice for >20 weeks. Colony-forming assays revealed the presence of large numbers of swine hematopoietic progenitor cells in the marrow of these mice at 20 weeks after bone marrow transplantation. Conclusions. These transgenic mice demonstrate for the first time that spontaneous migration of marrow donor antigen-presenting cells to an intact recipient thymus can occur and that porcine stem cells can persist in this highly disparate species combination. These data therefore support the feasibility of the eventual goal of tolerance induction by mixed chimerism in discordant xenogeneic combinations. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Surg Serv,Bone Marrow Transplantat Sect, Charlestown, MA 02129 USA. RP Yang, YG (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med,Transplantat Biol Res Ctr, Surg Serv,Bone Marrow Transplantat Sect, MGH E,Bldg 149-5102,13th St, Charlestown, MA 02129 USA. FU NHLBI NIH HHS [R01 HL 54038, R01 HL49915]; NIAID NIH HHS [P01 AI39755] NR 46 TC 36 Z9 40 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 2000 VL 69 IS 12 BP 2484 EP 2490 DI 10.1097/00007890-200006270-00005 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 335HU UT WOS:000088238700005 PM 10910267 ER PT J AU Giugliano, RP Lloyd-Jones, DM Camargo, CA Makary, MA O'Donnell, CJ AF Giugliano, RP Lloyd-Jones, DM Camargo, CA Makary, MA O'Donnell, CJ TI Association of unstable angina guideline care with improved survival SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID MYOCARDIAL-INFARCTION; PECTORIS; MANAGEMENT AB Background: An unstable angina guideline was published in 1994 by the Agency for Health Care Policy and Research, Bethesda, Md. However, the relationship between guideline-concordant care and patient outcomes is unknown. Objective: To determine whether guideline-concordant care is associated with improved outcomes. Methods: The study sample consisted of 275 consecutive nonreferral patients hospitalized with primary unstable angina. One-year survival and survival free of myocardial infarction were compared between patients who received care concordant with 8 selected guideline recommendations and patients who received discordant care. Results: Care concordant with the 8 key guideline recommendations was associated with improved 1-year survival (95% vs 81%; log-rank P<.001) and survival free of myocardial infarction (91% vs 74%; P<.001), compared with guideline-discordant care. Patients in high risk subgroups had the largest survival benefit associated with guideline-concordant care (aged greater than or equal to 65 years, 91% vs 74% [P=.005]; heart failure at presentation, 91% vs 68% [P=.10]). Aspirin therapy was the single recommendation most strongly associated with improved 1-year survival (94% vs 78%; P=.002). Conclusions: Care as outlined in the unstable angina clinical practice guideline is associated with improved 1-year outcomes. Subgroups of patients at highest risk and recommendations firmly based on randomized clinical trial data were mast strongly associated with better outcomes. These findings support the use of an evidence-based approach to guideline development and assessment of quality of care in patients with primary unstable angina. C1 Brigham & Womens Hosp, TIMI Study Off, Div Cardiovasc, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA USA. Georgetown Univ, Med Ctr, Dept Surg, Washington, DC 20007 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Giugliano, RP (reprint author), Brigham & Womens Hosp, TIMI Study Off, Div Cardiovasc, 333 Longwood Ave,Suite 402, Boston, MA 02115 USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 17 TC 27 Z9 27 U1 0 U2 0 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 26 PY 2000 VL 160 IS 12 BP 1775 EP 1780 DI 10.1001/archinte.160.12.1775 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 327TQ UT WOS:000087809900007 PM 10871970 ER PT J AU Flack, JM Yunis, C Preisser, J Holmes, CB Mensah, G McLean, B Saunders, E AF Flack, JM Yunis, C Preisser, J Holmes, CB Mensah, G McLean, B Saunders, E CA ATIME Res Grp TI The rapidity of drug dose escalation influences blood pressure response and adverse effects burden in patients with hypertension - The Quinapril Titration Interval Management Evaluation (ATIME) study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID TO-MODERATE HYPERTENSION; MILD HYPERTENSION; LONGITUDINAL DATA AB Background: Antihypertensive medication doses are typically increased within several weeks after initiation of therapy because of inadequate blood pressure (BP) control and/or adverse effects. Methods: We conducted a parallel-group clinical trial with 2935 subjects (53% women, n=1547) aged 21 to 75 years, with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure VI stages 1 to 2 hypertension, recruited from 365 physician practices in the southeastern United States. Participants were randomized either to a fast (every 2 weeks; n=1727) or slow (every 6 weeks; n=1208) drug titration. Therapy with quinapril, an angiotensin-converting enzyme inhibitor, was initiated at 20 mg once daily. The dose was doubled at the next 2 clinic visits until the BP was lower than 140/90 mm Hg or a dose of 80 mg was reached. Results: Pretreatment BP averaged 152/95 mm Hg. Patients with stage 2 hypertension reported more symptoms than those with stage 1. The BP averaged 140/86, 137/84, and 134/83 mm Hg in the slow group compared with 141/88, 137/85, and 135/84 mm Hg in the fastgroup at the 3 respective clinic visits. The BP control rates to lower than 140/90 mm Hg at the 3 clinic visits were (slow, fast, respectively) 41.3%, 35.7% (P<.001); 54.3%, 51.5% (P=.16); and 68%, 62.3% (P=.02). in the fast group, 10.7% of participants experienced adverse events vs 10.8% in the slow group; however, 21.0%, of adverse events in the fast group were "serious" vs only 12%; in the slow group. Conclusion: Slower dose escalation of the angiotensin-converting enzyme inhibitor quinapril provides higher BP control rates and fewer serious adverse events than more rapid drug dose escalation. C1 Wayne State Univ, Sch Med, Univ Hlth Ctr, Dept Community Med,Detroit Med Ctr, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Internal Med,Div Endocrinol Metab & Hyperten, Cardiovasc Epidemiol & Clin Applicat Program, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, John D Dingell Cet Adm Med Ctr, Detroit, MI 48201 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Surg Sci, Hypertens & Vasc Med Ctr, Winston Salem, NC USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Internal Med, Boston, MA USA. Augusta Vet Adm Med Ctr, Dept Cardiol, Augusta, GA USA. High Blood Pressure Ctr, Dept Internal Med, Birmingham, AL USA. Univ Maryland, Sch Med, Div Hypertens, Baltimore, MD 21201 USA. RP Flack, JM (reprint author), Wayne State Univ, Sch Med, Univ Hlth Ctr, Dept Community Med,Detroit Med Ctr, 4201 St Antoine,2E, Detroit, MI 48201 USA. OI Mensah, George/0000-0002-0387-5326 NR 13 TC 22 Z9 23 U1 0 U2 0 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 26 PY 2000 VL 160 IS 12 BP 1842 EP 1847 DI 10.1001/archinte.160.12.1842 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 327TQ UT WOS:000087809900016 PM 10871979 ER PT J AU Tandrup, T Woolf, CJ Coggeshall, RE AF Tandrup, T Woolf, CJ Coggeshall, RE TI Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE primary afferent neurons; sciatic nerve lesion; stereology ID PRIMARY SENSORY NEURONS; GROWTH-FACTOR; TRANSGANGLIONIC DEGENERATION; PATHOLOGICAL RESEARCH; CONDUCTION-VELOCITY; EMPIRICAL-METHOD; AFFERENT-FIBERS; SPINAL-CORD; SUBSTANCE-P; ADULT AB The present study deals with changes in numbers and sizes of primary afferent neurons (dorsal root ganglion [DRG] cells) after sciatic nerve transection. We find that this lesion in adult rats leads to death of some DRG cells by 8 weeks and 37% by 32 weeks after the lesion. The loss of cells appears earlier in and is more severe in B-cells (small, dark cells with unmyelinated axons) than A-cells (large, light cells with myelinated axons). With regard to mean cell volumes, there is a tendency for both categories of DRG cells to be smaller, but except for isolated time points, these differences are not statistically significant. These findings differ from most earlier reports in that the cell loss takes place later than usually reported, that the loss is more severe for B-cells, and that neither A- or B-cells change size significantly. Accordingly, we conclude that sciatic nerve transection in adult rats leads to a slowly developing but relatively profound loss of primary afferent neurons that is more severe for B-cells. These results can serve as a basis for studies to determine the effectiveness of trophic or survival factors in avoiding axotomy induced cell death. (C) 2000 Wiley-Liss, Inc. C1 Aarhus Univ Hosp, Dept Neurol, DK-8000 Aarhus C, Denmark. Aarhus Univ, Stereol Res Lab, DK-8000 Aarhus C, Denmark. UCL, Dept Anat & Dev Biol, London WC1E 6BT, England. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plastic Res Grp, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. Univ Texas, Med Branch, Dept Anat & Neurosci, Galveston, TX 77550 USA. RP Tandrup, T (reprint author), Aarhus Univ Hosp, Dept Neurol, DK-8000 Aarhus C, Denmark. EM trine@akhphd.au.dk FU NINDS NIH HHS [NS38253, NS10161, NS11255] NR 67 TC 145 Z9 154 U1 0 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUN 26 PY 2000 VL 422 IS 2 BP 172 EP 180 DI 10.1002/(SICI)1096-9861(20000626)422:2<172::AID-CNE2>3.0.CO;2-H PG 9 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 320BG UT WOS:000087380700002 PM 10842225 ER PT J AU von Gall, C Weaver, DR Kock, M Korf, HW Stehle, JH AF von Gall, C Weaver, DR Kock, M Korf, HW Stehle, JH TI Melatonin limits transcriptional impact of phosphoCREB in the mouse SCN via the Mel(1a) receptor SO NEUROREPORT LA English DT Article DE clock genes; melatonin receptor; mice; PACAP; phase-shifts; phosphoCREB ID SUPRACHIASMATIC CIRCADIAN CLOCK; FACTOR CREB; INDUCED PHOSPHORYLATION; GENE-EXPRESSION; PERIOD HOMOLOGS; NUCLEUS; LIGHT; GLUTAMATE; RESPONSES; STIMULI AB In the mouse, activity phase-shifts of the endogenous clock in the suprachiasmatic nucleus (SCN) are associated with phosphorylation of the transcription factor Ca2+/cAMP responsive element binding protein (CREB). CREB phosphorylation is induced by the retino-hypothalamic transmitter pituitary adenylate cyclase-activating polypeptide (PACAP). As detected by immunohistochemistry in SCN slices from wild-type mice, melatonin completely blocked PACAP-stimulated CREB phosphorylation at low concentrations (I nM). In Mel(la) melatonin receptor-deficient mice, the PACAP-induced CREB phosphorylation was inhibited only at melatonin concentrations of 100 nM. This inhibition was, however, blunted by blocking the Mel(lb) melatonin receptor. Thus, melatonin modulates PACAP-mediated retinal stimuli for clock entrainment primarily via the Melt, melatonin receptor through molecular interaction within the cAMP-signalling pathway. NeuroReport 11:1803-1807 (C) 2000 Lippincott Williams & Wilkins. C1 Univ Frankfurt, Inst Anat 2, D-60590 Frankfurt, Germany. Univ Frankfurt, TVA, D-60590 Frankfurt, Germany. Massachusetts Gen Hosp, Lab Dev Chronobiol, Serv Pediat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02114 USA. RP Stehle, JH (reprint author), Univ Frankfurt, Inst Anat 2, D-60590 Frankfurt, Germany. OI Weaver, David/0000-0001-7941-6719 FU NIA NIH HHS [AG09975] NR 25 TC 37 Z9 37 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD JUN 26 PY 2000 VL 11 IS 9 BP 1803 EP 1807 DI 10.1097/00001756-200006260-00002 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 326WH UT WOS:000087759800007 PM 10884023 ER PT J AU Barach, P Small, SD AF Barach, P Small, SD TI How the NHS can improve safety and learning SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02115 USA. Univ Chicago, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA. RP Barach, P (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02115 USA. RI Barach, paul/B-9915-2016 OI Barach, paul/0000-0002-7906-698X NR 14 TC 23 Z9 23 U1 0 U2 1 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8138 J9 BRIT MED J JI Br. Med. J. PD JUN 24 PY 2000 VL 320 IS 7251 BP 1683 EP 1684 DI 10.1136/bmj.320.7251.1683 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 329UJ UT WOS:000087926400003 PM 10864524 ER PT J AU Weaver, WD Reisman, MA Griffin, JJ Buller, CE Leimgruber, PP Henry, T D'Haem, C Clark, VL Martin, JS Cohen, DJ Neil, N Every, NR AF Weaver, WD Reisman, MA Griffin, JJ Buller, CE Leimgruber, PP Henry, T D'Haem, C Clark, VL Martin, JS Cohen, DJ Neil, N Every, NR CA OPUS-1 Investigators TI Optimum percutaneous transluminal coronary angioplasty compared with routine stent strategy trial (OPUS-1): a randomised trial SO LANCET LA English DT Article ID ANGIOGRAPHIC FOLLOW-UP; BALLOON ANGIOPLASTY; ARTERY DISEASE; THREATENED CLOSURE; IMPLANTATION; RESTENOSIS; DISSECTION; OUTCOMES AB Background Whether routine implantation of coronary stents is the best strategy to treat flow-limiting coronary stenoses is unclear. An alternative approach is to do balloon angioplasty and provisionally use stents only to treat suboptimum results. We did a multicentre trial to compare the outcomes of patients treated with these strategies. Methods We randomly assigned 479 patients undergoing single-vessel coronary angioplasty routine stent implantation or initial balloon angioplasty and provisional stenting. We followed up patients for 6 months to determine the composite rate of death, myocardial infarction, cardiac surgery, and target-vessel revascularisation. Results Stents were implanted in 227 (98.7%) of the patients assigned routine stenting. 93 (37%) patients assigned balloon angioplasty had at least one stent placed because of suboptimum angioplasty results. At 6 months the composite endpoint was significantly lower in the routine stent strategy (14 events, 6.1%) than with the strategy of balloon angioplasty with provisional stenting (37 events, 14.9%, p=0.003). The cost of the initial revascularisation procedure was higher than when a routine stent strategy was used (US$389 vs $339, p<0.001) but at 6 months, average per-patient hospital costs did not differ ($10 206 vs $10 490). Bootstrap replication of 6-month cost data showed continued economic benefit of the routine stent strategy. Interpretation Routine stent implantation leads to better acute and long-term clinical outcomes at a cost similar to that of initial balloon angioplasty with provisional stenting. C1 Henry Ford Hlth Syst, Inst Heart & Vasc, Div Cardiovasc Med, Detroit, MI 48202 USA. Swedish Med Ctr, Seattle, WA USA. Virginia Beach Med Ctr, Virginia Beach, VA USA. Vancouver Hosp & Med Ctr, Vancouver, BC, Canada. Heart Inst Spokane, Spokane, WA USA. Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. Michigan Capital Med Ctr, Lansing, MI USA. Beth Israel Hosp, Boston, MA 02215 USA. Univ Washington, Med Ctr, Seattle, WA 98195 USA. Virginia Mason Med Ctr, Seattle, WA 98101 USA. VA Puget Sound Healthcare Syst, Seattle, WA USA. RP Weaver, WD (reprint author), Henry Ford Hlth Syst, Inst Heart & Vasc, Div Cardiovasc Med, 2799 W Grand Blvd, Detroit, MI 48202 USA. RI Neil, Nancy/I-4913-2012 OI Neil, Nancy/0000-0002-1442-028X NR 29 TC 70 Z9 71 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 JUN 24 PY 2000 VL 355 IS 9222 BP 2199 EP 2203 DI 10.1016/S0140-6736(00)02403-X PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 327DX UT WOS:000087779000011 PM 10881893 ER PT J AU Tevosian, SG Deconinck, AE Tanaka, M Schinke, M Litovsky, SH Izumo, S Fujiwara, Y Orkin, SH AF Tevosian, SG Deconinck, AE Tanaka, M Schinke, M Litovsky, SH Izumo, S Fujiwara, Y Orkin, SH TI FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium SO CELL LA English DT Article ID ZINC-FINGER PROTEIN; CARDIAC DEVELOPMENT; SMOOTH-MUSCLE; RXR-ALPHA; VENTRAL MORPHOGENESIS; TRANSGENIC MICE; TUBE FORMATION; MOUSE EMBRYO; AVIAN HEART; DIFFERENTIATION AB We disrupted the FOG-2 gene in mice to define its requirement in vivo. FOG-2(-/-) embryos die at midgestation with a cardiac defect characterized by a thin ventricular myocardium, common atrioventricular canal, and the tetralogy of Fallot malformation. Remarkably, coronary vasculature is absent in FOG-2(-/-) hearts. Despite formation of an intact epicardial layer and expression of epicardium-specific genes, markers of cardiac vessel development (ICAM-2 and FLK-1) are not detected, indicative of failure to activate their expression and/or to initiate the epithelial to mesenchymal transformation of epicardial cells. Transgenic reexpression of FOG-2 in cardiomyocytes rescues the FOG-2(-/-) vascular phenotype, demonstrating that FOG-2 function in myocardium is required and sufficient for coronary vessel development. Our findings provide the molecular inroad into the induction of coronary vasculature by myocardium in the developing heart. C1 Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Dept Med,Div Cardiol, Boston, MA 02115 USA. Howard Hughes Med Inst, Boston, MA 02115 USA. RP Orkin, SH (reprint author), Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA. NR 64 TC 284 Z9 291 U1 1 U2 15 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUN 23 PY 2000 VL 101 IS 7 BP 729 EP 739 DI 10.1016/S0092-8674(00)80885-5 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 327YE UT WOS:000087821400007 PM 10892744 ER PT J AU Mummidi, S Bamshad, M Ahuja, SS Gonzalez, E Feuillet, PM Begum, K Galvis, MC Kostecki, V Valente, AJ Murthy, KK Haro, L Dolan, MJ Allan, JS Ahuja, SK AF Mummidi, S Bamshad, M Ahuja, SS Gonzalez, E Feuillet, PM Begum, K Galvis, MC Kostecki, V Valente, AJ Murthy, KK Haro, L Dolan, MJ Allan, JS Ahuja, SK TI Evolution of human and non-human primate CC chemokine receptor 5 gene and mRNA - Potential roles for haplotype and mRNA diversity, differential haplotype-specific transcriptional activity, and altered transcription factor binding to polymorphic nucleotides in the pathogenesis of HIV-1 and Simian immunodeficiency virus SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; AFRICAN-GREEN MONKEYS; DISEASE PROGRESSION; MESSENGER-RNA; 5'-END HETEROGENEITY; PROMOTER REGION; ANIMAL-MODELS; INFECTION; PROTEINS; ENTRY AB Polymorphisms in CC chemokine receptor 5 (CCR5), the major coreceptor of human immunodeficiency virus 1 (HIV-1) and simian immunodeficiency virus (SIV), have a major influence on HIV-1 transmission and disease progression. The effects of these polymorphisms may, in part, account for the differential pathogenesis of HIV-1 (immunosuppression) and SIV (natural resistance) in humans and non-human primates, respectively. Thus, understanding the genetic basis underlying species-specific responses to HIV-1 and SIV could reveal new anti-HIV-1 therapeutic strategies for humans. To this end, we compared CCR5 structure/evolution and regulation among humans, apes, Old World Monkeys, and New World Monkeys. The evolution of the CCR5 cis-regulatory region versus the open reading frame as well as among different domains of the open reading frame differed from one another. CCR5 cis-regulatory region sequence variation in humans was substantially higher than anticipated. Based on this variation, CCR5 haplotypes could be organized into seven evolutionarily distinct human haplogroups (HH) that we designated HHA, -B, -C, -D, -E, -F, and -G. HHA haplotypes were defined as ancestral to all other haplotypes by comparison to the CCR5 haplotypes of non-human primates. Different human and non-human primate CCR5 haplotypes were associated with differential transcriptional regulation, and various polymorphisms resulted in modified DNA-nuclear protein interactions, including altered binding of members of the NF-KB family of transcription factors. We identified novel CCR5 untranslated mRNA sequences that were conserved in human and non-human primates. In some primates, mutations at exon-intron boundaries caused loss of expression of selected CCR5 mRNA isoforms or production of novel mRNA isoforms. Collectively, these findings suggest that the response to HIV-1 and SN infection in primates may have been driven, in part, by evolution of the elements controlling CCR5 transcription and translation. C1 Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. S Texas Vet Hlth Care Syst, Audie L Murphy Div, Dept Med, San Antonio, TX 78229 USA. Univ Utah, Eccles Inst Human Genet, Dept Pediat, Salt Lake City, UT 84112 USA. SW Fdn Biomed Res, Dept Virol & Immunol, San Antonio, TX 78228 USA. Univ Texas, Dept Life Sci, San Antonio, TX 78249 USA. Wilford Hall USAF Med Ctr, Infect Dis Serv, Lackland AFB, San Antonio, TX 78236 USA. RP Ahuja, SK (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. RI Mummidi, Srinivas/C-1004-2008 OI Mummidi, Srinivas/0000-0002-4068-6380 FU NIAID NIH HHS [R01-AI41396, R01-AI43279, R29-AI46326] NR 67 TC 116 Z9 118 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 23 PY 2000 VL 275 IS 25 BP 18946 EP 18961 DI 10.1074/jbc.M000169200 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327VZ UT WOS:000087815900046 PM 10747879 ER PT J AU Schwartz, PT Perez-Villamil, B Rivera, A Moratalla, R Vallejo, M AF Schwartz, PT Perez-Villamil, B Rivera, A Moratalla, R Vallejo, M TI Pancreatic homeodomain transcription factor IDX1/IPF1 expressed in developing brain regulates somatostatin gene transcription in embryonic neural cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HOMEOBOX GENES; VENTROMEDIAL HYPOTHALAMUS; MAMMALIAN TELENCEPHALON; IMMUNOREACTIVE NEURONS; UPSTREAM ENHANCER; PRECURSOR CELLS; NEUROPEPTIDE-Y; MICE LACKING; ISLET CELLS; BETA-CELLS AB Hox-like homeodomain proteins play a critical role during embryonic development by regulating the transcription of genes that are important for the generation of specific organs or cell types. The homeodomain transcription factor IDX1/IPF1, the expression of which was thought until recently to be restricted to the pancreas and foregut, is required for pancreas development and for the expression of genes controlling glucose homeostasis. We report that IDX1/IPF1 is also expressed in embryonic rat brain at a time coincident with active neurogenesis. Electrophoretic mobility shift assays with nuclear extracts of embryonic brains indicated that IDX1/IPF1 binds to two somatostatin promoter elements, SMS-UE-B and the recently discovered SMS-TAAT3, The requirement of these elements for IDX1/IPF1 transactivation of the somatostatin gene in neural cells was confirmed in transfection studies using embryonic cerebral cortex-derived RC2.E10 cells. Immunohistochemical staining of rat embryos showed IDX1/IPF1-positive cells located near the ventricular surface in germinative areas of the developing central nervous system. Cellular colocalization of IDX1/IPF1 and somatostatin was found in several areas of the developing brain, including cortex, ganglionic eminence, hypothalamus, and inferior colliculus. These results support the notion that IDX1/IPF1 regulates gene expression during development of the central nervous system independent of its role on pancreas development and function. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Reprod Endocrine Unit, Boston, MA 02114 USA. CSIC, Inst Ramon Y Cajal, Madrid 28002, Spain. Univ Autonoma Madrid, Inst Invest Biomed, CSIC, E-28029 Madrid, Spain. RP Vallejo, M (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Reprod Endocrine Unit, Boston, MA 02114 USA. RI Rivera, Alicia/L-2098-2014; Moratalla, Rosario/H-9280-2015 OI Rivera, Alicia/0000-0002-7282-0441; Moratalla, Rosario/0000-0002-7623-8010 FU NIDDK NIH HHS [DK-49670] NR 73 TC 28 Z9 30 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 23 PY 2000 VL 275 IS 25 BP 19106 EP 19114 DI 10.1074/jbc.M000655200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327VZ UT WOS:000087815900065 PM 10751390 ER PT J AU Dunah, AW Wyszynski, M Marrin, DM Sheng, M Standaert, DG AF Dunah, AW Wyszynski, M Marrin, DM Sheng, M Standaert, DG TI alpha-actinin-2 in rat striatum: localization and interaction with NMDA glutamate receptor subunits SO MOLECULAR BRAIN RESEARCH LA English DT Article DE alpha-actinin-2; striatum; glutamate receptor; NMDA receptor; localization; immunoprecipitation ID ALPHA-ACTININ; MESSENGER-RNA; DIFFERENTIAL EXPRESSION; BASAL GANGLIA; INTERNEURONS; NEURONS; BRAIN; CALMODULIN; PROTEIN; CEREBELLUM AB Alpha-actinin (alpha-actinin-2) is a protein which links the NR1 and NR2B subunits of N-methyl-D-aspartate (NMDA) glutamate receptors to the actin cytoskeleton. Because of the importance of NMDA receptors in modulating the function of the striatum, we have examined the localization or alpha-actinin-2 protein and mRNA in striatal neurons, and its biochemical interaction with NMDA receptor subunits present in the rat striatum. Using an alpha-actinin-2-specific antibody, we found intense immunoreactivity in the striatal neuropil and within striatal neurons th;lt also expressed pa valbumin, calretinin and calbindin. Conversely, alpha-actinin-2 immunoreactivity was not detected in neurons expressing choline acetyltransferase and neuronal nitric oxide synthase. Dual-label in situ hybridization revealed that the highest expression of a-actinin-2 mRNA is in substance P-containing striatal projection neurons. The alpha-actinin-2. mRNA is also present in enkephalinergic projection neurons and interneurons expressing parvalbumin, choline acetyl transferase and the 67-kDa isoform of glutamic acid decarboxylase, but was not detected in somatostatin-expressing interneurons. Immunoprecipitation of membrane protein extracts showed that alpha-actinin-2 is present in heteromeric complexes of NMDA subunits, but is not associated with AMPA receptors in the striatum. A subunit-specific anti-NR1 antibody co-precipitated major fractions of NR2A and NR2B subunits, but only a minor fraction of striatal alpha-nctinin-2. Conversely, alpha-actinin-2 antibody immunoprecipitated only modest fractions of striatal NR1, NR2A and NR2B subunits. These data demonstrate that alpha-actinin-2 is a very abundant striatal protein, but exhibits cellular specificity in its expression, with very high levels in substance-P-containing projection neurons, and very low levels in somatostatin and neuronal nitric oxide synthase inter-neurons. Despite the high expression of this protein in the striatum, only a minority of NMDA receptors are linked to alpha-actinin-2. This interaction may identify a subset of receptors with distinct anatomical and functional properties. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Standaert, DG (reprint author), Massachusetts Gen Hosp, Dept Neurol, 408 Fruit St, Boston, MA 02114 USA. NR 30 TC 26 Z9 26 U1 0 U2 1 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 23 PY 2000 VL 79 IS 1-2 BP 77 EP 87 DI 10.1016/S0169-328X(00)00102-9 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 344ZM UT WOS:000088791000007 ER PT J AU Kohen, R Heidmann, DEA Anthony, J White, SS Hamblin, MW Szot, P AF Kohen, R Heidmann, DEA Anthony, J White, SS Hamblin, MW Szot, P TI Changes in 5-HT7 serotonin receptor mRNA expression with aging in rat brain SO MOLECULAR BRAIN RESEARCH LA English DT Article DE in situ hybridization histochemistry; aging; circadian rhythm; hippocampus; spatial learning; psychiatric disorders ID AUTORADIOGRAPHIC ANALYSIS; MOLECULAR-CLONING; F-18 ALTANSERIN; GENE-EXPRESSION; BINDING SITES; AGE; HIPPOCAMPUS; ADRENALECTOMY; HYPOTHALAMUS; STIMULATION AB We examined 5-HT7 receptor mRNA expression with in situ hybridization histochemistry in the brains of young (3 months), middle-aged (12 months) and old rats (24 months). In the ventral CA3 area of the hippocampus 5-HT7 mRNA expression is reduced by approximately 30% between young and middle age without further decline between middle and old age. In other brain areas 5-HT7 mRNA expression is unaffected by age. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Ctr Geriatr Res Educ & Clin, VA Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. VA Puget Sound Hlth Care Syst, Mental Illness Res Educ & Clin Ctr, Seattle, WA 98108 USA. Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Kohen, R (reprint author), Ctr Geriatr Res Educ & Clin, VA Puget Sound Hlth Care Syst, 182B,1660 S Columbian Way, Seattle, WA 98108 USA. NR 31 TC 11 Z9 11 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 23 PY 2000 VL 79 IS 1-2 BP 163 EP 168 DI 10.1016/S0169-328X(00)00103-0 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 344ZM UT WOS:000088791000017 ER PT J AU Hickey, RW Zhu, RL Alexander, HL Jin, KL Stetler, RA Chen, J Kochanek, PM Graham, SH AF Hickey, RW Zhu, RL Alexander, HL Jin, KL Stetler, RA Chen, J Kochanek, PM Graham, SH TI 10 kD mitochondrial matrix heat shock protein mRNA is induced following global brain ischemia in the rat SO MOLECULAR BRAIN RESEARCH LA English DT Article DE asphyxia; cardiac arrest; chaperonin; west shock protein; ischemia ID CEREBRAL-ISCHEMIA; ESCHERICHIA-COLI; MESSENGER-RNA; CHAPERONES; INDUCTION; ARREST; HSP10; MODEL AB Heat shock proteins (HSP's) are a family of highly conserved proteins whose expression is increased by stress. The expression of many HSP's is induced in neurons by ischemia; however, the response of the 10 kDa mitochondrial matrix HSP (HSP10) is less well characterized. To address this issue, asphyxial cardiac arrest was induced in 28 male Sprague-Dawley rats. Northern blot analysis revealed that hsp10 mRNA was increased 3.7-fold in asphyxiated rats compared to sham-operated controls. In situ hybridization demonstrated increased mRNA in the cortex, septal nuclei, hippocampus, thalamic nuclei, purkinje cell layer of the cerebellum, and isolated brainstem nuclei of asphyxiated rats. The increase of mRNA was most robust 8 h after the injury but remained increased for 72 h. These results show that hsp10 mRNA is increased following asphyxial cardiac arrest in rats and suggest that hsp10 could be another determinate of neuronal survival after ischemia. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pediat, Div Pediat Emergency Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Anesthesia Crit Care Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Safar Ctr Resuscitat Res, Pittsburgh, PA 15213 USA. VA Pittsburgh Hlth Syst, Ctr Geriatr Res Educ & Clin, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15213 USA. RP Hickey, RW (reprint author), Univ Pittsburgh, Childrens Hosp Pittsburgh, Dept Pediat, Div Pediat Emergency Med, 3705 5th Ave, Pittsburgh, PA 15213 USA. EM hickeyr@pitt.edu RI Kochanek, Patrick/D-2371-2015 OI Kochanek, Patrick/0000-0002-2627-913X FU NINDS NIH HHS [1PO1NS35965] NR 20 TC 7 Z9 9 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 23 PY 2000 VL 79 IS 1-2 BP 169 EP 173 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 344ZM UT WOS:000088791000018 PM 10925156 ER PT J AU Tarazi, FI Zhang, KH Baldessarini, RJ AF Tarazi, FI Zhang, KH Baldessarini, RJ TI Olanzapine, quetiapine, and risperidone: long-term effects on monoamine transporters in rat forebrain SO NEUROSCIENCE LETTERS LA English DT Article DE accumbens; autoradiography; atypical antipsychotic drugs; caudate nucleus; dopamine; serotonin; transporters ID DOPAMINE UPTAKE SITES; SEROTONIN TRANSPORTERS; H-3 PAROXETINE; SCHIZOPHRENIA; RECEPTORS; POSTMORTEM; DRUGS; HIPPOCAMPUS; DISORDER; BINDING AB Long-term effects of novel atypical antipsychotic drugs on monoamine transporters are unknown. We compared labeling of dopamine (DAT) and serotonin (SERT) transporter proteins in subregions of rat corpus striatum by quantitative auto radiography with [H-3]2-beta-carbomethoxy-3-beta-[4'-iodophenyl]tropane ([H-3]beta-CIT) and [H-3]paroxetine after 28 days of continuous subcutaneous infusion of olanzapine, quetiapine, risperidone, or vehicle controls. Drug treatment did not significantly alter the abundance of either transporter type in caudate-putamen or nucleus accumbens, indicating that transporter proteins required to inactivate synaptically released dopamine and serotonin resist adaptations to longterm treatment with novel antipsychotics that affect neurotransmission by these amines. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved. C1 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, Neurosci Program, Boston, MA 02115 USA. RP Tarazi, FI (reprint author), Massachusetts Gen Hosp, McLean Div, Mailman Res Ctr, Belmont, MA 02478 USA. FU NIMH NIH HHS [MH-34006, MH-47370] NR 20 TC 17 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 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD JUN 23 PY 2000 VL 287 IS 2 BP 81 EP 84 DI 10.1016/S0304-3940(00)01130-7 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 327QT UT WOS:000087804800001 PM 10854717 ER PT J AU Goldstein, LE Leopold, MC Huang, XD Atwood, CS Saunders, AJ Hartshorn, M Lim, JT Faget, KY Muffat, JA Scarpa, RC Chylack, LT Bowden, EF Tanzi, RE Bush, AI AF Goldstein, LE Leopold, MC Huang, XD Atwood, CS Saunders, AJ Hartshorn, M Lim, JT Faget, KY Muffat, JA Scarpa, RC Chylack, LT Bowden, EF Tanzi, RE Bush, AI TI 3-Hydroxykynurenine and 3-hydroxyanthranilic acid generate hydrogen peroxide and promote alpha-crystallin cross-linking by metal ion reduction SO BIOCHEMISTRY LA English DT Article ID CATARACTOUS HUMAN LENSES; NEURONAL CELL-DEATH; TRYPTOPHAN-METABOLITES; QUINOLINIC ACID; ANTIOXIDANT ACTIVITIES; HUNTINGTONS-DISEASE; LIPID-PEROXIDATION; ULTRAVIOLET FILTER; KYNURENINE PATHWAY; NUCLEAR CATARACT AB The kynurenine pathway catabolite 3-hydroxykynurenine (3HK) and redox-active metals such as copper and iron are implicated in cataractogenesis, Here we investigate the reaction of kynurenine pathway catabolites with copper and iron, as well as interactions with the major lenticular structural proteins, the alpha-crystallins. The o-aminophenol kynurenine catabolites 3HK and 3-hydroxyanthranilic acid (3HAA) reduced Cu(II)>Fe(III) to Cu(I) and Fe(II), respectively, whereas quinolinic acid and the nonphenolic kynurenine catabolites kynurenine and anthranilic acid did not reduce either metal. Both 3HK and 3HAA generated superoxide and hydrogen peroxide in a copper-dependent manner. In addition, 3HK and 3HAA fostered copper-dependent alpha-crystallin cross-linking. 3HK- or 3HAA-modifed alpha-crystallin showed enhanced redox activity in comparison to unmodified alpha-crystallin or ascorbate-modified alpha-crystallin. These data support the possibility that 3HK and 3HAA may be cofactors in the oxidative damage of proteins, such as alpha-crystallin, through interactions with redox-active metals and especially copper. These findings may have relevance for understanding cataractogenesis and other degenerative conditions in which the kynurenine pathway is activated. C1 Massachusetts Gen Hosp, Lab Oxidat Biol, Dept Psychiat, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Dept Neurol, Genet Aging Unit, Charlestown, MA 02129 USA. Brigham & Womens Hosp, Ctr Ophthalm Res, Boston, MA 02115 USA. N Carolina State Univ, Dept Chem, Raleigh, NC 27695 USA. RP Bush, AI (reprint author), Massachusetts Gen Hosp E, Lab Oxidat Biol, Bldg 149,13th St, Charlestown, MA 02129 USA. RI Muffat, Julien/P-2298-2014; Bush, Ashley/A-1186-2007; OI Bush, Ashley/0000-0001-8259-9069; Goldstein, Lee/0000-0001-8419-9800 NR 67 TC 85 Z9 86 U1 2 U2 8 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 20 PY 2000 VL 39 IS 24 BP 7266 EP 7275 DI 10.1021/bi992997s PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 327DQ UT WOS:000087778300027 PM 10852726 ER PT J AU Lewis, BA Kim, TK Orkin, SH AF Lewis, BA Kim, TK Orkin, SH TI A downstream element in the human beta-globin promoter: Evidence of extended sequence-specific transcription factor IID contacts SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA-POLYMERASE-II; TATA-BINDING PROTEIN; HISTONE OCTAMER; DNA COMPLEX; GENE; INITIATOR; CORE; BOX; DROSOPHILA; THALASSEMIA AB We describe here the identification and characterization of a functional downstream element in the human adult beta-globin promoter. The existence of this element was indicated by two mutations at +22 and +33 downstream of the beta-globin transcriptional start site in humans with beta-thalassemia. in vitro transcriptional analysis of these mutants, plus a third at +13, indicates that all three decrease transcription from the beta-globin promoter. Scanning mutagenesis from +10 to +45 indicates that this region contains a functional cis element(s) in vitro, and we designated this element the DCE (downstream core element), The DCE functions in concert with the beta-globin CATA box and initiator element, as well as in a heterologous, TATA-less context. A second set of mutants indicates that a particular geometry of the DCE and core promoter is necessary for promoter function. Lastly, DCE mutants show reduced affinity for transcription factor IID (TFIID), These data indicate that TFIID makes sequence-specific contacts to the DCE and that TFIID binding is necessary for DCE function. C1 Harvard Univ, Sch Med, Howard Hughes Med Inst,Div Hematol Oncol, Childrens Hosp Med Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Howard Hughes Med Inst, Dept Pediat,Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Biochem,Div Nucl Acids Enzymol, Howard Hughes Med Inst, Piscataway, NJ 08854 USA. RP Orkin, SH (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst,Div Hematol Oncol, Childrens Hosp Med Ctr, Enders,Room 761,300 Longwood Ave, Boston, MA 02115 USA. RI Brugnara, Carlo/A-8041-2010 OI Brugnara, Carlo/0000-0001-8192-8713 NR 40 TC 55 Z9 57 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7172 EP 7177 DI 10.1073/pnas.120181197 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600046 PM 10840054 ER PT J AU Kotani, T Banno, K Ikura, M Hinnebusch, AG Nakatani, Y Kawaichi, M Kokubo, T AF Kotani, T Banno, K Ikura, M Hinnebusch, AG Nakatani, Y Kawaichi, M Kokubo, T TI A role of transcriptional activators as antirepressors for the autoinhibitory activity of TATA box binding of transcription factor IID SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA-POLYMERASE-II; HERPES-SIMPLEX VIRUS; ARTIFICIAL RECRUITMENT; PREINITIATION COMPLEX; DNA-BINDING; IN-VITRO; PROTEIN; DOMAIN; YEAST; TBP AB The TATA box-binding activity of transcription factor IID (TFIID) is autoinhibited by the N-terminal domain of the Drosophila TATA box-binding protein- (TBP) associated factor 230/yeast TBP-associated factor 145 subunit, which binds to the TATA box-binding domain of TBP by mimicking the TATA box structure. Here, we propose a mechanism of transcriptional activation that involves antirepression of this autoinhibitory activity by transcriptional activators. Like the autoinhibitory domain of TFIID, various acidic activators interact with the TATA box-binding domain of TBP. Moreover, the autoinhibitory domain of TFIID, which is known to interact with only the TATA box-binding domain of Tap, acts as an activation domain when fused to the GAL4 DNA-binding domain, indicating that interaction with the TATA-binding domain of TBP is crucial for activation of transcription. In a reciprocal fashion, the acidic activation domains can function as the autoinhibitory domain when the latter is replaced by the former within TFIID. These results indicate that activation domains and the autoinhibitory domain of TFIID are interchangeable. supporting a role for transcriptional activators as antirepressors of the autoinhibitory activity of the TATA box binding of TFIID. C1 Nara Inst Sci & Technol, Div Gene Funct Anim, Nara 6300101, Japan. Univ Toronto, Ontario Canc Inst, Div Mol & Struct Biol, Toronto, ON M5G 2M9, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2M9, Canada. NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Kokubo, T (reprint author), Nara Inst Sci & Technol, Div Gene Funct Anim, 8916-5 Takayama, Nara 6300101, Japan. NR 39 TC 37 Z9 38 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7178 EP 7183 DI 10.1073/pnas.120074297 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600047 PM 10852950 ER PT J AU Wilson, SB Kent, SC Horton, HF Hill, AA Bollyky, PL Hafler, DA Strominger, JL Byrne, MC AF Wilson, SB Kent, SC Horton, HF Hill, AA Bollyky, PL Hafler, DA Strominger, JL Byrne, MC TI Multiple differences in gene expression in regulatory V alpha 24J alpha Q T cells from identical twins discordant for type 1 diabetes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MICE; ACTIVATION; ITK; SECRETION; DEFICIENT; MELLITUS; KINASE; GENOME AB Quantitative and qualitative defects in CD1d-restricted T cells have been demonstrated in human and murine autoimmune diseases. To investigate the transcriptional consequences of T cell receptor activation in human V alpha 24J alpha Q T cell clones, DNA microarrays were used to quantitate changes in mRNA levels after anti-CD3 stimulation of clones derived from identical twins discordant for type 1 diabetes and IL-4 secretion. Activation resulted in significant modulation of 226 transcripts in the IL-4 secreting clone and 86 in the IL-4-null clone. Only 28 of these genes were in common. The differences observed suggest both ineffective differentiation of diabetic V alpha 24J alpha Q T cells and a role for invariant T cells in the recruitment and activation of cells from the myeloid lineage. C1 Genet Inst, Cambridge, MA 02140 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. RP Wilson, SB (reprint author), Genet Inst, 87 Cambridge Pk Dr, Cambridge, MA 02140 USA. FU NCI NIH HHS [R35 CA47554]; NIAID NIH HHS [R01 AI045051, R01 AI44447]; NIDDK NIH HHS [R01 DK52127] NR 30 TC 90 Z9 91 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7411 EP 7416 DI 10.1073/pnas.120161297 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600087 PM 10840051 ER PT J AU Sampson, JH Crotty, LE Lee, S Archer, GE Ashley, DM Wikstrandt, CJ Hale, LP Small, C Dranoff, G Friedman, AH Friedman, HS Bigner, DD AF Sampson, JH Crotty, LE Lee, S Archer, GE Ashley, DM Wikstrandt, CJ Hale, LP Small, C Dranoff, G Friedman, AH Friedman, HS Bigner, DD TI Unarmed, tumor-specific monoclonal antibody effectively treats brain tumors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE central nervous system neoplasms; epidermal growth factor receptor; immunotherapy ID GROWTH-FACTOR RECEPTOR; PRIMARY INTRACRANIAL TUMORS; CENTRAL-NERVOUS-SYSTEM; CELL-MEDIATED-IMMUNITY; MALIGNANT GLIOMAS; COLORECTAL-CARCINOMA; HUMAN GLIOBLASTOMAS; LUNG CARCINOMAS; PHASE-II; EXPRESSION AB The epidermal growth factor receptor (EGFR) is often amplified and rearranged structurally in tumors of the brain, breast, lung, and ovary. The most common mutation, EGFRvIII, is characterized by an in-frame deletion of 801 base pairs, resulting in the generation of a novel tumor-specific epitope at the fusion junction. A murine homologue of the human EGFRvIII mutation was created, and an IgG2a murine mAb, Y10, was generated that recognizes the human and murine equivalents of this tumor-specific antigen. In vitro, Y10 was found to inhibit DNA synthesis and cellular proliferation and to induce autonomous, complement-mediated, and antibody-dependent cell-mediated cytotoxicity. Systemic treatment with i.p. Y10 of s.c. B16 melanomas transfected to express stably the murine EGFRvIII led to long-term survival in all mice treated (n = 20; P < 0.001). Similar therapy with i.p. Y10 failed to increase median survival of mice with EGFRvIII-expressing B16 melanomas in the brain; however, treatment with a single intratumoral injection of Y10 increased median survival by an average 286%, with 26% long-term survivors (n = 117; P < 0.001). The mechanism of action of Y10 in vivo was shown to be independent of complement, granulocytes, natural killer cells, and T lymphocytes through in vivo complement and cell subset depletions. Treatment with Y10 in Fc receptor knockout mice demonstrated the mechanism of Y10 to be Fe receptor-dependent. These data indicate that an unarmed, tumor-specific mAb may be an effective immunotherapy against human tumors and potentially other pathologic processes in the "immunologically privileged" central nervous system. C1 Duke Univ, Med Ctr, Dept Surg Neurosurg, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Univ Melbourne, Dept Paediat, Parkville, Vic 3052, Australia. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. RP Sampson, JH (reprint author), Duke Univ, Med Ctr, Dept Surg Neurosurg, Durham, NC 27710 USA. FU NCI NIH HHS [R01 CA074886, CA 11898, CA 74886, R37 CA011898]; NINDS NIH HHS [NS 20023, P50 NS020023] NR 54 TC 140 Z9 147 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 20 PY 2000 VL 97 IS 13 BP 7503 EP 7508 DI 10.1073/pnas.130166597 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600103 PM 10852962 ER PT J AU Miyamoto, T Weissman, IL Akashi, K AF Miyamoto, T Weissman, IL Akashi, K TI AML1/ETO-expressing nonleukemic stem cells in acute myelogenous leukemia with 8;21 chromosomal translocation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE NONLYMPHOCYTIC LEUKEMIA; MINIMAL RESIDUAL DISEASE; LONG-TERM REMISSION; BONE-MARROW; MULTISTEP PATHOGENESIS; AML1/ETO TRANSCRIPTS; MESSENGER-RNA; GENE; CHEMOTHERAPY AB Leukemia-specific AML1/ETO transcripts are detectable in most patients with t(8;21) acute myelogenous leukemia (AML) in long-term remission. To understand the inconsistency between the clinical cure and the presence of "residual disease" at a molecular level, we separated and identified the cells expressing AML1/ETO by phenotype and function. Here we demonstrate that AML1/ETO transcripts are present in a fraction of stem cells, monocytes, and a cells in remission marrow, and in a fraction of a cells in leukemic marrow, but not in T cells. AML1/ETO transcripts also were demonstrated in a fraction of colony-forming cells of erythroid. granulocyte-macrophage, and/or megakaryocyte lineages in both leukemic and remission marrow. These data strongly suggest that the acquisition of the t(8;21) occurs at the level of stem cells capable of differentiating into B cells as well as all myeloid lineages, and that a fraction of the AML1/ETO-expressing stem cells undergo additional oncogenic event(s) that ultimately leads to transformation into AML. C1 Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Dev Biol, Stanford, CA 94305 USA. RP Akashi, K (reprint author), Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Sm 770B,44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA42551] NR 40 TC 305 Z9 329 U1 1 U2 6 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 20 PY 2000 VL 97 IS 13 BP 7521 EP 7526 DI 10.1073/pnas.97.13.7521 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 327UH UT WOS:000087811600106 PM 10861016 ER PT J AU Haber, D AF Haber, D TI BRCA1: an emerging role in the cellular response to DNA damage SO LANCET LA English DT Editorial Material ID MEIOTIC CELLS; BREAST-CANCER; PHOSPHORYLATION; MUTATIONS; REPAIR; GENES; CYCLE; ATM C1 Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. RP Haber, D (reprint author), Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA. NR 17 TC 6 Z9 7 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 JUN 17 PY 2000 VL 355 IS 9221 BP 2090 EP 2091 DI 10.1016/S0140-6736(00)02371-0 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 325QD UT WOS:000087687100004 PM 10902618 ER PT J AU Ghosh-Choudhury, N Woodruff, K Qi, WB Celeste, A Abboud, SL Choudhury, GG AF Ghosh-Choudhury, N Woodruff, K Qi, WB Celeste, A Abboud, SL Choudhury, GG TI Bone morphogenetic protein-2 blocks MDA MB 231 human breast cancer cell proliferation by inhibiting cyclin-dependent kinase-mediated retinoblastoma protein phosphorylation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE BMP-2; pRb; p21; breast cancer cells ID EPIDERMAL GROWTH-FACTOR; DNA-SYNTHESIS; MESANGIAL CELLS; FACTOR RECEPTOR; EGF-RECEPTOR; IN-VIVO; FAMILY; P21; ACTIVATION; REGULATORS AB Bone morphogenetic protein-2 (BMP-2) has been shown to act as an antiproliferative agent for a number of different cell types. We show that BMP-2 dose-dependently inhibits growth of MDA MB 231 human breast cancer cells. Epidermal growth factor (EGF) stimulates DNA synthesis and entry of these cells into the S-phase. BMP-2 inhibits EGF-induced DNA synthesis by arresting them in G1 phase of the cell cycle. BMP-2 increases the level of cyclin kinase inhibitor p21. Furthermore, we show that exposure of MDA MB 231 cells to BMP-2 stimulates association of pal with cyclin D1 and with cyclin E resulting in the inhibition of their associated kinase activities. Finally, BMP-2 treatment is found to cause hypophosphorylation of the retinoblastoma protein (pRb), a key regulator of cell cycle progression. Our data provide a mechanism for the antiproliferative effect of BMP-2 in the breast cancer cells. (C) 2000 Academic Press. C1 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, GRECC, San Antonio, TX USA. Genet Inst, Boston, MA USA. RP Ghosh-Choudhury, N (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pathol, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. FU NIDDK NIH HHS [DK-50190] NR 35 TC 67 Z9 71 U1 0 U2 2 PU ACADEMIC PRESS INC 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 JUN 16 PY 2000 VL 272 IS 3 BP 705 EP 711 DI 10.1006/bbrc.2000.2844 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 327HD UT WOS:000087787700015 PM 10860819 ER PT J AU Auger, KR Wang, J Narsimhan, RP Holcombe, T Roberts, TM AF Auger, KR Wang, J Narsimhan, RP Holcombe, T Roberts, TM TI Constitutive cellular expression of PI 3-kinase is distinct from transient expression SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE PI 3-kinase; cytoskeleton; signal transduction; transformation ID PROTEIN-KINASE-B; GROWTH-FACTOR RECEPTOR; MIDDLE T-ANTIGEN; PHOSPHATIDYLINOSITOL 3-KINASE; PHOSPHOINOSITIDE 3-KINASE; SIGNAL-TRANSDUCTION; CATALYTIC SUBUNIT; S6 KINASE; ACTIVATION; TRANSFORMATION AB The discovery that the PTEN tumor suppressor encodes a phosphoinositide 3-phosphatase has raised interest in the effects of constitutive activation of PI 3-kinase. To gain insight into PI 3-kinase function, we have stably expressed a myristoylated form of the catalytic subunit p110 alpha (myr-p110) in cells. The myr-p110 associated with the endogenous p85 regulatory subunit and retained lipid and protein kinase activity. Stable lines expressing myr-p110 had 2- to 4-fold more PI 3-kinase activity than controls. Expression of myr-p110 altered cellular morphology and increased the saturation density in culture. These clones were morphologically transformed but Akt and pp70(s6k) were not constitutively activated in contrast to transient assays and from tumor cell lines deficient in PTEN. In addition, the ability of PDGF to induce activation of Akt and pp70(s6k) was diminished. Therefore, expression of a myristoylated PI 3-kinase in murine fibroblasts induces a morphological transformation of the cells. (C) 2000 Academic Press. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Auger, KR (reprint author), DuPont Pharmaceut Co, Glenolden Labs, 500 S Ridgeway Ave, Glenolden, PA 19036 USA. NR 48 TC 10 Z9 10 U1 0 U2 0 PU ACADEMIC PRESS INC 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 JUN 16 PY 2000 VL 272 IS 3 BP 822 EP 829 DI 10.1006/bbrc.2000.2806 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 327HD UT WOS:000087787700033 PM 10860837 ER PT J AU Yuan, PQ Yang, H AF Yuan, PQ Yang, H TI Localization of thyroid hormone receptor beta 2 in the ventral medullary neurons that synthesize thyrotropin-releasing hormone SO BRAIN RESEARCH LA English DT Article DE triiodothyronine; negative feedback; Raphe pallidus; Raphe obscurus; parapyramidal region ID DORSAL VAGAL COMPLEX; IN-SITU HYBRIDIZATION; MESSENGER-RNA; PARAVENTRICULAR NUCLEUS; GENE-EXPRESSION; RAPHE PALLIDUS; SUBSTANCE-P; NEGATIVE REGULATION; RAT HYPOTHALAMUS; NERVOUS-SYSTEM AB Altered thyroid statuses are associated with autonomic disorders. Thyrotropin-releasing hormone (TRH) synthesized in medullary raphe pallidus (Rpa), raphe obscurus (Rob) and the parapyramidal regions (PPR) regulates vagal and sympathetic preganglionic motoneurons. Hypothyroidism increased TRH gene expression and c-Fos immunoreactivity (IR) in these nuclei. Whether these increases represent a direct action of thyroid hormone was studied by detecting the presence of thyroid hormone receptor beta 2 (TR beta 2) in pro-TRH-synthesizing neurons in the Rpa. Rob and the PPR using immunohistochemistry with specific TR beta 2 antiserum and in situ hybridization with digoxigenin-labeled pro-TRH cRNA probe. TR beta 2 IR was widely distributed throughout the medulla and primarily localized within the cell nuclei. Particularly intense immunostaining was presented in the Rpa, Rob and the PPR neurons. The combination of immunohistochemistry with in situ hybridization revealed that all pro-TRH mRNA-positive neurons in these ventral medullary nuclei were also TR beta 2 IR positive. The numbers of TR beta 2 IR-positive neurons in each nucleus were identical in both euthyroid rats and hypothyroid rats induced by 6-n-propyl-2-thiouracil in drinking water for 4 weeks. The finding that TR beta 2 localized in pro-TRH-synthesizing neurons in the ventral medullary nuclei provides an anatomical substrate for a direct thyroid hormone action on these neurons in the regulation of TRH gene expression, which may contribute to the altered autonomic activity in different thyroid statuses. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Calif Los Angeles, CURE Digest Dis Res Ctr, Dept Med, Div Digest Dis, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90073 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. RP Yang, H (reprint author), Univ Calif Los Angeles, CURE Digest Dis Res Ctr, Dept Med, Div Digest Dis, Bldg 115,Room 203,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. FU NIDDK NIH HHS [DK 41301, DK 50255] NR 52 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 16 PY 2000 VL 868 IS 1 BP 22 EP 30 DI 10.1016/S0006-8993(00)02251-4 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 327EK UT WOS:000087780500003 PM 10841884 ER PT J AU Endo, K Oki, E Biedermann, V Kojima, H Yoshida, K Johannes, FJ Kufe, D Datta, R AF Endo, K Oki, E Biedermann, V Kojima, H Yoshida, K Johannes, FJ Kufe, D Datta, R TI Proteolytic cleavage and activation of protein kinase C mu by caspase-3 in the apoptotic response of cells to 1-beta-D-arabinofuranosylcytosine and other genotoxic agents SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTERNUCLEOSOMAL DNA FRAGMENTATION; LEUKEMIA-CELLS; CYTOCHROME-C; PKC-MU; INDUCTION; FAMILY; DOMAIN; DIACYLGLYCEROL; INVOLVEMENT; INHIBITION AB Protein kinase C (PKC) mu is a novel member of the PKC family that differs from the other isozymes in structural and biochemical properties, The precise function of PKC mu is not known. The present studies demonstrate that PKC mu is cleaved during apoptosis induced by 1-beta-D-arabinofuranosylcytosine (ara C) and other genotoxic agents, PKC mu cleavage is blocked in cells that overexpress the anti-apoptotic Bcl-x(L) protein or the baculovirus p35 protein, Our results demonstrate that PKC mu is cleaved by caspase-3 at the CQND(378)S site. Cleavage of PKC mu is associated with release of the catalytic domain and activation of its kinase function. We also show that, unlike the cleaved fragments of PKC delta and theta, overexpression of the PKC mu catalytic domain is not lethal. Cells stably expressing the catalytic fragment of PKC mu, however, are more sensitive to apoptosis induced by genotoxic stress. In addition, expression of the caspase-resistant PKC mu mutant partially inhibits DNA damage-induced apoptosis, These findings demonstrate that PKC mu is cleaved by caspase-3 and that expression of the catalytic domain sensitizes cells to the cytotoxic effects of ara-C and other anticancer agents. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Stuttgart, Inst Cell Biol & Immunol, D-7000 Stuttgart, Germany. RP Datta, R (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. EM rakesh_datta@dfci.harvard.edu FU NCI NIH HHS [CA29431]; NIGMS NIH HHS [GM58200] NR 41 TC 87 Z9 90 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 JUN 16 PY 2000 VL 275 IS 24 BP 18476 EP 18481 DI 10.1074/jbc.M002266200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CU UT WOS:000087659400077 PM 10764790 ER PT J AU Hauser, S Adelmant, G Sarraf, P Wright, HM Mueller, E Spiegelman, BM AF Hauser, S Adelmant, G Sarraf, P Wright, HM Mueller, E Spiegelman, BM TI Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID KINASE-MEDIATED PHOSPHORYLATION; PPAR-GAMMA; ESTROGEN-RECEPTOR; GENE-EXPRESSION; PROTEIN-KINASE; PROTEASOME; DIFFERENTIATION; ALPHA; THIAZOLIDINEDIONES; ADIPOGENESIS AB The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor that regulates several crucial biological processes such as adipogenesis, glucose homeostasis, and cell growth. It is also the functional receptor for a new class of insulin-sensitizing drugs, the thiazolidinediones, now widely used in the treatment of type 2 diabetes mellitus. Here we report that PPAR gamma protein levels are significantly reduced in adipose cells and fibroblasts in response to specific ligands such as thiazolidinediones. Studies with several doses of different ligands illustrate that degradation of PPAR gamma correlates well with the ability of ligands to activate this receptor. However, analyses of PPAR gamma mutants show that, although degradation does not strictly depend on the transcriptional activity of the receptor, it is dependent upon the ligand-gated activation function 2 (AF2) domain. Proteasome inhibitors inhibited the down-regulation of PPAR gamma and ligand activation enhanced the ubiquitination of this receptor. These data indicate that, although ligand binding and activation of the AF2 domain increase the transcriptional function of PPAR gamma, these same processes also induce ubiquitination and subsequent degradation of this receptor by the proteasome. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. RP Spiegelman, BM (reprint author), Dana Farber Canc Inst, 1 Jimmy Fund Way, Boston, MA 02115 USA. FU NIDDK NIH HHS [DKY1305] NR 40 TC 236 Z9 237 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 16 PY 2000 VL 275 IS 24 BP 18527 EP 18533 DI 10.1074/jbc.M001297200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 325CU UT WOS:000087659400084 PM 10748014 ER PT J AU Llevadot, J Giugliano, RP McCabe, CH Cannon, CP Antman, EM Murphy, S Gibson, CM AF Llevadot, J Giugliano, RP McCabe, CH Cannon, CP Antman, EM Murphy, S Gibson, CM TI Degree of residual stenosis in the culprit coronary artery after thrombolytic administration (Thrombolysis in Myocardial Infarction [TIMI] trials) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TISSUE-PLASMINOGEN-ACTIVATOR; FRAME COUNT; ANGIOGRAPHY; DISEASE; PROGRESSION; ATHEROSCLEROSIS; REPERFUSION; OCCLUSION; SEVERITY; LESIONS AB This study was undertaken to characterize residual stenosis after thrombolytic administration and to evaluate clinical and angiographic features and early outcomes of patients with mild residual obstruction after thrombolytic administration. Patients who underwent angiography at 90 minutes after thrombolytic: administration in the Thrombolysis In Myocardial Infarction 4, 10A, 10B, and 14 trials were divided into 3 groups according to the degree of residual stenosis measured by quantitative coronary angiography: patients with a patent culprit artery with <50% stenosis, patients with patent arteries and residual stenosis greater than or equal to 50%, and patients with occluded arteries. Only 8.9% of the patients (188 of 2,119) had an infarct-related artery luminal diameter stenosis of <50% 90 minutes after thrombolysis. Compared with patients with patent arteries and greater than or equal to 50% stenosis, patients with mild residual obstruction were younger (56.8 vs 58.6 years; p = 0.03), had fewer prior myocardial infarctions (6.9% vs 13.3%; p = 0.01), fewer eccentric (19.8% vs 42.1%; p <0.0001), ulcerated (7.5% vs 13.2%; p = 0.03), and collateralized (6.6% vs 13.2%, p = 0.01) lesions, but ct greater thrombus burden (29.7% vs 18.3%, p = 0.0002). Among patients with patent arteries, a residual stenosis of <50% was associated with a significantly lower composite of in-hospital death, myocardial infarction, and congestive heart failure (2.8% vs 7.1%, p = 0.03). Thus, a minority of patients have a mild residual obstruction at 90 minutes after thrombolytic administration. These patients have less complex lesions with greater thrombus burdens and better clinical outcomes. (C) 2000 by Excerpta Medica, Inc. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. Univ Calif San Francisco, Dept Med, Div Cardiovasc, San Francisco, CA 94143 USA. RP Giugliano, RP (reprint author), TIMI Study Off, 333 Longwood Ave,Suite 402, Boston, MA 02115 USA. NR 30 TC 16 Z9 16 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2000 VL 85 IS 12 BP 1409 EP 1413 DI 10.1016/S0002-9149(00)00786-4 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 322KB UT WOS:000087507800003 PM 10856384 ER PT J AU Vaccarino, V Parsons, L Every, NR Barron, HV Krumholz, HM AF Vaccarino, V Parsons, L Every, NR Barron, HV Krumholz, HM CA Natl Registry Myocardial Infarct TI Impact of history of diabetes mellitus on hospital mortality in men and women with first acute myocardial infarction SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID SEX-DIFFERENCES; HEART-DISEASE; HYPERGLYCEMIA; PREVALENCE; SURVIVAL; DISCHARGE; RISK AB This study addresses the question of whether a higher susceptibility to the adverse effects of diabetes can explain the higher hospital mortality of young and middle-aged women compared with men. Younger women had a higher hospital mortality than men, irrespective of diabetes status: effect modification due to diabetes did not play a role in the higher short-term mortality risk of young and middle-aged women compared with men. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Med Cardiol, New Haven, CT 06520 USA. VA Puget Sound Healthcare Syst, Hlth Serv Res & Dev Field Program, Seattle, WA USA. Univ Washington, Sch Med, Div Cardiol, Cardiovasc Outcomes Res Ctr, Seattle, WA 98195 USA. Univ Calif San Francisco, Div Cardiol, S San Francisco, CA 94080 USA. Genentech Inc, Div Med Affairs, S San Francisco, CA 94080 USA. Yale New Haven Hosp, Ctr Outcomes Res & Evaluat, New Haven, CT USA. RP Vaccarino, V (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, 60 Coll St,POB 208034, New Haven, CT 06520 USA. NR 20 TC 40 Z9 42 U1 0 U2 2 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUN 15 PY 2000 VL 85 IS 12 BP 1486 EP + DI 10.1016/S0002-9149(00)00800-6 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 322KB UT WOS:000087507800017 PM 10856398 ER PT J AU Starkebaum, G AF Starkebaum, G TI Leukemia of large granular lymphocytes and rheumatoid arthritis SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID FELTYS-SYNDROME; METHOTREXATE TREATMENT; T-CELLS; EXPANSIONS; NEUTROPENIA C1 Univ Washington, Sch Med, Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA 98108 USA. RP Starkebaum, G (reprint author), Univ Washington, Sch Med, Vet Affairs Puget Sound Hlth Care Syst, 1660 S Columbian Way, Seattle, WA 98108 USA. NR 21 TC 7 Z9 7 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 15 PY 2000 VL 108 IS 9 BP 744 EP 745 DI 10.1016/S0002-9343(00)00386-7 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 338YG UT WOS:000088450400010 PM 10924655 ER PT J AU McElroy, SL Suppes, T Keck, PE Frye, MA Denicoff, KD Altshuler, LL Brown, ES Nolen, WA Kupka, RW Rochussen, J Leverich, GS Post, RM AF McElroy, SL Suppes, T Keck, PE Frye, MA Denicoff, KD Altshuler, LL Brown, ES Nolen, WA Kupka, RW Rochussen, J Leverich, GS Post, RM TI Open-label adjunctive topiramate in the treatment of bipolar disorders SO BIOLOGICAL PSYCHIATRY LA English DT Article DE topiramate; bipolar disorders; mania; cycling; weight ID REFRACTORY PARTIAL EPILEPSY; PLACEBO-CONTROLLED TRIAL; DOSE-RANGING TRIAL; DOUBLE-BLIND; CALCIUM INFLUX; DAILY DOSAGES; LITHIUM; MONOTHERAPY; SEIZURES; CORTEX AB Background: To preliminarily explore the spectrum of effectiveness and tolerability of the new antiepileptic drug topiramate in bipolar disorder, we evaluated the response of 56 bipolar outpatients in the Stanley Foundation Bipolar Outcome Network (SFBN) who had been treated with adjunctive topiramate in an open-label, naturalistic fashion. Methods: In this case series, response to topiramate was assessed every 2 weeks for the first 3 months according to standard ratings in the SFBN, and monthly thereafter while patients remained on topiramate. Patients' weights, body mass indices (BMIs), and side effects were also assessed. Results: Of the 54 patients who completed at least 2 weeks of open-label, add-on topiramate treatment, 30 had manic, mixed, or cycling symptoms, 11 had depressed symptoms, and 13 were relatively euthymic at the time topiramate was begun. Patients who had been initially treated for manic symptoms displayed significant reductions in standard ratings scores after 4 weeks, after 10 weeks, and at the last evaluation. Those patients who were initially depressed or treated while euthymic showed no significant changes. Patients as a group displayed significant decreases in weight and BMI from topiramate initiation to week 4, to week 10, and to the last evaluation. The most common adverse side effects were neurologic and gastrointestinal. Conclusion: These preliminary open observations of adjunctive topiramate treatment suggest that it may have antimanic or anticycling effects in some patients with bipolar disorder, and may be associated in some patients with bipolar disorder, and may be associated with appetite suppression and weight loss that is often viewed as beneficial by the patient and clinician. Controlled studies of topiramate's acute and long-term efficacy and side-effects in bipolar disorder appear warranted. (C) 2000 Society of Biological Psychiatry. C1 Univ Cincinnati, Coll Med, Biol Psychiat Program ML559, Stanley Fdn Bipolar Outcome Network, Cincinnati, OH 45267 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. W Los Angeles VA Med Ctr, Los Angeles, CA 90024 USA. NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Utrecht, Med Ctr, Utrecht, Netherlands. HC Rumke Grp, Utrecht, Netherlands. Stanley Fdn, Data Coordinating Ctr, Bethesda, MD USA. RP McElroy, SL (reprint author), Univ Cincinnati, Coll Med, Biol Psychiat Program ML559, Stanley Fdn Bipolar Outcome Network, 231 Bethesda Ave, Cincinnati, OH 45267 USA. RI Nolen, Willem/E-9006-2014 NR 36 TC 165 Z9 173 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2000 VL 47 IS 12 BP 1025 EP 1033 DI 10.1016/S0006-3223(99)00316-9 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 324CK UT WOS:000087604100002 PM 10862801 ER PT J AU Vakili, K Pillay, SS Lafer, B Fava, M Renshaw, PF Bondello-Cintron, CM Yurgelun-Todd, DA AF Vakili, K Pillay, SS Lafer, B Fava, M Renshaw, PF Bondello-Cintron, CM Yurgelun-Todd, DA TI Hippocampal volume in primary unipolar major depression: A magnetic resonance imaging study SO BIOLOGICAL PSYCHIATRY LA English DT Article DE hippocampus; major depression; magnetic resonance imaging; gender ID BRAIN AB Background: Previous studies have shown that major depression is frequently accompanied by hypercortisolemia, There is some evidence suggesting that an increase in the glucocorticoid levels may make hippocampal cells more vulnerable to insults caused by hypoxia, hypoglycemia, or excitatory neurotransmitters. Using magnetic resonance imaging (MRI), the hippocampi of patients with major depression were measured and compared with values observed in control subjects. Methods: Thirty-eight patients with primary unipolar major depression were recruited. Twenty control subjects were matched for age, gender, and years of education. The hippocampal volume was measured from coronal MRI scans in all of the subjects. Patients were also grouped and compared as responders and nonresponders to treatment with fluoxetine of 20 mg/day, for 8 weeks. Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depression. Results: No significant differences were observed between the hippocampal volumes of patients with major depression and control subjects; however, a significant correlation was observed between the left hippocampal volume of men and their HDRS baseline values. In addition, female responders had a statistically significant higher mean light hippocampal volume than nonresponders. Conclusions: The results of our study indicate no reduction in the volume of rite hippocampus in patients with major depression. Nonetheless, the results do suggest that the effects of disease severity, gender, and treatment response may influence hippocampal volume. (C) 2000 Society of Biological Psychiatry. C1 Harvard Univ, McLean Hosp, Brain Imaging Ctr, Sch Med,Cognit Neuroimaging Lab, Belmont, MA 02178 USA. Boston Univ, Sch Med, Boston, MA 02215 USA. Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Consolidated Dept Psychiat, Boston, MA 02115 USA. RP Yurgelun-Todd, DA (reprint author), Harvard Univ, McLean Hosp, Brain Imaging Ctr, Sch Med,Cognit Neuroimaging Lab, 115 Mill St, Belmont, MA 02178 USA. RI Lafer, Beny/C-1055-2012; Lafer, Beny/F-9390-2015 OI Lafer, Beny/0000-0002-6132-9999; Lafer, Beny/0000-0002-6132-9999 NR 13 TC 217 Z9 227 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD JUN 15 PY 2000 VL 47 IS 12 BP 1087 EP 1090 DI 10.1016/S0006-3223(99)00296-6 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 324CK UT WOS:000087604100010 PM 10862809 ER PT J AU Apasov, S Chen, JF Smith, P Sitkovsky, M AF Apasov, S Chen, JF Smith, P Sitkovsky, M TI A(2A) receptor dependent and A(2A) receptor independent effects of extracellular adenosine on murine thymocytes in conditions of adenosine deaminase deficiency SO BLOOD LA English DT Article ID T-CELL DEVELOPMENT; COMBINED IMMUNODEFICIENCY; PURINERGIC RECEPTOR; DNA FRAGMENTATION; FLOW-CYTOMETRY; APOPTOSIS; INHIBITION; ATP; DIFFERENTIATION; MECHANISMS AB Adenosine deaminase (ADA) deficiency causes severe combined immunodeficiency (SCID) and is accompanied by T-cell depletion and accumulation of both intracellular and extracellular adenosine (extAdo) and deoxyadenosine, To better understand the causes of T-cell depletion in vivo and to discriminate between extracellular and intracellular effects of exogenously added adenosine in vitro, we investigated mechanisms of 2 different effects of adenosine on murine thymocytes. These effects of adenosine include direct induction of apoptosis in about 6% to 15% thymocytes and inhibition of T-cell receptor (TCR) induced activation of the majority of thymocytes with inhibited ADA, APA adenosine receptors, but not A(2B), All Or A(3) receptors, are shown to be mostly responsible for extAdo-triggered signaling (cyclic adenosine monophosphate [cAMP] accumulation) in murine thymocytes and this prompted studies of the effects of extAdo on thymocytes from A(2A)R gene-deficient mice. It is found that direct apoptotic effects of extAdo on CD4(+)CD8(+) double positive (DP) thymocytes are completely accounted for by signaling through A(2A)R, with no contribution of intracellular lymphotoxicity or of compensating A(2B)Rs because only A(2A)R +/+ but not A(2A)R -/- thymocytes were susceptible to apoptotic effects of extAdo, Studies of the effects of cAMP-raising agents support observations of extAdo/A(2A)R/cAMP-triggered apoptosis in Up thymocytes. Unexpectedly, the extAdo strongly inhibited TCR-triggered activation of both A(2A)R +/+ and A(2A)R -/- thymocytes in the presence of ADA inhibitors. This was confirmed with thymocytes from ADA gene-deficient mice, suggesting the existence of A(2A)R-independent effects of extAdo on thymocytes, The presented data raises questions about the identity and functional role of A(2A)R-expressing thyme cytes in T-cell differentiation and of the role of TCR-antagonizing effects of extAdo in conditions of ADA SCID. (C) 2000 by The American Society of Hematology. C1 NIAID, Immunol Lab, Biochem & Immunopharmacol Sect, NIH, Bethesda, MD 20982 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol,Mol Neurobiol Lab, Charlestown, MA USA. RP Sitkovsky, M (reprint author), NIAID, Immunol Lab, Biochem & Immunopharmacol Sect, NIH, Bldg 10, Bethesda, MD 20982 USA. NR 41 TC 41 Z9 42 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 15 PY 2000 VL 95 IS 12 BP 3859 EP 3867 PG 9 WC Hematology SC Hematology GA 325ME UT WOS:000087678700031 PM 10845921 ER PT J AU Heinrich, MC Silvey, KV Stone, S Zigler, AJ Griffith, DJ Montalto, M Chai, L Zhi, Y Hoatlin, ME AF Heinrich, MC Silvey, KV Stone, S Zigler, AJ Griffith, DJ Montalto, M Chai, L Zhi, Y Hoatlin, ME TI Posttranscriptional cell cycle-dependent regulation of human FANCC expression SO BLOOD LA English DT Article ID ANEMIA GROUP-C; ORNITHINE DECARBOXYLASE; NUCLEAR-LOCALIZATION; FUNCTIONAL-ACTIVITY; MAMMALIAN-CELLS; FANCONIS ANEMIA; PROTEIN; COMPLEX; GENE; FAC AB The Fanconi Anemia (FA) Group C complementation group gene (FANCC) encodes a protein, FANCC, with a predicted M-r of 63000 daltons, FANCC is found in both the cytoplasmic and the nuclear compartments and interacts with certain other FA complementation group proteins as well as with non-FA proteins, Despite intensive investigation, the biologic roles of FANCC and of the other cloned FA gene products (FANCA and FANCG) remain unknown. As an approach to understanding FANCC function. rye have studied the molecular FANCC expression, We found that although FANCC mRNA levels are constant throughout the cell cycle, FANCC is expressed in a cell cycle-dependent manner, with the lowest levels seen in cells synchronized at the G1/S boundary and the highest levels in the An-phase. Cell cycle-dependent regulation occurred despite deletion of the 5' and 3' FANCC untranslated regions, indicating that information in the FANCC coding sequence is sufficient to mediate cell cycle-dependent regulation. Moreover, inhibitors of proteasome function blocked the observed regulation. We conclude that FANCC expression is con-trolled by post-transcriptional mechanisms that are proteasome dependent. Recent work has demonstrated that the functional activity of FA proteins requires the physical interaction of at least FANCA, FANCC, and FANCG, and possibly of other FA and non-FA proteins. Our observation of dynamic control of FANCC expression by the proteasome has important implications for understanding the molecular regulation of the multiprotein complex. (C) 2000 by The American Society of nematology. C1 Portland Vet Affairs Med Ctr, Portland, OR 97207 USA. Oregon Hlth Sci Univ, Dept Med, Div Hematol & Med Oncol, Portland, OR 97201 USA. RP Heinrich, MC (reprint author), Portland Vet Affairs Med Ctr, 3710 SW US Vet Hosp Rd, Portland, OR 97207 USA. FU NHLBI NIH HHS [HL56045] NR 55 TC 18 Z9 18 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 2000 VL 95 IS 12 BP 3970 EP 3977 PG 8 WC Hematology SC Hematology GA 325ME UT WOS:000087678700046 PM 10845936 ER PT J AU Mach, N Gillessen, S Wilson, SB Sheehan, C Mihm, M Dranoff, G AF Mach, N Gillessen, S Wilson, SB Sheehan, C Mihm, M Dranoff, G TI Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or flt3-ligand SO CANCER RESEARCH LA English DT Article ID MONOCYTE-CONDITIONED MEDIUM; ANTIGEN-PRESENTING CELLS; CYTOTOXIC T-LYMPHOCYTES; MOUSE LYMPHOID ORGANS; LIGAND-TREATED MICE; MHC CLASS-I; FLT3 LIGAND; BONE-MARROW; ANTITUMOR IMMUNITY; NECROSIS-FACTOR AB Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and flt3-ligand (FL) induce the development of dendritic cells (DCs). To compare the functional properties of DCs stimulated by these cytokines in vivo, we used retroviral-mediated gene transfer to generate murine tumor cells secreting high levels of each molecule. Injection of tumor cells expressing either GM-CSF or FL resulted in the dramatic increase of CD11c(+) cells in the spleen and tumor infiltrate. However, vaccination with irradiated, GM-CSF-secreting tumor cells stimulated more potent antitumor immunity than vaccination with irradiated, FL-secreting tumor cells. The superior antitumor immunity elicited by GM-CSF involved a broad T cell cytokine response, in contrast to the limited Th1 response elicited by FL. DCs generated by GM-CSF were CD8 alpha(-) and expressed higher levels of B7-1 and CD1d than DCs cells generated by FL. Injection sites of metastatic melanoma patients vaccinated with irradiated, autologous tumor cells engineered to secrete GM-CSF demonstrated similar, dense infiltrates of DCs expressing high levels of B7-1, These findings reveal critical differences in the abilities of GM-CSF and FL to enhance the function of DCs bt vivo and have important implications for the crafting of tumor vaccines. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Albany Med Coll, Dept Pathol & Lab Med, Albany, NY 12208 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. RP Dranoff, G (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Dana 510E,44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA74886]; NIAID NIH HHS [AI45051] NR 66 TC 247 Z9 249 U1 0 U2 5 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 2000 VL 60 IS 12 BP 3239 EP 3246 PG 8 WC Oncology SC Oncology GA 325EZ UT WOS:000087664500023 PM 10866317 ER PT J AU Karras, JG McKay, RA Lu, T Pych, J Frank, DA Rothstein, TL Monia, BP AF Karras, JG McKay, RA Lu, T Pych, J Frank, DA Rothstein, TL Monia, BP TI STAT3 regulates the growth and immunoglobulin production of BCL1 B cell lymphoma through control of cell cycle progression SO CELLULAR IMMUNOLOGY LA English DT Article DE B lymphocytes; signal transduction; cell cycle; molecular biology; Jak-STAT pathway ID PERIPHERAL-BLOOD CELLS; CONSTITUTIVE ACTIVATION; TRANSCRIPTION FACTORS; TYROSINE PHOSPHORYLATION; SERINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; ANTISENSE OLIGONUCLEOTIDES; NUCLEAR EXPRESSION; JAK/STAT PROTEINS; B-1 LYMPHOCYTES AB STAT3 is constitutively phosphorylated on tyrosine(705) in self-renewing, CD5(+) murine B-1 lymphocytes, Nuclear extracts from untreated primary B-l or CD5(+) BCL1 B lymphoma cells were found to contain immunoreactive STAT3 protein that binds to a sis-inducible element present in the promoter of the p21(waf1/cip1) tumor suppressor gene and is constitutively phosphorylated on serine(727). To determine the functional significance of constitutive STAT3 activation in B lymphoma cells, a specific STAT3 antisense oligonucleotide was developed and used to examine basal BCL1 cell growth and IgM production. Abrogating STAT3 expression in BCL1 cells inhibited their proliferative capacity and induced a corresponding decrease in secretion of IgM, Cell cycle analysis showed a block in progression through G1 in BCL1 cells treated with the STAT3 antisense oligonucleotide, These results indicate that STATE controls cell growth and immunoglobulin secretion by enhancing progression through the G1 phase of the cell cycle in BCL1 B cell lymphoma, (C) 2000 Academic Press. C1 ISIS Pharmaceut, Dept Mol & Cellular Pharmacol, Carlsbad, CA 92008 USA. Boston Med Ctr, Dept Med & Microbiol, Boston, MA 02118 USA. Boston Med Ctr, Evans Mem Dept Clin Res, Boston, MA 02118 USA. Brigham & Womens Hosp, Dana Farber Canc Inst, Div Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Karras, JG (reprint author), ISIS Pharmaceut, Dept Mol & Cellular Pharmacol, 2292 Faraday Ave, Carlsbad, CA 92008 USA. FU NIAID NIH HHS [AI 29690] NR 76 TC 21 Z9 21 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD JUN 15 PY 2000 VL 202 IS 2 BP 124 EP 135 DI 10.1006/cimm.2000.1661 PG 12 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 340GW UT WOS:000088525600007 PM 10896772 ER PT J AU Bodenheimer, C Kerrigan, AJ Garber, SL Monga, TN AF Bodenheimer, C Kerrigan, AJ Garber, SL Monga, TN TI Sexuality in persons with lower extremity amputations SO DISABILITY AND REHABILITATION LA English DT Article ID ADULT AMPUTEES AB Purpose: There is a paucity of information regarding sexual functioning in persons with lower extremity amputations. The purpose of this study was to describe sexual and psychological functioning and health status in persons with lower extremity amputation. Methods: Self-report surveys assessed sexual functioning (Derogatis Inventory), depression (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), and health status (Health Status Questionnaire) in a convenience sample of 30 men with lower extremity amputations. Mean age of the participants was 57 years (range 32-79). Mean duration since amputation was 23 months (range 3-634 months). Twenty one subjects (70 %) had trans-tibial and seven subjects (23 %) had trans-femoral amputations. Results: A majority of subjects were experiencing problems in several domains of sexual functioning. Fifty three percent (n = 16) of the subjects were engaged in sexual intercourse or oral sex at least once a month. Twenty seven percent (n = 8) were masturbating at least once a month. Nineteen subjects (63 %) reported orgasmic problems and 67% were experiencing erectile difficulties. Despite these problems, interest in sex was high in over 90 % of the subjects. There was no evidence of increased prevalence of depression or anxiety in these subjects when compared to other outpatient adult populations. Conclusions: Sexual problems were common in the subjects studied. Despite these problems, interest in sex remained high. Few investigations have been directed toward identifying the psychological and social factors that may contribute to these problems and more research with a larger population is needed in this area. C1 Houston VAMC, Houston, TX 77030 USA. RP Bodenheimer, C (reprint author), Houston VAMC, 2020 Holcombe Blvd, Houston, TX 77030 USA. NR 23 TC 33 Z9 33 U1 1 U2 5 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 0963-8288 J9 DISABIL REHABIL JI Disabil. Rehabil. PD JUN 15 PY 2000 VL 22 IS 9 BP 409 EP 415 PG 7 WC Rehabilitation SC Rehabilitation GA 331KQ UT WOS:000088018600003 PM 10894204 ER PT J AU Kang, H Freund, C Duke-Cohan, JS Musacchio, A Wagner, G Rudd, CE AF Kang, H Freund, C Duke-Cohan, JS Musacchio, A Wagner, G Rudd, CE TI SH3 domain recognition of a proline-independent tyrosine-based RKxxYxxY motif in immune cell adaptor SKAP55 SO EMBO JOURNAL LA English DT Article DE protein-protein binding; SH3 domain; SKAP55; tyrosine ID CRYSTAL-STRUCTURE; T-CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; MOLECULAR-CLONING; INTERLEUKIN-2 PRODUCTION; PEPTIDE-BINDING; KINASE P59(FYN); PROTEIN SLP-76; RICH PEPTIDES; HUMAN FYN AB Src-homology 3 (SH3) domains recognize PXXP core motif preceded or followed by positively charged residue(s). Whether SH3 domains recognize motifs other than proline-based sequences is unclear. In this study, we report SH3 domain binding to a novel proline-independent motif in immune cell adaptor SKAP55, which is comprised of two N-terminal lysine and arginine residues followed by two tyrosines (i.e. RKxxYxxY). Domains capable of binding to class I proline motifs bound to the motif, while the class II domains failed to bind. Peptide precipitation, alanine scanning and in vivo co-expression studies demonstrated a requirement for the arginine, lysine and tandem tyrosines of the motif. Two-dimensional NMR analysis of the peptide bound FYN-SH3 domain showed overlap with the binding site of a proline-rich peptide on the charged surface of the SH3 domain, while resonance signals for other residues (W119, W120, Y137) were not perturbed by the RKGDYASY based peptide. Expression of the RKGDYASY peptide potently inhibited TcR zeta/CD3-mediated NF-AT transcription in T cells. Our findings extend the repertoire of SH3 domain binding motifs to include a tyrosine-based motif and demonstrate a regulatory role for this motif in receptor signaling. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. European Inst Oncol, Dept Expt Oncol, I-20141 Milan, Italy. RP Rudd, CE (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. OI Duke-Cohan, Jonathan/0000-0002-9478-9609 NR 46 TC 117 Z9 121 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD JUN 15 PY 2000 VL 19 IS 12 BP 2889 EP 2899 DI 10.1093/emboj/19.12.2889 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 329LR UT WOS:000087908900013 PM 10856234 ER PT J AU Jang, JC Fujioka, S Tasaka, M Seto, H Takatsuto, S Ishii, A Aida, M Yoshida, S Sheen, J AF Jang, JC Fujioka, S Tasaka, M Seto, H Takatsuto, S Ishii, A Aida, M Yoshida, S Sheen, J TI A critical role of sterols in embryonic patterning and meristem programming revealed by the fackel mutants of Arabidopsis thaliana SO GENES & DEVELOPMENT LA English DT Article DE Arabidopsis; brassinosteroids; C-14 sterol reductase; dwarf; embryogenesis; meristem; sterols ID LEMLI-OPITZ-SYNDROME; CUP-SHAPED COTYLEDON; BRASSINOSTEROID BIOSYNTHESIS; SACCHAROMYCES-CEREVISIAE; DELTA-7-STEROL REDUCTASE; MOLECULAR MECHANISMS; VASCULAR DEVELOPMENT; GENE MONOPTEROS; CELL ELONGATION; AXIS FORMATION AB Here we report a novel Arabidopsis dwarf mutant, fackel-J79, whose adult morphology resembles that of brassinosteroid-deficient mutants but also displays distorted embryos, supernumerary cotyledons, multiple shoot meristems, and stunted roots. We cloned the FACKEL gene and found that it encodes a protein with sequence similarity to both the human sterol reductase family and yeast C-14 sterol reductase and is preferentially expressed in actively growing cells. Biochemical analysis indicates that the fk-J79 mutation results in deficient C-14 sterol reductase activity, abnormal sterol composition, and reduction of brassinosteroids (BRs). Unlike other BR-deficient mutants, the defect of hypocotyl elongation in fk-J79 cannot be corrected by exogenous BRs. The unique phenotypes and sterol composition in fk-J79 indicate crucial roles of sterol regulation and signaling in cell division and cell expansion in embryonic and post-embryonic development in plants. C1 Ohio State Univ, Dept Hort & Crop Sci, Columbus, OH 43210 USA. RIKEN, Inst Phys & Chem Res, Wako, Saitama 3510198, Japan. Nara Inst Sci & Technol, Grad Sch Biosci, Nara 6300101, Japan. Joetsu Univ, Dept Chem, Joetsu, Niigata 9438512, Japan. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Jang, JC (reprint author), Ohio State Univ, Dept Hort & Crop Sci, Columbus, OH 43210 USA. NR 56 TC 143 Z9 151 U1 2 U2 10 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 2000 VL 14 IS 12 BP 1485 EP 1497 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 327NK UT WOS:000087799800007 PM 10859167 ER PT J AU Andres, PG Beck, PL Mizoguchi, E Mizoguchi, A Bhan, AK Dawson, T Kuziel, WA Maeda, N MacDermott, RP Podolsky, DK Reinecker, HC AF Andres, PG Beck, PL Mizoguchi, E Mizoguchi, A Bhan, AK Dawson, T Kuziel, WA Maeda, N MacDermott, RP Podolsky, DK Reinecker, HC TI Mice with a selective deletion of the CC chemokine receptors 5 or 2 are protected from dextran sodium sulfate-mediated colitis: Lack of CC chemokine receptor 5 expression results in a NK1.1(+) lymphocyte-associated Th2-type immune response in the intestine SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY BOWEL-DISEASE; MONOCYTE CHEMOTACTIC PROTEIN-1; ALPHA MUTANT MICE; ULCERATIVE-COLITIS; T-CELLS; EPITHELIAL-CELLS; CROHNS-DISEASE; INTERLEUKIN-10-DEFICIENT MICE; FUNCTIONAL EXPRESSION; CYTOKINE RESPONSES AB The chemokine receptors CCR2 and CCR5 and their respective ligands regulate leukocyte chemotaxis and activation, To determine the role of these chemokine receptors in the regulation of the intestinal immune response, we induced colitis in CCR2- acid CCR5-deficient mice by continuous oral administration of dextran sodium sulfate (DSS). Both CCR2- and CCR5-deficient mice were susceptible to DSS-induced intestinal inflammation, The lack of CCR2 or CCR5 did not reduce the DSS-induced migration of macrophages into the colonic lamina propria, However, both CCR5-deficient mice and, to a lesser degree, CCR2-deficient mice were protected from DSS-induced intestinal adhesions and mucosal ulcerations. CCR5-deficient mice were characterized by a greater relative infiltration of CD4(+) and NK1.1(+) lymphocyte in the colonic lamina propria when compared to wild-type and CCR2-deficient mice. In CCR5-deficient mice, mucosal mRNA expression of IL-4, IL-5, and IL-IO was increased, whereas that of IFN-gamma was decreased, corresponding to a Th2 pattern of T cell activation. In CCR2-deficient mice, the infiltration of Th2-type T cells in the lamina propria was absent, but increased levels of IL-10 and decreased levels of IFN-gamma may have down regulated mucosal inflammation, Our data indicate that CCR5 may be critical for the promotion of intestinal Th1-type immune responses in mice. C1 Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Ctr Study Inflammatory Bowel Dis, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. Univ Texas, Dept Mol Genet & Microbiol, Austin, TX 78712 USA. Univ Texas, Inst Mol & Cellular Biol, Austin, TX 78712 USA. Albany Med Coll, Div Gastroenterol, Albany, NY 12208 USA. RP Reinecker, HC (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, Dept Med, Ctr Study Inflammatory Bowel Dis, Jackson 7,32 Fruit St, Boston, MA 02114 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X FU NIDDK NIH HHS [DK 51003, DK 21474, DK 54427] NR 66 TC 181 Z9 186 U1 1 U2 6 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 2000 VL 164 IS 12 BP 6303 EP 6312 PG 10 WC Immunology SC Immunology GA 322KJ UT WOS:000087508500029 PM 10843684 ER PT J AU Marx, N Mach, F Sauty, A Leung, JH Sarafi, MN Ransohoff, RM Libby, P Plutzky, J Luster, AD AF Marx, N Mach, F Sauty, A Leung, JH Sarafi, MN Ransohoff, RM Libby, P Plutzky, J Luster, AD TI Peroxisome proliferator-activated receptor-gamma activators inhibit IFN-gamma-induced expression of the T cell-active CXC chemokines IP-10, Mig, and I-TAC in human endothelial cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GENE-EXPRESSION; PPAR-GAMMA; KAPPA-B; INDUCTION; ALPHA; TRANSCRIPTION; LIGANDS; ELEMENT; DIFFERENTIATION; CYTOKINES AB Peroxisome proliferator-activated receptor-gamma (PPAR gamma), a member of the nuclear hormone receptor superfamily originally shown to play an important role in adipocyte differentiation and glucose homeostasis, is now known to regulate inflammatory responses. Given the importance of endothelial cell (EC)-derived chemokines in regulating leukocyte function and trafficking, we studied the effects of PPAR gamma ligands on the expression of chemokines induced in ECs by the Th1 cytokine IFN-gamma, Treatment of ECs with PPAR gamma activators significantly inhibited IFN-gamma-induced mRNA and protein expression of the CXC chemokines IFN-inducible protein of 10 kDa (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-chemoattractant (I-TAC), whereas expression of the CC chemokine monocyte chemoattractant protein-1 was not altered. PPAR gamma activators decreased IFN-inducible protein of 10 kDa promoter activity and inhibited protein binding to the two NF-kappa B sites but not to the IFN-stimulated response element ISRE site. Furthermore, PPAR gamma ligands inhibited the release of chemotactic activity for CXC chemokine receptor 3 (CXCR3)-transfected lymphocytes from IFN-gamma-stimulated ECs, These data suggest that anti-diabetic PPAR gamma activators might attenuate the recruitment of activated T cells at sites of Th1-mediated inflammation. C1 Brigham & Womens Hosp, Vasc Med & Atherosclerosis Unit, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Charlestown, MA 02129 USA. Cleveland Clin Fdn, Dept Neurosci, Lerner Res Inst, Cleveland, OH 44195 USA. RP Luster, AD (reprint author), Massachusetts Gen Hosp East, Infect Dis Unit, Ctr AIDS Res, Bldg 149,13th St, Boston, MA 02129 USA. FU NCI NIH HHS [R01 CA069212, R01 CA69212]; NHLBI NIH HHS [R37 HL034636, HL34636, HL03107, R01 HL034636, R01 HL071745] NR 31 TC 235 Z9 249 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 15 PY 2000 VL 164 IS 12 BP 6503 EP 6508 PG 6 WC Immunology SC Immunology GA 322KJ UT WOS:000087508500053 PM 10843708 ER PT J AU Ferrante, RJ Andreassen, OA Jenkins, BG Dedeoglu, A Kuemmerle, S Kubilus, JK Kaddurah-Daouk, R Hersch, SM Beal, MF AF Ferrante, RJ Andreassen, OA Jenkins, BG Dedeoglu, A Kuemmerle, S Kubilus, JK Kaddurah-Daouk, R Hersch, SM Beal, MF TI Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease SO JOURNAL OF NEUROSCIENCE LA English DT Article DE creatine; mitochondria; Huntington's disease; transgenic mice; diabetes; N-acetylaspartate ID MITOCHONDRIAL PERMEABILITY TRANSITION; NEURONAL INTRANUCLEAR INCLUSIONS; NMR MAGNETIZATION-TRANSFER; EXPANDED CAG REPEAT; ENERGY-METABOLISM; IN-VIVO; WIDESPREAD EXPRESSION; H-1-NMR SPECTROSCOPY; INBORN ERROR; KINASE AB Huntington's disease (HD) is a progressive neurodegenerative illness for which there is no effective therapy. We examined whether creatine, which may exert neuroprotective effects by increasing phosphocreatine levels or by stabilizing the mitochondrial permeability transition, has beneficial effects in a transgenic mouse model of HD (line 6/2). Dietary creatine supplementation significantly improved survival, slowed the development of brain atrophy, and delayed atrophy of striatal neurons and the formation of huntingtin-positive aggregates in R6/2 mice. Body weight and motor performance on the rotarod test were significantly improved in creatine-supplemented R6/2 mice, whereas the onset of diabetes was markedly delayed. Nuclear magnetic resonance spectroscopy showed that creatine supplementation significantly increased brain creatine concentrations and delayed decreases in N-acetylaspartate concentrations. These results support a role of metabolic dysfunction in a transgenic mouse model of HD and suggest a novel therapeutic strategy to slow the pathological process. C1 New York Hosp Cornell Med Ctr, Dept Neurol, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Dept Neurol & Neurosci, New York, NY 10021 USA. Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. Avicena Grp Inc, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Charlestown, MA 02114 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Dept Radiol, Charlestown, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Neurol Serv, Neurochem Lab, Boston, MA 02114 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Pathol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Psychiat, Boston, MA 02118 USA. Bedford Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Bedford, MA 01730 USA. RP Beal, MF (reprint author), New York Hosp Cornell Med Ctr, Dept Neurol, 525 E 68th St, New York, NY 10021 USA. FU NINDS NIH HHS [NS35255, NS37102, NS38180] NR 59 TC 350 Z9 364 U1 4 U2 17 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 15 PY 2000 VL 20 IS 12 BP 4389 EP 4397 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 321GV UT WOS:000087448500005 PM 10844007 ER PT J AU Naisbitt, S Valtschanoff, J Allison, DW Sala, C Kim, E Craig, AM Weinberg, RJ Sheng, M AF Naisbitt, S Valtschanoff, J Allison, DW Sala, C Kim, E Craig, AM Weinberg, RJ Sheng, M TI Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein SO JOURNAL OF NEUROSCIENCE LA English DT Article DE postsynaptic density; motor protein; NMDA receptors; spine apparatus; receptor trafficking; cytoplasmic dynein ID NMDA RECEPTOR SUBUNITS; NITRIC-OXIDE SYNTHASE; D-ASPARTATE RECEPTORS; CYTOPLASMIC DYNEIN; DENSITY PROTEIN; UNCONVENTIONAL MYOSIN; HIPPOCAMPAL-NEURONS; GUANYLATE KINASES; RAT-BRAIN; PSD-95 AB NMDA receptors interact directly with postsynaptic density-95 (PSD-95), a scaffold protein that organizes a cytoskeletal-signaling complex at the postsynaptic membrane. The molecular mechanism by which the PSD-95-based protein complex is trafficked to the postsynaptic site is unknown but presumably involves specific motor proteins. Here we demonstrate a direct interaction between the PSD-95-associated protein guanylate kinase domain-associated protein (GKAP) and dynein light chain (DLC), a light chain subunit shared by myosin-V (an actin-based motor) and cytoplasmic dynein (a microtubule-based motor). A yeast two-hybrid screen with GKAP isolated DLC2, a novel protein 93% identical to the previously cloned 8 kDa dynein light chain (DLC1). A complex containing PSD-95, GKAP, DLC, and myosin-V can be immunoprecipitated from rat brain extracts. DLC colocalizes with PSD-95 and F-actin in dendritic spines of cultured neurons and is enriched in biochemical purifications of PSD. Immunogold electron microscopy reveals a concentration of DLC in the postsynaptic compartment of asymmetric synapses of brain in which it is associated with the PSD and the spine apparatus. We discuss the possibility that the GKAP/DLC interaction may be involved in trafficking of the PSD-95 complex by motor proteins. C1 Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ N Carolina, Dept Cell Biol & Anat, Chapel Hill, NC 27599 USA. Univ Illinois, Dept Cell & Struct Biol, Urbana, IL 61801 USA. Pusan Natl Univ, Dept Pharmacol, Pusan 609735, South Korea. RP Sheng, M (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Wellman 423,50 Blossom St, Boston, MA 02114 USA. RI Kim, Eunjoon/C-1566-2011; Sala, Carlo/A-2493-2009; Craig, Ann Marie/M-2054-2014 OI Sala, Carlo/0000-0003-0662-9523; FU NINDS NIH HHS [NS29879, NS33184, NS35050] NR 56 TC 165 Z9 171 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUN 15 PY 2000 VL 20 IS 12 BP 4524 EP 4534 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 321GV UT WOS:000087448500020 PM 10844022 ER PT J AU Maison, SF Liberman, MC AF Maison, SF Liberman, MC TI Predicting vulnerability to acoustic injury with a noninvasive assay of olivocochlear reflex strength SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cochlea; efferents; noise-induced hearing loss; otoacoustic emissions; ear; damage ID COCHLEAR EFFERENT SYSTEM; OTOACOUSTIC EMISSIONS; ELECTRIC STIMULATION; CONTRALATERAL SOUND; GUINEA-PIG; BUNDLE; NOISE; PROTECTION; DEPENDENCE; MECHANICS AB Permanent noise-induced damage to the inner ear is a major cause of hearing impairment, arising from exposures occurring during both work- and pleasure-related activities. Vulnerability to noise-induced hearing loss is highly variable: some have tough, whereas others have tender ears. This report documents, in an animal model, the efficacy of a simple nontraumatic assay of normal ear function in predicting vulnerability to acoustic injury. The assay measures the strength of a sound-evoked neuronal feedback pathway to the inner ear, the olivocochlear efferents, by examining otoacoustic emissions created by the normal ear, which can be measured with a microphone in the external ear. Reflex strength was inversely correlated with the degree of hearing loss after subsequent noise exposure. These data suggest that one function of the olivocochlear efferent system is to protect the ear from acoustic injury. This assay, or a simple modification of it, could be applied to human populations to screen for individuals most at risk in noisy environments. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol, Boston, MA 02114 USA. RP Liberman, MC (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [P30 DC005209, R01 DC-0188] NR 41 TC 148 Z9 155 U1 1 U2 1 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 2000 VL 20 IS 12 BP 4701 EP 4707 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 321GV UT WOS:000087448500037 PM 10844039 ER PT J AU Winawer, SJ Stewart, ET Zauber, AG Bond, JH Ansel, H Waye, JD Hall, D Hamlin, JA Schapiro, M O'Brien, MJ Sternberg, SS Gottlieb, LS AF Winawer, SJ Stewart, ET Zauber, AG Bond, JH Ansel, H Waye, JD Hall, D Hamlin, JA Schapiro, M O'Brien, MJ Sternberg, SS Gottlieb, LS CA Natl Polyp Study Work Grp TI A comparison of colonoscopy and double-contrast barium enema for surveillance after polypectomy. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COLORECTAL-CANCER; FOLLOW-UP; POLYPS; ADENOMAS; INTERVALS; DISEASE; REMOVAL; COLON AB Background: After patients have undergone colonoscopic polypectomy, it is uncertain whether colonoscopic examination or a barium enema is the better method of surveillance. Methods: As part of the National Polyp Study, we offered colonoscopic examination and double-contrast barium enema for surveillance to patients with newly diagnosed adenomatous polyps. Although barium enema was performed first, the endoscopist did not know the results. Results: A total of 973 patients underwent one or more colonoscopic examinations for surveillance. In the case of 580 of these patients, we performed 862 paired colonoscopic examinations and barium-enema examinations that met the requirements of the protocol. The findings on barium enema were positive in 222 (26 percent) of the paired examinations, including 94 of the 242 colonoscopic examinations in which one or more adenomas were detected (rate of detection of adenomas, 39 percent; 95 percent confidence interval, 33 to 45 percent). The proportion of examinations in which adenomatous polyps were detected by barium enema was significantly related to the size of the adenomas (P=0.009); the rate was 32 percent for colonoscopic examinations in which the largest adenomas detected were 0.5 cm or less, 53 percent for those in which the largest adenomas detected were 0.6 to 1.0 cm, and 48 percent for those in which the largest adenomas detected exceeded 1.0 cm. Among the 139 paired examinations with positive results on barium enema and negative results on colonoscopic examination in the same location, 19 additional polyps, 12 of which were adenomas, were detected on colonoscopic reexamination. Conclusions: In patients who have undergone colonoscopic polypectomy, colonoscopic examination is a more effective method of surveillance than double-contrast barium enema. (N Engl J Med 2000;342:1766-72.) (C)2000, Massachusetts Medical Society. C1 Mem Sloan Kettering Canc Ctr, Dept Med, Serv Gastroenterol & Nutr, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. Med Coll Wisconsin, Dept Radiol, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Froedtert Mem Lutheran Hosp, Milwaukee, WI 53226 USA. Minneapolis Vet Affairs Med Ctr, Dept Med, Minneapolis, MN USA. Minneapolis Vet Affairs Med Ctr, Dept Radiol, Minneapolis, MN USA. Mt Sinai Hosp, Dept Med, New York, NY 10029 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Cedars Sinai Med Ctr, Dept Radiol, Los Angeles, CA 90048 USA. Valley Presbyterian Hosp, Dept Med, Van Nuys, CA USA. Boston Med Ctr, Mallory Inst Pathol, Boston, MA USA. Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. Mt Sinai Hosp, Dept Radiol, New York, NY USA. Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. Valley Presbyterian Hosp, Dept Radiol, Van Nuys, CA USA. Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. RP Winawer, SJ (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Serv Gastroenterol & Nutr, 1275 York Ave, New York, NY 10021 USA. FU NCI NIH HHS [CA-26852] NR 25 TC 346 Z9 366 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 15 PY 2000 VL 342 IS 24 BP 1766 EP 1772 DI 10.1056/NEJM200006153422401 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 323PG UT WOS:000087573700001 PM 10852998 ER PT J AU Delaney, TF Shepard, JO Chakravarti, A Nielsen, GP Spiro, IJ Mark, EJ AF Delaney, TF Shepard, JO Chakravarti, A Nielsen, GP Spiro, IJ Mark, EJ TI A 45-year-old woman with a thoracic mass and Pancoast's syndrome - Intrathoracic fibromatosis (desmoid tumor). SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID DERMATOFIBROSARCOMA PROTUBERANS; PULMONARY INFECTION; AMYLOID NODULE; CHEST-WALL; TRISOMY-20 C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Delaney, TF (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 43 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 15 PY 2000 VL 342 IS 24 BP 1814 EP 1821 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 323PG UT WOS:000087573700008 ER PT J AU Buhler, L Awwad, M Basker, M Gojo, S Watts, A Treter, S Nash, K Oravec, G Chang, Q Thall, A Down, JD Sykes, M Andrews, D Sackstein, R White-Scharf, ME Sachs, DH Cooper, DKC AF Buhler, L Awwad, M Basker, M Gojo, S Watts, A Treter, S Nash, K Oravec, G Chang, Q Thall, A Down, JD Sykes, M Andrews, D Sackstein, R White-Scharf, ME Sachs, DH Cooper, DKC TI High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response SO TRANSPLANTATION LA English DT Article ID NONLETHAL PREPARATIVE REGIMEN; BONE-MARROW TRANSPLANTATION; RENAL-ALLOGRAFT REJECTION; TOLERANCE INDUCTION; ANTI-GAL-ALPHA-1-3GAL ANTIBODY; CARDIAC TRANSPLANTS; IN-VITRO; ENGRAFTMENT; PRIMATES; XENOTRANSPLANTATION AB Background. In pig-to-primate organ transplantation, hyperacute rejection can be prevented, but the organ is rejected within days by acute vascular rejection, in which induced high-affinity anti-Gal alpha 1-3Gal (alpha Gal) IgG and possibly antibodies directed against new porcine (non-alpha Gal) antigenic determinants are considered to play a major role. We have explored the role of an anti-CD40L monoclonal antibody in modifying the humoral response to porcine hematopoietic cells in baboons pretreated with a nonmyeloablative regimen. Methods, Porcine peripheral blood mobilized progenitor cells obtained by leukapheresis from both major histocompatibility complex-inbred miniature swine (n=7) and human decay-accelerating factor pigs (n=3) were transplanted into baboons. Group 1 baboons (n=3) underwent whole body (300 cGy) and thymic (700 cGy) irradiation, T cell depletion with ATG, complement depletion with cobra venom factor, short courses of cyclosporine, mycophenolate mofetil, porcine hematopoietic growth factors, and anti-alpha Gal antibody depletion by immunoadsorption before transplantation of high doses (2-4 x 10(10)/cells/kg) of peripheral blood mobilized progenitor cells. In group 2 (n=5), cyclosporine was replaced by eight doses of anti-CD40L monoclonal antibodies over 14 days. The group 3 baboons (n=2) received the group 1 regimen plus 2 doses of anti-CD40L monoclonal antibodies (on days 0 and 2), Results, In group 1, sensitization to alpha Gal (with increases in IgM and IgG; of 3- to 6-fold and 100-fold, respectively) and the development of antibodies to new non-alpha Gal porcine antigens occurred within 20 days. In group 2, no sensitization to alpha Gal or non-alpha Gal determinants was seen, but alpha Gal-reactive antibodies did return to their pre- peripheral blood mobilized progenitor cells transplant levels. In group 3, attenuated sensitization to alpha Gal antigens was seen after cessation of cyclosporine and mycophenolate mofetil therapy at 30 days (IgM 4-fold, IgG: 8-30-fold), but no antibodies developed against new porcine determinants. In no baboon did anti-CD40L monoclonal antibodies prevent sensitization to its own murine antigene. Conclusions. We believe these studies are the first to consistently demonstrate prevention of a secondary humoral response after cell or organ transplantation in a pig-to-primate model. The development of sensitization to the murine elements of the anti-CD40L monoclonal antibodies suggests that nonresponsiveness to cell membrane-bound antigen (e.g., alpha Gal) is a specific phenomenon and not a general manifestation of immunological unresponsiveness. T cell costimulatory blockade may facilitate induction of mixed hematopoietic chimerism and, consequently, of tolerance to pig organs and tissues. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Transplantat Biol Res Ctr, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02129 USA. BioTransplant Inc, Charlestown, MA 02129 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 37 TC 101 Z9 101 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 15 PY 2000 VL 69 IS 11 BP 2296 EP 2304 PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 325HD UT WOS:000087669400013 PM 10868629 ER PT J AU Liel-Cohen, N Guerrero, JL Otsuji, Y Handschumacher, MD Rudski, LG Hunziker, PR Tanabe, H Scherrer-Crosbie, M Sullivan, S Levine, RA AF Liel-Cohen, N Guerrero, JL Otsuji, Y Handschumacher, MD Rudski, LG Hunziker, PR Tanabe, H Scherrer-Crosbie, M Sullivan, S Levine, RA TI Design of a new surgical approach for ventricular remodeling to relieve ischemic mitral regurgitation - Insights from 3-dimensional echocardiography SO CIRCULATION LA English DT Article DE mitral valve; regurgitation; ischemia; echocardiography; surgery ID PAPILLARY-MUSCLE DYSFUNCTION; MYOCARDIAL-INFARCTION; VALVE REPAIR; MECHANISM; DOPPLER; RECONSTRUCTION; REPLACEMENT; DISEASE; INSUFFICIENCY; PATHOGENESIS AB Background-Mechanistic insights from 3D echocardiography (echo) can guide therapy. In particular, ischemic mitral regurgitation (MR) is difficult to repair, often persisting despite annular reduction. We hypothesized that (1) in a chronic infarct model of progressive MR, regurgitation parallels 3D changes in the geometry of mitral leaflet attachments, causing increased leaflet tethering and restricting closure; therefore, (2) MR can be reduced by restoring tethering geometry toward normal, using a new ventricular remodeling approach based on 3D echo findings. Methods and Results-We studied 10 sheep by 3D echo just after circumflex marginal ligation and 8 weeks later. MR, at first absent, became moderate as the left ventricle (LV) dilated and the papillary muscles shifted posteriorly and mediolaterally, increasing the leaflet tethering distance from papillary muscle tips to the anterior mitral annulus (P<0.0001). To counteract these shifts, the LV was remodeled by plication of the infarct region to reduce myocardial bulging, without muscle excision or cardiopulmonary bypass. Immediately and up to 2 months after plication, MR was reduced to trace-to-mild as tethering distance was decreased (P<0.0001). LV ejection fraction, global LV end-systolic volume, and mitral annular area were relatively unchanged. By multiple regression, the only independent predictor of MR was tethering distance (r(2)=0.81). Conclusions-Ischemic MR in this model relates strongly to changes in 3D mitral leaflet attachment geometry. These insights from quantitative 3D echo allowed us to design an effective LV remodeling approach to reduce MR by relieving tethering. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Surg Unit, Boston, MA 02114 USA. RP Levine, RA (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiac Ultrasound Lab, 55 Fruit St,VBK 508, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL-38176, HL-53702] NR 46 TC 149 Z9 151 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 13 PY 2000 VL 101 IS 23 BP 2756 EP 2763 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 323NM UT WOS:000087571900026 PM 10851215 ER PT J AU Asherson, P Barkley, R Barr, C Berg, K Biederman, J Castellanos, X Comings, D Curran, S Doyle, A Ebstein, R Eisenberg, J Ergelen, E Faraone, S Freund, L Geller, D Gill, M Holmes, J Hudziak, J Kennedy, J Kent, L Manor, I Mick, E Mitchell, H Navia, B Pato, C Pato, M Price, T Sargeant, J Simonoff, E Smalley, S Spencer, T Swanson, J Waldman, I Wilens, T Yazgan, Y AF Asherson, P Barkley, R Barr, C Berg, K Biederman, J Castellanos, X Comings, D Curran, S Doyle, A Ebstein, R Eisenberg, J Ergelen, E Faraone, S Freund, L Geller, D Gill, M Holmes, J Hudziak, J Kennedy, J Kent, L Manor, I Mick, E Mitchell, H Navia, B Pato, C Pato, M Price, T Sargeant, J Simonoff, E Smalley, S Spencer, T Swanson, J Waldman, I Wilens, T Yazgan, Y CA ADHD Mol Genetics Network TI Collaborative possibilities for molecular genetic studies of attention deficit hyperactivity disorder: Report from an international conference SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE ADHD; genetics; collaboration ID COMPLEX TRAITS; LINKAGE STRATEGIES; CHILDREN; ASSOCIATION; BEHAVIOR; SIBLINGS; PARENTS; ADHD AB Research on attention deficit hyperactivity disorder (ADHD) suggests that ADHD has a substantial genetic component. Although still in their infancy, molecular genetic studies have already implicated several genes as mediating susceptibility to ADHD, Nevertheless, given that ADHD's mode of inheritance is likely to be complex, much more work is needed to fully clarify the genetic architecture of the disorder. Because large samples and collaborative efforts will likely be needed to attain this goal, researchers in the field have convened a series of meetings to discuss measures for assessing ADHD, the feasibility of using common measures across sites, ways to increase communication among researchers, and strategies for defining genetically useful phenotypes. Am. J, Med, Genet, (Neuropsychiatr, Genet.) 96:251-257, 2000, (C) 2000 Wiley-Liss, Inc. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Boston, MA 02114 USA. RP Faraone, S (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, ACC 725,Fruit St, Boston, MA 02114 USA. RI Tahir Turanli, Eda/D-4989-2009; Simonoff, Emily/B-7593-2011; Price, Thomas/B-7372-2008; OI Price, Thomas/0000-0001-7356-2109; Faraone, Stephen/0000-0002-9217-3982 NR 29 TC 11 Z9 11 U1 0 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JUN 12 PY 2000 VL 96 IS 3 BP 251 EP 257 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 320DP UT WOS:000087386700003 ER PT J AU Desan, PH Oren, DA Malison, R Price, LH Rosenbaum, J Smoller, J Charney, DS Gelernter, J AF Desan, PH Oren, DA Malison, R Price, LH Rosenbaum, J Smoller, J Charney, DS Gelernter, J TI Genetic polymorphism at the CLOCK gene locus and major depression SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE circadian rhythms; genetic association; single nucleotide polymorphism; behavioral genetics; CLOCK gene; affective disorders ID DROSOPHILA PERIOD GENE; CIRCADIAN-RHYTHMS; WINTER DEPRESSION; SLEEP; POPULATION; PREFERENCE; VARIANT; PROTEIN; CLONING; LIGHT AB Genetic analysis in both mouse and Drosophila has indicated that the product of the CLOCK gene is an essential component of a circadian rhythm timing system. A single nucleotide polymorphism (SNP), T3111C, in the 3' flanking region of the human CLOCK gene has been identified. Homozygotes or heterozygotes for the 3111C allele have been reported to have higher mean scores on a measure of evening preference for activity (Vs, morning preference) than subjects homozygous for the 3111T allele, Since major depression is hypothesized to be closely linked to circadian rhythms, we explored whether this polymorphism might be related to susceptibility to major depression. We also ascertained allele frequency in an African-American control population, to begin to evaluate population variation at this locus. CLOCK T3111C allele frequencies were determined in 280 European American (EA) subjects, 143 with a history of major depression and 137 screened controls, and in 58 African American (AA) screened control subjects, using a polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) method. There was no significant difference between EA depressed and control subjects in allele frequency. There was a significant difference in allele frequency between EA and AA subjects, demonstrating a potential for population stratification. In none of these groups were significant deviations from Hardy-Weinberg equilibrium found. The present data do not support an association between CLOCK gene alleles at the T3111C locus and major depression. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:418-421, 2000. Published 2000 Wiley-Liss, Inc.dagger C1 VA Connecticut Healthcare Syst, W Haven, CT USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Connecticut Mental Hlth Ctr, New Haven, CT USA. Brown Univ, Dept Psychiat & Human Behav, Providence, RI 02912 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Gelernter, J (reprint author), VA CT Healthcare Syst 116A2, 950 Campbell Ave, W Haven, CT 06516 USA. FU NIMH NIH HHS [K02-MH01387, P30-MH30929] NR 30 TC 71 Z9 74 U1 4 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD JUN 12 PY 2000 VL 96 IS 3 BP 418 EP 421 DI 10.1002/1096-8628(20000612)96:3<418::AID-AJMG34>3.0.CO;2-S PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 320DP UT WOS:000087386700034 PM 10898925 ER PT J AU Ladenson, PW Singer, PA Ain, KB Bagchi, N Bigos, ST Levy, EG Smith, SA Daniels, GH AF Ladenson, PW Singer, PA Ain, KB Bagchi, N Bigos, ST Levy, EG Smith, SA Daniels, GH TI American thyroid association guidelines for detection of thyroid dysfunction SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID L-THYROXINE TREATMENT; SUBCLINICAL HYPOTHYROIDISM; DOUBLE-BLIND; BONE MASS; THERAPY; THYROTROPIN; HYPERTHYROIDISM; LEVOTHYROXINE; METAANALYSIS; COMMUNITY AB Objectives: To define the optimal approach to identify patients with thyroid dysfunction. Participants: The 8-member Standards of Care Committee of the American Thyroid Association prepared a draft, which was reviewed by the association's 780 members, 50 of whom responded with suggested revisions. Evidence: Relevant published studies were identified through MEDLINE and the associations membership's personal resources. Consensus Process: Consensus was reached at group meetings. The first draft was prepared by a single author (P.W.L.) after group discussion. Suggested revisions were incorporated after consideration by the committee. Conclusions: The American Thyroid Association recommends that adults be screened for thyroid dysfunction by measurement of the 35 years and every 5 years thereafter. The indication for screening is particularly compelling in women, but it can also be justified in men as a relatively cost-effective measure in the context of the periodic health examination. Individuals with symptoms and signs potentially attributable to thyroid dysfunction and those with risk factors for its development may require more frequent serum thyrotropin testing. C1 Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, Baltimore, MD 21287 USA. Univ So Calif, Los Angeles, CA USA. Univ Kentucky, Lexington, KY USA. Maine Med Ctr, Bangor, ME USA. Univ Miami, Miami, FL 33152 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Ladenson, PW (reprint author), Johns Hopkins Univ, Sch Med, Div Endocrinol & Metab, 1830 E Monument St,Suite 333, Baltimore, MD 21287 USA. RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 23 TC 228 Z9 252 U1 3 U2 7 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 12 PY 2000 VL 160 IS 11 BP 1573 EP 1575 DI 10.1001/archinte.160.11.1573 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 320XT UT WOS:000087426700003 PM 10847249 ER PT J AU Hylck, EM Chang, YC Skates, SJ Hughes, RA Singer, DE AF Hylck, EM Chang, YC Skates, SJ Hughes, RA Singer, DE TI Prospective study of the outcomes of ambulatory patients with excessive warfarin anticoagulation SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID RISK-FACTORS; BLEEDING COMPLICATIONS; THERAPY; DISCONTINUATION; OUTPATIENTS; HEMORRHAGE AB Background: Warfarin sodium therapy is highly effective in preventing thromboembolism. Its major toxic effect is hemorrhage, the risk of which increases with the international normalized ratio (INR). Data on the rate of major hemorrhage and the rate of INR decay after an episode of excessive anticoagulation therapy would help guide management of elevated INRs in the outpatient setting. Methods: We prospectively followed up outpatients in an anticoagulant therapy unit from April 24, 1995, through March 1, 1996. Study patients had to be taking warfarin for longer than 1 month and have an INR target range of 2.0 to 3.0. Consecutive outpatients with an INR greater than 6.0 were identified and compared with a randomly selected concurrent set of patients whose INR was in the target range. Major hemorrhage was defined as fatal, intracranial, or requiring hospitalization and transfusion of at least 2 U of blood. Results: One hundred fourteen patients with INRs greater than 6.0 were identified and compared with 268 patients with INRs in the target range. None of the patients had clinically apparent bleeding at the time of the INR measurement, and none received phytonadione (vitamin KI). Patients did not differ significantly in age, sex, indication, or duration of warfarin therapy. Ten patients with an INR greater than 6.0 (8.8%; 95% confidence interval, 4.3%-15.5%) sought medical attention for abnormal bleeding, and 5 of these experienced a major hemorrhage during 14-day follow-up (4.4%; 95% confidence interval, 1.4%-9.9%) compared with none of the patients with an in-range INR(P<.001). Thirty-three percent of patients with INRs greater than 6.0 had INRs less than 4.0 within 24 hours, 55% within 48 hours, 73% within 72 hours, and nearly 90% within 96 hours of temporary discontinuation of warfarin therapy. Conclusions: Outpatients with INRs seater than 6.0 face a significant short-term risk of major hemorrhage. Randomized trials are needed to determine the net benefit of preventive treatment with phytonadione. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gen Med Div,Clin Epidemion Unit S509, Boston, MA 02114 USA. RP Hylck, EM (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gen Med Div,Clin Epidemion Unit S509, Boston, MA 02114 USA. NR 20 TC 3 Z9 7 U1 0 U2 0 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 12 PY 2000 VL 160 IS 11 BP 1612 EP 1617 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 320XT UT WOS:000087426700009 ER PT J AU Naruse, K King, GL AF Naruse, K King, GL TI Protein kinase C and myocardial biology and function SO CIRCULATION RESEARCH LA English DT Editorial Material DE protein kinase C; cardiac; growth; contractility; ischemic preconditioning ID GAMMA MUTANT MICE; DIABETIC RATS; PKC-GAMMA; INTRACELLULAR RECEPTOR; GROWTH-FACTOR; EXPRESSION; BETA; ACTIVATION; EPSILON; ISOFORM C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. RP King, GL (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. NR 38 TC 67 Z9 71 U1 0 U2 4 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 9 PY 2000 VL 86 IS 11 BP 1104 EP 1106 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 323NL UT WOS:000087571800002 PM 10850959 ER PT J AU Chung, N Jenkins, G Hannun, YA Heitman, J Obeid, LM AF Chung, N Jenkins, G Hannun, YA Heitman, J Obeid, LM TI Sphingolipids signal heat stress-induced ubiquitin-dependent proteolysis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLASMA-MEMBRANE PROTEIN; YEAST URACIL PERMEASE; SACCHAROMYCES-CEREVISIAE; DEGRADATION; GENE; RESISTANCE; MUTANT; MULTIUBIQUITINATION; ENDOCYTOSIS; INHIBITION AB Sphingolipids are essential eukaryotic membrane lipids that are structurally and metabolically conserved through evolution. Sphingolipids have also been proposed to regulate eukaryotic stress responses as novel second messengers. Here we show that, in Saccharomyces cerevisiae, phytosphingosine, a putative sphingolipid second messenger, mediates heat stress signaling and activates ubiquitin-dependent proteolysis via the endocytosis vacuolar degradation and 26 S proteasome pathways. Inactivation of serine palmitoyltransferase, a key enzyme in generating endogenous phytosphingosine, prevents proteolysis during heat stress. Addition of phytosphingosine bypasses the requirement for serine palmitoyltransferase and restores proteolysis, Phytosphingosine-induced proteolysis requires multiubiquitin chain formation through the stress-responsive lysine 63 residue of ubiquitin, We propose that heat stress increases phytosphingosine and activates ubiquitin-dependent proteolysis. C1 Med Univ S Carolina, Ralph H Johnson Vet Adm, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Biochem, Charleston, SC 29403 USA. Duke Univ, Dept Pharmacol & Canc Biol, Program Mol Canc Biol, Med Ctr, Durham, NC 27710 USA. Duke Univ, Dept Cell Biol, Med Ctr, Durham, NC 27710 USA. Duke Univ, Dept Genet, Med Ctr, Durham, NC 27710 USA. Duke Univ, Dept Microbiol, Med Ctr, Durham, NC 27710 USA. Duke Univ, Dept Med, Med Ctr, Durham, NC 27710 USA. Duke Univ, Dept Med, Howard Hughes Med Inst, Med Ctr, Durham, NC 27710 USA. RP Obeid, LM (reprint author), Med Univ S Carolina, Ralph H Johnson Vet Adm, Charleston, SC 29403 USA. OI obeid, lina/0000-0002-0734-0847 FU NIA NIH HHS [AG12467]; NIAID NIH HHS [AI41937]; NIGMS NIH HHS [GM43825] NR 40 TC 84 Z9 87 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 9 PY 2000 VL 275 IS 23 BP 17229 EP 17232 DI 10.1074/jbc.C000229200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321ZJ UT WOS:000087485000003 PM 10764732 ER PT J AU Sun, XG Majumder, P Shioya, H Wu, F Kumar, S Weichselbaum, R Kharbanda, S Kufe, D AF Sun, XG Majumder, P Shioya, H Wu, F Kumar, S Weichselbaum, R Kharbanda, S Kufe, D TI Activation of the cytoplasmic c-Abl tyrosine kinase by reactive oxygen species SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DAMAGE-INDUCED APOPTOSIS; DNA-DAMAGE; OXIDATIVE STRESS; PROTEIN-KINASE; CELLULAR-RESPONSE; NUCLEAR; 1-BETA-D-ARABINOFURANOSYLCYTOSINE; ADAPTER; CRK AB The ubiquitously expressed c-Abl protein tyrosine kinase localizes to both the nucleus and cytoplasm. The nuclear form of c-Abl is activated in the cellular response to genotoxic stress. Here we show that cytoplasmic c-Abl is activated by oxidative stress, The results also demonstrate that mitochondrial cytochrome c is released in the cellular response to H2O2 and that this effect is mediated by a c-Abl-dependent mechanism. In concert with these results, we show that H2O2-induced apoptosis is attenuated in c-Abl-deficient cells. These findings demonstrate that cytoplasmic c-Abl is involved in the apoptotic response of cells to oxidative stress. 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 [CA42802] NR 35 TC 109 Z9 112 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 9 PY 2000 VL 275 IS 23 BP 17237 EP 17240 DI 10.1074/jbc.C000099200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321ZJ UT WOS:000087485000005 PM 10770918 ER PT J AU D'Souza, I Schellenberg, GD AF D'Souza, I Schellenberg, GD TI Determinants of 4-repeat tau expression - coordination between enhancing and inhibitory splicing sequences for exon 10 inclusion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MULTIPLE-SYSTEM TAUOPATHY; MICROTUBULE-ASSOCIATED PROTEINS; FAMILIAL PRESENILE-DEMENTIA; FRONTOTEMPORAL DEMENTIA; REGULATORY ELEMENTS; ALZHEIMERS-DISEASE; FTDP-17 MUTATIONS; NERVOUS-SYSTEM; CHROMOSOME-17 AB Mutations in the tau gene are pathogenic causing autosomal dominant frontotemporal dementia with Parkinsonism-chromosome 17 type (FTDP-17). Some mutations in tau exon 10 (E10) and immediately adjacent sequences cause disease by altering E10 splicing. To determine the mechanism of normal E10 splicing regulation and how FTDP-17 mutations alter splicing, mutational analysis of E10 was performed. The results show that E10 contains a complex array of both enhancer and inhibitor cia-acting elements that modulate usage of a weak 5' splice site. The 5' end of E10 contains a previously unrecognized multipartite exon splicing enhancer (ESE) composed of an SC35-like binding sequence, a purine-rich sequence, and an AC-rich element. Downstream of this ESE is a purine-rich exon splicing inhibitor. Intronic sequences immediately downstream of E10 also are inhibitory. The results support an alternative model in which I10 inhibitory sequences appear to function as a linear sequence. The cia-elements described are not redundant, and all appear required for normal E10 splicing. Results with double mutations demonstrate that the ESE and the intronic inhibitory element collaborate to regulate splicing. Thus splicing of tau E10 is regulated by a complex set of cia-acting elements that span nearly the entire exon and also include intronic sequences. C1 Seattle Div, Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. Univ Washington, Dept Med, Div Gerontol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Div Geriatr Med, Seattle, WA 98195 USA. Univ Washington, Dept Neurol, Seattle, WA 98195 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. RP Schellenberg, GD (reprint author), Seattle Div, Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle, WA 98108 USA. FU NIA NIH HHS [R01 AG11762] NR 35 TC 90 Z9 91 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 9 PY 2000 VL 275 IS 23 BP 17700 EP 17709 DI 10.1074/jbc.M909470199 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 321ZJ UT WOS:000087485000070 PM 10748133 ER PT J AU Woolf, CJ Salter, MW AF Woolf, CJ Salter, MW TI Neuroscience - Neuronal plasticity: Increasing the gain in pain SO SCIENCE LA English DT Review ID RAT SPINAL-CORD; PRIMARY SENSORY NEURONS; DORSAL HORN NEURONS; RESISTANT SODIUM CURRENT; PERIPHERAL-NERVE INJURY; PRIMARY AFFERENT-FIBERS; LONG-TERM POTENTIATION; ROOT GANGLION NEURONS; INFLAMMATORY PAIN; MESSENGER-RNA AB We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual frame- work for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp East, Sch Med, Charlestown, MA 02129 USA. Hosp Sick Children, Program Brain & Behav, Toronto, ON M5G 1X8, Canada. Univ Toronto, Ctr Study Pain, Toronto, ON M5G 1X8, Canada. RP Woolf, CJ (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Neural Plast Res Grp, Charlestown, MA 02129 USA. NR 73 TC 1954 Z9 2048 U1 15 U2 236 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 9 PY 2000 VL 288 IS 5472 BP 1765 EP 1768 DI 10.1126/science.288.5472.1765 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322HH UT WOS:000087503800038 PM 10846153 ER PT J AU Ryan, ET Kain, KC AF Ryan, ET Kain, KC TI Primary care: Health advice and immunizations for travelers SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; DRUG-THERAPY; HEPATITIS-A; MALARIA; PREVENTION; MEFLOQUINE; PROPHYLAXIS; DIARRHEA; EPIDEMIOLOGY C1 Massachusetts Gen Hosp, Div Infect Dis, Trop & Geog Med Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Infect Dis, Travelers Advice & Immunizat Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Toronto Gen Hosp, Div Infect Dis, Ctr Travel & Trop Med, Toronto, ON, Canada. Univ Toronto, Toronto, ON, Canada. RP Ryan, ET (reprint author), Massachusetts Gen Hosp, Div Infect Dis, Trop & Geog Med Ctr, Jackson 504,55 Fruit St, Boston, MA 02114 USA. FU NIAID NIH HHS [AI/K0801332] NR 65 TC 93 Z9 95 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 8 PY 2000 VL 342 IS 23 BP 1716 EP 1725 DI 10.1056/NEJM200006083422306 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 321HD UT WOS:000087449300006 PM 10841875 ER PT J AU Kistler, JP Furie, KL AF Kistler, JP Furie, KL TI Carotid endarterectomy revisited SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID DOPPLER ULTRASOUND CRITERIA; STENOSIS; SPECIMENS; STROKE C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Kistler, JP (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 16 TC 13 Z9 15 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD JUN 8 PY 2000 VL 342 IS 23 BP 1743 EP 1745 DI 10.1056/NEJM200006083422310 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 321HD UT WOS:000087449300010 PM 10841879 ER PT J AU Yoon, SK Mohr, L O'Riordan, CR Lachapelle, A Armentano, D Wands, JR AF Yoon, SK Mohr, L O'Riordan, CR Lachapelle, A Armentano, D Wands, JR TI Targeting a recombinant adenovirus vector to HCC cells using a bifunctional Fab-antibody conjugate SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE monoclonal antibody; targeting; adenovirus; human hepatocellular carcinoma ID HEPATOCELLULAR-CARCINOMA CELLS; VIRUS THYMIDINE KINASE; MEDIATED GENE-TRANSFER; IN-VIVO; CYTOSINE DEAMINASE; DELIVERY SYSTEM; THERAPY; EXPRESSION; MICE; IMMUNOLIPOSOMES AB We developed a specific adenoviral gene delivery system with monoclonal antibody (mAb) AF-20 that binds to a 180 kDa antigen highly expressed on human hepatocellular carcinoma (HCC) cells. A bifunctional Fab-antibody conjugate (2Hx-2-AF-20) was generated through AF-20 mAb crosslinkage to an anti-hexon antibody Fab fragment. Uptake of adenoviral particles and gene expression was examined in FOCUS HCC and NIH 3T3 cells by immunofluorescence; beta-galactosidase expression levels were determined following competitive inhibition of adenoviral CAR receptor by excess fibre knob protein. The chimeric complex was rapidly internalized at 37 degrees C, and enhanced levels of reporter gene expression was observed in AF-20 antigen positive HCC cells, but not in AF-20 antigen negative NM 3T3 control cells. Targeting of recombinant adenoviral vectors to a tumor associated antigen by a bifunctional Fab-antibody conjugate is a promising approach to enhance specificity and efficiency of gene delivery to HCC. (C) 2000 Academic Press. C1 Massachusetts Gen Hosp, Ctr Canc, Mol Hepatol Lab, Charlestown, MA 02129 USA. Genzyme Corp, Framingham, MA 01701 USA. Catholic Univ Korea, Coll Med, Dept Internal Med, Seoul 137701, South Korea. Univ Freiburg, Fac Med, Dept Med 2, Freiburg, Germany. RP Yoon, SK (reprint author), Massachusetts Gen Hosp, Ctr Canc, Mol Hepatol Lab, Charlestown, MA 02129 USA. FU NCI NIH HHS [CA35711]; NIAAA NIH HHS [AA-08169] NR 25 TC 19 Z9 23 U1 0 U2 0 PU ACADEMIC PRESS INC 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 JUN 7 PY 2000 VL 272 IS 2 BP 497 EP 504 DI 10.1006/bbrc.2000.2788 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 327HC UT WOS:000087787600033 PM 10833442 ER PT J AU Singh, N Singh, PN Hershman, JM AF Singh, N Singh, PN Hershman, JM TI Effect of calcium carbonate on the absorption of levothyroxine SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID INTESTINAL-ABSORPTION; ALUMINUM HYDROXIDE; THYROXINE; HYPOTHYROIDISM; SUCRALFATE; EFFICACY; THERAPY AB Context The effect of calcium carbonate on the absorption of levothyroxine has not been studied systematically. Such a potential drug interaction merits investigation because concurrent treatment with both drugs is common, particularly in postmenopausal women. Objective To investigate the potential interference of calcium carbonate in the absorption of levothyroxine. Design Prospective cohort study conducted from November 1998 to June 1999, supplemented with an in vitro study of thyroxine (T-4) binding to calcium carbonate. Setting Veterans Affairs Medical Center in West Los Angeles, Calif. Patients Twenty patients (age range, 27-78 years; n=11 men) with hypothyroidism who were taking a stable long-term regimen of levothyroxine were included in the study. All patients had serum free T-4 and thyrotropin values in the normal range before beginning the study. Intervention Subjects were instructed to take 1200 mg/d of elemental calcium as calcium carbonate, ingested with their levothyroxine, for 3 months. Main Outcome Measures Levels of free T-4, total T-4, total triiodothyronine (T-3), and thyrotropin, measured in all subjects at baseline (while taking levothyroxine alone), at 2 and 3 months (while taking calcium carbonate and levothyroxine), and 2 months after calcium carbonate discontinuation (while continuing to take levothyroxine). Results Mean free T-4 and total T-4 levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T-4 levels were 17 pmol/L (1.3 ng/dL) at baseline, 15 pmol/L (1.2 ng/dL) during the calcium period, and 18 pmol/L (1.4 ng/dL) after calcium discontinuation (overall P<.001); mean total T-4 levels were 118 nmol/L (9.2 mu g/dL) at baseline, 111 nmol/L (8.6 mu g/dL) during the calcium period, and 120 nmol/L (9.3 mu g/dL) after calcium discontinuation (overall P=.03), Mean thyrotropin levels increased significantly, from 1.6 mIU/L at baseline to 2.7 mIU/L during the calcium period, and decreased to 1.4 mIU/L after calcium discontinuation (P=.008). Twenty percent of patients had serum thyrotropin levels higher than the normal range during the calcium period; the highest observed level was 7.8 mIU/L. Mean T-3 levels did not change du ring the calcium period. The in vitro study of T-4 binding to calcium showed that adsorption of T-4 to calcium carbonate occurs at acidic pH levels. Conclusions This study of 20 patients receiving long-term levothyroxine replacement therapy indicates that calcium carbonate reduces T-4 absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability. C1 Univ Calif Los Angeles, Sch Med, VA Greater Los Angeles Healthcare Syst, Div Endocrinol & Metab, Los Angeles, CA 90073 USA. Loma Linda Med Ctr, Div Epidemiol, Loma Linda, CA USA. RP Singh, N (reprint author), Univ Calif Los Angeles, Sch Med, VA Greater Los Angeles Healthcare Syst, Div Endocrinol & Metab, 11301 Wilshire Blvd, Los Angeles, CA 90073 USA. RI Singh, Pramil/C-5285-2012 NR 17 TC 73 Z9 76 U1 0 U2 2 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 7 PY 2000 VL 283 IS 21 BP 2822 EP 2825 DI 10.1001/jama.283.21.2822 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 320BQ UT WOS:000087381500037 PM 10838651 ER PT J AU Katz, IR Coyne, JC AF Katz, IR Coyne, JC TI The public health model for mental health care for the elderly SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID DEPRESSION; INSTITUTIONALIZATION; DISEASE C1 Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Penn, Dept Family Practice, Philadelphia, PA 19104 USA. Philadelphia Vet Affairs Med Ctr, Vet Integrated Serv Network Mental Illness Res Ed, Philadelphia, PA USA. RP Katz, IR (reprint author), Univ Penn, Dept Psychiat, 3600 Market St,Room 758, Philadelphia, PA 19104 USA. FU NIMH NIH HHS [MH P30MH52129] NR 15 TC 8 Z9 8 U1 0 U2 0 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 7 PY 2000 VL 283 IS 21 BP 2844 EP 2845 DI 10.1001/jama.283.21.2844 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 320BQ UT WOS:000087381500042 PM 10838656 ER PT J AU Mutter, GL Lin, MC Fitzgerald, JT Kum, JB Baak, JPA Lees, JA Weng, LP Eng, C AF Mutter, GL Lin, MC Fitzgerald, JT Kum, JB Baak, JPA Lees, JA Weng, LP Eng, C TI Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ATYPICAL HYPERPLASIA; ALLELIC LOSS; MICROSATELLITE INSTABILITY; CHROMOSOME INACTIVATION; COWDEN-SYNDROME; CANCER; CARCINOMA; MUTATIONS; NEOPLASIA; REPRODUCIBILITY AB Background: PTEN tumor suppressor gene mutations are the most frequent genetic lesions in endometrial adenocarcinomas of the endometrioid subtype. Testing the hypothesis that altered PTEN function precedes the appearance of endometrial adenocarcinoma has been difficult, however, partly because of uncertainties in precancer diagnosis. Methods: Two series of endometrial cancer and precancer (endometrial intraepithelial neoplasia, as diagnosed by computerized morphometric analysis) tissue samples were studied, one for PTEN mutations by the use of denaturing gradient gel electrophoresis and another for PTEN protein expression by immunohistochemistry. Endometria altered by high estrogen levels that are unopposed by progestins-conditions known to increase cancer risk-were also studied by immunohistochemistry, Fisher's exact test was used for statistical analysis. Results: The PTEN mutation rate was 83% (25 of 30) in endometrioid endometrial adenocarcinomas and 55% (16 of 29) in precancers, and the difference in number of mutations was statistically significant (two-sided P = .025), No normal endometria showed PTEN mutations, Although most precancers and cancers had a mutation in only one PTEN allele, endometrioid endometrial adenocarcinomas showed complete loss of PTEN protein expression in 61% (20 of 33) of cases, and 97% (32 of 33) showed at least some diminution in expression. Cancers and most precancers exhibited contiguous groups of PTEN-negative glands, while endometria altered by unopposed estrogens showed isolated PTEN-negative glands. Conclusions: Loss of PTEN function by mutational or other mechanisms is an early event in endometrial tumorigenesis that may occur in response to known endocrine risk factors and offers an informative immunohistochemical biomarker for premalignant disease, Individual PTEN-negative glands in estrogen-exposed endometria are the earliest recognizable stage of endometrial carcinogenesis, Proliferation into dense clusters that form discrete premalignant lesions follows. C1 Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Natl Taiwan Univ Hosp, Dept Pathol, Taipei 100, Taiwan. Ohio State Univ, Ctr Comprehens Canc, Clin Canc Genet Program, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Human Canc Genet Program, Columbus, OH 43210 USA. Dana Farber Canc Inst, Charles A Dana Human Canc Genet Unit, Boston, MA 02115 USA. Medisch Centrum Alkmaar, Dept Pathol, Alkmaar, Netherlands. Free Univ Amsterdam Hosp, Amsterdam, Netherlands. MIT, Cambridge, MA 02139 USA. Univ Cambridge, Canc Res Campaign Human Canc Genet Res Grp, Cambridge CB2 1TN, England. RP Mutter, GL (reprint author), Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA. RI Mutter, George/C-5819-2009; OI Eng, Charis/0000-0002-3693-5145 NR 37 TC 474 Z9 523 U1 2 U2 14 PU NATL CANCER INSTITUTE PI BETHESDA PA 9030 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUN 7 PY 2000 VL 92 IS 11 BP 924 EP 931 DI 10.1093/jnci/92.11.924 PG 8 WC Oncology SC Oncology GA 321TV UT WOS:000087471500014 PM 10841828 ER PT J AU Seibold, JR Korn, JH Simms, R Clements, PJ Moreland, LW Mayes, MD Furst, DE Rothfield, N Steen, V Weisman, M Collier, D Wigley, FM Merkel, PA Csuka, ME Hsu, V Rocco, S Erikson, M Hannigan, J Harkonen, WS Sanders, ME AF Seibold, JR Korn, JH Simms, R Clements, PJ Moreland, LW Mayes, MD Furst, DE Rothfield, N Steen, V Weisman, M Collier, D Wigley, FM Merkel, PA Csuka, ME Hsu, V Rocco, S Erikson, M Hannigan, J Harkonen, WS Sanders, ME TI Recombinant human relaxin in the treatment of scleroderma - A randomized, double-blind, placebo-controlled trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article DE relaxin; recombinant proteins; scleroderma, systemic; skin diseases; fibrosis ID SKIN THICKNESS SCORE; SYSTEMIC-SCLEROSIS; IN-VITRO; INVOLVEMENT; VARIABILITY; FIBROBLASTS; COLLAGEN; FIBROSIS; DISEASE; VIVO AB Background: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs. Objective: To assess the efficacy, safety, and dose-response effect of recombinant human relaxin in patients with scleroderma. Design: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial. Setting: Academic referral centers. Patients: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years. Intervention: Recombinant human relaxin. 25 or 100 mu g/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks. Measurements: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis. Results: Patients who received 25 mu g/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, -3.6 at 4 weeks [P = 0.021], -7.5 at 12 weeks [P < 0.001], and -8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 mu g/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection). Conclusions: Twenty-four weeks of recombinant human relaxin. 25 mu g/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Scleroderma Program, New Brunswick, NJ 08903 USA. Boston Univ, Med Ctr, Boston, MA 02118 USA. Univ Calif Los Angeles, Sch Med, Div Rheumatol, Los Angeles, CA 90095 USA. Univ Alabama, Div Clin Immunol & Rheumatol, Birmingham, AL 35294 USA. Wayne State Univ, Detroit, MI 48201 USA. Virginia Mason Res Ctr, Seattle, WA 98101 USA. Univ Connecticut, Ctr Hlth, Farmington, CT 06030 USA. Georgetown Univ, Med Ctr, Div Rheumatol Allergy & Immunol, Washington, DC 20007 USA. Johns Hopkins Bayview Med Ctr, Baltimore, MD 21224 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80262 USA. Med Coll Wisconsin, Div Rheumatol, Milwaukee, WI 53226 USA. Connet Corp, Palo Alto, CA 94303 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ Calif San Diego, San Diego, CA 92103 USA. RP Seibold, JR (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Scleroderma Program, 1 Robert Wood Johnson Pl, New Brunswick, NJ 08903 USA. NR 31 TC 157 Z9 164 U1 0 U2 9 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD JUN 6 PY 2000 VL 132 IS 11 BP 871 EP + PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 319HF UT WOS:000087334900003 PM 10836913 ER PT J AU Carr, PL Ash, AS Friedman, RH Szalacha, L Barnett, RC Palepu, A Moskowitz, MM AF Carr, PL Ash, AS Friedman, RH Szalacha, L Barnett, RC Palepu, A Moskowitz, MM TI Faculty perceptions of gender discrimination and sexual harassment in academic medicine SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID WOMEN; SURGERY AB Background: Gender-based discrimination and sexual harassment are common in medical practice and may be even more prevalent in academic medicine. Objective: To examine the prevalence of gender-based discrimination and sexual harassment among medical school faculty and the associations of gender-based discrimination with number of publications, career satisfaction, and perceptions of career advancement. Design: A self-administered mailed questionnaire of U.S. medical school faculty that covered a broad range of topics relating to academic life. Setting: 24 randomly selected medical schools in the contiguous United States. Participants: A random sample of 3332 full-time faculty, stratified by specialty, graduation cohort, and sex. Measurements: Prevalence of self-reported experiences of discrimination and harassment, number of peer-reviewed publications, career satisfaction, and perception of career advancement. Results: Female faculty were more than 2.5 times more likely than male faculty to perceive gender-based discrimination in the academic environment (P < 0.001). Among women, rates of reported discrimination ranged from 47% for the youngest faculty to 70% for the oldest faculty. Women who reported experiencing negative gender bias had similar productivity but lower career satisfaction scores than did other women (P ( 0.001). About half of female faculty but few male faculty experienced some form of sexual harassment. These experiences were similarly prevalent across the institutions in the sample and in all regions of the United States. Female faculty who reported being sexually harassed perceived gender-specific bias in the academic environment more often than did other women (80% compared with 61%) and more often reported experiencing gender bias in professional advancement (72% compared with 47%). Publications, career satisfaction, and professional confidence were not affected by sexual harassment, and self-assessed career advancement was only marginally lower for female faculty who had experienced sexual harassment (P = 0.06). Conclusion: Despite substantial increases in the number of female faculty, reports of gender-based discrimination and sexual harassment remain common. C1 Harvard Univ, Boston, MA 02115 USA. Radcliffe Coll, Murray Res Ctr, Cambridge, MA 02138 USA. Boston Univ, Sch Med, Boston Med Ctr, Boston, MA 02118 USA. Massachusetts Gen Hosp, Womens Hlth Associates, Boston, MA 02114 USA. RP Carr, PL (reprint author), Massachusetts Gen Hosp, Womens Hlth Associates, Blake 10,32 Fruit St, Boston, MA 02114 USA. OI Palepu, Anita/0000-0002-7881-4800 NR 34 TC 94 Z9 96 U1 0 U2 5 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 6 PY 2000 VL 132 IS 11 BP 889 EP 896 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 319HF UT WOS:000087334900006 PM 10836916 ER PT J AU Hallen, S Fryklund, J Sachs, G AF Hallen, S Fryklund, J Sachs, G TI Inhibition of the human sodium/bile acid cotransporters by side-specific methanethiosulfonate sulfhydryl reagents: Substrate-controlled accessibility of site of inactivation SO BIOCHEMISTRY LA English DT Article ID CHANNEL-LINING RESIDUES; MEMBRANE-SPANNING SEGMENT; FUNCTIONAL EXPRESSION; TRANSPORT ACTIVITY; ILEAL; CLONING; NA+; IDENTIFICATION; RABBIT; VESICLES AB Mammalian sodium/bile acid cotransporters (SBATs) constitute a subgroup of the sodium cotransporter superfamily and function in the enterohepatic circulation of bile acids. They are glycoproteins with an exoplasmic N-terminus, seven or nine transmembrane segments, and a cytoplasmic C-terminus. They exhibit no significant homology with other members of the sodium cotransporter family and there is limited structure/function information available for the SBATs. Membrane-impermeant methanethiosulfonates (MTS) inhibited bile acid transport by alkylation of cysteine 270 (apical SBAT)/266 (basolateral SEAT) that is fully conserved among the sodium/bile acid cotransporters. The accessibility of this residue to MTS reagent is regulated by the natural substrates, sodium and bile acid. In experiments with the apical SEAT, sodium alone increases the reactivity with the thiol reagents as compared to sodium-free medium. In contrast, bile acids protect the SBATs from inactivation, although only in the presence of sodium, The inhibition and protection data suggest that cysteine 270/266 lies in a sodium-sensitive region of the SBATs that is implicated in bile acid transport. C1 Univ Calif Los Angeles, Los Angeles, CA 90073 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA 90073 USA. AstraZeneca R&D, Cell Biol & Biochem, S-43183 Molndal, Sweden. 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 [DK46917, DK53462] NR 26 TC 31 Z9 33 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 6 PY 2000 VL 39 IS 22 BP 6743 EP 6750 DI 10.1021/bi000577t PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 323TF UT WOS:000087580500019 PM 10828993 ER PT J AU Campanero, MR Armstrong, MI Flemington, EK AF Campanero, MR Armstrong, MI Flemington, EK TI CPG methylation as a mechanism for the regulation of E2F activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TUMOR-SUPPRESSOR GENE; DNA METHYLATION; HISTONE DEACETYLASE; BINDING-SITE; RETINOBLASTOMA PROTEIN; HUMAN CANCERS; MOUSE EMBRYO; PROMOTER; EXPRESSION; CELLS AB Regulation of gene expression in mammals through methylation of cytosine residues at CpG dinucleotides is involved in the development and progression of tumors. Because many genes that are involved in the control of cell proliferation are regulated by members of the E2F family of transcription factors and because some E2F DNA-binding sites are methylated in vivo, we have investigated whether CpG methylation can regulate E2F functions. We show here that methylation of E2F elements derived from the dihydrofolate reductase, E2F1, and cdc2 promoters prevents the binding of all E2F family members tested (E2F1 through E2F5). In contrast, methylation of the E2F elements derived from the c-myc and c-myb promoters minimally affects the binding of E2F2, E2F3, E2F4, and E2F5 but significantly inhibits the binding of E2F1. Consistent with these studies, E2F3. but not EZF1. activates transcription through methylated E2F sites derived from the c-myb and c-myc: genes whereas both E2F1 and E2F3 fail to transactivate a reporter gene that is under the control of a methylated dihydrofolate reductase E2F site. Together, these data illustrate a means through which E2F activity can be controlled. C1 Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Flemington, EK (reprint author), Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. RI Campanero, Miguel/A-4052-2013 OI Campanero, Miguel/0000-0003-1410-8621 FU NIGMS NIH HHS [R01 GM48045, R01 GM048045] NR 46 TC 130 Z9 137 U1 0 U2 6 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 6 PY 2000 VL 97 IS 12 BP 6481 EP 6486 DI 10.1073/pnas.100340697 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300046 PM 10823896 ER PT J AU Leung, JY McKenzie, FE Uglialoro, AM Flores-Villanueva, PO Sorkin, BC Yunis, EJ Hartl, DL Goldfeld, AE AF Leung, JY McKenzie, FE Uglialoro, AM Flores-Villanueva, PO Sorkin, BC Yunis, EJ Hartl, DL Goldfeld, AE TI Identification of phylogenetic footprints in primate tumor necrosis factor-alpha promoters SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN MONOCYTIC CELLS; NF-KAPPA-B; TNF-ALPHA; GENE-REGULATION; TRANSCRIPTIONAL ACTIVATION; 5'-FLANKING REGION; T-CELLS; POLYMORPHISM; LIPOPOLYSACCHARIDE; SEQUENCES AB The human tumor necrosis factor-alpha (TNF-alpha) gene encodes a pleiotropic cytokine that plays a critical role in basic immunologic processes. To investigate the TNF-alpha regulatory region in the primate lineage, we isolated TNF-alpha promoters from representative great apes, old World monkeys, and New World monkeys. We demonstrate that there is a nonuniform distribution of fixed human differences in the TNF-alpha promoter. We define a "fixed human difference" as a site that is not polymorphic in humans, but which differs in at least one of the seven primate sequences examined. Furthermore, we identify two human TNF-alpha promoter single nucleotide polymorphisms that are putative ancestral polymorphisms, because each of the human polymorphic nucleotides was found at the identical site in at least one of the other primate sequences. Strikingly, the largest conserved region among the primate species, a 69-nt "phylogenetic footprint." corresponds to a region of the human TNF-alpha promoter that forms the transcriptionally active nucleoprotein-DNA complex, essential for gene regulation. By contrast, other regions of the TNF-alpha promoter, which exhibit a high density of variable sites, are nonessential for gene expression, indicating that distinct TNF-alpha promoter regions have been subjected to different evolutionary constraints depending on their function. TNF-alpha is the first case in which a promoter region dissected by functional analyses can be correlated with nucleotide polymorphism and variability in primate lineages. The results suggest that patterns of polymorphism and divergence are likely to be useful in identifying candidate regions important for gene regulation in other immune-response genes. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. Dana Farber Canc Inst, Div AIDS & Immunol, Boston, MA 02115 USA. Forsyth Inst, Boston, MA 02115 USA. RP Goldfeld, AE (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. OI Sorkin, Barbara/0000-0001-8198-6921 FU Intramural NIH HHS [Z99 TW999999]; NHGRI NIH HHS [HG-02150]; NHLBI NIH HHS [HL-59838, R01 HL059838]; NIGMS NIH HHS [GM56492, R01 GM056492] NR 36 TC 34 Z9 34 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 6 PY 2000 VL 97 IS 12 BP 6614 EP 6618 DI 10.1073/pnas.97.12.6614 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300069 PM 10841560 ER PT J AU Ferguson, DO Sekiguchi, JM Chang, S Frank, KM Gao, YJ DePinho, RA Alt, FW AF Ferguson, DO Sekiguchi, JM Chang, S Frank, KM Gao, YJ DePinho, RA Alt, FW TI The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID STRAND-BREAK REPAIR; SEVERE COMBINED IMMUNODEFICIENCY; V(D)J RECOMBINATION; LIGASE-IV; TARGETED DISRUPTION; VERTEBRATE CELLS; MAMMALIAN-CELLS; MICE; GENE; IDENTIFICATION AB We have used spectral karyotyping to assess potential roles of three different components of the nonhomologous DNA end-joining pathway in the maintenance of genomic stability in mouse embryonic fibroblasts (MEFs), MEFs homozygous for mutations that inactivate either DNA ligase IV (Lig4) or Ku70 display dramatic genomic instability, even in the absence of exogenous DNA damaging agents. These aberrant events range from chromosomal fragmentation to nonreciprocal translocations that can involve several chromosomes. DNA-dependent protein kinase catalytic subunit deficiency also promotes genome instability. Deficiency for the p53 cell cycle checkpoint protein has little effect on spontaneous levels of chromosomal instability in Lig4-deficient fibroblasts. However, in the context of ionizing radiation treatment, p53 deficiency allowed visualization of massive acute chromosomal destruction in Lig4-deficient MEFs, which in surviving cells manifested as frequent nonreciprocal translocations, We conclude that nonhomologous DNA end-joining plays a crucial role as a caretaker of the mammalian genome, and that an alternative repair pathway exists that often leads to nonreciprocal translocations. C1 Childrens Hosp, Howard Hughes Med Inst, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Alt, FW (reprint author), Childrens Hosp, Howard Hughes Med Inst, Ctr Blood Res, Boston, MA 02115 USA. OI Sekiguchi, JoAnn/0000-0002-7178-4258 FU NIAID NIH HHS [AI01428, AI35714]; NICHD NIH HHS [R01HD34880] NR 34 TC 264 Z9 276 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 6 PY 2000 VL 97 IS 12 BP 6630 EP 6633 DI 10.1073/pnas.110152897 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300072 PM 10823907 ER PT J AU Morel, L Croker, BP Blenman, KR Mohan, C Huang, GL Gilkeson, G Wakeland, EK AF Morel, L Croker, BP Blenman, KR Mohan, C Huang, GL Gilkeson, G Wakeland, EK TI Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ANTIGEN-PRESENTING CELLS; CONGENIC MOUSE STRAINS; SLE PATHOGENESIS; AUTOANTIBODY PRODUCTION; B-CELLS; DISSECTION; SUSCEPTIBILITY; CD86; MICE; EXPRESSION AB We previously produced three congenic strains carrying lupus susceptibility genes (Sle1-Sle3) from the lupus-prone NZM2410 mouse on the C57BL/6 background and characterized their component phenotypes, Sle1 mediates the loss of tolerance to nuclear antigens; Sle2 lowers the activation threshold of B cells; and Sle3 mediates a dysregulation of CD4(+) T cells. We have now created a collection of bi- and tricongenic strains with these intervals and assessed the autoimmune phenotypes they elicit in various combinations. Our results indicate that Sle1 is key for the development of fatal lupus, The combination of Sle1 with Sle2, Sle3, or the BXSB-derived autoimmune accelerating gene yaa results in the development of systemic autoimmunity with variably penetrant severe glomerulonephritis culminating in kidney failure. In contrast, two locus combinations of Sle2, Sle3, and yaa failed to mediate fatal disease. These results indicate that the loss of tolerance to chromatin mediated by Sle1 is essential for disease pathogenesis and identify the pathway occupied by Sle1 as a strategic target for therapeutic intervention in systemic lupus erythematosus. The coexpression of Sle1, Sle2, and Sle3 as a B6-triple congenic results in severe systemic autoimmunity and fully penetrant, fatal glomerulonephritis. These results demonstrate the fulfillment of the genetic equivalent of Koch's postulate, where susceptibility loci in a lupus-prone strain have been identified by a genome scan, isolated and functionally characterized by congenic dissection, and finally shown to mediate full disease expression when recombined in a normal genome. C1 Univ Texas, SW Med Ctr, Ctr Immunol, Dallas, TX 75235 USA. Univ Florida, Dept Pathol, Gainesville, FL 32610 USA. N Florida S George Vet Hlth Syst, Gainesville, FL 32608 USA. Ralph H Johnson Vet Affaris Med Coll, Med Res Serv, Charleston, SC 29425 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ Florida, Dept Med, Gainesville, FL 32610 USA. RP Wakeland, EK (reprint author), Univ Texas, SW Med Ctr, Ctr Immunol, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. FU NIAID NIH HHS [P01 AI39824, P01 AI039824]; NIAMS NIH HHS [R01 AR42563] NR 36 TC 246 Z9 249 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUN 6 PY 2000 VL 97 IS 12 BP 6670 EP 6675 DI 10.1073/pnas.97.12.6670 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 322UA UT WOS:000087526300079 PM 10841565 ER PT J AU Callus, BA Mathey-Prevot, B AF Callus, BA Mathey-Prevot, B TI Hydrophobic residues Phe(751) and Leu(753) are essential for STAT5 transcriptional activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TERMINAL TRANSACTIVATION DOMAIN; DNA-BINDING; IFN-GAMMA; TYROSINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; ACTIVATION DOMAIN; ERYTHROPOIETIN RECEPTOR; CYTOKINE RECEPTORS; CRYSTAL-STRUCTURE; INTERFERON-GAMMA AB One facet of cytokine signaling is relayed to the nucleus by the activation, through tyrosine phosphorylation, of latent cytoplasmic signal transducers and activators of transcription (STAT) family members. It has been demonstrated that the C termini of STATs contain the transactivation domain and are essential for the transactivation of target genes. To better understand the function of the STAT C terminus, we have generated a series of C-terminal mutants in STAT5a and examined their effects on transactivation, tyrosine phosphorylation, and DNA binding. Using GAZA chimerae with the C terminus of STATE, we have defined a 12-amino acid region essential for STATE transactivation, Surprisingly, deletion of these 12 amino acids in the context of the native STATE backbone presented the overall transcriptional activity of the protein. Further analysis revealed that deletion of this region resulted in hyper-DNA binding activity, thus compensating for the weakened transactivation domain. Using site-directed mutagenesis, we show that within this 12-amino acid region the acidic residues were non-essential for transactivation. In contrast, the non-acidic residues were crucial for transactivation. Mutating either Phe(751) or Leu(763) to alanine abolished transactivation suggesting that these residues were essential for connecting STAT5 to the basal transcriptional machinery. C1 Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. RP Callus, BA (reprint author), Dana Farber Canc Inst, Dept Pediat Oncol, 44 Binney St, Boston, MA 02115 USA. FU NHLBI NIH HHS [R01 HL62434-01] NR 61 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUN 2 PY 2000 VL 275 IS 22 BP 16954 EP 16962 DI 10.1074/jbc.M909976199 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 320FY UT WOS:000087392200079 PM 10748177 ER PT J AU Wei, HG Camargo, CA AF Wei, HG Camargo, CA TI Patient education in the emergency department SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE emergency medicine; patient education; health education; disease management ID DISCHARGE INSTRUCTIONS; MYOCARDIAL-INFARCTION; HEALTH-EDUCATION; CARDIAC REHABILITATION; HOSPITAL DISCHARGE; DISEASE MANAGEMENT; HEART-FAILURE; FOLLOW-UP; INTERVENTION; PROGRAM AB The emergency department (ED) visit provides an opportunity for patient education. Many ED patients have poor access to regular health care, including patient education. Accreditation standards, legal considerations, and cost-efficiency concerns encourage the clinician to implement formal patient education in the ED. More importantly, published clinical studies evaluating patient education in both the ED and comparable settings support the hypothesis that ED-based patient education improves outcomes. The article discusses considerations for instructional material, highlights challenges to ED-based patient education, and suggests possibilities for future research. C1 Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Cornell Univ, Weill Med Coll, New York, NY USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. RP Camargo, CA (reprint author), Massachusetts Gen Hosp, Dept Emergency Med, Clin 397, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL-03533] NR 71 TC 29 Z9 29 U1 1 U2 2 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD JUN PY 2000 VL 7 IS 6 BP 710 EP 717 DI 10.1111/j.1553-2712.2000.tb02052.x PG 8 WC Emergency Medicine SC Emergency Medicine GA 324DF UT WOS:000087606000015 PM 10905653 ER PT J AU Gimelli, G Kalra, A Sabatine, MS Jang, IK AF Gimelli, G Kalra, A Sabatine, MS Jang, IK TI Primary versus rescue percutaneous corollary intervention in patients with acute myocardial infarction SO ACTA CARDIOLOGICA LA English DT Article DE acute myocardial infarction; percutaneous coronary intervention; primary angioplasty; rescue angioplasty; intracoronary stenting; thrombolysis ID TISSUE-PLASMINOGEN-ACTIVATOR; CORONARY-ARTERY DISEASE; IMMEDIATE ANGIOPLASTY; THROMBOLYTIC THERAPY; BALLOON ANGIOPLASTY; RECEPTOR BLOCKADE; TRIAL; ABCIXIMAB; OUTCOMES AB Objective - To compare angiographic and clinical outcomes of patients with acute myocardial infarction (AMI) who underwent primary percutaneous coronary intervention (PCI) versus rescue PCI following failed thrombolysis. Background - Patients presenting with AMI are treated either with primary PCI or with thrombolysis, When thrombolysis fails, rescue PCI is performed. Methods and Results - We compared the outcome of 105 consecutive patients with AMI who underwent either primary PCI (60 patients) or rescue PCI (45 patients) between January 1997 and January 1999, The patients were followed for up to 6 months. Time delay to reperfusion was significantly longer in the rescue PCI group (354 vs. 189 min; p < 0.001), The majority of patients received a stent (93%). Glycoprotein (GP) IIb/IIIa inhibitors were used in 53% of patients in the primary PCI group and in 22% in the rescue group. TIMI grade 3 flow was achieved in 93.3% of patients in the primary PCI group and in 88.8% in the rescue group (p = 0.08), Post-procedure ejection fraction was 53% in the primary PCI group and 47% in the rescue group (p = 0.014), A composite endpoint of death, recurrent MI, repeat PCI, coronary artery bypass grafting (CABG) and recurrent angina at 6 months occurred in 35% of the patients in the primary PCI group and 26.7% in the rescue group (p = 0.36), Conclusion - Despite a significant delay to reperfusion and a lower immediate post-procedure ejection fraction, the clinical outcome of patients treated with rescue PCI following failed thrombolysis appears to be similar to that of patients treated with primary PCI at 6 months. C1 Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. RP Jang, IK (reprint author), Massachusetts Gen Hosp, Div Cardiol, Bulfinch 105,55 Fruit St, Boston, MA 02114 USA. NR 25 TC 3 Z9 3 U1 0 U2 0 PU ACTA CARDIOLOGICA PI BRUSSELS PA AVENUE CIRCULAIRE 138A, 1180 BRUSSELS, BELGIUM SN 0001-5385 J9 ACTA CARDIOL JI Acta Cardiol. PD JUN PY 2000 VL 55 IS 3 BP 187 EP 192 DI 10.2143/AC.55.3.2005738 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 329YY UT WOS:000087937100007 PM 10902044 ER PT J AU Saphner, T Weller, EA Tormey, DC Pandya, KJ Falkson, CI Stewart, J Robert, NJ AF Saphner, T Weller, EA Tormey, DC Pandya, KJ Falkson, CI Stewart, J Robert, NJ TI 21-day oral etoposide for metastatic breast cancer - A phase II study and review of the literature SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE breast cancer; etoposide; VP-16 ID CLINICAL-TRIAL; ONCOLOGY-GROUP; DNA BREAKAGE; VP 16-213; TENIPOSIDE; VP-16-213; CHEMOTHERAPY; CARCINOMA; STRAND; CELLS AB Previous studies of etoposide for metastatic breast cancer commonly used bolus regimens given over a short period of time and included heavily pretreated patients. Results were poor. Chronic oral regimens would be expected to be superior to bolus doses based on pharmacologic studies and patients with less previous chemotherapy would be expected to have higher response rates. We studied the efficacy of oral etoposide at a dose of 50 mg/m(2)/day for 21 days of a 28-day cycle in good-risk patients with metastatic breast cancer. Healthy patients (Eastern Cooperative Oncology Group performance status 0, 1, or 2) who had not received chemotherapy for at least 1 year before study entry were selected for therapy. Thirty-four patients were entered: three patients were ineligible and one was cancelled. Thirty patients were available for analysis of response. One complete response and eight partial responses were documented (response rate, 30%: 95% confidence interval, 15-49%). A higher response rate was observed in those patients who never received chemotherapy compared with those who had received prior chemotherapy (57 vs. 6%, p = 0.004). There were two treatment-related deaths, both owing to myelosuppression and infection. We found long-term administration of oral etoposide to have a reasonable response rate for metastatic breast cancer (30%). Our response rate was comparable to those of other published studies of long-term oral etoposide regimens for metastatic breast cancer. Response rates in single-arm studies have generally been higher for long-term oral regimens than those for bolus regimens. We also found the regimen to be significantly toxic, an observation that may be underemphasized in the earlier literature. C1 Green Bay Oncol, Green Bay, WI 54307 USA. Fairfax Prince William Hematol Oncol, Annandale, VA USA. Univ Wisconsin, Ctr Comprehens Canc, Madison, WI USA. Univ Pretoria, ZA-0002 Pretoria, South Africa. Univ Rochester, Rochester, NY USA. AMC Canc Res Ctr, Denver, CO USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Saphner, T (reprint author), Green Bay Oncol, POB 13453, Green Bay, WI 54307 USA. FU NCI NIH HHS [CA21692, CA23318, CA21076] NR 33 TC 11 Z9 11 U1 0 U2 1 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 2000 VL 23 IS 3 BP 258 EP 262 DI 10.1097/00000421-200006000-00010 PG 5 WC Oncology SC Oncology GA 320EW UT WOS:000087389700010 PM 10857889 ER PT J AU Kucuk, O Young, ML Habermann, TM Wolf, BC Jimeno, J Cassileth, PA AF Kucuk, O Young, ML Habermann, TM Wolf, BC Jimeno, J Cassileth, PA TI Phase II trial of didemnin B in previously treated non-Hodgkin's lymphoma - An Eastern Cooperative Oncology Group (ECOG) study SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE didemnin B; non-Hodgkin's lymphoma; chemotherapy ID CLINICAL-TRIALS; CARIBBEAN TUNICATE; CANCER; DEPSIPEPTIDES; INVITRO; AGENTS AB Patients with non-Hodgkin's lymphoma (NHL) who fail initial therapy have a poor prognosis. We conducted a phase II study to determine the efficacy and toxicity of didemnin B, a non-myelosuppressive marine compound, in patients with NHL who relapsed or progressed after receiving one or two previous chemotherapy regimens. Fifty-one eligible patients were registered on this phase II study. Twenty-nine patients had intermediate or high grade (IG/HG) disease and 22 patients had low grade (LG) disease. Twenty-five patients received didemnin B at a dose of 6.3 mg/m(2) and the remainder received 5.6 mg/m(2), administered intravenously every 28 days. The patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and biopsy-proven relapsed disease. Objective responses were observed in two (7%) patients (one complete remission [CR] and one partial remission [PR]) with IG/HG disease and five (23%) patients (one CR and four PR) with LG disease. Patients with IG/HG disease had a median time to treatment failure (TTF) of 1.6 months and a median survival of 8.0 months. In contrast, the group with LG disease had a median TTF of 4.6 months and a median survival of 2.7 years. There were five grade V, 12 grade IV, and 57 grade III toxicities. Didemnin B appears to have modest activity in low grade NHL. However, the drug has considerable toxicity in this population of patients. C1 Univ Miami, Miami, FL 33152 USA. PharmaMar SA, Madrid, Spain. Albany Med Coll, Albany, NY 12208 USA. Mayo Clin, Rochester, MN USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48201 USA. RP Kucuk, O (reprint author), Wayne State Univ, Karmanos Canc Inst, 3990 John R St,5 Hudson, Detroit, MI 48201 USA. FU NCI NIH HHS [CA06594, CA13650, CA23318] NR 23 TC 27 Z9 29 U1 0 U2 1 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 2000 VL 23 IS 3 BP 273 EP 277 DI 10.1097/00000421-200006000-00013 PG 5 WC Oncology SC Oncology GA 320EW UT WOS:000087389700013 PM 10857892 ER PT J AU Natarajan, S Nietert, PJ Silverstein, MD AF Natarajan, S Nietert, PJ Silverstein, MD TI Variation by socioeconomic status in screening and prevalence of high cholesterol and hypertension. SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Meeting Abstract C1 Med Univ S Carolina, Ctr Hlth Care Res, Charleston, SC 29425 USA. Med Univ S Carolina, Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29425 USA. NR 0 TC 0 Z9 0 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 JUN 1 PY 2000 VL 151 IS 11 SU S MA 136 BP S34 EP S34 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 321MZ UT WOS:000087460400137 ER PT J AU Rivolta, C Sweklo, EA Berson, EL Dryja, TP AF Rivolta, C Sweklo, EA Berson, EL Dryja, TP TI Missense mutation in the USH2A gene: Association with recessive retinitis pigmentosa without hearing loss SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MYOSIN-VIIA GENE; SYNDROME TYPE-IIA; USHER-SYNDROME; DEAFNESS; PREVALENCE; PROTEIN; 1B AB Microdeletions Glu767(1-bp del), Thr967(1-bp del), and Leu1446(2-bp del) in the human USH2A gene have been reported to cause Usher syndrome type II, a disorder characterized by retinitis pigmentosa (RP) and mild-to-severe hearing loss. Each of these three frameshift mutations is predicted to lead to an unstable mRNA transcript that, if translated, would result in a truncated protein lacking the carboxy terminus. Here, we report Cys759Phe, a novel missense mutation in this gene that changes an amino-acid residue within the fifth laminin-epidermal growth factor-like domain of the USH2A gene and that is associated with recessive RP without hearing loss. This single mutation was found in 4.5% of 224 patients with recessive RP, suggesting that USH2A could cause more cases of nonsyndromic recessive RP than does any other gene identified to date. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, Boston, MA 02114 USA. Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02114 USA. RP Dryja, TP (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Mol Genet Inst, 243 Charles St, Boston, MA 02114 USA. FU NEI NIH HHS [EY00169, EY08683] NR 12 TC 128 Z9 132 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 5720 SOUTH WOODLAWN AVE, CHICAGO, IL 60637-1603 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUN PY 2000 VL 66 IS 6 BP 1975 EP 1978 DI 10.1086/302926 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 337QU UT WOS:000088373800026 PM 10775529 ER PT J AU Luck, J Peabody, JW Dresselhaus, TR Lee, M Glassman, P AF Luck, J Peabody, JW Dresselhaus, TR Lee, M Glassman, P TI How well does chart abstraction measure quality? A prospective comparison of standardized patients with the medical record SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID SIMULATED PATIENTS; GENERAL-PRACTITIONERS; VETERANS-AFFAIRS; HEALTH-CARE; PERFORMANCE AB PURPOSE: Despite widespread reliance on chart abstraction for quality measurement, concerns persist about its reliability and validity. We prospectively evaluated the validity of chart abstraction by directly comparing it with the gold standard of reports by standardized patients. SUBJECTS AND METHODS: Twenty randomly selected general internal medicine residents and attending faculty physicians at the primary care clinics of two Veterans Affairs Medical Centers blindly evaluated and treated actor-patients (standardized patients) who had one of four common diseases: diabetes, chronic obstructive pulmonary disease, coronary artery disease, or low back pain. Charts from the visits were abstracted using explicit quality criteria; standardized patients completed a checklist containing the same criteria. For each physician, quality was measured for two different cases of the four conditions (a total of 160 physician-patient encounters). We compared chart abstraction with standardized;patient reports for four aspects of the encounter: taking the history, examining the patient, making the diagnosis, and prescribing appropriate treat-ment. The sensitivity and specificity of chart abstraction were calculated. RESULTS: The mean (+/- SD) chart abstraction score was 54% +/- 9%, substantially less than the mean score on the standardized-patient checklist of 68% +/- 9% (P <0.001). This finding was similar for all four conditions and at both sites. "False positives"- chart-recorded necessary care actions not reported by the standardized patients-resulted in a specificity of only 81%. The overall sensitivity of chart abstraction for necessary care was only 70%. CONCLUSIONS: Chart abstraction underestimates the quality of care for common outpatient general medical conditions when compared with standardized-patient reports. The medical record is neither sensitive nor specific. Quality measurements derived from chart abstraction may have important shortcomings, particularly as the basis for drawing policy conclusions or making management decisions. (C) 2000 by Excerpta Medica, Inc. C1 Inst Global Hlth, San Francisco Vet Affairs Med Ctr, San Francisco, CA 94105 USA. Vet Affairs Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Vet Affairs Ctr Study Hlth Care Provider Behav, Sepulveda, CA USA. Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. San Diego Vet Affairs Med Ctr, San Diego, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. RAND, Santa Monica, CA USA. Inst Global Hlth, San Francisco, CA USA. RP Peabody, JW (reprint author), Inst Global Hlth, San Francisco Vet Affairs Med Ctr, 74 New Montgmery St,Suite 508, San Francisco, CA 94105 USA. RI Comba, Valentina/G-6210-2014 NR 52 TC 184 Z9 186 U1 2 U2 5 PU EXCERPTA MEDICA INC PI NEW YORK PA 245 WEST 17TH STREET, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUN 1 PY 2000 VL 108 IS 8 BP 642 EP 649 DI 10.1016/S0002-9343(00)00363-6 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 321QV UT WOS:000087466900006 PM 10856412 ER PT J AU Gion, N Stavrou, P Foster, CS AF Gion, N Stavrou, P Foster, CS TI Immunomodulatory therapy for chronic tubulointerstitial nephritis-associated uveitis SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID ACUTE INTERSTITIAL NEPHRITIS; ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES; BONE-MARROW GRANULOMAS; SYNDROME TINU SYNDROME; ANTERIOR UVEITIS; ADULT AB PURPOSE: To describe the clinical course and treatment with immunomodulatory agents in patients with tubulointerstitial nephritis and uveitis syndrome. METHODS: Retrospective analysis of the charts of six patients with tubulointerstitial nephritis and uveitis syndrome. RESULTS: The mean (+/-SD) age was 24.3 (+/-16.5) years, range 13 to 49 years. Four patients were children, and two were adults. Three were men, and three were women. Five of the six patients had anterior uveitis, and one had panuveitis. All patients had several relapses despite treatment with topical, regional, and oral steroids and methotrexate in one case. The introduction or modification of immunosuppressants (methotrexate, azathioprine, or cyclosporin A) achieved control of the uveitis and prevented relapses over a mean (+/-SD) follow-up period of 19.66 (+/-10.01) months, range 6 to 34 months. No treatment related side effects were observed, CONCLUSIONS: Tubulointerstitial nephritis and uveitis syndrome is a distinct disease entity in which the nephritis typically resolves, but the uveitis often becomes chronic and is treatment resistant. Immunomodulatory agents can achieve control of the inflammation and prevent relapses. (C) 2000 by Elsevier Science Inc. All rights reserved. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Immunol & Uveitis Serv, Boston, MA 02114 USA. RP Foster, CS (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Ocular Immunol & Uveitis Serv, 243 Charles St, Boston, MA 02114 USA. NR 31 TC 32 Z9 36 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUN PY 2000 VL 129 IS 6 BP 764 EP 768 DI 10.1016/S0002-9394(00)00482-7 PG 5 WC Ophthalmology SC Ophthalmology GA 342AD UT WOS:000088622400010 PM 10926986 ER PT J AU Harris, EW D'Amico, DJ Bhisitkul, R Priebe, GP Petersen, R AF Harris, EW D'Amico, DJ Bhisitkul, R Priebe, GP Petersen, R TI Bacterial subretinal abscess: A case report and review of the literature SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Review ID PYOGENIC LIVER-ABSCESS; KLEBSIELLA-PNEUMONIAE ENDOPHTHALMITIS; METASTATIC SEPTIC ENDOPHTHALMITIS; ENDOGENOUS ENDOPHTHALMITIS; RETINAL-DETACHMENT; DIABETIC-PATIENTS; HEPATIC-ABSCESS; ENDOCARDITIS; ASSOCIATION AB PURPOSE: To report a case of Klebsiella subretinal abscess with a successful visual outcome with treatment and to review the literature pertaining to focal intraocu lar infection in bacterial endophthalmitis, METHODS: Clinical data including medical history, findings on physical examination, blood cultures, and an abdominal computed tomographic scan were collected in a 32-year-old man with Klebsiella sepsis, liver abscesses, and a focal subretinal abscess. Ocular data including visual acuity, fundus photographs, fluorescein angiography, and ultrasound were evaluated, as were results of culture and histopathologic studies. RESULTS: Despite immediate intervention, including vitreous tap and intravitreal antibiotics, the eye deterio rated, with enlargement of the abscess. A pars plana vitrectomy was performed in which the subretinal abscess material was removed after an extensive retinectomy of the involved area in association with an endophotocoagulative barrier and intravitreal amikacin without gas or oil tamponade, Culture confirmed Klebsiella subretinal infection. A retinal detachment occurred 1 month postoperatively and was successfully repaired. Visual acuity was 20/30 and has remained stable for 14 months. CONCLUSION: Klebsiella endophthalmitis with subretinal abscess formation is a rare but devastating ocular condition. In the present case, prompt intervention with extensive retinectomy, complete abscess excision, and intravitreal antibiotic therapy resulted in unprecedented visual recovery. (C) 2000 by Elsevier Science Inc. All rights reserved. C1 Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. Harvard Univ, Sch Med, Div Infect Dis, Boston, MA USA. Harvard Univ, Sch Med, Ophthalmol Dept Childrens Hosp, Boston, MA USA. RP D'Amico, DJ (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. NR 31 TC 26 Z9 31 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUN PY 2000 VL 129 IS 6 BP 778 EP 785 DI 10.1016/S0002-9394(00)00355-X PG 8 WC Ophthalmology SC Ophthalmology GA 342AD UT WOS:000088622400012 PM 10926988 ER PT J AU Egan, R Lessell, S AF Egan, R Lessell, S TI Posterior subcapsular cataract in Degos disease SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article AB PURPOSE: To report an association of posterior subcapsular cataract with Degos disease. METHOD: Case report of a 42-year old man. RESULTS: A posterior subcapsular cataract developed in the patient's left eye at age 43 years, 1 year before his death. The diagnosis of Degos disease was confirmed pathologically by skin biopsy and at necropsy. CONCLUSION: Posterior subcapsular cataract may be associated with Degos disease in addition to previously reported findings, including visual field defects, third cranial nerve palsies, blepharoptosis, and optic atrophy. (C) 2000 by Elsevier Science Inc. All rights reserved. C1 Massachusetts Eye & Ear Infirm, Dept Neuroophthalmol, Boston, MA 02114 USA. Casey Eye Inst, Neuroophthalmol Unit, Portland, OR USA. RP Lessell, S (reprint author), Massachusetts Eye & Ear Infirm, Dept Neuroophthalmol, 243 Charles St, Boston, MA 02114 USA. NR 5 TC 8 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD JUN PY 2000 VL 129 IS 6 BP 806 EP 807 DI 10.1016/S0002-9394(00)00460-8 PG 2 WC Ophthalmology SC Ophthalmology GA 342AD UT WOS:000088622400020 PM 10926996 ER PT J AU Peterson, RM Yu, Q Stamenkovic, I Toole, BP AF Peterson, RM Yu, Q Stamenkovic, I Toole, BP TI Perturbation of hyaluronan interactions by soluble CD44 inhibits growth of murine mammary carcinoma cells in ascites SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ANCHORAGE-INDEPENDENT GROWTH; TUMOR-ASSOCIATED HYALURONAN; CANCER CELLS; FACTOR-BETA; IN-VIVO; NUDE-MICE; TGF-BETA; EXPRESSION; FIBROBLASTS; BINDING AB Hyaluronan accumulates in ascites during intraperitoneal proliferation of TA3/St murine mammary carcinoma cells and at sites of their invasion of the peritoneal wall. To determine whether hyaluronan is functionally involved in these events, ascites tumor formation was compared in mice injected intraperitoneally with stable transfectants of TA3/St cells that overexpress soluble CD44, a hyaluronan-binding protein, versus in mice injected with transfectants expressing mutated soluble CD44 that does not bind hyaluronan, The soluble CD44 transfectants temporarily grew at a reduced rate within the peritoneal cavity, then went into G(1) arrest and were subsequently cleared from the peritoneum, However, transfectants overexpressing mutant soluble CD44 that does not bind hyaluronan exhibited similar ascites accumulation, growth rates, and cell-cycle profiles in vivo to wild-type and vector-transfected TA3/St cells, all of which continued to grow until the tumors became fatal. The soluble CD44-transfected TA3/St cells also failed to attach to and form tumors in the peritoneal wall. When grown in vitro in soft agar, the soluble CD44 transfectants exhibited a dramatic reduction in colony formation compared to wild-type, vector-transfected, and mutant soluble CD44-transfected TA3/St cells. Thus, perturbation of hyaluronan interactions by soluble CD44 has a direct effect on the growth characteristics of these tumor cells, leading to inhibition of anchorage-independent growth in vitro and ascites growth in vivo. C1 Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. Massachusetts Gen Hosp, Mol Pathol Unit, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. RP Toole, BP (reprint author), Tufts Univ, Sch Med, Dept Anat & Cellular Biol, 136 Harrison Ave, Boston, MA 02111 USA. FU NCI NIH HHS [CA55735, CA73839, R01 CA073839]; NIGMS NIH HHS [GM48614] NR 40 TC 79 Z9 85 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD JUN PY 2000 VL 156 IS 6 BP 2159 EP 2167 DI 10.1016/S0002-9440(10)65086-9 PG 9 WC Pathology SC Pathology GA 321ZH UT WOS:000087484900033 PM 10854236 ER PT J AU Rickels, K Pollack, MH Sheehan, DV Haskins, JT AF Rickels, K Pollack, MH Sheehan, DV Haskins, JT TI Efficacy of extended-release venlafaxine in nondepressed outpatients with generalized anxiety disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID NATIONAL-COMORBIDITY-SURVEY; DEPRESSION; IMIPRAMINE; SYMPTOMS AB Objective: This study evaluated the efficacy and safety of fixed doses of once daily extended-release (XR) venlafaxine in outpatients with generalized anxiety disorder without concomitant major depressive disorder. Method: Adult outpatients with generalized anxiety disorder but not major depressive disorder with total scores of 18 or higher on the Hamilton Rating Scale for Anxiety and scores of 2 or higher on its anxious mood and tension factors were eligible. Patients were randomly assigned to receive placebo or venlafaxine XR (75, 150, or 225 mg/day) for 8 weeks. Primary efficacy variables were final total and psychic anxiety factor scores on the Hamilton anxiety scale and final severity and global improvement item scores on the Clinical Global impression (CGI) scale. Results: Of the 377 patients entering the study, 370 were included in a safety analysis and 349 in an efficacy analysis. Adjusted mean scores at 8 weeks (last-observation-carried-forward analysis) were significantly lower for one or more of the venlafaxine XR groups in four of four primary and three of four secondary outcome measures than for the placebo group. These included a change of 1.7 (versus 1.3) from baseline on CGI severity item scores and a final score of 2.2 (versus 2.6) on the CGI global improvement item. All doses of venlafaxine XR were well tolerated. Conclusions: Venlafaxine XR is an effective and well-tolerated option for the short-term treatment of generalized anxiety disorder in outpatients without major depressive disorder. C1 Univ Penn, Ctr Sci, Psychopharmacol Unit, Philadelphia, PA 19104 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Univ S Florida, Inst Psychiat Res, Tampa, FL USA. Wyeth Ayerst Labs, Philadelphia, PA USA. RP Rickels, K (reprint author), Univ Penn, Ctr Sci, Psychopharmacol Unit, 3600 Market St,Suite 803, Philadelphia, PA 19104 USA. NR 27 TC 160 Z9 166 U1 2 U2 4 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2000 VL 157 IS 6 BP 968 EP 974 DI 10.1176/appi.ajp.157.6.968 PG 7 WC Psychiatry SC Psychiatry GA 320VJ UT WOS:000087421300018 PM 10831478 ER PT J AU Henderson, DC Cagliero, E Gray, C Nasrallah, RA Hayden, DL Schoenfeld, DA Goff, DC AF Henderson, DC Cagliero, E Gray, C Nasrallah, RA Hayden, DL Schoenfeld, DA Goff, DC TI Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: A five-year naturalistic study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID GLUCOSE-TOLERANCE; SCHIZOPHRENIC-PATIENTS; KETOACIDOSIS; MORTALITY; PREVALENCE; VALPROATE; EPILEPSY; WOMEN AB Objective: The goal of this 5-year naturalistic study of patients treated with clozapine was to examine the incidence of treatment-emergent diabetes mellitus in relation to other factors, including weight gain, lipid abnormalities, age, clozapine dose, and treatment with valproate. Method: Data on age, gender, race, diagnosis, family history of diabetes, and age at clozapine initiation were collected from medical records of 82 outpatients with schizophrenia or schizoaffective disorder. Clozapine dose, data on use of valproate, and laboratory rest results were recorded at 6-month intervals. Results: The mean age at the time of clozapine initiation of the 82 patients was 36.4 years; 26.8% of the patients were women, and 91.5% were Caucasian. The mean baseline weight was 175.5 Ib, and the mean body mass index was 26.9 kg/m(2). Thirty patients (36.6%) were diagnosed nosed with diabetes during the 5-year follow-up. Weight gain, use of valproate, and total daily dose of clozapine were not significant risk factors for developing diabetes mellitus. Patients experienced significant weight gain that continued until approximately month 46 from initiation of clozapine. There was a nonsignificant increase in total serum cholesterol and a significant increase in serum triglycerides level. Conclusions: The results support the hypotheses that patients treated with clozapine experience significant weight gain and lipid abnormalities and appear to be at increased risk for developing diabetes. C1 Massachusetts Gen Hosp, Psychot Disorders Program, Diabet Clin Res Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Biostat Program, Boston, MA 02114 USA. Northeastern Univ, Boston, MA 02115 USA. RP Henderson, DC (reprint author), Harvard Univ, Sch Med, Freedom Trail Clin, 25 Staniford St, Boston, MA 02114 USA. NR 45 TC 469 Z9 505 U1 1 U2 9 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2000 VL 157 IS 6 BP 975 EP 981 DI 10.1176/appi.ajp.157.6.975 PG 7 WC Psychiatry SC Psychiatry GA 320VJ UT WOS:000087421300019 PM 10831479 ER PT J AU Rapaport, MH Pollack, M Wolkow, R Mardekian, J Clary, C AF Rapaport, MH Pollack, M Wolkow, R Mardekian, J Clary, C TI Is placebo response the same as drug response in panic disorder? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 151st Annual Meeting of the American-Psychiatric-Association CY MAY 30-JUN 05, 1998 CL TORONTO, CANADA SP Amer Psychiat Assoc ID QUALITY-OF-LIFE; MULTICENTER TRIAL; SERTRALINE AB Objective: The authors used seven definitions of response in panic disorder to compare patient-rated improvements in quality of life between patients with panic disorder who responded to sertraline and those who responded to placebo. Method: They combined and examined data from two multicenter, randomized, double-blind, parallel-group, flexible dose studies of panic disorder (N=302). Results: Significant differences in quality of life between patients who responded to sertraline and those who responded to placebo were apparent across all the definitions of clinical response. Conclusions: Patients who respond to placebo in panic disorder treatment studies may show symptom relief but may not experience improvement in quality of life. Determinations of quality of life should be included as components of both standard clinical assessment and clinical treatment studies of patients with panic disorder. C1 Univ Calif San Diego, Dept Psychiat, Psychopharmacol Res Program, La Jolla, CA 92037 USA. San Diego Vet Hlth Syst, Psychiat Serv, San Diego, CA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Anxiety Disorders Program, Boston, MA USA. Pfizer Inc, New York, NY USA. RP Rapaport, MH (reprint author), Univ Calif San Diego, Dept Psychiat, Psychopharmacol Res Program, 8950 Villa La Jolla Dr 2243, La Jolla, CA 92037 USA. NR 11 TC 44 Z9 45 U1 1 U2 1 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUN PY 2000 VL 157 IS 6 BP 1014 EP 1016 DI 10.1176/appi.ajp.157.6.1014 PG 3 WC Psychiatry SC Psychiatry GA 320VJ UT WOS:000087421300027 PM 10831487 ER PT J AU Shaaban, AM Duerinckx, AJ AF Shaaban, AM Duerinckx, AJ TI Wall shear stress and early atherosclerosis: A review SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Review ID HUMAN CORONARY-ARTERIES; HUMAN ABDOMINAL-AORTA; ENDOTHELIAL-CELLS; IN-VIVO; BLOOD-FLOW; CAROTID BIFURCATION; DOPPLER ULTRASOUND; VELOCITY PROFILES; FLUID-SHEAR; HEMODYNAMICS C1 VA Greater Los Angeles Healthcare Ctr, Serv Radiol, Los Angeles, CA 90073 USA. RP Duerinckx, AJ (reprint author), VA N Texas Healthcare Syst, Serv Radiol, Mail Code 114, Dallas, TX 75216 USA. NR 47 TC 127 Z9 131 U1 1 U2 11 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 2000 VL 174 IS 6 BP 1657 EP 1665 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 317EU UT WOS:000087213700035 PM 10845502 ER PT J AU Oliva, E Quinn, TR Amin, MB Eble, JN Epstein, JI Srigley, JR Young, RH AF Oliva, E Quinn, TR Amin, MB Eble, JN Epstein, JI Srigley, JR Young, RH TI Primary malignant melanoma of the urethra - A clinicopathologic analysis of 15 cases SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE urethra; malignant melanoma; primary neoplasm ID LONG-TERM SURVIVAL; FEMALE URETHRA; PRIMARY-CARCINOMA; PENIS; GENITALIA; PATIENT AB The clinical and pathologic features of 15 primary urethral melanomas occurring in patients (nine women and six men) age 44 to 96 years (mean age, 73 yrs) are described. In the men the tumor involved the distal urethra. In eight women it involved the distal urethra, usually the meatus; both the distal and proximal urethra were involved in one woman. The tumors were typically polypoid and ranged from 0.8 to 6 cm (mean, 2.6 cm) in maximum dimension. A vertical growth phase was present in all tumors, with a prominent nodular component in seven of them. A radial growth phase was seen in nine tumors. The depth of invasion ranged from 2 to 17 mm. The tumors had diffuse, nested, storiform, or mixed growth patterns. The neoplastic cells typically had abundant eosinophilic cytoplasm, large nuclei with prominent nucleoli, and brisk mitotic activity. Melanin pigment was seen in 12 tumors but was conspicuous in only six. At the time of diagnosis, 13 tumors were confined to the urethra and two patients had lymph node metastasis. Nine patients died of disease 13 to 56 months after initial diagnosis and treatment, and one patient had a local recurrence at 4 years and subsequently died of sepsis 1 year later. Three patients were alive and well at 11 months, 23 months, and 7 years. One patient died at the time of the initial operation, and one died of a ruptured aortic aneurysm at 3 years without evidence of melanoma at autopsy. Primary malignant melanomas of the urethra, one fifth of which are amelanotic, must he included in the differential diagnosis of a number of primary neoplasms that involve the urethra, including transitional cell carcinoma, sarcomatoid carcinoma, and sarcomas. Conventional prognostic factors, such as depth of invasion or tumor stage, do not seem to play as important a role in predicting survival as the mucosal location and the nodular growth present frequently in these tumors. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, James Homer Wright Pathol Labs, Boston, MA 02114 USA. Pathol Serv Inc, Cambridge, MA USA. Emory Univ, Atlanta, GA 30322 USA. Indiana Univ, Indianapolis, IN 46204 USA. Johns Hopkins Hosp, Baltimore, MD 21287 USA. McMaster Univ, Hamilton, ON, Canada. Credit Valley Hosp, Mississauga, ON, Canada. RP Oliva, E (reprint author), Massachusetts Gen Hosp, Dept Pathol, Fruit St, Boston, MA 02114 USA. NR 96 TC 38 Z9 42 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD JUN PY 2000 VL 24 IS 6 BP 785 EP 796 DI 10.1097/00000478-200006000-00003 PG 12 WC Pathology; Surgery SC Pathology; Surgery GA 319UK UT WOS:000087360600003 PM 10843280 ER PT J AU Wilens, TE Biederman, J Milberger, S Hahesy, AL Goldman, S Wozniak, J Spencer, TJ AF Wilens, TE Biederman, J Milberger, S Hahesy, AL Goldman, S Wozniak, J Spencer, TJ TI Is bipolar disorder a risk for cigarette smoking in ADHD youth? SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID SUBSTANCE USE DISORDERS; ATTENTION-DEFICIT HYPERACTIVITY; ADULT DRUG-USE; PSYCHIATRIC-DISORDERS; NICOTINE DEPENDENCE; EARLY-ONSET; YOUNG ADULTHOOD; ALCOHOL-USE; ADOLESCENT; COMORBIDITY AB Despite emerging literature linking juvenile bipolar disorder (BPD) and substance abuse, little is known about a link between BPD and cigarette smoking. To this end we evaluated the association between BPD and cigarette smoking in youth. Subjects were 31 bipolar adolescents derived from a cohort of boys with DSM-III-R ADHD (N = 128) and non-ADHD comparisons (N = 109) followed prospectively for 4 years into mid-adolescence. Information on cigarette smoking was obtained in a standardized manner blind to the proband's clinical status. Logistic regression models were used to determine risk far smoking at follow-up. BPD was associated with a higher risk for cigarette smoking in mid-adolescence, which was largely accounted for by, conduct disorder. The developmental onset of BPD in adolescence (age 13-18 years) conferred a greater risk for cigarette smoking compared to those youths with the onset of their BPD prepubertally ( less than or equal to 12 years; odds ratio = 10.8, p < 0.01), even after controlling for conduct disorder and other confounds. The naturalistic treatment of BPD with combined counseling and pharmacotherapy appeared to reduce the risk for cigarette smoking. BPD, particularly when it onsets in adolescence, is a significant risk factor for the early initiation of cigarette smoking in these A DHD youths. These data coupled with the literature strongly suggest that juveniles with BPD need to be carefully monitored for the early initiation of cigarette smoking and substance abuse. C1 Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin Res Program Pediat Psychopharmacol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Wilens, TE (reprint author), Massachusetts Gen Hosp, Pediat Psychopharmacol Unit, Clin Res Program Pediat Psychopharmacol, ACC 725, Boston, MA 02114 USA. FU NICHD NIH HHS [R01HD36317A02]; NIDA NIH HHS [R29DA11315, K01DA00029402] NR 61 TC 21 Z9 21 U1 3 U2 3 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SUM PY 2000 VL 9 IS 3 BP 187 EP 195 PG 9 WC Substance Abuse SC Substance Abuse GA 354JT UT WOS:000089327900001 PM 11000914 ER PT J AU Elman, I Krause, S Breiter, HC Gollub, RL Heintges, J Baumgartner, WA Rosen, BR Gastfriend, DR AF Elman, I Krause, S Breiter, HC Gollub, RL Heintges, J Baumgartner, WA Rosen, BR Gastfriend, DR TI The validity of self-reported drug use in non-treatment seeking individuals with cocaine dependence: Correlation with biochemical assays SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID CARBOHYDRATE-DEFICIENT TRANSFERRIN; HEAVY ALCOHOL-CONSUMPTION; HAIR ANALYSIS; ABUSE; METABOLITES; MARKERS; HEROIN; SERUM AB Accurate estimate of drug exposure plays an important role in studies of the neurobiology of drug dependence. The validity of self-reported drug use by subjects participating in such studies has not been well established. This study examined the relationship between self-reported drug use and biological markers in 18 non-treatment-seeking cocaine-dependent individuals participating in research on the effects of cocaine on the brain. A significant relationship was found between self-reported frequency of cocaine use and hair cocaine concentration. Frequency of alcohol use correlated significantly with plasma carbohydrate-deficient transferrin and aspartate aminotransferase levels. These results suggest that self-reported substance use in non-treatment seeking research subjects is generally valid. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Addict Serv, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Nucl Magnet Resonance Ctr, Boston, MA 02114 USA. Univ So Calif, Sch Pharm, Los Angeles, CA USA. W Los Angeles Vet Adm Med Ctr, Los Angeles, CA USA. RP Elman, I (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Psychiat,Addict Serv, 15 Parkman St,WACC-812, Boston, MA 02114 USA. OI Gollub, Randy L./0000-0002-9434-4044 NR 26 TC 16 Z9 16 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SUM PY 2000 VL 9 IS 3 BP 216 EP 221 PG 6 WC Substance Abuse SC Substance Abuse GA 354JT UT WOS:000089327900004 PM 11000917 ER PT J AU Pettinati, HM Rukstalis, MR Luck, GJ Volpicelli, JR O'Brien, CP AF Pettinati, HM Rukstalis, MR Luck, GJ Volpicelli, JR O'Brien, CP TI Gender and psychiatric comorbidity: Impact on clinical presentation of alcohol dependence SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID WOMEN ALCOHOLICS; MENTAL-DISORDERS; DRINKING; DEPRESSION; ABUSE AB We examined differences in clinical presentation for outpatient alcohol treatment in: 1) males and females, considering comorbidity; and 2) three comorbid groups, considering gender. Drinking indices and emotional, physical, and sexual abuse reports were compared in 127 male and 69 female alcohol-dependent patients who have a current (36.2%) or lifetime (20.4%) psychiatric disorder or who never had a psychiatric disorder (43.4%). Females reported more emotional and physical abuse than males. Females reported drinking smaller volumes of alcohol but on more days than males. All with current comorbidity, irrespective of gender, reported more days of heavy drinking than other groups. When evaluating drinking status, gender and comorbidity should be considered. C1 Univ Penn, Dept Psychiat, Treatment Res Ctr, Ctr Study Addict, Philadelphia, PA 19104 USA. Philadelphia Med Ctr Vet Affairs, Philadelphia, PA USA. RP Pettinati, HM (reprint author), Univ Penn, Dept Psychiat, Treatment Res Ctr, Ctr Study Addict, 3900 Chestnut St, Philadelphia, PA 19104 USA. FU NIAAA NIH HHS [K08AA-00251, R01AA-07517, R01AA-09544] NR 29 TC 18 Z9 19 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD SUM PY 2000 VL 9 IS 3 BP 242 EP 252 PG 11 WC Substance Abuse SC Substance Abuse GA 354JT UT WOS:000089327900007 PM 11000920 ER PT J AU Raje, N Kica, G Chauhan, D Zhang, YN Teoh, G Treon, SP Hideshima, T Deng, JH Gao, SJ Alsina, M Wally, J Davies, FE Tai, YT Pinkus, GS Pinkus, JL Skinner, M Comenzo, RL Anderson, KC AF Raje, N Kica, G Chauhan, D Zhang, YN Teoh, G Treon, SP Hideshima, T Deng, JH Gao, SJ Alsina, M Wally, J Davies, FE Tai, YT Pinkus, GS Pinkus, JL Skinner, M Comenzo, RL Anderson, KC TI Kaposi's sarcoma-associated herpesvirus gene sequences are detectable at low copy number in primary amyloidosis SO AMYLOID-INTERNATIONAL JOURNAL OF EXPERIMENTAL AND CLINICAL INVESTIGATION LA English DT Article DE Kaposi's sarcoma herpesvirus; amyloidosis; bone marrow ID MULTIPLE-MYELOMA PATIENTS; DOSE-INTENSIVE MELPHALAN; LIGHT-CHAIN AMYLOIDOSIS; BLOOD DENDRITIC CELLS; BONE-MARROW; DNA-SEQUENCES; INFECTION; HUMAN-HERPESVIRUS-8; IDENTIFICATION; SURVIVAL AB Primary amyloidosis (AL), like multiple myeloma (MM), results from a clonal proliferation of plasma cells. Recent detection of Kaposi's sarcoma-associated herpesvirus (KSHV) gene sequences in MM patients, although controversial, suggested that KSHV may also be present in AL. In the present study, we assayed for KSHV gene sequences in patients with primary AL independently in 2 laboratories. Nested polymerase chain reaction (PCR) was performed on DNA isolated from 21 bone marrow (BM) core biopsy samples to amplify orf26 and orf72, 2 regions of the KSHV genome. Eighteen of 21 (86%) BM core biopsy samples were KSHV PCR positive. BM aspirates from 16 of these 21 AL patients were cultured for 4-6 weeks to generate long term bone marrow stromal cells (LT-BMSCs), and 13 of 16 (81%) LT-BMSCs were also KSHV PCR positive. Results in all but 1 sample were consistent in the 2 laboratories. Sequencing of the PCR products in the 2 laboratories confirmed 94-98% and 95-98% homology to the published orf26 and orf 72 KSHV gene sequences respectively, with interpatient basepair differences. Despite the presence of KSHV gene sequences, only 4/18 (22%) KSHV PCR positive patients demonstrated KSHV lytic antibodies by immunoblot assay. A sensitivity assay performed on the BCBL-1 cell line confirmed the presence of KSHV at a very low copy number in AL. PCR using patient specific light chain gene primers also amplified DNA isolated from 2 AL BM core biopsies and 3 AL LT-BMSCs which were KSHV PCR positive, suggesting the presence of clonotypic cells. Our results therefore demonstrate KSHV gene sequences albeit at a very low copy number in the majority of BM core biopsies and LT-BMSCs from AL patients, and serological responses in only a minority of cases. Ongoing studies to identify, viral transcripts and gene products will determine the biological relevance of KSHV in AL disease pathogenesis. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Boston Med Ctr, Dept Med, Boston, MA USA. Univ Texas, Hlth Sci Ctr, Dept Pediat & Microbiol, San Antonio, TX USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02215 USA. RI Gao, Shou-Jiang/B-8641-2012 FU FDA HHS [FD-R-001346-01]; NCI NIH HHS [CA78378, CA50947] NR 36 TC 8 Z9 8 U1 0 U2 0 PU PARTHENON PUBLISHING GROUP PI CARNFORTH LANCASHIRE PA CASTERTON HALL, CARNFORTH LANCASHIRE LA6 2LA, ENGLAND SN 1350-6129 J9 AMYLOID JI Amyloid-Int. J. Exp. Clin. Investig. PD JUN PY 2000 VL 7 IS 2 BP 126 EP 132 DI 10.3109/13506120009146250 PG 7 WC Biochemistry & Molecular Biology; Medicine, General & Internal; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; General & Internal Medicine; Research & Experimental Medicine GA 315NU UT WOS:000087120500008 PM 10842716 ER PT J AU Weimann, J Ullrich, R Hromi, J Fujino, Y Clark, MWH Bloch, KD Zapol, WM AF Weimann, J Ullrich, R Hromi, J Fujino, Y Clark, MWH Bloch, KD Zapol, WM TI Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension SO ANESTHESIOLOGY LA English DT Article DE PDE5; phosphodiesterase ID INHALED NITRIC-OXIDE; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; RESPIRATORY-DISTRESS SYNDROME; ERECTILE DYSFUNCTION; RELAXING FACTOR; IN-VITRO; DIPYRIDAMOLE; INHIBITOR; ZAPRINAST; VASOCONSTRICTION AB Background: Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction, Methods: In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDES inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous L-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6). Results: Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of L-NAME abolished sildenafil-induced pulmonary vasodilation. Conclusions: Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action of inhaled NO. C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Zapol, WM (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 32 Fruit St, Boston, MA 02114 USA. FU NHLBI NIH HHS [HL55377, HL42397] NR 47 TC 132 Z9 149 U1 1 U2 6 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 2000 VL 92 IS 6 BP 1702 EP 1712 DI 10.1097/00000542-200006000-00030 PG 11 WC Anesthesiology SC Anesthesiology GA 320ER UT WOS:000087389300026 PM 10839922 ER PT J AU Bigatello, LM Hess, D Dennehy, KC Medoff, BD Hurford, WE AF Bigatello, LM Hess, D Dennehy, KC Medoff, BD Hurford, WE TI Sildenafil can increase the response to inhaled nitric oxide SO ANESTHESIOLOGY LA English DT Article DE acute pulmonary hypertension; hypoxemia; patent foramen ovale; phosphodiesterase inhibitors; pulmonary vasodilators ID RESPIRATORY-DISTRESS SYNDROME; PULMONARY-HYPERTENSION; DIPYRIDAMOLE C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. RP Bigatello, LM (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. RI Hurford, William/G-6386-2013 OI Hurford, William/0000-0003-1201-0313 NR 13 TC 32 Z9 41 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD JUN PY 2000 VL 92 IS 6 BP 1827 EP 1829 DI 10.1097/00000542-200006000-00044 PG 3 WC Anesthesiology SC Anesthesiology GA 320ER UT WOS:000087389300040 PM 10839936 ER PT J AU Boudreaux, ED Clark, S Camargo, CA AF Boudreaux, ED Clark, S Camargo, CA CA MARC Investigators TI Telephone follow-up after the emergency department visit: Experience with acute asthma SO ANNALS OF EMERGENCY MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the Society-of-Academic-Emergency-Medicine CY MAY 20-23, 1999 CL BOSTON, MASSACHUSETTS SP Soc Amer Emergency Med ID OUTPATIENT MANAGEMENT; CARE; INTERVENTION; CHILDREN; INFANTS; CITY AB Study objective: This study explored how a variety of demographic and illness-related factors were associated with telephone follow-up among patients visiting the emergency department for acute asthma. Methods: We performed a prospective cohort study as part of the Multicenter Airway Research Collaboration (MARC). The study was performed at 77 EDs in 22 US states and 4 Canadian provinces. ED patients, ages 2 to 54 years, who presented with acute asthma underwent a structured interview during their visit. Two weeks later, research personnel attempted to contact participants by telephone, using numbers obtained during the ED interview. Results: A total of 1,847 adult and 1,184 pediatric patients were interviewed in the ED. Of these, 1,308 (71%) adult patients and 1,026 (87%) pediatric patients were successfully reached for 2-week telephone follow-up. Multivariate analyses revealed the factor most strongly related to contact was age, with pediatric patients being 2.5 times more likely to be reached than adults (95% confidence interval 2.0 to 3.2). Also, participants who were black, low in socioeconomic status, lacking a primary care provider, and exposed to tobacco smoke were significantly less likely to have been reached tall P < .001). Conclusion: In contrast to some reports in the literature, telephone contact rates were high. However, successful contact was not equally likely among all patient groups. Although the high contact rates support the feasibility of telephone follow-up of asthmatic patients visiting the ED, the results also act as a reminder of the potential biases that may arise when using telephone contact for clinical, quality assurance, and research. C1 Earl K Long Med Ctr, Dept Emergency Med, Baton Rouge, LA 70805 USA. Massachusetts Gen Hosp, Dept Emergency Med, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. RP Boudreaux, ED (reprint author), Earl K Long Med Ctr, Dept Emergency Med, 5825 Airline Highway, Baton Rouge, LA 70805 USA. OI Boudreaux, Edwin/0000-0002-3223-6371 NR 35 TC 13 Z9 13 U1 0 U2 0 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0196-0644 J9 ANN EMERG MED JI Ann. Emerg. Med. PD JUN PY 2000 VL 35 IS 6 BP 555 EP 563 DI 10.1016/S0196-0644(00)70027-8 PG 9 WC Emergency Medicine SC Emergency Medicine GA 321HU UT WOS:000087450700002 PM 10828767 ER PT J AU Holtzman, DM Fagan, AM Mackey, B Tenkova, T Sartorius, L Paul, SM Bales, K Ashe, KH Irizarry, MC Hyman, BT AF Holtzman, DM Fagan, AM Mackey, B Tenkova, T Sartorius, L Paul, SM Bales, K Ashe, KH Irizarry, MC Hyman, BT TI Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer's disease model SO ANNALS OF NEUROLOGY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; BETA-PEPTIDE DEPOSITION; TRANSGENIC MICE; E EPSILON-4; CEREBRAL-HEMORRHAGE; CEREBROSPINAL-FLUID; TYPE-4 ALLELE; MOUSE MODEL; ANGIOPATHY; ONSET AB The epsilon 4 allele of apolipoprotein E (ApoE) is an important genetic risk factor for Alzheimer's disease (AD). Increasing evidence suggests that this association may be linked to the ability of ApoE to interact with the amyloid-beta (A beta) peptide and influence its concentration and structure. To determine the effect of ApoE on A beta and other AD pathology in vivo, we used APPsw transgenic mice and ApoE knockout (-/-) mice to generate APPsw animals that carried two (ApoE +/+), one (ApoE +/-), or no copies (ApoE -/-) of the normal mouse ApoE gene. At 12 months of age, A beta deposition was present in the cortex and hippocampus and was also prominent within leptomeningeal and cortical blood vessels of all APPsw ApoE +/+ mice. Importantly, although A beta deposition still occurred in APPsw ApoE -/- mice, no fibrillar A beta deposits were detected in the brain parenchyma or cerebrovasculature. There was also no neuritic degeneration associated with A beta deposition in the absence of ApoE. These data demonstrate that ApoE facilitates the formation of both neuritic and cerebrovascular plaques, which are pathological hallmarks of AD and cerebral amyloid angiopathy. C1 Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Ctr Study Nervous Syst Injury, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Lilly Res Labs, Neusci Discovery Res, Indianapolis, IN USA. Univ Minnesota, Univ Hosp, Dept Neurol, Minneapolis, MN USA. Massachusetts Gen Hosp, Neurol Serv, Boston, MA 02114 USA. RP Holtzman, DM (reprint author), Washington Univ, Sch Med, Dept Neurol, 660 S Euclid Ave,Box 8111, St Louis, MO 63110 USA. FU NIA NIH HHS [AG00861, AG13956] NR 59 TC 214 Z9 216 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD JUN PY 2000 VL 47 IS 6 BP 739 EP 747 DI 10.1002/1531-8249(200006)47:6<739::AID-ANA6>3.0.CO;2-8 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 320DM UT WOS:000087386500006 PM 10852539 ER PT J AU Jiang, J Verdolini, K Aquino, B Ng, J Hanson, D AF Jiang, J Verdolini, K Aquino, B Ng, J Hanson, D TI Effects of dehydration on phonation in excised canine larynges SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE canine; dehydration; excised larynx; phonation; phonation threshold pressure; subglottal pressure; vocal efficiency ID HYDRATION AB The effects of exposure to dry air on phonation were measured in an ex vivo model of vocal fold vibration. Excised canine larynges were mounted on an apparatus and made to phonate at a constant subglottal pressure by means of unhumidified airflow. The phonation threshold pressure (PTP), glottal airflow, sound intensity of the acoustic output, and effects on vocal efficiency were also assessed. Student's t-test was performed on the results. In 17 larynges, the average PTP increased from 10.0 cm H2O to 15.0 cm H2O after exposure to dry airflow (p <.001). In addition. the average flow increased from 585 mL/s to 801 mL/s at a constant suprathreshold subglottal pressure (p <.001), and from 323 mL/s to 610 mL/s at the PTP(p <.001). The average acoustic output levels, measured during stable phonation segments, markedly decreased with exposure to the dry airflow. from 91.5 dB to 88.5 dB (p <.001). The average vocal efficiency decreased from 3.63 x 10(-4) to 7.00 x 10(-5) (p <.001). No such changes were seen in control larynges phonated with 100% humidified air used for driving the airflow. The results support previously reported modeling and experimental Findings that dehydration of the vocal fold generally degrades laryngeal performance. C1 Northwestern Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Chicago, IL 60611 USA. Massachusetts Eye & Ear Infirm, Voice & Speech Lab, Boston, MA USA. Harvard Univ, Sch Med, Dept Commun Sci & Disorders, Boston, MA USA. Massachusetts Gen Hosp, Inst Hlth Profess, Boston, MA 02114 USA. RP Jiang, J (reprint author), Northwestern Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Searle Bldg 12-561,303 E Chicago Ave, Chicago, IL 60611 USA. FU NIDCD NIH HHS [P60 DC 94-002-02, R01 DC 00254-11, T32 DC 0015-15] NR 16 TC 52 Z9 54 U1 0 U2 1 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD JUN PY 2000 VL 109 IS 6 BP 568 EP 575 PG 8 WC Otorhinolaryngology SC Otorhinolaryngology GA 321FW UT WOS:000087446300007 PM 10855568 ER PT J AU Lairmore, TC Chen, VY DeBenedetti, MK Gillanders, WE Norton, JA Doherty, GM AF Lairmore, TC Chen, VY DeBenedetti, MK Gillanders, WE Norton, JA Doherty, GM TI Duodenopancreatic resections in patients with multiple endocrine neoplasia type 1 SO ANNALS OF SURGERY LA English DT Article; Proceedings Paper CT 111th Annual Meeting of the Southern-Surgical-Association CY DEC 05-08, 1999 CL HOT SPRINGS, VIRGINIA SP SO Surg Assoc ID ISLET-CELL TUMORS; SELECTIVE INTRAARTERIAL INJECTION; GERMLINE MUTATIONS; MEN1 GENE; LOCALIZATION; PANCREAS; EXPERIENCE AB Objective To review the authors' 7-year experience with a surgical approach for pancreatic and duodenal neuroendocrine tumors (NETs) in patients with multiple endocrine neoplasia type 1 (MEN 1) designed to remove all gross tumor with limited complications, preserving pancreatic function. Summary Background Data MEN 1 is an autosomal dominant familial neoplasia syndrome characterized by the development of NETs of the duodenum and pancreas. Some tumors are clinically insignificant or follow a benign course, although a subset pursues a malignant, lethal natural history, the risk of surgical management must be appropriate to the disease course. Methods The clinical, biochemical, genetic, and pathologic data were retrospectively reviewed for 21 consecutive MEN 1 patients undergoing pancreatic resection for NETs between 1993 and 1999 at one institution. Age at operation, presenting symptoms, results of preoperative and intraoperative localization studies, major and minor complications, and pathology, including metastases, were analyzed. Results The surgical approach was selected based on the location and size of the tumors. Five patients required pancreaticoduodenectomy, 11 patients underwent non-Whipple pancreatic resections, and 5 underwent simple enucleation of benign NETs. The incidence of regional lymph node metastases was 33%. Conclusions Major pancreatic procedures can be performed safely in most patients with MEN 1 and NETs. Because NETs are the most common MEN I-related cause of death in the authors' kindreds, an aggressive surgical approach, including early intervention before malignant spread and major pancreatic resection where indicated, appears justified. C1 Washington Univ, Sch Med, Sect Endocrine & Oncol Surg, Dept Surg, St Louis, MO 63110 USA. San Francisco VA Med Ctr, Surg Serv, San Francisco, CA USA. RP Lairmore, TC (reprint author), Washington Univ, Sch Med, Sect Endocrine & Oncol Surg, Dept Surg, Box 8109,660 S Euclid Ave, St Louis, MO 63110 USA. FU NCRR NIH HHS [M01RR00036, M01 RR000036] NR 25 TC 55 Z9 58 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD JUN PY 2000 VL 231 IS 6 BP 909 EP 916 DI 10.1097/00000658-200006000-00016 PG 8 WC Surgery SC Surgery GA 321UF UT WOS:000087472500031 PM 10816635 ER PT J AU Bisognano, C Vaudaux, P Rohner, P Lew, DP Hooper, DC AF Bisognano, C Vaudaux, P Rohner, P Lew, DP Hooper, DC TI Induction of fibronectin-binding proteins and increased adhesion of quinolone-resistant Staphylococcus aureus by subinhibitory levels of ciprofloxacin SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID FOREIGN-BODY INFECTION; DNA TOPOISOMERASE-IV; FLUOROQUINOLONE RESISTANCE; IN-VITRO; METHICILLIN RESISTANCE; ESCHERICHIA-COLI; GRLA MUTATIONS; PRIMARY TARGET; GYRASE; GENE AB We recently reported that strain EN1252a, a fluoroquinolone-resistant derivative of Staphylococcus aureus NCTC8325 with mutations in grlA and gyrA, expressed increased levels of fibronectin-binding proteins (FnBPs) and showed a significantly higher attachment to fibronectin-coated polymer surfaces after growth in the presence of subinhibitory concentrations of ciprofloxacin. The present study evaluated the occurrence and frequency of fluoroquinolone-induced FnBP-mediated adhesion in clinical isolates of fluoroquinolone-resistant methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA). Eight of ten MRSA isolates and four of six MSSA isolates with grlA and gyrA mutations exhibited significant increases in attachment to fibronectin-coated surfaces after growth in the presence of one-quarter the MIC of ciprofloxacin. Fluoroquinolone-induced FnBP-mediated adhesion of one clinical MRSA strain and the double mutant strain EN1252a also occurred on coverslips removed from the subcutaneous space of guinea pigs. For strain EN1252a, the regulation of fnb transcription by sub-MICs of ciprofloxacin was studied on reporter plasmids carrying fnb-luxAB fusions. One-quarter of the MIC of ciprofloxacin significantly increased fnbB, hut not fnbA, promoter activity of the fluoroquinolone-resistant mutant but not its fluoroquinolone-susceptible parent ISP794. This response was abolished by pretreatment with rifampin, indicating an effect at the level of transcription. Activation of the fnbB promoter was not due to an indirect effect of ciprofloxacin on growth rate and still occurred in an agr mutant of strain EN1252a. These data suggest that sub-MIC levels of ciprofloxacin activate the fnbB promoter of some laboratory and clinical isolates, thus contributing to increased production of FnBP(s) and leading to higher levels of bacterial attachment to fibronectin-coated or subcutaneously implanted coverslips. C1 Hop Cantonal Geneva, Div Infect Dis, CH-1211 Geneva 14, Switzerland. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Infect Dis Unit, Boston, MA 02114 USA. RP Vaudaux, P (reprint author), Hop Cantonal Geneva, Div Infect Dis, CH-1211 Geneva 14, Switzerland. FU NIAID NIH HHS [AI23988, R37 AI023988, R01 AI023988] NR 60 TC 77 Z9 79 U1 0 U2 6 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 2000 VL 44 IS 6 BP 1428 EP 1437 DI 10.1128/AAC.44.6.1428-1437.2000 PG 10 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 316FC UT WOS:000087156100003 PM 10817688 ER PT J AU Matzke, GR Frye, RF Joy, MS Palevsky, PM AF Matzke, GR Frye, RF Joy, MS Palevsky, PM TI Determinants of ceftazidime clearance by continuous venovenous hemofiltration and continuous venovenous hemodialysis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID RENAL REPLACEMENT THERAPY; ANTIMICROBIAL ACTIVITY; MEDICAL-CENTERS; PHARMACOKINETICS; ADJUSTMENTS; ANTIBIOTICS; MEMBRANES AB Although several dosage adjustment regimens have been proposed, there is little quantitative information to guide the initiation of ceftazidime therapy in patients who are receiving continuous renal replacement therapy. To determine the clearance of ceftazidime by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD), we performed controlled clearance studies with stable hemodialysis patients with three hemofilters: a 0.6-m(2) acrylonitrile copolymer (AN69; Hospal) filter, a 2.1-m(2) polymethylmethacrylate filter (PMMA; Toray) filter and a 0.65-m(2) polysulfone (PS; Fresenius) filter. Subjects received 1,000 mg of ceftazidime intravenously prior to the start of a clearance study. The concentration of ceftazidime in multiple plasma and dialysate or ultrafiltrate samples was determined by high-performance liquid chromatography. The diffusional clearances (CIdiffusion) and sieving coefficients of ceftazidime were compared by a mixed-model repeated-measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and the patient as a random effect. The fraction of ceftazidime bound to plasma proteins was 17% +/- 7% (range, 10 to 25%). The clearances of ceftazidime, urea, and creatinine by CVVHD were essentially constant at blood how rates of 75 to 250 ml/min for all three filters. Significant linear relationships (P < 0.0001) were observed between CIdiffusion of ceftazidime and clearance of urea for all three filters: AN69 (slope = 0.83), PMMA (slope = 0.89), and PS (slope = 1.03). Ceftazidime clearance was membrane independent during CVVH and CVVHD. CVVH and CVVHD can significantly augment the clearance of ceftazidime. Dosing strategies for initiation of ceftazidime therapy in patients receiving CVVH and CVVHD are proposed. C1 Univ Pittsburgh, Sch Pharm, Ctr Clin Pharmacol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15261 USA. VA Pittsburgh Hlth Care Syst, Renal Sect, Pittsburgh, PA USA. Univ N Carolina, Sch Med, Div Nephrol & Hypertens, Chapel Hill, NC USA. RP Matzke, GR (reprint author), Univ Pittsburgh, Sch Pharm, Ctr Clin Pharmacol, 724 Salk Hall, Pittsburgh, PA 15261 USA. OI Palevsky, Paul/0000-0002-7334-5400; Frye, Reginald/0000-0002-1841-1401 FU NCRR NIH HHS [5M01 RR00056, M01 RR000056] NR 27 TC 20 Z9 21 U1 1 U2 2 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 2000 VL 44 IS 6 BP 1639 EP 1644 DI 10.1128/AAC.44.6.1639-1644.2000 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 316FC UT WOS:000087156100036 PM 10817721 ER PT J AU Arsenault, JE Cline, AD AF Arsenault, JE Cline, AD TI Nutrient intakes and characteristics of normal weight, female military personnel consuming foods reduced in fat or energy content SO APPETITE LA English DT Article ID COMPENSATION; CARBOHYDRATE; HUMANS; IMPACT AB The nutritional implications of consuming reduced fat or reduced energy foods (RED) were examined in 50 women who were participating in a larger study of iron status while enrolled in the U.S. Army Medical Department Officer Basic Course. The subjects recorded their food intake for a 7-day period. Reduced fat or reduced energy foods were identified as foods labeled "reduced-calorie, reduced-fat, diet, or low-calorie". The women were divided into two groups, those eating > 14 RED per week (N=28) and those eating less than or equal to 14 RED (N=22). The > 14 RED group tended to be Caucasian, single, had a lower body mass index (21.2 vs. 22.5), and exercised more. The mean daily intake of the > 14 RED group was significantly higher in carbohydrate, dietary fiber, thiamin, riboflavin, niacin, vitamin B6, folacin, calcium, phosphorus, magnesium, iron, zinc, potassium, and sodium, and significantly lower in cholesterol. The percentage of energy from fat was significantly lower in the > 14 RED group than the less than or equal to 14 RED group (p < 0.01). There was no significant difference in energy intake between the two groups. More women in the > 14 RED group used dietary supplements. The > 14 group consumed more dairy products and less sweetened beverages. These results demonstrate that the consumption of reduced fat or energy foods did not have a significant impact on total energy intake in these normal weight women, individuals consuming these foods may subsequently consume less energy from fat and improve the nutrient composition of their diet by selecting healthier food choices. (C) 2000 Academic Press. RP Arsenault, JE (reprint author), Massachusetts Gen Hosp, Gastrointestinal Unit, 55 Fruit St,GRJ825, Boston, MA 02114 USA. RI Biguzzi, Felipe/E-4724-2015 NR 16 TC 6 Z9 6 U1 0 U2 6 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0195-6663 J9 APPETITE JI Appetite PD JUN PY 2000 VL 34 IS 3 BP 227 EP 233 DI 10.1006/appe.1999.0315 PG 7 WC Behavioral Sciences; Nutrition & Dietetics SC Behavioral Sciences; Nutrition & Dietetics GA 318CU UT WOS:000087267000001 PM 10888285 ER PT J AU Gragoudas, ES Lane, AM Regan, S Li, W Judge, HE Munzenrider, JE Seddon, JM Egan, KM AF Gragoudas, ES Lane, AM Regan, S Li, W Judge, HE Munzenrider, JE Seddon, JM Egan, KM TI A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID PROTON-BEAM IRRADIATION; UVEAL MELANOMA; MALIGNANT-MELANOMA; ENUCLEATION; THERAPY; RISK; EYE AB Objective: To determine if a reduction in proton radiation dose from the standard dose of 70 cobalt gray equivalents (CGE) to 50 CGE would decrease radiation-induced complications, thereby improving visual prognosis, without compromising local tumor control for patients with uveal melanoma at high risk of these complications. Design: Randomized, double-masked clinical trial. Participants: A total of 188 patients with small or medium-sized choroidal melanomas (<15 mm in diameter and <5 mm in height) near the optic disc or macula (within 4 disc diameters of either structure). Methods: Patients were treated with proton beam therapy at doses of either 50 CGE or 70 CGE between October 1989 and July 1994, and followed up biannually through April 1998. Outcomes included visual acuity, radiation complications, melanoma recurrence, and metastasis. Results: Proportions of patients retaining visual acuity of at least 20/200 were similar in the 2 dose groups at 5 years after radiation (approximately 55%). Similar numbers of patients in each group experienced tumor regrowth (2 patients at 50 CGE vs 3 patients at 70 CGE; P > .99) and metastasis (7 patients at 50 CGE vs 8 patients at 70 CGE; P = .79). Five-year rates of radiation maculopathy also were similar (for both groups, approximately 75% for tumors within 1 disc diameter and 40% for tumors > 1 disc diameter from the macula). Rates of radiation papillopathy were nonsignificantly decreased in the 50-CGE treatment group when tumors were located 1 disc diameter or less from the optic disc (P = .20). Patients treated with the lower dose also experienced significantly less visual field loss. Conclusions: This level of dose reduction did not result in a lesser degree of visual acuity loss. The lower-dose group did experience significantly less visual field loss. Local tumor recurrence and metastatic death rates were similar in both dose groups. C1 Massachusetts Eye & Ear Infirm, Retina Serv, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. RP Gragoudas, ES (reprint author), Massachusetts Eye & Ear Infirm, Retina Serv, 243 Charles St, Boston, MA 02114 USA. RI Li, Wenjun/F-5634-2015 OI Li, Wenjun/0000-0001-5335-7386 FU NCI NIH HHS [P01 CA21239] NR 23 TC 72 Z9 73 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUN PY 2000 VL 118 IS 6 BP 773 EP 778 PG 6 WC Ophthalmology SC Ophthalmology GA 322HB UT WOS:000087503200004 PM 10865313 ER PT J AU Rubin, PAD Fay, AM Remulla, HD AF Rubin, PAD Fay, AM Remulla, HD TI Primary placement of a motility coupling post in porous polyethylene orbital implants SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID HYDROXYAPATITE; COMPLICATIONS; ENUCLEATION; INGROWTH; MEDPOR AB The placement of a motility coupling post (MCP) to integrate the prosthesis with a porous orbital implant may enhance prosthetic motility following enucleation. Previously, MCP placement has required a second operation usually at least 6 months following enucleation. We developed a technique to place an MCP reliably and safely into a porous orbital implant at the time of enucleation. Eligibility criteria included high motivation to achieve maximal prosthetic motility, adequate conjunctiva to ensure desirable wound closure, and isolation of the 4 rectus muscles. Enucleation was performed in standard fashion with implantation of a conical porous polyethylene orbital. implant. implanted MCPs protruded anteriorly 2 to 4 mm. The Tenon capsule and conjunctiva were closed in separate layers over the protruding MCP. Thirty-two patients underwent primary placement. Follow-up ranged from 1 to 33 months (mean, 15 months). Nine MCPs spontaneously exposed within the first 4 months. One additional post autoexposed at 12 months. Three patients underwent a secondary procedure to expose the MCP. There were no cases of infection, explantation, or gross MCP malposition. Minor complications included pyogenic granuloma (n=2) and conjunctival overgrowth (n=1). All patients were successfully fit with prostheses. Prosthetic motility was acceptable in all patients. Motility coupling post placement at the time of enucleation surgery in selected patients is an effective, efficient surgical option. C1 Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Div Ophthalm Plast Orbital & Cosm, Boston, MA 02114 USA. RP Rubin, PAD (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Dept Ophthalmol,Div Ophthalm Plast Orbital & Cosm, 243 Charles St, Boston, MA 02114 USA. NR 12 TC 29 Z9 32 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD JUN PY 2000 VL 118 IS 6 BP 826 EP 832 PG 7 WC Ophthalmology SC Ophthalmology GA 322HB UT WOS:000087503200014 PM 10865322 ER PT J AU Evans, SRT Jackson, PG Czerniach, DR Kalan, MMH Iglesias, AR AF Evans, SRT Jackson, PG Czerniach, DR Kalan, MMH Iglesias, AR TI A stepwise approach to laparoscopic Nissen fundoplication - Avoiding technical pitfalls SO ARCHIVES OF SURGERY LA English DT Article ID SHORT GASTRIC VESSELS; RANDOMIZED TRIAL; EXPERIENCE; DIVISION AB Laparoscopic Nissen fundoplication is now widely used in the surgical management of gastroesophageal reflux disease. However, it is a complex operation that requires advanced laparoscopic skills. The learning curve is steep, and complications are directly related to the surgeon's experience level. Both experimental and clinical data demonstrate a decline in complications with increasing experience. We divided this complex procedure into logical and orderly components, to facilitate the learning process. We believe that this approach will not only reduce complications by highlighting potential problems at each stage but also make it easier to teach others. C1 George Washington Univ, Med Ctr, Dept Surg, Washington, DC 20037 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Evans, SRT (reprint author), George Washington Univ, Med Ctr, Dept Surg, 2150 Penn Ave NW, Washington, DC 20037 USA. NR 12 TC 5 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0004-0010 J9 ARCH SURG-CHICAGO JI Arch. Surg. PD JUN PY 2000 VL 135 IS 6 BP 723 EP 728 DI 10.1001/archsurg.135.6.723 PG 6 WC Surgery SC Surgery GA 321QK UT WOS:000087466000029 PM 10843374 ER PT J AU Brandt, KD Smith, GN Simon, LS AF Brandt, KD Smith, GN Simon, LS TI Intraarticular injection of hyaluronan as treatment for knee osteoarthritis - What is the evidence? SO ARTHRITIS AND RHEUMATISM LA English DT Review ID MEDIATED CARTILAGE CHONDROLYSIS; HUMAN SYNOVIAL FIBROBLASTS; INTRA-ARTICULAR INJECTION; SODIUM HYALURONATE; MOLECULAR-WEIGHT; CANINE KNEE; MULTICENTER TRIAL; FLUID HYALURONAN; ACID; JOINTS C1 Indiana Univ, Sch Med, Div Rheumatol, Indianapolis, IN 46202 USA. Indiana Univ, Multipurpose Arthritis & Musculoskeletal Dis Ctr, Indianapolis, IN 46202 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Brandt, KD (reprint author), Indiana Univ, Sch Med, Div Rheumatol, 541 Clin Dr,Room 492, Indianapolis, IN 46202 USA. FU NIAMS NIH HHS [AR-20582, AR-45383] NR 70 TC 114 Z9 117 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD JUN PY 2000 VL 43 IS 6 BP 1192 EP 1203 DI 10.1002/1529-0131(200006)43:6<1192::AID-ANR2>3.0.CO;2-L PG 12 WC Rheumatology SC Rheumatology GA 322HC UT WOS:000087503300002 PM 10857778 ER PT J AU Lingard, EA Berven, S Katz, JN AF Lingard, EA Berven, S Katz, JN CA Kinemax Outcomes Grp TI Management and care of patients undergoing total knee arthroplasty: Variations across different health care settings SO ARTHRITIS CARE AND RESEARCH LA English DT Article DE knee arthroplasty; process of care; international comparison; quality of care ID REPLACEMENT; ARTHRITIS; HIP AB Objectives. To examine variation in the process of care for total knee arthroplasty (TKA) and to highlight the need for rigorous research into the ideal management of TKA. We hypothesize that variation in the process of care for TKA across and within health care systems is associated with identifiable financial and historical factors. Methods. We compared access to TKA and typical postoperative rehabilitation management in 12 orthopedic centers in the United States (4 centers), United Kingdom (6 centers), and Australia (2 centers). We collected data from two sources: 1) Empirical data on length of stay and discharge management were collected as part of a prospective study of the outcomes of primary TKA for patients with a diagnosis of osteoarthritis; 2) Structured qualitative interviews were conducted at each of the participating centers to collect data on academic status and reimbursement structure, as well as waiting times for orthopedic consultation and TKA surgery once it had been scheduled. Results. We demonstrated differences in length of acute hospital stay, use of extended care facilities, home physical therapy, and outpatient physical therapy within our cohort of hospitals. The publicly funded hospitals had a significantly longer acute hospital length of stay (mean 11.8 days, SD 7.1) than the private hospitals (mean 6.6 days, SD 4.1; P < 0.0001). Variation in waiting times was associated with the method of surgeon reimbursement and whether the hospital is publicly funded or private. Patients attending private hospitals waif ed 1-8 weeks for the first consultation and 2-12 weeks for a surgical date after scheduling. In contrast, patients attending publicly funded hospitals waited 4-12 months for a first consultation and 12-18 months for a surgical date after scheduling. Conclusions. Our observations are consistent with the hypothesis that financial reimbursement schemes influence the management of TKA. Further research needs to be done to quantify effects of varying processes of care on the outcome of TKA surgery across different health care settings. This data would elucidate the optimal management of TKA using objective evidence rather than relying on financial incentives or the preservation of historical practices. C1 Brigham & Womens Hosp, Dept Orthoped Res, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Robert Brigham Multipurpose Arthrit & Musculoskel, Boston, MA USA. RP Lingard, EA (reprint author), Brigham & Womens Hosp, Dept Orthoped Res, MRB-114A,75 Francis St, Boston, MA 02115 USA. FU AHRQ HHS [HS09775]; NIAMS NIH HHS [AR-36308] NR 16 TC 49 Z9 50 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-7524 J9 ARTHRIT CARE RES JI Arthritis Care Res. PD JUN PY 2000 VL 13 IS 3 BP 129 EP 136 DI 10.1002/1529-0131(200006)13:3<129::AID-ANR1>3.3.CO;2-Y PG 8 WC Rheumatology SC Rheumatology GA 402YN UT WOS:000167015900001 PM 14635286 ER PT J AU Gow, DW AF Gow, DW TI One phonemic representation should suffice SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID SPEECH AB The Merge model suggests that lexical effects in phonemic processing reflect the activation of post-lexical phonemic representations are distinct from prelexical phonemic input representations. This distinction seems to be unmotivated; the phoneme fails to capture the richness of prelexical representation. Increasing the information content of input representations minimizes the potential necessity for top-down processes. C1 Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. RP Gow, DW (reprint author), Massachusetts Gen Hosp, Neuropsychol Lab, Boston, MA 02114 USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD JUN PY 2000 VL 23 IS 3 BP 331 EP + DI 10.1017/S0140525X00283246 PG 9 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 393MB UT WOS:000166471500008 ER PT J AU Means, RT AF Means, RT TI The anaemia of infection SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE anaemia; infection; cytokines; ferrokinetics; erythropoietin; iron; host defence ID TUMOR-NECROSIS-FACTOR; COLONY-FORMING-UNITS; RECOMBINANT-HUMAN-ERYTHROPOIETIN; PLASMODIUM-FALCIPARUM MALARIA; RHEUMATOID-ARTHRITIS; FACTOR-ALPHA; HEMOLYTIC-ANEMIA; CHRONIC DISEASE; TRANSFERRIN RECEPTORS; INTERFERON-GAMMA AB Anaemia is a common finding in infected individuals, and in many cases is an indicator of disease activity and/or duration. The term 'anaemia of infection' refers to a specific syndrome related to the more broadly defined 'anaemia of chronic disease', in this syndrome, cytokines produced as part of the host response to infection induce anaemia by well-defined pathophysiological mechanisms. In this chapter, the diagnosis, significance, pathophysiology and treatment of the anaemia of infection will be reviewed. Other mechanisms which can produce anaemia in infected individuals will also be reviewed. C1 Med Univ S Carolina, Div Hematol Oncol, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Hematol Oncol Sect, Charleston, SC USA. RP Means, RT (reprint author), Med Univ S Carolina, Div Hematol Oncol, 903 CSB,96 Jonathan Lucas St,POB 250623, Charleston, SC 29425 USA. RI Means, Robert/A-4454-2008 FU NHLBI NIH HHS [HL53703] NR 98 TC 54 Z9 56 U1 0 U2 0 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD JUN PY 2000 VL 13 IS 2 BP 151 EP 162 DI 10.1053/beha.1999.0065 PG 12 WC Hematology SC Hematology GA 344NA UT WOS:000088764700002 PM 10942618 ER PT J AU Evans, RH Scadden, DT AF Evans, RH Scadden, DT TI Haematological aspects of HIV infection SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Article DE acquired immunodeficiency syndrome/blood/*complications; HIV/immunology/*physiology; bone marrow/pathology; anaemia/aetiology; lymphopenia/aetiology; neutropenia/aetiology; thrombocytopenia/aetiology; blood coagulation; haematological diseases/*blood/immunology; human ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE THROMBOCYTOPENIC PURPURA; HEMATOPOIETIC GROWTH-FACTORS; RECOMBINANT-HUMAN-ERYTHROPOIETIN; PNEUMOCYSTIS-CARINII PNEUMONIA; COLONY-STIMULATING FACTOR; DEFICIENCY SYNDROME AIDS; T-CELL CLONES; BONE-MARROW; ACQUIRED-IMMUNODEFICIENCY AB Multiple interacting factors contribute to the haematological manifestations of HIV disease. The effects of HIV-I infection influence all haemopoietic cell lineages resulting in a spectrum of haematological abnormalities, Even in the absence of other pathological processes, bone marrow morphology is invariably abnormal, and anaemia, neutropenia and thrombocytopenia are all common during the course of disease. Intercurrent opportunistic infections may cause bone marrow suppression or induce specific cytopenias. Therapies used to treat HIV and its complications are frequently implicated as the cause of haematological dysfunction, and many have significant myelotoxic side-effects. insights into the molecular basis for many of these abnormalities have permitted a clearer understanding of the pathophysiology of HIV-I infection. Recombinant human growth factors that may be used to treat isolated cytopenias or to ameliorate the myelotoxic effects of other essential therapies. Lymph opoietic growth factors and the use of gene modified cells provide future therapeutic strategies that may alter the course of HIV disease. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, AIDS Res Ctr, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Canc, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dana Farber Canc Care,Immunodeficiency Dis Ctr, Boston, MA 02129 USA. RP Scadden, DT (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, AIDS Res Ctr, 149 13th St,Room 5212, Boston, MA 02129 USA. NR 95 TC 30 Z9 31 U1 1 U2 4 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD JUN PY 2000 VL 13 IS 2 BP 215 EP 230 DI 10.1053/beha.1999.0069 PG 16 WC Hematology SC Hematology GA 344NA UT WOS:000088764700006 PM 10942622 ER PT J AU Schumacher, HR AF Schumacher, HR TI Haemochromatosis SO BEST PRACTICE & RESEARCH IN CLINICAL RHEUMATOLOGY LA English DT Article DE iron; cartilage; metacarpophalangeal joint; chrondrocalcinosis; calcium pyrophosphate dihydrate (CPPD) ID IDIOPATHIC HEMOCHROMATOSIS; IRON OVERLOAD; GENETIC HEMOCHROMATOSIS; ARTHROPATHY; ARTHRITIS; FEATURES; BONE AB Arthropathy is a prominent but still underappreciated aspect of haemochromatosis. Clinical descriptions have characterized typical features, including involvement of the 2nd-3rd metacarpophalangeal joints with an osteoarthritic-like picture. Virtually any joint can be involved and can be a presenting clue to the underlying disease. The recent demonstration of the HFE gene on chromosome 6 with characteristic mutations should encourage further investigation. However, the pathogenesis of the arthropathy is not yet well understood. Treatment is also empirical and often unsatisfactory. Phlebotomies, although valuable to treat or prevent other features, do not predictably benefit the arthropathy. C1 Univ Penn, Sch Med, Div Rheumatol, Philadelphia, PA 19104 USA. Dept Vet Affairs Med Ctr, Rheumatol Immunol Ctr, Philadelphia, PA 19104 USA. RP Schumacher, HR (reprint author), Univ Penn, Sch Med, Div Rheumatol, Philadelphia, PA 19104 USA. NR 35 TC 8 Z9 8 U1 0 U2 1 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6942 J9 BEST PRACT RES CL RH JI Best Pract. Res. Clin. Rheumatol. PD JUN PY 2000 VL 14 IS 2 BP 277 EP 284 DI 10.1053/berh.2000.0065 PG 8 WC Rheumatology SC Rheumatology GA 336BV UT WOS:000088282800006 PM 10925745 ER PT J AU Mahomed, K Williams, MA Woelk, GB Mudzamiri, S Madzime, S King, IB Bankson, DD AF Mahomed, K Williams, MA Woelk, GB Mudzamiri, S Madzime, S King, IB Bankson, DD TI Leukocyte selenium, zinc, and copper concentrations in preeclamptic and normotensive pregnant women SO BIOLOGICAL TRACE ELEMENT RESEARCH LA English DT Article DE preeclampsia; pregnancy; trace elements; selenium; zinc; copper ID GLUTATHIONE-PEROXIDASE ACTIVITY; INDUCED HYPERTENSION; PLASMA; SUPPLEMENTATION; MAGNESIUM; GESTOSIS; CALCIUM; BLOOD AB Preeclampsia is an important cause of maternal and perinatal mortality worldwide. The etiology of this relatively common medical complication of pregnancy, however, remains unknown. We studied the relationship between maternal leukocyte selenium, zinc, and copper concentrations and the risk of preeclampsia in a large hospital-based case-control study. One hundred seventy-one women with proteinuric pregnancy-induced hypertension (with or without seizures) comprised the case group. Controls were 184 normotensive pregnant women. Leukocytes were separated from blood samples collected during the patients' postpartum labor and delivery admission. Leukocyte concentrations for the three cations were measured by inductively coupled plasma-mass spectrometry (ICP-MS). Concentrations for each cation were reported as micrograms per gram of total protein. Women with preeclampsia had significantly higher median leukocyte selenium concentrations than normotensive controls (3.23 vs 2.80 mu g/g total protein, p < 0.0001). Median leukocyte zinc concentrations were 31% higher in preeclamptics as compared with controls (179.15 vs 136.44 mu g/g total protein, p < 0.0001). Although median leukocyte copper concentrations were slightly higher for cases than controls, this difference did not reach statistical significance (17.72 vs 17.00 mu g/g total protein, p = 0.468). There was evidence of a linear increase in risk of preeclampsia with increasing concentrations of selenium and zinc. The relative risk for preeclampsia was 3.38 (adjusted odds ratio [OR] = 3.38, 95% confidence interval [CI] = 1.53-7.54) among women in the highest quartile of the control selenium distribution compared with women in the lowest quartile. The corresponding relative risk and 95% CI for preeclampsia was 5.30 (2.45-11.44) for women in the highest quartile of the control zinc distribution compared with women in the lowest quartile. There was no clear pattern of a linear trend in risk with increasing concentration of leukocyte copper concentrations (adjusted for Linear trend in risk = 0.299). Our results are consistent with some previous reports. Prospective studies are needed to determine whether observed alterations in selenium and zinc concentrations precede preeclampsia or whether the differences may be attributed to preeclampsia-related alterations in maternal and fetal-placental trace metal metabolism. C1 Univ Zimbabwe, Sch Med, Dept Obstet & Gynecol, Harare, Zimbabwe. Univ Zimbabwe, Sch Med, Dept Community Med, Harare, Zimbabwe. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. RP Mahomed, K (reprint author), Univ Zimbabwe, Sch Med, Dept Obstet & Gynecol, Harare, Zimbabwe. RI Mahomed, Kassam/M-1335-2013 FU FIC NIH HHS [T37-TW00049]; NICHD NIH HHS [HD/HL R01-32562] NR 25 TC 34 Z9 35 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0163-4984 J9 BIOL TRACE ELEM RES JI Biol. Trace Elem. Res. PD SUM PY 2000 VL 75 IS 1-3 BP 107 EP 118 DI 10.1385/BTER:75:1-3:107 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 333JX UT WOS:000088128100011 PM 11051601 ER PT J AU Folch, A Mezzour, S During, M Hurtado, O Toner, M Muller, R AF Folch, Albert Mezzour, Sonia Duering, Michael Hurtado, Octavio Toner, Mehmet Mueller, Ralph TI Stacks of Microfabricated Structures as Scaffolds for Cell Culture and Tissue Engineering SO BIOMEDICAL MICRODEVICES LA English DT Article DE BioMEMS; microfluidic patterning; PDMS; polyurethane; bone AB The fabrication of microscopic 3-dimensional structures for directing and inducing cell proliferation, migration and differentiation is a prevailing goal in tissue engineering. We have developed microfluidic molding methods to generate proof-of-principle polyurethane microstructures containing holes as models of synthetic tissue scaffolds. Molding is achieved by injecting sub-milliliter quantities of polyurethane precursor into a network of capped polydimethylsiloxane microchannels. After curing of the polyurethane, the microchannels can be opened to release a solid polyurethane structure which replicates the structure of the microchannel network. The microchannels can be reused to generate many exact replicas which can be stacked. We were able to design stacks that mimic various bone architectures. 3-dimensional microtomographic images were used for the first time for visualization and quality control of the stacked microfabricated structures. The polyurethane structures are amenable to cell culture. This technology could potentially be applied to microfabricate implanTable 3-dimensional scaffolds of specified architecture and composition for tissue growth and regeneration. C1 [Folch, Albert; Hurtado, Octavio; Toner, Mehmet] Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA. [Folch, Albert; Hurtado, Octavio; Toner, Mehmet] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Mezzour, Sonia; Duering, Michael; Mueller, Ralph] Beth Israel Deaconess Med Ctr, Orthoped Biomech Lab, Boston, MA 02215 USA. [Mezzour, Sonia; Duering, Michael; Mueller, Ralph] Harvard Univ, Sch Med, Boston, MA 02215 USA. RP Muller, R (reprint author), Beth Israel Deaconess Med Ctr, Orthoped Biomech Lab, 330 Brookline Ave,RN 115, Boston, MA 02215 USA. RI Muller, Ralph/A-1198-2008 OI Muller, Ralph/0000-0002-5811-7725 FU NIH [RR13322]; Maurice E. Muller Professorship in Biomechanics at Harvard Medical School FX This work was partially supported by NIH Grant RR13322 and by the Maurice E. Muller Professorship in Biomechanics at Harvard Medical School. We are grateful to Ulysses Balis for valuable assistance in microscopy image acquisition. NR 18 TC 30 Z9 31 U1 0 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1387-2176 EI 1572-8781 J9 BIOMED MICRODEVICES JI Biomed. Microdevices PD JUN PY 2000 VL 2 IS 3 BP 207 EP 214 DI 10.1023/A:1009932530375 PG 8 WC Engineering, Biomedical; Nanoscience & Nanotechnology SC Engineering; Science & Technology - Other Topics GA V33LA UT WOS:000209019100006 ER PT J AU Pauler, DK Laird, NM AF Pauler, DK Laird, NM TI A mixture model for longitudinal data with application to assessment of noncompliance SO BIOMETRICS LA English DT Article DE change-point models; compliance; longitudinal data; mixture model; reversible jump Markov chain Monte Carlo ID CLINICAL-TRIAL; ZIDOVUDINE; AIDS AB In clinical trials of a self-administered drug, repeated measures of a laboratory marker, which is affected by study medication and collected in all treatment arms, can provide valuable information on population and individual summaries of compliance. In this paper. we introduce a general finite mixture of nonlinear hierarchical models that allows estimates of component membership probabilities and random effect distributions for longitudinal data arising from multiple subpopulations, such as from noncomplying and complying subgroups in clinical trials. We outline a sampling strategy for fitting these models, which consists of a sequence of Gibbs. Metropolis-Hastings, and reversible jump steps, where the latter is required for switching between component models of different dimensions. Our model is applied to identify noncomplying subjects in the placebo arm of a clinical trial assessing the effectiveness of zidovudine (AZT) in the treatment of patients with HIV, where noncompliance was defined as initiation of AZT during the trial without the investigators' knowledge. We fit a hierarchical nonlinear change point model for increases in the marker MCV (mean corpuscular volume of erythrocytes) for subjects who noncomply and a constant mean random effects model for those who comply. As part of our Fully Bayesian analysis, we assess the sensitivity of conclusions to prior and modeling assumptions and demonstrate how external information and covariates call be incorporated to distinguish subgroups. C1 Massachusetts Gen Hosp, Ctr Biostat, Boston, MA 02114 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Pauler, DK (reprint author), Massachusetts Gen Hosp, Ctr Biostat, 50 Staniford St, Boston, MA 02114 USA. NR 16 TC 36 Z9 37 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 2000 VL 56 IS 2 BP 464 EP 472 DI 10.1111/j.0006-341X.2000.00464.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 325LR UT WOS:000087677500020 PM 10877305 ER PT J AU Lipsitz, SR Molenberghs, G Fitzmaurice, GM Ibrahim, J AF Lipsitz, SR Molenberghs, G Fitzmaurice, GM Ibrahim, J TI GEE with Gaussian estimation of the correlations when data are incomplete SO BIOMETRICS LA English DT Article DE binary response; missing data; multiple imputation; weighted estimating equations ID MISSING DATA; MODELS; REGRESSION; OUTCOMES AB This paper considers a modification of generalized estimating equations (GEE) for handling missing binary response data. The proposed method uses Gaussian estimation of the correlation parameters. i.e., the estimating function that yields an estimate of the correlation parameters is obtained from the multivariate normal likelihood. The proposed method yields consistent estimates of the regression parameters when data are missing completely at random (MCAR). However, when data are missing at random (MAR), consistency may not hold. In a simulation study with repeated binary outcomes that are missing at random, the magnitude of the potential bias that can arise is examined. The results of the simulation study indicate that, when the working correlation matrix is correctly specified, the bias is almost negligible for the modified GEE. In the simulation study, the proposed modification of GEE is also compared to the standard GEE. multiple imputation, and weighted estimating equations approaches. Finally, the proposed method is illustrated using data from a longitudinal clinical trial comparing two therapeutic treatments, zidovudine (AZT) and didanosine (ddI), in patients with HIV. C1 Med Univ S Carolina, Dept Biometry & Epidemiol, Charleston, SC 29425 USA. Limburgs Univ Ctr, Diepenbeek, Belgium. Harvard Sch Publ Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Lipsitz, SR (reprint author), Med Univ S Carolina, Dept Biometry & Epidemiol, Charleston, SC 29425 USA. FU NCI NIH HHS [CA 55576, CA 57253, CA 70101-01] NR 15 TC 38 Z9 39 U1 0 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 2000 VL 56 IS 2 BP 528 EP 536 DI 10.1111/j.0006-341X.2000.00528.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 325LR UT WOS:000087677500028 PM 10877313 ER PT J AU Gray, RJ AF Gray, RJ TI Estimation of regression parameters and the hazard function in transformed linear survival models SO BIOMETRICS LA English DT Article DE accelerated failure time model; penalized likelihood ID FAILURE TIME MODEL; CENSORED-DATA; RANK-TESTS AB An estimator of the regression parameters in a semiparametric transformed linear survival model is examined. This estimator consists of a single Newton-like update of the solution to a rank-based estimating equation from an initial consistent estimator. An automated penalized likelihood algorithm is proposed for estimating the optimal weight function for the estimating equations and the error hazard function that is needed in the variance estimator. In simulations, the estimated optimal weights are found to give reasonably efficient estimators of the regression parameters, and the variance estimators are found to perform well. The methodology is applied to an analysis of prognostic factors in non-Hodgkin's lymphoma. C1 Harvard Univ, Sch Publ Hlth, Dept Biostat Sci, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. RP Gray, RJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Biostat Sci, Dana Farber Canc Inst, 677 Huntington Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA57253] NR 20 TC 15 Z9 15 U1 0 U2 2 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 2000 VL 56 IS 2 BP 571 EP 576 DI 10.1111/j.0006-341X.2000.00571.x PG 6 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 325LR UT WOS:000087677500033 PM 10877318 ER PT J AU Lin, XH Ryan, L Sammel, M Zhang, DW Padungtod, C Xu, XP AF Lin, XH Ryan, L Sammel, M Zhang, DW Padungtod, C Xu, XP TI A scaled linear mixed model for multiple outcomes SO BIOMETRICS LA English DT Article DE asymptotic relative efficiency; effect sizes; estimating equations; global effect; maximum likelihood ID BINARY OUTCOMES; ENDPOINTS; TESTS AB We propose a scaled linear mixed model to assess the effects of exposure and other covariates on multiple continuous outcomes. The most general form of the model allows a different exposure effect for each outcome. An important special case is a model that represents the exposure effects using a common global measure that can be characterized in terms of effect sizes. Correlations among different outcomes within the same subject are accommodated using random effects. We develop two approaches to model fitting, including the maximum likelihood method and the working parameter method. A key feature of both methods is that they can be easily implemented by repeatedly calling software for fitting standard linear mixed models, e.g., SAS PROC MIXED. Compared to the maximum likelihood method, the working parameter method is easier to implement and yields fully efficient estimators of the parameters of interest. We illustrate the proposed methods by analyzing data from a study of the effects of occupational pesticide exposure on semen quality in a cohort of Chinese men. C1 Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Dana Farber Canc Inst, Dept Biostat Sci, Boston, MA 02115 USA. Harvard Univ, Dept Biostat, Boston, MA 02115 USA. Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. N Carolina State Univ, Dept Stat, Raleigh, NC 27695 USA. Harvard Univ, Dept Environm Hlth, Boston, MA 02115 USA. RP Lin, XH (reprint author), Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. RI Ryan, Louise/A-4562-2009 OI Ryan, Louise/0000-0001-5957-2490 FU NCI NIH HHS [CA48061, R29 CA76404] NR 15 TC 22 Z9 22 U1 0 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 2000 VL 56 IS 2 BP 593 EP 601 DI 10.1111/j.0006-341X.2000.00593.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 325LR UT WOS:000087677500037 PM 10877322 ER PT J AU Wiederschain, GY Koul, O Bovin, NV Nifant'ev, NE McCluer, R AF Wiederschain, GY Koul, O Bovin, NV Nifant'ev, NE McCluer, R TI The study of the substrate specificity of rat brain fucosyltransferase using synthetic acceptors SO BIOORGANICHESKAYA KHIMIYA LA Russian DT Article DE fucosyltransferase; substrate specificity; synthetic acceptors; rat brain ID FUCOSYL-TRANSFERASE; LEWIS-X; EXPRESSION; GLYCOSPHINGOLIPIDS; ADHESION AB The substrate specificity of fucosyltransferase (FT) from rat forebrain and cerebellum was studied using synthetic accepters. Of 16 accepters tested, only those containing the Gal beta 1-4GlcNAc beta 1-R fragment were subjected to enzymic fucosylation. The isomer with a 1-3 bond as well as lactose and oligosaccharides with an additional Neu5Ac residue attached to Gal or a Fuc residue attached to GlcNAc were not fucosylated whereas Fuc alpha 1-2Gal beta 1-4GlcNAc displayed the same substrate properties as Gal beta 1-4GlcNAc. FT from cerebellum and forebrain was shown to have the specificity similar to that of mammalian FT IV. The activity of the cerebellum FT with all types of substrates was higher than that of FT isolated from forebrain, the specificity profiles being similar. C1 Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117871, Russia. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. EK Shriver Ctr, Dept Biomed Sci, Waltham, MA 02452 USA. Russian Acad Sci, ND Zelinskii Organ Chem Inst, Moscow 117913, Russia. Univ Texas, Sch Med, Dept Pediat, Houston, TX 77030 USA. RP Bovin, NV (reprint author), Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Ul Miklukho Maklaya 16-10,GSP-7, Moscow 117871, Russia. NR 19 TC 1 Z9 1 U1 0 U2 0 PU MEZHDUNARODNAYA KNIGA PI MOSCOW PA 39 DIMITROVA UL., 113095 MOSCOW, RUSSIA SN 0132-3423 J9 BIOORG KHIM+ JI Bioorg. Khim. PD JUN PY 2000 VL 26 IS 6 BP 448 EP 451 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 340BY UT WOS:000088514300007 ER PT J AU Vedantham, V Cannon, SC AF Vedantham, V Cannon, SC TI Rapid and slow voltage-dependent conformational changes in segment IVS6 of voltage-gated Na+ channels SO BIOPHYSICAL JOURNAL LA English DT Article ID FAST-INACTIVATION GATE; SODIUM-CHANNEL; K+-CHANNEL; LOCAL-ANESTHETICS; POINT MUTATIONS; PERIODIC PARALYSIS; LIDOCAINE BLOCK; ALPHA-SUBUNIT; BATRACHOTOXIN; MOVEMENT AB Mutations in segment IVS6 of voltage-gated Nai channels affect fast-inactivation, slow-inactivation, local anesthetic action, and batrachotoxin (BTX) action. To detect conformational changes associated with these processes, we substituted a cysteine for a valine at position 1583 in the rat adult skeletal muscle sodium channel alpha-subunit, and examined the accessibility of the substituted cysteine to modification by 2-aminoethyl methanethiosulfonate (MTS-EA) in excised macropatches. MTS-EA causes an irreversible reduction in the peak current when applied both internally and externally, with a reaction rate that is strongly voltage-dependent. The rate increased when exposures to MTS-EA occurred during brief conditioning pulses to progressively more depolarized voltages, but decreased when exposures occurred at the end of prolonged depolarizations, revealing two conformational changes near site 1583, one coupled to fast inactivation, and one tightly associated with slow inactivation. Tetraethylammonium, a pore blocker, did not affect the reaction rate from either direction, while BTX, a lipophilic activator of sodium channels, completely prevented the modification reaction from occurring from either direction. We conclude that there are two inactivation-associated conformational changes in the vicinity of site 1583, that the reactive site most likely faces away from the pore, and that site 1583 comprises part of the BTX receptor. C1 Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Program Neurosci, Div Med Sci, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Neurobiol, Boston, MA 02114 USA. RP Cannon, SC (reprint author), Massachusetts Gen Hosp, Dept Neurol, EDR413A, Boston, MA 02114 USA. FU NIAMS NIH HHS [R01-AR42703] NR 41 TC 34 Z9 35 U1 0 U2 0 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUN PY 2000 VL 78 IS 6 BP 2943 EP 2958 PG 16 WC Biophysics SC Biophysics GA 323TE UT WOS:000087580400017 PM 10827974 ER PT J AU Weisberg, E Griffin, JD AF Weisberg, E Griffin, JD TI Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; BCR-ABL; GENE AMPLIFICATION; C-ABL; CHROMOSOME BREAKAGE; MARKER CHROMOSOMES; DRUG-RESISTANCE; POSITIVE CELLS; FRAGILE SITES; BLAST CRISIS AB The tyrosine kinase activity of the Bcr/Abl oncogene is required for transformation of hematopoietic cells. The tyrosine kinase inhibitor ST1571 (formerly called CGP57148B, Novartis Pharmaceuticals) inhibits BCR/ABL, TEL/ABL, and v-ABL kinase activity and inhibits growth and viability of cells transformed by any of these ABL oncogenes, Here we report the generation of 2 BCR/ABL-positive cell lines that have developed partial resistance to ST1571, BCR/ABL-transformed Ba/F3 hematopoietic cells and Philadelphia-positive human K562 cells were cultured in gradually increasing concentrations of ST1571 over a period of several months to generate resistant lines. Resistant Ba/F3.p210 cells were found to have an increase in Bcr/Abl messenger RNA, amplification of the Bcr/Abl transgene, and a greater than tenfold increase in the level of BCR/ABL protein. In contrast to Ba/F3.p210 cells, drug-resistant K562 cells did not undergo detectable amplification of the BCR/ABL gene, although they displayed a 2-fold to 3-fold increase in p210BCR/ABL protein. The addition of ST1571 to both resistant Ba/F3.p210 and K562 cells resulted in a rapid reduction of tyrosine phosphorylation of cellular proteins, similar to that observed for nonresistant cells, However, the inhibition of kinase activity was transient and partial and was not accompanied by apoptosis. The results suggest that resistance to ST1571 may be multifactorial. Increased expression of the target protein BCR/ABL was observed in both lines, and resulted from oncogene amplification in one line. However, altered drug metabolism, transport, or other related mechanisms may also contribute to drug resistance. (Blood, 2000;95:3498-3505) (C) 2000 by The American Society of Hematology. 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. RP Griffin, JD (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. NR 36 TC 328 Z9 344 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUN 1 PY 2000 VL 95 IS 11 BP 3498 EP 3505 PG 8 WC Hematology SC Hematology GA 319QA UT WOS:000087351600031 PM 10828035 ER PT J AU Aisenberg, AC AF Aisenberg, AC TI Historical review of lymphomas SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review ID NON-HODGKINS-LYMPHOMA; IMMUNOGLOBULIN GENE REARRANGEMENTS; T-CELL RECEPTOR; COMBINATION CHEMOTHERAPY; MALIGNANT-LYMPHOMA; BURKITT LYMPHOMAS; ANTIGEN RECEPTOR; DISEASE; CANCER; MARKER C1 Massachusetts Gen Hosp, Hematol Oncol Unit, Boston, MA 02114 USA. RP Aisenberg, AC (reprint author), Massachusetts Gen Hosp, Hematol Oncol Unit, Boston, MA 02114 USA. NR 120 TC 14 Z9 15 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUN PY 2000 VL 109 IS 3 BP 466 EP 476 DI 10.1046/j.1365-2141.2000.01988.x PG 11 WC Hematology SC Hematology GA 330WF UT WOS:000087983600002 PM 10886191 ER PT J AU Mischoulon, D Nierenberg, AA Kizilbash, L Rosenbaum, JF Fava, M AF Mischoulon, D Nierenberg, AA Kizilbash, L Rosenbaum, JF Fava, M TI Strategies for managing depression refractory to selective serotonin reuptake inhibitor treatment: A survey of clinicians SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Article; Proceedings Paper CT 152nd Annual Meeting of the American-Psychiatric-Association CY MAY 15-20, 1999 CL WASHINGTON, D.C. SP Amer Psychiat Assoc DE treatment-resistant depression; refractory depression; selective serotonin reuptake inhibitors; bupropion; augmentation ID BUSPIRONE AUGMENTATION; RESISTANT DEPRESSION; ANTIDEPRESSANT LATENCY; AUTORECEPTOR BLOCKADE; MAJOR DEPRESSION; FLUOXETINE; LITHIUM; PSYCHIATRISTS; PAROXETINE; BUPROPION AB Objective: To examine treatment practices in cases where selective serotonin reuptake inhibitors (SSRIs) are ineffective. Methods: We surveyed 801 clinicians (including 630 psychiatrists) attending the Massachusetts General Hospital's annual psychopharmacology review course. Clinicians were presented with a vignette about a patient with depression who had, responded partially to an SSRI and were asked to choose among various strategies available to manage this patient. Results: Of those surveyed, 466 clinicians had been in practice a mean of 16.6 years (SD 10.7). Not all clinicians chose to answer every question. Among 455 respondents, 84% (n = 382) chose to increase the dose of the SSRI, 10% (n = 47) chose augmentation or combination, and 7% (n = 31) opted for switching agents. When asked to switch to another agent, 448 responded of whom 52% (n = 235) chose a newer antidepressant, 34% (n = 152) chose another SSRI, 10% (n = 44) chose a tricyclic antidepressant (TCA), 2% (n = 8) chose a serotonin norepinephrine reuptake inhibitor (SNRI), 1% (n = 5) chose a monoamine oxidase inhibitor (MAOI), and 1% (n = 4) chose an undefined "other " agent. Among 445 respondents, bupropion was the most widely chosen augmenting agent (30%, n = 134),followed by lithium (22%, n = 98). West coast and Canadian clinicians preferred to switch to another SSRI rather than to a newer antidepressant. Canadian clinicians preferred lithium to bupropion as their first-choice augmenting agent, as did clinicians from academic settings. Clinicians from community, individual practice, or group settings favoured bupropion. More experienced clinicians preferred bupropion as a first-choice augmenter, whereas less experienced ones showed a slight preference for lithium. Canadian clinicians were more likely to use MAOIs as second-line agents. Conclusions: Clinicians in this sample often followed strategies different from those recommended in the literature. Bupropion may have an important role in augmentating treatment with SSRIs. C1 Massachusetts Gen Hosp, Depress Clin & Res Program, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Outpatient Psychiat Dept, Dept Psychiat, Boston, MA 02114 USA. RP Mischoulon, D (reprint author), Massachusetts Gen Hosp, Depress Clin & Res Program, Dept Psychiat, WAC-812,15 Parkman St, Boston, MA 02114 USA. NR 28 TC 57 Z9 57 U1 0 U2 2 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 260-441 MACLAREN ST, OTTAWA, ONTARIO K2H 2P3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD JUN PY 2000 VL 45 IS 5 BP 476 EP 481 PG 6 WC Psychiatry SC Psychiatry GA 329PQ UT WOS:000087916400009 PM 10900529 ER PT J AU Goldberg, SN Gazelle, GS Compton, CC Mueller, PR Tanabe, KK AF Goldberg, SN Gazelle, GS Compton, CC Mueller, PR Tanabe, KK TI Treatment of intrahepatic malignancy with radiofrequency ablation - Radiologic-pathologic correlation SO CANCER LA English DT Article DE radiofrequency; tumor ablation; minimally invasive therapy; thermal coagulation ID PERCUTANEOUS MICROWAVE COAGULATION; SMALL HEPATOCELLULAR-CARCINOMA; PHASE-II TRIAL; TISSUE ABLATION; LIVER METASTASES; HEPATIC METASTASES; THERMAL ABLATION; COLORECTAL-CARCINOMA; ETHANOL INJECTION; NEEDLE ELECTRODE AB BACKGROUND, Radiofrequency (RF)-induced tissue coagulation represents a new approach for the thermal destruction of tumors within the liver. The purpose of the current study was to 1) assess technique safety; 2) determine the extent and evolution of induced cellular damage; and 3) correlate the observed pathologic effects with radiologic studies. METHODS. Twenty-three tumors measuring less than or equal to 8 cm (19 colorectal metastases and 4 hepatomas) in 22 patients were treated with RF (range, 500-1550 milliamperes) using internally cooled electrodes. All treated tumors were resected to allow pathologic analysis. Eleven tumors were treated intraoperatively under ultrasonographic guidance and excised immediately. Twelve tumors were treated percutaneously using ultrasound or computed tomography (CT) guidance and subsequently were excised 3-7 days after ablation. Contrast-enhanced CT (n = 12) and magnetic resonance imaging (MRI) (n = 2) were performed after ablation of all percutaneously treated patients. RESULTS, Tumors treated intraoperatively did not demonstrate definitive coagulative necrosis. However, pathologic abnormalities suggestive of tissue injury were observed with hematoxylin and eosin staining, and absent cytosolic and mitochondrial enzyme activity suggested irreversible cellular damage. In contrast, specimens removed > 3 days after ablation showed definite, contiguous coagulative necrosis without intervening areas of viable tumor. CT and MRI scans demonstrated circumscribed hypodense, nonenhancing regions surrounding the electrode tract as early as 15 minutes after ablation, These corresponded within 2 mm to measurements of coagulation at pathology. CONCLUSIONS. RF ablation is a minimally invasive and safe approach to the treatment of tumors in the liver. Tumors treated with RF energy do not immediately demonstrate coagulative necrosis, but do show evidence of irreversible cellular damage. The extent of tumor necrosis correlates closely with findings at contrast-enhanced imaging. (C) 2000 American Cancer Society. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA. RP Goldberg, SN (reprint author), Beth Israel Deaconess Med Ctr, Dept Radiol, 330 Brookline Ave, Boston, MA 02215 USA. NR 36 TC 436 Z9 459 U1 2 U2 18 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD JUN 1 PY 2000 VL 88 IS 11 BP 2452 EP 2463 DI 10.1002/1097-0142(20000601)88:11<2452::AID-CNCR5>3.0.CO;2-3 PG 12 WC Oncology SC Oncology GA 316GZ UT WOS:000087160400005 PM 10861420 ER PT J AU Wong, AK Chin, L AF Wong, AK Chin, L TI An inducible melanoma model implicates a role for RAS in tumor maintenance and angiogenesis SO CANCER AND METASTASIS REVIEWS LA English DT Review DE mouse model; melanoma; RAS; tumor maintenance; angiogenesis ID ENDOTHELIAL GROWTH-FACTOR; HUMAN-MALIGNANT MELANOMA; TELOMERE MAINTENANCE; MELANOCYTIC LESIONS; FAMILIAL MELANOMA; FACTOR EXPRESSION; CARCINOMA-CELLS; INK4A LOCUS; IN-VIVO; SUPPRESSION AB The established tumor is maintained through complex and poorly understood host-tumor interactions guiding processes such as angiogenesis. The numerous and diverse genetic alterations that accompany tumor genesis raises questions as to whether experimental cancer-promoting mutations remain relevant to tumor maintenance. Utilizing a new doxycycline-inducible H-RAS(V12G) INK4a null mouse melanoma model, we have shown that melanoma genesis and maintenance are strictly dependent upon H-RAS(V12G) expression. Withdrawal of doxycycline and H-RAS(V12G) down-regulation resulted in clinical and histological regression of primary and explanted tumors. Moreover, the initial stages of regression were highlighted by dramatic activation of apoptosis in the tumor cells as well as host-derived endothelial cells. These data provide genetic evidence that H-RAS(V12G) plays a critical role in tumor maintenance and tumor angiogenesis. C1 Harvard Univ, Sch Med, Dept Dermatol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. RP Chin, L (reprint author), Harvard Univ, Sch Med, Dept Dermatol, 44 Binney St, Boston, MA 02115 USA. NR 72 TC 16 Z9 18 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD JUN PY 2000 VL 19 IS 1-2 BP 121 EP 129 DI 10.1023/A:1026537423753 PG 9 WC Oncology SC Oncology GA 376ZH UT WOS:000165486900017 PM 11191050 ER PT J AU Todo, T Rabkin, SD Martuza, RL AF Todo, T Rabkin, SD Martuza, RL TI Evaluation of ganciclovir-mediated enhancement of the antitumoral effect in oncolytic, multimutated herpes simplex virus type 1 (G207) therapy of brain tumors SO CANCER GENE THERAPY LA English DT Article DE herpes simplex virus; viral therapy; ganciclovir; bystander effect; thymidine kinase; brain neoplasm ID THYMIDINE KINASE GENE; LONG-TERM SURVIVAL; MALIGNANT GLIOMA; GAP-JUNCTIONS; HSVTK GENE; IN-VIVO; CELLS; REPLICATION; VECTOR; MUTANT AB G207 is a multimutated, conditionally replicating herpes simplex virus type 1 (HSV-1) that retains an intact viral thymidine kinase (HSV-tk) gene. The virus exhibits oncolytic activity in various tumors and is being evaluated in patients with recurrent malignant glioma. In view of the potentia I for ganciclovir (GCV) to either enhance or inhibit the antitumoral activity of HSV-tk-retaining HSV-1 vectors, we evaluated the effect of GCV administration on the antitumoral activity of G207. In culture, addition of GCV either had no effect or inhibited the cytocidal action of G207 at replication-permissive temperatures, while it significantly increased the cell killing in three of the four cell lines studied when virus replication was inhibited at nonpermissive temperatures. Using a G207-permissive immunocompetent mouse tumor model, subcutaneous N18 neuroblastoma in syngeneic A/J mice, we found that GCV treatment did not affect G207-mediated tumor growth inhibition at a variety of viral doses (10(5), 10(7), and 10(7) x 2 plaque-forming units). In A/J mice harboring intracerebral N18 tumors, GCV administration had no significant effect on the prolongation of survival by G207 inoculation. These findings suggest that GCV administration may not be beneficial to the efficacy of G207 tumor therapy under conditions that favor active viral replication, because the potential HSV-tk/GCV-mediated enhancement of G207 oncolytic activity may be balanced out by the inhibitory action of GCV on viral replication. C1 Georgetown Univ, Med Ctr, Dept Neurosurg, Mol Neurosurg Lab, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20007 USA. RP Todo, T (reprint author), Massachusetts Gen Hosp, Mol Neurosurg Lab CNY2, 149 13th St, Boston, MA 02129 USA. RI rabkin, samuel/C-2443-2012 OI rabkin, samuel/0000-0003-2344-2795 FU NINDS NIH HHS [NS32677] NR 58 TC 34 Z9 34 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD JUN PY 2000 VL 7 IS 6 BP 939 EP 946 DI 10.1038/sj.cgt.7700182 PG 8 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 326LU UT WOS:000087737700016 PM 10880026 ER PT J AU Pawlik, TM Nakamura, H Yoon, SS Mullen, JT Chandrasekhar, S Chiocca, EA Tanabe, KK AF Pawlik, TM Nakamura, H Yoon, SS Mullen, JT Chandrasekhar, S Chiocca, EA Tanabe, KK TI Oncolysis of diffuse hepatocellular carcinoma by intravascular administration of a replication-competent, genetically engineered herpesvirus SO CANCER RESEARCH LA English DT Article ID THYMIDINE KINASE GENE; SIMPLEX VIRUS; LIVER METASTASES; TUMOR-CELLS; THERAPY; CANCER; MUTANT; VECTOR; CYCLOPHOSPHAMIDE; ENHANCEMENT AB Herpes simplex virus type 1 (HSV-1) replication within tumors can mediate tumor regression (oncolysis). The genetically engineered, HSV-1 mutant rRp450 does not express viral ribonucleotide reductase and is therefore replication conditional. During the course of infection, rRp450 expresses the cytochrome P450 transgene and HSV-1 thymidine kinase gene, thereby enabling it to bioactivate the prodrugs cyclophosphamide and ganciclovir, respectively. rRp450 replication in hepatocellular carcinoma (HCC) cells is cytotoxic and liberates progeny virion that infect adjacent tumor cells. rRp450-mediated oncolysis is enhanced in the presence of cyclophosphamide, whereas it is inhibited in the presence of ganciclovir. As a consequence of defective viral ribonucleotide reductase expression, the yield of rRp450 progeny virions from infection of HCC cells is 3 to 4 log orders greater than that from infection of normal hepatocytes. This is associated with dramatic tumor reduction of diffuse HCC after a single intravascular administration of rRp450. rRp450 holds the promise of the dual therapeutic benefit of selective oncolysis and P450 transgene delivery. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Surg Oncol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurosurg Serv, Boston, MA 02114 USA. RP Tanabe, KK (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Surg,Div Surg Oncol, Cox Bldg 626,100 Blossom St, Boston, MA 02114 USA. FU NCI NIH HHS [CA64454, CA76183]; NIGMS NIH HHS [GM07035] NR 35 TC 81 Z9 83 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 2000 VL 60 IS 11 BP 2790 EP 2795 PG 6 WC Oncology SC Oncology GA 321BH UT WOS:000087434700010 PM 10850415 ER PT J AU Castells, A Gusella, JF Ramesh, V Rustgi, AK AF Castells, A Gusella, JF Ramesh, V Rustgi, AK TI A region of deletion on chromosome 22q13 is common to human breast and colorectal cancers SO CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; COMPARATIVE GENOMIC HYBRIDIZATION; CARCINOMA IN-SITU; ALLELIC LOSS; TARGET REGION; NEUROFIBROMATOSIS-2; HETEROZYGOSITY; TUMORIGENESIS; LOCALIZATION; CANDIDATE AB Chromosomal allelic losses have varying frequency in breast cancer, with key regions including chromosomes 1, 3p, 7q, 9p, 16q, 17, and 22q. Recently, we have been able to map a new target region of allelic loss on chromosome 22q involved in colorectal cancer. The aim of the current investigation was to determine whether this target region may also be involved in human breast carcinogenesis. Thirty-six pairs of matched normal and tumor specimens from breast cancer patients, as well as eight breast cancer-derived cell lines, were genotyped using 17 microsatellite markers spanning chromosome 22q. Allelic deletion was found in 19 of 36 tumors (53%), and the pattern observed in those cases with partial losses was consistent with a region flanked by D22S1171 and D22S928. This interval overlaps that identified ire colorectal cancer and comprises nearly 1.1 Mb. This study provides evidence of a common region of deletion on chromosome 22q13 involved in both breast and colorectal cancers and underscores the existence of putative tumor suppressor gene(s) at this location. C1 Univ Penn, Div Gastroenterol, Philadelphia, PA 19104 USA. Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. Univ Penn, Ctr Canc, Philadelphia, PA 19104 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Mol Neurogenet Unit, Charlestown, MA 02129 USA. RP Rustgi, AK (reprint author), Univ Penn, Div Gastroenterol, 415 Curie Blvd, Philadelphia, PA 19104 USA. FU NIDDK NIH HHS [DK56645]; NINDS NIH HHS [NS24279] NR 25 TC 66 Z9 68 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 2000 VL 60 IS 11 BP 2836 EP 2839 PG 4 WC Oncology SC Oncology GA 321BH UT WOS:000087434700019 PM 10850424 ER PT J AU Atwood, CS Huang, XD Khatri, A Scarpa, RC Kim, YS Moir, RD Tanzi, RE Roher, AE Bush, AI AF Atwood, CS Huang, XD Khatri, A Scarpa, RC Kim, YS Moir, RD Tanzi, RE Roher, AE Bush, AI TI Copper catalyzed oxidation of alzheimer A beta SO CELLULAR AND MOLECULAR BIOLOGY LA English DT Article DE human A beta 1-40; human A beta 1-42; human amyloid-derived A beta; amino acid analysis; copper; iron; metal catalyzed oxidation; histidine ID PLAQUE CORE PROTEIN; SUPEROXIDE-DISMUTASE; CU,ZN-SUPEROXIDE DISMUTASE; AMYLOID DEPOSITS; DISEASE; INACTIVATION; HISTIDINE; PEPTIDE; ENZYME; SITE AB A beta derived from amyloid plaques of Alzheimer's disease-affected brain contain several oxidative posttranslational modifications. In this study we have characterized the amino acid content of human amyloid-derived A beta and compared it with that of human synthetic A beta subjected to metal-catalyzed oxidation. Human amyloid derived A beta has an increased content of arginine (46%) and glutamate/glutamine residues (28%), but a decreased content of histidine residues (-32%) as compared to the expected amino acid content. Incubation of synthetic human A beta with Cu(II), but not Fe(III), in the presence of H2O2 similarly induced a decrease in histidine residues (-79%), but also a decrease in tyrosine residues (-28%). Our results suggest that histidine and tyrosine are most vulnerable to metal mediated oxidative attack, consistent with our earlier findings that Cu coordinated via histidine residues is redox competent. Our results suggest that the loss of histidine residues in human amyloid-derived A beta may be a result of Cu oxidation, and that unidentified post-translational mechanisms operate to modify other amino acids of A beta in vivo. C1 Harvard Univ, Massachusetts Gen Hosp E, Sch Med, Dept Psychiat & Genet,Lab Oxidat Biol, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp E, Sch Med, Aging Unit, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol & Genet, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Aging Unit, Charlestown, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Endocrine Unit, Prot Peptide Core Facil, Charlestown, MA 02129 USA. Sun Hlth Res Inst, Haldeman Lab Alzheimer Dis Res, Sun City, AZ 85351 USA. RP Bush, AI (reprint author), Harvard Univ, Massachusetts Gen Hosp E, Sch Med, Dept Psychiat & Genet,Lab Oxidat Biol, Bldg 149,13th St, Charlestown, MA 02129 USA. RI Bush, Ashley/A-1186-2007 OI Bush, Ashley/0000-0001-8259-9069 FU NIA NIH HHS [R03AG16933, R29AG12686] NR 38 TC 77 Z9 79 U1 0 U2 7 PU CELLULAR & MOLECULAR BIOLOGY PI NOISY-LE-GRAND PA PROF R WEGMANN RESIDENCE HAUSSMANN 1 AVENUE DU PAVE NEUF, 93160 NOISY-LE-GRAND, FRANCE SN 0145-5680 J9 CELL MOL BIOL JI Cell. Mol. Biol. PD JUN PY 2000 VL 46 IS 4 BP 777 EP 783 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 324QW UT WOS:000087633700008 PM 10875439 ER PT J AU Bartzokis, G Tishler, TA AF Bartzokis, G Tishler, TA TI MRI evaluation of basal ganglia ferritin iron and neurotoxicity in Alzheimer's and Huntingon's disease SO CELLULAR AND MOLECULAR BIOLOGY LA English DT Review DE Alzheimer's disease; Huntington's disease; magnetic resonance; ferritin; iron; basal ganglia; FDRI; relaxation; field-dependent ID AMYLOID PRECURSOR PROTEIN; DIFFERENT FIELD STRENGTHS; BRAIN IRON; MAGNETIC-RESONANCE; OXIDATIVE DAMAGE; FREE-RADICALS; PARKINSONS-DISEASE; METAL-IONS; IN-VITRO; NEUROFIBRILLARY TANGLES AB Background: The basal ganglia contain the highest levels of iron in the brain and post-mortem studies indicate a disruption of iron metabolism in the basal ganglia of patients with neurodegenerative disorders such as Alzheimer's disease (AD) and Huntington's disease (HD). Iron can catalyze free radical reactions and may contribute to oxidative damage observed in ND and HD brain. Magnetic resonance imaging (MRI) can quantify transverse relaxation rates, which can be used to quantify tissue iron stores as well as evaluate increases in MR-visible water tan indicator of tissue damage). Methods: A magnetic resonance imaging (MRI) method termed the field dependent relaxation rate increase (FDRI) was employed which quantifies the iron content of ferritin molecules (ferritin iron) with specificity through the combined use of high and low field-strength MRI instruments. Three basal ganglia structures (caudate, putamen and globus pallidus) and one comparison region (frontal lobe white matter) were evaluated. Thirty-one patients with AD and a group of 68 older control subjects, and 11 patients with HD and a group of 27 adult controls participated (4 subjects overlap between AD and HD controls). Results: Compared to their respective normal control groups, increases in basal ganglia FDRI levels were seen in both AD and HD. FDRI levels were significantly increased in the caudate (p = 0.007) and putamen (p = 0.008) of patients with AD with a trend toward an increase in the globus pallidus (p = 0.13). In the patients with HD, all three basal ganglia regions showed highly significant FDRI increases (p<0.001) and the magnitude of the increases were 2 to 3 times larger than those observed in AD versus control group comparison. For both HD and AD subjects, the basal ganglia FDRI increase was not a generalized phenomenon, as frontal lobe white matter FDRI levels were decreased in HD (p = 0.015) and remained unchanged in AD. Significant low field relaxation rate decreases (suggestive of increased MR-visible water and indicative of tissue damage) were seen in the frontal lobe white matter of both HD and AD but only the HD basal ganglia showed such decreases. Conclusions: The data suggest that basal ganglia ferritin iron is increased in HD and PLD. Furthermore, the increased iron levels do not appear to be a byproduct of the illness itself since they seem to be present at the onset of the diseases, and thus may be considered a putative risk factor. Published post-mortem studies suggest that the increase in basal ganglia ferritin iron may occur through different mechanisms in HD and AD. Consistent with the known severe basal ganglia damage, only HD basal ganglia demonstrated significant decreases in low field relaxation rates. MRI can be used to dissect differences in tissue characteristics, such as ferritin iron and MR-visible water, and thus could help clarify neuropathologic processes in vivo. Interventions aimed at decreasing brain iron levels, as well as reducing the oxidative stress associated with increased iron levels, may offer novel ways to delay the rate of progression and possibly defer the onset of AD and HD. C1 Univ Arkansas Med Sci, Dept Psychiat, Little Rock, AR 72205 USA. Cent Arkansas Vet Healthcare Syst, Mental Hlth Serv, Little Rock, AR 72214 USA. VA Greater Los Angeles Healthcare Syst, Mental Hlth Serv, Los Angeles, CA 90073 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Interdepartmental Program Neurosci, Los Angeles, CA 90024 USA. RP Bartzokis, G (reprint author), N Little Rock VA Med Ctr 116A, NLR, 2200 Ft Roots Dr,Bldg 170, N Little Rock, AR 72114 USA. RI Bartzokis, George/K-2409-2013 NR 102 TC 128 Z9 135 U1 5 U2 15 PU CELLULAR & MOLECULAR BIOLOGY PI NOISY-LE-GRAND PA PROF R WEGMANN RESIDENCE HAUSSMANN 1 AVENUE DU PAVE NEUF, 93160 NOISY-LE-GRAND, FRANCE SN 0145-5680 J9 CELL MOL BIOL JI Cell. Mol. Biol. PD JUN PY 2000 VL 46 IS 4 BP 821 EP 833 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 324QW UT WOS:000087633700012 PM 10875443 ER PT J AU Wong, IHN Chan, AT Johnson, PJ AF Wong, IHN Chan, AT Johnson, PJ TI Quantitative analysis of circulating tumor cells in peripheral blood of osteosarcoma patients using osteoblast-specific messenger RNA markers: A pilot study SO CLINICAL CANCER RESEARCH LA English DT Article ID POLYMERASE CHAIN-REACTION; HUMAN BREAST-CANCER; HEPATOCELLULAR-CARCINOMA; OSTEOPONTIN EXPRESSION; BONE SIALOPROTEIN; GENE-EXPRESSION; CYSTEINE SPARC; I COLLAGEN; PROTEIN; OSTEONECTIN AB Metastasis is a major cause of mortality and morbidity in osteosarcoma (OS) patients. To monitor tumor dissemination, we assessed the circulating tumor burden in OS patients by semiquantitative reverse transcription-PCR using osteocalcin, osteonectin, osteopontin, and type I collagen (COLL) mRNAs as molecular markers. We distinguished levels of the mRNAs in peripheral blood between OS patients and healthy subjects using an OS-derived cell line (Saos-2) as a reference standard. We prospectively analyzed 40 peripheral blood samples from 11 OS patients at diagnosis and 29 healthy subjects. In all 29 (100%) healthy subjects, we detected osteocalcin, osteonectin, and osteopontin mRNAs that were most likely attributed to illegitimate transcription in normal hematopoietic cells. In contrast, we found low COLL mRNA levels in only 35% (10 of 29) of healthy subjects, but significantly higher COLL mRNA levels In 91% (10 of 11) of OS patients (P < 0.0001). The reverse transcription-FCR assay for COLL mRNA was sensitive down to the detection of 10 Saos-2 cells among 10(6) normal peripheral blood nucleated cells. The upper limit of COLL mRNA determined among the healthy subjects was found exceeded by six OS patients. The substantially elevated COLL mRNA levels in peripheral blood seemed to originate from circulating malignant cells in these six OS patients, all of whom subsequently developed clinical metastases within 12 months of diagnosis (P = 0.002). Conversely, no metastases were detected in the remaining OS patients with normal COLL mRNA levels. Quantification of COLL mRNA may prove valuable for diagnosing OS micrometastasis and assessing prognosis. C1 Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anat & Cellular Pathol, Hong Kong, Hong Kong, Peoples R China. Chinese Univ Hong Kong, Prince Wales Hosp, Dept Clin Oncol, Hong Kong, Hong Kong, Peoples R China. Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Wong, IHN (reprint author), Chinese Univ Hong Kong, Prince Wales Hosp, Dept Anat & Cellular Pathol, Hong Kong, Hong Kong, Peoples R China. NR 43 TC 24 Z9 26 U1 0 U2 2 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 2000 VL 6 IS 6 BP 2183 EP 2188 PG 6 WC Oncology SC Oncology GA 322ZR UT WOS:000087540300009 PM 10873067 ER PT J AU Aronen, HJ Pardo, FS Kennedy, DN Belliveau, JW Packard, SD Hsu, DW Hochberg, FH Fischman, AJ Rosen, BR AF Aronen, HJ Pardo, FS Kennedy, DN Belliveau, JW Packard, SD Hsu, DW Hochberg, FH Fischman, AJ Rosen, BR TI High microvascular blood volume is associated with high glucose uptake and tumor angiogenesis in human gliomas SO CLINICAL CANCER RESEARCH LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; BRAIN-TUMORS; F-18 FLUORODEOXYGLUCOSE; MAGNETIC-SUSCEPTIBILITY; RADIATION NECROSIS; PROGNOSTIC FACTOR; CEREBRAL GLIOMAS; BREAST-CARCINOMA; CONTRAST AGENTS; MR CONTRAST AB The purpose of this investigation was to elucidate the association between microvascular blood volume and glucose uptake and to link these measures with tumor angiogenesis. We demonstrate a regionally specific correlation between tumor relative microvascular blood volume (CBV), determined in vivo with functional magnetic resonance imaging techniques, and tumor glucose uptake determined with fluorodeoxyglucose positron emission tomography, Regions of maximum glucose uptake were well matched with maximum CBV across all patients (n = 21; r = 0.572; P = 0.023). High-grade gliomas showed significantly elevated CBV and glucose uptake compared with low-grade gliomas, (P = 0.009 and 0.008, respectively). Correlations between CBV and glucose uptake were then determined on a voxel-by-voxel basis within each patient's glioma, Correlation indices varied widely, but in 16 of 21 cases of human glioma, CBV and glucose uptake were correlated (I > 0.150). These measures were well correlated in all cases when comparing healthy brain tissue in these same patients. Tumor vascularity, as determined immunohistochemically and morphometrically on clinical samples, revealed statistically significant relationships with functional imaging characteristics in vivo. Regional heterogeneities in glucose uptake were wed matched with functional magnetic resonance imaging CBV maps. Our findings support the concept that there is an association of microvascular density and tumor energy metabolism in most human gliomas. In addition, the findings are likely to have important clinical applications in the initial evaluation, treatment, and longitudinal monitoring of patients with malignant gliomas. C1 Massachusetts Gen Hosp, NMR Ctr, Boston, MA 02129 USA. Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Pathol Neuropathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurosurg, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Univ Helsinki, Cent Hosp, Dept Radiol, FIN-00290 Helsinki, Finland. New York Med Coll, Dept Radiat Med, Valhalla, NY 10595 USA. Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA. MIT, Dept Nucl Engn, Cambridge, MA 02139 USA. RP Rosen, BR (reprint author), Massachusetts Gen Hosp, NMR Ctr, 2nd Floor,Bldg 149,13th St, Boston, MA 02129 USA. RI Kennedy, David/H-3627-2012 FU FIC NIH HHS [1 F05 TW04520]; NCI NIH HHS [R01-CA40303]; NHLBI NIH HHS [R01-HL39810] NR 50 TC 108 Z9 113 U1 0 U2 4 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 2000 VL 6 IS 6 BP 2189 EP 2200 PG 12 WC Oncology SC Oncology GA 322ZR UT WOS:000087540300010 PM 10873068 ER PT J AU Dinovo, EC Renner, SW Rubin, SA Mody, FV AF Dinovo, EC Renner, SW Rubin, SA Mody, FV TI Discordant Troponin T results with the CardiacT as a function of total CK activity. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 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 2000 VL 46 IS 6 SU S MA 349 BP A91 EP A91 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600351 ER PT J AU Gudrais, P AF Gudrais, P TI Automating CA 125 - TOSOH AIA-PACK CA 125 NexIA vs. CENTOCOR RIAII. SO CLINICAL CHEMISTRY 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 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 2000 VL 46 IS 6 SU S MA 616 BP A159 EP A160 PN 2 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600615 ER PT J AU Khoury, RH Sluss, PM MacRae, AR AF Khoury, RH Sluss, PM MacRae, AR TI Evaluation of inhibin B assay in human serum and its potential use as a marker for gonadal function. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. Lakeridge Hlth Corp, Inst Res, Oshawa, ON, Canada. 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 2000 VL 46 IS 6 SU S MA 490 BP A128 EP A128 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600490 ER PT J AU Lewandrowski, EL Misiano, D Tochka, L Lewandrowski, KB AF Lewandrowski, EL Misiano, D Tochka, L Lewandrowski, KB TI Process improvement for bedside capillary glucose testing in a large academic medical center: The impact of new technology on point-of-care testing. 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 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 2000 VL 46 IS 6 SU S MA 46 BP A12 EP A12 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600047 ER PT J AU Palmer-Toy, DE Szczepiorkowski, ZM Shih, V Van Cott, EM AF Palmer-Toy, DE Szczepiorkowski, ZM Shih, V Van Cott, EM TI Compatibility of the Abbott IMx Homocysteine assay with citrate-anticoagulated plasma. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Szczepiorkowski, Zbigniew/A-1359-2007 OI Szczepiorkowski, Zbigniew/0000-0003-2357-9564 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 2000 VL 46 IS 6 SU S MA 527 BP A137 EP A137 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600527 ER PT J AU Sakamoto, H Sakamoto, M Nader, R Leary, C Zhao, L Kradin, R AF Sakamoto, H Sakamoto, M Nader, R Leary, C Zhao, L Kradin, R TI Measurement of plasma bleomycin concentration by high-performance liquid chromatography and fluorometric detection. SO CLINICAL CHEMISTRY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 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 2000 VL 46 IS 6 SU S MA 545 BP A141 EP A141 PN 2 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 326GU UT WOS:000087725600545 ER PT J AU Ring, D Jupiter, JB AF Ring, D Jupiter, JB TI Percutaneous and limited open fixation of fractures of the distal radius SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article AB Percutaneous and limited open fixation of fractures of the distal radius is an important method of treatment for many unstable fractures such as unstable dorsal bending fractures, shearing fractures of the radial styloid and lunate facet, and simple articular fractures. The quality of the reduction is monitored with image intensification and the tactic of the reduction is based on manipulation of the fracture fragments by longitudinal traction, percutaneous manipulation, and in some instances by direct manipulation through small incisions. The role of arthroscopy remains uncertain and may represent an alternative to open exposure of the articular surface in some patients although bone grafting may be necessary in patients with fractures with significant metaphyseal defects. C1 Massachusetts Gen Hosp, Dept Orthopaed, Hand Surg Serv, Boston, MA 02114 USA. RP Ring, D (reprint author), 11 Hancock St,Unit 4, Boston, MA 02114 USA. NR 19 TC 16 Z9 17 U1 0 U2 0 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 2000 IS 375 BP 105 EP 115 PG 11 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 319VX UT WOS:000087365000013 PM 10853159 ER PT J AU Lietman, SA Tomford, WW Gebhardt, MC Springfield, DS Mankin, HJ AF Lietman, SA Tomford, WW Gebhardt, MC Springfield, DS Mankin, HJ TI Complications of irradiated allografts in orthopaedic tumor surgery SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID CROSS-LINKING; MECHANICAL-PROPERTIES; COLLAGEN; PROTEIN AB Massive structural allografts used for replacement of bone defects after removal of bone tumors have several complications, including fracture, infection, and nonunion. To decrease the rate of infection, irradiation of selected allografts before their implantation was performed. This study evaluated the complications in patients with these irradiated grafts, Twenty-four patients were identified who had received allografts from 1987 through 1991 that were irradiated before implantation. The dosage of radiation was between 10 kGy and 30 kGy, The mean length of followup of the patients was 5 years (range, 2-9 years). These grafts were compared with a control group of grafts that were not irradiated but were implanted during the same time and used for similar diagnostic problems with defects of similar size. The outcomes of the groups differed significantly only in the incidence of allograft fracture. These findings indicate that high-dose irradiation to bone allografts is associated with a higher rate of fracture than are similar reconstructions using nonirradiated allografts. C1 Johns Hopkins Univ, Sch Med, Dept Orthoped Surg, Baltimore, MD 21287 USA. Massachusetts Gen Hosp, Dept Orthoped Surg, Boston, MA 02114 USA. Mt Sinai Hosp, Dept Orthoped Surg, New York, NY 10029 USA. RP Lietman, SA (reprint author), Johns Hopkins Univ, Sch Med, Dept Orthoped Surg, JHOC 5251,601 N Caroline St, Baltimore, MD 21287 USA. NR 19 TC 58 Z9 61 U1 0 U2 5 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 2000 IS 375 BP 214 EP 217 PG 4 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 319VX UT WOS:000087365000026 PM 10853172 ER PT J AU George, MS AF George, Mark S. TI New Methods of Brain Stimulation Are Improving Research and Therapy in Obsessive-Compulsive Disorder SO CNS SPECTRUMS LA English DT Article AB Over the past decade, new functional neuroimaging tools have enabled researchers to identify the specific brain regions involved in obsessive-compulsive disorder (OCD). More recently, researchers have perfected several new techniques for stimulating the brain. With some exception's, these new brain stimulation techniques are regionally specific and less invasive than older methods. As a class, these "somatic interventions" build on prior neuroanatomic information about OCD. This article reviews the past and current status of these brain stimulation methodologies, which promise to revolutionize neuropsychiatric research and therapy over the next 10 to 20 years. As the brain circuits in. OCD and the pharmacology within those circuits become better understood, these brain stimulation techniques hold particular promise in. helping to understand and perhaps treat OCD. CNS Spectrums 2000;5(6)suppl 4:12-17 C1 [George, Mark S.] Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. [George, Mark S.] Ralph H Johnson Vet Hosp, Charleston, SC USA. [George, Mark S.] MUSC Funct Neuroimaging Res Div, Charleston, SC USA. RP George, MS (reprint author), Med Univ S Carolina, Dept Radiol, 171 Ashley Ave, Charleston, SC 29425 USA. NR 39 TC 5 Z9 5 U1 0 U2 0 PU M B L COMMUNICATIONS, INC PI NEW YORK PA 333 HUDSON ST, 7TH FLOOR, NEW YORK, NY 10013 USA SN 1092-8529 J9 CNS SPECTRUMS JI CNS Spectr. PD JUN PY 2000 VL 5 IS 6 BP 12 EP 17 PG 6 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA V04RD UT WOS:000207074600002 ER PT J AU Follette, VM Batten, SV AF Follette, VM Batten, SV TI The role of emotion in psychotherapy supervision: A contextual behavioral analysis SO COGNITIVE AND BEHAVIORAL PRACTICE LA English DT Article ID EXPERIENTIAL AVOIDANCE; IMPACT AB Mile much has been written regarding the importance of emotional expression in psychotherapy, much less attention has been paid to the role of emotion in clinical supervision. Recently, several radical behavioral psychotherapies have been developed that may shed light on theoretical issues important to the expression of emotion in supervision. This paper describes the theoretical viewpoints of two such contextual therapies, Functional Analytic Psychotherapy (FAP) and Acceptance and Commitment Therapy (ACT), and applies the frameworks of these therapies to the process of clinical supervision. C1 Univ Nevada, Dept Psychol, Reno, NV 89557 USA. Natl Ctr PTSD, Boston, MA USA. RP Follette, VM (reprint author), Univ Nevada, Dept Psychol, Reno, NV 89557 USA. NR 20 TC 10 Z9 10 U1 2 U2 5 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 2000 VL 7 IS 3 BP 306 EP 312 DI 10.1016/S1077-7229(00)80088-7 PG 7 WC Psychology, Clinical SC Psychology GA 473UR UT WOS:000171066900008 ER PT J AU Safren, SA Heimberg, RG Lerner, J Henin, A Warman, M Kendall, PC AF Safren, SA Heimberg, RG Lerner, J Henin, A Warman, M Kendall, PC TI Differentiating anxious and depressive self-statements: Combined factor structure of the anxious self-statements questionnaire and the automatic thoughts questionnaire-revised SO COGNITIVE THERAPY AND RESEARCH LA English DT Article DE depression; anxiety; automatic thoughts; cognition; self-statements ID CONTENT-SPECIFICITY HYPOTHESIS; COGNITIVE CONTENT-SPECIFICITY; HIERARCHICAL ARRANGEMENT; NEGATIVE AFFECTIVITY; ANXIETY DISORDERS; TRIPARTITE MODEL; SOCIAL ANXIETY; INVENTORY; THINKING; RELIABILITY AB Cognitive models of negative emotion suggest that depression and anxiety are associated with different cognitive features. However, distinguishing anxious form depressive self-talk is difficult because of the overlap between anxiety and depression. The Automatic Thoughts Questionnaire-Revised was developed to assess self-statements related to anxiety. However, confirmatory factor analyses of the pooled items from both measures suggested that this implicit two-factor model did not fit the data. Instead, an exploratory common factor analysis yielded four orthogonal factors: self-statements reflecting depression/hopelessness, self-statements reflecting one's inability to cope, self-statements reflecting anxiety/uncertainty about the future, and positive affect self-statements. In an exploratory hierarchical factor analysis, the first three factors loaded onto a single higher order factor, while positive affect self-statements. In an exploratory hierarchical factor analysis, the first three factors loaded onto a single higher order factor, while positive affect self-statements dod not. Attempts to predict depression and trait anxiety on the basis of these factor scores produced complex results, at least potentially due to th relative impurity of the criterion measures. These results provide evidence for the differentiation of anxious and depressive self-talk as well as for the common ground shared by these aspects of internal dialogue. They also support the future study of the factors from the ATQ-R and ASSQ in relation to more construct-pure measures of anxiety and depression. C1 Temple Univ, Dept Psychol, Philadelphia, PA 19122 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02115 USA. RP Heimberg, RG (reprint author), Temple Univ, Dept Psychol, Weiss Hall,1701 N 13th St, Philadelphia, PA 19122 USA. NR 49 TC 23 Z9 23 U1 0 U2 9 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0147-5916 J9 COGNITIVE THER RES JI Cogn. Ther. Res. PD JUN PY 2000 VL 24 IS 3 BP 327 EP 344 DI 10.1023/A:1005515421103 PG 18 WC Psychology, Clinical SC Psychology GA 326LA UT WOS:000087735900005 ER PT J AU Buergler, JM Tio, FO Schulz, DG Khan, MM Mazur, W French, BA Raizner, AE Ali, NM AF Buergler, JM Tio, FO Schulz, DG Khan, MM Mazur, W French, BA Raizner, AE Ali, NM TI Use of nitric-oxide-eluting polymer-coated coronary stents for prevention of restenosis in pigs SO CORONARY ARTERY DISEASE LA English DT Article DE nitric oxide; angioplasty; animal model ID CONTROLLED BIOLOGICAL RELEASE; VASCULAR SMOOTH-MUSCLE; BALLOON ANGIOPLASTY; NUCLEOPHILE COMPLEXES; RELAXING FACTOR; ARTERY DISEASE; NO DONOR; ENDOTHELIUM; PROLIFERATION; AGENTS AB Background Restenosis after angioplasty remains an unresolved problem despite an increase in use of coronary stents. It has been theorized that nitric oxide (NO) exerts several actions that can prevent restenosis. These include inhibition of proliferation of smooth muscle cells, prevention of arterial spasms, and decreasing aggregation of platelets in response to exposure to collagen. Objective To determine whether NO coated stents decrease restenosis in a pig balloon injury model. Methods We used coronary stents impregnated with a slow-release precursor of NO in the porcine model of restenosis. Tantalum coil coronary stents (Cordis) were coated with a polymer impregnated with a slow-release precursor of NO. Polymer-coated stents without active precursors were used as controls. Oversized stents were mounted on a delivery balloon and subsequently deployed in the right coronary and left anterior descending arteries of each animal. Results Repeated recording of angiograms demonstrated that changes in minimum lumen diameter on going iron? immediately after stenting to 28-day follow-up for the control and NO-eluting-stent groups were similar, namely decreases of 1.89 +/- 0.33 and 2.08 +/- 0.28 mm, respectively The morphometric results, showing that severe luminal narrowing occurred for both groups, were similar The percentage area stenoses were 85 +/- 5% for the control group and 84 +/- 6% for the NO-eluting group. Histology demonstrated that profuse formation of neointima and an inflammatory cell infiltrate occurred. Conclusions Severe diameter stenosis occurred both for control and for treatment groups. The degree of angiographic stenosis was markedly worse than that previously reported for this model. Sustained release of a precursor of NO did not prevent restenosis in this model. This might have been due to a lack of efficacy of nitric oxide or to a profuse and overwhelming stimulatory effect of the polymer in the coated stents. Coron Artery Dis 11:351-357 (C) 2000 Lippincott Williams & Wilkins. C1 Baylor Coll Med, Dept Med, Cardiol Sect, VA Med Ctr, Houston, TX 77030 USA. Methodist Hosp, Houston, TX 77030 USA. Univ Texas, Dept Pathol, San Antonio, TX 78285 USA. RP Ali, NM (reprint author), Baylor Coll Med, Dept Med, Cardiol Sect, VA Med Ctr, Mail Stn 111B,2002 Holcombe Blvd, Houston, TX 77030 USA. NR 37 TC 17 Z9 23 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0954-6928 J9 CORONARY ARTERY DIS JI Coronary Artery Dis. PD JUN PY 2000 VL 11 IS 4 BP 351 EP 357 DI 10.1097/00019501-200006000-00009 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 321HX UT WOS:000087451000009 PM 10860179 ER PT J AU Stoeckle, JD AF Stoeckle, JD TI From service to commodity: Corporization, competition, commodification, and customer culture transforms health care SO CROATIAN MEDICAL JOURNAL LA English DT Article DE corporate practice; costs and cost analysis; doctor-patient relations; health care market; healthcare industry; health services; marketing of health services; patient selection; priorities; health; rationing; health care AB Corporate medical practice, a market economy, and a consumer culture are transforming health care. The service relationships of doctors with patients are now commodities. The doctor, directed by disease management protocols (to improve outcomes, reduce costs, and standardize care), is, in effect, providing programmed service commodities. In addition, medical-surgical specialties, now "packaged" for the care of body parts and conditions (as Breast, Stroke, Obesity, Aneurysm Centers), are also made service commodities, marketed by newspaper advertisements, TV, radio, and Internet to patient-customers in search of a healthy body. In sum, the promise of corporate practice in a competitive market economy is greater efficiency and productivity to reduce the costs of care that are a burden on industries and the state. Viewed from office encounters with patients, such transformation of services to commodities changes the doctor-patient relationship and the moral mission of care. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Stoeckle, JD (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 19 TC 9 Z9 9 U1 1 U2 6 PU PABST SCIENCE PUBLISHERS PI LENGERICH PA EICHENGRUND 28, D-49525 LENGERICH, GERMANY SN 0353-9504 J9 CROAT MED J JI Croat. Med. J. PD JUN PY 2000 VL 41 IS 2 BP 141 EP 143 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 331PF UT WOS:000088026900003 PM 10853040 ER PT J AU Guarente, L Silver, PA AF Guarente, L Silver, PA TI Nucleus and gene expression - Function following form in the nucleus - Editorial overview SO CURRENT OPINION IN CELL BIOLOGY LA English DT Editorial Material C1 MIT, Dept Biol, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Guarente, L (reprint author), MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2000 VL 12 IS 3 BP 279 EP 279 DI 10.1016/S0955-0674(00)00088-0 PG 1 WC Cell Biology SC Cell Biology GA 315XL UT WOS:000087138200001 ER PT J AU Lee, DG Bell, SP AF Lee, DG Bell, SP TI ATPase switches controlling DNA replication initiation SO CURRENT OPINION IN CELL BIOLOGY LA English DT Review ID ESCHERICHIA-COLI CHROMOSOME; NUCLEOTIDE-BINDING SITE; MCM PROTEINS; IN-VIVO; SACCHAROMYCES-CEREVISIAE; LAMBDA-P; S-PHASE; COMPLEX; HELICASE; ORIGINS AB Proteins that bind and hydrolyze ATP are frequently involved in the early steps of DNA replication. Recent studies of Saccharomyces cerevisiae suggest that two members of the AAA+ ATPase family - the origin recognition complex and Cdc6p - have separable roles for ATP binding and ATP hydrolysis during eukaryotic DNA replication. Intriguingly, the proposed regulation of these eukaryotic replication proteins by ATP has functional similarities to the ATP-dependent control of the DnaA and DnaC initiation factors from Escherichia coli. Comparison of the ATP regulation of these factors suggests that ATP binding and hydrolysis acts as a molecular switch that couples key events during initiation of replication. This switch results in a significant change in protein function. C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. MIT, Dept Biol, Cambridge, MA 02139 USA. RP Lee, DG (reprint author), Massachusetts Gen Hosp, Wellman Bldg,10th Floor,50 Blossom St, Boston, MA 02114 USA. NR 36 TC 88 Z9 88 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD JUN PY 2000 VL 12 IS 3 BP 280 EP 285 DI 10.1016/S0955-0674(00)00089-2 PG 6 WC Cell Biology SC Cell Biology GA 315XL UT WOS:000087138200002 PM 10801458 ER PT J AU Onouye, T Menaker, G Christian, M Moy, R AF Onouye, T Menaker, G Christian, M Moy, R TI Occlusive dressing versus oxygen mist therapy following CO2 laser resurfacing SO DERMATOLOGIC SURGERY LA English DT Article ID CARBON-DIOXIDE LASER; SKIN; SURGERY; CARE AB BACKGROUND. Oxygen is an essential element for collagen synthesis and reepithelialization. The use of topical oxygen after CO2 laser resurfacing has not been studied. OBJECTIVE. TO compare the rate and quality of healing in wounds treated with an oxygen mist to those treated with occlusive dressing following CO2 laser resurfacing. METHODS, Three patients underwent CO2 laser resurfacing to each half of the face 3 weeks apart. Postoperatively, half of the face was treated with an oxygen mist protocol for 5 days, while the other half was treated with occlusive dressing for 4 days. RESULTS. At postoperative day 5, significantly less crusting was observed on the half of the face treated with the oxygen mist protocol (p < 0.05). CONCLUSION. The oxygen mist postoperative protocol may offer patients similar overall healing rates and significantly less crusting compared to occlusive dressing. C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Massachusetts Gen Hosp, Dept Dermatol Surg, Boston, MA 02114 USA. Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, Div Dermatol, Los Angeles, CA USA. RP Moy, R (reprint author), 100 UCLA Med Plaza,Suite 590, Los Angeles, CA 90095 USA. NR 22 TC 4 Z9 4 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1076-0512 J9 DERMATOL SURG JI Dermatol. Surg. PD JUN PY 2000 VL 26 IS 6 BP 572 EP 576 DI 10.1046/j.1524-4725.2000.99060.x PG 5 WC Dermatology; Surgery SC Dermatology; Surgery GA 320KX UT WOS:000087401300015 PM 10848939 ER PT J AU Behroozan, DS Christian, MM Moy, RL AF Behroozan, DS Christian, MM Moy, RL TI Mycobacterium fortuitum infection following neck liposuction: A case report SO DERMATOLOGIC SURGERY LA English DT Article C1 Univ Calif Los Angeles, W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA USA. RP Moy, RL (reprint author), 100 UCLA Med Plaza,Suite 590, Los Angeles, CA 90024 USA. NR 12 TC 19 Z9 20 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 1076-0512 J9 DERMATOL SURG JI Dermatol. Surg. PD JUN PY 2000 VL 26 IS 6 BP 588 EP 590 DI 10.1046/j.1524-4725.2000.99165.x PG 3 WC Dermatology; Surgery SC Dermatology; Surgery GA 320KX UT WOS:000087401300020 PM 10848943 ER PT J AU Majumdar, A Drummond, IA AF Majumdar, A Drummond, IA TI The zebrafish floating head mutant demonstrates podocytes play an important role in directing glomerular differentiation SO DEVELOPMENTAL BIOLOGY LA English DT Article DE zebrafish; floating head; pronephros; glomerulus; podocyte; sclerotome ID ENDOTHELIAL GROWTH-FACTOR; SONIC-HEDGEHOG; FLOOR PLATE; DANIO-RERIO; SCLEROTOME INDUCTION; VASCULAR DEVELOPMENT; PANCREAS DEVELOPMENT; KIDNEY DEVELOPMENT; FACTOR VEGF; NOTOCHORD AB In zebrafish, the pronephric glomerulus occupies a midline position underneath the notochord and is vascularized through angiogenic capillary ingrowth from the dorsal aorta. The midline mutants floating head (flh), sonic you (syu), and you-too (yot) provide the opportunity to study glomerular differentiation in the absence of the notochord and vascularization from the dorsal aorta. In flh, syu, and yot mutants, glomeruli differentiate at ectopic lateral positions within the embryo and contain morphologically identifiable podocyte and endothelial cell types. In the absence of the dorsal aorta, endothelia from an alternate source are recruited by podocytes during glomerular vascularization to make functional glomeruli. Our results suggest that midline signals are required for proper glomerular morphogenesis but not for the differentiation of podocytes. Podocytes appear to play an important role in directing cellular recruitment events leading to glomerular differentiation. Furthermore, we find defects in sclerotomal development that correlate with defects in glomerular morphogenesis suggesting a possible link between the formation of these embryonic structures, (C) 2000 Academic Press. C1 Massachusetts Gen Hosp, Renal Unit, Charlestown, MA 02129 USA. RP Majumdar, A (reprint author), Massachusetts Gen Hosp, Renal Unit, 149 13th St, Charlestown, MA 02129 USA. FU NIDDK NIH HHS [DK09763, P01 DK54711, R01 DK53093] NR 57 TC 37 Z9 38 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 BP 147 EP 157 DI 10.1006/dbio.2000.9642 PG 11 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500012 PM 10885753 ER PT J AU Barbara, PDS Roberts, DJ AF Barbara, PDS Roberts, DJ TI Hoxa-13 mutant expression downregulates Bapx1 homeodomain gene and leads to hindgut and tail malformations in chicken. SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 142 BP 246 EP 246 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500155 ER PT J AU Serluca, FC Fishman, MC AF Serluca, FC Fishman, MC TI Mutations affecting the form and function of the zebrafish pronephros SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 170 BP 251 EP 251 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500183 ER PT J AU Huang, NN Walhout, AJ Vidal, M Hunter, CP AF Huang, NN Walhout, AJ Vidal, M Hunter, CP TI MEX-3 interacting proteins required to regulate pal-1 translation SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 222 BP 259 EP 259 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500232 ER PT J AU Nielsen, CM Murtaugh, LC Roberts, DJ AF Nielsen, CM Murtaugh, LC Roberts, DJ TI Bapx1, Bmp4, and Nkx2.5 are involved in patterning regions of the chick gut SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 256 BP 265 EP 265 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500264 ER PT J AU Chan, J Mabiy, JDD Chen, JN Goldstein, NB Thomas, M Cleary, J Fishman, MC Roberts, TM AF Chan, J Mabiy, JDD Chen, JN Goldstein, NB Thomas, M Cleary, J Fishman, MC Roberts, TM TI EPH signaling is required for gastrulation and prechordal plate movement SO DEVELOPMENTAL BIOLOGY LA English DT Meeting Abstract C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Massachusetts Gen Hosp E, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUN 1 PY 2000 VL 222 IS 1 MA 290 BP 271 EP 271 PG 1 WC Developmental Biology SC Developmental Biology GA 323AN UT WOS:000087542500294 ER PT J AU Mironova, MA Klein, RL Virella, GT Lopes-Virella, MF AF Mironova, MA Klein, RL Virella, GT Lopes-Virella, MF TI Anti-modified LDL antibodies, LDL-containing immune complexes, and susceptibility of LDL to in vitro oxidation in patients with type 2 diabetes SO DIABETES LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; MONOCYTE-DERIVED MACROPHAGES; CHOLESTERYL ESTER SYNTHESIS; CORONARY-ARTERY DISEASE; FATTY-ACID COMPOSITION; OXIDIZED LDL; MUSCLE TRIGLYCERIDE; RADICAL GENERATION; LIPID-PEROXIDATION; METABOLIC CONTROL AB We investigated the hypothesis that modified lipoproteins trigger an immune response leading to the production of autoantibodies and subsequently to the formation of atherogenic immune complexes (IC). We recruited 20 type 2 diabetic patients with macrovascular disease, 14 nondiabetic patients with coronary artery disease (CAD), and 34 healthy control subjects matched for age, sex, and race. Serum antibodies to oxidized and glycated LDL did not differ significantly among the 3 groups. Serum IC contained variable, but not statistically different, amounts of IgG, IgM, and IgA. In contrast, the content of cholesterol in IC isolated from diabetic patients was significantly higher than that in IC isolated from control subjects, and the content of apolipoprotein (apo)-B was significantly higher than that in IC isolated from control subjects and patients with CAD. Cholesteryl ester accumulation in human monocyte-derived macrophages incubated with IC, a measure of the atherogenic potential of IC, was significantly higher in macrophages incubated with red blood cell-adsorbed IC isolated from diabetic patients compared with IC isolated from control subjects (P < 0.03) or from patients with CAD (P < 0.04) and was strongly correlated with the content of apoB (r = 0.68, P < 0.001) and cholesterol(r = 0.61, P < 0.001) in IC. LDL from diabetic patients was more susceptible to oxidation in vitro, was significantly smaller, and contained significantly less or-tocopherol than LDL isolated from subjects in the other groups. In addition, the n-3 polyunsaturated fatty acid content of phospholipids and cholesteryl. esters in LDL isolated from diabetic patients was significantly increased (P < 0.05) compared with that from patients with CAD or from control subjects. me postulate that LDL size, susceptibility to oxidation, and Lipid fatty acid composition may play a critical role in the production of antibodies to oxidized LDL and consequently in the formation of LDL-containing IC in patients with type 2 diabetes. C1 Ralph H Johnson Dept Vet Affairs Med Ctr, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA. Med Univ S Carolina, Div Endocrinol Metab & Med Genet, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. RP Lopes-Virella, MF (reprint author), Ralph H Johnson Dept Vet Affairs Med Ctr, Strom Thirmond Bldg,Rm 529,109 Bee St, Charleston, SC 29403 USA. NR 50 TC 43 Z9 45 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2000 VL 49 IS 6 BP 1033 EP 1041 DI 10.2337/diabetes.49.6.1033 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 318ZG UT WOS:000087314100020 PM 10866057 ER PT J AU Fogarty, DG Hanna, LS Wantman, M Warram, JH Krolewski, AS Rich, SS AF Fogarty, DG Hanna, LS Wantman, M Warram, JH Krolewski, AS Rich, SS TI Segregation analysis of urinary albumin excretion in families with type 2 diabetes SO DIABETES LA English DT Article; Proceedings Paper CT 58th Annual Meeting of the American-Diabetes-Association CY JUN 13-16, 1998 CL CHICAGO, ILLINOIS SP Amer Diabet Assoc ID PIMA-INDIANS; GENETIC SUSCEPTIBILITY; FOLLOW-UP; NEPHROPATHY; MELLITUS; MICROALBUMINURIA; DISEASE; MORTALITY; NIDDM; PROTEINURIA AB Elevated urinary albumin excretion (UAE) is a predictor of the development of nephropathy and cardiovascular mortality. To study whether genetic factors may determine UAE, we examined familial aggregation of UAE in 96 large multigenerational pedigrees ascertained for type 2 diabetes. A total of 1,269 subjects had UAE measured as the urinary albumin-to-creatinine ratio (ACR). This included 630 subjects with type 2 diabetes and 639 subjects without diabetes. A significant correlation (Spearman's correlation 0.34, P < 0.001) was found between the median ACR values determined separately in nondiabetic and diabetic members of the same family To determine whether this familial aggregation of ACR could be explained by the transmission of 1 or more major genes and thus be suitable for gene mapping studies, segregation analyses were performed. In these analyses, ACR was modeled as a continuous trait with the inclusion of age, sex, and duration of diabetes as covariates. Likelihood ratio tests were performed to test competing hypotheses, and Akaike's information criterion was used to determine the most parsimonious models. The Mendelian model with multifactorial inheritance was supported more strongly than Mendelian inheritance alone. These analyses suggested that the best model for ACR levels was multifactorial with evidence for a common major gene. When the analyses were repeated for diabetic subjects only, the evidence for Mendelian inheritance was improved, although a single major locus with additional multifactorial effects was more strongly supported. The results from the current study suggest that levels of UAE are determined by a mixture of genes with large and small effects as well as other measured covariates, such as diabetes. C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. RP Krolewski, AS (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. RI Fogarty, Damian/A-8925-2011 FU NCRR NIH HHS [1 P41 RR03655]; NIDDK NIH HHS [DK-41526, DK-47475] NR 39 TC 46 Z9 49 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUN PY 2000 VL 49 IS 6 BP 1057 EP 1063 DI 10.2337/diabetes.49.6.1057 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 318ZG UT WOS:000087314100023 PM 10866060 ER PT J AU Vasir, B Reitz, P Xu, G Sharma, A Bonner-Weir, S Weir, GC AF Vasir, B Reitz, P Xu, G Sharma, A Bonner-Weir, S Weir, GC TI Effects of diabetes and hypoxia on gene markers of angiogenesis (HGF, cMET, uPA and uPAR, TGF-alpha, TGF-beta, bFGF and Vimentin) in cultured and transplanted rat islets SO DIABETOLOGIA LA English DT Article DE diabetes; islet transplantation; angiogenesis; hepatocyte growth factor and c-MET receptor; and urokinase plasminogen activator; bFGF; TGF-beta; TGF-alpha ID HEPATOCYTE GROWTH-FACTOR; FACTOR SCATTER FACTOR; UROKINASE RECEPTOR EXPRESSION; VASCULAR ENDOTHELIAL-CELLS; PLASMINOGEN-ACTIVATOR; PANCREATIC-ISLETS; MOLECULAR-CLONING; EPITHELIAL-CELLS; KIDNEY CAPSULE; MESSENGER-RNA AB Aims/hypothesis. The vascularisation of newly transplanted islets originates from the recipients. Because islets transplanted into a diabetic do less well than those transplanted into a euglycaemic environment, we examined the hypothesis that gene expression of angiogenic factors in grafts is delayed in diabetes. These factors include hepatocyte growth factor (HGF) and its receptor c-MET, and urokinase plasminogen activator (uPA) and its receptor uPAR, basic fibroblast growth factor (bFGF), TGF-alpha and TGF beta-1. Methods. Isolated rat islets were studied in vitro under normoxic and hypoxic culture conditions and gene expression was determined with semi-quantitative multiplex RT-PCR. We found that HGF but not c-MET expression was induced by hypoxia in vitro. Using syngeneic Lewis rats, gene expression was also studied in grafts on days 1, 3, 5, 7 and 14 after transplantation. Results. In grafts of normoglycaemic rats, HGF expression was enhanced on day 3 and maintained whereas expression of c-MET fell and remained down until day 14. Expression of uPA was up at day 3 and remained high; expression of uPAR was also up at day 3 but then fell to control levels at day 14. Expression of bFGF, TGF-alpha and TGF beta-1 persisted throughout. Vimentin, a marker of fibroblasts, had increased expression at day 1 which was further enhanced in subsequent days. In the grafts of diabetic recipients the expression of HGF, uPA and uPAR were delayed, being clearly expressed at day 5 rather than day 3. Vimentin expression was similarly delayed. Conclusion/interpretation. This apparent delay in angiogenesis provides a potential mechanism for the less favourable outcomes of islets transplanted into diabetic recipients. C1 Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Div Res, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Weir, GC (reprint author), Joslin Diabet Ctr, Sect Islet Transplantat & Cell Biol, Div Res, 1 Joslin Pl, Boston, MA 02215 USA. FU NIDDK NIH HHS [DK-36836, DK-50657] NR 52 TC 61 Z9 65 U1 1 U2 5 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD JUN PY 2000 VL 43 IS 6 BP 763 EP 772 DI 10.1007/s001250051374 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 329HU UT WOS:000087902200011 PM 10907122 ER PT J AU Wu, AW Gifford, A Asch, S Cohn, SE Bozzette, SA Yurk, R AF Wu, AW Gifford, A Asch, S Cohn, SE Bozzette, SA Yurk, R TI Quality-of-care indicators for HIV/AIDS SO DISEASE MANAGEMENT & HEALTH OUTCOMES LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; NATIONAL PROBABILITY SAMPLES; LOW-PREVALENCE DISEASES; HIV-INFECTED VETERANS; MEDICAL OUTCOMES; SERVICES UTILIZATION; UNITED-STATES; HEALTH SURVEY; PREDICTING OUTCOMES; CLINICAL PREDICTORS AB As care for HIV/AIDS becomes more concentrated within specific providers and organisations, it would be useful to have indicators to describe the quality of care. This paper reviews concepts related to quality of care, and practical issues including sampling and risk adjustment. Indicators can be collected using a combination of administrative, chart review and survey data to reflect clinical, patient and societal perspectives. We suggest that for adults with HIV/AIDS, indicators might include measures of health status and patient satisfaction, and essential care processes. Health status measures could include CD4+ T-lymphocyte count and HIV-RNA, progression to AIDS. symptom scores, health-related quality of life scores. patient utility and disability days. Essential care processes could include receipt of acceptable antiretroviral treatment, CD4+ and HIV-RNA monitoring, screening for opportunistic infections, prophylaxis against Pneumocystis carinii pneumonia, handling of symptoms and pneumococcal vaccination. For those at increased risk for HIV, potential indicators include screening for HIV risk behaviours and HIV testing. Data from indicators such as these could be used by individuals to select among providers, purchasers of carl to select among health plans and payers to hold provider groups accountable. In addition, data could be used by groups of providers to improve the quality of care. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Univ Calif San Diego, San Diego, CA 92103 USA. RAND Corp, Santa Monica, CA USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Rochester, Med Ctr, Rochester, NY 14642 USA. Fdn Accountabil, Portland, OR USA. RP Wu, AW (reprint author), Hlth Serv Res & Dev Ctr, 624 N Broadway, Baltimore, MD 21205 USA. NR 85 TC 7 Z9 7 U1 3 U2 3 PU ADIS INTERNATIONAL LTD PI AUCKLAND PA 41 CENTORIAN DR, PRIVATE BAG 65901, MAIRANGI BAY, AUCKLAND 10, NEW ZEALAND SN 1173-8790 J9 DIS MANAG HEALTH OUT JI Dis. Manag. Health Outcomes PD JUN PY 2000 VL 7 IS 6 BP 315 EP 330 DI 10.2165/00115677-200007060-00003 PG 16 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 329GK UT WOS:000087898700003 ER PT J AU Kovacs, TO Jensen, DM AF Kovacs, TO Jensen, DM TI Endoscopic treatment of acute esophageal variceal bleeding SO DRUGS OF TODAY LA English DT Review ID PROSPECTIVE RANDOMIZED TRIAL; CONTROLLED CLINICAL-TRIAL; INJECTION SCLEROTHERAPY; PORTAL-HYPERTENSION; COMPARING SOMATOSTATIN; CIRRHOTIC-PATIENTS; BALLOON TAMPONADE; PORTACAVAL-SHUNT; ORAL PROPRANOLOL; REBLEEDING RATE AB Improvements in pharmacologic and endoscopic therapy have greatly benefited patients with portal hypertension and acute UGI hemorrhage. The advent of endoscopic band ligation has provided a valuable therapeutic option. Sclerotherapy remains an important treatment alternative, especially in the setting of active bleeding and in cases of small varices that cannot be adequately treated with band ligation. Long-term prevention of variceal hemorrhage is possible only if obliteration is maintained. Regular endoscopic surveillance and retreatment are critical since varices may recur regardless of which endoscopic method is used for treatment (C) 2000 Prous Science. All rights reserved. C1 VA Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr, Los Angeles, CA 90073 USA. RP Kovacs, TO (reprint author), VA Greater Los Angeles Healthcare Syst, CURE Digest Dis Res Ctr, Bldg 115,Room 211,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. NR 87 TC 0 Z9 0 U1 0 U2 0 PU PROUS SCIENCE, SA PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0025-7656 J9 DRUGS TODAY JI Drugs Today PD JUN PY 2000 VL 36 IS 6 BP 339 EP 353 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 333DH UT WOS:000088113100001 PM 12861356 ER PT J AU McHorney, CA Bricker, DE Kramer, AE Rosenbek, JC Robbins, J Chignell, KA Logemann, JA Clarke, C AF McHorney, CA Bricker, DE Kramer, AE Rosenbek, JC Robbins, J Chignell, KA Logemann, JA Clarke, C TI The SWAL-QOL outcomes tool for oropharyngeal dysphagia in adults: I. Conceptual foundation and item development SO DYSPHAGIA LA English DT Article DE health outcomes; quality of life; patient satisfaction; quality of care; outcomes measurement; deglutition; deglutition disorders ID QUALITY-OF-LIFE; NECK-CANCER-PATIENTS; HEALTH-STATUS SCALES; CLINICAL-TRIALS; MALIGNANT DYSPHAGIA; ESOPHAGEAL CANCER; LASER THERAPY; ENDOSCOPIC INTUBATION; FUNCTIONAL STATUS; HEART-FAILURE AB In the past two decades, noteworthy advances have been made in measuring the physiologic outcomes of dysphagia, including measurement of duration of structure and bolus movements, stasis, and penetration-aspiration. However, there is a paucity of data on health outcomes from the patients' perspective, such as quality of life and patient satisfaction. A patient-based, dysphagia-specific outcomes tool is needed to enhance information on treatment variations and treatment effectiveness. We present the conceptual foundation and item generation process for the SWAL-QOL, a quality of life and quality of care outcomes tool under development for dysphagia researchers and clinicians. C1 Univ Kentucky, Med Ctr, Ctr Hlth Serv Res & Management, Lexington, KY 40536 USA. Lexington VA Med Ctr, HSR&D Program, Lexington, KY USA. Marquette Univ, Coll Profess Studies, Milwaukee, WI 53233 USA. Univ Wisconsin, Dept Surg, Madison, WI USA. William S Middleton Mem Vet Hosp, Madison, WI USA. Univ Wisconsin, Sch Med, Madison, WI USA. Northwestern Univ, Dept Commun Sci & Disorders, Chicago, IL 60611 USA. Northwestern Univ, Dept Otolaryngol & Neurol, Chicago, IL 60611 USA. RP McHorney, CA (reprint author), Univ Kentucky, Med Ctr, Ctr Hlth Serv Res & Management, 121 Washington Ave, Lexington, KY 40536 USA. NR 81 TC 92 Z9 111 U1 2 U2 6 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0179-051X J9 DYSPHAGIA JI Dysphagia PD SUM PY 2000 VL 15 IS 3 BP 115 EP 121 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 324TF UT WOS:000087636900001 PM 10839823 ER PT J AU McHorney, CA Bricker, DE Robbins, J Kramer, AE Rosenbek, JC Chignell, KA AF McHorney, CA Bricker, DE Robbins, J Kramer, AE Rosenbek, JC Chignell, KA TI The SWAL-QOL outcomes tool for oropharyngeal dysphagia in adults: II. Item reduction and preliminary scaling SO DYSPHAGIA LA English DT Article DE quality of life; patient satisfaction; quality of care; outcomes measurement; psychometrics; deglutition; deglutition disorders ID QUALITY-OF-LIFE; HEALTH-STATUS; CARE; SF-36; QUESTIONNAIRES; SATISFACTION; DISEASE AB The SWAL-QOL outcomes tool was constructed for use in clinical research for patients with oropharyngeal dysphagia. The SWAL-QOL was constructed a priori to enable preliminary psychometric analyses of items and scales before its final validation. This article describes data analysis from a pretest of the SWAL-QOL. We evaluated the different domains of the SWAL-QOL for respondent burden, data quality, item variability, item convergent validity, internal consistency reliability as measured by Cronbach's alpha, and range and skewness of scale scores upon aggregation and floor and ceiling effects. The item reduction techniques outlined reduced the SWAL-QOL from 185 to 93 items. The pretest of the SWAL-QOL afforded us the opportunity to select items for the ongoing validation study which optimally met our a priori psychometric criteria of high data quality, normal item distributions, and robust evidence of item convergent validity. C1 Univ Kentucky, Med Ctr, Ctr Hlth Serv Res & Management, Lexington, KY 40536 USA. Lexington VA Med Ctr, HSR&D Program, Lexington, KY USA. Marquette Univ, Coll Professional Studies, Milwaukee, WI 53233 USA. Univ Wisconsin, Sch Med, Madison, WI USA. Univ Wisconsin, Dept Surg, Madison, WI USA. William S Middleton Mem Vet Hosp, Madison, WI USA. RP McHorney, CA (reprint author), Univ Kentucky, Med Ctr, Ctr Hlth Serv Res & Management, 121 Washington Ave, Lexington, KY 40536 USA. NR 28 TC 77 Z9 90 U1 1 U2 5 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0179-051X J9 DYSPHAGIA JI Dysphagia PD SUM PY 2000 VL 15 IS 3 BP 122 EP 133 PG 12 WC Otorhinolaryngology SC Otorhinolaryngology GA 324TF UT WOS:000087636900002 PM 10839824 ER PT J AU Dahia, PLM AF Dahia, PLM TI PTEN, a unique tumor suppressor gene SO ENDOCRINE-RELATED CANCER LA English DT Review ID PROTEIN-KINASE-B; INOSITOL POLYPHOSPHATE PHOSPHATASE; GLYCOGEN-SYNTHASE KINASE-3; PRIMARY PROSTATE-CANCER; COWDEN-DISEASE; BREAST-CANCER; CAENORHABDITIS-ELEGANS; GERMLINE MUTATIONS; JUVENILE POLYPOSIS; PTEN/MMAC1 GENE C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA. RP Dahia, PLM (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, 44 Binney St SM1010, Boston, MA 02215 USA. NR 101 TC 176 Z9 199 U1 1 U2 6 PU SOC ENDOCRINOLOGY PI BRISTOL PA 17/18 THE COURTYARD, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4NQ, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD JUN PY 2000 VL 7 IS 2 BP 115 EP 129 DI 10.1677/erc.0.0070115 PG 15 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 339UT UT WOS:000088496800004 PM 10903528 ER PT J AU Withers, DJ White, M AF Withers, DJ White, M TI Perspective: The insulin signaling system - A common link in the pathogenesis of type 2 diabetes SO ENDOCRINOLOGY LA English DT Editorial Material ID GLUCOSE-TOLERANCE; RECEPTOR GENE; MICE; RESISTANCE; IRS-2; DISRUPTION; MECHANISM; KNOCKOUT C1 Harvard Univ, Sch Med, Joslin Diabet Ctr, Howard Hughes Med Inst, Boston, MA 02215 USA. Univ London Imperial Coll Sci Technol & Med, Sch Med, Dept Metab Med, London W12 0NN, England. RP White, M (reprint author), Harvard Univ, Sch Med, Joslin Diabet Ctr, Howard Hughes Med Inst, 1 Joslin Pl, Boston, MA 02215 USA. EM morris.white@joslin.harvard.edu RI Withers, Dominic/D-7671-2014 OI Withers, Dominic/0000-0002-8009-7521 NR 23 TC 85 Z9 96 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2000 VL 141 IS 6 BP 1917 EP 1921 DI 10.1210/en.141.6.1917 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 337WM UT WOS:000088386100002 PM 10830270 ER PT J AU Bonner-Weir, S AF Bonner-Weir, S TI Perspective: Postnatal pancreatic beta cell growth SO ENDOCRINOLOGY LA English DT Editorial Material ID ENDOCRINE PANCREAS; CHRONIC HYPERGLYCEMIA; INSULIN-SECRETION; DIABETIC-RATS; HUMAN ISLETS; OVAL CELLS; MICE; APOPTOSIS; MASS; DIFFERENTIATION C1 Joslin Diabet Ctr, Boston, MA 02215 USA. RP Bonner-Weir, S (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM susan.bonner-weir@joslin.harvard.edu OI Bonner-Weir, Susan/0000-0003-4682-0656 NR 37 TC 180 Z9 193 U1 0 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2000 VL 141 IS 6 BP 1926 EP 1929 DI 10.1210/en.141.6.1926 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 337WM UT WOS:000088386100004 PM 10830272 ER PT J AU Sakai, Y Demay, MB AF Sakai, Y Demay, MB TI Evaluation of keratinocyte proliferation and differentiation in vitamin D receptor knockout mice SO ENDOCRINOLOGY LA English DT Article ID HORMONE-RELATED PROTEIN; EPIDERMAL DIFFERENTIATION; CALCIUM REGULATION; GENE-EXPRESSION; GROWTH; RICKETS; ALOPECIA; HAIRLESS; CULTURE; CELLS AB The biological effects of 1,25-dihydroxyvitamin D-3 are mediated by a nuclear receptor, the vitamin D receptor (VDR). Targeted ablation of the VDR in mice results in hypocalcemia, hypophosphatemia, hyperparathyroidism, rickets, osteomalacia, and alopecia. Normalization of mineral ion homeostasis prevents these abnormalities with the exception of the alopecia. Because 1,25(OH)(2)D-3 has been shown to play a role in keratinocyte proliferation and differentiation, we undertook studies in primary keratinocytes and skin isolated from VDR null mice to determine ifs keratinocyte abnormality could explain the alopecia observed. The basal proliferation rate of the VDR null and wild-type keratinocytes was identical both under proliferating and differentiating conditions. Assessment of in vivo keratinocyte proliferation at 4 days of age confirmed that VDR ablation did not have a significant effect. There was no difference in the basal expression of markers of keratinocyte differentiation (keratin 1, involucrin, and loricrin) in the keratinocytes isolated from VDR-ablated mice when compared with those isolated from control littermates. Similarly, in vivo expression of these genes was not altered at 4 days of age. When anagen was induced by depilation at 18 days of age, the VDR null mice had a profound impairment in initiation of the hair cycle. These data suggest that the alopecia in the VDR null mice is not attributable to an intrinsic defect in keratinocyte proliferation or differentiation, but rather to an abnormality in initiation of the hair cycle. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. RP Demay, MB (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Endocrine Unit, Wellman 501,50 Blossom St, Boston, MA 02114 USA. EM demay@helix.mgh.harvard.edu FU NIDDK NIH HHS [DK-46974] NR 28 TC 67 Z9 69 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD JUN PY 2000 VL 141 IS 6 BP 2043 EP 2049 DI 10.1210/en.141.6.2043 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 337WM UT WOS:000088386100020 PM 10830288 ER PT J AU Brower, MC Price, BH AF Brower, Montgomery C. Price, Bruce H. TI Epilepsy and Violence: When Is the Brain to Blame? SO EPILEPSY & BEHAVIOR LA English DT Editorial Material C1 [Price, Bruce H.] McLean Hosp, Dept Neurol, Belmont, MA 02478 USA. [Brower, Montgomery C.] Univ Massachusetts, Sch Med, Dept Psychiat, Law & Psychiat Program, Worcester, MA 01655 USA. [Brower, Montgomery C.] Bridgewater State Hosp, Bridgewater, MA USA. [Price, Bruce H.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Price, Bruce H.] Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. RP Price, BH (reprint author), McLean Hosp, Dept Neurol, 115 Mill St, Belmont, MA 02478 USA. EM priceb@mclean.harvard.edu NR 27 TC 6 Z9 6 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 1525-5050 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD JUN PY 2000 VL 1 IS 3 BP 145 EP 149 DI 10.1006/ebeh.2000.0069 PG 5 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA V21JJ UT WOS:000208203600001 PM 12609146 ER PT J AU Hermann, BP Seidenberg, M Bell, B Woodard, A Rutecki, P Sheth, R AF Hermann, Bruce P. Seidenberg, Michael Bell, Brian Woodard, Austin Rutecki, Paul Sheth, Raj TI Comorbid Psychiatric Symptoms in Temporal Lobe Epilepsy: Association with Chronicity of Epilepsy and Impact on Quality of Life SO EPILEPSY & BEHAVIOR LA English DT Article DE quality of life; temporal lobe epilepsy; complex partial seizures; behavior; mood; depression AB Purpose. The goals of this work were to determine: (1) the nature and extent of differences in self-reported psychiatric symptoms between patients with temporal lobe epilepsy and matched healthy controls, (2) the relationship between chronicity (duration) of temporal lobe epilepsy and comorbid interictal psychiatric symptoms, and (3) the impact of comorbid psychiatric symptoms on self-reported health-related quality of life. Methods. Patients with temporal lobe epilepsy (n = 54) and healthy controls (n = 38) were administered the Symptom Checklist-90-Revised (SCL-90-R) to assess the nature and severity of psychiatric symptomatology and epilepsy patients completed the Quality of Life in Epilepsy-89 (QOLIE-89) to define health-related quality of life. Among epilepsy patients the SCL-90-R scales were examined in relation to chronicity of temporal lobe epilepsy as well as the impact of comorbid emotional-behavioral distress on health-related quality of life. Results. Compared with healthy controls, patients with epilepsy exhibited significantly higher (worse) scores across all but one of the 12 SCL-90-R scales. Among patients with epilepsy, increasing chronicity was associated with significantly higher (worse) scores across all SCL-90-R scales and increased emotional-behavioral distress was associated with lower (worse) scores across all 17 QOLIE-89 scales. Conclusion. Comorbid interictal psychiatric symptoms are elevated among patients with temporal lobe epilepsy compared with healthy controls and appear to be modestly associated with increasing chronicity (duration) of epilepsy. This comorbid emotional-behavioral distress is specifically associated with a significantly poorer health-related quality of life, and suggests that quality-of-life research should devote greater attention to the potential impact of comorbid psychiatric distress. (C) 2000 Academic Press C1 [Hermann, Bruce P.] Univ Wisconsin, Dept Neurol, Matthews Neuropsychol Lab, Madison, WI 53792 USA. [Seidenberg, Michael] Chicago Med Sch, Dept Psychol, N Chicago, IL 60064 USA. [Woodard, Austin; Rutecki, Paul] Middleton Vet Adm Hosp, Francis Forster Epilepsy Ctr, Madison, WI 53705 USA. RP Hermann, BP (reprint author), Univ Wisconsin, Dept Neurol, Matthews Neuropsychol Lab, 600 N Highland Ave, Madison, WI 53792 USA. EM hermann@neurology.wisc.edu FU NIH [37738]; NARSAD FX Supported in part by NIH 37738 and NARSAD. NR 22 TC 54 Z9 55 U1 4 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-5050 J9 EPILEPSY BEHAV JI Epilepsy Behav. PD JUN PY 2000 VL 1 IS 3 BP 184 EP 190 DI 10.1006/ebeh.2000.0066 PG 7 WC Behavioral Sciences; Clinical Neurology; Psychiatry SC Behavioral Sciences; Neurosciences & Neurology; Psychiatry GA V21JJ UT WOS:000208203600007 PM 12609152 ER PT J AU Senn, HJ Canellos, GP AF Senn, HJ Canellos, GP TI Special issue - Tumour prevention and genetics - Introduction SO EUROPEAN JOURNAL OF CANCER LA English DT Editorial Material C1 Ctr Tumour Detect & Prevent, CH-9006 St Gallen, Switzerland. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Senn, HJ (reprint author), Ctr Tumour Detect & Prevent, Rorschacherstr 150, CH-9006 St Gallen, Switzerland. NR 0 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD JUN PY 2000 VL 36 IS 10 BP 1187 EP 1188 DI 10.1016/S0959-8049(00)00117-9 PG 2 WC Oncology SC Oncology GA 327KJ UT WOS:000087792800001 ER PT J AU Elahi, D Muller, DC AF Elahi, D Muller, DC TI Carbohydrate metabolism in the elderly SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Workshop of the International-Dietary-Energy-Consultative-Group CY MAY, 1999 CL TUFS UNIV, USDA HUMAN NUTRIT RES CTR, BOSTON, MASSACHUSETTS SP Int Dietary Energy Consultat Grp HO TUFS UNIV, USDA HUMAN NUTRIT RES CTR DE aging; carbohydrate metabolism; glucose tolerance; diabetes ID IMPAIRED GLUCOSE-TOLERANCE; BODY-FAT DISTRIBUTION; INSULIN RESISTANCE; BETA-CELL; DIABETES-MELLITUS; PLASMA-GLUCOSE; AGE; INTOLERANCE; POPULATION; WOMEN AB In this short review we summarize the effect of age on glucose homeostasis. The concept of decreased glucose tolerance with increasing age is introduced, followed by evidence for this phenomenon. Specifically we review the evidence for changes in fasting glucose as a function of age and the effect of age on HbA1c. The role of age on hepatic glucose production and glucose uptake is then discussed in detail and we review the evidence that supports the concept that with advancing age hepatic glucose sensitivity to insulin is unaltered. We then review the large evidence for the role of age on the purported decrease in peripheral tissue sensitivity to insulin and conclude that the issue is unsettled. The decrease attributed to age is no longer significant when confounders are controlled for, the largest being obesity. We next present evidence that beta-cell sensitivity to glucose remains intact with aging. A review of age-related disorders due to hyperglycemia and confounding effects on the relationships of age and glucose tolerance is presented next. Finally we present new evidence that when the revised criteria for the diagnosis of type 2 diabetics as proposed by the American Diabetes Association and WHO are used, a greater percentage of the elderly will not be diagnosed. We conclude that, although glucose intolerance increases with aging, which is accompanied with other disorders, it is possible to ameliorate this effect with alteration of diet and exercise. C1 Massachusetts Gen Hosp, Geriat Res Lab, Boston, MA 02114 USA. NIA, Gerontol Res Ctr, Clin Invest Lab, Baltimore, MD 21224 USA. RP Elahi, D (reprint author), Massachusetts Gen Hosp, Geriat Res Lab, GRB SB 0015C,55 Fruit St, Boston, MA 02114 USA. NR 66 TC 23 Z9 23 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD JUN PY 2000 VL 54 SU 3 BP S112 EP S120 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 333FG UT WOS:000088118600015 PM 11041082 ER PT J AU Davies, FE Anderson, KC AF Davies, FE Anderson, KC TI Novel therapeutic targets in multiple myeloma SO EUROPEAN JOURNAL OF HAEMATOLOGY LA English DT Review DE multiple myeloma; novel treatment; bone marrow microenvironment; adhesion molecules; angiogenesis; IL-6; serotherapy ID HUMAN INTERLEUKIN-6 RECEPTOR; BONE-MARROW TRANSPLANTATION; PROTEIN-KINASE CASCADE; PLASMA-CELL LEUKEMIA; MONOCLONAL-ANTIBODIES; MULTIDRUG-RESISTANCE; SIGNAL-TRANSDUCTION; ADHESION MOLECULES; CD56 EXPRESSION; XENOGRAFT MODEL AB Multiple myeloma remains an incurable disease, and a new perspective on the approach to therapy is required. The aim of this review is to focus on a number of key areas where recent advances in the biology of the disease have not only yielded an understanding of the disease pathogenesis but have also suggested novel treatment approaches. Factors mediating myeloma cell growth, survival and the complex interaction of myeloma cells with the bone marrow microenvironment have provided a framework for the rational design of therapeutic agents. The development of such biologically based treatments which target both the tumour cell and the microenvironment, in order to achieve more complete and selective eradication of myeloma cells and the maintenance of minimal residual disease states, may ultimately lead to improved disease-free survival and potentially a cure. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, 44 Binney St, Boston, MA 02115 USA. FU NCI NIH HHS [CA 78373] NR 74 TC 11 Z9 11 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0902-4441 J9 EUR J HAEMATOL JI Eur. J. Haematol. PD JUN PY 2000 VL 64 IS 6 BP 359 EP 367 DI 10.1034/j.1600-0609.2000.9r233.x PG 9 WC Hematology SC Hematology GA 332PJ UT WOS:000088082400002 PM 10901589 ER PT J AU Li, XL Carter, RH AF Li, XL Carter, RH TI CD19 signal transduction in normal human a cells: linkage to downstream pathways requires phosphatidylinositol 3-kinase, protein kinase C and Ca2+ SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE CD19; B lymphocyte; signal transduction; human ID B-LYMPHOCYTE DEVELOPMENT; ANTIGEN RECEPTOR; TYROSINE KINASE; CROSS-LINKING; LINEAGE CELLS; MEMBRANE IGM; MAP KINASE; ACTIVATION; COMPLEX; PHOSPHORYLATION AB CD19 is required for normal antibody responses in mice. We have shown that CD19 enhances the activation of extracellular signal-regulated kinase (ERK) 2 by membrane (m) IgM but otherwise little is known of CD19 signaling in primary human cells. We now ask which pathways link CD19 with ERK2 in human tonsillar B cells. In analyses of signaling intermediates, the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin partially suppressed the release of Ca2+ induced by coligation of CD19 and mlgM but the selective PKC inhibitor bisindolylmaieimide I (BIM-I) did not. The Cd2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, BIM-I and wortmannin each had only a small effect on ERK2 activation induced by surface IgM alone but blocked the enhancement of that activation by CD19/mlgM coligation. To analyze the mitogen-activated protein kinase (MAPK) cascade, we measured activation of Raf, MAPK- or ERK kinase (MEK) 1 and ERK2. CD19 consistently enhanced activation of ERK2 and MEK1. However, synergistic activation of Raf was variably observed. in subpopulation analyses, synergistic activation of Raf1 was consistently observed in the IgD(low) but not in the lgD(high) cells. Thus, in normal human B cells, PI3K is upstream of the Ca2+ response while PI3K, Ca2+ release and protein kinase C are all required for ERK2 activation, and CD19 enhances the MAPK cascade at multiple levels, depending on the state of differentiation. C1 Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Carter, RH (reprint author), 409 LHRB,701 19th St S, Birmingham, AL 35294 USA. FU NIAID NIH HHS [R01 AI42265]; NIAMS NIH HHS [P60 AR20614] NR 50 TC 15 Z9 15 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 2000 VL 30 IS 6 BP 1576 EP 1586 DI 10.1002/1521-4141(200006)30:6<1576::AID-IMMU1576>3.0.CO;2-0 PG 11 WC Immunology SC Immunology GA 322KA UT WOS:000087507700007 PM 10898493 ER PT J AU Tsuchihashi, N Matsuda, S Reinherz, EL Koyasu, S AF Tsuchihashi, N Matsuda, S Reinherz, EL Koyasu, S TI Two YxxL segments of a single immunoreceptor tyrosine-based activation motif in the CD3 zeta molecule differentially activate calcium mobilization and mitogen-activated protein kinase family pathways SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE immunoreceptor tyrosine-based activation motif; calcium mobilization; mitogen-activated protein kinase family; ZAP-70; IL-2 ID CELL ANTIGEN RECEPTOR; TANDEM SH2 DOMAINS; T-CELLS; ZETA-CHAIN; SIGNAL-TRANSDUCTION; NUCLEAR FACTOR; COACTIVATORS P300; MURINE THYMOCYTES; CO-STIMULATION; ZAP-70 KINASE AB Immunoreceptor tyrosine-based activation motifs (ITAM), consisting of two YxxL segments, transmit signals leading to IL-2 gene activation in T cells. We investigated here the functional difference in signal transduction between these two YxxL segments in the CDBT, membrane-proximal ITAM. N-terminal YxxL mutants failed to induce ZAP-70 phosphorylation, elevation of intracellular Ca2+ concentration ([Ca2+](i)) or extracellular signal-regulated kinase (ERK) activation even in the presence of CD28 co-stimulation, whereas a mutant of the leucine residue at the C-terminal YxxL segment retained the ability to induce these events although this mutation abrogated the ability to induce IL-2 gene activation. In marked contrast to ERK activation, c-Jun N-terminal kinase (JNK) activation was observed in all mutants when costimulated with CD28. The mutant of the leucine residue at the C-terminal YxxL segment had a defect in the transcriptional activation at the NF-AT cis-element, which was restored to wild-type level by addition of a Ca2+ ionophore, suggesting that the intensity and/or duration of [Ca2+](i) elevation defines the threshold of T cell activation in this mutant. Our data collectively indicate that the activation pathways of ERK, JNK and Ca2+ mobilization are differentially regulated through YxxL segments of an ITAM. C1 Keo Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, Tokyo 168582, Japan. Harvard Univ, Sch Med, Dana Faber Canc Inst,Dept Med, Immunobiol Lab, Boston, MA USA. RP Koyasu, S (reprint author), Keo Univ, Sch Med, Dept Microbiol & Immunol, Shinjuku Ku, 35 Shinanomachi, Tokyo 168582, Japan. RI Koyasu, Shigeo/J-5583-2015 OI Koyasu, Shigeo/0000-0001-9585-3038 FU NIAID NIH HHS [AI 19807] NR 47 TC 5 Z9 5 U1 0 U2 4 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD JUN PY 2000 VL 30 IS 6 BP 1785 EP 1793 DI 10.1002/1521-4141(200006)30:6<1785::AID-IMMU1785>3.0.CO;2-T PG 9 WC Immunology SC Immunology GA 322KA UT WOS:000087507700031 PM 10898517 ER PT J AU Zhang, YP Kent, RL Margolis, HC AF Zhang, YP Kent, RL Margolis, HC TI Enamel demineralization under driving forces found in dental plaque fluid SO EUROPEAN JOURNAL OF ORAL SCIENCES LA English DT Article DE caries; demineralization; enamel; plaque ID CARIES-POSITIVE INDIVIDUALS; HUMAN TOOTH ENAMEL; IN-VITRO; ACID-SOLUTIONS; DISSOLUTION; SOLUBILITY; KINETICS; SATURATION; LESIONS; PRODUCT AB The present study was carried out to examine the kinetics of enamel demineralization in vitro under driving forces for demineralization (i.e., the degree of saturation with respect to enamel, DSEn) similar to those found in dental plaque fluid, Thin sections of human enamel were exposed at 25 degrees C to lactic acid solutions with DSEn values (DSEn = [(Ca2+)(5)(OH-)(PO43-)(3)/K-En](1/9). K-En = 5.5 x 10(-55)) ranging from 0.28 to 0.79, Lesion development was monitored by quantitative microradiography, Enamel mineral loss in solutions with DSEn values of 0.28, 0.32 and 0.36 was first detected after 3, 3, and 7 wk of continuous exposure, respectively. Consistent with previous findings, subsurface demineralization was observed and rates of mineral loss increased significantly with decreasing DSEn values. However, no mineral loss was observed in sections of enamel exposed to solutions with DSEn values of 0.41 and 0.79, even after 11 months. These results suggest that (outer) enamel mineral behaves as a mineral phase that is less soluble than that dictated by the solubility product constant (K-En) used in this study, Furthermore, these results indicate that the kinetics and general features of the demineralization process are maintained over a wide range of DSEn values, including conditions that better reflect those found in the oral cavity. These findings are particularly relevant to the assessment of the cariogenic potential of dental plaque fluids. C1 Forsyth Inst, Dept Biomineralization, Boston, MA 02115 USA. Forsyth Inst, Dept Biostat, Boston, MA 02115 USA. Colgate Palmol Co, Piscataway, NJ USA. RP Margolis, HC (reprint author), Forsyth Inst, Dept Biomineralization, 140 Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE-07009, DE-07493] NR 20 TC 17 Z9 20 U1 1 U2 3 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0909-8836 J9 EUR J ORAL SCI JI Eur. J. Oral Sci. PD JUN PY 2000 VL 108 IS 3 BP 207 EP 213 DI 10.1034/j.1600-0722.2000.108003207.x PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 323LM UT WOS:000087566900007 PM 10872991 ER PT J AU Angelaki, DE Merfeld, DM Hess, BJM AF Angelaki, DE Merfeld, DM Hess, BJM TI Low-frequency otolith and semicircular canal interactions after canal inactivation SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE eye movements; vestibular; vestibule-ocular; gaze; spatial orientation; gravity; neural computation; rhesus monkeys; adaptation; primates; canal plugging ID VESTIBULO-OCULAR REFLEX; EYE-MOVEMENT RESPONSES; LINEAR HEAD MOTION; SQUIRREL-MONKEY; RHESUS-MONKEYS; 3-DIMENSIONAL ORGANIZATION; INERTIAL REPRESENTATION; KINEMATIC PRINCIPLES; VIEWING DISTANCE; ANGULAR MOTION AB During sustained constant velocity and low-frequency off-vertical axis rotations (OVAR), otolith signals contribute significantly to slow-phase eye velocity. The adaptive plasticity of these responses was investigated here after semicircular canal plugging. Inactivation of semicircular canals results in a highly compromised and deficient vestibule-ocular reflex (VOR). Based on the VOR enhancement hypothesis, one could expect an adaptive increase of otolith-borne angular velocity signals due to combined otolith/canal inputs after inactivation of the semicircular canals. Contrary to expectations, however, the steady-state slow-phase velocity during constant velocity OVAR decreased in amplitude over time. A similar progressive decrease in VOR gain was also observed during low-frequency off-vertical axis oscillations. This response deterioration was present in animals with either lateral or vertical semicircular canals inactivated and was limited to the plane(s) of the plugged canals. The results are consistent with the idea that the low-frequency otolith signals do not simply enhance VOR responses. Rather, the nervous system appears to correlate vestibular sensory information from the otoliths and the semicircular canals to generate an integral response to head motion. C1 Washington Univ, Sch Med, Dept Anat & Neurobiol, St Louis, MO 63110 USA. Massachusetts Eye & Ear Infirm, Jenks Vestibular Physiol Lab, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otol & Laryngol, Boston, MA 02115 USA. Univ Zurich Hosp, Dept Neurol, CH-8091 Zurich, Switzerland. RP Angelaki, DE (reprint author), Washington Univ, Sch Med, Dept Anat & Neurobiol, Box 8108,660 S Euclid Ave, St Louis, MO 63110 USA. FU NEI NIH HHS [EY10851]; NIDCD NIH HHS [DC03065] NR 75 TC 26 Z9 28 U1 0 U2 2 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 2000 VL 132 IS 4 BP 539 EP 549 DI 10.1007/s002210000364 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 329MJ UT WOS:000087910500013 PM 10912835 ER PT J AU Kim, LH Taylor, AE Barbieri, RL AF Kim, LH Taylor, AE Barbieri, RL TI Insulin sensitizers and polycystic ovary syndrome: can a diabetes medication treat infertility? SO FERTILITY AND STERILITY LA English DT Editorial Material ID RESISTANCE; WOMEN C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Reprod Endocrine Unit, Boston, MA USA. RP Barbieri, RL (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet & Gynecol, 75 Francis St,ASB1-3, Boston, MA 02115 USA. FU NICHD NIH HHS [HD-29164] NR 4 TC 28 Z9 29 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD JUN PY 2000 VL 73 IS 6 BP 1097 EP 1098 DI 10.1016/S0015-0282(00)00540-9 PG 2 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 323DC UT WOS:000087548700002 PM 10856463 ER PT J AU Chandrasekar, B Colston, JT Geimer, J Cortez, D Freeman, GL AF Chandrasekar, B Colston, JT Geimer, J Cortez, D Freeman, GL TI Induction of nuclear factor kappa B but not kappa B-responsive cytokine expression during myocardial reperfusion injury after neutropenia SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE reperfusion injury; ischemia; NF-kappa B; proinflammatory cytokines; neutrophils; anti-PMN antiserum; free radicals ID PROINFLAMMATORY CYTOKINE; POSTISCHEMIC MYOCARDIUM; ISCHEMIA; NEUTROPHILS; DEPLETION; DYSFUNCTION; ACTIVATION; LEUKOCYTE; DOG; MECHANISMS AB Neutrophils may contribute to myocardial ischemia/reperfusion (I/R) injury by generating reactive oxygen intermediates (ROIs). ROIs activate nuclear factor (NF)-kappa B, which regulates genes for cytokines with negative inotropic effects (interleukin [IL]-1 beta, IL-6, and tumor necrosis factor [TNF]-alpha). We investigated the impact of neutrophil depletion on NF-kappa B DNA binding activity, and expression of these cytokines during myocardial IIR injury. Male WKY rats (n = 28) received a single dose of antineutrophil antiserum (i/v). Twenty two hours later, when the peripheral blood neutrophil counts were profoundly decreased (94% reduction), the animals underwent 15 min of left anterior descending coronary artery ligation followed by reperfusion for 0.25, 0.5, 1, 2, 3, and 6 h (n = 4/group). Saline-treated animals underwent a similar protocol, and served as controls (n = 28, 4/group). Neutrophil accumulation, defined by myeloperoxidase activity, was present in controls, but not in anti-PMN antisera-treated animals (at least p <0.05 at 1, 2, 3, and 6 h R). Despite this difference, in both saline- and antiserum-treated animals, the GSH levels were very similar and fell significantly (p < 0.0001) at 15 min R; the levels increased gradually over time. In contrast, GSSG levels rose at 15 and 30 min R (p < 0.05), and declined thereafter. NF-kappa B DNA binding activity increased in both groups at 15 min and again at 3 h of R. Both NF-kappa Bp50 and p65 subunits were detected by supershift assay. In saline-injected controls both mRNA and protein for IL-1 beta, IL-6, and TNF-alpha were detected at 1 h R; levels remained high until 3 h, then fell (except IL-6, which was elevated at 6 h). In neutropenic animals, however, a significant decrease in mRNA (at least 1.7-fold, p ( 0.05) as well as protein levels (at least 2.3-fold, p ( 0.01) for all three cytokines was observed. Thus, while neutrophils had minimal effects on oxidative stress (GSH/GSSG) and oxidative stress-responsive NF-kappa B activity, they contributed significantly to myocardial cytokine expression. (C) 2000 Elsevier Science Inc. C1 S Texas Vet Hlth Care Syst, Audie L Murphy Div, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. RP Freeman, GL (reprint author), Univ Texas, Hlth Sci Ctr, Dept Med Cardiol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. NR 36 TC 23 Z9 25 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD JUN 1 PY 2000 VL 28 IS 11 BP 1579 EP 1588 DI 10.1016/S0891-5849(00)00273-2 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 344GG UT WOS:000088750400001 PM 10938453 ER PT J AU Pahlavani, MA AF Pahlavani, MA TI Caloric restriction and immunosenescence: A current perspective SO FRONTIERS IN BIOSCIENCE-LANDMARK LA English DT Review DE caloric restriction; immune function; signal transduction; aging; review ID TRANSCRIPTION FACTOR NFAT; HUMAN T-LYMPHOCYTES; DIETARY RESTRICTION; FOOD RESTRICTION; IMMUNE FUNCTIONS; FISCHER-344 RATS; PERIPHERAL-BLOOD; RHESUS-MONKEYS; WISTAR RATS; PRONE MICE AB The age-related decrease in immunologic function is believed to be the major predisposing factor contributing to increased morbidity and mortality with age. Hence, the restoration of immunologic function is expected to have a beneficial effect in reducing pathology and maintaining a healthy condition in advanced age. Among various intervention strategies, caloric restriction (CR) has been shown to be the most powerful modulator of aging process. It is the most efficacious means of increasing longevity and reducing pathology. Several mechanisms have been proposed to explain its beneficial and robust action on various physiological systems, including the immune system. Experimental evidence suggests that CR increases longevity and reduces pathology through its action on the immune system. The observation that CR attenuates immunosenescence has provided a rationale for studying whether CR exerts its action through modulation of gene expression. The available data indicate that the effect of CR on signal transduction and gene expression can vary considerably from gene to gene and from one signaling molecule to another. This review summarizes the studies on the influence of CR on aging immune system and discusses the current state of knowledge on the molecular mechanisms responsible for the immunomodulatory action of caloric restriction. C1 S Texas Vet Hlth Care Syst, Ctr Geriatr Res Educ & Clin, San Antonio, TX 78284 USA. Univ Texas, Hlth Sci Ctr, Dept Physiol, San Antonio, TX 78284 USA. RP Pahlavani, MA (reprint author), Audie L Murphy Mem Vet Adm Med Ctr, GRECC 182, 7400 Merton Minter Blvd, San Antonio, TX 78284 USA. EM Pahlavani@uthscsa.edu FU NIA NIH HHS [AG00677, AG14088] NR 63 TC 30 Z9 30 U1 0 U2 1 PU FRONTIERS IN BIOSCIENCE INC PI MANHASSET PA C/O NORTH SHORE UNIV HOSPITAL, BIOMEDICAL RESEARCH CENTER, 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1093-9946 J9 FRONT BIOSCI-LANDMRK JI Front. Biosci. PD JUN 1 PY 2000 VL 5 BP D580 EP D587 DI 10.2741/Pahlavani PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 360JK UT WOS:000089664000002 PM 10833464 ER PT J AU Kinugasa, T Sakaguchi, T Gu, XB Reinecker, HC AF Kinugasa, T Sakaguchi, T Gu, XB Reinecker, HC TI Claudins regulate the intestinal barrier in response to immune mediators SO GASTROENTEROLOGY LA English DT Article ID TIGHT JUNCTION STRANDS; INFLAMMATORY BOWEL-DISEASE; ACTIVATED PROTEIN-KINASE; MAP KINASE; EPITHELIAL BARRIER; MEMBRANE-PROTEIN; CROHNS-DISEASE; PERMEABILITY; CELLS; PHOSPHORYLATION AB Background & Aims: To determine the functional role of immune mediators in the formation of the intestinal barrier, we have examined the regulation of claudin expression by interleukin (IL)-17 in human intestinal epithelial cells. Methods: Expression of claudins, extracellular signal-related (ERK) mitogen-activated protein kinases (MAPKs), and activated ERK MAPKs was determined by immunoblotting, Claudin membrane association was assessed by immunohistochemistry and claudin messenger RNA expression by Northern blot analysis. Intestinal epithelial barrier function was characterized through transepithelial electrical resistance and mannitol tracer flux. Results: IL-17 induced the development of a paracellular barrier of T84 cell monolayers. Inhibition of ERK activation with the MEK inhibitor PD98059 blocked IL-17 as well as basal development of tight junctions in T84 cells. IL-17 induced formation of tight junctions correlated with up-regulation of claudin-1 and claudin-2 gene transcription. Inhibition of MEK reduced the activated and basal expression of claudin-2 messenger RNA and protein expression. Functional MEK was required for the expression and membrane association of claudin-2 but not claudin-1 in T84 cells. Conclusions: MEK activity is required for claudin-mediated formation of tight junctions. IL-17 is able to regulate the intestinal barrier through the ERK MARK pathway. C1 Massachusetts Gen Hosp, Ctr Study Inflammatory bowel Dis, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Reinecker, HC (reprint author), Massachusetts Gen Hosp, Ctr Study Inflammatory bowel Dis, Dept Med, Gastrointestinal Unit, Boston, MA 02114 USA. NR 48 TC 231 Z9 241 U1 3 U2 10 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 2000 VL 118 IS 6 BP 1001 EP 1011 DI 10.1016/S0016-5085(00)70351-9 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 317TL UT WOS:000087243000005 PM 10833473 ER PT J AU Savides, TJ Jensen, DM AF Savides, TJ Jensen, DM TI Therapeutic endoscopy for nonvariceal gastrointestinal bleeding SO GASTROENTEROLOGY CLINICS OF NORTH AMERICA LA English DT Article ID PEPTIC-ULCERS; EPINEPHRINE INJECTION; CONTROLLED TRIAL; BAND LIGATION; MULTIPOLAR ELECTROCOAGULATION; DIEULAFOYS-DISEASE; RANDOMIZED TRIAL; NATURAL-HISTORY; VISIBLE VESSEL; SENTINEL CLOT AB This article reviews the role of therapeutic endoscopy in the diagnosis and treatment of nonvariceal upper and lower gastrointestinal (GI) hemorrhage. The initial approach to patients with GI bleeding is reviewed. Endoscopic treatment of various stigmata of recent peptic ulcer hemorrhage is discussed in detail. Management of less common causes of nonvariceal bleeding, such as Dieulafoy's lesions, Mallory-Weiss tears, angiomas, and bleeding colonic diverticula is described. Recommendations for endoscopic techniques are based on the results of UCLA-CURE hemostasis studies. C1 Univ Calif San Diego, Dept Clin Med, Div Gastroenterol, San Diego, CA 92103 USA. Univ Calif Los Angeles, Dept Med, Div Digest Dis, Los Angeles, CA USA. VA Greater Los Angeles Hlth Syst, Los Angeles, CA USA. RP Savides, TJ (reprint author), UCSD Gastroenterol 8413, 200 W Arbor Dr, San Diego, CA 92103 USA. NR 63 TC 50 Z9 55 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 0889-8553 J9 GASTROENTEROL CLIN N JI Gastroenterol. Clin. North Am. PD JUN PY 2000 VL 29 IS 2 BP 465 EP + DI 10.1016/S0889-8553(05)70123-0 PG 24 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 318KQ UT WOS:000087283500008 PM 10836190 ER PT J AU Rosen, ED Walkey, CJ Puigserver, P Spiegelman, BM AF Rosen, ED Walkey, CJ Puigserver, P Spiegelman, BM TI Transcriptional regulation of adipogenesis SO GENES & DEVELOPMENT LA English DT Review ID PROLIFERATOR-ACTIVATED RECEPTOR; ENHANCER-BINDING-PROTEIN; PROMOTES ADIPOCYTE DIFFERENTIATION; NUCLEAR HORMONE RECEPTORS; BROWN ADIPOSE-TISSUE; RETINOID-X-RECEPTOR; PPAR-GAMMA; GENE-EXPRESSION; C/EBP-ALPHA; RETINOBLASTOMA PROTEIN C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA. RP Rosen, ED (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, 44 Binney St, Boston, MA 02115 USA. FU NIDDK NIH HHS [R37DK31405, DK54477, KO8DK02535] NR 149 TC 1160 Z9 1220 U1 10 U2 99 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 2000 VL 14 IS 11 BP 1293 EP 1307 PG 15 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 321KP UT WOS:000087454900001 PM 10837022 ER PT J AU Malynn, BA de Alboran, IM O'Hagan, RC Bronson, R Davidson, L DePinho, RA Alt, FW AF Malynn, BA de Alboran, IM O'Hagan, RC Bronson, R Davidson, L DePinho, RA Alt, FW TI N-myc can functionally replace c-myc in murine development, cellular growth, and differentiation SO GENES & DEVELOPMENT LA English DT Article DE N-myc; c-myc; murine development; proliferation; knock-in; gene replacement ID EMBRYONIC LETHALITY; TARGETED DISRUPTION; ONCOGENIC ACTIVITY; GENE-EXPRESSION; TRANSGENIC MICE; PROTO-ONCOGENE; IN-VIVO; MOUSE; CELLS; FAMILY AB Members of the myc family of cellular oncogenes have been implicated as transcriptional regulators in pathways that govern cellular proliferation and death. In addition, N-myc and c-myc are essential for completion of murine embryonic development. However, the basis for the evolutionary conservation of myc gene family has remained unclear. To elucidate this issue, we have generated mice in which the endogenous c-myc coding sequences have been replaced with N-myc coding sequences. Strikingly, mice homozygous for this replacement mutation can survive into adulthood and reproduce. Moreover, when expressed from the c-myc locus, N-myc is similarly regulated and functionally complementary to c-myc in the context of various cellular growth and differentiation processes. Therefore, the myc gene family must have evolved, to a large extent, to facilitate differential patterns of expression. C1 Ctr Blood Res, Boston, MA 02115 USA. Childrens Hosp, Howard Hughes Med Inst, Boston, MA 02115 USA. Childrens Hosp, Dept Pediat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, 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 Alt, FW (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NCI NIH HHS [CA61009]; NEI NIH HHS [EY09300]; NIAID NIH HHS [P01 AI035714]; NICHD NIH HHS [HD28317] NR 46 TC 167 Z9 172 U1 0 U2 2 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 2000 VL 14 IS 11 BP 1390 EP 1399 PG 10 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 321KP UT WOS:000087454900010 PM 10837031 ER PT J AU Huang, LW Garrett, AP Bell, DA Welch, WR Berkowitz, RS Mok, SC AF Huang, LW Garrett, AP Bell, DA Welch, WR Berkowitz, RS Mok, SC TI Differential expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 protein and mRNA in epithelial ovarian tumors SO GYNECOLOGIC ONCOLOGY LA English DT Article DE MMP-9; TIMP-1; ovarian tumor; ISH; mRNA ID RNA HYBRIDIZATION TECHNIQUE; HUMAN COLON-CANCER; MESSENGER-RNA; COLORECTAL TUMORIGENESIS; CARCINOMA-CELLS; STROMAL CELLS; METASTASIS; MMP-9 AB Objective. Matrix metalloproteinase-9 (MMP-9) can degrade gelatin and type IV collagen and is known to play an important role in tumor cell invasion across the basement membrane. The tissue inhibitor of metalloproteinase-1 (TIMP-1) is able to prevent activation of pro-MMP-9 and forms a 1:1 complex with the active form of MMP-9. The aim of the present study was to investigate the expression of MMP-9 and TIMP-1 in benign, borderline, and invasive epithelial ovarian tumors. Materials and methods. A total of 90 patients with epithelial ovarian tumor were treated at the Brigham and Women's Hospital and were used as the study population. Immunohistochemistry and in situ hybridization were performed to detect protein and mRNA expression of MMP-9 and TIMP-1. Results, In the 90 epithelial ovarian tumors tested, MMP-9 expression in tumor cells was found to be significantly enhanced in serous and mucinous ovarian carcinomas compared with benign and borderline tumors. We also observed the immunostaining of MMP-9 in stromal cells of benign, borderline, and invasive epithelial ovarian tumors. Moreover, the expression levels of TIMP-1 in tumor cells were significantly higher in borderline and invasive ovarian tumors than in benign tumors. Conclusion. Using an in situ hybridization technique, we disclosed a direct correlation between the presence of mRNA and protein expression for both MMP-9 and TIMP-1. The present data suggest that high levels of MMP-9 protein in invasive epithelial ovarian carcinoma are strongly associated with tumor cell invasion, Enhanced expression of TIMP-1 protein in borderline and invasive tumors indicates that endogenous TIMP-1 protein may play a paradoxical role in ovarian tumor progression. (C) 2000 Academic Press. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Obstet Gynecol & Reprod Biol, Lab Gynecol Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Obstet Gynecol & Reprod Biol, Div Gynecol Oncol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Shin Kong Wu Ho Su Mem Hosp, Dept Obstet & Gynecol, Taipei, Taiwan. RP Mok, SC (reprint author), Lab Gynecol Oncol, RFB-472,221 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [R01CA63381, R01CA69291, R01CA69453] NR 28 TC 44 Z9 65 U1 0 U2 0 PU ACADEMIC PRESS INC 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 2000 VL 77 IS 3 BP 369 EP 376 DI 10.1006/gyno.2000.5806 PG 8 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 323CH UT WOS:000087546900005 PM 10831344 ER PT J AU Tuncer, ZS Vegh, GL Fulop, V Genest, DR Mok, SC Berkowitz, RS AF Tuncer, ZS Vegh, GL Fulop, V Genest, DR Mok, SC Berkowitz, RS TI Expression of epidermal growth factor receptor-related family products in gestational trophoblastic diseases and normal placenta and its relationship with development of postmolar tumor SO GYNECOLOGIC ONCOLOGY LA English DT Article DE epidermal growth factor receptor; c-erbB-3; c-erbB-4; hydatidiform mole; choriocarcinoma; placenta ID CHORIOCARCINOMA; C-ERBB-3; CARCINOMAS; CELLS; ONCOPROTEINS; ERBB3; EGF AB Objective. The goal of this work was to study the expression of epidermal growth factor receptor (EGFR) acid c-erbB-3 and c-erbB-4 oncogenes in gestational trophoblastic diseases and normal first-trimester placenta. Study design. Paraffin sections of 16 cases of partial mole, 25 cases of complete mole, 10 cases of gestational choriocarcinoma, and 11 cases of therapeutic abortion were studied immunohistochemically for EGFR, c-erbB-3, and c-erbB-4 proteins. The presence of EGFR mRNA was studied using in situ hybridization. Results. Staining for EGFR was detected immunohistochemically in all cell types in gestational trophoblastic diseases and normal placenta. In situ hybridization for EGFR mRNA correlated with immunostaining for EGFR in all tissues studied. All 10 cases of choriocarcinoma exhibited strong immunoreactivity for EGFR. The levels of expression of EGFR in choriocarcinoma and syncytiotrophoblasts and cytotrophoblasts in complete mole were significantly greater than those in syncytiotrophoblasts and cytotrophoblasts in both normal placenta and partial mole (P < 0.01, P < 0.01). Expression of c-erbB-3 did not significantly differ among placental and gestational trophoblastic disease tissues and trophoblastic cell types except for significantly increased expression in choriocarcinoma as compared with cytotrophoblasts of partial mole (P = 0.02). The placenta, complete and partial mole, and choriocarcinoma tissues demonstrated similar immunoreactivity for c-erbB-4. Strong immunostaining for EGFR (P = 0.02) and c-erbB-3 (P < 0.01) in extravillous trophoblasts of complete mole was found to be significantly correlated with the development of persistent postmolar gestational trophoblastic tumor. Conclusion. The EGFR-related family of oncogenes may be important in the pathogenesis of gestational trophoblastic diseases. The increased expression of EGFR and c-erbB-3 in complete mole may also influence the development of persistent gestational trophoblastic tumor. (C) 2000 Academic Press. C1 Harvard Univ, Brigham & Womens Hosp,Sch Med, Dept Obstet & Gynecol,Div Gynecol Oncol, Dana Farber Canc Inst,Lab Gynecol Oncol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp,Sch Med, Dept Pathol,Div Womens & Perinatal Pathol, Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp,Sch Med, Gillette Ctr Womens Canc, Dana Farber Canc Inst,New England Trophoblast Dis, Boston, MA 02115 USA. Imre Haynal Univ Hlth Sci, Dept Obstet & Gynecol, Budapest, Hungary. RP Berkowitz, RS (reprint author), Harvard Univ, Brigham & Womens Hosp,Sch Med, Dept Obstet & Gynecol,Div Gynecol Oncol, Dana Farber Canc Inst,Lab Gynecol Oncol, 75 Francis St, Boston, MA 02115 USA. NR 25 TC 41 Z9 43 U1 0 U2 0 PU ACADEMIC PRESS INC 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 2000 VL 77 IS 3 BP 389 EP 393 DI 10.1006/gyno.2000.5777 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 323CH UT WOS:000087546900008 PM 10831347 ER PT J AU Bailey, GP Sewell, WF AF Bailey, GP Sewell, WF TI Contribution of glutamate receptors to spontaneous and stimulus-evoked discharge in afferent fibers innervating hair cells of the Xenopus lateral line organ SO HEARING RESEARCH LA English DT Article DE glutamate; cochlea; synapse; 6-cyano-7-nitroquinoxaline-2,3-dione; lateral line ID GUINEA-PIG COCHLEA; ION-DEPENDENT CONDUCTANCES; AUDITORY-NERVE FIBERS; METHYL-D-ASPARTATE; NEUROTRANSMITTER RELEASE; CONCANAVALIN-A; QUISQUALATE RECEPTORS; SYNAPTIC TRANSMISSION; HIPPOCAMPAL-NEURONS; VESTIBULAR ORGANS AB The relative contributions of NMDA (N-methyl-D-aspartate) and non-NMDA glutamate receptors to spontaneous and stimulus-evoked transmission at the hair cell/afferent fiber synapse were determined in the Xenopus laevis lateral line organ. The non-NMDA receptor antagonist, CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) reversibly reduced both spontaneous and stimulus-evoked discharge rate with an EC50 of 0.5 mu M. NMDA receptor antagonism with the combination of chlorokynurenic acid (100 mu M) and elevated magnesium (1.1 mM), or elevated magnesium alone, blocked responses to NMDA without significantly altering spontaneous or stimulus-evoked discharge rate or the responses to kainate. All non-NMDA receptor agonists tested increased discharge rate at low concentrations and. at higher concentrations, increased, then suppressed discharge rate. The EC(50)s were: domoic acid (2.4 mu M) < quisqualic acid (6 mu M) < kainic acid (18 mu M) < AMPA (82 mu M) << glutamate (1150 mu M). NMDA and ibotenic acid also produced an increase in discharge followed by a suppression, but the suppressive phase of the response predominated and maximum increases in discharge rates were low compared to effects of the non-NMDA agonists. The EC(50)s were: NMDA (148 mu M) < ibotenic acid (463 mu M). The EC50 for the suppression of afferent discharge that followed the initial excitatory effect was similar to the EC50 for excitation. Perfusion with active concentrations of kainate, AMPA. or NMDA did not alter the threshold for electrical stimulation of these nerve fibers. We conclude that most of the postsynaptic signal normally seen in afferent fibers is mediated by non-NMDA receptors. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Otolaryngol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA. Boston Univ, Dept Pathol, Boston, MA 02115 USA. RP Sewell, WF (reprint author), Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, 243 Charles St, Boston, MA 02114 USA. FU NIDCD NIH HHS [DC 00767] NR 79 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD JUN PY 2000 VL 144 IS 1-2 BP 8 EP 20 DI 10.1016/S0378-5955(00)00023-X PG 13 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 320YK UT WOS:000087428000002 PM 10831861 ER PT J AU Abnet, CC Freeman, DM AF Abnet, CC Freeman, DM TI Deformations of the isolated mouse tectorial membrane produced by oscillatory forces SO HEARING RESEARCH LA English DT Article DE cochlea; tectorial membrane; magnetic bead; viscoelastic; mechanical coupling; anisotropy; micromechanics; mouse ID POLYELECTROLYTE GEL MODEL; COCHLEAR MICROMECHANICS; EQUILIBRIUM BEHAVIOR; LOCAL MEASUREMENTS; COLLAGEN; ORGAN; CORTI; GLYCOSAMINOGLYCANS; ORGANIZATION; PROTEOGLYCAN AB Mechanical properties of the isolated tectorial membrane (TM) of the mouse were measured by applying oscillatory shear forces to the TM with a magnetic bead (radius similar to 10 um). Sinusoidal forces at 10 Hz with amplitudes from 5 to 33 nN were applied tangentially to the surfaces of 11 TMs. The ratio of force to bead displacement ranged from 0.04 to 0.98 N/m (median: 0.18 N/m, interquartile range: 0.11-0.30 N/m, n = 90). Increasing frequency from 10 to 100 Hz decreased the magnitude of the displacement of the magnetic bead by 6-7.3 dB/decade. The phase of the displacement lagged that of the stimulus current by approximately 27-44 degrees across frequencies. Displacement of the adjacent tissue decreased as the distance from the magnetic bead increased. Space constants were of the order of tens of micrometers. Forces with equal amplitude and frequency were applied radially and longitudinally. Longitudinal displacements in response to longitudinal forces were 1-10 times as large as radial displacements in response to radial forces in 85% of 560 paired measurements. These results suggest that the following mechanical properties of the TM are important. (1) Viscoelasticity: The frequency dependence of TM displacement lies between that of a purely viscous and a purely elastic material, suggesting that both are important. (2) Mechanical coupling: Space constants indicate that hair bundles could interact mechanically with adjacent hair bundles via the TM. (3) Anisotropy: The mechanical impedance is greater in the radial direction than it is in the longitudinal direction. This mechanical anisotropy correlates with anatomical anisotropies, such as the radially oriented fibrillar structure of the TM. (C) 2000 Elsevier Science B.V. All rights reserved. C1 MIT, Dept Elect Engn & Comp Sci, Cambridge, MA 02139 USA. MIT, Dept Mech Engn, Cambridge, MA 02139 USA. MIT, Elect Res Lab, Cambridge, MA 02139 USA. Massachusetts Eye & Ear Infirm, Eaton Peabody Lab Auditory Physiol, Boston, MA 02114 USA. RP Freeman, DM (reprint author), MIT, Dept Elect Engn & Comp Sci, Room 36-889,50 Vassar St, Cambridge, MA 02139 USA. NR 62 TC 43 Z9 43 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD JUN PY 2000 VL 144 IS 1-2 BP 29 EP 46 DI 10.1016/S0378-5955(00)00041-1 PG 18 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 320YK UT WOS:000087428000004 PM 10831863 ER PT J AU Baker, PM Young, RH AF Baker, PM Young, RH TI Radiation-induced pseudocarcinomatous proliferations of the urinary bladder: A report of 4 cases SO HUMAN PATHOLOGY LA English DT Article DE bladder; radiation injury; pseudocarcinoma ID PROSTATE; MALIGNANCIES; IRRADIATION; CARCINOMA; FEATURES; CYSTITIS; TRACT AB Four cases of radiation cystitis that caused diagnostic difficulty because of an epithelial proliferation with architectural complexity and reactive cytologic atypia are described. The patients, 2 male, 2 female, were from 43 to 77 years of age. Two presented with hematuria. Cystoscopy disclosed abnormalities in 3 patients. Microscopic examination showed irregularly shaped and arranged aggregates of epithelial cells in the upper and mid zones of the lamina propria. The cells, which typically showed at least mild, and sometimes severe, pleomorphism, were usually transitional, but squamous differentiation was seen focally in 3 cases. Ulceration of the overlying epithelium was present in all cases and was prominent and associated with conspicuous fibrin and hemorrhage in one of them. Edema of the lamina propria tvas present in 3 cases, whereas lamina propria fibrosis and chronic inflammation were present in all cases. The presence in all 4 cases of vascular ectasia and other changes characteristic of radiation injury, such as atypical fibroblasts, prompted investigation of the clinical history in 2 cases in which the pathologist was unaware that the patient had received radiation. Pseudocarcinomatous proliferations in the bladder caused by radiation injury have received limited attention in the literature. Our cases illustrate the potential diagnostic errors with which these lesions may be associated. HUM PATHOL 31:678-683. Copyright (C) 2000 by W.B. Saunders Company. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Pathol Labs, Boston, MA 02114 USA. RP Young, RH (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Pathol,James Homer Wright Pathol Labs, 32 Fruit St, Boston, MA 02114 USA. NR 25 TC 28 Z9 29 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 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD JUN PY 2000 VL 31 IS 6 BP 678 EP 683 DI 10.1053/hupa.2000.7894 PG 6 WC Pathology SC Pathology GA 325TH UT WOS:000087692100008 PM 10872660 ER PT J AU Tannous, ZS Lerner, LH Duncan, LM Mihm, MC Flotte, TJ AF Tannous, ZS Lerner, LH Duncan, LM Mihm, MC Flotte, TJ TI Progression to invasive melanoma from malignant melanoma in situ, lentigo maligna type SO HUMAN PATHOLOGY LA English DT Article DE lentigo maligna melanoma; lentigo maligna; tumor progression ID IN-SITU; EXPRESSION; EVOLUTION; NEVI AB We have previously hypothesized that lesions that have been termed lentigo maligna can be divided into 2 categories: 1 represents a pigmented lesion that is a precursor to melanoma, and the other melanoma in situ. We and others have hypothesized that there is a progressive acquisition of attributes in pigmented lesions that results in malignant melanoma. Based on these 2 hypotheses, we have predicted that the intraepidermal component of invasive malignant melanomas, lentigo maligna type; should be similar to those lesions that we have termed malignant melanoma in situ, lentigo maligna type rather than lentigo maligna. The intraepidermal component of 42 consecutive cases of invasive malignant melanoma, lentigo maligna type was evaluated by all of the authors. Malignant melanoma in situ, lentigo maligna type is characterized by pagetoid spread, confluence, and nesting of atypical melanocytes. All of the cases evaluated showed features diagnostic of malignant melanoma in situ, lentigo maligna type, in the epidermis overlying the invasive dermal component. We conclude that invasive lentigo maligna melanoma arises in association with those lesions that we have termed malignant melanoma in situ, lentigo maligna type, which may represent a step in the progression between atypical melanocytic hyperplasia (lentigo maligna) and invasive melanoma. This finding supports the distinction of these entities and may have therapeutic implications. HUM PATHOL 31:705-708. Copyright (C) 2000 by W.B. Saunders Company. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Boston, MA 02114 USA. RP Flotte, TJ (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Warren 827,55 Fruit St, Boston, MA 02114 USA. RI Duncan, Lyn/E-9878-2013 NR 22 TC 39 Z9 39 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 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD JUN PY 2000 VL 31 IS 6 BP 705 EP 708 DI 10.1053/hupa.2000.7640 PG 4 WC Pathology SC Pathology GA 325TH UT WOS:000087692100012 PM 10872664 ER PT J AU Badawi, RD Kohlmyer, SG Harrison, RL Vannoy, SD Lewellen, TK AF Badawi, RD Kohlmyer, SG Harrison, RL Vannoy, SD Lewellen, TK TI The effect of camera geometry on singles flux, scatter fraction and trues and randoms sensitivity for cylindrical 3D PET - A simulation study. SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article; Proceedings Paper CT 1999 Medical Imaging Conference (MIC) CY OCT 24-30, 1999 CL SEATTLE, WASHINGTON ID MULTI-SLICE PET; COLLIMATION; SCANNER; RATES; MODEL AB Preliminary results of an assessment of the effects of changing the axial field of view (AFOV) and detector ring diameter (DRD) of a cylindrical PET tomograph on count-rate performance are presented. The assessment was made using Monte Carlo simulations of an anthropomorphic phantom based on the Zubal phantom. This phantom was modified to include cylinders approximating arms and legs, and was sequentially stepped through the AFOV to simulate a whole-body scan covering an axial region of interest of Im. DRD was varied from similar to 60 cm to similar to 108 cm, and AFOV was varied from 10 cm to 60 cm. A simple activity distribution and deadtime model was assumed to allow the calculation of noise-equivalent count (NEC) rates for a situation similar to that of a typical 18F-FDG study. Both the scatter fraction and singles flux were found to be strongly dependent on DRD, but only weakly dependent on AFOV when the latter was greater than similar to 25 cm. Trues and randoms sensitivity were strongly dependent on AFOV, and randoms sensitivity was also strongly dependent on DRD. Scatter and singles flux do not appear to be limiting factors for extended AFOV configurations, and randoms rates, while high, appear to be manageable with existing detector technology. This initial assessment suggests that for whole-body applications, substantial gains in NEC may be possible by extending the AFOV. C1 Univ Washington, Div Nucl Med, Seattle, WA 98195 USA. Dana Farber Canc Inst, Div Nucl Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Badawi, RD (reprint author), Univ Washington, Div Nucl Med, Seattle, WA 98195 USA. OI Vannoy, Steven/0000-0003-3029-8306 NR 13 TC 44 Z9 44 U1 0 U2 3 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0018-9499 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD JUN PY 2000 VL 47 IS 3 BP 1228 EP 1232 DI 10.1109/23.856575 PN 3 PG 5 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA 337TW UT WOS:000088378600041 ER PT J AU Agarwal, S Avni, O Rao, A AF Agarwal, S Avni, O Rao, A TI Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo SO IMMUNITY LA English DT Article ID INTERFERON-GAMMA PROMOTER; CYTOKINE GENE-EXPRESSION; ACTIVATED T-CELLS; FACTOR GATA-3; NUCLEAR FACTOR; TH2 CELLS; C-MAF; TH2-SPECIFIC EXPRESSION; HYPERSENSITIVE SITE; REGULATORY ELEMENTS AB By DNase I hypersensitivity analysis, we have identified an inducible, cyclosporin A-sensitive enhancer located 3' of the interleukin-4 (IL-4) gene. The enhancer binds the Th2-specific transcription factor GATA3 in vivo but is not perceptibly influenced by the absence of a second Th2-specific factor, cMaf. The antigen-inducible transcription factor NFAT1 binds the IL-4 enhancer and the IL-4 promoter only in stimulated Th2 cells; conversely, NFAT1 binds to the interferon (IFN)-gamma promoter only in stimulated Th1 cells. Our results support a model whereby transcription factors such as NFAT1, which are nonselectively induced in antigen-stimulated T cells, gain access to cytokine regulatory regions only in the appropriate subset of differentiated T cells in vivo. This restricted access enables antigen-dependent and subset-specific transcription of cytokine genes. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Ctr Blood Res, Boston, MA 02115 USA. RP Rao, A (reprint author), Harvard Univ, Sch Med, Dept Pathol, 200 Longwood Ave, Boston, MA 02115 USA. FU NCI NIH HHS [R01 CA42471]; NIAID NIH HHS [P01 AI35297, R01 AI44432] NR 69 TC 201 Z9 205 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN PY 2000 VL 12 IS 6 BP 643 EP 652 DI 10.1016/S1074-7613(00)80215-0 PG 10 WC Immunology SC Immunology GA 329ZA UT WOS:000087937300006 PM 10894164 ER PT J AU Weninger, W Ulfman, LH Cheng, G Souchkova, N Quackenbush, EJ Lowe, JB von Andrian, UH AF Weninger, W Ulfman, LH Cheng, G Souchkova, N Quackenbush, EJ Lowe, JB von Andrian, UH TI Specialized contributions by alpha(1,3)-fucosyltransferase-IV and FucT-VII during leukocyte rolling in dermal microvessels SO IMMUNITY LA English DT Article ID SELECTIN-DEFICIENT MICE; ADHESION IN-VIVO; P-SELECTIN; CONTACT HYPERSENSITIVITY; RABBIT MESENTERY; T-CELLS; VENULES; SKIN; RECRUITMENT; CYTOKINE AB Noninflamed skin venules support constitutive leukocyte rolling. P-selectin controls the rolling frequency, whereas E-selectin dictates rolling velocity (V-roll). Fucosylated selectin ligands are essential for all interactions, as rolling was absent in mice doubly deficient in alpha 1,3-fucosyltransferase (FucT)-IV and FucT-VII. The rolling fraction was reduced in FucT-VII-/- animals but normal in FucT-IV-/- mice. However, V-roll was markedly increased in both strains. P-selectin ligands generated by FucT-VII are crucial for initial leukocyte tethering, whereas E-selectin ligands that permit maximum slowing of V-roll require simultaneous expression of FucT-IV and FucT-VII. These results demonstrate a role for FucT-IV in selectin-dependent adhesion and suggest that the endothelial selectins and FucTs have distinct but overlapping functions in the immunosurveillance of the skin. C1 Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Pathol,Div Clin Genet, Boston, MA 02115 USA. Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48105 USA. RP von Andrian, UH (reprint author), Harvard Univ, Sch Med, Ctr Blood Res, Boston, MA 02115 USA. RI von Andrian, Ulrich/A-5775-2008; OI Weninger, Wolfgang/0000-0003-3133-8699 FU NHLBI NIH HHS [HL48675, HL54936, HL56949] NR 41 TC 193 Z9 197 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD JUN PY 2000 VL 12 IS 6 BP 665 EP 676 DI 10.1016/S1074-7613(00)80217-4 PG 12 WC Immunology SC Immunology GA 329ZA UT WOS:000087937300008 PM 10894166 ER PT J AU Busch, NA Zanzot, EM Loiselle, PM Carter, EA Allaire, JE Yarmush, ML Warren, HS AF Busch, NA Zanzot, EM Loiselle, PM Carter, EA Allaire, JE Yarmush, ML Warren, HS TI A model of infected burn wounds using Escherichia coli O18 : K1 : H7 for the study of gram-negative bacteremia and sepsis SO INFECTION AND IMMUNITY LA English DT Article AB A difficulty that has emerged in the development and preclinical evaluation of adjuvant therapies for gram-negative sepsis is the lack of easily studied animal models that closely mimic human infection. An objective of this study was to adapt a previously described model of infection in burned mice to rats with a defined bacterial strain of Escherichia coli. Challenge with two colonies of live E, coli O18:K1:H7 bacteria into an 8% full-thickness burn of the dorsal skin surface of rats produced predictable bacteremia at 24 to 48 h and 80 to 100% mortality at 3 to 4 days. E. coli O18:K1:H7 was approximately 10-million-fold more virulent than several other gram-negative bacterial strains. The model should be a useful tool in studying the pathogenicity of burn wound infections and in evaluating the efficacy of novel adjuvant therapies for gram-negative sepsis. C1 Harvard Univ, Infect Dis Unit, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. Harvard Univ, Ctr Engn Med, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. Harvard Univ, Surg Serv, Massachusetts Gen Hosp, Sch Med, Charlestown, MA 02129 USA. Shriners Burns Res Inst, Infect Dis Unit, Boston, MA 02114 USA. RP Warren, HS (reprint author), Harvard Univ, Infect Dis Unit, Massachusetts Gen Hosp, Sch Med, 5th Floor,149 13th St, Charlestown, MA 02129 USA. FU NIAID NIH HHS [AI28943] NR 11 TC 17 Z9 18 U1 0 U2 0 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 2000 VL 68 IS 6 BP 3349 EP 3351 DI 10.1128/IAI.68.6.3349-3351.2000 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 316LF UT WOS:000087167900040 PM 10816484 ER PT J AU Allen, JH Utley, M Van den Bosch, H Nuijten, P Witvliet, M McCormick, BA Krogfelt, KA Licht, TR Brown, D Mauel, M Leatham, MP Laux, DC Cohen, PS AF Allen, JH Utley, M Van den Bosch, H Nuijten, P Witvliet, M McCormick, BA Krogfelt, KA Licht, TR Brown, D Mauel, M Leatham, MP Laux, DC Cohen, PS TI A functional cra gene is required for Salmonella enterica serovar typhimurium virulence in BALB/c mice SO INFECTION AND IMMUNITY LA English DT Article ID ESCHERICHIA-COLI; DELETION MUTANTS; INTESTINAL MUCUS; AVIRULENT; REGULON; PROTEIN AB A minitransposon mutant of Salmonella enterica serovar Typhimurium SR-11, SR-11 Fad(-), is unable to utilize gluconeogenic substrates as carbon sources and is avirulent and immunogenic when administered perorally to BALB/c mice (M. J. Utley et al., FEMS Microbiol. Lett., 163:129-134, 1998). Here, evidence is presented that the mutation in SR-11 Fad(-) that renders the strain avirulent is in the cra gene, which encodes the Cra protein, a regulator of central carbon metabolism. C1 Univ Rhode Isl, Dept Biochem Microbiol & Mol Genet, Kingston, RI 02881 USA. Intervet Int, Bacteriol & Immunol Res & Dev, NL-5830 AA Boxmeer, Netherlands. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Combined Program Pediat Gastroenterol & Nutr, Charlestown, MA 02120 USA. Statens Serum Inst, Dept Gastrointestinal Infect, DK-2300 Copenhagen, Denmark. Tech Univ Denmark, Dept Microbiol, DK-2800 Lyngby, Denmark. Stobhill NHS Trust, Scottish Salmonella Reference Lab, Glasgow G21 3UW, Lanark, Scotland. RP Cohen, PS (reprint author), Univ Rhode Isl, Dept Biochem Microbiol & Mol Genet, Morrill Sci Bldg,45 Lower Coll Rd, Kingston, RI 02881 USA. RI Krogfelt , Karen Angeliki/O-8145-2016 OI Krogfelt , Karen Angeliki/0000-0001-7536-3453 FU NIDDK NIH HHS [DK50989] NR 23 TC 17 Z9 17 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 2000 VL 68 IS 6 BP 3772 EP 3775 DI 10.1128/IAI.68.6.3772-3775.2000 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 316LF UT WOS:000087167900102 PM 10816546 ER PT J AU Saint, S Veenstra, DL Lipsky, BA AF Saint, S Veenstra, DL Lipsky, BA TI The clinical and economic consequences of nosocomial central venous catheter-related infection: Are antimicrobial catheters useful? SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT Risk and Prevention Conferene CY FEB 24-25, 2000 CL PARIS, FRANCE ID BLOOD-STREAM INFECTION; CRITICALLY ILL PATIENTS; ANTISEPTIC-IMPREGNATED CATHETER; CONTINUOUS QUALITY IMPROVEMENT; RANDOMIZED CONTROLLED TRIALS; INTENSIVE-CARE UNIT; BACTERIAL-COLONIZATION; PARENTERAL-NUTRITION; ATTRIBUTABLE MORTALITY; COST-EFFECTIVENESS AB Central venous catheters (CVCs) are essential for many hospitalized patients, but they are associated with important infectious complications. Recent studies have indicated that CVCs coated with antimicrobial agents reduce the incidence of catheter-related bloodstream infection (CR BSI). To estimate the clinical and economic consequences of short-term central venous catheter-related infection and the potential usefulness of antimicrobial-coated catheters, we reviewed and synthesized the available relevant literature. Statistical pooling was used to estimate the incidence of both catheter colonization and CR BSI. The attributable mortality of CR BSI was also evaluated. In addition, the economic consequences of both local and systemic catheter-related infection was estimated from literature reports that used micro-costing and other techniques. Among patients in whom standard, noncoated CVCs are in place for an average of 8 days, 24.7% are expected to develop catheter colonization (95% confidence interval [CI95], 22.00%-27.5%). Approximately 5.2% (CI95 3.9%-6.5%) will develop CR BSI. The attributable mortality of CR BSI remains unclear, but recent studies are consistent with a range from 4% to 20%;. An episode of local catheter-related infection leads to an additional cost of approximately $400, whereas the additional cost of CR BSI ranges from approximately $6,005 to $9,738. Formal economic analyses indicate that CVCs coated with antibacterial agents (such as chlorhexidine-silver sulfadiazine or minocycline-rifampin) likely reduce infectious complications, yielding economic advantages. In light of the substantial clinical and economic burden of catheter-related infection, hospital personnel should adopt proven cost-effective methods to reduce this common and important nosocomial complication (Infect Control Hosp Epidemiol 2000;21:375-380). C1 Univ Washington, Sch Pharm, Pharmaceut Outcomes Res & Policy Program, Seattle, WA 98195 USA. Univ Michigan, Sch Med, Dept Med, Ann Arbor, MI 48109 USA. Ann Arbor Vet Affairs Hlth Serv, Res & Dev Serv, Ann Arbor, MI USA. Vet Affairs Puget Sound Healthcare Syst, Seattle Div, Seattle, WA USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. RP Veenstra, DL (reprint author), Univ Washington, Sch Pharm, Pharmaceut Outcomes Res & Policy Program, Box 357630, Seattle, WA 98195 USA. OI Lipsky, Benjamin A./0000-0001-9886-5114 NR 48 TC 80 Z9 81 U1 1 U2 2 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD JUN PY 2000 VL 21 IS 6 BP 375 EP 380 DI 10.1086/501776 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 325GK UT WOS:000087667700004 PM 10879567 ER PT J AU Hurford, WE AF Hurford, WE TI Techniques for endotracheal intubation SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID NOSOCOMIAL MAXILLARY SINUSITIS; CARBON-DIOXIDE CONCENTRATION; ESOPHAGEAL DETECTOR DEVICE; PARA-NASAL SINUSITIS; INTENSIVE-CARE UNIT; NASOTRACHEAL INTUBATION; TRACHEAL INTUBATION; AIRWAY MANAGEMENT; CARDIOPULMONARY RESUSCITATION; RADIOGRAPHIC CONFIRMATION C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Hurford, WE (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 5 Fruit St, Boston, MA 02114 USA. RI Hurford, William/G-6386-2013 OI Hurford, William/0000-0003-1201-0313 NR 72 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SUM PY 2000 VL 38 IS 3 BP 1 EP 28 DI 10.1097/00004311-200007000-00003 PG 28 WC Anesthesiology SC Anesthesiology GA 345KF UT WOS:000088814600002 PM 10984844 ER PT J AU Campo, SL Denman, WT AF Campo, SL Denman, WT TI The laryngeal mask airway: Its role in the difficult airway SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID INTUBATION; MANAGEMENT; INSERTION; CHILDREN C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Campo, SL (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. NR 28 TC 4 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SUM PY 2000 VL 38 IS 3 BP 29 EP 45 DI 10.1097/00004311-200007000-00004 PG 17 WC Anesthesiology SC Anesthesiology GA 345KF UT WOS:000088814600003 PM 10984845 ER PT J AU George, E Haspel, KL AF George, E Haspel, KL TI The difficult airway SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID TRACHEAL INTUBATION; MANAGEMENT; ANESTHESIOLOGISTS; LARYNGOSCOPE C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP George, E (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. NR 29 TC 3 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SUM PY 2000 VL 38 IS 3 BP 47 EP 63 DI 10.1097/00004311-200007000-00005 PG 17 WC Anesthesiology SC Anesthesiology GA 345KF UT WOS:000088814600004 PM 10984846 ER PT J AU Dunn, PF Goulet, RL AF Dunn, PF Goulet, RL TI Endotracheal tubes and airway appliances SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID LOW-PRESSURE CUFF; PREVENT ASPIRATION; TRACHEOSTOMY; TRACHEOTOMY; INTUBATION; COMPLICATIONS; PNEUMONIA; VALVE C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. RP Dunn, PF (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. NR 45 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SUM PY 2000 VL 38 IS 3 BP 65 EP 94 DI 10.1097/00004311-200007000-00006 PG 30 WC Anesthesiology SC Anesthesiology GA 345KF UT WOS:000088814600005 PM 10984847 ER PT J AU Peralta, R Hurford, WE AF Peralta, R Hurford, WE TI Airway trauma SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID PENETRATING NECK INJURIES; ANESTHETIC MANAGEMENT; LARYNGEAL TRAUMA; LARYNGOTRACHEAL TRAUMA; CERVICAL TRACHEA; INTUBATION; WOUNDS C1 Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Peralta, R (reprint author), Massachusetts Gen Hosp, Dept Surg, 55 Fruit St, Boston, MA 02114 USA. RI Hurford, William/G-6386-2013 OI Hurford, William/0000-0003-1201-0313 NR 65 TC 7 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SUM PY 2000 VL 38 IS 3 BP 111 EP 127 DI 10.1097/00004311-200007000-00008 PG 17 WC Anesthesiology SC Anesthesiology GA 345KF UT WOS:000088814600007 PM 10984849 ER PT J AU Dennehy, KC Pian-Smith, MCM AF Dennehy, KC Pian-Smith, MCM TI Airway management of the parturient SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID DIFFICULT TRACHEAL INTUBATION; OBSTETRIC ANESTHESIA; CESAREAN-SECTION; MALLAMPATI SCORE; PREGNANCY; OMEPRAZOLE; WOMEN C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Dennehy, KC (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. NR 24 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SUM PY 2000 VL 38 IS 3 BP 147 EP 159 DI 10.1097/00004311-200007000-00010 PG 13 WC Anesthesiology SC Anesthesiology GA 345KF UT WOS:000088814600009 PM 10984851 ER PT J AU Hess, D Chatmongkolchart, S AF Hess, D Chatmongkolchart, S TI Techniques to avoid intubation: Noninvasive positive pressure ventilation and heliox therapy SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Review ID ACUTE RESPIRATORY-FAILURE; OBSTRUCTIVE PULMONARY-DISEASE; UPPER AIRWAY-OBSTRUCTION; ACUTE SEVERE ASTHMA; CONVENTIONAL MECHANICAL VENTILATION; RANDOMIZED CONTROLLED TRIAL; SUPPORT VENTILATION; OXYGEN MIXTURES; FACE MASK; ACUTE EXACERBATIONS C1 Massachusetts Gen Hosp, Dept Resp Care, Boston, MA 02114 USA. RP Hess, D (reprint author), Massachusetts Gen Hosp, Dept Resp Care, 55 Fruit St, Boston, MA 02114 USA. NR 118 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SUM PY 2000 VL 38 IS 3 BP 161 EP 187 DI 10.1097/00004311-200007000-00011 PG 27 WC Anesthesiology SC Anesthesiology GA 345KF UT WOS:000088814600010 PM 10984852 ER PT J AU Fulling, PD Roberts, JT AF Fulling, PD Roberts, JT TI Fiberoptic intubation SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID LARYNGEAL MASK AIRWAY; TRACHEAL INTUBATION; ENDOTRACHEAL INTUBATION; NEUROSURGICAL PATIENTS; DIFFICULT INTUBATION; OXYGEN INSUFFLATION; AWAKE INTUBATION; ANESTHESIA; LARYNGOSCOPY; LIDOCAINE C1 Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Fulling, PD (reprint author), Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, 55 Fruit St, Boston, MA 02114 USA. NR 50 TC 14 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SUM PY 2000 VL 38 IS 3 BP 189 EP 217 DI 10.1097/00004311-200007000-00012 PG 29 WC Anesthesiology SC Anesthesiology GA 345KF UT WOS:000088814600011 PM 10984853 ER PT J AU Goldsmith, T AF Goldsmith, T TI Evaluation and treatment of swallowing disorders following endotracheal intubation and tracheostomy SO INTERNATIONAL ANESTHESIOLOGY CLINICS LA English DT Article ID BLUE-DYE VISUALIZATION; GAG REFLEX; PULMONARY ASPIRATION; CLOSURE; COORDINATION; TRACHEOTOMY; RESPIRATION; EXTUBATION; DYSPHAGIA; OCCLUSION C1 Massachusetts Gen Hosp, Dept Speech Language Pathol, Boston, MA 02114 USA. RP Goldsmith, T (reprint author), Massachusetts Gen Hosp, Dept Speech Language Pathol, 15 Parkman St, Boston, MA 02114 USA. NR 39 TC 33 Z9 41 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-5907 J9 INT ANESTHESIOL CLIN JI Int. Anesthesiol. Clin. PD SUM PY 2000 VL 38 IS 3 BP 219 EP 242 DI 10.1097/00004311-200007000-00013 PG 24 WC Anesthesiology SC Anesthesiology GA 345KF UT WOS:000088814600012 PM 10984854 ER PT J AU Kawai, T Seki, M Watanabe, H Eastcott, JW Smith, DJ Taubman, MA AF Kawai, T Seki, M Watanabe, H Eastcott, JW Smith, DJ Taubman, MA TI T(h)1 transmigration anergy: a new concept of endothelial cell-T cell regulatory interaction SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE anergy; B7; MHC class II; T cell migration; vascular endothelium ID VASCULAR ENDOTHELIUM; ADHESION MOLECULE; GINGIVAL TISSUES; LYMPHOCYTE-T; TH1 CELLS; EXPRESSION; ANTIGEN; RAT; INDUCTION; RESPONSES AB Stimulation of endothelial cells (EC) with IFN-gamma generates selective enhancement of T(h)1 cell transmigration and Induction of MHC class II expression on EC, In the present study, we tested whether antigen presentation by EC could influence transmigrating T cells in an in vitro system, Bacterial antigen presentation by EC from primary culture and after cloning induced antigen-specific anergy of transmigrating T(h)1 clone cells in a MHC class Ii-dependent manner as characterized by non-responsiveness to subsequent antigen presentation and inability to produce IL-2, This T cell transmigration anergy induced by EC was abrogated by anti-rat CD28 mAb, suggesting that lack of B7 co-stimulatory signals by EC might be related to the induction of anergy, While MHC class II expression on primary and cloned EC was observed after IFN-gamma stimulation, these cells never expressed B7, B7-1 gene-transfected endothelial clone cells (ECC/B7-1) were developed to elucidate the influence of B7 co-stimulation by EC, ECC/B7-1 induced proliferation of T(h)1 clone cells, whereas ECC did not induce proliferation in co-culture of T(h)1 clone cells and EC stimulated with IFN-gamma and antigen. in the transmigration assay, ECC/B7-1 did not induce transmigration anergy of T(h)1 clones or T(h)1 lines unless anti-rat B7-1 blocking mAb was added. Therefore, in rats, the T cell anergy induced during transmigration across a layer of EC seemed to be due to antigen presentation in the absence of B7 on the EC. We introduce the concept of transmigration anergy In this manuscript. Thus, EC can play a critical immune regulatory role in the context of antigen presentation by MHC class II to transmigrating T cells. C1 Forsyth Inst, Dept Immunol, Boston, MA 02115 USA. Mitsubishi Tokyo Pharmaceut, Aoba Ku, Yokohama, Kanagawa 227, Japan. Tokyo Med & Dent Univ, Dept Periodontol, Bunkyo Ku, Tokyo 113, Japan. RP Taubman, MA (reprint author), Forsyth Inst, Dept Immunol, 140 Fenway, Boston, MA 02115 USA. FU NIDCR NIH HHS [DE-03420] NR 48 TC 9 Z9 9 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD JUN PY 2000 VL 12 IS 6 BP 937 EP 948 DI 10.1093/intimm/12.6.937 PG 12 WC Immunology SC Immunology GA 329JQ UT WOS:000087904200021 PM 10837421 ER PT J AU Mystkowski, P Shankland, E Schreyer, SA LeBouef, RC Schwartz, RS Cummings, DE Kushmerick, M Schwartz, MW AF Mystkowski, P Shankland, E Schreyer, SA LeBouef, RC Schwartz, RS Cummings, DE Kushmerick, M Schwartz, MW TI Validation of whole-body magnetic resonance spectroscopy as a tool to assess murine body composition SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE proton spectroscopy; obesity; body composition; mice ID EARLY-ONSET OBESITY; TARGETED DISRUPTION; RECEPTOR; RATS; MICE; ABSORPTIOMETRY; MUTATION; HUMANS; GENE AB OBJECTIVE: To evaluate proton magnetic resonance spectroscopy (MRS) as a tool for the non-invasive assessment of murine body composition. DESIGN: Twenty C57/BL6 male mice with a wide range of body adiposities underwent both pre- and post-mortem whole-body MRS to assess body composition. MRS measures were compared to the results obtained by chemical carcass analysis, the current 'gold standard' for determination of body composition. MEASUREMENTS: Areas under the curve (AUC) for lipid and water peaks of whole body MRS spectra (AUC(lipid) and AUC(H2O), respectively) were used to determine percentages of body fat (%FAT(MRS)) and fat free mass by MRS (%FFMMRS) Total body fat, total body water, fat free mass, and total lean mass were determined by chloroform/methanol extraction of lipid from dessicated whole carcass and compared to MRS measures (%FAT(MRS), %FFMMRS, AUC(lipid), and AUC(H2O)) The variability of the MRS technique was assessed by determining the coefficients of variation (COV) associated with %FAT(MRS), AUC(lipid), and AUC(H2O) for mice of three different adiposities. RESULTS: %FAT(MRS) in live mice was highly correlated with body fat percentage (r = 0.994, P < 0.001) and total body fat (r = 0.980, P < 0.001) derived from chemical carcass analysis over a broad range of adiposities (7-48% body fat content by carcass analysis). There was no difference in %FAT(MRS) measured pre- vs post-mortem (r = 1.00, P < 0.001). AUC(lipid) was highly correlated with chemically derived total fat mass (r = 0.996, P < 0.001) and body fat percentage (r = 0.981, P < 0.001), while %FFMMRS was strongly correlated to chemical determinations of percentage body water (r = 0.994, P < 0.001), percentage fat free mass (r = 0.993, P < 0.001), and percentage lean mass (r = 0.792, P < 0.001). AUC(H2O) was strongly associated with carcass analysis determinations of total body water (r = 0.964, P < 0.001), total fat free mass (r = 0.953, P < 0.001), and total lean mass (r = 0.89, P < 0.001). In mice of 6%, 12%, and 43% body fat, COVs determined for %FAT(MRS) and AUC(lipid) were less than 10%. The COVs for AUC(H2O) were less than 2%. CONCLUSIONS: MRS provides precise, accurate, rapid, and non-invasive measures of body fat, body water, fat free mass, and lean mass in living mice with a broad range of adiposities. C1 Univ Washington, Harborview Med Ctr, Div Endocrinol Metab, Dept Internal Med, Seattle, WA 98104 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. Univ Washington, Dept Pathobiol & Nutr, Seattle, WA 98195 USA. VA Puget Sound Hlth Care Syst, Seattle, WA USA. Univ Washington, Dept Radiol, Seattle, WA 98195 USA. Univ Colorado, Hlth Sci Ctr, Dept Internal Med, Denver, CO USA. RP Schwartz, MW (reprint author), Univ Washington, Harborview Med Ctr, Div Endocrinol Metab, Dept Internal Med, 325 9Th Ave,Box 359757, Seattle, WA 98104 USA. RI Schwartz, Michael/H-9950-2012 FU NHLBI NIH HHS [HL07028-24]; NIDDK NIH HHS [DK52989]; NINDS NIH HHS [NS32273] NR 22 TC 35 Z9 36 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD JUN PY 2000 VL 24 IS 6 BP 719 EP 724 DI 10.1038/sj.ijo.0801231 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 321QN UT WOS:000087466300008 PM 10878678 ER PT J AU Troulis, MJ Kearns, GJ Perrott, DH Kaban, LB AF Troulis, MJ Kearns, GJ Perrott, DH Kaban, LB TI Extended genioplasty: long-term cephalometric, morphometric and sensory results SO INTERNATIONAL JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article DE genioplasty; microgenia; longterm follow-up ID SPECIAL BONE PLATE; ADVANCEMENT GENIOPLASTY; CHIN; OSTEOTOMIES; PEDICLE; BROAD AB The incision, dissection, osteotomy design and fixation are important technical considerations when performing a genioplasty. The purpose of this study was to describe an extended genioplasty technique and to evaluate stability of position, form, surface area of the chin and incidence of postoperative sensory deficit. Records of 15 consecutive adult patients who underwent the extended genioplasty procedure were reviewed. The technique included incision in the labial vestibule from 2nd premolar to 2nd premolar, dissection, mobilization and retraction of the mental nerves, osteotomy parallel to the occlusal plane extending proximally to the antegonial notch and rigid fixation. Lateral cephalograms pre- and postoperatively and at the latest follow-up (> 6 months) were analyzed by linear and computer morphometric measurements to evaluate changes in position, shape and surface area of the chin. Neurosensory data from examination or questionnaire were recorded. Immediately postoperatively (T-1), mean advancement in the sagittal plane was +8.7 mm and increase in surface area was +1.1 cm(2). At the end of follow-up (T-2), there were no significant changes (T-2-T-1) in chin position or surface area. Inferior border form was rated as smooth in all cases. Neurosensory evaluation revealed that 12/12 patients evaluated had functional sensory return at T-2. C1 Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Boston, MA 02114 USA. RP Kaban, LB (reprint author), Massachusetts Gen Hosp, Dept Oral & Maxillofacial Surg, Warren Bldg 1201,55 Fruit St, Boston, MA 02114 USA. NR 41 TC 5 Z9 6 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0901-5027 J9 INT J ORAL MAX SURG JI Int. J. Oral Maxillofac. Surg. PD JUN PY 2000 VL 29 IS 3 BP 167 EP 175 DI 10.1034/j.1399-0020.2000.290303.x PG 9 WC Dentistry, Oral Surgery & Medicine; Surgery SC Dentistry, Oral Surgery & Medicine; Surgery GA 346AH UT WOS:000088847600003 PM 10970077 ER PT J AU Rosqvist, J Egan, D Thomas, J Willis, S AF Rosqvist, J Egan, D Thomas, J Willis, S TI Home-based CBT treatment of chronic, refractory OCD can be effective: Single case analysis of four patients SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD JUN-AUG PY 2000 VL 35 IS 3-4 SI SI BP 168 EP 168 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 337XP UT WOS:000088388801647 ER PT J AU Roach, M Lu, JD Pilepich, MV Asbell, SO Mohuidden, M Terry, R Grignon, D Lawton, C Shipley, W Cox, J AF Roach, M Lu, JD Pilepich, MV Asbell, SO Mohuidden, M Terry, R Grignon, D Lawton, C Shipley, W Cox, J TI Predicting long-term survival, and the need for hormonal therapy: A meta-analysis of RTOG prostate cancer trials SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE prostate cancer; radiotherapy; long-term survival; hormonal therapy ID RADIATION-THERAPY; ONCOLOGY GROUP; DEFINITIVE RADIOTHERAPY; RADICAL PROSTATECTOMY; CARCINOMA; GOSERELIN AB Purpose: To assess the impact of short-term and long-term androgen suppression on the disease-specific and overall survival of 2200 men treated with radiotherapy on one of 5 prospective randomized trials when stratified by prognostic risk groups. Methods and Materials: Between 1975 and 1992, 2742 men were treated for clinically localized prostate cancer on one of 5 consecutive prospective Phase III randomized trials. Patients were selected for this analysis if they were deemed evaluable and eligible for the trial, and if follow-up information was available. For this analysis patients were stratified into four previously described prognostic risk groups: Group 1 patients had a Gleason score (GS) = 2-6, and T1-2Nx; Group 2: GS = 2-6, T3Nx; or GS = 2-6, Nf, or GS = 7, T1-2Nx; Group 3: T3Nx, GS = 7; or Nf, GS = 7, or T1-2Nx, GS = 8-10; and Group 4 patients were T3Nx, GS = 8-10, or N+, GS = 8-10. The median pretreatment prostate-specific antigen (PSA) was 25 ng/ml for the 434 evaluable patients for whom this information was available. The median follow-up times for patients treated on early studies exceeded 11 years, and for more recent studies 6 years. Results: Risk group 2 patients with "bulky" or T3 disease appeared to have a disease-specific survival benefit at 8 years with the addition of 4 months of goserelin and flutamide. Group 3 and 4 patients were noted to have an approximately 20% higher survival at 8 years with the addition of long-term hormonal therapy (p less than or equal to 0.0004). Conclusions: Based on this meta-analysis of RTOG trials, subsets of patients can be identified who either do not appear to benefit from the use of hormonal therapy, benefit from short-term hormonal therapy, or who benefit only from long-term hormonal therapy. These observations should be confirmed by prospective randomized trials before they can be considered conclusive. In the meantime, however, these observations provide rational guidelines for deciding who should receive hormonal therapy and for how long. (C) 2000 Elsevier Science Inc. C1 Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med Oncol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA. RTOG Stat Headquarters, Philadelphia, PA USA. Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. Albert Einstein Med Ctr, Dept Radiat Oncol, Philadelphia, PA 19141 USA. Univ Kentucky, Dept Radiat Oncol, Lexington, KY USA. Univ So Calif, Dept Pathol, Los Angeles, CA 90089 USA. Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. Med Coll Wisconsin, Dept Radiat Oncol, Madison, WI USA. Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA. RP Roach, M (reprint author), Univ Calif San Francisco, Dept Radiat Oncol, 505 Parnassus Ave, San Francisco, CA 94143 USA. EM roach@radonc17.ucsf.edu NR 23 TC 127 Z9 130 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 EI 1879-355X J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUN 1 PY 2000 VL 47 IS 3 BP 617 EP 627 DI 10.1016/S0360-3016(00)00577-0 PG 11 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 320GR UT WOS:000087393900012 ER PT J AU Primack, JD Azar, DT AF Primack, JD Azar, DT TI Refractive surgery for hyperopia SO INTERNATIONAL OPHTHALMOLOGY CLINICS LA English DT Article ID PHAKIC INTRAOCULAR-LENS; AUTOMATED LAMELLAR KERATOPLASTY; IN-SITU KERATOMILEUSIS; LASER PHOTOREFRACTIVE KERATECTOMY; CORRECT HYPEROPIA; EXCIMER-LASER; HEXAGONAL KERATOTOMY; THERMAL KERATOPLASTY; EYES; EXTRACTION AB While early efforts in refractive surgery concentrated on the correction of myopia, attention has been turning toward developing and adapting technologies to treat hyperopia. Surgeons have various modalities from which to choose when approached by a hyperopic patient who desires less dependence on corrective lenses. These options include thermokeratoplasty (TK), photorefractive keratectomy (PRK), laser-assisted in situ keratomileusis (LASIK), and lens surgery. Treatment decisions are influenced by multiple factors, including the patient's age and accommodative status, the degree of hyperopia, and the surgeons' comfort level with the specific surgical technique. In this chapter, we describe several treatment modalities that have been employed to treat hyperopia (figure) and emphasize those with proven effectiveness, greater likelihood for success, and lower potential for side effects (table). C1 Massachusetts Eye & Ear Infirm, Boston, MA 02114 USA. RP Primack, JD (reprint author), Massachusetts Eye & Ear Infirm, 243 Charles St, Boston, MA 02114 USA. NR 48 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0020-8167 J9 INT OPHTHALMOL CLIN JI Int. Ophthalmol. Clin. PD SUM PY 2000 VL 40 IS 3 BP 151 EP 163 DI 10.1097/00004397-200007000-00018 PG 13 WC Ophthalmology SC Ophthalmology GA 339FG UT WOS:000088466500017 PM 10941656 ER PT J AU Cai, WY Rook, SL Jiang, ZY Takahara, N Aiello, LP AF Cai, WY Rook, SL Jiang, ZY Takahara, N Aiello, LP TI Mechanisms of hepatocyte growth factor-induced retinal endothelial cell migration and growth SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID PROLIFERATIVE DIABETIC-RETINOPATHY; ACTIVATED PROTEIN-KINASE; FACTOR SCATTER FACTOR; C-MET; SERUM CONCENTRATIONS; VITREOUS LEVELS; FACTOR RECEPTOR; EXPRESSION; INHIBITOR; KERATINOCYTES AB PURPOSE. Hepatocyte growth factor (HGF), also called scatter factor, stimulates growth and motility in nonocular endothelial cells and smooth muscle cells through its receptor c-Met. Recent reports suggest that HGF is increased in the serum and vitreous of patients with proliferative diabetic retinopathy and that smooth muscle cells and retinal pigment epithelial cells secrete HGF in the eye. However, little is known about HGF's action in the retina In this study, the activity, expression, and signaling pathways of HGF were investigated in bovine retinal microvascular endothelial cells (BRECs). METHODS. Mitogenic and motogeneic effects of HGF on BRECs were examined using cell counts, thymidine uptake, and migration assays. MAP kinase (MAPK) phosphorylation was examined by Western blot analysis. Protein kinase C (PKC), MAPK, and PI3 kinase involvement were evaluated using selective inhibitors and activity assays. Expression of HGF and c-Met was evaluated by reverse transcription-polymerase chain reaction. RESULTS. HGF and c-Met were both expressed in BRECs. HGF stimulated BREC growth in a time- and dose-dependent manner, observed at HGF concentrations of 5 ng/ml or more and maximal (410%) at 100 ng/ml (P < 0.001). HGF increased BREC migration in a dose-dependent manner with a maximal 3.4-fold increase at 50 ng/ml after 5 hours. HGF induced time- and dose-dependent MAPK phosphorylation, initially evident at 5 minutes (P < 0.001) or 5 ng/ml (P < 0.050) and maximal after 15 minutes (>80-fold, P < 0.001) or 50 ng/ml (>20-fold, P < 0.001), respectively. MAPK phosphorylation was maintained for more than 2 hours. This response was inhibited 31% by 0.1 mu m wortmannin and 76% by 30 mu m LY294002, another PI3 kinase inhibitor. The non-isoform-selective PKC inhibitor GFX inhibited HGF-induced MAPK phosphorylation by only 15% at 5 mu m. Combined PKC and PI3 kinase inhibition was additive (P < 0.05). Cell migration was inhibited 30% by wortmannin (P < 0.01) and 32% by GFX (P < 0.05), and again the effect was additive (P < 0.001). HGF-induced BREC growth was suppressed by PI3 kinase, PKC, or MAPK inhibition (all P < 0.01). HGF (50 ng/ml) stimulated PI3 kinase activity 347% (P < 0.001) and PKC activity 37% (P < 0.05). HGF-induced MAPK phosphorylation and mitogenesis were not inhibited by vascular endothelial growth factor (VEGF)-neutralizing antibody. CONCLUSIONS. HGF and its receptor are expressed in BREC, and HGF stimulates both BREC growth and migration at concentrations observed in the human eye with diabetic retinopathy. HGF signaling appears to involve activation of both PKC and PI3 kinase, inducing MAPK phosphorylation that is critical for migration and growth. However, VEGF does not appear to mediate these initial HGF effects. These results indicate that HGF could have a significant role in mediating retinal endothelial cell proliferation and migration in diabetic retinopathy, and they begin to elucidate the signal transduction pathway by which this action may occur. C1 Joslin Diabet Ctr, Div Res, Boston, MA 02115 USA. Joslin Diabet Ctr, Beetham Eye Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA. RP Aiello, LP (reprint author), Joslin Diabet Ctr, Div Res, 1 Joslin Pl, Boston, MA 02115 USA. FU NEI NIH HHS [EY-10827]; PHS HHS [36836] NR 51 TC 47 Z9 47 U1 0 U2 2 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 2000 VL 41 IS 7 BP 1885 EP 1893 PG 9 WC Ophthalmology SC Ophthalmology GA 320DV UT WOS:000087387300039 PM 10845613 ER PT J AU Schlesinger, N Neustadter, L Schumacher, HR AF Schlesinger, N Neustadter, L Schumacher, HR TI Lytic bone lesions as a prominent feature in Waldenstrom's macroglobulinemia SO JCR-JOURNAL OF CLINICAL RHEUMATOLOGY LA English DT Article DE osteolysis; calcifications; Waldenstrom's macroglobulinemia ID MULTIPLE-MYELOMA; CALCIFICATION AB We report a patient with Waldenstrom's macroglobulinemia who had diffuse plasmacytoid infiltration in the bone marrow, immunoglobulin M monoclonal gammopathy, wide-spread osteolytic lesions, recurrent pathologic fractures, and diffuse subcutaneous soft tissue calcifications. The bony lesions were even more pronounced than those usually seen with multiple myeloma and are a rare manifestation of this disease. Such malignant plasma-cell dyscrasia with macroglobulinemia and lytic osseous lesions is best handled clinically according to its general presenting features rather than according to whether it is Waldenstrom's macroglobulinemia or an immunoglobulin M myeloma. The bone lesions may require local palliative radiotherapy and orthopedic measures. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Rheumatol Sect, Newark, NJ 07103 USA. Univ Penn, Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Div Rheumatol, Vet Affairs Med Ctr, Philadelphia, PA 19104 USA. Vet Affairs Med Ctr, Arthrit Immunol Ctr, Philadelphia, PA USA. RP Schlesinger, N (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Rheumatol Sect, MSB I-506,185 S Orange Ave, Newark, NJ 07103 USA. NR 14 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1076-1608 J9 JCR-J CLIN RHEUMATOL JI JCR-J. Clin. Rheumatol. PD JUN PY 2000 VL 6 IS 3 BP 150 EP 153 DI 10.1097/00124743-200006000-00007 PG 4 WC Rheumatology SC Rheumatology GA 322XJ UT WOS:000087534300010 PM 19078464 ER PT J AU Hausdorff, JM Lertratanakul, A Cudkowicz, ME Peterson, AL Kaliton, D Goldberger, AL AF Hausdorff, JM Lertratanakul, A Cudkowicz, ME Peterson, AL Kaliton, D Goldberger, AL TI Dynamic markers of altered gait rhythm in amyotrophic lateral sclerosis SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE nervous system diseases; Huntington's disease; Parkinson's disease; motor control; nonlinear dynamics ID LONG-RANGE CORRELATIONS; STRIDE-INTERVAL; HUNTINGTONS-DISEASE; PARKINSONS-DISEASE; FRACTAL DYNAMICS; VARIABILITY; MUSCLE; STIMULATION; PARAMETERS; WALKING AB Amyotrophic lateral sclerosis (ALS) is a disorder marked by loss of motoneurons. We hypothesized that subjects with ALS would have an altered gait rhythm, with an increase in both the magnitude of the stride-to-stride fluctuations and perturbations in the fluctuation dynamics. To test for this locomotor instability, we quantitatively compared the gait rhythm of subjects with ALS with that of normal controls and with that of subjects with Parkinson's disease (PD) and Huntington's disease (HD), pathologies of the basal ganglia. Subjects walked for 5 min at, their usual pace wearing an ankle-worn recorder that enabled determination of the duration of each stride and of stride-to-stride fluctuations. We found that the gait of patients with ALS is less steady and more temporally disorganized compared with that of healthy controls. In addition, advanced ALS, HD, and PD were associated with certain common, as well as apparently distinct, features of altered stride dynamics. Thus stride-to-stride control of gait rhythm is apparently compromised with ALS. Moreover, a matrix of markers based on gait dynamics may be useful in characterizing certain pathologies of motor control and, possibly, in quantitatively monitoring disease progression and evaluating therapeutic interventions. C1 Beth Israel Deaconess Med Ctr, Margaret & HA Rey Lab Nonlinear Dynam Med, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Gerontol Div, Boston, MA 02215 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Hausdorff, JM (reprint author), Beth Israel Deaconess Med Ctr, Margaret & HA Rey Lab Nonlinear Dynam Med, 330 Brookline Ave,Rm KSB-28, Boston, MA 02215 USA. FU NIA NIH HHS [AG-00294, AG-08812, AG-14100] NR 36 TC 149 Z9 154 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD JUN PY 2000 VL 88 IS 6 BP 2045 EP 2053 PG 9 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 324CA UT WOS:000087603200016 PM 10846017 ER PT J AU Hendrickson, EL Guevera, P Penaloza-Vazquez, A Shao, J Bender, C Ausubel, FM AF Hendrickson, EL Guevera, P Penaloza-Vazquez, A Shao, J Bender, C Ausubel, FM TI Virulence of the phytopathogen Pseudomonas syringae pv. maculicola is rpoN dependent SO JOURNAL OF BACTERIOLOGY LA English DT Article ID PLANT-DISEASE RESISTANCE; PATHOGENESIS-RELATED PROTEINS; ALTERNATE SIGMA-FACTOR; HRP GENE-CLUSTER; PHYTOTOXIN CORONATINE; AVIRULENCE GENE; HYPERSENSITIVE REACTION; MOLECULAR CHARACTERIZATION; BRADYRHIZOBIUM-JAPONICUM; ANTIFUNGAL HYDROLASES AB We cloned the rpoN (ntrA and glnF) gene encoding sigma(54) from the phytopathogen Pseudomonas syringae pv. maculicola strain ES4326. The P, syringae E4326 rpoN gene complemented Pseudomonas aeruginosa, Escherichia coli, and Klebsiella aerogenes rpoN mutants for a variety of rpoN mutant phenotypes, including the inability to utilize nitrate as sole nitrogen source. DNA sequence analysis of the P. syringae ES4326 rpoN gene revealed that the deduced amino acid sequence was most similar (86% identity; 95% similarity) to the sigma(54) protein encoded by the Pseudomonas putida rpoN gene. A marker exchange protocol was used to construct an ES4326 rpoN insertional mutation, rpoN::Km(r). In contrast to wild-type ES4326, ES4326 rpoN::Km(r) was nonmotile and could not utilize nitrate, urea, C(4)-dicarboxylic acids, several amino acids, or concentrations of ammonia below 2 mM as nitrogen sources. rpoN was essential for production of the phytotoxin coronatine and for expression of the structural genes encoding coronamic acid. In addition, ES4326 rpoN::Km(r) did not multiply or elicit disease symptoms when infiltrated into Arabidopsis thaliana leaves, did not elicit the accumulation of several Arabidopsis defense-related mRNAs, and did not elicit a hypersensitive response (HR) when infiltrated into tobacco (Nicotiana tabacum) leaves. Furthermore, whereas P. syringae ES4326 carrying the avirulence gene avrRpt2 elicited an HR when infiltrated into Arabidopsis ecotype Columbia leaves, ES4326 rpoN::Km(r) carrying avrRpt2 elicited no response. Constitutive expression of ES4326 hrpL in ES4326 rpoN::Km(r) partially restored defense-related mRNA accumulation, showing a direct role for the hrp cluster in host defense gene induction in a compatible host-pathogen interaction However, constitutive expression of hrpL in ES4326 rpoN::Km(r) did not restore coronatine production, showing that coronatine biosynthesis requires factors other than hrpL. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. Oklahoma State Univ, Dept Entomol & Plant Pathol, Stillwater, OK 74078 USA. RP Ausubel, FM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Wellman 10, Boston, MA 02114 USA. FU NIGMS NIH HHS [R37 GM048707, GM48707, R01 GM048707] NR 95 TC 38 Z9 41 U1 1 U2 15 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUN PY 2000 VL 182 IS 12 BP 3498 EP 3507 DI 10.1128/JB.182.12.3498-3507.2000 PG 10 WC Microbiology SC Microbiology GA 318WM UT WOS:000087307700025 PM 10852883 ER PT J AU Hendrickson, EL Guevera, P Ausubel, FM AF Hendrickson, EL Guevera, P Ausubel, FM TI The alternative sigma factor RpoN is required for hrp activity in Pseudomonas syringae pv. maculicola and acts at the level of hrpL transcription SO JOURNAL OF BACTERIOLOGY LA English DT Article ID AVIRULENCE GENE AVRRPT2; PROGRAMMED CELL-DEATH; HYPERSENSITIVE RESPONSE; PHYTOTOXIN CORONATINE; MOLECULAR CHARACTERIZATION; BRADYRHIZOBIUM-JAPONICUM; PHYTOPATHOGENIC BACTERIA; ARABIDOPSIS-THALIANA; RHIZOBIUM-MELILOTI; SECRETION SYSTEM AB beta-Glucuronidase (uidA) reporter gene fusions were constructed for the hrpZ hrpL, and hrpS genes from the phytopathogen Pseudomonas syringae pv. maculicola strain ES4326. These reporters, as well as an avrRpt2-uidA. fusion, were used to measure transcriptional activity in ES4326 and a ES4326 rpoN mutant. rpoN was required for the expression of avrRpt2, hrpZ, and hrpL in vitro in minimal media and in vivo when infiltrated into Arabidopsis thaliana leaves. In contrasts the expression of hrpS was essentially the same in wild-type and rpoN mutant strains. Constitutive expression of hrpL in an rpoN mutant restored hrpZ transcription to wild-type levels, restored the hypersensitive response when infiltrated into tobacco (Nicotiaita tobacum), and partially restored the elicitation of virulence-related symptoms but not growth when infiltrated into. Arabidopsis leaves. These data indicate that rpoN-mediated control of hrp gene expression acts at the level of hrpL and that in planta growth of P. syringae is not required for the elicitation of disease symptoms. C1 Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA. RP Ausubel, FM (reprint author), Massachusetts Gen Hosp, Dept Mol Biol, Wellman 10, Boston, MA 02114 USA. EM ausubel@frodo.mgh.harvard.edu FU NIGMS NIH HHS [R01 GM048707, GM48707, R37 GM048707] NR 82 TC 60 Z9 61 U1 1 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD JUN PY 2000 VL 182 IS 12 BP 3508 EP 3516 DI 10.1128/JB.182.12.3508-3516.2000 PG 9 WC Microbiology SC Microbiology GA 318WM UT WOS:000087307700026 PM 10852884 ER PT J AU Warner, JJP AF Warner, JJP TI Management of massive irreparable rotator cuff tears: The role of tendon transfer SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Editorial Material ID MUSCLE; REPAIR; DEBRIDEMENT; SHOULDERS; RUPTURE; BICEPS C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Warner, JJP (reprint author), Massachusetts Gen Hosp, Profess Off Bldg,Suite 403,275 Cambridge st, Boston, MA 02114 USA. NR 55 TC 21 Z9 21 U1 0 U2 0 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 2000 VL 82A IS 6 BP 878 EP 887 PG 10 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 321YR UT WOS:000087483400018 ER PT J AU Watson, PH Fraher, LJ Hendy, GN Chung, UI Kisiel, M Natale, BV Hodsman, AB AF Watson, PH Fraher, LJ Hendy, GN Chung, UI Kisiel, M Natale, BV Hodsman, AB TI Nuclear localization of the type 1 PTH/PTHrP receptor in rat tissues SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE PTH/PTHrP receptor; immunohistochemistry; PTKrP; nuclear localization ID HORMONE-RELATED PROTEIN; MESSENGER RIBONUCLEIC-ACIDS; OSTEOBLAST-LIKE CELLS; PARATHYROID-HORMONE; PEPTIDE PTHRP; GROWTH-FACTORS; EXPRESSION; GENE; BONE; OSTEOSARCOMA AB The localization of PTH/PTH-related peptide (PTHrP) receptor (PTHR) has traditionally been performed by autoradiography, Specific polyclonal antibodies to peptides unique to the PTHR are now available, which allow a more precise localization of the receptor in cells and tissues. We optimized the IHC procedure for the rat PTHR using 5-mu m sections of paraffin-embedded rat kidney, liver, small intestine, uterus, and ovary. Adjacent sections were analyzed for the presence of PTHR mRNA (by in situ hybridization) and PTHrP peptide. A typical pattern of staining for both receptor protein and mRNA was observed in kidney in cells lining the proximal tubules and collecting ducts. In uterus and gut, the receptor and its mRNA are present in smooth muscle layers (PTHrP target) and in glandular cuboidal cells and surface columnar epithelium, This suggests that PTH, or more likely PTHrP, plays a role in surface/secretory epithelia that is as yet undefined. In the ovary, PTHR was readily detectable in the thecal layer of large antral follicles and oocytes, and was present in the cytoplasm and/or nucleus of granulosa cells, regions that also contained receptor transcripts. PTHR protein and mRNA were found in the liver in large hepatocytes radiating outward from central veins. Immunoreactive cells were also present around the periphery of the liver but not within two or three cell layers of the surface. Clear nuclear localization of the receptor protein was present in liver cells in addition to the expected cytoplasmic/peripheral staining. PTHR immunoreactivity was present in the nucleus of some cells in every tissue examined. RT-PCR confirmed the presence of PTHR transcripts in these same tissues. Examination of the hindlimbs of PTHR gene-ablated mice showed no reaction to this antibody, whereas hindlimbs from their wild-type littermates stained positively. The results emphasize that the PTHR is highly expressed in diverse tissues and, in addition, show that the receptor protein itself can be localized to the cell nucleus. Nuclear localization of the receptor suggests that there is a role for PTH and/or PTHrP in the regulation of nuclear events, either on the physical environment (nucleoskeleton) or directly on gene expression. C1 Lawson Res Inst, London, ON N6A 4V2, Canada. Univ Western Ontario, Dept Med, London, ON N6A 3K7, Canada. Univ Western Ontario, Dept Biochem, London, ON N6A 3K7, Canada. McGill Univ, Dept Med, Montreal, PQ, Canada. Royal Victoria Hosp, Calcium Res Labs, Montreal, PQ H3A 1A1, Canada. Massachusetts Gen Hosp, Endocrine Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Watson, PH (reprint author), Lawson Res Inst, Room H425,268 Grosvenor St, London, ON N6A 4V2, Canada. NR 48 TC 68 Z9 68 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 1200 19TH ST, N W, STE 300, WASHINGTON, DC 20036-2422 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD JUN PY 2000 VL 15 IS 6 BP 1033 EP 1044 DI 10.1359/jbmr.2000.15.6.1033 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 317FW UT WOS:000087216200006 PM 10841172 ER PT J AU Sheng, M Kim, E AF Sheng, M Kim, E TI The Shank family of scaffold proteins SO JOURNAL OF CELL SCIENCE LA English DT Article DE postsynaptic density; cell junction; PDZ domain; SH3 domain; ankyrin repeat; SAM domain; Homer; cortactin; glutamate receptor; GKAP; PSD-95 ID 90/POSTSYNAPTIC DENSITY-95-ASSOCIATED PROTEIN; METABOTROPIC GLUTAMATE RECEPTORS; POSTSYNAPTIC DENSITY PROTEINS; BINDING-PROTEIN; SYNAPTIC PROTEINS; ADAPTER PROTEINS; AMPA RECEPTORS; CORTACTIN; INTERACTS; DOMAIN AB Shank proteins make up a new family of scaffold proteins recently identified through their interaction with a variety of membrane and cytoplasmic proteins, Shank polypeptides contain multiple sites for protein-protein interaction, including ankyrin repeats, an SH3 domain, a PDZ domain, a long proline-rich region, and a SAM domain. Binding partners for most of these domains have been identified: for instance, the PDZ domain of Shank proteins interacts with GKAP (a postsynaptic-density protein) as well as several G-protein-coupled receptors, The specific localization of Shank proteins at postsynaptic sites of brain excitatory synapses suggests a role for this family of proteins in the organization of cytoskeletal/signaling complexes at specialized cell junctions. C1 Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurobiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Pusan Natl Univ, Dept Pharmacol, Pusan 609735, South Korea. RP Sheng, M (reprint author), Massachusetts Gen Hosp, Howard Hughes Med Inst, Boston, MA 02114 USA. RI Kim, Eunjoon/C-1566-2011 NR 29 TC 290 Z9 306 U1 0 U2 16 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUN PY 2000 VL 113 IS 11 BP 1851 EP 1856 PG 6 WC Cell Biology SC Cell Biology GA 326KM UT WOS:000087734700002 PM 10806096 ER PT J AU Stipp, CS Hemler, ME AF Stipp, CS Hemler, ME TI Transmembrane-4-superfamily proteins CD151 and CD81 associate with alpha 3 beta 1 integrin, and selectively contribute to alpha 3 beta 1-dependent neurite outgrowth SO JOURNAL OF CELL SCIENCE LA English DT Article DE integrin; transmembrane-4-superfamily; neuron; neurite; laminin-5 ID MIGRATION IN-VITRO; CELL-MIGRATION; HUMAN NEURONS; T-CELLS; ALPHA-5-BETA-1 INTEGRIN; COLLAGEN RECEPTOR; LAMININ ISOFORMS; TM4SF PROTEINS; NERVOUS-SYSTEM; MOUSE-BRAIN AB Proteins in the transmembrane-4-superfamily (TM4SF) form many different complexes with proteins in the integrin family, but the functional utility of these complexes has not yet been demonstrated. Were we show that TM4SF proteins CD151, CD81, and CD63 co-distribute with alpha 3 beta 1 integrin on neurites and growth cones of human NT2N cells. Also, stable CD151-alpha 3 beta 1 and CD81-alpha 3 beta 1 complexes were recovered in NT2N detergent lysates, Total NT2N neurite outgrowth on laminin-5 (a ligand for alpha 3 beta 1 integrin) was strongly inhibited by anti-CD151 and -CD81 antibodies either together (similar to 85% inhibition) or alone (similar to 45% inhibition). Notably, these antibodies had no inhibitory effect on NT2N neurites formed on laminin-l or fibronectin, when alpha 3 beta 1 integrin was not engaged. Neurite number, length, and rate of extension were all affected by anti-TM4SF antibodies. In summary: (1) these substrate-dependent inhibition results strongly suggest that CD151 and CD81 associations with alpha 3 beta 1 are functionally relevant, (2) TM4SF proteins CD151 and CD81 make a strong positive contribution toward neurite number, length, and rate of outgrowth, and (3) NT2N cells, a well-established model of immature central nervous system neurons, can be a powerful system for studies of integrin function in neurite outgrowth and growth cone motility. 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. RP Hemler, ME (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St, Boston, MA 02115 USA. FU NIGMS NIH HHS [GM38903]; NINDS NIH HHS [NS10344] NR 78 TC 78 Z9 79 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUN PY 2000 VL 113 IS 11 BP 1871 EP 1882 PG 12 WC Cell Biology SC Cell Biology GA 326KM UT WOS:000087734700004 PM 10806098 ER PT J AU Zeitzer, JM Ayas, NT Shea, SA Brown, R Czeisler, CA AF Zeitzer, JM Ayas, NT Shea, SA Brown, R Czeisler, CA TI Absence of detectable melatonin and preservation of cortisol and thyrotropin rhythms in tetraplegia SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SPINAL-CORD INJURY; HUMAN CIRCADIAN PACEMAKER; PITUITARY-THYROID AXES; BRIGHT LIGHT; PINEAL-GLAND; ADRENAL-FUNCTION; SERUM MELATONIN; SLEEP; PLASMA; HYPOTHALAMUS AB The human circadian timing system regulates the temporal organization of several endocrine functions, including the production of melatonin (via a neural pathway that includes the spinal cord), TSH, and cortisol. In traumatic spinal cord injury, afferent and efferent circuits that influence the basal production of these hormones may be disrupted. We studied five subjects with chronic spinal cord injury (three tetraplegic and two paraplegic, all neurologically complete injuries) under stringent conditions in which the underlying circadian rhythmicity of these hormones could be examined. Melatonin production was absent in the three tetraplegic subjects with injury to their lower cervical spinal cord and was of normal amplitude and timing in the two paraplegic subjects with injury to their upper thoracic spinal cord. The amplitude and the timing of TSH and cortisol rhythms were robust in the paraplegics and in the tetraplegics. Our results indicate that neurologically complete cervical spinal injury results in the complete loss of pineal melatonin production and that neither the loss of melatonin nor the loss of spinal afferent information disrupts the rhythmicity of cortisol or TSH secretion. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Med,Endocrine Div, Circadian Neuroendocrine & Sleep Disorders Sect, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. Vet Adm Med Ctr W Roxbury, Spinal Cord Injury Serv, Pulm & Crit Care Med Sect, Boston, MA 02132 USA. RP Czeisler, CA (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med,Dept Med,Endocrine Div, Circadian Neuroendocrine & Sleep Disorders Sect, 221 Longwood Ave,Room 438A, Boston, MA 02115 USA. EM caczeisler@gcrc.bwh.harvard.edu FU NCRR NIH HHS [M01-RR-02635]; NHLBI NIH HHS [HL-26149]; NIMH NIH HHS [R01-MH-45130] NR 53 TC 58 Z9 58 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2000 VL 85 IS 6 BP 2189 EP 2196 DI 10.1210/jc.85.6.2189 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 339CR UT WOS:000088460500023 PM 10852451 ER PT J AU Roder, ME Schwartz, RS Prigeon, RL Kahn, SE AF Roder, ME Schwartz, RS Prigeon, RL Kahn, SE TI Reduced pancreatic B cell compensation to the insulin resistance of aging: Impact on proinsulin and insulin levels SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID DEPENDENT DIABETES-MELLITUS; IMPAIRED GLUCOSE-TOLERANCE; DISPROPORTIONATELY ELEVATED PROINSULIN; JAPANESE-AMERICAN MEN; SECRETORY CAPACITY; INTACT PROINSULIN; PLASMA-GLUCOSE; AGE; NIDDM; SENSITIVITY AB Type 2 diabetes mellitus is associated with insulin resistance, reduced B cell function, and an increase in the proinsulin (PI) to immunoreactive insulin (IRI) ratio (PI/IRI); the latter is thought to be an indication of B cell dysfunction. Normal aging is associated with insulin resistance and reduced B cell function, but it is not known whether changes in PI and the PI/IRI ratio are also a feature of the aging-associated B cell dysfunction. Therefore, we tested whether the aging-associated changes in insulin sensitivity and B cell function result in changes in PI and IRI levels that are proportionate or whether they are disproportionate as in type 2 diabetes. Twenty-six healthy older (mean +/- SEM age, 67 +/- 1 yr) and 22 younger (28 +/- 1 yr) subjects with similar body mass indexes (27.9 +/- 0.6 vs. 26.3 +/- 1.0 kg/m(2)) were studied. PI was measured by a RIA recognizing both intact PI and its conversion intermediates. The insulin sensitivity index (S-I) was quantified using the minimal model, and B cell function was measured as fasting insulin levels, the acute insulin response to glucose (AIRglucose), and as the acute insulin response to arginine at maximal glycemic potentiation (AIRmax). B cell function was also adjusted for S-I based on the known hyperbolic relationship between these two variables. Older and younger subjects had similar fasting glucose (5.3 +/- 0.1 vs. 5.2 +/- 0.1 mmol/L), IRI (83 +/- 8 vs. 76 +/- 9 pmol/L), PI (8.9 +/- 0.8 vs. 10.6 +/- 2.0 pmol/L), and PI/IRI ratio (12.3 +/- 1.3% vs. 13.9 +/- 1.6%; all P = NS) despite a 50% reduction of insulin sensitivity (S-I, 1.94 +/- 0.21 vs. 3.88 +/- 0.38 x 10(-5) min(-1)/pmol.L; P < 0.001) and in B cell function [S-I x fasting IRI, 139 +/- 18 vs. 244 +/- 24 x 10(-5) (P < 0.001); S-I x AIRglucose, 0.75 +/- 0.13 vs. 1.70 +/- 0.15 x 10(-2) min(-1) (P < 0.001); S-I x AIRmax, 3.63 +/- 0.53 vs. 6.81 +/- 0.70 x 10(-2) min(-1) (P < 0.001)] in the older subjects. These findings suggest that the B cell dysfunction in older subjects is not associated with disproportionate proinsulinemia. However, in older subjects the B cell response to the insulin resistance of aging is reduced whether measured as fasting levels of PI or IRI or as the acute response to secretagogues. Thus, when examined in terms of the degree of insulin sensitivity, the lower fasting IRI levels in older subjects suggest that the utility of fasting insulin levels as a surrogate measure of insulin resistance in older individuals may be limited. C1 Harborview Med Ctr, V