FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Iyer, VR Eisen, MB Ross, DT Schuler, G Moore, T Lee, JCF Trent, JM Staudt, LM Hudson, J Boguski, MS Lashkari, D Shalon, D Botstein, D Brown, PO AF Iyer, VR Eisen, MB Ross, DT Schuler, G Moore, T Lee, JCF Trent, JM Staudt, LM Hudson, J Boguski, MS Lashkari, D Shalon, D Botstein, D Brown, PO TI The transcriptional program in the response of human fibroblasts to serum SO SCIENCE LA English DT Article ID GENE-EXPRESSION PATTERNS; SYNCHRONIZATION; MICROARRAY AB The temporal program of gene expression during a model physiological response of human cells, the response of fibroblasts to serum, was explored with a complementary DNA microarray representing about 8600 different human genes. Genes could be clustered into groups on the basis of their temporal patterns of expression in this program. Many features of the transcriptional program appeared to be related to the physiology of wound repair, suggesting that fibroblasts play a larger and richer role in this complex multicellular response than had previously been appreciated. C1 Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Res Genet Inc, Huntsville, AL 35801 USA. Incyte Pharmaceut, Fremont, CA 94555 USA. Natl Human Genome Res Inst, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Div Clin Sci, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA. RP Brown, PO (reprint author), Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. OI Eisen, Michael/0000-0002-7528-738X FU NCI NIH HHS [CA 77097]; NHGRI NIH HHS [HG00450, T32 HG00450] NR 15 TC 1321 Z9 1358 U1 6 U2 24 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD JAN 1 PY 1999 VL 283 IS 5398 BP 83 EP 87 DI 10.1126/science.283.5398.83 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 155ZH UT WOS:000077976600055 PM 9872747 ER PT B AU Anderson, NB AF Anderson, NB BE Contrada, RJ Ashmore, RD TI Self, social identity and physical health - Interdisciplinary explorations - Foreword SO SELF, SOCIAL IDENTITY, AND PHYSICAL HEALTH: INTERDISCIPLINARY EXPLORATIONS SE RUTGERS SERIES ON SELF AND SOCIAL IDENTITY LA English DT Proceedings Paper CT 2nd Rutgers Symposium on Self and Social Identity CY APR, 1997 CL RUTGERS UNIV, NEW BRUNSWICK, NJ SP Rutgers Univ HO RUTGERS UNIV C1 NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI NEW YORK PA 198 MADISON AVENUE, NEW YORK, NY 10016 USA BN 0-19-512731-5 J9 RUTG SELF SOC ID PY 1999 VL 2 BP V EP XII PG 8 WC Psychology, Social SC Psychology GA BP71L UT WOS:000085948700001 ER PT J AU Kwak, LW Thielemans, K Massaia, M AF Kwak, LW Thielemans, K Massaia, M TI Idiotypic vaccination as therapy for multiple myeloma SO SEMINARS IN HEMATOLOGY LA English DT Article ID B-CELL LYMPHOMA; TRANSPLANTATION RESISTANCE; IMMUNIZATION C1 NCI, FCRDC, Dept Expt Transplantat & Immunol, Div Clin Sci, Ft Detrick, MD 21702 USA. Free Univ Brussels, Sch Med, Brussels, Belgium. Univ Turin, Div Ematol, Turin, Italy. RP Kwak, LW (reprint author), NCI, FCRDC, Dept Expt Transplantat & Immunol, Div Clin Sci, Bldg 567,Room 205, Ft Detrick, MD 21702 USA. NR 15 TC 13 Z9 14 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 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD JAN PY 1999 VL 36 IS 1 SU 3 BP 34 EP 37 PG 4 WC Hematology SC Hematology GA 160NP UT WOS:000078237000008 PM 9989488 ER PT J AU Austin, HA Balow, JE AF Austin, HA Balow, JE TI Natural history and treatment of lupus nephritis SO SEMINARS IN NEPHROLOGY LA English DT Review ID ACUTE NONLYMPHOCYTIC LEUKEMIA; STAGE RENAL-DISEASE; LONG-TERM; CONTROLLED TRIAL; PULSE CYCLOPHOSPHAMIDE; MEMBRANOUS NEPHROPATHY; INTRAVENOUS CYCLOPHOSPHAMIDE; PROGNOSTIC FACTORS; NEPHROTIC SYNDROME; PREDICTIVE VALUE C1 NIDDKD, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. RP Austin, HA (reprint author), NIDDKD, Kidney Dis Sect, NIH, Bldg 10,Rm 3N112, Bethesda, MD 20892 USA. NR 85 TC 54 Z9 60 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 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD JAN PY 1999 VL 19 IS 1 BP 2 EP 11 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 158XA UT WOS:000078141700002 PM 9952276 ER PT J AU Berger, JR Major, EO AF Berger, JR Major, EO TI Progressive multifocal leukoencephalopathy SO SEMINARS IN NEUROLOGY LA English DT Article DE progressive multifocal leukoencephalopathy; JC virus; highly active antiretroviral therapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN POLYOMAVIRUS JC; CEREBROSPINAL-FLUID; HUMAN-BRAIN; GLIAL-CELLS; NEUROLOGIC COMPLICATIONS; REGULATORY SEQUENCES; IMMUNE-DEFICIENCY; NERVOUS-SYSTEM; HIV-INFECTION AB Before the AIDS epidemic, progressive multifocal leukoencephalopathy (PML) was a rare disorder occuring most often in association with leukemia and lymphoma. Current estimates indicate that PML ultimately develops in up to 5% of all patients with AIDS. This demyelinating disease results from infection with JC virus, a papova virus, that most of the world's population is exposed to prior to adulthood. Although PML commonly occurs in the setting of advanced immunosuppression, it may be observed in patients with CD4 lymphocyte counts in excess of 200 cells/mm(3), Focal neurological symptoms and signs coupled with hyperintense signals abnormalities of the white matter on T2-weighted cranial magnetic resonance imaging are highly suggestive of the disease. In this setting, a positive CSF polymerase chain reaction for JCV DNA has been felt to be sufficiently diagnostic to elimate the need for brain biopsy. Survival of AIDS-associated PML is poor with median survivals averaging just 6 months. However, as many as 10% of AIDS patients with PML will have prolonged (>12 months) survival and partial recovery. Highly active antiretroviral therapy (HAART) has been demonstrated to have a salutary effect on survival. C1 Univ Kentucky, Coll Med, Dept Neurol, Kentucky Clin L445, Lexington, KY 40536 USA. NINDS, NIH, Lab Mol Med & Neurosci, Bethesda, MD USA. RP Berger, JR (reprint author), Univ Kentucky, Coll Med, Dept Neurol, Kentucky Clin L445, Lexington, KY 40536 USA. NR 88 TC 126 Z9 130 U1 1 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0271-8235 J9 SEMIN NEUROL JI Semin. Neurol. PY 1999 VL 19 IS 2 BP 193 EP 200 DI 10.1055/s-2008-1040837 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 243XP UT WOS:000083023000011 PM 10718540 ER PT J AU Shiloach, J Kaufman, JB AF Shiloach, J Kaufman, JB TI The combined use of expanded-bed adsorption and gradient elution for capture and partial purification of mutant diphtheria toxin (CRM 9) from Corynebacterium diphtheriae SO SEPARATION SCIENCE AND TECHNOLOGY LA English DT Article ID VACCINES; PROTEIN AB Expanded-bed adsorption (EBA) is a new approach for performing the initial recovery or capture of proteins from various crude feedstocks. The essence of the method is direct adsorption of the desired protein from the unclarified suspension by passing it through a stable expanded bed of the adsorbent. This type of operation replaces centrifugation, clarification, dialysis, and concentration with one simple unit operation. The recovery is done by pumping the feedstock upward on the expanded column and eluting it downward in a step mode from the packed bed. One of the unique properties of the expanded bed is its behavior as a true plug-flow column, which makes it possible to use gradient elution and to achieve better purification in addition to the other benefits. In this work the ''traditional'' recovery and purification process of the extracellular mutant diphtheria toxin (CRM 9) was replaced with an expanded bed adsorption process in which the protein was eluted using a linear salt gradient in an upward mode instead of the standard downward step elution. This combined procedure is a simpler, shorter process that yielded a purified protein preparation (that only had to pass through a gel filtration column instead of through the next ion-exchange step). Twenty grams of protein suitable for clinical use was prepared using this method. C1 NIDDK, Biotechnol Unit, LCDB, NIH, Bethesda, MD 20892 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Unit, LCDB, NIH, Bldg 6 Rm B1-33, Bethesda, MD 20892 USA. NR 18 TC 4 Z9 4 U1 0 U2 1 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 0149-6395 J9 SEPAR SCI TECHNOL JI Sep. Sci. Technol. PY 1999 VL 34 IS 1 BP 29 EP 40 DI 10.1081/SS-100100634 PG 12 WC Chemistry, Multidisciplinary; Engineering, Chemical SC Chemistry; Engineering GA 165LZ UT WOS:000078523800003 ER PT J AU Risbud, A Chan-Tack, K Gadkari, D Gangakhedkar, RR Shepherd, ME Bollinger, R Mehendale, S Gaydos, C Divekar, A Rompalo, A Quinn, TC AF Risbud, A Chan-Tack, K Gadkari, D Gangakhedkar, RR Shepherd, ME Bollinger, R Mehendale, S Gaydos, C Divekar, A Rompalo, A Quinn, TC TI The etiology of genital ulcer disease by multiplex polymerase chain reaction and relationship to HIV infection among patients attending sexually transmitted disease clinics in Pune, India SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; TREPONEMA-PALLIDUM; RISK FACTOR; ASSOCIATION; DIAGNOSIS; TYPE-1; SEROCONVERSION; TRANSMISSION; DUCREYI; HEALTH AB Objectives: To determine the etiology of genital ulcer disease (GUD) among patients attending sexually transmitted disease (STD) clinics in Pune, India, and to examine the relationship to HIV infection and compare the clinical diagnosis of GUD with the results of a multiplex polymerase chain reaction (M-PCR) assay for Treponema pallidum, herpes simplex virus (HSV), and Hemophilus ducreyi infection. Methods: Between June 20, 1994, and September 26, 1994, 302 patients with a genital ulcer were evaluated. Clinical etiology of GUD was based on physical appearance and microbiologic evaluations which included darkfield microscopy and serology for syphilis. Swabs of each genital ulcer were tested for HSV antigen by enzyme immunoassay (Herpchek; Dupont, Wilmington, DE) and processed in a multiplex PCR assay (M-PCR; Roche, Branchburg, NJ) for simultaneous detection of HSV, Treponema pallidum, and Hemophilus ducreyi. Results: Two hundred seventy-seven men and 25 women with a median age of 25 were evaluated. The seroprevalence of HIV was 22.2%. The etiology of GUD as determined by M-PCR was HSV (26%), H. ducreyi (23%), T. pallidum (10%), and multiple infections (7%); no etiology was identified in 34%. HIV seroprevalence was higher among those patients positive for HSV compared with other etiologies (OR = 2.1, CI: 1.2-3.7; p = 0.01), When compared with M-PCR, the Herpchek test was 68.5% sensitive and 99.5% specific. Darkfield detection for T. pallidum was 39% sensitive and 82% specific, in contrast to rapid plasma reagin and fluorescent treponemal antibody absorption test, which was 66% sensitive and 90% specific, Clinical diagnosis alone or in combination with basic laboratory tests showed poor agreement with M-PCR. Conclusions: The etiology of GUD among STD patients in India is multifactorial with a predominance of herpes and chancroid infections. Herpes was more common among HIV-positive individuals, possibly reflecting underlying immunosuppression. These data demonstrate that clinical diagnosis is not dependable for identification of GUD etiology especially in HIV seropositive cases. In areas where diagnostic tests are limited, a syndromic approach using antibiotics directed against both syphilis and chancroid, and where prevalent, lymphogranuloma venereum and donovanosis is recommended for patients with GUD. C1 Johns Hopkins Univ, Div Infect Dis, Baltimore, MD 21205 USA. Natl AIDS Res Inst, Pune, Maharashtra, India. NIAID, NIH, Bethesda, MD 20892 USA. RP Quinn, TC (reprint author), Johns Hopkins Univ, Div Infect Dis, Ross Res Bldg Room 1159,720 Rutland Ave, Baltimore, MD 21205 USA. RI Gaydos, Charlotte/E-9937-2010 NR 31 TC 78 Z9 83 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD JAN PY 1999 VL 26 IS 1 BP 55 EP 62 DI 10.1097/00007435-199901000-00009 PG 8 WC Infectious Diseases SC Infectious Diseases GA 156DR UT WOS:000077986600009 PM 9918324 ER PT J AU Kaneko, I Hussain, SP Ichimiya, M Chang, SH Berezesky, IK Trump, BF Harris, CC Amstad, PA AF Kaneko, I Hussain, SP Ichimiya, M Chang, SH Berezesky, IK Trump, BF Harris, CC Amstad, PA TI p53-induced apoptosis is mediated by an increase in the production of reactive oxygen species (ROS) followed by intracellular calcium mobilization. SO SHOCK LA English DT Meeting Abstract C1 Univ Maryland, Dept Pathol, Baltimore, MD 21201 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMEDICAL PRESS PI AUGUSTA PA 1021 15TH ST, BIOTECH PARK STE 9,, AUGUSTA, GA 30901 USA SN 1073-2322 J9 SHOCK JI Shock PY 1999 VL 11 SU 1 MA 209 BP 60 EP 61 DI 10.1097/00024382-199906001-00210 PG 2 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 195YH UT WOS:000080279600210 ER PT J AU Zhong, Z Enomoto, N Connor, HD Moss, N Mason, RP Thurman, RG AF Zhong, Z Enomoto, N Connor, HD Moss, N Mason, RP Thurman, RG TI Glycine improves survival after hemorrhagic shock in the rat. SO SHOCK LA English DT Meeting Abstract C1 Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Physiol, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMEDICAL PRESS PI AUGUSTA PA 1021 15TH ST, BIOTECH PARK STE 9,, AUGUSTA, GA 30901 USA SN 1073-2322 J9 SHOCK JI Shock PY 1999 VL 11 SU 1 MA 275 BP 80 EP 80 DI 10.1097/00024382-199906001-00276 PG 1 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 195YH UT WOS:000080279600276 ER PT S AU Sagui, C Darden, TA AF Sagui, C Darden, TA BE Pratt, LR Hummer, G TI P3M and PME: a comparison of the two methods SO SIMULATION AND THEORY OF ELECTROSTATIC INTERACTIONS IN SOLUTION: COMPUTATIONAL CHEMISTRY, BIOPHYSICS, AND AQUEOUS SOLUTIONS SE AIP CONFERENCE PROCEEDINGS LA English DT Proceedings Paper CT Workshop on Treatment of Electrostatic Interactions in Computer Simulations of Condensed Media CY JUN 23-25, 1999 CL SANTA FE, NM SP Ctr Nonlinear Studies, Los Alamos Natl Lab, Univ Utah, Henry Eyring Ctr Theoret Chem ID PARTICLE MESH EWALD; SYSTEMS; SUMS AB The PME approach to Ewald summation is based on local spline ap proximation of the complex exponentials appearing in the Ewald reciprocal sum. In this paper we show how the optimal influence function of Hockney and Eastwood can be easily derived using this approach. This result is used to explain why the force-interpolated PME method using least-squares spline approximation has the same accuracy as force-interpolated P3M. C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Sagui, C (reprint author), Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. NR 13 TC 29 Z9 29 U1 1 U2 5 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 1-56396-906-8 J9 AIP CONF PROC PY 1999 VL 492 BP 104 EP 113 DI 10.1063/1.1301523 PG 10 WC Biophysics; Chemistry, Multidisciplinary; Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Biophysics; Chemistry; Physics GA BP14C UT WOS:000084221000005 ER PT S AU Rick, SW AF Rick, SW BE Pratt, LR Hummer, G TI The influence of electrostatic truncation on simulations of polarizable systems SO SIMULATION AND THEORY OF ELECTROSTATIC INTERACTIONS IN SOLUTION: COMPUTATIONAL CHEMISTRY, BIOPHYSICS, AND AQUEOUS SOLUTIONS SE AIP Conference Proceedings LA English DT Proceedings Paper CT Workshop on Treatment of Electrostatic Interactions in Computer Simulations of Condensed Media CY JUN 23-25, 1999 CL SANTA FE, NM SP Ctr Nonlinear Studies, Los Alamos Natl Lab, Univ Utah, Henry Eyring Ctr Theoret Chem ID MOLECULAR-DYNAMICS SIMULATIONS; LONG-RANGE FORCES; LIQUID WATER; MONTE-CARLO; DIELECTRIC-PROPERTIES; COMPUTER-SIMULATIONS; CHARGE MODEL; EWALD; FIELDS; SIZE AB Different schemes for the treatment of long-ranged electrostatic interactions will be examined for water simulations using the polarizable fluctuating charge potential. Several different methods are compared, including Ewald sums, potential shifting, spherical truncation and reaction field corrections. For liquid water, properties such as the energy, pressure, dynamics and structure are more sensitive to the treatment of the long-ranged interactions with polarizable than with non-polarizable potentials. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Adv Biomed Comp Ctr, Winston Salem, NC 27102 USA. RP NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Adv Biomed Comp Ctr, Winston Salem, NC 27102 USA. NR 41 TC 5 Z9 5 U1 0 U2 1 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 1-56396-906-8 J9 AIP CONF PROC PY 1999 VL 492 BP 114 EP 126 DI 10.1063/1.1301524 PG 13 WC Biophysics; Chemistry, Multidisciplinary; Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Biophysics; Chemistry; Physics GA BP14C UT WOS:000084221000006 ER PT S AU Tawa, GJ Topol, IA Burt, SK Rashin, AA AF Tawa, GJ Topol, IA Burt, SK Rashin, AA BE Pratt, LR Hummer, G TI On the hydration of monoatomic ions SO SIMULATION AND THEORY OF ELECTROSTATIC INTERACTIONS IN SOLUTION: COMPUTATIONAL CHEMISTRY, BIOPHYSICS, AND AQUEOUS SOLUTIONS SE AIP CONFERENCE PROCEEDINGS LA English DT Proceedings Paper CT Workshop on Treatment of Electrostatic Interactions in Computer Simulations of Condensed Media CY JUN 23-25, 1999 CL SANTA FE, NM SP Ctr Nonlinear Studies, Los Alamos Natl Lab, Univ Utah, Henry Eyring Ctr Theoret Chem ID CONTINUUM SOLVATION MODELS; DENSITY-FUNCTIONAL THEORY; WATER CLUSTERS; HIV-1 PROTEASE; FREE-ENERGY; AB-INITIO; VIBRATIONAL SPECTROSCOPY; EXCHANGE-ENERGY; REACTION FIELD; CHARGE AB It is shown that an understanding of some key biological processes such as the thermodynamics of enzyme-ligand binding or the selectivity of ion-channels is ultimately dependent on an understanding of the details of ion hydration. Therefore, a model for calculating the hydration free energy of ions in aqueous solvent is presented. The model is used to first calculate the proton hydration free energy, Delta G(hyd)(H+), in an effort to resolve the uncertainty concerning its exact value. In the model we define Delta G(hyd)(H+) as the free energy change associated with the following process: Delta G{H+(gas) + [H2O](n)(aq)-->H+[H2O](n)(aq)}, where the solvent is represented by a neutral n-water cluster embedded in a dielectric continuum and the solvated proton is represented by a protonated n-water cluster also in the continuum. All solvated species are treated as quantum mechanical solutes (B3LYP, MP2, MP4, CCSD(T)) coupled to a dielectric continuum using a self consistent reaction field (SCRF) cycle. An investigation of the behavior of Delta G(hyd)(H+) as the number of explicit waters of hydration is increased reveals convergence by n = 4. The converged value is -262.23 kcal/mol and is independent of the ab inito method used. These results indicate that the first hydration shell of the proton is composed of at least 4 water molecules. The result strongly suggests that the proton hydration free energy is at the far lower end of the range of values obtained from the literature. The methodology is then used to calculate the hydration free energies of other ions relative to that of the proton. These include cationic forms of the alkali earth elements Li, Na, and K, and anionic forms of the halogens F, Cl, and Br. The relative ion hydration free energy is defined as Delta[Delta G(hyd)(Z(+/-))]= G(Z(+/-)[H2O](n)(aq)) - G(H+[H2O](n)(aq))- G(Z(+/-)(gas))-G(H+(gas)), where the solvated ions are represented by ion-water clusters coupled to a dielectric continuum using a self-consistent reaction field (SCRF) cycle. An investigation of the behavior of Delta[Delta G(hyd)(Z(+/-))]as the number of explicit waters of hydration is increased reveals convergence by n = 4. This convergence indicates that the free energy change for addition of water to a solvated proton-water complex is the same as the free energy change associated with the addition of water to a solvated Z(+/-)-water complex. This is true as long as there are four explicitly solvating waters associated with the ion. This convergence is independent of the type of monatomic ion studied and it occurs before the first hydration shell of the ions (typically greater than or equal to 6) is satisfied. Structural analysis of the ion-water clusters reveals that waters within the cluster are more likely to form hydrogen bonds with themselves when clustering around anions, than when clustering around cations. This suggests that for small ion-water clusters, anions are more likely to be externally solvated than cations. C1 Frederick Canc Res & Dev Ctr, NCI Frederick, SAIC Frederick, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Tawa, GJ (reprint author), Frederick Canc Res & Dev Ctr, NCI Frederick, SAIC Frederick, Adv Biomed Comp Ctr, POB B, Frederick, MD 21702 USA. NR 52 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0094-243X BN 1-56396-906-8 J9 AIP CONF PROC PY 1999 VL 492 BP 382 EP 410 DI 10.1063/1.1301538 PG 29 WC Biophysics; Chemistry, Multidisciplinary; Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Biophysics; Chemistry; Physics GA BP14C UT WOS:000084221000020 ER PT J AU Williams, JK Boykin, F AF Williams, JK Boykin, F TI The role of social work in HIV/AIDS clinical trials SO SOCIAL WORK IN HEALTH CARE LA English DT Article DE HIV/AIDS; clinical trials; social work; screening; retention; adherence; compliance ID HIV-INFECTION; RECRUITMENT AB The social worker can facilitate screening, retention and patient adherence in HIV/AIDS clinical trials. This paper introduces the process and its key vocabulary, and uses three case studies to demonstrate how social workers can assist clients who may wish to participate in, or are already enrolled in a clinical trial. After examining five major issues that affect the client in a clinical trial (informed consent; treatment vs, research; risks and side effects; altruism; the role of family members; and gender, race and class issues), the authors elaborate on interventions at the screening level, and concrete services and psychosocial interventions for study participants. C1 NIH, HIV Counseling Program, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Williams, JK (reprint author), NIH, HIV Counseling Program, Bldg 10,Room 1N252,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 17 TC 4 Z9 4 U1 0 U2 0 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0098-1389 J9 SOC WORK HEALTH CARE JI Soc. Work Health Care PY 1999 VL 29 IS 1 BP 35 EP 56 DI 10.1300/J010v29n01_03 PG 22 WC Social Work SC Social Work GA 219JT UT WOS:000081604700003 PM 10482128 ER PT S AU Anderson, NB AF Anderson, NB BE Adler, NE Marmot, M McEwen, B Stewart, J TI Solving the puzzle of socioeconomic status and health: The need for integrated, multilevel, interdisciplinary research SO SOCIOECONOMIC STATUS AND HEALTH IN INDUSTRIAL NATIONS: SOCIAL, PSYCHOLOGICAL, AND BIOLOGICAL PATHWAYS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Socioeconomic Status and Health in Industrial Nations - Social, Psychological, and Biological Pathways CY MAY 10-12, 1999 CL NIH, BETHESDA, MARYLAND SP John D & Catherine T MacArthur Fdn Res Network Socioecon Statius & Hlth, New York Acad Sci HO NIH C1 Off Behav & Social Sci Res, NIH, Bethesda, MD 20892 USA. RP Anderson, NB (reprint author), Off Behav & Social Sci Res, NIH, Bldg 1,Room 326,1 Ctr Dr, Bethesda, MD 20892 USA. NR 6 TC 18 Z9 20 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-211-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 1999 VL 896 BP 302 EP 312 DI 10.1111/j.1749-6632.1999.tb08125.x PG 11 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Biomedical Social Sciences GA BP47L UT WOS:000085238100026 PM 10681906 ER PT S AU Drury, TF Garcia, I Adesanya, M AF Drury, TF Garcia, I Adesanya, M BE Adler, NE Marmot, M McEwen, B Stewart, J TI Socioeconomic disparities in adult oral health in the United States SO SOCIOECONOMIC STATUS AND HEALTH IN INDUSTRIAL NATIONS: SOCIAL, PSYCHOLOGICAL, AND BIOLOGICAL PATHWAYS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Socioeconomic Status and Health in Industrial Nations - Social, Psychological, and Biological Pathways CY MAY 10-12, 1999 CL NIH, BETHESDA, MARYLAND SP John D & Catherine T MacArthur Fdn Res Network Socioecon Statius & Hlth, New York Acad Sci HO NIH C1 NIDCR, NIH, Bethesda, MD 20892 USA. RP Drury, TF (reprint author), NIDCR, NIH, Bldg 45,Room 3AN-44, Bethesda, MD 20892 USA. NR 0 TC 42 Z9 42 U1 1 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-211-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 1999 VL 896 BP 322 EP 324 DI 10.1111/j.1749-6632.1999.tb08129.x PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Biomedical Social Sciences GA BP47L UT WOS:000085238100030 PM 10681910 ER PT S AU Mulatu, MS Schooler, C AF Mulatu, MS Schooler, C BE Adler, NE Marmot, M McEwen, B Stewart, J TI Longitudinal effects of occupational, psychological, and social background characteristics on health of older workers SO SOCIOECONOMIC STATUS AND HEALTH IN INDUSTRIAL NATIONS: SOCIAL, PSYCHOLOGICAL, AND BIOLOGICAL PATHWAYS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Socioeconomic Status and Health in Industrial Nations - Social, Psychological, and Biological Pathways CY MAY 10-12, 1999 CL NIH, BETHESDA, MARYLAND SP John D & Catherine T MacArthur Fdn Res Network Socioecon Statius & Hlth, New York Acad Sci HO NIH C1 NIMH, SSES, NIH, Bethesda, MD 20892 USA. RP Mulatu, MS (reprint author), NIMH, SSES, NIH, 7550 Wisconsin Ave,Room B1A-14, Bethesda, MD 20892 USA. NR 3 TC 4 Z9 4 U1 1 U2 4 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-211-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 1999 VL 896 BP 406 EP 408 DI 10.1111/j.1749-6632.1999.tb08155.x PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Biomedical Social Sciences GA BP47L UT WOS:000085238100056 PM 10681936 ER PT S AU Muntaner, C Oates, G Lynch, J AF Muntaner, C Oates, G Lynch, J BE Adler, NE Marmot, M McEwen, B Stewart, J TI Social class and social cohesion: A content validity analysis using a nonrecursive structural equation model SO SOCIOECONOMIC STATUS AND HEALTH IN INDUSTRIAL NATIONS: SOCIAL, PSYCHOLOGICAL, AND BIOLOGICAL PATHWAYS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Socioeconomic Status and Health in Industrial Nations - Social, Psychological, and Biological Pathways CY MAY 10-12, 1999 CL NIH, BETHESDA, MARYLAND SP John D & Catherine T MacArthur Fdn Res Network Socioecon Statius & Hlth, New York Acad Sci HO NIH C1 Univ Maryland, Sch Nursing, Dept Psychiat & Community Hlth, Baltimore, MD 21201 USA. NIMH, Bethesda, MD 20892 USA. Univ Connecticut, Dept Sociol, Storrs, CT 06269 USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. RP Muntaner, C (reprint author), Univ Maryland, Sch Nursing, Dept Psychiat & Community Hlth, POB 1579,655 W Lombard St, Baltimore, MD 21201 USA. RI Lynch, John/A-4797-2008 OI Lynch, John/0000-0003-2781-7902 FU NIMH NIH HHS [Z01 MH02610-04, Z01 MH02610-05]; PHS HHS [U48/CCU310821] NR 6 TC 17 Z9 19 U1 0 U2 3 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-211-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 1999 VL 896 BP 409 EP 413 DI 10.1111/j.1749-6632.1999.tb08156.x PG 5 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Biomedical Social Sciences GA BP47L UT WOS:000085238100057 PM 10681937 ER PT S AU Anderson, L Fullilove, M Scrimshaw, S Fielding, J Normand, J Zaza, S Wright-DeAguero, L Higgins, D AF Anderson, L Fullilove, M Scrimshaw, S Fielding, J Normand, J Zaza, S Wright-DeAguero, L Higgins, D BE Adler, NE Marmot, M McEwen, B Stewart, J TI A framework for evidenced-based reviews of interventions for supportive social environments SO SOCIOECONOMIC STATUS AND HEALTH IN INDUSTRIAL NATIONS: SOCIAL, PSYCHOLOGICAL, AND BIOLOGICAL PATHWAYS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Socioeconomic Status and Health in Industrial Nations - Social, Psychological, and Biological Pathways CY MAY 10-12, 1999 CL NIH, BETHESDA, MARYLAND SP John D & Catherine T MacArthur Fdn Res Network Socioecon Statius & Hlth, New York Acad Sci HO NIH C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Columbia Univ, New York, NY 10032 USA. Univ Illinois, Chicago, IL 60637 USA. Los Angeles Cty Dept Hlth, Los Angeles, CA 90095 USA. NIH, Bethesda, MD 20892 USA. RP Anderson, L (reprint author), Ctr Dis Control & Prevent, 1600 Clifton Rd,Mailstop Mail K-73, Atlanta, GA 30333 USA. NR 2 TC 7 Z9 7 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-211-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 1999 VL 896 BP 487 EP 489 DI 10.1111/j.1749-6632.1999.tb08177.x PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Biomedical Social Sciences GA BP47L UT WOS:000085238100078 PM 10681958 ER PT S AU Frick, KD Simonsick, EM AF Frick, KD Simonsick, EM BE Adler, NE Marmot, M McEwen, B Stewart, J TI SES, medicare coverage, and flu shot utilization among vulnerable women in the women's health and aging study SO SOCIOECONOMIC STATUS AND HEALTH IN INDUSTRIAL NATIONS: SOCIAL, PSYCHOLOGICAL, AND BIOLOGICAL PATHWAYS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on Socioeconomic Status and Health in Industrial Nations - Social, Psychological, and Biological Pathways CY MAY 10-12, 1999 CL NIH, BETHESDA, MARYLAND SP John D & Catherine T MacArthur Fdn Res Network Socioecon Statius & Hlth, New York Acad Sci HO NIH C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Frick, KD (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, 624 N Broadway,Rm 606, Baltimore, MD 21205 USA. NR 2 TC 4 Z9 4 U1 1 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-211-8 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 1999 VL 896 BP 493 EP 496 DI 10.1111/j.1749-6632.1999.tb08179.x PG 4 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Biomedical Social Sciences GA BP47L UT WOS:000085238100080 PM 10681960 ER PT S AU Misik, V Riesz, P AF Misik, V Riesz, P BE Crum, LA Mason, TJ Reisse, JL Suslick, KS TI Detection of primary free radical species in aqueous sonochemistry by EPR spectroscopy SO SONOCHEMISTRY AND SONOLUMINESCENCE SE NATO ADVANCED SCIENCE INSTITUTES SERIES, SERIES C, MATHEMATICAL AND PHYSICAL SCIENCES LA English DT Proceedings Paper CT NATO Advanced Study Institute on Sonochemistry and Sonoluminescence CY AUG 18-29, 1997 CL LEAVENWORTH, WA SP NATO, Sci & Environm Affairs Div ID HYDRATED ELECTRONS; HYDROXYL RADICALS; CYTOCHROME-C; ULTRASOUND; SONOLYSIS; SUPEROXIDE; GENERATION; WATER; YIELD; ARGON AB In this paper we discuss the identification of the primary free radical species produced by sonolysis of noble gas-saturated aqueous solutions (i.e. H-., (OH)-O-., O-2(.-)) and in N-2-containing aqueous solutions (i.e. H-., (OH)-O-., O-2(.-), and (NO)-N-.) predominantly by means of electron paramagnetic resonance (EPR) spectroscopy with spin napping. The EPR experiments which show that no detectable level of hydrated electrons is formed in the sonolysis of water at neutral pH are summarized. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. RP Misik, V (reprint author), NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NR 30 TC 1 Z9 1 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0258-2023 BN 0-7923-5549-0 J9 NATO ADV SCI I C-MAT PY 1999 VL 524 BP 225 EP 236 PG 12 WC Acoustics; Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Acoustics; Chemistry; Physics GA BM63B UT WOS:000079308400018 ER PT S AU Melnick, RL Kohn, MC AF Melnick, RL Kohn, MC BE Capen, CC Dybing, E Rice, JM Wilbourn, JD TI Possible mechanisms of induction of renal tubule cell neoplasms in rats associated with alpha(2u)-globulin: role of protein accumulation versus ligand delivery to the kidney SO SPECIES DIFFERENCES IN THYROID, KIDNEY AND URINARY BLADDER CARCINOGENESIS SE IARC SCIENTIFIC PUBLICATIONS LA English DT Proceedings Paper CT Workshop on Species Differences in Thyroid, Kidney and Urinary Bladder Carcinogenesis CY NOV 03-07, 1997 CL LYON, FRANCE SP US Natl Inst Environm Hlth Sci, US EPA, European Commiss ID MALE FISCHER-344 RATS; ACID-BINDING PROTEIN; BROMATE KBRO3 CARCINOGENESIS; HYALINE DROPLET NEPHROPATHY; T-BUTYL ALCOHOL; UNLEADED GASOLINE; ALPHA-2U-GLOBULIN NEPHROPATHY; POTASSIUM BROMATE; PROXIMAL TUBULE; F344 RATS C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Melnick, RL (reprint author), Natl Inst Environm Hlth Sci, POB 12233, Res Triangle Pk, NC 27709 USA. NR 78 TC 1 Z9 1 U1 0 U2 0 PU INT AGENCY RESEARCH CANCER PI LYONS PA 150, COURS ALBERT THOMAS, 69372 LYONS, FRANCE SN 0300-5038 BN 92-832-2147-8 J9 IARC SCI PUBL PY 1999 IS 147 BP 119 EP 137 PG 19 WC Oncology SC Oncology GA BQ97W UT WOS:000165216800009 PM 10457914 ER PT S AU Huff, J AF Huff, J BE Capen, CC Dybing, E Rice, JM Wilbourn, JD TI Chemicals associated with tumours of the kidney, urinary bladder and thyroid gland in laboratory rodents from 2000 US National Toxicology Program National Cancer Institute bioassays for carcinogenicity SO SPECIES DIFFERENCES IN THYROID, KIDNEY AND URINARY BLADDER CARCINOGENESIS SE IARC SCIENTIFIC PUBLICATIONS LA English DT Proceedings Paper CT Workshop on Species Differences in Thyroid, Kidney and Urinary Bladder Carcinogenesis CY NOV 03-07, 1997 CL LYON, FRANCE SP US Natl Inst Environm Hlth Sci, US EPA, European Commiss ID EPIDEMIOLOGIC EVIDENCE; EXPERIMENTAL-ANIMALS; IARC MONOGRAPHS; B6C3F1 MICE; EXPOSURE; TRICHLOROETHENE; NEOPLASIA; CHLORIDE; BENZENE; HUMANS C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), Natl Inst Environm Hlth Sci, POB 12233, Res Triangle Pk, NC 27709 USA. NR 46 TC 3 Z9 3 U1 1 U2 1 PU INT AGENCY RESEARCH CANCER PI LYONS PA 150, COURS ALBERT THOMAS, 69372 LYONS, FRANCE SN 0300-5038 BN 92-832-2147-8 J9 IARC SCI PUBL PY 1999 IS 147 BP 211 EP 225 PG 15 WC Oncology SC Oncology GA BQ97W UT WOS:000165216800014 PM 10457919 ER PT J AU Lin, SZ Hoffer, BJ Kaplan, P Wang, Y AF Lin, SZ Hoffer, BJ Kaplan, P Wang, Y TI Osteogenic protein-1 protects against cerebral infarction induced by MCA ligation in adult rats SO STROKE LA English DT Article DE bone morphogenetic proteins; cerebral infarction; cerebral ischemia; neuroprotection; rats ID BONE MORPHOGENETIC PROTEINS; MIDBRAIN DOPAMINERGIC-NEURONS; SERINE/THREONINE KINASE RECEPTORS; FAMILY MEDIATOR SMAD1; NEUROTROPHIC FACTOR; II RECEPTOR; ARTERY OCCLUSION; BRAIN EDEMA; IN-VITRO; EXPRESSION AB Background and Purpose-Osteogenic protein-1 (OP1) not only possesses trophic activity on bone tissue but also influences neuronal survival and differentiation in vitro. Specific receptors for OP1 are present in brain and spinal cord and can be upregulated during cerebral contusion. OP1 is a member of the transforming growth factor-p superfamily, several of whose members possess neuroprotective activity. In this study, the neuroprotective effect of OP1 in cerebral ischemia was evaluated in adult animals. Methods-Adult male Sprague-Dawley rats were anesthetized with chloral hydrate. OP1 or vehicle was administered intracortically or intracerebroventricularly to the rats. Thirty minutes, 24 hours, or 72 hours after OP1 injection, the right middle cerebral artery (MCA) was ligated for 90 minutes. Twenty-four hours after reperfusion, animals were tested for motor behavior. The animals were subsequently anesthetized with urethane and perfused intracardially with saline. Brain tissue was removed, sliced, and incubated with 2% triphenyltetrazolium chloride to localize the area of infarction. Results-Only animals pretreated with OP1 24 hours before MCA ligation showed a reduction in motor impairment. OP1, given 30 minutes or 72 hours before MCA ligation, did not reduce cortical infarction. In contrast, pretreatment with OP1 24 hours before MCA ligation significantly attenuated the volume of infarction in the cortex, in agreement with the behavioral findings. Conclusions-Intracerebral administration of OP1 24 hours before MCA ligation reduces ischemia-induced injury in the cerebral cortex. C1 Natl Def Med Ctr, Dept Pharmacol & Neurosurg, Taipei, Taiwan. Univ Colorado, Hlth Sci Ctr, Dept Pharmacol, Denver, CO 80262 USA. Creat Biomol Inc, Boston, MA USA. RP Wang, Y (reprint author), NIDA, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIA NIH HHS [AG-04418] NR 48 TC 57 Z9 64 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 1999 VL 30 IS 1 BP 126 EP 132 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 155EW UT WOS:000077934200024 PM 9880400 ER PT J AU Hurn, PD Sampei, K Crain, BJ Sawada, M Aikayed, NJ Traystman, RJ Korach, KS Demas, GE Nelson, RJ AF Hurn, PD Sampei, K Crain, BJ Sawada, M Aikayed, NJ Traystman, RJ Korach, KS Demas, GE Nelson, RJ TI Estrogen receptor alpha subtype and experimental stroke SO STROKE LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. NIEHS, Res Triangle Pk, NC 27709 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 1999 VL 30 IS 1 MA 11 BP 233 EP 233 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 155EW UT WOS:000077934200062 ER PT J AU Sood, SL Ruetzler, C LaBiche, R Azhar, S DeGraba, TJ AF Sood, SL Ruetzler, C LaBiche, R Azhar, S DeGraba, TJ TI Differential expression of TNF-alpha in symptomatic and asymptomatic human atherosclerotic plaques SO STROKE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 1999 VL 30 IS 1 MA 49 BP 240 EP 240 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 155EW UT WOS:000077934200106 ER PT J AU Marler, JR Tilley, BC Lu, M Brott, T Lyden, P Broderick, JP Grotta, J Levine, SR Frankel, M Horowitz, S Kwiatkowski, T AF Marler, JR Tilley, BC Lu, M Brott, T Lyden, P Broderick, JP Grotta, J Levine, SR Frankel, M Horowitz, S Kwiatkowski, T CA NINDS rt-PA Stroke Study Grp TI Earlier treatment associated with better outcome in the NINDS TPA stroke study. SO STROKE LA English DT Meeting Abstract C1 Emory Univ, Atlanta, GA 30322 USA. Henry Ford Hlth Sci Ctr, Detroit, MI USA. Henry Ford Hosp, Detroit, MI 48202 USA. Mayo Clin & Mayo Fdn, Jacksonville, FL USA. NINDS, Bethesda, MD 20892 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Univ Missouri, Columbia, MO 65201 USA. Univ Texas, Houston, TX USA. Wayne State Univ, Detroit, MI 48202 USA. NR 0 TC 25 Z9 27 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 1999 VL 30 IS 1 MA 76 BP 244 EP 244 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 155EW UT WOS:000077934200127 ER PT J AU Brey, RL Abbott, RD Sharp, DS Ross, GW Curb, JD Stallworth, CL Kittner, SJ AF Brey, RL Abbott, RD Sharp, DS Ross, GW Curb, JD Stallworth, CL Kittner, SJ TI Beta-2-glycoprotein 1-dependent (B2GP1-dep) anticardiolipin antibodies (aCL) are an independent risk factor for ischemic stroke in the Honolulu heart cohort SO STROKE LA English DT Meeting Abstract C1 Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Univ Virginia, Sch Med, Charlottesville, VA 22908 USA. NHLBI, Bethesda, MD 20892 USA. Univ Hawaii, John A Burns Sch Med, Honolulu, HI 96822 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 1999 VL 30 IS 1 MA 121 BP 252 EP 252 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 155EW UT WOS:000077934200178 ER PT J AU Hurn, PD Sampei, K Sawada, M Alkayed, NJ Korach, KS Nelson, RJ Traystman, RJ Crain, BJ AF Hurn, PD Sampei, K Sawada, M Alkayed, NJ Korach, KS Nelson, RJ Traystman, RJ Crain, BJ TI Paradoxical neuroprotection from stroke in estrogen receptor a-deficient mice SO STROKE LA English DT Meeting Abstract C1 Johns Hopkins Med Inst, Baltimore, MD 21205 USA. Johns Hopkins Med Univ, Baltimore, MD USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JAN PY 1999 VL 30 IS 1 MA P33 BP 273 EP 273 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 155EW UT WOS:000077934200300 ER PT B AU Ludlow, CL AF Ludlow, CL BE Ratner, NB Healey, EC TI A conceptual framework for investigating the neurobiology of stuttering SO STUTTERING RESEARCH AND PRACTICE: BRIDGING THE GAP LA English DT Review CT 3rd Annual Leadership Conference on Research and Treatment - Bridging the Gap CY 1996 CL MONTEREY, CA SP Amer Speech Language Hearing Assoc ID POSITRON EMISSION TOMOGRAPHY; DOPA-RESPONSIVE DYSTONIA; CEREBRAL BLOOD-FLOW; PHONOLOGICAL CHARACTERISTICS; FUNCTIONAL-ORGANIZATION; LANGUAGE DISORDERS; SPEECH PRODUCTION; YOUNG STUTTERERS; AUTOMATIC SPEECH; GENETIC-ASPECTS C1 Natl Inst Deafness & Other Commun Disorders, Voice & Speech Sect, NIH, Bethesda, MD USA. NR 145 TC 5 Z9 5 U1 4 U2 7 PU LAWRENCE ERLBAUM ASSOC PUBL PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430 USA BN 0-8058-2459-6 PY 1999 BP 63 EP 84 PG 22 WC Education, Special; Psychology, Developmental; Rehabilitation SC Education & Educational Research; Psychology; Rehabilitation GA BM74P UT WOS:000079674800006 ER PT J AU Weatherby, NL McCoy, HV Metsch, LR Bletzer, KV McCoy, CB de la Rosa, MR AF Weatherby, NL McCoy, HV Metsch, LR Bletzer, KV McCoy, CB de la Rosa, MR TI Crack cocaine use in rural migrant populations: Living arrangements and social support SO SUBSTANCE USE & MISUSE LA English DT Article; Proceedings Paper CT Symposium on Rural/Urban Continuum CY OCT, 1996 CL UNIV KENTUCKY, LEXINGTON, KY SP Univ Kentucky HO UNIV KENTUCKY DE crack cocaine; family; social support; migrant farmworker; rural population ID ILLICIT DRUG-USE; PREGNANT-WOMEN; HIV-INFECTION; BELLE-GLADE; INNER-CITY; AIDS; BEHAVIOR; FLORIDA; RISK; NETWORKS AB Correlates of crack cocaine use were studied among a targeted sample of migrant workers and their sexual partners (n = 571) in rural Southern Florida. Employment among men and recent drug-user treatment among men and women are positively related to crack use, as is involvement in crime and prostitution. Among women but not men, living with children is negatively related to crack use. Drug use and HIV prevention programs should intervene with individuals and their families and social groups. Migrant workers and their sexual partners also need effective drug-user treatment with long-term relapse prevention services. C1 Univ Miami, Sch Med, Comprehens Drug Res Ctr, Miami, FL 33136 USA. Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. Univ Miami, Dept Sociol, Miami, FL 33124 USA. Florida Int Univ, Dept Publ Hlth, Miami, FL 33181 USA. NIDA, Special Populat Off, Rockville, MD 20857 USA. RP Weatherby, NL (reprint author), Univ Miami, Sch Med, Comprehens Drug Res Ctr, 1400 NW 10th Ave,11th Floor D-93, Miami, FL 33136 USA. EM nweather@mednet.med.miami.edu FU NIDA NIH HHS [DA07694] NR 74 TC 10 Z9 10 U1 1 U2 2 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1082-6084 J9 SUBST USE MISUSE JI Subst. Use Misuse PY 1999 VL 34 IS 4-5 BP 685 EP 706 DI 10.3109/10826089909037238 PG 22 WC Substance Abuse; Psychiatry; Psychology SC Substance Abuse; Psychiatry; Psychology GA 183BK UT WOS:000079534000013 PM 10210100 ER PT J AU Agar, MH Kozel, NJ AF Agar, MH Kozel, NJ TI Special issue on ethnography and substance use: Talking numbers - Introduction SO SUBSTANCE USE & MISUSE LA English DT Editorial Material C1 Ethnoworks, Takoma Pk, MD 20913 USA. NIDA, NIH, Rockville, MD 20852 USA. RP Agar, MH (reprint author), Ethnoworks, POB 5804, Takoma Pk, MD 20913 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 1082-6084 J9 SUBST USE MISUSE JI Subst. Use Misuse PY 1999 VL 34 IS 14 BP 1935 EP 1949 DI 10.3109/10826089909039433 PG 15 WC Substance Abuse; Psychiatry; Psychology SC Substance Abuse; Psychiatry; Psychology GA 256VQ UT WOS:000083747500001 PM 10573299 ER PT J AU Hayashi, T Su, TP Kagaya, A Nishida, A Shimizu, M Yamawaki, S AF Hayashi, T Su, TP Kagaya, A Nishida, A Shimizu, M Yamawaki, S TI Neuroleptics with differential affinities at dopamine D-2 receptors and sigma receptors affect differently the N-methyl-D-aspartate-induced increase in intracellular calcium concentration: Involvement of protein kinase SO SYNAPSE LA English DT Article DE NMDA; sulpiride; sigma receptor; intracellular calcium; neuroleptics; dopamine D-2; PKA ID GUINEA-PIG BRAIN; CHRONIC-SCHIZOPHRENIC PATIENTS; POST-MORTEM BRAINS; PREFRONTAL CORTEX; HIPPOCAMPAL-NEURONS; NMDA RECEPTORS; GLUTAMATE RECEPTORS; ANTIPSYCHOTIC-DRUGS; CORTICAL-NEURONS; GENE-EXPRESSION AB This study examined the effect of chronic antipsychotic treatment on the NMDA-elicited changes in intracellular free Ca2+ concentration ([Ca2+](i)) in the primary culture of rat frontal cortical neurons. Antipsychotics used in the study were chosen for their differential affinities at dopamine D-2 receptors and sigma receptors. The potential involvement of protein kinases in this action of antipsychotics were also examined. Chronic treatment of cells with antipsychotics (sulpiride, clozapine, and chlorpromazine) which are known to be potent dopamine D-2 receptor ligands, whereas possessing low or no appreciable affinity for sigma receptors, caused a dose-dependent potentiation of the NMDA-induced increase in [Ca2+](i). On the contrary, haloperidol, which is as potent a sigma receptor ligand as a dopamine D-2 receptor ligand, did not affect the NMDA-elicited increase in [Ca2+](i). Sulpiride increased the maximum effect afforded by different concentrations of NMDA and shifted the dose-response curve of NMDA to the left (EC50 value from 12.5 mu M to 1.39 mu M). Consistent with sulpiride's affinity at dopamine D-2 receptors, this action of sulpiride was stereoselective: S(-)-sulpiride was active whereas R(+)-sulpiride was inactive. Treatment of cells with dopamine (3 mu M) tends to decrease the NMDA-induced increase in [Ca2+](i). Sulpiride at 1 mu M totally abolished this action of dopamine and restored its potentiating action on the NMDA-induced increase in [Ca2+](i). Haloperidol, a potent dopamine Da and sigma receptor ligand, did not affect the sulpiride's potentiating action on the NMDA-induced responses. On the other hand, chronic treatment of cells with a sigma receptor agonist, DTG, at a concentration producing no effect of its own (10 nM), led to an enhancement of the potentiating effect of sulpiride on NMDA-induced increase in [Ca2+](i). This action of DTG was abolished by haloperidol. Further, chronic, but not acute, treatment of cells with either a protein kinase inhibitor H-7 or a cAMP-dependent protein kinase (PKA) inhibitor H-89 abolished this effect of sulpiride on the NMDA-induced [Ca2+](i) changes. These results indicate that the action of NMDA in the primary cortical neurons are regulated differently by ligands with differential affinities at dopamine D-2 and sigma receptors. The results with protein kinase inhibitors indicate that the potentiation of NMDA responses by sulpiride involves intracellular biochemical events. Synapse 31:20-28, 1999. Published 1999 Wiley-Liss, Inc.dagger. C1 NIDA, Cellular Pathobiol Unit, Mol Neuropsychiat Sect, NIH,Intramural Res Program, Baltimore, MD 21224 USA. Hiroshima Univ, Sch Med, Dept Psychiat & Neurosci, Minami Ku, Hiroshima 734, Japan. Kure Natl Hosp, Inst Clin Res, Dept Psychiat & Neurosci, Hiroshima, Japan. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Unit, Mol Neuropsychiat Sect, NIH,Intramural Res Program, POB 5180, Baltimore, MD 21224 USA. RI Hayashi, Teruo/A-9690-2008 NR 52 TC 11 Z9 11 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JAN PY 1999 VL 31 IS 1 BP 20 EP 28 DI 10.1002/(SICI)1098-2396(199901)31:1<20::AID-SYN4>3.0.CO;2-2 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 145KG UT WOS:000077369700004 PM 10025680 ER PT J AU Kiesewetter, DO Carson, RE Jagoda, EM Herscovitch, P Eckelman, WC AF Kiesewetter, DO Carson, RE Jagoda, EM Herscovitch, P Eckelman, WC TI In vivo muscarinic binding of 3-(alkylthio)-3-thiadiazolyl tetrahydropyridines SO SYNAPSE LA English DT Article DE autoradiography; brain; fluorine 18; muscarinic acetylcholine receptor; positron emission tomography; rats; rhesus monkey ID IODINE-125-LABELED 1-AZABICYCLO<2.2.2>OCT-3-YL ALPHA-HYDROXY-ALPHA-(1-IODO-1-PRO; CHOLINERGIC RECEPTOR-BINDING; REGIONAL DISTRIBUTION; RAT-BRAIN; M2; SELECTIVITY; LIGAND; LOCALIZATION; TOMOGRAPHY; AGONISTS AB Based on encouraging in vitro data indicating M-2 subtype selectivity, we synthesized, radiolabeled with F-18, and evaluated 3-(3-(2-fluoroethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine [FE-TZTP], and 3-(3-(3-fluoropropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine [FP-TZTP] for muscarinic subtype selectivity in vivo. [F-18]FE-TZTP displays high uptake in vivo but is inhibited only weakly by coinjecting unlabeled P-TZTP. Contrarily, [F-18]FP-TZTP shows significant inhibition of uptake by coinjecting unlabeled P-TZTP or the muscarinic agonist L-687,306 (3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-1-azabicyclo[2.2.1]heptane). Using in vivo autoradiography, [F-18]FP-TZTP displays regional distribution consistent with M-2 subtype distribution. In addition, [F-18]FP-TZTP shows specific uptake in the heart at 5 min. Analysis of metabolites in the awake rat brain revealed that the parent compound represents >95% of the extractable activity at 30 min. In vivo studies in rhesus monkeys revealed rapid brain uptake of [F-18]FP-TZTP, with clearance sustained over 2 h. Administration of P-TZTP or FP-TZTP (80 nmol/kg) at 60 min after injection of [F-18]FP-TZTP results in a significant displacement of brain activity in all regions. Metabolite analysis in monkey plasma shows that parent compound represents 20% of the extractable radioactivity at 40 min postinjection. One metabolite, which increases with time, has similar lipophilicity to the parent. However, based on metabolism in rat we believe metabolites are not in the brain to any significant extent in monkeys during the time of imaging studies. Regional uptake, autoradiographic distribution, and clearance rates in the brain are consistent with the hypothesis that [F-18]FP-TZTP is M-2 selective in vive. Synapse 31:29-40, 1999, Published 1999 Wiley-Liss, Inc.dagger. C1 NIH, Warren G Magnuson Clin Ctr, PET Dept, Bethesda, MD 20892 USA. RP Kiesewetter, DO (reprint author), NIH, Warren G Magnuson Clin Ctr, PET Dept, Bldg 10,Room 1C401,10 Ctr Dr MSC 1180, Bethesda, MD 20892 USA. RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 FU NIMH NIH HHS [N01MH20003] NR 23 TC 22 Z9 22 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD JAN PY 1999 VL 31 IS 1 BP 29 EP 40 DI 10.1002/(SICI)1098-2396(199901)31:1<29::AID-SYN5>3.0.CO;2-9 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 145KG UT WOS:000077369700005 PM 10025681 ER PT S AU Condorelli, DF Conti, F Gallo, V Kirchhoff, F Seifert, G Steinhauser, C Verkhratsky, A Yuan, XQ AF Condorelli, DF Conti, F Gallo, V Kirchhoff, F Seifert, G Steinhauser, C Verkhratsky, A Yuan, XQ BE Matsas, R Tsacopoulos, M TI Expression and functional analysis of glutamate receptors in glial cells SO THE FUNCTIONAL ROLES OF GLIAL CELLS IN HEALTH AND DISEASE: DIALOGUE BETWEEN GLIA AND NEURONS SE ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT III European Meeting on Glial Cell Function in Health and Disease CY MAY 06-10, 1998 CL ATHENS, GREECE ID AMINO-ACID RECEPTORS; RAT CEREBRAL-CORTEX; ASTROCYTES IN-SITU; 2',3'-CYCLIC NUCLEOTIDE 3'-PHOSPHODIESTERASE; METABOTROPIC GLUTAMATE; MESSENGER-RNA; CULTURED ASTROCYTES; CORTICAL ASTROCYTES; HIPPOCAMPAL ASTROCYTES; PROGENITOR CELLS AB The brain consists of a complex network in which neurones and glial cells are structurally and functionally interwoven. Astrocytes, the most numerous member of the glial family, were originally considered, along with the whole glial population,to be only of structural importance (Virchow, 1846). For example, during development the radial glia, the precursors of astrocytes, serve as a scaffold at which neurones migrate to form the layered structure of different brain regions such as the cortex, the hippocampus or the cerebellum. During the last two decades, considerable knowledge about astrocytes has accumulated regarding their physiological function. One exciting function is their contribution to the regulation of the extracellular space and, thereby, also of brain excitability (Walz, 1989). Qualities such as their capacity for uptake and metabolism of transmitters, buffering capacity of ions and ability to convey external signals via surface receptors to biological responses within the cells indicate an intimate crosstalk between glial cells and neurones. The other major glial population in the brain are the oligodendrocytes. As small cells with few processes they form the myelin sheath, a highly lipid enriched stack of cell membranes enwrapping 50 to 300 mu m long axonal segments to enhance the conduction of electrical signals and to inhibit electrical crosstalk between individual axons. Oligodendrocytes are capable of myelinating up to 50 axonal segments simultaneously. Mature oligodendrocytes develop from progenitors originating from the subventricular zone as the germinative layer (Miller, 1996). In vertebrates, progenitors start to migrate to their final destination regions, the presumptive white matter, during the first postnatal week. On macroglia, i.e. on astrocytes, oligodendrocytes, and their progenitors, a variety of functional ligand- and voltage-gated ion channels has been unambiguously demonstrated in vivo (Porter and McCarthy, 1996; Verkhratsky and Kettenmann, 1996; Steinhauser and Gallo, 1996; Ransom and Orkand, 1996; Sontheimer et al., 1996; Theodosis and MacVicar, 1996). However, the physiological role of these membrane proteins in non-neuronal cells is still largely unknown. Among all neurotransmitter receptors, glutamate receptors are the best studied receptors on glial cells. Here, we will present a series of studies investigating the functional and molecular properties of ionotropic and metabotropic glutamate receptors in different glial cell types. C1 Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. Univ Catania, Inst Biochem, I-95125 Catania, Italy. Univ Ancona, Inst Human Physiol, I-60020 Ancona, Italy. NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. Univ Bonn, D-53105 Bonn, Germany. RP Kirchhoff, F (reprint author), Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany. RI Kirchhoff, Frank/B-9335-2008; Verkhratsky, Alexei/J-4527-2013 OI Kirchhoff, Frank/0000-0002-2324-2761; Verkhratsky, Alexei/0000-0003-2592-9898 NR 108 TC 33 Z9 34 U1 1 U2 2 PU KLUWER ACADEMIC / PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0065-2598 BN 0-306-46205-2 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 1999 VL 468 BP 49 EP 67 PG 19 WC Allergy; Cell Biology; Medicine, Research & Experimental; Neurosciences SC Allergy; Cell Biology; Research & Experimental Medicine; Neurosciences & Neurology GA BP33F UT WOS:000084730400005 PM 10635019 ER PT S AU Londos, C Brasaemle, DL Schultz, CJ Adler-Wailes, DC Levin, DM Kimmel, AR Rondinone, CM AF Londos, C Brasaemle, DL Schultz, CJ Adler-Wailes, DC Levin, DM Kimmel, AR Rondinone, CM BE Hansen, BC Saye, J Wennogle, LP TI On the control of lipolysis in adipocytes SO THE METABOLIC SYNDROME X: CONVERGENCE OF INSULIN RESISTANCE, GLUCOSE INTOLERANCE, HYPERTENSION, OBESITY, AND DYSLIPIDEMIAS-SEARCHING FOR THE UNDERLYING DEFECTS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on The Metabolic Syndrome X - Convergence of Insulin Resistance, Glucose Intolerance, Hypertension, Obesity, and Dyslipidemias-Searching for the Underlying Defects CY FEB 19-22, 1999 CL JACKSONVILLE, FLORIDA SP New York Acad Sci, Parke Davis Pharmaceut Res Inst, Janssen Res Fdn, Knoll Pharmaceut Co, Novartis Pharma AG, Amer Heart Assoc Council Circulat, Bristol Myers Squibb, Pharmaceut Res Inst, DuPont Pharmaceut Co, GelTex Pharmaceut Inc, Genome Therapeut Corp, Inst Diabet Discovery Inc, Lilly Res Labs, Div Endocrine Res & Clin Invest, Merck Res Labs, Schering Plough Res Inst, Smithkline Beecham Pharmaceut ID HORMONE-SENSITIVE LIPASE; DEPENDENT PROTEIN-KINASE; DIFFERENTIATION-RELATED PROTEIN; LIPID STORAGE DROPLET; TUMOR-NECROSIS-FACTOR; RAT ADIPOCYTES; FAT-CELLS; ADENYLATE-CYCLASE; ADIPOSE-TISSUE; PERILIPIN-A AB The lipolytic reaction in adipocytes is one of the most important reactions in the management of bodily energy reserves, and dysregulation of this reaction may contribute to the symptoms of Type 2 diabetes mellitus. Yet, progress on reserving the molecular details of this reaction has been relatively slow. However, recent developments at the molecular level begin to paint a clearer picture of lipolysis and point to a number of unanswered questions. While HSL has long been known to be the rate-limiting enzyme of lipolysis, the mechanism by which HSL attacks the droplet lipids is not yet firmly established. Certainly, the immunocytochemical evidence showing the movement of HSL to the lipid droplet upon stimulation leaves little doubt that this translocation is a key aspect of the lipolytic reaction, but whether or not HSL phosphorylation contributes to the translocation, and at which site(s), is as yet unresolved. It will be important to establish whether there is an activation step in addition to the translocation reaction. The participation of perilipin A is indicated by the findings that this protein can protect neutral lipids within droplets from hydrolysis, but active participation in the lipolytic reaction is yet to be proved. Again, it will be important to determine whether mutations of serine residues of PKA phosphorylation sites of perilipins prevent lipolysis, and whether such modifications abolish the physical changes in the droplet surfaces that accompany lipolysis. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Londos, C (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bldg 6,Room B1-32,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Brasaemle, Dawn/0000-0002-8553-8285 NR 67 TC 177 Z9 186 U1 0 U2 14 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-207-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 1999 VL 892 BP 155 EP 168 DI 10.1111/j.1749-6632.1999.tb07794.x PG 14 WC Cell Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Physiology SC Cell Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Physiology GA BP20K UT WOS:000084392400014 PM 10842661 ER PT S AU Reitman, ML Mason, MM Moitra, J Gavrilova, O Marcus-Samuels, B Eckhaus, M Vinson, C AF Reitman, ML Mason, MM Moitra, J Gavrilova, O Marcus-Samuels, B Eckhaus, M Vinson, C BE Hansen, BC Saye, J Wennogle, LP TI Transgenic mice lacking white fat: Models for understanding human lipoatrophic diabetes SO THE METABOLIC SYNDROME X: CONVERGENCE OF INSULIN RESISTANCE, GLUCOSE INTOLERANCE, HYPERTENSION, OBESITY, AND DYSLIPIDEMIAS-SEARCHING FOR THE UNDERLYING DEFECTS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT Conference on The Metabolic Syndrome X - Convergence of Insulin Resistance, Glucose Intolerance, Hypertension, Obesity, and Dyslipidemias-Searching for the Underlying Defects CY FEB 19-22, 1999 CL JACKSONVILLE, FLORIDA SP New York Acad Sci, Parke Davis Pharmaceut Res Inst, Janssen Res Fdn, Knoll Pharmaceut Co, Novartis Pharma AG, Amer Heart Assoc Council Circulat, Bristol Myers Squibb, Pharmaceut Res Inst, DuPont Pharmaceut Co, GelTex Pharmaceut Inc, Genome Therapeut Corp, Inst Diabet Discovery Inc, Lilly Res Labs, Div Endocrine Res & Clin Invest, Merck Res Labs, Schering Plough Res Inst, Smithkline Beecham Pharmaceut ID FACTOR HMGI-C; ADIPOSE-TISSUE; DNA-BINDING; OBESITY; GENE; EXPRESSION; LIPODYSTROPHY; RESISTANT; PROTEIN; MOUSE AB The human disease lipoatrophic (or lipodystrophic) diabetes is a rare syndrome in which a deficiency of adipose tissue is associated with Type 2 diabetes. This disease is an interesting contrast to the usual situation in which diabetes is associated with obesity, an excess of fat. Aside from obesity, patients with lipodystrophic diabetes have the other features associated with Metabolic Syndrome X, including hypertension and dyslipidemia. The contrast between diabetes,vith a lack of fat and diabetes,vith an excess of fat provides an opportunity to study the mechanisms causing Type 2 diabetes and its complications. Recently, three laboratories have produced transgenic mice that are deficient in white adipose tissue. These mice have insulin resistance and other features of lipoatrophic diabetes, and are a faithful model for the human disease. Here we review the different murine models of fat ablation and compare the murine and human diseases, addressing the questions: Is the lack of fat causative of the diabetes, and if so by what mechanism? How could the other clinical features be explained mechanistically? And finally, what can be gleaned about insight into treatment options? C1 NIDDKD, Diabet Branch, Bethesda, MD 20892 USA. NCI, Biochem Lab, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. RP Reitman, ML (reprint author), NIDDK, NIH, Bldg 10,Room 8N-250, Bethesda, MD 20892 USA. RI Reitman, Marc/B-4448-2013 OI Reitman, Marc/0000-0002-0426-9475 NR 26 TC 53 Z9 54 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-207-X J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 1999 VL 892 BP 289 EP 296 DI 10.1111/j.1749-6632.1999.tb07802.x PG 8 WC Cell Biology; Endocrinology & Metabolism; Multidisciplinary Sciences; Physiology SC Cell Biology; Endocrinology & Metabolism; Science & Technology - Other Topics; Physiology GA BP20K UT WOS:000084392400022 PM 10842669 ER PT J AU Swanson, WF McRae, MA Wildt, DE Rall, WF AF Swanson, WF McRae, MA Wildt, DE Rall, WF TI Cryoprotectant toxicity and cryopreservation success in IVF-derived domestic cat embryos after embryo transfer SO THERIOGENOLOGY LA English DT Meeting Abstract C1 Cincinnati Zoo & Bot Garden, Ctr Res Endangered Wildlife, Cincinnati, OH USA. Smithsonian Inst, Conservat & Res Ctr, Front Royal, VA USA. NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RI Rall, William/C-5104-2008 NR 0 TC 12 Z9 13 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0093-691X J9 THERIOGENOLOGY JI Theriogenology PD JAN 1 PY 1999 VL 51 IS 1 BP 174 EP 174 DI 10.1016/S0093-691X(99)91733-8 PG 1 WC Reproductive Biology; Veterinary Sciences SC Reproductive Biology; Veterinary Sciences GA 154AM UT WOS:000077865900034 ER PT J AU Elhassan, YM Tasca, RJ Westhusin, ME AF Elhassan, YM Tasca, RJ Westhusin, ME TI Levels of amino acids in bovine oviductal and uterine fluids in comparison to levels available in a culture medium supplemented with commercial stocks SO THERIOGENOLOGY LA English DT Meeting Abstract C1 Texas A&M Univ, Dept Vet Physiol & Pharmacol, College Stn, TX 77843 USA. NIH, Dept Hlth & Human Serv, Publ Hlth Serv, Bethesda, MD 20892 USA. NR 0 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 0093-691X J9 THERIOGENOLOGY JI Theriogenology PD JAN 1 PY 1999 VL 51 IS 1 BP 237 EP 237 DI 10.1016/S0093-691X(99)91796-X PG 1 WC Reproductive Biology; Veterinary Sciences SC Reproductive Biology; Veterinary Sciences GA 154AM UT WOS:000077865900097 ER PT J AU Puri, RK AF Puri, RK TI Development of a recombinant interleukin-4-Pseudomonas exotoxin for therapy of glioblastoma SO TOXICOLOGIC PATHOLOGY LA English DT Article DE interleukin-4 receptors; recombinant chimeric protein; interleukin-4 Pseudomonas exotoxin; glioblastoma; cytotoxicity; antitumor activity; toxicology ID RECEPTOR GAMMA-CHAIN; CELL-CARCINOMA-CELLS; CIRCULARLY PERMUTED INTERLEUKIN-4; PSEUDOMONAS EXOTOXIN; CHIMERIC PROTEIN; FUNCTIONAL COMPONENT; IL-13 RECEPTOR; SARCOMA-CELLS; EXPRESSION; CANCER AB About 12,000 Americans are diagnosed with malignant astrocytoma each year. Despite surgery, radiotherapy, and chemotherapy, the prognosis of these patients remains poor. Targeted toxins based on the identification of novel antigens or receptors provide a promising new approach to treating cancer. We have identified one such cell surface protein in the form of interleukin (IL)-4 receptors (IL-4R) on human malignant astrocytoma. Normal brain tissues from frontal cortex and temporal lobe cortex do not express IL-4R. To target IL-4R, we generated a chimeric fusion protein composed of IL-4 and Pseudomonas exotoxin (IL4-PE). This toxin is highly cytotoxic to IL-4R-bearing human brain cancer cells. Preclinical toxicologic experiments were performed in mice, rats, and guinea pigs to determine an maximum tolerated dose. Intrathecal administration in cynomolgus monkeys produced high cerebrospinal fluid levels without any central nervous system or other abnormalities. When IL4-PE was injected into the right frontal cortex of rats, localized necrosis was observed at 1,000 but not less than or equal to 100 mu g/ml doses. Intravenous administration of this biologic to monkeys produced reversible grade 3 or grade 4 elevations of hepatic enzymes in a dose-dependent manner. These results indicate that localized administration can produce nontoxic levels of IL4-PE that may have significant activity against astrocytoma. In vivo experiments with nude mice have demonstrated that IL4-PE has significant antitumor activity against human glioblastoma tumor model. Intratumor administration of IL4-PE has been initiated for the treatment of malignant astrocytoma in a phase I clinical trial. C1 NIH, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,Food & Drug Adm, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), NIH, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res,Food & Drug Adm, Bldg 29B,Room 2NN10,29 Lincoln Dr,MSC 4555, Bethesda, MD 20892 USA. NR 28 TC 21 Z9 22 U1 0 U2 1 PU SOC TOXICOLOGIC PATHOLOGISTS PI MT ROYAL PA 19 MANTUA RD, MT ROYAL, NJ 08061 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD JAN-FEB PY 1999 VL 27 IS 1 BP 53 EP 57 DI 10.1177/019262339902700111 PG 5 WC Pathology; Toxicology SC Pathology; Toxicology GA 165GT UT WOS:000078513200011 PM 10367674 ER PT J AU Peters, JM Narotsky, MG Elizondo, G Fernandez-Salguero, PM Gonzalez, FJ Abbott, BD AF Peters, JM Narotsky, MG Elizondo, G Fernandez-Salguero, PM Gonzalez, FJ Abbott, BD TI Amelioration of TCDD-induced teratogenesis in aryl hydrocarbon receptor (AhR)-Null mice SO TOXICOLOGICAL SCIENCES LA English DT Article DE aryl hydrocarbon receptor (AhR); 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); developmental toxicity; teratogenicity ID AH RECEPTOR; DEVELOPMENTAL TOXICITY; GROWTH-FACTORS; RETINOIC ACID; CLEFT-PALATE; EXPRESSION; GENES; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; LACKING; HYDRONEPHROSIS AB The aryl hydrocarbon receptor (AhR) mediates many of the biological effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and transcriptional activation of genes encoding a number of xenobiotic metabolizing enzymes. Prenatal exposure of mice to TCDD causes severe alterations in embryo and fetal development, including hydronephrosis and cleft palate. However, the mechanisms underlying these effects are unclear. In this work, the teratogenicity of TCDD in AhR-null mice was evaluated to determine if this effect is mediated by the AhR. Homozygous wild-type (+/+) or AhR-null (-/-) female mice were mated with males of the same genotype overnight. On gestation day (GD)-10, mice were intubated orally with either corn oil (vehicle control) or 25 mu g/kg TCDD. Fetuses were examined on GD18 for visceral and skeletal alterations. For non-TCDD-exposed litters, all developmental endpoints were comparable between genotypes, with the exception of a lower incidence of large interfrontal bones in (-/-) mice. For TCDD-exposed litters, (+/+) fetuses had a significantly greater incidence of cleft palate, hydronephrosis, small kidneys, tortuous ureters and greater dilation of the renal pelves and ureters compared to (-/-) fetuses. Interestingly, an increased resorption rate was observed in (-/-) fetuses exposed to TCDD. Results from this work demonstrate that fetal development per se is generally unaffected by the absence of the AhR or that other genes may have compensated for the loss of the AhR. More importantly, these data indicate that the AhR mediates TCDD-induced teratogenicity. Further, since a higher percentage of resorptions was observed in (-/-) litters from TCDD-treated dams, it is possible that AhR-independent mechanisms contribute to TCDD-induced developmental toxicity. C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. US EPA, Natl Hlth & Environm Effects Res Lab, Reprod Toxicol Div, Res Triangle Pk, NC 27711 USA. RP Peters, JM (reprint author), NCI, Metab Branch, NIH, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. RI Peters, Jeffrey/D-8847-2011; OI Fernandez-Salguero, Pedro M./0000-0003-2839-5027 NR 32 TC 150 Z9 157 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD JAN PY 1999 VL 47 IS 1 BP 86 EP 92 DI 10.1093/toxsci/47.1.86 PG 7 WC Toxicology SC Toxicology GA 251PT UT WOS:000083454600010 PM 10048156 ER PT J AU Garry, VF Burroughs, B Tarone, R Kesner, JS AF Garry, VF Burroughs, B Tarone, R Kesner, JS TI Herbicides and adjuvants: an evolving view SO TOXICOLOGY AND INDUSTRIAL HEALTH LA English DT Article DE adjuvants; herbicides; hormone analysis; human study; micronucleus assay ID CHROMOSOME-ABERRATIONS; PESTICIDE APPLIERS; HUMAN-LYMPHOCYTES; MUTAGENICITY; INVITRO; INVIVO; ASSAYS; CELLS; CYTOTOXICITY; GENOTOXICITY AB The present report examines the br vitro genotoxicity (micronucleus assay) of herbicides and adjuvants and reports on an in vivo human study on potential endocrine effects of pesticides, including herbicides. Adjuvants are used in conjunction with 2,4-dichlorophenoxy acetic acid (2,4-D) and other herbicides. Earlier pesticide applier survey results (n = 709) show that 59% of the applicators used adjuvants, and the majority of this group used paraffinic oils and/or surfactant mixtures. As a beginning effort to explore the role of adjuvants and herbicides in hormonally based reproductive effects, a prospective, controlled study was performed to analyze blood specimens from three different exposure groups (applicators using herbicides only; applicators using both herbicides and insecticides; and applicators using fumigants in addition to herbicides and insecticides; and a control group composed of other agricultural workers including organic farmers). The applicators and controls were age- and smoking-matched. Study subjects (n = 78) were tested before, during, and after completion of pesticide application season for the effects of pesticide products on hormone levels in the bloodstream. Of the applicator exposure groups examined, only the herbicide group showed significant endocrinologic differences from controls. Free testosterone levels were significantly elevated in post-season measurements (p = 0.032), and follicle-stimulating hormone (FSH) was significantly decreased at the height of the season (p = 0.016) and in the post-season (p = 0.010) as compared to controls. These endocrinologic findings are discussed in terms of their possible relationship to potential endocrine effects of herbicides, herbicide contaminants, and adjuvants. In vitro genotoxicity examination compared four different commercially available surfactant mixtures with 12 different commercial herbicide products, including six different chlorophenoxy herbicides. Only one herbicide yielded a significant dose-response curve. All four adjuvants showed positive dose-response effects. These preliminary data suggest that adjuvants are not inert but are toxicologically active components added to herbicide mixtures. Whether adjuvant toxicant effects are additive or are independent of herbicide effects is poorly understood. C1 Univ Minnesota, Environm Med & Pathol Program, Stone Lab 1, Lab Environm Med & Pathol, Minneapolis, MN 55414 USA. NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. NIOSH, Expt Toxicol Branch, Cincinnati, OH 45226 USA. RP Garry, VF (reprint author), Univ Minnesota, Environm Med & Pathol Program, Stone Lab 1, Lab Environm Med & Pathol, 1st Floor,421 29th Ave SE, Minneapolis, MN 55414 USA. FU NIEHS NIH HHS [ESO8161] NR 44 TC 14 Z9 14 U1 2 U2 9 PU STOCKTON PRESS PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0748-2337 J9 TOXICOL IND HEALTH JI Toxicol. Ind. Health PD JAN-MAR PY 1999 VL 15 IS 1-2 BP 159 EP 167 DI 10.1191/074823399678846619 PG 9 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 295BF UT WOS:000085945500013 PM 10188198 ER PT B AU Ziemann, U AF Ziemann, U BE Paulus, W Hallett, M Rossini, PM Rothwell, JC TI Intracortical inhibition and facilitation in the conventional paired TMS paradigm SO TRANSCRANIAL MAGNETIC STIMULATIO N SE ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY SUPPLEMENT LA English DT Proceedings Paper CT International Symposium on Transcranial Magnetic Stimulation CY SEP 30-OCT 04, 1998 CL GOTTINGEN, GERMANY ID HUMAN MOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; AMYOTROPHIC-LATERAL-SCLEROSIS; ISCHEMIC NERVE BLOCK; I-WAVE INTERACTION; CORTICAL EXCITABILITY; CORTICOCORTICAL INHIBITION; ELECTRICAL-STIMULATION; CORTICOSPINAL NEURONS; GENERALIZED EPILEPSY C1 Univ Gottingen, Dept Clin Neurophysiol, D-37075 Gottingen, Germany. RP Ziemann, U (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N242,10 Ctr Dr, Bethesda, MD 20892 USA. RI Paulus, Walter/A-3544-2009 OI Paulus, Walter/0000-0001-5549-8377 NR 67 TC 15 Z9 15 U1 2 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 0-444-50070-7 J9 EEG CL N SU PY 1999 IS 51 BP 127 EP 136 PG 10 WC Clinical Neurology; Physiology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Physiology; Radiology, Nuclear Medicine & Medical Imaging GA BP09N UT WOS:000084107600013 PM 10590943 ER PT B AU Topper, R Foltys, H Mottaghy, FM Boroojerdi, B AF Topper, R Foltys, H Mottaghy, FM Boroojerdi, B BE Paulus, W Hallett, M Rossini, PM Rothwell, JC TI Repetitive transcranial magnetic stimulation of the parietal cortex influences motor imagery SO TRANSCRANIAL MAGNETIC STIMULATIO N SE ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY SUPPLEMENT LA English DT Proceedings Paper CT International Symposium on Transcranial Magnetic Stimulation CY SEP 30-OCT 04, 1998 CL GOTTINGEN, GERMANY ID MENTAL REPRESENTATION; EXTRAPERSONAL SPACE; HAND MOVEMENTS; PERFORMANCE; EXECUTION; IDEATION; BRAIN; TASK C1 Aachen Tech Univ, Dept Neurol, D-52057 Aachen, Germany. Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Unit, NIH, Bethesda, MD USA. RP Topper, R (reprint author), Aachen Tech Univ, Dept Neurol, Pauwelsstr 30, D-52057 Aachen, Germany. NR 30 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 0-444-50070-7 J9 EEG CL N SU PY 1999 IS 51 BP 145 EP 150 PG 6 WC Clinical Neurology; Physiology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Physiology; Radiology, Nuclear Medicine & Medical Imaging GA BP09N UT WOS:000084107600015 ER PT B AU Cohen, LG Ziemann, U Chen, R AF Cohen, LG Ziemann, U Chen, R BE Paulus, W Hallett, M Rossini, PM Rothwell, JC TI Mechanisms, functional relevance and modulation of plasticity in the human central nervous system SO TRANSCRANIAL MAGNETIC STIMULATIO N SE ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY SUPPLEMENT LA English DT Review CT International Symposium on Transcranial Magnetic Stimulation CY SEP 30-OCT 04, 1998 CL GOTTINGEN, GERMANY ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; LONG-TERM POTENTIATION; MASSIVE CORTICAL REORGANIZATION; FREQUENCY-DISCRIMINATION TASK; PRIMARY SOMATOSENSORY CORTEX; UPPER-LIMB AMPUTATION; CEREBRAL BLOOD-FLOW; ADULT OWL MONKEYS; BRAIN-STIMULATION C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 10,Room 5N234-1430, Bethesda, MD 20892 USA. RI Chen, Robert/B-3899-2009 OI Chen, Robert/0000-0002-8371-8629 NR 128 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 0-444-50070-7 J9 EEG CL N SU PY 1999 IS 51 BP 174 EP 182 PG 9 WC Clinical Neurology; Physiology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Physiology; Radiology, Nuclear Medicine & Medical Imaging GA BP09N UT WOS:000084107600019 PM 10590949 ER PT B AU Hallett, M Chen, R Ziemann, U Cohen, LG AF Hallett, M Chen, R Ziemann, U Cohen, LG BE Paulus, W Hallett, M Rossini, PM Rothwell, JC TI Reorganization in motor cortex in amputees and in normal volunteers after ischemic limb deafferentation SO TRANSCRANIAL MAGNETIC STIMULATIO N SE ELECTROENCEPHALOGRAPHY AND CLINICAL NEUROPHYSIOLOGY SUPPLEMENT LA English DT Proceedings Paper CT International Symposium on Transcranial Magnetic Stimulation CY SEP 30-OCT 04, 1998 CL GOTTINGEN, GERMANY ID TRANSCRANIAL MAGNETIC STIMULATION; HORIZONTAL CONNECTIONS; CORTICAL EXCITABILITY; DYNAMIC ORGANIZATION; TARGET MUSCLES; NERVE LESIONS; ADULT-RATS; BLOOD-FLOW; FOREARM; MODULATION C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. RI Chen, Robert/B-3899-2009 OI Chen, Robert/0000-0002-8371-8629 NR 24 TC 17 Z9 17 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS BN 0-444-50070-7 J9 EEG CL N SU PY 1999 IS 51 BP 183 EP 187 PG 5 WC Clinical Neurology; Physiology; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Physiology; Radiology, Nuclear Medicine & Medical Imaging GA BP09N UT WOS:000084107600020 ER PT J AU Mozes, MM Kopp, JB Singletary, S Bryant, JL AF Mozes, MM Kopp, JB Singletary, S Bryant, JL TI A pharmaceutical preparation of human chorionic gonadotropin modulates transgene RNA expression and ameliorates wasting in HIV-transgenic mice SO TRANSGENICS LA English DT Article DE HIV-associated wasting; transgenic mice; human chorionic gonadotropin ID HORMONE RECEPTOR GENE; KAPOSIS-SARCOMA; HCG; NEPHROPATHY; AIDS AB Recent studies suggest that some pharmaceutical preparations of the pregnancy-related hormone human chorionic gonadotropin (hCG) modulate HIV replication in cultured lymphocytic cells and exert a cytotoxic effect on Kaposi's sarcoma cells in culture, in tumor transplants in mice, and in HIV-infected patients, We have investigated the activity of a preparation of hCG with activity against Kaposi's sarcoma cells in vitro in an HIV-transgenic mouse model: characterized by wasting and premature death in the homozygote. HIV RNA is expressed in multiple tissues, most abundantly in muscle. Hemizygous transgenic female mice were treated subcutaneously with hCG or vehicle twice weekly from the litter birthdate until 3 weeks post-partum; the hCG was shown to be transferred to the pups via the breast milk, The survival and growth of homozygous transgenic mice were strikingly improved by hCG therapy, Northern analysis of skeletal muscle demonstrated that this therapy was associated with a 60-80% reduction in steady-state levels of HIV RNA at one and two weeks of age, Quantitatively smaller reductions in HIV-transgene expression were seen in kidney, Parenteral administration of hCG directly to the pups resulted in high hCG serum levels and were associated with increased HIV transgene expression, These results indicate that low-dose therapy with this hCG preparation prolongs survival in an HIV-transgenic mouse, possibly by reducing steady-state HIV transgene mRNA levels. The mechanism for the stimulatory effect at higher doses is unknown, but might reflect biphasic dose-response curve, differences in the catabolism of hCG or a contaminant in the hCG preparation. C1 NIDDK, Kidney Dis Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, Metab Dis Branch, NIH, 10-3N116, Bethesda, MD 20892 USA. RI Mozes, Miklos/E-9003-2011; OI Kopp, Jeffrey/0000-0001-9052-186X NR 17 TC 0 Z9 0 U1 0 U2 0 PU HARWOOD ACAD PUBL GMBH PI READING PA C/O STBS LTD, PO BOX 90, READING, BERKS, ENGLAND RG1 8JL SN 1023-6171 J9 TRANSGENICS JI Transgenics PY 1999 VL 3 IS 1 BP 1 EP 10 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 273CU UT WOS:000084690400001 ER PT J AU May, AP Ponting, CP AF May, AP Ponting, CP TI Integrin alpha- and beta 4-subunit domain homologues in cyanobacterial proteins SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Article ID CELL-ADHESION; SIGNAL-TRANSDUCTION; NA+-CA2+ EXCHANGER; LIGAND-BINDING; CLONING; SPONGE; SUBUNITS; GROWTH; WALL C1 Univ Oxford, Fibrinolysis Res Unit, Old Observ, Oxford OX1 3RH, England. Natl Lib Med, NCBI, NIH, Bethesda, MD 20894 USA. RP May, AP (reprint author), Univ Oxford, Lab Mol Biophys, Dept Biochem, S Pk Rd, Oxford OX1 3QU, England. NR 20 TC 19 Z9 19 U1 1 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD JAN PY 1999 VL 24 IS 1 BP 12 EP 13 DI 10.1016/S0968-0004(98)01310-3 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 180VR UT WOS:000079406300004 PM 10087915 ER PT J AU Chien, KR AF Chien, KR TI Good fences make good neighbors: Cardiovascular science and medicine at the end of the millennium (Reprinted from Circulation, vol 99, pg 6-7, 1999) SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Reprint C1 Univ Calif San Diego, Sch Med, NHLBI, Program Mol Med,Dept Med, La Jolla, CA 92037 USA. Univ Calif San Diego, Sch Med, Ctr Mol Genet, La Jolla, CA 92037 USA. RP Chien, KR (reprint author), Univ Calif San Diego, Sch Med, NHLBI, Program Mol Med,Dept Med, La Jolla, CA 92037 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 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 JAN-FEB PY 1999 VL 9 IS 1-2 BP 1 EP 2 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 176YD UT WOS:000079179100001 ER PT J AU Wassarman, KM Zhang, AX Storz, G AF Wassarman, KM Zhang, AX Storz, G TI Small RNAs in Escherichia coli SO TRENDS IN MICROBIOLOGY LA English DT Review ID RIBONUCLEASE-P; ANTISENSE RNA; GENE-EXPRESSION; MESSENGER-RNA; DICB OPERON; STABLE RNAS; 6S RNA; DIVISION; TRANSCRIPTION; TRANSLATION AB Bacterial cells contain several small RNAs (sRNAs) that are not translated. These stable, abundant RNAs act by multiple mechanisms, such as RNA-RNA basepairing, RNA-protein interactions and intrinsic RNA activity, and regulate diverse cellular functions, including RNA processing, mRNA stability, translation, protein stability and secretion. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Wassarman, KM (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. OI Storz, Gisela/0000-0001-6698-1241 NR 48 TC 144 Z9 149 U1 0 U2 9 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0966-842X J9 TRENDS MICROBIOL JI Trends Microbiol. PD JAN PY 1999 VL 7 IS 1 BP 37 EP 45 PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 206UT UT WOS:000080898200009 PM 10068996 ER PT S AU Kita, T Heyes, MP Morrison, PF Markey, SP AF Kita, T Heyes, MP Morrison, PF Markey, SP BE Huether, G Kochen, W Simat, TJ Steinhart, H TI Labeled kynurenine pharmacokinetic modeling studies in gerbils - Nonequilibrium between infused and endogenous kynurenine SO TRYPTOPHAN, SEROTONIN AND MELATONIN: BASIC ASPECTS AND APPLICATIONS SE ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY LA English DT Article; Proceedings Paper CT 9th Meeting of the International-Study-Group-for-Tryptophan-Research (ISTRY 98) CY OCT 10-14, 1998 CL UNIV HAMBURG, HAMBURG, GERMANY SP Fresenius AG, Amino, H Wilhelm Schaumann Stift, Ajinomoto Europe, Esparma, Deutsch Forsch Gemeinsch, Ardeypharm, Niddapharm, Wissensch Behorde, Hamburg HO UNIV HAMBURG ID QUINOLINIC ACID; BRAIN; QUANTIFICATION AB In order to complete pharmacokinetic studies on the central vs. peripheral origin of several tryptophan metabolites, we infused gerbils with labelled kynurenine (H-2(4) or N-15(2)) Osmotic minipumps charged with kynurenine solutions were surgically implanted subcutaneously in adult female gerbils (50-60 g). After a variable number of hours, the gerbils were sacrificed and organs taken for determination of labelled/unlabelled kynurenine ratios using mass spectrometric assay of a pentafluorobenzyl derivative as described previously. Surprisingly high ratios of H-2 to H-1-kynurenine were measured in the kidney (0.25-0.40) and urine (4.0-8.0), although the ratio of deuterium labelled to endogenous kynurenine remained below detection limits (<0.05) in serum and other tissues. Infusion of greater quantities of H-2(4)-kynurenine confirmed these observations in gerbils in which ratios of H-2(4)-to-H-1 kynurenine were measurable in serum and tissues. Synthesis and infusion of N-15(2)-kynurenine demonstrated that these effects were not due to deuterium isotope substitution. The data demonstrate a non-equilibrium between infused and endogenous kynurenine, which is related to differential rates of protein binding and the rapid clearance of free, infused kynurenine by kidney. C1 NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. RP Kita, T (reprint author), NIMH, Lab Neurotoxicol, Bethesda, MD 20892 USA. NR 6 TC 2 Z9 2 U1 0 U2 0 PU KLUWER ACADEMIC / PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0065-2598 BN 0-306-46204-4 J9 ADV EXP MED BIOL JI Adv.Exp.Med.Biol. PY 1999 VL 467 BP 315 EP 320 PG 6 WC Chemistry, Analytical; Medicine, Research & Experimental; Pharmacology & Pharmacy; Psychiatry SC Chemistry; Research & Experimental Medicine; Pharmacology & Pharmacy; Psychiatry GA BP97A UT WOS:000086779600040 PM 10721071 ER PT J AU Presciuttini, S Gismondi, V Scarcello, E Sala, P D'Elia, F Rossetti, C Caroti-Ghelli, C Molina, F Groden, J Mosca, F Bertario, L Varesco, L AF Presciuttini, S Gismondi, V Scarcello, E Sala, P D'Elia, F Rossetti, C Caroti-Ghelli, C Molina, F Groden, J Mosca, F Bertario, L Varesco, L TI Different expressivity of two adjacent mutations of the APC gene SO TUMORI LA English DT Article DE FAP; genotype-phenotype; APC mutations ID FAMILIAL ADENOMATOUS POLYPOSIS; IDENTIFICATION; ONSET; CANCER; DEATH; AGE AB Aims and background: The phenotypic expression of different APC mutations in familial adenomatous polyposis (FAP) is variable: two to three variants of the disease have been defined based on the severity of colonic manifestations, Age of onset and number of polypectomies per person-year of postsurgical follow-up were compared in two FAP families with very close mutation sites in the APC gene, in order to ascertain mutation-specific variation of expressivity. Families and APC mutations: Family A (5 patients) carried a newly characterized mutation, a four bp deletion at codon 843. Family B (5 patients) carried a previously identified mutation at codon 835, Results: Mean age of onset was 49.7 years in family A and 30.5 years in family B; number of polypectomies per person-year of follow-up was 1.05 for family A and 10.1 for family B (P<0.001). Conclusions: There is significant variation of expressivity (allelic heterogeneity) in FAP between two mutations separated by only eight codons, located at the 5' extremity of APC gene exon 15. C1 Ist Nazl Studio & Cura Tumori, Italian Polyposis Registry, I-20133 Milan, Italy. Ist Nazl Ric Canc, I-16132 Genoa, Italy. Univ Pisa, Ist Chirurg Gen & Sperimentale, Pisa, Italy. Univ Cincinnati, Coll Med, Cincinnati, OH USA. RP Presciuttini, S (reprint author), Natl Human Genome Res Inst, 333 Cassel Dr, Baltimore, MD 21224 USA. NR 20 TC 6 Z9 6 U1 0 U2 0 PU PENSIERO SCIENTIFICO EDITOR PI ROME PA VIA BRADANO 3/C, 00199 ROME, ITALY SN 0300-8916 J9 TUMORI JI Tumori PD JAN-FEB PY 1999 VL 85 IS 1 BP 28 EP 31 PG 4 WC Oncology SC Oncology GA 204BH UT WOS:000080742700006 PM 10228493 ER PT S AU Duyn, JH AF Duyn, JH BE Naruse, S Watari, H TI Burst imaging SO ULTRAFAST MAGNETIC RESONANCE IMAGING IN MEDICINE SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT International Symposium on Ultrafast Magnetic Resonance Imaging in Medicine (ISUM 99) CY JAN 27-29, 1999 CL KYOTO, JAPAN SP Japan Soc Magnet Resonance Med ID FREQUENCY-SHIFTED BURST; SEQUENCE; NMR; MRI; EXCITATION; ECHOES; SSFP C1 NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Duyn, JH (reprint author), NIH, Lab Diagnost Radiol Res, Bldg 10,Room B1N256,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 34 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-50280-7 J9 INT CONGR SER PY 1999 VL 1192 BP 49 EP 54 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA BP49P UT WOS:000085322100007 ER PT S AU Balaban, RS Epstein, FH Wen, H Aletras, AH Arai, AE AF Balaban, RS Epstein, FH Wen, H Aletras, AH Arai, AE BE Naruse, S Watari, H TI High speed cardiac MRI SO ULTRAFAST MAGNETIC RESONANCE IMAGING IN MEDICINE SE INTERNATIONAL CONGRESS SERIES LA English DT Proceedings Paper CT International Symposium on Ultrafast Magnetic Resonance Imaging in Medicine (ISUM 99) CY JAN 27-29, 1999 CL KYOTO, JAPAN SP Japan Soc Magnet Resonance Med ID SIGNAL-TO-NOISE; 4 T; PHASED-ARRAY; IN-VIVO; 1.5 T; CONTRAST; HEART; FIELD AB The motion of the heart coupled with the rapid transverse relaxation rate of heart water, limits the type of MRI acquisitions that can be performed. In general, the amount of time that can be spent in the transverse plane, 10's of milliseconds, is much shorter than for most tissues or structures. The latest high performance gradient systems and development of segmented imaging schemes has provided MRI approaches that have overcome many of these limitations. Very short TE gradient recalled echo sequences collecting data in a cine mode provide a rapid method for imaging the whole heart over the entire cardiac cycle. Fast spin echo techniques overcome the short T-2* values in the chest using refocusing pulses and provide very high resolution images of the cardiac anatomy. Stimulated echo imaging techniques, that store magnetization along the longitudinal axis, have also recently been revived due to the rapid gradient performance reducing intra-voxel dephasing. Using stimulated echoes new methods of collecting high-resolution displacement measurements have been developed. Segmented linear (EPI) and spiral k-space trajectories are providing very rapid methods of covering the entire myocardium for functional, perfusion and angiographic purposes. With these new applications, MRI is quickly moving to become a mainstream-imaging tool in the study of the heart. C1 NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20817 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, NIH, Bldg 10, Bethesda, MD 20817 USA. NR 19 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA SARA BURGERHARTSTRAAT 25, PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0531-5131 BN 0-444-50280-7 J9 INT CONGR SER PY 1999 VL 1192 BP 309 EP 316 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA BP49P UT WOS:000085322100054 ER PT B AU Shatkay, H AF Shatkay, H BE Laskey, KB Prade, H TI Learning hidden Markov models with geometrical constraints SO UNCERTAINTY IN ARTIFICIAL INTELLIGENCE, PROCEEDINGS LA English DT Proceedings Paper CT 15th Conference on Uncertainty in Artificial Intelligence CY JUL 30-AUG 01, 1999 CL ROYAL INST TECHNOL, STOCKHOLM, SWEDEN SP AT&T Labs, Fair, Isaac & Co Inc, Hewlett Packard Co, Hugin Expert A/S, Informat Extract & Transport Inc, Knowledge Ind, Microsoft Res, Norsys Software Corp, Rockwell Int HO ROYAL INST TECHNOL AB Hidden Markov models (HMMs) and partially observable Markov decision processes (POMDPs) form a useful tool for modeling dynamical systems. They are particularly useful for representing environments such as road networks and office buildings, which are typical for robot navigation and planning. The work presented here is concerned with acquiring such models. We demonstrate how domain-specific information and constraints can be incorporated into the statistical estimation process, greatly improving the learned models in terms of the model quality, the number of iterations required for convergence and robustness to reduction in the amount of available data. We present new initialization heuristics which can be used even when the data suffers from cumulative rotational error, new update rules for the model parameters, as an instance of generalized EM, and a strategy for enforcing complete geometrical consistency in the model. Experimental results demonstrate the effectiveness of our approach for both simulated and real robot data, in traditionally hard-to-learn environments. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Shatkay, H (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. NR 25 TC 0 Z9 0 U1 0 U2 0 PU MORGAN KAUFMANN PUB INC PI SAN FRANCISCO PA 340 PINE STR, 6TH FLR, SAN FRANCISCO, CA 94104-3205 USA BN 1-55860-614-9 PY 1999 BP 602 EP 611 PG 10 WC Computer Science, Artificial Intelligence SC Computer Science GA BQ80C UT WOS:000089548100068 ER PT S AU Huff, J AF Huff, J BE Bailer, AJ Maltoni, C Bailar, JC Belpoggi, F Brazier, JV Soffritti, M TI Long-term chemical carcinogenesis bioassays predict human cancer hazards - Issues, controversies, and uncertainties SO UNCERTAINTY IN THE RISK ASSESSMENT OF ENVIRONMENTAL AND OCCUPATIONAL HAZARDS SE ANNALS OF THE NEW YORK ACADEMY OF SCIENCES LA English DT Article; Proceedings Paper CT International Workshop on Uncertainty in the Risk Assessment of Environmental and Occupational Hazards CY SEP 24-26, 1998 CL BOLOGNA, ITALY SP European Fdn Oncol & Environm Sci B Ramazzini, Int Stat Inst, Miami Univ, Univ Chicago, Natl Ctr Toxicol Res, NIEHS, NIOSH, Akzo Nobel NV, Reg Agcy Prevent & Envoronm, Agcy Tox Subst & Dis Registry, Collegium Ramazzini, DSM ID NATIONAL TOXICOLOGY PROGRAM; LIVER-TUMOR INDUCTION; HAMSTER EMBRYO CELLS; MAJOR RISK FACTOR; B6C3F(1) MICE; DRINKING-WATER; RODENT CARCINOGENICITY; EXPERIMENTAL-ANIMALS; RAS PROTOONCOGENE; NTP CHEMICALS AB Long-term carcinogenesis bioassays are the most valued and predictive means for identifying potential carcinogenic hazards of various agents to humans. Agents mag: be chemicals, chemical mixtures, multiple chemicals, combinations of chemicals, residues and contaminants, commercial products and formulations, and various exposure circumstances, Life-styles, dietary factors, and occupational exposure circumstances are very difficult, but not totally impossible, to evaluate experimentally. Historically, the first chemical bioassay took place in the early part of this century: Yamagiwa and Ichikawa(1) in 1915, showed that coal tar applied experimentally to rabbit ears caused skin carcinomas. Since then, nearly 1500-2000 bioassays of one sort or another have been carried out. Importantly, however, some of these bioassays must be considered inadequate for judging the absence of carcinogenicity, since there were various limitations on the wag they Here performed: tao few animals, too short a duration, too low exposure concentrations, too limited pathology, as examples. Thus, each bioassay must be critically evaluated, especially those reported to be negative, because "false negatives" are certainly more hazardous to human health than are "false positives". Likewise, one must be careful not to discount bioassay results simply because a target organ in rodents may not have a direct counterpart in humans (e.g., Zymbal glands(2)), or because an organ site in rodents may not be a major site of cancers in humans (e.g., mouse liver). The design and conduct of a bioassay is not simple, however, and one must be fully aware of possible pitfalls as well as viable and often necessary alternatives. Simiiarly, evaluating results and interpreting findings must be approached with the utmost objectivity and consistency. These and other select issues, controversies, and uncertainties possibly encountered in long-term bioassays are covered in this paper. One fact remains abundantly clear: for every known human carcinogen that has been tested adequately in laboratory animals, the findings of carcinogenicity are concordant. C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. NR 169 TC 71 Z9 72 U1 0 U2 2 PU NEW YORK ACAD SCIENCES PI NEW YORK PA 2 EAST 63RD ST, NEW YORK, NY 10021 USA SN 0077-8923 BN 1-57331-236-3 J9 ANN NY ACAD SCI JI Ann.NY Acad.Sci. PY 1999 VL 895 BP 56 EP 79 DI 10.1111/j.1749-6632.1999.tb08077.x PG 24 WC Public, Environmental & Occupational Health; Multidisciplinary Sciences SC Public, Environmental & Occupational Health; Science & Technology - Other Topics GA BP49Z UT WOS:000085328100005 PM 10676409 ER PT J AU Senderowicz, AM Reid, R Headlee, D Abornathy, T Horti, J Lush, RM Reed, E Figg, WD Sausville, EA AF Senderowicz, AM Reid, R Headlee, D Abornathy, T Horti, J Lush, RM Reed, E Figg, WD Sausville, EA TI A phase II trial of gallium nitrate in patients with androgen-metastatic prostate cancer SO UROLOGIA INTERNATIONALIS LA English DT Article DE toxicity; vision loss; hormone, refractory; heavy metal; anemia; prostate-specific antigen; pharmacokinetics; atomic absorption spectrometry ID ANTITUMOR-ACTIVITY; BONE TURNOVER; CHEMOTHERAPY; INHIBITION; HYPERCALCEMIA; COMBINATION; CARCINOMA; LYMPHOMA AB Introduction: Due to in vitro data suggesting antitumor activity with gallium nitrate, we sought to evaluate the safety and activity in patients with androgen-independent prostate cancer. Method: Patients were eligible for this study if they had an ECOG performance status of less than or equal to 2, stage D2 metastatic prostate cancer that was progressing following combined androgen ablation (medical or surgical castration plus antiandrogen) and had failed antiandrogen withdrawal. Therapy consisted of gallium nitrate 1200 mg/m(2)/day) as a continuous infusion for 7 days, administered every 21 days, with hydration (100 ml/m(2)/h). individuals that had previously received suramin were treated at a dose of 150 mg/m(2)/day of gallium nitrate. Results: Eight patients were enrolled: 4 patients at the 200 mg/m(2)/day dose level and 4 patients at the lower dosage (150 mg/m(2)/day). One of 8 patients had a >75% decline in prostate-specific antigen (PSA), 3 patients had stable PSA values for 17, 18 and 22 weeks, and 4 patients had progression by PSA (>50% increase over baseline). Anemia requiring transfusion occurred in 5 of 8 patients (63%). Two patients (25%) developed grade 4 toxicity: 1 patient developed complete blindness with partial reversal over 12 months, and another patient had pulmonary infiltrates, hypoxemia, and fever. Serious adverse events were not correlated to prior suramin exposure, or gallium plasma concentrations (total or free), but appeared to be related to cumulative cycles of gallium nitrate. Remaining adverse events were grade 1 or 2. No patients developed renal or neurological toxicity. Conclusion: This trial was prematurely terminated because repeated administration of gallium nitrate was poorly tolerated in an elderly population with androgen-independent prostate cancer. Gallium had modest clinical activity in this disease. Copyright (C) 1999 S. Karger AG, Basel. C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Med Branch, Div Clin Sci, NIH, Bldg 10,Room 5A01, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 21 TC 9 Z9 10 U1 0 U2 0 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0042-1138 J9 UROL INT JI Urol.Int. PY 1999 VL 63 IS 2 BP 120 EP 125 DI 10.1159/000030430 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 267PG UT WOS:000084368000007 PM 10592501 ER PT S AU Devereux, TR Risinger, JI Barrett, JC AF Devereux, TR Risinger, JI Barrett, JC BE McGregor, DB Rice, JM Venitt, S TI Mutations and altered expression of human cancer genes: What they tell us about causes SO USE OF SHORT- AND MEDIUM-TERM TESTS FOR CARCINOGENS AND DATA ON GENETIC EFFECTS IN CARCINOGENIC HAZARD EVALUATION SE IARC SCIENTIFIC PUBLICATIONS LA English DT Proceedings Paper CT Workshop on the Use of Short-and Meduim-Term Tests for Carcinogens and Data on Genetic Effects in Carcinogenic Hazard Evaluation CY OCT 06-10, 1997 CL LYON, FRANCE SP US Natl Inst Environm Hlth Serv, US EPA, European Commiss ID TUMOR-SUPPRESSOR GENE; RAS ONCOGENE ACTIVATION; EPIDERMAL GROWTH-FACTOR; CELL LUNG-CANCER; FACTOR RECEPTOR GENE; HUMAN BREAST-CANCER; IN-VIVO ALTERATIONS; MISMATCH REPAIR; COLORECTAL-CANCER; SOMATIC MUTATIONS AB To understand the causes of cancer, it is necessary to elucidate the molecular basis and environmental factors that influence the carcinogenesis process. Cancers are progressive diseases characterized by the accumulation of defects in many different genes. The patterns of mutation of some genes identified in tumours suggest a direct action of chemicals binding to and altering DNA. Other cancer-associated genes may be altered as a consequence of endogenous mutagens, germ-line mutations, spontaneous mutations that occur during cell replication or increased genetic instability in precancerous cells. Recent advances in molecular biology and genetics have provided new tools and concepts for studying the causes of cancer. We know that cancers are caused by a combination of environmental and genetic factors, and the discovery of the molecular alterations that occur at various stages in different tumours is increasing our understanding of these causes. Thus, we are now beginning to discover which genes are involved, how they function normally and in tumour tissues and why cancers develop after a series of genetic and epigenetic changes in certain cells. As data from studies on cancer-associated genes have accrued, the categories of genes and molecular pathways that have been found to play a role in carcinogenesis have also increased. Genes involved in development and other normal cellular processes have been implicated in cancer. These include genes involved in signal transduction, cell cycle control, DNA repair, cell growth and differentiation (growth factors and growth factor receptors), transcriptional regulation, senescence and apoptosis. Genes involved in angiogenesis, immune regulation, cellular responses to stress, motility, adhesion and invasion are also involved, but less is known about their relationship to carcinogenesis, and these processes are not discussed in this review. The diverse nature of these categories of cancer-related genes indicates the variety of processes that must be disrupted in order for tumours to develop. Many of the genes have several functional domains, and the functions of some have only recently been proposed. In this review, we describe some of the major classes of genes implicated in human cancers and some of the major findings on genetic alterations and dysfunction in human tumours. Comparisons are made with certain rodent models. C1 NIEHS, Environm Carcinogenesis Program, Res Triangle Pk, NC 27709 USA. NR 187 TC 2 Z9 2 U1 0 U2 2 PU INT AGENCY RESEARCH CANCER PI LYONS PA 150, COURS ALBERT THOMAS, 69372 LYONS, FRANCE SN 0300-5038 BN 92-832-2146-X J9 IARC SCI PUBL JI IARC Sci. Publ. PY 1999 IS 146 BP 19 EP 42 PG 14 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA BR70V UT WOS:000167234600002 PM 10353382 ER PT S AU Sills, RC Boorman, GA Neal, JE Hong, HL Devereux, TR AF Sills, RC Boorman, GA Neal, JE Hong, HL Devereux, TR BE McGregor, DB Rice, JM Venitt, S TI Mutations in ras genes in experimental tumours of rodents SO USE OF SHORT- AND MEDIUM-TERM TESTS FOR CARCINOGENS AND DATA ON GENETIC EFFECTS IN CARCINOGENIC HAZARD EVALUATION SE IARC SCIENTIFIC PUBLICATIONS LA English DT Proceedings Paper CT Workshop on the Use of Short-and Meduim-Term Tests for Carcinogens and Data on Genetic Effects in Carcinogenic Hazard Evaluation CY OCT 06-10, 1997 CL LYON, FRANCE SP US Natl Inst Environm Hlth Serv, US EPA, European Commiss ID METHYL-N-NITROSOUREA; INDUCED LUNG-TUMORS; C-HA-RAS; MOUSE-LIVER TUMORS; SQUAMOUS-CELL CARCINOMAS; COLONIC ABERRANT CRYPTS; DNA ADDUCT FORMATION; STRAIN A/J MICE; K-RAS; ONCOGENE ACTIVATION AB Studies of carcinogenesis in rodents are valuable for examining mutagenesis in vivo. An advantage of evaluating the frequency and spectra of ras mutations in chemically induced neoplasms is that the additional data at the molecular level indicate whether the carcinogenic effect is due to the chemical and is not a spontaneous event, as illustrated by the numerous examples in Appendices 1 and 2. In addition, data on the frequency and spectra of ras mutations in spontaneous and chemically induced neoplasms clearly expand the toxicological database by providing information helpful for understanding the pathogenesis of carcinogenesis. For example: (1)ozone-induced lung neoplasms had two unique mutations, one (codon 61 K-ras CTA mutation) consistent with a direct genotoxic event and a second(codon 12 K-ras G --> T transversion) consistent with an indirect genotoxic effect; (2) isoprene-induced Harderian gland neoplasms had a unique K-ras A --> T transversion at codon 61 which provided evidence that formation of an epoxide intermediate was involved; (3) 1,3 -butadiene-induced neoplasms had a characteristic K-ras G --> C transversion mutation at codon 13 which was also consistent with a chemical-specific effect; (4) methylene chloride-induced liver neoplasms had an H-ras mutation profile at codon 61 similar to that of spontaneous tumours, suggesting that methylene chloride promotes cells with 'spontaneously initiated' ras mutations and (5) oxazepam-induced liver neoplasms had a low frequency of ras mutations, suggesting a nonmutagenic pathway of carcinogenesis. By extending the evaluation of rodent tumours to include molecular studies on ras mutation spectra and abnormalities in other cancer genes with human homologues, a number of hypotheses can be tested, allowing the most complete understanding of carcinogenesis in rodents and in potential extrapolation to the human risk situation. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 160 TC 20 Z9 20 U1 0 U2 1 PU INT AGENCY RESEARCH CANCER PI LYONS PA 150, COURS ALBERT THOMAS, 69372 LYONS, FRANCE SN 0300-5038 BN 92-832-2146-X J9 IARC SCI PUBL JI IARC Sci. Publ. PY 1999 IS 146 BP 55 EP 86 PG 16 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA BR70V UT WOS:000167234600004 PM 10353384 ER PT S AU Perantoni, AO Rice, JM AF Perantoni, AO Rice, JM BE McGregor, DB Rice, JM Venitt, S TI Mutation patterns in non-ras oncogenes and tumour suppressor genes in experimentally induced tumours SO USE OF SHORT- AND MEDIUM-TERM TESTS FOR CARCINOGENS AND DATA ON GENETIC EFFECTS IN CARCINOGENIC HAZARD EVALUATION SE IARC SCIENTIFIC PUBLICATIONS LA English DT Proceedings Paper CT Workshop on the Use of Short-and Meduim-Term Tests for Carcinogens and Data on Genetic Effects in Carcinogenic Hazard Evaluation CY OCT 06-10, 1997 CL LYON, FRANCE SP US Natl Inst Environm Hlth Serv, US EPA, European Commiss ID TRANSFORMING GROWTH-FACTOR; LIVER EPITHELIAL-CELLS; POLYMERASE CHAIN-REACTION; MULTIPLE INTESTINAL NEOPLASIA; ALPHA TRANSGENIC MICE; METHYL-N-NITROSOUREA; CONGENITAL MESOBLASTIC NEPHROMA; DIRECT SEQUENCING ANALYSIS; INDUCED MAMMARY-TUMORS; P53 POINT MUTATIONS C1 NCI, Frederick Canc Res & Dev Ctr, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NR 204 TC 0 Z9 1 U1 0 U2 1 PU INT AGENCY RESEARCH CANCER PI LYONS PA 150, COURS ALBERT THOMAS, 69372 LYONS, FRANCE SN 0300-5038 BN 92-832-2146-X J9 IARC SCI PUBL PY 1999 IS 146 BP 87 EP 122 PG 16 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA BR70V UT WOS:000167234600005 PM 10353385 ER PT S AU Tennant, RW Stasiewicz, S Mennear, J French, JE Spalding, JW AF Tennant, RW Stasiewicz, S Mennear, J French, JE Spalding, JW BE McGregor, DB Rice, JM Venitt, S TI Genetically altered mouse models for identifying carcinogens SO USE OF SHORT- AND MEDIUM-TERM TESTS FOR CARCINOGENS AND DATA ON GENETIC EFFECTS IN CARCINOGENIC HAZARD EVALUATION SE IARC SCIENTIFIC PUBLICATIONS LA English DT Proceedings Paper CT Workshop on the Use of Short-and Meduim-Term Tests for Carcinogens and Data on Genetic Effects in Carcinogenic Hazard Evaluation CY OCT 06-10, 1997 CL LYON, FRANCE SP US Natl Inst Environm Hlth Serv, US EPA, European Commiss ID HA-RAS GENE; TRANSGENIC TG.AC MICE; CELL-CYCLE CHECKPOINT; INDUCED SKIN TUMORS; P53-DEFICIENT MICE; WILD-TYPE; RODENT CARCINOGENICITY; PAPILLOMA DEVELOPMENT; INDUCED TUMORIGENESIS; ULTRAVIOLET-B C1 NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. FU NIEHS NIH HHS [N01-ES65399] NR 86 TC 18 Z9 18 U1 0 U2 0 PU INT AGENCY RESEARCH CANCER PI LYONS PA 150, COURS ALBERT THOMAS, 69372 LYONS, FRANCE SN 0300-5038 BN 92-832-2146-X J9 IARC SCI PUBL PY 1999 IS 146 BP 123 EP 150 PG 16 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA BR70V UT WOS:000167234600006 PM 10353386 ER PT J AU Fattom, A Cho, YH Chu, CY Fuller, S Fries, L Naso, R AF Fattom, A Cho, YH Chu, CY Fuller, S Fries, L Naso, R TI Epitopic overload at the site of injection may result in suppression of the immune response to combined capsular polysaccharide conjugate vaccines SO VACCINE LA English DT Article DE combination vaccines; conjugate vaccines; interference; immune response ID INFLUENZAE TYPE-B; STAPHYLOCOCCUS-AUREUS TYPE-5; ANTIBODY-RESPONSES; PNEUMOCOCCAL POLYSACCHARIDE; IMMUNOGENICITY; DIPHTHERIA; TETANUS; INFANTS; CARRIER; PERTUSSIS AB Capsular polysaccharide (CP) conjugate vaccines targeting a variety of bacterial infections are currently under development and clinical evaluation. The inclusion of multiple CP serotypes combined in a single injection is an important maneuver being evaluated. The combination of CP conjugate vaccines into a single multivalent injection may result in competition among the different components and adversely affect the immunogenicity of any individual conjugate. We observed a reduction of 30-90% in antibody responses to several serotypes in mice when immunogenicity of a 12-valent Escherichia coli (E. coli) lipopolysaccharide (LPS) conjugate vaccine was compared to the immunogenicity of each monovalent vaccine evaluated separately. A reduction of 30% was observed in the Staphylococcus aureus (S. aureus) type 8 CP antibodies when a type 8-rEPA conjugate was combined with a type 5-rEPA conjugate. S. aureus types 5 and 8-rEPA conjugates were combined with 100 mu g of either rEPA (homologous) or diphtheria toroid (DT) (heterologous) carrier proteins, and evaluated in rEPA or DT primed mice. The addition of the homologous protein resulted in a 64% reduction in type 5 CP antibodies. The heterologous protein did not affect the immunogenicity of the type 5. We postulate that the free protein competed with the conjugate and recruited most of the rEPA primed T cells. In the case of the DT conjugates, the DT targeted different populations of the T cells, thus interference was not observed. These data suggested that the epitopic load rather than the antigenic load at the site of injection caused reduced immunogenicity of the conjugates. We theorize that individual components of multivalent CP vaccines conjugated to the same carrier proteins would compete for a limited number of specific carrier protein primed T cells. This would result in one or more components being unavailable in eliciting a sufficient immune response. The use of multiple carrier proteins should be considered as an approach to reduce interference when multivalent conjugate vaccines are to be formulated into a single injection. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NABI, Walter Karakawa Microbial Pathogenesis Lab, Rockville, MD 20852 USA. NIH, LDMI, Bethesda, MD 20892 USA. RP Fattom, A (reprint author), NABI, Walter Karakawa Microbial Pathogenesis Lab, Rockville, MD 20852 USA. EM afatom@nabi.com NR 42 TC 70 Z9 74 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD JAN PY 1999 VL 17 IS 2 BP 126 EP 133 DI 10.1016/S0264-410X(98)00162-5 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 133JK UT WOS:000076683300006 PM 9987146 ER PT J AU Crowe, JE Randolph, V Murphy, BR AF Crowe, JE Randolph, V Murphy, BR TI The live attenuated subgroup B respiratory syncytial virus vaccine candidate RSV 2B33F is attenuated and immunogenic in chimpanzees, but exhibits partial loss of the ts phenotype following replication in vivo SO VIRUS RESEARCH LA English DT Article DE live attenuated vaccine; respiratory syncytial virus; chimpanzees; temperature sensitive mutant ID TEMPERATURE-SENSITIVE MUTANT; SERONEGATIVE CHIMPANZEES; COTTON RATS; IN-VITRO; INFANTS; GENE; MUTATIONS; CHILDREN; IMMUNIZATION; MUTAGENESIS AB The cold-adapted (ca), temperature-sensitive (ts) respiratory syncytial virus (RSV) subgroup B vaccine candidate, designated RSV 2B33F, was found previously to be restricted in replication, immunogenic, and protective against wild-type (wt) virus challenge in rodents and African green monkeys. We sought to investigate the level of attenuation, immunogenicity and genetic stability of this vaccine candidate in seronegative chimpanzees. The 2B33F vaccine candidate was attenuated in chimpanzees and manifested a ten- and 1000-fold restriction in replication in the upper and lower respiratory tracts respectively, compared with its wt RSV 2B parent virus. Despite this attenuation, chimpanzees immunized with RSV 2B33F were completely resistant to respiratory tract disease and virus replication upon challenge with wt virus. The ts phenotype of the RSV 2B33F mutant exhibited some alteration during replication in vivo in three of four chimpanzees tested. Virus present in nasopharyngeal swab or tracheal lavage secretions of these three chimpanzees was biologically cloned by plaque passage in Vero cells at permissive temperature. The plaque progeny retained the ts phenotype, but uniformly produced plaques at 39 and 40 degrees C to a level intermediate between that of the 2B33F input virus and the 2B wt parent virus, indicating that partial loss of the level of temperature sensitivity occurred following replication in vivo. The implications of these findings for RSV vaccine development are discussed. (C) 1999 Elsevier Science B.V. All rights reserved. C1 NIAID, Infect Dis Lab, Resp Viruses Sect, NIH, Bethesda, MD 20892 USA. Wyeth Lederle Vaccines & Pediat, Pearl River, NY 10965 USA. RP Crowe, JE (reprint author), Vanderbilt Univ, Med Ctr, Div Infect Dis, D-7235 Med Ctr N,1161 21st Ave S, Nashville, TN 37232 USA. RI Crowe, James/B-5549-2009 OI Crowe, James/0000-0002-0049-1079 NR 29 TC 10 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD JAN PY 1999 VL 59 IS 1 BP 13 EP 22 DI 10.1016/S0168-1702(98)00118-X PG 10 WC Virology SC Virology GA 166CY UT WOS:000078559700002 PM 10854162 ER PT J AU Nelson, R Schaffner, AE Li, YX Walton, MK AF Nelson, R Schaffner, AE Li, YX Walton, MK TI Distribution of GABA(c)-like responses among acutely dissociated rat retinal neurons SO VISUAL NEUROSCIENCE LA English DT Article DE retina; bipolar cell; GABA; oxonol; rat ID GABA-LIKE IMMUNOREACTIVITY; BIPOLAR CELL TERMINALS; CAT RETINA; HORIZONTAL CELLS; GANGLION-CELLS; XENOPUS OOCYTES; RECEPTOR SUBUNIT; LIPID-MEMBRANES; FUNCTIONAL-ROLE; GATED CURRENTS AB GABAergic responses of acutely dissociated rat retinal neurons, including both bipolar cells (BCs) and other, morphologically round cells (RCs), were assayed with the fluorescent (FL), voltage-sensitive probe oxonol DiBaC(4)(5). Using intensified video microscopy and simultaneous recording, GABA responses were identified in one-third of cells in a typical microscope field; of these 85% hyperpolarized (0.05-0.3 log unit FL decreases) while the remainder depolarized (0.05-0.2 log unit FL increases). GABA-sensitive cells were also TACA-sensitive (trans-4-Aminocrotonic acid), and these ligands appeared interchangeable in ability to evoke responses. In RCs, an asymmetric co-responsive pattern was observed between GABA- and muscimol-evoked events. Muscimol-sensitive RCs responded well to GABA, but not all GABA-sensitive RCs responded to muscimol. In GABA-sensitive BCs, muscimol responses were typically weak or absent. Few BCs or RCs responded to CACA (cis-4-Aminocrotonic acid). Bicuculline-resistant GABA responses occurred in similar to 80% of GABA-responsive RCs and BCs. Both bicuculline-sensitive (GABA(A)-like) and bicuculline-insensitive (GABA(C)-like) responses were resistant to picrotoxin. Although a small minority of GABA-sensitive cells hyperpolarized in response to R(+)baclofen, bicuculline-insensitive responses were not antagonized by 2-hydroxysaclofen, and were abolished in low [Cl-](o). Results suggested (1) that bicuculline-insensitive, Cl--dependent, GABA(C)-like responses were broadly distributed and predominant among dissociated rat retinal neurons; (2) that muscimol was a particularly weak agonist for rat retinal BCs; and (3) that oxonol was a sensitive probe for retinal GABA responses. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Div Clin Trial Design & Anal, OTRR, CBER, Rockville, MD 20857 USA. RP Nelson, R (reprint author), NINDS, Neurophysiol Lab, NIH, Bldg 36,Room 2C02,36 Convent Dr,MSC 4066, Bethesda, MD 20892 USA. NR 50 TC 8 Z9 8 U1 0 U2 0 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 JAN-FEB PY 1999 VL 16 IS 1 BP 179 EP 190 PG 12 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 163GV UT WOS:000078397100016 PM 10022489 ER PT J AU Torpy, DJ Stratakis, CA Chrousos, GP AF Torpy, DJ Stratakis, CA Chrousos, GP TI Hyper- and hypoaldosteronism SO VITAMINS AND HORMONES - ADVANCES IN RESEARCH AND APPLICATIONS, VOL 57 SE VITAMINS AND HORMONES-ADVANCES IN RESEARCH AND APPLICATIONS LA English DT Review ID GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM; CONGENITAL ADRENAL-HYPERPLASIA; PLASMA-RENIN ACTIVITY; HYPERALDOSTERONISM TYPE-II; EPITHELIAL SODIUM-CHANNEL; HYPORENINEMIC HYPOALDOSTERONISM; ANGIOTENSIN-II; SUPPRESSIBLE HYPERALDOSTERONISM; 11-BETA-HYDROXYLASE DEFICIENCY; HYPERRENINEMIC HYPOALDOSTERONISM C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Torpy, DJ (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. NR 156 TC 17 Z9 19 U1 2 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B STREET, SUITE 1900, SAN DIEGO, CA 92101-4495 USA SN 0083-6729 J9 VITAM HORM PY 1999 VL 57 BP 177 EP 216 PG 40 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA BM98Q UT WOS:000080337400007 PM 10232050 ER PT J AU Busch, M Chamberland, M Epstein, J Kleinman, S Khabbaz, R Nemo, G AF Busch, M Chamberland, M Epstein, J Kleinman, S Khabbaz, R Nemo, G TI Oversight and monitoring of blood safety in the United States SO VOX SANGUINIS LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSFUSION-TRANSMITTED VIRUSES; FROZEN WHOLE-BLOOD; NON-A; POSTTRANSFUSION HEPATITIS; INFECTION; RISK; DONORS; HIV-1; TRANSMISSION AB The US blood safety vigilance system is composed of a network of interwoven programs, now organized under a formal structure, with the Assistant Secretary of Health and DHHS Blood Safety Committee bearing overall responsibility. It takes advantage of the breadth of expertise and close collaborative relationship of transfusion medicine and infectious disease scientists within and outside of the government. Core elements include an array of ongoing surveillance programs for monitoring established as well as new and emerging infectious agents that may pose a risk to blood safety, and the existence of historical and contemporary repositories of donor and recipient specimens that enable rapid investigation of putative new risks. This report summarizes the historical events that shaped the US blood safety oversight system, reviews the current organization and decision-making processes related to blood safety issues, and highlights key surveillance systems and research programs which monitor the US and global blood supplies for known and potential emerging risks. C1 Blood Ctr Pacific, Res Serv, San Francisco, CA 94118 USA. Blood Ctr Pacific, Sci Serv, San Francisco, CA 94118 USA. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Div Viral & Rickettsial Dis, AIDS Program, Atlanta, GA USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. Univ British Columbia, Victoria, BC, Canada. Westat Inc, Rockville, MD USA. NHLBI, US Natl Inst Hlth, Div Blood Dis & Resources, Bethesda, MD 20892 USA. RP Busch, M (reprint author), Blood Ctr Pacific, Res Serv, 270 Masonic Ave, San Francisco, CA 94118 USA. NR 62 TC 30 Z9 31 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PY 1999 VL 77 IS 2 BP 67 EP 76 DI 10.1159/000031079 PG 10 WC Hematology SC Hematology GA 242BV UT WOS:000082919100001 PM 10516550 ER PT J AU Soubes, SC Reid, ME Kaneko, O Miller, LH AF Soubes, SC Reid, ME Kaneko, O Miller, LH TI Search for the sialic acid-independent receptor on red blood cells for invasion by Plasmodium falciparum SO VOX SANGUINIS LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; MALARIA PARASITES; GLYCOPHORIN-A; MONOCLONAL-ANTIBODIES; INVADE ERYTHROCYTES; FLOW-CYTOMETRY; HETEROGENEITY; EXPRESSION; MEMBRANE; BINDING AB Objectives: Plasmodium falciparum uses multiple red blood cell (RBC) receptors and parasite ligands to invade RBCs, One pathway uses a sialic acid-independent protein or carbohydrate for invasion. The present study searches for this RBC receptor, Materials and Methods: We determined whether antigen-negative and null RBCs (including PNH cells that lack all glycosylphosphatidyl inositol-linked proteins) could be invaded after neuraminidase treatment. We used two P falciparum clones for the study: one that requires sialic acid for invasion and was an indication of removal of sialic acid and a second clone that can invade neuraminidase-treated RBCs, Results: All neuraminidase-treated variant RBCs in this study were invaded. Conclusion: This study indicates that some molecule other than those studied (e.g., a carbohydrate) is the receptor for the sialic acid-independent pathway. This powerful tool for the identification of receptors for microorganisms should be used more extensively. C1 NIAID, NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. New York Blood Ctr, Immunohematol Lab, New York, NY 10021 USA. RP Miller, LH (reprint author), NIAID, NIH, Parasit Dis Lab, 4 Ctr Dr,Room 126, Bethesda, MD 20892 USA. NR 36 TC 10 Z9 11 U1 1 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PY 1999 VL 76 IS 2 BP 107 EP 114 DI 10.1159/000031029 PG 8 WC Hematology SC Hematology GA 179YQ UT WOS:000079358300007 PM 10085527 ER PT J AU Gomberg, ESL Siefert, K de la Rosa, IA AF Gomberg, ESL Siefert, K de la Rosa, IA TI Nonfamilial roles of alcoholic women in treatment SO WOMEN & HEALTH LA English DT Article DE alcoholism; workplace; women's health; women's health services; age factors; education; case-control studies ID EMPLOYEE ASSISTANCE PROGRAMS; CONSUMPTION; MEN; DEPRESSION; DRINKING; WORK; ATTITUDES; ABUSE AB This study compared the educational achievement and employment-related experiences of a sample of 301 alcoholic women in treatment with 137 non-alcoholic matched controls. Alcoholic women were significantly more likely than controls to marry at a younger age and have their first child earlier, had less education, and were more likely to be employed in blue collar settings than non-alcoholic women. Alcoholic women were significantly Less likely to be working outside the home, and employed alcoholic women were more likely to report boredom in the workplace than employed non-alcoholic women. The lives of alcoholic women include more than their familial roles. More attention to issues of education, employment, and occupational status on the part of health care providers is needed. C1 Univ Michigan, Alcohol Res Ctr, Dept Psychiat, Ann Arbor, MI 48108 USA. Univ Michigan, Alcohol Res Ctr, Sch Social Work, Ann Arbor, MI 48108 USA. Univ Michigan, NIMH, Ctr Poverty Risk & Mental Hlth, Sch Social Work, Ann Arbor, MI 48108 USA. RP Gomberg, ESL (reprint author), Univ Michigan, Alcohol Res Ctr, Dept Psychiat, 400 E Eisenhower Pkwy,Suite 2A, Ann Arbor, MI 48108 USA. NR 31 TC 0 Z9 0 U1 0 U2 0 PU HAWORTH PRESS INC PI BINGHAMTON PA 10 ALICE ST, BINGHAMTON, NY 13904-1580 USA SN 0363-0242 J9 WOMEN HEALTH JI Women Health PY 1999 VL 29 IS 1 BP 73 EP 88 PG 16 WC Public, Environmental & Occupational Health; Women's Studies SC Public, Environmental & Occupational Health; Women's Studies GA 214XF UT WOS:000081352300006 PM 10427642 ER PT B AU Pinn, VW Chunko, MT Manolio, T AF Pinn, VW Chunko, MT Manolio, T BE Paoletti, R Crosignani, PG Kenemans, P Wenger, NK Jackson, AS TI Women's health and menopause epidemiology: The USA experience SO WOMEN'S HEALTH AND MENOPAUSE: RISK REDUCTION STRATEGIES - IMPROVED QUALITY OF HEALTH SE MEDICAL SCIENCE SYMPOSIA SERIES LA English DT Proceedings Paper CT 3rd International Symposium on Womens Health and Menopause CY JUN 13-16, 1998 CL FLORENCE, ITALY ID POSTMENOPAUSAL ESTROGEN USE; CARDIOVASCULAR RISK-FACTORS; REPLACEMENT THERAPY; DISEASE; POPULATION; MORTALITY; AGE C1 NIH, Off Res Womens Hlth, Bethesda, MD 20892 USA. RP Pinn, VW (reprint author), NIH, Off Res Womens Hlth, Bldg 1,Room 201,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 27 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS BN 0-7923-5906-2 J9 MED SCI SYMP SER PY 1999 VL 13 BP 157 EP 164 PG 8 WC Endocrinology & Metabolism; Geriatrics & Gerontology; Obstetrics & Gynecology SC Endocrinology & Metabolism; Geriatrics & Gerontology; Obstetrics & Gynecology GA BP50J UT WOS:000085341300023 ER PT J AU Banerjee, HN Verma, M Hou, LH Ashraf, M Dutta, SK AF Banerjee, HN Verma, M Hou, LH Ashraf, M Dutta, SK TI Cytotoxicity of TNT and its metabolites SO YALE JOURNAL OF BIOLOGY AND MEDICINE LA English DT Article AB The production and storage of explosives has resulted in the environmental accumulation of 2,4,6-trinitrotoluene (TNT). The biotransformation products of the nitroaromatic compound TNT and metabolites in mammalian cells in culture and their cytotoxicity are studied. We report after our analysis by reverse phase high performance liquid chromatography (HPLC) that the most prevalent biotransformation product of TNT in the NG108 neuroblastoma cells is primarily monoamino-dini-trotoluene (2Am-DNT). It causes toxic effects based on trypan blue exclusion: and LDH-release colorimetric assays. C1 Howard Univ, Dept Biol, Mol Genet Lab, Washington, DC 20059 USA. Howard Univ, Canc Res Ctr, Washington, DC 20059 USA. NIAID, NIH, Bethesda, MD 20892 USA. Howard Univ, Dept Biol, Parasitol Lab, Washington, DC 20059 USA. RP Banerjee, HN (reprint author), Howard Univ, Dept Biol, Mol Genet Lab, 415 Coll St NW, Washington, DC 20059 USA. FU NIGMS NIH HHS [S06-GM08016] NR 4 TC 17 Z9 17 U1 0 U2 8 PU YALE J BIOL MED INC PI NEW HAVEN PA 333 CEDAR ST, NEW HAVEN, CT 06510 USA SN 0044-0086 J9 YALE J BIOL MED JI Yale J. Biol. Med. PD JAN-FEB PY 1999 VL 72 IS 1 BP 1 EP 4 PG 4 WC Biology; Medicine, General & Internal; Medicine, Research & Experimental SC Life Sciences & Biomedicine - Other Topics; General & Internal Medicine; Research & Experimental Medicine GA 281QX UT WOS:000085173200001 PM 10691043 ER PT J AU Joshi, M Fragata, M AF Joshi, M Fragata, M TI Heat-induced changes in the photochemical centres and the protein secondary structures of photosystem II studied by variable fluorescence and difference FT-IR spectroscopy SO ZEITSCHRIFT FUR NATURFORSCHUNG C-A JOURNAL OF BIOSCIENCES LA English DT Article DE FT-IR spectroscopy; heat inactivation; photosystem II; thermal transitions; variable fluorescence ID TRANSFORM INFRARED-SPECTROSCOPY; SPINACH CHLOROPLAST MEMBRANES; OXYGEN-EVOLVING COMPLEX; THYLAKOID MEMBRANES; DENATURATION TRANSITION; IDENTIFICATION; TEMPERATURE; EVOLUTION; INACTIVATION; MANGANESE AB Variable fluorescence (F-v), i.e., F-v = F-m - F-o where F-o is the minimal fluorescence and F-m the maximum fluorescence, and difference Fourier transform infrared (FT-IR) spectroscopy were used to study the effect of heat stress in the 25-55 degrees C range on photosystem II (PSII) structure and function. First, the F-v intensity reflects accurately the changes in the number of open photochemical centers in PSII. Secondly, the use of F-v in combination with FT-IR spectroscopy can disclose structure-function correlations in the heat inactivation of the PSII complex. Analysis of the midpoint temperatures of thermal denaturation, i.e., 50% inactivation, reported so far in investigations of the thylakoid membrane components has revealed that most of the thermal transitions attributed to PSII are in the 39-46 degrees C range. In this work, it is shown specifically that the midpoint temperature of PSII inactivation is at about 40 degrees C. Moreover, it was clearly demonstrated that the heat-induced changes above 40 degrees C are the result of a marked decrease in the number of open photochemical centers in PSII. It was also seen that above this same temperature the loss of photochemical centers has its structural counterpart in overall modifications of the secondary structures of the PSII proteins resulting from the decrease in the alpha-helix content concomitant with the increase in extended chain (beta-strand) conformations. In brief, a novel finding reported here is that the number of open photochemical centers in PSII is dependent on a dynamic equilibrium between the contents of the PSII proteins in alpha-helix and extended chains (beta-strands), but not in beta-sheets and beta-turn structures except for the antiparallel-beta-sheet conformations. This therefore associates the thermal inactivation of the photochemical centers in photosystem II with distinct conformational changes in the proteins of the PSII supramolecular complex. In the particular context of the present study, these findings constitute a significant contribution to the investigation of structure-function correlations in the photosynthetic membrane. In a broader context, this information might be essential for the comprehension of the molecular arrangements or local structure order that are involved directly or indirectly in biological catalysis. C1 Univ Quebec, Dept Chim & Biol, Chim Sect, Trois Rivieres, PQ G9A 5H7, Canada. NHLBI, NIH, Bethesda, MD 20892 USA. Univ Quebec, Grp Rech Energie & Informat Biomol, Trois Rivieres, PQ G9A 5H7, Canada. RP Fragata, M (reprint author), Univ Quebec, Dept Chim & Biol, Chim Sect, Trois Rivieres, PQ G9A 5H7, Canada. NR 33 TC 6 Z9 6 U1 0 U2 2 PU VERLAG Z NATURFORSCH PI TUBINGEN PA POSTFACH 2645, W-7400 TUBINGEN, GERMANY SN 0939-5075 J9 Z NATURFORSCH C JI Z.Naturforsch.(C) PD JAN-FEB PY 1999 VL 54 IS 1-2 BP 35 EP 43 PG 9 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 173MU UT WOS:000078985000006 PM 10097406 ER PT J AU Kim, SY Bae, CD AF Kim, SY Bae, CD TI Calpain inhibitors reduce the cornified cell envelope formation by inhibiting proteolytic processing of transglutaminase 1 SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE calpain inhibitor; transglutaminase 1; cornified envelope ID TERMINAL DIFFERENTIATION; TISSUE TRANSGLUTAMINASE; EPIDERMAL-KERATINOCYTES; GUINEA-PIG; MEMBRANE; ENZYME; ACTIVATION; EXPRESSION; DELETION; DISTINCT AB Calpain I (mu-calpain) and II (m-calpain) are well known calcium-activated neutral cysteine proteases. Many reports have shown that activation of calpain is related to cataract formation, neuronal degeneration, blood clotting, ischemic injuries, muscular dystrophy and cornified cell envelope (CE) formation. Here, we report that insoluble CE formation was reduced after treatment with calpain I inhibitor (N-acetyl-leucyl-leucyl-norleucinal) on normal human epidermal keratinocytes (NHEK), whereas serine and thiol protease inhibitors had no effect on the reduction of CE. When NHEK cells were confluent, keratinocytes were treated with Various concentrations (0.5 mu M - 0.5 mM) of calpain I inhibitor or serine and thiol protease inhibitors under calcium induced differentiation. Insoluble CE formation was reduced about 90 % in the 50 mu M calpain inhibitor I treated group by day 9 of culture, whereas insoluble CE was reduced only 10 % in the same condition. Interestingly TGase activity was blocked by 90 % in the 0.5 mM calpain inhibitor treated group within 72 h, whereas TGase activity was retained by 80 % in the 0.5 mM serine protease inhibitor treated group at 7 day treatment. Therefore it can be suggested that cysteine protease calpains might be responsible for the activation of the TGase 1 enzyme to complete insoluble CE formation during epidermal differentiation. C1 Hallym Univ, Coll Med, Dept Biochem, Chunchon 200702, Kangwondo, South Korea. NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. EM cdbae@sun.hallym.ac.kr NR 29 TC 23 Z9 24 U1 0 U2 1 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD DEC 31 PY 1998 VL 30 IS 4 BP 257 EP 262 PG 6 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 155PJ UT WOS:000077955300013 PM 9894158 ER PT J AU Daly, JW AF Daly, JW TI Bernard Witkop - A chemist in a biomedical institute SO HETEROCYCLES LA English DT Biographical-Item C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0385-5414 J9 HETEROCYCLES JI Heterocycles PD DEC 31 PY 1998 VL 49 BP 5 EP 8 PG 4 WC Chemistry, Organic SC Chemistry GA 169YP UT WOS:000078777900002 ER PT J AU Coop, A Rice, KC AF Coop, A Rice, KC TI A novel synthesis of thebaine from codeine SO HETEROCYCLES LA English DT Article ID MORPHINE ALKALOIDS AB Codeine was converted into thebaine through methylation of the enolate of codeinone. C1 NIDDKD, Med Chem Lab, Bethesda, MD 20892 USA. RP Coop, A (reprint author), NIDDKD, Med Chem Lab, Bldg 8,Rm B1-23, Bethesda, MD 20892 USA. NR 20 TC 8 Z9 8 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0385-5414 J9 HETEROCYCLES JI Heterocycles PD DEC 31 PY 1998 VL 49 BP 43 EP 47 PG 5 WC Chemistry, Organic SC Chemistry GA 169YP UT WOS:000078777900007 ER PT J AU Tokuyama, T Shimada, A Garraffo, HM Spande, TF Daly, JW AF Tokuyama, T Shimada, A Garraffo, HM Spande, TF Daly, JW TI The isolation and structure of the novel cis-fused indolizidine 249H from frog skin: cis- vs. trans-fused indolizidines distinguished by NMR SO HETEROCYCLES LA English DT Article ID ENANTIOSELECTIVE SYNTHESIS; STEREOSELECTIVE SYNTHESIS; (+/-)-INDOLIZIDINES 167B; (-)-INDOLIZIDINE 209B; ALKALOIDS; 205A; 207A AB A 5,6,8-trisubstituted indolizidine structure (1) is proposed for alkaloid 249H isolated from dendrobatid frogs based upon NMR and IR spectroscopy and MS spectrometry. It has an unusual (E)-3-hexen-3-yl side-chain, the first branched substituent reported among the simple indolizidines from frog skin, an unusual cis-fused indolizidine ring and finally an atypical E configuration of H-5 relative to H-9. C1 Osaka City Univ, Fac Sci, Osaka 558, Japan. Takara Shuzo Co Ltd, Shiga 5250052, Japan. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tokuyama, T (reprint author), 2-8-16 Daido, Osaka 543, Japan. NR 15 TC 5 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0385-5414 J9 HETEROCYCLES JI Heterocycles PD DEC 31 PY 1998 VL 49 BP 427 EP 436 PG 10 WC Chemistry, Organic SC Chemistry GA 169YP UT WOS:000078777900054 ER PT J AU Pei, XF Greig, NH Brossi, A AF Pei, XF Greig, NH Brossi, A TI Syntheses and biological evaluation of (+/-)-3a-phenyl congeners of physostigmine and phenserine SO HETEROCYCLES LA English DT Article ID ANTICHOLINESTERASE ACTIVITY; ALZHEIMERS-DISEASE; CARBAMATE ANALOGS; INHIBITORS; BUTYRYLCHOLINESTERASE; ACETYLCHOLINESTERASE AB (+/-)3a-Phenyl congeners of physostigmine and phenserine, synthesized for the first time by a modification of the Julian total synthesis of physostigmine, were evaluated for anticholinesterase action against human acetyl- and butyrylcholinesterase. These analogues were found to lack cholinesterase inhibitory activity, demonstrating that sterically bulky substitution at the 3a position is poorly tolerated. C1 NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. RP Greig, NH (reprint author), NIA, Cellular & Mol Biol Lab, NIH, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 21 TC 9 Z9 9 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0385-5414 J9 HETEROCYCLES JI Heterocycles PD DEC 31 PY 1998 VL 49 BP 437 EP 444 PG 8 WC Chemistry, Organic SC Chemistry GA 169YP UT WOS:000078777900055 ER PT J AU Yang, FQ Zhang, TY Zhang, R Ito, Y AF Yang, FQ Zhang, TY Zhang, R Ito, Y TI Application of analytical and preparative high-speed counter-current chromatography for separation of alkaloids from Coptis chinensis Franch SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Coptis chinensis Franch; high-speed counter-current chromatography; alkaloids ID THERMOSPRAY MASS-SPECTROMETRY; COIL PLANET CENTRIFUGE; NATURAL-PRODUCTS AB Analytical high-speed counter-current chromatography (HSCCC) was used for the systematic selection and optimization of the two-phase solvent system to separate alkaloids from Coptis chinensis Franch. The optimum solvent system thus obtained led to the successful separation of alkaloids from C. chinensis Franch by preparative HSCCC. One batch separation yielded four pure alkaloids, including palmatine, berberine, epiberberine and coptisine from the crude alkaloid extract. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Beijing Inst New Technol Applicat, Beijing 100035, Peoples R China. Beijing Union Univ, Chem Engn Coll, Beijing 100029, Peoples R China. RP Ito, Y (reprint author), NHLBI, Biophys Chem Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 18 TC 76 Z9 87 U1 2 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD DEC 31 PY 1998 VL 829 IS 1-2 BP 137 EP 141 DI 10.1016/S0021-9673(98)00776-6 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 157UN UT WOS:000078080200010 PM 9923080 ER PT J AU Liu, QY Schaffner, AE Chang, YH Barker, JL AF Liu, QY Schaffner, AE Chang, YH Barker, JL TI Astrocyte-conditioned saline supports embryonic rat hippocampal neuron differentiation in short-term cultures SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE astrocyte; hippocampal neuron; rat; development; neurotransmitter receptor; GABA; glycine; glutamate ID CELLS AB Embryonic rat hippocampal neurons were cultured for 1-2 days in serum-free, HERES-buffered Tyrode's solution. The effects of cortical astrocytes and astrocyte-conditioned saline on neuron survival, membrane surface area and the expression of functional amino acid neurotransmitter receptors were studied. Neurons grown in Tyrode's solution alone survived well for 1 day but deteriorated thereafter both in terms of percent neurons surviving and the amplitudes and densities of GABA-, glycine-, kainate- and NMDA-induced currents. Neurons grown in Tyrode's previously conditioned by astrocytes for 24 h had significantly larger apparent plasma membrane surface area, as indexed by whole-cell membrane capacitance, and larger amplitudes and densities of the amino acid-induced currents after both 1 and 2 days. The survival rate and neurite outgrowth were also greater in the astrocyte-conditioned saline group after 2 days in culture. Similarly, neurons cultured on glass cover-slips facing a confluent monolayer of astrocyte were larger in apparent plasma membrane area and amino acid-induced currents than neurons cultured in Tyrode's alone. Neurons cultured in saline conditioned by astrocytes provide a strategy to study the physiological basis of astrocyte-directed neuronal differentiation in the absence of ambiguities arising from the inclusion of sera and other additives often used in vitro. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Liu, QY (reprint author), NINDS, Neurophysiol Lab, NIH, Bldg 36 Rm 2C02,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 8 TC 7 Z9 7 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD DEC 31 PY 1998 VL 86 IS 1 BP 71 EP 77 DI 10.1016/S0165-0270(98)00146-0 PG 7 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 153ZB UT WOS:000077862600008 PM 9894787 ER PT J AU Jun, D Park, HK Nordin, AA Nagel, JE Kim, YH AF Jun, D Park, HK Nordin, AA Nagel, JE Kim, YH TI Characterization of the murine cdc2 gene SO MOLECULES AND CELLS LA English DT Article DE cDNA sequence; genomic structure; murine cdc2; promoter activity ID CELL-CYCLE CONTROL; MATURATION-PROMOTING FACTOR; PROTEIN-KINASE; C-MYC; MAMMALIAN-CELLS; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; FUNCTIONAL-ANALYSIS; DEPENDENT KINASE-2; BINDING PROTEIN AB A 1204 bp full-length cDNA encoding murine cdc2 was isolated and used as a probe to obtain four overlapping cdc2 genomic clones which span the entire cdc2 sequence. Characterization of these clones revealed that the cdc2 mRNA is distributed over 28 kb and in 8 exons ranging in size from 63 to similar to 303 bp, Since the 5'-untranslated sequence is interrupted by intron 1, the initiation codon is located in exon 2, The PSTAIRE region is in exon 3, and the stop codon is in exon 8, Primer extension analysis of cdc2 mRNA isolated from immobilized anti-CD3 activated T-cells demonstrated that the murine cdc2 gene utilizes multiple transcriptional start sites, No consensus sequence for a TATA box exists at an appropriate position within the promoter region. Instead, several putative transcription factor binding sites for PEA3, CREB, C/EBP, E box factor, YY1, ATF-like, Sp1, and E2F were detected. Analysis of the promoter activity of the 5'-flanking region suggests that the sequence between -188 to -38, which possesses two Spl and one E2F motif, contains a major positive regulatory activity for the expression of murine cdc2. C1 Kyungpook Natl Univ, Dept Microbiol, Coll Nat Sci, Taegu 702701, South Korea. NIA, Immunol Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Kim, YH (reprint author), Kyungpook Natl Univ, Dept Microbiol, Coll Nat Sci, Taegu 702701, South Korea. NR 55 TC 5 Z9 6 U1 0 U2 0 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1016-8478 J9 MOL CELLS JI Mol. Cells PD DEC 31 PY 1998 VL 8 IS 6 BP 731 EP 740 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 153YA UT WOS:000077860000013 PM 9895127 ER PT J AU Lee, C Kim, MG Jeon, SH Park, DE Park, SD Seong, RH AF Lee, C Kim, MG Jeon, SH Park, DE Park, SD Seong, RH TI Two Species of mRNAs for the fyn proto-oncogene are produced by an alternative polyadenylation SO MOLECULES AND CELLS LA English DT Article DE alternative polyadenylation; fyn; Northern hybridization; protein tyrosine kinase ID PHOSPHATIDYLINOSITOL 3-KINASE; TYROSINE KINASE; T-CELLS; DOMAIN; PHOSPHORYLATION; RECEPTOR; FAMILY; GENE; NCK AB Two mRNA species with different sizes (3.8 kb and 2.8 kb) for the fyn proto-oncogene have been noticed during Northern hybridization analysis, However, the difference between the two mRNA species has not been resolved yet. By screening a phage expression library using the monoclonal antibody (mAb) B16-5 which recognizes Src homology 3 (SH3) domains of phospholipase C-gamma and Nck, we have cloned a cDNA encoding the larger species of fyn mRNA, The size of the clone was 3.5 kb and DNA sequencing analysis of the clone showed that it was fyn expressed mainly in T-cells,fyn (T), with an untranslated region 1 kb longer than the previously reported one. The 3'-end fragment of the clone hybridized only to the larger species (3.8 kb) of fyn mRNA but not to the smaller one (2.8 kb) on Northern blot analysis. Furthermore, an additional polyadenylation signal sequence was found at the end of this clone. These results indicate that the two mRNA species for fyn are produced by alternative polyadenylation. C1 Seoul Natl Univ, Inst Mol Biol & Genet, Seoul 151742, South Korea. Seoul Natl Univ, Coll Nat Sci, Dept Biol Mol, Seoul 151742, South Korea. NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Seong, RH (reprint author), Seoul Natl Univ, Inst Mol Biol & Genet, Seoul 151742, South Korea. NR 17 TC 5 Z9 6 U1 0 U2 0 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1016-8478 J9 MOL CELLS JI Mol. Cells PD DEC 31 PY 1998 VL 8 IS 6 BP 746 EP 749 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 153YA UT WOS:000077860000015 PM 9895129 ER PT J AU Johnson, RT Gibes, CJ AF Johnson, RT Gibes, CJ TI Creutzfeldt-Jakob disease and related transmissible spongiform encephalopathies SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID FATAL FAMILIAL INSOMNIA; PRION DISEASES; PERSON TRANSMISSION; CEREBROSPINAL-FLUID; MINK ENCEPHALOPATHY; HUMAN-BLOOD; VARIANT; SCRAPIE; PROTEIN; MICE C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Natl Neurosci Inst Singapore, Singapore, Singapore. NIH, Cent Nervous Syst Studies Lab, Bethesda, MD 20892 USA. RP Johnson, RT (reprint author), Johns Hopkins Hosp, Meyer 6-181, Baltimore, MD 21287 USA. NR 82 TC 191 Z9 200 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 31 PY 1998 VL 339 IS 27 BP 1994 EP 2004 DI 10.1056/NEJM199812313392707 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 152XX UT WOS:000077803800007 PM 9869672 ER PT J AU Breman, JG Henderson, DA AF Breman, JG Henderson, DA TI Poxvirus dilemmas - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID HIV C1 NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 21205 USA. RP Breman, JG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 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 DEC 31 PY 1998 VL 339 IS 27 BP 2027 EP 2028 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 152XX UT WOS:000077803800026 ER PT J AU Watts, RG Huang, CS Young, MR Li, JJ Dong, ZG Pennie, WD Colburn, NH AF Watts, RG Huang, CS Young, MR Li, JJ Dong, ZG Pennie, WD Colburn, NH TI Expression of dominant negative Erk2 inhibits AP-1 transactivation and neoplastic transformation SO ONCOGENE LA English DT Article DE MAP kinases; transcription factors; tumor promotion; neoplastic transformation ID ACTIVATED PROTEIN-KINASE; SERUM RESPONSE ELEMENT; PROMOTER-INDUCED TRANSFORMATION; SIGNAL-REGULATED KINASES; GROWTH-FACTOR RECEPTOR; C-FOS EXPRESSION; TERNARY COMPLEX; MAP KINASE; JB6 CELLS; S6 KINASE AB The mitogen activated protein (MAP) kinases or extracellular signal-regulated kinases (Erks) are activated in response to Ras expression or exposure to tumor promoters or to growth factors, and have been implicated in AP-I transactivation in some models. We have shown that tumor promoter induced activation of the transcription factor AP-1 is required for induced neoplastic transformation in the Balb/C JB6 cell model. Jun and Fos family protein levels have been found not to be limiting for AP-l response. The present study asks whether activation of Erks1 and 2 is required for AP-1 transactivation and transformation of JB6 cells and whether Erks might be targeted for cancer prevention. Expression of either of two different dominant negative kinase inactive Erk2 mutants in transformation sensitive (P+) JB6 cells substantially inhibited the tumor promoter induced activation of Erks1 and 2 and of AP-I measured by a collagenase-luciferase reporter. Multiple mutant Erk2 expressing clonal lines were also rendered non-responsive to induced neoplastic transformation. These observations, together with our recent finding attributing AP-1 non-responsiveness to Erk deficiency in a clonal line of transformation resistant (P-) cells, argue for a requirement for Erks1 and/or 2 activation in AP-1 transactivation in the mouse JB6 neoplastic progression model, and suggest the utility of Erks as a prevention target. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Biochem Pathol, Frederick, MD 21702 USA. Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. RP Colburn, NH (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Biochem Pathol, Bldg 560, Frederick, MD 21702 USA. NR 45 TC 102 Z9 103 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 31 PY 1998 VL 17 IS 26 BP 3493 EP 3498 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 157XD UT WOS:000078086200010 PM 10030673 ER PT J AU Modzelewska, B Sipowicz, MA Saavedra, JE Keefer, LK Kostrzewska, A AF Modzelewska, B Sipowicz, MA Saavedra, JE Keefer, LK Kostrzewska, A TI Involvement of K-ATP(+) channels in nitric oxide-induced inhibition of spontaneous contractile activity of the nonpregnant human myometrium SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID UTERINE CONTRACTILITY; POTASSIUM CHANNELS; PREGNANCY; ARTERY; UTERUS; HYPERPOLARIZATION; ENDOTHELIUM; ACTIVATION; CGMP AB Nitric oxide (NO), an important endogenous substance, is known to be a strong relaxant of smooth muscle, including myometrium. It has been postulated that the relaxing effect of NO on smooth muscle is achieved by the stimulation of soluble guanylyl cyclase, which leads to an increase in the cyclic guanosine 3',5'-monophosphate (cGMP) levels and hyperpolarization of the cellular membrane. The aim of our study was to investigate the involvement of K-ATP(+) channels in the mechanism of cGMP-independent nitric oxide-induced inhibition of contractile activity of the nonpregnant human myometrium, obtained at hysterectomy. Nitric oxide's influence on contractile activity was recorded in the presence of methylene blue and glybenclamide, blockers of soluble guanylyl cyclase and K-ATP(+) channels, respectively. Nitric oxide, generated by the NO donor DEA/NO, caused a dose-dependent inhibition of the spontaneous contractile activity of human nonpregnant myometrium. Preincubation with methylene blue (5 mu M) did not prevent NO-induced relaxation of uterine strips, while 1.5 mu M glybenclamide blocked this effect. Our results indicate that nitric oxide relaxes human non-pregnant uterus through K-ATP(+) channels, independent of the cGMP pathway. (C) 1998 Academic Press. C1 Inst Obstet & Gynecol, Sch Med, PL-15276 Bialystok, Poland. Dept Biophys, PL-15276 Bialystok, Poland. NCI, SAIC Frederick, Intramural Res Support Program, Federick, MD 21702 USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Federick, MD 21702 USA. RP Sipowicz, MA (reprint author), Inst Obstet & Gynecol, Sch Med, Sklodowskiej Curie 24A, PL-15276 Bialystok, Poland. RI Keefer, Larry/N-3247-2014; Modzelewska, Beata/G-8106-2016 OI Keefer, Larry/0000-0001-7489-9555; Modzelewska, Beata/0000-0002-1051-7906 NR 28 TC 18 Z9 18 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 DEC 30 PY 1998 VL 253 IS 3 BP 653 EP 657 DI 10.1006/bbrc.1998.9844 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 153RR UT WOS:000077846900018 PM 9918782 ER PT J AU Kim, M Katayose, Y Li, QD Rakkar, ANS Li, ZW Hwang, SG Katayose, D Trepel, J Cowan, KH Seth, P AF Kim, M Katayose, Y Li, QD Rakkar, ANS Li, ZW Hwang, SG Katayose, D Trepel, J Cowan, KH Seth, P TI Recombinant adenovirus expressing Von Hippel-Lindau-mediated cell cycle arrest is associated with the induction of cyclin-dependent kinase inhibitor p27(Kip1) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE VHL; p27(Kip1); adenovirus; cell cycle; gene therapy; cyclin-dependent kinase ID TUMOR-SUPPRESSOR GENE; PRODUCT; PROTEIN; GROWTH; CANCER; COMPLEX AB A recombinant adenovirus containing the Von Hippel-Lindau (VHL) cDNA was constructed (AdVHL) and used to investigate the function of this tumor suppressor gene. Exposure of renal and breast cancer cell lines to AdVHL resulted in high levels of VHL mRNA and protein. AdVHL infection resulted in G1 cell cycle arrest and growth inhibition of renal and breast cancer cell lines. AdVHL-mediated cell cycle arrest was associated with induction of the cyclin-dependent kinase inhibitor (CDKI) p27(Kip1) and inhibition of CDK2 and cyclinB1-dependent cdc2 activities. Nuclear run-on analyses and actinomycin D inhibition studies indicate that the induction of p27(Kip1) RNA by VHL is mediated at least in part through an increase in p27(Kip1) mRNA synthesis. Furthermore, [S-35]methionine pulse-chase studies indicate that the increase in p27(Kip) expression is also regulated through posttranscriptional control mechanisms. These studies support a novel concept that the tumor suppressor gene VHL controls cell cycle progression by regulation of p27(Kip1) at both the mRNA and protein levels. (C) 1998 Academic Press. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Seth, P (reprint author), NCI, Med Branch, NIH, Bldg 10,Room 12 N 226, Bethesda, MD 20892 USA. EM pseth@box-p.nih.gov RI Unno, Michiaki/A-8633-2010 OI Unno, Michiaki/0000-0002-2145-6416 NR 20 TC 44 Z9 46 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 DEC 30 PY 1998 VL 253 IS 3 BP 672 EP 677 DI 10.1006/bbrc.1998.9839 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 153RR UT WOS:000077846900022 PM 9918786 ER PT J AU Combadiere, C Gao, JL Tiffany, HL Murphy, PM AF Combadiere, C Gao, JL Tiffany, HL Murphy, PM TI Gene cloning, RNA distribution, and functional expression of mCX(3)CR1, a mouse chemotactic receptor for the CX3C chemokine fractalkine SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE cytokine receptors; chemokines; chemotaxis; molecular biology AB Human fractalkine and its apparent murine counterpart neurotactin are the only members identified so far of the CX3C subfamily of chemokines, Recently, a human fractalkine receptor was identified and named CX(3)CR1, Here we have identified a mouse counterpart of this receptor. The receptor was identified by analysis of a mouse genomic clone named PC2 isolated by homology hybridization using CX(3)CR1 as probe. Clone PC2 has a 354-codon open reading frame that has 83% amino acid identity to CX(3)CR1. PC2 RNA was abundant in brain and lung and comparatively less abundant in lung, liver, kidney, testis, and peripheral blood leukocytes, a pattern similar to that found for CX(3)CR1. The recombinant fractalkine, but no other chemokines tested, induced chemotaxis and transient increases in [Ca2+](i) in HEK 293 cells transfected with PC2, whereas untransfected cells did not respond. Furthermore, fractalkine bound specifically to the transfected cells (K-d = 4 nM). Thus, fractalkine is a functional ligand for this receptor and we propose to name it mCX(3)CR1 for murine CX3C chemokine receptor 1. (C) 1998 Academic Press. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. CHU Bichat, INSERM, U479, F-75877 Paris 18, France. RP Murphy, PM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. RI Combadiere, Christophe/I-5639-2013 OI Combadiere, Christophe/0000-0002-1755-4531 NR 13 TC 46 Z9 48 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 DEC 30 PY 1998 VL 253 IS 3 BP 728 EP 732 DI 10.1006/bbrc.1998.9849 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 153RR UT WOS:000077846900031 PM 9918795 ER PT J AU Jiang, J Liang, L Kim, SO Zhang, Y Mandler, R Frank, SJ AF Jiang, J Liang, L Kim, SO Zhang, Y Mandler, R Frank, SJ TI Growth hormone-dependent tyrosine phosphorylation of a GH receptor-associated high molecular WEIGHT protein immunologically related to JAK2 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID SIGNAL-TRANSDUCTION; JANUS KINASE; SUBSTRATE-1; ACTIVATION; BINDING; DOMAIN; GAMMA; CELLS; IDENTIFICATION; INTERFERON AB A critical step in growth hormone (GH) signalling is the GH-induced activation of the GH receptor (GHR)associated tyrosine kinase, JAK2. JAK2 is a 120 kD member of the Janus family of tyrosine kinases, whose other mammalian members include JAK1, JAK3, and TYK2. Using 3T3-F442A murine preadipocytes, we now report detection of a M-r similar to 170 kD protein, referred to as HMW ("high molecular weight") JAK2, that is specifically reactive in immunoprecipitation and immunoblotting experiments with three independently-derived anti JAK2 antibodies-two directed at carboxyl-terminal regions of the molecule and one directed at the amino-terminus. Like JAK2, HMW JAK2 is tyrosine phosphorylated in response to GH treatment of cells and is coimmunoprecipitated with anti-GHR serum. Thus, HMW JAK2 is a protein not heretofore described that is immunologically related to JAK2 and is physically and functionally associated with the GHR. (C) 1998 Academic Press. C1 Univ Alabama, Dept Med, Div Endocrinol & Metab, DREB, Birmingham, AL 35294 USA. Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA. Vet Affairs Med Ctr, Birmingham, AL 35294 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Frank, SJ (reprint author), Univ Alabama, Dept Med, Div Endocrinol & Metab, DREB, Room 756,UAB Stn, Birmingham, AL 35294 USA. FU NIDDK NIH HHS [DK46395] NR 35 TC 44 Z9 44 U1 0 U2 1 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 DEC 30 PY 1998 VL 253 IS 3 BP 774 EP 779 DI 10.1006/bbrc.1998.9793 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 153RR UT WOS:000077846900039 PM 9918803 ER PT J AU Huber, R Mazzarella, R Chen, CN Chen, E Ireland, M Lindsay, S Pilia, G Crisponi, L AF Huber, R Mazzarella, R Chen, CN Chen, E Ireland, M Lindsay, S Pilia, G Crisponi, L TI Glypican 3 and glypican 4 are juxtaposed in Xq26.1 SO GENE LA English DT Article DE X chromosome; proteoglycan; Simpson-Golabi-Behmel syndrome ID HEPARAN-SULFATE PROTEOGLYCAN; BECKWITH-WIEDEMANN-SYNDROME; GROWTH FACTOR-II; GPC3 GENE; MUTATIONS; DELETIONS; IGF2 AB Recently, we have shown that mutations in the X-linked glypican 3 (GPC3) gene cause the Simpson-Golabi-Behmel overgrowth syndrome (SGBS; Pilia et al., 1996). The next centromeric gene detected is another glypican, glypican 4 (GPC4), with its 5' end 120 763 bp downstream of the 3' terminus of GPC3. One recovered GPC4 cDNA with an open reading frame of 1668 nt encodes a putative protein containing three heparan sulfate glycosylation signals and the 14 signature cysteines of the glypican family. This protein is 94.3% identical to mouse GPC4 and 26% identical to human GPC3. In contrast to GPC3, which produces a single transcript of 2.3 kb and is stringently restricted in expression to predominantly mesoderm-derived tissues, Northern analyses show that GPC4 produces two transcripts, 3.4 and 4.6 kb, which are very widely expressed (though at a much higher level in fetal lung and kidney). Interestingly, of 20 SGBS patients who showed deletions in GPC3, one was also deleted for part of GPC4. Thus, GPC4 is not required for human viability, even in the absence of GPC3. This patient shows a complex phenotype, including the unusual feature of hydrocephalus; but because an uncle with SGBS is less affected, it remains unclear whether the GPC4 deletion itself contributes to the phenotype. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. Washington Univ, Sch Med, Inst Biomed Comp, St Louis, MO 63110 USA. Washington Univ, Sch Med, Ctr Genet Med, St Louis, MO 63110 USA. Adv Ctr Genet Technol, Appl Biosyst Div, Foster City, CA 94404 USA. Univ Newcastle Upon Tyne, Dept Human Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Cagliari, Osped Microcitemico, CNR, IRTAM, Cagliari, Italy. RP Huber, R (reprint author), DuPont Pharmaceut Co, Appl Biotechnol, Expt Stn, POB 80336,E336-225, Wilmington, DE 19880 USA. EM Reid.M.Huber@dupontpharma.com NR 24 TC 9 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD DEC 28 PY 1998 VL 225 IS 1-2 BP 9 EP 16 DI 10.1016/S0378-1119(98)00549-6 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 156XZ UT WOS:000078029200002 PM 9931407 ER PT J AU Coorssen, JR Blank, PS Tahara, M Zimmerberg, J AF Coorssen, JR Blank, PS Tahara, M Zimmerberg, J TI Biochemical and functional studies of cortical vesicle fusion: The SNARE complex and Ca2+ sensitivity SO JOURNAL OF CELL BIOLOGY LA English DT Article DE calcium; cytoplasmic vesicles; exocytosis; membrane fusion; secretion ID SEA-URCHIN EGGS; ADRENAL CHROMAFFIN CELLS; CALCIUM-TRIGGERED FUSION; BOTULINUM TOXIN-A; PLASMA-MEMBRANE; NEUROTRANSMITTER RELEASE; DEPENDENT EXOCYTOSIS; TRANSMITTER RELEASE; PROTEIN-TRANSPORT; SYNTAXIN 1A AB Cortical vesicles (CV) possess components critical to the mechanism of exocytosis. The homotypic fusion of CV centrifuged or settled into contact has a sigmoidal Ca2+ activity curve comparable to exocytosis (CV-PM fusion). Here we show that Sr2+ and Ba2+ also trigger CV-CV fusion, and agents affecting different steps of exocytotic fusion block Ca2+, Sr2+, and Ba2+-triggered CV-CV fusion. The maximal number of active fusion complexes per vesicle, < n >(Max), was quantified by NEM inhibition of fusion, showing that CV-CV fusion satisfies many criteria of a mathematical analysis developed for exocytosis. Both < n >(Max) and the Ca2+ sensitivity of fusion complex activation were comparable to that determined for CV-PM fusion. Using Ca2+-induced SNARE complex disruption, we have analyzed the relationship between membrane fusion (CV-CV and CV-PM) and the SNARE complex, Fusion and complex disruption have different sensitivities to Ca2+ Sr2+, and Ba2+, the complex remains Ca2+- sensitive on fusion-incompetent CV, and disruption does not correlate with the quantified activation of fusion complexes. Under conditions which disrupt the SNARE complex, CV on the PM remain docked and fusion competent, and isolated CV still dock and fuse, but with a markedly reduced Ca2+ sensitivity. Thus, in this system, neither the formation, presence, nor disruption of the SNARE complex is essential to the Ca2+-triggered fusion of exocytotic membranes. Therefore the SNARE complex alone cannot be the universal minimal fusion machine for intracellular fusion. We suggest that: this complex modulates the Ca2+ sensitivity of fusion. C1 NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Coorssen, JR (reprint author), NICHHD, Lab Cellular & Mol Biophys, NIH, Bldg 10,Room 10D14,10 Ctr Dr,MSC 1855, Bethesda, MD 20892 USA. NR 89 TC 116 Z9 119 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD DEC 28 PY 1998 VL 143 IS 7 BP 1845 EP 1857 DI 10.1083/jcb.143.7.1845 PG 13 WC Cell Biology SC Cell Biology GA 154QQ UT WOS:000077900300007 PM 9864359 ER PT J AU Wu, XF Bowers, B Rao, K Wei, Q Hammer, JA AF Wu, XF Bowers, B Rao, K Wei, Q Hammer, JA TI Visualization of melanosome dynamics within wild-type and dilute melanocytes suggests a paradigm for myosin V function in vivo SO JOURNAL OF CELL BIOLOGY LA English DT Article DE myosin V; dilute; melanosomes; microtubule motors; organelle motility ID COAT COLOR; SUBCELLULAR-LOCALIZATION; SQUID AXOPLASM; PURKINJE-CELLS; GENE; ACTIN; TRANSPORT; MOTORS; GROWTH; LOCUS AB Unlike wild-type mouse melanocytes, where melanosomes are concentrated in dendrites and dendritic tips, melanosomes in dilute (myosin Va(-)) melanocytes are concentrated in the cell center. Here we sought to define the role that myosin Va plays in melanosome transport and distribution. Actin filaments that comprise a cortical shell running the length of the dendrite were found to exhibit a random orientation, suggesting that myosin Va could drive the outward spreading of melanosomes by catalyzing random walks. In contrast to this mechanism, time lapse video microscopy revealed that melanosomes undergo rapid (similar to 1.5 mu m/s) microtubule-dependent movements to the periphery and back again. This bidirectional traffic occurs in both wild-type and dilute melanocytes, but it is more obvious in dilute melanocytes because the only melanosomes in their periphery are those undergoing this movement. While providing an efficient means to transport melanosomes to the periphery, this component does not by itself result in their net accumulation there. These observations, together with previous studies showing extensive colocalization of myosin Va and melanosomes in the actin-rich periphery, suggest a mechanism in which a myosin Va-dependent interaction of melanosomes with F-actin in the periphery prevents these organelles from returning on microtubules to the cell center, causing their distal accumulation. This "capture" model is supported by the demonstration. that (a) expression of the myosin Va tail domain within wild-type cells creates a dilute-like phenotype via a process involving initial colocalization of tail domains with melanosomes in the periphery, followed by an similar to 120-min, microtubule-based redistribution of melanosomes to the cell center; (b) microtubule-dependent melanosome movement appears to be damped by myosin Va; (c) intermittent, microtubule-independent, similar to 0.14 mu m/s melanosome movements are seen only in wild-type melanocytes; and (d) these movements do not drive obvious spreading of melanosomes over 90 min. We conclude that long-range, bidirectional, microtubule-dependent melanosome movements, coupled with actomyosin Va-dependent capture of melanosomes in the periphery, is the predominant mechanism responsible for the centrifugal transport and peripheral accumulation of melanosomes in mouse melanocytes. This mechanism represents an alternative to straight-orward transport models when interpreting other myosin V mutant phenotypes. C1 NHLBI, Cell Biol Lab, Sect Mol Cell Biol, NIH, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, Sect Mol Cell Biol, NIH, Bldg 3,Room B1-22, Bethesda, MD 20892 USA. EM hammerj@fido.nhlbi.nih.gov NR 51 TC 287 Z9 290 U1 1 U2 15 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD DEC 28 PY 1998 VL 143 IS 7 BP 1899 EP 1918 DI 10.1083/jcb.143.7.1899 PG 20 WC Cell Biology SC Cell Biology GA 154QQ UT WOS:000077900300011 PM 9864363 ER PT J AU Bohr, V Anson, RM Mazur, S Dianov, G AF Bohr, V Anson, RM Mazur, S Dianov, G TI Oxidative DNA damage processing and changes with aging SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 8th International Congress of Toxicology CY JUL 05-09, 1998 CL PARIS, FRANCE SP Soc Francaise Toxicol DE oxidative damage; aging ID RNA-POLYMERASE-II; COCKAYNE-SYNDROME; EXCISION-REPAIR; TRANSCRIPTION; CELLS; EXTRACTS; NUCLEAR; DEFECT AB Living organisms are constantly exposed to oxidative stress from environmental agents and from endogenous metabolic processes. The resulting oxidative modifications occur in proteins, lipids and DNA. Since proteins and lipids are readily degraded and resynthesized, the most significant consequence of the oxidative stress is thought to be the DNA modifications, which can become permanent via the formation of mutations and other types of genomic instability. Many different DNA base changes have been seen following some form of oxidative stress, and these lesions are widely considered as instigators for the development of cancer and are also implicated in the process of aging. Several studies have documented that oxidative DNA lesions accumulate with aging, and it appears that the major site of this accumulation is mitochondrial DNA rather than nuclear DNA. The DNA repair mechanisms involved in the removal of oxidative DNA lesions are much more complex than previously considered. They involve base excision repair (BER) pathways and nucleotide excision repair (NER) pathways, and there is currently a great deal of interest in clarification of the pathways and their interactions. We have used a number of different approaches to explore the mechanism of the repair processes, and we are able to examine the repair of different types of lesions and to measure different steps of the repair processes. Furthermore, we can measure the DNA damage processing in the nuclear DNA and separately, in the mitochondrial DNA. Contrary to widely held notions, mitochondria have efficient DNA repair of oxidative DNA damage and we are exploring the mechanisms. In a human disorder, Cockayne syndrome (CS), characterized by premature aging, there appear to be deficiencies in the repair of oxidative DNA damage in the nuclear DNA, and this may be the major underlying cause of the disease. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. RP Bohr, V (reprint author), NIA, Mol Genet Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 16 TC 15 Z9 16 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 28 PY 1998 VL 103 BP 47 EP 52 PG 6 WC Toxicology SC Toxicology GA 164KE UT WOS:000078462400008 PM 10022231 ER PT J AU Cone, EJ AF Cone, EJ TI Recent discoveries in pharmacokinetics of drugs of abuse SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 8th International Congress of Toxicology CY JUL 05-09, 1998 CL PARIS, FRANCE SP Soc Francaise Toxicol DE cocaine; heroin; marijuana; tetrahydrocannabinol; pharmacokinetics ID PLASMA-CONCENTRATIONS; BLOOD CANNABINOIDS; MARIJUANA; PHARMACODYNAMICS; ABSORPTION; COCAINE; SMOKING; THCCOOH; HEROIN; TIME AB Controlled human dosing studies with drugs of abuse have revealed the importance of the chosen route of administration on the delivery of drugs to the bloodstream and to their site of action. Recently, the intranasal and smoked routes have become favored by some populations for the administration of illicit drugs. Research studies with experienced heroin and cocaine users indicated that an intranasally administered drug generally provided lower blood concentrations of drug and a slower onset of action compared to the intravenous route; however, intranasal doses are easily manipulated by the user and adequate bioavailability and desired drug effects can be achieved. In addition, the trauma of needle use is avoided and disease exposure is reduced by this route. For marijuana, the smoked route of administration has always been the preferred route. In recent studies with smoked marijuana, it was revealed that single puffs of marijuana smoke produced detectable blood concentrations of tetrahydrocannabinol, the active ingredient of marijuana. Continued smoking produced rapid increases in blood concentrations with peak concentrations and effects occurring before or near the end of smoking, demonstrating the rapidity and efficacy of the smoking route for marijuana. The smoked route has also become popular with cocaine and heroin users. This route provided equivalent peak blood concentrations and time of onset of drug effects as the intravenous route. In addition, arterial boli drug concentrations reaching the brain are likely to be higher following the smoked route compared to the intravenous route. Overall, these studies demonstrated that the smoked and intranasal routes are highly efficacious for the delivery of illicit drugs and produce a similar profile of drug action to the intravenous route of administration. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NIDA, Addict Res Ctr, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Cone, EJ (reprint author), NIDA, Addict Res Ctr, Intramural Res Program, NIH, POB 5180, Baltimore, MD 21224 USA. NR 8 TC 6 Z9 6 U1 4 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 28 PY 1998 VL 103 BP 97 EP 101 PG 5 WC Toxicology SC Toxicology GA 164KE UT WOS:000078462400016 ER PT J AU Gonzalez, FJ AF Gonzalez, FJ TI The study of xenobiotic-metabolizing enzymes and their role in toxicity in vivo using targeted gene disruption SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 8th International Congress of Toxicology CY JUL 05-09, 1998 CL PARIS, FRANCE SP Soc Francaise Toxicol DE genetic polymorphism; cytochrome P450; gene knockout; transgenic mice; acetaminophen; caffeine ID ACETAMINOPHEN HEPATOTOXICITY; MICE DEFICIENT; CYP2E1; ACID; SUPERFAMILY; EXPRESSION; OXIDATION; CAFFEINE; LACKING; CYP1A2 AB Most of the chemicals that cause toxicity in animals are metabolized and this metabolism can either increase or decrease the extent of toxicity. A targe number of enzymes are involved in the metabolism of xenobiotics. Cytochromes P450 are among the most important and these enzymes are primarily involved in metabolic activation through oxidative metabolism. Transferases, including the glutathione S-transferases, N-acetyltransferases, UDP-glucuronosyltransferases, microsomal and cytosolic epoxide hydrolases, and NAD(P)H quinone oxidoreductase are also significant in xenobiotic metabolism and can play a role in chemical sensitivities. Polymorphisms in P450s and transferases have been found in experimental animals and humans in which a certain segment of the population, usually greater than 1%, are lacking expression of a particular enzyme. In humans, polymorphisms have been associated with adverse drug reactions but have not been shown to cause any serious developmental or physiological defects thus suggesting that in mammals, xenobiotic-metabolizing enzymes may only be required for metabolism of foreign chemicals and have no other critical role. To determine the roles of xenobiotic-metabolizing enzymes in mammalian development and physiological homeostasis, and in sensitivities to chemical toxicity and carcinogenesis, targeted gene disruption was carried out to produce gene knockout mice. Several lines of mice were produced and characterized and these are discussed. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, NIH, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. NR 31 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 28 PY 1998 VL 103 BP 161 EP 166 PG 6 WC Toxicology SC Toxicology GA 164KE UT WOS:000078462400026 ER PT J AU Portier, CJ Bell, DA AF Portier, CJ Bell, DA TI Genetic susceptibility: significance in risk assessment SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 8th International Congress of Toxicology CY JUL 05-09, 1998 CL PARIS, FRANCE SP Soc Francaise Toxicol DE risk assessment; polymorphism; mathematical modeling; dose-response ID POLYMORPHISM; EXPOSURE; BLADDER; CANCER AB Polymorphisms in metabolism and DNA-repair genes can increase the risks of cancer associated with exposure to chemical and physical agents in the environment. These types of gene-environment interactions may alter our view of dose-response patterns and how to characterize risk in an exposed population. Depending upon the action of the different forms of these genes, differing patterns of dose-response may be seen in a study population and these patterns can effect our interpretation of the degree of hazard as well as the risk in the general population, This short report describes some of the key issues associated with how variation in genetic make-up can result in different dose-response patterns for cancer following exposure to environmental agents. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP Portier, CJ (reprint author), NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 12 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 28 PY 1998 VL 103 BP 185 EP 189 PG 5 WC Toxicology SC Toxicology GA 164KE UT WOS:000078462400029 ER PT J AU Hussain, SP Harris, CC AF Hussain, SP Harris, CC TI Molecular epidemiology of human cancer SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 8th International Congress of Toxicology CY JUL 05-09, 1998 CL PARIS, FRANCE SP Soc Francaise Toxicol DE cancer epidemiology; human cancer; molecular epidemiology ID TUMOR-SUPPRESSOR GENE; P53 GENE; SKIN-CANCER; HEPATOCELLULAR-CARCINOMA; HUMAN LIVER; CHEMICAL CARCINOGENS; MUTATIONAL HOTSPOTS; EPITHELIAL-CELLS; UV; APOPTOSIS AB A challenging goal of molecular epidemiology is to identify an individual's risk of cancer. Molecular epidemiology integrates molecular biology, in vitro and in vivo laboratory models, biochemistry, and epidemiology to infer individual cancer risk. Molecular dosimetry of carcinogen exposure is an important facet of molecular epidemiology and cancer risk assessment. Carcinogen macromolecular adduct levels, cytogenetic alterations and somatic cell mutations can be measured to determine the biologically-effective doses of carcinogens. Molecular epidemiology also explores host cancer susceptibilities, such as carcinogen metabolism, DNA repair, and epigenetic and genetic alterations in tumor suppressor genes. p53 is a prototype tumor suppressor gene and is well suited for analysis of mutational spectrum in human cancer. The analyses of germline and somatic mutation spectra of the p53 tumor suppressor gene provide important clues for cancer risk assessment in molecular epidemiology. For example, characteristic p53 mutation spectra have been associated with: dietary aflatoxin B-1 exposure and hepatocellular carcinoma; sunlight exposure and skin carcinoma; and cigarette smoking and lung cancer. The mutation spectrum also reveals those p53 mutants that provide cells with a selective clonal-expansion advantage during the multistep process of carcinogenesis. The p53 gene encodes a multifunctional protein involved in the cellular response to stress including DNA damage and hypoxia. Certain p53 mutants lose tumor suppressor activity and gain oncogenic activity, which is one explanation for the commonality of p53 mutations in human cancer. Molecular epidemiological results can be evaluated for causation by inference of the Bradford-Hill criteria, i.e. strength of association (consistency, specificity and temporality) and biological plausibility, which utilizes the 'weight of the evidence principle'. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Rm 2C01,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov NR 44 TC 3 Z9 3 U1 1 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 28 PY 1998 VL 103 BP 219 EP 225 PG 7 WC Toxicology SC Toxicology GA 164KE UT WOS:000078462400034 ER PT J AU Tennant, RW Tice, RR Spalding, JW AF Tennant, RW Tice, RR Spalding, JW TI The transgenic Tg.AC mouse model for identification of chemical carcinogens SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 8th International Congress of Toxicology CY JUL 05-09, 1998 CL PARIS, FRANCE SP Soc Francaise Toxicol DE transgenic mice; chemical carcinogens; bioassays; Tg.AC mice; transgenic models ID PAPILLOMA DEVELOPMENT; EXPRESSION; MICE AB The Tg.AC (zetaglobin promoted v-Ha-ras) transgenic mouse is being evaluated as a short-term carcinogenicity bioassay. In order to harmonize the evaluation effort in diverse laboratories, an operational bioassay protocol has been established. Data, based principally on retrospective assay of known carcinogens or tumor promoters and non-carcinogens, are presented that support the operational protocol. The Laboratory of Environmental Carcinogenesis and Mutagenesis at the NIEHS has been evaluating transgenic rodent models for utility in differentiating carcinogens from non-carcinogens. Our main approach in this method development effort has been to retrospectively study responses of the models to chemicals of known rodent carcinogenic potential. To this end we have tested mainly chemicals that have been previously studied in chronic rat and/or mouse bioassays by the National Toxicology Program. Development of the data base and assessment of the utility of the models will be immeasurably aided by the availability of a standardized experimental protocol. The purpose of this communication is to present the elements of the Laboratory of Environmental Carcinogenesis and Mutagenesis Tg.AC mouse bioassay protocol and to show experimental results that led to the development of our study design. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved. C1 NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. Integrated Lab Syst, Res Triangle Pk, NC 27709 USA. RP Tennant, RW (reprint author), NIEHS, Lab Environm Carcinogenesis & Mutagenesis, POB 12233,MD F1-05, Res Triangle Pk, NC 27709 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD DEC 28 PY 1998 VL 103 BP 465 EP 471 PG 7 WC Toxicology SC Toxicology GA 164KE UT WOS:000078462400074 ER PT J AU Ojo, AO Wolfe, RA Agodoa, LY Held, PJ Port, FK Leavey, SF Callard, SE Dickinson, DM Schmouder, RL Leichtman, AB AF Ojo, AO Wolfe, RA Agodoa, LY Held, PJ Port, FK Leavey, SF Callard, SE Dickinson, DM Schmouder, RL Leichtman, AB TI Prognosis after primary renal transplant failure and the beneficial effects of repeat transplantation - Multivariate analyses from the United States Renal Data System SO TRANSPLANTATION LA English DT Article; Proceedings Paper CT 17th Annual Meeting of the American-Society-of-Transplant-Physicians CY MAY 09-13, 1998 CL CHICAGO, ILLINOIS SP Amer Soc Transplant Physicians ID DIALYSIS; ACCESS; RACE AB Background, Survival of transplant recipients after primary renal allograft failure has not been well studied, Methods. A cohort of 19,208 renal transplant recipients with primary allograft failure between 1985 and 1995 were followed from the date of allograft loss until death, repeat transplantation, or December 31, 1996, The mortality, wait-listing, and repeat transplantation rates were assessed. The mortality risks associated with repeat transplantation were estimated with a time-dependent survival model. Results. In total, 34.5% (n=6,631) of patients died during follow-up. Of these deaths, 82.9% (n=5,498) occurred in patients not wait-listed for repeat transplantation, 11.9% (n=789) occurred in wait-listed patients, and 5.2% (n=344) occurred in second transplant recipients, Before repeat transplantation, the adjusted 5-year patient survival was 36%, 49%, and 65% for type I diabetes mellitus (DM), type II DM, and nondiabetic end-stage renal disease, respectively (P<0.001; DM vs. nondiabetics). The adjusted 5-year patient survival was lower in Caucasians (57%, P<0.001) compared with African-Americans (67%) and other races (64%). The 5-yr repeat transplantation rate was 29%, 15%, and 19%, whereas the median waiting time for a second transplant was 32, 90, and 81 months for Caucasians, African-Americans, and other races, respectively (P<0.0001 each). Repeat transplantation was associated with 45% and 23% reduction in 5-year mortality for type I DM and nondiabetic end-stage renal disease, respectively, when compared with their wait-listed dialysis counterparts with prior transplant failure. Conclusions. The loss of a primary renal allograft was associated with significant mortality, especially in recipients with type I DM. Repeat transplantation was associated with a substantial improvement in 5-year patient survival. Recipients with type I DM achieved the greatest proportional benefit from repeat transplantation. C1 Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. NIDDKD, US Renal Data Syst, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. RP Ojo, AO (reprint author), Univ Michigan, Med Ctr, Dept Internal Med, 3914 Taubman Ctr,Box 0364, Ann Arbor, MI 48109 USA. EM aojo@umich.edu NR 14 TC 137 Z9 138 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD DEC 27 PY 1998 VL 66 IS 12 BP 1651 EP 1659 DI 10.1097/00007890-199812270-00014 PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 155QU UT WOS:000077958500014 PM 9884254 ER PT J AU Shors, ST Efiok, BJS Harkin, SJ Safer, B AF Shors, ST Efiok, BJS Harkin, SJ Safer, B TI Formation of alpha-Pal/Max heterodimers synergistically activates the eIF2-alpha promoter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EUKARYOTIC INITIATION FACTOR-2-ALPHA; TRANSCRIPTION FACTOR; PROTEIN-SYNTHESIS; MAMMALIAN-CELLS; C-MYC; KINASE; PKR; BINDING; GENES; MAX AB The transcription factor alpha-Pal recognizes two tandem palindromic repeats within the promoter of eukaryotic translation initiation factor 2-alpha (eIF2-alpha). Whereas both binding sites have the same "core domain" sequence (CGCATGCG), they differ with respect to their flanking sequences. Of the two sites, the 5'-cap proximal site has a higher binding affinity for cu-Pal than does the 5'-cap distal site (Jacob, W. F., Silverman, T. A., Cohen, R. B., and Safer, B. (1989) J. Biol. Chem. 264, 20372-20384). The well characterized transcription factor Max binds to sequences that are remarkably similar to the core domain that alpha-Pal recognizes. To date, all of the Max heterodimer partners lack DNA binding domains and are thus dependent on Max interacting with DNA. Here we report that the two alpha-Pal sites have very different binding activities with respect to the E-box-binding protein Max. The 5'-cap distal or low alpha-Pal affinity site binds both alpha-Pal and Max. Furthermore, both heterodimers and homodimers of each of these proteins bind to this site. In contrast to the low affinity site, the high affinity site does not bind Max as a homodimer. This is the first documented case where Max heterodimerizes with a transcription factor that has affinity for DNA independent of Max. C1 NHLBI, Mol Hematol Branch, DIR, NIH, Bethesda, MD 20892 USA. RP Safer, B (reprint author), NHLBI, Mol Hematol Branch, DIR, NIH, Bldg 10,Rm 7D18,MSC 1654, Bethesda, MD 20892 USA. EM besafer@helix.nih.gov NR 27 TC 6 Z9 6 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 DEC 25 PY 1998 VL 273 IS 52 BP 34703 EP 34709 DI 10.1074/jbc.273.52.34703 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 151KR UT WOS:000077719700010 PM 9856992 ER PT J AU Horton, MR McKee, CM Bao, G Liao, F Farber, JM Hodge-DuFour, J Pure, E Oliver, BL Wright, TM Noble, PW AF Horton, MR McKee, CM Bao, G Liao, F Farber, JM Hodge-DuFour, J Pure, E Oliver, BL Wright, TM Noble, PW TI Hyaluronan fragments synergize with interferon-gamma to induce the C-X-C chemokines Mig and interferon-inducible protein-10 in mouse macrophages SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IDIOPATHIC PULMONARY FIBROSIS; NECROSIS-FACTOR-ALPHA; BRONCHOALVEOLAR LAVAGE FLUID; NITRIC-OXIDE SYNTHASE; FACTOR KAPPA-B; ALVEOLAR MACROPHAGES; GENE-EXPRESSION; IFN-GAMMA; MURINE MACROPHAGES; T-LYMPHOCYTES AB Hallmarks of chronic inflammation and tissue fibrosis are increased influx of activated inflammatory cells, mediator release, and increased turnover and production of the extracellular matrix (ECM). Recent evidence has suggested that fragments of the ECM component hyaluronan play a role in chronic inflammation by inducing macrophage expression of chemokines. Interferon-gamma (IFN-gamma), an important regulator of macrophage functions, has been shown to induce the C-X-C chemokines Mig and IP-10. These chemokines affect T-cell recruitment and inhibit angiogenesis. The purpose of this investigation was to determine the effect of hyaluronan (HA) on IFN-gamma-induced Mig and IP-10 expression in mouse macrophages. We found a marked synergy between HA and IFN-gamma on Mig and IP-10 mRNA and protein expression in mouse macrophages. This was most significant with Mig, which was not induced by HA alone. The synergy was specific for HA, was not dependent on new protein synthesis, was not mediated by tumor necrosis factor-cy, was selective for Mig and IP-10, and occurred at the level of gene transcription. These data suggest that the ECM component HA may influence chronic inflammatory states by working in concert with IFN-gamma to alter macrophage chemokine expression. C1 Yale Univ, Sch Med, Dept Vet Affairs Connecticut Healthcare Syst, Pulm Sect, W Haven, CT 06516 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Wistar Inst, Pittsburgh, PA 15261 USA. Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. RP Noble, PW (reprint author), Yale Univ, Sch Med, Dept Vet Affairs Connecticut Healthcare Syst, Pulm Sect, 950 Campbell Ave,111A, W Haven, CT 06516 USA. EM paul.noble@yale.edu FU NHLBI NIH HHS [K11HL02880, 5F32HL09614-02, R01HL60539] NR 52 TC 124 Z9 126 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 DEC 25 PY 1998 VL 273 IS 52 BP 35088 EP 35094 DI 10.1074/jbc.273.52.35088 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 151KR UT WOS:000077719700061 PM 9857043 ER PT J AU Chen, E Hrdlickova, R Nehyba, J Longo, DL Bose, HR Li, CCH AF Chen, E Hrdlickova, R Nehyba, J Longo, DL Bose, HR Li, CCH TI Degradation of proto-oncoprotein c-Rel by the ubiquitin-proteasome pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; V-REL; IN-VITRO; ONCOGENIC TRANSFORMATION; FAMILY MEMBERS; PEST SEQUENCES; EXPRESSION; ALPHA; PROTEINS; CELLS AB The c-rel proto-oncogene product, c-Rel, belongs to the Rel/NF-kappa B transcription factor family, which regulates a large variety of cellular functions. The activation of NF-KB involves the degradation of the inhibitor, I kappa B, through the ubiquitin-proteasome (Ub-Pr)-mediated pathway. Here we report that the turnover of c-Rel is also regulated by the Ub-Pr pathway, thus adding another level of complexity to the regulation of NF-KB. High molecular weight ubiquitinated c-Rel conjugates are detected in cells and accumulate in cells treated with proteasome inhibitors. In a cell-free in vitro degradation assay, c-Rel is degraded specifically through the Ub-Pr pathway. N-terminally truncated c-Rel is readily degraded, implying the dispensability of N-terminal sequence; in contrast, a series of deletion mutants missing C-terminal sequences display a reduced susceptibility to the degradation. Interestingly, the sequence between residues 118 and 171 of c-Rel, i.e. the region immediately following the c-Rel/v-Rel homology domain, appears to play an important role in mediating ubiquitin conjugation and the subsequent degradation. Together with our previous study showing an elevated tumorigenic potential for C-terminally truncated mutants, our data suggest that the C-terminal domain of c-Rel plays an important role in mediating c-Rel degradation and growth control. C1 NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. Univ Texas, Dept Microbiol, Austin, TX 78712 USA. Univ Texas, Inst Mol & Cellular Biol, Austin, TX 78712 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Li, CCH (reprint author), NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Frederick, MD 21702 USA. FU NCI NIH HHS [CA33192] NR 54 TC 27 Z9 27 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 DEC 25 PY 1998 VL 273 IS 52 BP 35201 EP 35207 DI 10.1074/jbc.273.52.35201 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 151KR UT WOS:000077719700076 PM 9857058 ER PT J AU Chougnet, C Fowke, KR Mueller, BU Smith, S Zuckerman, J Jankelevitch, S Steinberg, SM Luban, N Pizzo, PA Shearer, GM AF Chougnet, C Fowke, KR Mueller, BU Smith, S Zuckerman, J Jankelevitch, S Steinberg, SM Luban, N Pizzo, PA Shearer, GM TI Protease inhibitor and triple-drug therapy: cellular immune parameters are not restored in pediatric AIDS patients after 6 months of treatment SO AIDS LA English DT Article DE interleukin-12; interleukin-10; tumor necrosis factor-alpha; tumor necrosis factor receptors; cytokines; cellular immunity; apoptosis; antiretroviral therapy; pediatrics ID HUMAN-IMMUNODEFICIENCY-VIRUS; TUMOR-NECROSIS-FACTOR; TYPE-1 INFECTION; FACTOR RECEPTORS; FACTOR-ALPHA; INTERLEUKIN-12 PRODUCTION; MONONUCLEAR-CELLS; HIV-1 INFECTION; HUMAN MONOCYTES; TNF RECEPTORS AB Objective: To assess whether treatment of HIV-positive children by antiretroviral drugs for a 6-month period would improve immune function significantly. Design and methods: Immunological assessment of 89 HIV-positive children who received protease inhibitor monotherapy for 12-16 weeks as part of phase I/II studies, followed by triple antiretroviral therapy for an additional 12 weeks, was conducted. Immunological parameters were assessed in vitro at four time points (at enrollment, at weeks 2-4, at weeks 12-16, and at weeks 24-28). Assessments included: cytokine production by monocytes, T-cell proliferation to mitogen or recall antigens (including an HIV antigen) and apoptotic cell death. Plasma levels of tumor necrosis factor (TNF)-alpha and soluble TNF receptor (sTNF-R) were also measured, in addition to CD4+ T-lymphocyte counts and viral load. In addition, limited analyses were performed on samples from 17 children after 120 weeks of therapy, including 104 weeks of triple therapy. Results: At enrollment, the 89 children exhibited severe immune defects. Antiretroviral therapy raised CD4+ T-lymphocyte counts significantly and decreased viral loads. In contrast, the in vitro immune parameters studied were not improved, except for plasma levels of sTNF-RII which decreased in parallel with the decrease in viral load. In addition, there was a trend towards increased skin test reactivity for the ritonavir-treated children. No differences were seen in the immune parameters whether the patients were treated with mono- or triple therapy. Results obtained after 120 weeks of therapy demonstrated that defective interleukin-12 production was not restored by long-term therapy. Conclusions: After 6 months of therapy, with the exception of decreased sTNF-RII levels, and a trend towards increased skin test reactivity, restoration of several defective cellular immune responses did not occur despite significantly decreased viral loads and increased CD4+ T-lymphocyte counts. (C) 1998 Lippincott Williams & Wilkins. C1 NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. NCI, NIH, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Lab Med, Washington, DC 20010 USA. RP Shearer, GM (reprint author), NCI, NIH, Expt Immunol Branch, Bldg 10,Room 4B17,9000 Rockville Pike, Bethesda, MD 20892 USA. OI Fowke, Keith/0000-0001-8227-6649 NR 35 TC 20 Z9 20 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD DEC 24 PY 1998 VL 12 IS 18 BP 2397 EP 2406 DI 10.1097/00002030-199818000-00008 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 148TX UT WOS:000077550000008 PM 9875577 ER PT J AU Belshe, RB Gorse, GJ Mulligan, MJ Evans, TG Keefer, MC Excler, JL Duliege, AM Tartaglia, J Cox, WI McNamara, J Hwang, KL Bradney, A Montefiori, D Weinhold, KJ AF Belshe, RB Gorse, GJ Mulligan, MJ Evans, TG Keefer, MC Excler, JL Duliege, AM Tartaglia, J Cox, WI McNamara, J Hwang, KL Bradney, A Montefiori, D Weinhold, KJ CA NIAID AIDS Vaccine Evaluation Grp TI Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and gp120 SF-2 recombinant vaccines in uninfected volunteers SO AIDS LA English DT Article DE HIV vaccines,; cytotoxic T cells; neutralizing antibody ID NEUTRALIZING ANTIBODY; RABIES GLYCOPROTEIN; NAIVE ADULTS; TYPE-1; GP160; INFECTION; IMMUNOGENICITY; SAFETY AB Objective: To determine the ability of live attenuated canarypox virus expressing HIV antigens to induce CD8+ cytotoxic T-cell responses and to prime for neutralizing antibody responses to boosting with purified recombinant gp120 subunit vaccine. Design: A prospective, double-blind, randomized, immunogenicity and safety study was conducted in healthy adults at low risk for acquiring HIV infection and who were seronegative for HIV. Methods: CD8+ cytotoxic T-cells directed against Env or Gag expressing target cells were measured after live recombinant canarypox-HIV-1 vaccine priming (vaccine given at days 0, 7, 14 and 21). Neutralizing antibodies were measured after subunit boosting (vaccine given at days 28 and 84). Results: CD8+ CTL were induced in 64% of volunteers by the live recombinant canarypox-HIV-1 vaccine. All volunteers who received two doses of subunit vaccine after live recombinant canarypox priming developed neutralizing antibodies directed against laboratory strains of HIV-1 and seven out of eight volunteers tested developed neutralizing antibodies to the primary isolate, BZ167, but to none of eight other primary isolates. Unprimed controls had low or absent neutralizing antibodies after two doses of subunit vaccine. Conclusions: The live canarypox vector was safe, stimulated cytotoxic T-cells and primed for a vigorous neutralizing antibody response upon boosting with subunit gp120 vaccine. This vaccine combination should be evaluated further for inducing protection against HIV infection. (C) 1998 Lippincott Williams & Wilkins. C1 St Louis Univ, Ctr Hlth Sci, Dept Internal Med, Div Infect Dis & Immunol,Sch Med, St Louis, MO 63110 USA. St Louis Vet Adm Med Ctr, St Louis, MO 63110 USA. Univ Alabama, Birmingham, AL 35294 USA. Univ Rochester, Sch Med & Dent, Rochester, NY USA. Pasteur Merieux Connaught, Marnes La Coquette, France. Chiron Vaccines, Emeryville, CA USA. Virogenet Corp, Troy, NY USA. NIAID, Div Aids, Vaccine & Prevent Res Program, Clin Dev Branch, Rockville, MD 20852 USA. EMMES Corp, Potomac, MD USA. Duke Univ, Cent Immunol Lab, Durham, NC 27706 USA. RP Belshe, RB (reprint author), St Louis Univ, Ctr Hlth Sci, Dept Internal Med, Div Infect Dis & Immunol,Sch Med, 3635 Vista Ave,FDT-8N, St Louis, MO 63110 USA. FU NIAID NIH HHS [N01 AI-45208, N01 AI-45211, N01 AI-65305] NR 21 TC 156 Z9 158 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD DEC 24 PY 1998 VL 12 IS 18 BP 2407 EP 2415 DI 10.1097/00002030-199818000-00009 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 148TX UT WOS:000077550000009 PM 9875578 ER PT J AU Ioannidis, JPA O'Brien, TR Goedert, JJ AF Ioannidis, JPA O'Brien, TR Goedert, JJ TI Evaluation of guidelines for initiation of highly active antiretroviral therapy in a longitudinal cohort of HIV-infected individuals SO AIDS LA English DT Article DE antiretroviral therapy; guidelines; viral load; cohort study; HIV-1; model ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL LOAD; DISEASE PROGRESSION; CLINICAL-PRACTICE; AIDS; RECOMMENDATIONS; ZIDOVUDINE; MARKERS; IMPACT; TRIALS AB Objectives: Expert panels have developed several guidelines for initiating highly active antiretroviral therapy (HAART) in patients with HIV infection. To evaluate these guidelines, we simulated their application in a cohort of HIV-infected patients established and followed before HAART was available, and determined how long such patients survived without disease progression in the absence of HAART. Methods: Longitudinal data was used that had been collected from 1982 to 1995 on a prospective cohort of 133 homosexual men with known or closely approximated dates of HIV-I seroconversion and negligible antiretroviral exposure. The main definition of disease progression was CD4 cell count less than or equal to 300 x10(6)/l or development of clinical AIDS diagnosis within 12 months. Results: The mean number of years between the recommended initiation of therapy and when disease progression occurred in the absence of HAART were as follows: initiation of treatment at first visit, 4.81 years [median, 3.78 years; interquartile range (IQR), 1.85-6.59 years]; CD4 cell count < 500 x 10(6)/l or serum RNA > 5000 copies/ml (at least 10000 copies/ml fresh plasma), 4.35 years (median, 3.22 years; IQR, 1.56-6.19 years); CD4 cells < 500 x 10(6)/l or serum RNA > 20000 copies/ml (at least 40000 copies/ml fresh plasma), 3.61 years (median, 2.70 years; IQR, 1.40-5.11 years); and CD4 cells < 500 x 10(6)/l, 2.72 years (median, 2.17 years; IQR, 0.81-4.25 years). The percentage of patients who had disease progression before HAART would have been recommended was 0.8, 1.6, 3.2 and 13.6% with each of these four approaches, respectively. Conclusions: Implementation of recommended treatment guidelines will result in a substantial proportion of patients being treated for long periods before immunologic or clinical disease progression would have occurred in the absence of HAART. These findings should be considered in the clinical care of HIV-infected patients and in future recommendations for the initiation of HAART. (C) 1998 Lippincott Williams & Wilkins. C1 NCI, DCEG, Viral Epidemiol Branch, NIH, Rockville, MD 20852 USA. NIAID, Div Aids, Therapeut Res Program, HIV Res Branch, Bethesda, MD 20892 USA. RP O'Brien, TR (reprint author), NCI, DCEG, Viral Epidemiol Branch, NIH, EPN 434,6130 Execut Blvd, Rockville, MD 20852 USA. RI Ioannidis, John/G-9836-2011 NR 28 TC 7 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD DEC 24 PY 1998 VL 12 IS 18 BP 2417 EP 2423 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 148TX UT WOS:000077550000010 PM 9875579 ER PT J AU Parenti, DM Williams, PL Hafner, R Jacobs, MR Hojczyk, P Hooton, TM Barber, TW Simpson, G van der Horst, C Currier, J Powderly, WG Limjoco, M Ellner, JJ AF Parenti, DM Williams, PL Hafner, R Jacobs, MR Hojczyk, P Hooton, TM Barber, TW Simpson, G van der Horst, C Currier, J Powderly, WG Limjoco, M Ellner, JJ CA AIDS Clin Trials Grp Protocol 135 Stud Tea TI A phase II/III trial of antimicrobial therapy with or without amikacin in the treatment of disseminated Mycobacterium avium infection in HIV-infected individuals SO AIDS LA English DT Article; Proceedings Paper CT 2nd National Conference on Human Retroviruses and Related Infections CY JAN 29-FEB 02, 1995 CL WASHINGTON, D.C. DE Mycobacterium avium; MAC; AIDS; HIV; bacteremia; amikacin ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; IMMUNE-DEFICIENCY SYNDROME; COMPLEX INFECTION; ANTIMYCOBACTERIAL AGENTS; BEIGE MICE; AIDS; INTRACELLULARE; CLOFAZIMINE; ETHAMBUTOL; CIPROFLOXACIN AB Objective: To determine the clinical and microbiologic benefit of adding amikacin to a four-drug oral regimen for treatment of disseminated Mycobacterium avium infection in HIV-infected patients. Design: A randomized, open-labeled, comparative trial. Setting: Outpatient clinics. Patients: Seventy-four patients with HIV and symptomatic bacteremic M. avium infection. Interventions: Rifampin 10 mg/kg daily, ciprofloxacin 500 mg twice daily, clofazimine 100 mg every day, and ethambutol 15 mg/kg orally daily for 24 weeks, with or without amikacin 10 mg/kg intravenously or intramuscularly 5 days weekly for the first 4 weeks. Main outcome measure: Clinical and microbiologic response at 4 weeks; quantitative level of bacteremia with M. avium. Results: No difference in clinical response was noted with the addition of amikacin to the four-drug oral regimen, and only 25% in either group had a complete or partial response at 4 weeks. A comparable quantitative decrease in bacteremia was noted in both treatment groups, with 16% of patients being culture-negative at 4 weeks and 38% at 12 weeks. Toxicities were mainly gastrointestinal. Amikacin was well tolerated. Median survival was 30 weeks in both groups. C1 George Washington Univ, Med Ctr, Div Infect Dis, Washington, DC 20037 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Hosp, Cleveland, OH 44106 USA. Frontier Sci & Res Technol Fdn, Amherst, NY USA. Univ Washington, Seattle, WA 98195 USA. Boston City Hosp, Boston, MA 02118 USA. Harbor Univ Calif, Torrance, CA USA. Univ N Carolina, Chapel Hill, NC 27599 USA. Beth Israel Hosp, Boston, MA 02215 USA. Univ Washington, St Louis, MO 63110 USA. RP Parenti, DM (reprint author), George Washington Univ, Med Ctr, Div Infect Dis, 2150 Penn Ave NW, Washington, DC 20037 USA. FU NIAID NIH HHS [AI-25867, AI-25879, AI-27664] NR 32 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD DEC 24 PY 1998 VL 12 IS 18 BP 2439 EP 2446 DI 10.1097/00002030-199818000-00013 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 148TX UT WOS:000077550000013 PM 9875582 ER PT J AU El-Sadr, WM Murphy, RL Yurik, RM Luskin-Hawk, R Cheung, TW Balfour, HH Eng, R Hooton, TM Kerkering, TM Schutz, M van der Horst, C Hafner, R AF El-Sadr, WM Murphy, RL Yurik, RM Luskin-Hawk, R Cheung, TW Balfour, HH Eng, R Hooton, TM Kerkering, TM Schutz, M van der Horst, C Hafner, R CA Community Program Clin Res AIDS AIDS Clin Trial TI Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS INFECTION; PROPHYLAXIS; SULFAMETHOXAZOLE; METAANALYSIS; ENCEPHALITIS; INTOLERANT; EFFICACY; 566C80; AIDS AB Background Although trimethoprim-sulfamethoxazole is the drug of choice for the prevention of Pneumocystis carinii pneumonia, many patients cannot tolerate it and must switch to an alternative agent. Methods We conducted a multicenter, open-label, randomized trial comparing daily atovaquone (1500-mg suspension) with daily dapsone (100 mg) for the prevention of P. carinii pneumonia among patients infected with the human immunodeficiency virus who could not tolerate trimethoprim-sulfamethoxazole. The median follow-up period was 27 months. Results Of 1057 patients enrolled, 298 had a history of P. carinii pneumonia. P. carinii pneumonia developed in 122 of 536 patients assigned to atovaquone (15.7 cases per 100 person-years), as compared with 135 of 521 in the dapsone group (18.4 cases per 100 person-years; relative risk for atovaquone vs, dapsone, 0.85; 95 percent confidence interval, 0.67 to 1.09; P = 0.20). The relative risk of death was 1.07 (95 percent confidence interval, 0.89 to 1.30; P = 0.45), and the relative risk of discontinuation of the assigned medication because of adverse events was 0.94 (95 percent confidence interval, 0.74 to 1.19; P = 0.59). Among the 546 patients who were receiving dapsone at base line, the relative risk of discontinuation because of adverse events was 3.78 for atovaquone as compared with dapsone (95 percent confidence interval, 2.37 to 6.01; P < 0.001); among those not receiving dapsone at base line, it was 0.42 (95 percent confidence interval, 0.30 to 0.58; P < 0.001). Conclusions Among patients who cannot tolerate trimethoprim-sulfamethoxazole, atovaquone and dapsone are similarly effective for the prevention of Fi carinii pneumonia. Our results support the continuation of dapsone prophylaxis among patients who are already receiving it. However, among those not receiving dapsone, atovaquone is better tolerated and may be the preferred choice for prophylaxis against Fl carinii pneumonia. (N Engl J Med 1998;339:1889-95.) (C) 1998, Massachusetts Medical Society. C1 Harlem Hosp Med Ctr, Div Infect Dis, New York, NY 10037 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. St Josephs Med Ctr, Chicago, IL USA. Mt Sinai Med Ctr, New York, NY 10029 USA. E Orange Vet Affairs Hosp, E Orange, NJ USA. Univ Washington, Seattle, WA 98195 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. Illinois Masonic Med Ctr, Chicago, IL 60657 USA. Univ N Carolina, Chapel Hill, NC USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. RP El-Sadr, WM (reprint author), Harlem Hosp Med Ctr, Div Infect Dis, Rm 3107,506 Lenox Ave, New York, NY 10037 USA. OI Murphy, Robert/0000-0003-3936-2052 NR 20 TC 90 Z9 92 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 DEC 24 PY 1998 VL 339 IS 26 BP 1889 EP 1895 DI 10.1056/NEJM199812243392604 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 150ZN UT WOS:000077696600004 PM 9862944 ER PT J AU Amundson, SA Myers, TG Fornace, AJ AF Amundson, SA Myers, TG Fornace, AJ TI Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress SO ONCOGENE LA English DT Review DE cell cycle; stress-response; p53; functional genomics ID WILD-TYPE P53; CELL-CYCLE CHECKPOINT; NATIONAL-CANCER-INSTITUTE; GENE-EXPRESSION PATTERNS; ANTICANCER DRUG SCREEN; TUMOR-SUPPRESSOR GENE; ABL TYROSINE KINASE; DIFFERENTIAL CYTOTOXICITY DATA; NUCLEOTIDE EXCISION-REPAIR; P53-DEPENDENT G(1) ARREST AB The tumor suppressor gene p53 plays a major role in regulation of the mammalian cellular stress response, in part through the transcriptional activation of genes involved in cell cycle control, DNA repair, and apoptosis. Many factors contribute to control of the activation of p53, and the downstream response to its activation may also vary depending on the cellular environment or other modifying factors in the cell. The complexity of the p53 response makes this an ideal system for application of newly emerging rapid throughput analysis techniques and informatics analysis. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, NIH, Bethesda, MD 20892 USA. RP Amundson, SA (reprint author), NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 212 TC 345 Z9 351 U1 1 U2 10 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 24 PY 1998 VL 17 IS 25 BP 3287 EP 3299 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 157EW UT WOS:000078048200010 PM 9916991 ER PT J AU Wheeler, A Bernard, GR Schoenfeld, D Steinberg, K AF Wheeler, A Bernard, GR Schoenfeld, D Steinberg, K TI Methylprednisolone for unresolving ARDS SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, ARDS Network, Bethesda, MD 20892 USA. RP Wheeler, A (reprint author), NIH, ARDS Network, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 10 Z9 10 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 DEC 23 PY 1998 VL 280 IS 24 BP 2074 EP 2074 DI 10.1001/jama.280.24.2074 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 149LE UT WOS:000077606100024 PM 9875869 ER PT J AU Cleeman, JI Lenfant, C AF Cleeman, JI Lenfant, C TI The National Cholesterol Education Program - Progress and prospects SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY HEART-DISEASE; HIGH BLOOD CHOLESTEROL; UNITED-STATES ADULTS; MYOCARDIAL-INFARCTION; MEN; PRAVASTATIN; PREVALENCE; PREVENTION; MORTALITY; STROKE AB The National Cholesterol Education Program (NCEP) is a prime example of the role the National Heart, Lung, and Blood institute has played, in its 50 years; of existence, as a catalyst for translating research advances into improved clinical and public health practices. Since its inception in 1985, the NCEP has adhered to 2 principles in mounting educational campaigns for professionals and the public: building on a strong science base and working in partnership with other organizations. In slightly more than a decade, the NCEP has made significant progress toward its goal of reducing the prevalence of high blood cholesterol. The impact of cholesterol education is clearly visible in 4 major trends: increasing professional and public cholesterol awareness; declining dietary intakes of saturated fat, total fat, and cholesterol; falling serum cholesterol levels; and a continuing decline in coronary heart disease (CHD) mortality rates. Nevertheless, cholesterol levels are still being undertreated, especially in patients with CHD, and substantial scientific and educational challenges remain. bs it looks forward to the 21st century, the NCEP plans to make continued progress by using emerging scientific developments and pursuing the powerful combination of cholesterol lowering in CHD patients and in primary prevention. C1 NHLBI, Natl Cholesterol Educ Program, Bethesda, MD 20892 USA. RP NHLBI, Natl Cholesterol Educ Program, 31 Ctr Dr,Bldg 31,Room 4A16, Bethesda, MD 20892 USA. EM cleemanj@gwgate.nhlbi.nih.gov NR 44 TC 87 Z9 87 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 23 PY 1998 VL 280 IS 24 BP 2099 EP 2104 DI 10.1001/jama.280.24.2099 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 149LE UT WOS:000077606100034 PM 9875878 ER PT J AU Rosa, P Bono, J Elias, A Errett, J Kupko, J Stevenson, B Taylor, G Tilly, K AF Rosa, P Bono, J Elias, A Errett, J Kupko, J Stevenson, B Taylor, G Tilly, K TI Genetic studies in Borrelia burgdorferi SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Review DE Borrelia burgdorferi; Lyme disease; spirochete; pathogenesis; genetics ID LYME-DISEASE AGENT; CIRCULAR PLASMID; BACILLUS-SUBTILIS; ETIOLOGIC AGENT; SPORULATION; SPIROCHETE; GYRB AB Borrelia burgdorferi, the agent of Lyme disease, has recently joined a growing number of microorganisms for which the entire genomic sequence is known. Despite this wealth of information, little is known about the contribution of specific spirochetal components to the pathogenesis of Lyme disease or their function in the normal life cycle of the organism. This discrepancy is due in part to the lack of a well-developed genetic system in B. burgdorferi, which in turn can be attributed to its relatively recent isolation and the dissimilarity of Borrelia from other genetically tractable bacteria. We are interested in several plasmid-encoded gene products in B. burgdorferi that may play a role in sensing and adaptation to the different environments the spirochete encounters as it completes an infectious cycle between the tick vector and the mammalian host. We are developing genetic tools with which to test the roles of specific B. burgdorferi gene products in the transmission cycle in an animal model of Lyme disease. We have demonstrated targeted gene inactivation by allelic exchange, using the gyrB(r) gene encoding coumermycin-resistant topoisomerase as a selectable marker. Spirochetes are transformed by electroporation and coumermycin-resistant colonies are screened by PCR for allelic exchange at the targeted locus. We have successfully inactivated several genes of interest in the type strain B31. We are investigating the utility of additional antibiotic resistance genes as selectable markers in B. burgdorferi. Targeted gene inactivation is a powerful tool with which to investigate the role of particular proteins in the basic biology and virulence of a pathogenic microorganism. We have made significant advances in our ability to genetically manipulate B. burgdorferi in order to address these issues. However, the available methods are incomplete and far from routine. We are currently improving existing methods as well as developing additional genetic tools with which to augment genetic studies in B. burgdorferi. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Rosa, P (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 24 TC 4 Z9 4 U1 0 U2 2 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0043-5325 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD DEC 23 PY 1998 VL 110 IS 24 BP 859 EP 862 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 156XD UT WOS:000078026900004 PM 10048165 ER PT J AU Elias, A Bono, JL Tilly, K Rosa, P AF Elias, A Bono, JL Tilly, K Rosa, P TI Growth of infectious and non-infectious B-burgdorferi at different salt concentrations SO WIENER KLINISCHE WOCHENSCHRIFT LA English DT Article DE Borrelia burgdorferi; growth; osmotic strength ID LYME-DISEASE SPIROCHETE; BORRELIA-BURGDORFERI; ESCHERICHIA-COLI; CULTIVATION; BACTERIA; HOMOLOGS; MUTANTS; TICKS; AGENT AB Borrelia burgdorferi, the causative agent of Lyme disease, grows in vitro in modified Barbour-Stoenner-Kelly (BSK-H) medium. We have studied the effect of increased osmotic strength of culture media on growth of infectious and non-infectious B. burgdorferi strains B31 and N40. Relatively small increases in the NaCl concentration of the medium significantly inhibited growth in infectious as well as non-infectious strains. Growth of low passage, infectious clone B31-4a was more sensitive to increased NaCl concentrations than high passage, non-infectious clone B31-a. Growth of two infectious N40 strains, one low passage (N40-Lp) and one high passage (N40-P31) was more resistant to increased NaCl concentration than growth of infectious B31-4a. Osmotic strength is an important physical parameter for growth of B. burgdorferi in vitro and could influence its ability to adapt and to establish an infection within ticks and mammals. C1 NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, Hamilton, MT 59840 USA. RP Elias, A (reprint author), NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. NR 19 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG WIEN PI VIENNA PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 VIENNA, AUSTRIA SN 0043-5325 J9 WIEN KLIN WOCHENSCHR JI Wien. Klin. Wochen. PD DEC 23 PY 1998 VL 110 IS 24 BP 863 EP 865 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 156XD UT WOS:000078026900005 PM 10048166 ER PT J AU Hansen, JC Tse, C Wolffe, AP AF Hansen, JC Tse, C Wolffe, AP TI Structure and function of the core histone N-termini: more than meets the eye SO BIOCHEMISTRY LA English DT Article ID HIGHER-ORDER STRUCTURE; SILENT MATING LOCI; SECONDARY STRUCTURE; SACCHAROMYCES-CEREVISIAE; CHROMATIN STRUCTURE; CRYSTAL-STRUCTURE; TAIL DOMAINS; NUCLEOSOME; REPRESSION; YEAST AB For two decades, the core histone N-termini generally have been thought of as unstructured domains whose function is to bind to DNA and screen negative charge. New data indicates that both the molecular mechanisms of action and biological functions of the core histone N-termini in chromatin are considerably more complex. At the level of the chromatin fiber, multiple distinct functions of the N-termini are required to achieve higher order chromatin condensation, two of which apparently involve protein-protein rather than protein-DNA interactions. In addition, the N-termini have been documented to participate in specific inter-actions with many chromatin-associated regulatory proteins. Here, we discuss evidence supporting the new concepts that when functioning in their natural chromatin context, (1) the N-termini are engaged primarily in protein-protein interactions, (2) as a consequence of these interactions the N-termini adopt specific secondary structure, (3) posttranslational modifications such as acetylation disrupt the ability of the N-termini to form secondary structure, and (4) because the N-termini perform essential roles in both chromatin condensation and also bind specific chromatin-associated proteins, the global structure and function of any given region of the genome will be determined predominantly by the core histone N-termini and their specific interaction partners. C1 Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78284 USA. NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Hansen, JC (reprint author), Univ Texas, Hlth Sci Ctr, Dept Biochem, 7703 Floyd Curl Dr, San Antonio, TX 78284 USA. EM hansen@bioc02.uthscsa.edu FU NIGMS NIH HHS [GM45916] NR 57 TC 180 Z9 182 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 22 PY 1998 VL 37 IS 51 BP 17637 EP 17641 DI 10.1021/bi982409v PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153TH UT WOS:000077848400001 PM 9922128 ER PT J AU Groves, MR Yao, ZJ Roller, PP Burke, TR Barford, D AF Groves, MR Yao, ZJ Roller, PP Burke, TR Barford, D TI Structural basis for inhibition of the protein tyrosine phosphatase 1B by phosphotyrosine peptide mimetics SO BIOCHEMISTRY LA English DT Article ID SIGNAL-TRANSDUCTION; POTENT INHIBITION; CRYSTAL-STRUCTURE; DEPHOSPHORYLATION; CRYSTALLOGRAPHY; IDENTIFICATION; RECOGNITION; REFINEMENT; DOMAIN; DESIGN AB Protein tyrosine phosphatases regulate diverse cellular processes and represent important targets for therapeutic intervention in a number of diseases, The crystal structures of protein tyrosine phosphatase 1B (PTP1B) in complex with small molecule inhibitors based upon two classes of phosphotyrosine mimetics, the (difluoronaphthylmethyl)phosphonic acids and the fluoromalonyl tyrosines, have been determined to resolutions greater than 2.3 Angstrom. The fluoromalonyl tyrosine residue was incorporated within a cyclic hexapeptide modeled on an autophosphorylation site of the epidermal growth factor receptor. The structure of this inhibitor bound to PTP1B represents the first crystal structure of a non-phosphonate-containing inhibitor and reveals the mechanism of phosphotyrosine mimicry by the fluoromalonyl tyrosine residue and the nature of its interactions within the catalytic site of PTP1B, In contrast to complexes of PTP1B with phosphotyrosine-containing peptides, binding of the fluoromalonyl tyrosine residue to the catalytic site of PTP1B is not accompanied by closure of the catalytic site WPD loop. Structures of PTP1B in complex with the (difluoronaphthylmethyl)phosphonic acid derivatives reveal that substitutions of the naphthalene ring modulate the mode of inhibitor binding to the catalytic site and provide the potential for enhanced inhibitor affinity and the generation of PTP-specific inhibitors. These results provide a framework for the rational design of higher affinity and more specific phosphotyrosine mimetic inhibitors of not only protein tyrosine phosphatases but also SH2 and PTB domains. C1 Univ Oxford, Dept Biochem, Mol Biophys Lab, Oxford OX1 3QU, England. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Barford, D (reprint author), Univ Oxford, Dept Biochem, Mol Biophys Lab, S Parks Rd, Oxford OX1 3QU, England. EM davidb@biop.ox.ac.uk RI Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 NR 39 TC 94 Z9 98 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 22 PY 1998 VL 37 IS 51 BP 17773 EP 17783 DI 10.1021/bi9816958 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153TH UT WOS:000077848400016 PM 9922143 ER PT J AU Chertova, EN Kane, BP McGrath, C Johnson, DG Sowder, RC Arthur, LO Henderson, LE AF Chertova, EN Kane, BP McGrath, C Johnson, DG Sowder, RC Arthur, LO Henderson, LE TI Probing the topography of HIV-1 nucleocapsid protein with the alkylating agent N-ethylmaleimide SO BIOCHEMISTRY LA English DT Article ID MURINE LEUKEMIA-VIRUS; ZINC FINGERS; RNA ENCAPSIDATION; GENOMIC RNA; DOMAIN; MUTATIONS; SEQUENCE; BINDING; MUTANTS AB Retroviral nucleocapsid (NC) proteins contain one or two zinc fingers (ZFs) consisting of a CCHC peptide motif that coordinates Zn(II), Mutational and biochemical analyses have shown that NC ZFs an directly involved in multiple stages of viral replication, including genomic RNA encapsidation, virus maturation, and the early infection process. The multiple roles of the conserved retroviral ZFs make them attractive targets for antiviral agents. We have previously shown that a variety of chemical compounds can inactivate the whole virus by attacking NC ZFs, For the enhancement of the specificity of antiviral reagents, it is desirable to have a detailed knowledge of the spatial organization of reactive sites on the NC protein in its free and oligonucleotide-bound states. A method has been developed using chemical probes to assess the reactivity of specific Cys residues in the NC protein, and is being used to investigate the topography of ZFs in different contexts. In this study we focus on the reaction mechanism of N-ethylmaleimide (NEM) with free HIV-1 NCp7 protein. Our results show that the conformation of free NCp7 restricts the initial site of attack to Cys-49 (the most distal Cys residue in the second ZF) and that the reactivity of thiols in full-length protein differs from that of the isolated ZF peptides. A moderate to near complete reduction in reaction rate was observed when NCp7 was complexed with different oligonucleotides. These findings provide a set of experimentally determined parameters that can serve to guide computational modeling of the NC protein and will be useful for the rational design of drugs directed against retroviral ZFs. C1 NCI, Frederick Canc Res & Dev Ctr, Prot Chem Lab, AIDS Vaccine Program ,SAIC Frederick, Frederick, MD 21702 USA. RP Chertova, EN (reprint author), NCI, Frederick Canc Res & Dev Ctr, Prot Chem Lab, AIDS Vaccine Program ,SAIC Frederick, POB B,Bldg 535,Room 424, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 24 TC 43 Z9 45 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 22 PY 1998 VL 37 IS 51 BP 17890 EP 17897 DI 10.1021/bi980907y PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153TH UT WOS:000077848400029 PM 9922156 ER PT J AU Russell, MW Kemp, P Wang, LH Brody, LC Izumo, S AF Russell, MW Kemp, P Wang, LH Brody, LC Izumo, S TI Molecular cloning of the human HAND2 gene SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE HAND2; cDNA sequence; cardiac myocyte; basic helix-loop-helix; transcription factor; chromosomal localization ID EXPRESSION; PROTEIN; EHAND; DELETION; CONTIG AB We have cloned and characterized the coding sequence of the human HAND2 basic helix-loop-helix transcription factor. The amino acid sequence includes an amino-terminal polyalanine repeat which is precisely conserved in the rat HAND2 gene. Northern analysis indicates that the HAND2 transcript is 2.3 kb in length and strongly expressed in the human heart. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Univ Michigan, Dept Pediat & Commun Dis, Ann Arbor, MI 48109 USA. Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England. NIH, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Russell, MW (reprint author), Div Pediat Cardiol, F1310 MCHS,Box 0204,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM mruss@umich.edu FU NHLBI NIH HHS [NIH-HL51253, NIH-HL03686-01] NR 22 TC 17 Z9 19 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD DEC 22 PY 1998 VL 1443 IS 3 BP 393 EP 399 DI 10.1016/S0167-4781(98)00237-1 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 156CK UT WOS:000077983700016 PM 9878849 ER PT J AU Darden, T Pearlman, D Pedersen, LG AF Darden, T Pearlman, D Pedersen, LG TI Ionic charging free energies: Spherical versus periodic boundary conditions SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; FINITE-SIZE CORRECTIONS; PARTICLE MESH EWALD; ELECTROSTATIC INTERACTIONS; AQUEOUS-SOLUTION; HYDRATION; WATER; POTENTIALS; ARTIFACTS; SYSTEMS AB Ionic charging free energies calculated by Ewald summation differ substantially from those calculated in spherical cluster calculations, with or without the inclusion of a Born correction in the latter. Using Gauss' law, we derive an electrostatic potential for ions in spherical clusters that involves contributions only from the interior solvent. This "interior" potential agrees with the "P-summation" approach proposed by Hummer et al. [J. Phys. Chem. B 101, 3017 (1997)], and leads to charging free energies which agree, within simulation error, with those given by Ewald summation with finite-size corrections. The difference in charging free energies between this approach and the conventional cluster free energies including the Born correction is traced to the surface potential of water. (C) 1998 American Institute of Physics. [S0021-9606(98)50948-8]. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Vertex Pharmaceut, Cambridge, MA 02139 USA. Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Darden, T (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. RI Pedersen, Lee/E-3405-2013 OI Pedersen, Lee/0000-0003-1262-9861 NR 41 TC 89 Z9 90 U1 2 U2 20 PU AMER INST PHYSICS PI WOODBURY PA CIRCULATION FULFILLMENT DIV, 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2999 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD DEC 22 PY 1998 VL 109 IS 24 BP 10921 EP 10935 DI 10.1063/1.477788 PG 15 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 148QB UT WOS:000077542400040 ER PT J AU Wang, ZY Wang, F Sellers, JR Korn, ED Hammer, JA AF Wang, ZY Wang, F Sellers, JR Korn, ED Hammer, JA TI Analysis of the regulatory phosphorylation site in Acanthamoeba myosin IC by using site-directed mutagenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HEAVY-CHAIN KINASE; P21-ACTIVATED KINASE; 3RD ISOFORM; AMINO-ACID; ACTIN; CASTELLANII; IA; SEQUENCE; BINDING; COMPLEX AB The actin-activated ATPase activity of Acanthamoeba myosin IC is stimulated 15- to 20-fold by phosphorylation of Ser-329 in the heavy chain. In most myosins, either glutamate or aspartate occupies this position, which lies within a surface loop that forms part of the actomyosin interface. To investigate the apparent need for a negative charge at this site, we mutated Ser-329 to alanine, asparagine, aspartate, or glutamate and coexpressed the Flag-tagged wild-type or mutant heavy chain and light chain in baculovirus-infected insect cells. Recombinant wild-type myosin IC was indistinguishable from myosin IC purified from Acanthamoeba as determined by (i) the dependence of its actin-activated ATPase activity on heavy-chain phosphorylation, (ii) the unusual triphasic dependence of its ATPase activity on the concentration of F-actin, (iii) its K-m for ATP, and (iv) its ability to translocate actin filaments. The Ala and Asn mutants had the same low actin-activated ATPase activity as unphosphorylated wild-type myosin IC. The Glu mutant, like the phosphorylated wild-type protein, was 16-fold more active than unphosphorylated wild type, and the Asp mutant was 8-fold more active. The wild-type and mutant proteins had the same K-m for ATP. Unphosphorylated wild-type protein and the Ala and Asn mutants were unable to translocate actin filaments, whereas the Glu mutant translocated filaments at the same velocity, and the Asp mutant at 50% the velocity, as phosphorylated wild-type proteins. These results demonstrate that an acidic amino acid can supply the negative charge in the surface loop required for the actin-dependent activities of Acanthamoeba myosin IC in vitro and indicate that the length of the side chain that delivers this charge is important. C1 NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. NHLBI, Mol Cardiol Lab, Bethesda, MD 20892 USA. RP NHLBI, Cell Biol Lab, Bldg 3,Room B1-22, Bethesda, MD 20892 USA. EM edk@nih.gov RI Korn, Edward/F-9929-2012 NR 45 TC 32 Z9 32 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 DEC 22 PY 1998 VL 95 IS 26 BP 15200 EP 15205 DI 10.1073/pnas.95.26.15200 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150ZV UT WOS:000077697200013 PM 9860946 ER PT J AU Carragher, BO Cheng, NQ Wang, ZY Korn, ED Reilein, A Belnap, DM Hammer, JA Steven, AC AF Carragher, BO Cheng, NQ Wang, ZY Korn, ED Reilein, A Belnap, DM Hammer, JA Steven, AC TI Structural invariance of constitutively active and inactive mutants of Acanthamoeba myosin IC bound to F-actin in the rigor and ADP-bound states SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID 3-DIMENSIONAL STRUCTURE; UNCONVENTIONAL MYOSINS; ELECTRON-MICROSCOPY; IMAGE-ANALYSIS; MUSCLE MYOSIN; AMINO-ACID; SEQUENCE; COMPLEX; PHOSPHORYLATION; IDENTIFICATION AB The three single-headed monomeric myosin I isozymes of Acanthamoeba castellanii (AMIs)-AMIA, AMIB, and AMIC-are among the best-studied of all myosins, We have used AMIC to study structural correlates of myosin's actin-activated ATPase, This activity is normally controlled by phosphorylation of Ser-329, but AMIC may be switched into constitutively active or inactive states by substituting this residue with Glu or Ala, respectively, To determine whether activation status is reflected in structural differences in the mode of attachment of myosin to actin, these mutant myosins were bound to actin filaments in the absence of nucleotide (rigor state) and visualized at 24-Angstrom resolution by using cryoelectron microscopy and image reconstruction. No such difference was observed. Consequently, we suggest that regulation may be affected not by altering the static (time-averaged) structure of AMIC but by modulating its dynamic properties, i.e,, molecular breathing. The tail domain of vertebrate intestinal brush-border myosin I has been observed to swing through 31 degrees on binding of ADP, However, it was predicted on grounds of differing kinetics that any such effects with AMIC should be small [Jontes, J. D., Ostap, E, M,, Pollard, T, D, & Milligan, R, A. (1998) J, Cell Biol. 141, 155-162], We have confirmed this hypothesis by observing actin-associated AMIC in its ADP-bound state, Finally, we compared AMIC to brush-border myosin I and AMIB, which were previously studied under similar conditions. In each case, the shape and angle of attachment to F-actin of the catalytic domain is largely conserved, but the domain structure and disposition of the tail is distinctively different for each myosin. C1 NIH, NHLBI, Cell Biol Lab, Bethesda, MD 20892 USA. Univ Illinois, Beckman Inst, Imaging Technol Grp, Urbana, IL 61801 USA. NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. RP Korn, ED (reprint author), NIH, NHLBI, Cell Biol Lab, Bldg 3,Room B1-22,MSC 0301, Bethesda, MD 20892 USA. EM edk@nih.gov RI Korn, Edward/F-9929-2012; OI Carragher, Bridget/0000-0002-0624-5020 NR 35 TC 18 Z9 18 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 DEC 22 PY 1998 VL 95 IS 26 BP 15206 EP 15211 DI 10.1073/pnas.95.26.15206 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150ZV UT WOS:000077697200014 PM 9860947 ER PT J AU Vandewiele, D Borden, A O'Grady, PI Woodgate, R Lawrence, CW AF Vandewiele, D Borden, A O'Grady, PI Woodgate, R Lawrence, CW TI Efficient translesion replication in the absence of Escherichia coli Umu proteins and 3 '-5 ' exonuclease proofreading function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE translesion replication; UV mutagenesis; umuDC; SOS response; UVM ID DNA-POLYMERASE-III; UV-INDUCED MUTAGENESIS; T CYCLOBUTANE DIMER; SALMONELLA-TYPHIMURIUM; EPSILON-SUBUNIT; EDITING SUBUNIT; CIS-SYN; IN-VIVO; HOLOENZYME; REPAIR AB Translesion replication (TR) past a cyclobutane pyrimidine dimer in Escherichia coli normally requires the UmuD'C-2 complex, RecA protein, and DNA polymerase III holoenzyme (pol III). However, we find that efficient TR can occur in the absence of the Umu proteins if the 3'-5' exonuclease proofreading activity of the pol III epsilon-subunit also is disabled. TR was measured in isogenic uvrA6 Delta umuDC strains carrying the dominant negative dnaQ allele, mutD5, or Delta dnaQ spq-2 mutations by transfecting them with single-stranded M13-based vectors containing a specifically located cis-syn T-T dimer, As expected, little TR was observed in the Delta umuDC dnaQ(+) strain. Surprisingly, 26% TR occurred in UV-irradiated Delta umuDC mutD5 cells, one-half the frequency found in a uvrA6 umuDC(+)mutD5 strain, lexA3 (Ind(-)) derivatives of the strains showed that this TR was contingent on two inducible functions, one LexA-dependent, responsible for approximate to 70% of the TR, and another LexA-independent, responsible for the remaining approximate to 30%. Curiously, the Delta umuDC Delta dnaQ spq-2 strain exhibited only the LexA-independent level of TR, The cause of this result appears to be the spq-2 allele, a dnaE mutation required for viability in Delta dnaQ strains, since introduction of spq-2 into the Delta umuDC mutD5 strain also reduces the frequency of TR to the LexA-independent level, The molecular mechanism responsible for the LexA-independent TR is unknown but may be related to the UVM phenomenon [Palejwala, V. A., Wang, G. E., Murphy, H. S. & Humayun, M. Z. (1995) J. Bacteriol. 177, 6041-6048]. LexA-dependent TR does not result from the induction of pol II, since TR in the Delta umuDC mutD5 strain is unchanged by introduction of a Delta polB mutation. C1 Univ Rochester, Sch Med & Dent, Dept Biochem & Biophys, Rochester, NY 14642 USA. NICHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Lawrence, CW (reprint author), Univ Rochester, Sch Med & Dent, Dept Biochem & Biophys, Rochester, NY 14642 USA. EM christopher_lawrence@urmc.rochester.edu FU NIGMS NIH HHS [GM32885] NR 57 TC 23 Z9 24 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 DEC 22 PY 1998 VL 95 IS 26 BP 15519 EP 15524 DI 10.1073/pnas.95.26.15519 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150ZV UT WOS:000077697200068 PM 9861001 ER PT J AU Major, EO Neel, JV AF Major, EO Neel, JV TI The JC and BK human polyoma viruses appear to be recent introductions to some South American Indian tribes: There is no serological evidence of cross-reactivity with the simian polyoma virus SV40 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LARGE T-ANTIGEN; HUMAN-DIPLOID FIBROBLASTS; CHROMOSOME-ABERRATIONS; CHERNOBYL ACCIDENT; ROGUE CELLS; PLEURAL MESOTHELIOMA; YANOMAMA INDIANS; DNA-SEQUENCES; LYMPHOCYTES; TRANSMISSION AB In an effort to understand the unusual cytogenetic damage earlier encountered in the Yanomama Indians, plasma samples from 425 Amerindians representing 14 tribes have been tested for hemagglutination inhibition antibodies to the human JC polyoma virus and from 369 Amerinds from 13 tribes for hemagglutination inhibition antibodies to the human BK polyoma virus, There is for both viruses highly significant heterogeneity between tribes for the prevalence of serum antibody titers greater than or equal to 1/40, the pattern of infection suggesting that these two viruses only relatively recently have been introduced into some of these tribes. Some of these samples, from populations with no known exposure to the simian polyoma virus SV40, also were tested for antibodies to this virus by using an immunospot assay. In contrast to the findings of Brown et al. (Brown, P., Tsai, T. & Gajdusek, D. C. (1975) Am. J. Epidemiol. 102, 331-340), none of the samples was found to possess antibodies to SV40, In addition, no significant titers to SV40 were found in a sample of 97 Japanese adults, many of whom had been found to exhibit elevated titers to the JC and BK viruses, This study thus suggests that these human sera contain significant antibody titers to the human polyoma viruses JC and BK but do not appear to contain either cross-reactive antibodies to SV40 or primary antibodies resulting from SV40 infection. C1 NINDS, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, Bldg 36,Room 5W21, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA26803] NR 56 TC 16 Z9 16 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 DEC 22 PY 1998 VL 95 IS 26 BP 15525 EP 15530 DI 10.1073/pnas.95.26.15525 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150ZV UT WOS:000077697200069 PM 9861002 ER PT J AU Ginns, EI St Jean, P Philibert, RA Galdzicka, M Damschroder-Williams, P Thiel, B Long, RT Ingraham, LJ Dalwaldi, H Murray, MA Ehlert, M Paul, S Remortel, BG Patel, AP Anderson, MCH Shaio, C Lau, E Dymarskaia, I Martin, BM Stubblefield, B Falls, KM Carulli, JP Keith, TP Fann, CSJ Lacy, LG Allen, CR Hostetter, AM Elston, RC Schork, NJ Egeland, JA Paul, SM AF Ginns, EI St Jean, P Philibert, RA Galdzicka, M Damschroder-Williams, P Thiel, B Long, RT Ingraham, LJ Dalwaldi, H Murray, MA Ehlert, M Paul, S Remortel, BG Patel, AP Anderson, MCH Shaio, C Lau, E Dymarskaia, I Martin, BM Stubblefield, B Falls, KM Carulli, JP Keith, TP Fann, CSJ Lacy, LG Allen, CR Hostetter, AM Elston, RC Schork, NJ Egeland, JA Paul, SM TI A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID GENETIC DISSECTION; LINKAGE ANALYSIS; COMPLEX TRAITS; DNA MARKERS; ASSOCIATION; RELIABILITY; PEDIGREE; ILLNESS; ALLELES; MICE AB Bipolar affective disorder (BPAD; manic-depressive illness) is characterized by episodes of mania and/or hypomania interspersed with periods of depression. Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD. To date, however, linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD. To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD, similar to what is observed in other genetic disorders, we used mental health wellness (absence of any psychiatric disorder) as the phenotype in our genome-wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD. We have found strong evidence for a locus on chromosome 4p at D4S2939 (maximum GENEHUNTER-PLUS nonparametric linkage score = 4.05, P = 5.22 x 10(-4); SIBPAL P-empirical value <3 x 10(-5)) and suggestive evidence for a locus on chromosome 4q at D4S397 (maximum GENEHUNTER-PLUS nonparametric linkage score 3.29, P = 2.57 x 10(-3); SIBPAL P-empirical value <1 x 10(-3)) that are linked to mental health wellness. These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders. C1 NIMH, Clin Neurosci Branch, Intramural Res Program, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44109 USA. Genome Therapeut Corp, Waltham, MA 02154 USA. Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10467 USA. Univ Miami, Sch Med, Dept Psychiat, Miami, FL 33136 USA. Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46285 USA. Indiana Univ, Sch Med, Dept Pharmacol, Indianapolis, IN 46285 USA. Indiana Univ, Sch Med, Dept Toxicol, Indianapolis, IN 46285 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Ginns, EI (reprint author), NIMH, Clin Neurosci Branch, Intramural Res Program, Bldg 49,Room B1EE16,49 Convent Dr,MSC4405, Bethesda, MD 20892 USA. EM ginnse@irp.nimh.nih.gov FU NCRR NIH HHS [RR03655, P41 RR003655]; NIMH NIH HHS [MH28287]; PHS HHS [28356] NR 38 TC 67 Z9 68 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 DEC 22 PY 1998 VL 95 IS 26 BP 15531 EP 15536 DI 10.1073/pnas.95.26.15531 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150ZV UT WOS:000077697200070 PM 9861003 ER PT J AU Naramura, M Kole, HK Hu, RJ Gu, H AF Naramura, M Kole, HK Hu, RJ Gu, H TI Altered thymic positive selection and intracellular signals in Cb1-deficient mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LYMPHOCYTE ANTIGEN RECEPTORS; PROTOONCOGENE C-CBL; T-CELL DEVELOPMENT; NEGATIVE SELECTION; TRANSGENIC MICE; TYROSINE KINASE; THYMOCYTE DIFFERENTIATION; CD4(+)CD8(+) THYMOCYTES; CD4+8+ THYMOCYTES; MAP KINASE AB Cbl is the product of the protooncogene c-cbl and is involved in T cell antigen receptor (TCR)-mediated signaling. To understand the role of Cbl for immune system development and function, we generated a Cbl-deficient mouse strain. In Cbl-deficient mice, positive selection of the thymocytes expressing major histocompatibility complex class II-restricted transgenic TCR was significantly enhanced. Two factors may have contributed to the altered thymic selection. First, Cbl deficiency markedly up-regulated the activity of ZAP-70 and mitogen-activated protein kinases. The mitogen-activated protein kinase pathway was shown previously to be involved in thymic positive selection. Second, Cbl-deficient thymocytes expressed CD3 and CD4 molecules at higher levels, which consequently may increase the avidity of TCR/major histocompatibility complex/coreceptor interaction, Thus, Cbl plays a novel role in modulating TCR-mediated multiple signaling pathways and fine-tunes the signaling threshold for thymic selection. C1 NIAID, Immunol Lab, NIH, Rockville, MD 20852 USA. RP Gu, H (reprint author), NIAID, Immunol Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. OI Naramura, Mayumi/0000-0003-3658-0767 NR 54 TC 253 Z9 256 U1 0 U2 5 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 DEC 22 PY 1998 VL 95 IS 26 BP 15547 EP 15552 DI 10.1073/pnas.95.26.15547 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150ZV UT WOS:000077697200073 PM 9861006 ER PT J AU Bogue, MA Jhappan, C Roth, DB AF Bogue, MA Jhappan, C Roth, DB TI Analysis of variable (diversity) joining recombination in DNA-dependent protein kinase (DNA-PK)-deficient mice reveals DNA-PK-independent pathways for both signal and coding joint formation 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; COMBINED IMMUNE-DEFICIENCY; SCID MOUSE THYMOCYTES; V(D)J RECOMBINATION; CATALYTIC SUBUNIT; MAMMALIAN-CELLS; SACCHAROMYCES-CEREVISIAE; KU86-DEFICIENT MICE; IONIZING-RADIATION AB Previous studies have suggested that ionizing radiation causes irreparable DNA double-strand breaks in mice and cell lines harboring mutations in any of the three subunits of DNA-dependent protein kinase (DNA-PK) (the catalytic subunit, DNA-PKcs, or one of the DNA-binding subunits, Ku70 or Ku86), In actuality, these mutants vary in their ability to resolve double-strand breaks generated during variable (diversity) joining [V(D)J] recombination, Mutant cell lines and mice with targeted deletions in Ku70 or Ku86 are severely compromised in their ability to form coding and signal joints, the products of V(D)J recombination, It is noteworthy, however, that severe combined immunodeficient (SCID) mice, which bear a nonnull mutation in DNA-PKcs, are substantially less impaired in forming signal joints than coding joints, The current view holds that the defective protein encoded by the murine SCID allele retains enough residual function to support signal joint formation. An alternative hypothesis proposes that DNA-PKcs and Ku perform different roles in V(D)J recombination, with DNA-PKcs required only for coding joint formation. To resolve this issue, we examined V(D)J recombination in DNA-PKcs-deficient (SLIP) mice. We found that the effects of this mutation on coding and signal joint formation are identical to the effects of the SCID mutation. Signal-joints are formed at levels 10-fold lower than in wild type, and one-half of these joints are aberrant. These data are incompatible with the notion that signal joint formation in SCID mice results from residual DNA-PKcs function, and suggest a third possibility: that DNA-PKcs normally plays an important but nonessential role in signal joint formation. C1 Baylor Coll Med, Howard Hughes Med Inst, Houston, TX 77030 USA. Baylor Coll Med, Dept Microbiol & Immunol, Houston, TX 77030 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Roth, DB (reprint author), Baylor Coll Med, Howard Hughes Med Inst, Immunol M929,1 Baylor Plaza, Houston, TX 77030 USA. EM davidbr@bcm.tmc.edu FU NCI NIH HHS [CA-76317, R01 CA076317]; NIAID NIH HHS [AI-36420, R01 AI036420] NR 64 TC 68 Z9 68 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 22 PY 1998 VL 95 IS 26 BP 15559 EP 15564 DI 10.1073/pnas.95.26.15559 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150ZV UT WOS:000077697200075 PM 9861008 ER PT J AU Krege, JH Hodgin, JB Couse, JF Enmark, E Warner, M Mahler, JF Sar, M Korach, KS Gustafsson, JA Smithies, O AF Krege, JH Hodgin, JB Couse, JF Enmark, E Warner, M Mahler, JF Sar, M Korach, KS Gustafsson, JA Smithies, O TI Generation and reproductive phenotypes of mice lacking estrogen receptor beta SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene targeting; estrogen action; ovary; folliculogenesis; fertility ID FOLLICLE-STIMULATING-HORMONE; ALPHA-DEFICIENT MICE; MESSENGER-RNA; ER-BETA; TARGETED DISRUPTION; LUTEINIZING-HORMONE; GENE DISRUPTION; RAT; MOUSE; EXPRESSION AB Estrogens influence the differentiation and maintenance of reproductive tissues and affect lipid metabolism and bone remodeling. Two estrogen receptors (ERs) have been identified to date, ER alpha and ER beta. We previously generated and studied knockout mice lacking estrogen receptor alpha and reported severe reproductive and behavioral phenotypes including complete infertility of both male and female mice and absence of breast tissue development. Here we describe the generation of mice lacking estrogen receptor beta (ER beta -/-) by insertion of a neomycin resistance gene into exon 3 of the coding gene by using homologous recombination in embryonic stem cells. Mice lacking this receptor develop normally and are indistinguishable grossly and histologically as young adults from their littermates. RNA analysis and immunocytochemistry show that tissues from ER beta -/- mice lack normal ER beta RNA and protein. Breeding experiments with young, sexually mature females show that they are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice. Superovulation experiments indicate that this reduction in fertility is the result of reduced ovarian efficiency. The mutant females have normal breast development and lactate normally. Young, sexually mature male mice show no overt abnormalities and reproduce normally. Older mutant males display signs of prostate and bladder hyperplasia, Our results indicate that ER beta is essential for normal ovulation efficiency but is not essential for female or male sexual differentiation, fertility, or lactation. Future experiments are required to determine the role of ER beta in bone and cardiovascular homeostasis. C1 Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA. Guilford Med Associates, Greensboro, NC 27405 USA. NIEHS, NIH, Reprod & Dev Toxicol Lab, Receptor Biol Sect, Res Triangle Pk, NC 27709 USA. NIEHS, NIH, Expt Pathol Lab, Res Triangle Pk, NC 27709 USA. Karolinska Inst, Novum, Dept Med Nutr, S-14186 Huddinge, Sweden. Chem Ind Inst Toxicol, Res Triangle Pk, NC 27709 USA. RP Smithies, O (reprint author), Univ N Carolina, Dept Pathol, Room 71,Brinkhous Bullitt Bldg, Chapel Hill, NC 27599 USA. EM jhlynch@med.unc.edu OI Korach, Kenneth/0000-0002-7765-418X FU NIGMS NIH HHS [F31 GM020069, GM20069, R01 GM020069] NR 45 TC 1113 Z9 1142 U1 3 U2 29 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 DEC 22 PY 1998 VL 95 IS 26 BP 15677 EP 15682 DI 10.1073/pnas.95.26.15677 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150ZV UT WOS:000077697200096 PM 9861029 ER PT J AU Teitelbaum, R Glatman-Freedman, A Chen, B Robbins, JB Unanue, E Casadevall, A Bloom, BR AF Teitelbaum, R Glatman-Freedman, A Chen, B Robbins, JB Unanue, E Casadevall, A Bloom, BR TI A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CRYPTOCOCCUS-NEOFORMANS INFECTION; NITRIC-OXIDE SYNTHASE; INTERFERON-GAMMA; MONOCLONAL-ANTIBODIES; T-CELLS; MICE; RESISTANCE; MACROPHAGES; GLUCURONOXYLOMANNAN; EXPRESSION AB Murine mAbs reactive with the surface of Mycobacterium tuberculosis were assayed ed for their ability to affect the course of infection in mice challenged with virulent organisms. An IgG3 mAb (9d8) specific for arabinomannan and reactive with purified antigen from a clinical isolate of M. tuberculosis conferred partial protection on mice after respiratory challenge (30-60% survival >75 days; P less than or equal to 0.05). Control mice pretreated with an irrelevant mAb of the same isotype succumbed to tuberculosis within 30 days. Mice with gene disruptions in interferon gamma and major histocompatibility complex Class II also were partially protected from challenge. The protective mAb was neither bactericidal nor inhibitory of infection or bacterial replication. Nevertheless, it profoundly altered the nature of the granulomas in the infected lungs. Mice treated with mAb 9d8 and challenged with M. tuberculosis localized the pathogen within granuloma centers, suggesting that the mAb conferred protection by enhancing a cellular immune response. C1 Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10064 USA. Albert Einstein Coll Med, Howard Hughes Med Inst, Bronx, NY 10064 USA. NIH, Dept Pediat, Jacobi Med Ctr, Bethesda, MD 20892 USA. NIH, NICHHD, Bethesda, MD 20892 USA. Washington Univ, Dept Pathol, St Louis, MO 63110 USA. RP Bloom, BR (reprint author), Albert Einstein Coll Med, Dept Microbiol & Immunol, 1300 Morris Pk Ave, Bronx, NY 10064 USA. EM bloom@aecom.yu.edu FU NHLBI NIH HHS [R01 HL059842]; NIAID NIH HHS [R01 AI033142, AI07118, AI33142, R01 AI007118, R37 AI033142]; PHS HHS [23545] NR 38 TC 166 Z9 173 U1 0 U2 5 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 DEC 22 PY 1998 VL 95 IS 26 BP 15688 EP 15693 DI 10.1073/pnas.95.26.15688 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150ZV UT WOS:000077697200098 PM 9861031 ER PT J AU Bystricky, S Szu, SC Zhang, J Kovac, P AF Bystricky, S Szu, SC Zhang, J Kovac, P TI Conformational differences among mono- and oligosaccharide fragments of the O-specific polysaccharides of Vibrio cholerae O1 revealed by circular dichroism SO CARBOHYDRATE RESEARCH LA English DT Article DE Vibrio cholerae; polysaccharides; O-antigens ID METHYL ALPHA-GLYCOSIDE; REPEATING UNIT; SEROTYPE-OGAWA; CRYSTAL-STRUCTURE; ANTIGEN; INABA; O/1; O-1; LIPOPOLYSACCHARIDE AB The circular dichroism (CD) of synthetic mono- and oligosaccharides that represent the terminal, non-reducing group of O-antigens of Vibrio choler ne O1 from the subtypes Ogawa and Inaba was measured in various solvents. We found differences in the CD of the monosaccharides of these subtypes that decrease with increasing chain lengths of the oligosaccharides. The differences can be explained by different orientations of the N-acyl side chain of the terminal monosaccharides. The linear relationship of ellipticity versus the number of residues in an oligosaccharide chain follows the principle of optical superposition. This, together with a similar contribution by internal units to the overall ellipticity, suggests an identical, regular conformation of oligosaccharide fragments of both Ogawa and Inaba series. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 Slovak Acad Sci, Inst Chem, Bratislava 84238, Slovakia. NICHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bystricky, S (reprint author), Slovak Acad Sci, Inst Chem, Dubravska Cesta 9, Bratislava 84238, Slovakia. NR 18 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD DEC 21 PY 1998 VL 314 IS 1-2 BP 135 EP 139 DI 10.1016/S0008-6215(98)00265-1 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 186ED UT WOS:000079713600013 PM 10230041 ER PT J AU Durum, SK Candeias, S Nakajima, H Leonard, WJ Baird, AM Berg, LJ Muegge, K AF Durum, SK Candeias, S Nakajima, H Leonard, WJ Baird, AM Berg, LJ Muegge, K TI Interleukin 7 receptor control of T cell receptor gamma gene rearrangement: Role of receptor-associated chains and locus accessibility SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE T cell receptor; thymus; VDJ recombination; interleukin 7; T cell receptor gamma locus; gamma/delta T cells ID DEFECTIVE LYMPHOID DEVELOPMENT; VARIABLE REGION GENES; JAK-3 JANUS KINASE; MICE LACKING JAK3; V(D)J RECOMBINATION; DEFICIENT MICE; IL-2 RECEPTOR; B-CELLS; ALPHA-BETA; ENHANCER AB VDJ recombination of T cell receptor and immunoglobulin loci occurs in immature lymphoid cells. Although the molecular mechanisms of DNA cleavage and ligation have become more clear, it is not understood what controls which target loci undergo rearrangement. In interleukin 7 receptor (IL-7R)alpha(-/-) murine thymocytes, it has been shown that rearrangement of the T cell receptor (TCR)-gamma locus is virtually abrogated, whereas other rearranging loci are less severely affected. By examining different strains of mice with targeted mutations, we now observe that the signaling pathway leading from IL-7R alpha to rearrangement of the TCR-gamma locus requires the gamma(c) receptor chain and the gamma(c)-associated Janus kinase Jak3. Production of sterile transcripts from the TCR-gamma locus, a process that generally precedes rearrangement of a locus, was greatly repressed in IL-7R alpha(-/-) thymocytes. The repressed transcription was not due to a lack in transcription factors since the three transcription factors known to regulate this locus were readily detected in IL-7R alpha(-/-) thymocytes. Instead, the TCR-gamma locus was shown to be methylated in IL-7R alpha(-/-) thymocytes. Treatment of IL-7R alpha(-/-) precursor T cells with the specific histone deacetylase inhibitor trichostatin A released the block of TCR-gamma gene rearrangement. This data supports the model that IL-7R promotes TCR-gamma gene rearrangement by regulating accessibility of the locus via demethylation and histone acetylation of the locus. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. Univ Massachusetts, Med Ctr, Dept Pathol, Worcester, MA 01605 USA. RP Muegge, K (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC, Intramural Res Support Program, Bldg 560,Rm 31-45, Frederick, MD 21702 USA. EM muegge@mail.ncifcrf.gov FU PHS HHS [N01-C0-56000] NR 65 TC 96 Z9 96 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 21 PY 1998 VL 188 IS 12 BP 2233 EP 2241 DI 10.1084/jem.188.12.2233 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 151HA UT WOS:000077713600005 PM 9858510 ER PT J AU Azzam, HS Grinberg, A Lui, K Shen, H Shores, EW Love, PE AF Azzam, HS Grinberg, A Lui, K Shen, H Shores, EW Love, PE TI CD5 expression is developmentally regulated by T cell receptor (TCR) signals and TCR avidity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE CD5; thymocyte; development; signal transduction ID ANTIGEN RECEPTOR; CD4(+)CD8(+) THYMOCYTES; POSITIVE SELECTION; TRANSGENIC MICE; DEFICIENT MICE; MONOCLONAL-ANTIBODIES; LYMPHOCYTES-T; ZETA-CHAIN; B-CELLS; IN-VIVO AB Recent data indicate that the cell surface glycoprotein CD5 functions as a negative regulator of T cell receptor (TCR)-mediated signaling. In this study, we examined the regulation of CD5 surface expression during normal thymocyte ontogeny and in mice with developmental and/or signal transduction defects. The results demonstrate that low level expression of CDS on CD4(-)CD8(-) (double negative, DN) thymocytes is independent of TCR gene rearrangement; however, induction of CD5 surface expression on DN thymocytes requires engagement of the pre-TCR and is dependent upon the activity of p56(lck). At the CD4(+)CD8(+) (double positive, DP) stage, intermediate CD5 levels are maintained by low affinity TCR-major histocompatibility complex (MHC) interactions, and. CD5 surface expression is proportional to both the surface level and signaling capacity of the TCR. High-level expression of CD5 on DP and CD4(+) or CD8(+) (single positive, SP) thymocytes is induced by engagement of the alpha/beta-TCR by (positively or negatively) selecting ligands. Significantly, CD5 surface expression on mature SP thymocytes and T cells was found to directly parallel the avidity or signaling intensity of the positively selecting TCR-MHC-ligand interaction. Taken together, these observations suggest that the developmental regulation of CD5 in response to TCR signaling and TCR avidity represents a mechanism for tine tuning of the TCR signaling response. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Hematol Prod, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. EM pel@helix.nih.gov NR 52 TC 341 Z9 341 U1 0 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 21 PY 1998 VL 188 IS 12 BP 2301 EP 2311 DI 10.1084/jem.188.12.2301 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 151HA UT WOS:000077713600011 PM 9858516 ER PT J AU Pike, SE Yao, L Jones, KD Cherney, B Appella, E Sakaguchi, K Nakhasi, H Teruya-Feldstein, J Wirth, P Gupta, G Tosato, G AF Pike, SE Yao, L Jones, KD Cherney, B Appella, E Sakaguchi, K Nakhasi, H Teruya-Feldstein, J Wirth, P Gupta, G Tosato, G TI Vasostatin, a calreticulin fragment, inhibits angiogenesis and suppresses tumor growth SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE endothelial cells; angiogenesis; cell growth; cancer; antitumor agent ID INTERFERON-INDUCIBLE PROTEIN-10; NECROSIS IN-VIVO; HUMAN B-CELLS; NITRIC-OXIDE; INTEGRIN ALPHA(V)BETA(3); ENDOTHELIAL-CELLS; POTENT INHIBITOR; TERMINAL DOMAIN; RECEPTOR; REGRESSION AB All endothelial cell inhibitor sas purified from supernatant of an Epstein-Barr virus-immortalized cell line and identified as fragments of calreticulin. The purified recombinant NH2-terminal domain of calreticulin (amino acids 1-180) inhibited the proliferation of endothelial cells, but not calls of other lineages, and suppressed angiogenesis in vivo. We have named this NH2 terminal domain of calreticulin vasostatin. When inoculated into athymic mice, vasostatin significantly reduced growth of human Burkitt lymphoma and human colon carcinoma. Compared with other inhibitors of angiogenesis, vasostatin is a small, soluble, and stable molecule that is easy to produce and deliver. As an angiogenesis inhibitor that specifically targets proliferating endothelial cells, vasostatin has a unique potential for cancer treatment. C1 Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. NCI, Cell Biol Lab, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Tosato, G (reprint author), Ctr Biol Evaluat & Res, Bldg 29A,Room 2D16,HFM535,1401 Rockville Pike, Rockville, MD 20852 USA. NR 46 TC 204 Z9 226 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 21 PY 1998 VL 188 IS 12 BP 2349 EP 2356 DI 10.1084/jem.188.12.2349 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 151HA UT WOS:000077713600016 PM 9858521 ER PT J AU Hein, K Lorenz, MGO Siebenkotten, G Petry, K Christine, R Radbruch, A AF Hein, K Lorenz, MGO Siebenkotten, G Petry, K Christine, R Radbruch, A TI Processing of switch transcripts is required for targeting of antibody class switch recombination SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE class switch; recombination; splicing; switch transcript; B lymphocytes ID IMMUNOGLOBULIN CLASS SWITCH; REGION SEQUENCES; DEFICIENT MICE; B-CELLS; RNA; DNA; SPECIFICITY; INTERLEUKIN-4; EXPRESSION; EFFICIENCY AB Antibody class switching is mediated by somatic recombination between switch regions of the immunoglobulin heavy chain gene locus. Targeting of recombination to particular switch regions is strictly regulated by cytokines through the: induction of switch transcripts starting 5' of the repetitive switch regions. However, switch transcription as such is not sufficient to target switch recombination. This has been shown in mutant mice, in which the I-exon and its promoter upstream of the switch region wt rr replaced with heterologous promoters. Here we show that, in the murine germline targeted replacement of the endogenous gamma 1 promoter, I-exon, and I-exon splice donor site by heterologous promoter and splice donor sites directs switch recombination in activated B lymphocytes constitutively to the gamma 1 switch region. In contrast, switch recombination to IgG1 is inhibited in mutant mice, in which the replacement does riot include the heterologous splice donor rite. Our data unequivocally demonstrate that targeting of switch recombination to IgG1 in vivo requires processing of the I gamma 1 switch transcripts, either the processing machinery or the processed transcripts are involved in class switch recombination. C1 Deutsch Rheumaforschungszentrum Berlin, D-10115 Berlin, Germany. NCI, NIH, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. Deutsch Rheumaforschungszentrum Berlin, AMAXA GmbH, D-10115 Berlin, Germany. RP Radbruch, A (reprint author), Deutsch Rheumaforschungszentrum Berlin, Hannoversche Str 27, D-10115 Berlin, Germany. NR 33 TC 110 Z9 110 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 21 PY 1998 VL 188 IS 12 BP 2369 EP 2374 DI 10.1084/jem.188.12.2369 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 151HA UT WOS:000077713600018 PM 9858523 ER PT J AU Grill, SE Rosenberger, WF Boyle, K Cannon, M Hallett, M AF Grill, SE Rosenberger, WF Boyle, K Cannon, M Hallett, M TI Perception of timing of kinesthetic stimuli SO NEUROREPORT LA English DT Article DE kinesthesia; perception; velocity ID MUSCLE-SPINDLE AFFERENTS; CUTANEOUS MECHANORECEPTORS; EVOKED-POTENTIALS; MOVEMENT; ONSET; INFORMATION; RESPONSES; VELOCITY AB A psychophysical method was used to estimate the timing of perception of kinesthetic stimuli with different velocities in normal volunteers. A 1 ms auditory click occurred randomly before or after an imposed flexion movement at either 20, 40 or 60 deg/s of the metacarpophalangeal joint. Subjects reported whether the click was perceived before or after the movement onset (experiment 1) or perception of movement velocity (experiment 2). The time at which there was a 50% chance that subjects reported movement or velocity perception after the click was taken as an estimate of the time subjects perceived the stimuli. The difference in time of perceived movement velocity discrimination and movement onset was only significant when the velocity was 20 deg/s (52 ms). This suggests that movement onset and identification of the velocity of the faster movements are perceived nearly simultaneously. (C) 1998 Lippincott Williams & Wilkins. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Neurol Specialists PA, Movement Disorders Clin, Columbia, MD 21044 USA. Univ Maryland, Dept Math & Stat, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. RP Grill, SE (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 14 TC 4 Z9 4 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD DEC 21 PY 1998 VL 9 IS 18 BP 4001 EP 4005 DI 10.1097/00001756-199812210-00003 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 158QY UT WOS:000078128400004 PM 9926837 ER PT J AU Tycko, R AF Tycko, R TI Optical pumping of dipolar order in a coupled nuclear spin system SO MOLECULAR PHYSICS LA English DT Article ID 2-DIMENSIONAL ELECTRON-GAS; GAAS QUANTUM-WELLS; HIGH-PURITY GAAS; MAGNETIC-RESONANCE; GALLIUM-ARSENIDE; PUMPED NMR; POLARIZATION; RELAXATION; STATES; FIELD AB A possible mechanism for the direct generation of dipolar order in a coupled nuclear spin system by optical pumping is investigated theoretically. This work is motivated by recent optically pumped nuclear magnetic resonance experiments on single-crystal indium phosphide wafers, which have revealed that optical pumping can generate a state of nuclear spin dipolar order in a system of coupled spins without the application of radiofrequency fields or pulse sequences. The theory proceeds by evaluating the steady-state populations of the eigenstates of a coupled nuclear spin system when simultaneous nuclear and electron spin transitions are driven by fluctuating hyperfine couplings of the nuclei to an electron with a non-equilibrium spin polarization. In the case of two coupled spin-1/2 nuclei, substantial dipolar order results when the hyperfine couplings are of the dipolar, but not the Fermi contact, type. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. NR 28 TC 14 Z9 14 U1 2 U2 4 PU TAYLOR & FRANCIS LTD PI LONDON PA ONE GUNPOWDER SQUARE, LONDON EC4A 3DE, ENGLAND SN 0026-8976 J9 MOL PHYS JI Mol. Phys. PD DEC 20 PY 1998 VL 95 IS 6 BP 1169 EP 1176 DI 10.1080/002689798166189 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 153WY UT WOS:000077857300010 ER PT J AU Crowe, JE Firestone, CY Crim, R Beeler, JA Coelingh, KL Barbas, CF Burton, DR Chanock, RM Murphy, BR AF Crowe, JE Firestone, CY Crim, R Beeler, JA Coelingh, KL Barbas, CF Burton, DR Chanock, RM Murphy, BR TI Monoclonal antibody-resistant mutants selected with a respiratory syncytial virus-neutralizing human antibody Fab fragment (Fab 19) define a unique epitope on the fusion (F) glycoprotein SO VIROLOGY LA English DT Article ID IMMUNOTHERAPY; INFECTION AB A recombinant human antibody fragment, designated RSV Fab 19, efficiently neutralizes respiratory syncytial virus (RSV), Here we report the results of our sequence analysis of antibody escape mutants that identified F glycoprotein amino acids critical for binding of human or murine RSV F-neutralizing antibodies. (C) 1998 Academic Press. C1 NIAID, Resp Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, La Jolla, CA 92037 USA. RP Crowe, JE (reprint author), Vanderbilt Univ, Med Ctr, Dept Pediat, Div Pediat Infect Dis, D-7235 MCN,1161 21st Ave S, Nashville, TN 37232 USA. RI Crowe, James/B-5549-2009 OI Crowe, James/0000-0002-0049-1079 NR 10 TC 28 Z9 28 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 20 PY 1998 VL 252 IS 2 BP 373 EP 375 DI 10.1006/viro.1998.9462 PG 3 WC Virology SC Virology GA 151UN UT WOS:000077739200010 PM 9878616 ER PT J AU Brown, P Bradley, R AF Brown, P Bradley, R TI 1755 and all that: a historical primer of transmissible spongiform encephalopathy SO BRITISH MEDICAL JOURNAL LA English DT Review ID PROTEIN; PRION; MICE C1 NINCDS, CNS Studies Lab, NIH, Bethesda, MD 20892 USA. MAFF, Cent Vet Lab, Addlestone KT15 3NB, Surrey, England. RP Brown, P (reprint author), NINCDS, CNS Studies Lab, NIH, Bldg 36,Room 5B20, Bethesda, MD 20892 USA. EM pwb@codon.nih.gov NR 20 TC 60 Z9 67 U1 1 U2 3 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 DEC 19 PY 1998 VL 317 IS 7174 BP 1688 EP 1692 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 151VX UT WOS:000077742300015 PM 9857129 ER PT J AU Munzar, P Nosal, R Goldberg, SR AF Munzar, P Nosal, R Goldberg, SR TI Potentiation of the discriminative-stimulus effects of methamphetamine by the histamine H-3 receptor antagonist thioperamide in rats SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE methamphetamine; histamine H-3 receptor; thioperamide; R-alpha-methylhistamine; drug-discrimination; (rat) ID D-AMPHETAMINE; BRAIN PENETRATION; DOPAMINE; RELEASE; MOUSE; (R)-ALPHA-METHYLHISTAMINE; IODOPHENPROPIT; STEREOISOMERS; SEROTONIN; STRIATUM AB In order to assess the role of histamine H-3 receptors in the discriminative-stimulus effects of methamphetamine, rats were trained to discriminate 1.0 mg/kg methamphetamine, i.p., from saline under a fixed-ratio schedule of food presentation. The histamine H-3 receptor antagonist thioperamide (1.0 mg/kg s.c.), which facilitates histamine release, significantly shifted the methamphetamine dose-response curve to the left when tested together with different doses of methamphetamine and markedly extended the time-course of methamphetamine's discriminative-stimulus effects. The histamine H-3 receptor agonist R-alpha-methylhistamine (3.0 mg/kg i.p.), which blocks histamine release, did not produce any effects when given alone, but it attenuated the effects of thioperamide on the methamphetamine dose-response curve when both drugs were given together. Thus, methamphetamine's discriminative-stimulus effects are markedly potentiated by the blockade of histamine H-3 receptors by thioperamide. This is Likely due to thioperamide's actions at histamine H-3 autoreceptors on histaminergic neurons to facilitate release of histamine by methamphetamine or at histamine H-3 heteroreceptors on other monoaminergic neurons (e.g., dopaminergic, serotonergic or noradrenergic) to facilitate release of other neurotransmitters. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDA, Preclin Pharmacol Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Masaryk Univ, Fac Med, Dept Pharmacol, CS-66243 Brno, Czech Republic. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Lab, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 34 TC 27 Z9 27 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD DEC 18 PY 1998 VL 363 IS 2-3 BP 93 EP 101 DI 10.1016/S0014-2999(98)00789-4 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 149VP UT WOS:000077627200001 PM 9881573 ER PT J AU Gurguis, GNM Turkka, J Karanian, J Linnoila, M AF Gurguis, GNM Turkka, J Karanian, J Linnoila, M TI The combined effects of chronic ethanol/desipramine treatment on beta-adrenoceptor density and coupling efficiency in rat brain SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE ethanol; desipramine; antidepressant; G(s) protein; coupling; depression; alcoholism ID ADRENERGIC-RECEPTOR BINDING; CHRONIC ANTIDEPRESSANT TREATMENT; ETHANOL-INDUCED DESENSITIZATION; DEPENDENT PROTEIN-KINASE; ADENYLATE-CYCLASE SYSTEM; MOUSE CEREBRAL-CORTEX; GUANINE-NUCLEOTIDE; CHRONIC EXPOSURE; DOWN-REGULATION; MESSENGER-RNA AB Both ethanol and desipramine influence beta-adrenoceptor regulation. We reported previously that ethanol partially counteracted desipramine's effects on beta-adrenoceptor. Previous studies utilized beta-adrenoceptor radioligands that also bind to 5-HT1B receptors, thus, changes in 5-HT1B receptors could have confounded the results. The effects of chronic ethanol, desipramine and ethanol/desipramine treatment on beta-adrenoceptor coupling efficiency to G(s) protein in rat brain were examined using I-125-iodocyanopindolol after blocking binding to 5-HT1B receptors. In the frontal cortex, ethanol uncoupled beta-adrenoceptor from G(s). Desipramine decreased beta-adrenoceptor density, particularly in the high-conformational state, with no effect on coupling. In combined treatment, desipramine prevented ethanol-induced uncoupling. In the hippocampus, desipramine enhanced beta-adrenoceptor coupling, but ethanol had no effect. In combination with desipramine, ethanol enhanced desipramine-induced decrease in beta-adrenoceptor density in the high-conformational state, but uncoupled beta-adrenoceptors, an effect not observed with ethanol alone. These results suggest a complex interplay between ethanol and antidepressants in modulating beta-adrenoceptor function. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Dept Vet Affairs Med Ctr, Dallas, TX 75216 USA. Oulu Univ, Dept Neurol, Oulu, Finland. NIAAA, Clin Studies Lab, DICBR, Bethesda, MD 20892 USA. RP Gurguis, GNM (reprint author), Vet Adm Med Ctr, Lab Clin Neurosci, Mental Hlth 116A,4500 S Lancaster Rd, Dallas, TX 75216 USA. EM gurguis.george@dallas.va.gov NR 96 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD DEC 18 PY 1998 VL 363 IS 2-3 BP 241 EP 251 DI 10.1016/S0014-2999(98)00810-3 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 149VP UT WOS:000077627200023 PM 9881595 ER PT J AU Tardieux, I Liu, X Poupel, O Parzy, D Dehoux, P Langsley, G AF Tardieux, I Liu, X Poupel, O Parzy, D Dehoux, P Langsley, G TI A Plasmodium falciparum novel gene encoding a coronin-like protein which associates with actin filaments SO FEBS LETTERS LA English DT Article DE actin dynamic; coronin; WD motif; apicomplexa ID HOST-CELL INVASION; TOXOPLASMA-GONDII; BINDING-PROTEIN; MALARIAL PARASITES; GLIDING MOTILITY; WD-REPEAT; CYTOSKELETON; SPOROZOITES; MEMBRANE; ERYTHROCYTES AB Plasmodium falciparum, the major causative agent of human malaria, is an Apicomplexa protozoan parasite which invades in its intermediate host hepatocytes and erythrocytes. The driving force underlying internalization into the host cell is thought to involve both polymerization of parasite actin, as entry is inhibited by the cytochalasins, and an actin motor-associated protein. In the related Apicomplexa parasite, Toxoplasma gondii, the involvement of parasite actin during both processes of motility and host cell entry has been genetically established. In a search for molecules that can regulate actin dynamics within Apicomplexa parasites, we have identified a P. falciparum homologue of the actin associated protein called coronin originally described in the amoeba Dictyostelium discoideum. The single copy gene displays a strong homology with the amoeba sequence and with the bovine and human coronin homologues recently cloned. This homology lies not only within the N-terminus containing the five WD repeats that characterize coronin but also extends in the C-terminal part. Furthermore, using an affinity-purified mouse monoclonal antibody against D. discoideum coronin, we have detected in extracts of P. falciparum young and mature schizonts a 42-kDa polypeptide which binds this antibody and is present in a Triton insoluble fraction that also contains parasite actin filaments. In addition, the recombinant protein encoded by the homologue nucleotidic sequence of P. falciparum coronin is indeed recognized by the antibody against D. discoideum coronin. Finally, the cross-reactive polypeptide displays the ability to cosediment with exogenous F-actin, a property which fits with its involvement in actin dynamics. (C) 1998 Federation of European Biochemical Societies. C1 Inst Pasteur, Lab Biochim & Biol Mol Insectes, F-75724 Paris 15, France. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Serv Sante Armees, Inst Trop Med, F-13998 Marseille, France. Inst Pasteur, Unite Interact Bacteries Cellules, Paris, France. Inst Pasteur, Dept Immunol, CNRS, Unite Parasitol Expt,URA 1960, Paris, France. RP Tardieux, I (reprint author), Inst Pasteur, Lab Biochim & Biol Mol Insectes, 28 Rue Dr Roux, F-75724 Paris 15, France. EM tardieux@pasteur.fr RI Tardieux, Isabelle/G-4733-2014 NR 45 TC 40 Z9 44 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD DEC 18 PY 1998 VL 441 IS 2 BP 251 EP 256 DI 10.1016/S0014-5793(98)01557-9 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 152PE UT WOS:000077785300020 PM 9883894 ER PT J AU Boucheron, C Dumon, S Constantino, S Santos, R Moriggl, R Hennighausen, L Gisselbrecht, S Gouilleux, F AF Boucheron, C Dumon, S Constantino, S Santos, R Moriggl, R Hennighausen, L Gisselbrecht, S Gouilleux, F TI A single amino acid in the DNA binding regions of STAT5A and STAT5B confers distinct DNA binding specificities SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COLONY-STIMULATING FACTOR; ERYTHROLEUKEMIA CELL-LINE; RECEPTOR-ALPHA GENE; GROWTH-HORMONE; ERYTHROID-DIFFERENTIATION; TRANSCRIPTION FACTORS; SIGNAL-TRANSDUCTION; CYTOKINE RECEPTORS; STAT5-LIKE FACTOR; LYMPHOID-CELLS AB STAT5A and STAT5B are two highly related transcription factors encoded by two distinct genes. STAT5A and STAT5B are activated by a broad range of cytokines and growth factors, Although they can be differentially activated, the functional difference between these two molecules relative to their structure is not known. Here we demonstrated that STAT5A and STAT5B homodimers have distinct DNA binding preferences; Chimeric STATE molecules allowed us to identify a region between amino acid 420 and 545 responsible for the DNA binding specificity. This region is located in the previously characterized DNA binding region of STAT proteins. Sequence comparison between STAT5A and STAT5B from different species showed a difference of 5 amino acids in the region 420-545 between STAT5A and STAT5B. Substitution of these amino acids demonstrated that a glycine residue at position 433 in STAT5B and a glutamic residue at a similar position in STAT5A determined the DNA binding specificity. These data indicate that STAT5A and STAT5B homodimers may have distinct function and probably regulate the expression of common as well as distinct genes. C1 Hop Cochin, Inst Cochin Genet Mol, INSERM, U363, F-75014 Paris, France. Univ Tennessee, Sch Med, Dept Biochem, Memphis, TN 38105 USA. NIH, Biochem & Metab Lab, Bethesda, MD 20892 USA. RP Gouilleux, F (reprint author), Hop Cochin, Inst Cochin Genet Mol, INSERM, U363, 27 Rue Fbg St Jacques, F-75014 Paris, France. NR 62 TC 64 Z9 65 U1 1 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 DEC 18 PY 1998 VL 273 IS 51 BP 33936 EP 33941 DI 10.1074/jbc.273.51.33936 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148PZ UT WOS:000077542200011 PM 9852045 ER PT J AU Reardon, BJ Lombardo, CR Sander, M AF Reardon, BJ Lombardo, CR Sander, M TI Drosophila Rrp1 domain structure as defined by limited proteolysis and biophysical analyses SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN SECONDARY STRUCTURE; ESCHERICHIA-COLI; DNA-REPAIR; EXONUCLEASE-III; APURINIC ENDONUCLEASE; FUNCTIONAL DOMAINS; STRAND TRANSFERASE; CIRCULAR-DICHROISM; ENZYME; RECOGNITION AB Drosophila Rrp1 is a DNA repair nuclease whose C-terminal region shares extensive homology with Escherichia coli exonuclease III, has nuclease activity, and provides resistance to oxidative and alkylating agents in repair-deficient E. coli strains. The N-terminal 421 amino acid region of Rrp1, which binds and renatures homologous single-stranded DNA, does not share homology with any known protein. Proteolysis by endoproteinase Glu-C (protease V8) reduces the Rrp1 protein to a single, cleavage-resistant peptide. The peptide (referred to as Rrp1-C274) begins with the sequence TKTTV, corresponding to cleavage between Glu-405 and Thr-406 of Rrp1, We determined that nuclease activity is intrinsic to Rrp1-C274 although altered when compared with Rrp1; 3'-exonuclease activity is reduced 210-fold, 3'-phosphodiesterase activity is reduced 6.8-fold, and no difference in apurinic/apyrimidinic endonuclease activity is observed. Rrp1 and Rrp1-C274 are both monomers with frictional coefficients of 2.2 and 1.4, respectively. Circular dichroism results indicate that Rrp1-C274 is predominantly cu-helical, while the N-terminal 399 amino acids is predominantly random coil. These results suggest that Rrp1 may have a bipartite structural organization; a highly organized, globular C-terminal domain; and an asymmetric, protease-sensitive random coil-enriched N-terminal region. A shape model for this bipartite structure is proposed and discussed. C1 NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Chapel Hill, NC 27599 USA. RP Reardon, BJ (reprint author), NIEHS, Genet Mol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 48 TC 5 Z9 5 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 DEC 18 PY 1998 VL 273 IS 51 BP 33991 EP 33999 DI 10.1074/jbc.273.51.33991 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148PZ UT WOS:000077542200019 PM 9852053 ER PT J AU Yang, XH Stennicke, HR Wang, BK Green, DR Janicke, RU Srinivasan, A Seth, P Salvesen, GS Froelich, CJ AF Yang, XH Stennicke, HR Wang, BK Green, DR Janicke, RU Srinivasan, A Seth, P Salvesen, GS Froelich, CJ TI Granzyme B mimics apical caspases - Description of a unified pathway for trans-activation of executioner caspase-3 and -7 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOCHROME-C; PROTEASE; APOPTOSIS; FAMILY; CPP32; DELIVERY; HOMOLOG AB Granzyme B (GrB) is predicted to trigger apoptosis by activating preferred caspases, but the zymogens that are directly processed by the granzyme and the requirements for these interactions remain unclarified. We examined this dilemma by comparing the kinetics and pattern of GrB-mediated activation of the executioner caspase-7 in vitro and in vivo. GrB rapidly activates procaspase-7 in vitro by cleaving between the large and small subunits leaving the propeptide intact. During GrB-mediated apoptosis, the caspase-7 propeptide is removed and cleavage occurs between the subunits, Strikingly, caspase-7 is unprocessed in caspase-3-deficient MCF-7 cells exposed to GrB bud is rapidly activated when the cells are solubilized. Transfection with caspase-3 restores the removal of the caspase-7 propeptide and the capacity of GrB to subsequently activate the caspase. The data suggest that GrB activates caspase-3, which then removes the propeptide of caspase-7 allowing activation by GrB, Thus GrB initiates the death pathway by processing the accessible caspase-3, and the caspase-7 propeptide regulates transactivation of the zymogen by granzyme. As a consequence, two proteases, caspase-3 and GrB, are required to activate procaspase-7. C1 Evanston NW Healthcare Res Inst, Evanston, IL 60201 USA. Burnham Inst, La Jolla, CA 92307 USA. Natl Univ Singapore, Inst Mol & Cell Biol, Singapore 117548, Singapore. IDUN Pharmaceut, La Jolla, CA 92037 USA. La Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Froelich, CJ (reprint author), Evanston NW Healthcare Res Inst, WH Bldg,Rm B643,2650 Ridge Ave, Evanston, IL 60201 USA. EM granzyme@merle.acns.nwu.edu RI Yang, Jim/B-3776-2010; ASTAR, IMCB/E-2320-2012 FU NHLBI NIH HHS [HL51399-04]; NIA NIH HHS [R01 AG15402]; PHS HHS [A140646] NR 34 TC 136 Z9 144 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 DEC 18 PY 1998 VL 273 IS 51 BP 34278 EP 34283 DI 10.1074/jbc.273.51.34278 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148PZ UT WOS:000077542200058 PM 9852092 ER PT J AU Liu, W Clark, WA Sharma, P Northup, JK AF Liu, W Clark, WA Sharma, P Northup, JK TI Mechanism of allosteric regulation of the rod cGMP phosphodiesterase activity by the helical domain of transducin alpha subunit SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYCLIC-GMP PHOSPHODIESTERASE; RESONANCE ENERGY-TRANSFER; GTP-GAMMA-S; G-PROTEIN; OUTER SEGMENTS; ADENYLYL-CYCLASE; SIGNAL-TRANSDUCTION; RETINAL RODS; INHIBITORY SUBUNIT; MOLECULAR-CLONING AB The G protein alpha subunit (G alpha) is composed of two distinct folding domains: a GTP-binding Ras-like domain and an alpha helical domain QID). We have recently reported that the helical domain (HDt) of the vertebrate visual transducin alpha subunit (G alpha(t)) synergizes activation of retinal cyclic GMP phosphodiesterase (PDE) by activated G alpha(t) (Liu, W., and Northup, J. K., (1998) Proc. Natl. Acad. Sci. U.S.A. 95, 12878-12883). Here, we examine the molecular basis for this HD-based signaling regulation, and we provide a new model for the activation of the target effector. The HD proteins derived from visual transducin or taste gustducin alpha subunits, but no other Get HD proteins, each attenuate the PDE catalytic core (P alpha beta) and synergize G alpha(t) stimulation of the holoPDE (P alpha beta gamma(2)) with similar apparent affinities. The data from studies of both HDt-mediated attenuation and stimulation indicate that the HDt and the PDE inhibitory subunit (P gamma) interact with PDE at independent sites and that P alpha beta contains the binding sites for HD. The saturation of both processes by HDt displays positive cooperativity with Hill coefficients of 1.5 for the attenuation of P alpha beta activity and 2.1 for synergism of holoPDE activation. Our data suggest the that G alpha(t)-HDt regulates PDE by allosterically decreasing the affinity of P alpha beta for P gamma and thus simultaneously facilitating the interaction of the activated G alpha(t)-Ras-like domain with P gamma. Thus, we propose a new model for the high efficiency of PDE activation as well as deactivation, and, overall, a novel mechanism for controlling fidelity, sensitivity, and efficacy of G protein signaling. C1 NIDCD, Lab Cellular Biol, NIH, Rockville, MD 20850 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Northup, JK (reprint author), NIDCD, Lab Cellular Biol, NIH, 5 Res Ct, Rockville, MD 20850 USA. NR 60 TC 19 Z9 19 U1 0 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 DEC 18 PY 1998 VL 273 IS 51 BP 34284 EP 34292 DI 10.1074/jbc.273.51.34284 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148PZ UT WOS:000077542200059 PM 9852093 ER PT J AU Miki, E Eddy, EM AF Miki, E Eddy, EM TI Identification of tethering domains for protein kinase A type I alpha regulatory subunits on sperm fibrous sheath protein FSC1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANCHORING PROTEINS; MOUSE SPERM; TARGETED DISRUPTION; EPIDIDYMAL SPERM; BINDING-PROTEINS; BETA SUBUNIT; RAT SPERM; LOCALIZATION; CELLS; CDNA AB The fibrous sheath is a unique cytoskeletal structure in the sperm flagellum believed to modulate sperm motility. FSC1 is the major structural protein of the fibrous sheath. The yeast two-hybrid system was used to identify other proteins that contribute to the structure of the fibrous sheath or participate in sperm motility. When FSC1 was used as the bait to screen a mouse testis cDNA library, two clones were isolated encoding the type I alpha regulatory subunit (RI alpha) of cAMP-dependent protein kinase. Deletion analysis using the yeast two-hybrid system and in vitro binding assays with glutathione S-transferase-FSC1 fusion proteins identified two RI alpha tethering domains on FSC1. A domain located at residues 219-232 (termed domain A) corresponds to the reported tethering domain for a type II regulatory subunit (RII) of cAMP-dependent protein kinase, indicating that this binding domain has dual specificity to RI and RII. Another RI alpha tethering site (termed domain B) at residues 335-344 shows specific binding of RI alpha and had no significant sequence homology with known RII tethering domains. However, helical wheel projection analysis indicates that domain B is likely to form an amphipathic helix, the secondary structure of RII tethering domains of protein kinase A anchoring proteins. This was supported by the finding that site-directed mutagenesis to disrupt the amphipathic helix eliminated RI alpha binding. This is apparently the first report of an RI alpha-specific protein kinase A anchoring protein tethering domain. C1 NIEHS, Gamete Biol Grp, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Eddy, EM (reprint author), NIEHS, Gamete Biol Grp, Reprod & Dev Toxicol Lab, NIH, MD C4-01, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov NR 43 TC 48 Z9 48 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 DEC 18 PY 1998 VL 273 IS 51 BP 34384 EP 34390 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148PZ UT WOS:000077542200070 ER PT J AU Ray, K Clapp, P Goldsmith, PK Spiegel, AM AF Ray, K Clapp, P Goldsmith, PK Spiegel, AM TI Identification of the sites of N-linked glycosylation on the human calcium receptor and assessment of their role in cell surface expression and signal transduction SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PUTATIVE PHEROMONE RECEPTORS; HUMAN CA2+ RECEPTOR; SENSING RECEPTOR; FUNCTIONAL EXPRESSION; EXTRACELLULAR CALCIUM; MOLECULAR-CLONING; MULTIGENE FAMILY; HORMONE-BINDING; LIGAND-BINDING; RAT AB The human calcium receptor (hCaR) is a G-protein-coupled receptor containing 11 potential N-linked glycosylation sites in the large extracellular domain. The number of potential N-linked glycosylation sites actually modified, and the effect on cell surface expression and signal transduction of blocking glycosylation at these sites, was examined by site-directed mutagenesis. Asparagine residues of the consensus sequences (Asn-Xaa-Ser/Thr) for N-linked glycosylation were mutated to glutamine individually and in various combinations to disrupt the potential N-linked glycosylation sites in the context of the full-length receptor. The cDNA constructs were transiently transfected into HEK-293 cells lacking endogeneous hCaR, and expressed receptors were analyzed by mobility differences on irnmunoblots, glycosidase digestion, intact cell enzyme-linked immunoassay, and extracellular calcium-stimulated phosphoinositide hydrolysis assay. Immunoblot analyses and glycosidase digestion studies of the wild type versus mutant receptors demonstrate that, of the 11 potential sites for N-linked glycosylation, eight sites (Asn-90, -130, -261, -287, -446, -468, -488, and -541) are glycosylated; the three remaining sites (Asn-386, -400, and -594) may not be efficiently glycosylated in the native receptor. Sequential mutagenesis of multiple N-linked glycosylation sites and analyses by immunoblotting, immunofluorescence, biotinylation of cell surface proteins, and intact cell enzyme-linked immunoassay indicated that disruption of as few as three glycosylation sites impairs proper processing and expression of the receptor at the cell surface, Disruption of five glycosylation sites reduced cell surface expression by 50-90% depending on which five sites were disrupted. Phosphoinositide hydrolysis assay results for various glycosylation-defective mutant receptors in general correlated well with the level of cell surface expression. Our results demonstrate that among 11 potential N-linked glycosylation sites on the hCaR, eight sites are actually utilized; glycosylation of at least three sites is critical for cell surface expression of the receptor, but glycosylation does not appear to be critical for signal transduction. C1 NIDDK, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Spiegel, AM (reprint author), NIDDK, Metab Dis Branch, NIH, Bldg 10,Rm 9N-222, Bethesda, MD 20892 USA. NR 31 TC 107 Z9 109 U1 0 U2 8 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 DEC 18 PY 1998 VL 273 IS 51 BP 34558 EP 34567 DI 10.1074/jbc.273.51.34558 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148PZ UT WOS:000077542200092 PM 9852126 ER PT J AU Kashanchi, F Duvall, JF Kwok, RPS Lundblad, JR Goodman, RH Brady, JN AF Kashanchi, F Duvall, JF Kwok, RPS Lundblad, JR Goodman, RH Brady, JN TI The coactivator CBP stimulates human T-cell lymphotrophic virus type I Tax transactivation in vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CREB-BINDING-PROTEIN; RNA-POLYMERASE-II; LONG TERMINAL REPEAT; GENERAL TRANSCRIPTION FACTORS; LEUKEMIA-VIRUS; HTLV-I; 21-BASE-PAIR REPEATS; ACTIVATION DOMAIN; DNA-BINDING; HISTONE ACETYLTRANSFERASES AB Tax interacts with the cellular cyclic AMP-responsive element binding protein (CREB) and facilitates the binding of the coactivator CREB binding protein (CBP), forming a multimeric complex on the cyclic AMP-responsive element (CRE)-like sites in the human T-cell lymphotrophic virus type I (HTLV-I) promoter. The trimeric complex is believed to recruit additional regulatory proteins to the HTLV-I long terminal repeat, but there has been no direct evidence that CBP is required for Tax-mediated transactivation. We present evidence that Tax and CBP activate transcription from the HTLV-I 21 base pair repeats on naked DNA templates. Transcriptional activation of the HTLV-I sequences required both Tax and CBP and could be mediated, by either the N-terminal activation domain of CBP or the full-length protein. Fluorescence polarization binding assays indicated that CBP does not markedly enhance the affinity of Tax for the trimeric complex. Transcription analyses suggest that CBP activates Tax-dependent transcription by promoting transcriptional initiation and reinitiation. The ability of CBP to activate the HTLV-I promoter does not involve the stabilization of Tax binding, but rather depends upon gene activation properties of the co-activator that function in the context of a naked DNA template. C1 NCI, Lab Receptor Biol & Gene Express, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Med, Div Mol Med, Portland, OR 97201 USA. RP Brady, JN (reprint author), NCI, Lab Receptor Biol & Gene Express, Div Basic Sci, NIH, Bldg 41,Rm B403, Bethesda, MD 20892 USA. EM bradyj@exchange.nih.gov FU NIDDK NIH HHS [DK50014] NR 71 TC 62 Z9 63 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 DEC 18 PY 1998 VL 273 IS 51 BP 34646 EP 34652 DI 10.1074/jbc.273.51.34646 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148PZ UT WOS:000077542200104 PM 9852138 ER PT J AU Liu, HJ Sanuda-Pena, MC Harvey-White, JD Kalra, S Cohen, SA AF Liu, HJ Sanuda-Pena, MC Harvey-White, JD Kalra, S Cohen, SA TI Determination of submicromolar concentrations of neurotransmitter amino acids by fluorescence detection using a modification of the 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate method for amino acid analysis SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 22nd International Symposium on High Performance Liquid Phase Separations and Related Techniques CY MAY 02-08, 1998 CL ST LOUIS, MISSOURI DE amino acids; neurotransmitter amino acids; gamma-aminobutyric acid; glutamate ID PERFORMANCE LIQUID-CHROMATOGRAPHY; IN-VIVO MICRODIALYSIS; CAPILLARY ELECTROPHORESIS; BRAIN MICRODIALYSIS; O-PHTHALALDEHYDE; DERIVATIZATION; GLUTAMATE; REAGENT; DERIVATIVES; TECHNOLOGY AB A sensitive method for quantitatively determining submicromolar levels of neurotransmitter amino acids (e.g. Asp, Glu and gamma-aminobutyric acid) in microdialysates from brain and cerebrospinal fluids is reported. 6-Aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) was employed as the derivatization reagent, followed by HPLC separation and fluorescence detection of the derivatives. The derivatization was conducted simply by mixing the AQC directly with the microdialysis samples. The reaction was complete within seconds after mixing at room temperature. Separation development optimizing the gradient profile, eluent pH and column temperature resulted in an excellent separation of the required amino acids in less than 30 min. Other resolved amino acids in the same profile include Gly, taurine, and Pro. Recoveries for the amino acids of interest spiked into high salt containing perfusion buffers were greater than 97%. The sensitivity of the method was increased by employing a 16-mu l flow cell in the detector and analyzing 20-mu l aliquots of the derivatization mixtures. With the optimized conditions, the detection limits were 3-7 nM (fmol/mu l). Typical reproducibility (%R.S.D.) for quantitation of these amino acids at submicromolar levels was approximately 2%. Excellent linearity (r(2)>0.999) was achieved over the range 0.2-20 mu M. The low detection limits permitted the analysis of a number of different microdialysate samples including those from cerebrospinal fluid, as well as substantia nigra and hypothalamus from brain samples, even at basal levels when gamma-aminobutyric acid concentration may be <50 nM. The excellent sensitivity made it easy to distinguish basal from stimulated levels of neurotransmitter amino acids, even from sample sizes as small as 10 mu l. (C) 1998 Published by Elsevier Science B.V. All rights reserved. C1 Waters Corp, Milford, MA 01757 USA. Brown Univ, Dept Psychiat, Providence, RI 02912 USA. NIH, Bethesda, MD 20892 USA. Univ Florida, Coll Med, Dept Neurosci, Gainesville, FL 32610 USA. RP Cohen, SA (reprint author), Waters Corp, 34 Maple St, Milford, MA 01757 USA. EM steven_cohen@waters.com FU NIDDK NIH HHS [DK37273] NR 35 TC 58 Z9 63 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD DEC 18 PY 1998 VL 828 IS 1-2 BP 383 EP 395 DI 10.1016/S0021-9673(98)00836-X PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 152ZP UT WOS:000077808500042 PM 9916319 ER PT J AU Rifkind, JM Abugo, OO Peddada, RR Patel, N Speer, D Balagopalakrishna, C Danon, D Ingram, DK Spangler, EL AF Rifkind, JM Abugo, OO Peddada, RR Patel, N Speer, D Balagopalakrishna, C Danon, D Ingram, DK Spangler, EL TI Maze learning impairment is associated with stress hemopoiesis induced by chronic treatment of aged rats with human recombinant erythropoietin SO LIFE SCIENCES LA English DT Article DE erythropoiesis; aging; erythrocyte deformability; hematology; learning ID ERYTHROCYTE TRANSIT TIMES; CELL AGE; PERFORMANCE; ANEMIA; DEFORMABILITY; MICROPORES; DONOR AB Mean cell volume (MCV) of erythrocytes has been reported to increase with age in humans, and to be negatively correlated with memory performance in humans and rats. We evaluated hematological changes in 21-mo old male Fischer 344 rats undergoing a 3-mo twice weekly subcutaneous injection of human recombinant erythropoietin (EPO). A baseline hematocrit (HCT) was obtained initially and repeated at monthly intervals to determine the effectiveness of EPO treatment. At 24-mo of age and after 3 mo EPO treatment, the rats were tested for their ability to learn a 14-unit T maze. Following maze testing, blood was drawn for hematologic analyses, including HCT, MCV, maximum swollen cell volume (MCVS), mean cell transit time (MCTT), and the membrane shear modulus of elasticity (G), the latter a derived measure of the relative elasticity of the red cell membrane. After 1 mo EPO treatment, HCT significantly increased compared to saline-injected controls. After 2 mo treatment, HCT began to decline but remained elevated above baseline levels even after 3 mo treatment. After 3 mo EPO treatment, MCV was significantly lower in EPO-treated rats compared to controls. These changes imply altered hemopoiesis to produce cells which undergo shrinkage associated with accelerated cellular aging. The lower MCV would have predicted a shorter MCTT which instead was unchanged. This observation suggested the presence of an additional factor contributing to the MCTT. The G, which measures the membrane contribution to deformability, very significantly increased with EPO treatment. This finding indicates an increased contribution of membrane properties to the MCTT after EPO treatment, which cancels the expected decrease in MCTT for smaller cells. After 3 mo of EPO treatment, aged rats exhibited significantly impaired maze learning compared to controls. A relationship between, changes in erythrocyte membrane properties and impaired function was indicated by a significant correlation (r=0.67, p <0.04) between G and errors in the lif-unit T-maze. These findings suggest that stress-induced erythropoiesis produces accelerated aging in the red blood cell population that may have functional implications (i.e., impaired learning ability). C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Univ Maryland, Dept Mech Engn, Catonsville, MD 21228 USA. RP Rifkind, JM (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 36 TC 2 Z9 2 U1 1 U2 1 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 DEC 18 PY 1998 VL 64 IS 4 BP 237 EP 247 DI 10.1016/S0024-3205(98)00559-1 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 152FW UT WOS:000077766500003 ER PT J AU Licinio, J AF Licinio, J TI Freud: Conflict and culture SO SCIENCE LA English DT Book Review C1 NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Licinio, J (reprint author), NIMH, Clin Neuroendocrinol Branch, NIH, Bldg 10,Room 2D-46,10 Ctr Dr,MSC-1284, Bethesda, MD 20892 USA. RI Licinio, Julio/L-4244-2013 OI Licinio, Julio/0000-0001-6905-5884 NR 1 TC 2 Z9 2 U1 1 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 18 PY 1998 VL 282 IS 5397 BP 2197 EP 2198 DI 10.1126/science.282.5397.2197 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150CR UT WOS:000077645800025 ER PT J AU Lee, KM Chuang, E Griffin, M Khattri, R Hong, DK Zhang, WG Straus, D Samelson, LE Thompson, CB Bluestone, JA AF Lee, KM Chuang, E Griffin, M Khattri, R Hong, DK Zhang, WG Straus, D Samelson, LE Thompson, CB Bluestone, JA TI Molecular basis of T cell inactivation by CTLA-4 SO SCIENCE LA English DT Article ID SH2-CONTAINING PHOSPHOTYROSINE PHOSPHATASE; TYROSINE PHOSPHORYLATION; RECEPTOR; ACTIVATION; KINASES; ZETA; EXPRESSION; SUBUNIT; COMPLEX; DOMAIN AB CTLA-4, a negative regulator of T cell function, was found to associate with the T cell receptor (TCR) complex zeta chain in primary T cells, The association of TCR zeta with CTLA-4, reconstituted in 293 transfectants, was enhanced by p56(lck)- induced tyrosine phosphorylation. Coexpression of the CTLA-4-associated tyrosine phosphatase, SHP-2, resulted in dephosphorylation of TCR zeta bound to CTLA-4 and abolished the p56(lck)-inducible TCR zeta-CTLA-4 interaction. Thus, CTLA-4 inhibits TCR signal transduction by binding to TCR zeta and inhibiting tyrosine phosphorylation after T cell activation. These findings have broad implications for the negative regulation of T cell function and T cell tolerance. C1 Univ Chicago, Ben May Inst Canc Res, Howard Hughes Med Inst, Chicago, IL 60637 USA. Univ Chicago, Comm Immunol, Chicago, IL 60637 USA. Univ Chicago, Gwen Knapp Ctr Lupus & Immunol Res, Chicago, IL 60637 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Pathol & Med, Chicago, IL 60637 USA. RP Bluestone, JA (reprint author), Univ Chicago, Ben May Inst Canc Res, Howard Hughes Med Inst, Chicago, IL 60637 USA. RI Griffin, Matthew/A-1688-2009 OI Griffin, Matthew/0000-0002-8701-8056 FU NIAID NIH HHS [P01 AI35294-6] NR 28 TC 394 Z9 407 U1 4 U2 8 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 DEC 18 PY 1998 VL 282 IS 5397 BP 2263 EP 2266 DI 10.1126/science.282.5397.2263 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150CR UT WOS:000077645800049 PM 9856951 ER PT J AU Kodjabachian, L Lemaire, P AF Kodjabachian, L Lemaire, P TI Embryonic induction: Is the Nieuwkoop centre a useful concept? SO CURRENT BIOLOGY LA English DT Article ID EARLY XENOPUS-EMBRYOS; BETA-CATENIN; DETERMINANTS; ZEBRAFISH; AXIS AB Regionalisation of the amphibian embryo is classically thought to involve induction by the Spemann organiser, itself induced by the Nieuwkoop centre. This model has now been extended to teleosts, with the identification of a gene that appears to define the zebrafish equivalent of the Nieuwkoop centre. C1 NICHD, NIH, Mol Genet Lab, Bethesda, MD 20892 USA. Univ Aix Marseille 2, Inst Biol Dev Marseille, Lab Genet & Physiol Dev, CNRS,UMR 6545, F-13288 Marseille 9, France. RP Kodjabachian, L (reprint author), NICHD, NIH, Mol Genet Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kodja@nih.gov; lamaire@ibdm.univ-mrs.fr RI Lemaire, Patrick/D-4237-2009; Lemaire, Patrick/B-5560-2012 OI Lemaire, Patrick/0000-0003-4925-2009 NR 15 TC 8 Z9 8 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD DEC 17 PY 1998 VL 8 IS 25 BP R918 EP R921 DI 10.1016/S0960-9822(98)00009-8 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 151VC UT WOS:000077740500009 PM 9889093 ER PT J AU Thomas, JB Fall, MJ Cooper, JB Rothman, RB Mascarella, SW Xu, H Partilla, JS Dersch, CM McCullough, KB Cantrell, BE Zimmerman, DM Carroll, FI AF Thomas, JB Fall, MJ Cooper, JB Rothman, RB Mascarella, SW Xu, H Partilla, JS Dersch, CM McCullough, KB Cantrell, BE Zimmerman, DM Carroll, FI TI Identification of an opioid kappa receptor subtype-selective N-substituent for (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BINDING-SITES; ANTAGONISTS; LIBRARIES; BINALTORPHIMINE; DISCOVERY; AGONISTS; POTENT; DESIGN AB A three-component library of compounds was prepared in parallel using multiple simultaneous solution-phase synthetic methodology. The compounds were biased toward opioid receptor antagonist activity by incorporating (+)-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (a potent, nonselective opioid pure antagonist) as one of the monomers. The other two monomers, which included N-substituted or unsubstituted Boc-protected amino acids and a range of substituted aryl carboxylic acids, were selected to add chemical diversity. Screening of these compounds in competitive binding experiments with the kappa opioid receptor selective ligand [H-3]-U69,593 led to the discovery of a novel kappa opioid receptor selective ligand, N-{(2'S)-[3-(4-hydroxyphenyl)propanamido]-3'-methylbutyl}-(3R,4R)-dimethyl-4-(3-hydroxyphenyl) -4-(3-hydroxyphenyl)piperidine (8, RTI-5989-29). Additional structure-activity relationship studies suggested that 8 possesses Lipophilic and hydrogen-bonding sites that are important to its opioid receptor potency and selectivity. These sites appear to exist predominantly within the kappa receptor since the selectivity arises from a 530-fold loss of affinity of 8 for the mu receptor and an 18-fold increase in affinity for the kappa receptor relative to the mu-selective ligand, (+)-N-[trans-4-phenyl-2-butenyl]-(3R,4R)-dimethyl-4-(3-hydroxyphenyl)piperidine (5a). The degree of selectivity observed in the radioligand binding experiments was not observed in the functional assay. According to its ability to inhibit agonist stimulated binding of [S-35]GTP gamma S at all three opioid receptors, compound 8 behaves as a mu/kappa opioid receptor pure antagonist with negligible affinity for the delta receptor. C1 Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIDA, Addict Res Sect, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Carroll, FI (reprint author), Res Triangle Inst, POB 12194, Res Triangle Pk, NC 27709 USA. FU NIDA NIH HHS [DA09045] NR 20 TC 52 Z9 53 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 17 PY 1998 VL 41 IS 26 BP 5188 EP 5197 DI 10.1021/jm980511k PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 149LA UT WOS:000077605700008 PM 9857089 ER PT J AU Smith, RH Jorgensen, WL Tirado-Rives, J Lamb, ML Janssen, PAJ Michejda, CJ Smith, MBK AF Smith, RH Jorgensen, WL Tirado-Rives, J Lamb, ML Janssen, PAJ Michejda, CJ Smith, MBK TI Prediction of binding affinities for TIBO inhibitors of HIV-1 reverse transcriptase using Monte Carlo simulations in a linear response method SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MOLECULAR-DYNAMICS SIMULATIONS; LONE-PAIR DIRECTIONALITY; FREE-ENERGIES; NONNUCLEOSIDE INHIBITORS; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; HYDROGEN-BOND; HYDRATION; DNA AB Monte Carlo (MC) simulations in combination with a linear response approach were used to estimate the free energies of binding for a series of 12 TIBO nonnucleoside inhibitors of HIV-1 reverse transcriptase. Separate correlations were made for the R-6 and S-6 absolute conformations of the inhibitors, as well as for the analogous N6-monoprotonated species. Models based upon the neutral unbound inhibitors produced overall better fits to experimental values than did those using the protonated unbound inhibitors, with only slight differences between the neutral R-6 and S-6 cases. The best results were obtained with a three-parameter linear response equation containing van der Waals (alpha), electrostatic (beta), and solvent accessible surface area (SASA, gamma) terms. The averaged (R-6 and S-6) rms error was approximately 0.88 kcal/mol for the observed range of 4.06 kcal/mol in inhibitor activities. The averaged values of alpha, beta, and gamma mere -0.150, 0.114, and 0.0286, respectively. Omission of the alpha term gave beta 0.152 and gamma 0.022 with a rms of 0.92. The unweighted van der Waals components were found to be highly attractive but failed to correlate well across the series of inhibitors. Contrastingly, while the electrostatic components are all repulsive, they show a direct correlation with inhibitor activity as measured by Delta G(binding). The role of gamma is primarily to produce an overall negative binding energy, and it can effectively be replaced with a negative constant. During the MC simulations of the unbound solvated inhibitors, the R-6 and S-6 absolute conformations do not interconvert; due to the formation of a favorable hydrogen bond to solvent. In the complex, however, interconversion of these conformations of the inhibitor is observed during the course of the simulations, a phenomenon which is apparently not observed in the crystalline state of the complex. Hydrogen bonding of the inhibitor to the backbone NH of K101 and the lack of such an interaction with the C=O of K101 or with solvent correlate with enhanced activity, as does the ability to assume a number of different orientations of the inhibitor dimethylallyl moiety with respect to residues Y181 and Y188 while retaining contact with W229. Overall, the use of a combination of MC simulation with a linear response method shows promise as a relatively rapid means of estimating inhibitor activities. This approach should be useful in the preliminary evaluation of potential modifications to known inhibitors to enhance activity. C1 Western Maryland Coll, Dept Chem, Westminster, MD 21157 USA. NCI, ABL, Basic Res Program, Frederick Res & Dev Ctr, Ft Detrick, MD 21702 USA. Yale Univ, Dept Chem, New Haven, CT 06520 USA. CMD, Janssen Res Fdn, B-2350 Vosselaar, Belgium. RP Smith, RH (reprint author), Western Maryland Coll, Dept Chem, Westminster, MD 21157 USA. RI Tirado-Rives, Julian/A-4992-2012 OI Tirado-Rives, Julian/0000-0001-7330-189X NR 44 TC 85 Z9 87 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 17 PY 1998 VL 41 IS 26 BP 5272 EP 5286 PG 15 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 149LA UT WOS:000077605700014 PM 9857095 ER PT J AU Douek, DC McFarland, RD Keiser, PH Gage, EA Massey, JM Haynes, BF Polis, MA Haase, AT Feinberg, MB Sullivan, JL Jamieson, BD Zack, JA Picker, LJ Koup, RA AF Douek, DC McFarland, RD Keiser, PH Gage, EA Massey, JM Haynes, BF Polis, MA Haase, AT Feinberg, MB Sullivan, JL Jamieson, BD Zack, JA Picker, LJ Koup, RA TI Changes in thymic function with age and during the treatment of HIV infection SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; T-CELLS; V(D)J RECOMBINATION; LYMPHOCYTES; CD4+; THYMOPOIESIS; REGENERATION; PRODUCTS; THERAPY; VIRGIN AB The thymus represents the major site of the production and generation of T cells expressing alpha beta-type T-cell antigen receptors(1). Age-related involution(2) may affect the ability of the thymus to reconstitute T cells expressing CD4 cell-surface antigens that are lost during HIV infection(3); this effect has been seen after chemotherapy and bone-marrow transplantation(4,5). Adult HIV-infected patients treated with highly active antiretroviral therapy (HAART) show a progressive increase in their number of naive CD4-positive T cells(6,7). These cells could arise through expansion of existing naive T cells in the periphery(8) or through thymic production of new naive T cells(9,10). Here we quantify thymic output by measuring the excisional DNA products of TCR-gene rearrangement. We find that, although thymic function declines with age, substantial output is maintained into late adulthood. HIV infection leads to a decrease in thymic function that can be measured in the peripheral blood and lymphoid tissues. In adults treated with HAART, there is a rapid and sustained increase in thymic output in most subjects. These results indicate that the adult thymus fan contribute to immune reconstitution following HAART. C1 Univ Texas, SW Med Ctr, Dept Med, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75235 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Sch Med, Dept Microbiol, Minneapolis, MN 55455 USA. Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA. Univ Massachusetts, Med Ctr, Dept Pediat, Worcester, MA 01605 USA. Univ Massachusetts, Med Ctr, Dept Mol Med, Worcester, MA 01605 USA. Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Sch Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Sch Med, Dept Microbiol & Mol Genet, Los Angeles, CA 90095 USA. UCLA Inst, Los Angeles, CA 90095 USA. RP Koup, RA (reprint author), Univ Texas, SW Med Ctr, Dept Med, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. OI Polis, Michael/0000-0002-9151-2268 NR 30 TC 1237 Z9 1299 U1 3 U2 35 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 17 PY 1998 VL 396 IS 6712 BP 690 EP 695 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150YT UT WOS:000077694200057 PM 9872319 ER PT J AU Rosman, NP Cloyd, TC Bell, WE AF Rosman, NP Cloyd, TC Bell, WE TI Treatment of acute repetitive seizures - reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 New England Med Ctr, Boston, MA 02111 USA. Univ Minnesota, Minneapolis, MN 55455 USA. NIH, Bethesda, MD 20892 USA. RP Rosman, NP (reprint author), New England Med Ctr, 750 Washington St, Boston, MA 02111 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MASS MEDICAL SOC PI BOSTON PA 10 SHATTUCK, BOSTON, MA 02115 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 17 PY 1998 VL 339 IS 25 BP 1857 EP 1857 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 148RJ UT WOS:000077545800015 ER PT J AU Shen, SX Weaver, Z Xu, XL Li, CL Weinstein, M Chen, L Guan, XY Ried, T Deng, CX AF Shen, SX Weaver, Z Xu, XL Li, CL Weinstein, M Chen, L Guan, XY Ried, T Deng, CX TI A targeted disruption of the murine Brca1 gene causes gamma-irradiation hypersensitivity and genetic instability SO ONCOGENE LA English DT Article DE BRCA1; p53; radiation sensitivity and chromosome abnormality ID EARLY EMBRYONIC LETHALITY; CYCLIN-DEPENDENT KINASES; STRANDED-DNA ENDS; BREAST-CANCER; P53; MOUSE; RAD51; MICE; MUTATIONS; RECOMBINATION AB Germline mutations of the Brca1 gene are responsible for most cases of familial breast and ovarian cancers, but somatic mutations are rarely detected in sporadic events. Moreover, mouse embryos deficient for Brca1 have been shown to die during early embryogenesis due to a proliferation defect, These findings seem incompatible with the tumor suppress function assigned to this gene and raise questions about the mechanism by which Brca1 mutations cause tumorigenesis. We now directly demonstrate that BRCA1 is responsible for the integrity of the genome, Murine embryos carrying a Brca1 null mutation are developmentally retarded and hypersensitive to gamma-irradiation, suggesting a failure in DNA damage repair. This notion is supported by spectral karyotyping (SKY) of metaphase chromosomes, which display numerical and structural aberrations. However, massive chromosomal abnormalities are only observed when a p53(-/-) background is introduced, Thus, a p53 dependent cell cycle checkpoint arrests the mutant embryos and prevents the accumulation of damaged DNA, Brca1(-/-) fibroblasts are not viable, nor are Brca1(-/-):p53(-/-) fibroblasts, However, proliferative foci arise from Brca1(-/-):p53(-/-) cells, probably due to additional mutations that are a consequence of the accumulating DNA damage, We believe that the increased incidence of such additional mutations accounts for the mechanism of tumorigenesis associated with Brca1 mutations in humans. C1 NIDDKD, Biochem & Metab Lab, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, Biochem & Metab Lab, NIH, Bldg 10,9N105, Bethesda, MD 20892 USA. RI Guan, Xin-Yuan/A-3639-2009; deng, chuxia/N-6713-2016 OI Guan, Xin-Yuan/0000-0002-4485-6017; NR 50 TC 255 Z9 258 U1 1 U2 4 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD DEC 17 PY 1998 VL 17 IS 24 BP 3115 EP 3124 DI 10.1038/sj.onc.1202243 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 147VF UT WOS:000077517400005 PM 9872327 ER PT J AU Turner, M AF Turner, M TI Sun safety: Avoiding noonday sun, wearing protective clothing, and the use of sunscreen SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID BASAL-CELL CARCINOMA; MALIGNANT-MELANOMA; MELANOCYTIC NEVI; RISK FACTOR; EXPOSURE; AUSTRALIA C1 NCI, Div Clin Sci, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Turner, M (reprint author), NCI, Div Clin Sci, Dermatol Branch, NIH, Bldg 10,Rm N238,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 18 TC 16 Z9 16 U1 0 U2 0 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 DEC 16 PY 1998 VL 90 IS 24 BP 1854 EP 1855 DI 10.1093/jnci/90.24.1854 PG 2 WC Oncology SC Oncology GA 148GN UT WOS:000077497000001 PM 9862615 ER PT J AU Croyle, RT AF Croyle, RT TI Depression as a risk factor for cancer: Renewing a debate on the psychobiology of disease SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PSYCHOLOGICAL SYMPTOMS; BREAST-CANCER; PERSONALITY; MORTALITY; MORBIDITY; WOMEN C1 NCI, Div Canc Control & Populat Sci, Behav Res Program, NIH, Bethesda, MD 20892 USA. RP Croyle, RT (reprint author), NCI, Div Canc Control & Populat Sci, Behav Res Program, NIH, 6130 Execut Blvd,MSC 7326, Bethesda, MD 20892 USA. NR 15 TC 17 Z9 17 U1 0 U2 3 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 DEC 16 PY 1998 VL 90 IS 24 BP 1856 EP 1857 DI 10.1093/jnci/90.24.1856 PG 2 WC Oncology SC Oncology GA 148GN UT WOS:000077497000002 PM 9862616 ER PT J AU Carroll, MW Overwijk, WW Surman, DR Tsung, K Moss, B Restifo, NP AF Carroll, MW Overwijk, WW Surman, DR Tsung, K Moss, B Restifo, NP TI Construction and characterization of a triple-recombinant vaccinia virus encoding B7-1, interleukin 12, and a model tumor antigen SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ESTABLISHED PULMONARY METASTASES; HUMAN PAPILLOMAVIRUS TYPE-16; T-CELLS; ANTITUMOR IMMUNITY; CYTOTOXIC LYMPHOCYTES; ACTIVE IMMUNOTHERAPY; CYTOKINE PRODUCTION; EXPRESSION VECTORS; GAMMA PRODUCTION; GENE AB Background: Construction of recombinant viruses that can serve as vaccines for the treatment of experimental murine tumors has recently been achieved, The cooperative effects of immune system modulators, including cytokines such as interleukin 12 (IL-12) and costimulatory molecules such as B7-1, may be necessary for activation of cytotoxic T lymphocytes, Thus, we have explored the feasibility and the efficacy of inclusion of these immunomodulatory molecules in recombinant virus vaccines in an experimental antitumor model in mice that uses Escherichia coli P-galactosidase as a target antigen. Methods: We developed a "cassette" system in which three loci of the vaccinia virus genome were used for homologous recombination, A variety of recombinant vaccinia viruses were constructed, including one virus, vB7/beta/ IL-12, that contains the following five transgenes: murine B7-1, murine IL-12 subunit p35, murine IL-12 subunit p40, E, coli lacZ (encodes P-galactosidase, the model antigen), and E, coli gpt (xanthine-guanine phosphoribosyltransferase, a selection gene). The effects of the recombinant viruses on lung metastases and survival were tested in animals that had been given an intravenous injection of beta-galactosidase-expressing murine colon carcinoma cells 3 days before they received the recombinant virus by intravenous inoculation. Results: Expression of functional B7-1 and IL-12 by virally infected cells was demonstrated ia vitro. Lung tumor nodules (i,e,, metastases) were reduced in mice by more than 95% after treatment with the virus vB7/beta/IL-12; a further reduction in lung tumor nodules was observed when exogenous IL-12 was also given. Greatest survival of tumor-bearing mice was observed in those treated with viruses encoding P-galactosidase and B7-1 plus exogenous IL-12, Conclusion: This study shows the feasibility of constructing vaccinia viruses that express tumor antigens and multiple immune cofactors to create unique immunologic microenvironments that can modulate immune responses to cancer. C1 NCI, Div Clin Sci, Surg Branch, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Washington Univ, Dept Surg, St Louis, MO USA. RP Restifo, NP (reprint author), NCI, Div Clin Sci, Surg Branch, NIH, Bldg 10,Rm 2B42, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z99 CA999999, Z01 BC010763-01] NR 41 TC 42 Z9 42 U1 0 U2 0 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 DEC 16 PY 1998 VL 90 IS 24 BP 1881 EP 1887 DI 10.1093/jnci/90.24.1881 PG 7 WC Oncology SC Oncology GA 148GN UT WOS:000077497000012 PM 9862625 ER PT J AU Penninx, BWJH Guralnik, JM Pahor, M Ferrucci, L Cerhan, JR Wallace, RB Havlik, RJ AF Penninx, BWJH Guralnik, JM Pahor, M Ferrucci, L Cerhan, JR Wallace, RB Havlik, RJ TI Chronically depressed mood and cancer risk in older persons SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID KILLER-CELL PHENOTYPES; BODY-MASS INDEX; LUNG-CANCER; CYTOTOXIC ACTIVITY; MAJOR DEPRESSION; BREAST-CANCER; IMMUNE-SYSTEM; CORTISOL; SAMPLE; SCALE AB Background: Depression has been proposed as a predisposing factor for cancer, but prospective studies have been inconclusive, We examined whether a high level of depressive symptoms, present for a long time, is associated with increased risk of cancer in the elderly, Methods: Data were obtained and analyzed from persons who lived in three communities (Massachusetts, Iowa, and Connecticut) of the Established Populations for Epidemiologic Studies of the Elderly, a prospective cohort study with a mean follow-up of 3.8 years that included 4825 persons (1708 men and 3117 women) aged 71 years and older. Chronically depressed mood was defined as present when the number of depressive symptoms exceeded specific cut points on the Center for Epidemiologic Studies-Depression scale at baseline (1988) and 3 and 6 years before baseline. New cases of cancer were identified from Medicare hospitalization records and death certificates. Results: Of the 4825 persons studied, 146 (3.0%) were chronically depressed, The incidence rate of cancer was 30.5 per 1000 person-years for the 146 persons with chronic depression and 21.9 per 1000 person-years for the 4679 nonchronically depressed persons. After adjustment for age, sex, race, disability, hospital admissions, alcohol intake, and smoking, the hazard ratio for cancer associated with chronically depressed mood was 1.88 (95% confidence interval = 1.13-3.14), The excess risk of cancer associated with chronic depression was consistent for most types of cancer and was not specific to cigarette smokers. Conclusion: When present for at least 6 years, depression was associated with a generally increased risk of cancer. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. Univ Tennessee, Dept Prevent Med, Memphis, TN USA. Ist Nazl Ric & Cura Anziani, Dept Geriatr, Florence, Italy. Univ Iowa, Dept Prevent Med & Environm Hlth, Iowa City, IA 52242 USA. RP Guralnik, JM (reprint author), NIA, Epidemiol Demog & Biometry Program, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. FU NIA NIH HHS [N01AG02106, N01AG02107, N01AG0215] NR 45 TC 188 Z9 191 U1 2 U2 16 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 DEC 16 PY 1998 VL 90 IS 24 BP 1888 EP 1893 DI 10.1093/jnci/90.24.1888 PG 6 WC Oncology SC Oncology GA 148GN UT WOS:000077497000013 PM 9862626 ER PT J AU Rosenberg, SA Zhai, YF Yang, JC Schwartzentruber, DJ Hwu, P Marincola, F Topalian, SL Restifo, NP Seipp, CA Einhorn, JH Roberts, B White, DE AF Rosenberg, SA Zhai, YF Yang, JC Schwartzentruber, DJ Hwu, P Marincola, F Topalian, SL Restifo, NP Seipp, CA Einhorn, JH Roberts, B White, DE TI Immunizing patients with metastatic melanoma using recombinant adenoviruses encoding MART-1 or gp100 melanoma antigens SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID MEDIATED GENE-TRANSFER; TUMOR-INFILTRATING LYMPHOCYTES; CANCER REGRESSION ANTIGENS; CYTOLYTIC T-LYMPHOCYTES; CYSTIC-FIBROSIS; IN-VIVO; IMMUNE-RESPONSES; VIRAL-ANTIGENS; CFTR CDNA; THERAPY AB Background: The characterization of the genes encoding melanoma-associated antigens MART-1 or gp100, recognized by T cells, has opened new possibilities for the development of immunization strategies for patients with metastatic melanoma, With the use of recombinant adenoviruses expressing either MART-1 or gp100 to immunize patients with metastatic melanoma, we evaluated the safety, immunologic, and potential therapeutic aspects of these immunizations. Methods: In phase I studies, 54 patients received escalating doses (between 10(7) and 10(11) plaque-forming units) of recombinant adenovirus encoding either MART-1 or gp100 melanoma antigen administered either alone or followed by the administration of interleukin 2 (IL-2). The immunologic impact of these immunizations on the development of cellular and antibody reactivity was assayed. Results: Recombinant adenoviruses expressing MART-1 or gp100 were safely administered. One of 16 patients with metastatic melanoma receiving the recombinant adenovirus MART-1 alone experienced a complete response. Other patients achieved objective responses, but they had received IL-2 along with an adenovirus, and their responses could be attributed to the cytokine, Immunologic assays showed no consistent immunization to the MART-1 or gp100 transgenes expressed by the recombinant adenoviruses. High levels of neutralizing antibody were found in the pretreatment sera of the patients. Conclusions: High doses of recombinant adenoviruses could be safely administered to cancer patients. High levels of neutralizing antibody present in patients' sera prior to treatment may have impaired the ability of these viruses to immunize patients against melanoma antigens. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Genzyme Corp, Framingham, MA 01701 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, Bldg 10,Rm 2B42, Bethesda, MD 20892 USA. RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 47 TC 221 Z9 225 U1 1 U2 3 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 DEC 16 PY 1998 VL 90 IS 24 BP 1894 EP 1900 DI 10.1093/jnci/90.24.1894 PG 7 WC Oncology SC Oncology GA 148GN UT WOS:000077497000014 PM 9862627 ER PT J AU Lloyd-Jones, DM Martin, DO Larson, MG Levy, D AF Lloyd-Jones, DM Martin, DO Larson, MG Levy, D TI Accuracy of death certificates for coding coronary heart disease as the cause of death SO ANNALS OF INTERNAL MEDICINE LA English DT Article DE coronary disease; death certificates; cause of death; mortality; epidemiologic methods ID MORTALITY; AUTOPSY; POPULATION; TRENDS; COMPLETION; STATISTICS; DECLINE; ERRORS; MEN AB Background: Death certificates are widely used in epidemiologic and clinical investigations and for national statistics. Objective: To examine the accuracy of death certificates for coding coronary heart disease as the underlying cause of death. Design: Community-based inception cohort followed since 1948. Setting: Framingham, Massachusetts. Patients: 2683 deceased Framingham Heart Study participants. Measurements: Sensitivity, specificity, and predictive values of the death certificate. The reference standard was cause of death adjudicated by a panel of three physicians. Results: Among 2683 decedents, the death certificate coded coronary heart disease as the underlying cause of death for 942; the physician panel assigned coronary heart disease for 758. The death certificate had a sensitivity of 83.8% (95% CI, 81.1% to 86.4%), positive predictive value of 67.4% (CI, 64.4% to 70.4%), specificity of 84.1% (CI, 82.4% to 85.7%1), and negative predictive value of 92.9% (CI, 91.7% to 94.1 %) for coronary heart disease. The death certificate assigned coronary heart disease in 51.2% of 242 deaths (9.0% of total deaths) for which the physician panel could not determine a ca use. Compared with the physician panel, the death certificate attributed 24.3% more deaths to coronary heart disease overall and more than twice as many deaths to coronary heart disease in decedents who were at least 85 years of age. When deaths that were assigned unknown cause by the physician panel were excluded, the death certificate still assigned more deaths to coronary heart disease (7.9% overall and 43.1% in the oldest age group). Conclusions: Coronary heart disease may be overrepresented as a cause of death on death certificates. National mortality statistics, which are based on death certificate data, may overestimate the frequency of coronary heart disease by 7.9% to 24.3% overall and by as much as twofold in older persons. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA USA. Boston Univ, Sch Med, Boston, MA 02118 USA. RP Levy, D (reprint author), Framingham Heart Study, 5 Thurber St, Framingham, MA 01702 USA. RI Lloyd-Jones, Donald/C-5899-2009 FU NHLBI NIH HHS [N01-HC-38038] NR 39 TC 276 Z9 279 U1 1 U2 8 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 DEC 15 PY 1998 VL 129 IS 12 BP 1020 EP + PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 147DC UT WOS:000077471900004 PM 9867756 ER PT J AU Lenfant, C Friedman, L Thom, T AF Lenfant, C Friedman, L Thom, T TI Fifty years of death certificates: The Framingham Heart Study SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID DISEASE MORTALITY; CORONARY C1 NIH, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NIH, Bldg 31,Room 5A52,31 Ctr Dr, Bethesda, MD 20892 USA. NR 12 TC 29 Z9 29 U1 0 U2 1 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 DEC 15 PY 1998 VL 129 IS 12 BP 1066 EP 1067 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 147DC UT WOS:000077471900011 PM 9867763 ER PT J AU Auer, KL Park, JS Seth, P Coffey, RJ Darlington, G Abo, A McMahon, M DePinho, RA Fisher, PB Dent, P AF Auer, KL Park, JS Seth, P Coffey, RJ Darlington, G Abo, A McMahon, M DePinho, RA Fisher, PB Dent, P TI Prolonged activation of the mitogen-activated protein kinase pathway promotes DNA synthesis in primary hepatocytes from p21(Cip-1/WAF1)-null mice, but not in hepatocytes from p16(INK4a)-null mice SO BIOCHEMICAL JOURNAL LA English DT Article ID ADULT-RAT HEPATOCYTES; CELL-CYCLE ARREST; P53-INDEPENDENT INDUCTION; INDUCED PROLIFERATION; LIVER-REGENERATION; TUMOR SUPPRESSION; INK4A LOCUS; EXPRESSION; GENE; P53 AB In primary rat hepatocytes, prolonged activation of the p42/44 mitogen-activated protein kinase (MAPK) pathway is associated with a decrease in DNA synthesis and increased expression of the cyclin-dependent kinase inhibitor (CKI) proteins p21(Cip-1/WAF1) and p16(INK4a). To evaluate the relative importance of these CKIs in mediating this response, we determined the impact of prolonged MAPK activation on DNA synthesis in primary cultures of hepatocytes derived from mice embryonically deleted (null) for either p21(Cip-1/WAF1) or p16(INK4a). When MAPK was activated in wild-type mouse hepatocytes for 24 h, via infection with a construct to express an inducible oestrogen receptor-Raf-1 fusion protein (Delta Raf: ER), the expression of p21(Cip-1/WAF1) and p16(INK1a) CKI proteins increased, cyclin-dependent kinase 2 (cdk2) and cdk4 activities decreased, and DNA synthesis decreased, Inhibition of RhoA GTPase function increased the basal expression of p21(Cip-1/WAF1) and p27(Kip-1) but not p16(INK4a), and enhanced the ability of MAPK signalling to decrease DNA synthesis. Ablation of the expression of CCAATT enhancer-binding protein alpha (C/EBP alpha), but not of the expression of C/EBP beta, decreased the ability of MAPK signalling to induce p21(Cip-1/WAF1). When MAPK was activated in p16(INK4a)-null hepatocytes for 24 h, the expression of p21(Cip-1/WAF1) increased, cdk2 and cdk4 activities decreased and DNA synthesis decreased. In contrast with these findings, prolonged activation of the MAPK pathway in hepatocytes from p21(Cip-1/WAF1)-null mice enhanced cdk1 and cdk4 activities and caused a large increase in DNA synthesis, despite elevated expression of p16(INK4a). Inhibition of RhoA GTPase activity in p21(Cip-1/WAF1)-null cells partly blunted both the basal levels of DNA synthesis and the ability of prolonged MAPK signalling to increase DNA synthesis. Expression of anti-sense p21(Cip-1/WAF1) in either wild-type or p16(INK4a)-null hepatocytes decreased the ability of prolonged MAPK signalling to increase the expression of P21(Cip-1/WAF1), and permitted MAPK signalling to increase both cdk2 and cdk4 activities and DNA synthesis. These results argue that the ability of prolonged MAPK signalling to inhibit DNA synthesis in hepatocytes requires the expression of p21(Cip-1/WAF1), and that the increased expression of p16(INK4a) has a smaller role in the ability of this stimulus to mediate growth arrest. Our results also suggest that RhoA function can modulate DNA synthesis in primary hepatocytes via the expression of p21(CiP-1/WAF1) and p27(Kip-1). C1 Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. NCI, Breast Canc Sect, Med Branch, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Gastroenterol & Med Oncol, Nashville, TN 37232 USA. Baylor Coll Med, Dept Pathol, Houston, TX 77071 USA. Onyx Pharmaceut, Richmond, CA 94806 USA. Univ Calif San Francisco, Mt Zion Canc Ctr, Canc Res Inst, San Francisco, CA 94115 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Columbia Univ Coll Phys & Surg, Dept Urol & Pathol, New York, NY 10032 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. RP Dent, P (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. EM pdent@hsc.vcu.edu NR 43 TC 53 Z9 54 U1 0 U2 3 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 15 PY 1998 VL 336 BP 551 EP 560 PN 3 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153RW UT WOS:000077847300007 PM 9841865 ER PT J AU Bortner, CD Cidlowski, JA AF Bortner, CD Cidlowski, JA TI A necessary role for cell shrinkage in apoptosis SO BIOCHEMICAL PHARMACOLOGY LA English DT Editorial Material DE apoptosis; cell volume; cell shrinkage; regulatory volume increase; regulatory volume decrease; potassium ID CEREBELLAR GRANULE NEURONS; POTASSIUM CHANNEL; VOLUME REGULATION; FLOW-CYTOMETRY; RAT THYMOCYTES; T-LYMPHOCYTES; K+ CHANNELS; DEOXYRIBONUCLEIC-ACID; ION-CHANNEL; DEATH AB The loss of cell volume is a fundamental and universal characteristic of programmed cell death. However, what was once thought to be a passive, secondary feature of the cell death process has now become an area of research interest. Recent studies have integrated cell volume regulation and the movement of ions with the activation of apoptosis. A dramatic reduction of potassium and sodium concentration has been shown to occur in apoptotic cells that exhibit a shrunken morphology. Furthermore, maintaining the normal physiological intracellular concentration of monovalent ions, particularly potassium, inhibits the activation and activity of the death cascades. Thus, the role ions play during apoptosis is more extensive than just facilitation of the loss of cell volume. In this article, we will review the concepts of cell Volume regulation and the loss of volume during apoptosis. Additionally, we will underscore our current understanding of ion movement as it relates to the activation of the cell death process. BIOCHEM PHARMACOL 56;12:1549-1559, 1998. (C) 1998 Elsevier Science Inc. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233,MD E2-02, Res Triangle Pk, NC 27709 USA. NR 68 TC 159 Z9 164 U1 1 U2 5 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 DEC 15 PY 1998 VL 56 IS 12 BP 1549 EP 1559 DI 10.1016/S0006-2952(98)00225-1 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 147HZ UT WOS:000077484600002 PM 9973175 ER PT J AU Hyman, SE AF Hyman, SE TI Brain neurocircuitry of anxiety and fear: Implications for clinical research and practice SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material C1 NIMH, Rockville, MD 20857 USA. RP Hyman, SE (reprint author), NIMH, Room 17-99,5600 Fishers Lane, Rockville, MD 20857 USA. NR 7 TC 10 Z9 13 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 DEC 15 PY 1998 VL 44 IS 12 BP 1201 EP 1203 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 147JC UT WOS:000077484900001 PM 9861461 ER PT J AU Lang, PJ Bradley, MM Cuthbert, BN AF Lang, PJ Bradley, MM Cuthbert, BN TI Emotion, motivation, and anxiety: Brain mechanisms and psychophysiology SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT Research Symposium on Brain Neurocircuitry of Anxiety and Fear - Implications for Clinical Research and Practice CY MAR 26, 1998 CL BOSTON, MASSACHUSETTS SP Anxiety Disorders Assoc Amer, NIMH, Wyeth Ayerst Labs DE emotion; anxiety; brain mechanisms; motivation; fear ID STARTLE REFLEX MODULATION; STRIA TERMINALIS; CENTRAL NUCLEUS; BED NUCLEUS; FEAR; AMYGDALA; ATTENTION; PLEASURE; LESIONS; SENSITIZATION AB The organization of response systems in emotion is founded on two basic motive systems, appetitive and defensive. The subcortical and deep cortical structures that determine primary motivated behavior are similar across mammalian species. Animal research has illuminated these neural systems and defined their reflex outputs. Although motivated behavior is more complex and varied in humans, the simpler underlying response patterns persist in affective expression. These basic phenomena are elucidated here in the context of affective perception. Thus, the research examines human beings watching uniquely human stimuli-primarily picture media (but also words and sounds) that prompt emotional arousal-showing how the underlying motivational structure is apparent in the organization of visceral and behavioral responses, in the priming of simple reflexes, and in the reentrant processing of these symbolic representations in the sensory cortex. Implications of the work for understanding pathological emotional states are discussed, emphasizing research on psychopathy and the anxiety disorders. Biol Psychiatry 1998;44:1248-1263 (C) 1998 Society of Biological Psychiatry. C1 Univ Florida, NIMH, Ctr Study Emot & Attent, Gainesville, FL 32610 USA. RP Lang, PJ (reprint author), Univ Florida, NIMH, Ctr Study Emot & Attent, Box 100165 HSC, Gainesville, FL 32610 USA. RI Frank, David/E-8213-2012 FU NIMH NIH HHS [MH37757, MH43975, P50-MH52384] NR 84 TC 482 Z9 485 U1 11 U2 85 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 DEC 15 PY 1998 VL 44 IS 12 BP 1248 EP 1263 DI 10.1016/S0006-3223(98)00275-3 PG 16 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 147JC UT WOS:000077484900008 PM 9861468 ER PT J AU Randad, RS Lubkowska, L Eissenstat, MA Gulnik, SV Yu, B Bhat, TN Clanton, DJ House, T Stinson, SF Erickson, JW AF Randad, RS Lubkowska, L Eissenstat, MA Gulnik, SV Yu, B Bhat, TN Clanton, DJ House, T Stinson, SF Erickson, JW TI Unsymmetric nonpeptidic HIV protease inhibitors containing anthranilamide as a P2 ' ligand SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID SYMMETRY-BASED INHIBITORS; ANTIVIRAL ACTIVITY; DESIGN AB A series of novel unsymmetrical anthranilamide-containing HIV protease inhibitors was designed. The structure-activity studies revealed a series of potent P2-P3' inhibitors that incorporate an anthranilamide group the P2' position. A reduction in molecular weight and lipophilicity is achieved by a judicious choice of P2 ligands (i.e., aromatic, heteroaromatic, carbamate, and peptidic). A systematic investigation led to the 5-thiazolyl carbamate analog 8m, which exhibited a favorable C-max/EC50 ratio (>30), plasma half-life (>8 h), and potent in vitro antiviral activity (EC50 = 0.2 uM). (C) 1998 Published by Elsevier Science Ltd. All rights reserved. C1 NCI, Frederick Canc Res & Dev Ctr, Struct Biochem Program, AIDS Drug Screening & Dev Lab,SAIC Frederick, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, DCTDC, Dev Therapeut Program, Frederick, MD 21702 USA. RP Randad, RS (reprint author), NCI, Frederick Canc Res & Dev Ctr, Struct Biochem Program, AIDS Drug Screening & Dev Lab,SAIC Frederick, Frederick, MD 21702 USA. FU NCI NIH HHS [N01-CO-56000] NR 19 TC 2 Z9 3 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 15 PY 1998 VL 8 IS 24 BP 3537 EP 3542 DI 10.1016/S0960-894X(98)00657-X PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 153TE UT WOS:000077848100020 PM 9934467 ER PT J AU Manne, U Weiss, HL Myers, RB Danner, OK Moron, C Srivastava, S Grizzle, WE AF Manne, U Weiss, HL Myers, RB Danner, OK Moron, C Srivastava, S Grizzle, WE TI Nuclear accumulation of p53 in colorectal adenocarcinoma - Prognostic importance differs with race and location of the tumor SO CANCER LA English DT Article DE nuclear accumulation of p53; colorectal adenocarcinomas; African-American; white; proximal colon; prognosis ID STORED PARAFFIN SLIDES; MARKER-IMMUNOSTAINING INTENSITY; CANCER SURVIVAL; BREAST-CANCER; COLON-CANCER; ALLELIC LOSS; ANATOMICAL DISTRIBUTION; GENETIC ALTERATIONS; RACIAL-DIFFERENCES; RISK-FACTORS AB BACKGROUND, Although several studies have been conducted to examine the role of p53 genetic abnormalities and their prognostic value in colorectal carcinoma, the incidence of nuclear accumulation of p53 and the prognostic importance of nuclear accumulation of p53 in African-American and white patients have not been investigated separately. Therefore, the authors evaluated the prognostic significance of p53 nuclear accumulation in these two racial groups. METHODS. Nuclear accumulation of p53 was evaluated immunohistochemically in archival tissue specimens from 204 African-American and 300 white patients with primary colorectal adenocarcinomas who had undergone surgery. Survival times from colorectal adenocarcinoma were analyzed using Kaplan-Meier survival estimates and the Cox proportional hazards model for nuclear accumulation of p53 with adjustments for other confounding demographic and clinical variables. RESULTS, Approximately equivalent proportions of distal (54%) and proximal adenocarcinomas (47%) were positive for nuclear accumulation of p53 in African-American patients. In contrast, distal colorectal adenocarcinomas from white patients more frequently were positive for nuclear accumulation of p53 than adenocarcinomas of the proximal colon (63% vs. 38%, respectively). Nuclear ac cumulation of p53 was found to be a strong predictor of poor survival in white patients (hazard ratio = 6.77; P = 0.0001) but not in African-American patients with primary adenocarcinomas of the proximal colon. Nuclear accumulation of p53 was not of prognostic value in patients of either race with primary adenocarcinomas of the distal colorectum. CONCLUSIONS. Nuclear accumulation of p53 is a valuable indicator of poor prognosis only for white patients with adenocarcinomas of the proximal colon. The current study also suggests that the role of p53 dysregulation in colorectal adenocarcinomas may vary with the anatomic location of the tumor and the race of the patient. These findings suggest that the demographic characteristics of patients should be considered in the evaluation of prognostic markers of colorectal neoplasia. Cancer 1998;83:2456-67, (C) 1998 American Cancer, Society. C1 Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Ctr Comprehens Canc, Biostat Unit, Birmingham, AL 35294 USA. Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. NCI, Early Detect Res Network, Bethesda, MD USA. RP Grizzle, WE (reprint author), Univ Alabama, Dept Pathol, Univ Stn, Birmingham, AL 35294 USA. RI Manne, Upender/D-5613-2009 FU NCI NIH HHS [N01-CN-15340-03] NR 68 TC 47 Z9 50 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 15 PY 1998 VL 83 IS 12 BP 2456 EP 2467 DI 10.1002/(SICI)1097-0142(19981215)83:12<2456::AID-CNCR8>3.0.CO;2-5 PG 12 WC Oncology SC Oncology GA 151QJ UT WOS:000077731700008 PM 9874449 ER PT J AU Gerber, LH AF Gerber, LH TI A review of measures of lymphedema SO CANCER LA English DT Article; Proceedings Paper CT American-Cancer-Society Workshop on Breast Cancer Treatment-Related Lymphedema CY FEB 20-22, 1997 CL NEW YORK, NEW YORK SP Amer Canc Soc DE lymphedema; assessment; circumferential measurements; volumetrics; tonometry; ultrasound AB BACKGROUND, Lymphedema usually is identified by patients, and rarely is it screened for routinely. Many assessments have been reported and have been used in evaluating a variety of treatments for lymphedema. METHODS, A review of the literature was undertaken. RESULTS, Five frequently used measures of lymphedema include circumferential measures of limbs at various points (usually at bony landmarks); volumetric measures using limb submersion in water; skin tonometry, in which soft tissue compression is quantified: imaging techniques to describe tissue characteristics as well as to quantify soft tissue swelling (magnetic resonance imaging and computerized tomography; and ultrasound with and without Doppler flow studies for volumetric measures. Circumferential measures with calculations designed to compute limb volumes and volumetric measures are used most frequently, but these have some difficulty with reliability. No significant effort has been made to develop a patient based questionnaire that describes the size as well as the impact of lymphedema on an individual's functional level. CONCLUSIONS, Existing physical measures of lymphedema are available that are easy to use, inexpensive, have limited reliability, and do not address the issue of functional impact. Imaging techniques may provide valuable qualitative and quantitative information in selected populations. Cancer 1998;83:2803-4. (C) 1998 American Cancer Society. C1 NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Gerber, LH (reprint author), NIH, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NR 12 TC 61 Z9 65 U1 1 U2 7 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 DEC 15 PY 1998 VL 83 IS 12 SU 2 BP 2803 EP 2804 DI 10.1002/(SICI)1097-0142(19981215)83:12B+<2803::AID-CNCR29>3.0.CO;2-W PG 2 WC Oncology SC Oncology GA 151QT UT WOS:000077732500006 PM 9874401 ER PT J AU Augustine, E Corn, M Danoff, J AF Augustine, E Corn, M Danoff, J TI Lymphedema management training for physical therapy students in the United States SO CANCER LA English DT Article; Proceedings Paper CT American-Cancer-Society Workshop on Breast Cancer Treatment-Related Lymphedema CY FEB 20-22, 1997 CL NEW YORK, NEW YORK SP Amer Canc Soc DE lymphedema; education; survey; physical therapy; modalities AB BACKGROUND. The objective of this study was to determine to what extent accredited physical therapy programs in the United States were presenting the principles of lymphedema management and whether regional differences existed. METHODS. Stares were grouped into four geographic regions: Northeast, South, Midwest, and West. From mid-June to mid-July, 1997, 63 of 148 (42.6%) accredited physical therapy (PT) programs in the United States completed and returned the questionnaires. Participants received a cover letter, consent form, and lymphedema survey by e-mail, facsimile, or regular post. The lymphedema survey covered a wide variety of issues relating to five areas: 1) general and 2) specific anatomy and physiology of the lymphatic system, 3) pathogenesis of lymphedema, 4) traditional (compression pumps/garments), and 5) innovative (European/Australian) treatment techniques for lymphedema. "Yes" responses indicated that specific information was included in the curriculum. Frequency of yes responses for each of the five areas were counted and converted into percentages. Regional responses were compared with the total combined responses with a modified binomial technique. RESULTS. PT programs in the United States were providing 89% of our designated content in the general anatomy and physiology of the lymphatic system, 73% in the pathogenesis of lymphedema, 65% in traditional treatment techniques, 48% in innovative treatment techniques, and 42% in the specific anatomy and physiology of the lymphatic system. No individual region differed significantly (P > 0.05) from the combined results. CONCLUSIONS, The participating PT programs appeared to be providing instruction in general anatomy and physiology of the lymphatic system, pathogenesis of lymphedema, and traditional treatment techniques. However, far less instruction on the specific anatomy and physiology of the lymphatic system and innovative treatment techniques is offered. We believe that PT students would benefit with more curricular content in these latter two categories in order to acquire the knowledge and skills to combat the devastating effects of lymphedema. Cancer 1998;83:2869-73. (C) 1998 American Cancer Society. C1 NIH, Dept Rehabil Med, Phys Therapy Sect, Bethesda, MD 20892 USA. PT Resources, Telluride, CO USA. Howard Univ, Dept Phys Therapy, Washington, DC 20059 USA. RP Augustine, E (reprint author), NIH, Dept Rehabil Med, Phys Therapy Sect, Bldg 10,Room 6s235, Bethesda, MD 20892 USA. NR 11 TC 2 Z9 2 U1 1 U2 2 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 DEC 15 PY 1998 VL 83 IS 12 SU 2 BP 2869 EP 2873 DI 10.1002/(SICI)1097-0142(19981215)83:12B+<2869::AID-CNCR41>3.0.CO;2-U PG 5 WC Oncology SC Oncology GA 151QT UT WOS:000077732500018 PM 9874413 ER PT J AU Dean, M AF Dean, M TI Cancer as a complex developmental disorder - Nineteenth Cornelius P. Rhoads Memorial Award Lecture SO CANCER RESEARCH LA English DT Article; Proceedings Paper CT 89th Annual Meeting of the American-Association-for-Cancer-Research CY MAR 27-APR 01, 1998 CL NEW ORLEANS, LOUISIANA SP Amer Assoc Canc Res ID CELL CARCINOMA SYNDROME; TUMOR-SUPPRESSOR PROTEIN; HUMAN HOMOLOG; SONIC-HEDGEHOG; DROSOPHILA HOMOLOG; SIGNALING PATHWAY; BETA-CATENIN; GENE; POLARITY; MUTATIONS AB The processes of differentiation and tumorigenesis have been long thought to be connected. The recent identification of Patched, a gene essential for Drosophila embryonic development, as a tumor suppressor has focused attention on the concept that tumorigenesis involves abnormalities of development. In fact, a large number of genes in the signalling pathway of the Patched gene are either tumor suppressors or oncogenes, This supports the concept that growth control is a critical requirement of differentiation, and that aberrant cellular development can contribute to malignancy. Whereas the identification of genes that result in dominantly inherited cancer syndromes has played a vital role in understanding cancer, the vast majority of "sporadic" cancers have properties of a complex genetic disease. Approaches to identify common alleles in cancer-associated genes promise to increase our understanding of the disease and aid the rational design of preventative and therapeutic strategies. C1 NCI, Frederick Canc Res & Dev Ctr, Human Genet Sect, Lab Genom Divers, Frederick, MD 21702 USA. RP Dean, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, Human Genet Sect, Lab Genom Divers, Bldg 560,Room 21-18, Frederick, MD 21702 USA. EM dean@fcrfv1.ncifcrf.gov RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 NR 50 TC 31 Z9 32 U1 0 U2 1 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 DEC 15 PY 1998 VL 58 IS 24 BP 5633 EP 5636 PG 4 WC Oncology SC Oncology GA 148HT UT WOS:000077499800002 PM 9865711 ER PT J AU Ciolino, HP Daschner, PJ Yeh, GC AF Ciolino, HP Daschner, PJ Yeh, GC TI Resveratrol inhibits transcription of CYP1A1 in vitro by preventing activation of the aryl hydrocarbon receptor SO CANCER RESEARCH LA English DT Article ID HUMAN AH RECEPTOR; PLATELET-AGGREGATION; SIGNAL-TRANSDUCTION; REGULATORY ELEMENTS; CANCER PREVENTION; GENE-EXPRESSION; RETINOIC ACID; DNA-ADDUCTS; RAT COLON; PROTEIN AB Resveratrol, a compound present in a variety of plants, was recently shown to have potent chemopreventive activity against aryl hydrocarbon-induced tumorigenesis in mice. Therefore, in the present study, we examined the effect of resveratrol on the function of the aryl hydrocarbon receptor (AHR) and the transcription of CYP1A1 in human HepG2 hepatoma cells, Resveratrol inhibited the increase in cytochrome P450 (CYP) 1A1 mRNA caused by the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in a concentration-dependent manner. The induction of transcription of an aryl hydrocarbon-responsive reporter vector containing the CYP1A1 promoter by TCDD was likewise inhibited by resveratrol. Resveratrol also inhibited the constitutive level of CYP1A1 mRNA and reporter vector transcription in HepG2 cells. The increase in CYP1A1 enzyme activity induced by TCDD was inhibited by resveratrol. Resveratrol prevented the TCDD-induced transformation of the cytosolic AHR to its nuclear DNA-binding form. However, resveratrol had no effect on the binding of TCDD to the cytosolic AHR, These data demonstrate that resveratrol inhibits CYP1A1 expression in vitro, and that it does this by preventing the binding of the AHR to promoter sequences that regulate CYP1A1 transcription. This activity may be an important part of the chemopreventive activity of resveratrol. C1 NCI, Frederick Canc Res & Dev Ctr, Basic Res Lab,Div Basic Sci, Cellular Def & Carcinogenesis Sect,NIH, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Intramural Res Support Program,NIH, Frederick, MD 21702 USA. RP Ciolino, HP (reprint author), NCI, Frederick Canc Res & Dev Ctr, Basic Res Lab,Div Basic Sci, Cellular Def & Carcinogenesis Sect,NIH, Bldg 560,Room 12-05,POB B, Frederick, MD 21702 USA. EM hciolino@mail.ncifcrf.gov FU NCI NIH HHS [N01-CO-56000] NR 54 TC 203 Z9 208 U1 0 U2 4 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 DEC 15 PY 1998 VL 58 IS 24 BP 5707 EP 5712 PG 6 WC Oncology SC Oncology GA 148HT UT WOS:000077499800018 PM 9865727 ER PT J AU Kontny, HU Lehrnbecher, TM Chanock, SJ Mackall, CL AF Kontny, HU Lehrnbecher, TM Chanock, SJ Mackall, CL TI Simultaneous expression of fas and nonfunctional Fas ligand in Ewing's sarcoma SO CANCER RESEARCH LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; TUMOR-NECROSIS-FACTOR; ANTI-FAS; NEUROECTODERMAL TUMORS; LYMPHOCYTE APOPTOSIS; MONOCLONAL-ANTIBODY; MEDIATED APOPTOSIS; GENE-MUTATIONS; T-LYMPHOCYTES; CANCER CELLS AB Fas-Fas ligand interactions play a central role in the regulation of the immune response. Fas ligand expression by tumors has been implicated in the abrogation of the host antitumor response by killing of Fas-positive effector lymphocytes. We have studied the presence and functional status of Pas and Pas ligand in Ewing's sarcoma. All Ewing's sarcoma cell lines tested expressed Fas on their surface. Three of the cell lines were readily killed after ligation of the Fas receptor. Four additional cell lines exhibited Pas-mediated apoptosis after preincubation with IFN-gamma and/or cycloheximide, whereas two cell lines were resistant to Fas-mediated killing. With regard to Fas ligand, all cell lines examined were positive for protein by immunoblot, and specificity was confirmed by reverse transcription-PCR. However, using flow cytometric analysis, Fas ligand could only be detected in Ewing's sarcoma cells after permeabilization, Furthermore, the cell lines were not capable of inducing apoptosis of Pas-sensitive Jurkat cells. In addition, Ewing's sarcoma cell lines were able to serve as stimulators for the generation of cytotoxic effector lymphocytes and were susceptible to lysis by them. Therefore, Pas ligand is expressed in Ewing's sarcoma but is not functional, suggesting that Ewing's sarcoma is a potential target for immunotherapy. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,Room 13N240,10 Ctr DR MSC 1928, Bethesda, MD 20892 USA. NR 58 TC 35 Z9 36 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 DEC 15 PY 1998 VL 58 IS 24 BP 5842 EP 5849 PG 8 WC Oncology SC Oncology GA 148HT UT WOS:000077499800035 PM 9865744 ER PT J AU Thompson, MW Miller, J Maurizi, MR Kempner, E AF Thompson, MW Miller, J Maurizi, MR Kempner, E TI Importance of heptameric ring integrity for activity of Escherichia coli ClpP SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Article DE ATP-dependent protease; ClpP; radiation target analysis ID ENERGY-DEPENDENT PROTEASES; RADIATION TARGET ANALYSIS; PROTEIN-DEGRADATION; MOLECULAR CHAPERONE; INACTIVATION; PROTEOLYSIS; PHENYLALANINE; SPECIFICITY; MECHANISM; COMPONENT AB Radiation target analysis has been used to identify the minimal functional unit for expression of activity of ClpP, the proteolytic component of the ATP-dependent ClpAP protease. Radiation target sizes determined for small peptide hydrolysis, for ClpA-activated and nucleotide-activated oligopeptide cleavage, and for ClpA-activated ATP-dependent protein degradation were 154, 118, and 160 kDa, respectively. Thus, the hydrolytic activity of ClpP, subunit M-r 21500, is dependent on the native oligomeric structure. The quaternary structure of ClpP determined by electron microscopy and hydrodynamic studies consists of two face-to-face seven-membered rings. The radiation target sizes are consistent with a requirement for conformational integrity of an entire ring for expression of hydrolytic activity. Radiation damage led to disruption of inter-ring contacts, giving rise to isolated rings of ClpP. Thus, contacts between rings of ClpP are less stable and more easily disrupted than contacts between subunits within the rings. Our data suggest that cooperative interactions between subunits within the ClpP rings are important for maintaining the active conformation of the proteolytic active site. C1 NIH, Struct Biol Res Lab, NIAMSD, Bethesda, MD 20892 USA. NIH, Phys Biol Lab, NIAMSD, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kempner, E (reprint author), NIH, Struct Biol Res Lab, NIAMSD, Bldg 6 Room 140, Bethesda, MD 20892 USA. NR 31 TC 8 Z9 8 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD DEC 15 PY 1998 VL 258 IS 3 BP 923 EP 928 DI 10.1046/j.1432-1327.1998.2580923.x PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 151LU UT WOS:000077722200002 PM 9990309 ER PT J AU Gonzalez, M Frank, EG Levine, AS Woodgate, R AF Gonzalez, M Frank, EG Levine, AS Woodgate, R TI Lon-mediated proteolysis of the Escherichia coli UmuD mutagenesis protein: in vitro degradation and identification of residues required for proteolysis SO GENES & DEVELOPMENT LA English DT Article DE UmuD '; ATP-dependent protease; SOS mutagenesis; degradation signal ID SOS MUTAGENESIS; MU-TRANSPOSASE; RECA PROTEIN; INTACT UMUD; CLEAVAGE; DNA; PURIFICATION; SULA; OVERPRODUCTION; STABILITY AB Most SOS mutagenesis in Escherichia coli is dependent on the UmuD and UmuC proteins. Perhaps as a consequence, the activity of these proteins is exquisitely regulated. The intracellular level of UmuD and UmuC is normally quite low but increases dramatically in lon(-) strains, suggesting that both proteins are substrates of the Lon protease. We report here that the highly purified UmuD protein is specifically degraded in vitro by Lon in an ATP-dependent manner. To identify the regions of UmuD necessary for Lon-mediated proteolysis, we performed 'alanine-stretch' mutagenesis on umuD and followed the stability of the mutant protein in vivo. Such an approach allowed us to localize the site(s) within UmuD responsible for Lon-mediated proteolysis. The primary signal is located between residues 15 and 18 (FPLF), with an auxiliary site between residues 26 and 29 (FPSP), of the amino terminus of UmuD. Transfer of the amino terminus of UmuD (residues 1-40) to an otherwise stable protein imparts Lon-mediated proteolysis, thereby indicating that the amino terminus of UmuD is sufficient for Lon recognition and the ensuing degradation of the protein. C1 NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. EM woodgate@helix.nih.gov NR 52 TC 99 Z9 102 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD DEC 15 PY 1998 VL 12 IS 24 BP 3889 EP 3899 DI 10.1101/gad.12.24.3889 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 153YX UT WOS:000077862200013 PM 9869642 ER PT J AU Geiman, TM Durum, SK Muegge, K AF Geiman, TM Durum, SK Muegge, K TI Characterization of gene expression, genomic structure, and chromosomal localization of Hells (Lsh) SO GENOMICS LA English DT Article ID INSITU HYBRIDIZATION; HOMEOBOX GENE; REPAIR GENE; HELICASES; DNA; RECOMBINATION; RAD54 AB Hells (Lsh) is a lymphoid-specific presumptive helicase with highest expression in lymphoid precursor cells, Other members of the helicase family participate in maintenance of genome stability, DNA repair, and transcriptional control. Here we report the structure and chromosomal location of the Hells gene. The open reading frame of the murine Hells gene spans at least 26.6 kb of chromosomal DNA and is composed of 18 exons. The genomic structure of the seven helicase domains closely resembles that of mammalian Rad54, a gene whose product appears to be involved in recombination and double-strand break repair. The human homologue, the HELLS gene, has a mRNA expression pattern that is similar to murine Hells expression. Low-stringency hybridization in a Southern analysis reveals homologous Hells genes in a variety of species including Saccharomyces cerevisiae, FISH analysis maps the murine Hells gene to region C3-D1 on chromosome 19, The human homologue maps to a region of synteny on chromosome 10q23-q24, a breakpoint region frequently involved in human leukemia. (C) 1998 Academic Press. C1 NCI, SAIC, Lab Mol Immunoregulat, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Muegge, K (reprint author), NCI, SAIC, Lab Mol Immunoregulat, Intramural Res Support Program, Bldg 560,Room 31-45, Frederick, MD 21702 USA. FU PHS HHS [N01-C0-56000] NR 18 TC 31 Z9 32 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD DEC 15 PY 1998 VL 54 IS 3 BP 477 EP 483 DI 10.1006/geno.1998.5557 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 155DY UT WOS:000077932000013 PM 9878251 ER PT J AU Lambert, JS McNamara, J Katz, SL Fenton, T Kang, MH VanCott, TC Livingston, R Hawkins, E Moye, J Borkowsky, W Johnson, D Yogev, S Duliege, AM Francis, L Gershon, A Wara, D Martin, N Levin, F McSherry, F Smith, G AF Lambert, JS McNamara, J Katz, SL Fenton, T Kang, MH VanCott, TC Livingston, R Hawkins, E Moye, J Borkowsky, W Johnson, D Yogev, S Duliege, AM Francis, L Gershon, A Wara, D Martin, N Levin, F McSherry, F Smith, G CA Natl Inst Hlth Pediat AIDS Clinical Trials Grp TI Safety and immunogenicity of HIV recombinant envelope vaccines in HIV-infected infants and children SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Article DE HIV; vaccines; pediatrics; immunotherapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; LYMPHOCYTE DECLINE; AIDS; INDIVIDUALS; ANTIBODIES; THERAPY; IMMUNIZATION; DISEASE; TYPE-1; BLOOD AB Study objectives were to evaluate the safety and immunogenicity of three HIV recombinant glycoproteins in HIV-infected infants and children between 1 month and 18 years of age with asymptomatic (P-1) infection. Using Chiron rgp 120 (SF-2) 15 or 50 mu g; MicroGeneSys rgp 160 (IIIB) 40 or 320 mu g; Genentech rgp120 (MN) 75 or 300 mu g; or adjuvant control (Alum or MF-59), children were randomized to a double-blind, placebo-controlled, dose-escalating study of vaccine administered intramuscularly at entry and 1, 2, 3, 4, and 6 months later. No adverse events were attributed to study vaccines. Between 30% and 56% of volunteers exhibited a lymphoproliferative response as defined in terms of stimulation index (SI) to vaccine antigens; 65% of vaccinees but none of placebo recipients exhibited moderate or strong responses after enzyme immunoassay to HIV specific antigens. CD4 cell counts and quantitative HIV culture did not differ significantly among vaccine and control groups, nor were differences found among groups in HIV disease progression. The rgp160 and gp120 subunit vaccines were safe and immunogenic in this population. C1 Johns Hopkins Univ, Baltimore, MD USA. NIAID, Vaccine Res & Dev Branch, Div Aids, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Durham, NC USA. Frontier Sci & Technol Res Fdn, Brookline, MA USA. Henry M Jackson Fdn, Rockville, MD USA. AIDS Clin Trials Grp, Operat Off, Bethesda, MD USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. NYU, Bellevue Hosp, New York, NY USA. Univ Chicago, Wyler Childrens Hosp, Chicago, IL 60637 USA. Northwestern Univ, Childrens Mem Hosp, Evanston, IL USA. Biocine Co, Emeryville, CA USA. Genentech Inc, S San Francisco, CA 94080 USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. Univ Calif San Francisco, Moffitt Hosp, San Francisco, CA USA. Univ Colorado, Denver, CO 80202 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. MicroGeneSys, Meriden, CT USA. RP Lambert, JS (reprint author), Univ Maryland, Baltimore Sch Med, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. EM lambert@umbi.umd.edu OI moye, john/0000-0001-9976-8586 FU NICHD NIH HHS [N01-HD-3-3162]; PHS HHS [U0-A1-25883, U0-A1-27565] NR 46 TC 21 Z9 22 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. PD DEC 15 PY 1998 VL 19 IS 5 BP 451 EP 461 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 146JA UT WOS:000077424500003 PM 9859958 ER PT J AU Pitt, J Schluchter, M Jenson, H Kovacs, A LaRussa, P McIntosh, K Boyer, P Cooper, E Goldfarb, J Hammill, H Hodes, D Peavy, H Sperling, R Tuomala, R Shearer, W AF Pitt, J Schluchter, M Jenson, H Kovacs, A LaRussa, P McIntosh, K Boyer, P Cooper, E Goldfarb, J Hammill, H Hodes, D Peavy, H Sperling, R Tuomala, R Shearer, W CA Pediat Pulmon Cardiovasc Complic Vert Transm HIV1 Infect Stud Grp TI Maternal and perinatal factors related to maternal-infant transmission of HIV-1 in the (PC2)-C-2 HIV study: The role of EBV shedding SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Article DE HIV-1 maternal-infant transmission; EBV and CMV infection; duration of ruptured membranes ID HUMAN-IMMUNODEFICIENCY-VIRUS; EPSTEIN-BARR-VIRUS; HOMOSEXUAL MEN; VERTICAL TRANSMISSION; INFECTION; LYMPHOCYTES; ZIDOVUDINE; EXPRESSION; REDUCTION; TYPE-1 AB The association of maternal and perinatal factors with mother-infant transmission of HIV-1 was examined in a prospective multicenter cohort of singleton Live births to 508 HIV-1-infected women with children of known HIV-1 infection status (91 [18%] HIV-1-infected, 417 [82%] uninfected). From multivariate logistic regression, independent predictors of HIV-1 transmission included maternal CD4 percentage (CD4%) (odds ratio [OR] per 10% increase in CD4% = 0.70; p =.003), ruptured membranes <24 hours (OR = 3.15; p =.02), and maternal bleeding (OR = 2.90; p =.03), whereas maternal zidovudine (ZDV) use was marginally associated (OR = 0.60; p =.08). The associations of maternal urinary cytomegalovirus (CMV) shedding, oropharyngeal Epstein-Barr virus (EBV) shedding, and serology profiles during pregnancy with HIV-1 transmission were examined in the subset of mothers in whom the CMV and EBV measurements were available. Maternal EBV seropositivity, CMV shedding, and CMV seropositivity were 100% (279 of 279), 7% (16 of 229), and 92% (270 of 274), respectively. These rates did not differ between transmitting and nontransmitting mothers. In univariate analyses, maternal EBV shedding was higher among transmitting than nontransmitting mothers (40 of 49 [82%] compared with 154 of 226 [68%]; p =.06) and was independently associated with transmission in multivariate logistic analyses adjusting for CD4%, ruptured membranes, and ZDV use, with an OR of 2.45 (95% confidence interval (CI), 1.03-5.84; p =.04). This permits the conclusion that EBV shedding is associated with maternal-infant HIV-1 transmission, independent of CD4%. C1 Columbia Univ Coll Phys & Surg, Dept Pediat, Div Infect Dis, New York, NY 10032 USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Univ So Calif, Sch Med, LAC USC Med Ctr, Div Pediat Infect Dis, Los Angeles, CA USA. Boston City Hosp, Dept Pediat Infect Dis, Boston, MA 02118 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. Cleveland Clin Fdn, Div Pediat & Adolescent Med, Cleveland, OH 44195 USA. Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. Mt Sinai Sch Med, Dept Pediat, New York, NY USA. NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Dept Obstet & Gynecol, New York, NY USA. Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA 02115 USA. Texas Childrens Hosp, Baylor Coll Med, Dept Allergy & Immunol, Houston, TX 77030 USA. RP Pitt, J (reprint author), Columbia Univ Coll Phys & Surg, Dept Pediat, Div Infect Dis, 650 W 168th St, New York, NY 10032 USA. OI Jenson, Hal/0000-0002-6549-860X FU NHLBI NIH HHS [N01-HR-96039, N01-HR-96038, N01-HR-96037] NR 27 TC 18 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. PD DEC 15 PY 1998 VL 19 IS 5 BP 462 EP 470 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 146JA UT WOS:000077424500004 PM 9859959 ER PT J AU Sheon, AR Wagner, L McElrath, MJ Keefer, MC Zimmerman, E Israel, H Berger, D Fast, P AF Sheon, AR Wagner, L McElrath, MJ Keefer, MC Zimmerman, E Israel, H Berger, D Fast, P TI Preventing discrimination against volunteers in prophylactic HIV vaccine trials: Lessons from a phase II trial SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Article DE HIV-I vaccines; discrimination; homosexuality, male; intravenous drug users; social harm; HIV testing; HIV antibodies; controlled clinical trials; HIV infections; patient participation ID INJECTION-DRUG USERS; EFFICACY TRIALS; AIDS VACCINES; SOCIAL RISK; PARTICIPATE; INFECTION; ISSUES AB Context: Preventive HIV vaccines can temporarily cause uninfected individuals to have positive results on HIV testing. As preparations are underway to mount larger efficacy trials, the social risks of trial participation should be studied. Objective: To describe frequency of HIV testing and discrimination among participants in a preventive phase II HIV vaccine trial. Participants: 266 vaccine trial volunteers were eligible; 247 participated in a confidential survey. Results: 63 volunteers (26% of respondents) reported 185 HIV tests during the prior 12 to 24 months; most tests were for other research studies, health care, insurance, incarceration, or employment. Only 5 volunteers reported having positive HIV test results. Volunteers reported 99 adverse social incidents or problems, 53 of which were related to the trial. The most common type of event occurred when volunteers disclosed their trial participation and were mistakenly presumed to be infected with HIV. Few reported difficulty obtaining insurance, job loss, and inadvertent disclosure of their participation in the trial. Conclusion: In this vaccine trial, few serious social harms were reported. Those who conduct HIV tests for insurance, employment, health care, or other reasons should be made aware that HIV vaccines can cause false-positive HIV test results. Those planning future trials must continue to provide needed support to volunteers. Social harms should be monitored with the same vigilance accorded to physical harms. C1 NIAID, Div Aids, NIH, Rockville, MD USA. Vanderbilt Univ, Nashville, TN USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Sch Med, Seattle, WA 98195 USA. Univ Rochester, Sch Med & Dent, Rochester, NY USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD USA. St Louis Univ, Sch Med, St Louis, MO USA. Univ Washington, Sch Med, Seattle, WA USA. RP Sheon, AR (reprint author), POB 4594, Ann Arbor, MI 48106 USA. FU NIAID NIH HHS [N01AI45211, N01AI45208, N01AI45207] NR 39 TC 40 Z9 41 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. PD DEC 15 PY 1998 VL 19 IS 5 BP 519 EP 526 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 146JA UT WOS:000077424500012 PM 9859967 ER PT J AU Richards, AL Giri, A Iskandriati, D Pamungkas, J Sie, A Rosen, L Anthony, RL Franchini, G AF Richards, AL Giri, A Iskandriati, D Pamungkas, J Sie, A Rosen, L Anthony, RL Franchini, G TI Simian T-lymphotropic virus type I infection among wild-caught Indonesian pig-tailed macaques (Macaca nemestrina) SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Article DE STLV-I; Macaca nemestrina; polymerase chain reaction; tax gene; Indonesia ID CELL LEUKEMIA-VIRUS; NON-HUMAN PRIMATES; STLV-I; PHYLOGENETIC ANALYSES; NUCLEOTIDE-SEQUENCE; HTLV-I; ANTIBODY; MONKEYS; HAMADRYAS; ANTIGENS AB Evidence for the presence of simian T-lymphotropic viruses (STLV-I) was identified in Live-caught pig-tailed macaques from two locations in southern Sumatra, Indonesia. Of 60 animals tested, 13.3% of the animals showed seroreactivity to HTLV rm enzyme-linked immunosorbent assay (ELISA) antigens. Of these, 75% showed indeterminate reactivity and 25% showed positive reactivity to HTLV-I/II Western blot antigens. Polymerase chain reaction (PCR) analysis of 6 of 8 seroreactive mon keys' peripheral blood mononuclear cell (PBMC) DNA showed production of proper size molecular weight product that hybridized specifically to an STLV-I tax gene-specific probe. Phylogenic analyses of tau gene fragment sequences from the PCR products of two samples, 930287 and 930306, indicated that these animals were infected with retroviruses related to those of the Asian STLV-I clade. C1 USN, Med Res Unit 2, Dept Immunol, Jakarta, Indonesia. NCI, Lab Tumor Biol, NIH, Bethesda, MD 20892 USA. Bogor Agr Univ, IPB PRC, Primate Res Ctr, Bogor, Indonesia. Inst Pasteur, Unite Epidemiol Virus Oncogenes, Paris, France. RP Richards, AL (reprint author), USN, Med Res Unit 2, Jakarta Publicat Div, Box 3, APO, AP 96520 USA. NR 24 TC 12 Z9 13 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. PD DEC 15 PY 1998 VL 19 IS 5 BP 542 EP 545 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 146JA UT WOS:000077424500015 PM 9859970 ER PT J AU Belyakov, IM Ahlers, JD Brandwein, BY Earl, P Kelsall, BL Moss, B Strober, W Berzofsky, JA AF Belyakov, IM Ahlers, JD Brandwein, BY Earl, P Kelsall, BL Moss, B Strober, W Berzofsky, JA TI The importance of local mucosal HIV-specific CD8(+) cytotoxic T lymphocytes for resistance to mucosal viral transmission in mice and enhancement of resistance by local administration of IL-12 SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE immunity; mucosal; immunity; cellular; AIDS vaccines; T lymphocytes; cytotoxic; Peyer's patches ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECOMBINANT VACCINIA VIRUS; LYMPH-NODE IMMUNIZATION; IMMUNE-RESPONSE; INTRAEPITHELIAL LYMPHOCYTES; NEUTRALIZING ANTIBODY; PEPTIDE VACCINE; TYPE-1 ENVELOPE; RHESUS MACAQUES; RECTAL MUCOSA AB Although crucial to mucosal vaccine development, the mechanisms of defense against mucosal viral infection are still poorly understood. Protection, cytotoxic T lymphocytes (CTL), and neutralizing antibodies have all been observed, but cause and effect have been difficult to determine. The ability of CTL in the mucosa to mediate protection against mucosal viral transmission has never been proven. Here, we use an HIV peptide immunogen and an HIV-1 gp160-expressing recombinant vaccinia viral intrarectal murine challenge system, in which neutralizing antibodies do not play a role, to demonstrate for the first time that long-lasting immune resistance to mucosal viral transmission can be accomplished by CD8(+) CTL that must be present in the mucosal site of exposure. The resistance is ablated by depleting CD8(+) cells in vivo and requires CTL in the mucosa, whereas systemic (splenic) CTL are shown to be unable to protect against mucosal challenge, Furthermore, the resistance as well as the CTL response can be increased by local mucosal delivery of IL-12 with the vaccine. These results imply that induction of local mucosal CTL may be critical for success of a vaccine against viruses transmitted through a mucosal route, such as HIV. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, Bethesda, MD 20892 USA. NIAID, Mucosal Immun Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, Bldg 10,Room 6B-12,MSC 1578, Bethesda, MD 20892 USA. NR 46 TC 138 Z9 140 U1 0 U2 2 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 DEC 15 PY 1998 VL 102 IS 12 BP 2072 EP 2081 DI 10.1172/JCI5102 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 151GJ UT WOS:000077712100006 PM 9854042 ER PT J AU Budinger, L Borradori, L Yee, C Eming, R Ferencik, S Grosse-Wilde, H Merk, HF Yancey, K Hertl, M AF Budinger, L Borradori, L Yee, C Eming, R Ferencik, S Grosse-Wilde, H Merk, HF Yancey, K Hertl, M TI Identification and characterization of autoreactive T cell responses to bullous pemphigoid antigen 2 in patients and healthy controls SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE hemidesmosome; extracellular domain; autoreactive Th1/Th2 cells; cytokines; HLA class II restriction ID PRIMERS PCR-SSP; HUMAN B-CELLS; ACETYLCHOLINE-RECEPTOR; EXTRACELLULAR DOMAIN; BASEMENT-MEMBRANE; AUTOANTIBODIES; BP180; VULGARIS; COMPLEX; PROTEIN AB Antibodies against the extracellular domain of bullous pemphigoid antigen 2 (BPAG2) are thought to play a key role in the pathogenesis of bullous pemphigoid (BP), the most frequent autoimmune bullous disease of the skin. Autoreactive T cell responses to BPAG2 were investigated in 16 BP patients and 24 healthy controls by coculture of PBMC with two recombinant BPAG2 proteins (extracellular domain of BPAG2). Primary in vitro T cell responses to BPAG2 were observed in 10/12 BP patients expressing the BP-associated HLA-DQB1*0301 allele and 8/10 DQB1*0301 positive healthy individuals. DQB1*0301 also restricted three autoreactive T cell lines from two BP patients and a healthy donor. In contrast, PBMC from 14 normal patients carrying HLA class II alleles other than DQB1*0301 were not stimulated by BPAG2. Autoreactive BPAG2-specific CD4(+) T cell lines and clones from five BP patients produced both Th1 and Th2 cytokines, whereas three autoreactive T cell lines from three DQB1*0301 positive normal patients produced exclusively IFN-gamma. The absence of BPAG2-specific Th2 cells in healthy individuals strongly suggests that autoreactive Th2 responses to BPAG2 are restricted to BP patients and may thus be critical in the pathogenesis of BP. C1 Rhein Westfal TH Klinikum, Hautklin, D-52074 Aachen, Germany. Univ Geneva, Hop Cantonal, Dermatol Clin, CH-1211 Geneva, Switzerland. NCI, Dermatol Branch, Bethesda, MD 20892 USA. Univ Essen Gesamthsch Klinikum, Inst Immunol, D-45122 Essen, Germany. RP Hertl, M (reprint author), Rhein Westfal TH Klinikum, Hautklin, Pauwelsstr 30, D-52074 Aachen, Germany. EM MHert1@compuserve.com NR 41 TC 117 Z9 117 U1 1 U2 4 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 DEC 15 PY 1998 VL 102 IS 12 BP 2082 EP 2089 DI 10.1172/JCI3335 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 151GJ UT WOS:000077712100007 PM 9854043 ER PT J AU Foster, CB Lehrnbecher, T Mol, F Steinberg, SM Venzon, DJ Walsh, TJ Noack, D Rae, J Winkelstein, JA Curnutte, JT Chanock, SJ AF Foster, CB Lehrnbecher, T Mol, F Steinberg, SM Venzon, DJ Walsh, TJ Noack, D Rae, J Winkelstein, JA Curnutte, JT Chanock, SJ TI Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE myeloperoxidase; Fc receptor; mannose binding lectin; gastric outlet obstruction; rheumatological disorders ID SYSTEMIC LUPUS-ERYTHEMATOSUS; INTERLEUKIN-1 RECEPTOR ANTAGONIST; IIA CD32 POLYMORPHISM; FACTOR-ALPHA PROMOTER; SINGLE AMINO-ACID; FC-GAMMA-RIIIA; GENE POLYMORPHISM; BINDING PROTEIN; ULCERATIVE-COLITIS; HUMAN MONOCYTES AB Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte function in which defective superoxide production results in deficient microbicidal activity. CGD patients suffer from recurrent, life-threatening infections, and nearly half develop chronic gastrointestinal (GI) complications (colitis, gastric outlet obstruction, or perirectal abscess) and/or autoimmune/rheumatologic disorders (AIDs). To identify genetic modifiers of disease severity, we studied a cohort of 129 CGD patients, in whom seven candidate genes (myeloperoxidase [MPO], mannose binding lectin [MBL], Fc gamma receptors IIa, IIIa, IIIb, TNF-alpha, and IL-1 receptor antagonist), each containing a physiologically relevant polymorphism predicted to influence the host inflammatory response, were selected for analysis. Genotypes of MPO (P = 0.003) and Fc gamma RIIIb (P = 0.007) were strongly associated with an increased risk for GI complications, while an Fc gamma RIIa (P = 0.05) genotype was suggestive for an association. Patients with all three associated genotypes had the highest risk for GI complications (P < 0.0001). The risk of AIDs was strongly associated with variant alleles of MBL (P = 0.01) and weakly associated with an Fc gamma RIIa genotype (P = 0.04). Patients with variant forms of both MBL and Fc gamma RIIa had the highest risk of developing an AID (P = 0.003). C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. Genentech Inc, Dept Immunol, S San Francisco, CA 94080 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21218 USA. Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. RP Chanock, SJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Room 13N240,9000 Rockville Pike, Bethesda, MD 20892 USA. EM SC83a@nih.gov RI Venzon, David/B-3078-2008 NR 82 TC 180 Z9 186 U1 0 U2 3 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 DEC 15 PY 1998 VL 102 IS 12 BP 2146 EP 2155 DI 10.1172/JCI5084 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 151GJ UT WOS:000077712100014 PM 9854050 ER PT J AU Dong, F Liu, XW de Koning, JP Touw, IP Henninghausen, L Larner, A Grimley, PM AF Dong, F Liu, XW de Koning, JP Touw, IP Henninghausen, L Larner, A Grimley, PM TI Stimulation of stat5 by granulocyte colony-stimulating factor (G-CSF) is modulated by two distinct cytoplasmic regions of the G-CSF receptor SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SEVERE CONGENITAL NEUTROPENIA; PROTEIN-TYROSINE-PHOSPHATASE; DNA-BINDING ACTIVITY; GENE-EXPRESSION; TRANSCRIPTION FACTOR; SIGNAL-TRANSDUCTION; RAPID ACTIVATION; MOTH-EATEN; INTERFERON; MUTATIONS AB In a manner similar to many other cytokines, treatment of cells with granulocyte CSP (G-CSF) has been shown to induce the tyrosine phosphorylation of the STAT proteins. Activation of Stat1 and Stat5 by G-CSF requires the membrane-proximal cytoplasmic domain of the receptor, including box1 and box2, while G-CSF-stimulated tyrosine phosphorylation of Stat3 also requires a region distal to box 2, In this study, we show that although the membrane-proximal 55 amino acids of the G-CSF receptor are sufficient for activation of Stat5, the maximal rate of Stat5 activation requires an additional 30 amino acids of the cytoplasmic domain. In contrast, the distal carboxyl-terminal region of the receptor appears to down-regulate Stat5 activation in that deletion of this carboxyl terminus results in increased amplitude and prolonged duration of Stat5 activation by G-CSF, Significantly, expression of a truncated dominant-negative Stat5 protein in hemopoietic cells not only inhibits G-CSF-dependent cell proliferation, but also suppresses cell survival upon G-CSF withdrawal. We further show that a potential protein tyrosine phosphatase may play a critical role in the down-regulation of G-CSF-stimulated Stat5 activation. These results demonstrate that two distinct cytoplasmic regions of the G-CSF receptor are involved in the regulation of the intensity and duration of Stat5 activation, and that Stat5 may be an important player in G-CSF-mediated cell proliferation and survival. C1 Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. US FDA, Ctr Biol Evaluat & Res, Div Cytokine Biol, Bethesda, MD 20892 USA. NIDDKD, Biochem & Metab Lab, NIH, Bethesda, MD 20892 USA. Erasmus Univ, Inst Hematol, Rotterdam, Netherlands. RP Larner, A (reprint author), Cleveland Clin Fdn, Lerner Res Inst, Dept Immunol, 9500 Euclid Ave,FFb-37, Cleveland, OH 44195 USA. NR 50 TC 64 Z9 65 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 1998 VL 161 IS 12 BP 6503 EP 6509 PG 7 WC Immunology SC Immunology GA 146NG UT WOS:000077436400010 PM 9862674 ER PT J AU Williams, MS Noguchi, S Henkart, PA Osawa, Y AF Williams, MS Noguchi, S Henkart, PA Osawa, Y TI Nitric oxide synthase plays a signaling role in TCR-triggered apoptotic death SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FAS-LIGAND EXPRESSION; PROGRAMMED CELL-DEATH; TYROSINE KINASE; CYCLOSPORINE-A; T-LYMPHOCYTES; B-LYMPHOCYTE; ACTIVATION; INHIBITION; NITROTYROSINE; HYBRIDOMAS AB A functional role For stimulated nitric oxide (NO) production was tested in the TCR-triggered death of mature T lymphocytes. In purified peripheral human T cell blasts or the 2B4 murine T cell hybridoma, apoptotic cell death induced by immobilized anti-CD3 was blocked by inhibitors of NO synthase (NOS) in a stereospecific and concentration-dependent manner. This effect appeared to be selective since apoptotic death induced by anti-Fas Ab or the steroid dexamethasone was not affected by NOS inhibitors. TCR-stimulated expression of Functional Fas ligand was attenuated in a stereospecific manner by NOS inhibitors, but these compounds did not inhibit TCR-stimulated IL-2 secretion or CD69 surface expression, Nitrosylated tyrosines, a stable marker for NO generation, were immunochemically detected in T cells using flow cytometry, TCR signals induced NO production, as measured by an increase in nitrotyrosine-specific staining. NOS enzymatic activity was detected in lysates of 2B4 cells, and Western blot analysis suggests that the activity is due to expression of the neuronal isoform of NOS, Thus, T cells have the capacity to generate NO upon Ag signaling, which may affect signal transduction, Fas ligand surface expression, and apoptotic cell death of mature T lymphocytes. C1 Amer Red Cross, Jerome H Holland Lab, Dept Immunol, Rockville, MD 20855 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. RP Williams, MS (reprint author), Amer Red Cross, Jerome H Holland Lab, Dept Immunol, 15601 Crabbs Branch Way, Rockville, MD 20855 USA. FU NIEHS NIH HHS [ES08365] NR 46 TC 65 Z9 66 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 1998 VL 161 IS 12 BP 6526 EP 6531 PG 6 WC Immunology SC Immunology GA 146NG UT WOS:000077436400013 PM 9862677 ER PT J AU Ding, L Shevach, EM AF Ding, L Shevach, EM TI Differential effects of CD28 engagement and IL-12 on T cell activation by altered peptide ligands SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN-PRESENTING CELLS; RECEPTOR TRANSGENIC MICE; CLASS-II MHC; CD40 LIGAND; B-CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; COSTIMULATORY ACTIVITY; DENDRITIC CELLS; UP-REGULATION; INDUCTION AB To further our understanding of the mechanisms underlying the diverse effects of altered peptide Ligands (APL) on T cell activation, we used a population of nonactivated spleen cells from mice that expressed a transgenic TCR specific for myelin basic protein Acl-ll and peptide analogues that display either enhanced or decreased affinities for TCR/MHC to address the question whether APL-induced signaling through the TCR can regulate the capability of APC to activate T cells, We demonstrate that weak agonists APL are poor inducers of all aspects of the activation of both the responder T cells and the APC, Enhancement of the antigenic signal by augmenting the binding of the weak agonists to MHC reversed their defective activating capacity, Enhancement of costimulation by engagement of CD28 only resulted in augmentation of the capacity of the weak agonist APL to induce proliferation and IL-2/IL-3 production, but not CD40L or IL-12R beta 2 chain expression on T cells, CD80/CD86 expression on APC, IL-12 secretion, or IFN-gamma production, Exogenous IL-12 promoted IFN-gamma production in the presence of the weak agonists, These studies demonstrate that there is a critical threshold of antigenic signal required for full activation of the T cell-APC interactions needed for the differentiation of Th1 cells. The provision of excess costimulation can overcome some of the defects in T cell activation by weak agonists, but is insufficient to induce a sufficient level of CD40L expression needed for engagement of CD40 on APC with subsequent IL-12 production and induction of IL-12R beta 2 chain expression. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Rm 11N315,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. NR 45 TC 13 Z9 13 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 1998 VL 161 IS 12 BP 6614 EP 6621 PG 8 WC Immunology SC Immunology GA 146NG UT WOS:000077436400025 PM 9862689 ER PT J AU Davenpeck, KL Zagorski, J Schleimer, RP Bochner, BS AF Davenpeck, KL Zagorski, J Schleimer, RP Bochner, BS TI Lipopolysaccharide-induced leukocyte rolling and adhesion in the rat mesenteric microcirculation: Regulation by glucocorticoids and role of cytokines SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; VASCULAR ENDOTHELIAL-CELLS; NEUTROPHIL CHEMOATTRACTANT CINC; PULMONARY INFLAMMATION MODEL; L-SELECTIN; P-SELECTIN; HUMAN-MONOCYTES; SEPTIC SHOCK; FACTOR-ALPHA; IN-VIVO AB A common side effect of high dose glucocorticoid therapy is increased susceptibility to bacterial infection, an effect that is in part mediated through inhibition of leukocyte recruitment to infected areas, However, the sites at which glucocorticoids act to prevent the multistep process of leukocyte recruitment have not been fully established. In this study, the effects of the glucocorticoid dexamethasone (DEX) on leukocyte-endothelial interactions, in response to bacterial LPS, were examined utilizing a model of rat mesenteric intravital microscopy, Pretreatment of rats with DEX (0.5 mg/kg) for 18 h or 30 min before stimulation with LPS significantly inhibited LPS-induced leukocyte rolling and adhesion in mesenteric postcapillary venules, Pretreatment with DEX also inhibited LPS-induced changes in expression of L-selectin and a shared epitope of CD11b/c on circulating neutrophils. These effects of DEX may be due to DEX inhibition of IL-1, TNF, and cytokine-induced neutrophil chemoattractant-l (CINC-1) generation, since antagonists to these mediators were able to mimic DEX effects on leukocyte-endothelial interactions and circulating leukocyte phenotype. These data indicate that inhibition of cytokine- and chemokine-induced leukocyte-endothelial interactions may be a primary mechanism by which glucocorticoids inhibit leukocyte recruitment to bacterial agents and thus increase susceptibility to infection. C1 Johns Hopkins Univ, Sch Med, Dept Med,Johns Hopkins Asthma & Allergy Ctr, Div Clin Immunol, Baltimore, MD 21224 USA. NIDR, Immunol Lab, Bethesda, MD 20892 USA. RP Bochner, BS (reprint author), Johns Hopkins Univ, Sch Med, Dept Med,Johns Hopkins Asthma & Allergy Ctr, Div Clin Immunol, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM bbochner@welchlink.welch.jhu.edu FU NHLBI NIH HHS [HL-49545]; NIAID NIH HHS [AI-07056] NR 55 TC 62 Z9 69 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 1998 VL 161 IS 12 BP 6861 EP 6870 PG 10 WC Immunology SC Immunology GA 146NG UT WOS:000077436400054 PM 9862718 ER PT J AU Kawakami, Y Robbins, PF Wang, X Tupesis, JP Parkhurst, MR Kang, XQ Sakaguchi, K Appella, E Rosenberg, SA AF Kawakami, Y Robbins, PF Wang, X Tupesis, JP Parkhurst, MR Kang, XQ Sakaguchi, K Appella, E Rosenberg, SA TI Identification of new melanoma epitopes on melanosomal proteins recognized by tumor infiltrating T lymphocytes restricted by HLA-A1, -A2, and -A3 alleles SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IN-VIVO; CANCER-IMMUNOTHERAPY; ANTIGEN GP100; TYROSINASE; CELLS; GENE; GROWTH AB To isolate melanoma Ags recognized by T cells, cDNA libraries made from melanoma cell lines were screened with four CTLs derived from tumor infiltrating lymphocytes (TIL) that were able to recognize melanoma cells in a HLA-A1, -A2, or -A3 restricted manner. Although cDNAs encoding the previously identified melanoma Ags, tyrosinase and gp100, were isolated, these TIL were found to recognize previously unidentified peptides, An HLA-Al-restricted CTL, TIL1388, was found to recognize a tyrosinase peptide (SSDYVIPIGTY), and an HLA-A3-restricted CTL, TIL1351, recognized a gp100 peptide (LIYRRRLMK), CTL clones isolated from the HLA-A2-restricted TIL1383 recognized a gp100 peptide (RLMKQDFSV), HLA-A2-restricted CTL, TIL1200, recognized a gp100 peptide (RLPRIFCSC), Replacement of either cysteine residue with alpha-amino butyric acid in the gp100 peptide, RLPRIFCSC, enhanced CTL recognition, suggesting that the peptide epitope naturally presented on the tumor cell surface may contain reduced cysteine residues. Oxidation of these cysteines might have occurred during the course of the synthesis or pulsing of the peptide in culture. These modifications may have important implications for the development of efficient peptide-based vaccines. These newly identified peptide epitopes can extend the ability to perform immunotherapy using synthetic peptides to a broader population of patients, especially those expressing HLA-A1 or HLA-A3 for whom only a few melanoma epitopes have previously been identified. C1 NCI, Surg Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, Div Clin Sci, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Kawakami, Yutaka /E-7429-2013 OI Kawakami, Yutaka /0000-0003-4836-2855 NR 37 TC 75 Z9 76 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 1998 VL 161 IS 12 BP 6985 EP 6992 PG 8 WC Immunology SC Immunology GA 146NG UT WOS:000077436400070 PM 9862734 ER PT J AU Sriram, K Shankar, SK Boyd, MR Ravindranath, V AF Sriram, K Shankar, SK Boyd, MR Ravindranath, V TI Thiol oxidation and loss of mitochondrial complex I precede excitatory amino acid-mediated neurodegeneration SO JOURNAL OF NEUROSCIENCE LA English DT Article DE excitatory amino acids; mitochondrial electron transport; NADH ubiquinone-1 oxidoreductase (complex I); brain; L-BOAA; oxidative stress; glutathione; protein thiol oxidation ID AMYOTROPHIC-LATERAL-SCLEROSIS; ELECTRON-TRANSPORT CHAIN; MOTOR-NEURON DISEASE; PARKINSONS-DISEASE; BRAIN; INHIBITION; STRESS; ABNORMALITIES; GLUTATHIONE; NEUROTOXIN AB Human ingestion of "chickling peas" from the plant Lathyrus sativus, which contains an excitatory amino acid, L-BOAA (L-beta-N-oxalylamino-L-alanine), leads to a progressive corticospinal neurodegenerative disorder, neurolathyrism. Exposure to L-BOAA, but not its optical enantiomer D-BOAA, causes mitochondrial dysfunction as evidenced by loss of complex I activity in vitro in male mouse brain slices and in vivo in selected regions of mouse CNS (lumbosacral cord and motor cortex). Loss of complex I activity in lumbosacral cord after L-BOAA administration to mice was accompanied by concurrent loss of glutathione. The inhibited complex I activity in mitochondria isolated from lumbosacral cord of animals treated with L-BOAA rebounded after incubation with the thiol-reducing agent dithiothreitol, indicating that oxidation of protein thiols to disulfides was responsible for enzyme inhibition. The inhibition of complex I could be abolished by pretreatment with antioxidant thiols such as glutathione ester and a-lipoic acid. Chronic treatment of male mice, but not female mice, with L-BOAA resulted in loss of complex I activity and vacuolation and dendritic swelling of neurons in the motor cortex and lumbar cord, paralleling the regionality of the aforementioned biochemical effects on CNS mitochondria. These results support the view that thiol oxidation and concomitant mitochondrial dysfunction (also implicated in other neurodegenerative disorders), occurring downstream of glutamate receptor activation by L-BOAA, are primary events leading to neurodegeneration. Maintenance of protein thiol homeostasis by thiol delivery agents could potentially offer protection against excitotoxic insults such as those seen with L-BOAA. C1 Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Bangalore 560029, Karnataka, India. Natl Inst Mental Hlth & Neurosci, Dept Neuropathol, Bangalore 560029, Karnataka, India. NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Ravindranath, V (reprint author), Natl Inst Mental Hlth & Neurosci, Dept Neurochem, Hosur Rd, Bangalore 560029, Karnataka, India. NR 40 TC 68 Z9 70 U1 1 U2 3 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 DEC 15 PY 1998 VL 18 IS 24 BP 10287 EP 10296 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 149LM UT WOS:000077606800007 PM 9852566 ER PT J AU Harris-White, ME Chu, T Balverde, Z Sigel, JJ Flanders, KC Frautschy, SA AF Harris-White, ME Chu, T Balverde, Z Sigel, JJ Flanders, KC Frautschy, SA TI Effects of transforming growth factor-beta (isoforms 1-3) on amyloid-beta deposition, inflammation, and cell targeting in organotypic hippocampal slice cultures SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Alzheimer's disease; aging; trauma; injury; growth factor; amyloid ID CENTRAL-NERVOUS-SYSTEM; ALZHEIMERS-DISEASE; TGF-BETA; MICROGLIAL CELLS; PRECURSOR PROTEIN; RAT-BRAIN; HEPARAN-SULFATE; DIFFERENTIAL EXPRESSION; MESSENGER-RNA; KNOCKOUT MICE AB The transforming growth factor-beta (TGF-beta) family consists of three isoforms and is part of a larger family of cytokines regulating differentiation, development, and tissue repair. Previous work from our laboratory has shown that TGF-beta 1 can increase amyloid-beta protein (A beta) immunoreactive (A beta ir) plaque-like deposits in rat brain. The aim of the current study was to evaluate all three isoforms of TGF-beta for their ability to affect the deposition and neurotoxicity of A beta in an organotypic, hippocampal slice culture model of A beta deposition. Slice cultures were treated with A beta either with or without one of the TGF-beta isoforms. All three isoforms can increase A beta accumulation (over A beta treatment alone) within the slice culture, as determined by ELISA. However, there are striking differences in the pattern of A beta ir among the three isoforms of TGF-beta. Isoforms 1 and 3 produced a cellular pattern of AP staining that colocalizes with GS lectin staining (microglia). TGF-beta 2 produces dramatic A beta staining of pyramidal neurons in layers CA1-CA2. In addition to cellular A beta staining, plaque-like deposits are increased by all of the TGF-beta s. Although no gross toxicity was observed, morphological neurodegenerative changes were seen in the CAI region when the slices were treated with A beta plus TGF-beta 2. Our results demonstrate important functional differences among the TGF-beta isoforms in their ability to alter the cellular distribution and degradation of A beta. These changes may be relevant to the pathology of Alzheimer's disease (AD). C1 Univ Calif Los Angeles, Dept Med, Sepulveda, CA 91343 USA. Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Sepulveda, CA 91343 USA. Univ Calif Los Angeles, Dept Neurol, Sepulveda, CA 91343 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Harris-White, ME (reprint author), Univ Calif Los Angeles, Dept Med, 16111 Plummer St 151, Sepulveda, CA 91343 USA. FU BLRD VA [I01 BX000542]; NCCIH NIH HHS [R01 AT003008]; NIA NIH HHS [P50 AG016570, R01 AG013741, R01 AG010685, R01 AG016793, AG10685] NR 77 TC 44 Z9 44 U1 0 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 DEC 15 PY 1998 VL 18 IS 24 BP 10366 EP 10374 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 149LM UT WOS:000077606800015 PM 9852574 ER PT J AU Bornstein, SR Willenberg, HS Scherbaum, WA AF Bornstein, SR Willenberg, HS Scherbaum, WA TI Advances in molecular medicine: Laser capture microdissection SO MEDIZINISCHE KLINIK LA German DT Article DE Laser Capture Microdissection (LCM); molecular medicine; cell-cell interaction; tumorigenesis; Cancer Genome Anatomy Project (CGAP) ID CUSHINGS-SYNDROME; THERAPY; TISSUE AB Background: With the unravelling of the human genome. we now face the challenge of defining the function and clinical relevance of single genes. To do this, we should be able to isolate normal and diseased cells from complex tissue structures to make them accessible to sensitive molecular analyses. Laser Capture Microdissection (LCM) was developed to meet this challenge. Method and Application: LCM allows the precise dissection of cells with the help of a laser beam under direct visualization in the microscope, and the sterile transfer of these cells into a DNA or RNA isolation buffer. The technique is ideal for investigating cell-cell interactions, for performing mutation analyses, and for the production of high-quality cDNA libraries. Expression studies of known and unknown genes art currently employed successfully to define tissue- and simple cell-specific patterns which help elucidate the etiology and pathogenesis of colon, lung, breast, prostate, adrenal, ovary, and other organ tumors. The LCM system developed at the NIH is, therefore, an important part of the Cancer-Genome Anatomy Project (CGAP), which sequences and publishes the structures of genes that are expressed in human tumors. In combination with the modern cDNA arrays, it will thus be possible to analyze the expression of several thousands of genes in one step and to develop individual therapeutic strategies in the not too distant future. Conclusions: The LCM is a major advance in molecular medicine, enabling us to combine highly-sensitive gene analysis techniques with conventional histologic and morphologic methods. Applications range from research to diagnosis, and to monitoring disease progression. C1 NINCDS, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Bornstein, SR (reprint author), NINCDS, Dev Endocrinol Branch, NIH, Bldg 10,Room 10N262, Bethesda, MD 20892 USA. NR 26 TC 7 Z9 8 U1 0 U2 0 PU URBAN & VOGEL PI MUNICH PA LINDWURMSTRASSE 95, D-80337 MUNICH, GERMANY SN 0723-5003 J9 MED KLIN JI Med. Klin. PD DEC 15 PY 1998 VL 93 IS 12 BP 739 EP 743 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 152WQ UT WOS:000077800500010 PM 10024845 ER PT J AU Bicout, DJ Weiss, GH AF Bicout, DJ Weiss, GH TI A measure of photon penetration into tissue in diffusion models SO OPTICS COMMUNICATIONS LA English DT Article ID WAVE SPECTROSCOPY; MIGRATION; TIME; TRANSILLUMINATION; ABSORPTION; MEDIA AB In application of laser-based techniques to estimate optical parameters of tissue it is necessary to know the parts of the tissue that have been sampled by the photons. Towards this end it is desirable to define an average depth of a photon trajectory. This has been done earlier for lattice random walk models of photon trajectories where one simply counts the number of visits to a given set of sites. Here we calculate the equivalent quantity in the diffusion picture by equating the average depth of penetration to the local time of a diffusion process. We show that for a semi-infinite medium bounded by a plane the average depth probed by a photon trajectory in a continuous-wave (cw) experiment has the same functional form as that calculated from a random walk model. The local time, or average depth is shown to take a very simple form in the case of a time-gated experiment. We extend our results to the cw transillumination experiment. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Chem Phys Lab, Bethesda, MD 20892 USA. NIH, Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Bicout, DJ (reprint author), NIDDKD, Chem Phys Lab, Bldg 2, Bethesda, MD 20892 USA. NR 18 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0030-4018 J9 OPT COMMUN JI Opt. Commun. PD DEC 15 PY 1998 VL 158 IS 1-6 BP 213 EP 220 DI 10.1016/S0030-4018(98)00529-X PG 8 WC Optics SC Optics GA 152AH UT WOS:000077752700032 ER PT J AU Zhong, Z Connor, HD Mason, RP Lemasters, JJ Thurman, RG AF Zhong, Z Connor, HD Mason, RP Lemasters, JJ Thurman, RG TI Ethanol, not fat accumulation per se, increases free radical production in a low-flow, reflow liver perfusion model SO TRANSPLANTATION LA English DT Article ID PRIMARY NONFUNCTION; RAT-LIVER; REPERFUSION INJURY; KUPFFER CELLS; DIETARY FAT; ALCOHOL; TRANSPLANTATION; INTOXICATION; MOBILIZATION; ACTIVATION AB Background Ethanol increases primary graft failure after liver transplantation, yet whether it acts via mechanisms involving fat accumulation remains unclear. Methods. Rats were pair-fed a modified Lieber-De-Carli liquid diet containing 35% (high-fat) or 12% (low-fat) of calories as fat combined with 36% of calories as ethanol or isocaloric maltose-dextrin for 4-5 weeks. Reperfusion injury to the liver was studied using a low-flow, reflow perfusion model and a liver transplantation model, and free radicals were detected using electron spin resonance and the spin trapping technique. Results. As expected, basal hepatic triglycerides were similar in livers from rats fed low- and high-fat control diets. Ethanol did not alter triglyceride levels significantly in rats fed a low-fat diet, but increased values about 2.4-fold in rats fed a high-fat diet. Ethanol increased lactate dehydrogenase release during reperfusion from 10 to 26 IU/g/h in rats fed a low-fat diet and from 17 to 34 IU/g/h in rats fed a high-fat diet, respectively. Portal pressure increased from about 3 to 10.5 cm H(2)O upon reperfusion in livers from high-fat, ethanol-fed rats, but only reached values of 9.1 in the low-fat, ethanol-fed group. A free radical adduct signal was detected in the bile of livers from ethanol-treated rats, and the magnitude of this signal was similar in livers of ethanol-treated rats fed high- or low-fat diets. However, radical adducts could not be detected in either group in the absence of dietary ethanol, Moreover, 67-77% rats given low-fat or high-fat control diets survived after liver transplantation, but only 11% survived if treated with ethanol, Conclusions. It is concluded that ethanol plays a major role in hepatic reperfusion injury, most likely via mechanisms involving free radicals. Increased hepatic fat content alone plays only a minor role, probably by causing slight disturbances in the hepatic microcirculation. C1 Univ N Carolina, Dept Pharmacol, Lab Hepatol & Toxicol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Cell Biol & Anat, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Thurman, RG (reprint author), Univ N Carolina, Dept Pharmacol, Lab Hepatol & Toxicol, CB 7365,Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. EM thurman@med.unc.edu NR 44 TC 13 Z9 13 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD DEC 15 PY 1998 VL 66 IS 11 BP 1431 EP 1438 DI 10.1097/00007890-199812150-00005 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 150LQ UT WOS:000077666700005 PM 9869083 ER PT J AU Kimes, AS Maldonado, R Ambrosio, E Koob, GF London, ED AF Kimes, AS Maldonado, R Ambrosio, E Koob, GF London, ED TI Cerebral glucose metabolism during opioid withdrawal following methylnaloxonium injection into the locus coeruleus SO BRAIN RESEARCH LA English DT Article DE locus coeruleus; opioid withdrawal; opiate withdrawal; cerebral glucose metabolism; central amygdala; opioid abstinence; rat; intracerebral injections; methylnaloxonium ID PRECIPITATED MORPHINE-WITHDRAWAL; OPIATE-WITHDRAWAL; NUCLEUS-ACCUMBENS; DEPENDENT RATS; BRAIN ACETYLCHOLINE; NEURONS; CLONIDINE; CERULEUS; SUPPRESSION; NALOXONE AB Previous studies have demonstrated a widespread stimulation of regional cerebral metabolic rate(s) for glucose (rCMRglc) in morphine-dependent rats subjected to opioid withdrawal precipitated by systemic injection of naloxone. Nonetheless, many of the behavioral signs of opioid withdrawal are produced by intracerebral injections of an opioid antagonist, methylnaloxonium (MN), into the locus coeruleus (LC). The purpose of the present work was to determine the extent to which cerebral metabolic alterations in opioid withdrawal could be initiated by a local action in LC, Intracerebral injections of MN into LC increased rCMRglc in morphine-dependent rats, and the anatomical distribution of this effect was similar to that produced by systemic injections of naloxone. The present data support the view that LC is a major substrate of opioid withdrawal in the brain, and they suggest that LC plays an important role in changing rCMRglc during opioid withdrawal induced by systemic naloxone administration. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDA, Brain Imaging Ctr, Intramural Res Progran, Baltimore, MD 21224 USA. INSERM, U266, Paris, France. Univ Nacl Educ Distancia, Dept Psicobiol, Madrid, Spain. Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA USA. RP Kimes, AS (reprint author), NIDA, Brain Imaging Ctr, Intramural Res Progran, 5500 NAthan Shock Dr, Baltimore, MD 21224 USA. RI Maldonado, Rafael/F-5657-2014; koob, george/P-8791-2016 OI Maldonado, Rafael/0000-0002-4359-8773; FU NIDA NIH HHS [DA 04043] NR 49 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 14 PY 1998 VL 814 IS 1-2 BP 1 EP 12 DI 10.1016/S0006-8993(98)00813-0 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 153TT UT WOS:000077849300001 PM 9838021 ER PT J AU Cross, HR Lu, LY Steenbergen, C Philipson, KD Murphy, E AF Cross, HR Lu, LY Steenbergen, C Philipson, KD Murphy, E TI Overexpression of the cardiac Na+/Ca2+ exchanger increases susceptibility to ischemia/reperfusion injury in male, but not female, transgenic mice SO CIRCULATION RESEARCH LA English DT Article DE alternans; estrogen; ischemia Na+/Ca2+ exchange; protein expression ID SODIUM-CALCIUM EXCHANGE; NUCLEAR-MAGNETIC-RESONANCE; PERFUSED FERRET HEARTS; CYTOSOLIC FREE CALCIUM; SARCOPLASMIC-RETICULUM; GUINEA-PIG; NA+-CA2+ EXCHANGE; CA2+ RELEASE; RAT HEARTS; INTRACELLULAR CALCIUM AB Influx of Ca2+ into myocytes via Na+/Ca2+ exchange may be stimulated by the high levels of intracellular Na+ and the changes in membrane potential known to occur during ischemia/reperfusion. This increased influx could, in turn, lead to Ca2+ overload and injury. Overexpression of the cardiac Na+/Ca2+ exchanger therefore may increase susceptibility to ischemia/reperfusion injury. To test this hypothesis, the hearts of male and female transgenic mice, overexpressing the Na+/Ca2+ exchange protein, and hearts of their wild-type littermates, were perfused with Krebs-Henseleit buffer and subjected to 20 minutes of ischemia and 40 minutes of reperfusion. Preischemic left ventricular developed pressures and +dP/dt(max), as well as -dP/dt(min), were higher in the male transgenic hearts compared with wild-type, implying a role for Na+/Ca2+ exchange in the contraction, as well as the relaxation, phases of the cardiac beat. Postischemic function was lower in male transgenic than in male wild-type hearts (7+/-2% versus 32+/-6% of preischemic function), but there was no difference between female transgenic and female wild-type hearts, both at approximate to 30% of preischemic function. To assess whether this male/female difference was due to female-specific hormones such as estrogen, the hearts of bilaterally ovariectomized and sham-operated transgenic females were subjected to the same protocol. The functional recoveries of ovariectomized female transgenic hearts were lower (17+/-3% of preischemic function) than those of wild-type and sham-operated transgenic females. The lower postischemic functional recovery in the male transgenic and female ovariectomized transgenic hearts correlated with lower recoveries of the energy metabolites, ATP and phosphocreatine, as measured by P-31 nuclear magnetic resonance spectroscopy. Alternans were observed during reperfusion in male transgenic and female ovariectomized transgenic hearts only, consistent with intracellular Ca2+ overload. Western analyses showed that alterations in the expression of the Na+/Ca2+ exchange or L-type Ca2+ channel proteins were not responsible for the protection observed in the female transgenic hearts. In conclusion, in males, overexpression of the Na+/Ca2+ exchanger reduced postischemic recovery of both contractile function and energy metabolites, indicating that the Na+/Ca2+ exchanger may play a role in ischemia/reperfusion injury. From the studies of females, however, it appears that this exacerbation of ischemia/reperfusion injury by overexpression of the Na+/Ca2+ exchanger can be overcome partially by female-specific hormones such as estrogen. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Calif Los Angeles, Sch Med, Cardiovasc Res Labs, MacDonald Res Labs, Los Angeles, CA USA. Duke Univ, Dept Pathol, Durham, NC 27706 USA. RP Cross, HR (reprint author), NIEHS, Mail Drop D2-03, Res Triangle Pk, NC 27709 USA. FU NHLBI NIH HHS [R01 HL039752] NR 48 TC 142 Z9 148 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD DEC 14 PY 1998 VL 83 IS 12 BP 1215 EP 1223 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 147WW UT WOS:000077521200004 PM 9851938 ER PT J AU Mathew, M Fowler, BO Breuer, E Golomb, G Alferiev, IS Eidelman, N AF Mathew, M Fowler, BO Breuer, E Golomb, G Alferiev, IS Eidelman, N TI Synthesis, characterization, and crystal structure of dicalcium glutarylbis (phosphonate) dihydrate: A covalently pillared layer structure with the potential for epitaxial growth on hydroxyapatite SO INORGANIC CHEMISTRY LA English DT Article ID DIRECTED INORGANIC CRYSTALLIZATION; RAY-POWDER STRUCTURES; ORIENTED NUCLEATION; LANGMUIR MONOLAYERS; METAL PHOSPHONATES; BARITE CRYSTALS; CALCIFICATION; CALCIUM; BISACYLPHOSPHONATES; BISPHOSPHONATES AB A new bis(acylphosphonate), glutarylbis(phosphonate) (GlBP), was synthesized. Sodium and calcium salts of the GlBP, disodium dihydrogen glutarylbis(phosphonate), NaHO3PC(O)(CH2)(3)(O)PO3HNa, and dicalcium glutarylbis(phosphonate) dihydrate, Ca-2[O3PC(O)(CH2)(3)C(O)PO3]. 2H(2)O, were prepared and characterized by chemical analyses, thermogravimetry and Fourier transform infrared spectroscopy (FTIR); The crystal structure of the Ca salt was determined by single-crystal X-ray diffraction. The crystals are orthorhombic with a 10.970(1) Angstrom, b = 23.694(2) Angstrom, 5.580(1) Angstrom, space group Pnma, and Z= 4. This study provides the first example of a structure of a calcium complex involving a nongeminal bis(phosphonate). The structure can be described in terms of a covalently pillared layer-type arrangement of neutral Ca-GlBP-Ca units along the b-axis. Each oxygen atom of the phosphonate group is bonded to a different Ca; ion, and each Ca in turn is linked to three phosphonate groups. The Ca octahedra and the phosphonate tetrahedra form a two-dimensional polar sheet perpendicular to the b-axis. The chelate bonds involving the keto groups appear to be important links in the stabilization of the structure and, in turn,. to the biological activity of bis(acylphosphonates). A near-perfect lattice match, found between the Ca phosphonate layer and the major crystal faces of hydroxyapatite, indicates that epitaxial growth or incorporation of GlBP can occur on the apatitic surface which may be the mode of action in the inhibition of calcification. C1 NIST, Amer Dent Assoc Hlth Fdn, Paffenbarger Res Ctr, Gaithersburg, MD 20899 USA. NIST, NIDR, Craniofacial & Skeletal Dis Branch, Res Associate Program, Gaithersburg, MD 20899 USA. Hebrew Univ Jerusalem, Sch Pharm, Dept Pharmaceut Chem, IL-91120 Jerusalem, Israel. Hebrew Univ Jerusalem, Sch Pharm, Dept Pharmaceut, IL-91120 Jerusalem, Israel. Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. RP Mathew, M (reprint author), NIST, Amer Dent Assoc Hlth Fdn, Paffenbarger Res Ctr, Gaithersburg, MD 20899 USA. EM mathai.mathew@nist.gov RI Breuer, Eli/E-8382-2011; OI Golomb, Gershon/0000-0002-7369-9831 NR 46 TC 22 Z9 22 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0020-1669 J9 INORG CHEM JI Inorg. Chem. PD DEC 14 PY 1998 VL 37 IS 25 BP 6485 EP 6494 DI 10.1021/ic980374h PG 10 WC Chemistry, Inorganic & Nuclear SC Chemistry GA 148ZR UT WOS:000077581600012 ER PT J AU Hock, R Scheer, U Bustin, M AF Hock, R Scheer, U Bustin, M TI Chromosomal proteins HMG-14 and HMG-17 are released from mitotic chromosomes and imported into the nucleus by active transport SO JOURNAL OF CELL BIOLOGY LA English DT Article DE HMG proteins; nuclear transport; cell cycle; localization; nuclear proteins ID NUCLEOCYTOPLASMIC TRANSPORT; MAMMALIAN-CELLS; IN-VIVO; CHROMATIN; TRANSCRIPTION; SEQUENCE; DNA; REPLICATION; NUCLEOSOMES; ANTIBODIES AB The high mobility group 14/17 (HMG-14/-17) proteins form specific complexes with nucleosome core particles and produce distinct footprints on nucleosomal DNA, Therefore, they could be an integral part of the chromatin fiber. Here we show that during the cell cycle these proteins are transiently dissociated from chromatin, They colocalize with the nuclear DNA in interphase and prophase but not in metaphase and anaphase. They relocate into the nucleus and colocalize again with the DNA in late telophase, concomitantly with the appearance of the nuclear envelope. Thus, these nucleosomal binding proteins are not always associated with chromatin. Using reconstituted nuclei and permeabilized cells, we demonstrate that these two small proteins, with a molecular mass <10 kD, are actively imported into the nucleus. We identify the major elements involved in the nuclear import of these chromosomal proteins: HMG-14/-17 proteins contain an intrinsic bipartite nuclear localization signal, and their entry into the nucleus through nuclear pores requires energy and the participation of importin alpha. These findings suggest that the cell cycle-related association of HMG-14/-17 with chromatin is dependent on, and perhaps regulated by, nuclear import processes. C1 NCI, Prot Sect, Mol Carcinogenesis Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. Univ Wurzburg, Biozentrum, Dept Cell & Dev Biol, D-97074 Wurzburg, Germany. RP Bustin, M (reprint author), NCI, Prot Sect, Mol Carcinogenesis Lab, Div Basic Sci,NIH, Bethesda, MD 20892 USA. RI Bustin, Michael/G-6155-2015 NR 45 TC 52 Z9 59 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD DEC 14 PY 1998 VL 143 IS 6 BP 1427 EP 1436 DI 10.1083/jcb.143.6.1427 PG 10 WC Cell Biology SC Cell Biology GA 150CF UT WOS:000077644800002 PM 9852141 ER PT J AU Hirschberg, K Miller, CM Ellenberg, J Presley, JF Siggia, ED Phair, RD Lippincott-Schwartz, J AF Hirschberg, K Miller, CM Ellenberg, J Presley, JF Siggia, ED Phair, RD Lippincott-Schwartz, J TI Kinetic analysis of secretory protein traffic and characterization of Golgi to plasma membrane transport intermediates in living cells SO JOURNAL OF CELL BIOLOGY LA English DT Article DE Golgi-to-plasma membrane traffic; GFP; secretion; kinetics; transport intermediates ID GREEN FLUORESCENT PROTEIN; ENDOPLASMIC-RETICULUM; INTRACELLULAR-TRANSPORT; BREFELDIN-A; CULTURED FIBROBLASTS; PERMEABILIZED CELLS; COAT PROTEINS; APPARATUS; VESICLES; NETWORK AB Quantitative time-lapse imaging data of single cells expressing the transmembrane protein, vesicular stomatitis virus ts045 G protein fused to green fluorescent protein (VSVG-GFP), were used for kinetic modeling of protein traffic through the various compartments of the secretory pathway. A series of first order rate laws was sufficient to accurately describe VSVG-GFP transport, and provided compartment residence times and rate constants for transport into and out of the Golgi complex and delivery to the plasma membrane. For ER to Golgi transport the mean rate constant (i.e., the fraction of VSVG-GFP moved per unit of time) was 2.8% per min, for Golgi to plasma membrane transport it was 3.0% per min, and for transport from the plasma membrane to a degradative site it was 0.25% per min. Because these rate constants did not change as the concentration of VSVG-GFP in different compartments went from high (early in the experiment) to low (late in the experiment), secretory transport machinery was never saturated during the experiments. The processes of budding, translocation, and fusion of post-Golgi transport intermediates carrying VSVG-GFP to the plasma membrane were also analyzed using quantitative imaging techniques. Large pleiomorphic tubular structures, rather than small vesicles, were found to be the primary vehicles for Golgi to plasma membrane transport of VSVG-GFP, These structures budded as entire domains from the Golgi complex and underwent dynamic shape changes as they moved along microtubule tracks to the cell periphery. They carried up to 10,000 VSVG-GFP molecules and had a mean life time in COS cells of 3.8 min. In addition, they fused with the plasma membrane without intersecting other membrane transport pathways in the cell. These properties suggest that the post-Golgi intermediates represent a unique transport organelle for conveying large quantities of protein cargo from the Golgi complex directly to the plasma membrane. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Ctr Studies Phys & Biol, New York, NY 10021 USA. Bioinformat Serv, Rockville, MD 20854 USA. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T, Bethesda, MD 20892 USA. RI Ellenberg, Jan/I-4688-2014 OI Ellenberg, Jan/0000-0001-5909-701X NR 76 TC 415 Z9 426 U1 4 U2 23 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD DEC 14 PY 1998 VL 143 IS 6 BP 1485 EP 1503 DI 10.1083/jcb.143.6.1485 PG 19 WC Cell Biology SC Cell Biology GA 150CF UT WOS:000077644800007 PM 9852146 ER PT J AU Schumacher, JM Golden, A Donovan, PJ AF Schumacher, JM Golden, A Donovan, PJ TI AIR-2: An Aurora/Ip11-related protein kinase associated with chromosomes and midbody microtubules is required for polar body extrusion and cytokinesis in Caenorhabditis elegans embryos SO JOURNAL OF CELL BIOLOGY LA English DT Article DE cytokinesis; Aurora; chromosomes; meiosis; polar bodies; RNAi ID CYCLE-DEPENDENT EXPRESSION; MITOTIC SPINDLE POLES; CELL-CYCLE; C-ELEGANS; CENTROSOME SEPARATION; MONOPOLAR SPINDLES; MOTOR PROTEINS; MITOSIS; DYNAMICS; KINESIN AB An emerging family of kinases related to the Drosophila Aurora and budding yeast Ipl1 proteins has been implicated in chromosome segregation and mitotic spindle formation in a number of organisms. Unlike other Aurora/Ipl1-related kinases, the Caenorhabditis elegans orthologue, AIR-2, is associated with meiotic and mitotic chromosomes. AIR-2 is initially localized to the chromosomes of the most mature prophase I-arrested oocyte residing next to the spermatheca. This localization is dependent on the presence of sperm in the spermatheca. After fertilization, AIR-2 remains associated with chromosomes during each meiotic division. However, during both meiotic anaphases, AIR-2 is present between the separating chromosomes. AIR-2 also remains associated with both extruded polar bodies. In the embryo, AIR-2 is found on metaphase chromosomes, moves to midbody microtubules at anaphase, and then persists at the cytokinesis remnant. Disruption of AIR-2 expression by RNA-mediated interference produces entire broods of one-cell embryos that have executed multiple cell cycles in the complete absence of cytokinesis. The embryos accumulate large amounts of DNA and microtubule asters. Polar bodies are not extruded, but remain in the embryo where they continue to replicate. The cytokinesis defect appears to be late in the cell cycle because transient cleavage furrows initiate at the proper location, but regress before the division is complete. Additionally, staining with a marker of midbody microtubules revealed that at least some of the components of the midbody are not well localized in the absence of AIR-2 activity. Our results suggest that during each meiotic and mitotic division, AIR-2 may coordinate the congression of metaphase chromosomes with the subsequent events of polar body extrusion and cytokinesis. C1 NCI, Frederick Canc Res & Dev Ctr, Cell Biol Dev & Differentiat Grp, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Dev Signal Transduct Grp, ABL Basic Res Program, Frederick, MD 21702 USA. RP Donovan, PJ (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, 705 BLSB,233 S 10th St, Philadelphia, PA 19107 USA. RI Schumacher, Jill/B-2932-2012 NR 70 TC 227 Z9 234 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD DEC 14 PY 1998 VL 143 IS 6 BP 1635 EP 1646 DI 10.1083/jcb.143.6.1635 PG 12 WC Cell Biology SC Cell Biology GA 150CF UT WOS:000077644800017 PM 9852156 ER PT J AU Jhamandas, JH Harris, KH Petrov, T Yang, HYT Jhamandas, KH AF Jhamandas, JH Harris, KH Petrov, T Yang, HYT Jhamandas, KH TI Activation of neuropeptide FF neurons in the brainstem nucleus tractus solitarius following cardiovascular challenge and opiate withdrawal SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE morphine modulatory peptide; parabrachial nucleus; opiate withdrawal; hypotension; hypertension ID CENTRAL-NERVOUS-SYSTEM; C-FOS EXPRESSION; AREA POSTREMA; RAT-BRAIN; CHRONIC MORPHINE; PRECIPITATED WITHDRAWAL; PARAVENTRICULAR NUCLEUS; EFFERENT PROJECTIONS; PARABRACHIAL NUCLEUS; SPINAL MORPHINE AB Neuropeptide FF (NPFF), a morphine modulatory peptide, is localized within discrete autonomic regions including the brainstem nucleus tractus solitarius (NTS) and the parabrachial nucleus (PBN). We investigated the activation of NPFF neurons in the NTS of rats induced by cardiovascular challenge and centrally generated opiate withdrawal. For hypotensive stimulation, we used systemic infusions of sodium nitroprusside (NP) or hemorrhage (HEM), and hypertension was achieved by intravenous phenylephrine (PHENYL) or angiotensin II (AII). In rats that received continuous intracerebroventricular injections of morphine, intraperitoneal injections of naloxone precipitated behavioural signs of opioid withdrawal. Activated NTS neurons were identified by using a combined immunohistochemistry for Fos and NPFF, and neurons projecting to the PEN were determined with a retrograde tracer. HEM, administration of vasoactive drugs, and opiate withdrawal produced a very robust activation of NTS neurons. In NP and HEM groups, 25.6 +/- 3.2% and 7.6 +/- 1.3% of NPFF neurons were activated, respectively. Lesser numbers of NPFF neurons were activated in the PHENYL (4.6 +/- 1.6%) and AII (2.4 +/- 0.8%) groups. However, following opiate withdrawal, virtually no Fos expression was observed in NPFF neurons. NPFF neurons activated during NP infusion constituted the largest number of cells projecting to the PEN. This study shows that NPFF neurons in NTS that project to the PEN respond selectively to NP as opposed to other cardiovascular challenges or opiate withdrawal. These data support an emerging and important role for NPFF in the context of central cardiovascular regulation. J. Comp. Neurol. 402:210-221, 1998. (C) 1998 Wiley-Liss, Inc. C1 Univ Alberta, Div Neurol, Dept Med Neurol, Edmonton, AB T6G 2B7, Canada. Queens Univ, Dept Pharmacol & Toxicol, Kingston, ON K7L 3N6, Canada. NIMH, Dept Hlth & Human Sci, Neurosci Ctr St Elizabeths, Washington, DC 20032 USA. RP Jhamandas, KH (reprint author), Univ Alberta, Div Neurol, Dept Med Neurol, 2E3-17 Walter Mackenzie Ctr, Edmonton, AB T6G 2B7, Canada. EM jack.jhamandas@ualberta.ca NR 45 TC 21 Z9 21 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD DEC 14 PY 1998 VL 402 IS 2 BP 210 EP 221 PG 12 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 148BX UT WOS:000077533700006 PM 9845244 ER PT J AU Balajee, AS May, A Dianova, I Bohr, VA AF Balajee, AS May, A Dianova, I Bohr, VA TI Efficient PCNA complex formation is dependent upon both transcription coupled repair and genome overall repair SO MUTATION RESEARCH-DNA REPAIR LA English DT Article DE DNA repair; transcription coupled DNA repair; proliferating cell nuclear antigen (PCNA); nuclear matrix ID CELL NUCLEAR ANTIGEN; DNA-REPAIR; ULTRAVIOLET-LIGHT; EXCISION-REPAIR; CYCLOBUTANE DIMERS; 6-4 PHOTOPRODUCTS; MAMMALIAN-CELLS; CYTO-TOXICITY; CHO CELLS; REPLICATION AB The protein proliferating cell nuclear antigen (PCNA) is an auxiliary factor for DNA polymerase delta and is involved in the resynthesis step of nucleotide excision repair (NER). After UV irradiation of quiescent cells, PCNA forms an insoluble complex with nuclear substructures. We have investigated associations between NER and its subcomponent pathway, transcription coupled repair (TCR) on PCNA complex formation using genetically related hamster cell lines with different repair characteristics. In DNA repair proficient cells, the PCNA complex was readily detectable within 30 min after UV irradiation by both immunofluorescence and western blot analyses. This complex formation after UV occurs efficiently in quiescent cells. In UV5 (human XP-D homolog) and UV 24 (human XP-B homolog) cells, which are totally deficient in NER, the PCNA complex was not detectable at 30 min after UV. The PCNA complex formation is restored to normal levels in UV5 cells after transfection with the human XPD gene, encoding a subunit of the basal transcription factor, TFIIH. In UV61 (Human CS-B homolog) cells, that are defective only in transcription coupled repair (TCR) of cyclobutane pyrimidine dimers (CPDs), the rate of PCNA complex formation was 2-fold slower than in repair proficient cells. This defect was complemented by transfection of the CSB gene into the UV61 cells. We thus conclude that efficient PCNA complex formation after UV is dependent upon both the NER and TCR pathways in hamster cells. The association of several other DNA repair proteins including XPA, RPA, TFIIH: and p53 with the insoluble PCNA complex in UV treated cells suggests a central role for PCNA in different steps of NER. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Genet Mol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov NR 33 TC 24 Z9 24 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0921-8777 J9 MUTAT RES-DNA REPAIR JI Mutat. Res.-DNA Repair PD DEC 14 PY 1998 VL 409 IS 3 BP 135 EP 146 DI 10.1016/S0921-8777(98)00051-2 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 149FD UT WOS:000077593700004 PM 9875289 ER PT J AU Sharma, K Sheng, HZ Lettieri, K Li, H Karavanov, A Potter, S Westphal, H Pfaff, SL AF Sharma, K Sheng, HZ Lettieri, K Li, H Karavanov, A Potter, S Westphal, H Pfaff, SL TI LIM homeodomain factors Lhx3 and Lhx4 assign subtype identities for motor neurons SO CELL LA English DT Article ID HOMEOBOX GENE LHX3; CHICK SPINAL-CORD; SONIC HEDGEHOG; NEUROENDOCRINE TISSUES; PROJECTION PATTERNS; FLOOR PLATE; EXPRESSION; SPECIFICATION; PITUITARY; ORGANIZATION AB The circuits that control movement are comprised of discrete subtypes of motor neurons. How motor neuron subclasses develop and extend axons to their correct targets is still poorly understood. We show that LIM homeodomain factors Lhx3 and Lhx4 are expressed transiently in motor neurons whose axons emerge ventrally from the neural tube (V-MN). Motor neurons develop in embryos deficient in both Lhx3 and Lhx4, but v-MN cells switch their subclass identity to become motor neurons that extend axons dorsally from the neural tube (d-MN). Conversely, the misexpression of Lhx3 in dorsal-exiting motor neurons is sufficient to reorient their axonal projections ventrally. Thus, Lhx3 and Lhx4 act in a binary fashion during a brief period in development to specify the trajectory of motor axons from the neural tube. C1 Salk Inst, Gene Express Lab, La Jolla, CA 92037 USA. NICHHD, Lab Mammalian Genet & Dev, Bethesda, MD 20892 USA. NICHHD, Mol Genet Lab, Bethesda, MD 20892 USA. Acad Sinica, Inst Mol Biol, Taipei, Taiwan. Childrens Hosp, Cincinnati, OH 45229 USA. RP Pfaff, SL (reprint author), Salk Inst, Gene Express Lab, La Jolla, CA 92037 USA. FU NINDS NIH HHS [NS37116] NR 55 TC 317 Z9 324 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD DEC 11 PY 1998 VL 95 IS 6 BP 817 EP 828 DI 10.1016/S0092-8674(00)81704-3 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 148HG UT WOS:000077498800011 PM 9865699 ER PT J AU Muller, U Grams, A Martinez-Noel, G Copeland, NG Gilbert, DJ Jenkins, NA Harbers, K AF Muller, U Grams, A Martinez-Noel, G Copeland, NG Gilbert, DJ Jenkins, NA Harbers, K TI Structure of the gene encoding the ubiquitin-conjugating enzyme Ubcm4, characterization of its promoter, and chromosomal location SO GENE LA English DT Article DE exon-intron structure; gene mapping; mouse; multiple transcripts; ubiquitylation ID CARRIER PROTEIN; HUMAN HOMOLOG; CELL-CYCLE; CLONING; SYSTEM; YEAST; DEGRADATION; IDENTIFICATION; E2; ORGANIZATION AB Ubiquitin-conjugating enzymes (E2 or Ubc) play a key role in the post-translational modification of proteins by ubiquitylation. They are encoded by a large family of genes that are closely related to each other. In this paper we present the first complete structural analysis, including the promoter and the chromosomal location, of a member of this family, the mouse Ubcm4 gene. At the genomic level the Ubcm4 gene spans approx. 50 kb and is composed of four exons. Only about 1% of the total gene codes for amino acids. The four different Ubcm4 specific RNAs encode the same protein and differ only in the length of the 3' untranslated region. The polyadenylation signals used by the four different RNAs are all within the 3' terminal exon. At the 5' end of the gene, multiple transcriptional start sites were mapped within a region of 25 bp. The region proximal to the initiation sites does not contain a TATA box and is not GC-rich. Transient chloramphenicol acetyltransferase assays, however, showed that this region can promote the expression of a reporter gene and that 15 bp upstream of the first initiation site were sufficient for basal expression. The Ubcm4 gene was mapped by interspecific backcross analysis to the proximal region of mouse chromosome 16. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Univ Hamburg, Heinrich Pette Inst Expt Virol & Immunol, D-20251 Hamburg, Germany. NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Harbers, K (reprint author), Univ Hamburg, Heinrich Pette Inst Expt Virol & Immunol, Martinistr 52, D-20251 Hamburg, Germany. EM harbers@hpi.uni-hamburg NR 37 TC 6 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD DEC 11 PY 1998 VL 224 IS 1-2 BP 109 EP 116 DI 10.1016/S0378-1119(98)00515-0 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 156XR UT WOS:000078028300013 PM 9931461 ER PT J AU Liu, XB O'Connell, A Ambudkar, IS AF Liu, XB O'Connell, A Ambudkar, IS TI Ca2+-dependent inactivation of a store-operated Ca2+ current in human submandibular gland cells - Role of a staurosporine-sensitive protein kinase and the intracellular Ca2+ pump SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED CALCIUM CURRENT; DIVALENT-CATION ENTRY; PAROTID ACINAR-CELLS; PANCREATIC ACINI; CA-2+ ENTRY; MAST-CELLS; DEPLETION; INFLUX; STIMULATION; LINE AB Stimulation of human submandibular gland cells with carbachol, inositol trisphosphate (IP3), thapsigargin, or tert-butylhydroxyquinone induced an inward current that was sensitive to external Ca2+ concentration ([Ca2+](e)) and was also carried by external Na+ or Ba2+ (in a Ca2+-free medium) with amplitudes in the order Ca2+ > Ba2+ > Na+. All cation currents were blocked by La3+ and Gd3+ but not by Zn2+. The IP3-stimulated current with 10 mu M 3-deoxy-3-fluoro-D-myo-inositol 1,4,5-triphosphate and 10 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid in the pipette solution, showed 50% inactivation in <5 min and >5 min with 10 and 1 mM [Ca2+](e), respectively. The Na+ current was not inactivated, whereas the Ba2+ current inactivated at a slower rate. The protein kinase inhibitor, staurosporine, delayed the inactivation and increased the amplitude of the current, whereas the protein Ser/Thr phosphatase inhibitor, calyculin A, reduced the current. Thapsigargin- and tert-butylhydroxyquinone-stimulated Ca2+ currents inactivated faster. Importantly, these agents accelerated the inactivation of the IP3-stimulated current. The data demonstrate that internal Ca2+ store depletion-activated Ca2+ current (I-SOC) in this salivary cell line is regulated by a Ca2+-dependent feedback mechanism involving a staurosporine-sensitive protein kinase and the intracellular Ca2+ pump. We suggest that the Ca2+ pump modulates I-SOC by regulating [Ca2+](i) in the region of Ca2+ influx. C1 NIDR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), NIDR, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1N-113, Bethesda, MD 20892 USA. EM ambudkar@yoda.nidr.nih.gov OI O'Connell, Anne C/0000-0002-1495-3983 NR 30 TC 48 Z9 48 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 DEC 11 PY 1998 VL 273 IS 50 BP 33295 EP 33304 DI 10.1074/jbc.273.50.33295 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 146YY UT WOS:000077462500032 PM 9837902 ER PT J AU Yu, LJ Orlandi, L Wang, P Orr, MS Senderowicz, AM Sausville, EA Silvestrini, R Watanabe, N Piwnica-Worms, H O'Connor, PM AF Yu, LJ Orlandi, L Wang, P Orr, MS Senderowicz, AM Sausville, EA Silvestrini, R Watanabe, N Piwnica-Worms, H O'Connor, PM TI UCN-01 abrogates G(2) arrest through a Cdc2-dependent pathway that is associated with inactivation of the Wee1Hu kinase and activation of the Cdc25C phosphatase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-DAMAGE CHECKPOINT; HAMSTER OVARY CELLS; PROTEIN-KINASE; SELECTIVE INHIBITOR; TYROSINE KINASE; FISSION YEAST; G2 PHASE; PHOSPHORYLATES CDC2; ANTITUMOR-ACTIVITY; P34(CDC2) KINASE AB We have previously demonstrated that UCN-01, a potent protein kinase inhibitor currently in phase I clinical trials for cancer treatment, abrogates G(2) arrest following DNA damage. Here we used murine FT210 cells, which contain temperature-sensitive Cdc2 mutations, to determine if UCN-01 abrogates G(2) arrest through a Cdc2-dependent pathway. We report that UCN-01 cannot induce mitosis in DNA-damaged FT210 cells at the nonpermissive temperature for Cdc2 function. Failure to abrogate G(2) arrest was not due to UCN-01-inactivation at the elevated temperature because parental FM3A cells, which have wild-type Cdc2, were sensitive to UCN-01-induced G(2) checkpoint abrogation. Having established that UCN-01 acted through Cdc2, we next assessed UCN-01's effect on the Cdc2-inhibitory kinase, WeelHu, and the Cdc2-activating phosphatase, Cdc25C, We found that WeelHu was indeed inactivated in UCN01-treated cells, possibly just prior to Cdc2 activation and entry of DNA-damaged cells into mitosis, This inhibition appeared, however, to be a consequence of a further upstream action since in vitro studies revealed purified WeelHu was relatively resistant to UCN-01-inhibition. Consistent with such an upstream action, UCN-01 also promoted the hyperphosphorylation (activation) of Cdc25C in DNA-damaged cells, Our results suggest that UCN-01 abrogates G(2) checkpoint function through inhibition of a kinase residing upstream of Cdc2, WeelHu, and Cdc25C, and that changes observed in these mitotic regulators are downstream consequences of UCN-01's actions. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. NCI, Clin Trials Unit, Med Branch,Div Clin Sci, NIH, Bethesda, MD 20892 USA. Ist Nazl Studio & Cura Tumori, I-20133 Milan, Italy. Tsukuba Life Sci Ctr, Gene Bank, Ibaraki 3050074, Japan. Washington Univ, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. Washington Univ, Howard Hughes Med Inst, St Louis, MO 63110 USA. RP O'Connor, PM (reprint author), Agouron Pharmaceut Inc, 3565 Gen Atom Ct, San Diego, CA 92121 USA. RI Piwnica-Worms, Helen/C-5214-2012 NR 61 TC 95 Z9 96 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 DEC 11 PY 1998 VL 273 IS 50 BP 33455 EP 33464 DI 10.1074/jbc.273.50.33455 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 146YY UT WOS:000077462500054 PM 9837924 ER PT J AU Tahara, M Coorssen, JR Timmers, K Blank, PS Whalley, T Scheller, R Zimmerberg, J AF Tahara, M Coorssen, JR Timmers, K Blank, PS Whalley, T Scheller, R Zimmerberg, J TI Calcium can disrupt the SNARE protein complex on sea urchin egg secretory vesicles without irreversibly blocking fusion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TOXIN LIGHT-CHAIN; CORTICAL-GRANULE EXOCYTOSIS; TETANUS TOXIN; CLOSTRIDIAL NEUROTOXINS; CHROMAFFIN CELLS; PROTEOLYTIC CLEAVAGE; SYNAPTIC VESICLES; TRIGGERED FUSION; MEMBRANE-FUSION; YEAST VACUOLES AB The homotypic fusion of sea urchin egg cortical vesicles (CV) is a system in which to correlate the biochemistry and physiology of membrane fusion, Homologues of vesicle-associated membrane protein (VAMP), syntaxin, and SNAP-25 were identified in CV membranes. A VAMP and syntaxin immunoreactive band at a higher apparent molecular mass (approximate to 70 kDa) was detected; extraction and analysis confirmed that the band contained VAMP, SNAP-25, and syntaxin. This complex was also identified by immunoprecipitation and by sucrose gradient analysis. VAMP in the complex was insensitive to proteolysis by tetanus toxin, All criteria identify the SNARE complex as that described in other secretory systems. Complexes exist pre-formed on individual CV membranes and form between contacting CV, Most notably, CV SNARE complexes are disrupted in response to [Ca2+](free) that trigger maximal fusion. N-Ethylmaleimide, which blocks fusion at or before the Ca2+-triggering step, blocks complex disruption by Ca2+. However, disruption is not blocked by lysophosphatidylcholine, which transiently arrests a late stage of fusion, Since removal of lysophosphatidylcholine from Ca2+-treated CV is known to allow fusion, complex disruption occurs independently from the membrane fusion step. As Ca2+ disrupts rather than stabilizes the complex, the presumably coiled coil SNARE interactions are not needed at the time of fusion, These findings rule out models of fusion in which SNARE complex formation goes to completion ("zippers-up") after Ca2+ binding removes a "fusion clamp." C1 NICHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Univ Stirling, Dept Biol & Mol Sci, Stirling FK9 4LA, Scotland. Stanford Univ, Med Ctr,Howard Hughes Med Inst, Beckman Ctr Mol & Genet Med, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA. RP Zimmerberg, J (reprint author), NICHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. OI Whalley, Tim/0000-0003-3362-0006 NR 61 TC 75 Z9 76 U1 0 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 DEC 11 PY 1998 VL 273 IS 50 BP 33667 EP 33673 DI 10.1074/jbc.273.50.33667 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 146YY UT WOS:000077462500082 PM 9837952 ER PT J AU Kim, Y Ratziu, V Choi, SG Lalazar, A Theiss, G Dang, Q Kim, SJ Friedman, SL AF Kim, Y Ratziu, V Choi, SG Lalazar, A Theiss, G Dang, Q Kim, SJ Friedman, SL TI Transcriptional activation of transforming growth factor beta 1 and its receptors by the Kruppel-like factor Zf9/core promoter-binding protein and Sp1 - Potential mechanisms for autocrine fibrogenesis in response to injury SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEPATIC STELLATE CELLS; ZINC-FINGER PROTEIN; RAT-LIVER FIBROSIS; GENE-EXPRESSION; TGF-BETA; FACTOR-BETA-1 GENE; ITO CELLS; GROWTH-FACTOR-BETA-1; LIPOCYTES; DISEASE AB We have explored the regulation of transforming growth factor beta (TGF-beta) activity in tissue repair by examining the interactions of Zf9/core promoter-binding protein, a Kruppel-like zinc finger transcription factor induced early in hepatic stellate cell (HSC) activation, with promoters for TGF-beta 1 and TGF-beta receptors, types I and II. Nuclear extracts from culture-activated HSCs bound avidly by electrophoretic mobility shift assay to two tandem GC boxes within the TGF-beta 1 promoter but minimally to a single GC box; these results correlated with transactivation by Zf9 of TGF-beta 1 promoter-reporters, Zf9 transactivated the full-length TGF-beta 1 promoter in either primary HSCs, HSC-T6 cells (an SV40-immortalized rat RSC line), Hep G2 cells, or Drosophila Schneider (S2) cells. Recombinant Zf9-GST also bound to GC box sequences within the promoters for the types I and II TGF-beta receptors. Both type I and type II TGF-beta receptor promoters were also transactivated by Zf9 in mammalian cells but not in S2 cells. In contrast, Spl significantly transactivated both receptor promoters in S2 cells. These results suggest that (a) Zf9/core promoterbinding protein may enhance TGF-beta activity through transactivation of both the TGF-beta 1 gene and its key signaling receptors, and (b) transactivating potential of Zf9 and Sp1 toward promoters for TGF-beta 1 and its recep tors are not identical and depend on the cellular context. C1 CUNY Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. NCI, Lab Cell Regulat & Carcinogenesis, Div Basic Sci, NIH, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, Dept Liver Dis, New York, NY 10029 USA. Bayer AG, D-42096 Wuppertal, Germany. RP Friedman, SL (reprint author), CUNY Mt Sinai Sch Med, Dept Med, Box 1123,1425 Madison Ave,Rm 1170-F, New York, NY 10029 USA. FU NIDDK NIH HHS [DK37340] NR 46 TC 196 Z9 203 U1 1 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 DEC 11 PY 1998 VL 273 IS 50 BP 33750 EP 33758 DI 10.1074/jbc.273.50.33750 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 146YY UT WOS:000077462500093 PM 9837963 ER PT J AU Dianov, G Bischoff, C Piotrowski, J Bohr, VA AF Dianov, G Bischoff, C Piotrowski, J Bohr, VA TI Repair pathways for processing of 8-oxoguanine in DNA by mammalian cell extracts SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; POLYMERASE-BETA; OXIDATIVE DAMAGE; NUCLEAR ANTIGEN; GLYCOSYLASE; RECONSTITUTION; REQUIREMENT; PROTEIN; CLONING; TRANSCRIPTION AB The repair pathways involved in the removal of 8-oxo-7,8-dihydroguanine (8-oxoguanine) in DNA by mammalian cell extracts have been examined. Closed circular DNA constructs containing a single 8-oxoguanine at a defined site were used as substrates to determine the patch size generated after in vitro repair by mammalian cell extracts. Restriction analysis of the repair incorporation in the vicinity of the lesion indicated that up to 75% of the 8-oxoguanine was repaired via the single nucleotide replacement mechanism in both human and mouse cell extracts. Approximately 25% of the 8-oxoguanine lesions were repaired by the long patch repair pathway. Repair incorporation 5' to the lesion, characteristic for nucleotide excision repair, was not significant. Elimination of the DNA polymerase beta (pol beta)-dependent single nucleotide base excision repair pathway in extracts prepared from pol beta-deficient mouse cells resulted in extension of the repair gap to 4-5 nucleotides 3' to the lesion in 50% of the repair events, suggesting the increased involvement of the long patch repair pathway. However, about one-half of the 8-oxoguanine repair was still accomplished through replacement of only one nucleotide in the pol beta-deficient cell extracts. These data indicate the existence of an alternative pol beta-independent single nucleotide repair patch pathway for processing of 8-oxoguanine in DNA. C1 NIA, Genet Mol Lab, NIH, Baltimore, MD 21224 USA. Aarhus Univ, Inst Struct & Mol Biol, DK-8000 Aarhus, Denmark. RP Bohr, VA (reprint author), NIA, Genet Mol Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 39 TC 173 Z9 175 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 DEC 11 PY 1998 VL 273 IS 50 BP 33811 EP 33816 DI 10.1074/jbc.273.50.33811 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 146YY UT WOS:000077462500101 PM 9837971 ER PT J AU Zhu, T Goh, ELK LeRoith, D Lobie, PE AF Zhu, T Goh, ELK LeRoith, D Lobie, PE TI Growth hormone stimulates the formation of a multiprotein signaling complex involving p130(Cas) and CrkII - Resultant activation of c-Jun N-terminal kinase/stress-activatedprotein kinase (JNK/SAPK) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FOCAL ADHESION KINASE; INSULIN-RECEPTOR SUBSTRATE-1; PROMOTED TYROSYL PHOSPHORYLATION; SRC FAMILY KINASES; PHOSPHATIDYLINOSITOL 3-KINASE; IN-VIVO; PROTOONCOGENE PRODUCT; HEMATOPOIETIC-CELLS; PROLACTIN RECEPTOR; ACTIN CYTOSKELETON AB We have demonstrated previously that growth hormone (GH) activates focal adhesion kinase (FAK), and this activation results in the tyrosine phosphorylation of two FAK substrates, namely paxillin and tensin, We now show here in Chinese hamster ovary cells stably transfected with rat GH receptor cDNA that human (h)GH induces the formation of a large multiprotein signaling complex centered around another FAK-associated protein, p130(Cas) and the adaptor protein CrkII, hGH stimulates the tyrosine phosphorylation of both p130(Cas) and CrkII, their association, and the association of multiple other tyrosine-phosphorylated proteins to the complex. Both the c-Src and c-Fyn tyrosine kinases are tyrosine phosphorylated and activated by cellular hGH stimulation and form part of the multiprotein signaling complex as does tensin, paxillin, IRS-1, the p85 subunit of phosphatidylinositol 3-kinase, C3G, SHC, Grb-2, and Sos-1. c-Cbl and Nck are also tyrosine-phosphorylated by cellular stimulation with hGH and associate with the p130(Cas)-CrkII complex, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) is activated in response to hGH in accordance with the formation of the abovementioned signaling complex, and hGH stimulated JNK/SAPK activity is increased in CrkII overexpressing NIH3T3 cells compared with vector transfected NIH3T3 cells. The formation of such a large multiprotein signaling complex by GH, with the resultant activation of multiple downstream effector molecules, may be central to many of the pleiotropic effects of GH. C1 Natl Univ Singapore, Inst Mol & Cell Biol, Singapore 117609, Singapore. Natl Univ Singapore, Def Med Res Inst, Singapore 117609, Singapore. NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Lobie, PE (reprint author), Natl Univ Singapore, Inst Mol & Cell Biol, 30 Med Dr, Singapore 117609, Singapore. RI ASTAR, IMCB/E-2320-2012; Goh, Eyleen/A-8006-2013 NR 68 TC 63 Z9 64 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 DEC 11 PY 1998 VL 273 IS 50 BP 33864 EP 33875 DI 10.1074/jbc.273.50.33864 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 146YY UT WOS:000077462500108 PM 9837978 ER PT J AU Ding, JP Das, K Hsiou, Y Sarafianos, SG Clark, AD Jacobo-Molina, A Tantillo, C Hughes, SH Arnold, E AF Ding, JP Das, K Hsiou, Y Sarafianos, SG Clark, AD Jacobo-Molina, A Tantillo, C Hughes, SH Arnold, E TI Structure and functional implications of the polymerase active site region in a complex of HIV-1 RT with a double-stranded DNA template-primer and an antibody Fab fragment at 2.8 angstrom resolution SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE AIDS; polymerase active site; polymerase structure; protein-nucleic acid interaction; X-ray crystallography ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE MUTANTS; NONNUCLEOSIDE INHIBITORS; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURES; RESISTANCE MUTATIONS; COMBINATION THERAPY; CROSS-RESISTANCE; THUMB SUBDOMAIN; MECHANISM AB The structure of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) complexed with a 19-mer/18-mer double-stranded DNA template-primer (dsDNA) and the Fab fragment of monoclonal antibody 28 (Fab28) has been refined at 2.8 Angstrom resolution. The structures of the polymerase active site and neighboring regions are described in detail and a number of novel insights into mechanisms of polymerase catalysis and drug inhibition are presented. The three catalytically essential amino acid residues (Asp110, Asp185, and Asp186) are located dose to the 3' terminus of the primer strand. Observation of a hydrogen bond between the 3'-OH of the primer terminus and the side-chain of Asp185 suggests that the carboxylate of Asp185 could act as a general base in initiating the nucleophilic attack during polymerization. Nearly all of the close protein-DNA interactions involve atoms of the sugar-phosphate backbone of the nucleic acid. However, the phenoxyl side-chain of Tyr183, which is part of the conserved YMDD motif, has hydrogen-bonding interactions with nucleotide bases of the second duplex base-pair and is predicted to have at least one hydrogen bond with all Watson-Crick base-pairs at this position. Comparison of the structure of the active site region in the HIV-1 RT/dsDNA complex with all other HIV-1 RT structures suggests that template-primer binding is accompanied by significant conformational changes of the YMDD motif that may be relevant for mechanisms of both polymerization and inhibition by non-nucleoside inhibitors. interactions of the "primer grip" (the beta 12-beta 13 hairpin) with the 3' terminus of the primer strand primarily involve the main-chain atoms of Met230 and Gly231 and the primer terminal phosphate. Alternative positions of the primer grip observed in different HIV-1 RT structures may be related to conformational changes that normally occur during DNA polymerization and translocation. Ln the vicinity of the polymerase active site, there are a number of aromatic residues that are involved in energetically favorable pi-pi interactions and may be involved in the transitions between different stages of the catalytic process. The protein structural elements primarily responsible for precise positioning of the template-primer (including the primer grip, template grip, and helices alpha H and alpha I of the p66 thumb) can be thought of functioning as a "translocation track" that guides the relative movement of nucleic acid and protein during polymerization. (C) 1998 Academic Press. C1 Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ 08854 USA. NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, 679 Hoes Lane, Piscataway, NJ 08854 USA. EM arnold@cabm.rutgers.edu FU NIAID NIH HHS [AI 27690] NR 92 TC 265 Z9 269 U1 1 U2 11 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD DEC 11 PY 1998 VL 284 IS 4 BP 1095 EP 1111 DI 10.1006/jmbi.1998.2208 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 147BD UT WOS:000077467300022 PM 9837729 ER PT J AU Blanco, FJ Serrano, L Forman-Kay, JD AF Blanco, FJ Serrano, L Forman-Kay, JD TI High populations of non-native structures in the denatured state are compatible with the formation of the native folded state SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE denatured state; helix; secondary structure; beta-sheet; NMR ID NMR CHEMICAL-SHIFTS; SPECTRIN SH3 DOMAIN; STAPHYLOCOCCAL NUCLEASE; RESONANCE SPECTROSCOPY; EMPIRICAL PARAMETERS; IMPROVED SENSITIVITY; FOLDING TRANSITION; RESIDUAL STRUCTURE; HETERONUCLEAR NMR; CRYSTAL-STRUCTURE AB The structures of the denatured states of the spectrin SH3 domain and a mutant designed to have a non-native helical tendency at the N terminus have been analyzed under mild acidic denaturing conditions by nuclear magnetic resonance methods with improved resolution. The wild-type denatured state has little residual structure. However, the denatured state of the mutant has an approximately 50% populated helical structure from residues 2 to 14, a region that forms part of the beta-sheet structure in the folded state. Comparison with a peptide corresponding to the same sequence shows that the helix is stabilized in the whole domain, likely by non-local interactions with other parts of the protein as suggested by changes in a region far from the mutated sequence. These results demonstrate that high populations of-non-native secondary structure elements in the denatured state are compatible with the formation of the native folded structure. (C) 1998 Academic Press. C1 European Mol Biol Lab, D-69012 Heidelberg, Germany. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Biochem, Toronto, ON M5G 1X8, Canada. RP Blanco, FJ (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Blanco, Francisco/D-4401-2009; Serrano, Luis/B-3355-2013 OI Blanco, Francisco/0000-0003-2545-4319; Serrano, Luis/0000-0002-5276-1392 NR 57 TC 48 Z9 48 U1 0 U2 0 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD DEC 11 PY 1998 VL 284 IS 4 BP 1153 EP 1164 DI 10.1006/jmbi.1998.2229 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 147BD UT WOS:000077467300026 PM 9837733 ER PT J AU Hayakawa, Y Kimoto, H Cohen, LA Kirk, KL AF Hayakawa, Y Kimoto, H Cohen, LA Kirk, KL TI Syntheses of (trifluoromethyl)imidazoles with additional electronegative substituents. An approach to receptor-activated affinity labels SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID HISTIDINE ANALOGS; PLASMODIUM-FALCIPARUM; IMIDAZOLES; PERFLUOROALKYLATION; INVITRO AB Electrophilic substitution in 2- and 4-(trifluoromethyl)imidazoles provides derivatives containing one or two nitro, chloro, bromo, or iodo groups. Fluoro and chloro derivatives were also prepared by photochemical trifluoromethylation of the respective haloimidazole. The results demonstrate that (trifluoromethyl)imidazoles behave fairly typically under the conditions of electrophilic nitration and halogenation. Of the alternative routes to the desired bifunctional and trifunctional imidazoles, electrophilic substitution on the preformed (trifluoromethyl)imidazole appears to be the method of choice in most cases. A large number of the products show herbicidal or insecticidal activity. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Natl Ind Res Inst Nagoya, Kita Ku, Nagoya, Aichi 462, Japan. RP Kirk, KL (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 33 TC 21 Z9 21 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD DEC 11 PY 1998 VL 63 IS 25 BP 9448 EP 9454 DI 10.1021/jo9814952 PG 7 WC Chemistry, Organic SC Chemistry GA 148HC UT WOS:000077498400049 ER PT J AU Gilman, S Low, PA Quinn, N Albanese, A Ben-Shlomo, Y Fowler, CJ Kaufmann, H Klockgether, T Lang, AE Lantos, PL Litvan, I Mathias, CJ Oliver, E Robertson, D Schatz, I Wenning, GK AF Gilman, S Low, PA Quinn, N Albanese, A Ben-Shlomo, Y Fowler, CJ Kaufmann, H Klockgether, T Lang, AE Lantos, PL Litvan, I Mathias, CJ Oliver, E Robertson, D Schatz, I Wenning, GK TI Consensus statement on the diagnosis of multiple system atrophy SO JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM LA English DT Article DE multiple system atrophy; parkinsonism; cerebellar ataxia; autonomic insufficiency; urinary dysfunction; glial cytoplasmic inclusions ID CLINICAL-FEATURES; NATURAL-HISTORY; DYSFUNCTION; CRITERIA AB We report the results of a consensus conference on the diagnosis of multiple system atrophy (MSA). We describe the clinical features of the disease, which include four domains: autonomic failure/urinary dysfunction, parkinsonism and cerebellar ataxia, and corticospinal dysfunction. We set criteria to define the relative importance of these features. The diagnosis of possible MSA requires one criterion plus two features from separate other domains. The diagnosis of probable MSA requires the criterion for autonomic failure/urinary dysfunction plus poorly levodopa responsive parkinsonism or cerebellar ataxia. The diagnosis of definite MSA requires pathological conformation. (C) 1998 Elsevier Science B.V. All rights reserved. C1 Univ Michigan, Med Ctr, Dept Neurol, Ann Arbor, MI 48109 USA. Mayo Clin & Mayo Fdn, Dept Neurol, Rochester, MN 55905 USA. Natl Hosp Neurol & Neurosurg, Dept Neurol, London WC1N 3BG, England. Univ Cattolica Sacro Cuore, Ist Neurol, Dept Neurol, I-00168 Rome, Italy. Dept Social Med, Bristol BS8 2P, Avon, England. CUNY, Mt Sinai Med Ctr, Dept Neurol, New York, NY 10029 USA. Univ Bonn, Dept Neurol, D-53105 Bonn, Germany. Toronto Western Hosp, Dept Neurol, Toronto, ON MP11 304, Canada. Inst Psychiat, Dept Neuropathol, London SE5 8AF, England. NINDS, NIH, Bethesda, MD 20892 USA. St Marys Hosp, Imperial Coll, Sch Med, Dept Neurovasc Med, London W2 1NY, England. Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. Vanderbilt Univ, Dept Neurol, Nashville, TN 37232 USA. Univ Hawaii Manoa, Dept Med, Honolulu, HI 96813 USA. Univ Innsbruck, Neurol Klin, A-6020 Innsbruck, Austria. Natl Hosp Neurol & Neurosurg, Autonom Unit, London WC1N 3BG, England. RP Gilman, S (reprint author), Univ Michigan, Med Ctr, Dept Neurol, 1500 E Med Ctr Dr,1914 TC, Ann Arbor, MI 48109 USA. EM sgilman@umich.edu RI Fowler, Clare /B-2812-2009; OI Litvan, Irene/0000-0002-3485-3445 NR 26 TC 177 Z9 185 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-1838 J9 J AUTONOM NERV SYST JI J. Auton. Nerv. Syst. PD DEC 11 PY 1998 VL 74 IS 2-3 BP 189 EP 192 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 150WZ UT WOS:000077690200017 PM 9915636 ER PT J AU Chervitz, SA Aravind, L Sherlock, G Ball, CA Koonin, EV Dwight, SS Harris, MA Dolinski, K Mohr, S Smith, T Weng, S Cherry, JM Botstein, D AF Chervitz, SA Aravind, L Sherlock, G Ball, CA Koonin, EV Dwight, SS Harris, MA Dolinski, K Mohr, S Smith, T Weng, S Cherry, JM Botstein, D TI Comparison of the complete protein sets of worm and yeast: Orthology and divergence SO SCIENCE LA English DT Review ID NEMATODE CAENORHABDITIS-ELEGANS; CELL-LINEAGE; GENES; IDENTIFICATION; GENERATION; CEREVISIAE; SEQUENCES; DOMAINS; HOMOLOG; CYCLE AB Comparative analysis of predicted protein sequences encoded by the genomes of Caenorhabditis elegans and Saccharomyces cerevisiae suggests that most of the core biological functions are carried out by orthologous proteins (proteins of different species that can be traced back to a common ancestor) that occur in comparable numbers. The specialized processes of signal transduction and regulatory control that are unique to the multicellular worm appear to use novel proteins, many of which re-use conserved domains. Major expansion of the number of some of these domains seen in the worm may have contributed to the advent of multicellularity, The proteins conserved in yeast and worm are Likely to have orthologs throughout eukaryotes; in contrast, the proteins unique to the worm may well define metazoans. C1 Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. Boston Univ, Dept Biomed Engn, Boston, MA 02115 USA. RP Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. RI Sherlock, Gavin/B-1831-2009; Sherlock, Gavin/E-9110-2012 FU NHGRI NIH HHS [U41 HG001315, HG 00044, HG01315, K22 HG000044, P41 HG001315, P41 HG001315-16, T32 HG000044] NR 40 TC 329 Z9 338 U1 1 U2 6 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD DEC 11 PY 1998 VL 282 IS 5396 BP 2022 EP 2028 DI 10.1126/science.282.5396.2022 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 147BB UT WOS:000077467100036 PM 9851918 ER PT J AU Braddon, VR Chiorini, JA Wang, SL Kotin, RM Baum, BJ AF Braddon, VR Chiorini, JA Wang, SL Kotin, RM Baum, BJ TI Adenoassociated virus-mediated transfer of a functional water channel into salivary epithelial cells in vitro and in vivo SO HUMAN GENE THERAPY LA English DT Article ID INTEGRAL MEMBRANE-PROTEIN; SITE-SPECIFIC INTEGRATION; GENE-TRANSFER; TRANSGENE EXPRESSION; ADENOVIRAL VECTORS; AQUAPORIN CHIP; MOUSE-LIVER; AAV VECTORS; IN-VIVO; GLANDS AB Aquaporin 1 (AQP1) is the archetypal member of a family of integral membrane proteins that function as water channels. Previously we have shown that this protein can be expressed transiently from a recombinant adenovirus (AdhAQP1) in vitro in different epithelial cell lines, and in vivo in rat submandibular glands. In the present study we have constructed a recombinant adenoassociated virus (rAAV) containing the human aquaporin 1 gene (rAAVhAQP1). rAAVhAQP1 was produced at relatively high titers. approximate to 10(11)-10(12) particles/ml and approximate to 10(8)-10(9) transducing units/ml. We show that the rAAVhAQP1 can transduce in vitro four epithelial cell lines of different origins, at a level sufficient to detect the recombinant hAQP1 protein by either Western blot or confocal microscopic analysis. The recombinant hAQP1 was correctly targeted to the plasma membranes in all cell lines. Function of the recombinant hAQP1 was measured as fluid flow, in response to an osmotic gradient, across a monolayer of transduced epithelial cells. The data show that even at a low level of transduction, typically approximate to 10% of the cells in the monolayer, transepithelial fluid movement is enhanced about threefold above basal levels, In addition, we report that rAAVhAQP1 can transduce epithelial cells in the salivary glands and liver of mice in vivo. These results suggest that rAAVs may be useful gene transfer vectors to direct the production of functional transgenes in salivary epithelial cell types. C1 NIDCR, Gene Therapy & Therapuet Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Mol Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, Gene Therapy & Therapuet Branch, NIH, Bethesda, MD 20892 USA. RI kotin, robert/B-8954-2008 NR 45 TC 36 Z9 37 U1 1 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 DEC 10 PY 1998 VL 9 IS 18 BP 2777 EP 2785 DI 10.1089/hum.1998.9.18-2777 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 150JK UT WOS:000077661600013 PM 9874275 ER PT J AU Roseboom, PH Namboodiri, MAA Zimonjic, DB Popescu, NC Rodriguez, IR Gastel, JA Klein, DC AF Roseboom, PH Namboodiri, MAA Zimonjic, DB Popescu, NC Rodriguez, IR Gastel, JA Klein, DC TI Natural melatonin 'knockdown' in C57BL/6J mice: rare mechanism truncates serotonin N-acetyltransferase SO MOLECULAR BRAIN RESEARCH LA English DT Article DE pineal; retina; C3H/HeJ; circadian; RNA splicing; cryptic splice acceptor site ID HYDROXYINDOLE-O-METHYLTRANSFERASE; PINEAL-GLAND; INDOLE METABOLISM; MOUSE STRAINS; GENE; EXPRESSION; LOCALIZATION; PROTEINS; RHYTHM; LIGHT AB Pineal melatonin synthesis (serotonin --> N-acetylserotonin --> melatonin) is severely compromised in most inbred strains of mice, in many cases because serotonin is not acetylated by serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT). We have found that in the C57BL/6J strain, AANAT mRNA encodes a severely truncated AANAT protein, because a pseudo-exon containing a stop codon is spliced in. This is the first identification of a natural mutation which knocks down melatonin synthesis. The decrease in melatonin signaling may have been a selective factor in the development of laboratory strains of mice because melatonin can inhibit reproduction and modify circadian rhythmicity. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NEI, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), NICHHD, Sect Neuroendocrinol, Dev Neurobiol Lab, NIH, Bldg 49,Room 6A 82, Bethesda, MD 20892 USA. NR 45 TC 116 Z9 118 U1 0 U2 2 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 DEC 10 PY 1998 VL 63 IS 1 BP 189 EP 197 DI 10.1016/S0169-328X(98)00273-3 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 147MA UT WOS:000077570500019 ER PT J AU Hildesheim, A Schiffman, M Brinton, LA Fraumeni, JF Herrero, R Bratti, MC Schwartz, P Mortel, R Barnes, W Greenberg, M McGowan, L Scott, DR Martin, M Herrera, JE Carrington, M AF Hildesheim, A Schiffman, M Brinton, LA Fraumeni, JF Herrero, R Bratti, MC Schwartz, P Mortel, R Barnes, W Greenberg, M McGowan, L Scott, DR Martin, M Herrera, JE Carrington, M TI p53 polymorphism and risk of cervical cancer SO NATURE LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Int Agcy Res Canc, F-69372 Lyon, France. Caja Costarriciense Seguro Social, San Jose, Costa Rica. Yale Univ, Sch Med, New Haven, CT 06519 USA. Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Grad Hosp Philadelphia, Philadelphia, PA 19146 USA. George Washington Univ, Med Ctr, Washington, DC 20037 USA. Kaiser Permanente, Portland, OR 97227 USA. NCI, Intramural Res Support Program, SAIC Frederick, FCRDC, Frederick, MD 21702 USA. RP Hildesheim, A (reprint author), NCI, Div Canc Epidemiol & Genet, 6130 Execut Blvd, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 5 TC 88 Z9 90 U1 0 U2 3 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW SN 0028-0836 J9 NATURE JI Nature PD DEC 10 PY 1998 VL 396 IS 6711 BP 531 EP 532 DI 10.1038/25040 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 147AY UT WOS:000077466800041 PM 9859989 ER PT J AU Boyes, J Byfield, P Nakatani, Y Ogryzko, V AF Boyes, J Byfield, P Nakatani, Y Ogryzko, V TI Regulation of activity of the transcription factor GATA-1 by acetylation SO NATURE LA English DT Article ID DNA-BINDING DOMAIN; HISTONE ACETYLTRANSFERASE; MEGAKARYOCYTIC DIFFERENTIATION; ZINC-FINGER; ACTIVATION; CHROMATIN; COMPLEX; CGATA-1; PROTEIN; CELLS AB Modification of histones, DNA-binding proteins found in chromatin, by addition of acetyl groups occurs to a greater degree when the histones are associated with transcriptionally active DNA(1,2). A breakthrough in understanding how this acetylation is mediated was the discovery that various transcriptional co-activator proteins have intrinsic histone acetyltransferase activity (for example, Gcn5p (ref. 3), PCAF(4), TAF(II)250 (ref. 5) and p300/ CBp(6,7)). These acetyltransferases also modify certain transcription factors (TFIIE beta, TFIIF, EKLF and p53 (refs 8-10)). GATA-1 is an important transcription factor in the haematopoietic lineage(11) and is essential for terminal differentiation of erythrocytes and megakaryocytes(12,13). It is associated in vivo with the acetyltransferase p300/CBP14, sere we report that GATA-1 is acetylated in vitro by p300. This significantly increases the amount of GATA-1 bound to DNA and alters the mobility of GATA-1-DNA complexes, suggestive of a conformational change in GATA-1. GATA-1 is also acetylated in vivo and acetylation directly stimulates GATA-1-dependent transcription. Mutagenesis of important acetylated residues shows that there is a relationship between the acetylation and in viva function of GATA-1. We propose that acetylation of transcription factors can alter interactions between these factors and DNA and among different transcription factors, and is an integral part of transcription and differentiation processes. C1 Inst Canc Res, Chester Beatty Labs, Sect Gene Funct & Regulat, London SW3 6JB, England. Hammersmith Hosp, MRC, Ctr Clin Sci, London W12 0NN, England. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Boyes, J (reprint author), Inst Canc Res, Chester Beatty Labs, Sect Gene Funct & Regulat, 237 Fulham Rd, London SW3 6JB, England. RI Ogryzko, Vasily/M-6665-2015 OI Ogryzko, Vasily/0000-0002-8548-1389 NR 27 TC 565 Z9 574 U1 3 U2 17 PU MACMILLAN MAGAZINES LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON, ENGLAND N1 9XW SN 0028-0836 J9 NATURE JI Nature PD DEC 10 PY 1998 VL 396 IS 6711 BP 594 EP 598 DI 10.1038/25166 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 147AY UT WOS:000077466800063 PM 9859997 ER PT J AU Imafuku, I Waragai, M Takeuchi, S Kanazawa, I Kawabata, M Mouradian, MM Okazawa, H AF Imafuku, I Waragai, M Takeuchi, S Kanazawa, I Kawabata, M Mouradian, MM Okazawa, H TI Polar amino acid-rich sequences bind to polyglutamine tracts SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID DOPAMINE-RECEPTOR GENE; INTRANUCLEAR INCLUSIONS; PROTEIN; HUNTINGTIN; BRAIN; TRANSCRIPTION; ACTIVATION; INTERACTS; HOMOLOG AB Polyglutamine tracts are found in different proteins including transcription factors and cofactors as well as in triplet repeat disease gene products. To characterize the protein motif that binds to the polyglutamine tract, we screened a human embryonic brain cDNA library with the polyglutamine tract of Brn-2 as bait using the yeast two-hybrid method. All six isolated clones encoding polyglutamine tract binding proteins were rich in polar amino acids. Three of these clones could form polar helical structures. These observations suggest that polar amino acid-rich sequences are essential for binding to the polyglutamine tract. (C) 1998 Academic Press. C1 Univ Tokyo, Grad Sch Med, Dept Neurol, Grp Mol Neurobiol,Bunkyo Ku, Tokyo 113, Japan. Japanese Fdn Canc Res, Inst Canc, Dept Biochem, Toshima Ku, Tokyo 170, Japan. NINDS, Genet Pharmacol Unit, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Okazawa, H (reprint author), Univ Tokyo, Grad Sch Med, Dept Neurol, Grp Mol Neurobiol,Bunkyo Ku, 7-3-1 Hongo, Tokyo 113, Japan. OI Mouradian, M. Maral/0000-0002-9937-412X NR 20 TC 20 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 9 PY 1998 VL 253 IS 1 BP 16 EP 20 DI 10.1006/bbrc.1998.9725 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 148VU UT WOS:000077554900003 PM 9875212 ER PT J AU Sabol, SL Li, RN Lee, TY Abdul-Khalek, R AF Sabol, SL Li, RN Lee, TY Abdul-Khalek, R TI Inhibition of apoptosis-associated DNA fragmentation activity in nonapoptotic cells: The role of DNA fragmentation factor-45 (DFF45/ICAD) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID FAS-MEDIATED APOPTOSIS; T-LYMPHOCYTES; EXTRACTS; REQUIREMENT; ACTIVATION; INDUCTION; PROTEASES; EVENTS; DEATH; BCL-2 AB We have investigated the mechanism whereby nuclear DNA fragmentation activity emerging during early apoptosis is inhibited during normal cell life. In a cell free system, cytosol fractions from diverse non-apoptotic human cell lines (Jurkat T-cell leukemia, HeLa carcinoma, SK-N-MC neuroblastoma, and WI-38 embryonic lung fibroblast) potently neutralized the nuclear DNA fragmentation activity of cytosol from apoptotic anti-Fas treated Jurkat cells. Recombinant human DNA fragmentation factor 45 kDa subunit (DFF45/ICAD), an inhibitor of the caspase-activated DNase DFF40/CAD, substituted for healthy cytosol in inhibiting DNA fragmentation, An antiserum against human DFF45 detected 44 and 34 kDa proteins (major and minor, respectively) in the cytosols but not in the nuclear or membrane fractions of various cultured human cells. Cytosols depleted of DFF45/ICAD by immunoadsorption had little or no inhibitor of nuclear DNA fragmentation activity and no caspase-activated DNA fragmentation activity. We conclude that immunoreactive DFF45/ICAD is the principal inhibitor of apoptotic DNase activity in the cytosol of healthy cells, (C) 1998 Academic Press. C1 NHLBI, Lab Biochem Genet, Bethesda, MD 20892 USA. RP Sabol, SL (reprint author), NHLBI, Lab Biochem Genet, Bldg 36,Room 1C06, Bethesda, MD 20892 USA. NR 26 TC 40 Z9 40 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 DEC 9 PY 1998 VL 253 IS 1 BP 151 EP 158 DI 10.1006/bbrc.1998.9770 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 148VU UT WOS:000077554900027 PM 9875236 ER PT J AU Luo, XC Kato, RH Collins, JR AF Luo, XC Kato, RH Collins, JR TI Dynamic flexibility of protein-inhibitor complexes: A study of the HIV-1 protease KNI-272 complex SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID BINDING DOMAIN; MD SIMULATIONS; RELAXATION; ALLOPHENYLNORSTATINE; SPECTROSCOPY; TRANSITION; MOTIONS; STATE; WATER AB The dynamics and flexibility of protein-ligand complexes is central to understanding and predicting binding geometries and energetics. We have calculated various measures of the dynamic flexibility of a pseudo-C2-symmetric protein, HIV-1 protease, complexed with the asymmetric inhibitor KNI-272 based on molecular dynamics simulations. This system is expected to be an excellent candidate for observing asymmetric dynamics between the two monomers due to the differences in the interactions between the two monomers of the protease and the inhibitor. Experimental methods have thus far been unable to observe the expected asymmetry in this system. Our calculated results are in excellent agreement with the available experimental data for the main-chain order parameters from a parallel N-15 NMR study of the same inhibitor-protein complex, as well as the Debye-Waller temperature factors from X-ray crystallography. In our simulations, asymmetry between the monomers is found almost exclusively in the side-chain order parameters of the inhibitor and protease (especially residues 84A and 84B), for which experimental data are not yet available. We analyze the dynamic information obtained from the different methods and discuss protein-ligand interactions responsible for the dynamical behavior of the complex. C1 NCI, SAIC Frederick, Frederick Biomed Supercomp Ctr, Frederick, MD 21702 USA. RP Collins, JR (reprint author), NCI, SAIC Frederick, Frederick Biomed Supercomp Ctr, 430 Miller Dr, Frederick, MD 21702 USA. NR 33 TC 8 Z9 8 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 9 PY 1998 VL 120 IS 48 BP 12410 EP 12418 DI 10.1021/ja9824066 PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 146ZM UT WOS:000077463800004 ER PT J AU Towler, EM Gulnik, SV Bhat, TN Xie, D Gustschina, E Sumpter, TR Robertson, N Jones, C Sauter, M Mueller-Lantzsch, N Debouck, C Erickson, JW AF Towler, EM Gulnik, SV Bhat, TN Xie, D Gustschina, E Sumpter, TR Robertson, N Jones, C Sauter, M Mueller-Lantzsch, N Debouck, C Erickson, JW TI Functional characterization of the protease of human endogenous retrovirus, K10: Can it complement HIV-1 protease? SO BIOCHEMISTRY LA English DT Article ID MUTAGENESIS; EXPRESSION; PROTEINASE; ALLOPHENYLNORSTATINE; DISSOCIATION; ASSOCIATION; INHIBITORS; GENERATION; SEQUENCES; PARTICLES AB TO investigate the biochemical properties of the protease encoded by the human endogenous retrovirus, K10 (HERV-K), 213 amino acids of the 3'-end of the HERV-K protease (PR) open reading frame were expressed in Escherichia coli. Autocatalytic cleavage of the expressed polypeptide resulted in an 18.2 kDa protein which was shown to be proteolytically active against a fluorogenic peptide used as a substrate for HIV-1 protease. On the basis of sequence homology and molecular modeling, the 106 N-terminal amino acids of HERV-K PR were predicted to comprise a retroviral protease core domain. An 11.6 kDa protein corresponding to this region was expressed and shown to be a fully functional enzyme. The 11.6 kDa domain of HERV-K PR is unusually stable over a wide pH range, exhibits optimal catalytic activity between pH 4.0 and 5.0, and exists as a dimer at pH 7.0 with a K-d of 50 mu M. Like HIV-1 PR, the HERV-K PR core domain is activated by high salt concentrations and processes HIV-1 matrix-capsid polyprotein at the authentic HIV-1 PR recognition site. However, both the 18.2 and 11.6 kDa forms of HERV-K PR were highly resistant to a number of clinically useful HIV-1 PR inhibitors, including ritonavir, indinavir, and saquinavir. This raises the possibility that HERV-K PR may complement HIV-1 PR during infection, and could have implications for protease inhibitor therapy and drug resistance. C1 NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Prot Chem Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Struct Biochem Program, Frederick, MD 21702 USA. SmithKline Beecham Pharmaceut, Dept Mol Genet, King Of Prussia, PA 19406 USA. Univ Saarlandes Kliniken, Inst Med Mikrobiol & Hyg, Abt Virol, D-66421 Homburg, Germany. RP Towler, EM (reprint author), NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Prot Chem Lab, POB B, Frederick, MD 21702 USA. FU NIGMS NIH HHS [R01 GM50579] NR 26 TC 36 Z9 37 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 8 PY 1998 VL 37 IS 49 BP 17137 EP 17144 DI 10.1021/bi9818927 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148WD UT WOS:000077555800005 PM 9860826 ER PT J AU Huster, D Arnold, K Gawrisch, K AF Huster, D Arnold, K Gawrisch, K TI Influence of docosahexaenoic acid and cholesterol on lateral lipid organization in phospholipid mixtures SO BIOCHEMISTRY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; ACYL-CHAIN; ORIENTATIONAL ORDER; NMR-SPECTROSCOPY; PHASE-EQUILIBRIA; DISK MEMBRANES; MAGIC-ANGLE; PHOSPHATIDYLCHOLINE; BILAYERS; UNSATURATION AB We investigated lateral lipid organization in membranes with a lipid composition relevant to neural and retinal membranes [phosphatidylcholine (PC)/phosphatidylethanolamine (PE)/phosphatidylserine (PS)/cholesterol, 4/4/1/1, mol/mol/mol/mol]. The mixed-chain phospholipids contained saturated stearic acid (18:0) in the sn-l position and the monounsaturated oleic acid (18:1) or polyunsaturated docosahexaenoic acid (22:6) in sn-2. Lateral lipid organization was evaluated by H-2 NMR order parameter measurements on stearic acid of all individual types of phospholipids in the mixture and, through a novel approach, two-dimensional NOESY H-1 NMR spectroscopy with magic angle spinning (MAS). The docosahexaenoic acid chain order was evaluated from H-1 NMR chain signal MAS-sideband intensities. Averaged over all lipids, the cholesterol-induced increase in sn-1 chain order is 2-fold larger in monounsaturated than in polyunsaturated lipids, and the order of both saturated and polyunsaturated hydrocarbon chains increases. Addition of cholesterol increases lipid order in the sequence 18:0-18:1 PE > 18:0-18:1 PC > 18:0-18:1 PS for the monounsaturated and 18:0-22:6 PC much greater than 18:0-22:6 PE > 18:0-22:6 PS for polyunsaturated mixtures. The variation of order parameters between lipid species suggests that cholesterol induces the formation of lipid microdomains with a headgroup and chain unsaturation-dependent lipid composition. The preferential interaction between cholesterol and polyunsaturated 18:0-22:6 PC, followed by 18:0-22:6 PE and 18:0-22:6 PS, was confirmed by H-1 MAS NOESY cross-relaxation rate differences. Furthermore, cholesterol preferentially associates with saturated chains in mixed-chain lipids reflected by higher saturated chain-to-cholesterol cross-relaxation rates. We propose that cholesterol forms PC-enriched microdomains in the polyunsaturated 18:0-22:6 PC/18:0-22:6 PE/18:0-22:6 PS/cholesterol membranes in which the saturated sn-l chains are preferentially oriented toward the cholesterol molecules. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. Univ Leipzig, Inst Med Phys & Biophys, D-04103 Leipzig, Germany. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 12420 Parklawn Dr,Room 158, Rockville, MD 20852 USA. EM gawrisch@helix.nih.gov NR 65 TC 196 Z9 200 U1 1 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 8 PY 1998 VL 37 IS 49 BP 17299 EP 17308 DI 10.1021/bi980078g PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148WD UT WOS:000077555800023 PM 9860844 ER PT J AU Shears, SB AF Shears, SB TI The versatility of inositol phosphates as cellular signals SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review DE inositol phosphate; signal transduction; second messenger ID PROTEIN-KINASE-C; CAPACITATIVE CALCIUM-ENTRY; ADRENAL GLOMERULOSA CELLS; CYSTIC-FIBROSIS AIRWAY; 1,4,5-TRISPHOSPHATE 3-KINASE; RAT-LIVER; ENDOPLASMIC-RETICULUM; PLASMA-MEMBRANE; ACINAR-CELLS; MYOINOSITOL 1,3,4,5,6-PENTAKISPHOSPHATE AB Cells from across the phylogenetic spectrum contain a variety of inositol phosphates. Many different functions have been ascribed to this group of compounds. However, it is remarkable how frequently several of these different inositol phosphates have been linked to various aspects of signal transduction. Therefore, this review assesses the evidence that inositol phosphates have evolved into a versatile family of second messengers. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIEHS, Inositide Signalling Sect, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Shears, SB (reprint author), NIEHS, Inositide Signalling Sect, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov NR 200 TC 130 Z9 130 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD DEC 8 PY 1998 VL 1436 IS 1-2 BP 49 EP 67 DI 10.1016/S0005-2760(98)00131-3 PG 19 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 176NZ UT WOS:000079159300005 PM 9838040 ER PT J AU Balla, T AF Balla, T TI Phosphatidylinositol 4-kinases SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review ID EPIDERMAL GROWTH-FACTOR; YEAST SACCHAROMYCES-CEREVISIAE; PROTEIN-KINASE-C; ADRENAL GLOMERULOSA CELLS; LIGHT-CHAIN KINASE; PHOSPHOLIPASE-C; BOVINE BRAIN; A431 CELLS; RAT-BRAIN; PHOSPHOINOSITIDE KINASES C1 NIH, Endocrinol & Reprod Res Branch, Bethesda, MD 20892 USA. RP Balla, T (reprint author), NIH, Endocrinol & Reprod Res Branch, 49 Convent Dr, Bethesda, MD 20892 USA. EM tambal@box-t.nih.gov OI Balla, Tamas/0000-0002-9077-3335 NR 125 TC 84 Z9 84 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI BBA-Mol. Cell. Biol. Lipids PD DEC 8 PY 1998 VL 1436 IS 1-2 BP 69 EP 85 DI 10.1016/S0005-2760(98)00134-9 PG 17 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 176NZ UT WOS:000079159300006 PM 9838049 ER PT J AU Bella, JN Devereux, RB Roman, MJ O'Grady, MJ Welty, TK Lee, ET Fabsitz, RR Howard, BV AF Bella, JN Devereux, RB Roman, MJ O'Grady, MJ Welty, TK Lee, ET Fabsitz, RR Howard, BV CA Strong Heart Study Investigators TI Relations of left ventricular mass to fat-free and adipose body mass - The strong heart study SO CIRCULATION LA English DT Article DE obesity; echocardiography; hypertension; hypertrophy ID CORONARY-ARTERY DISEASE; X-RAY ABSORPTIOMETRY; BIOELECTRICAL-IMPEDANCE; AMERICAN-INDIANS; BLOOD-PRESSURE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ESSENTIAL-HYPERTENSION; NORMOTENSIVE CHILDREN; ADULTS AB Background-It is unclear whether increased left ventricular (LV) mass in overweight individuals is related to their adiposity or to greater fat-free mass (FFM). Methods and Results-We compared echocardiographic LV mass to FFM and adipose body mass by bioelectric impedance and to anthropometric measurements in 3107 American Indian participants in the Strong Heart Study. In men and women, the relations of LV mass and FFM (r=0.37 and 0.38, P<0.001) were closer (P<0.05 to <0.001) than they were with adipose mass, waist/hip ratio, body mass index, systolic blood pressure, height, or height(2.7). Regression analyses showed that in men LV mass had the strongest independent relation with FFM, followed by systolic blood pressure and age tall P<0.001); in women, LV mass was related to FFM more strongly than it was to systolic blood pressure, age tall P<0.001), and diabetes (P=0.012). Adipose mass had no independent relation to LV mass. When waist/hip ratio or body mass index were substituted for adipose mass, LV mass was independently related to FFM (P<0.001) and body mass index (P=0.02) but not to waist/hip ratio in men and was independently related to FFM and waist/hip ratio (both P<0.001) but not to body mass index in women. Using 97.5 percentile gender-specific partitions for LV mass/FFM in reference individuals, we found that LV hypertrophy occurred in 20.8% of Strong Heart Study participants with hypertension, overweight, or diabetes compared with 10.5% and 16.7% by LV mass indexed for body surface area or height(2.7). Conclusions-LV mass is more strongly related to FFM than to adipose mass, waist/hip ratio, body mass index, or height-based surrogates for lean body weight; LV mass/FFM criteria may increase sensitivity to detect LV hypertrophy. C1 New York Hosp, Cornell Med Ctr, Div Cardiol, Dept Med, New York, NY 10021 USA. Indian Hlth Serv, Aberdeen Area, Rapid City, SD USA. Univ Oklahoma, Sch Publ Hlth Serv, Oklahoma City, OK USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Medlant Res Inst, Washington, DC USA. RP Devereux, RB (reprint author), New York Hosp, Cornell Med Ctr, Div Cardiol, Dept Med, Box 222, New York, NY 10021 USA. FU NHLBI NIH HHS [U01-HL41642, U01-HL41652, U01-HL41654] NR 60 TC 142 Z9 144 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 8 PY 1998 VL 98 IS 23 BP 2538 EP 2544 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 144QF UT WOS:000077325600007 PM 9843460 ER PT J AU Casey, M Mah, C Merliss, AD Kirschner, LS Taymans, SE Denio, AE Korf, B Irvine, AD Hughes, A Carney, JA Stratakis, CA Basson, CT AF Casey, M Mah, C Merliss, AD Kirschner, LS Taymans, SE Denio, AE Korf, B Irvine, AD Hughes, A Carney, JA Stratakis, CA Basson, CT TI Identification of a novel genetic locus for familial cardiac myxomas and Carney complex SO CIRCULATION LA English DT Article DE genetics; cardiovascular diseases; growth substances; genes; myxoma ID MULTIPLE; LINKAGE; INTERLEUKIN-6; HISTOGENESIS; MUTATIONS; NEOPLASIA AB Background-Intracardiac myxomas are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. In the autosomal dominant syndrome Carney complex, intracardiac myxomas arise in the setting of lentiginosis and other lesions associated with cutaneous hyperpigmentation, extracardiac myxomas, and nonmyxomatous tumors. Genetic factors that regulate cardiac tumor growth remain unknown. Methods and Results-We used the molecular genetic techniques of linkage analysis to study 4 kindreds affected by Carney complex to determine the genetic basis of this syndrome. Our investigation confirmed genetic heterogeneity of Carney complex, Moreover, genetic linkage analysis with polymorphic short tandem repeats on the long arm of chromosome 17 revealed maximal pairwise LOD scores of 5.9, 1.5, 1.8, and 2.9 for families YA, YB, YC01, and YC11, respectively. Haplotype analysis excluded a founder effect at this locus. These data identify a major 17 cM locus on chromosome 17q2 that contains the Carney complex disease gene. Conclusions-The ultimate identification and analysis of the Carney complex disease gene at this human chromosome 17q2 locus will facilitate diagnosis and treatment of cardiac myxomas and will foster new concepts in regulation of cardiac cell growth and differentiation. C1 Cornell Univ, Coll Med, New York Hosp, Dept Med,Cardiol Div, New York, NY 10021 USA. Cornell Univ, Coll Med, New York Hosp, Dept Cell Biol & Anat, New York, NY 10021 USA. MeritCare Heart Serv, Pacing & Electrophysiol, Fargo, ND USA. NICHHD, NIH, Bethesda, MD 20892 USA. Ctr Arthrit & Rheumat Dis, Virginia Beach, VA USA. Harvard Univ, Childrens Hosp, Sch Med, Dept Genet, Boston, MA 02115 USA. Royal Victoria Hosp, Dept Dermatol, Belfast BT12 6BA, Antrim, North Ireland. Queens Univ, Dept Med Genet, Belfast, Antrim, North Ireland. Mayo Clin, Dept Pathol, Rochester, MN USA. RP Basson, CT (reprint author), Cornell Univ, Coll Med, New York Hosp, Dept Med,Cardiol Div, Starr 4,525 E 68th St, New York, NY 10021 USA. EM ctbasson@mail.med.cornell.edu OI Irvine, Alan/0000-0002-9048-2044 FU NHLBI NIH HHS [HL-03468] NR 29 TC 132 Z9 139 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 8 PY 1998 VL 98 IS 23 BP 2560 EP 2566 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 144QF UT WOS:000077325600010 PM 9843463 ER PT J AU Bernstein, HD AF Bernstein, HD TI Membrane protein biogenesis: The exception explains the rules SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID SIGNAL RECOGNITION PARTICLE; ESCHERICHIA-COLI; ENDOPLASMIC-RETICULUM; M13 PROCOAT; CHAIN-LENGTH; TRANSLOCATION; SEQUENCE; INSERTION; MUTATIONS; EXPORT C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NR 33 TC 8 Z9 8 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 DEC 8 PY 1998 VL 95 IS 25 BP 14587 EP 14589 DI 10.1073/pnas.95.25.14587 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146NJ UT WOS:000077436700001 PM 9843931 ER PT J AU Chadwick, RS AF Chadwick, RS TI Compression, gain, and nonlinear distortion in an active cochlear model with subpartitions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE multiple scale asymptotics; outer hair cell saturation ID GUINEA-PIG COCHLEA; OUTER HAIR-CELLS; BASILAR-MEMBRANE; MECHANICS; CHINCHILLA; RESPONSES; INNER; BASE; EAR AB The propagation of inhomogeneous, weakly nonlinear waves is considered in a cochlear model having two degrees of freedom that represent the transverse motions of the tectorial and basilar membranes within the organ of Corti. It is assumed that nonlinearity arises from the saturation of outer hair cell active force generation. I use multiple scale asymptotics and treat nonlinearity as a correction to a linear hydroelastic wave. The resulting theory is used to explain experimentally observed features of the response of the cochlear partition to a pure tone, including: the amplification of the response in a healthy cochlea vs a dead one; the less than linear growth rate of the response to increasing sound pressure level; and the amount of distortion to be expected at high and low frequencies at basal and apical locations, respectively. I also show that the outer hair cell nonlinearity generates retrograde waves. C1 NIDCD, Auditory Mech Sect, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Chadwick, RS (reprint author), NIDCD, Auditory Mech Sect, Lab Cellular Biol, NIH, Bldg 9,Room 1E-116,9 Ctr Dr,MSC 0922, Bethesda, MD 20892 USA. NR 21 TC 14 Z9 14 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 DEC 8 PY 1998 VL 95 IS 25 BP 14594 EP 14599 DI 10.1073/pnas.95.25.14594 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146NJ UT WOS:000077436700004 PM 9843934 ER PT J AU Conway, JF Cheng, N Zlotnick, A Stahl, SJ Wingfield, PT Steven, AC AF Conway, JF Cheng, N Zlotnick, A Stahl, SJ Wingfield, PT Steven, AC TI Localization of the N terminus of hepatitis B virus capsid protein by peptide-based difference mapping from cryoelectron microscopy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hepatitis B virus core antigen; virus capsid structure; three-dimensional image reconstruction ID X-RAY CRYSTALLOGRAPHY; HERPES-SIMPLEX VIRUS; CORE-PROTEIN; ELECTRON CRYOMICROSCOPY; 3-DIMENSIONAL RECONSTRUCTION; C-TERMINUS; PARTICLES; ANTIGEN; IMMUNOGENICITY; DETERMINES AB Recently, cryoelectron microscopy of isolated macromolecular complexes has advanced to resolutions below 10 Angstrom, enabling direct visualization of alpha-helical secondary structure. To help correlate such density maps with the amino acid sequences of the component proteins, we advocate peptide-based difference mapping, i.e., insertion of peptides, approximate to 10 residues long, at targeted points in the sequence and visualization of these peptides as bulk labels in cryoelectron microscopy-derived difference maps. As proof of principle, we have appended an extraneous octapeptide at the N terminus of hepatitis B virus capsid protein and determined its location on the capsid surface by difference imaging at 11 Angstrom resolution Hepatitis B virus capsids are icosahedral particles, approximate to 300 Angstrom in diameter, made up of T-shaped dimers (subunit M-r, 16-21 kDa, depending on construct). The stems of the Ts protrude outward as spikes, whereas the crosspieces pack to form the contiguous shell. The two N termini per dimer reside on either side of the spike-stem, at the level at which it enters the shell. This location is consistent with formation of the known intramolecular disulfide bond between the cysteines at positions 61 and -7 (in the residual propeptide) in the "e-antigen" form of the capsid protein and has implications for why this clinically important antigen remains unassembled in vivo. C1 NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bldg 6,Room B2-34,MSC 2717, Bethesda, MD 20892 USA. RI Conway, James/A-2296-2010 OI Conway, James/0000-0002-6581-4748 NR 31 TC 29 Z9 30 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 DEC 8 PY 1998 VL 95 IS 25 BP 14622 EP 14627 DI 10.1073/pnas.95.25.14622 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146NJ UT WOS:000077436700009 PM 9843939 ER PT J AU Komissarova, N Kashlev, M AF Komissarova, N Kashlev, M TI Functional topography of nascent RNA in elongation intermediates of RNA polymerase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ESCHERICHIA-COLI; TRANSCRIPT CLEAVAGE; TERNARY COMPLEXES; CHAIN ELONGATION; DNA; TERMINATION; SITE; INITIATION; PROMOTER; BINARY AB To determine the dynamics of transcript extrusion from Escherichia coli RNA polymerase (RNAP), we used degradation of the RNA by RNases T1 and A in a series of consecutive elongation complexes (ECs). In intact ECs, even extremely high doses of the RNases were unable to cut the RNA closer than 14-16 nt from the 3' end. Our results prove that ail of the cuts detected within the 14-nt zone are derived from the EC that is denatured during inactivation of the RNases. The protected zone monotonously translocates along the RNA after addition of new nucleotides to the transcript. The upstream region of the RNA heading toward the 5' end is cleaved and dissociated from the EC, with no effect on the stability and activity of the EC. Most of the current data suggest that an 8- to 10-nt RNA DNA hybrid is formed in the EC. Here, we show that an 8- to 10-nt RNA obtained by truncating the RNase-generated products further with either GreB or pyrophosphate is sufficient for the high stability and activity of the EC. This result suggests that the transcript-RNAP interaction that is required for holding the EC together can be limited to the RNA region involved in the 8- to 10-nt RNA.DNA hybrid. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Kashlev, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. FU NIGMS NIH HHS [GM49242] NR 33 TC 68 Z9 69 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 8 PY 1998 VL 95 IS 25 BP 14699 EP 14704 DI 10.1073/pnas.95.25.14699 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146NJ UT WOS:000077436700022 PM 9843952 ER PT J AU Vindevoghel, L Lechleider, RJ Kon, A de Caestecker, MP Uitto, J Roberts, AB Mauviel, A AF Vindevoghel, L Lechleider, RJ Kon, A de Caestecker, MP Uitto, J Roberts, AB Mauviel, A TI SMAD3/4-dependent transcriptional activation of the human type VII collagen gene (COL7A1) promoter by transforming growth factor beta SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene expression; signal transduction; transcription factors ID TUMOR-SUPPRESSOR; MAMMALIAN-CELLS; SMAD PROTEINS; DNA; RECEPTOR; BINDING; PHOSPHORYLATION; SMAD4/DPC4; ANTAGONIST; EXPRESSION AB The human type VII collagen gene (COL7A1) recently has been identified as an immediate-early response gene for transforming growth factor beta (TGF-beta)/SMAD signaling pathway. In this study, by using MDA-MB-468 SMAD4-/- breast carcinoma cells, we demonstrate that expression of SMAD4 is an absolute requirement for SMAD-mediated promoter activity. We also demonstrate that the SMAD binding sequence (SBS) representing the TGF-beta response element in the region -496/-444 of the COL7A1 promoter functions as an enhancer in the context of a heterologous promoter. Electrophoretic mobility-shift assays with nuclear extracts from COS-1 cells transfected with expression vectors for SMADs 1-5 indicate that SMAD3 forms a complex with a migration similar to that of the endogenous TGF-beta-specific complex observed in fibroblast extracts. Electrophoretic mobility-shift assays using recombinant glutathione S-transferase-SMAD fusion proteins indicate that both SMAD4 and C-terminally truncated SMAD3 but not SMAD2, can bind the COL7A1 SBS. Coexpression of SMAD3 and SMAD4 in COS-1 cells leads to the formation of two complexes: a DNA/protein complex containing SMAD3 alone and another slower-migrating complex containing both SMAD3 and SMAD4, the latter complex not being detected in fibroblasts. Maximal transactivation of COL7A1 SBS-driven promoters in either MDA-MB-468 carcinoma cells or fibroblasts requires concomitant overexpression of SMAD3 and SMAD4. These data may represent the first identification of a functional homomeric SMAD3 complex regulating a human gene. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Mol Pharmacol & Biochem, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Jefferson Inst Mol Med, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Mauviel, A (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dept Dermatol & Cutaneous Biol, 233 S 10th St,Room 430, Philadelphia, PA 19107 USA. EM alain.mauviel@mail.tju.edu RI MAUVIEL, Alain/F-6251-2013 FU NIAMS NIH HHS [R01-AR41439, P01-AR38923, R29-AR43751, R01 AR041439, P01 AR038923] NR 39 TC 124 Z9 133 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 DEC 8 PY 1998 VL 95 IS 25 BP 14769 EP 14774 DI 10.1073/pnas.95.25.14769 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146NJ UT WOS:000077436700034 PM 9843964 ER PT J AU DeJarnette, JB Sommers, CL Huang, K Woodside, KJ Emmons, R Katz, K Shores, EW Love, PE AF DeJarnette, JB Sommers, CL Huang, K Woodside, KJ Emmons, R Katz, K Shores, EW Love, PE TI Specific requirement for CD3 epsilon in T cell development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ANTIGEN RECEPTOR; ALPHA-BETA; SURFACE EXPRESSION; TCR/CD3 COMPLEX; MICE; GENE; CD3-DELTA; CHAIN; REARRANGEMENT; THYMOCYTES AB T cell antigen receptor (TCR) and pre-TCR complexes are composed of clonotypic heterodimers in association with dimers of signal transducing invariant subunits (CD3 gamma, -delta, -epsilon, and zeta). The role of individual invariant subunits in T cell development has been investigated by generating gene-specific mutations in mice. Mutation of CD3 gamma, -delta, or zeta results in an incomplete block in development, characterized by reduced numbers of mature T cells that express low levels of TCR. In contrast, mature T cells are absent from CD3 epsilon(-/-) mice, and thymocyte development is arrested at the early CD4(-)CD8(-) stage, Although these results suggest that CD3 epsilon is essential for pre-TCR and TCR expression/function, their interpretation is complicated by the fact that expression of the CD3 gamma and CD3 delta genes also is reduced in CD3 epsilon(-/-) mice. Thus, it is unclear whether the phenotype of CD3 epsilon(-/-) mice reflects the collective effects of CD3 gamma, -delta, and -epsilon deficiency. By removing the selectable marker (PGH-NEO) from the targeted CD3 epsilon gene via Cre/loxP-mediated recombination, we generated mice that lack CD3 epsilon yet retain normal expression of the closely linked CD3 gamma and CD3 delta genes. These (CD3 epsilon(Delta/Delta)) mice exhibited an early arrest in T cell development, similar to that of CD3 epsilon(-/-) mice. Moreover, the developmental defect could be rescued by expression of a CD3 epsilon transgene. These results identify an essential role for CD3E in T cell development not shared by the CD3 gamma, CD3 delta, or zeta-family proteins and provide further evidence that PGK-NEO can influence the expression of genes in its proximity. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Hematol Prod, Bethesda, MD 20892 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bldg 6B,Room 2B-210 MSC-2780,9000 Rockville Pike, Bethesda, MD 20892 USA. EM pel@helix.nih.gov NR 28 TC 83 Z9 83 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 DEC 8 PY 1998 VL 95 IS 25 BP 14909 EP 14914 DI 10.1073/pnas.95.25.14909 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146NJ UT WOS:000077436700059 PM 9843989 ER PT J AU Wolfgang, M Park, HS Hayes, SF van Putten, JPM Koomey, M AF Wolfgang, M Park, HS Hayes, SF van Putten, JPM Koomey, M TI Suppression of an absolute defect in Type IV pilus biogenesis by loss-of-function mutations in pilT, a twitching motility gene in Neisseria gonorrhoeae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SOCIAL GLIDING MOTILITY; PSEUDOMONAS-AERUGINOSA; PATHOGENIC NEISSERIA; GONOCOCCUS INFECTION; MYXOCOCCUS-XANTHUS; CELL-SURFACE; PROTEIN; IDENTIFICATION; BINDING; LOCUS AB Type IV pili of Neisseria gonorrhoeae, the Gramnegative etiologic agent of gonorrhea, facilitate colonization of the human host. Gonococcal PilT, a protein belonging to a large family of molecules sharing a highly conserved nucleotide binding domain moth, has been shown to be dispensable for organelle biogenesis but essential for twitching motility and competence for genetic transformation. Here, we show that the defect in pilus biogenesis resulting from mutations in the pilC gene, encoding a putative pilus-associated adhesin for human tissue, can be suppressed by the absence of functional PilT. These data conclusively demonstrate that PilT influences the Type IV pilus biogenesis pathway and strongly suggest that organelle expression is a dynamic process. In addition, these Endings imply that PilT antagonizes the process of organelle biogenesis and provide the basis for a model for how the counteractive roles of PilT and PilC might relate mechanistically to the phenomenon of twitching motility. C1 Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. NIAID, Rocky Mt Labs, Microbial Struct & Funct Lab, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, Microscopy Branch, NIH, Hamilton, MT 59840 USA. RP Koomey, M (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, 6711 Med Sci Bldg 2, Ann Arbor, MI 48109 USA. EM mkoomey@umich.edu OI van Putten, Jos/0000-0002-4126-8172 FU NCRR NIH HHS [M01 RR000042, MO1 RR 00042]; NIAID NIH HHS [AI27837] NR 29 TC 104 Z9 107 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 DEC 8 PY 1998 VL 95 IS 25 BP 14973 EP 14978 DI 10.1073/pnas.95.25.14973 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146NJ UT WOS:000077436700070 PM 9844000 ER PT J AU Meiri, N Sun, MK Segal, Z Alkon, DL AF Meiri, N Sun, MK Segal, Z Alkon, DL TI Memory and long-term potentiation (LTP) dissociated: Normal spatial memory despite CA1 LTP elimination with Kv1.4 antisense SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ELEMENT-BINDING PROTEIN; WATER-MAZE; POTASSIUM CHANNELS; KINASE-II; RAT; HIPPOCAMPUS; MECHANISMS; DIVERSITY; CURRENTS; GRAFTS AB Long-term potentiation (LTP) in the hippocampal slice preparation has been proposed as an in vitro model for long-term memory. However, correlation of LTP with memory in living animals has been difficult to demonstrate. Furthermore, in the last few years evidence has accumulated that dissociate the two. Because potassium channels might determine the weight of synapses in networks, we studied the role of Kv1.4, a presynaptic A-type voltage-dependent K+ channel, in both memory and LTP. Reverse transcription-PCR and Western blot analysis with specific antibodies showed that antisense oligodeoxyribonucleotide to Kv1.4 microinjected intraventricularly into rat brains obstructed hippocampal Kv1.4 mRNA, "knocking down" the protein in the hippocampus. This antisense knockdown had no effect on rat spatial maze learning, memory, or exploratory behavior, but eliminated both early- and late-phase LTP and reduced paired-pulse facilitation (a presynaptic effect) in CA1 pyramidal neurons without affecting dentate gyrus LTP. This presynaptic Kv1.4 knockdown together with previous postsynaptic Kv1.1 knockdown demonstrates that CA1 LTP is neither necessary nor sufficient for rat spatial memory. C1 NIH, Lab Adapt Syst, Bethesda, MD 20892 USA. RP Alkon, DL (reprint author), NINDS, Lab Adapt Syst, 36 Convent Dr,MSC 4124,Bldg 36,Room 4A24, Bethesda, MD 20892 USA. RI yu, yan/C-2322-2012 NR 40 TC 59 Z9 60 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 8 PY 1998 VL 95 IS 25 BP 15037 EP 15042 DI 10.1073/pnas.95.25.15037 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146NJ UT WOS:000077436700081 PM 9844011 ER PT J AU Sham, JSK Song, LS Chen, Y Deng, LH Stern, MD Lakatta, EG Cheng, HP AF Sham, JSK Song, LS Chen, Y Deng, LH Stern, MD Lakatta, EG Cheng, HP TI Termination of Ca2+ release by a local inactivation of ryanodine receptors in cardiac myocytes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RAT VENTRICULAR MYOCYTES; CALCIUM-INDUCED RELEASE; SARCOPLASMIC-RETICULUM; HEART-CELLS; CONTROL MECHANISM; PURKINJE-CELL; CONTRACTION; CHANNELS; MUSCLE; TRANSIENTS AB In heart, a robust regulatory mechanism is required to counteract the regenerative Ca2+-induced Ca2+ release from the sarcoplasmic reticulum. Several mechanisms, including inactivation, adaptation, and stochastic closing of ryanodine receptors (RyRs) have been proposed, but no conclusive evidence has yet been provided. We probed the termination process of Ca2+ release by using a technique of imaging local Ca2+ release, or "Ca2+ spikes", at subcellular sites; and we tracked the kinetics of Ca2+ release triggered by L-type Ca2+ channels. At 0 mV, Ca2+ release occurred and terminated within 40 ms after the onset of clamp pulses (0 mV). Increasing the open-duration and promoting the reopenings of Ca2+ channels with the Ca2+ channel agonist, FPL64176, did not prolong or trigger secondary Ca2+ spikes, even though two-thirds of the sarcoplasmic reticulum Ca2+ remained available for release. Latency of Ca2+ spikes coincided with the first openings but not with the reopenings of L-type Ca2+ channels. After an initial maximal release, even a multi-fold increase in unitary Ca2+ current induced by a hyperpolarization to -120 mV failed to trigger additional release, indicating absolute refractoriness of RyRs. When the release was submaximal (e.g., at +30 mV), tail currents did activate additional. Ca2+ spikes; confocal images revealed that they originated from RyRs unfired during depolarization. These results indicate that Ca2+ release is terminated primarily by a highly localized, use-dependent inactivation of RyRs but not by the stochastic closing or adaptation of RyRs in intact ventricular myocytes. C1 Johns Hopkins Med Inst, Div Pulm & Crit Care Med, Baltimore, MD 21224 USA. NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Sham, JSK (reprint author), Johns Hopkins Med Inst, Div Pulm & Crit Care Med, Baltimore, MD 21224 USA. EM jsks@welchlink.welch.jhu.edu; chengp@grc.nia.nih.gov RI Song, Long-Sheng/D-5899-2012 FU NHLBI NIH HHS [HL-52652] NR 54 TC 134 Z9 140 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 DEC 8 PY 1998 VL 95 IS 25 BP 15096 EP 15101 DI 10.1073/pnas.95.25.15096 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146NJ UT WOS:000077436700091 PM 9844021 ER PT J AU Ma, W Liu, QY Jung, D Manos, P Pancrazio, JJ Schaffner, AE Barker, JL Stenger, DA AF Ma, W Liu, QY Jung, D Manos, P Pancrazio, JJ Schaffner, AE Barker, JL Stenger, DA TI Central neuronal synapse formation on micropatterned surfaces SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE self-assembled monolayer; synaptogenesis; synapsin I; spontaneous postsynaptic current; evoked postsynaptic current ID TISSUE-CULTURE POLYSTYRENE; EARLY POSTNATAL LIFE; HIPPOCAMPAL-NEURONS; EXCITATORY TRANSMITTER; NEUROBLASTOMA-CELLS; SERUM VITRONECTIN; GABA; ATTACHMENT; NETWORKS; FIBRONECTIN AB Controlling synapse formation is a key to patterning of neurons into functional circuits and networks in vitro. However, the process of synapse formation among neurons grown on artificial surfaces is relatively unstudied. We cultured embryonic hippocampal cells on trimethoxysilylpropyl-diethylenetriamine (DETA) and tridecafluoro-1,1,2,2-tetrahydrooctyl-1-dimethylchlorosilane (13F), and on patterns composed of DETA lines separated by 13F spaces. For comparison, neurons were concurrently plated on surfaces coated with uniform poly-D-lysine (PDL). Pre- and postsynaptic specializations were identified by immunostaining for synapsin I and microtubule-associated protein-2 (MAP-2). Spontaneous (SPCs) and evoked (EPCs) postsynaptic currents were recorded using dual patch-clamp techniques. We found that DETA promoted synapse formation, whereas evidence for synapse formation on 13F was barely detected. MAP-2(+) neuronal soma and rapidly growing dendrites were co-localized with synapsin I puncta faithfully along DETA lines. The expression of synapsin I puncta, and MAP-2(+) soma and dendrites correlated well with the appearance of SPCs. Synapsin I, MAP-2 and SPCs emerged together at days 3-4 and increased at day 7, when EPCs appeared. Synaptic signals occurring during 4-7 days in culture were all GABAergic. These results indicate that fully functional synapses are formed on silane surfaces, demonstrating the suitability of patterned silane surfaces for organizing synapse formation in vitro. (C) 1998 Published by Elsevier Science B.V. All rights reserved. C1 USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. Sci Applicat Int Corp, Rockville, MD 20850 USA. NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Stenger, DA (reprint author), USN, Res Lab, Ctr Biomol Sci & Engn, Code 9600,4555 Overlook Ave SW, Washington, DC 20375 USA. EM dstenger@cbmse.nrl.navy.mil RI Pancrazio, Joseph/M-3206-2015 OI Pancrazio, Joseph/0000-0001-8276-3690 NR 41 TC 56 Z9 57 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD DEC 7 PY 1998 VL 111 IS 2 BP 231 EP 243 DI 10.1016/S0165-3806(98)00142-4 PG 13 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 147KY UT WOS:000077568200009 PM 9838136 ER PT J AU Hansson, SR Cabrera-Vera, TM Hoffman, BJ AF Hansson, SR Cabrera-Vera, TM Hoffman, BJ TI Infraorbital nerve transection alters serotonin transporter expression in sensory pathways in early postnatal rat development SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE somatosensory cortex; whisker; lateral geniculate; vibrissae; cingulate cortex; autoradiography; in situ hybridization ID LESION-INDUCED REORGANIZATION; PRIMARY SOMATOSENSORY CORTEX; KITTEN VISUAL-CORTEX; CRITICAL PERIOD; THALAMOCORTICAL AFFERENTS; TRIGEMINAL SYSTEM; SENSITIVE PERIOD; CEREBRAL-CORTEX; TERMINAL ARBORS; BRAIN-STEM AB The serotonin transporter MRNA has been found throughout the trigeminal sensory system late in gestation and during early postnatal development, a period known to be critical for maturation of the sensory circuitry. The purpose of the present study was to determine whether sensory denervation in newborn rat pups would alter either the density or pattern of expression of the 5-HT transporter (5-HTT) within the trigeminal system. We combined autoradiographic localization of 5-HT transporters and in situ hybridization techniques to visualize both the transporter protein and mRNA in thalamic sensory neurons and in the somatosensory cortex following unilateral infraorbital nerve transection at postnatal day 1. For comparative purposes, similar measurements were conducted in thalamic visual neurons as well as in the visual cortex. Lesion of the infraorbital nerve decreased the [H-3]citalopram labelling of 5-HT transporters in the ventral basal and ventral medial areas of the thalamus contralateral to the lesion, while labelling of 5-HT transporters was decreased in both contralateral and ipsilateral sides of the lateral genicuate (visual thalamus). Citalopram labelling of 5-HT transporters was not significantly altered in somatosensory or in cingulate cortex, however a significant decrease was observed in the visual cortex. In contrast, there were no obvious changes in the intensity of the 5-HT mRNA hybridization signal in sensory or visual thalamic areas. Given that the serotonin transporter regulates extracellular concentrations of 5-HT, the present data suggest that altered peripheral innervation and thereby altered sensory inputs to the thalamus during fetal development can potentially influence 5-HT transporter densities and thus, may influence extracellular levels of 5-HT in thalamus and cortex during a critical period of synapse formation. In turn, modulation of 5-HT transporter levels may influence extracellular concentrations of 5-HT in thalamus and cortex during a critical period of synapse formation. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIMH, Unit Mol Pharmacol, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. Northwestern Univ, Inst Neurosci, Chicago, IL 60611 USA. Lilly Corp Ctr, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Hansson, SR (reprint author), Univ Lund, Wallenberg Neurosci Ctr, Dept Physiol & Neurosci, Solvegatan 17, S-22362 Lund, Sweden. NR 54 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-3806 J9 DEV BRAIN RES JI Dev. Brain Res. PD DEC 7 PY 1998 VL 111 IS 2 BP 305 EP 314 DI 10.1016/S0165-3806(98)00148-5 PG 10 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 147KY UT WOS:000077568200017 ER PT J AU Ambalavanar, R Ludlow, CL Wenthold, RJ Tanaka, Y Damirjian, M Petralia, RS AF Ambalavanar, R Ludlow, CL Wenthold, RJ Tanaka, Y Damirjian, M Petralia, RS TI Glutamate receptor subunits in the nucleus of the tractus solitarius and other regions of the medulla oblongata in the cat SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE immunohistochemistry; cat; nucleus tractus solitarii; AMPA; NMDA; glutamate ID BRAIN-STEM PROJECTIONS; METHYL-D-ASPARTATE; DORSAL VAGAL COMPLEX; ADULT-RAT BRAIN; NMDA RECEPTOR; MESSENGER-RNAS; MOTOR COMPONENTS; NERVOUS-SYSTEM; AMPA RECEPTORS; SPINAL-CORD AB The nucleus of the tractus solitarius (NTS) is a primary termination zone for laryngeal, gustatory, cardiovascular, respiratory, gastrointestinal, and other visceral afferents. Although considerable information is available on the neurochemical aspects of the NTS in general, very little is known about glutamate receptors that may underlie many of the different functions mediated by the NTS. In addition, most previous glutamate receptor distribution studies were performed in the rat, whereas the cat, the subject of many physiological experiments involving the NTS, has received little attention. In the present study, the immunohistochemical distribution of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-selective glutamate receptor subunits (GluR1, GluR2/3, GluR4) and the N-methyl-D-aspartate (NMDA) receptor subunit NR1 in the cat caudal brainstem was investigated by using subunit-specific antibodies. In the NTS, statistically significant differences were seen in the distribution of each antibody. Highest labeling was seen for GluR2/3 in most subnuclei, whereas GluR1-immunoreactive neurons were found more frequently than were NR1- or GluR4-immunoreactive neurons. GluR1 immunolabeling was particularly high in the interstitial subnucleus, whereas GluR2/3 immunolabeling was particularly high in the intermediate subnucleus. Qualitatively, labeling for GluR4 was most common in glia. The present results indicate that glutamate receptors show different subunit distributions in the subnuclei of the NTS and in other adjacent structures. This finding suggests that neurons in these structures are designed to respond differently to excitatory input. J. Comp. Neurol. 402.75-92, 1998. (C) 1998 Wiley-Liss, Inc.dagger. C1 NIDCD, Voice & Speech Sect, NIH, Bethesda, MD 20892 USA. NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Ambalavanar, R (reprint author), NIDCD, Voice & Speech Sect, NIH, 10 Ctr Dr MSC 1416, Bethesda, MD 20892 USA. OI Ludlow, Christy/0000-0002-2015-6171 FU NIDCD NIH HHS [NIDCD 653] NR 99 TC 53 Z9 54 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD DEC 7 PY 1998 VL 402 IS 1 BP 75 EP 92 PG 18 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 135ZT UT WOS:000076833500006 PM 9831047 ER PT J AU Imada, K Bloom, ET Nakajima, H Horvath-Arcidiacono, JA Udy, GB Davey, HW Leonard, WJ AF Imada, K Bloom, ET Nakajima, H Horvath-Arcidiacono, JA Udy, GB Davey, HW Leonard, WJ TI Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE natural killer cells; Stat5b; Stat5a; interleukin 2; interleukin 15 ID RECEPTOR-BETA-CHAIN; DEFECTIVE LYMPHOID DEVELOPMENT; COLONY-STIMULATING FACTOR; MICE LACKING JAK3; IL-2 RECEPTOR; TARGETED DISRUPTION; GENE-EXPRESSION; DEFICIENT MICE; GAMMA-CHAIN; SIGNAL-TRANSDUCTION AB We have analyzed the immune system in Stat5-deficient mice. Although Stat5a(-/-) splenocytes have a partial defect in anti-CD3-induced proliferation that can be overcome by high dose interleukin (IL)-2, we now demonstrate that defective proliferation in Stat5b(-/-) splenocytes cannot be corrected by this treatment. Interestingly, this finding may be at least partially explained by diminished expression of the IL-2 receptor beta chain (IL-2R beta), which is a component of the receptors for both IL-2 and IL-15, although other defects may also exist. Similar to the defect in proliferation ill activated splenocytes, freshly isolated splenocytes from Stat5b(-/-) mice exhibited greatly diminished proliferation ill response to IL-2 and IL-15. This results from both a decrease in the number and responsiveness of natural killer (NK) cells. Corresponding to the diminished proliferation, basal as well as IL-2- and IL-15-mediated boosting of NK cytolytic activity was also greatly diminished. These data indicate an essential nonredundant role for Stat5b for potent NK cell-mediated proliferation and cytolytic activity. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. US FDA, Div Cell & Gene Therapy, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. Minist Agr & Forestry, Verificat Agcy, Te Kuiti, New Zealand. AgRes, Dairy Sci Grp, Hamilton, New Zealand. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 7N252, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov NR 49 TC 200 Z9 201 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 7 PY 1998 VL 188 IS 11 BP 2067 EP 2074 DI 10.1084/jem.188.11.2067 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 147JA UT WOS:000077484700010 PM 9841920 ER PT J AU Edwards, AD Nelson, KB AF Edwards, AD Nelson, KB TI Neonatal encephalopathies - Time to reconsider the cause of encephalopathies SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID INFANTS C1 Hammersmith Hosp, Imperial Coll, Sch Med, London W12 0NN, England. NINDS, Neuroepidemiol Branch, Bethesda, MD 20892 USA. RP Edwards, AD (reprint author), Hammersmith Hosp, Imperial Coll, Sch Med, London W12 0NN, England. NR 9 TC 21 Z9 21 U1 0 U2 0 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 DEC 5 PY 1998 VL 317 IS 7172 BP 1537 EP 1538 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 146VC UT WOS:000077451700001 PM 9836647 ER PT J AU Wickline, S Wu, K Didisheim, P Anderson, JM Budinger, TF Fuster, V Harker, LA Kottke-Marchant, K Maki, DG Strauss, W Callahan, TH Watson, JT Berson, A AF Wickline, S Wu, K Didisheim, P Anderson, JM Budinger, TF Fuster, V Harker, LA Kottke-Marchant, K Maki, DG Strauss, W Callahan, TH Watson, JT Berson, A TI NHLBI/FDA conference on thrombosis and infections with cardiovascular devices SO JOURNAL OF BIOMEDICAL MATERIALS RESEARCH LA English DT Article C1 NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Berson, A (reprint author), NHLBI, Div Heart & Vasc Dis, 6701 Rockledge Dr,Room 9182, Bethesda, MD 20892 USA. EM ab51u@nih.gov RI Wu, Kenneth Kun-Yu/B-1070-2010 NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9304 J9 J BIOMED MATER RES JI J. Biomed. Mater. Res. PD DEC 5 PY 1998 VL 42 IS 3 BP 341 EP 346 DI 10.1002/(SICI)1097-4636(19981205)42:3<341::AID-JBM1>3.0.CO;2-J PG 6 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 125XK UT WOS:000076262200018 ER PT J AU Stauber, RH Pavlakis, GN AF Stauber, RH Pavlakis, GN TI Intracellular trafficking and interactions of the HIV-1 Tat protein SO VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RNA-POLYMERASE-II; TRANSCRIPTION-ELONGATION COMPLEX; GREEN FLUORESCENT PROTEIN; METAL-LINKED DIMER; TYPE-1 TAT; TRANS-ACTIVATION; GENE-EXPRESSION; NUCLEAR EXPORT; NUCLEOCYTOPLASMIC TRANSPORT AB Fusions of the human immunodeficiency virus type 1 (HIV-I) transactivator protein Tat to the green fluorescent protein (GFP) were used to study the intracellular localization, trafficking, and interactions of Tat in human cells. Tagging Tat with GFP did not change its nuclear localization or ability to act as a transactivator. Tat-GFP expressed at low levels was found in the nucleus, whereas overexpression resulted in nucleolar accumulation. A Tat-GFP hybrid protein containing in addition the HIV-I Rev nuclear export signal (NES) localized predominantly to the cytoplasm. This shuttle protein, Tat-GFP-NES, transactivated the HIV-1 long terminal repeat. Thus a Tat molecule being only transiently present in the nucleus is active and nucleolar accumulation of Tat is not prerequisite for function. A coexpression assay previously used to define protein interaction domains in the HIV-1 Rev protein [R. H. Stauber, E. Afonina, S. Gulnik, J. Erickson, and G. N. Pavlakis (1998a). Virology 251, 38-48.] indicated that Tat exists predominantly as a monomer and does not form stable multimers with B23 in living cells. Using a heterokaryon fusion assay, we found that Tat-GFP was able to shuttle between the nucleus and the cytoplasm. Tat therefore has the potential to perform functions in the nucleus as well as in the cytoplasm. C1 NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Human Retrovirus Sect, Frederick, MD 21701 USA. RP Pavlakis, GN (reprint author), NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Human Retrovirus Sect, POB B, Frederick, MD 21701 USA. EM pavlakis@mail.ncifcrf.gov OI Stauber, Roland/0000-0002-1341-4523 NR 63 TC 97 Z9 99 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 5 PY 1998 VL 252 IS 1 BP 126 EP 136 DI 10.1006/viro.1998.9400 PG 11 WC Virology SC Virology GA 148ZH UT WOS:000077564700014 PM 9875323 ER PT J AU Huang, B Ning, Y Lamb, AN Sandlin, CJ Jamehdor, M Ried, T Bartley, J AF Huang, B Ning, Y Lamb, AN Sandlin, CJ Jamehdor, M Ried, T Bartley, J TI Identification of an unusual marker chromosome by spectral karyotyping SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE marker chromosome; alpha-satellite sequence; centromere; fluorescence in situ hybridization; spectral karyotyping; tetrasomy of chromosome 15 ID ALPHA-SATELLITE DNA; MOLECULAR CHARACTERIZATION; HUMAN CENTROMERE; HYBRIDIZATION; ORIGIN AB We ascertained a newborn girl with multiple congenital anomalies including severe hypotonia, cardiovascular defects, hearing loss, central nervous system anomalies, and facial anomalies. The infant died at 12 days. Cytogenetic analysis showed a de novo supernumerary marker chromosome. Fluorescence in situ hybridization (FISH) with a combination of chromosome specific alpha-satellite probes and an all-human centromere probe failed to show hybridization to the marker, indicating that the marker chromosome lacked detectable alpha satellite sequences. Spectral karyotyping (SKY) was performed and showed that the marker was chromosome 15 in origin. This was confirmed by FISH with a 15q specific subtelomeric probe, which showed hybridization to both ends of the marker chromosome. Based on FISH information and G-banding pattern, the marker was determined to be an inverted duplication of 15q25-qter, leading to partial tetrasomy for chromosome 15, Although the marker chromosome lacked detectable centromeric alpha-satellite sequences, it seemed to have a functional centromere as it is mitotically stable, This observation is consistent with previous studies on acentric marker chromosomes, which suggested that the DNA sequence at the breakpoint could function similarly to alpha-satellite sequences once activated through marker formation. Am. J. Med. Genet. 80:368-372, 1998. (C) 1998 Wiley-Liss, Inc. C1 Genzyme Genet, Long Beach, CA USA. Univ Calif Irvine, Med Ctr, Div Med Genet, Irvine, CA USA. Natl Human Genome Res Inst, Bethesda, MD USA. Genzyme Genet, Santa Fe, NM USA. So Calif Permanente Med Grp, Los Angeles, CA 90027 USA. RP Huang, B (reprint author), Genzyme Genet, 1054 Town & Country Rd, Orange, CA 92868 USA. EM genzyme@earthlink.net NR 29 TC 32 Z9 34 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD DEC 4 PY 1998 VL 80 IS 4 BP 368 EP 372 DI 10.1002/(SICI)1096-8628(19981204)80:4<368::AID-AJMG12>3.0.CO;2-B PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 144FG UT WOS:000077302900012 PM 9856565 ER PT J AU Lalwani, AK Attaie, A Randolph, T Deshmukh, D Wang, C Mhatre, A Wilcox, E AF Lalwani, AK Attaie, A Randolph, T Deshmukh, D Wang, C Mhatre, A Wilcox, E TI Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE Waardenburg syndrome; MITF; PAX3; ARMS; transcription factor; deafness ID ENDOTHELIN-3 GENE; DISEASE AB Waardenburg syndrome (WS) is an autosomal-dominant neural crest cell disorder phenotypically characterized by hearing impairment and disturbance of pigmentation. A presence of dystopia canthorum is indicative of WS type 1, caused by loss of function mutation in the PAX3 gene, In contrast, type 2 WS (WS2) is characterized by normally placed medial canthi and is genetically heterogeneous; mutations in MITF (microphthalmia associated transcription factor) associated with WS2 have been identified in some but not all affected families. Here, we report on a three-generation Indian family with a point mutation in the MITF gene causing WS2, This mutation, initially reported in a Northern European family, creates a stop codon in exon 7 and is predicted to result in a truncated protein lacking the HLH-Zip or Zip structure necessary for normal interaction with its target DNA motif. Comparison of the phenotype between the two families demonstrates a significant difference in pigmentary disturbance of the eye. This family, with the first documented case of two unrelated WS2 families harboring identical mutations, provides additional evidence for the importance of genetic background on the clinical phenotype, Am. J. Med. Genet. 80:406-409, 1998. (C) 1998 Wiley-Liss, Inc. C1 Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, Lab Mol Otol, Epstein Labs, San Francisco, CA 94143 USA. Rotary Deaf Sch, Ichalkaranji, Maharashtra, India. NIDOCD, Mol Genet Lab, NIH, Bethesda, MD USA. RP Lalwani, AK (reprint author), Univ Calif San Francisco, Dept Otolaryngol Head & Neck Surg, Lab Mol Otol, Epstein Labs, 533 Parnassus Ave,U490A, San Francisco, CA 94143 USA. NR 17 TC 15 Z9 17 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD DEC 4 PY 1998 VL 80 IS 4 BP 406 EP 409 DI 10.1002/(SICI)1096-8628(19981204)80:4<406::AID-AJMG20>3.3.CO;2-G PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 144FG UT WOS:000077302900020 PM 9856573 ER PT J AU Hill, RM Morresey, KS Coates, LC Mezey, E Fell, B Bratt, T Trapani, JA Birch, NP AF Hill, RM Morresey, KS Coates, LC Mezey, E Fell, B Bratt, T Trapani, JA Birch, NP TI A new intracellular serine protease inhibitor expressed in the rat pituitary gland complexes with granzyme B SO FEBS LETTERS LA English DT Article DE inhibitor; pituitary; serpin; serine protease; granzyme B ID PLASMINOGEN-ACTIVATOR; PROTEINASE-INHIBITORS; PLASMA; ALPHA-1-ANTITRYPSIN; PLATELETS; CLONING; SERPINS; FAMILY AB We have cloned a novel serpin (raPIT5a) from a rat pituitary cDNA library which is structurally related to members of the ovalbumin subfamily of serine protease inhibitors. This new cDNA encodes a 374-amino acid protein, designated raPIT5a. raPIT5a was expressed in specific cells in the intermediate and anterior lobes of the pituitary. Recombinant raPIT5a was not secreted suggesting raPIT5a functions to inhibit intracellular proteases, Recombinant raPIT5a formed an SDS-stable complex with human granzyme B, a serine protease which induces apoptosis by activating members of the caspase enzyme family. These data suggest raPIT5a may have a role in regulating granzyme B or related enzymes and apoptosis in the pituitary gland. (C) 1998 Federation of European Biochemical Societies. C1 Univ Auckland, Sch Biol Sci, Mol Neuroendocrinol Grp, Auckland 1, New Zealand. NINDS, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. Austin Res Inst, Cellular Cytotox Lab, Heidelberg, Vic, Australia. RP Birch, NP (reprint author), Univ Auckland, Sch Biol Sci, Mol Neuroendocrinol Grp, Private Bag 92019, Auckland 1, New Zealand. RI Birch, Nigel/H-2498-2011 OI Birch, Nigel/0000-0002-8417-3587 NR 25 TC 7 Z9 7 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD DEC 4 PY 1998 VL 440 IS 3 BP 361 EP 364 DI 10.1016/S0014-5793(98)01475-6 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 149FZ UT WOS:000077595600023 PM 9872403 ER PT J AU Rehrauer, WM Bruck, I Woodgate, R Goodmann, MF Kowalczykowski, SC AF Rehrauer, WM Bruck, I Woodgate, R Goodmann, MF Kowalczykowski, SC TI Modulation of RecA nucleoprotein function by the mutagenic UmuD ' C protein complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; ESCHERICHIA-COLI; UV-MUTAGENESIS; HOMOLOGOUS RECOMBINATION; LEXA REPRESSOR; ULTRAVIOLET-LIGHT; SOS MUTAGENESIS; REPAIR; CLEAVAGE; PURIFICATION AB The RecA, UmuC, and UmuD' proteins are essential for error-prone, replicative bypass of DNA lesions. Normally, RecA protein mediates homologous pairing of DNA. We show that purified Umu(D')(2)C blocks this recombination function. Biosensor measurements establish that the mutagenic complex binds to the RecA nucleoprotein filament with a stoichiometry of one Umu(D')(2)C complex for every two RecA monomers, Furthermore, Umu(D')(2)C competitively inhibits LexA repressor cleavage but not ATPase activity, implying that Umu(D')(2)C binds in or proximal to the helical groove of the RecA nucleoprotein filament. This binding reduces joint molecule formation and even more severely impedes DNA heteroduplex formation by RecA protein, ultimately blocking all DNA pairing activity and thereby abridging participation in recombination function. Thus, Umu(D')(2)C restricts the activities of the RecA nucleoprotein filament and presumably, in this manner, recruits it for mutagenic repair function. This modulation by Umu(D')(2)C is envisioned as a key event in the transition from a normal mode of genomic maintenance by "error-free" recombinational repair, to one of "error-prone" DNA replication. C1 Univ Calif Davis, Microbiol Sect, Div Biol Sci, Davis, CA 95616 USA. Univ Calif Davis, Sect Mol & Cellular Biol, Div Biol Sci, Davis, CA 95616 USA. Univ So Calif, Dept Biol Sci, Hedco Mol Biol Labs, Los Angeles, CA 90089 USA. NICHD, Sect DNA Replicat Repair & Mutagenesis, NIH, Bethesda, MD 20892 USA. RP Kowalczykowski, SC (reprint author), Univ Calif Davis, Microbiol Sect, Div Biol Sci, Hutchison Hall, Davis, CA 95616 USA. FU NIAID NIH HHS [AI-18987]; NIGMS NIH HHS [GM-42554] NR 40 TC 33 Z9 34 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 DEC 4 PY 1998 VL 273 IS 49 BP 32384 EP 32387 DI 10.1074/jbc.273.49.32384 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144RP UT WOS:000077329100005 PM 9829966 ER PT J AU Torrents, D Estevez, R Pineda, M Fernandez, E Lloberas, J Shi, YB Zorzano, A Palacin, M AF Torrents, D Estevez, R Pineda, M Fernandez, E Lloberas, J Shi, YB Zorzano, A Palacin, M TI Identification and characterization of a membrane protein (y(+)L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y(+)L - A candidate gene for lysinuric protein intolerance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID XENOPUS-LAEVIS OOCYTES; SURFACE-ANTIGEN; HEAVY-CHAIN; EXPRESSION CLONING; RENAL REABSORPTION; CELL ACTIVATION; SYSTEM; CYSTINE; KIDNEY; PREDICTION AB We have identified a new human cDNA (y(+)L amino acid transporter-1 (y(+)LAT-1)) that induces system y+L transport activity with 4F2hc (the surface antigen 4F2 heavy chain) in oocytes. Human y(+)LAT-1 is a new member of a family of polytopic transmembrane proteins that are homologous to the yeast high affinity methionine permease MUP1. Other members of this family, the Xenopus laevis IU12 and the human KIAA0245 cDNAs, also co-express amino acid transport activity with 4F2hc in oocytes, with characteristics that are compatible with those of systems L and y(+)L, respectively. y(+)LAT-1 protein forms a approximate to 135-kDa, disulfide bond-dependent heterodimer with 4F2hc in oocytes, which upon reduction results in two protein bands of approximate to 85 kDa (i.e. 4F2hc) and approximate to 40 kDa (y(+)LAT-1). Mutation of the human 4F2hc residue cysteine 109 (Cys-109) to serine abolishes the formation of this heterodimer and drastically reduces the coexpressed transport activity, These data suggest that y(+)LAT-1 and other members of this family are different 4F2 light chain subunits, which associated with 4F2hc, constitute different amino acid transporters. Human y(+)LAT-1 mRNA is expressed in kidney >> peripheral blood leukocytes >> lung > placenta = spleen > small intestine. The human y(+)LAT-1 gene localizes at chromosome 14q11.2 (17cR approximate to 374 kb hom D1451350), within the lysinuric protein intolerance (LPI) locus (Lauteala, T., Sistonen, P., Savontaus, M. L., Mykkanen, J., Simell, J., Lukkarinen, M,, Simmell, O., and Aula, P. (1997) Am. J. Hum. Genet. 60, 1479-1486). LPI is an inherited autosomal disease characterized by a defective dibasic amino acid transport in kidney, intestine, and other tissues. The pattern of expression of human y(+)LAT-1, its coexpressed transport activity with 4F2hc, and its chromosomal location within the LPI locus, suggest y(+)LAT-1 as a candidate gene for LPI. C1 Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, E-08028 Barcelona, Spain. Univ Barcelona, Fac Biol, Dept Fisiol Immunol, E-08028 Barcelona, Spain. NICHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Palacin, M (reprint author), Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, Avda Diagonal 645, E-08028 Barcelona, Spain. RI Estevez, Raul/D-8610-2015; Lloberas, Jorge/D-4303-2014; Torrents, David/G-5785-2015 OI Estevez, Raul/0000-0003-1579-650X; Lloberas, Jorge/0000-0001-7075-4201; Torrents, David/0000-0002-6086-9037 NR 57 TC 239 Z9 248 U1 1 U2 8 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 DEC 4 PY 1998 VL 273 IS 49 BP 32437 EP 32445 DI 10.1074/jbc.273.49.32437 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144RP UT WOS:000077329100013 PM 9829974 ER PT J AU Nomizu, M Kuratomi, Y Malinda, KM Song, SY Miyoshi, K Otaka, A Powell, SK Hoffman, MP Kleinman, HK Yamada, Y AF Nomizu, M Kuratomi, Y Malinda, KM Song, SY Miyoshi, K Otaka, A Powell, SK Hoffman, MP Kleinman, HK Yamada, Y TI Cell binding sequences in mouse laminin alpha 1 chain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TERMINAL GLOBULAR DOMAIN; AMINO-ACID-SEQUENCE; A-CHAIN; SYNTHETIC PEPTIDE; NEURITE OUTGROWTH; HEPARIN-BINDING; METASTASIS FORMATION; IKVAV SEQUENCE; TUMOR-GROWTH; S-LAMININ AB Laminin-1, a multifunctional glycoprotein of the basement membrane, consists of three different subunits, alpha 1, beta 1, and gamma 1 chains. Previously, we used synthetic peptides to screen for biologically active sequences in the laminin alpha 1 chain C-terminal globular domain (G domain) and identified several cell binding sequences (Nomizu, M., Kim, W. H., Yamamura, K., Utani, A., Song, S. Y., Otaka, A., Roller, P. P., Kleinman, H. K., and Yamada, Y. (1995) J. Biol. Chem. 270, 20583-20590). Here, we identify new cell binding sequences on the remainder of the laminin alpha 1 chain by systematic peptide screening, using 208 overlapping synthetic peptides encompassing the central and N-terminal portions of the alpha 1 chain. HT-1080 cell attachment activity to the peptides was evaluated using peptide-coated plastic substrates and peptide-conjugated Sepharose beads. Twenty five peptides showed cell attachment activities on either the peptide-coated plastic substrates and/or the peptide-conjugated Sepharose beads. A-13 (RQVFQVAYIIIKA) showed strongest cell attachment activity in both the assays. Cell attachment to 14 of the peptides was inhibited by heparin. EDTA and integrin antibodies inhibited cell adhesion to two of the peptides, A-13 and A-25, suggesting that these sites likely bind to integrins. These peptides inhibited cell attachment to laminin-l but not to collagen I, suggesting these active sites are available on the intact molecule. Most of active sequences were localized on globular domains suggesting that these structures play a critical role in binding to cell-surface receptors. C1 NIDR, CDBRB, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Fac Pharmaceut Sci, Sakyo Ku, Kyoto 606, Japan. RP Yamada, Y (reprint author), NIDR, CDBRB, NIH, Bldg 30,Rm 405, Bethesda, MD 20892 USA. NR 51 TC 120 Z9 120 U1 1 U2 9 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 DEC 4 PY 1998 VL 273 IS 49 BP 32491 EP 32499 DI 10.1074/jbc.273.49.32491 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144RP UT WOS:000077329100021 PM 9829982 ER PT J AU Abrami, L Fivaz, M Decroly, E Seidah, NG Jean, F Thomas, G Leppla, SH Buckley, JT van der Goot, FG AF Abrami, L Fivaz, M Decroly, E Seidah, NG Jean, F Thomas, G Leppla, SH Buckley, JT van der Goot, FG TI The pore-forming toxin proaerolysin is activated by furin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENVELOPE GLYCOPROTEIN GP160; PLANAR LIPID BILAYERS; PROTEOLYTIC ACTIVATION; PROTECTIVE ANTIGEN; MEMBRANE-CHANNEL; CELL-SURFACE; PROPROTEIN CONVERTASE; PSEUDOMONAS-EXOTOXIN; ERYTHROCYTE RECEPTOR; DIPHTHERIA-TOXIN AB Aerolysin is secreted as an inactive dimeric precursor by the bacterium Aeromonas hydrophila. Proteolytic cleavage within a mobile loop near the C terminus of the protoxin is required for oligomerization and channel formation. This loop contains the sequence KVRRAR(432), which should be recognized by mammalian proprotein convertases such as furin, PACE4, and PC5/6A. Here we show that these three proteases cleave proaerolysin after Arg-432 in vitro, yielding active toxin. We also investigated the potential role of these enzymes in the in vivo activation of the protoxin. We found that Chinese hamster ovary cells were able to convert the protoxin to aerolysin in the absence of exogenous proteases and that activation did not require internalization of the toxin, The furin inhibitor alpha(1)-antitrypsin Portland reduced the rate of proaerolysin activation in vivo, and proaerolysin processing was even further reduced in furin-deficient FD11 Chinese hamster ovary cells, The cells were also less sensitive to proaerolysin than wild type cells; however, transient transfection of FD11 cells with the cDNA encoding furin conferred normal sensitivity to the protoxin. Together these findings argue that furin catalyzes the cell-surface activation of proaerolysin in vivo. C1 Univ Geneva, Dept Biochem, CH-1211 Geneva, Switzerland. Clin Res Inst Montreal, Biochem Neuroendocrinol Lab, Montreal, PQ H2W 1R7, Canada. Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97201 USA. NIDR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 3P6, Canada. RP van der Goot, FG (reprint author), Univ Geneva, Dept Biochem, 30 Quai E Ansermet, CH-1211 Geneva, Switzerland. RI van der Goot, Francoise/B-2279-2012; Seidah, Nabil/I-3596-2013; OI Seidah, Nabil/0000-0001-6503-9342; van der Goot, Gisou/0000-0002-8522-274X FU NICHD NIH HHS [HD30236] NR 58 TC 94 Z9 95 U1 0 U2 5 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 DEC 4 PY 1998 VL 273 IS 49 BP 32656 EP 32661 DI 10.1074/jbc.273.49.32656 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144RP UT WOS:000077329100045 PM 9830006 ER PT J AU Lubkowski, J Yang, F Alexandratos, J Merkel, G Katz, RA Gravuer, K Skalka, AM Wlodawer, A AF Lubkowski, J Yang, F Alexandratos, J Merkel, G Katz, RA Gravuer, K Skalka, AM Wlodawer, A TI Structural basis for inactivating mutations and pH-dependent activity of avian sarcoma virus integrase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETROVIRAL INTEGRATION; CATALYTIC DOMAIN; DIVALENT-CATIONS; RESIDUES; SITE AB Crystallographic studies of the catalytic core domain of avian sarcoma virus integrase (ASV IN) have provided the most detailed picture so far of the active site of this enzyme, which belongs to an important class of targets for designing drugs against AIDS. Recently, cryst als of an inactive D64N mutant were obtained under conditions identical to those used for the native enzyme. Data were collected at different pH values and in the presence of divalent cations, Data were also collected at low pH for the crystals of the native ASV IN core domain. In the structures of native ASV IN at pH 6.0 and below, as well as in all structures of the D64N mutants, the side chain of the active site residue Asx-64 (Asx denotes Asn or Asp) is rotated by similar to 150 degrees around the C alpha-C beta bond, compared with the structures at higher pH. In the new structures, this residue makes hydrogen bands with the amide group of Asn-160, and thus, the usual metal-binding site, consisting of Asp-64, Asp-121, and Glu-157, is disrupted. Surprisingly, however, a single Zn2+ can still bind to Asp-121 in the mutant, without restoration of the activity of the enzyme. These structures have elucidated an unexpected mechanism of inactivation of the enzyme by lowering the pH or by mutation, in which a protonated side chain of Asx-64 changes its orientation and interaction partner. C1 NCI, Macromol Struct Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr,NIH, Frederick, MD 21702 USA. Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. RP Wlodawer, A (reprint author), NCI, Macromol Struct Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr,NIH, Frederick, MD 21702 USA. FU NCI NIH HHS [CA-06927, CA-47486] NR 16 TC 16 Z9 17 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 DEC 4 PY 1998 VL 273 IS 49 BP 32685 EP 32689 DI 10.1074/jbc.273.49.32685 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144RP UT WOS:000077329100049 PM 9830010 ER PT J AU Mueller, PP Grueter, P Hinnebusch, AG Trachsel, H AF Mueller, PP Grueter, P Hinnebusch, AG Trachsel, H TI A ribosomal protein is required for translational regulation of GCN4 mRNA - Evidence for involvement of the ribosome in eIF2 recycling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INITIATION FACTOR-II; ACID BIOSYNTHETIC GENES; OPEN READING FRAMES; SACCHAROMYCES-CEREVISIAE; MESSENGER-RNA; CELL-CYCLE; YEAST; ACTIVATOR; SUBUNIT; PHOSPHORYLATION AB In amino acid-starved yeast cells, inhibition of the guanine nucleotide exchange factor eIF2B by phosphorylated translation initiation factor 2 results in increased translation of GCN4 mRNA. We isolated a suppressor of a mutant eIF2B. The suppressor prevents efficient GCN4 mRNA translation due to inactivation of the small ribosomal subunit protein Rps31 and results in low amounts of mutant 40 S ribosomal subunits. Deletion of one of two genes encoding ribosomal protein Rps17 also reduces the amounts of 40 S subunits but does not suppress eIF2B mutations or prevent efficient GCN4 translation. Our findings show that Rps31-deficient ribosomes are altered in a way that decreases the eIF2B requirement and that the small ribosomal subunit mediates the effects of low eIF2B activity on cell viability and translational regulation in response to eIF2 phosphorylation. C1 Univ Bern, Inst Biochem & Mol Biol, CH-3012 Bern, Switzerland. NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. Natl Res Inst Biotechnol, RDIF, GBF, D-38124 Braunschweig, Germany. RP Mueller, PP (reprint author), Univ Bern, Inst Biochem & Mol Biol, Buhlstr 28, CH-3012 Bern, Switzerland. EM PMU@GBF.DE OI Mueller, Peter/0000-0002-1209-7546 NR 45 TC 9 Z9 9 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 DEC 4 PY 1998 VL 273 IS 49 BP 32870 EP 32877 DI 10.1074/jbc.273.49.32870 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144RP UT WOS:000077329100074 PM 9830035 ER PT J AU Nony, P Hannon, R Gould, H Felsenfeld, G AF Nony, P Hannon, R Gould, H Felsenfeld, G TI Alternate promoters and developmental modulation of expression of the chicken GATA-2 gene in hematopoietic progenitor cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; DNA-BINDING SPECIFICITIES; XENOPUS GATA-2; ERYTHROID-DIFFERENTIATION; HYPERSENSITIVE SITES; ENDOTHELIAL-CELLS; FACTOR FAMILY; PROTEINS; INDUCTION; MESODERM AB We have isolated and characterized the chicken GATA-2 (cGATA-2) gene. We show that, as in the case of some other members of the GATA gene family, the gene is expressed from alternative first exons. One of the resulting mRNAs represents only a minor form of the GATA-2 mRNA in the cells and tissues we analyzed; the other is ubiquitously expressed. We have defined the minimal promoter that controls expression of this most abundant mRNA and that is necessary for full activity in hematopoietic progenitor cells. The activity of this promoter in transient assays is consistent with developmental differences of expression levels in these cells. We identify within the promoter a previously unrecognized extended CCAAT motif essential for its activity. The organization of the cGATA-2 gene, with alternative first exons and a CCAAT box in the proximal promoter, is similar to that recently described for mouse GATA-2, and the proximal promoter also resembles the only promoter so far described in Xenopus. Nonetheless, the roles of the promoters in development and tissue-specific expression are quite different in these organisms, most strikingly in the mouse, which assigns developmental roles to its proximal and distal promoters that are quite different from those in the chicken. We suggest that although the overall organization may remain the same, the role assigned to each promoter varies among organisms. We identify distant upstream regulatory elements in the cGATA-2 gene that modulate expression from the proximal promoter and that may be responsible for this variation. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Kings Coll London, Div Biomol Sci, London WC2B 5RL, England. RP NIDDK, Mol Biol Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. NR 50 TC 14 Z9 14 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 4 PY 1998 VL 273 IS 49 BP 32910 EP 32919 DI 10.1074/jbc.273.49.32910 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144RP UT WOS:000077329100080 PM 9830041 ER PT J AU McVicar, DW Taylor, LS Gosselin, P Willette-Brown, J Mikhael, AI Geahlen, RL Nakamura, MC Linnemeyer, P Seaman, WE Anderson, SK Ortaldo, JR Mason, LH AF McVicar, DW Taylor, LS Gosselin, P Willette-Brown, J Mikhael, AI Geahlen, RL Nakamura, MC Linnemeyer, P Seaman, WE Anderson, SK Ortaldo, JR Mason, LH TI DAP12-mediated signal transduction in a natural killer cells - A dominant role for the Syk protein-tyrosine kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MHC-RECOGNIZING RECEPTORS; PROTOONCOGENE C-CBL; FC-GAMMA RECEPTOR; CLASS-I MOLECULES; PHOSPHATIDYLINOSITOL 3-KINASE; INHIBITORY RECEPTORS; ANTIGEN RECEPTOR; T-LYMPHOCYTES; NK CELLS; HLA-C AB The murine Ly49 family contains nine genes in two subgroups: the inhibitory receptors (Ly49A, B, C, E, F, G2, and I) and the noninhibitory receptors (Ly49D and H), Unlike their inhibitory counterparts, Ly49D and H do not contain immunoreceptor tyrosine-based inhibitory motifs but associate with a recently described coreceptor, DAP12, to transmit positive signals to natural killer (NK) cells. DAP12 is also expressed in myeloid cells, but the receptors coupled to it there are unknown. Here we document the signaling pathways of the Ly49D/ DAP12 complex in NK cells. We show that ligation of Ly49D results in 1) tyrosine phosphorylation of several substrates, including phospholipase C gamma 1, Cbl, and p44/ p42 mitogen-activated protein kinase, and 2) calcium mobilization. Moreover, we demonstrate that although human DAP12 reportedly binds the SH2 domains of both Syk and Zap-70, ligation of Ly49D leads to activation of Syk but not Zap-70. Consistent with this observation, Ly49D/DAP12-mediated calcium mobilization is blocked by dominant negative Syk but not by catalytically inactive Zap-70. These data demonstrate the dependence of DAP12-coupled receptors on Syk and suggest that the outcome of Ly49D/DAP12 engagement mill be regulated by Cbl and culminate in the activation of transcription factors. C1 NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr,NIH, Frederick, MD 21702 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Purdue Univ, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Vet Adm Med Ctr, San Francisco, CA 94121 USA. RP McVicar, DW (reprint author), NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr,NIH, Bldg 560,Room 31-93, Frederick, MD 21702 USA. EM mcvicar@nih.gov RI Anderson, Stephen/B-1727-2012; McVicar, Daniel/G-1970-2015 OI Anderson, Stephen/0000-0002-7856-4266; FU NCI NIH HHS [CA37372, N01-CO-56000] NR 63 TC 159 Z9 161 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 DEC 4 PY 1998 VL 273 IS 49 BP 32934 EP 32942 DI 10.1074/jbc.273.49.32934 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144RP UT WOS:000077329100083 PM 9830044 ER PT J AU Lambert, PF Kashanchi, F Radonovich, MF Shiekhattar, R Brady, JN AF Lambert, PF Kashanchi, F Radonovich, MF Shiekhattar, R Brady, JN TI Phosphorylation of p53 serine 15 increases interaction with CBP SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; TRANSCRIPTION FACTOR TFIIH; TUMOR-SUPPRESSOR PROTEIN; CREB-BINDING PROTEIN; DNA-DAMAGE; MDM-2 ONCOGENE; IN-VITRO; COACTIVATORS; APOPTOSIS; COMPLEX AB p53 exerts its cell cycle regulatory effects through its ability to function as a sequence-specific DNA binding transcription factor. CREB-binding protein (CBP)/p300, through its interaction with the N terminus of p53, acts as a coactivator for p53 and increases the sequence-specific DNA-binding activity of p53 by acetylating its C terminus. The same N-terminal domain of p53 has recently been shown to be phosphorylated at Ser(15) in response to gamma-irradiation. Remarkably, we now demonstrate that phosphorylation of p53 at Ser(15) increases its ability to recruit CBP/p300. The increase in CBP/p300 binding was followed by an increase in the overall level of acetylation of the C terminus of p53. These results provide a mechanism for the activation of p53-regulated genes following DNA damage, through a signaling pathway linking p53 N-terminal kinase and C-terminal acetyltransferase activities. C1 NCI, Virus Tumor Biol Sect, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Wistar Inst, Philadelphia, PA 19104 USA. RP Brady, JN (reprint author), NCI, Virus Tumor Biol Sect, Lab Receptor Biol & Gene Express, NIH, Bldg 41,Rm B403, Bethesda, MD 20892 USA. NR 50 TC 312 Z9 316 U1 0 U2 10 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 DEC 4 PY 1998 VL 273 IS 49 BP 33048 EP 33053 DI 10.1074/jbc.273.49.33048 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144RP UT WOS:000077329100098 PM 9830059 ER PT J AU Kehle, J Beuchle, D Treuheit, S Christen, B Kennison, JA Bienz, M Muller, J AF Kehle, J Beuchle, D Treuheit, S Christen, B Kennison, JA Bienz, M Muller, J TI dMi-2, a hunchback-interacting protein that functions in Polycomb repression SO SCIENCE LA English DT Article ID HOMEOTIC GENE-EXPRESSION; DROSOPHILA-MELANOGASTER; SEGMENTAL DETERMINATION; SPATIAL EXPRESSION; BITHORAX COMPLEX; MI-2 AUTOANTIGEN; ULTRABITHORAX; EMBRYOS; DOMAIN; REGION AB Early in Drosophila embryogenesis, gap gene products directly repress transcription of homeotic (HOX) genes and thereby delimit HOX expression domains. Subsequently, Polycomb-group proteins maintain this repression. Currently, there is no known molecular Link between gap and Polycomb-group proteins. Here, dMi-2 is identified as a protein that binds to a domain in the gap protein Hunchback that is specifically required for the repression of HOX genes. Genetic analyses show that dMi-2 participates in both Hunchback and Polycomb repression in vivo. Hence, recruitment of dMi-2 may serve as a link between repression of HOX genes by Hunchback and Polycomb proteins. C1 Max Planck Inst Entwicklungsbiol, D-72076 Tubingen, Germany. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Muller, J (reprint author), Max Planck Inst Entwicklungsbiol, Spemannstr 35-3, D-72076 Tubingen, Germany. NR 39 TC 272 Z9 276 U1 0 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD DEC 4 PY 1998 VL 282 IS 5395 BP 1897 EP 1900 DI 10.1126/science.282.5395.1897 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 144WG UT WOS:000077338100051 PM 9836641 ER PT J AU Martin, MP Dean, M Smith, MW Winkler, C Gerrard, B Michael, NL Lee, B Doms, RW Margolick, J Buchbinder, S Goedert, JJ O'Brien, TR Hilgartner, MW Vlahov, D O'Brien, SJ Carrington, M AF Martin, MP Dean, M Smith, MW Winkler, C Gerrard, B Michael, NL Lee, B Doms, RW Margolick, J Buchbinder, S Goedert, JJ O'Brien, TR Hilgartner, MW Vlahov, D O'Brien, SJ Carrington, M TI Genetic acceleration of AIDS progression by a promoter variant of CCR5 SO SCIENCE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CHEMOKINE RECEPTOR GENE; HIV-1 INFECTION; DISEASE PROGRESSION; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; MIP-1-ALPHA; MIP-1-BETA; RESISTANCE; RANTES AB The CCR5 gene encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for macrophage-tropic (R5) strains of human immunodeficiency virus-type 1 (HIV-1). Genetic association analysis of five cohorts of people with acquired immunodeficiency syndrome (AIDS) revealed that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. Composite genetic epidemiologic analyses of genotypes bearing CCR5P1, CCR5-Delta 32, CCR2-641, and SDF1-3'A affirmed distinct regulatory influences for each gene on AIDS progression. An estimated 10 to 17 percent of patients who develop AIDS within 3.5 years of HIV-1 infection do so because they are homozygous for CCR5P1/P1, and 7 to 13 percent of all people carry this susceptible genotype. The cumulative and interactive influence of these AIDS restriction genes illustrates the multigenic nature of host factors Limiting AIDS disease progression. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA. Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD 20850 USA. Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. San Francisco Dept Publ Hlth, San Francisco, CA 94102 USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. Cornell Univ, Med Ctr, New York Hosp, Div Pediat Hematol & Oncol, New York, NY 10021 USA. RP O'Brien, TR (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM obrien@ncifcrf.gov RI Smith, Michael/B-5341-2012; Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU NCI NIH HHS [N01-CO-56000] NR 48 TC 334 Z9 345 U1 0 U2 13 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 DEC 4 PY 1998 VL 282 IS 5395 BP 1907 EP 1911 DI 10.1126/science.282.5395.1907 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 144WG UT WOS:000077338100054 PM 9836644 ER PT J AU Zhang, Y Williams, W Torrence-Campbell, C Bowen, WD Rice, KC AF Zhang, Y Williams, W Torrence-Campbell, C Bowen, WD Rice, KC TI Characterization of novel N,N '-disubstituted piperazines as sigma receptor ligands SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID H-3 (+)-PENTAZOCINE; ANTIPSYCHOTIC-DRUGS; HIGHLY POTENT; RAT-BRAIN; AFFINITY; BINDING; CELLS; ANALOGS; SUGGEST; SITE AB sigma Receptors have been the focus of extensive studies because of their potential functional role in several important physiological and biochemical processes. To further evaluate the properties of a receptors, especially sigma-1 and sigma-2 subtypes, we have synthesized a series of N,N'-disubstituted piperazine compounds (1-32). The design of these compounds was based upon the early structure-activity relationship (SAR) studies of the minimum structural requirements of a molecule necessary to elicit sigma receptor binding activity. In the N-(3-phenylpropyl)piperazine series, compounds with the ethylenediamine moiety (8-11, 15-17) showed 6-20-fold higher affinity for sigma-1 and 2-40-fold higher affinity for sigma-2 relative to their corresponding amides (1-7). The (m-nitrophenethyl)piperazine 10 exhibits a subnanomolar affinity for the sigma-1 site, whereas the corresponding o-nitro compound 9 shows the highest affinity for the sigma-2 site (K-i = 4.9 nM). Compounds with a free amino terminus were designed as precursors for use as bioconjugated affinity compounds. Some of these compounds displayed high affinity for sigma-1 and moderate affinity for sigma-2 sites and are currently used for the purification and characterization of the receptor subtypes. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, NIH, 8 Ctr Dr,MSC 0815, Bethesda, MD 20892 USA. NR 40 TC 21 Z9 23 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 3 PY 1998 VL 41 IS 25 BP 4950 EP 4957 DI 10.1021/jm980143k PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 146ZB UT WOS:000077462800007 PM 9836612 ER PT J AU Tutonda, MG Buckheit, RW Agrawal, VK Broom, AD AF Tutonda, MG Buckheit, RW Agrawal, VK Broom, AD TI Antiviral oligo- and polyribonucleotides containing selected triazolo[2,3-a]purines SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID AIDS-RELATED COMPLEX; PHASE-I; HIV-1; CYTOMEGALOVIRUS; THERAPY; TRIAL; CELLS; AZT AB Several amphipathic (hydrophobic base, hydrophilic backbone) polyribonucleotides have recently been shown to have potent antiviral activity against HIV and human cytomegalovirus (HCMV). The working hypothesis developed during these studies was that the ability to form an ordered, non-hydrogen-bonded array in solution was an important criterion for activity. To explore further the role of structure and molecular size on the inhibition of virus replication, one new polynucleotide and two 32-mer oligonucleotides based on the triazolo[2,3-a]purine ring system have now been prepared. High-molecular-weight polynucleotide 4a (PTPR) and sulfur-containing 32-mer 5b (TTPR) were moderately active against HIV but showed greater potency against HDMV than ganciclovir. Both 4a and 5b gave clear evidence of cooperative melting behavior, whereas inactive 32-mer 5a showed no such behavior. C1 Univ Utah, Dept Med Chem, Salt Lake City, UT 84112 USA. Aral Biosynthet Inc, Salt Lake City, UT 84115 USA. Frederick Canc Res & Dev Ctr, So Res Inst, Frederick, MD 21701 USA. RP Broom, AD (reprint author), Univ Utah, Dept Med Chem, 20 South 2030 East,295 Biomed Polymers Res Bldg, Salt Lake City, UT 84112 USA. FU NCI NIH HHS [P30 CA 42014]; NIAID NIH HHS [R01 AI 27692] NR 21 TC 8 Z9 8 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 3 PY 1998 VL 41 IS 25 BP 4958 EP 4964 DI 10.1021/jm9802057 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 146ZB UT WOS:000077462800008 PM 9836613 ER PT J AU Coop, A Rice, KC AF Coop, A Rice, KC TI L-selectride as a convenient reagent for the selective cleavage of carbamates SO TETRAHEDRON LETTERS LA English DT Article DE carbamates; cleavage reactions AB L-Selectride(R) was shown to Selectively cleave methyl carbamates in the presence of more sterically demanding carbamates, including the selective cleavage of a methyl carbamate in the presence of an N-Boc group. Published by Elsevier Science Ltd. C1 NIDDKD, Med Chem Lab, Bethesda, MD 20892 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, Bldg 8,Rm B1-23, Bethesda, MD 20892 USA. NR 9 TC 4 Z9 4 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD DEC 3 PY 1998 VL 39 IS 49 BP 8933 EP 8934 DI 10.1016/S0040-4039(98)02018-8 PG 2 WC Chemistry, Organic SC Chemistry GA 140GU UT WOS:000077080000003 ER PT J AU Ravenscroft, MS Bateman, KE Shaffer, KM Schessler, HM Jung, DR Schneider, TW Montgomery, CB Custer, TL Schaffner, AE Liu, QY Li, YX Barker, JL Hickman, JJ AF Ravenscroft, MS Bateman, KE Shaffer, KM Schessler, HM Jung, DR Schneider, TW Montgomery, CB Custer, TL Schaffner, AE Liu, QY Li, YX Barker, JL Hickman, JJ TI Developmental neurobiology implications from fabrication and analysis of hippocampal neuronal networks on patterned silane-modified surfaces SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SELF-ASSEMBLED MONOLAYERS; COPLANAR MOLECULAR ASSEMBLIES; CELL ATTACHMENT; SPATIAL-DISTRIBUTION; MAMMALIAN-CELLS; IN-VITRO; CULTURE; GROWTH; RAT; FILMS AB We have determined the parameters necessary to fabricate reproducible neuronal patterns which we are using to begin studying fundamental issues in developmental neurobiology. The addition of a beam homogenizer, as well as a new surface preparation, has enabled the routine production of reproducible, high-resolution (2-20 mu m) organosilane patterns. The effects of surface preparation and beam dosage were monitored using X-ray photoelectron spectroscopy (XPS) and proof of patterning is provided by high-resolution imaging XPS. We also report the guidance of neuronal adhesion and neurite outgrowth and the creation of reproducibly defined circuits of embryonic (E18-19) rat hippocampal neurons using these patterned surfaces in vitro. We have achieved a >50% rate of pattern formation, and at times the rate approaches 90%. We are using these patterns to address the issue of how geometric pattern cues might be used to affect cell-to-cell communication and we report the preliminary results on the synaptic development of the hippocampal neurons using dual patch-clamp electrophysiology. We monitored neurite outgrowth and the emergence of both spontaneous and evoked synaptic activity for both patterned and unpatterned (control) hippocampal cultures. The results indicate the intriguing possibility that geometry itself may be a modulating or trophic factor for cell development. C1 Sci Applicat Int Corp, Biotechnol Res & Applicat Div, Rockville, MD 20850 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Hickman, JJ (reprint author), George Washington Univ, Dept Chem, Washington, DC 20052 USA. EM jhickman@gwu.edu NR 58 TC 84 Z9 87 U1 0 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 2 PY 1998 VL 120 IS 47 BP 12169 EP 12177 DI 10.1021/ja973669n PG 9 WC Chemistry, Multidisciplinary SC Chemistry GA 145JG UT WOS:000077367000001 ER PT J AU Ottiger, M Bax, A AF Ottiger, M Bax, A TI Determination of relative N-H-N N-C ', C-alpha-C ', andC(alpha)-H-alpha effective bond lengths in a protein by NMR in a dilute liquid crystalline phase SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SOLID-STATE NMR; CHEMICAL-SHIFT ANISOTROPY; MAGNETIC-FIELD DEPENDENCE; HUMAN UBIQUITIN; PHOSPHOLIPID MICELLES; PEPTIDE-BOND; ANGLE-PSI; RELAXATION; DIPOLAR; SPECTROSCOPY AB Weak alignment of solute macromolecules with the magnetic field can be achieved in a dilute, aqueous liquid crystalline phase of planar phospholipid micelles, consisting of mixtures of dimyristoylphosphatidylcholine (DMPC) and dihexanoylphosphatidylcholine (DHPC). Alignment of proteins in sub a medium is sufficiently weak to retain the simplicity of the isotropic solution NMR spectrum but strong enough to permit accurate measurement of residual one-bond dipolar couplings. Highly accurate one-bond N-H-N, C-alpha-H-alpha, C-alpha-C', and C'-N and two-bond C'-H-N dipolar couplings were measured in C-13/N-15-enriched ubiquitin. Together with knowledge of the protein's three-dimensional structure, the dipolar couplings permit calculation of the relative, vibrationally corrected average bond lengths for these interactions. Assuming a C'-N bond length of 1.329 Angstrom (Engh, R. A.; Huber, R. Acta Crystallogr. 1992, A47, 392-400), the relative C-alpha-C' distance of 1.526 Angstrom is found to be in excellent agreement with results from Engh and Huber (1.525 Angstrom). Using a C'-N bond length of 1.329 Angstrom as a reference, N-H-N (1.041 @ 0.006 Angstrom) and C-alpha-H-alpha (1.117 @ 0.007 Angstrom) are considerably longer than equilibrium or average internuclear distances derived from ab initio calculations, electron diffraction, neutron diffraction, or microwave spectroscopy. The increase in effective N-H-N and C-alpha-H-alpha bond lengths is attributed to a decrease in the corresponding dipolar couplings resulting from fast librations, which must be of considerably larger amplitude than the C-alpha-C' and C'-N angular fluctuations. Accurate knowledge of the relative effective N-H-N, C-alpha-H-alpha, C-alpha-C', C'-N, and two-bond C'-H-N effective internuclear distances is essential for determining the magnitude of the molecular alignment tensor, for using the dipolar couplings in macromolecular structure determination, and for extracting angular information from recently described cross correlation experiments. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. NR 83 TC 192 Z9 194 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD DEC 2 PY 1998 VL 120 IS 47 BP 12334 EP 12341 DI 10.1021/ja9826791 PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 145JG UT WOS:000077367000020 ER PT J AU Newton, DL Rybak, SM AF Newton, DL Rybak, SM TI Unique recombinant human ribonuclease and inhibition of Kaposi's sarcoma cell growth SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HUMAN CHORIONIC-GONADOTROPIN; NONSECRETORY RIBONUCLEASE; PREGNANT-WOMEN; PROTEIN; LINE; CYTOTOXICITY; EXPRESSION; SEQUENCE; HOMOLOGY; RNASE AB Background: Preparations of human chorionic gonadotropin (hCG) have been shown to exhibit anti-Kaposi's sarcoma (KS) activity, but the identity of the responsible agent(s) remains controversial. One candidate agent is an eosinophil-derived neurotoxin (EDN)-like polypeptide that contaminates preparations of hCG, We have genetically engineered a unique form of hEDN, which is a ribonuclease, and have evaluated the cytotoxic effects of the recombinant protein on KS Y-1 cells and on cells of other cancer types. Methods: The amino-terminus of hEDN was extended by four amino acid residues, corresponding to the proximal part of the hEDN signal peptide (serine, leucine, histidine, and valine; positions -4 to -1, respectively), by use of the polymerase chain reaction and an hEDN complementary DNA, The recombinant protein was isolated from bacterial inclusion bodies. The cytotoxic activity of this hEDN variant, (-4)rhEDN, was tested on KS Y-1 cells and human glioma, melanoma, breast carcinoma, and renal carcinoma cells. Results: Approximately half of the anti-KS activity in a crude commercial preparation of hCG was associated with a polypeptide that reacted with anti-recombinant-hEDN (rhEDN) polyclonal antibodies, Although rhEDN protein displayed little cytotoxicity against KS Y-l cells (IC50 [50% inhibition concentration] = >100 mu g/mL), (-4)rhEDN markedly inhibited cell viability (IC50 = 6 mu g/mL). Neither version of rhEDN inhibited the viability of other tested human cancer cell types. Conclusions: A four amino acid extension of the amino-terminus of rhEDN confers cytotoxicity against KS Y-1 cells in vitro, Design of the (-4)rhEDN variant was based on the sequence of a natural human protein associated with hCG, Our results suggest that (-4)rhEDN is one of the agents in hCG responsible for anti-KS activity. A purified molecule is thus available for in vitro and in vivo mechanistic and, possibly, future clinical studies. C1 NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Pharmacol & Expt Therapeut Sect, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21701 USA. RP Rybak, SM (reprint author), NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Bldg 567,Rm 162, Frederick, MD 21702 USA. FU NCI NIH HHS [N01CO56000] NR 27 TC 29 Z9 31 U1 0 U2 0 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 DEC 2 PY 1998 VL 90 IS 23 BP 1787 EP 1791 DI 10.1093/jnci/90.23.1787 PG 5 WC Oncology SC Oncology GA 144CV UT WOS:000077296900011 PM 9839518 ER PT J AU Wolmark, N Bryant, J Smith, R Grem, J Allegra, C Hyams, D Atkins, J Dimitrov, N Oishi, R Prager, D Fehrenbacher, L Romond, E Colangelo, L Fisher, B AF Wolmark, N Bryant, J Smith, R Grem, J Allegra, C Hyams, D Atkins, J Dimitrov, N Oishi, R Prager, D Fehrenbacher, L Romond, E Colangelo, L Fisher, B TI Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National surgical adjuvant breast and bowel project protocol C-05 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ADVANCED COLORECTAL-CARCINOMA; CLINICAL-TRIALS; FLUOROURACIL; CANCER AB Background: National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 showed a benefit from leucovorin (LV)-modulated 5-fluorouracil (5-FU) adjuvant therapy (5-FU + LV) in patients with Dukes' stage B or C carcinoma of the colon. Preclinical and clinical phase I/II data suggested that interferon alfa-2a (IFN) enhanced the efficacy of 5-FU therapy, Accordingly, in NSABP protocol C-05, the addition of recombinant IFN to 5-FU + LV adjuvant therapy was evaluated, Methods: Data are presented for 2176 patients with Dukes' stage B or C cancer entered onto protocol C-05 during the period from October 1991 through February 1994, Individuals with an Eastern Cooperative Oncology Group performance status of 0-2 (ranges from fully active to ambulatory and capable of self-care but unable to work), a life expectancy of at least 10 years, and curative resection were stratified by sex, disease stage, and number of involved lymph nodes and were randomly assigned to receive either 5-FU + LV or 5-FU + LV + IFN; the mean time on the study as of June 30, 1997, was 54 months, All statistical tests were two-sided. Results: There was no statistically significant difference in either disease-free survival (5-FU + LV, 69%; 5-FU + LV + IFN, 70%) or overall survival (5-FU + LV, 80%; 5-FU + LV + IFN, 81%) at 4 years of follow-up. Toxic effects of grade 3 or higher were observed in 61.8% of subjects in the group treated with 5-FU + LV and in 72.1% of subjects in the group treated with 5-FU + LV + IFN; fewer patients in the latter group completed protocol-mandated 5-FU + LV therapy than in the former group (77.1% versus 88.5%), Conclusion: The addition of IFN to 5-FU + LV adjuvant therapy confers no statistically significant benefit, but it does increase toxicity. C1 NSABP, Operat Ctr, Pittsburgh, PA 15212 USA. NSABP, Ctr Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Dept Stat, Pittsburgh, PA USA. Univ Pittsburgh, Dept Biostat, Pittsburgh, PA 15261 USA. NCI, Bethesda, MD 20892 USA. Allegheny Univ Hlth Sci, Pittsburgh, PA USA. S Eastern Med Oncol Ctr, Goldsboro, NC USA. Michigan State Univ, E Lansing, MI 48824 USA. Univ Hawaii, Honolulu, HI 96822 USA. Lehigh Valley Hosp Ctr, Allentown, PA 18102 USA. Kaiser Permanente Med Ctr, Vallejo, CA USA. Univ Kentucky, Lexington, KY USA. RP Wolmark, N (reprint author), NSABP, Operat Ctr, E Commons Profess Bldg,4 Allegheny Ctr,5th Floor, Pittsburgh, PA 15212 USA. NR 25 TC 79 Z9 81 U1 0 U2 1 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 DEC 2 PY 1998 VL 90 IS 23 BP 1810 EP 1816 DI 10.1093/jnci/90.23.1810 PG 7 WC Oncology SC Oncology GA 144CV UT WOS:000077296900014 PM 9839521 ER PT J AU Rakkar, ANS Li, ZW Katayose, Y Kim, M Cowan, KH Seth, P AF Rakkar, ANS Li, ZW Katayose, Y Kim, M Cowan, KH Seth, P TI Adenoviral expression of the cyclin-dependent kinase inhibitor p27(Kip1): a strategy for breast cancer gene therapy SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID IN-VIVO; P53; ARREST; CELLS; APOPTOSIS C1 NCI, Med Breast Canc Sect, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP Seth, P (reprint author), NIH, Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. NR 16 TC 20 Z9 20 U1 0 U2 1 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 DEC 2 PY 1998 VL 90 IS 23 BP 1836 EP 1838 DI 10.1093/jnci/90.23.1836 PG 3 WC Oncology SC Oncology GA 144CV UT WOS:000077296900018 PM 9839525 ER PT J AU Litvan, I AF Litvan, I TI Progressive supranuclear palsy revisited (vol 98, pg 73, 1998) SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Correction ID STEELE-RICHARDSON-OLSZEWSKI; POSITRON EMISSION TOMOGRAPHY; MULTIPLE SYSTEM ATROPHY; FRONTAL-LOBE DYSFUNCTION; E EPSILON-4 ALLELE; TAU-POSITIVE GLIA; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; STRIATONIGRAL DEGENERATION; CORTICOBASAL DEGENERATION AB Current understanding on the historic, epidemiologic, genetic, clinical, neuropathologic, neurochemical, diagnostic and therapeutic aspects of progressive supranuclear palsy (PSP) are revisited. In addition, new research directions are described. C1 Natl Inst Neurol Disorders & Stroke, NIH, Neuropharmacol Unit,Def & Vet Head Injury Program, Henry M Jackson Fdn,Med Neurol Branch, Bethesda, MD 20892 USA. RP Litvan, I (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Neuropharmacol Unit,Def & Vet Head Injury Program, Henry M Jackson Fdn,Med Neurol Branch, Fed Bldg,Room 714, Bethesda, MD 20892 USA. NR 145 TC 1 Z9 1 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD DEC PY 1998 VL 98 IS 6 BP 468 EP A84 PG 13 WC Clinical Neurology SC Neurosciences & Neurology GA 150TD UT WOS:000077680600019 ER PT J AU Hiraiwa, H Hamazaki, M Tsuruta, S Hattori, H Mimaya, J Hasegawa, S Kohno, S Aoki, K AF Hiraiwa, H Hamazaki, M Tsuruta, S Hattori, H Mimaya, J Hasegawa, S Kohno, S Aoki, K TI Infantile hemangioendothelioma of the thymus with massive pleural effusion and Kasabach-Merritt syndrome: Histopathological, flow cytometrical analysis of the tumor SO ACTA PAEDIATRICA JAPONICA LA English DT Article DE DNA ploidy; infantile hemangioendothelioma; Kasabach-Merritt syndrome; massive pleural effusion; thymus AB Infantile hemangioendothelioma of the thymus is a rare disease. We describe a patient who developed a large anterior mediastinal mass, severe thrombotytopenia and massive pleural effusion at 1 month of age. Glucocorticosteroid and irradiation therapy had no effect on either the tumor size or clinical symptoms and the tumor was resected subtotally. Three months after the subtotal resection, the remaining tumor had almost disappeared and the symptoms had resolved. The patient has now been well far 1 year after surgery without evidence of recurrence. The tumor tissue was characterized by prominent vascular endothelial proliferation intermixed with a normal thymic structure, producing a picture consistent with that of an infantile hemangioendothelioma in the thymus. Immunohistochemically, the tumor cells showed positive staining for vimentin, factor Vm and CD34. The DNA stemline and proliferative activity were examined by how cytometry, which revealed a diploid stemline with a low growth fraction. DNA content and cell cycle analyses of the tumor tissue may be useful for predicting the biological behavior of the tumor. C1 Shizuoka Childrens Hosp, Dept Pathol, Shizuoka 420, Japan. Shizuoka Childrens Hosp, Dept Pediat, Shizuoka 420, Japan. Shizuoka Childrens Hosp, Dept Surg, Shizuoka 420, Japan. Shizuoka Childrens Hosp, Dept Radiol, Shizuoka 420, Japan. RP Hiraiwa, H (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bldg 10,Room 9S241, Bethesda, MD 20892 USA. NR 10 TC 3 Z9 3 U1 0 U2 0 PU BLACKWELL SCIENCE ASIA PI CARLTON PA 54 UNIVERSITY ST, P O BOX 378, CARLTON, VICTORIA 3053, AUSTRALIA SN 0374-5600 J9 ACTA PAEDIATR JAPON JI Acta Pediatr. Jpn. PD DEC PY 1998 VL 40 IS 6 BP 604 EP 607 PG 4 WC Pediatrics SC Pediatrics GA 153TR UT WOS:000077849200015 PM 9893299 ER PT J AU Chalovich, JM Sen, A Resetar, A Leinweber, B Fredricksen, RS Lu, F Chen, YD AF Chalovich, JM Sen, A Resetar, A Leinweber, B Fredricksen, RS Lu, F Chen, YD TI Caldesmon: binding to actin and myosin and effects on elementary steps in the ATPase cycle SO ACTA PHYSIOLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT 3rd Acta Physiologica Scandinavica International Symposium on Signalling Mechanisms in Vascular Smooth Muscle CY MAY 21-25, 1998 CL MARGRETETORP, SWEDEN SP Acta Physiol Scandinav DE actin binding; ATPase activity; caldesmon; kinetics; product release; regulation of contraction; smooth muscle contraction; weak binding ID SMOOTH-MUSCLE CALDESMON; DIMENSIONAL HOMOGENEOUS LATTICE; ACTOMYOSIN SUBFRAGMENT-1 ATPASE; RELAXED FIBER STIFFNESS; COOPERATIVE BINDING; HEAVY-MEROMYOSIN; TROPONIN-TROPOMYOSIN; PARALLEL INHIBITION; MOLECULAR-WEIGHT; FORCE GENERATION AB The actin binding protein caldesmon inhibits the actin-activation of myosin ATPase activity. The steps in the cycle of ATP hydrolysis that caldesmon could inhibit include: (1) the binding of myosin to actin, (2) the transition between any two actin-myosin states and (3) the distribution between inactive and active states of actin. The analysis of these possibilities is complicated because caldesmon binds to both myosin and actin and because each caldesmon molecule binds to several actin monomers. This paper reviews procedures for analysing these interactions and summarizes current information on the stability and dynamics of the interaction of caldesmon with actin and myosin. Possible effects of caldesmon on transitions within the ATPase cycle of actomyosin are also discussed. C1 E Carolina Univ, Sch Med, Dept Biochem, Greenville, NC 27858 USA. NIDDKD, Math Res Branch, NIH, Bethesda, MD 20814 USA. RP Chalovich, JM (reprint author), E Carolina Univ, Sch Med, Dept Biochem, 5E-122 Brody Bldg, Greenville, NC 27858 USA. OI Chalovich, Joseph/0000-0002-1243-4055 FU NIAMS NIH HHS [AR35216] NR 59 TC 39 Z9 39 U1 0 U2 0 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0001-6772 J9 ACTA PHYSIOL SCAND JI Acta Physiol. Scand. PD DEC PY 1998 VL 164 IS 4 BP 427 EP 435 PG 9 WC Physiology SC Physiology GA 153RX UT WOS:000077847400011 PM 9887966 ER PT J AU Metter, EJ Conwit, R Metter, B Pacheco, T Tobin, J AF Metter, EJ Conwit, R Metter, B Pacheco, T Tobin, J TI The relationship of peripheral motor nerve conduction velocity to age-associated loss of grip strength SO AGING-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE age; grip strength; muscle force; nerve conduction velocity; motor nerve ID MUSCLE MASS; MEN; ADULTS; WOMEN; UNITS; STIMULATION; NUMBERS AB Age-associated loss of muscle strength is attributed to decreasing muscle mass. Both strength and mass are dependent on peripheral innervation. However, the association between nerve Junction and age-associated strength loss has not been studied directly. The median nerve contribution to grip strength was estimated using nerve conduction velocity (NCV). Grip strength and NCV were measured in 197 male participants of the Baltimore Longitudinal Study of Aging (age 59.0+/-13.9 years). Multiple regression and path analyses were used separately to examine the association between median NCV and grip strength. Grip strength showed a negative quadratic relationship with increasing age (r(2)=0.32, p<0.001) with a major change in slope occurring after 64.7 years of age. Median NCV (r(2)=0.14, p<0.001) declined linearly with age. Median NCV significantly contributed to grip strength (p<0.001) while controlling for forearm muscle mass (forearm circumference), self-reported 24-hour caloric expenditures, and age. The median nerve has an independent contribution to age-associated levels of muscle strength. The level of the effect was smaller than what could be attributed to forearm muscle mass or age. (C) 1998, Editrice Kurtis. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Metter, EJ (reprint author), NIA, Gerontol Res Ctr, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 39 TC 27 Z9 27 U1 0 U2 5 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 0394-9532 J9 AGING-CLIN EXP RES JI Aging-Clin. Exp. Res. PD DEC PY 1998 VL 10 IS 6 BP 471 EP 478 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 164FU UT WOS:000078453200007 PM 10078317 ER PT J AU Skurnick, JH Abrams, J Kennedy, CA Valentine, SN Cordell, JR AF Skurnick, JH Abrams, J Kennedy, CA Valentine, SN Cordell, JR TI Maintenance of safe sex behavior by HIV-serodiscordant heterosexual couples SO AIDS EDUCATION AND PREVENTION LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INJECTING DRUG-USERS; CONDOM USE; RISK; PARTNERS; TRANSMISSION; INFECTION; MEN AB We present findings from a prospective study of heterosexual HIV transmission in stable New Jersey couples who are serodiscordant for HIV and in which the uninfected partner is at risk solely from heterosexual contact. One hundred thirty-one couples were interviewed at enrollment and 6-month follow-up. This report describes couples' sexual behavior before and after knowledge of infective risk and examines associations of behavior with clinical and demographic characteristics. We observed that HIV serodiscordant couples' habitual sexual practices, drug and alcohol use, and measure of psychological distress may predict difficulty in adopting and maintaining safe sex. An understanding of common risky sexual behavior patterns and characteristic correlates of risk taking may prove useful for counseling individuals at risk and their infected partners and may contribute to the development of effective public health messages targeted to eliminate unsafe sexual contact. C1 Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Prevent Med & Community Hlth, Newark, NJ 07103 USA. Henry Ford Hlth Syst, Div Biostat & Res Epidemiol, Detroit, MI USA. Procter & Gamble Pharmaceut, Cincinnati, OH USA. NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Psychiat, Newark, NJ 07103 USA. RP Skurnick, JH (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Prevent Med & Community Hlth, MSB-F514,185 S Orange Ave, Newark, NJ 07103 USA. FU PHS HHS [N01-A1-95013] NR 22 TC 25 Z9 25 U1 0 U2 0 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0899-9546 J9 AIDS EDUC PREV JI Aids Educ. Prev. PD DEC PY 1998 VL 10 IS 6 BP 493 EP 505 PG 13 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 155MD UT WOS:000077950200002 PM 9883285 ER PT J AU Deuschl, G Hallett, M AF Deuschl, G Hallett, M TI Focal dystonias: From occupational cramp to sensomotor disease that can be treated SO AKTUELLE NEUROLOGIE LA German DT Review ID IDIOPATHIC TORSION DYSTONIA; PRIMARY SOMATOSENSORY CORTEX; GANGLIA MOTOR CONTROL; MASSETER INHIBITORY REFLEX; REPETITIVE STRAIN INJURY; BASAL GANGLIA; SPASMODIC TORTICOLLIS; RECIPROCAL INHIBITION; WRITERS CRAMP; SUBTHALAMIC NUCLEUS AB Focal dystonias have been clinically described in detail since the last century and have been referred to by Oppenheim as occupational cramps ("Beschaftigungskrampfe"). However, they have long been interpreted as psychogenic disorders. Since the seventies of this century an increasing body of evidence has shown that the main symptom of involuntary muscular hyperactivity is associated with a disturbance of inhibitory spinal and brainstem reflexes. This is believed to be due to abnormalities of cortical movement preparation and probably also to an alteration of the cortical processing of afferent information. Genetic studies and recently developed animal experiments provide new clues to the classification of dystonic disorders and the interpretation of such curious findings as the geste antagoniste-manoeuver or the causalgia-dystonia syndrome. Parallel to this development of pathogenetic research new therapeutic strategies mainly dominated by the application of botulinum toxin have been developed to treat these conditions. C1 Univ Kiel, Neurol Klin, D-24105 Kiel, Germany. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Deuschl, G (reprint author), Univ Kiel, Neurol Klin, Niemannsweg 147, D-24105 Kiel, Germany. RI Deuschl, Gunther/A-7986-2010 NR 102 TC 5 Z9 5 U1 0 U2 0 PU GEORG THIEME VERLAG PI STUTTGART PA P O BOX 30 11 20, D-70451 STUTTGART, GERMANY SN 0302-4350 J9 AKTUEL NEUROL JI Aktuelle Neurol. PD DEC PY 1998 VL 25 IS 8 BP 320 EP 328 DI 10.1055/s-2007-1017707 PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 160ZD UT WOS:000078262500002 ER PT J AU Monroe, MB Tataranni, PA Pratley, R Manore, MM Skinner, JS Ravussin, E AF Monroe, MB Tataranni, PA Pratley, R Manore, MM Skinner, JS Ravussin, E TI Lower daily energy expenditure as measured by a respiratory chamber in subjects with spinal cord injury compared with control subjects SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE respiratory chamber; energy expenditure; sympathetic nervous system; spontaneous physical activity; spinal cord injury; thermic effect of food; respiratory quotient ID SOFT-TISSUE COMPOSITION; X-RAY ABSORPTIOMETRY; BODY-WEIGHT GAIN; FACULTATIVE THERMOGENESIS; GLUCOSE; OBESE; MUSCLE; MEN AB Background: This study was designed to determine the effect of chronic spinal cord injury on daily energy expenditure. Objective: We hypothesized that both resting and total energy expenditure would be lower in spinal cord-injured (SCI) subjects than in control subjects because of lower sympathetic nervous system activity and reduced levels of physical activity in SCI subjects. Design: Twenty-four-hour energy expenditure (24-h EE), resting metabolic rate (RMR), sleeping metabolic rate, spontaneous physical activity, the thermic effect of food (TEF), and 24-h respiratory quotient were measured by using a respiratory chamber in 10 male SCI subjects (injury ranged from level C6 to L3) and 59 age-matched, noninjured, male control subjects. Results: The 24-h EE was lower in SCI than in control subjects (7824 =/- 305 compared with 9941 +/- 188 kJ, P < 0.01). After adjustment for fat-free mass, fat mass, and age, 24-h EE was still lower (-753 kJ/d, P < 0.01) in SCI than in control subjects. Spontaneous physical activity measured by a radar system was also significantly lower (4.6 +/- 0.6% compared with 6.5 +/- 0.3% of time, P < 0.01) in SCI than in control subjects. In absolute value (7347 +/- 268 compared with 9251 +/- 1326 kJ/d, P < 0.01) or after adjustment for fat-free mass, fat mass, and age (-678 kJ/d, P < 0.01), RMR was also lower in SCI than in control subjects. TEF was significantly lower in SCI than in control subjects (987 +/- 142 compared with 1544 +/- 213 kJ/d, representing 12.9% and 15.9% of total energy intake, respectively, P < 0.05). The sleeping metabolic rate and 24-h respiratory quotient did not differ significantly between groups. Conclusions: The 24-h EE was significantly lower in SCI than in control subjects. This difference can be explained by the lower levels of physical activity, and lower RMR and TEF values, in SCI subjects. C1 Univ Colorado, Boulder, CO 80309 USA. Arizona State Univ, Dept Exercise Sci & Phys Educat, Tempe, AZ 85287 USA. NIDDK, Natl Inst Hlth, Phoenix, AZ USA. RP Monroe, MB (reprint author), Univ Colorado, Campus Box 354, Boulder, CO 80309 USA. EM monroem@Colorado.edu FU NIOSH CDC HHS [OH94-DK-P011] NR 31 TC 72 Z9 73 U1 0 U2 8 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 1998 VL 68 IS 6 BP 1223 EP 1227 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 144FW UT WOS:000077304200013 PM 9846850 ER PT J AU Wu, AH Ziegler, RG Nomura, AMY West, DW Kolonel, LN Horn-Ross, PL Hoover, RN Pike, MC AF Wu, AH Ziegler, RG Nomura, AMY West, DW Kolonel, LN Horn-Ross, PL Hoover, RN Pike, MC TI Soy intake and risk of breast cancer in Asians and Asian Americans SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT 2nd International Symposium on the Role of Soy in Preventing and Treating Chronic Disease CY SEP 15-19, 1996 CL BRUSSELS, BELGIUM SP Alpo Nat Soyfoods, Amer Inst Canc Res, Amer Soybean Assoc, Archer Daniels Midland Co, Cent Soya Co, Foreign Agr Serv, Illinois Soybean Assoc & Illinois Soybean Program Operating Board, Indiana Soybean Dev Council, Infant Formula Council, Iowa Soybean Promot Board, Michigan Soybean Promot Comm, Minnesota Soybean Res & Promot Council, Monsanto Co, Morinaga Nutr Foods Inc, Nebraska Soybean Board, Ohio Soybean Council, Ontario Soybean Growers Mkt Board, Protein Technol Int, Sanitarium Hlth Foods, Sojaxa, Soyfoods Assoc Amer, United Soybean Board, Wyeth Nutr Int DE diet; soy; breast cancer; Asians; Asian Americans; hormones; women ID POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; MENOPAUSAL STATUS; DIET; ESTROGENS; HORMONES; JAPAN; FAT; WESTERNIZATION; REDUCTION AB Evidence from case-control studies suggests, although not entirely consistently, that soy intake may protect against breast cancer. The designs and findings of studies conducted in Asian women living in Japan, Singapore, China, and the United States are reviewed. Because of the considerably higher intake of soy by native Asians than by Asian Americans living in California and Hawaii, these studies investigated different segments of the dose-response relation between soy intake and breast cancer risk. Data are not sufficient to determine the amount or frequency of soy intake effective in protecting against breast cancer. Of concern is that soy intake may be homogeneously high in Asia, making it difficult to identify differences in breast cancer risk between high and moderate daily consumers. In studies conducted in Asian Americans, it is difficult to be certain that soy intake is not a marker of other factors related to Western lifestyle that are causally associated with risk of breast cancer. Additional studies assessing the role of soy and breast cancer are needed. These studies should assess intake of all food sources of soy, considering portion size as well as other dietary and nondietary factors that may confound the soy-breast cancer association. A better understanding of the mechanisms whereby soy intake may influence the risk of breast cancer is also needed. Dietary intervention studies with soy will provide information on the acute effects of soy on endogenous hormone concentrations. Cross-sectional and longitudinal studies are necessary to investigate the longer-term relations between hormone concentrations and soy intake in women. C1 Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. NCI, Environm Epidemiol Branch, Div Canc Etiol, Bethesda, MD 20892 USA. Univ Hawaii, Canc Res Ctr Hawaii, Program Epidemiol, Honolulu, HI 96813 USA. No Calif Canc Ctr, Union City, CA 94587 USA. RP Wu, AH (reprint author), Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, 1441 Eastlake Ave MS44,POB 33800, Los Angeles, CA 90033 USA. EM annawu@hsc.usc.edu NR 46 TC 126 Z9 134 U1 0 U2 8 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC PY 1998 VL 68 IS 6 SU S BP 1437S EP 1443S PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 145VM UT WOS:000077392300020 PM 9848513 ER PT J AU Riley, NM Bild, DE Cooper, L Schreiner, P Smith, DE Sorlie, P Thompson, JK AF Riley, NM Bild, DE Cooper, L Schreiner, P Smith, DE Sorlie, P Thompson, JK TI Relation of self-image to body size and weight loss attempts in black women - The CARDIA study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE blacks; body constitution; body image; body mass index; self concept; weight loss; weight perception; women ID CORONARY-ARTERY DISEASE; CARDIOVASCULAR-DISEASE; RACIAL-DIFFERENCES; AFRICAN-AMERICAN; NATIONAL-HEALTH; BLOOD-PRESSURE; HEART-DISEASE; YOUNG BLACK; WHITE WOMEN; OBESITY AB It has been suggested that the prevalence of obesity in black women is high partly because self-image in black women is not strongly dependent on body size. To determine associations between self-image, body size, and dieting behavior among black women, the authors assessed an Appearance Evaluation Subscale (AES)score (range, Id), a Body Image Satisfaction (BIS) score(range,2-11),and reported dieting behavior in a population-based sample of 1,143 black women aged 24-42 years from the fourth follow-up examination (1992-1993) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Lower AES and BIS scores indicate poorer self-image and lower body size satisfaction, respectively. After adjustment for age, education, smoking, and physical activity, women in the lowest, middle, and highest tertiles of body mass index (weight (kg)/height (m)(2)) had mean AES scores of 3.7, 3.3, and 2.9, respectively (p < 0.001), and mean BIS scores of 7.8, 6.7, and 5.9, respectively (p < 0.001). After additional control for body mass index as a continuous variable, both AES and BIS scores were inversely related to ever dieting, current dieting, and previous weight loss of 10 pounds (4.5 kg) or more in all tertiles of body mass index. These results suggest that among black women, a higher body mass index is associated with poorer self-image and lower body size satisfaction and that these perceptions may be an avenue to promoting weight control. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Alabama, Sch Med, Div Prevent Med, Birmingham, AL USA. Univ S Florida, Dept Psychol, Coll Arts & Sci, Tampa, FL 33620 USA. RP Riley, NM (reprint author), NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [N01-HC-48047, N01-HC-48048, TP-HL-1000] NR 40 TC 43 Z9 43 U1 2 U2 3 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 1 PY 1998 VL 148 IS 11 BP 1062 EP 1068 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 145CR UT WOS:000077353900006 PM 9850128 ER PT J AU Ioannidis, JPA Lau, J AF Ioannidis, JPA Lau, J TI Heterogeneity of the baseline risk within patient populations of clinical trials - A proposed evaluation algorithm SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE algorithms; clinical trials; epidemiologic methods; meta-analysis; models; statistical; randomization; risk; study design ID IMMUNODEFICIENCY-VIRUS INFECTION; RANDOMIZED TRIALS; HIV-1 INFECTION; METAANALYSIS; PROGRESSION; ZIDOVUDINE; EXAMPLE; DISEASE; PLASMA; MODELS AB In this paper, the authors present an evaluation algorithm fell systematic assessment of the observed heterogeneity in disease risk within trial populations. Predictive models are used to estimate the predicted patient hazards, the odds of having an event in the upper risk quartile (ODU) and the lower risk quartile (ODL), and the odds ratio (rate ratio for time-to-event analyses) for having an event in the upper risk quartile versus the lower risk quartile (extreme quartile odds ratio (EQuOR) and extreme quartile rate ratio (EQuRR)). The ranges for these metrics depend on the extent to which predictors of the outcome of interest exist and are known and the extent to which data are collected in the trial, as well as on the eligibility criteria and the specific patients who are actually enrolled. ODU, ODL, and EQuOR values are used to systematically interpret the results for patients at different levels of risk, to evaluate generalizability, and to determine the need for subgroup analyses. Individual data for five outcomes from three trials (n = 842, 913, and 1,001, respectively) are used as examples. Observed EQuOR values ranged from 1.5 (very little predicted heterogeneity) to 59 (large heterogeneity). EQuRR values ranged from 2 to 46. ODU values ranged from 0.24 to 3.19 (generally high risk), and ODL values ranged from 0.01 (clinically negligible risk) to 0.16 (clinically meaningful risk). The algorithm may also be used for comparing diverse trials (e.g., in meta-analyses) and used prospectively for designing future trials, as shown in simulations. C1 NIAID, Therapeut Res Program, HIV Res Branch, Bethesda, MD 20892 USA. Tufts Univ, Sch Med, New England Med Ctr, Div Clin Care Res, Boston, MA 02111 USA. RP Ioannidis, JPA (reprint author), NIAID, Therapeut Res Program, HIV Res Branch, Solar Bldg 2C31,6003 Execut Blvd, Bethesda, MD 20892 USA. RI Ioannidis, John/G-9836-2011 NR 35 TC 41 Z9 41 U1 0 U2 1 PU JOHNS HOPKINS UNIV SCHOOL HYGIENE PUB HEALTH PI BALTIMORE PA 111 MARKET PLACE, STE 840, BALTIMORE, MD 21202-6709 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 1 PY 1998 VL 148 IS 11 BP 1117 EP 1126 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 145CR UT WOS:000077353900013 PM 9850135 ER PT J AU Cassady, JM DiPiro, JT Foster, TS Hak, LJ Hill, WT Kirshstein, R Lindley, CM Nahata, MC Robinson, JR Stinnett, AA Murphy, JE Manasse, HR Witmer, DR AF Cassady, JM DiPiro, JT Foster, TS Hak, LJ Hill, WT Kirshstein, R Lindley, CM Nahata, MC Robinson, JR Stinnett, AA Murphy, JE Manasse, HR Witmer, DR CA ASHP Task Force Science TI Report of the ASHP Task Force on Science SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Article C1 Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. Med Coll Georgia, Dept Pharm, Augusta, GA 30912 USA. Univ Kentucky, Coll Pharm, Lexington, KY 40536 USA. Univ Tennessee, Coll Pharm, Dept Clin Pharm, Memphis, TN 38163 USA. Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. Univ Wisconsin, Madison, WI 53706 USA. Univ Alabama, Sch Publ Hlth, Dept Hlth Care Org & Policy, Birmingham, AL 35294 USA. Univ Arizona, Coll Pharm, Dept Pharm Practice & Sci, Tucson, AZ 85721 USA. Amer Soc Hlth Syst Pharm, ASHP Sect Scli Specialists, Bethesda, MD 20814 USA. RP Cassady, JM (reprint author), Ohio State Univ, Coll Pharm, 500 W 12th Ave, Columbus, OH 43210 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD DEC 1 PY 1998 VL 55 IS 23 BP 2519 EP 2524 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 145CP UT WOS:000077353700015 ER PT J AU McIntosh, I Dreyer, SD Clough, MV Dunston, JA Eyaid, W Roig, CM Montgomery, T Ala-Mello, S Kaitila, I Winterpacht, A Zabel, B Frydman, M Cole, WG Francomano, CA Lee, B AF McIntosh, I Dreyer, SD Clough, MV Dunston, JA Eyaid, W Roig, CM Montgomery, T Ala-Mello, S Kaitila, I Winterpacht, A Zabel, B Frydman, M Cole, WG Francomano, CA Lee, B TI Mutation analysis of LMX1B gene in nail-patella syndrome patients SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID ANTENNAPEDIA HOMEODOMAIN; VERTEBRATE LIMB; SPECTROSCOPY; DOMAIN AB Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that NPS is the result of haploin-sufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations. C1 Johns Hopkins Univ, Inst Med Genet, Baltimore, MD 21287 USA. Johns Hopkins Univ, Predoctoral Training Program Human Genet, Baltimore, MD 21287 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD USA. Univ Newcastle, Dept Human Genet, Newcastle Upon Tyne, Tyne & Wear, England. Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland. Univ Mainz, Dept Pediat, Mainz, Germany. Chaim Sheba Med Ctr, Inst Human Genet, IL-52621 Tel Hashomer, Israel. Hosp Sick Children, Div Orthoped, Toronto, ON M5G 1X8, Canada. RP McIntosh, I (reprint author), Johns Hopkins Univ, Inst Med Genet, 600 N Wolfe St,Blalock 1012G, Baltimore, MD 21287 USA. FU NIAMS NIH HHS [AR44702, AR44738]; NIGMS NIH HHS [GM07814] NR 33 TC 84 Z9 85 U1 0 U2 1 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 DEC PY 1998 VL 63 IS 6 BP 1651 EP 1658 DI 10.1086/302165 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 151EL UT WOS:000077707700010 PM 9837817 ER PT J AU Montgomery, RA Geraghty, MT Bull, E Gelb, BD Johnson, M McIntosh, I Francomano, CA Dietz, HC AF Montgomery, RA Geraghty, MT Bull, E Gelb, BD Johnson, M McIntosh, I Francomano, CA Dietz, HC TI Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID EGF-LIKE DOMAIN; CALCIUM-BINDING; FIBRILLIN GENE; MISSENSE MUTATION; FBN1 MUTATIONS; DISORDERS; ORGANIZATION; MICROFIBRILS; FIBROBLASTS; PHENOTYPE AB Mutations in the FBN1 gene, which encodes fibrillin-1, cause Marfan syndrome (MFS) and have been associated with a wide range of milder, overlap phenotypes. The factors that modulate phenotypic severity, both between and within families, remain to be determined. This study examines the relationship between the FBN1 genotype and phenotype in families with extremely mild phenotypes and in those that show striking clinical variation among apparently affected individuals. In one family, clinically similar but etiologically distinct disorders are segregating independently. In another, somatic mosaicism for a mutant FBN1 allele is associated with subdiagnostic manifestations, whereas germ-line transmission of the identical mutation causes severe and rapidly progressive disease. A third family cosegregates mild mitral valve prolapse syndrome with a mutation in FBN1 that can be functionally distinguished from those associated with the classic MFS phenotype. These data have immediate relevance for the diagnostic and prognostic counseling of patients and their family members. C1 Johns Hopkins Univ, Sch Med, Dept Surg, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. Mt Sinai Hosp, Mt Sinai Sch Med, Dept Pediat, New York, NY 10029 USA. Mt Sinai Hosp, Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA. Nat Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD USA. RP Dietz, HC (reprint author), Johns Hopkins Univ Hosp, Dept Med, Ross 1170,720 Rutland Ave, Baltimore, MD 21205 USA. FU NIAMS NIH HHS [R01-AR41135] NR 29 TC 58 Z9 61 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 DEC PY 1998 VL 63 IS 6 BP 1703 EP 1711 DI 10.1086/302144 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 151EL UT WOS:000077707700016 PM 9837823 ER PT J AU Gladen, BC Sandler, DP Zahm, SH Kamel, F Rowland, AS Alavanja, MCR AF Gladen, BC Sandler, DP Zahm, SH Kamel, F Rowland, AS Alavanja, MCR TI Exposure opportunities of families of farmer pesticide applicators SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE agriculture; agrochemicals; pesticides; environmental exposure; occupational exposure; family ID AGRICULTURAL HEALTH; CANCER; WOMEN AB Background Families of farmer pesticide applicators have unusual opportunities for exposure, directly or indirectly, to pesticides. these exposures are not well characterized. Methods Subjects were 26,793 licensed private pesticide applicators enrolled in the Agricultural Health Study, a cohort study being conducted in Iowa and North Carolina Questionnaires were completed by the applicators and their spouses. Results Many indirect exposure opportunities exist;for example, 21% of homes are within 50 yards of pesticide mixing areas, 27% of applicators stare pesticides in their homes and 94% of clothing worn for pesticide work is washed in the same machine as other laundry Direct exposure opportunities also occur; for example, 51% of wives of applicators worked in the fields in the last growing season, 40% of wives have ever mired or applied pesticides, and over half of children aged II or more do farm chores. Discussion/Conclusions The extent of the opportunities for exposure of family members of farmer pesticide applicators makes studies of their health important. (C) 1998 Wiley-Liss, Inc.dagger C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NCI, Bethesda, MD USA. RP Gladen, BC (reprint author), NIEHS, Biostat Branch, Mail Drop A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. RI Zahm, Shelia/B-5025-2015; OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 NR 20 TC 42 Z9 44 U1 1 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD DEC PY 1998 VL 34 IS 6 BP 581 EP 587 DI 10.1002/(SICI)1097-0274(199812)34:6<581::AID-AJIM6>3.0.CO;2-U PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 136JG UT WOS:000076855200006 PM 9816416 ER PT J AU Jones, CA McQuillan, GM Kusek, JW Eberhardt, MS Herman, WH Coresh, J Salive, M Jones, CP Agodoa, LY AF Jones, CA McQuillan, GM Kusek, JW Eberhardt, MS Herman, WH Coresh, J Salive, M Jones, CP Agodoa, LY TI Serum creatinine levels in the US population: Third National Health and Nutrition Examination Survey SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE NHANES III; cross-sectional population survey; serum creatinine; ethnicity/race; sex; age; kidney; renal function ID STAGE RENAL-DISEASE; UNITED-STATES POPULATION; NON-HISPANIC WHITES; MEXICAN-AMERICANS; EXCESS INCIDENCE; BLOOD-PRESSURE; HYPERTENSION; NIDDM; COMPLICATIONS; PREVALENCE AB This report describes the distribution of serum creatinine levels by sex, age, and ethnic group in a representative sample of the US population. Serum creatinine level was evaluated in the third National Health and Nutrition Examination Survey (NHANES III) in 18,723 participants aged 12 years and older who were examined between 1988 and 1994. Differences in mean serum creatinine levels were compared for subgroups defined by sex, age, and ethnicity (non-Hispanic white, non-Hispanic black, and Mexican-American). The mean serum creatinine value was 0.96 mg/dL for women in the United States and 1.16 mg/dL for men. Overall mean creatinine levels were highest in non-Hispanic blacks (women, 1.01 mg/dL; men, 1.25 mg/dL), lower in non-Hispanic whites (women, 0.97 mg/dL; men, 1.16 mg/dL), and lowest in Mexican-Americans (women, 0.86 mg/dL; men, 1.07 mg/dL). Mean serum creatinine levels increased with age among both men and women in all three ethnic groups, with total US mean levels ranging from 0.88 to 1.10 mg/dL in women and 1.00 to 1.29 mg/dL in men. The highest mean creatinine level was seen in non-Hispanic black men aged 60+ years. In the total US population, creatinine levels of 1.5 mg/dL or greater were seen in 9.74% of men and 1.78% of women. Overall, among the US noninstitutionalized population, 10.9 million people are estimated to have creatinine values of 1.5 mg/dL or greater, 3.0 million have values of 1.7 mg/dL or greater, and 0.8 million have serum creatinine levels of 2.0 mg/dL or greater. Mean serum creatinine values are higher in men, non-Hispanic blacks, and older persons and are lower in Mexican-Americans. In the absence of information on glomerular filtration rate (GFR) or lean body mass, it is not clear to what extent the variability by sex, ethnicity, and age reflects normal physiological differences rather than the presence of kidney disease. Until this information is known, the use of a single cutpoint to define elevated serum creatinine values may be misleading. (C) 1998 by the National Kidney Foundation, Inc. C1 NIDDKD, Program Epidemiol, NIH, DKUHD, Bethesda, MD 20892 USA. NIDDKD, Clin Trials Program, NIH, DKUHD, Bethesda, MD 20892 USA. NIDDKD, End Stage Renal Dis Program, NIH, DKUHD, Bethesda, MD 20892 USA. NIDDKD, Minor Hlth Program, NIH, DKUHD, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Hyattsville, MD 20782 USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. US FDA, Ctr Biol Evaluat & Res, Div Biostat & Epidemiol, Rockville, MD 20857 USA. Univ Michigan, Med Ctr, Dept Internal Med, Div Endocrinol & Metab, Ann Arbor, MI 48109 USA. Harvard Univ, Sch Publ Hlth, Dept Hlth & Social Behav, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Jones, CP (reprint author), NIDDKD, Program Epidemiol, NIH, DKUHD, Natcher Bldg,Room 6AS-13K,45 Ctr Dr,MSC 6600, Bethesda, MD 20892 USA. NR 33 TC 365 Z9 377 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 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 1998 VL 32 IS 6 BP 992 EP 999 DI 10.1016/S0272-6386(98)70074-5 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 145QY UT WOS:000077383900011 PM 9856515 ER PT J AU Mukherjee, AB Kundu, GC Mandal, AK Pattabiraman, N Yuan, CJ Zhang, ZJ AF Mukherjee, AB Kundu, GC Mandal, AK Pattabiraman, N Yuan, CJ Zhang, ZJ TI Uteroglobin: Physiological role in normal glomerular function uncovered by targeted disruption of the uteroglobin gene in mice SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Review DE uteroglobulin; Clara cell 10-kd protein; fibronectin; glomerulopathy; gene knockout ID AMINO-ACID-SEQUENCE; CELL 10-KDA PROTEIN; ANTIINFLAMMATORY PEPTIDES ANTIFLAMMINS; PHOSPHOLIPASE-A2 INHIBITORY PROTEIN; RECOMBINANT HUMAN UTEROGLOBIN; PROGESTERONE-BINDING PROTEIN; PLATELET-ACTIVATING-FACTOR; TISSUE-SPECIFIC EXPRESSION; REGULATED MAMMALIAN GENE; RABBIT UTEROGLOBIN AB Blastokinin or uteroglobin (UG) is an evolutionarily conserved, steroid-inducible, homodimeric, multifunctional, secreted protein with potent immunomodulatory/antiinflammatory properties. Recently, a UG-receptor expressed on several malignant and normal cell types has been characterized. Although the biochemistry, structural, and molecular biology of UG have been extensively studied, its physiological function(s), until recently, remained unknown. By generating UG-null (UG(-/-)) mice, we determined that an essential role of UG is to prevent severe renal disease caused by an abnormal deposition of predominantly multimeric fibronectin (Fn) and collagen in the glomerulus. The molecular mechanisms by which UG prevents this disease in control (UG(+/+)) mice, at least in part, is attributable to its high-affinity binding to Fn and the formation of Fn-UG heteromers, which counteract both Fn-Fn and Fn-collagen interactions, required for abnormal tissue deposition. In addition, by inhibiting secretory phospholipase A(2)(sPLA(2)) activity and decreasing the level of lysophosphatidic acid (LPA), UG may indirectly prevent the activation of integrins leg, (alpha(5)beta(1)) that enhance abnormal tissue deposition of Fn. The mechanism(s) of UG action is likely to be even more complex, because it also functions through a receptor-mediated pathway that has not yet been clearly defined. Nevertheless, the UG gene-knockout mice provide a valuable animal model for investigation of human glomerulopathies in general and familial Fn-deposit glomerulopathy in particular. (C) 1998 by the National Kidney Foundation, Inc. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. FCRDC, NCI, SAIC, Frederick Biomed Supercomp Ctr, Frederick, MD USA. RP Mukherjee, AB (reprint author), Bldg 10,Room 9S241, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov NR 149 TC 18 Z9 18 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD DEC PY 1998 VL 32 IS 6 BP 1106 EP 1120 DI 10.1016/S0272-6386(98)70093-9 PG 15 WC Urology & Nephrology SC Urology & Nephrology GA 145QY UT WOS:000077383900032 PM 9856533 ER PT J AU Goldenberg, RL Mercer, BM Miodovnik, M Thurnau, GR Meis, PJ Moawad, A Paul, RH Bottoms, SF Das, A Roberts, JM McNellis, D Tamura, T AF Goldenberg, RL Mercer, BM Miodovnik, M Thurnau, GR Meis, PJ Moawad, A Paul, RH Bottoms, SF Das, A Roberts, JM McNellis, D Tamura, T TI Plasma ferritin, premature rupture of membranes, and pregnancy outcome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE ferritin; neonatal sepsis; premature rupture of membranes ID SERUM FERRITIN; BIRTH AB OBJECTIVE: The objective of this study was to determine whether plasma ferritin levels predict maternal or neonatal outcomes in women with preterm rupture of membranes at <32 weeks' gestation. METHODS: Plasma from 223 women with premature rupture of membranes at <32 weeks' gestation who had participated in a randomized antibiotic trial were analyzed for ferritin at random assignment and at delivery, and the results were compared with the development of clinical chorioamnionitis, latency until delivery, neonatal sepsis, and a composite adverse neonatal outcome variable. RESULTS: The mean plasma ferritin level rose from 19.2 +/- 29.1 mu g/L on admission to 38.3 +/- 54.3 mu g/L at delivery, with a mean latency of 9.3 +/- 14.6 days. Plasma ferritin levels were significantly higher at both times in mothers whose infants acquired sepsis than in those whose infants did not, especially at delivery (68.5 +/- 96.3 mu g/L vs 32.5 +/- 40.5 mu g/L, P=.01), and neonatal sepsis was 2 to 3 times more common among women with plasma ferritin levels above the median than among those with levels below the median. CONCLUSIONS: Among women with premature rupture of membranes at <32 weeks' gestation, plasma ferritin levels were significantly associated with neonatal sepsis. These data suggest that higher plasma ferritin levels may serve as a marker of infection among women with premature rupture of membranes; however, the clinical utility of plasma ferritin levels in predicting neonatal outcome appears limited. C1 NICHHD, Maternal Fetal Med Units Network, Bethesda, MD 20892 USA. RP Goldenberg, RL (reprint author), NICHHD, Maternal Fetal Med Units Network, Bethesda, MD 20892 USA. FU NICHD NIH HHS [HD21414, HD21410, HD21434] NR 13 TC 16 Z9 16 U1 0 U2 1 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 1998 VL 179 IS 6 BP 1599 EP 1604 DI 10.1016/S0002-9378(98)70032-8 PN 1 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 151CD UT WOS:000077702500051 PM 9855604 ER PT J AU Stevenson, DK Wright, LL Lemons, JA Oh, W Korones, SB Papile, LA Bauer, CR Stoll, BJ Tyson, JE Shankaran, S Fanaroff, AA Donovan, EF AF Stevenson, DK Wright, LL Lemons, JA Oh, W Korones, SB Papile, LA Bauer, CR Stoll, BJ Tyson, JE Shankaran, S Fanaroff, AA Donovan, EF TI Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1993 through December 1994 SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE very low birth weight; morbidity; mortality; National Institute of Child Health and; Human Development Neonatal Research Network; prematurity; preterm delivery ID INFANTS AB OBJECTIVES: Our purpose was to determine the mortality and morbidity rates for infants weighing 501 to 1500 g according to gestational age, birth weight, and gender. STUDY DESIGN: Perinatal data were collected prospectively on an inborn cohort from January 1993 through December 1994 by 12 participating centers of the National Institute of Child Health and Human Development Neonatal Research Network and were compared with the corresponding data from previous reports. Sociodemographic factors, perinatal events, and the neonatal course to 120 days of life, discharge, or death were evaluated. RESULTS: Eighty-three percent of infants survived until discharge to home or to a long-term care facility (compared with 74% in 1988). Survival to discharge was 49% for infants weighing 501 to 750 g at birth, 85% for those 751 to 1000 g, 93% for those 1001 to 1250 g, and 96% for those 1251 to 1500 g. The majority of deaths occurred within the first 3 days of life. Mortality rates were greater for male than far female infants. Respiratory distress syndrome was the most frequent pulmonary disease (52%). Chronic lung disease (defined as an oxygen requirement at 36 weeks after conception) developed in 19%. Thirty-two percent of infants had evidence of intracranial hemorrhage. Periventricular leukomalacia was noted in 6% of infants who had ultrasonography after 2 weeks. The average duration of hospitalization for survivors was 68 days (122 days for surviving infants weighing 501 to 750 g, compared with an average of 43 days for surviving infants 1251 to 1500 g). Among infants who died, the average length of stay was 19 days. CONCLUSIONS: The mortality rate for infants weighing between 501 and 1500 g at birth continues to decline. This increase in survival is not accompanied by an increase in medical morbidity. There are interactions between birth weight, gestational age, sex, and survival rates. C1 Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. NICHHD, Bethesda, MD 20892 USA. Indiana Univ, Indianapolis, IN 46204 USA. Brown Univ, Women & Infants Hosp, Providence, RI USA. Univ Tennessee, Memphis, TN USA. Univ New Mexico, Albuquerque, NM 87131 USA. Univ Miami, Miami, FL 33152 USA. Emory Univ, Atlanta, GA 30322 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Wayne State Univ, Detroit, MI USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Cincinnati, Cincinnati, OH USA. Yale Univ, New Haven, CT USA. George Washington Univ, Ctr Biostat, Washington, DC 20052 USA. NICHHD, Rockville, MD USA. RP Stevenson, DK (reprint author), Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. FU NICHD NIH HHS [U10 HD27856, U10 HD27904, U10 HD27880] NR 9 TC 229 Z9 238 U1 0 U2 2 PU MOSBY-YEAR BOOK INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 1998 VL 179 IS 6 BP 1632 EP 1639 DI 10.1016/S0002-9378(98)70037-7 PN 1 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 151CD UT WOS:000077702500056 PM 9855609 ER PT J AU Germolec, DR Spalding, J Yu, HS Chen, GS Simeonova, PP Humble, MC Bruccoleri, A Boorman, GA Foley, JF Yoshida, T Luster, MI AF Germolec, DR Spalding, J Yu, HS Chen, GS Simeonova, PP Humble, MC Bruccoleri, A Boorman, GA Foley, JF Yoshida, T Luster, MI TI Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID V-HA-RAS; ALPHA TRANSGENIC MICE; TGF-ALPHA; MOUSE SKIN; HUMAN KERATINOCYTES; EPIDERMAL GROWTH; GM-CSF; C-MYC; CARCINOGENESIS; OVEREXPRESSION AB Although numerous epidemiological studies have shown that inorganic arsenicals cause skin cancers and hyperkeratoses in humans, there are currently no established mechanisms for their action or animal models, previous studies in our laboratory using primary human keratinocyte cultures demonstrated that micromolar concentrations of inorganic arsenite increased cell proliferation via the production of keratinocyte-derived growth factors. As recent reports demonstrate that overexpression of keratinocyte-derived growth factors, such as transforming growth factor (TGF)-alpha, promote the formation of skin tumors, we hypothesized that similar events may be responsible for those associated with arsenic skin diseases. Thus, the influence of arsenic in humans with arsenic skin disease and on mouse skin tumor development in transgenic mice was studied. After low-dose application of tetradecanoyl phorbol acetate (TPA), a marked increase in the number of skin pap illomas occurred in Tg,AC mice, which carry the v-Ha-ras oncogene, that received arsenic in the drinking water as compared with control drinking water, whereas no papillomas developed in arsenic-treated transgenic mice that did not receive TPA or arsenic/TPA-treated wild-type FVB/N mice. Consistent with earlier in vitro findings, increases in granulocyte/macrophage colony-stimulating factor (GM-CSF) and TGF-alpha mRNA transcripts were found in the epidermis at clinically normal sites within 10 weeks after arsenic treatment, Immunohistochemical staining localized TGF-alpha overexpression to the hair follicles, Injection of neutralizing antibodies to GM-CSF after TPA application reduced the number of papillomas in Tg,AC mice. Analysis of gene expression in samples of skin lesions obtained from humans chronically exposed to arsenic via their drinking water also showed similar alterations in growth factor expression. Although confirmation will be required in nontransgenic mice, these results suggest that arsenic enhances development of skin neoplasias via the chronic stimulation of keratinocyte-derived growth factors and may be a rare example of a chemical carcinogen that acts as a co-promoter. C1 NIEHS, Environm Immunol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Carcinogenesis Program, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. Kaohsiung Med Coll, Dept Dermatol, Kaohsiung, Taiwan. NIOSH, Toxicol & Mol Biol Branch, Morgantown, WV USA. Tokai Univ, Sch Med, Dept Environm Hlth, Kanagawa, Japan. RP Germolec, DR (reprint author), NIEHS, Environm Immunol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Yu, Hsin-Su/C-6051-2009; Chen, Gwo-Shing/D-5516-2009 NR 59 TC 152 Z9 154 U1 0 U2 0 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 DEC PY 1998 VL 153 IS 6 BP 1775 EP 1785 DI 10.1016/S0002-9440(10)65692-1 PG 11 WC Pathology SC Pathology GA 143VP UT WOS:000077278000014 PM 9846968 ER PT J AU Mitsiades, N Poulaki, V Kotoula, V Leone, A Tsokos, M AF Mitsiades, N Poulaki, V Kotoula, V Leone, A Tsokos, M TI Fas ligand is present in tumors of the Ewing's sarcoma family and is cleaved into a soluble form by a metalloproteinase SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; MATRIX METALLOPROTEINASES; CD95 LIGAND; MOLECULAR-CLONING; INDUCED APOPTOSIS; IMMUNE PRIVILEGE; IN-VIVO; EXPRESSION; CELLS; ACTIVATION AB Fas ligand (FasL) exists in transmembrane and soluble forms and induces apoptosis on cross-linking with the Fas receptor. We evaluated the biological significance of Fast and Fas in 61 tumor tissues and 9 cell lines of the Ewing's sarcoma family of tumors (ESFT). Fast was present in 62.5% and Fas in 79.4% of primary ESFT, Metastatic tumors had higher expression of Fast (95%), suggesting association with a metastatic phenotype. Fast was detected in the cytoplasm and membrane of ESFT cells by immunofluorescence. Western blotting revealed transmembrane and soluble Fast in cytosolic extracts and soluble Fast in conditioned media. Both transmembrane and soluble Fast induced apoptosis of Fas-sensitive Jurkat cells in co-culture experiments with ESFT cells or their media. Treatment with phenanthroline and the synthetic metalloproteinase inhibitor BB-3103 reduced the levels of soluble Fast in the media, suggesting that in ESFT, Fast is processed by a metalloproteinase and released in the extracellular milieu. The released soluble Fast may serve to attack cells of the immune system and/or interfere with the binding of transmembrane Fast with Fas, and results in down-regulation of transmembrane Fast. Synthetic metalloproteinase inhibitors may modify the ratio of transmembrane to soluble FasL. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Mitsiades, N (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2A10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM nmitsiad@box-n.nih.gov RI Leone, Alvaro/K-6410-2016 OI Leone, Alvaro/0000-0003-3815-9052 NR 55 TC 77 Z9 82 U1 0 U2 0 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 DEC PY 1998 VL 153 IS 6 BP 1947 EP 1956 DI 10.1016/S0002-9440(10)65708-2 PG 10 WC Pathology SC Pathology GA 143VP UT WOS:000077278000030 PM 9846984 ER PT J AU McLeskey, SW Tobias, CA Vezza, PR Filie, AC Kern, FG Hanfelt, J AF McLeskey, SW Tobias, CA Vezza, PR Filie, AC Kern, FG Hanfelt, J TI Tumor growth of FGF or VEGF transfected MCF-7 breast carcinoma cells correlates with density of specific microvessels independent of the transfected angiogenic factor SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ENDOTHELIAL-CELLS; NUDE-MICE; FACTOR-IV; IN-VITRO; APOPTOSIS; PROLIFERATION; METASTASIS; TAMOXIFEN; KINETICS; NECROSIS AB We have previously shown that fibroblast growth factor (FGF)-1-, FGF-4-, or vascular endothelial growth factor (VEGF/VPF)-transfected MCF-7 breast carcinoma cells growing as tumors in nude mice are tamoxifen resistant and/or estrogen independent. These transfectants provide opportunity for study of in situ tumor-induced angiogenesis promoted by the individual angiogenic factors under growth-promoting versus growth-inhibiting hormonal conditions. In the present study, vessels in tumors harvested at varying times after tumor cell injection were immunohistochemically highlighted and vessel morphology and topography were scored on a scale of 0 to 4 by blinded observers, In tumors produced by all cell Lines under all growth-promoting hormonal conditions, there was significantly increased abundance (P < 0.05) of edge-associated and intratumor microvessels, but not of stromally located microvessels, when compared with tumor nodules harvested under growth-inhibiting conditions, regardless of the identity of the angiogenic factor or the hormonal treatment. Image analysis of bromodeoxyuridine (BrdU)-labeled nuclei of tumors produced by all cell Lines under all hormonal conditions harvested at early time points showed that mean labeling indices were highest for hormonal conditions that produced the most robust growth in that particular cell line, implying that a high BrdU labeling index is a predictor of future tumor growth in individual tumors. These results confirm previous studies that established the importance of neovascularization for tumor growth and provide validation for use of these cell lines to study the process of angiogenesis in vivo, Study of gene expression in endothelial cells in edge-associated or intratumor vessels using this model might reveal mechanisms important in tumor-induced angiogenesis in human breast cancer. C1 Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Pathol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Sch Nursing, Washington, DC 20007 USA. Natl Canc Inst, Pathol Lab, Bethesda, MD USA. So Res Inst, Birmingham, AL 35255 USA. RP McLeskey, SW (reprint author), Georgetown Univ, Med Ctr, Lombardi Canc Ctr, E304 Res Bldg, Washington, DC 20007 USA. FU NCI NIH HHS [R01 CA50376, P30 CA051008, P30 CA51008, R01 CA050376, R29 CA66154] NR 49 TC 51 Z9 51 U1 1 U2 2 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 DEC PY 1998 VL 153 IS 6 BP 1993 EP 2006 DI 10.1016/S0002-9440(10)65713-6 PG 14 WC Pathology SC Pathology GA 143VP UT WOS:000077278000035 PM 9846989 ER PT J AU Cobelli, C Bettini, F Caumo, A Quon, MJ AF Cobelli, C Bettini, F Caumo, A Quon, MJ TI Overestimation of minimal model glucose effectiveness in presence of insulin response is due to undermodeling SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE intravenous glucose tolerance test; glucose kinetics ID LABELED IVGTT; DISAPPEARANCE; SENSITIVITY AB Glucose effectiveness is an important determinant of glucose tolerance that can be derived from minimal model analysis of an intravenous glucose tolerance test (IVGTT). However, recent evidence suggests that glucose effectiveness is overestimated by minimal model analysis. Here we compare a new model-independent estimate of glucose effectiveness with the minimal model estimate by reanalyzing published data in which insulin-dependent diabetic subjects were each given IVGTTs under two conditions (Quon, M. J., C. Cochran, S. I. Taylor, and R. C. Eastman. Diabetes 43: 890-896, 1994). In one case, a basal insulin level was maintained (BI-IVGTT). In the second case, a dynamic insulin response was recreated (DI-IVGTT). Our results show that minimal model glucose effectiveness is very similar to the model-independent measurement during a BI-IVGTT but is three times higher during a DI-IVGTT. To investigate the causes of minimal model overestimation in the presence of a dynamic insulin response, Monte Carlo simulation studies on a two-compartment model of glucose kinetics with various insulin response patterns were performed. Results suggest that minimal model overestimation is due to single-compartment representation of glucose kinetics that results in a critical oversimplification in the presence of increasingly dynamic insulin secretion patterns. C1 Univ Padua, Dept Elect & Informat, I-35131 Padua, Italy. San Raffaele Sci Inst, I-20132 Milan, Italy. NHLBI, Hypertens Endocrine Branch, NIH, Bethesda, MD 20892 USA. RP Cobelli, C (reprint author), Univ Padua, Dept Elect & Informat, Via Gradenigo 6-A, I-35131 Padua, Italy. RI Quon, Michael/B-1970-2008; Caumo, Andrea/N-1062-2016 OI Caumo, Andrea/0000-0002-2507-0780 NR 13 TC 44 Z9 44 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD DEC PY 1998 VL 275 IS 6 BP E1031 EP E1036 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 151XV UT WOS:000077746700016 PM 9843746 ER PT J AU Dean, DJ Brozinick, JT Cushman, SW Cartee, GD AF Dean, DJ Brozinick, JT Cushman, SW Cartee, GD TI Calorie restriction increases cell surface GLUT-4 in insulin-stimulated skeletal muscle SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE food restriction; insulin signaling ID GLUCOSE-TRANSPORT ACTIVITY; BRIEF DIETARY RESTRICTION; RAT ADIPOSE-CELLS; PHOSPHATIDYLINOSITOL 3-KINASE; WEIGHT-LOSS; EXERCISE; RECEPTOR; ACTIVATION; PHOTOLABEL; METABOLISM AB Reduced calorie intake [calorie restriction (CR); 60% of ad libitum (AL)] leads to enhanced glucose transport without altering total GLUT-4 glucose transporter abundance in skeletal muscle. Therefore, we tested the hypothesis that CR (20 days) alters the subcellular distribution of GLUT-I. Cell surface GLUT-4 content was higher in insulin-stimulated epitrochlearis muscles from CR vs. AL rats. The magnitude of this increase was similar to the CR-induced increase in glucose transport, and GLUT-4 activity (glucose transport rate divided by cell surface GLUT-4) was unaffected by diet. The CR effect was specific to the insulin-mediated pathway, as evidenced by the observations that basal glucose transport and cell surface GLUT-4 content, as well as hypoxia-stimulated glucose transport, were unchanged by diet. CR did not alter insulin's stimulation of insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase (PI3K) activity. Muscle abundance of IRS-2 and p85 subunit of PI3K were unaltered by diet, but IRS-1 content was lower in CR vs. AL. These data demonstrate that, despite IRS-1-PI3K activity similar to AL, CR specifically increases insulin's activation of glucose transport by enhancing the steady-state proportion of GLUT-4 residing on the cell surface. C1 Univ Wisconsin, Dept Kinesiol, Biodynam Lab, Madison, WI 53706 USA. Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. NIDDKD, Expt Diabet Metab & Nutr Sect, Diabet Branch, Bethesda, MD 20892 USA. RP Cartee, GD (reprint author), Univ Wisconsin, Dept Kinesiol, Biodynam Lab, 2000 Observ Dr, Madison, WI 53706 USA. FU NIA NIH HHS [AG-10026] NR 46 TC 66 Z9 66 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD DEC PY 1998 VL 275 IS 6 BP E957 EP E964 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 151XV UT WOS:000077746700007 PM 9843737 ER PT J AU Nielsen, S Maunsbach, AB Ecelbarger, CA Knepper, MA AF Nielsen, S Maunsbach, AB Ecelbarger, CA Knepper, MA TI Ultrastructural localization of Na-K-2Cl cotransporter in thick ascending limb and macula densa of rat kidney SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE NKCC-2; Henle's loop; urinary concentrating mechanism; tubuloglomerular feedback ID K-CL COTRANSPORTER; COLLECTING DUCT; RABBIT KIDNEY; MOLECULAR-CLONING; WATER CHANNEL; HENLES LOOP; VASOPRESSIN; EXPRESSION; TRANSPORT; HETEROGENEITY AB A bumetanide-sensitive Na-K-2Cl cotransporter, BSC-1, is believed to mediate the apical component of transcellular NaCl absorption in the thick ascending limb (TAL) of Henle's loop. To study its ultrastructural localization in kidney, we used an affinity-purified, peptide-derived polyclonal antibody against rat BSC-1. Immunoblots from rat kidney cortex and outer medulla revealed a solitary 161-kDa band in membrane fractions. Immunocytochemistry of 1-mu m cryosections demonstrated strong BSC-1 labeling of the apical and subapical regions of medullary and cortical TAL cells. Notably, macula densa cells also exhibited distinct labeling. Distal convoluted tubules and other renal tubule segments were unlabeled. Immunoelectron microscopy demonstrated that BSC-1 labeling was associated with the apical plasma membrane and with subapical intracellular vesicles in medullary and cortical TAL and in macula densa cells. Smooth-surfaced TAL cells, in particular, had extensive BSC-1 labeling of intracellular vesicles. These results support the view that BSC-1 provides the apical pathway for NaCl transport across the TAL and that an extensive intracellular reservoir of BSC-1 is present in a subpopulation of TAL cells. Furthermore, the BSC-1 localization in the apical plasma membrane of macula densa cells is consistent with its proposed role in tubuloglomerular feedback. C1 NHLBI, LKEM, NIH, Bethesda, MD 20892 USA. Aarhus Univ, Dept Cell Biol, DK-8000 Aarhus C, Denmark. RP Knepper, MA (reprint author), NHLBI, LKEM, NIH, Bldg 10,Rm 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 26 TC 91 Z9 91 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 1998 VL 275 IS 6 BP F885 EP F893 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 151XX UT WOS:000077746900005 PM 9843905 ER PT J AU Traynor, T Yang, TX Huang, YG Arend, L Oliverio, MI Coffman, T Briggs, JP Schnermann, J AF Traynor, T Yang, TX Huang, YG Arend, L Oliverio, MI Coffman, T Briggs, JP Schnermann, J TI Inhibition of adenosine-1 receptor-mediated preglomerular vasoconstriction in AT(1A) receptor-deficient mice SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE micropuncture; mouse; angiotensin II type 1A receptor; gene knockout; tubuloglomerular feedback; adenosine type 1 receptor ID TUBULOGLOMERULAR FEEDBACK RESPONSES; ANGIOTENSIN-II RECEPTOR; RAT-KIDNEY; FILTRATION-RATE; CONVERTING ENZYME; EXPRESSION; GENE; PRESSURE; BLOCKADE; BRAIN AB The effect of the adenosine type 1 receptor agonist N(6)-cyclohexyladenosine (CHA) on glomerular vascular reactivity was studied in male angiotensin II type 1A (AT(1A)) receptor knockout mice (9). Vascular reactivity was assessed as the response of stop-flow pressure (P(SF)) to infusion of CHA into loops of Henle using micropuncture techniques. In AT(1A) +/+ mice at ambient arterial blood pressure (96.7 +/- 2.8 mmHg), the presence of CHA (10(-5) M) in the perfusate increased P(SF) responses from 6.8 +/- 0.6 to 14.3 +/- 0.9 mmHg when the loop of Henle of the index nephron was perfused and from 0.7 +/- 0.3 to 12.3 +/- 1.0 mmHg when the loop of an adjacent nephron was perfused. At reduced arterial blood pressure (82.8 +/- 1.3 mmHg), index nephron perfusion with CHA increased P(SF) responses from 4.5 +/- 0.3 to 9.4 +/- 0.4 mmHg. In AT(1A) -/- mice with a mean arterial blood pressure of 80 +/- 1.9 mmHg, CHA increased P(SF) responses only from 0.1 +/- 0.3 to 3.6 +/- 0.54 mmHg during index nephron perfusion and from 0.25 +/- 0.2 to 2.7 +/- 0.55 mmHg during adjacent nephron perfusion, significantly less than in wild-type animals (P < 0.001). Responses to CHA were intermediate in AT(1A) +/- mice. Thus AT(1A) receptor knockout mice show a markedly reduced constrictor response to CHA both in the presence and absence of simultaneous activation of the tubuloglomerular feedback system. These data support the notion of a functional interaction between adenosine and angiotensin II in the regulation of afferent arteriolar tone. C1 NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Physiol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Duke Univ, Dept Med, Durham, NC 27710 USA. RP Schnermann, J (reprint author), NIDDKD, Div Kidney Urol & Hematol Dis, NIH, Bldg 10,Room 4D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU NIDDK NIH HHS [DK-37448, DK-39255, DK-40042] NR 35 TC 45 Z9 45 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 1998 VL 275 IS 6 BP F922 EP F927 PG 6 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 151XX UT WOS:000077746900009 PM 9843909 ER PT J AU Goldberg, TE Aloia, MS Gourovitch, ML Missar, D Pickar, D Weinberger, DR AF Goldberg, TE Aloia, MS Gourovitch, ML Missar, D Pickar, D Weinberger, DR TI Cognitive substrates of thought disorder, I: The semantic system SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID WORKING-MEMORY; SCHIZOPHRENIC SPEECH; ATTENTION; LANGUAGE; DYSFUNCTION; PERFORMANCE; RETRIEVAL; SYMPTOMS; SCALE AB Objective: Few studies have explored in detail the relation of cognitive deficits in attention, working memory, and semantics to thought disorder. The authors sought to determine whether thought disorder resides in the semantic system or elsewhere. Method: Twenty-three normal comparison subjects and 23 patients with schizophrenia participated in the study. Ail subjects received tests of executive function and working memory, including the Wisconsin Card Sorting Test and the Letter-Number Span test; a test of deployment of attentional resources; and tests of semantic processing and language comprehension, including the Peabody Picture Vocabulary Test, the Speed and Capacity of Language-Processing Test, the Boston Naming Test, and tests of semantic verbal fluency and phonologic verbal fluency, from which was derived a difference score. All patients were also administered the Scale for the Assessment of Thought, Language, and Communication to assess thought disorder. Results: The normal subjects were compared with the schizophrenic patients who were rated as having mild thought disorder (N=13) or moderate to severe thought disorder (N=10). While differences between the schizophrenic subgroups and the comparison subjects were observed on nearly all tests, a large difference in effect size between the two schizophrenic subgroups was apparent only in the verbal fluency difference score. in a series of multiple regression analyses, two variables made significant contributions to the prediction of positive thought disorder: the verbal fluency difference score and the Peabody Picture Vocabulary Test score. Conclusions: These results suggest that clinically rated thought disorder is associated with and may result from semantic processing abnormalities. In particular, patients with more severe thought disorder may have difficulty accessing semantic items because of disorganization of the semantic systems and, to a more limited degree, may also lack a semantic or conceptual knowledge base. C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIMH, Expt Therapeut Branch, Bethesda, MD 20892 USA. RP Goldberg, TE (reprint author), NIMH, Clin Brain Disorders Branch, Bldg 10,Rm 4S235,MSC 1379, Bethesda, MD 20892 USA. NR 40 TC 180 Z9 183 U1 0 U2 8 PU AMER PSYCHIATRIC ASSOCIATION PI WASHINGTON PA 1400 K ST NW, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 1998 VL 155 IS 12 BP 1671 EP 1676 PG 6 WC Psychiatry SC Psychiatry GA 144FQ UT WOS:000077303700004 PM 9842774 ER PT J AU Aloia, MS Gourovitch, ML Missar, D Pickar, D Weinberger, DR Goldberg, TE AF Aloia, MS Gourovitch, ML Missar, D Pickar, D Weinberger, DR Goldberg, TE TI Cognitive substrates of thought disorder, II: Specifying a candidate cognitive mechanism SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID SCHIZOPHRENIC-PATIENTS; WORD PRONUNCIATION; LEXICAL DECISION; ACTIVATION; NETWORK AB Objective: In part I of this series, the authors found that semantic knowledge and organization accounted for most of the variance in thought disorder in a group of chronic schizophrenic patients. In the present study, they examined a possible cognitive mechanism within the semantic system that might produce thought disorder. Method: Twenty patients with chronic schizophrenia and 21 normal comparison subjects were assessed on priming (the ability to respond to a stimulus word more quickly when it is preceded by a semantically related word than when it is preceded by an unrelated word). The patients were divided into subgroups with high (N=9) and low (N=11) levels of thought disorder. The word pairs in the priming paradigm differed in their degree of association but shared a categorical membership. The paradigm involved short stimulus onset asynchronies to maximize automatic processing and required pronunciation of words to minimize decision making. All subjects were also administered neuropsychological tests to assess language, executive function, real-world knowledge, and mental status. Results: Comparison subjects showed appropriate priming in stepwise fashion at the three different fevers of word association, as did the patients with mild thought disorder. The patients with high thought disorder showed inhibited responses to high and medium associates compared with their baseline reaction times. Correlations between priming and cognitive variables were significant only with measures of semantic processing. Priming abnormalities were uniformly related to ratings of global thought disorder. Conclusions: These results suggest that aberrations in the automatic spread of activation or facilitation in semantic networks may be a candidate cognitive mechanism in semantic accounts of thought disorder. C1 NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. NIMH, Expt Therapeut Branch, Bethesda, MD 20892 USA. RP Goldberg, TE (reprint author), NIMH, Clin Brain Disorders Branch, Bldg 10,Rm 4S235,MSC 1379, Bethesda, MD 20892 USA. NR 24 TC 79 Z9 81 U1 7 U2 9 PU AMER PSYCHIATRIC ASSOCIATION PI WASHINGTON PA 1400 K ST NW, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD DEC PY 1998 VL 155 IS 12 BP 1677 EP 1684 PG 8 WC Psychiatry SC Psychiatry GA 144FQ UT WOS:000077303700005 PM 9842775 ER PT J AU James, SL AF James, SL TI Making the connection: Perspectives on tropical medicine research in the United States SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Editorial Material C1 NIAID, Parasitol & Int Programs Branch, NIH, Rockville, MD 20852 USA. RP James, SL (reprint author), NIAID, Parasitol & Int Programs Branch, NIH, Solar Bldg, Rockville, MD 20852 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DRIVE SUITE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 1998 VL 59 IS 6 BP 847 EP 851 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 154RE UT WOS:000077901900001 PM 9886186 ER PT J AU Bradley, JE Atogho, BM Elson, L Stewart, GR Boussinesq, M AF Bradley, JE Atogho, BM Elson, L Stewart, GR Boussinesq, M TI A cocktail of recombinant Onchocerca volvulus antigens for serologic diagnosis with the potential to predict the endemicity of onchocerciasis infection SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID OCULAR ONCHOCERCIASIS; IVERMECTIN TREATMENT; ANTIBODY-RESPONSE; WEST-AFRICA; INTENSITY; COMMUNITY; SIMULIUM; FOREST; FOCI AB We report here the evaluation of the potential of a serologic test to determine the endemicity of onchocercal infection in hyper, meso, and hypoendemic communities by the detection of antibodies to a cocktail of recombinant antigens. Parasitologic parameters of infection prevalence and intensity were compared with serologic results. Infection prevalence by serology was consistently but not significantly higher than that defined by parasitology. Differences between the communities defined by microfilarial load (CMFL) and a measurement of Onchocerca volvulus-specific antibody levels (serologic index [SI]) were similar. When stratified by age, differences were more significant in the younger age groups. If a sentinel population of 5-15-year-old individuals was used to compare communities, all could be equally ranked by serologic and parasitologic parameters. The SI of the sentinel population gave a better distinction between each community than the SI of the whole and would be sufficiently sensitive to measure the changes in endemicity that would be required for onchocerciasis control programs. C1 Univ London Imperial Coll Sci Technol & Med, Dept Biol, London, England. Univ Yaounde, Ctr Biotechnol, Yaounde, Cameroon. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. Inst Francais Rech Sci Dev Cooperat, Yaounde, Cameroon. RP Bradley, JE (reprint author), Univ Salford, Dept Biol Sci, Salford M5 4WT, Lancs, England. RI Boussinesq, Michel/J-7256-2016; OI Boussinesq, Michel/0000-0001-6312-0681; Bradley, Janette/0000-0003-3973-7977 NR 18 TC 16 Z9 17 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DRIVE SUITE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 1998 VL 59 IS 6 BP 877 EP 882 PG 6 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 154RE UT WOS:000077901900008 PM 9886193 ER PT J AU Gozalo, A Lucas, C Cachay, M Wellde, BT Hall, T Bell, B Wood, J Watts, D Wooster, M Lyon, JA Moch, JK Haynes, JD Williams, JS Holland, C Watson, E Kester, KE Kaslow, DC Ballou, WR AF Gozalo, A Lucas, C Cachay, M Wellde, BT Hall, T Bell, B Wood, J Watts, D Wooster, M Lyon, JA Moch, JK Haynes, JD Williams, JS Holland, C Watson, E Kester, KE Kaslow, DC Ballou, WR TI Passive transfer of growth-inhibitory antibodies raised against yeast-expressed recombinant Plasmodium falciparum merozoite surface protein-1(19) SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID AOTUS MONKEYS; MONOCLONAL-ANTIBODY; PROTECTIVE IMMUNITY; IMMUNIZATION; MALARIA; INFECTION; PRECURSOR; INDUCTION; ADJUVANT; ANTIGENS AB Purified rabbit immunoglobulin raised against yeast-expressed recombinant FVO or 3D7 Plasmodium falciparum merozoite surface protein-1 (MSP-1) 19k-D C terminal fragment (MSP-1(19)) was transfused into malaria-naive Aotus nancymai monkeys that were immediately challenged with FVO asexual stage malaria parasites. Control monkeys received rabbit immunoglobulin raised against the sexual stage antigen Pfs25 or Aotus hyperimmune serum obtained from monkeys immunized by P. falciparum infection and drug cure. Passive transfer of rabbit anti-MSP-1(19) failed to protect against homologous or heterologous challenge and, when compared with negative controls, there were no differences in prepatent periods or time to treatment. Interestingly, rabbit anti-MSP-1(19), but not anti-Pfs25, immunoglobulin, and immune monkey serum prevented the development of antibodies directed against MSP-1(19) fragment by infected monkeys, indicating that the antibodies were reactive with native MSP-1(19) antigen in vivo. The prepatent period and time to treatment was greatly delayed in the two monkeys that received Aotus immune serum, both of which developed a chronic intermittent low level infection. In vitro parasite growth inhibition assays (GIAs) confirmed the presence of inhibitory activity (40% maximum inhibition) in concentrated anti-MSP-1(19) immunoglobulin (4.8 mg/ml), but the peak concentrations we achieved in vivo (1 mg/ml) were not inhibitory in vitro. Subinhibitory levels of anti-MSP-1(19) antibodies achieved by passive transfer were not protective against P. falciparum challenge. C1 Walter Reed Army Inst Res, Dept Immunol, Washington, DC 20307 USA. Walter Reed Army Inst Res, Dept Biol Res, Washington, DC 20307 USA. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. USN, Med Res Inst Detachment, Lima, Peru. RP Ballou, WR (reprint author), Walter Reed Army Inst Res, Dept Immunol, Washington, DC 20307 USA. RI Kester, Kent/A-2114-2011; Holland, Carolyn/B-7880-2011 OI Kester, Kent/0000-0002-5056-0802; NR 17 TC 11 Z9 12 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DRIVE SUITE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD DEC PY 1998 VL 59 IS 6 BP 991 EP 997 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 154RE UT WOS:000077901900026 PM 9886211 ER PT J AU Chamberlain, RS Kaufman, HL Danforth, DN AF Chamberlain, RS Kaufman, HL Danforth, DN TI Enterocutaneous fistula in cancer patients: Etiology, management, outcome, and impact on further treatment SO AMERICAN SURGEON LA English DT Article ID GASTROINTESTINAL FISTULAS; CYTOREDUCTIVE SURGERY; PARENTERAL-NUTRITION; RADIATION INJURIES; TRACT; SOMATOSTATIN AB Enterocutaneous fistulae that develop in patients with cancer represent a difficult management situation, which is often complicated by prior treatment including surgery, radiation therapy, and chemotherapy. A fistula may in turn delay potentially beneficial treatment of the underlying malignancy. To provide a better understanding of this problem, we reviewed the National Institutes of Health experience with enterocutaneous fistulae in adult patients with cancer. The medical records of patients with cancer who developed a fistula from the gastrointestinal tract during the period 1980 through 1994 were reviewed. Etiology, management, outcome, and impact on further treatment were assessed. Twenty-five patients with gastrointestinal fistulae were identified. The most common primary tumor site was the colon/rectum in males and the ovary in women. The majority of patients had metastatic disease at diagnosis and a history of prior therapy and presented with anorexia and weight loss. The fistula was usually single, most commonly developed from the jejunum/ileum (13 patients) or colon/rectum (6 patients), and occurred postoperatively after procedures on the small bowel (10 patients) or colon (8 patients). Malnutrition and sepsis developed in 60 per cent of patients. Thirty-day mortality was 16 per cent and correlated with prior radiation therapy, location and output from the fistula, and hypoalbuminemia. An enterocutaneous fistula negatively impacted on the provision of further therapy for the majority of patients (63%). Enterocutaneous fistula in the patient with cancer occurs most frequently in the setting of extensive prior therapy and is associated with prolonged morbidity. Identification of high-risk patients and early management of fistulas once they develop may prevent delays in subsequent cancer therapy and decrease morbidity. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Danforth, DN (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B38, Bethesda, MD 20892 USA. NR 22 TC 19 Z9 19 U1 0 U2 0 PU SOUTHEASTERN SURGICAL CONGRESS PI ATLANTA PA 141 WEST WIEUCA RD, STE B100, ATLANTA, GA 30342 USA SN 0003-1348 J9 AM SURGEON JI Am. Surg. PD DEC PY 1998 VL 64 IS 12 BP 1204 EP 1211 PG 8 WC Surgery SC Surgery GA 141JF UT WOS:000077139500022 PM 9843347 ER PT J AU Schuck, P Millar, DB Kortt, AA AF Schuck, P Millar, DB Kortt, AA TI Determination of binding constants by equilibrium titration with circulating sample in a surface plasmon resonance biosensor SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE optical biosensor; reversible binding; protein-protein interaction; protein-DNA interactions; affinity chromatography ID QUANTITATIVE AFFINITY-CHROMATOGRAPHY; MONOCLONAL-ANTIBODY; KINETIC-ANALYSIS; MASS-TRANSPORT; LIGAND-BINDING; BIACORE; DISSOCIATION; TECHNOLOGY; PEPTIDES; RECEPTOR AB A commercial surface plasmon resonance biosensor, BIACORE X, is employed as a detector in a closed loop of a small sample volume. The sample is continuously circulated by an external syringe pump over two sensor spots, one functionalized with immobilized binding sites to a soluble binding partner in the mobile phase and one serving as a reference surface. A binding isotherm for the interacting macromolecules can be obtained by a stepwise titration of the soluble reactant into the circulating loop, each step followed by observation of the signal increase until equilibrium is attained. Binding constants can be measured under conditions free of mass transport artifacts and without the requirement for regeneration of the immobilized binding sites. This procedure is similar to the stepwise titration procedure described for the cuvette-based sensor design (D. R. Hall and D. J. Winter, 1997, Anal. Biochem. 244, 152-160). In the presented configuration, the high baseline stability of the instrument combined with the availability of a reference surface for the detection of nonspecific binding permits refractive index changes upon addition of the aliquots to be measured, as well as accounting for temperature or instrumental drifts, and allows for a very long experimental time. This feature extends the applicability of equilibrium titration to systems with higher affinity or slower dissociation rate constants. Furthermore a solution competition titration is described that avoids artifacts from the immobilization procedure to provide a method for measurement of binding constants in solution. Kinetic information on the complex dissociation can also be obtained by combination of sample delivery via the external pump with the injection of competitor via the microfluidics of the biosensor. The rapid injection of high concentrations of competitor allows the observation of fast dissociation processes under conditions minimizing rebinding. C1 NIH, Mol Interact Resource, Bioengn & Phys Sci Program, ORS, Bethesda, MD 20892 USA. NIDDK, Sect Phys Biochem, Biochem Pharmacol Lab, NIH, Bethesda, MD 20892 USA. CSIRO, Parkville, Vic 3052, Australia. CRC Diagnost Technol, Parkville, Vic 3052, Australia. RP Schuck, P (reprint author), NIH, Mol Interact Resource, Bioengn & Phys Sci Program, ORS, Bldg 10, Bethesda, MD 20892 USA. EM pschuck@helix.nih.gov OI Schuck, Peter/0000-0002-8859-6966 NR 37 TC 58 Z9 58 U1 0 U2 9 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD DEC 1 PY 1998 VL 265 IS 1 BP 79 EP 91 DI 10.1006/abio.1998.2872 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 145EZ UT WOS:000077359200012 PM 9866711 ER PT J AU Kain, ZN Caramico, LA Mayes, LC Genevro, JL Bornstein, MH Hofstadter, MB AF Kain, ZN Caramico, LA Mayes, LC Genevro, JL Bornstein, MH Hofstadter, MB TI Preoperative preparation programs in children: A comparative examination SO ANESTHESIA AND ANALGESIA LA English DT Article; Proceedings Paper CT 4th Annual Meeting of the Society-for-Pediatric-Anesthesia / American-Academy-of-Pediatrics CY FEB 13-14, 1998 CL PHOENIX, ARIZONA SP Soc Pediatr Anesthesia, Amer Acad Pediatr ID ANXIETY; HOSPITALIZATION; SURGERY AB We sought to determine whether an extensive behavioral preparation program for children undergoing surgery is more effective than a Limited behavioral program. The primary end point was child and parent anxiety during the preoperative period. Secondary end points included behavior of the child during the induction of anesthesia and the postoperative recovery period. Several days before surgery, children (n = 75) aged 2-12 yr randomly received either an information-based program (OR tour), an information + modeling-based program (OR tour + videotape), or an information + modeling + coping-based program (OR tour + videotape + child-life preparation). Using behavioral and physiological measures of anxiety, we found that children who received the extensive program exhibited less anxiety immediately after the intervention, in the holding area on the day of surgery, and on separation to the operating room. These findings, however, achieved statistical significance only in the holding area on the day of surgery (44[10-72] vs 32[8-50] vs 9[6-33]; P = 0.02). Similarly, parents in the extensive program were significantly less anxious on the day of surgery in the preoperative holding area, as assessed by behavioral (P = 0.015) and physiological measures (P = 0.01). In contrast, no differences were found among the groups during the induction of anesthesia, recovery room period, or 2 wk postoperatively. We conclude that children and parents who received the extensive preoperative preparation program exhibited lower levels of anxiety during the preoperative period, but not during the intraoperative or postoperative periods. Implications: The extensive behavioral preoperative program that we undertook had limited anxiolytic effects. These effects were localized to the preoperative period and did not extended to the induction of anesthesia or the postoperative recovery period. C1 Yale Univ, Sch Med, Dept Anesthesiol, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA. Yale Univ, Sch Med, Childrens Clin Res Ctr, New Haven, CT 06510 USA. NICHHD, Bethesda, MD 20892 USA. RP Kain, ZN (reprint author), Yale Univ, Sch Med, Dept Anesthesiol, 333 Cedar St, New Haven, CT 06510 USA. FU NCRR NIH HHS [M01 RR06022-08] NR 23 TC 78 Z9 83 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 1998 VL 87 IS 6 BP 1249 EP 1255 DI 10.1097/00000539-199812000-00007 PG 7 WC Anesthesiology SC Anesthesiology GA 142AP UT WOS:000077178000007 PM 9842807 ER PT J AU Harukuni, I Bhardwaj, A Traystman, RJ Crain, B London, ED Kirsch, JR AF Harukuni, I Bhardwaj, A Traystman, RJ Crain, B London, ED Kirsch, JR TI Neuroprotection from focal ischemia by 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) is dependent on treatment duration in rats SO ANESTHESIA AND ANALGESIA LA English DT Article ID CEREBRAL-ARTERY OCCLUSION; METHYL-D-ASPARTATE; DECREASES BRAIN INJURY; SIGMA-RECEPTOR LIGAND; MEDIATED NEUROTOXICITY; INFARCT VOLUME; GLUTAMATE; NMDA; CULTURE; NEURONS AB The IV administration of the potent sigma(1)-receptor ligand 4-phenyl-1-(4-phenylbutyl)piperidine (PPBP) provides neuroprotection against focal cerebral ischemia. We tested the hypothesis that prolonged, continuous administration of PPBP would provide further neuroprotection in a rat model of transient focal ischemia and reperfusion. Under controlled conditions of normoxia, normocarbia, and normothermia, halothane-anesthetized male Wister rats were subjected to 2 h of middle cerebral artery occlusion by the intraluminal occlusion technique. Sixty minutes after the onset of ischemia, rats were randomly assigned to six treatment groups to receive a continuous IV infusion of PPBP (1 mu mol . kg(-1). h(-1)) for 1, 2, 3, or 4 days or saline for 1 or 4 days. The infarction volume was assessed by triphenyltetrazolium chloride (TTC) staining on Day 4 after ischemia in all rats. The TTC-determined infarction volume of the ipsilateral cerebral cortex was smaller in rats treated with PPBP for 1 day (42 +/- 13 mm(3); 10% +/- 3% of ipsilateral hemisphere; P < 0.05) (mean +/- SEM) compared with that in corresponding 1-day control rats (124 +/- 22 mm; 29% +/- 5% of ipsilateral hemisphere; P < 0.05) or 4-day control rats (112 +/- 10 mm; 26% +/- 2% of ipsilateral hemisphere; P < 0.05). Cortical infarction volumes in 2-, 3-, and 4-day PPBP-treated rats were not different compared with 1- and 4-day saline-treated controls. These data demonstrate that the sigma(1)-receptor ligand PPBP attenuates ischemic injury when administration is initiated 60 min after the onset of focal ischemia but that prolonged continuous treatment with PPBP beyond 24 h provides no neuroprotection Implications: sigma-ligands decrease infarction size in various animal models when given after the onset of stroke. Prolonged treatment with a potent sigma-ligand is associated with loss of therapeutic efficacy for this compound. C1 Johns Hopkins Univ, Sch Med, Dept Anesthesiol Crit Care Med, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21218 USA. Natl Inst Drug Abuse, Baltimore, MD USA. RP Kirsch, JR (reprint author), Johns Hopkins Hosp, Blalock 1412,600 N Wolfe St, Baltimore, MD 21287 USA. FU NINDS NIH HHS [NS20020] NR 33 TC 15 Z9 16 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD DEC PY 1998 VL 87 IS 6 BP 1299 EP 1305 DI 10.1097/00000539-199812000-00016 PG 7 WC Anesthesiology SC Anesthesiology GA 142AP UT WOS:000077178000016 PM 9842816 ER PT J AU Schneider, T Stallmach, A von Herbay, A Marth, T Strober, W Zeitz, M AF Schneider, T Stallmach, A von Herbay, A Marth, T Strober, W Zeitz, M TI Treatment of refractory Whipple disease with interferon-gamma SO ANNALS OF INTERNAL MEDICINE LA English DT Article C1 Univ Saarland, D-66421 Homburg, Germany. Univ Heidelberg, Inst Pathol, D-69120 Heidelberg, Germany. NIAID, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. RP Zeitz, M (reprint author), Univ Saarland, D-66421 Homburg, Germany. NR 17 TC 53 Z9 57 U1 0 U2 0 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 DEC 1 PY 1998 VL 129 IS 11 BP 875 EP 877 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 143DF UT WOS:000077239200005 PM 9867729 ER PT J AU Lehky, TJ Levin, MC Kubota, R Bamford, RN Flerlage, AN Soldan, SS Leist, TP Xavier, A White, JD Brown, M Fleisher, TA Top, LE Light, S McFarland, HF Waldmann, TA Jacobson, S AF Lehky, TJ Levin, MC Kubota, R Bamford, RN Flerlage, AN Soldan, SS Leist, TP Xavier, A White, JD Brown, M Fleisher, TA Top, LE Light, S McFarland, HF Waldmann, TA Jacobson, S TI Reduction in HTLV-I proviral load and spontaneous lymphoproliferation in HTLV-I-associated myelopathy/tropical spastic paraparesis patients treated with humanized anti-Tac SO ANNALS OF NEUROLOGY LA English DT Article ID T-CELL LEUKEMIA; VIRUS TYPE-I; CENTRAL-NERVOUS-SYSTEM; INTERLEUKIN-2 RECEPTOR; MONOCLONAL-ANTIBODY; LYMPHOCYTES; THERAPY; P40X; IMMUNOTHERAPY; ZIDOVUDINE AB Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disease that results from an interaction of retroviral infection and immune activation. In this study, five doses (1 mg/kg) of humanized anti-Tac antibody were administered to 9 HAM/TSP patients at weeks 0, 2, 6, 10, and 14. Preliminary immunological studies on HAM/TSP patients treated with humanized anti-Tac indicate that there is a selective down-regulation of activated T cells and a decrease in the HTLV-I viral load in peripheral blood lymphocytes, most likely through the selective removal of HTLV-I-infected, activated CD4(+) lymphocytes. C1 NIAID, HIV Res Branch, DAIDS, NIH, Bethesda, MD 20892 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NIH, Immunol Lab, Ctr Clin, Bethesda, MD 20892 USA. Univ Tennessee, Memphis, TN USA. Hoffmann La Roche Inc, Nutley, NJ 07110 USA. RP Lehky, TJ (reprint author), NIAID, HIV Res Branch, DAIDS, NIH, 6003 Execut Blvd, Bethesda, MD 20892 USA. NR 30 TC 47 Z9 48 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 1998 VL 44 IS 6 BP 942 EP 947 DI 10.1002/ana.410440613 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 145QF UT WOS:000077382300012 PM 9851439 ER PT J AU Leube, B Auburger, G AF Leube, B Auburger, G TI Questionable role of adult-onset focal dystonia among sporadic dystonia patients SO ANNALS OF NEUROLOGY LA English DT Letter ID CHROMOSOME 18P C1 Univ Hosp Dusseldorf, Dept Neurol, Dusseldorf, Germany. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. RP Leube, B (reprint author), Univ Hosp Dusseldorf, Dept Neurol, Dusseldorf, Germany. NR 4 TC 11 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 1998 VL 44 IS 6 BP 984 EP 985 DI 10.1002/ana.410440623 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 145QF UT WOS:000077382300022 PM 9851449 ER PT J AU Zappa, M Ciatto, S Bonardi, R Mazzotta, A AF Zappa, M Ciatto, S Bonardi, R Mazzotta, A TI Overdiagnosis of prostate carcinoma by screening: An estimate based on the results of the Florence Screening Pilot Study SO ANNALS OF ONCOLOGY LA English DT Article DE cancer; diagnosis; overdiagnosis; prostate; screening ID DIGITAL RECTAL EXAMINATION; CANCER; ANTIGEN AB Objectives: To estimate overdiagnosis (detection of latent carcinomas) as a consequence of screening for prostate cancer. Design: Based on actual screen (first or repeat) detected and interval prostate cancer rates observed in the Florence screening pilot study, a scenario was simulated where males aged 60 years (or 65) had six biennal screens and were followed up for four years. Overdiagnosis was determined as the proportional excess of cancers detected by screening with respect to that expected in its absence. Setting: City of Florence, Italy, from 1992 through 1995. Population: 2,740 resident males, aged 60 to 74 years. Results: Overdiagnosis was estimated to be 51% (95% confidence limits: 44%-55%) or 93% (85%-101%) for age 60 or 65 at entry. Comparison with other screening experiences obtaining higher detection rates suggests that a more aggressive screening approach could be associated with overdiagnosis estimates as big as 200%-250%. Conclusions: Screening for prostate cancer is associated with a relevant risk of overdioagnosis. As latent carcinomas can not be presently identified, this would lead to overtreatment in most overdiagnosed cases. The negative consequences of overdiagnosis (knowledge of having a cancer) and of overtreatment (impotence, incontinence, perioperatory death) may be extremely serious. In absence of any scientific evidence of screening benefits (if any) screening should not be recommended as a current practice, but should be limited to prospective controlled studies designed to assess its cost-effectiveness. C1 Ctr Studio & Prevenz Oncol, I-50131 Florence, Italy. Natl Canc Inst, Genoa, Italy. RP Ciatto, S (reprint author), Ctr Studio & Prevenz Oncol, Viale A Volta 171, I-50131 Florence, Italy. NR 15 TC 58 Z9 58 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD DEC PY 1998 VL 9 IS 12 BP 1297 EP 1300 DI 10.1023/A:1008492013196 PG 4 WC Oncology SC Oncology GA 162EC UT WOS:000078331700014 PM 9932159 ER PT J AU Pettit, GR Rhodes, MR Herald, DL Chaplin, DJ Stratford, MRL Hamel, E Pettit, RK Chapuis, JC Oliva, D AF Pettit, GR Rhodes, MR Herald, DL Chaplin, DJ Stratford, MRL Hamel, E Pettit, RK Chapuis, JC Oliva, D TI Antineoplastic agents 393. Synthesis of the trans-isomer of combretastatin A-4 prodrug SO ANTI-CANCER DRUG DESIGN LA English DT Article DE antimicrobial agents; antineoplastic agents; trans-combretastatin A-4 prodrug; phosphate esters ID P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; ANTIMITOTIC AGENT; POTENT; TUBULIN; ANALOGS AB The (E)-stilbene isomer (2a) of the (Z)-combretastatin A-4 prodrug (1b) was efficiently prepared from (E)-combretastatin A-4 by a reaction sequence employing phosphorylation (dibenzyl chlorophosphite), cleavage (trimethyliodosilane) of the benzyl ester and reaction of the resulting phosphoric acid with sodium methoxide. The sodium phosphate product (2c) was also found to be an important side-product, presumably from iodine-catalyzed isomerization, when the analogous synthetic route was used to obtain the combretastatin A-4 prodrug (1b). The phosphoric acid precursor of prodrug Ib derived from (Z)-combretastatin A-4 (1a) was converted into a series of metal cation and ammonium cation salts to evaluate effects on human cancer cell growth, antimicrobial activities and solubility behavior. C1 Arizona State Univ, Canc Res Inst, Tempe, AZ 85287 USA. Arizona State Univ, Dept Chem, Tempe, AZ 85287 USA. Mt Vernon Hosp, Canc Res Trust, Gray Lab, Northwood HA6 2JR, Middx, England. NCI, Frederick Canc Res & Dev Ctr, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick, MD 21702 USA. Western Oregon Univ, Dept Biol, Monmouth, OR 97361 USA. RP Pettit, RK (reprint author), Arizona State Univ, Canc Res Inst, POB 872404, Tempe, AZ 85287 USA. FU NCI NIH HHS [CA44344-05-09] NR 23 TC 58 Z9 59 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0266-9536 J9 ANTI-CANCER DRUG DES JI Anti-Cancer Drug Des. PD DEC PY 1998 VL 13 IS 8 BP 981 EP 993 PG 13 WC Biochemistry & Molecular Biology; Oncology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Oncology; Pharmacology & Pharmacy GA 197AV UT WOS:000080343200009 PM 10335271 ER PT J AU Mueller, BU Lewis, LL Yuen, GJ Farley, M Keller, A Church, JA Goldsmith, JC Venzon, DJ Rubin, M Pizzo, PA Balis, FM AF Mueller, BU Lewis, LL Yuen, GJ Farley, M Keller, A Church, JA Goldsmith, JC Venzon, DJ Rubin, M Pizzo, PA Balis, FM TI Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID REVERSE-TRANSCRIPTASE; PHASE I/II; 2'-DEOXY-3'-THIACYTIDINE; 3TC; (-)-2'-DEOXY-3'-THIACYTIDINE; ZIDOVUDINE; INHIBITOR; TOXICITY; BCH-189; INVITRO AB We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children,vas 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m(2) of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 mu M for greater than or equal to 8 h of 24 h on the twice daily oral dosing schedule with doses of greater than or equal to 2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h. C1 NCI, Pediat Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Glaxo Wellcome Inc, Res Triangle Pk, NC 27709 USA. Childrens Hosp, Los Angeles, CA 90027 USA. RP Mueller, BU (reprint author), Childrens Hosp, Dept Med, 300 Longwood Ave,Hunnewell 302, Boston, MA 02115 USA. RI Venzon, David/B-3078-2008 NR 25 TC 29 Z9 29 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD DEC PY 1998 VL 42 IS 12 BP 3187 EP 3192 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 145ER UT WOS:000077358500024 PM 9835513 ER PT J AU Guadagno, MA Herrmann, D AF Guadagno, MA Herrmann, D TI Further consideration of the role of socio-economic status in memory performance SO APPLIED COGNITIVE PSYCHOLOGY LA English DT Article AB In his commentary, Richardson criticizes the analysis of the relationship between socioeconomic status (SES) and memory performance as presented by Herrmann and Guadagno (1997). Richardson's criticism addresses Herrmann and Guadagno's procedures for classifying economic backgrounds of subjects and the statistics they used to analyze the effects of SES and memory. We believe that all of these points are worth considering but suggest that it is too early in this research area to definitively settle on either (a) the best procedure for classifying SES or (b) the most effective statistical method for post-hoc analysis of memory data. The underlying issues are too complex and the number of investigations too few to argue that one procedure or method is right and the other wrong. Alternatively, Richardson's commentary agrees with ours in two important ways. Richardson's article and ours both assert that economic background is clearly a relevant variable in explaining memory performance. In addition, both articles recommend that memory and cognitive researchers take account of economic well being in future memory research. (C) 1998 John Wiley & Sons, Ltd. C1 NIA, Bethesda, MD 20892 USA. Indiana State Univ, Terre Haute, IN 47809 USA. RP Guadagno, MA (reprint author), NIA, Bethesda, MD 20892 USA. NR 24 TC 1 Z9 1 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0888-4080 J9 APPL COGNITIVE PSYCH JI Appl. Cogn. Psychol. PD DEC PY 1998 VL 12 IS 6 BP 611 EP 616 DI 10.1002/(SICI)1099-0720(1998120)12:6<611::AID-ACP580>3.0.CO;2-P PG 6 WC Psychology, Experimental SC Psychology GA 145QQ UT WOS:000077383200005 ER PT J AU Caraco, C Aloj, L Eckelman, WC AF Caraco, C Aloj, L Eckelman, WC TI The gallium-deferoxamine complex: Stability with different deferoxamine concentrations and incubation conditions SO APPLIED RADIATION AND ISOTOPES LA English DT Article ID RADIONUCLIDES; INHIBITION; CHELATION; CELL AB Previous studies report that deferoxamine (DFO) binds metallic ions such as Fe3+, In3+ and Ga3+ with very high affinity. This property of DFO has been utilized to label DFO-coupled compounds with radiometals such as Ga-67 and In-111. We have studied the effect of low DFO concentrations and of different incubation conditions on the stability of the Ga-67-DFO complex. In our experience high (>5 mu M) DFO concentration appears to be critical in obtaining high radiochemical purity of such complexes. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NIH, Positron Emiss Tomog Dept, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. RP Eckelman, WC (reprint author), NIH, Positron Emiss Tomog Dept, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. NR 12 TC 16 Z9 16 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0969-8043 J9 APPL RADIAT ISOTOPES JI Appl. Radiat. Isot. PD DEC PY 1998 VL 49 IS 12 BP 1477 EP 1479 DI 10.1016/S0969-8043(97)10107-5 PG 3 WC Chemistry, Inorganic & Nuclear; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Chemistry; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 112KR UT WOS:000075494300003 PM 9745687 ER PT J AU Regier, DA AF Regier, DA TI Midtown Manhattan prevalence rates and the implied need for treatment: Meeting the challenge of public mental health - In reply SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Letter ID VALIDITY C1 NIMH, Bethesda, MD 20892 USA. RP Regier, DA (reprint author), NIMH, 31 Ctr Dr,Suite 4A52, Bethesda, MD 20892 USA. NR 10 TC 2 Z9 2 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD DEC PY 1998 VL 55 IS 12 BP 1147 EP 1148 PG 2 WC Psychiatry SC Psychiatry GA 147UB UT WOS:000077514900016 ER PT J AU Dalakas, MC AF Dalakas, MC TI Molecular immunology and genetics of inflammatory muscle diseases SO ARCHIVES OF NEUROLOGY LA English DT Review ID CELL RECEPTOR REPERTOIRE; INCLUSION-BODY MYOSITIS; T-CELLS; TRANSFORMING GROWTH-FACTOR-BETA-1; INFILTRATING LYMPHOCYTES; POLYMYOSITIS; DERMATOMYOSITIS; EXPRESSION; MYOPATHIES; FIBERS AB Polymyositis, dermatomyositis, and inclusion body myositis, although immunopathologically distinct, share 3 dominant histological features: inflammation, fibrosis, and loss of muscle fibers. Progress in molecular immunology and immunogenetics has enhanced our understanding of these cellular processes. Based on the T-cell receptor gene rearrangement, the autoinvasive CD8(+) T cells in polymyositis and inclusion body myositis, but not dermatomyositis, are specifically selected and clonally expanded in situ by heretofore unkown muscle-specific autoantigens. The messenger RNA of cytokines is variably expressed, except for a persistent up-regulation of interleukin 1 beta in inclusion body myositis and transforming growth factor beta in dermatomyositis. In inclusion body myositis, the interleukin 1, secreted by the chronically activated endomysial inflammatory cells, may participate in the formation of amyloid because it up-regulates beta-amyloid precursor protein (beta-APP) gene expression and beta-APP promoter and colocalizes with beta-APP within the vacuolated muscle fibers. In dermatomyositis, transforming growth factor beta is overexpressed in the perimysial connective tissue but: is down-regulated after successful immunotherapy and reduction of inflammation and fibrosis. The degenerating muscle fibers express several antiapoptotic molecules, such as Bcl-2, and resist apoptosis-mediated cell death. In myositis, several of the identified molecules and adhesion receptors play a role in the process of inflammation, fibrosis, and muscle fiber loss, and could be targets for the design of semispecific therapeutic interventions. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. NR 22 TC 77 Z9 79 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 1998 VL 55 IS 12 BP 1509 EP 1512 DI 10.1001/archneur.55.12.1509 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 147VK UT WOS:000077517900002 PM 9865793 ER PT J AU Fitzgibbons, PL Henson, DE Hutter, RVP AF Fitzgibbons, PL Henson, DE Hutter, RVP CA Canc Comm Coll Am Pathologists TI Benign breast changes and the risk for subsequent breast cancer - An update of the 1985 consensus statement SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID ATYPICAL HYPERPLASIA; FOLLOW-UP; DISEASE; WOMEN; DIAGNOSIS; ADENOSIS; BIOPSY AB The Cancer Committee of the College of American Pathologists has prepared an update of the consensus statement on premalignant breast lesions and breast cancer risk that was originally published in the Archives of Pathology & Laboratory Medicine in 1986. The objective of this publication is to better define the relative breast cancer risk associated with specific histologic abnormalities by incorporating data derived from recent case-control studies. Explanatory notes are used to document and explain specific risk classifications. In addition to refining the degree of risk associated with individual lesions, such as fibroadenoma and atypical hyperplasia, this update includes a discussion of age-specific breast cancer risk and provides examples that can be used when counseling patients. C1 Good Samaritan Hosp, Dept Pathol, Los Angeles, CA 90017 USA. NCI, Div Canc Prevent & Control, Early Detect Branch, Bethesda, MD USA. St Barnabas Med Ctr, Dept Pathol, Livingston, NJ USA. RP Fitzgibbons, PL (reprint author), Good Samaritan Hosp, Dept Pathol, 1225 Wilshire Blvd, Los Angeles, CA 90017 USA. OI Fitzgibbons, Patrick/0000-0002-2998-6913 NR 19 TC 147 Z9 159 U1 1 U2 3 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD DEC PY 1998 VL 122 IS 12 BP 1053 EP 1055 PG 3 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 150CW UT WOS:000077646200009 PM 9870852 ER PT J AU Grizzle, WE Aamodt, R Clausen, K LiVolsi, V Pretlow, TG Qualman, S AF Grizzle, WE Aamodt, R Clausen, K LiVolsi, V Pretlow, TG Qualman, S TI Providing human tissues for research - How to establish a program SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID NETWORK AB The Cooperative Human Tissue Network is a group composed of cooperating academic institutions that supply human tissues to researchers studying a wide range of neoplastic and other diseases. The experience of the Cooperative Human Tissue Network in establishing methods of prospective tissue collection and in developing tumor banks is discussed to aid institutions in establishing tissue resources for their local investigators, who may wish to use human tissues in current or future research projects. The advantages to pathology departments and to associated medical institutions of establishing an organized tissue resource include ensuring proper institutional review board approval of research projects using human tissues, protecting diagnostic specimens, creating new opportunities for extramural research, increasing the speed of diagnostic specimen transport to surgical pathology, and providing educational and research opportunities for pathologists and pathology residents. Methods of tissue collection, processing, storage, data collection, and supply are outlined. Also, resources necessary to begin organized tissue collection, including personnel, space, equipment, and supplies, are discussed. C1 Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. NCI, Bethesda, MD 20892 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Penn, Med Ctr, Philadelphia, PA 19104 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH 44106 USA. Childrens Hosp, Columbus, OH 43205 USA. RP Grizzle, WE (reprint author), Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. NR 13 TC 39 Z9 41 U1 0 U2 2 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 DEC PY 1998 VL 122 IS 12 BP 1065 EP 1076 PG 12 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 150CW UT WOS:000077646200011 PM 9870854 ER PT J AU Hediger, ML Overpeck, MD Maurer, KR Kuczmarski, RJ McGlynn, A Davis, WW AF Hediger, ML Overpeck, MD Maurer, KR Kuczmarski, RJ McGlynn, A Davis, WW TI Growth of Infants and Young Children Born Small or Large for Gestational Age - Findings from the Third National Health and Nutrition Examination Survey SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID LOW-BIRTH-WEIGHT; LONG-TERM MORBIDITY; CHILDHOOD GROWTH; BODY-COMPOSITION; PRETERM INFANTS; VARIED SAMPLE; FETAL GROWTH; SIZE; RETARDATION; PATTERNS AB Objectives: To compare the growth profiles of infants and young children born small for gestational age (SGA, <10th percentile birth weight for gestation) or large for gestational age (LGA, greater than or equal to 90th percentile) with those appropriate for gestational age, and to document the expected growth patterns through early childhood based on national health examination survey data. Sample: Infants and children, 2 to 47 months of age, who were born in the United States and examined using the Third National Health and Nutrition Examination Survey (1988-1994). Main Outcome Measures: Measurements of growth status based on normalized distributions (z scores or standard deviation units [SDUs] for weight, length, and head circumference. Results: Prevalence rates were as follows: SGA infants, 8.6%; appropriate for gestational age infants, 80.9%; and LGA infants, 10.5%. Infants who were SGA appeared to catch up in weight in the first 6 months, but thereafter maintained a deficit of about -0.75 SDUs compared with infants who were appropriate for gestational age. The weight status of LGA infants remained at about +0.50 SDUs through 47 months of age. Length and head circumference were also associated with birth weight status, averaging over -0.60 SDUs for SGA infants and +0.43 SDUs for LGA infants. Conclusions: Birth weight status is related to growth rates in infancy and early childhood, which underscores the importance of considering child growth relative to birth status when using growth charts. Small for gestational age infants remain shorter and lighter and have smaller head circumferences, while LGA infants grow longer and heavier and have larger head circumferences. C1 NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Atlanta, GA 30333 USA. Klemm Anal Grp, Hyattsville, MD USA. RP Overpeck, MD (reprint author), NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. NR 46 TC 98 Z9 103 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD DEC PY 1998 VL 152 IS 12 BP 1225 EP 1231 PG 7 WC Pediatrics SC Pediatrics GA 146PH UT WOS:000077439200012 PM 9856434 ER PT J AU Gulko, PS Kawahito, Y Remmers, EF Reese, VR Wang, JP Dracheva, SV Ge, L Longman, RE Shepard, JS Cannon, GW Sawitzke, AD Wilder, RL Griffiths, MM AF Gulko, PS Kawahito, Y Remmers, EF Reese, VR Wang, JP Dracheva, SV Ge, L Longman, RE Shepard, JS Cannon, GW Sawitzke, AD Wilder, RL Griffiths, MM TI Identification of a new non-major histocompatibility complex genetic locus on chromosome 2 that controls disease severity in collagen-induced arthritis in rats SO ARTHRITIS AND RHEUMATISM LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; SYSTEMIC LUPUS-ERYTHEMATOSUS; T-CELL RECEPTOR; RHEUMATOID-ARTHRITIS; LINKAGE MAP; II COLLAGEN; MULTIPLE-SCLEROSIS; RATTUS-NORVEGICUS; POLYGENIC CONTROL; MURINE LOCI AB Objective. To identify novel non-major histocompatibility complex (non-MHC) genetic loci controlling the severity of homologous rat type II collagen-induced arthritis (CIA), Methods. We conducted a genome-wide scan to identify CIA regulatory quantitative trait loci (QTL) in an F-2 cross between DA (CIA highly susceptible) and ACI (CIA resistant) inbred rats immunized with homologous rat type II collagen (RII). These strains share the MHC/RT1(av1) haplotype required for susceptibility to RII-induced CIA. Results. F-2 females had higher median arthritis scores than did males. Relative resistance in the males was determined by inheriting either a DA or an ACI Y chromosome and was independent of the source of the X chromosome. Tn addition, a major QTL was localized on chromosome 2 (Cia7, logarithm of odds score 4.6). Cia7 is in a region that shows linkage conservation with chromosomal regions that regulate autoimmune diabetes and experimental autoimmune encephalomyelitis in mice and multiple sclerosis in humans, Conclusion. Sex chromosomes and Cia7 play an important role in regulating CIA. in response to RII. This rat model should facilitate positional cloning and functional characterization of regulatory genes that may play a role in several forms of autoimmune disease, including rheumatoid arthritis. C1 NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Utah, Salt Lake City, UT USA. Vet Affairs Med Ctr, Salt Lake City, UT 84148 USA. RP Wilder, RL (reprint author), NIAMSD, Arthrit & Rheumatism Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 9N228, Bethesda, MD 20892 USA. NR 70 TC 73 Z9 73 U1 0 U2 0 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 DEC PY 1998 VL 41 IS 12 BP 2122 EP 2131 DI 10.1002/1529-0131(199812)41:12<2122::AID-ART7>3.0.CO;2-# PG 10 WC Rheumatology SC Rheumatology GA 149QL UT WOS:000077616700006 PM 9870869 ER PT J AU Hoffman, GS Drucker, Y Cotch, MF Locker, GA Easley, K Kwoh, K AF Hoffman, GS Drucker, Y Cotch, MF Locker, GA Easley, K Kwoh, K TI Wegener's granulomatosis - Patient-reported effects of disease on health, function, and income SO ARTHRITIS AND RHEUMATISM LA English DT Article ID CLASSIFICATION; CRITERIA AB Objective. To evaluate the patient-perceived effects of Wegener's granulomatosis (WG) on health, function, income, and interpersonal relationships. Methods. A self-administered questionnaire, originally designed by the authors and subsequently revised with the aid of a patient focus group, was completed by 60 patients with well-defined features of WG, Patients had WG for a median period of 5 years. Results. Patients with chronic WG experienced substantial medical and functional morbidity and incurred significant socioeconomic losses. A prolonged delay in diagnosis (mean 16.8 months) and the need for multiple consultations prior to initiation of therapy may have contributed to medical morbidity, Although 73% of patients perceived their disease to be in remission following therapy, 78% of these patients required continuing immunosuppressive treatment many years after diagnosis. Eighty percent of patients reported that their normal activities of daily living were compromised. Half of those who were employed prior to diagnosis were required to modify their job or accept total disability (31%). A 26% (median) reduction in income within 1 year after diagnosis was reported. The effects of the disease on interpersonal relationships with a patient's spouse, family, and friends varied considerably, Conclusion. Advances in medical care have, for most patients, transformed WG from being a disease with a high potential for short-term mortality to being a chronic illness. This is the first study that has evaluated patients' assessments of the medical, socioeconomic, and quality of life effects of WG and its treatment. The effects of mortality, disability, and outpatient medical expenses indicate that the financial impact alone substantially exceeds prior estimates of $30 million per year in charges for hospitalizations in the US. C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. NEI, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Sch Med, Cleveland, OH USA. Vet Affairs Med Ctr, Cleveland, OH USA. RP Hoffman, GS (reprint author), Cleveland Clin Fdn, A50,9500 Euclid Ave, Cleveland, OH 44195 USA. RI Easley, Kirk/K-6910-2015; OI Easley, Kirk/0000-0003-4419-2617; Cotch, Mary Frances/0000-0002-2046-4350 FU Intramural NIH HHS [Z99 EY999999] NR 11 TC 55 Z9 55 U1 0 U2 0 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 DEC PY 1998 VL 41 IS 12 BP 2257 EP 2262 DI 10.1002/1529-0131(199812)41:12<2257::AID-ART22>3.0.CO;2-K PG 6 WC Rheumatology SC Rheumatology GA 149QL UT WOS:000077616700020 PM 9870883 ER PT J AU De Weerd, P AF De Weerd, P TI Linking spread of neural activity and filling-in: A few more arguments in favor SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material AB The commentary sides with Pessoa and his colleagues in arguing that some types of perceptual filling-in are linked with a spread of cortical activity, a hypothesis that has often been rejected on philosophical grounds. Some recent data are discussed that strengthen this linking hypothesis and indicate that a spread of cortical activity may be essential for normal surface perception. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP De Weerd, P (reprint author), NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. NR 4 TC 1 Z9 1 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 DEC PY 1998 VL 21 IS 6 BP 754 EP + DI 10.1017/S0140525X98291758 PG 9 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 163HU UT WOS:000078400600009 ER PT J AU Berch, DB Foley, EJ AF Berch, DB Foley, EJ TI Processing demands associated with relational complexity: Testing predictions with dual-task methodologies SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material AB We discuss how modified dual-task approaches may be used to verify the degree to which cognitive tasks are capacity demanding. We also delineate some of the complexities associated with the use of the "double easy-to-hard" paradigm for testing claim of Halford, Wilson & Phillips that hierarchical reasoning imposes processing demands equivalent to those of transitive reasoning. C1 NICHHD, Child Dev & Behav Branch, Bethesda, MD 20892 USA. Univ Cincinnati, Dept Psychol, Cincinnati, OH 45221 USA. RP Berch, DB (reprint author), NICHHD, Child Dev & Behav Branch, Bethesda, MD 20892 USA. NR 5 TC 1 Z9 1 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 DEC PY 1998 VL 21 IS 6 BP 832 EP + DI 10.1017/S0140525X98231761 PG 7 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 163HU UT WOS:000078400600042 ER PT J AU Murray, EA Baxter, MG Gaffan, D AF Murray, EA Baxter, MG Gaffan, D TI Monkeys with rhinal cortex damage or neurotoxic hippocampal lesions are impaired on spatial scene learning and object reversals SO BEHAVIORAL NEUROSCIENCE LA English DT Article ID FORNIX-TRANSECTED MONKEYS; RHESUS-MONKEYS; PERIRHINAL CORTEX; CA1 FIELD; PREFRONTAL CORTEX; ENTORHINAL CORTEX; TEMPORAL-LOBE; PLACE MEMORY; 2 VERSIONS; AREA TE AB Rhesus monkeys (Macaca mulatta) with lesions of the rhinal cortex or parahippocampal gyrus (made by aspiration) or hippocampus (made with ibotenic acid) and unoperated controls were tested on object discrimination and reversal, place discrimination and reversal, and spatial scene learning to determine the contribution of these temporal lobe structures to these forms of learning and memory. Rhinal cortex lesions produced a severe deficit in object reversal learning; hippocampal lesions produced a milder deficit. Monkeys with rhinal cortex removals and those with hippocampal lesions were equally impaired on spatial scene learning. None of the lesions impaired place discrimination or reversal. These results argue against the idea that the mnemonic contributions of the rhinal cortex and hippocampus are limited to object and spatial domains, respectively. C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. RP Murray, EA (reprint author), NIMH, Neuropsychol Lab, Bldg 9,Room 1B80, Bethesda, MD 20892 USA. OI Murray, Elisabeth/0000-0003-1450-1642 NR 44 TC 141 Z9 143 U1 0 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD DEC PY 1998 VL 112 IS 6 BP 1291 EP 1303 DI 10.1037//0735-7044.112.6.1291 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 157UW UT WOS:000078080900001 PM 9926813 ER PT J AU Keppler-Hafkemeyer, A Brinkmann, U Pastan, I AF Keppler-Hafkemeyer, A Brinkmann, U Pastan, I TI Role of caspases in immunotoxin-induced apoptosis of cancer cells SO BIOCHEMISTRY LA English DT Article ID FAS-MEDIATED APOPTOSIS; SEGREGATION GENE CSE1; POLY(ADP-RIBOSE) POLYMERASE; PSEUDOMONAS EXOTOXIN; DIPHTHERIA-TOXIN; ICE/CED-3 PROTEASE; RECOMBINANT TOXINS; DNA FRAGMENTATION; HUMAN HOMOLOG; DEATH AB Immunotoxins composed of antibodies linked to plant or bacterial toxins are being evaluated in the treatment of cancer. It is known that the toxin moieties of immunotoxins, including Pseudomonas exotoxin A (PE), diphtheria toxin, and ricin, are capable of inducing apoptosis. Since the efficiency of induction of apoptosis and the apoptosis pathway may have direct effects on the therapeutic usefulness of immunotoxins, we have studied how B3(Fv)-PE38, a genetically engineered immunotoxin in which the Fv fragment of an antibody is fused to a mutated form of PE, induces apoptosis of the MCF-7 breast cancer cell line. We show for the first time that a PE-containing immunotoxin activates ICE/ced-3 proteases, now termed caspases, and causes characteristic cleavage of the "death substrate" poly(ADP)-ribose polymerase (PARP) to an 89 kDa fragment with a time course of cleavage comparable to that induced by TNF alpha. Also the fluorescent substrate? DEVD-AFC, is cleaved 2-4-fold more rapidly by lysates from B3(Fv)-PE38 treated MCF-7 cells than untreated control cells, suggesting that a CPP32-like caspase is involved in B3(Fv)-PE38-mediated apoptosis. B3(Fv)-PE38 -induced PARP cleavage is inhibited by several protease inhibitors known to inhibit caspases (zVAD-fmk, zDEVD-fmk, zIETD-fmk) as well as by overexpression of Bcl-2 providing additional evidence for caspase involvement. zVAD-fmk, a broad spectrum inhibitor of most mammalian caspases, prevents the early morphological changes and loss of cell membrane integrity produced by B3(Fv)-PE38, but not its ability to inhibit protein synthesis, arrest cell growth, and subsequently kill cells. Despite inhibition of apoptosis, the immunotoxin is still capable of selective cell killing, which indicates that B3(Fv)-PE38 kills cells by two mechanisms: one requires caspase activation, and the other is due to the arrest of protein synthesis caused by inactivation of elongation factor 2. The fact that an immunotoxin can specifically kill tumor cells without the need of inducing apoptosis makes such agents especially valuable for the treatment of cancers that are protected against apoptosis, e.g., by overexpression of Bcl-2. C1 NCI, Mol Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Div Basic Sci, NIH, Bldg 37,Room 4E16,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. NR 51 TC 77 Z9 80 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 1 PY 1998 VL 37 IS 48 BP 16934 EP 16942 DI 10.1021/bi980995m PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 144WX UT WOS:000077339600011 PM 9836586 ER PT J AU Chen, A Mannen, H Li, SSL AF Chen, A Mannen, H Li, SSL TI Characterization of mouse ubiquitin-like SMT3A and SMT3B cDNAs and gene/pseudogenes SO BIOCHEMISTRY AND MOLECULAR BIOLOGY INTERNATIONAL LA English DT Article ID NUCLEAR-PORE COMPLEX; PROTEIN CENP-C; CENTROMERE PROTEIN; SACCHAROMYCES-CEREVISIAE; HUMAN HOMOLOG; GENE; MIF2; COMPONENT; RANGAP1 AB Mouse SMT3A and SMT3B cDNAs encoding ubiquitin-like proteins of 110 and 95 amino acids, respectively, were isolated and sequenced. The sequence of the first 92 amino acids (ending with the conserved Gly-Gly) of mouse SMT3A exhibited two differences at amino acid no. 38 and 76 in comparison with that of human SMT3A. The C-terminal 18 amino acid sequence of mouse SMT3A was completely different from the C-terminal 11 amino acid sequence of human SMT3A. Mouse and human SMT3B were identical for a sequence of 95 amino acids. Mouse SMT3A genomic DNAs were amplified by polymerase-chain-reaction and sequenced. The nucleotide sequence of a PCR-amplified SMT3A genomic DNA fragment was found to be identical to that of SMT3A cDNA, indicating the absence of intron(s) in its protein coding region. Another genomic DNA fragment of 1,531 nucleotides, containing 7% differences from that of cDNA, is unable to encode a functional protein, and thus, it is a SMT3A processed pseudogene. Three mouse SMT3B processed pseudogenes were cloned and sequenced. The genuine mouse SMT3B gene has not yet been isolated. Mouse SMT3A transcript of 1.8kb was predominantly expressed in most tissues, while SMT3B transcript of 1.0 kb was abundantly present in all tissues analyzed. C1 NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Natl Sun Yat Sen Univ, Dept Biol Sci, Kaohsiung 80424, Taiwan. RP Li, SSL (reprint author), NIEHS, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 15 TC 31 Z9 37 U1 0 U2 1 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1039-9712 J9 BIOCHEM MOL BIOL INT JI Biochem. Mol. Biol. Int. PD DEC PY 1998 VL 46 IS 6 BP 1161 EP 1174 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 155WB UT WOS:000077968400011 PM 9891849 ER PT J AU Momchilova, A Markovska, T Pankov, R AF Momchilova, A Markovska, T Pankov, R TI Phospholipid dependence of membrane-bound phospholipase A(2) in ras-transformed NIH 3T3 fibroblasts SO BIOCHIMIE LA English DT Article DE phospholipase A(2); ras; arachidonic acid; phosphatidic acid ID PROTEIN-KINASE-C; FATTY-ACIDS; CELLS; LIVER; METABOLISM; ENZYMES; GENES; LAYER AB Although the activation of phospholipase A(2) (PLA(2)) in ms-transformed cells has been well documented, the mechanisms underlying this activation are poorly understood. In this study we tried to elucidate whether the membrane phospholipid composition and physical state influence the activity of membrane-associated PLA(2) in ras-transformed fibroblasts. For this purpose membranes from non-transfected and ms-transfected NM 3T3 fibroblasts were enriched with different phospholipids by the aid of partially purified lipid transfer protein. The results showed that of all tested phospholipids only phosphatidylcholine (PC) increased PLA(2) activity in the control cells, whereas in their transformed counterparts both PC and phosphatidic acid (PA) induced such effect. Further we investigated whether the activatory effect was due only to the polar head of these phospholipids, or if it was also related to their acyl chain composition. The results demonstrated that the arachidonic acid-containing PC and PA molecules induced a more pronounced increase of membrane-associated PLA(2) activity in ras-transformed cells compared to the corresponding palmitate stearate- or oleate- containing molecular species. However, we did not observe any specific effect of the phospholipid fatty acid composition in non-transformed NM 3T3 fibroblasts. In ras-transformed cells incubated with increasing concentrations of arachidonic acid, PLA(2) activity was altered in parallel with the changes of the cellular content of this fatty acid. The role of phosphatidic and arachidonic acids as specific activators of PLA(2) in ras-transformed cells is discussed with respect to their possible role in the signal transduction pathways as well as in the processes of malignant transformation of cells. (C) Societe francaise de biochimie et biologie moleculaire / Elsevier, Paris. C1 Bulgarian Acad Sci, Inst Biophys, BU-1113 Sofia, Bulgaria. NIDR, Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Momchilova, A (reprint author), Bulgarian Acad Sci, Inst Biophys, Acad G Bonchev Str Bl 21, BU-1113 Sofia, Bulgaria. RI Pankov, Roumen/B-3284-2014 OI Pankov, Roumen/0000-0002-3157-3659 NR 32 TC 9 Z9 9 U1 0 U2 0 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS CEDEX 15 PA 23 RUE LINOIS, 75724 PARIS CEDEX 15, FRANCE SN 0300-9084 J9 BIOCHIMIE JI Biochimie PD DEC PY 1998 VL 80 IS 12 BP 1055 EP 1062 DI 10.1016/S0300-9084(99)80012-1 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 197JY UT WOS:000080362700012 PM 9924985 ER PT J AU Chapin, RE Ku, WW Kenney, MA McCoy, H AF Chapin, RE Ku, WW Kenney, MA McCoy, H TI The effects of dietary boric acid on bone strength in rats SO BIOLOGICAL TRACE ELEMENT RESEARCH LA English DT Article DE dietary boron; vertebra; strength; male rat ID BORON AB The effects of dietary boron (B) (from boric acid [BA]) on bone strength were evaluated using male F344 rats. B was administered by dietary admixture of BA to NIH-07 feed at concentrations of 200, 1000, 3000, and 9000 ppm. The latter two levels were found in previous studies to be reproductively toxic to both males and the developing fetus. The first two levels are below and just at, respectively, the levels for producing fetal malformations, and are below the dose required to produce male reproductive toxicity. Resistance to destructive testing was measured on femora, tibiae, and lumbar vertebrae. Although femur and tibia resistance to bending force were not affected by any amount of dietary B, vertebral resistance to a crushing force was increased by approximate to 10%, at all dose levels (200-9000 ppm). These data show that even levels of BA that are not reproductively toxic can affect the strength of the axial skeleton in rats. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Univ Arkansas, Agr Expt Stn, Fayetteville, AR 72701 USA. RP Chapin, RE (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. OI Chapin, Robert/0000-0002-5997-1261 NR 8 TC 37 Z9 38 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 WIN PY 1998 VL 66 IS 1-3 BP 395 EP 399 DI 10.1007/BF02783150 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 166EM UT WOS:000078563300030 PM 10050932 ER PT J AU Bush, MR Mele, JM Couchman, GM Walmer, DK AF Bush, MR Mele, JM Couchman, GM Walmer, DK TI Evidence of juxtacrine signaling for transforming growth factor alpha in human endometrium SO BIOLOGY OF REPRODUCTION LA English DT Article ID TYROSINE PROTEIN-KINASE; AMINO-TERMINAL DOMAIN; FACTOR RECEPTOR EGFR; TGF-ALPHA; PERIIMPLANTATION PERIOD; CYTOPLASMIC DOMAINS; MENSTRUAL-CYCLE; MOUSE UTERUS; EXPRESSION; TRANSMEMBRANE AB 0To determine the mechanism of signaling for transforming growth factor alpha (TGF alpha) in human endometrium, uterine luminal fluid proteins were retrieved by ravage followed by collection of the adjacent endometrium at hysterectomy, In the endometrium we observed the presence of the full-length transmembrane TGF alpha protein and the phosphorylation of its only known receptor, the epidermal growth factor receptor (EGFR), by immunoprecipitation-Western blot; TCF alpha mRNA via reverse transcription-polymerase chain reaction; and immunolocalization of TCF alpha to the surface endometrium adjacent to the uterine lumen. Despite this demonstration of TGF alpha: in functional endometrium, we could not detect measurable amounts of TGF alpha in any of the 16 endometrial washings by either immunoprecipitation-Western blot or by ELISA. Recovery rate for intraluminal fluid spiked with TGF alpha control peptide was 93.4-97%, The inability to detect TGF alpha in intraluminal fluid despite its high concentration in cells directly adjacent to the uterine lumen, along with the absence of any cleaved TGF alpha species identified in the endometrium, suggests that TCF alpha signals its receptor as a transmembrane ligand, Since the EGFR is present in the endometrium and on the surface of embryos, these data are consistent with a juxtacrine mode of signaling for TGF alpha between endometrial cells, and between the luminal surface epithelium and preimplantation embryos. C1 Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Reprod Endocrinol & Infertil, Durham, NC 27710 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Bush, MR (reprint author), Madigan Army Med Ctr, MCHG OG, Div Reprod Endocrinol & Infertil, Tacoma, WA 98431 USA. NR 36 TC 8 Z9 10 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD DEC PY 1998 VL 59 IS 6 BP 1522 EP 1529 DI 10.1095/biolreprod59.6.1522 PG 8 WC Reproductive Biology SC Reproductive Biology GA 148CF UT WOS:000077534700034 PM 9828201 ER PT J AU Faraggi, D AF Faraggi, D TI Bayesian variable selection method for censored survival data SO BIOMETRICS LA English DT Article DE Bayesian analysis; censored data; missing data; proportional hazards model; subset model; variable selection ID MODEL; REGRESSION; INFORMATION; EFFICIENCY; CHOICE AB A Bayesian variable selection method for censored data is proposed in this paper. Based on the sufficiency and asymptotic normality of the maximum partial likelihood estimator, we approximate the posterior distribution of the parameters in a proportional hazards model. We consider a parsimonious model as the full model with some covariates unobserved and replaced by their conditional expected values. A loss function based on the posterior expected estimation error of the log-risk for the proportional hazards model is used to select a parsimonious model. We derive computational expressions for this loss function for both continuous and binary covariates. This approach provides an extension of Lindley's (1968, Journal of the Royal Statistical Society, Series B 30, 31-66) variable selection criterion for the linear case. Data from a randomized clinical trial of patients with primary biliary cirrhosis of the liver (PBC) (Fleming and Harrington, 1991, Counting Processes and Survival Analysis) is used to illustrate the proposed method and a simulation study compares it with the backward elimination procedure. C1 Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. NCI, Biometr Res Branch, Rockville, MD 20852 USA. RP Faraggi, D (reprint author), Univ Haifa, Dept Stat, IL-31999 Haifa, Israel. NR 22 TC 26 Z9 28 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 DEC PY 1998 VL 54 IS 4 BP 1475 EP 1485 DI 10.2307/2533672 PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 154PZ UT WOS:000077898700022 PM 9883546 ER PT J AU Baker, SG AF Baker, SG TI Evaluating the age to begin periodic breast cancer screening using data from a few regularly scheduled screenings SO BIOMETRICS LA English DT Article DE noncompliance; nonrandomized trials; observational studies; periodic screening evaluation; Poisson regression ID DISEASE; MORTALITY; BENEFITS; EFFICACY AB To evaluate various ages to begin periodic breast cancer screening, we propose a method of analysis that can be applied to either a nonrandomized or a randomized study involving only a few screenings at regular intervals. For the analysis of data from a nonrandomized study, we assume (i) once breast cancer can be detected on screening and confirmed by biopsy, it will stay that way; (ii) given age, the probability of breast cancer detection does not depend on year of birth; and (iii) subjects who refuse screening have the same rates of breast cancer mortality following diagnosis as screened subjects had they not received screening. The key idea is that older screened subjects are controls for younger screened subjects. For the analysis of data from a randomized study, we relax assumption (iii). Based on the HIP randomized trial and assumptions (i) and (ii), we estimate that starting periodic breast cancer screening with mammography and physical examination at age 40 instead of age 50 reduces breast cancer mortality by 14 per 10,000 with a 95% confidence interval of (-4/10,000, 32/10,000). This must be weighed against an estimated increase in the number of biopsies that do not detect cancer of 580 per 10,000 with a 95% confidence interval of (520/10,000, 650/10,000). C1 NCI, Biometry Branch, Div Canc Prevent, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Branch, Div Canc Prevent, EPN 344,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 24 TC 6 Z9 6 U1 1 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 DEC PY 1998 VL 54 IS 4 BP 1569 EP 1578 DI 10.2307/2533681 PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 154PZ UT WOS:000077898700031 PM 9883553 ER PT J AU Park, TS AF Park, TS TI An approach to categorical data with nonignorable nonresponse SO BIOMETRICS LA English DT Article DE Bayesian estimators; ERI algorithm; log-linear models; maximum likelihood estimators; nonignorable missing data; prior distribution ID MAXIMUM-LIKELIHOOD ESTIMATION; INCOMPLETE MULTINOMIAL DATA; PATTERN-MIXTURE MODELS; CONTINGENCY-TABLES; CLASSIFIED DATA; LINEAR-MODELS; MISSING DATA; DROP-OUT; SUBJECT AB Log-linear models have been used to adjust for nonresponse when categorical outcomes are subject to nonignorable nonresponse. The log models are fitted to the data in an augmented frequency table in which one index corresponds to whether the subject is a respondent. Park and Brown (1994, Journal of the American Statistical Association 89, 44-52) proposed a pseudo-Bayesian method that has the effect of smoothing the unobserved cell frequencies. Their approach assigns prior observations only to the unobserved cells. Their method was shown to perform better than the maximum likelihood method, which can produce unstable boundary estimates. Generalizing their approach, we propose a new approach that assigns prior observations to both observed and unobserved cells. Through a simulation study, we compare the proposed approach with Park and Brown's and the maximum likelihood approach. C1 Hankuk Univ Foreign Studies, Dept Stat, Kyungki Do 449791, South Korea. NICHHD, Biometry & Math Stat Branch, Bethesda, MD 20892 USA. RP Park, TS (reprint author), Hankuk Univ Foreign Studies, Dept Stat, Kyungki Do 449791, South Korea. NR 30 TC 12 Z9 12 U1 2 U2 3 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 DEC PY 1998 VL 54 IS 4 BP 1579 EP 1590 DI 10.2307/2533682 PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 154PZ UT WOS:000077898700032 PM 9883554 ER PT J AU Park, T Shin, DW Park, CG AF Park, T Shin, DW Park, CG TI A generalized estimating equations approach for testing ordered group effects with repeated measurements SO BIOMETRICS LA English DT Article DE isotonic regression; ordered hypothesis; quasi-likelihood estimation; repeated measures analysis ID LONGITUDINAL DATA-ANALYSIS; RESTRICTED INFERENCE; LEVEL PROBABILITIES; LINEAR-MODELS AB In repeated measures studies, we are often interested in comparing group effects in which groups are associated with a certain order relation. We propose testing procedures for ordered group effects using the generalized estimating equations (GEE) approach of Liang and Zeger (1986, Biometrika 73, 13-22). The order-constrained GEE estimators of group effects are approximated by the isotonic regression of the unconstrained GEE estimators. Based on these constrained estimators, we construct test statistics for detecting ordered group effects. The limiting distributions of the test statistics are mixtures of chi-square distributions. A Monte Carlo experiment shows improved performances of the proposed tests over the usual chi-square tests in detecting ordered group effects. The proposed test procedures are illustrated by familial polyposis supplementation trial data. C1 Hankuk Univ Foreign Studies, Dept Stat, Seoul 449791, South Korea. NICHHD, Biometry Branch, Bethesda, MD 20892 USA. Ewha Womans Univ, Dept Stat, Seoul 120750, South Korea. Univ Suwon, Dept Appl Stat, Suwon 445743, South Korea. RP Park, CG (reprint author), Hankuk Univ Foreign Studies, Dept Stat, Seoul 449791, South Korea. EM tspark@stat.hufs.ac.kr NR 23 TC 9 Z9 9 U1 1 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 DEC PY 1998 VL 54 IS 4 BP 1645 EP 1653 DI 10.2307/2533689 PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 154PZ UT WOS:000077898700039 PM 9883556 ER PT J AU Laws, ML Roberts, RR Nicholson, JM Butcher, R Stables, JP Goodwin, AM Smith, CA Scott, KR AF Laws, ML Roberts, RR Nicholson, JM Butcher, R Stables, JP Goodwin, AM Smith, CA Scott, KR TI Synthesis, characterization, and anticonvulsant activity of enaminones. Part 5: Investigations on 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-one derivatives SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE anticonvulsants; NMR; X-ray crystal structures AB A new series of anticonvulsant 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-ones is herein reported. 2-Aminothiophenols underwent cyclocondensation with 4-carboalkoxy-5-methylcyclohexane-1,3-diones in refluxing dimethylsulfoxide (DMSO) to yield 3-carboalkoxy-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-ones, 4a-k. In the case of the carbo-tert-butoxy derivatives (4c and 4k) prolonged reaction times led to the isolation of the respective 3-unsubstituted-2-methyl-2,3-dihydro-1H-phenothiazin-4[10H]-ones (41 and 4m) instead. Significant anticonvulsant activity was displayed by these analogues, most particularly 4k, which was active at 30 mg/kg intraperitoneally tip) in mice in the maximal electroshock seizure (MES) evaluation, with no toxicity noted at dosages up to 300 mg/kg. Oral (po) rat evaluation of 4k in the MES evaluation provided an ED50 Of 17.60 mg/kg, with no toxicity noted at dosages up to 500 mg/kg, providing a protective index (PI = TD50/ED50) > 28.40. These compounds represent the first reported series of phenothiazines which possess anticonvulsant activity. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 Howard Univ, Coll Pharm Nursing & Allied Hlth Sci, Dept Pharmaceut Sci, Washington, DC 20059 USA. NINDS, Div Convuls Dev & Neuromuscular Disorders, Epilepsy Branch, Bethesda, MD 20894 USA. Howard Univ, Grad Sch Arts & Sci, Dept Chem, Washington, DC 20059 USA. 3M Co, Corp Res, 3M Ctr, Sci Res Lab, St Paul, MN 55144 USA. Dupont Merck Pharmaceut Co, Chem & Phys Sci, R&D Expt Stn, Wilmington, DE 19880 USA. RP Scott, KR (reprint author), Howard Univ, Coll Pharm Nursing & Allied Hlth Sci, Dept Pharmaceut Sci, Washington, DC 20059 USA. EM rroberts2@mmm.com; kscott@fac.howard.edu FU NIGMS NIH HHS [GM08244-06] NR 30 TC 21 Z9 21 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD DEC PY 1998 VL 6 IS 12 BP 2289 EP 2299 DI 10.1016/S0968-0896(98)80009-6 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 154CA UT WOS:000077869900006 PM 9925291 ER PT J AU Benzaria, S Bienfait, B Nacro, K Wang, SM Lewin, NE Beheshti, M Blumberg, PM Marquez, VE AF Benzaria, S Bienfait, B Nacro, K Wang, SM Lewin, NE Beheshti, M Blumberg, PM Marquez, VE TI Conformationally constrained analogues of diacylglycerol (DAG). 15. The indispensable role of the sn-1 and sn-2 carbonyls in the binding of DAG-lactones to protein kinase C (PK-C) SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID 5-DISUBSTITUTED TETRAHYDRO-2-FURANONE TEMPLATE; PHORBOL ESTER; TUMOR PROMOTERS; LIGANDS AB The binding mode of DAG-lactones to PK-C was investigated using the C1b domain from the Xray structure of the phorbol ester/C1b complex of PK-C delta as a template. Modeling experiments revealed two binding alternatives in which one of the carbonyls of the DAG lactones remained uninvolved with the protein. Experimentally, however, the removal of either sn-1 or sn-2 carbonyls caused a dramatic drop in binding affinity towards PK-C. Although it was not possible to discriminate between the two binding alternatives of the DAG-lactones, the study demonstrates an important role for the additional carbonyl group. The function of this group could be equivalent to that of the C-9(OH)/C-13 (C=O) motif in phorbol esters, which also appears free of interactions in the phorbol ester/C1b complex. This role presumably reflects interaction with the phosholipid head groups required for high affinity binding under the conditions of the biological assays. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Marquez, VE (reprint author), NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NR 14 TC 20 Z9 20 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 1 PY 1998 VL 8 IS 23 BP 3403 EP 3408 DI 10.1016/S0960-894X(98)00614-3 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 147JK UT WOS:000077485600024 PM 9873742 ER PT J AU Norwood, D Dimitrov, DS AF Norwood, D Dimitrov, DS TI Sensitive method for measuring telomere lengths by quantifying telomeric DNA content of whole cells SO BIOTECHNIQUES LA English DT Article ID HUMAN FIBROBLASTS AB Recently, a new method for measuring telomere lengths based on telomere DNA content was developed. The method, which is based on the ratio of telomere to centromere DNA content (TC ratio), is highly sensitive, allowing the analysis of small quantities of DNA. However, the method required the isolation of DNA, which can be difficult or impossible for small numbers of cells. Here, we suggest an improvement of this method that can directly estimate telomere lengths from whole cells. We optimized the method for whole cells and purified DNA and found that accurate TC ratios can be obtained from as little as 9 ng of DNA or 800 whole cells. There was no statistically significant difference between the ratios obtained with purified DNA or with whole cells, indicating that the isolation of DNA is not necessary for small samples. C1 NCI, Lab Expt & Computat Biol, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. RP Norwood, D (reprint author), NCI, Lab Expt & Computat Biol, Frederick Canc Res & Dev Ctr, NIH, Bldg 469,Room 216, Frederick, MD 21702 USA. NR 8 TC 18 Z9 21 U1 0 U2 2 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD DEC PY 1998 VL 25 IS 6 BP 1040 EP + PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 147KV UT WOS:000077511300021 PM 9863059 ER PT J AU Frankel, AE Lilly, M Kreitman, R Hogge, D Beran, M Freedman, MH Emanuel, PD McLain, C Hall, P Tagge, E Berger, M Eaves, C AF Frankel, AE Lilly, M Kreitman, R Hogge, D Beran, M Freedman, MH Emanuel, PD McLain, C Hall, P Tagge, E Berger, M Eaves, C TI Diphtheria toxin fused to granulocyte-macrophage colony-stimulating factor is toxic to blasts from patients with juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia SO BLOOD LA English DT Article ID ACUTE MYELOBLASTIC-LEUKEMIA; GM-CSF RECEPTOR; PROGENITOR CELLS; CYTOPLASMIC DOMAIN; HEMATOPOIETIC STEM; BONE-MARROW; TUMOR-CELLS; EXPRESSION; GROWTH; PROTEIN AB We have previously demonstrated that human granulocyte-macrophage colony-stimulating factor fused to a truncated diphtheria toxin (DT388-GM-CSF) is toxic to patient acute myeloid leukemia progenitors bearing the GM-CSF receptor, but not normal marrow progenitors. We now report that exposure of mononuclear cells from five of seven (71%) juvenile myelomonocytic leukemia (JMML) patients and from 12 of 20 (60%) adult chronic myelomonocytic leukemia (CMML) patients to 10(-9) mol/L DT388-GM-CSF for 48 hours in culture reduces the number of cells capable of forming colonies in semisolid medium (colony-forming units-leukemia) 10-fold to 300-fold (1 to 2.5 log decrease). In contrast, normal myeloid progenitors (colony-forming unit-granulocyte-macrophage) from six different donors treated and assayed under identical conditions were consistently insensitive to the same fusion toxin even when treated as highly purified CD34(+) cells. The leukemic progenitors from the two other JMML patients showed intermediate sensitivity to DT388-GM-CSF and the leukemic progenitors from eight of the 20 (40%) CMML patients were not different from normal progenitors. Parallel measurements of the number and affinity of GM-CSF receptors on cells from the same samples showed no consistent differences between JMML, CMML, and normal light density or CD34+ bone marrow cells. The increased sensitivity of leukemic progenitors from all JMML progenitors and some CMML patients to the fusion toxin is therefore not likely to be explained by an increased density of GM-CSF receptors on these cells. We also examined the DT388-GM-CSF sensitivity of two murine cell lines transfected with cDNAs encoding varying portions of the human GM-CSF receptor or and/or beta chains. These studies showed that high-affinity ligand binding was sufficient for DT388-GM-CSF-induced toxicity, as this could occur even in the absence of functional signal transduction and that the background of the host cell had a major influence on the degree to which this decreased the toxicity of DT388-GM-CSF. The selective sensitivity to DT388-GM-CSF of leukemic progenitors from a majority of JMML and CMML patients suggests that this agent could have therapeutic potential for some patients with these diseases; (C) 1998 by The American Society of Hematology. C1 Wake Forest Univ, Bowman Gray Sch Med, Ctr Comprehens Canc, Winston Salem, NC 27157 USA. Univ Washington, Dept Med, Div Med Oncol, Seattle, WA USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. Univ Texas, MD Anderson Cancer Ctr, Leukemia Dept, Houston, TX 77030 USA. Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada. Univ Alabama, Ctr Comprehens Canc, Birmingham, AL 35294 USA. Med Univ S Carolina, Dept Surg, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Pharmaceut Sci, Charleston, SC 29425 USA. RP Frankel, AE (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Ctr Comprehens Canc, Hanes 4046,Med Ctr Dr, Winston Salem, NC 27157 USA. OI Emanuel, Peter/0000-0002-9764-2434 FU NCI NIH HHS [CA45672, R01CA76178, U01CA60407] NR 37 TC 34 Z9 34 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 0006-4971 J9 BLOOD JI Blood PD DEC 1 PY 1998 VL 92 IS 11 BP 4279 EP 4286 PG 8 WC Hematology SC Hematology GA 142HH UT WOS:000077194300035 PM 9834234 ER PT J AU Maran, A Waller, CF Paranjape, JM Li, GY Xiao, W Zhang, K Kalaycio, ME Maitra, RK Lichtin, AE Brugger, W Torrence, PF Silverman, RH AF Maran, A Waller, CF Paranjape, JM Li, GY Xiao, W Zhang, K Kalaycio, ME Maitra, RK Lichtin, AE Brugger, W Torrence, PF Silverman, RH TI 2 ',5 '-oligoadenylate-antisense chimeras cause RNase L to selectively degrade bcr/abl mRNA in chronic myelogenous leukemia cells SO BLOOD LA English DT Article ID MYB ANTISENSE OLIGODEOXYNUCLEOTIDES; TYROSINE KINASE-ACTIVITY; BCR-ABL; PHILADELPHIA-CHROMOSOME; 2-5A ANTISENSE; TARGETING RNA; MICE; INHIBITION; EXPRESSION; GROWTH AB We report an RNA targeting strategy, which selectively degrades bcr/abl mRNA in chronic myelogenous leukemia (CML) cells. A 2',5'-tetraadenylate activator (2-5A) of RNase L was chemically linked to oligonucleotide antisense directed against either the fusion site or against the translation start sequence in bcr/abl mRNA. Selective degradation of the targeted RNA sequences was demonstrated in assays with purified RNase L and decreases of p210(bcr/abt) kinase activity levels were obtained in the CML cell line, K562, Furthermore, the 2-5A-antisense chimeras suppressed growth of K562, while having substantially reduced effects on the promyelocytic leukemia cell line, HL60. Findings were extended to primary CML cells isolated from bone marrow of patients. The 2-5A-antisense treatments both suppressed proliferation of the leukemia cells and selectively depleted levels of bcr/abl mRNA without affecting levels of beta-actin mRNA, determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The specificity of this approach was further shown with control oligonucleotides, such as chimeras containing an inactive dimeric form of 2-5A, antisense lacking 2-5A, or chimeras with altered sequences including several mismatched nucleotides. The control oligonucleotides had either reduced or no effect on CML cell growth and bcr/abl mRNA levels. These findings show that CML cell growth can be selectively suppressed by targeting bcr/abl mRNA with 2-5A-antisense for decay by RNase L and suggest that these compounds should be further explored for their potential as ex vivo purging agents of autologous hematopoietic stem cell transplants from CML patients. (C) 1998 by The American Society of Hematology. C1 Cleveland Clin Fdn, Dept Canc Biol, Lerner Res Inst, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Dept Hematol & Oncol, Cleveland, OH 44195 USA. NIDDKD, Sect Biomed Chem, NIH, Bethesda, MD 20892 USA. RP Silverman, RH (reprint author), Cleveland Clin Fdn, Dept Canc Biol, Lerner Res Inst, 9500 Euclid Ave,NB40, Cleveland, OH 44195 USA. FU NCI NIH HHS [1 PO1 CA 62220] NR 33 TC 30 Z9 34 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 1 PY 1998 VL 92 IS 11 BP 4336 EP 4343 PG 8 WC Hematology SC Hematology GA 142HH UT WOS:000077194300041 PM 9834240 ER PT J AU Britos-Bray, M Ramirez, M Cao, WS Wang, XP Liu, PP Civin, CI Friedman, AD AF Britos-Bray, M Ramirez, M Cao, WS Wang, XP Liu, PP Civin, CI Friedman, AD TI CBF beta-SMMHC, expressed in M4eo acute myeloid leukemia, reduces p53 induction and slows apoptosis in hematopoietic cells exposed to DNA-damaging agents SO BLOOD LA English DT Article ID ACUTE NONLYMPHOCYTIC LEUKEMIA; RADIATION-INDUCED APOPTOSIS; FETAL LIVER HEMATOPOIESIS; BINDING-FACTOR-BETA; MYOSIN HEAVY-CHAIN; ANTICANCER AGENTS; GROWTH ARREST; GENE; AML1; FAMILY AB CBF beta-SMMHC is expressed in M4Eo acute myeloid leukemia (AML) as a result of inv(16), but how it contributes to leukemogenesis is unknown. p53 mutations are rare in de novo AML, but they are common in many malignancies. Expression of CBF beta-SMMHC in Ba/F3 cells reduced p53 induction in response to ionizing radiation or etoposide 3- to 4-fold. However, p53 induction was normal in Ba/F3 cells expressing a CBF beta-SMMHC variant that does not interfere with DNA binding by CBF, indicating that a CBF genetic target regulates p53 induction. The p53 gene may be regulated by CBF, because p53 mRNA levels were reduced by CBF beta-SMMHC. Reduced p53 induction was not caused by slowed cell proliferation, a consequence of CBF beta-SMMHC expression, because p53 was induced similarly in control cultures and in cultures propagated in 10-fold less interleukin-3 (IL-3), CBF beta-SMMHC did not slow apoptosis resulting from IL-3 withdrawal, where p53 induction is minimal, but slowed apoptosis in Ba/F3 cells exposed to 10 Gy of ionizing radiation or 3 to 8 mu g/mL etoposide, providing 2-fold protection at 6 or 18 hours. Inhibition of apoptosis was temporary, because all the cells exposed to these doses ultimately died, and clonal survival assays performed using 0.04 mu g/mL etoposide did not show protection by CBF beta-SMMHC. p21 levels were increased in cells subjected to DNA damage, regardless of CBF beta-SMMHC expression and attenuated p53 induction. Bcl-2, bcl-x(L), bcl-x(S), and bax levels were unaffected by CBF beta-SMMHC. Attenuated p53 induction may contribute to leukemogenesis by CBF beta-SMMHC by slowing apoptosis via a p21-independent mechanism. (C) 1998 by The American Society of Hematology. C1 Johns Hopkins Oncol Ctr, Div Pediat Oncol, Baltimore, MD 21287 USA. Natl Human Genome Res Inst, Bethesda, MD USA. RP Friedman, AD (reprint author), Johns Hopkins Oncol Ctr, Div Pediat Oncol, Room 3-109,600 N Wolfe St, Baltimore, MD 21287 USA. RI Liu, Paul/A-7976-2012; Ramirez, Manuel/H-7710-2015 OI Liu, Paul/0000-0002-6779-025X; Ramirez, Manuel/0000-0003-0332-6973 FU NHLBI NIH HHS [HL51388] NR 51 TC 38 Z9 38 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 0006-4971 J9 BLOOD JI Blood PD DEC 1 PY 1998 VL 92 IS 11 BP 4344 EP 4352 PG 9 WC Hematology SC Hematology GA 142HH UT WOS:000077194300042 PM 9834241 ER PT J AU Baer, M Williams, SC Dillner, A Schwartz, RC Johnson, PF AF Baer, M Williams, SC Dillner, A Schwartz, RC Johnson, PF TI Autocrine signals control CCAAT enhancer binding protein beta expression, localization, and activity in macrophages SO BLOOD LA English DT Article ID NF-KAPPA-B; TRANSCRIPTION FACTORS NF-IL6; ACUTE-PHASE RESPONSE; C/EBP-BETA; INDUCIBLE EXPRESSION; GEL-ELECTROPHORESIS; REGULATORY SYSTEM; FAMILY MEMBERS; LEUCINE ZIPPER; MESSENGER-RNA AB The transcription factor CCAAT/enhancer binding protein beta (C/EBP beta, or NF-IL6) is expressed in macrophages, where it participates in lipopolysaccharide (LPS)-mediated induction of proinflammatory cytokine genes such as interleukin-6 (IL-6) and IL-1 beta. We have identified activities in conditioned medium from a macrophage tumor cell line that regulates the expression, localization, and transcriptional activity of C/EBP beta. One factor was shown to be tumor necrosis factor-alpha (TNF-alpha), which increased C/EBP beta expression by a posttranscriptional mechanism. A second activity, designated autocrine macrophage factor (AMF), elicited a change in C/EBP beta localization from a punctate nuclear staining pattern to diffuse nuclear distribution. The punctate form of C/EBP beta correlated with increased susceptibility of this protein to cleavage by an endogenous protease during nuclear extract preparation. Conditioned medium stimulated the ability of C/EBP beta to transactivate a reporter gene and activated the expression of two cytokine genes that are putative targets of C/EBP beta. These observations suggest that diffuse distribution of C/EBP beta in the nucleus corresponds to an activated form of this protein. AMF activity could not be mimicked by an extensive set of recombinant cytokines and growth factors and therefore may represent a novel extracellular factor. This is a US government work. There are no restrictions on its use. C1 NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Johnson, PF (reprint author), NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, POB B, Frederick, MD 21702 USA. EM johnsopf@mail.ncifcrf.gov RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 NR 48 TC 34 Z9 34 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 0006-4971 J9 BLOOD JI Blood PD DEC 1 PY 1998 VL 92 IS 11 BP 4353 EP 4365 PG 13 WC Hematology SC Hematology GA 142HH UT WOS:000077194300043 PM 9834242 ER PT J AU Sloand, EM Maciejewski, JP Dunn, D Moss, J Brewer, B Kirby, M Young, NS AF Sloand, EM Maciejewski, JP Dunn, D Moss, J Brewer, B Kirby, M Young, NS TI Correction of the PNH defect by GPI-anchored protein transfer SO BLOOD LA English DT Article ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; DECAY-ACCELERATING FACTOR; MOLECULAR-BASIS; ERYTHROCYTES; CELLS; PLASMA; BLOOD; MODEL; CD59 AB Hemolytic anemia is a major feature of paroxysmal nocturnal hemoglobinuria (PNH). Intravascular red blood cell (RBC) destruction is caused by increased sensitivity of the abnormal erythrocyte to complement-mediated lysis, due to the GPI absence of a membrane-bound glycosylphosphatidylinositol (GPI)-linked protein, which functions as an inhibitor of reactive lysis (CD59). Both in vivo and in vitro models have suggested the feasibility of cell-to-cell transfer of GPI proteins, and patients with hemolysis could potentially benefit from transfer of CD59 to their deficient erythrocytes. We studied the ability of RBC components prepared from outdated packed RBC collections, as well as high-density lipoprotein (HDL) preparations, rich in CD55 and CD59, to promote protein transfer, as assessed by flow cytometry, immunoblotting, and susceptibility to complement-mediated lysis. By flow cytometry, CD55 and CD59 were present on RBC-derived microvesicles that stained with an antiglycophorin antibody Ab; in addition, soluble CD59 and CD55 were detected by immunoblot in soluble fractions eluated from RBC units stored for more than 35 days, but not in fresh blood. Both commercial HDL preparations and those prepared in our laboratory contained CD55 and CD59, as assayed by immunoblot. When RBC that were deficient (GPI)anchored protein, obtained from five patients, with PNH were incubated with HDL preparations for 2 to 4 hours, there was significant transfer of both proteins to the cell surface, as demonstrated by flow cytometry. Washed RBC microvesicles, prepared by ultrasonification, also mediated transfer of GPI-linked proteins to deficient RBC. Pretreatment of microvesicles, RBC eluate preparations, and HDL with phosphatidylinositol-specific, phospholipase C, abrogated protein transfer to deficient cells, indicating that increased eel-associated CD55 and CD59 levels were related to insertion of the intact GPI moiety, rather than to simple adhesion. PNH RBC that were exposed to HDL, RBC eluate preparations, or microvesicles demonstrated decreased in vitro complement-mediated hemolysis in the Ham test. Transfer of GPI-linked proteins from soluble preparations containing CD55 and CD59 to PNH erythrocytes is feasible and may have clinical utility. This is a US government work. There are no restrictions on its use. C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NHLBI, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. NHLBI, Mol Dis Branch, Bethesda, MD 20892 USA. RP Sloand, EM (reprint author), 31 Ctr Dr,MSC 2490,Bldg 31,Room 4A11, Bethesda, MD 20892 USA. NR 18 TC 41 Z9 43 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 1 PY 1998 VL 92 IS 11 BP 4439 EP 4445 PG 7 WC Hematology SC Hematology GA 142HH UT WOS:000077194300052 PM 9834251 ER PT J AU Berch, DB Krikorian, R Huha, EM AF Berch, DB Krikorian, R Huha, EM TI The Corsi block-tapping task: Methodological and theoretical considerations SO BRAIN AND COGNITION LA English DT Article DE nonverbal; serial; spatial memory; visuospatial ID SPATIAL WORKING-MEMORY; SHORT-TERM-MEMORY; SEX-DIFFERENCES; IMMEDIATE MEMORY; ALZHEIMER-TYPE; COGNITIVE PERFORMANCE; PARKINSONS-DISEASE; SPAN; DEMENTIA; INFORMATION AB The Corsi block-tapping task has enjoyed extensive use in clinical and experimental studies for a quarter of a century and is arguably the single most important nonverbal task in neuropsychological research. Nevertheless, there has been considerable inconsistency not only in the administration and scoring of this measure, but also in the physical properties of the test apparatus. In this paper, we survey a wide range of studies that have made use of the block-tapping task during the past 25 years and provide a detailed appraisal of the manifold methodological variations. Additionally, we discuss the historical context in which the Corsi originated and offer a critical examination of the cognitive processing operations purported to underlie performance on this task. (C) 1998 Academic Press. C1 NIH, Biobehav & Social Sci IRG, Ctr Sci Review, Bethesda, MD 20892 USA. Univ Cincinnati, Cincinnati, OH 45221 USA. RP Berch, DB (reprint author), NIH, Biobehav & Social Sci IRG, Ctr Sci Review, 6701 Rockledge Dr,Rm 5204, Bethesda, MD 20892 USA. NR 73 TC 189 Z9 191 U1 14 U2 70 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0278-2626 J9 BRAIN COGNITION JI Brain Cogn. PD DEC PY 1998 VL 38 IS 3 BP 317 EP 338 DI 10.1006/brcg.1998.1039 PG 22 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 147XC UT WOS:000077521900003 PM 9841789 ER PT J AU Kustova, Y Sei, Y Morse, HC Basile, AS AF Kustova, Y Sei, Y Morse, HC Basile, AS TI The influence of a targeted deletion of the IFN gamma gene on emotional behaviors SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Article DE interferon-gamma; C57B1/6; BALB/c; inbred mouse strains; emotionality; knockout; behavior ID INBRED MOUSE STRAINS; QUANTITATIVE TRAIT LOCI; ELEVATED PLUS-MAZE; INTERFERON-GAMMA; LOCOMOTOR-ACTIVITY; NERVOUS-SYSTEM; MICE; CYTOKINES; PHENOTYPES; IMMUNE AB Evidence suggests that interferon-gamma (IFN gamma) plays an important rule in CNS function and development. While the paucity of agents that selectively modify IFN gamma production or interaction with its receptor makes analyses of its potential behavioral relevance difficult, mice with null mutations of the IFN gamma gene have been used to investigate the potential role of IFN gamma in emotional behaviors. C57B1/6 (B6) mice with null mutations of the IFN gamma gene (IFN gamma (-/-) showed significantly increased emotionality compared to the wild-type (IFN gamma (+/+)) B6 mice. This was manifested in performance in the elevated plus maze as well as increased defecation scores and decreased locomotor activity both in novel environments and following a sonic stimulus. In contrast, the general level of emotionality of both IFN gamma (+/+) and (-/-) BALB/c (C) mice was substantially greater than that of either of the BS mouse groups. While C IFN gamma (-/-) showed increased immobility in response to novelty, other indices of emotionality of C IFN gamma (-/-) mice were not significantly different from those of the C IFN gamma(+/+) mice. In summary, the lack of IFN gamma appears to contribute to increased emotionality, but the basal behaviors of the parental strain (e.g., BALB/c) may overshadow the expression of this emotionality. While mice with null mutations of the IFN gamma gene may be useful tools for investigating the rule of IFN gamma in brain function and behavior. the influence of the parent strain genome(s) on the behaviors in question must be taken into account. (C) 1998 Academic Press. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Anesthesiol, Bethesda, MD 20892 USA. RP Kustova, Y (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 NR 41 TC 38 Z9 38 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD DEC PY 1998 VL 12 IS 4 BP 308 EP 324 DI 10.1006/brbi.1998.0546 PG 17 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 179ZG UT WOS:000079359800005 PM 10080860 ER PT J AU Lancaster, JM Carney, ME Gray, J Myring, J Gumbs, C Sampson, J Wheeler, D France, E Wiseman, R Harper, P Futreal, PA AF Lancaster, JM Carney, ME Gray, J Myring, J Gumbs, C Sampson, J Wheeler, D France, E Wiseman, R Harper, P Futreal, PA TI BRCA1 and BRCA2 in breast cancer families from Wales: moderate mutation frequency and two recurrent mutations in BRCA1 SO BRITISH JOURNAL OF CANCER LA English DT Article DE BRCA1; BRCA2; breast and ovarian cancer; Wales ID OVARIAN-CANCER; JEWISH WOMEN; GENE AB Mutations in the BRCA1/BRCA2 genes account for varying proportions of breast cancer families studied, and demonstrate considerable variation in mutational spectra coincident with ethnic and geographical diversity. We have screened for mutations in 17 families from Wales with two or more cases of breast cancer under age 50 and/or ovarian cancer. Eight out of 17 (47%) families had demonstrable mutations. Six out of 17 (35%) carried BRCA1 mutations and 2 out of 17 (12%) carried BRCA2 mutations. Two recurrent mutations in BRCA1 were identified, which appear to represent founder mutations in this population. These data support the existence of additional breast and ovarian cancer susceptibility genes. C1 Duke Univ, Ctr Med, Dept Surg, Div Gynecol Oncol, Durham, NC 27707 USA. Univ Wales Hosp, Inst Med Genet, Cardiff CF4 4XN, S Glam, Wales. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Genet, Durham, NC 27710 USA. RP Futreal, PA (reprint author), Duke Univ, Ctr Med, Dept Surg, Div Gynecol Oncol, Box 2611, Durham, NC 27707 USA. FU NCI NIH HHS [P50-CA68348] NR 21 TC 10 Z9 11 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 DEC PY 1998 VL 78 IS 11 BP 1417 EP 1420 DI 10.1038/bjc.1998.701 PG 4 WC Oncology SC Oncology GA 139EX UT WOS:000077015900005 PM 9836472 ER PT J AU Tang, DC Rodgers, GP AF Tang, DC Rodgers, GP TI Activation of the human delta-globin gene promoter in primary adult erythroid cells SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE primary adult erythroid cells; delta-globin gene; transcription; CCAAT box; EKLF binding site ID BETA-GLOBIN; CCAAT BOX; EXPRESSION; TRANSCRIPTION; THALASSEMIA; HEMOGLOBIN; ANEMIA AB Restoration of the CCAAT box or insertion of an erythroid Kruppel-like factor (EKLF) binding site in the delta promoter activates its expression in several erythroid cell lines, We extended these studies using a novel primary human adult erythroid cell (hAEC) system to investigate these effects at the late erythroblast stage, Restoration of the CCAAT box: at -70 bp, or insertion of an EKLF binding site at -85 bp or -95 bp in the promoter significantly increased delta globin gene expression in hAEC. Our results demonstrate that the altered CCAAT box (CCAAC) and the lack of an EKLF binding site in delta-globin contribute to its low level of expression in the hAEC model as well. C1 NIDDK, Clin & Mol Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIDDK, Clin & Mol Hematol Branch, NIH, Bldg 10,Rm 9N318,10 Ctr Dr, Bethesda, MD 20892 USA. NR 12 TC 6 Z9 6 U1 0 U2 0 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 DEC 1 PY 1998 VL 103 IS 3 BP 835 EP 838 DI 10.1046/j.1365-2141.1998.01052.x PG 4 WC Hematology SC Hematology GA 146XD UT WOS:000077457400037 PM 9858241 ER PT J AU Pourquier, P Pommier, Y AF Pourquier, P Pommier, Y TI Topoisomerases I: New targets for cancer chemotherapy and mechanisms of resistance SO BULLETIN DU CANCER LA French DT Article DE topoisomerases; camptothecins; resistance ID DNA TOPOISOMERASE; CLEAVAGE SITES; CAMPTOTHECIN; REPLICATION; PHOSPHORYLATION; INHIBITORS; SEQUENCE; CELLS AB DNA topoisomerases I are ubiquitous enzymes that play a crucial role in DNA condensation, replication, transcription, and repair Eukaryotic enzymes are highly conserved and specifically targeted by natural anticancer agents such as camptothecin and its derivatizes. These drugs poison top 1 by inhibiting the enzyme via trapping of top 1 clivage complexes, which ultimately generate cell death. New camptothecin derivatives with better pharmacologic characteristics are tinder developpement. Understanding top 1 functions and structures will help to discover more specific and less toxic top 1 inhibitors in order to circumvent drug resistance. C1 NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Pourquier, P (reprint author), NCI, Mol Pharmacol Lab, Bldg 37,Room 5D02, Bethesda, MD 20892 USA. NR 29 TC 3 Z9 4 U1 0 U2 0 PU JOHN LIBBEY EUROTEXT LTD PI MONTROUGE PA 127 AVE DE LA REPUBLIQUE, 92120 MONTROUGE, FRANCE SN 0007-4551 J9 B CANCER JI Bull. Cancer PD DEC PY 1998 SI SI BP 5 EP 10 PG 6 WC Oncology SC Oncology GA 160NW UT WOS:000078237600001 ER PT J AU Lee, MM Wang, RT Hsing, AW Gu, FL Wang, T Spitz, M AF Lee, MM Wang, RT Hsing, AW Gu, FL Wang, T Spitz, M TI Case-control study of diet and prostate cancer in China SO CANCER CAUSES & CONTROL LA English DT Article DE case-control; China; diet; prostate ID PHYSICAL-ACTIVITY; FAT CONSUMPTION; UNITED-STATES; NUTRITION; RISK; EPIDEMIOLOGY; CARCINOMA; SHANGHAI; COHORT; HAWAII AB Introduction: A higher incidence of prostate cancer is observed in the Western world than in Asian countries. Although it is relatively rare in China, an increased incidence has been reported in recent years. Studies in highrisk populations have suggested that dietary fat may play a role in enhancing the risk of developing prostate cancer. However, limited epidemiologic study has never examined the role of diet in low risk populations. Methods: A case-control study was conducted in 12 cities in China to evaluate the relationship between dietary factors and prostate cancer risk. We conducted personal interviews with 133 histopathologically confirmed prostate cancer cases diagnosed between 1989 to 1992 and 265 neighborhood controls of similar age. Results: Cases were more likely than controls to consume food with high fat and from animal sources (p < 0.01). The daily fat intake and the percentage of energy from fat were statistically significantly higher among cases than among controls (p < 0.01), The adjusted odds ratio for total fat between lowest quartiles and highest quartiles was OR = 3.6 (95 percent C.I. 1.8-7.2); for saturated fat, OR = 2.9 (95 percent C.I. 1.5-5.7); and for unsaturated fat, OR = 3.3 (95 percent C.H. 1.7-6.3), Discussion: The data suggest that dietary fat, both saturated and unsaturated, are associated with an increased risk for prostate cancer in a low risk population. C1 Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Beijing Med Univ, Dept Epidemiol, Beijing 100083, Peoples R China. Beijing Med Univ, Dept Urol, Beijing 100083, Peoples R China. NCI, Dept Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX USA. RP Lee, MM (reprint author), Univ Calif San Francisco, Dept Epidemiol & Biostat, MU 420 W, San Francisco, CA 94143 USA. EM mlee@epi.ucsf.edu NR 42 TC 95 Z9 100 U1 0 U2 5 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 1998 VL 9 IS 6 BP 545 EP 552 DI 10.1023/A:1008840105531 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 168VR UT WOS:000078714300002 PM 10189039 ER PT J AU Gammon, MD Schoenberg, JB Teitelbaum, SL Brinton, LA Potischman, N Swanson, CA Brogan, DJ Coates, RJ Malone, KE Stanford, JL AF Gammon, MD Schoenberg, JB Teitelbaum, SL Brinton, LA Potischman, N Swanson, CA Brogan, DJ Coates, RJ Malone, KE Stanford, JL TI Cigarette smoking and breast cancer risk among young women (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE breast neoplasms; cigarette smoking ID ESTROGEN-RECEPTOR STATUS; AGE 45 YEARS; ALCOHOL-CONSUMPTION; ORAL-CONTRACEPTIVES; PASSIVE SMOKING; MENOPAUSE; PROGESTERONE; EXPOSURE; HEALTH AB Objectives: To evaluate whether heavy cigarette smoking as a teenager or long-term smoking increases breast cancer risk or, alternatively, whether smoking acts as an anti-estrogen and reduces risk. Methods: Data from a multi-center, population-based, case-control study among women under age 55 were analyzed. Results: Among women under age 45, there was at modest inverse relation with current (OR = 0.82, 95% CI = 0.67, 1.01) but not past (OR = 0.99, 95% CI = 0.81, 1.21) smoking. Odds ratios were decreased for current smokers who began at an early age (0.59 for less than or equal to 15, 95% CI = 0.41, 0.85) or continued for long periods of time (0.70 for >21 years, 95% CI = 0.52, 0.94). In subgroup analyses, reduced odds ratios were observed among current smokers who were ever users of oral contraceptives (0.79, 95% CI = 0.63, 0.98), were in the lowest quartile of adult body size (0.53, 95% CI = 0.34, 0.81), or never or infrequently drank alcohol (0.68, 95% CI = 0.47, 0.98). Among women ages 45-54, there was little evidence for an association with smoking. Conclusions: These results suggest that breast cancer risk among women under age 45 may be reduced among current smokers who began smoking at an early age, or long-term smokers, but require confirmation from other studies. C1 Columbia Univ, Sch Publ Hlth, Div Epidemiol, New York, NY USA. New Jersey Dept Hlth & Senior Serv, Appl Canc Epidemiol Program, Trenton, NJ USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA 30322 USA. Emory Univ, Div Biol & Biomed Sci, Atlanta, GA 30322 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Gammon, MD (reprint author), 622 W 168th St,PH18, New York, NY 10032 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 57 TC 37 Z9 37 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 1998 VL 9 IS 6 BP 583 EP 590 DI 10.1023/A:1008868922799 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 168VR UT WOS:000078714300006 PM 10189043 ER PT J AU Sinha, R Kulldorff, M Curtin, J Brown, CC Alavanja, MCR Swanson, CA AF Sinha, R Kulldorff, M Curtin, J Brown, CC Alavanja, MCR Swanson, CA TI Fried, well-done red meat and risk of lung cancer in women (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE cooking methods; heterocyclic amines; lung cancer; red meat ID HETEROCYCLIC AMINES; DIETARY-CHOLESTEROL; SATURATED FAT; BREAST-CANCER; URUGUAY; MISSOURI; CONSUMPTION; HAWAII; HEALTH; FOODS AB Objective: Some epidemiological studies suggest that diets high in fat, saturated fat, or cholesterol are associated with increased risk of lung cancer. Since meat consumption is correlated with the intake of saturated fat and cholesterol, we investigated the role of meat intake and cooking practices in relation to lung cancer risk. Methods: A population-based case-control study of both non-smoking and smoking women was conducted in Missouri. A 100-item food frequency questionnaire (FFQ) with detailed questions on meat consumption was completed by 593 cases and 623 frequency matched controls. We estimated quantity of meat eaten (grams/day) according to cooking method, and doneness level. Odds ratios (ORs) and 95% confidence intervals (C.I.s) were calculated using logistic regression. Multivariate models included age, packyears of smoking, body mass index (BMI, kg/m(2)), education, and intake of calories, fat, fruit/fruit juices, and vegetables. Results: When comparing 90th and 10th percentiles, lung cancer risk increased for total meat consumption (OR = 1.6, C.I. 1.1-2.4), red meat (OR = 1.8, C.I., 1.2-2.7), well-done red meat (OR = 1.5, C.I.s, 1.1-2.1) and fried red meat (OR = 1.5, C.I., 1.1-2.0), The odds ratios for 5th vs. 1st quintiles using the categorical variable for well-done red meat and fried red meat were essentially the same as reported above; however, the increase in risk was associated mainly with the 5th quintile. The ORs for a 10-gram increase in consumption were, 1.04 for total meat, 1.06 for red meat, 1.08 for well done red meat, and 1.09 for fried red meat. Conclusions: Consumption of red meat, especially fried and/or well-done red meat, was associated with increased risk of lung cancer. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Sinha, R (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI Kulldorff, Martin/H-4282-2011; Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Kulldorff, Martin/0000-0002-5284-2993 NR 41 TC 86 Z9 87 U1 0 U2 9 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD DEC PY 1998 VL 9 IS 6 BP 621 EP 630 DI 10.1023/A:1008805525525 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 168VR UT WOS:000078714300011 PM 10189048 ER PT J AU Dorgan, JP Albanes, D Virtamo, J Heinonen, OP Chandler, DW Galmarini, M McShane, LM Barrett, MJ Tangrea, J Taylor, PR AF Dorgan, JP Albanes, D Virtamo, J Heinonen, OP Chandler, DW Galmarini, M McShane, LM Barrett, MJ Tangrea, J Taylor, PR TI Relationships of serum androgens and estrogens to prostate cancer risk: Results from a prospective study in Finland SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HORMONE LEVELS; MEN; HYPERPLASIA; CARCINOMA; TESTOSTERONE AB Several lines of evidence suggest that sex hormones may be involved in the etiology of prostate cancer. We conducted a prospective nested case-control study to evaluate the relationships of serum androgens and estrogens to prostate cancer using serum collected at baseline for the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The 29,133 male smokers who participated in the trial were 50-69 years old at baseline, During 5-8 years of follow-up, 246 men were diagnosed with prostate cancer, and 116 of these were randomly selected for inclusion in the current study. For each case, two controls matched on age, date of blood collection, intervention group, and study center were selected, Hormones were measured in serum by RIA using standard procedures. None of the individual androgens or estrogens was significantly related to prostate cancer, These findings were unaltered by simultaneous evaluation of serum androgen and estrogen concentrations in multivariate models, These results do not support a strong relationship of serum androgens and estrogens with prostate cancer in smokers. Within-person variation in concentrations of some hormones may have contributed to the lack of significant associations. C1 NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, SF-00300 Helsinki, Finland. Endocrine Sci Inc, Calabasas Hills, CA 91301 USA. Quest Diagnost Inc, San Juan Capistrano, CA 92690 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Dorgan, JP (reprint author), NCI, Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Execut Pl N,Room 443,6130 Execut Blvd, Bethesda, MD 20892 USA. EM jd7g@nih.gov RI Albanes, Demetrius/B-9749-2015 NR 40 TC 61 Z9 62 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 1998 VL 7 IS 12 BP 1069 EP 1074 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 146HU UT WOS:000077423900001 PM 9865423 ER PT J AU Byrne, C Sinha, R Platz, EA Giovannucci, E Colditz, GA Hunter, DJ Speizer, FE Willett, WC AF Byrne, C Sinha, R Platz, EA Giovannucci, E Colditz, GA Hunter, DJ Speizer, FE Willett, WC TI Correspondence re: C. Byrne et al., Predictors of dietary heterocyclic amine intake in three prospective cohorts. Cancer epidemiol. Biomark. Prev., 7 : 523-529, 1998 - Reply SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter C1 Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Byrne, C (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. RI Byrne, Celia/K-2964-2015; Colditz, Graham/A-3963-2009 OI Byrne, Celia/0000-0001-8289-4252; Colditz, Graham/0000-0002-7307-0291 NR 8 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD DEC PY 1998 VL 7 IS 12 BP 1153 EP 1154 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 146HU UT WOS:000077423900013 ER PT J AU Guan, XY Zhang, HG Yang, JM Wang, J Taetle, R Meltzer, PS Trent, JM AF Guan, XY Zhang, HG Yang, JM Wang, J Taetle, R Meltzer, PS Trent, JM TI Detection of chromosome 6 abnormalities in melanoma cell lines by chromosome arm painting probes SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID INSITU HYBRIDIZATION; CYTOGENETIC FINDINGS; MALIGNANT-MELANOMA; UVEAL MELANOMA; TUMORIGENICITY; IDENTIFICATION AB Chromosome 6 abnormalities, particularly the deletion of 6q, are among the most frequent chromosomal changes in human malignant melanoma. In this study, chromosome 6 rearrangements in 21 melanoma cell lines were identified by fluorescence in situ hybridization (FISH) with the use of chromosome 6 arm specific painting probes (CAPs). Structural abnormalities of chromosome 6 were detectable in 18 of 21 (86%) cases, including the identification of structural abnormalities that were not detectable by routine G-banding analysis. The results of this study correlate the frequency of 6q alterations and demonstrate that FISH with CAPs can be of considerable use for rapid screening of specific chromosome abnormalities in melanoma. Published by Elsevier Science Inc. C1 NIH, Canc Genet Branch, Natl Human Genome Res Inst, Bethesda, MD 20892 USA. Univ Arizona, Ctr Comprehens Canc, Tucson, AZ USA. RP Trent, JM (reprint author), NIH, Canc Genet Branch, Natl Human Genome Res Inst, 49 Convent Dr MSC 4470, Bethesda, MD 20892 USA. RI Guan, Xin-Yuan/A-3639-2009 OI Guan, Xin-Yuan/0000-0002-4485-6017 NR 14 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD DEC PY 1998 VL 107 IS 2 BP 89 EP 92 DI 10.1016/S0165-4608(98)00080-6 PG 4 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 141WL UT WOS:000077167200001 PM 9844599 ER PT J AU Ryan, KM Al-Mulla, F Jamieson, T Birnie, GD AF Ryan, KM Al-Mulla, F Jamieson, T Birnie, GD TI Hemizygosity of the MAX gene locus in HL60 cells SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID DNA-BINDING; MYC; DIFFERENTIATION; EXPRESSION; AMPLIFICATION; DIMERIZATION; DELETIONS; PROTEIN; REGION AB The oncogenic activity of c-MYC is well known, and genetic aberrations in this locus are associated with a variety of human neoplasms. Because the encoded MYC protein has transcriptional activity only when dimerized with MAX, it is possible that mutations of MAX also could have phenotypic consequences. We have now found, by fluorescence in situ hybridization and quantified Southern blot analyses, that the MAX gene has been reduced to hemizygosity in HL60 cells. Although the sequence of the coding region of the remaining allele of the MAX gene is not mutated, this reduction in gene dosage may be the cause of a lower abundance of MAX protein in these cells that could result in an imbalance in the complex transcription factor network in which MAX has a pivotal role. (C) Elsevier Science Inc., 1998. C1 Beatson Inst Canc Res, CRC Beatson Labs, Glasgow G61 1BD, Lanark, Scotland. RP Birnie, GD (reprint author), NCI, ABL Basic Res Program, FCRDC, Bldg 560,Room 22-45, Frederick, MD 21702 USA. RI Al-Mulla, Fahd/E-2068-2015 OI Al-Mulla, Fahd/0000-0001-5409-3829 NR 27 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 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD DEC PY 1998 VL 107 IS 2 BP 93 EP 97 DI 10.1016/S0165-4608(98)00091-0 PG 5 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 141WL UT WOS:000077167200002 PM 9844600 ER PT J AU Harada, M Tamada, K Abe, K Li, TL Onoe, Y Tada, H Tatsugami, K Ando, T Kimura, G Komoto, K AF Harada, M Tamada, K Abe, K Li, TL Onoe, Y Tada, H Tatsugami, K Ando, T Kimura, G Komoto, K TI Characterization of B16 melanoma-specific cytotoxic T lymphocytes SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE B16 melanoma; cytotoxic T-lymphocytes; Tcl; tyrosinase-related protein-2 ID TUMOR-INFILTRATING LYMPHOCYTES; LYMPH-NODE CELLS; IN-VIVO; ANTITUMOR-ACTIVITY; GENE MAGE-3; ANTIGEN; IDENTIFICATION; CTL; REJECTION; RESPONSES AB A Bid melanoma-specific CD8(+) T cell line (AB1) was established from the spleen cells of C57BL/6 mice cured of B16 melanoma with interleukin (IL)-12 treatment. The AB1 line exclusively used T cell receptor V-beta 11. The AB1 cells exhibited a cytolytic activity against both syngeneic B16 melanoma and allogeneic p815 mastocytoma. whereas a cold inhibition assay revealed specificity of the AB1 cells against B16 melanoma. Their lostability to kill a class I loss variant of B16 melanoma was restored by the transfection of H-2K(b) gene. In addition, their interferon production was significantly suppressed by the addition of anti-H-2K(b) monoclonal antibody, an RT-PCR analysis showed that the AB1 line expressed the mRNA encoding IFN-gamma, but not IL-4 or IL-10. The experiment using synthetic peptides of tyrosinase-related protein-2 (TRP-2) revealed that the AB1 cells could recognize TRP-2(181-188) peptide Moreover, the AB1 cells showed an in vivo antitumor effect against established pulmonary metastases of B16 melanoma. Overall, these results indicate that the Tc1-type V-beta 11(+) AB1 cells exert an antitumor activity against syngeneic B16 melanoma through recognition of TRP-2(181-188) peptide in an H-2K(b)-restricted manner. C1 Kyushu Univ, Med Inst Bioregulat, Dept Virol, Fukuoka 812, Japan. Kyushu Univ, Fukuoka 812, Japan. RP Harada, M (reprint author), NCI, Surg Branch, Bldg 10,2B42, Bethesda, MD 20892 USA. NR 31 TC 16 Z9 16 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD DEC PY 1998 VL 47 IS 4 BP 198 EP 204 DI 10.1007/s002620050521 PG 7 WC Oncology; Immunology SC Oncology; Immunology GA 153LA UT WOS:000077833500003 PM 9875672 ER PT J AU Glaser, EM AF Glaser, EM TI Inherited predisposition to colon cancer SO CANCER NURSING LA English DT Article DE familial adenomatous polyposis; gene; hereditary; nonpolyposis colon cancer; mismatch repair; mutation; tumorigenesis ID NONPOLYPOSIS COLORECTAL-CANCER; GENETIC-BASIS; HNPCC; CARE AB Colorectal cancer is one of the most common malignancies in the United States. Although both genetic and environmental factors play a role in colorectal tumorigenesis, recent advances in genetics have more clearly defined the impact of inheritance in the multistep process of the disease. Researchers have identified single genes that confer a susceptibility to familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). Because these genes are inherited in an autosomal dominant fashion, offspring of carriers have a 50% chance of inheriting the gene mutation and its associated risk The FAP gene, when mutated, initiates the neoplastic process. HNPCC gene mutations disrupt mismatch repair, thus inducing progression of tumor formation. Discovery of these genes has helped our understanding of sporadic colon cancer as well. Genetic testing for the FAP and HNPCC genes is now available, and results of this testing have implications for surveillance and management. In addition, resting raises complex psychosocial and ethical issues. At present, genetic testing is primarily conducted in the research setting, but it will soon be available in the clinical arena. To prepare for the challenges that these new advances will present, nurses must begin now to enhance their knowledge of genetics and its application to oncology. C1 NCI, Natl Naval Med Ctr, NIH, Bethesda, MD 20892 USA. RP Glaser, EM (reprint author), 3613 Hathaway Rd, Durham, NC 27707 USA. NR 30 TC 1 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0162-220X J9 CANCER NURS JI Cancer Nurs. PD DEC PY 1998 VL 21 IS 6 BP 377 EP 383 DI 10.1097/00002820-199812000-00001 PG 7 WC Oncology; Nursing SC Oncology; Nursing GA 142RY UT WOS:000077215200001 PM 9848995 ER PT J AU Gruber, SB Entius, MM Petersen, GM Laken, SJ Longo, PA Boyer, R Levin, AM Mujumdar, UJ Trent, JM Kinzler, KW Vogelstein, B Hamilton, SR Polymeropoulos, MH Offerhaus, GJ Giardiello, FM AF Gruber, SB Entius, MM Petersen, GM Laken, SJ Longo, PA Boyer, R Levin, AM Mujumdar, UJ Trent, JM Kinzler, KW Vogelstein, B Hamilton, SR Polymeropoulos, MH Offerhaus, GJ Giardiello, FM TI Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome SO CANCER RESEARCH LA English DT Article ID MUTATIONS; CANCER; POLYPS; GENE AB Peutz-Jeghers syndrome (PJS) is an antosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS, Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA, Analysis of hamartomas and adenocarcinomas from patients with PJS identified Loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS, The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry, None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras protooncogene, These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma, Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the Later stages of tumor progression seen in the majority of colorectal carcinomas. C1 Univ Michigan, Div Med & Mol Genet, Ann Arbor, MI 48109 USA. Johns Hopkins Univ, Johns Hopkins Oncol Ctr, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD 21287 USA. Johns Hopkins Univ, Dept Internal Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21287 USA. Howard Hughes Med Inst, Baltimore, MD 21231 USA. Univ Amsterdam, Acad Med Ctr, Dept Pathol & Clin Epidemiol, NL-1105 AZ Amsterdam, Netherlands. NIH, Natl Ctr Human Genome Res, Bethesda, MD 20892 USA. RP Gruber, SB (reprint author), Univ Michigan, Div Med & Mol Genet, 4301 MSRB 3, Ann Arbor, MI 48109 USA. EM sgruber@umich.edu FU NCI NIH HHS [CA53801, CA62924, R01 CA63721] NR 25 TC 121 Z9 126 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 DEC 1 PY 1998 VL 58 IS 23 BP 5267 EP 5270 PG 4 WC Oncology SC Oncology GA 144YL UT WOS:000077343400003 PM 9850045 ER PT J AU Tamm, I Wang, Y Sausville, E Scudiero, DA Vigna, N Oltersdorf, T Reed, JC AF Tamm, I Wang, Y Sausville, E Scudiero, DA Vigna, N Oltersdorf, T Reed, JC TI IAP-family protein Survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs SO CANCER RESEARCH LA English DT Article ID PROGRAMMED CELL-DEATH; GRANZYME-B; PROTEASES; GENE; HOMOLOGS; ACTIVATION; BCL-2; CRMA AB Survivin is a member of the inhibitor of apoptosis protein (IAP) family. We investigated the antiapoptotic mechanism of Survivin, as well as its expression in 60 human tumor cell Lines used for the National Cancer Institute's anticancer drug screening program. In cotransfection experiments, cell death induced by Bax or Fas (CD 95) was partially inhibited (mean +/- SD, 65% +/- 8%) by Sunivin, whereas XIAP, another IAP family member, almost completely blocked cell death (93% +/- 4%) under the same conditions. Survivin and XIAP also protected 293 cells from apoptosis induced by overexpression of procaspase-3 and -7 and inhibited the processing of these zymogens into active caspases. In vitro binding experiments indicated that, like other IAP-family proteins, Survivin binds specifically to the terminal effector cell death proteases, caspase-3 and -7, but not to the proximal initiator protease caspase-8. Using a cell-free system in which cytosolic extracts were derived from control- or Survivin-transfected cells and where caspases were activated either by addition of cytochrome c and dATP or by adding recombinant active caspase-8. Survivin was able to substantially reduce caspase activity, as measured by cleavage of a tetrapeptide substrate, AspGluValAsp-aminofluorocoumarin. Similar results were obtained in intact cells when Survivin was overexpressed by gene transfection and caspase activation was induced by the anticancer drug etoposide. Sunivin was expressed in all 60 cancer cell lines analyzed, with highest levels in breast and lung cancers and lowest Levels in renal cancers. These findings indicate that Survivin, which is commonly expressed in human tumor cell lines, can bind the effector cell death proteases caspase-3 and -7 in vitro and inhibits caspase activity and cell death in cells exposed to diverse apoptotic stimuli. Although quantitative differences may exist, these observations suggest commonality in the mechanisms used by IAP-family proteins to suppress apoptosis. C1 Burnham Inst, La Jolla, CA 92037 USA. Idun Pharmaceut, La Jolla, CA 92037 USA. NCI, Frederick Canc Res & Dev Ctr, Dev Therapeut Program, Frederick, MD 21702 USA. RP Reed, JC (reprint author), Burnham Inst, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM jreed@burnham-inst.org FU NIA NIH HHS [AG-15402] NR 40 TC 915 Z9 1099 U1 6 U2 57 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 DEC 1 PY 1998 VL 58 IS 23 BP 5315 EP 5320 PG 6 WC Oncology SC Oncology GA 144YL UT WOS:000077343400014 PM 9850056 ER PT J AU Peterson, LA Brown, MR Carlisle, AJ Kohn, EC Liotta, LA Emmert-Buck, MR Krizman, DB AF Peterson, LA Brown, MR Carlisle, AJ Kohn, EC Liotta, LA Emmert-Buck, MR Krizman, DB TI An improved method for construction of directionally cloned cDNA libraries from microdissected cells SO CANCER RESEARCH LA English DT Article ID REVERSE-TRANSCRIPTASE; DNA AB Here, we developed an improved method for constructing microdisected cDNA libraries, based on strand-switching properties of reverse transcriptase, followed by PCR amplification with primers to mediate unidirectional insert cloning. Using RNA from microdissected ovarian carcinoma cells, we constructed a cDNA library consisting of 1.3 x 10(6) unidirectional recombinants with an average insert size of 500 bp. Single-pass sequencing of 100 clones with the T7 primer revealed 89 inserts derived from known genes, anonymous expressed sequence tags (ESTs), or novel sequences. Among these clones were known genes and ESTs previously found in cDNA libraries from bulk ovarian tissue RNA, sequences seen for the first time in an ovarian-derived library, and novel sequences not previously seen in any cDNA library. These results demonstrate a methodology for constructing quality cDNA libraries that are cloned in a unidirectional fashion, are complex and diverse, and reflect the tissue of origin. C1 NCI, Ctr Adv Technol, Pathol Lab, Bethesda, MD 20892 USA. RP Krizman, DB (reprint author), NCI, Ctr Adv Technol, Pathol Lab, 134F,8717 Grovemont Circle, Bethesda, MD 20892 USA. OI Peterson, Lisa/0000-0001-8715-4480 NR 8 TC 43 Z9 53 U1 0 U2 1 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 DEC 1 PY 1998 VL 58 IS 23 BP 5326 EP 5328 PG 3 WC Oncology SC Oncology GA 144YL UT WOS:000077343400016 PM 9850058 ER PT J AU Slebos, RJC Resnick, MA Taylor, JA AF Slebos, RJC Resnick, MA Taylor, JA TI Inactivation of the p53 tumor suppressor gene via a novel Alu rearrangement SO CANCER RESEARCH LA English DT Article ID HOMOLOGOUS RECOMBINATION; REPEATS; SEQUENCES; FREQUENT AB Inactivation of the p53 tumor suppressor gene is a common finding in human cancer. In most cases, inactivation is due to a point mutation in the gene, but rearrangement of the p53 gene is sometimes observed. We analyzed the inactivation of p53 in the human pancreas cancer cell line Hs766T, which harbors a structural alteration in the p53 gene. This inactivation was found to be the result of a complex deletion/insertion event involving at least two different Alu elements. The rearrangement eliminated exons 2-4 from the p53 gene, whereas a 175-bp Alu fragment was inserted between the breakpoints of the deletion. DNA sequence analysis of this Alu fragment revealed that it is identical to an Alu element in intron 1 of the p53 gene. This is the first report of p53 inactivation due to a rearrangement involving Alu elements. This type of inactivation may go unnoticed when only traditional methods to detect p53 alterations are used. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. RP Slebos, RJC (reprint author), NIEHS, Mol Carcinogenesis Lab, POB 12233,C2-01, Res Triangle Pk, NC 27709 USA. EM slebos@niehs.nih.gov OI taylor, jack/0000-0001-5303-6398 NR 20 TC 29 Z9 31 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 DEC 1 PY 1998 VL 58 IS 23 BP 5333 EP 5336 PG 4 WC Oncology SC Oncology GA 144YL UT WOS:000077343400018 PM 9850060 ER PT J AU Allikmets, R Schriml, LM Hutchinson, A Romano-Spica, V Dean, M AF Allikmets, R Schriml, LM Hutchinson, A Romano-Spica, V Dean, M TI A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance SO CANCER RESEARCH LA English DT Article ID DROSOPHILA WHITE GENE; MOLECULAR-CLONING; TRANSPORTER; HOMOLOG; SUPERFAMILY; PROTEINS AB We characterized a new human ATP-binding cassette (ABC) transporter gene that is highly expressed in the placenta. The gene, ABCP, produces two transcripts that differ at the 5' end and encode the same 655-amino acid protein. The predicted protein is closely related to the Drosophila white and yeast ADP1 genes and is a member of a subfamily that includes several multidrug resistance transporters. ABCP, white, and ADP1 all have a single ATP-binding domain at the NH, terminus and a single COOH-terminal set of transmembrane segments. ABCP maps to human chromosome 4q22, between the markers D4S2462 and D4S1557, and the murine gene (Abcp) is located on chromosome 6 28-29 cM from the centromere, ABCP defines a new syntenic segment between human chromosome 4 and mouse chromosome 6, The abundant expression of this gene in the placenta suggests that the protein product has an important role in transport of specific molecule(s) into or out of this tissue. C1 NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Lab Genom Diversity, Frederick, MD 21702 USA. Univ Cattolica Sacro Cuore, Fac Med, Inst Hyg & Publ Hlth, I-00168 Rome, Italy. RP Dean, M (reprint author), NCI, Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. EM dean@mail.ncifcrf.gov RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Schriml, Lynn/0000-0001-8910-9851 FU NCI NIH HHS [N01-CO-56000] NR 25 TC 562 Z9 604 U1 1 U2 13 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 DEC 1 PY 1998 VL 58 IS 23 BP 5337 EP 5339 PG 3 WC Oncology SC Oncology GA 144YL UT WOS:000077343400019 PM 9850061 ER PT J AU Jarrard, JA Linnoila, RI Lee, HR Steinberg, SM Witschi, H Szabo, E AF Jarrard, JA Linnoila, RI Lee, HR Steinberg, SM Witschi, H Szabo, E TI MUC1 is a novel marker for the type II pneumocyte lineage during lung carcinogenesis SO CANCER RESEARCH LA English DT Article ID SURFACTANT-ASSOCIATED PROTEIN; GENE-EXPRESSION; BREAST-CANCER; EPITHELIAL-CELLS; MESSENGER-RNA; ANTIGEN; TISSUES; GROWTH; DIFFERENTIATION; PROGRESSION AB Abnormalities in mucin-type glycoprotein expression have been documented in a variety of cancers, identifying these molecules as targets for immunologically based therapies and prognostic/diagnostic assays. We examined the expression of the membrane-bound MUC1 mucin in normal, histologically atypical, and neoplastic lung to determine its potential contribution to lung carcinogenesis. Zn vivo, intense MUC1 immunoreactivity was present in normal type II pneumocytes as well as In a range of atypical lesions derived from type II cells and >60% of primary and metastatic non-small cell lung cancers. Expression was not associated with altered survival, although it was highly correlated with the adenocarcinoma histology. A carcinogenesis model using 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone-exposed hamsters revealed that MUC1 mRNA increased prior to the histological appearance of tumors. In vitro studies using MUC1 expressing non-small cell lung cancer cell lines revealed that differentiation away from a type II cell lineage was associated with dramatic down-regulation of MUC1. We propose that MUC1 is a powerful new marker for the type II pneumocyte cell lineage that allows us to follow the type II pneumocyte lineage during the process of lung carcinogenesis. C1 NCI, Cell & Canc Biol Dept, Med Branch, Div Clin Sci, Rockville, MD 20850 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Univ Calif Davis, Inst Toxicol & Environm Hlth, Livermore, CA 95616 USA. RP Szabo, E (reprint author), NCI, Cell & Canc Biol Dept, Med Branch, Div Clin Sci, 9610 Med Ctr Dr,Room 300, Rockville, MD 20850 USA. EM szaboe@bprb.nci.nih.gov FU NIEHS NIH HHS [ES-05707] NR 60 TC 51 Z9 52 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 1 PY 1998 VL 58 IS 23 BP 5582 EP 5589 PG 8 WC Oncology SC Oncology GA 144YL UT WOS:000077343400056 PM 9850098 ER PT J AU Bolontrade, MF Stern, MC Binder, RL Zenklusen, JC Gimenez-Conti, IB Conti, CJ AF Bolontrade, MF Stern, MC Binder, RL Zenklusen, JC Gimenez-Conti, IB Conti, CJ TI Angiogenesis is an early event in the development of chemically induced skin tumors SO CARCINOGENESIS LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; INBRED SENCAR MICE; MOUSE SKIN; VERRUCOUS CARCINOMA; HUMAN ENDOMETRIUM; BREAST-CARCINOMA; HA-RAS; CARCINOGENESIS; PROGRESSION AB In this study we have analyzed the vascular response induced in the two-stage carcinogenesis model in SENCAR mice. The role of angiogenesis has not been explored in this model, which is the paradigm of multistage carcinogenesis and a model for neoplastic lesions derived from exophytic premalignant lesions (e.g, colon carcinoma, bladder papilloma). We investigated if angiogenesis is involved in the formation of papillomas and in the progression from papilloma to carcinoma. To this end we analyzed the vasculature of normal and hyperplastic skin, focal epidermal hyperplasias that are precursors of papillomas, papillomas at different stages and squamous cell carcinomas. We also analyzed the vascularization of papillomas induced in two strains of mice that differ in their susceptibility to malignant progression. We show here that angiogenesis is turned on in the earliest stages of papilloma formation. In late stages, regardless of state of progression, the predominant response is an increase in the size of blood vessels. Thus, in the SENCAR mouse model, representative of exophytic tumors, the angiogenesis switch is a very early event, probably mechanistically related to the development of the primarily exophytic lesions. Therefore, the density of blood vessels cannot be used as a predictor of malignant progression in this model. C1 Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA. Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. Procter & Gamble Co, Miami Valley Labs, Cincinnati, OH 45253 USA. RP Conti, CJ (reprint author), Univ Texas, MD Anderson Cancer Ctr, Dept Carcinogenesis, Sci Pk Res Div, Smithville, TX 78957 USA. FU NCI NIH HHS [CA16672, CA69146, CA76540] NR 56 TC 62 Z9 64 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD DEC PY 1998 VL 19 IS 12 BP 2107 EP 2113 DI 10.1093/carcin/19.12.2107 PG 7 WC Oncology SC Oncology GA 154LL UT WOS:000077890600007 PM 9886564 ER PT J AU Chi, WJ Doong, SL Lin-Shiau, SY Boone, CW Kelloff, GJ Lin, JK AF Chi, WJ Doong, SL Lin-Shiau, SY Boone, CW Kelloff, GJ Lin, JK TI Oltipraz, a novel inhibitor of hepatitis B virus transcription through elevation of p53 protein SO CARCINOGENESIS LA English DT Article ID HEPATOCELLULAR-CARCINOMA; DNA-DAMAGE; VIRAL-DNA; REPLICATION; GENE; SEQUENCES; EXPRESSION; INDUCTION; MUTATION; INVITRO AB Molecular epidemiological studies of populations at high risk for liver cancer have shown that hepatitis B virus (HBV) and aflatoxin B1 exposures are two major risk factors for this disease. Oltipraz is currently being considered for clinical trial to protect against aflatoxin B1-induced hepatocarcinogenesis based on its proven protective effect in many different animal models. In addition, oltipraz inhibits human immunodeficiency virus (HIV) replication. The inactivation of reverse transcriptase of HIV appears to be the antiviral mechanism. It has been demonstrated that a number of compounds that inhibit HIV replication also inhibit HBV replication in vitro. Therefore, we tested the possibility of oltipraz blocking HBV replication in 2.2.15 cells (clonal cells derived from HepG2 cells that were transfected with a plasmid containing HBV DNA) in vitro. Results of the experiments indicate that oltipraz has a dose-dependent inhibitory effect on HBV replication and specifically blocks HBV transcription in 2.2.15 cells. In addition, oltipraz induces endogenous wild-type p53 protein in a dose- and time-course-dependent manner. Taken together, we speculate that the effects of oltipraz against replication of HBV and specific blocking of HBV transcription may be through the induction of p53-mediated pathway in 2.2.15 cells. In addition to its known chemopreventive action on aflatoxin B1 hepatocarcinogenesis, oltipraz was shown here to inhibit HBV replication. These dual effects put oltipraz as the excellent candidate for the chemopreventive agent of human hepatocellular carcinoma. C1 Natl Taiwan Univ, Coll Med, Inst Biochem, Taipei, Taiwan. Natl Taiwan Univ, Coll Med, Inst Microbiol, Taipei, Taiwan. Natl Taiwan Univ, Coll Med, Inst Toxicol, Taipei, Taiwan. NCI, Chemoprevent Branch, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Lin, JK (reprint author), Natl Taiwan Univ, Coll Med, Inst Biochem, No 1,Sect 1,Jen Ai Rd, Taipei, Taiwan. OI DOONG, SHIN-LIAN/0000-0002-0936-3858; CHI, HUNG-YUAN/0000-0001-9229-8729 NR 36 TC 23 Z9 24 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD DEC PY 1998 VL 19 IS 12 BP 2133 EP 2138 DI 10.1093/carcin/19.12.2133 PG 6 WC Oncology SC Oncology GA 154LL UT WOS:000077890600011 PM 9886568 ER PT J AU Shiao, YH Palli, D Buzard, GS Caporaso, NE Amorosi, A Saieva, C Fraumeni, JF Anderson, LM Rice, JM AF Shiao, YH Palli, D Buzard, GS Caporaso, NE Amorosi, A Saieva, C Fraumeni, JF Anderson, LM Rice, JM TI Implications of p53 mutation spectrum for cancer etiology in gastric cancers of various histologic types from a high-risk area of central Italy SO CARCINOGENESIS LA English DT Article ID HELICOBACTER-PYLORI INFECTION; DIFFUSE TYPES; INTESTINAL-TYPE; TIME TRENDS; CARCINOMA; 5-METHYLCYTOSINE; ADENOCARCINOMAS; CARCINOGENESIS; EPIDEMIOLOGY; LESIONS AB Examination of p53 mutation spectra may provide clues to molecular mechanisms involved in different histologic types of gastric cancer. A total of 105 gastric cancer cases classified according to the Lauren's system were selected from a high-risk area around Florence, Italy. Exons 5-8 of the p53 gene were examined for mutations by the polymerase chain reaction-single strand conformation polymorphism technique and DNA sequencing, using DNA from formalin-fixed paraffin-embedded tissues. Mutation frequency was similar in intestinal-type (12/28) and unclassified tumors (9/18), but was significantly lower in diffuse cancers (12/57, P < 0.05), A similar frequency of p53 mutations was observed among tumor stages in both intestinal-type and unclassified cancers, but in diffuse tumors mutations tended to be associated with invasion beyond the muscularis propria, When base changes were considered, G:C-->A:T transitions at CpG sites were the most common mutations for all the three tumor types with 6 of 11 (55%) in intestinal type, 8 of 12 (67%) in diffuse type, and 5 of 8 (63%) in unclassified tumors. Frequent p53 mutations in both intestinal-type and unclassified tumors support the hypothesis that unclassified tumors represent variants of the intestinal type and suggest that unclassified tumors, like the intestinal type, may also associate with environmental exposures. The predominance of G:C-->A:T transitions at CpG sites, which are associated with methyltransferase-induced DNA methylation at carbon 5 of cytosine, in all three tumor types suggests that the status of DNA methylation may be the major determinant for p53 mutations and may be also equally important in gastric carcinogenesis regardless of histology. C1 NCI, Comparat Carcinogenesis Lab, FCRDC, Frederick, MD 21702 USA. AO Careggi, CSPO, Epidemiol Unit, Florence, Italy. SAIC Frederick, IRSP, Frederick, MD 21702 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Florence, Dept Pathol, Florence, Italy. RP Shiao, YH (reprint author), NCI, Comparat Carcinogenesis Lab, FCRDC, POB B,Bldg 538,Room 205E, Frederick, MD 21702 USA. EM shiao@mail.ncifcrf.gov OI saieva, calogero/0000-0002-0117-1608; PALLI, Domenico/0000-0002-5558-2437 FU NCI NIH HHS [N01-CO-56000] NR 37 TC 18 Z9 22 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD DEC PY 1998 VL 19 IS 12 BP 2145 EP 2149 DI 10.1093/carcin/19.12.2145 PG 5 WC Oncology SC Oncology GA 154LL UT WOS:000077890600013 PM 9886570 ER PT J AU Thompson, HJ McGinley, JN Wolfe, P Singh, M Steele, VE Kelloff, GJ AF Thompson, HJ McGinley, JN Wolfe, P Singh, M Steele, VE Kelloff, GJ TI Temporal sequence of mammary intraductal proliferations, ductal carcinomas in situ and adenocarcinomas induced by 1-methyl-1-nitrosourea in rats SO CARCINOGENESIS LA English DT Article ID BREAST-CANCER; TUMORIGENESIS; PATHOLOGY; INDUCTION; INJECTION; LESIONS; TUMORS AB An experimental model for mammary carcinogenesis has been described in which intraductal proliferations, ductal carcinomas in situ and adenocarcinomas can be readily detected and the frequency of their occurrence quantified, The objective of the experiment reported in this study was to determine the latency period between carcinogen administration and the occurrence of each of these types of lesion. A total of 150 female Sprague-Dawley rats were injected i.p. with 50 mg 1-methyl-1-nitrosourea (MNU)/kg body wt at 21 days of age. Groups of 30 rats each were killed at 7, 14, 21, 28 and 35 days post-carcinogen. Mammary intraductal proliferations were the first detected lesions and were observed in 20% of the animals at 14 days following carcinogen administration. At 21 days post-carcinogen ductal carcinomas in situ and adenocarcinomas were observed. The number of each type of lesion increased with time post-carcinogen, but the temporal pattern of occurrence was different among lesion types. The pattern of lesion occurrence was consistent with intraductal proliferations being a precursor lesion for ductal carcinomas in situ and adenocarcinomas, Furthermore, the data imply that ductal carcinomas in situ represent one pathway of morphological progression by which intraductal proliferations evolve into invasive carcinomas, but that this lesion type, as currently defined histologically, may not be an obligatory intermediate in morphologic progression. These findings are consistent with emerging evidence of multiple but distinct pathogenetic pathways leading to mammary carcinomas that display different morphological patterns and biological activities. C1 AMC Canc Res Ctr, Ctr Biometr, Lakewood, CO 80214 USA. AMC Canc Res Ctr, Ctr Canc Causat & Prevent, Lakewood, CO 80214 USA. Univ Iowa Hosp & Clin, Dept Pathol, Ames, IA USA. NCI, Chemoprevent Branch, NIH, Washington, DC USA. RP Wolfe, P (reprint author), AMC Canc Res Ctr, Ctr Biometr, 1600 Pierce St, Lakewood, CO 80214 USA. EM thompsonh@amc.org RI Thompson, Henry/K-7242-2012 OI Thompson, Henry/0000-0002-3730-9322 FU NCI NIH HHS [N01-CN-55178] NR 18 TC 32 Z9 32 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD DEC PY 1998 VL 19 IS 12 BP 2181 EP 2185 DI 10.1093/carcin/19.12.2181 PG 5 WC Oncology SC Oncology GA 154LL UT WOS:000077890600019 PM 9886576 ER PT J AU Gobel, FL Stewart, WJ Campeau, L Hickey, A Herd, JA Forman, S White, CW Rosenberg, Y AF Gobel, FL Stewart, WJ Campeau, L Hickey, A Herd, JA Forman, S White, CW Rosenberg, Y CA Post CABG Clinical Trial Investigators TI Safety of coronary arteriography in clinically stable patients following coronary bypass surgery SO CATHETERIZATION AND CARDIOVASCULAR DIAGNOSIS LA English DT Article DE clinical trials; Post CABG Trial; diagnostic coronary arteriography ID FEMORAL-ARTERY CATHETERIZATION; CARDIAC-CATHETERIZATION; VASCULAR COMPLICATIONS; ARTERIOVENOUS-FISTULA; ANGIOGRAPHY; PSEUDOANEURYSM; RISK; INTERVENTIONS; MANAGEMENT; REGISTRY AB The frequent use of diagnostic coronary arteriography and its importance in evaluating results of intervention in clinical trials emphasize the necessity of continued assessment of procedural risk. Several studies have described such risks, but they have often included a diverse group of patients with varying levels of clinical stability. Furthermore, this risk has not been well established in a population of patients with saphenous vein bypass grafts. There is need to define the risk of coronary arteriography in a group of patients who are both clinically similar and stable, and to evaluate the influence of improved technology and increased operator experience on the risk of the procedure. The National Heart, Lung, and Blood Institute-funded Post Coronary Artery Bypass Graft Trial offered the opportunity to evaluate the risk of elective diagnostic coronary arteriography in clinically stable patients studied at two points in time: pre-enrollment and 4-5 years after study entry. In this group of 2,635 angiograms from clinically stable patients over 5 years there were no deaths and the risk of myocardial infarction was 0.08%, while 0.7% had clinically important complications. Non-elective, urgent studies (311 angiograms) on unstable patients were more likely to include angioplasty and were associated with a risk of death of 0.6% and myocardial infarction of 1.3%. Complications did not vary with age or gender. Vascular trauma was more likely to occur using the brachial than the femoral artery entry sites, These results indicate that elective angiography on stable patients can be accomplished with a very low risk of mortality (0% in this study) or serious cardiovascular complication. This supports the safety and usefulness of angiography for clinical intervention trials. Cathet. Cardiovasc. Diagn. 45:376-381, 1998. (C) 1998 Wiley-Liss, Inc. C1 Minneapolis Heart Inst Fdn, Dept Res, Minneapolis, MN 55407 USA. Cleveland Clin Fdn, Dept Med, Div Cardiol, Cleveland, OH 44195 USA. Montreal Heart Inst, Res Dept, Montreal, PQ H1T 1C8, Canada. Cedars Sinai Med Ctr, Dept Med, Div Cardiol, Los Angeles, CA 90048 USA. Baylor Coll Med, Dept Med, Atherosclerosis Sect, Houston, TX 77030 USA. Maryland Med Res Inst, Baltimore, MD USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. NHLBI, Sci Res Grp, Bethesda, MD 20892 USA. RP Gobel, FL (reprint author), Minneapolis Heart Inst Fdn, Dept Res, 920 E 28th St,Suite 300, Minneapolis, MN 55407 USA. NR 28 TC 21 Z9 21 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 0098-6569 J9 CATHETER CARDIO DIAG JI Catheter. Cardiovasc. Diagn. PD DEC PY 1998 VL 45 IS 4 BP 376 EP 381 DI 10.1002/(SICI)1097-0304(199812)45:4<376::AID-CCD5>3.0.CO;2-X PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 143WB UT WOS:000077279300005 PM 9863740 ER PT J AU Hughes, FM Evans-Storms, RB Cidlowski, JA AF Hughes, FM Evans-Storms, RB Cidlowski, JA TI Evidence that non-caspase proteases are required for chromatin degradation during apoptosis SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE apoptosis; endonuclease; protease; caspase ID INTERNUCLEOSOMAL DNA CLEAVAGE; DEOXYRIBONUCLEIC-ACID; CA2+/MG2+-DEPENDENT ENDONUCLEASE; RAT THYMOCYTES; LYMPHOCYTES-T; FRAGMENTATION; IDENTIFICATION; DEATH; GLUCOCORTICOIDS; PURIFICATION AB Chromatin degradation into oligonucleosomal and approximate to 30-50 Kb fragments is a hallmark of apoptosis. Crude nuclear extract from apoptotic rat thymocytes is able to recapitulate both types of DNA fragmentation in an assay using HeLa cell nuclei as an exogenous substrate. Using size exclusion chromatography we have identified a novel activity( approximate to 260 Kd) that produces only approximate to 30-50 Kb DNA fragments, and a 25 Kd activity that generates both approximate to 30-50 Kb and oligonucleosomal fragments. Both activities produced DNA fragments with 3'-OH termini, are dependent on Ca2+ and Mg2+ and are inhibited by N-ethyl-maleimide, sodium tetrathionate, aurin-tricarboxylic acid and sodium chloride, similar to other nucleases implicated in apoptosis. These activities were inhibited by the serine protease inhibitors N-tosyl-L-phenylalanine chloromethyl ketone and Na-p-tosyl-L-lysine chloromethyl ketone, but not by the serine protease inhibitor diisopropyl fluorophosphate, or by calpain inhibitors I or II, or the capsase inhibitors Ac-Asp-Glu-Val-Asp-aldehyde, Ac-TyrVal-Ala-Asp-aldehyde, or Z-Val-Ala-Asp-fluoromethyl ketone. Both activities were insensitive to protease inhibitors when extracts were incubated with naked linear DNA, indicating the presence of both nuclease and protease activities in the preparation. Together, these observations suggest the involvement of non-caspase proteases in apoptosis which perhaps function by altering chromatin substructure and exposing it to nucleolytic attack. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), POB 12233,MD E2-02, Res Triangle Pk, NC 27709 USA. NR 38 TC 46 Z9 48 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD DEC PY 1998 VL 5 IS 12 BP 1017 EP 1027 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 147YZ UT WOS:000077526500004 PM 9894608 ER PT J AU Kadiiska, MB Morrow, JD Awad, JA Roberts, LJ Mason, RP AF Kadiiska, MB Morrow, JD Awad, JA Roberts, LJ Mason, RP TI Identification of free radical formation and F-2-isoprostanes in vivo by acute Cr(VI) poisoning SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID LIPID-PEROXIDATION; SOYBEAN LIPOXYGENASE; FATTY-ACIDS; CATALYZED MECHANISM; HEXAVALENT CHROMIUM; MASS-SPECTROMETRY; LINOLEIC-ACID; RATS; TOXICITY; NONCYCLOOXYGENASE AB We previously reported the detection of a carbon-centered radical adduct of alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (POBN) in the bile of rats acutely poisoned with Cr(VI) utilizing an electron spin resonance spin-trapping technique. These former studies suggested that the free radical metabolite was derived from a polyunsaturated fatty acid. The present studies were undertaken to further characterize this radical adduct and to determine whether its formation is associated with enhanced lipid peroxidation in vivo. This report demonstrates that electron spin resonance (ESR) spectra with hyperfine coupling constants a(N) of 15.71 G and a(beta)(H) of 2.90 G were present in bile from Cr(VI)-poisoned rats. We found out that virtually identical ESR spectra were obtained when authentic POBN-pentyl radical adducts generated from the reaction of POBN with either pentylhydrazine or linoleic or arachidonic acid with lipoxygenase were added to bile. The hyperfine coupling constants for the POBN-pentyl radical adducts added to bile were as follows: a(N) = 15.85 G and a(beta)(H) = 2.60 G for the reaction between pentylhydrazine and POBN; a(N) = 15.72 G and a(beta)(H) = 2.61 G for the reaction between arachidonic acid, lipoxygenase, and POBN: and a(N) = 15.85 Cr and a(beta)(H) = 2.85 G for the reaction between linoleic acid, lipoxygenase, and POBN. In addition, the formation of this radical adduct was associated with lipid per oxidation as quantified by increases in F-2-isoprostane levels in bile. These studies, therefore, provide additional evidence that acute Cr(IV) poisoning is associated with enhanced generation of F-2-isoprostanes in vivo and tentatively identify the radical species that is produced as the POBN-pentyl radical adduct. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. RP Kadiiska, MB (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. FU NIDDK NIH HHS [DK48831]; NIGMS NIH HHS [GM15431, GM42056] NR 30 TC 28 Z9 29 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD DEC PY 1998 VL 11 IS 12 BP 1516 EP 1520 DI 10.1021/tx980169e PG 5 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 151TY UT WOS:000077737800018 PM 9860496 ER PT J AU Salomaa, ER Liippo, K Taylor, P Palmgren, J Haapakoski, J Virtamo, J Heinonen, OP AF Salomaa, ER Liippo, K Taylor, P Palmgren, J Haapakoski, J Virtamo, J Heinonen, OP TI Prognosis of patients with lung cancer found in a single chest radiograph screening SO CHEST LA English DT Article DE lung cancer; screening; survival ID SURVIVAL; NECROPSY AB Background: The prognosis of patients with lung cancer is better when the diagnosis is made early; the disease is localized, and radical surgery is possible. Screening for lung cancer with mass radiography or sputum cytology should contribute to a more favorable prognosis. Large-scale screening studies have improved the survival rates for lung cancer but have yielded. no reduction in mortality rates, Methods: The histologic types, stages, treatments, and survival rates were studied in 93 men who were found to have lung cancer in a single chest radiograph screening of more than 33,000 men who smoked and were 50 to 69 years old ("screened cases"), and in 239 men of the same age range whose lung cancer was detected through ordinary health care system ("other cases") during the screening period, Results: The distribution of the histology was similar in the two groups, but screening detected more instances of early-stage disease that were resectable more often than in the other group (37 vs 19%), The 5-year survival rate for men in the screened cases was 19%, and that of men in the other cases was 10% (relative risk, 0.65; 95% confidence interval [CI], 0.50 to 0.84), The survival rate of men in the screened cases remained significantly higher than that of men in the other cases even after adjustments for age, smoking status, histology, stage of the disease, and resectability of the disease (relative risk, 0.74; 95% CI, 0.55 to 1.00), Conclusions: According to this study, chest radiograph screening might improve the prognosis of lung cancer. Our results are, however, subject to many factors that were only partially controlled for, and they should be interpreted cautiously. C1 Turku Univ Hosp, Dept Pulm Dis & Clin Allergol, FIN-21540 Preitila, Finland. NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Dept Nutr, Helsinki, Finland. Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. RP Salomaa, ER (reprint author), Turku Univ Hosp, Dept Pulm Dis & Clin Allergol, FIN-21540 Preitila, Finland. EM eirisa@utu.fi OI Palmgren, Juni/0000-0002-9031-8615 FU NCI NIH HHS [N01-CN-45165] NR 19 TC 20 Z9 21 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 DEC PY 1998 VL 114 IS 6 BP 1514 EP 1518 DI 10.1378/chest.114.6.1514 PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 149PF UT WOS:000077613600008 PM 9872181 ER PT J AU Crook, JL Breathnach, OS Cruser, D Johnson, BE AF Crook, JL Breathnach, OS Cruser, D Johnson, BE TI Lung carcinoma metastasis at the site of central venous access SO CHEST LA English DT Article DE case report; central venous catheterization; lung neoplasm; malignant pleural effusion; non-small cell carcinoma AB Tumor metastases rarely are reported in association with central,venous catheters. The case reported herein is that of a solid tumor metastasis at the site of a previous indwelling line ipsilateral to a pleural effusion in a patient with non-small cell lung cancer. A review of the literature reveals a single case of intrathoracic malignancy seeding at the site of a central venous catheter, Other investigators are urged to collect information about the development of tumor implants at the site of catheter insertion in patients with cancer and pleural effusions to further define the extent of the problem. C1 USN, Med Branch, Natl Naval Med Ctr, Dept Med & Pathol,Div Clin Sci,NCI, Bethesda, MD 20889 USA. RP Johnson, BE (reprint author), USN, Med Branch, Natl Naval Med Ctr, Dept Med & Pathol,Div Clin Sci,NCI, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. NR 7 TC 2 Z9 2 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 DEC PY 1998 VL 114 IS 6 BP 1772 EP 1774 DI 10.1378/chest.114.6.1772 PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 149PF UT WOS:000077613600045 PM 9872218 ER PT J AU Rubin, KH Hastings, P Chen, XY Stewart, S McNichol, K AF Rubin, KH Hastings, P Chen, XY Stewart, S McNichol, K TI Intrapersonal and maternal correlates of aggression, conflict, and externalizing problems in toddlers SO CHILD DEVELOPMENT LA English DT Article ID PSYCHOLOGICAL ADJUSTMENT; SOCIAL COMPETENCE; CHILD-CARE; GENDER; PRESCHOOLERS; PREDICTORS; BEHAVIOR; EMOTION AB Research has shown that 2-year-olds engage in peer-directed aggression and initiation of conflict. However, there has been little consideration of the factors associated with variability in toddlers' aggression. One hundred and four toddlers (52 females) were observed for 35 min of free play with a same-sex peer, with both mothers present. Experience in early out-of-home care was not related to aggression. Toddlers' observed and mother-rated dysregulated temperament, and mothers' use of warmth and negative dominance during interactions with their children, were used to predict toddlers' aggression and maternal ratings of externalizing difficulties. Boys were observed to be more aggressive than girls. Regression analyses showed that, after controlling for main effects, the interaction of child gender, temperament, and maternal negative dominance predicted both outcomes. Observed aggression and mother-reported externalizing problems were associated significantly with dysregulated temperament only for boys with mothers who demonstrated relatively high levels of negative dominance. C1 Univ Maryland, Ctr Children Relationships & Culture, College Pk, MD 20742 USA. Univ Western Ontario, London, ON N6A 3K7, Canada. Univ Waterloo, Waterloo, ON N2L 3G1, Canada. NIMH, Bethesda, MD 20892 USA. RP Rubin, KH (reprint author), Univ Maryland, Ctr Children Relationships & Culture, 3304 Benjamin Bldg, College Pk, MD 20742 USA. EM krubin@rubinlab.umd.edu NR 57 TC 86 Z9 88 U1 2 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD DEC PY 1998 VL 69 IS 6 BP 1614 EP 1629 PG 16 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 155CN UT WOS:000077928600010 PM 9914642 ER PT J AU Bautista, S Valles, H Walker, RL Anzick, S Zeillinger, R Meltzer, P Theillet, C AF Bautista, S Valles, H Walker, RL Anzick, S Zeillinger, R Meltzer, P Theillet, C TI In breast cancer, amplification of the steroid receptor coactivator gene AIB1 is correlated with estrogen and progesterone receptor positivity SO CLINICAL CANCER RESEARCH LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; DNA AMPLIFICATION; OVARIAN-TUMORS; PATTERNS; REGIONS; CARCINOMAS; SELECTION; SEQUENCES; MDM2 AB The AIB1 gene was isolated upon microdissection of the homogeneously staining regions observed in breast cancer cell lines. It was subsequently shown to map at a region at 20q12 that is frequently amplified in breast tumors. In a screen of breast tumor cell lines, of all the genes mapping to the region, AIB1 appeared to be the most consistently amplified and overexpressed, AIB1 shares homology with the SRC-1 family of nuclear receptor coactivators. It was found to interact in a ligand-dependent manner with the estrogen receptor (ER) and to result in increased levels of estrogen-dependent transcription, These properties could be of important biological significance in breast and ovarian cancerigenesis, and me were, therefore, interested in determining whether the amplification of the AIB1 gene was associated with a particular phenotype or subgroup in these tumors, We tested a population of 1157 breast and 122 ovarian tumors in which DNA amplification had been determined previously at 15 chromosomal locations, Amplification of the AIB1 gene was observed in 4.8% of breast cancers and 7.4% of ovarian cancers. In breast tumors, AIB1 was correlated with ER and progesterone receptor positivity, as well as with tumor size. Correlation mas also observed with the amplification of MDM2 and FGFR1 genes, but interestingly, no correlation was found with the amplification of CCND1, which is known to be strongly associated with ER, Furthermore, analyzing at 20q12-q13 range, we show the existence of three amplification cores, represented by AIB3/AIB4, AIB1, and RMC20C001, AIB1 and CCND1 amplifications may, thus, represent two different subsets of ER-positive breast tumors. C1 CNRS, Ctr Rech, Equipe Genome & Canc, UMR 5535,CRLC Val Aurelle, F-34298 Montpellier 05, France. Natl Human Genome Res Inst, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. Univ Vienna, Dept Gynecol & Obstet, A-1090 Vienna, Austria. RP Theillet, C (reprint author), CNRS, Ctr Rech, Equipe Genome & Canc, UMR 5535,CRLC Val Aurelle, F-34298 Montpellier 05, France. NR 21 TC 180 Z9 185 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 DEC PY 1998 VL 4 IS 12 BP 2925 EP 2929 PG 5 WC Oncology SC Oncology GA 146HR UT WOS:000077423700001 PM 9865902 ER PT J AU Risinger, JI Hayes, K Maxwell, GL Carney, ME Dodge, RK Barrett, JC Berchuck, A AF Risinger, JI Hayes, K Maxwell, GL Carney, ME Dodge, RK Barrett, JC Berchuck, A TI PTEN mutation in endometrial cancers is associated with favorable clinical and pathologic characteristics SO CLINICAL CANCER RESEARCH LA English DT Article ID COWDEN-DISEASE; GERMLINE MUTATIONS; TUMOR-SUPPRESSOR; PROSTATE-CANCER; GENE-MUTATIONS; CARCINOMA; P53; PTEN/MMAC1; FREQUENT; OVEREXPRESSION AB Mutation of the PTEN tumor suppressor gene is a frequent event in endometrial cancers. In other types of cancers, PTEN mutation has been associated with metastatic behavior and advanced stage. To examine the relationship between PTEN mutation and clinical features of endometrial cancers, we screened 136 cases for mutations in the nine exons and intronic splice sites of the PTEN gene, using single-strand conformation analysis, and aberrant bands were sequenced. Mutations were noted in 44 of 136 (32%) endometrial cancers, and two mutations were present in 8 cases, There were 36 cases with mutations resulting in truncated protein products, 6 cases with missense mutations in the phosphatase domain, 1 case with an in-frame deletion, and 1 case with a large insertion. Mutation of the PTEN gene correlated most closely with endometrioid histology; mutations were seen in only 5% (1 of 21) of serous/clear cell cancers compared with 37% (43 of 115) of endometrioid cancers (P = 0.004). PTEN mutation was associated with early stage, nonmetastatic disease and more favorable survival in both the entire group of 136 cases and in the 115 endometrioid cases. In addition, PTEN mutation correlated with other molecular features associated with favorable clinical behavior, including microsatellite instability and absence of p53 overexpression, Microsatellite instability was found in 60% of cases with PTEN mutations compared with only 25% of cases without mutations (P = 0.004). Overexpression of p53 was seen in only 14% of cases with PTEN mutations compared to 39% of cases without mutations (P = 0.006). In conclusion, PTEN mutation is associated with endometrioid histology and other favorable pathological, clinical, and molecular features rather than with increased metastatic potential as has been noted in some other types of cancers. C1 Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Biostat, Durham, NC 27710 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Berchuck, A (reprint author), Duke Univ, Med Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Box 3079, Durham, NC 27710 USA. NR 26 TC 175 Z9 187 U1 1 U2 5 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 DEC PY 1998 VL 4 IS 12 BP 3005 EP 3010 PG 6 WC Oncology SC Oncology GA 146HR UT WOS:000077423700012 PM 9865913 ER PT J AU Migueles, S Kumar, P AF Migueles, S Kumar, P TI Primary cutaneous Acanthamoeba infection in a patient with AIDS SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 2nd Annual Regional Associates Meeting of the American-College-of-Physicians CY MAY 06, 1995 CL WASHINGTON, D.C. SP Amer Coll Physicians C1 NIAID, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Med, Div Infect Dis, Washington, DC 20007 USA. RP Migueles, S (reprint author), NIAID, NIH, Bldg 10,Room 11S231,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 14 Z9 14 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 DEC PY 1998 VL 27 IS 6 BP 1547 EP 1548 DI 10.1086/517750 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 148UU UT WOS:000077552300049 PM 9868688 ER PT J AU Kurtzman, HS Maser, JD Ingram, RE AF Kurtzman, HS Maser, JD Ingram, RE TI Special issue: Cognition and anxiety SO COGNITIVE THERAPY AND RESEARCH LA English DT Editorial Material C1 NIMH, Rockville, MD 20857 USA. San Diego State Univ, San Diego, CA 92182 USA. RP Kurtzman, HS (reprint author), NIMH, Rockville, MD 20857 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 1998 VL 22 IS 6 BP 535 EP 537 DI 10.1023/A:1018733902508 PG 3 WC Psychology, Clinical SC Psychology GA 151TE UT WOS:000077736100001 ER PT J AU Bos, AJG Brant, LJ Morrell, CH Fleg, JL AF Bos, AJG Brant, LJ Morrell, CH Fleg, JL TI The relationship of obesity and the development of coronary heart disease to longitudinal changes in systolic blood pressure SO COLLEGIUM ANTROPOLOGICUM LA English DT Article ID AGE; MEN; FRAMINGHAM; ADULTS; RISK AB In an investigation of the relationship of obesity and the development of coronary heart disease (CHD) to longitudinal changes in systolic blood pressure (SBP), a sample of 1029 male participants from the Baltimore Longitudinal Study of Baltimore (BLSA), who were free of CHD at the beginning of the study, were examined with a total of 4111 examinations (mean of four examinations per person) conducted during the study period. The mean follow-up time was 8.1 years with a maximum of 16 examinations and 30.9 years of follow-up. Luring the follow-up period, 192 participants developed CHD, and these participants' data collected after the CHD event were Excluded from the analysis. A proportional hazards regression model was used to calculate the relative risk of developing CHD for several CHD risk factors. Both simple and multiple proportional hazards regression models indicate a strong association between body mass index: (BMI), cholesterol cigarette smoking, and systolic blood pressure (SBP) with the risk of developing CHD. In addition, a linear mixed-effects model was used to examine changes in SEP measurements over time and to identify factors, including the age at first examination and time in study that are related to that change. The results from the linear mixed-effecs model analysis indicate that those in. the obese group (BMI greater than or equal to 30 kg/m(2)) have SEP measurements that are on average 9.0 mm Hg higher than those in. the normal group (20 less than or equal to BMI < 25). Also, SPB measurements were on average 6.6 mm Hg higher in those who developed CHD during the study period than those who remained free of disease. In addition, SPB showed a quadratic relationship with time, and its patterns of change with time were different among the different age groups. Also, the relationship between changes in. SEP with respect to cholesterol was dependent on time in the study as well. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Bos, AJG (reprint author), NIA, Gerontol Res Ctr, NIH, 4940 Eastern Ave, Baltimore, MD 21224 USA. NR 22 TC 5 Z9 5 U1 1 U2 2 PU COLLEGIUM ANTROPOLOGICUM PI ZAGREB PA INST ANTHROPOLOGICAL RES, P O BOX 290, ULICA GRADA VUKOVARA 72/IV, 10000 ZAGREB, CROATIA SN 0350-6134 J9 COLLEGIUM ANTROPOL JI Coll. Anthropol. PD DEC PY 1998 VL 22 IS 2 BP 333 EP 344 PG 12 WC Anthropology SC Anthropology GA 153YC UT WOS:000077860300002 PM 9887591 ER PT J AU Lenfant, C Friedman, L Weinmann, G AF Lenfant, C Friedman, L Weinmann, G TI Clinical trials and treatment effects monitoring - Comment SO CONTROLLED CLINICAL TRIALS LA English DT Editorial Material C1 NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. NHLBI, Airway Biol & Dis Program, Div Lung Dis, NIH, Bethesda, MD 20892 USA. RP Lenfant, C (reprint author), NHLBI, Div Epidemiol & Clin Applicat, NIH, Bldg 31,Room 5A52, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 1998 VL 19 IS 6 BP 523 EP 524 PG 2 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 149MN UT WOS:000077609400002 ER PT J AU Kupfer, C AF Kupfer, C TI Clinical trials and treatment effects monitoring - Comment SO CONTROLLED CLINICAL TRIALS LA English DT Editorial Material C1 NEI, NIH, Bethesda, MD 20892 USA. RP Kupfer, C (reprint author), NEI, NIH, Bldg 31,Rm 6A03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 1998 VL 19 IS 6 BP 537 EP 538 PG 2 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 149MN UT WOS:000077609400009 ER PT J AU Senturia, YD Mortimer, KM Baker, D Gergen, P Mitchell, H Joseph, C Wedner, HJ AF Senturia, YD Mortimer, KM Baker, D Gergen, P Mitchell, H Joseph, C Wedner, HJ TI Successful techniques for retention of study participants in an inner-city population SO CONTROLLED CLINICAL TRIALS LA English DT Article DE pediatric asthma; retention; cohort study; minorities ID PREVENTION RESEARCH; ATTRITION; ASTHMA AB The purpose of this work was to describe methods of retaining participants in studies of inner-city populations, including the timing and intensity of contacts; and to describe the characteristics of participants who did not complete all follow-up interviews and/or return all peak flow diaries in the National Cooperative Inner-City Asthma Study. A cohort study design was used involving hospital emergency rooms and community clinics in seven major urban areas. Participants included 1337 4- to 9-year-old asthmatic children and their caretakers. Nearly 89% of participants completed 3-, 6-, and 9-month follow-up interviews. The 15% of participants who completed a baseline interview on the weekends were significantly more likely to complete follow-up interviews on a weekend. The percent of follow-up interviews conducted in person increased over time from 5% to 8%. The percent of participants with complete follow-up increased as the number of contact names increased (86% with zero contacts, 91% with two contracts; p = 0.03, test for trend). Participants who required at least four phone calls to complete the 3- and 6-month assessment were significantly mole likely to be black, have higher participant stress, and have a smoker in the household (p < 0.05). Multiple logistic regression suggests that higher social support and lower parental stress were both predictors of completed interviews. Within our study sample of inner-city minority participants with asthmatic children, only a small proportion of participants missed any follow-up interviews. Increased caretaker stress, decreased social support, and inability to provide several alternate contacts were all predictive of retention problems, Having a flexible staff, computer tracking, and face-to-face recruitment appear essential to achieving nearly complete follow-up within a population historically difficult to follow. Controlled Clin Trials 1998;19:544-554 (C) Elsevier Science Inc. 1998. C1 Childrens Mem Hosp, Chicago, IL 60614 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Calif Irvine, Ctr Environm & Occupat Hlth, Irvine, CA 92717 USA. NIAID, NIH, Bethesda, MD 20892 USA. New England Res Inst, Watertown, MA 02172 USA. Henry Ford Hosp, Detroit, MI 48202 USA. Washington Univ, Sch Med, St Louis, MO USA. RP Senturia, YD (reprint author), Albert Einstein Coll Med, 1300 Morris Pk,Nurses Residence 7S12, Bronx, NY 10461 USA. FU NIAID NIH HHS [AI-30752, AI-30756, UO1 AI-30751] NR 10 TC 57 Z9 57 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 1998 VL 19 IS 6 BP 544 EP 554 DI 10.1016/S0197-2456(98)00032-4 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 149MN UT WOS:000077609400011 PM 9875834 ER PT J AU Dignam, JJ Bryant, J Wieand, HS Fisher, B Wolmark, N AF Dignam, JJ Bryant, J Wieand, HS Fisher, B Wolmark, N TI Early stopping of a clinical trial when there is evidence of no treatment benefit: Protocol B-14 of the National Surgical Adjuvant Breast and Bowel Project SO CONTROLLED CLINICAL TRIALS LA English DT Article DE stopping rules; data monitoring; stochastic curtailment; Bayesian methods; breast cancer; tamoxifen; clinical trials ID RECEPTOR-POSITIVE TUMORS; TAMOXIFEN THERAPY; SEQUENTIAL-TESTS; CANCER; DESIGNS; POWER; LONG AB Although several randomized clinical trials in the 1980s indicated a benefit from the use of tamoxifen in the treatment of early-stage breast cancer, questions have remained regarding the optimal duration of drug administration. In 1982, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated a randomized trial to compare 5 years of tamoxifen to placebo among breast cancer patients with estrogen receptor-positive tumors and no evidence of axillary node involvement. By 1987, evidence of a substantial benefit for tamoxifen led the NSABP to extend this trial to determine whether longer duration tamoxifen therapy would be additionally beneficial. This study randomized patients who had completed 5 years of tamoxifen free of breast cancer recurrence or other events to either tamoxifen or placebo for an additional 5 years. By 1994, 1172 women had entered the study and accrual was closed. In late 1995, the trial was terminated on the basis of interim findings indicating that a benefit for continuing tamoxifen would not be realized. The closure has prompted controversy among cancer researchers, because there are currently at least three tamoxifen duration trials in progress, whereas results from two other studies evaluating 5-year duration therapy versus longer therapy were recently published. Here, we provide details of the statistical rationale contributing to our decision to recommend early closure of the study. We then consider other possible approaches to assessing the appropriateness of early termination in the face of evidence against a benefit, including Bayesian methods, which can be used to incorporate a range of prior beliefs regarding the efficacy of a treatment with accruing information from the trial. We also briefly discuss results of the other published studies. Controlled Clin Trials 1998;19:575-588 (C) Elsevier Science Inc. 1998. C1 NSABP, Ctr Biostat, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Allegheny Gen Hosp, NSABP Chairmans Off, Pittsburgh, PA 15212 USA. Allegheny Gen Hosp, NSABP Sci Directors Off, Pittsburgh, PA 15212 USA. RP Dignam, JJ (reprint author), NSABP, Ctr Biostat, 230 McKee Pl, Pittsburgh, PA 15213 USA. FU NCI NIH HHS [U10CA37377, U10CA39086, U10CA12027] NR 26 TC 30 Z9 30 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD DEC PY 1998 VL 19 IS 6 BP 575 EP 588 DI 10.1016/S0197-2456(98)00041-5 PG 14 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 149MN UT WOS:000077609400014 PM 9875837 ER PT J AU Sirigu, A Cohen, L Zalla, T Pradat-Diehl, P Van Eeckhout, P Grafman, J Agid, Y AF Sirigu, A Cohen, L Zalla, T Pradat-Diehl, P Van Eeckhout, P Grafman, J Agid, Y TI Distinct frontal regions for processing sentence syntax and story grammar SO CORTEX LA English DT Article DE sequence processing; frontal lesion; neuropsychology ID PREFRONTAL CORTEX; WORKING-MEMORY; DEFICITS; LESIONS; TASKS; BEHAVIOR; LOBE AB Time is a fundamental dimension of cognition. It is expressed in the sequential ordering of individual elements in a wide variety of activities such as language, motor control or in the broader domain of long range goal-directed actions. Several studies have shown the importance of the frontal lobes in sequencing information. The question addressed in this study is whether this brain region hosts a single supramodal sequence processor, or whether separate mechanisms are required for different kinds of temporally organised knowledge structures such as syntax and action knowledge. Here we show that so-called agrammatic patients, with lesions in Broca's area, ordered word groups correctly to form a logical sequence of actions but they were severely impaired when similar word groups had to be ordered as a syntactically well-formed sentence. The opposite performance was observed in patients with dorsolateral prefrontal lesions, that is, while their syntactic processing was intact at the sentence level, they demonstrated a pronounced deficit in producing temporally coherent sequences of actions. Anatomical reconstruction of lesions from brain scans revealed that the sentence and action grammar deficits involved distinct, non-overlapping sites within the frontal lobes. Finally, in a third group of patients whose lesions encompassed both Broca's area and the prefrontal cortex, the two types of deficits were found. We conclude that sequence processing is specific to knowledge domains and involves different networks within the frontal lobes. C1 Hop La Pitie Salpetriere, INSERM, U289, Paris, France. Hop La Pitie Salpetriere, Neurol Serv, Paris, France. Hop La Pitie Salpetriere, Serv Reeduc Neurol, Paris, France. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Ecole Polytech, CREA, F-91128 Palaiseau, France. RP Sirigu, A (reprint author), CNRS, Inst Cognit Sci, 67 Blvd Pinel, F-69675 Bron, France. EM sirigu@isc.cnrs.fr OI Grafman, Jordan H./0000-0001-8645-4457 NR 17 TC 62 Z9 63 U1 0 U2 2 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD DEC PY 1998 VL 34 IS 5 BP 771 EP 778 DI 10.1016/S0010-9452(08)70780-9 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 148HF UT WOS:000077498700012 PM 9872379 ER PT J AU Natanson, C Esposito, CJ Banks, SM AF Natanson, C Esposito, CJ Banks, SM TI The sirens' songs of confirmatory sepsis trials: Selection bias and sampling error SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE sepsis; clinical trials; anti-inflammatory agents; infection; Gram-negative ID INTERLEUKIN-1 RECEPTOR ANTAGONIST; PLACEBO-CONTROLLED TRIAL; NECROSIS-FACTOR-ALPHA; CONTROLLED MULTICENTER TRIAL; DOUBLE-BLIND; SEPTIC SHOCK; MONOCLONAL-ANTIBODY; CLINICAL-TRIAL; SAFETY; IBUPROFEN C1 NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Natanson, C (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bldg 10,Room 7D43,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 23 TC 103 Z9 105 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 1998 VL 26 IS 12 BP 1927 EP 1931 DI 10.1097/00003246-199812000-00001 PG 5 WC Critical Care Medicine SC General & Internal Medicine GA 151RA UT WOS:000077733400001 PM 9875887 ER PT J AU Susla, GM AF Susla, GM TI Propofol toxicity in critically ill pediatric patients: Show us the proof SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE propofol; pediatric; lactic acidemia; bradyarrhythmia; hypertension; lipemia; oliguria; intensive care; critically ill ID INTENSIVE-CARE; METABOLIC-ACIDOSIS; INFUSION; CHILDREN; SEDATION C1 NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. RP Susla, GM (reprint author), NIH, Ctr Clin, Dept Pharm, 10 Ctr Dr,MSC 1196, Bethesda, MD 20892 USA. NR 15 TC 20 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 1998 VL 26 IS 12 BP 1959 EP 1960 DI 10.1097/00003246-199812000-00019 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 151RA UT WOS:000077733400017 PM 9875903 ER PT J AU McDermott, AM Kern, TS Reid, TW Russell, P Murphy, CJ AF McDermott, AM Kern, TS Reid, TW Russell, P Murphy, CJ TI Effect of substance P, insulin-like growth factor-1 and vasoactive intestinal polypeptide on corneal re-epithelialization in galactosemic rats SO CURRENT EYE RESEARCH LA English DT Article DE cornea; re-epithelialization; galactosemia; substance P; insulin-like growth factor-1; vasoactive intestinal polypeptide ID I IGF-I; RABBIT CORNEA; MESSENGER-RNA; WOUND CLOSURE; DIABETIC RATS; CELL-GROWTH; HUMAN KERATINOCYTES; ENDOTHELIAL-CELLS; PROLIFERATION; RECEPTOR AB Purpose. The purpose of the study was to examine the effect of topical application of substance P (SP), insulin-like growth factor-1 (IGF-1) and vasoactive intestinal polypeptide (VIP) on corneal re-epithelialization in galactosemic rats. Methods. Experimental galactosemia was induced by feeding a diet containing 30% galactose for 4-6 months. The corneal epithelium was debrided bi-laterally by scraping with a blunted scalpel blade. One eye (control) received only a saline solution whilst the other eye received a solution of SP and/or IGF-1 or VIP. A single drop of control or test solution was administered 4 times daily until wound closure. Corneas were stained with fluorescein and videotaped under ultraviolet illumination at regular time intervals after debridement. After digitizing the video image, the wound area was calculated using an image analysis program (NIH Image). Results. Corneal re-epithelialization was significantly delayed in galactosemic compared to normal animals. Rates of healing were 1.3 +/- 0.07 mm(2)/hour and 1.02 +/- 0.02 mm(2)/hour for normal and galactosemic animals, respectively. Topical application of SP in concentrations ranging from 25 pg/ml up to 250 mu g/ml had no significant effect on the rate of corneal re-epithelialization. Similarly, IGF-1 (1 mu g/ml) or VIP (1 mu g/ml) when applied alone did not affect re-epithelialization. Furthermore, resurfacing of the debrided area was not affected by co-application of SP (250 mu g/ml) and IGF-1 or VIP. Conclusions. Independent or combined topical application of SP, VIP or IGF-1 at the concentrations tested, does not modulate corneal epithelial wound healing in rats with galactosemia induced by 30% galactose. C1 Univ Wisconsin, Sch Vet Med, Dept Surg Sci, Madison, WI 53706 USA. Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI 53706 USA. Texas Tech Univ, Dept Ophthalmol & Visual Sci, Lubbock, TX 79409 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Murphy, CJ (reprint author), Univ Wisconsin, Sch Vet Med, Dept Surg Sci, 2015 Linden Dr W, Madison, WI 53706 USA. FU NEI NIH HHS [EY 00300, EY 10841] NR 50 TC 7 Z9 9 U1 0 U2 0 PU AEOLUS PRESS PI BUREN PA PO BOX 740, 4116 ZJ BUREN, NETHERLANDS SN 0271-3683 J9 CURR EYE RES JI Curr. Eye Res. PD DEC PY 1998 VL 17 IS 12 BP 1143 EP 1149 DI 10.1076/ceyr.17.12.1143.5131 PG 7 WC Ophthalmology SC Ophthalmology GA 148ED UT WOS:000077491000006 PM 9872536 ER PT J AU Gonzalez-Fernandez, F Baer, CA Baker, E Okajima, TIL Wiggert, B Braiman, MS Pepperberg, DR AF Gonzalez-Fernandez, F Baer, CA Baker, E Okajima, TIL Wiggert, B Braiman, MS Pepperberg, DR TI Fourth module of Xenopus interphotoreceptor retinoid-binding protein: activity in retinoid transfer between the retinal pigment epithelium and rod photoreceptors SO CURRENT EYE RESEARCH LA English DT Article DE interphotoreceptor retinoid-binding protein (IRBP); retinoid visual cycle; Xenopus laevis; retinal pigment epithelium (RPE) ID RHODOPSIN REGENERATION; FATTY-ACIDS; 4TH REPEAT; IRBP; EXPRESSION; GLYCOPROTEIN; CLONING; MATRIX; ADULT; GENE AB Purpose. Interphotoreceptor retinoid-binding protein (IRBP), an extracellular protein believed to support the exchange of retinoids between the neural retina and retinal pigment epithelium (RPE) in the vertebrate eye, exhibits a modular, i.e., repeat, structure. The present study was undertaken to determine whether an individual module of IRBP has activity in retinoid transfer between the RPE and rod photoreceptors. Methods. The retinoid transfer activity of a recombinant protein corresponding to the fourth module of Xenopus laevis IRBP (X4IRBP) was examined in two ways. First, X4IRBP was tested for its ability to support the regeneration of porphyropsin in detached/reattached Xenopus retina/RPE-eyecups. Following illumination and removal of native IRBP, Xenopus eyecups supplemented with 42 mu M X4IRBP or (as a control) Ringer's solution were incubated in darkness and then analyzed for regenerated porphyropsin. Second, toad (Bufo marinus) RPE-eyecup preparations were used to evaluate X4IRBP's ability to promote the release of 11-cis retinal from the RPE. Results. The regeneration of porphyropsin in X4IRBP-supplemented Xenopus retina/RPE-eyecups (0.45 +/- 0.04 nmol; mean +/- SEM, n = 11) exceeded that in controls (0.13 +/- 0.02 nmol, n = 11). For promoting the release of 11-cis retinal from the toad RPE, 42 mu M X4IRBP was more effective than equimolar bovine serum albumin although considerably less than that of 26 mu M native bovine IRBP. Conclusions. The results indicate a low but significant activity of IRBP's fourth module in reactions relevant to retinoid exchange. C1 Univ Virginia, Hlth Sci Ctr, Dept Ophthalmol, Charlottesville, VA 22908 USA. Univ Virginia, Hlth Sci Ctr, Dept Pathol Neuropathol, Charlottesville, VA 22908 USA. Univ Virginia, Hlth Sci Ctr, Grad Program Neurosci, Charlottesville, VA 22908 USA. Univ Illinois, Coll Med, Dept Ophthalmol & Visual Sci, Chicago, IL USA. NEI, NIH, Bethesda, MD 20892 USA. RP Gonzalez-Fernandez, F (reprint author), Univ Virginia, Hlth Sci Ctr, Dept Ophthalmol, Box 475, Charlottesville, VA 22908 USA. FU NEI NIH HHS [EY05494, EY09412]; NIGMS NIH HHS [GM 07267] NR 44 TC 12 Z9 13 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 0271-3683 J9 CURR EYE RES JI Curr. Eye Res. PD DEC PY 1998 VL 17 IS 12 BP 1150 EP 1157 DI 10.1076/ceyr.17.12.1150.5129 PG 8 WC Ophthalmology SC Ophthalmology GA 148ED UT WOS:000077491000007 PM 9872537 ER PT J AU Panchision, D Hazel, T McKay, R AF Panchision, D Hazel, T McKay, R TI Plasticity and stem cells in the vertebrate nervous system SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID BONE MORPHOGENETIC PROTEIN-4; MAMMALIAN NEURAL CREST; ZONE PROGENITOR CELLS; SUBVENTRICULAR ZONE; GROWTH-FACTOR; XENOPUS-LAEVIS; NEURONS; DIFFERENTIATION; GLIA; MIGRATION AB How and when do vertebrate neural precursor cells choose their fates? While some studies suggest a series of commitments on the road to fate choice, many recent experiments indicate that precursor fate choices can often be changed. Additionally, the identification of common gene control mechanisms in precursors suggest that these cells share fundamental properties throughout development. C1 NINDS, Mol Biol Lab, Bethesda, MD 20892 USA. RP Panchision, D (reprint author), NINDS, Mol Biol Lab, 36 Convent Dr,MSC 4092, Bethesda, MD 20892 USA. NR 75 TC 22 Z9 23 U1 0 U2 0 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LE, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 1998 VL 10 IS 6 BP 727 EP 733 DI 10.1016/S0955-0674(98)80114-2 PG 7 WC Cell Biology SC Cell Biology GA 146XL UT WOS:000077458500008 PM 9914183 ER PT J AU Blum, A Cannon, RO AF Blum, A Cannon, RO TI Effects of oestrogens and selective oestrogen receptor modulators on serum lipoproteins and vascular function SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review ID ESTROGEN REPLACEMENT THERAPY; CORONARY-ARTERY DISEASE; INDUCED MYOCARDIAL-ISCHEMIA; POSTMENOPAUSAL WOMEN; NITRIC-OXIDE; ENDOTHELIAL-CELLS; HORMONE-REPLACEMENT; PLASMINOGEN-ACTIVATOR; OVARIECTOMIZED RATS; HEART-DISEASE AB Epidemiological observations, clinical studies, and basic laboratory research suggest that oestrogen replacement therapy is associated with beneficial cardiovascular effects in postmenopausal women. Oestrogen has a multitude of biological effects that may account for this apparent benefit (which remain to be proven in randomized clinical trials), including favourable effects on the lipid profile, a direct effect on the vascular endothelium with increased nitric oxide bioactivity, and improved fibrinolysis, However, long-term oestrogen therapy increases the risk of breast and endometrial cancers. Raloxifene, a benzothiophene derivative that binds to the oestrogen receptor, is a selective oestrogen receptor modulator, producing oestrogen-agonistic effects in some tissues (liver, bone), and oestrogen-antagonistic effects in others (breast, uterus), and may prove to be an option for women with atherosclerosis and its associated risk factors who might benefit from oestrogen therapy. This review updates the current knowledge of the biological effects of oestrogen and selective oestrogen receptor modulators of potential cardiovascular importance in postmenopausal women. Curr Opin Lipidol 9:575-586. (C) 1998 Lippincott Williams & Wilkins. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NHLBI, NIH, Bldg 10,Room 7B15,10 Ctr Dr,MSC-1650, Bethesda, MD 20892 USA. EM cannonr@gwgate.nhlbi.nih.gov NR 96 TC 36 Z9 37 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-9672 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD DEC PY 1998 VL 9 IS 6 BP 575 EP 586 DI 10.1097/00041433-199812000-00010 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 149NG UT WOS:000077611100010 PM 9868594 ER PT J AU Caminiti, R Ferraina, S Mayer, AB AF Caminiti, R Ferraina, S Mayer, AB TI Visuomotor transformations: early cortical mechanisms of reaching SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID POSTERIOR PARIETAL CORTEX; PRIMATE MOTOR CORTEX; DIFFERENT ARM ORIENTATIONS; SIMILAR HAND PATHS; PREMOTOR CORTEX; MACAQUE MONKEY; 3-DIMENSIONAL SPACE; DIFFERENT PARTS; VISUAL TARGETS; INDIVIDUAL CELLS AB Recent studies of visually guided reaching in monkeys support the hypothesis that the visuomotor transformations underlying arm movements to spatial targets involve a parallel mechanism that simultaneously engages functionally related frontal and parietal areas linked by reciprocal cortico-cortical connections. The neurons in these areas possess similar combinations of response properties. The multimodal combinatorial properties of these neurons and the gradient architecture of the parieto-frontal network emerge as a potential substrate to link the different sensory and motor signals that arise during reaching behavior into common hybrid reference frames. This convergent combinatorial process is evident at early stages of visual information processing in the occipito-parietal cortex, suggesting the existence of re-entrant motor influences on cortical areas once believed to have only visual functions. C1 Univ Rome La Sapienza, Ist Fisiol Umana, I-00185 Rome, Italy. NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Dept Vet Affairs Med Ctr, Brain Sci Ctr, Minneapolis, MN 55417 USA. RP Caminiti, R (reprint author), Univ Rome La Sapienza, Ist Fisiol Umana, Piazzale Aldo Moro 5, I-00185 Rome, Italy. EM caminitir@axrma.uniroma1.it; sf@lsr.nei.nih.gov; mayer025@tc.umn.edu RI Battaglia-Mayer, Alexandra/B-3749-2010 NR 71 TC 96 Z9 96 U1 2 U2 9 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LE, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD DEC PY 1998 VL 8 IS 6 BP 753 EP 761 DI 10.1016/S0959-4388(98)80118-9 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 151TR UT WOS:000077737200011 PM 9914239 ER PT J AU Hurley, JH AF Hurley, JH TI The adenylyl and guanylyl cyclase superfamily SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Article ID CALMODULIN-BINDING DOMAIN; CYTOSOLIC DOMAINS; CATALYTIC MECHANISM; FORSKOLIN; INHIBITION; G(S-ALPHA); SITE; FORM; CORE; ATP AB New structures solved in 1997 revealed that the adenylyl cyclase core consists of a pair of catalytic domains arranged in a wreath. Homologous catalytic domains are arranged in diverse adenylyl and guanylyl cyclases as symmetric homodimers or pseudosymmetric heterodimers. The kinship of the adenylyl and guanylyl cyclases has been confirmed by the structure-based interconversion of their nucleotide specificities. Catalysis is activated when two metal-binding aspartate residues on one domain are juxtaposed with a key aspargine-arginine pair on the other. Allosteric activators of mammalian adenylyl cyclase, forskolin and the stimulatory G protein alpha subunit, promote the catalytically optimal juxtaposition of the two domains. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NR 41 TC 61 Z9 64 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 34-42 CLEVELAND STREET, LONDON W1P 6LE, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD DEC PY 1998 VL 8 IS 6 BP 770 EP 777 DI 10.1016/S0959-440X(98)80097-3 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 149PN UT WOS:000077614300014 PM 9914257 ER PT J AU Steingrimsson, E Tessarollo, L Reid, SW Jenkins, NA Copeland, NG AF Steingrimsson, E Tessarollo, L Reid, SW Jenkins, NA Copeland, NG TI The bHLH-Zip transcription factor Tfeb is essential for placental vascularization SO DEVELOPMENT LA English DT Article DE Tfeb transcription factor; gene targeting; placenta; vascularization ID ENDOTHELIAL GROWTH-FACTOR; LOOP-HELIX PROTEIN; TYROSINE KINASE; EMBRYONIC LETHALITY; MOUSE; GENE; MAX; CELLS; MICE; MYC AB Tfcb is a member of the basic Helix-Loop-Helix-Zipper family of transcription factors. In vitro studies have shown that TFEB can bind DNA as a homodimer or as a heterodimer with three closely related family members: MITF, TFE3 and TFEC. While mutations of Mitf have been shown to affect the development of a number of cell types including melanocytes, osteoclasts, and masts cells, little is known about the phenotypic consequences of mutations at Tfe3, Tfcb and Tfec, Here we show that mice with a targeted disruption of Tfeb die between 9.5 and 10.5 days in embryonic development and have severe defects in placental vascularization, Tfeb is expressed at low levels in the embryo but at high levels in the labyrinthine trophoblast cells of the placenta. While labyrinthine cells are present in the mutant Tfeb placenta, they fail to express VEGF, a potent mitogen required for normal vasculogenesis of the embryo and extraembryonic tissues. In Tfeb mutant embryos the embryonic vasculature forms normally but few vessels are seen entering the placenta and those that do enter fail to thrive and branch normally. Our results indicate that Tfeb plays a critical role in the signal transduction processes required for normal vascularization of the placenta. C1 NCI, Mammalian Genet Lab, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Neural Dev Grp, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Steingrimsson, E (reprint author), Univ Iceland, Fac Med, Dept Biochem & Mol Biol, IS-101 Reykjavik, Iceland. EM eirikurs@rhi.hi.is NR 43 TC 91 Z9 94 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL SN 0950-1991 J9 DEVELOPMENT JI Development PD DEC PY 1998 VL 125 IS 23 BP 4607 EP 4616 PG 10 WC Developmental Biology SC Developmental Biology GA 151VW UT WOS:000077742200003 PM 9806910 ER PT J AU Takuma, N Sheng, HZ Furuta, Y Ward, JM Sharma, K Hogan, BLM Pfaff, SL Westphal, H Kimura, S Mahon, KA AF Takuma, N Sheng, HZ Furuta, Y Ward, JM Sharma, K Hogan, BLM Pfaff, SL Westphal, H Kimura, S Mahon, KA TI Formation of Rathke's pouch requires dual induction from the diencephalon SO DEVELOPMENT LA English DT Article DE Rathke's pouch; pituitary morphogenesis; induction; diencephalon; homeobox gene; Bmp4; T/ebp; Nkx2.1; Fgf8; Lhx3; Isl1 ID BONE-MORPHOGENETIC PROTEIN-4; TRANSCRIPTION FACTOR GENE; ANTERIOR NEURAL PLATE; HOMEODOMAIN FACTOR; RAT ADENOHYPOPHYSIS; PITUITARY-GLAND; HOMEOBOX GENES; MOUSE; LIM; FAMILY AB Targeted disruption of the homeobox gene T/ebp (Nkx2.1, Ttf1, TitfI) in mice results in ablation of the pituitary, Paradoxically, while T/ebp is expressed in the ventral diencephalon during forebrain formation, it is not expressed in Rathke's pouch or in the pituitary gland at any time of embryogenesis. Examination of pituitary development in the T/ebp homozygous null mutant embryos revealed that a pouch rudiment is initially formed but is eliminated by programmed cell death before formation of a definitive pouch. In the diencephalon of the mutant, Bmp4 expression is maintained, whereas Fgf8 expression is not detectable. These data and additional genetic and molecular observations suggest that Rathke's pouch develops in a two-step process that requires at least two sequential inductive signals from the diencephalon. First, BMP4 is required for induction and formation of the pouch rudiment, a role confirmed by analysis of Bmp4 homozygous null mutant embryos. Second, FGF8 is necessary for activation of the key regulatory gene Lhx3 and subsequent development of the pouch rudiment into a definitive pouch. This study provides firm molecular genetic evidence that morphogenesis of the pituitary primordium is induced in vivo by signals from the adjacent diencephalon. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NCI, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Med Ctr, Howard Hughes Med Inst, Nashville, TN 37232 USA. NCI, Vet & Tumor Pathol Sect, Frederick, MD 21702 USA. Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NR 40 TC 201 Z9 203 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL SN 0950-1991 J9 DEVELOPMENT JI Development PD DEC PY 1998 VL 125 IS 23 BP 4835 EP 4840 PG 6 WC Developmental Biology SC Developmental Biology GA 151VW UT WOS:000077742200024 PM 9806931 ER PT J AU Choo, D Sanne, JL Wu, DK AF Choo, D Sanne, JL Wu, DK TI The differential sensitivities of inner ear structures to retinoic acid during development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE chick embryo; inner ear; retinoic acid; perturbation; dose-dependent; sensory organ; BMP4; SOHo-1; Msx-1 ID MUTATIONS AFFECTING DEVELOPMENT; SEMICIRCULAR CANAL FORMATION; HOX GENES; LIMB-BUD; EXPRESSION; ZEBRAFISH; CHICKEN; INDUCTION; IDENTITY; PATTERN AB In order to examine the mechanisms that underlie development of the inner ear, the normal processes were perturbed using all-trans-retinoic acid (RA). By implanting a resin exchange bead saturated with RA into stage 16 (Hamburger and Hamilton, 1951, J. Morphol. 88, 49-92) embryonic day 2.5 chick ears, it was possible to analyze its in vivo effects on inner ear development. There is a temporal window during which the developing chick inner ear is particularly susceptible to the effects of RA (stages 16-19). This RA period of sensitivity precedes evidence of gross morphologic or histologic differentiation by at least 24 h, suggesting that mechanisms controlling formation of key inner ear structures are already in progress. There is a dose dependence on RA, with increasing doses of RA generating increasingly severe phenotypic abnormalities. Data indicate that these effects are due to differential sensitivities of the various inner ear structures to RA during their formation. In general, the vestibular structures were more susceptible to RA effects than the cochlear duct. Furthermore, nonsensory structures such as semicircular canals seemed to display a greater susceptibility to RA than their associated sensory structures (i.e., cristae). Among the three semicircular canals, the superior canal was the most susceptible to RA treatment, whereas the common crus was particularly resistant, suggesting that the molecular mechanisms for each structure's formation are different. The defect in semicircular canal formation is due to problems in the initial outgrowth of the canal plate which in turn is related to a down-regulation of early otocyst cell proliferation. This perturbation model provides valuable insight into the processes involved in producing the intricate patterning of the inner ear. C1 NIDCD, Mol Biol Lab, NIH, Rockville, MD 20850 USA. RP Wu, DK (reprint author), NIDCD, Mol Biol Lab, NIH, 5 Res Court,Room 2B34, Rockville, MD 20850 USA. EM wud@nidcd.nih.gov NR 38 TC 31 Z9 31 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 DEC 1 PY 1998 VL 204 IS 1 BP 136 EP 150 DI 10.1006/dbio.1998.9095 PG 15 WC Developmental Biology SC Developmental Biology GA 148WJ UT WOS:000077556600011 PM 9851848 ER PT J AU Pellegrini, M Pilia, G Pantano, S Lucchini, F Uda, M Fumi, M Cao, A Schlessinger, D Forabosco, A AF Pellegrini, M Pilia, G Pantano, S Lucchini, F Uda, M Fumi, M Cao, A Schlessinger, D Forabosco, A TI Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome SO DEVELOPMENTAL DYNAMICS LA English DT Article DE glypican-3; Gpc3; glypican-related integral membrane heparan sulfate proteoglycans; mouse; in situ hybridization; gene expression; Simpson-Golabi-Behmel syndrome ID II GENE-EXPRESSION; MANNOSE 6-PHOSPHATE RECEPTORS; IGF-II; MESSENGER-RNA; GROWTH-FACTORS; MOUSE EMBRYOGENESIS; DEVELOPING RAT; PATTERN; LOCALIZATION; OVERGROWTH AB Interest in glypican-3 (GPC3), a member of the glypican-related integral membrane heparan sulfate proteoglycans (GRIPS) family, has increased with the finding that it is mutated in the Simpson-Golabi-Behmel overgrowth syndrome (Pilia et al. [1996] Nat. Genet. 12:241-247). The working model suggested that the membrane-bound protein acts locally to limit tissue and organ growth and that it may function by interacting with insulin-like growth factor 2 (IGFS) to limit its local effective level. Here we have tested two predictions of the model. In situ hybridization with the mouse gene cDNA was used to study the expression pattern during embryonic and fetal development. In agreement with predictions, the gene is expressed in precisely the organs that overgrow in its absence; and the patterns of expression of Gpc3 and those reported for Igf2 are strictly correlated. Dev. Dyn. 1998;213:431-439. (C) 1998 Wiley-Liss, Inc. C1 Univ Modena, Dipartimento Sci Morfol & Med Legali, Sez Istol Embriol & Genet, I-41100 Modena, Italy. CNR, Ist Ric Talassemi & Anemie Mediterranee, Cagliari, Italy. Univ Cagliari, Ist Clin & Biol Eta Evolut, I-09124 Cagliari, Italy. Univ Cattolica Sacro Cuore, Ctr Ric Biotechnol, Cremona, Italy. NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Pellegrini, M (reprint author), Univ Modena, Dipartimento Sci Morfol & Med Legali, Sez Istol Embriol & Genet, Via Pozzo 71, I-41100 Modena, Italy. RI Pellegrini, Massimo/P-6359-2016; OI Pellegrini, Massimo/0000-0002-0091-0077; Lucchini, Franco/0000-0003-0280-7062 FU Telethon [E.0357] NR 29 TC 72 Z9 72 U1 2 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD DEC PY 1998 VL 213 IS 4 BP 431 EP 439 DI 10.1002/(SICI)1097-0177(199812)213:4<431::AID-AJA8>3.0.CO;2-7 PG 9 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 148CE UT WOS:000077534500008 PM 9853964 ER PT J AU Chai, Y Bringas, P Mogharei, A Shuler, CF Slavkin, HC AF Chai, Y Bringas, P Mogharei, A Shuler, CF Slavkin, HC TI PDGF-A and PDGFR-alpha regulate tooth formation via autocrine mechanism during mandibular morphogenesis in vitro SO DEVELOPMENTAL DYNAMICS LA English DT Article DE PDGF-A; PDGFR-alpha; mouse tooth development; in vitro organ culture ID GROWTH-FACTOR RECEPTOR; DIFFERENT DIMERIC FORMS; TISSUE INTERACTIONS; DEVELOPMENTAL EXPRESSION; DIFFERENT ISOFORMS; MECKELS CARTILAGE; HUMAN-PLATELETS; DEFICIENT MICE; HOMEOBOX GENE; MOUSE EMBRYO AB Platelet-derived growth factor A (PDGF-A) binding to the PDGF receptor alpha (PDGFR-alpha) mediates signal transduction processes related to DNA synthesis, cell migrations, cytodifferentiation, and wound healing. Recent studies indicate that PDGFR-alpha functions during cranial neural crest cell migrations and first branchial arch morphogenesis (Stephenson et al. [1991] Proc, Natl, Acad, Sci. USA 88:6-10; Morrison-Graham ct al, [1992] Development 115:133-142; Hu et al. [1995] Int. J. Dev. Biol. 39:939-945; Soriano [1997] Development 124:2691-2700). The present studies were designed to test the hypothesis that PDGF-A, interacts with its cognate receptor PDGFR-alpha via an autocrine mechanism that regulates the timing, rates, and size of embryonic mouse tooth morphogenesis. Both PDGF-A and PDGFR-alpha transcripts were coordinately expressed in mandibular prominences prior to and during tooth formation using reverse transcriptase-polymerase chain reaction (RT-PCR). During the dental lamina stage, ligand and receptor were present in both enamel organ epithelium and adjacent mesenchymal cells. During the bud stage, ligand and receptor were localized mainly to the enamel organ epithelium. Exogenous PDGF-A at 20 ng/ml enhanced tooth development to reach the cap stage with increased tooth size (P < 0.05) using embryonic day (E)10 mandibular explants cultured in serumless, chemically defined medium. A significant increase in DNA synthesis was observed within enamel organ epithelium at E10+4 when the mandibular explants were treated with PDGF-A at 20 ng/ml, These data suggest that PDGF-A and its cognate receptor (PDGFR-alpha) regulate the size and stage of tooth development via an autocrine mechanism during odontogenesis in vitro. Dev. Dyn. 1998;213:500-511. (C) 1998 Wiley-Liss, Inc. C1 Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. NIAMSD, Craniofacial Dev Sect, NIH, Bethesda, MD 20892 USA. RP Chai, Y (reprint author), Univ So Calif, Sch Dent, Ctr Craniofacial Mol Biol, Hlth Sci Campus,2250 Alcazar St,CSA 103, Los Angeles, CA 90033 USA. EM ychai@zygote.hsc.usc.edu FU NIDCR NIH HHS [DE-09165] NR 56 TC 17 Z9 18 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD DEC PY 1998 VL 213 IS 4 BP 500 EP 511 DI 10.1002/(SICI)1097-0177(199812)213:4<500::AID-AJA14>3.0.CO;2-A PG 12 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 148CE UT WOS:000077534500014 PM 9853970 ER PT J AU Liao, DP Sloan, RP Cascio, WE Folsom, AR Liese, AD Evans, GW Cai, JW Sharrett, AR AF Liao, DP Sloan, RP Cascio, WE Folsom, AR Liese, AD Evans, GW Cai, JW Sharrett, AR TI Multiple metabolic syndrome is associated with lower heart rate variability - The atherosclerosis risk in communities study SO DIABETES CARE LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CARDIAC AUTONOMIC FUNCTION; INSULIN-RESISTANCE; SPECTRAL-ANALYSIS; DISEASE; HYPERTENSION; MORTALITY; HYPERINSULINEMIA; HUMANS; SYSTEM AB OBJECTIVE - To test at the population level whether people with multiple metabolic syndrome (MMS) disorders have reduced cardiac autonomic activity (CAA). RESEARCH DESIGN AND METHODS - We examined the association between the level of CAA and MMS disorders, at the degree of clustering and the segregate combination levels, using a random sample of 2,359 men and women aged 45-64 years from the biracial, population-based Atherosclerosis Risk in Communities (ARIC) Study. Supine resting 2-min beat-to-beat heart rate data were collected. High-frequency (HF) (0.15-0.35 Hz) and low-frequency (LF) (0.025-0.15 Hz) spectral powers, the ratio of LF to HF; and the SD of all normal R-R intervals (SDNN) were used as the conventional indices of heart rate variability (HRV) to measure CAA. The MMS disorders included hypertension, type 2 diabetes, and dyslipidemia. RESULTS - HRV indices were significantly lower in individuals with MMS disorders. The multivariable adjusted mean HF was 0.85 (beat/min)(2) in subjects with all three MMS disorders, in contrast to 1.31 (beat/min)(2) in subjects without any MMS disorder. At the segregated combination level, the multivariable adjusted means +/- SEM of HF were 1.34 +/- 0.05, 1.16 +/- 0.05, 1.01 +/- 0.17, and 1.34 +/- 0.05 (beat/min)(2), respectively, for subjects without any MMS disorder, with hypertension only, with diabetes only, and with dyslipidemia only, and the means +/- SEM of HF were 0.93 +/- 0.04, 0.70 +/- 0.15, and 1.20 +/- 0.05 (beat/min)(2), respectively, for subjects with diabetes and hypertension, diabetes and dyslipidemia, and hypertension and dyslipidemia. An increase in fasting insulin of 1 SD was associated with 88% higher odds of having a lower HF: The pattern of associations was similar for LF and SDNN. CONCLUSIONS - These findings suggest that MMS disorders adversely affect cardiac autonomic control and a reduced cardiac autonomic control may contribute to the increased risk of subsequent cardiovascular events in individuals who exhibit MMS disorders. C1 Penn State Med Coll, Dept Hlth Evaluat Sci, Hershey, PA 17033 USA. Univ N Carolina, Sch Med, Div Cardiol, Chapel Hill, NC USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10025 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Munster, Inst Epidemiol & Social Med, D-4400 Munster, Germany. RP Liao, DP (reprint author), Penn State Med Coll, Dept Hlth Evaluat Sci, H173,500 Univ Dr, Hershey, PA 17033 USA. EM dliao@psu.edu FU NHLBI NIH HHS [5-R01-HL55669, N01-HC-55015, N01-HC-55016] NR 37 TC 129 Z9 131 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD DEC PY 1998 VL 21 IS 12 BP 2116 EP 2122 DI 10.2337/diacare.21.12.2116 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 141UP UT WOS:000077162900012 PM 9839103 ER PT J AU Harris, MI AF Harris, MI TI Diabetes in America: Epidemiology and scope of the problem SO DIABETES CARE LA English DT Article; Proceedings Paper CT Workshop on the Worldwide Burden of Diabetes CY DEC 06-07, 1996 CL PHOENIX, ARIZONA SP Amylin Pharmaceut Inc ID DISEASE; HYPERGLYCEMIA; RISK; CARE AB Epidemiological studies performed over the past 40 years have shown that the prevalence of diagnosed diabetes has increased dramatically in the U.S. and that a substantial proportion of the population has undiagnosed diabetes, impaired fasting glucose, and impaired glucose tolerance. Diabetes is most prevalent in minority populations, such as African-Americans, Native Americans, and Mexican Americans. Increasing prevalence of diabetes has led to increases in microvascular complications such as blindness, end-stage renal disease, and lower limb amputations. Poor glycemic control contributes to the high incidence of these complications, yet community-based studies of diabetic patients show their mean fasting plasma glucose concentration is generally >180 mg/dl compared with 100 mg/dl for nondiabetic individuals. In people with diabetes, risk factors for cardiovascular disease including elevated fasting plasma glucose, blood pressure, total cholesterol, triglycerides, and obesity partly explain the high proportion of deaths (60-70%) caused by cardiovascular disease in people with diabetes. More intensive diabetes management and improved glycemic control could minimize long-term complications of the disease and would be expected to reduce the morbidity, mortality, and costs associated with diabetes. C1 NIDDKD, Bethesda, MD 20892 USA. RP Harris, MI (reprint author), NIDDK, NIH, Bldg 45,Room 5AN24, Bethesda, MD 20892 USA. NR 17 TC 217 Z9 223 U1 0 U2 9 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD DEC PY 1998 VL 21 SU 3 BP C11 EP C14 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 143MT UT WOS:000077260000004 PM 9850480 ER PT J AU Herman, WH Eastman, RC AF Herman, WH Eastman, RC TI The effects of treatment on the direct costs of diabetes SO DIABETES CARE LA English DT Article; Proceedings Paper CT Workshop on the Worldwide Burden of Diabetes CY DEC 06-07, 1996 CL PHOENIX, ARIZONA SP Amylin Pharmaceut Inc ID MELLITUS; POPULATION; ROCHESTER; MINNESOTA AB Treatment of diabetic complications consumes health care resources. Intensive therapy was shown by the Diabetes Control and Complications Trial (DCCT) to avert complications. Economic analyses and models have been used to evaluate the cost-effectiveness of intensive therapy for people with type 1 and type 2 diabetes. An economic analysis of the DCCT estimated the cost of intensive therapy to be two to three times greater than that of conventional therapy In contrast, an economic model predicts that intensive therapy as compared with conventional therapy, could reduce blindness from 34 to 20% or by 41%, end-stage renal disease from 24 to 7% or by 71%, and lower-extremity amputations from 7 to 4% or by 43%. Although intensive therapy is more expensive, when the costs of complications are factored in, it becomes cost-effective for treatment of type 1 diabetes. Similarly, a model to evaluate the cost-effectiveness of intensive therapy for people with type 2 diabetes found that the lifetime costs of general and diabetes-related medical care would be approximately two times greater However, the reduction in lifetime costs of complications, which would produce substantial reductions in costs of treatment, largely offsets the difference. Intensive therapy for type 1 and type 2 diabetes may be more expensive than conventional therapy, but from an economic perspective, it is comparable in cost to pharmacological therapies for people with hypertension and hypercholesterolemia. From a health system viewpoint, intensive therapy represents a fruitful long-term financial investment. C1 Univ Michigan, Med Ctr, Ann Arbor, MI 48109 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Herman, WH (reprint author), Univ Michigan, Med Ctr, 3920 Taubman Ctr,Box 0354, Ann Arbor, MI 48109 USA. NR 16 TC 55 Z9 56 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1660 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD DEC PY 1998 VL 21 SU 3 BP C19 EP C24 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 143MT UT WOS:000077260000006 PM 9850482 ER PT J AU Varmus, H Henney, JE AF Varmus, H Henney, JE TI Abstracts of the NIH-FDA Conference "Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications" - Foreword SO DISEASE MARKERS LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. US FDA, Rockville, MD 20857 USA. RP Varmus, H (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU IOS PRESS PI AMSTERDAM PA VAN DIEMENSTRAAT 94, 1013 CN AMSTERDAM, NETHERLANDS SN 0278-0240 J9 DIS MARKERS JI Dis. Markers PD DEC PY 1998 VL 14 IS 4 BP 188 EP 188 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental; Pathology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine; Pathology GA 220PE UT WOS:000081673700001 ER PT J AU Gonzalez, FJ Fernandez-Salguero, P AF Gonzalez, FJ Fernandez-Salguero, P TI The aryl hydrocarbon receptor - Studies using the AHR-null mice SO DRUG METABOLISM AND DISPOSITION LA English DT Article; Proceedings Paper CT Colloquium in Honor of Anthony Y H Lu on Drug Metabolism in the New Millennium CY APR 18, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Pharmacol & Exptl Therapeut ID NUCLEAR TRANSLOCATOR ARNT; RETINOIC ACID; DEFICIENT MICE; CLEFT-PALATE; CDNA CLONING; GROWTH; EXPRESSION; TCDD; BINDING; LACKING AB The aryl hydrocarbon receptor (AHR) is believed to mediate the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), polychlorinated biphenyls, and polycyclic aromatic hydrocarbons. AHR is a member of the Per, ARNT, Sim/basic-helix-loop-helix superfamily of ligand-activated transcription factors that also harbors the transcription factors involved in the hypoxia response, development of the central nervous system, and day-night adaptations. To investigate the role of AHR in chemical toxicity and carcinogenesis and to determine any possible function in mammalian development and physiological homeostasis, AHR-null mice were developed, The AHR-null mice were resistant to the acute toxicity of TCDD and had an altered teratogenic response to this compound. These mice were found to have a number of abnormal phenotypes, thus confirming that AHR plays an important developmental and physiological role. Among the most consistent phenotypes was an altered liver pathology that was associated with accelerated rates of apoptosis. Evidence suggests that this may be related to an abnormal accumulation of levels of hepatic retinoic acid that cause an activation of transforming growth factor beta, resulting in stimulation of apoptosis, AHR may directly or indirectly control levels of a cytochrome P450 that is responsible for catabolizing retinoic acid. C1 NCI, Div Basic Sci, Bethesda, MD 20892 USA. Univ Extremadura, Fac Ciencias, Dept Bioquim & Biol Mol, E-06071 Badajoz, Spain. RP Gonzalez, FJ (reprint author), NCI, Div Basic Sci, Bldg 37,Room 3E-24, Bethesda, MD 20892 USA. OI Fernandez-Salguero, Pedro M./0000-0003-2839-5027 NR 41 TC 235 Z9 243 U1 0 U2 6 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD DEC PY 1998 VL 26 IS 12 BP 1194 EP 1198 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 150WV UT WOS:000077689700008 PM 9860927 ER PT J AU Halpert, JR Domanski, TL Adali, O Biagini, CP Cosme, J Dierks, EA Johnson, EF Jones, JP de Montellano, PO Philpot, RM Sibbesen, O Wyatt, WK Zheng, ZP AF Halpert, JR Domanski, TL Adali, O Biagini, CP Cosme, J Dierks, EA Johnson, EF Jones, JP de Montellano, PO Philpot, RM Sibbesen, O Wyatt, WK Zheng, ZP TI Structure-function of cytochromes P450 and flavin-containing monooxygenases - Implications for drug metabolism SO DRUG METABOLISM AND DISPOSITION LA English DT Article; Proceedings Paper CT Colloquium in Honor of Anthony Y H Lu on Drug Metabolism in the New Millennium CY APR 18, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Pharmacol & Exptl Therapeut ID SITE-DIRECTED MUTAGENESIS; TRYPANOTHIONE REDUCTASE; SUBSTRATE-SPECIFICITY; GLUTATHIONE-REDUCTASE; CATALYTIC MECHANISM; PRIMARY ALKYLAMINES; ESCHERICHIA-COLI; AMINO-ACID; PROTEIN; BINDING AB This article is a report on a symposium held at Experimental Biology '98 in San Francisco, California. Recent developments in site-directed mutagenesis, computer-modeling, and mechanistic analysis of cytochromes P450 and flavin-containing monooxygenases are described. A unifying theme is the elaboration of general approaches for understanding and predicting the function of individual forms of these enzymes. A related goal is the production of soluble forms of mammalian cytochromes P450 for X-ray crystallography. C1 Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA. Scripps Res Inst, Dept Mol & Expt Med NX4, La Jolla, CA 92037 USA. Washington State Univ, Dept Chem, Pullman, WA 99164 USA. Univ Calif San Francisco, Sch Pharm, Dept Chem & Pharmacol, San Francisco, CA 94143 USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC USA. RP Halpert, JR (reprint author), Univ Texas, Med Branch, Dept Pharmacol & Toxicol, 301 Univ Blvd, Galveston, TX 77555 USA. EM jhalpert@utmb.edu FU NIGMS NIH HHS [GM25515, GM31001, GM54995] NR 69 TC 18 Z9 19 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD DEC PY 1998 VL 26 IS 12 BP 1223 EP 1231 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 150WV UT WOS:000077689700014 PM 9860932 ER PT J AU Morgan, ET Sewer, MB Iber, H Gonzalez, FJ Lee, YH Tukey, RH Okino, S Vu, T Chen, YH Sidhu, JS Omiecinski, CJ AF Morgan, ET Sewer, MB Iber, H Gonzalez, FJ Lee, YH Tukey, RH Okino, S Vu, T Chen, YH Sidhu, JS Omiecinski, CJ TI Physiological and pathophysiological regulation of cytochrome P450 SO DRUG METABOLISM AND DISPOSITION LA English DT Article; Proceedings Paper CT Colloquium in Honor of Anthony Y H Lu on Drug Metabolism in the New Millennium CY APR 18, 1998 CL SAN FRANCISCO, CALIFORNIA SP Amer Soc Pharmacol & Exptl Therapeut ID PROTEIN-KINASE-C; ARYL-HYDROCARBON RECEPTOR; TISSUE-SPECIFIC EXPRESSION; RAT HEPATOCYTE CULTURES; DIOXIN RECEPTOR; GENE-EXPRESSION; NITRIC-OXIDE; TRANSCRIPTIONAL ACTIVATION; PHENOBARBITAL INDUCTION; CYP1A1 GENE AB This article is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the April 1998 Experimental Biology '98 meeting in San Francisco. The presentations focused on the mechanisms of regulation of cytochrome P450 gene expression by developmental factors and by hormones and cytokines, as well as on the interplay between physiological and chemical regulation. Approaches and systems used to address these questions included conditional gene knockouts in mice, primary hepatocyte cultures, immunofluorescence imaging of cells, and cell lines stably expressing reporter gene constructs. C1 Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Pharmacol, San Diego, CA 92103 USA. Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. RP Morgan, ET (reprint author), Emory Univ, Sch Med, Dept Pharmacol, Atlanta, GA 30322 USA. OI Morgan, Edward/0000-0003-4273-2261 FU NIDDK NIH HHS [T32DK07298]; NIGMS NIH HHS [GM46897, GM53093, R01 GM032281] NR 78 TC 56 Z9 59 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD DEC PY 1998 VL 26 IS 12 BP 1232 EP 1240 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 150WV UT WOS:000077689700015 PM 9860933 ER PT J AU Chen, N Chrambach, A AF Chen, N Chrambach, A TI Preparative application of commercial automated gel electrophoresis apparatus to subcellular-sized particles: Sequential isolations, fractions re-run, sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, yield and purity SO ELECTROPHORESIS LA English DT Article DE microsome; subcellular-sized particle; particle sieving; resolution; sieving media; agarose; laterally aggregated polyacrylamide; electroelution; yield; purity ID POLYMER-SOLUTION; FIELD-STRENGTH; PROTEIN; SEPARATION; BUFFER; SYSTEM AB The analytical and preparative potential of automated gel electrophoresis apparatus with intermittent fluorescence scanning of the mi,oration path, the HPGE-1000 apparatus (LabIntelligence, Belmont, CA) was further developed in application to subcellular-sized particles. Resolution between two rat liver microsome components in agarose (MetaPhor) gel electrophoresis was found to increase with decreasing agarose concentration to 0.04%. It was less, even in an agarose solution at that low concentration, than that in laterally aggregated 4% polyacrylamide gel. The three components of the microsomal preparation were sequentially isolated from 0.6 and 0.8% agarose gel electropherograms. One fraction when reelectrophoresed was found to exhibit the original mobility and did not give rise to the other components. Yields of each component were near-quantitative after one or two electroelution steps. Based on protein content, no impurities could be detected in two of the microsome fractions; the third fraction contained 2% of nonmicrosome impurity. Sodium dodecyl sulfate-polyacrylamide gel electrophore sis (SDS-PAGE) patterns of all three microsome fractions were indistinguishable from one another and from that of the unfractionated microsome preparation. C1 NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), NICHHD, Macromol Anal Sect, Lab Cellular & Mol Biophys, NIH, Bldg 10,Rm 9D50, Bethesda, MD 20892 USA. EM ACC@CU.NIH.GOV NR 20 TC 4 Z9 4 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI BERLIN PA MUHLENSTRASSE 33-34, D-13187 BERLIN, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD DEC PY 1998 VL 19 IS 18 BP 3096 EP 3102 DI 10.1002/elps.1150191810 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 159ZA UT WOS:000078204800009 PM 9932801 ER PT J AU Hock, R Wilde, F Scheer, U Bustin, M AF Hock, R Wilde, F Scheer, U Bustin, M TI Dynamic relocation of chromosomal protein HMG-17 in the nucleus is dependent on transcriptional activity SO EMBO JOURNAL LA English DT Article DE chromatin; chromosomal proteins; HMG-proteins; interchromatin granules; transcription ID RNA-POLYMERASE-II; MOBILITY GROUP PROTEIN-14; CHROMATIN STRUCTURE; HISTONE ACETYLATION; GENE-EXPRESSION; NUCLEOSOMES; CELLS; ORGANIZATION; ACTIVATION; INHIBITION AB Chromosomal proteins HMG-14/-17 are nucleosomal binding proteins, which alter the structure of the chromatin fiber and enhance transcription, but only from chromatin templates. Here we show that in tissue culture cells, HMG-17 protein colocalizes with sites of active transcription. Incubation of permeabilized cells with a peptide corresponding to the nucleosomal binding domains of HMG-14/-17 specifically arrested polymerase II-dependent transcription. In these cells the peptide displaces HMG-17 from chromatin and reduces the cellular content of the protein. These results suggest that the presence of HMG-14/-17 in chromatin is required for efficient polymerase II transcription. In non-permeabilized, actively transcribing cells, the protein is dispersed in a punctate pattern, throughout the nucleus. Upon transcriptional inhibition by a-amanitin or actinomycin D, the protein gradually redistributes until it localizes fully to interchromatin granule clusters, together with the splicing factor SC35, The results suggest that the association of HMG-17 with chromatin is dynamic rather than static, and that in the absence of transcription, HMG-17 is released from chromatin and accumulates in interchromatin granule clusters. Thus, the intranuclear distribution of chromosomal proteins which act as architectural elements of chromatin structure may be dynamic and functionally related to the transcriptional activity of the cell. C1 Univ Wurzburg, Dept Cell & Dev Biol, Bioctr, D-97074 Wuerzburg, Germany. NCI, Prot Sect, LMC, DBS,NIH, Bethesda, MD 20892 USA. RP Hock, R (reprint author), Univ Wurzburg, Dept Cell & Dev Biol, Bioctr, D-97074 Wuerzburg, Germany. EM rhock@biozentrum.uni-wuerzburg.de RI Bustin, Michael/G-6155-2015 NR 57 TC 50 Z9 52 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD DEC 1 PY 1998 VL 17 IS 23 BP 6992 EP 7001 DI 10.1093/emboj/17.23.6992 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 149VA UT WOS:000077625600024 PM 9843505 ER PT J AU Sanjuan, X Bryant, BR Sobel, ME Merino, MJ AF Sanjuan, X Bryant, BR Sobel, ME Merino, MJ TI Clonality analysis of benign parathyroid lesions by human androgen receptor (HUMARA) gene assay SO ENDOCRINE PATHOLOGY LA English DT Article; Proceedings Paper CT 1998 Annual Endocrine-Society Companion Meeting of the United-States-and-Canadian-Academy-of-Pathology CY FEB 28, 1998 CL BOSTON, MASSACHUSETTS SP Endocrine Soc, US & Canadian Acad Pathol DE parathyroid hyperplasia; parathyroid adenoma; clonality; HUMARA assay; X-chromosome inactivation; microdissection ID POLYMERASE CHAIN-REACTION; X-INACTIVATION; METHYLATION PATTERNS; CHROMOSOME-X; HYPERPARATHYROIDISM; AMPLIFICATION; HYPERPLASIA; ADENOMAS; M27-BETA; MONOCLONALITY AB Benign conditions of the parathyroid gland have been classified as adenomas and hyperplasias. These entities however are difficult to distinguish when only a single gland is enlarged. Adenomas are defined as neoplastic clonal growths whereas hyperplasias are considered to be reactive processes of polyclonal origin. In order to analyze the clonal pattern of these lesions, we have studied hyperplasias and adenomas of parathyroid glands from women by the human androgen receptor (HUMARA) assay, a recently reliable and highly-informative technique based on the X-chromosome inactivation pattern in females. Samples consisted of formalin-fixed as well as frozen tissues. Informativeness with HUMARA marker was 87% (13/15 cases). All hyperplasias (5/5) and 6/8 adenomas yielded polyclonal results, since two alleles of similar intensity appeared when the lesion was HpaII-digested. Two parathyroid adenomas had a loss of one X-allele for the HUMARA gene and they were interpreted as monoclonal. These results show that parathyroid hyperplasias and adenomas, considered as multigland or monogland involvement diseases respectively, may be both polyclonal in origin, and that only a small subset of adenomas is found to be clonal. Consequently, clonality analysis cannot allow a clear distinction between these two entities as classically diagnosed. A different approach should be considering hyperplasia or adenoma when a polyclonal or monoclonal result has been obtained by clonality analysis. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Room 2N212,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 27 TC 7 Z9 8 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1046-3976 J9 ENDOCR PATHOL JI Endocr. Pathol. PD WIN PY 1998 VL 9 IS 4 BP 293 EP 300 DI 10.1007/BF02739689 PG 8 WC Endocrinology & Metabolism; Pathology SC Endocrinology & Metabolism; Pathology GA 170DL UT WOS:000078790800003 ER PT J AU Vaccari, C Lolait, SJ Ostrowski, NL AF Vaccari, C Lolait, SJ Ostrowski, NL TI Comparative distribution of vasopressin V1b and oxytocin receptor messenger ribonucleic acids in brain SO ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT Wenner-Gren Conference CY 1996 CL STOCKHOLM, SWEDEN ID CENTRAL-NERVOUS-SYSTEM; RAT-BRAIN; BINDING-SITES; AUTORADIOGRAPHIC LOCALIZATION; SUPRACHIASMATIC NUCLEUS; MOLECULAR-CLONING; ARGININE-VASOPRESSIN; SUPRAOPTIC NUCLEI; V2 RECEPTOR; EXPRESSION AB The comparative distributions of the vasopressin V1b receptor (V1bR) and the oxytocin receptor (OTR) messenger RNAs (mRNAs) are described in male rat brain using in, situ hybridization histochemistry. V1bR transcripts were present in forebrain and hypothalamus and were less abundant in mid- and hindbrain regions, similar to the gradient observed with OTR transcripts. Microscopic analyses indicated that V1bR expressing cells typically demonstrated the morphology of neurons and confirmed V1bR gene expression in regions including the olfactory bulb, supraoptic, suprachiasmatic, and dorsomedial hypothalamic nuclei, piriform and entorhinal cortices, hippocampus, substantia nigra, and dorsal motor nucleus of the vagus. Most regions that expressed V1bR mRNA also expressed OTR mRNA, although OTR gene expression was much more extensive than that of the V1bR. V1bR and OTR mRNA distributions were distinct from each other and from that of the Via receptor mRNA in brain. A few brain regions express only V1bR transcripts such as the dorsomedial hypothalamic nucleus and the external plexiform layer of the olfactory bulb. Other brain regions, such as the fields of Ammon's horn, the suprachiasmatic nucleus, the substantia nigra pars compacta, and the piriform cortex express mRNAs that encode all three receptor subtypes (V1a, V1b, and OTR), whereas brain areas including the red nucleus and supraoptic nucleus express V1bR and OTR transcripts only. These data suggest functional specialization of the V1b, OTR and Via receptors in brain. C1 NIMH, Sect Behav Pharmacol, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIMH, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. RP Ostrowski, NL (reprint author), Eli Lilly & Co, Lilly Corp Ctr, Bldg 22,Drop Code 2244, Indianapolis, IN 46285 USA. NR 54 TC 187 Z9 191 U1 0 U2 10 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 DEC PY 1998 VL 139 IS 12 BP 5015 EP 5033 DI 10.1210/en.139.12.5015 PG 19 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 140TG UT WOS:000077104000032 PM 9832441 ER PT J AU Ogawa, S Washburn, TF Taylor, J Lubahn, DB Korach, KS Pfaff, DW AF Ogawa, S Washburn, TF Taylor, J Lubahn, DB Korach, KS Pfaff, DW TI Modifications of testosterone-dependent behaviors by estrogen receptor alpha gene disruption in male mice SO ENDOCRINOLOGY LA English DT Article ID BETA MESSENGER-RNA; ER-BETA; TARGETED DISRUPTION; TISSUE DISTRIBUTION; KNOCKOUT MOUSE; FEMALE MICE; INFANTICIDE; ANDROGEN; BINDING; AGGRESSION AB The role of the a form of estrogen receptor (ER alpha) gene expression in the regulation of testosterone-dependent male reproductive behaviors was investigated using ER knockout mice (ERKO), which are specifically deficient in functional ER alpha, but not ER beta, gene expression. Previous studies in gonadally intact ERKO mice revealed that male aggressive behavior was greatly reduced by the lack of a functional ER alpha gene. In the present study the almost complete suppression of male-typical offensive attacks was further confirmed in ERKO mice that had been singly housed since weaning. Regarding aggression, it was also found that ER alpha gene disruption virtually abolished the propensity to initiate offensive attacks, even though ERKO mice could elicit attacks from resident C57BL/6J mice as wild-type (WT) and heterozygous littermates. Daily injection of testosterone propionate (TP) was completely ineffective in inducing aggressive behavior in gonadectomized ERKO mice, whereas it successfully restored aggression in WT mice. In contrast, male sexual behaviors, mounts and intromissions, were induced by daily injection of TP in both gonadectomized ERKO and WT mice. In addition to TP, dihydrotestosterone propionate (DHTP) was also effective in restoring mounts in ERKO mice, although DHTP was much more potent in WT mice than in ERKO mice. Neither TP nor DHTP, however, ever induced ejaculation in ERKO mice. These results together with previous findings in gonadally intact ERKO mice suggest that ER alpha may be responsible for the regulation by testosterone of consummatory, but not motivational, aspects of male sexual behavior. Finally, ERKO male mice retrieved newborn pups placed in their home cage with similar latencies to males of the two other genotypes. During parental behavior tests, however, a higher percentage of ERKO mice (70%) showed infanticide compared with WT mice (35%). The latter result was interpreted as showing that ER alpha activation by testosterone during the perinatal period may exert a suppressive effect on testosterone-inducible infanticide in adulthood. With respect to three major testosterone-dependent behavioral systems reflecting masculinization, these findings demonstrate three different types of effects due to ER alpha gene disruption. C1 Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. Univ Missouri, Dept Child Hlth, Columbia, MO 65211 USA. RP Ogawa, S (reprint author), Rockefeller Univ, Neurobiol & Behav Lab, 1230 York Ave,Box 275, New York, NY 10021 USA. EM ogawa@rockvax.rockefeller.edu OI Korach, Kenneth/0000-0002-7765-418X NR 38 TC 171 Z9 175 U1 0 U2 7 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 DEC PY 1998 VL 139 IS 12 BP 5058 EP 5069 DI 10.1210/en.139.12.5058 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 140TG UT WOS:000077104000036 PM 9832445 ER PT J AU Ogawa, S Eng, V Taylor, J Lubahn, DB Korach, KS Pfaff, DW AF Ogawa, S Eng, V Taylor, J Lubahn, DB Korach, KS Pfaff, DW TI Roles of estrogen receptor alpha gene expression in reproduction-related behaviors in female mice SO ENDOCRINOLOGY LA English DT Article ID PUP-KILLING BEHAVIOR; BETA MESSENGER-RNA; AGGRESSIVE-BEHAVIOR; ER-BETA; TESTOSTERONE EXPOSURE; TISSUE DISTRIBUTION; REGULATORY SYSTEMS; SEXUAL RECEPTIVITY; KNOCKOUT MOUSE; DISRUPTION AB The role of gene expression of the estrogen receptor-alpha form (ER alpha) in the regulation of female reproductive behavior was investigated in estrogen receptor knockout (ERKO) mice, deficient specifically for the ER alpha, but not the ER beta, gene. Estrogen- or estrogen- plus progesterone-treated gonadectomized ERKO mice did not show any lordosis response. Detailed behavioral analysis revealed that ERKO females were also deficient in sexual behavioral interactions preceding the lordosis response. They were extremely rejective toward attempted mounts by stud male mice, which could not show any intromissions. During resident-intruder aggression tests, gonadally intact ERKO females were more aggressive toward female intruder mice than wildtype (WT) mice. Gonadectomy did not influence the levels of aggressive behavior, and their genotype differences when mice were tested both before and after gonadectomy. However, when mice were tested after gonadectomy for the first time, very few ERKO mice showed aggression. In contrast to aggression, male-type sexual behavior shown by resident mice toward female intruder mice during aggression tests was not different between ERKO and WT mice and was completely abolished after gonadectomy of the resident mice. Finally, it was also found that ERKO females showed greatly reduced levels of parental behavior toward newborn pups placed in their home cage. These changes in parental behavior were not influenced by gonadectomy. ERKO females retrieved significantly fewer numbers of pups with longer latencies compared with wild-type (WT) or heterozygous (HZ) littermates when they were tested as gonadally intact or 20-65 days after gonadectomy. In addition, during parental behavior tests, a significantly higher percentage of ERKO mice exhibited infanticide compared with WT and HZ mice, which rarely showed infanticide. Taken together, these findings suggest that ER alpha gene expression plays a key role in female mice, not only for sexual behavior but also for other interrelated behaviors, such as parental and aggressive behaviors. In addition, persistence of genotype differences in parental and aggressive behavior after gonadectomy indicates that ER alpha activation during neural developmental processes may also be involved in the regulation of these behaviors. C1 Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. Univ Missouri, Dept Biochem, Columbia, MO 65211 USA. Univ Missouri, Dept Child Hlth, Columbia, MO 65211 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Ogawa, S (reprint author), Rockefeller Univ, Neurobiol & Behav Lab, 1230 York Ave,Box 275, New York, NY 10021 USA. EM ogawa@rockvax.rockefeller.edu OI Korach, Kenneth/0000-0002-7765-418X NR 35 TC 290 Z9 298 U1 3 U2 18 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 DEC PY 1998 VL 139 IS 12 BP 5070 EP 5081 DI 10.1210/en.139.12.5070 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 140TG UT WOS:000077104000037 PM 9832446 ER PT J AU Kalantaridou, SN Davis, SR Nelson, LM AF Kalantaridou, SN Davis, SR Nelson, LM TI Premature ovarian failure SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Review ID FOLLICLE-STIMULATING-HORMONE; MAJOR HISTOCOMPATIBILITY COMPLEX; RECEPTOR GENE-EXPRESSION; AGE-RELATED DECLINE; AUTOIMMUNE OOPHORITIS; ADDISONS-DISEASE; X-CHROMOSOME; 17-ALPHA-HYDROXYLASE DEFICIENCY; GONADOTROPIN RECEPTORS; STEROIDOGENIC ENZYMES AB Premature ovarian failure is a condition causing amenorrhea, infertility, sex steroid deficiency, and elevated gonadotropins in women 40 years old or younger. Premature ovarian failure is not merely an early natural menopause. Young women with premature ovarian failure may ovulate intermittently and, indeed, pregnancies have occurred after the diagnosis of ovarian failure. Premature ovarian failure may be associated with other autoimmune disorders, such as autoimmune adrenal failure, hypothyroidism,diabetes mellitus. Premature ovarian failure has both significant psychosocial sequelae and major health implications. Young women with this disorder need a thorough assessment, sex steroid replacement, and long-term surveillance to monitor their therapy and minimize their health risks in later life. C1 NICHHD, Sect Womens Hlth, DEB, NIH, Bethesda, MD 20892 USA. Jean Hailes Fdn Res Unit, Melbourne, Vic, Australia. RP Nelson, LM (reprint author), NICHHD, Sect Womens Hlth, DEB, NIH, Bldg 10,Room 10N262, Bethesda, MD 20892 USA. RI Davis, Susan/A-3111-2009; OI Davis, Susan R/0000-0002-2955-0415 NR 125 TC 105 Z9 128 U1 1 U2 3 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD DEC PY 1998 VL 27 IS 4 BP 989 EP + DI 10.1016/S0889-8529(05)70051-7 PG 20 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 146RQ UT WOS:000077444600014 PM 9922918 ER PT J AU Hooper, K Petreas, MX Chuvakova, T Kazbekova, G Druz, N Seminova, G Sharmanov, T Hayward, D She, JW Visita, P Winkler, J McKinney, M Wade, TJ Grassman, J Stephens, RD AF Hooper, K Petreas, MX Chuvakova, T Kazbekova, G Druz, N Seminova, G Sharmanov, T Hayward, D She, JW Visita, P Winkler, J McKinney, M Wade, TJ Grassman, J Stephens, RD TI Analysis of breast milk to assess exposure to chlorinated contaminants in Kazakstan: High levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in agricultural villages of southern Kazakstan SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE breast milk; co-planar PCBs; dioxins; exposure assessment; furans; Kazakstan; TCDD ID DIOXIN-LIKE COMPOUNDS; POLYCHLORINATED-BIPHENYLS; PERINATAL EXPOSURE; BODY BURDEN; P-DIOXIN; PCBS; WORKSHOP; PCDD AB To assess levels of chlorinated contaminants in breast milk, we measured organochlorine pesticides, polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs) in breast milk samples collected in 1994 according to the World Health Organization protocol From 92 donors that were representative of regional populations in southern Kazakstan. High levels (10-120 pg/g fat) of: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic of the PCDD/PCDF congeners, were found in breast milk samples from an agricultural region. TCDD was the major contributor (75%) to the international toxicity equivalents of these samples. The same distinctive PCDD/PCDF congener pattern was found in 15 breast milk samples and 4 serum samples collected in 1996 in a follow-up study, and has now been confirmed by three analytical laboratories. C1 Calif Environm Protect Agcy, Hazardous Mat Lab, Berkeley, CA 94707 USA. Kazakstan Minist Hlth, Phys Inst Postgrad Training, Almaty, Kazakhstan. Kazmekhanobr Res Ind Ecol, Almaty, Kazakhstan. Inst Nutr, Almaty, Kazakhstan. US FDA, Ctr Food Safety & Appl Nutr, Washington, DC 20204 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Hooper, K (reprint author), Calif Environm Protect Agcy, Hazardous Mat Lab, 2151 Berkeley Way, Berkeley, CA 94707 USA. NR 40 TC 40 Z9 41 U1 3 U2 6 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 DEC PY 1998 VL 106 IS 12 BP 797 EP 806 DI 10.1289/ehp.98106797 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 155PB UT WOS:000077954600020 PM 9831540 ER PT J AU Burkhart, JG Helgen, JC Fort, DJ Gallagher, K Bowers, D Propst, TL Gernes, M Magner, J Shelby, MD Lucier, G AF Burkhart, JG Helgen, JC Fort, DJ Gallagher, K Bowers, D Propst, TL Gernes, M Magner, J Shelby, MD Lucier, G TI Induction of mortality and malformation in Xenopus laevis embryos by water sources associated with field frog deformities SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE amphibian malformations; environmental sentinels; FETAX; teratogenesis ID THYROID-HORMONE; ULTRAVIOLET-RADIATION; RETINOIC ACID; HOMEOTIC TRANSFORMATION; BINDING PROTEIN; COMET ASSAY; LIMBS; FETAX; GENE; GENOTOXICITY AB Water samples from several ponds in Minnesota were evaluated for their capacity to induce malformations in embryos of Xenopus laevis. The FETAX assay was used to assess the occurrence of malformations following a 96-hr period of exposure to water samples. These studies were conducted following reports of high incidences of malformation in natural populations of frogs in Minnesota wetlands. The purpose of these studies was to determine if a biologically active agent(s) was present in the waters and could be detected using the FETAX assay. Water samples from ponds with high incidences of frog malformations (affected sites), along with water samples from ponds with unaffected frog populations (reference sites), were studied, initial experiments clearly showed that water from affected sites induced mortality and malformation in Xenopus embryos, while water from reference sites had little or no effect. Induction of malformation was dose dependent and highly reproducible, both with stored samples and with samples taken at different times throughout the summer. The biological activity of the samples was reduced or eliminated when samples were passed through activated carbon. Limited evidence from these samples indicates that the causal factor(s) is not an infectious organism nor are ion concentrations or metals responsible for the effects observed. Results do indicate that the water matrix has a significant effect on the severity of toxicity. Based on the FETAX results and the occurrence of frog malformations observed in the field, these studies suggest that water in the affected sites contains one or more unknown agents that induce developmental abnormalities in Xenopus. These same factors may contribute to the increased incidence of malformation in native species. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Minnesota Pollut Control Agcy, St Paul, MN 55157 USA. Stover Grp, Stillwater, OK 74075 USA. Univ Minnesota, Dept Fisheries & Wildlife, St Paul, MN 55108 USA. RP Burkhart, JG (reprint author), NIEHS, MD C4-07,POB 12233, Res Triangle Pk, NC 27709 USA. NR 45 TC 66 Z9 71 U1 3 U2 14 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 DEC PY 1998 VL 106 IS 12 BP 841 EP 848 DI 10.2307/3434128 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 155PB UT WOS:000077954600025 PM 9831545 ER PT J AU Bucher, JR Lucier, G AF Bucher, JR Lucier, G TI Current approaches toward chemical mixture studies at the National Institute of Environmental Health Sciences and the US National Toxicology Program SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material DE chemical mixture studies; transgenic mice; toxic equivalence factors; functional toxicology; biomarkers of exposure; exposure assessment AB The National institute of Environmental Health Sciences (NIEHS) has several new initiatives involving chemical mixtures and has recognized the need to develop new experimental approaches to enhance our efforts in this area. Responding to recent increases in nominations of complex occupational exposures for toxicologic assessment by the U.S. National Toxicology Program, the NIEHS and the National Institute for Occupational Safety and Health have begun a program to characterize exposures through field studies, identify biomarkers of exposure in workers. and recreate relevant mixed exposures in a laboratory setting, a second initiative with the National Center for Environmental Health/Centers for Disease Control and Prevention will examine brood samples from the U.S. National Health and Nutrition Examination Survey population surveys for selected endocrine-disrupting agents and For common patterns of persistent xenobiotics, providing critical information for the design of animal studies to assess risks of relevant chemical mixtures to humans. New toxicology testing methods (lower cost, faster) will enhance our ability to study chemical mixtures (e.g., dioxin and dioxinlike chemicals, combination BIDS therapies). Ongoing method development efforts involve in vitro functional toxicology assays, screens for estrogenic activity, and carcinogenesis studies in transgenic mice. A major scientific initiative with mixtures involves studies of individual and mixtures of dioxin and dioxinlike chemicals to determine if toxic equivalence factors predict carcinogenic potency in traditional and transgenic bioassays. Complementing these studies is an increased emphasis on physiologically based pharmacokinetic modeling, an activity central to the proper interpretation of chemical mixture studies. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Bucher, JR (reprint author), NIEHS, Environm Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM bucher@niehs.nih.gov NR 11 TC 10 Z9 10 U1 0 U2 0 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 DEC PY 1998 VL 106 SU 6 BP 1295 EP 1298 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 156NT UT WOS:000078008100006 PM 9860884 ER PT J AU Boorman, GA AF Boorman, GA TI EMF working group SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter C1 NIEHS, EMF RAPID Program, Res Triangle Pk, NC 27709 USA. RP Boorman, GA (reprint author), NIEHS, EMF RAPID Program, POB 12233, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 DEC PY 1998 VL 106 IS 12 BP A584 EP A584 DI 10.2307/3434105 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 155PB UT WOS:000077954600005 PM 10048946 ER PT J AU Huff, J Waalkes, M Chan, P AF Huff, J Waalkes, M Chan, P TI Arsenic: Evidence of carcinogenicity in animals SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID INDUCTION; BENZENE; CANCER; RATS C1 NIEHS, NCI, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, NCI, POB 12233, Res Triangle Pk, NC 27709 USA. NR 22 TC 5 Z9 5 U1 0 U2 0 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 DEC PY 1998 VL 106 IS 12 BP A582 EP A583 DI 10.2307/3434103 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 155PB UT WOS:000077954600003 ER PT J AU Berkovich, AJ Berkovic, SF Cascino, GD Chiron, C Duncan, JS Gadian, DG Jackson, GD Kuzniecky, RI McLachlan, RS Meencke, HJ Palmini, A Sadzot, B Stefan, H Theodore, WH AF Berkovich, AJ Berkovic, SF Cascino, GD Chiron, C Duncan, JS Gadian, DG Jackson, GD Kuzniecky, RI McLachlan, RS Meencke, HJ Palmini, A Sadzot, B Stefan, H Theodore, WH CA Comm on Neuroimaging of the Int League Against TI Guidelines for neuroimaging evaluation of patients with uncontrolled epilepsy considered for surgery SO EPILEPSIA LA English DT Editorial Material C1 NINCDS, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), NINCDS, Clin Epilepsy Sect, NIH, Bldg 10,Room 5N-250,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Gadian, David/C-4961-2008; Jackson, Graeme/A-9064-2013; OI Jackson, Graeme/0000-0002-7917-5326; Berkovic, Samuel/0000-0003-4580-841X NR 0 TC 58 Z9 60 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD DEC PY 1998 VL 39 IS 12 BP 1375 EP 1376 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 147LF UT WOS:000077568900022 ER PT J AU Vrasti, R Grant, BF Chatterji, S Ustun, BT Mager, D Olteanu, I Badoi, M AF Vrasti, R Grant, BF Chatterji, S Ustun, BT Mager, D Olteanu, I Badoi, M TI Reliability of the Romanian version of the alcohol module of the WHO Alcohol Use Disorder and Associated Disabilities: Interview Schedule-Alcohol/Drug-Revised SO EUROPEAN ADDICTION RESEARCH LA English DT Article DE reliability; alcohol assessment; psychiatric research ID AUDADIS-ADR; CLINICAL-ASSESSMENT; DRUG MODULES; SCAN; DIAGNOSES; NEUROPSYCHIATRY; CONCORDANCE; CRITERIA; CIDI AB Alcohol Use Disorder and Associated Disabilities Interview Schedule - Alcohol/Drug-Revised (AUDADIS-A/D-R) is a fully structured, standardized and preceded instrument designed to evaluate alcohol and drug use disorders according to DSM-III-R, DSM-IV, and ICD-10 criteria. The AUDADIS-A/D-R has shown good to excellent reliability in both large clinical and general population samples, but prior to the conduct of the present study no data on the reliability of the Romanian version of the AUDADIS-A/D-R existed. The purpose of the present study was to examine the test-retest reliability of the alcohol module of the AUDADIS-A/D-R in a general population and clinical sample in Romania. The overall reliability of ICD-10 and DSM-IV abuse, harmful. and dependence diagnoses, was found to be good to excellent, but was somewhat lower for abuse and harmful use diagnoses. The results are discussed in terms of the cultural applicability of the symptom items and within the context of the analysis of discrepant responses between the test and retest interviews. C1 Hosp Psychiat, Dept Res, RO-1922 Jebel, Timis, Romania. NIAAA, Div Biometry & Epidemiol, Bethesda, MD 90034 USA. Natl Inst Mental Hlth & Neurosci, Bangalore 560029, Karnataka, India. WHO, Epidemiol & Managerial Support Div, CH-1211 Geneva, Switzerland. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. RP Vrasti, R (reprint author), Hosp Psychiat, Dept Res, RO-1922 Jebel, Timis, Romania. NR 19 TC 91 Z9 91 U1 1 U2 2 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1022-6877 J9 EUR ADDICT RES JI Eur. Addict. Res. PD DEC PY 1998 VL 4 IS 4 BP 144 EP 149 DI 10.1159/000018947 PG 6 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 152WZ UT WOS:000077801300002 PM 9852366 ER PT J AU Vercelli, M Quaglia, A Casella, C Parodi, S Capocaccia, R Garcia, CM AF Vercelli, M Quaglia, A Casella, C Parodi, S Capocaccia, R Garcia, CM CA EUROCARE Working Grp TI Relative survival in elderly cancer patients in Europe SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE relative survival rates; elderly patients; cancer; Europe ID BREAST-CANCER; OLDER PATIENTS; POPULATION; WOMEN; STAGE; AGE; DETERMINANTS; DIAGNOSIS; HISTOLOGY; CONTRASTS AB In this paper different patterns of survival by age and gender are presented for 17 European countries which participated in the EUROCARE II programme. Survival data were available for 701 521 patients aged between 65 and 99 years from 44 population-based cancer registries. Age-standardised relative survival rates at 1 and 5 years from diagnosis were computed. Relative risks (RRs) of death for those aged between 65 and 99 years compared with those aged between 55 and 64 years were estimated by gender and country. In general, the elderly had a large survival disadvantage, particularly 1 year after diagnosis and in women. Poorer survival rates in the elderly were observed for patients from Eastern European countries for almost all sites. However, relative survival of the elderly with respect to younger patients was similar in the different geographic areas. The results are in agreement with other population-based studies, confirming a worse prognosis for the elderly in both sexes. This may be explained by changes in biology and the natural history of the tumour and the occurrence of severe comorbidities, potentially affecting preventive, diagnostic and therapeutic strategies. The lack of equality in providing adequate treatment to elderly cancer patients should be addressed as a matter of urgency by health-care providers. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 Univ Genoa, Dept Clin & Expt Oncol, Genoa, Italy. Natl Canc Inst, Canc Registry Sect, Genoa, Italy. Ist Super Sanita, Epidemiol & Biostat Lab, I-00161 Rome, Italy. Escuela Andaluza Salud Publ, Granada, Spain. RP Vercelli, M (reprint author), Univ Genoa, Dept Clin & Expt Oncol, Genoa, Italy. OI Vercelli, Marina/0000-0002-9757-2616 NR 30 TC 50 Z9 50 U1 1 U2 1 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 DEC PY 1998 VL 34 IS 14 BP 2264 EP 2270 DI 10.1016/S0959-8049(98)00325-6 PG 7 WC Oncology SC Oncology GA 155ZU UT WOS:000077977600019 PM 10070297 ER PT J AU Fuss, IJ Strober, W Cuccherini, BA Pearlstein, GR Bossuyt, X Brown, M Fleisher, TA Horgan, K AF Fuss, IJ Strober, W Cuccherini, BA Pearlstein, GR Bossuyt, X Brown, M Fleisher, TA Horgan, K TI Intestinal lymphangiectasia, a disease characterized by selective loss of naive CD45RA(+) lymphocytes into the gastrointestinal tract SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE lymphangiectasia; lymphocyte; cytokine ID T-CELL ACTIVATION; HELPER-INDUCER; CD4+ LYMPHOCYTES; HIV-INFECTION; IN-VIVO; B-CELL; DIFFERENTIATION; SUBSETS; EXPRESSION; CD27 AB Intestinal lymphangiectasia (InL) is a disease characterized by hypoproteinemia and lymphocytopenia resulting from blocked intestinal lymphatics and loss of lymph fluid into the gastrointestinal tract. This leads to immunologic abnormalities including hypogammaglobulinemia, skin anergy and impaired allograft rejection. In the present study, we evaluated whether the above immunologic abnormalities are secondary to a quantitative or qualitative disorder of T cells. In initial studies we demonstrated that adult Int patients' peripheral blood contain strikingly (and significantly) reduced numbers of CD4(+)/CD45RA(+) T cells, whereas the numbers of CD4(+)/CD45RO(-) T cells were only moderately (and not significantly) reduced. In addition, the CD4(+)/CD45RO(+) T cell population contained an increased percentage of highly differentiated and previously sensitized cells, as demonstrated by decreased CD27 and CD31 expression and increased HLA-DR and CD69 expression. In subsequent functional studies, we showed that the InL CD4(+)/CD45RO(+) T cells, when stimulated in vitro, proliferate fivefold less than control CD4(+)/CD45RO(+) T cells and produce fourfold more IL-4 and threefold less IFN-gamma and IL-2. Thus, this cytokine production profile also reflects the highly differentiated nature of the residual cell population. Overall, these studies provide new information on the trafficking of naive/mature and Th1/Th2 T cell populations in this disease model. C1 NIAID, LCI, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Hlth, Warren G Magnuson Clin Ctr, Serv Immunol, Bethesda, MD USA. Univ Calif Los Angeles, Sch Med, Div Gastroenterol, Los Angeles, CA USA. RP Fuss, IJ (reprint author), NIAID, LCI, Mucosal Immun Sect, NIH, Bldg 10,Room 11N238, Bethesda, MD 20892 USA. NR 58 TC 33 Z9 34 U1 0 U2 2 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 DEC PY 1998 VL 28 IS 12 BP 4275 EP 4285 DI 10.1002/(SICI)1521-4141(199812)28:12<4275::AID-IMMU4275>3.3.CO;2-G PG 11 WC Immunology SC Immunology GA 148QC UT WOS:000077542500040 PM 9862365 ER PT J AU Gulyas, AI Toth, K McBain, CJ Freund, TF AF Gulyas, AI Toth, K McBain, CJ Freund, TF TI Stratum radiatum giant cells: a type of principal cell in the rat hippocampus SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE inhibitory neurons; long-term potentiation; N-methyl-D-aspartate receptor ID LONG-TERM POTENTIATION; DEPENDENT PROTEIN-KINASE; CEREBRAL-CORTEX; GABAERGIC NEURONS; PYRAMIDAL CELLS; INTERNEURONS; CA1; PARVALBUMIN; CALMODULIN; SYNAPSES AB Neurons of a distinct type in CA1 area stratum radiatum of the rat hippocampus have been found to express a direct cellular form of long-term potentiation (LTP, Maccaferri & McBain, 1996, J. Neurosci. 16, 5334), but their functional identity, i.e. whether interneuron or principal cell, remained unknown. Whole cell recording from hippocampal slices in vitro was combined with light and electron microscopy to answer this question. LTP was robustly induced by a pairing protocol and physiological properties were measured in radiatum giant cells (RGCs) using biocytin containing pipettes. Reconstruction of the cells' dendritic and axonal arbor revealed morphological properties similar to CAI pyramidal cells with some characteristic differences. They typically had two large diameter apical dendrites, or when only one dendrite arose, it soon bifurcated. Apical dendrites formed a dendritic tuft in stratum lacunosum-moleculare and the dendrites, but not the somata, were densely covered with conventional spines. The axon arose from the basal pole of the soma, descended to stratum oriens and emitted several axon terminals bearing collaterals that travelled horizontally, remaining in stratum oriens. The main, myelinated axon trunks turned towards the fimbria. In the electron microscope axon terminals were found to form asymmetrical synapses on postsynaptic dendritic shafts and dendritic spines in stratum oriens. The dendrites received asymmetrical synapses, mostly on their spines. The axon initial segments also received several synapses, a feature never observed on interneurons. All the above characteristics support the conclusion that RGCs are excitatory principal neurons. C1 Hungarian Acad Sci, Inst Expt Med, H-1450 Budapest, Hungary. NICHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Freund, TF (reprint author), Hungarian Acad Sci, Inst Expt Med, POB 67, H-1450 Budapest, Hungary. EM freund@koki.hu NR 34 TC 45 Z9 46 U1 0 U2 3 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD DEC PY 1998 VL 10 IS 12 BP 3813 EP 3822 DI 10.1046/j.1460-9568.1998.00402.x PG 10 WC Neurosciences SC Neurosciences & Neurology GA 153CK UT WOS:000077815400023 PM 9875359 ER PT J AU Kobayashi, S Ogren, SO Hoffer, BJ Olson, L AF Kobayashi, S Ogren, SO Hoffer, BJ Olson, L TI Dopamine D-1 and D-2 receptor-mediated acute and long-lasting behavioral effects of glial cell line-derived neurotrophic factor administered into the striatum SO EXPERIMENTAL NEUROLOGY LA English DT Article DE glial cell line-derived neurotrophic factor; (GDNF); locomotor activity; intrastriatal injection; intracerebroventricular injection; acute effect; distribution; dopamine D-1 receptor; dopamine D-2 receptor ID GDNF MESSENGER-RNA; ADRENAL-MEDULLARY AUTOGRAFTS; NERVE GROWTH-FACTOR; NEURONS IN-VIVO; STEREOTYPED BEHAVIOR; PARKINSONS-DISEASE; RATS; EXPRESSION; ADULT; 6-HYDROXYDOPAMINE AB To determine the differences in behavioral effects between intrastriatal and intracerebroventricular glial cell-derived neurotrophic factor (GDNF) administration, spontaneous locomotor activity was measured after intrastriatal or intracerebroventricular injection of GDNF (10 mu g) in normal adult rats with implanted guide cannulae, In addition, the distribution of GDNF after intracerebral injection was studied immunohistochemically. Intrastriatal administration of GDNF significantly increased rearing behavior 3-4 h after injection. Increases in all three aspects of locomotor activity (motility, locomotion, and rearing) were most pronounced 3 days after intrastriatal injection, and they lasted for several days. This hyperactivity was blocked by the selective dopamine D-1 receptor antagonist SCH22390 and by the selective D-2 receptor antagonist raclopride at doses of the dopamine receptor antagonists, which by themselves did not affect spontaneous locomotor activity. These results suggest that GDNF has both acute and long-lasting pharmacological effects on dopamine neurons in adult animals and stimulates locomotor activity by activating both dopamine D-1 and D-2 receptors. On the other hand, intracerebroventricular administration of the same dose of GDNF failed to increase locomotor activity at any time during the test period (12 days). The immunohistochemical study demonstrated widespread distribution of GDNF in the entire body of the striatum within 24 h after intrastriatal injection. It also revealed deep penetration of GDNF from the ventricular space into the brain parenchyma after intracerebroventricular injection. GDNF-immunoreactive neuronal cell bodies were seen in the ipsilateral substantia nigra pars compacta most frequently 6 h after intrastriatal injection. The number of such cell bodies after intracerebroventricular administration, on the other hand, was much lower than that seen after intrastriatal administration. Taken together, these data suggest that intrastriatal administration of GDNF is an effective approach for affecting DA transmission. Longlasting behavior effects are mediated via dopamine D-1 and D-2 receptors. Higher doses of GDNF would probably be needed using the intracerebroventricular route as compared to intraparenchymal delivery to exert effects on the nigrostriatal system in Parkinson's disease patients. (C) 1998 Academic Press. C1 Karolinska Inst, Dept Neurosci, Stockholm, Sweden. NIDA, NIH, Baltimore, MD 21224 USA. RP Olson, L (reprint author), Karolinska Inst, Dept Neurosci, Stockholm, Sweden. OI Ogren, Sven Ove/0000-0003-2573-5276 NR 49 TC 16 Z9 16 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 DEC PY 1998 VL 154 IS 2 BP 302 EP 314 DI 10.1006/exnr.1998.6952 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 157TW UT WOS:000078078600004 PM 9878169 ER PT J AU Li, JJ Oberley, LW Fan, M Colburn, NH AF Li, JJ Oberley, LW Fan, M Colburn, NH TI Inhibition of AP-1 and NF-kappa B by manganese-containing superoxide dismutase in human breast cancer cells SO FASEB JOURNAL LA English DT Article DE tumor suppressor gene; redox; transcription factor; MCF-7 cells; TPA ID EPIDERMAL GROWTH-FACTOR; PHORBOL ESTER; TRANSCRIPTION FACTOR; HYDROGEN-PEROXIDE; NEOPLASTIC TRANSFORMATION; LUNG FIBROBLASTS; MAMMALIAN-CELLS; MESSENGER-RNA; JB6 CELLS; CIS-FOS AB One of the primary antioxidant enzymes, manganese-containing superoxide dismutase (MnSOD), has shown the ability to reverse malignant phenotypes in a variety of human tumor cells that are low or absent in MnSOD expression. We have observed that overexpression of human MnSOD in human breast cancer MCF-7 cells inhibits tumor growth both in vitro and in vivo. The signaling pathway underlying the MnSOD induced tumor suppression is unknown. We demonstrate here that transcriptional and DNA binding ability of AP-1 and NF-kappa B, but not SP-1, were inhibited (by 50%) in the MCF-7 cell line overexpressing MnSOD, When transiently expressing, MnSOD inhibited AP-I but increased NF-kappa B transactivation, which can be abolished by sodium pyruvate, a hydrogen peroxide scavenger. To analyze the target genes responsible for MnSOD-induced tumor suppression, genes related to tumor growth and responsive to AP-1 or NF-kappa B were analyzed. AP-1 responsive collagenase I, stromelysin I, and NF-kappa B responsive IL-1 and IL-6 were down-regulated in the MnSOD stable transfectants compared to the control cell lines. Since TPA induces differentiation in human breast cancer cells and up-regulates MnSOD gene in HeLa cells, MnSOD expression and AP-1 and NF-kappa B activity were measured under TPA treatment. The results showed that TPA induced endogenous MnSOD expression and inhibited both AP-1 and NF-kappa B, Together, these results suggest that tumor suppression by overexpressing MnSOD is related to a modulation of AP-1 and NF-kappa B, which causes a downregulation of genes responsible for tumor malignant phenotype. C1 NCI, Gene Regulat Sect, Lab Biochem Physiol, Frederick, MD 21702 USA. Univ Iowa, Radiat Res Lab, Iowa City, IA 52242 USA. RP Li, JJ (reprint author), NCI, Gene Regulat Sect, Lab Biochem Physiol, Frederick, MD 21702 USA. EM lij@mail.ncifcrf.gov FU NCI NIH HHS [CA 41267] NR 67 TC 86 Z9 90 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD DEC PY 1998 VL 12 IS 15 BP 1713 EP 1723 PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 147NZ UT WOS:000077574500013 PM 9837861 ER PT J AU Dougherty, C Barucha, J Schofield, PR Jacobson, KA Liang, BT AF Dougherty, C Barucha, J Schofield, PR Jacobson, KA Liang, BT TI Cardiac myocytes rendered ischemia resistant by expressing the human adenosine A(1) or A(3) receptor SO FASEB JOURNAL LA English DT Article DE heart; purinergic; ventricular myocyte; gene transfer ID INTRACORONARY ADENOSINE; REPERFUSION; INJURY; CLONING; GENE AB Adenosine is an important mediator of the endogenous defense against ischemia-induced injury in the heart. Adenosine can achieve cardioprotection by mediating the effect of ischemic preconditioning and by protecting against myocyte injury when it is present during the infarct-producing ischemia. A novel adenosine A(3) receptor can mediate this protective function. One approach to achieve cardioprotection is to enhance myocardial sensitivity to the endogenous adenosine by increasing the number of adenosine receptors instead of administering an adenosine receptor agonist. The objective of the present study was to investigate whether genetic manipulation of the cardiac myocyte, achieved by gene transfer and overexpression of the human A(3) receptor cDNA, renders the myocytes resistant to the deleterious effect of ischemia. Prolonged hypoxia with glucose deprivation, causing myocyte injury and adenosine release, was used to simulate ischemia in cultured chick embryo ventricular myocytes. During simulated ischemia, cultured myocytes with enhanced expression of the human A(3) receptor and showed significantly higher ATP content, fewer cells killed, and less creatine kinase released into the medium than either control or mock-transfected myocytes. Also, increased expression of the A(3) receptor caused an enhanced cardioprotective effect by the preconditioning ischemia. Overexpressing the adenosine A(1) receptor also led to increased protection against ischemia-induced myocyte injury as well as an enhanced preconditioning effect. Thus, increasing the receptor level improves the myocyte sensitivity to the endogenous adenosine, which in turn causes all of the cardioprotective effects found for exogenously administered adenosine agonists. The study provides the first proof for the new concept that an increased expression of the human A(3) receptor in the cardiac myocyte can be an important cardioprotective therapeutic approach. C1 Univ Penn, Med Ctr, Dept Med, Div Cardiovasc, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Dept Pharmacol, Philadelphia, PA 19104 USA. Garvan Inst Med Res, Sydney, NSW, Australia. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Liang, BT (reprint author), Univ Penn, Med Ctr, Dept Med, Div Cardiovasc, 3610 Hamilton Walk, Philadelphia, PA 19104 USA. RI Schofield, Peter/C-9669-2011; Jacobson, Kenneth/A-1530-2009 OI Schofield, Peter/0000-0003-2967-9662; Jacobson, Kenneth/0000-0001-8104-1493 FU NHLBI NIH HHS [R01 HL48225] NR 22 TC 53 Z9 54 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD DEC PY 1998 VL 12 IS 15 BP 1785 EP 1792 PG 8 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 147NZ UT WOS:000077574500021 PM 9837869 ER PT J AU Wooten, HB Hoelter, HJ AF Wooten, HB Hoelter, HJ TI Operation spotlight: The community probation community police team process SO FEDERAL PROBATION LA English DT Article C1 Natl Ctr Inst & Alternat, Alexandria, VA USA. RP Wooten, HB (reprint author), Natl Ctr Inst & Alternat, Alexandria, VA USA. NR 28 TC 1 Z9 1 U1 1 U2 2 PU US COURTS PI WASHINGTON PA ADMIN OFFICE SUPREME COURT BLDG, WASHINGTON, DC 20544 USA SN 0014-9128 J9 FED PROBAT JI Fed. Probat. PD DEC PY 1998 VL 62 IS 2 BP 30 EP 35 PG 6 WC Criminology & Penology; Law SC Criminology & Penology; Government & Law GA 179JX UT WOS:000079324500005 ER PT J AU Snyderwine, EG Sadrieh, N King, RS Schut, HAJ AF Snyderwine, EG Sadrieh, N King, RS Schut, HAJ TI Formation of DNA adducts of the food-derived mutagen 2-amino-9H-pyrido[2,3-b]indole (A(alpha)C) and bioassay of mammary gland carcinogenicity in Sprague-Dawley rats SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE heterocyclic amines; diet; breast cancer; postlabelling assay; cooked meat ID CIGARETTE-SMOKE CONDENSATE; AMINO-ALPHA-CARBOLINES; HETEROCYCLIC AMINES; COOKED FOOD; IN-VIVO; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE PHIP; P-32-POSTLABELING METHOD; SOYBEAN GLOBULIN; LIVER-MICROSOMES; SALIVARY-GLANDS AB 2-amino-9H-pyrido[2,3-b]indole (A alpha C) is a heterocyclic amine found at relatively high concentrations in barbecued or grilled meats. In the current study, the mammary gland carcinogenicity of A alpha C was examined in female Sprague-Dawley rats given IO doses of A alpha C (75 mg/kg, orally, once per day starting at 43 days of age) and placed on a defined high-fat diet (23.5% corn oil), a strong promotional factor for rat mammary gland carcinogenesis. Within 1 year, one out of 20 rats dosed with A alpha C developed a tubulopapillary carcinoma, indicating that the-bioassay was largely negative. As DNA adduct formation is considered to play a role in carcinogenesis, A alpha C-DNA adduct levels were measured in the mammary gland and other tissues by the P-32-postlabelling method. Under intensification conditions, one major adduct and up to three minor adducts were detected in isolated mammary gland epithelial cells and other tissues (liver, stomach, small intestine, colon and kidney) of A alpha C-treated rats; the adduct patterns were similar in all tissues examined. The major adduct, comprising 60-100% of total DNA adduct levels in tissues, was chromatographically identical to the principal adduct found in 3'-dGp-A alpha C (synthesized by reacting 3'-phospho-2'-deoxyguanosine (3'-dGp) with N-acetoxy-A alpha C). Of the tissues examined, the highest A alpha C-DNA adduct levels were found in the liver. In male rats given a single dose of A alpha C (75 mg/kg, orally, 3 hr prior to necropsy), no A alpha C-DNA adducts were detected in extrahepatic tissues. In female rats given a single dose or 12 daily doses of A alpha C, hepatic DNA adduct levels were at least 12-13-fold higher than those in any other tissue. Mean total A alpha C-DNA adduct levels in mammary gland epithelial cells and liver from female rats given multiple doses of A alpha C were 3.5 and 50.7 (RAL x 10(7)), respectively. Although factors in addition to DNA adduct formation are likely to play a role in mammary gland carcinogenesis, the results suggest that the weak mammary gland carcinogenicity of A alpha C may in part be associated with low A alpha C-DNA adduct levels in the mammary gland epithelium. Published by Elsevier Science Ltd. C1 NCI, Expt Carcinogenesis Lab, Chem Carcinogenesis Sect, NIH, Bethesda, MD 20892 USA. Natl Ctr Toxicol Res, Div Mol Epidemiol, Jefferson, AR 72079 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43614 USA. RP Snyderwine, EG (reprint author), NCI, Expt Carcinogenesis Lab, Chem Carcinogenesis Sect, NIH, Bldg 37,Room 3C28, Bethesda, MD 20892 USA. RI King, Roberta/A-1749-2010 OI King, Roberta/0000-0002-3550-4255 NR 49 TC 13 Z9 13 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD DEC PY 1998 VL 36 IS 12 BP 1033 EP + DI 10.1016/S0278-6915(98)00088-X PG 8 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 147QK UT WOS:000077577400001 PM 9862644 ER PT J AU Pennington, JAT AF Pennington, JAT TI Dietary exposure models for nitrates and nitrites SO FOOD CONTROL LA English DT Review DE dietary exposure; exposure models; nitrates/nitrites ID DOUBLY LABELED WATER; VOLATILE N-NITROSAMINES; SUPERCRITICAL-FLUID EXTRACTION; TOTAL-ENERGY EXPENDITURE; SPECTROPHOTOMETRIC METHOD; NITROSO COMPOUNDS; FRESH VEGETABLES; TRACE-ELEMENTS; FLOW-INJECTION; MEAT-PRODUCTS AB Models to assess dietary exposure of population groups to nitrates and nitrites should be based on the major sources of these substances in foods. Most models require the use of food consumption information and will, therefore, be flawed by the problems that exist with current dietary intake assessment methods. The Total Diet Study model would probably not provide representative coverage of the nitrites in processed meats. A nitrate/nitrite database model requires the gathering and compiling of published data and data from industry on the nitrate and nitrite content of foods. A nitrate/nitrite core food model requires the identification of the foods most responsible for nitrate/nitrite consumption in the U.S. and routine collection and analyses of these products. The large database model uses the database of a national food consumption survey and assigns nitrate and nitrite values to all the foods (based on available data and imputation). A processed meat production/consumption model focuses only on nitrites added to processed, cured meats. The nitrate/nitrite core food model is the preferred approach. Published by Elsevier Science Ltd. C1 NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. RP Pennington, JAT (reprint author), NIH, Div Nutr Res Coordinat, Natcher Bldg,Room 5AN32A,45 Ctr Dr, Bethesda, MD 20892 USA. NR 115 TC 52 Z9 54 U1 1 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0956-7135 J9 FOOD CONTROL JI Food Control PD DEC PY 1998 VL 9 IS 6 BP 385 EP 395 DI 10.1016/S0956-7135(98)00019-X PG 11 WC Food Science & Technology SC Food Science & Technology GA 137YR UT WOS:000076945100007 ER PT J AU Segovia, J Vergara, P Brenner, M AF Segovia, J Vergara, P Brenner, M TI Astrocyte-specific expression of tyrosine hydroxylase after intracerebral gene transfer induces behavioral recovery in experimental Parkinsonism SO GENE THERAPY LA English DT Article DE tyrosine hydroxylase; glial fibrillary acidic protein; promoter; intracerebral gene transfer; Parkinson's disease; 6-hydroxydopamine (6-OHDA) ID FIBRILLARY ACIDIC PROTEIN; IN-VITRO CHARACTERIZATION; PRODUCE L-DOPA; RAT MODEL; TRANSGENIC MICE; DOPAMINERGIC DENERVATION; MOUSE ASTROCYTES; DISEASE; GRAFTS; CELLS AB Parkinson's neurodegenerative disorder characterized by the depletion of dopamine in the caudate putamen. Dopamine replacement with levodopa, a precursor of the neurotransmitter, is presently the most common treatment for this disease. However. in an effort to obtain better therapeutic results, tissue or cells that synthesize catecholamines have been grafted into experimental animals and human patients. In this paper, we present a novel technique to express tyrosine hydroxylase (TH) in the host's own astrocytes. This procedure uses a transgene in which the expression of a TH cDNA is under the control of a glial fibrillary acidic protein (GFAP) promoter, which confers astrocyte-specific expression and also increases its-specific expression and also increases its activity in response to brain injury. The method was tested in a rat model of Parkinson ase produced by lesioning the striatum with 6-hydroxydopamine. Following microinjection of the transgene into the denervated striatum as a DNA-liposome complex, expression of the transgene was detected by RT-PCR and TH protein was observed specifically in astrocytes by using double-labeling immunofluorescence for GFAP and TH coupled with laser confocal microscopy. Efficacy was demonstrated by significant behavioral recovery, as assessed by a decrease in the pharmacologically induced turning behavior generated by the unilateral denervation of the rat striatum. These results suggest this is a valuable technique to express molecules of therapeutic interest in the brain. C1 IPN, Ctr Invest & Estudios Avanzados, Dept Fisiol Biofis & Neurociencias, Mexico City 07300, DF, Mexico. NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Segovia, J (reprint author), IPN, Ctr Invest & Estudios Avanzados, Dept Fisiol Biofis & Neurociencias, Av Inst Politecn Nacl 2508, Mexico City 07300, DF, Mexico. RI Segovia, Jose/C-9277-2011 OI Segovia, Jose/0000-0001-8215-4772 NR 45 TC 39 Z9 46 U1 0 U2 3 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD DEC PY 1998 VL 5 IS 12 BP 1650 EP 1655 DI 10.1038/sj.gt.3300776 PG 6 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 145NX UT WOS:000077378900009 PM 10023444 ER PT J AU Touraine, RL Ishii-Morita, H Ramsey, WJ Blaese, RM AF Touraine, RL Ishii-Morita, H Ramsey, WJ Blaese, RM TI The bystander effect in the HSVtk/ganciclovir system and its relationship to gap junctional communication SO GENE THERAPY LA English DT Article DE herpes simplex virus thymidine kinase; ganciclovir; bystander effect; gap junction; gene therapy ID THYMIDINE KINASE GENES; DYE TRANSFER; IN-VITRO; INTERCELLULAR COMMUNICATION; METABOLIC COOPERATION; SUICIDE GENES; BRAIN-TUMORS; HSVTK GENE; CELLS; THERAPY AB The bystander effect (BSE) is an interesting and important property of the herpes thymidine kinase/ganciclovir (hTK/GCV) system of gene therapy for cancer. With the BSE, not only are the hTK expressing cells killed upon ganciclovir (GCV) exposure but also neighboring wild-type tumor cells. On testing a large number of tumor cell lines in vitro, a wide range of sensitivity to bystander killing was found. Since transfer of toxic GCV metabolites from hTK-modified to wild-type tumor cells to wild-type tumor cells via gap junctions (GJ) seemed to be a likely mechanism of the BSE, we tested GJ function in these various tumors with a dye transfer technique and pharmacological agents known to affect GJ communication. We confirmed that mixtures of tumor cells resistant to the BSE did not show dye transfer from cell to cell while bystander-sensitive tumor cells did. Dieldrin, a drug known to decrease GJ communication, diminished dye transfer and also inhibited the BSE. Forskolin, an up-regulator of cAMP did increase GJ, but directly inhibited hTK and therefore its effect on BSE could not be determined. We conclude that these observations further support the concept that functional GJ play an important role in the BSE and further suggest that pharmacological manipulation of GJ may influence the outcome of cancer therapy with hTK/GCV. C1 Natl Human Genome Res Inst, Clin Gene Therapy Branch, NIH, Bethesda, MD USA. RP Touraine, RL (reprint author), Hop Necker Enfants Malad, Ctr Human Genet, U393,Tour Lavoisier,2eme Etage,149 Rue Sevres, F-75743 Paris 15, France. NR 30 TC 73 Z9 74 U1 0 U2 0 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD DEC PY 1998 VL 5 IS 12 BP 1705 EP 1711 DI 10.1038/sj.gt.3300784 PG 7 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 145NX UT WOS:000077378900015 PM 10023450 ER PT J AU Chaganti, SR Rao, PH Chen, WY Dyomin, V Jhanwar, SC Parsa, NZ Dalla-Favera, R Chaganti, RSK AF Chaganti, SR Rao, PH Chen, WY Dyomin, V Jhanwar, SC Parsa, NZ Dalla-Favera, R Chaganti, RSK TI Deregulation of BCL6 in non-Hodgkin lymphoma by insertion of IGH sequences in complex translocations involving band 3q27 SO GENES CHROMOSOMES & CANCER LA English DT Article ID B-CELL LYMPHOMA; GERMINAL-CENTER FORMATION; CHROMOSOMAL TRANSLOCATIONS; FINGER PROTEIN; GENE; REGION; REARRANGEMENTS; HYBRIDIZATION; INFLAMMATION; EXPRESSION AB Chromosomal band 3q27 frequently engages in translocations with a number of sites within the genome, including those containing IG and other genes, during the development of B-cell lymphoma. The BCL6 gene, mapped at 3q27, is deregulated in these translocations and was isolated from a t(3; 14)(q27;q32) translocation. It encodes a zinc-finger transcription repressor protein, which is expressed mainly in the germinal center (GC) B cells and plays a key role in GC development and T-cell-dependent immune response. BCL6 deregulation in 3q27 translocations is brought about by substitution of its 5' regulatory sequences by promoters of the rearranging genes. BCL6-rearranging genes studied so far (IGH, IGLL, TTF, BOBI, H4) displayed a broader pattern of expression than BCL6 during B-cell development. This observation has led to the suggestion that continued expression of BCL6 beyond its developmentally regulated point of downregulation under the direction of substituted promoters may keep the GC B cell in a cycling mode and lead to clonal expansion and lymphoma development. However, the rearranging partners of BCL6 in several of the 3q27 translocations have not yet been identified. In a molecular cloning analysis of two such translocations, t(1;3)(q21;q27) and t(3;6)(q27;p25), and an immunoblastic lymphoma cell line, OSI-LY8, we identified a novel mechanism of BCL6 deregulation. This comprised replacement of BCL6 5' regulatory sequences by insertion of IG gene transcriptional regulatory sequences at the translocation junction. These studies demonstrate novel features of instability of 3q27, and of the BCL6 and IGH genes, in B-cell lymphomagenesis. Genes Chromosomes Cancer 23:328-336, 1998. (C) 1998 Wiley-Liss, Inc. C1 Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst Canc Res, Canc Genet Lab, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Mem Hosp, Dept Human Genet, New York, NY 10021 USA. Natl Human Genome Res Inst, Canc Genet Lab, Bethesda, MD USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, Div Oncol, New York, NY USA. RP Chaganti, RSK (reprint author), Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst Canc Res, Canc Genet Lab, 1275 York Ave, New York, NY 10021 USA. FU NCI NIH HHS [CA44029, CA66699] NR 33 TC 21 Z9 21 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD DEC PY 1998 VL 23 IS 4 BP 328 EP 336 DI 10.1002/(SICI)1098-2264(199812)23:4<328::AID-GCC8>3.0.CO;2-M PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 134ZK UT WOS:000076773900008 PM 9824206 ER PT J AU Holland, EC Hively, WP Gallo, V Varmus, HE AF Holland, EC Hively, WP Gallo, V Varmus, HE TI Modeling mutations in the G(1) arrest pathway in human gliomas: overexpression of CDK4 but not loss of INK4a-ARF induces hyperploidy in cultured mouse astrocytes SO GENES & DEVELOPMENT LA English DT Article DE G(1) arrest; CDK4 amplification; INK4a-ARF loss; glioma-genesis; mouse astrocytes ID CELL-CYCLE ARREST; TUMOR SUPPRESSION; GROWTH-FACTOR; GENE; AMPLIFICATION; DELETION; LOCUS; P16; IMMORTALIZATION; GLIOBLASTOMAS AB Nearly all human gliomas exhibit alterations in one of three genetic loci governing G(1) arrest: INK4a-ARF, CDK4, or RE. To discern the roles of CDK4 amplification and INK4a-ARF loss in gliomagenesis, we compared the behavior of astrocytes lacking a functional INK4a-ARF locus with astrocytes overexpressing CDK4. Either a deficiency of p16(INK4a) and p19(ARF) or an increase in Cdk4 allows cultured astrocytes to grow without senescence. Astrocytes overexpressing CDK4 grow more slowly than INK4a-ARF-deficient astrocytes and convert to a tetraploid state at high efficiency; in contrast, INK4a-ARF-deficient cells remain pseudodiploid, consistent with properties observed in human gliomas with corresponding lesions in these genes. C1 NICHHD, Lab Cellular & Mol Neurophysiol, NIH, Bethesda, MD 20892 USA. NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Holland, EC (reprint author), MD Anderson Cancer Ctr, Dept Neurosurg, Houston, TX 77030 USA. NR 28 TC 85 Z9 86 U1 1 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 DEC 1 PY 1998 VL 12 IS 23 BP 3644 EP 3649 DI 10.1101/gad.12.23.3644 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 149WU UT WOS:000077630000003 PM 9851971 ER PT J AU Anderson, J Phan, L Cuesta, R Carlson, BA Pak, M Asano, K Bjork, GR Tamame, M Hinnebusch, AG AF Anderson, J Phan, L Cuesta, R Carlson, BA Pak, M Asano, K Bjork, GR Tamame, M Hinnebusch, AG TI The essential Gcd10p-Gcd14p nuclear complex is required for 1-methyladenosine modification and maturation of initiator methionyl-tRNA SO GENES & DEVELOPMENT LA English DT Article DE Gcd10p-Gcp14p nuclear complex; 1-methyladenosine; tRNA; initiator maturation ID TRANSFER-RNA GENES; SACCHAROMYCES-CEREVISIAE; TRANSLATION INITIATION; MAMMALIAN-CELLS; YEAST; ACID; PROTEINS; SUBUNIT; GCN4 AB Gcd10p and Gcd14p are essential proteins required for the initiation of protein synthesis and translational repression of GCN4 mRNA. The phenotypes of gcd10 mutants were suppressed by high-copy-number IMT genes, encoding initiator methionyl tRNA (tRNA(i)(Met)), or LHP1, encoding the yeast homolog of the human La autoantigen. The gcd10-504 mutation led to a reduction in steady-state levels of mature tRNA(i)(Met), attributable to increased turnover rather than decreased synthesis of pre-tRNA(i)(Met). Remarkably, the lethality of a GCD10 deletion was suppressed by high-copy-number IMT4, indicating that its role in expression of mature tRNA(i)(Met) is the essential function of Gcd10p. A gcd14-2 mutant also showed reduced amounts of mature tRNA(i)(Met), but in addition, displayed a defect in pre-tRNA(i)(Met) processing. Gcd10p and Gcd14p were found to be subunits of a protein complex with prominent nuclear localization, suggesting a direct role in tRNA(i)(Met) maturation. The chromatographic behavior of elongator and initiator tRNA(Met) on a RPC-5 column indicated that both species are altered structurally in gcd10 Delta cells, and analysis of base modifications revealed that 1-methyladenosine (m(1)A) is undetectable in gcd10 Delta tRNA. Interestingly, gcd10 and gcd14 mutations had no effect on processing or accumulation of elongator tRNA(Met), which also contains m(1)A at position 58, suggesting a unique requirement for this base modification in initiator maturation. C1 NICHHD, Eukaryot Mol Genet Lab, Bethesda, MD 20892 USA. NCI, Basic Res Lab, Div Basic Sci, Bethesda, MD 20892 USA. Univ Salamanca, Inst Microbiol Bioquim, CSIC, E-37008 Salamanca, Spain. Umea Univ, Dept Microbiol, S-90187 Umea, Sweden. RP Hinnebusch, AG (reprint author), NICHHD, Eukaryot Mol Genet Lab, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov NR 44 TC 131 Z9 138 U1 1 U2 7 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 DEC 1 PY 1998 VL 12 IS 23 BP 3650 EP 3662 DI 10.1101/gad.12.23.3650 PG 13 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 149WU UT WOS:000077630000004 PM 9851972 ER PT J AU Holland, EC Hively, WP DePinho, RA Varmus, HE AF Holland, EC Hively, WP DePinho, RA Varmus, HE TI A constitutively active epidermal growth factor receptor cooperates with disruption of G(1) cell-cycle arrest pathways to induce glioma-like lesions in mice SO GENES & DEVELOPMENT LA English DT Article DE EGFR; gliomagenesis; cell cycle arrest ID EGFR GENE AMPLIFICATION; WNT-1 TRANSGENIC MICE; GLIOBLASTOMA-MULTIFORME; MAMMARY CARCINOGENESIS; CDK4 AMPLIFICATION; TUMOR SUPPRESSION; INK4A LOCUS; EXPRESSION; P53; DELETION AB The epidermal growth factor receptor (EGFR) gene is amplified or mutated in 30%-50% of human gliobastoma multiforme (GBM). These mutations are associated usually with deletions of the INK4a-ARF locus, which encodes two gene products (p16(INK4a) and p19(ARF)) involved in cell-cycle arrest and apoptosis. We have investigated the role of EGFR mutation in gliomagenesis, using avian retroviral vectors to transfer a mutant EGER gene to glial precursors and astrocytes in transgenic mice expressing tv-a, a gene encoding the retrovirus receptor. TVA, under control of brain cell type-specific promoters. We demonstrate that expression of a constitutively active, mutant form of EGER in cells in the glial lineage can induce lesions with many similarities to human gliomas. These lesions occur more frequently with gene transfer to mice expressing tv-a from the progenitor-specific nestin promoter than to mice expressing tv-a from the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, suggesting that tumors arise more efficiently from immature cells in the glial lineage. Furthermore, EGFR-induced gliomagenesis appears to require additional mutations in genes encoding proteins involved in cell-cycle arrest pathways. We have produced these combinations by simultaneously infecting tv-a transgenic mice with vectors carrying cdk4 and EGFR or by infecting tv-a transgenic mice bearing a disrupted INK4a-ARF locus with the EGFR-carrying vector alone. Moreover, EGFR-induced gliomagenesis does not occur in conjunction with p53 deficiency, unless the mice are also infected with a vector carrying cdk4. The gliomagenic combinations of genetic lesions required in mice are similar to those found in human gliomas. C1 NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Holland, EC (reprint author), MD Anderson Cancer Ctr, Dept Neurosurg, Houston, TX 77030 USA. EM eholland@notes.mdacc.tmc.edu FU NEI NIH HHS [EY11267] NR 41 TC 334 Z9 342 U1 1 U2 7 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 DEC 1 PY 1998 VL 12 IS 23 BP 3675 EP 3685 DI 10.1101/gad.12.23.3675 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 149WU UT WOS:000077630000006 PM 9851974 ER PT J AU Collins, FS Brooks, LD Chakravarti, A AF Collins, FS Brooks, LD Chakravarti, A TI A DNA polymorphism discovery resource for research on human genetic variation SO GENOME RESEARCH LA English DT Article ID CYSTIC-FIBROSIS GENE; IDENTIFICATION C1 Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA. Case Western Reserve Univ, Ctr Human Genet, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. RP Brooks, LD (reprint author), Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. NR 16 TC 470 Z9 497 U1 3 U2 27 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD DEC PY 1998 VL 8 IS 12 BP 1229 EP 1231 PG 3 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 153YG UT WOS:000077860700001 PM 9872978 ER PT J AU Hacia, JC Sun, B Hunt, N Edgemon, K Mosbrook, D Robbins, C Fodor, SPA Tagle, DA Collins, FS AF Hacia, JC Sun, B Hunt, N Edgemon, K Mosbrook, D Robbins, C Fodor, SPA Tagle, DA Collins, FS TI Strategies for mutational analysis of the large multiexon ATM gene using high-density oligonucleotide arrays SO GENOME RESEARCH LA English DT Article ID ATAXIA-TELANGIECTASIA; BREAST-CANCER; DNA ARRAYS; HYBRIDIZATION AB Mutational analysis of large genes with complex genomic structures plays an important role in medical genetics. Technical limitations associated with current mutation screening protocols have placed increased emphasis on the development of new technologies to simplify these procedures. High-density arrays of >90,000-oligonucleotide probes, 25 nucleotides in length, were designed to screen For all possible heterozygous germ-line mutations in the 9.17-kb coding region of the ARI gene. A strategy For rapidly developing multiexon PCR amplification protocols in DNA chip-based hybridization analysis was devised and implemented in preparing target for the 62 ATM coding exons. Improved algorithms For interpreting data From two-color experiments, where reference and test samples are cohybridized to the arrays, were developed. In a blinded study, 17 of 18 distinct heterozygous and 8 of 8 distinct homozygous sequence variants in the assayed region were detected accurately along with five false-positive calls while scanning >200 kb in 22 genomic DNA samples. Of eight heterozygous sequence changes found in more than one sample, six were detected in all cases. Five previously unreported sequence changes, not found by other mutational scanning methodologies on these same samples, were detected that led to either amino acid changes or premature truncation of the ATM protein. DNA chip-based assays should play a valuable role in high throughput sequence analysis of complex genes. C1 Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. Affymetrix, Santa Clara, CA 95051 USA. RP Collins, FS (reprint author), Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. EM fc23a@nih.gov OI Sun, Bryan/0000-0002-0740-0125 FU NHGRI NIH HHS [5POLHGO1323-03] NR 37 TC 96 Z9 104 U1 0 U2 6 PU COLD SPRING HARBOR LAB PRESS PI PLAINVIEW PA 1 BUNGTOWN RD, PLAINVIEW, NY 11724 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD DEC PY 1998 VL 8 IS 12 BP 1245 EP 1258 PG 14 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 153YG UT WOS:000077860700003 PM 9872980 ER PT J AU Jin, HM Copeland, NG Gilbert, DJ Jenkins, NA Kirkpatrick, RB Rosenberg, M AF Jin, HM Copeland, NG Gilbert, DJ Jenkins, NA Kirkpatrick, RB Rosenberg, M TI Genetic characterization of the murine Ym1 gene and identification of a cluster of highly homologous genes SO GENOMICS LA English DT Article ID CHITINASE PROTEIN FAMILY; HUMAN CARTILAGE GP-39; MOLECULAR CHARACTERIZATION; CHROMOSOMAL LOCALIZATION; OVIDUCTAL GLYCOPROTEIN; CLONING; MEMBER; CHITOTRIOSIDASE; SEQUENCE; MARKERS AB The murine Ym1 gene belongs to a family of mammalian genes that are homologous to the chitinases from lower organisms, such as insects, nematodes, bacteria, and plants. All of these homologous mammalian proteins (except one member) have no demonstrable chitinase activity and therefore cannot be considered chitinases. The biological functions of these proteins remain unknown. However, these proteins may function through binding to carbohydrate polymers. In an effort to characterize the murine Ym1 gene better, we have delineated its genomic structure. We mapped the chromosomal location of the Ym1 gene to a central region of mouse chromosome 3 (in the region syntenic to human chromosome 1p13) and that of another murine chitinase-like gene, Brp39, to a central region of mouse chromosome 1 (in the region syntenic to human chromosome 1q31). In addition, we identified several genes highly homologous to Ym1 that cluster at the Ym1 locus. We show that these genes are expressed selectively in different mouse tissues. (C) 1998 Academic Press. C1 SmithKline Beecham Pharmaceut, Res & Dev, King Of Prussia, PA 19406 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Frederick, MD 21702 USA. RP Jin, HM (reprint author), SmithKline Beecham Pharmaceut, Res & Dev, UE0548,709 Swedeland Rd, King Of Prussia, PA 19406 USA. NR 24 TC 56 Z9 61 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD DEC 1 PY 1998 VL 54 IS 2 BP 316 EP 322 DI 10.1006/geno.1998.5593 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 145BF UT WOS:000077350500014 PM 9828134 ER PT J AU Xie, JP Zhang, BW Lan, MS Notkins, AL AF Xie, JP Zhang, BW Lan, MS Notkins, AL TI Genomic structure and promoter sequence of the insulin-dependent diabetes mellitus autoantigen, IA-2 (PTPRN) SO GENOMICS LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; TRANSMEMBRANE PROTEIN; MOLECULAR-CLONING; GENE; IA-2-BETA; FAMILY; BINDING; AUTOANTIBODIES; IDENTIFICATION; TRANSCRIPTION AB IA-2 is a transmembrane protein tyrosine phosphatase, expressed in neuroendocrine cells, and a major autoantigen in insulin-dependent diabetes mellitus. In the present study we elucidated the structure of the IA-2 gene (HGMW-approved symbol PTPRN) and its promoter sequence. A 40-kb genomic clone covering the whole IA-2 coding sequence and 4 kb proximal 5'-upstream sequence was isolated and mapped. The IA-2 gene encompasses approximately 20 kb with 23 exons ranging from 34 bp to more than 650 bp. The extracellular domain is encoded by exons 1-12, the transmembrane region by exon 13, and the intracellular domain by exons 14-23. The transcriptional start site(s) of the IA-2 gene was mapped by 5' rapid amplification of cDNA ends to 97 bp upstream of the translational start site. A 3-kb 5'-upstream region was sequenced, revealing a GC-rich region and TATA-less sequence containing several potential transcription-regulating sites (i.e., Spl, CREB, GATA-1, and MZF). Functional promoter activity was confirmed by transient transfection of U87MG cells with deletion mutants linked to a luciferase reporter gene. (C) 1998 Academic Press. C1 NIDR, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Notkins, AL (reprint author), NIDR, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bldg 30,Room 121,30 Convent Dr MSC 4322, Bethesda, MD 20892 USA. EM notkins@yoda.nidr.nih.gov NR 25 TC 15 Z9 15 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD DEC 1 PY 1998 VL 54 IS 2 BP 338 EP 343 DI 10.1006/geno.1998.5583 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 145BF UT WOS:000077350500018 PM 9828138 ER PT J AU Burbelo, PD Kozak, CA AF Burbelo, PD Kozak, CA TI Mapping of the murine LZIP gene (Creb3) to chromosome 4 SO GENOMICS LA English DT Article ID FAMILY; VP16; HCF C1 Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. RI Burbelo, Peter/B-1027-2009 NR 6 TC 5 Z9 5 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD DEC 1 PY 1998 VL 54 IS 2 BP 357 EP 358 DI 10.1006/geno.1998.5574 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 145BF UT WOS:000077350500024 PM 9828144 ER PT J AU Liu, X Mashour, GA Webster, HD Kurtz, A AF Liu, X Mashour, GA Webster, HD Kurtz, A TI Basic FGF and FGF receptor 1 are expressed in microglia during experimental autoimmune encephalomyelitis: Temporally distinct expression of midkine and pleiotrophin SO GLIA LA English DT Article DE demyelination; heparin-binding growth factors; microglia; multiple sclerosis ID FIBROBLAST GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; EPITHELIAL-MESENCHYMAL INTERACTIONS; SPINAL-CORD INJURY; ADULT-RAT BRAIN; HB-GAM; CELL-PROLIFERATION; MESSENGER-RNA; RETINOIC ACID; OLIGODENDROCYTE DEVELOPMENT AB Heparin-binding growth factors have been implicated in central nervous system development, regeneration and pathology. To assess the expression pattern and possible function in multiple sclerosis, the heparin-binding growth factors pleiotrophin (PTN), midkine (MK), basic fibroblast growth factor (FGF-2) and one of its receptors (FGFR1/flg) mRNA and protein levels were examined in an experimental autoimmune encephalomyelitis (EAE) model in the Lewis rat. We assessed the time course of expression of PTN, MK and FGF-2 during EAE and determined the cellular origin of FGF-2 and FGFR1 in normal spinal cord and during inflammatory demyelination. Basal expression of PTN and MK mRNAs in normal spinal cords was significantly upregulated after induction of EAE. MK expression was upregulated two to threefold correlating with disease progression, whereas PTN expression reached peak levels threefold above basal levels during the clinical recovery period. FGF-2 mRNA expression was low in normal spinal cord and dramatically increased in correlation with progressive demyelination. FGF-2 was confined to neurons in normal tissue and shifted dramatically to microglia, paralleling their activation during EAE. Double immunohistochemistry revealed colocalization of FGF-2 to activated microglia/macrophages with strongest expression in the macrophage-rich perivascular core area and microglial expression at the edges of white and gray matter perivascular regions. FGFR1, like its ligand, was induced in activated macrophages/microglia. Growth factor expression in demyelinating diseases could serve several functions, e.g., to modulate the activity of microglia/macrophage in an autocrine fashion, to induce the expression of other factors like insulin-like growth factor 1 or plasminogen activator, which can effect regeneration or degeneration, respectively, and finally to stimulate directly localized proliferation and/or regeneration of oligodendrocytes within the lesion area. GLIA 24:390-397, 1998. (C) 1998 Wiley-Liss, Inc. C1 Georgetown Univ, Dept Neurosurg, Washington, DC 20007 USA. NINDS, Expt Neuropathol Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Pharmacol, Washington, DC 20007 USA. RP Kurtz, A (reprint author), Georgetown Univ, Dept Neurosurg, 3970 Reservoir Rd, Washington, DC 20007 USA. NR 57 TC 54 Z9 56 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0894-1491 J9 GLIA JI Glia PD DEC PY 1998 VL 24 IS 4 BP 390 EP 397 DI 10.1002/(SICI)1098-1136(199812)24:4<390::AID-GLIA4>3.0.CO;2-1 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 131UN UT WOS:000076593800004 PM 9814819 ER PT J AU Trimble, EL Kosary, C Park, RC AF Trimble, EL Kosary, C Park, RC TI Lymph node sampling and survival in endometrial cancer SO GYNECOLOGIC ONCOLOGY LA English DT Article ID PARAAORTIC LYMPHADENECTOMY; MYOMETRIAL INVASION; ADENOCARCINOMA AB Objective. To determine the impact of pelvic lymph node sampling on survival in women with FIGO stage I and II endometrial adenocarcinoma. Methods. We reviewed data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program on 9185 women with stage I endometrial cancer and 881 women with stage II endometrial cancer. Life table analysis was used to compare survival rates. Results. Overall, lymph node sampling did not appear to convey survival benefit. The 5-year relative survival for 6363 women with stage I endometrial cancer who did not undergo lymph node sampling was 0.98, compared to 0.96 for 2831 women who did undergo lymph node sampling at the time of hysterectomy, a nonsignificant difference. Lymph node sampling (LNS) was associated with increased survival among those with stage I, grade 3 disease, but not grade 1 or grade 2. Women with stage I, grade 3 disease who underwent LNS had a relative 5-year survival of 0.89, compared to 0.81 for those who did not undergo LNS (P = 0.0110). Nonsignificantly improved survival associated with LNS for women with grade 3 disease was observed in International Federation of Gynecology and Obstetrics stages Ib, Ic, and II. Conclusions. The observed survival benefit associated with lymph node sampling may be due to identification of women with more advanced endometrial cancer. Accurate determination of grade and extent of tumor is necessary to delineate which patients may benefit from lymph node sampling at hysterectomy. Effective cooperation between surgical pathology and gynecology services may be required to ensure adequate examination of the hysterectomy specimen. A surgeon with expertise in performing lymph node sampling should be available if operative findings render lymph node sampling appropriate, (C) 1998 Academic Press. C1 NCI, Bethesda, MD 20892 USA. Gynecol Oncol Grp, Philadelphia, PA 19107 USA. RP Trimble, EL (reprint author), NCI, Bethesda, MD 20892 USA. NR 15 TC 98 Z9 106 U1 1 U2 1 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 DEC PY 1998 VL 71 IS 3 BP 340 EP 343 DI 10.1006/gyno.1998.5254 PG 4 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 156XX UT WOS:000078029000002 PM 9887227 ER PT J AU Frolenkov, GI Belyantseva, IA Kurc, M Mastroianni, MA Kachar, B AF Frolenkov, GI Belyantseva, IA Kurc, M Mastroianni, MA Kachar, B TI Cochlear outer hair cell electromotility can provide force for both low and high intensity distortion product otoacoustic emissions SO HEARING RESEARCH LA English DT Article DE cochlear amplifier; outer hair cell motility; otoacoustic emission; sulfhydryl reagent; guinea pig ID GUINEA-PIG COCHLEA; 2 DISCRETE SOURCES; ACOUSTIC DISTORTION; ETHACRYNIC-ACID; IMPAIRED EARS; SALICYLATE; RESPONSES; GENTAMICIN; DEPENDENCE; VULNERABILITY AB It is generally believed that the force for the otoacoustic emission (OAE) generation is provided by a mechanism of electromotility, observed in isolated cochlear outer hair cells (OHCs). OHC electromotility is resistant to several ototoxic reagents, it does not depend on ATP hydrolysis, but it can be blocked by specific sulfhydryl reagents: p-chloromercuriphenylsulfonic acid (pCMPS) and p-hydroxymercuriphenylsulfonic acid (pHMPS). We have used these reagents to test whether they also affect OAE. Application of pCMPS and pHMPS on the round window membrane of anesthetized guinea pigs produced a dose-dependent inhibition of the cubic (2F(1)-F(2)) distortion product OAE (DPOAE). The inhibition developed progressively from high to low frequencies, reflecting the diffusion of the drugs through the cochlear compartment. The effect of pCMPS and pHMPS was different from the effects of furosemide and lethal anoxia, which impair cochlear function but do not block OHC electromotility. pHMPS suppressed DPOAE completely at all sound intensities tested (45-80 dB SPL), whereas furosemide or lethal anoxia caused DPOAE to disappear at low-level stimulation (45-60 dB SPL) only. Our results suggest that the OHC electromotility might provide the force for DPOAE generation not only at low, but also at high stimulus intensities. (C) 1998 Elsevier Science B.V. All rights reserved. C1 NIDCD, Sect Struct Cell Biol, Lab Cellular Biol, NIH, Rockville, MD 20852 USA. RP Kachar, B (reprint author), NIDCD, Sect Struct Cell Biol, Lab Cellular Biol, NIH, Bldg 36-5D15, Rockville, MD 20852 USA. EM bkachar@pop.nidcd.nih.gov NR 52 TC 34 Z9 34 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD DEC PY 1998 VL 126 IS 1-2 BP 67 EP 74 DI 10.1016/S0378-5955(98)00150-6 PG 8 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 146VA UT WOS:000077451500008 PM 9872135 ER PT J AU Seeff, LB AF Seeff, LB TI The natural history of hepatitis C - A quandary SO HEPATOLOGY LA English DT Editorial Material ID NON-B-HEPATITIS; HEPATOCELLULAR-CARCINOMA; NON-A; TRANSFUSION; CIRRHOSIS; ALPHA C1 NIDDK, NIH, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. Georgetown Univ, Sch Med, Washington, DC USA. RP Seeff, LB (reprint author), NIDDK, NIH, 31 Ctr Dr, Bethesda, MD 20892 USA. EM seeffl@extra.niddk.nih.gov NR 27 TC 31 Z9 32 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 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 1998 VL 28 IS 6 BP 1710 EP 1712 DI 10.1002/hep.510280636 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 143LL UT WOS:000077257100036 PM 9828240 ER PT J AU Torpy, DJ Bornstein, SR Chrousos, GP AF Torpy, DJ Bornstein, SR Chrousos, GP TI Leptin and interleukin-6 in sepsis SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE leptin; interleukin-6; critical illness; sepsis ID PITUITARY-ADRENAL AXIS; NONTHYROIDAL ILLNESS; SERUM INTERLEUKIN-6; CYTOKINES; HUMANS; EXPRESSION; ELEVATION; IL-6; ACTIVATION; INFECTION AB Both leptin and interleukin-6 (IL-6) are hypersecreted in acute critical illness, such as sepsis. Leptin is produced by adipocytes, it inhibits appetite and stimulates the sympathetic nervous system, thereby reducing adipose mass. IL-6 is produced by immune cells and adipocytes, it reduces the production of other inflammatory cytokines and stimulates release of acute phase proteins by the liver, participating in the control of inflammation. Leptin inhibits, whereas IL-6 stimulates, the hypothalamic-pituitary-adrenal axis. While high IL-6 levels are associated with poor outcome in critically ill patients, the role of leptin in critical illness and its importance for survival are not known. To examine the relation between IL-6, leptin and cortisol in critical illness, we performed frequent 4 h plasma sampling in eight patients on day 1 of intensive care unit admission for acute sepsis. Sampling was repeated on days 3 and 5 in the five survivors. The levels of all three hormones were markedly elevated; there was a lack of the normal diurnal rhythmicity of leptin and IL-6 and a blunted diurnal rhythmicity of cortisol secretion. A strong negative correlation between mean 24 h plasma IL-6 and leptin was revealed. Although such a relationship could possibly be explained by the negative and positive effects of cortisol hypersecretion on each hormone respectively, a negative correlation between leptin and cortisol was detected, whereas there was no significant correlation between IL-6 and cortisol. Mean IL-6 values were higher (1389.5+/-644.9 vs. 658.8+/-250.5) and leptin levels were lower (2.73+/-1.1 vs. 26.5+/-11.6) in the non-survivors than in the survivors. These findings suggest that IL-6 is not the principal stimulus of leptin hypersecretion in critically ill patients with sepsis. The negative relation between IL-6 and leptin is of potential importance, as high IL-6 levels have been associated with poor outcome in critically ill patients, and relatively low leptin levels may impair sympathetic system and immune functions. C1 NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. RP Bornstein, SR (reprint author), NIH, 10 Ctr Dr,Bldg 10,Rm 10N262, Bethesda, MD 20892 USA. EM BORNSTES@cci.nichd.nih.gov NR 31 TC 81 Z9 87 U1 0 U2 2 PU GEORG THIEME VERLAG PI STUTTGART PA P O BOX 30 11 20, D-70451 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD DEC PY 1998 VL 30 IS 12 BP 726 EP 729 DI 10.1055/s-2007-978967 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 159DL UT WOS:000078156500006 PM 9930630 ER PT J AU Portier, CJ Ye, F AF Portier, CJ Ye, F TI U-shaped dose-response curves for carcinogens SO HUMAN & EXPERIMENTAL TOXICOLOGY LA English DT Article DE cancer; mathematical modeling; dose-response; risk assessment ID EXPRESSION C1 NIEHS, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC 27709 USA. RP Portier, CJ (reprint author), NIEHS, Lab Computat Biol & Risk Anal, POB 12233, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 10 TC 1 Z9 1 U1 0 U2 1 PU STOCKTON PRESS PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0144-5952 J9 HUM EXP TOXICOL JI Hum. Exp. Toxicol. PD DEC PY 1998 VL 17 IS 12 BP 705 EP 707 DI 10.1191/096032798678908198 PG 3 WC Toxicology SC Toxicology GA 160BP UT WOS:000078210700011 PM 9988376 ER PT J AU Kleiderlein, JJ Nisson, PE Jessee, J Li, WB Becker, KG Derby, ML Ross, CA Margolis, RL AF Kleiderlein, JJ Nisson, PE Jessee, J Li, WB Becker, KG Derby, ML Ross, CA Margolis, RL TI CCG repeats in cDNAs from human brain SO HUMAN GENETICS LA English DT Article ID PROGRESSIVE MYOCLONUS EPILEPSY; CYSTATIN-B GENE; TRINUCLEOTIDE REPEATS; CTG REPEAT; MYOTONIC-DYSTROPHY; CAG TRINUCLEOTIDE; CAG/CTG REPEATS; MOLECULAR-BASIS; TRIPLET REPEAT; HUMAN GENOME AB Expansion mutations of trinucleotide repeats and other units of unstable DNA have been proposed to account for at least some of the genetic susceptibility to a number of neuropsychiatric disorders, including bipolar affective disorder, schizophrenia, autism, and panic disorder. To generate additional candidate genes for these and other disorders, cDNA libraries from human brain were probed at high stringency for clones containing CCG, CGC, GCC, CGG, GCG, and GGC repeats (referred to collectively as CCG repeats). Some 18 cDNAs containing previously unpublished or uncharacterized repeats were characterized for chromosomal locus, repeat length polymorphism, and similarity to genes of known function. The cDNAs were also compared with the 37 human genes with eight or more consecutive CCG triplets in GenBank. The repeats were mapped to a number of loci, including 1p34, 2p11.2, 2q30-32 3p21, 3p22, 4q35, 6q22, 7qter, 13p13, 17q24, 18p11, 14p13.3, 20q12, 20q13.3, and 22q12. Length polymorphism was detected in 50% of the repeats. The newly cloned cDNAs in elude a complete transcript of human neurexin-1B, a portion of BCNG-1 (a newly described brain-specific ion channel), a previously unreported polymolphic repeat located in the 5' UTR legion of the guanine nucleotide-binding protein (G-protein) beta 2 subunit, and a human version of the mouse proline-rich protein 7. This list of cDNAs should expedite the search for expansion mutations associated with diseases of the central nervous system. C1 Johns Hopkins Univ, Sch Med, Labs Genet Neurobiol & Mol Neurobiol, Div Neurobiol,Dept Psychiat, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Program Cellular & Mol Med, Baltimore, MD 21287 USA. Life Technol Inc, Rockville, MD 20850 USA. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Margolis, RL (reprint author), Johns Hopkins Univ, Sch Med, Labs Genet Neurobiol & Mol Neurobiol, Div Neurobiol,Dept Psychiat, 600 N Wolfe St,Meyer 2-181, Baltimore, MD 21287 USA. EM rmargoli@jhmi.edu RI Ross, Christopher/H-8395-2013; OI Becker, Kevin/0000-0002-6794-6656 FU NIMH NIH HHS [MH50763, MH01275] NR 55 TC 26 Z9 28 U1 0 U2 3 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD DEC PY 1998 VL 103 IS 6 BP 666 EP 673 DI 10.1007/s004390050889 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 154UP UT WOS:000077907900007 PM 9921901 ER PT J AU Alexander, J Del Guercio, MF Fikes, JD Chesnut, RW Chisari, FV Chang, KM Appella, E Sette, A AF Alexander, J Del Guercio, MF Fikes, JD Chesnut, RW Chisari, FV Chang, KM Appella, E Sette, A TI Recognition of a novel naturally processed, A2 restricted, HCV-NS4 epitope triggers IFN-gamma release in absence of detectable cytopathicity SO HUMAN IMMUNOLOGY LA English DT Article ID HEPATITIS-C VIRUS; CYTOTOXIC T-LYMPHOCYTES; B VIRUS; INTRACELLULAR INACTIVATION; NONSTRUCTURAL PROTEIN-3; HLA-A2.1 MOLECULES; VIRAL-INFECTION; PEPTIDE BINDING; CTL RESPONSES; HUMANS AB Using short term CTL lines derived from HLA A2/K-b transgenic mice and IFN-gamma release assays we demonstrate that the NS4.1769 epitope, is generated from natural processing of the NS4 antigen, and presented in the context of the A2/K-b molecules. Interestingly, T cell recognition of che naturally processed form of the NS4.1769 epitope was associated with significant IFN-gamma release, but no direct cytolytic activity. Epitopes of this phenotype might be of interest, in terms of therapy of chronic HCV infection by associating the benefit of localized lymphokine release with low or absent direct cytopathicity. Human Immunology 59, 776-782 (1998). (C) American Society for Histocompatibility and Immunogenetics, 1998. Published by Elsevier Science Inc. C1 Epimmune Inc, San Diego, CA 92121 USA. Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Alexander, J (reprint author), Epimmune Inc, 6555 Nancy Ridge Dr,Suite 200, San Diego, CA 92121 USA. EM jalexander@epimmune.com RI Chisari, Francis/A-3086-2008; OI Chisari, Francis/0000-0002-4832-1044 FU NIAID NIH HHS [2R44 AI 38620-02, N01-AI-45241, R01-AI-20001] NR 28 TC 19 Z9 19 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0198-8859 J9 HUM IMMUNOL JI Hum. Immunol. PD DEC PY 1998 VL 59 IS 12 BP 776 EP 782 DI 10.1016/S0198-8859(98)00080-9 PG 7 WC Immunology SC Immunology GA 137DN UT WOS:000076899700004 PM 9831133 ER PT J AU Stairs, DB Gardner, HP Ha, SI Copeland, NG Gilbert, DJ Jenkins, NA Chodosh, LA AF Stairs, DB Gardner, HP Ha, SI Copeland, NG Gilbert, DJ Jenkins, NA Chodosh, LA TI Cloning and characterization of Krct, a member of a novel subfamily of serine/threonine kinases SO HUMAN MOLECULAR GENETICS LA English DT Article ID POLYMERASE CHAIN-REACTION; TYROSINE KINASE; BREAST-CANCER; CONSERVED FEATURES; TRANSGENIC MICE; MAMMARY-TUMORS; DIFFERENTIATION; GROWTH; FAMILY; EXPRESSION AB Protein kinases frequently play key roles in the normal regulation of growth and development in eukaryotic organisms. As a consequence, aberrant expression or mutations in this family of molecules frequently result in transformation. Previously, we have conducted a screen to identify protein kinases that are expressed in the mouse during mammary gland development and in breast cancer cell lines. We now describe the molecular cloning, characterization and expression of Krct, a navel serine/threonine protein kinase unrelated to previously defined families of protein kinases, At the mRNA level, Krct is widely expressed throughout murine development and in adult tissues. Despite its ubiquitous expression, Krct is expressed preferentially within specific cellular compartments in multiple tissues, in particular within the testis and gastrointestinal tract. At the amino acid level, Krct is most closely related to four previously undescribed kinases in Saccharomyces cerevisiae, Arabidopsis thaliana and Caenorhabditis elegans. Together, these kinases appear to define a novel subfamily of serine/threonine protein kinases, Krct possesses an unusually long 5'-untranslated region containing multiple upstream initiation codons and, in this regard, is similar to many proto-oncogenes that regulate normal growth and differentiation. In addition, Krct is located on mouse chromosome 11 closely linked to the epidermal growth factor receptor and, therefore, is likely to be coamplified in a variety of human tumors. C1 Univ Penn, Sch Med, Dept Mol & Cellular Engn, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Stellar Chance Labs, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mammalian Genet Lab, Ft Detrick, MD 21702 USA. RP Chodosh, LA (reprint author), Univ Penn, Sch Med, Dept Mol & Cellular Engn, Room 309A,422 Curie Blvd, Philadelphia, PA 19104 USA. EM chodosh@mail.med.upenn.edu FU NCI NIH HHS [CA71513, CA78410] NR 29 TC 20 Z9 22 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC PY 1998 VL 7 IS 13 BP 2157 EP 2166 DI 10.1093/hmg/7.13.2157 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 147PY UT WOS:000077576700022 PM 9817935 ER PT J AU Lujan AF Lujan TI Detection of microsporidia spore-specific antigens by monoclonal antibodies (vol 17, pg 237, 1998) SO HYBRIDOMA LA English DT Correction C1 NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lujan (reprint author), NIH, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0272-457X J9 HYBRIDOMA JI Hybridoma PD DEC PY 1998 VL 17 IS 6 BP 581 EP 581 PG 1 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Immunology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Immunology GA 153YN UT WOS:000077861300011 ER PT J AU Vaquero, JJ Seidel, J Siegel, S Gandler, WR Green, MV AF Vaquero, JJ Seidel, J Siegel, S Gandler, WR Green, MV TI Performance characteristics of a compact position-sensitive LSO detector module SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE intercrystal scatter; lutetium oxyorthosilicate : Ce (LSO); position-sensitive photomultiplier tubes; small animal positron emission tomography (PET) ID DOPED LUTETIUM OXYORTHOSILICATE; POSITRON EMISSION TOMOGRAPHY; HIGH-RESOLUTION PET; LIGHT OUTPUT; DESIGN; CRYSTALS; ARRAY; PROBE AB We assembled a compact detector module comprised of an array of small, individual crystals of lutetium oxyorthosilicate:Ce (LSO) coupled directly to a miniature, metal-can, position-sensitive photomultiplier tube (PSPMT). We exposed this module to sources of 511-keV annihilation radiation and beams of 30- and 140-keV photons and measured spatial linearity; spatial variations in module gain, energy resolution, and event positioning; coincidence timing; the accuracy and sensitivity of identifying the crystal-of-first-interaction at 511 keV; and the effects of intercrystal scatter and LSO background radioactivity. The results suggest that this scintillator/phototube combination should be highly effective in the coincidence mode and can be used, with some limitations, to image relatively low-energy single photon emitters. Photons that are completely absorbed on their first interaction at 511 keV are positioned by the module at the center of a crystal. Intercrystal scatter events, even those that lead to total absorption of the incident photon, are placed by the module in a regular "connect-the-dot" pattern that joins crystal centers, As a result, the accuracy of event positioning can be made to exceed 90%, though at significantly reduced sensitivity, by retaining only events that occur within small regions-of-interest around each crystal center and rejecting events that occur outside these regions in the connect-the-dot pattern. C1 NIH, Dept Nucl Med, Bethesda, MD 20892 USA. RP Green, MV (reprint author), NIH, Dept Nucl Med, Bldg 10,Room 1C401 MSC 1180, Bethesda, MD 20892 USA. RI Vaquero, Juan Jose/D-3033-2009 OI Vaquero, Juan Jose/0000-0001-9200-361X NR 27 TC 35 Z9 36 U1 2 U2 4 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI NEW YORK PA 345 E 47TH ST, NEW YORK, NY 10017-2394 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD DEC PY 1998 VL 17 IS 6 BP 967 EP 978 DI 10.1109/42.746629 PG 12 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 166TH UT WOS:000078592900011 PM 10048853 ER PT J AU Riddell, C Barker, WC Bacharach, SL AF Riddell, C Barker, WC Bacharach, SL TI Limited sinogram completion for transmission SPECT imaging SO IEEE TRANSACTIONS ON NUCLEAR SCIENCE LA English DT Article; Proceedings Paper CT 1997 Medical Imaging Conference CY NOV 13-15, 1997 CL ALBUQUERQUE, NEW MEXICO ID ATTENUATION CORRECTION; RECONSTRUCTION; EMISSION; ALGORITHMS; TOMOGRAPHY; CT AB Truncation artifacts can occur in simultaneous emission transmission SPECT imaging even with parallel geometry, especially when the acquisition geometry is optimized for emission at the expense of the transmission data. We hypothesized that the addition of only a few projections sampling truncated areas (by shifting the bed/camera) would permit a significant improvement in image quality with only a small increase in imaging time. In parallel geometry, data are preprocessed and the;additional projections are merged into the original sinogram, thereby partially completing it. For fan-beam data, the projector routine is modified to take into account different bed positions. Both cases require the use of an iterative reconstruction algorithm. Improvements due to partial completion are shown for different increases of total imaging time for both geometries, On simulated and true data, a 15% increase of imaging time led to a better recovery of the truncated area than obtained from a priori knowledge of the body contour. C1 NIH, Bethesda, MD 20892 USA. RP Riddell, C (reprint author), NIH, Bldg 10,Room 1C401, Bethesda, MD 20892 USA. NR 18 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 0018-9499 J9 IEEE T NUCL SCI JI IEEE Trans. Nucl. Sci. PD DEC PY 1998 VL 45 IS 6 BP 3036 EP 3044 DI 10.1109/23.737661 PN 2 PG 9 WC Engineering, Electrical & Electronic; Nuclear Science & Technology SC Engineering; Nuclear Science & Technology GA 149UQ UT WOS:000077624500008 ER PT J AU Sogn, JA AF Sogn, JA TI Tumor immunology: The glass is half full SO IMMUNITY LA English DT Review ID SIGNAL-TRANSDUCTION MOLECULES; CYTOTOXIC T-LYMPHOCYTES; ANTIGENIC CANCER-CELLS; BEARING MICE; IMMUNE-RESPONSE; TRANSGENIC MICE; SOLID TUMORS; FAS-LIGAND; IN-VIVO; LYMPHOMA C1 NCI, Div Canc Biol, Canc Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Sogn, JA (reprint author), NCI, Div Canc Biol, Canc Immunol Branch, NIH, Bethesda, MD 20892 USA. NR 73 TC 108 Z9 113 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC PY 1998 VL 9 IS 6 BP 757 EP 763 DI 10.1016/S1074-7613(00)80641-X PG 7 WC Immunology SC Immunology GA 153MJ UT WOS:000077836600001 PM 9881966 ER PT J AU Tanchot, C Rocha, B AF Tanchot, C Rocha, B TI The organization of mature T-cell pools SO IMMUNOLOGY TODAY LA English DT Review ID POSITIVE SELECTION; DEFICIENT MICE; LIFE-SPAN; MEMORY; SURVIVAL; RECEPTOR; CD4(+); NAIVE; PROLIFERATION; LYMPHOCYTES AB The repertoire of naive T cells must be sufficiently diverse to recognize a broad range of antigens, while efficient immune responses depend on the maintenance of a memory T-cell pool. Here, Corinne Tanchot and Benedita Rocha focus on the strategies used by the mature T-cell pool to maintain versatility and efficiency throughout life. C1 NIAID, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. Inst Necker, INSERM U345, F-75015 Paris, France. RP Tanchot, C (reprint author), NIAID, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. NR 36 TC 93 Z9 93 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0167-5699 J9 IMMUNOL TODAY JI Immunol. Today PD DEC PY 1998 VL 19 IS 12 BP 575 EP 579 DI 10.1016/S0167-5699(98)01344-9 PG 5 WC Immunology SC Immunology GA 147QX UT WOS:000077578500009 PM 9864949 ER PT J AU DosReis, GA Shevach, EM AF DosReis, GA Shevach, EM TI Peripheral T-cell self-reactivity and immunological memory SO IMMUNOLOGY TODAY LA English DT Letter ID MIXED LEUKOCYTE REACTION; SURVIVAL; LYMPHOCYTES; SELECTION; ANTIGENS C1 Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Immunobiol Program, BR-21944970 Rio De Janeiro, Brazil. NIAID, Immunol Lab, NIH, Bethesda, MD 20814 USA. RP DosReis, GA (reprint author), Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Immunobiol Program, BR-21944970 Rio De Janeiro, Brazil. NR 14 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0167-5699 J9 IMMUNOL TODAY JI Immunol. Today PD DEC PY 1998 VL 19 IS 12 BP 587 EP 588 DI 10.1016/S0167-5699(98)01369-3 PG 2 WC Immunology SC Immunology GA 147QX UT WOS:000077578500012 PM 9864952 ER PT J AU Porgador, A Staats, HF Itoh, Y Kelsall, BL AF Porgador, A Staats, HF Itoh, Y Kelsall, BL TI Intranasal immunization with cytotoxic T-lymphocyte epitope peptide and mucosal adjuvant cholera toxin: Selective augmentation of peptide-presenting dendritic cells in nasal mucosa-associated lymphoid tissue SO INFECTION AND IMMUNITY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ADP-RIBOSYLTRANSFERASE ACTIVITY; TUMOR-NECROSIS-FACTOR; INFLAMMATORY RESPONSE; ANTIBODY-RESPONSES; IN-VIVO; ORAL TOLERANCE; B-SUBUNIT; ANTIGEN; INHIBITION AB We previously reported that cholera toxin (CT) was required as a mucosal adjuvant for the induction of peptide-specific cytotoxic T lymphocytes (CTL) following intranasal immunization with CTL epitope peptides (A. Porgador et al., J. Immunol. 158:834-841, 1997). The present study was performed to identify the site and the antigen-presenting cell (APC) population responsible for the presentation of intranasally administered CTL epitope peptide immunogens and to determine whether CT directly affects antigen presentation by these APCs. For these experiments, C57BL/6 mice were intranasally immunized with the ovalbumin H-2K(b)-restricted CTL epitope SIINFEKL, with or without CT. Cells were then isolated from the cervical lymph nodes (CLN) and the nasal mucosa-associated lymphoid tissue (NALT) and tested for the ability to stimulate the B3Z T-cell hybridoma, which recognizes SIINFEKL in association with H-2K(b). Dendritic cell (DC)-enriched CLN cells from mice immunized with peptide and CT or peptide only could stimulate B3Z cells, while DC-depleted CLN cells from either group were unable to stimulate B3Z cells. NALT cells of mice immunized with peptide and CT, but not with peptide alone, were able to efficiently stimulate B3Z hybridomas. Depletion of N418-positive DC from these NALT cells resulted in significant reduction of B3Z activation. Our results indicate that DC are the APC responsible for the presentation of CTL epitope peptides following intranasal immunization and that CT augments the ability of dendritic cells in the NALT, but not in the draining CLN, to present CLT epitope peptides. This finding suggests that CT acts locally as a mucosal adjuvant and that NALT DC are the predominant APC involved with the induction of immunity after intranasal immunization with peptide immunogens and CT. C1 NIAID, Immune Cell Interact Unit, Mucosal Immun Sect, Lab Clin Invest,NIH, Bethesda, MD 20892 USA. NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. Duke Univ, Sch Med, Dept Med, Ctr AIDS Res, Durham, NC 27706 USA. RP Kelsall, BL (reprint author), NIAID, Immune Cell Interact Unit, Mucosal Immun Sect, Lab Clin Invest,NIH, 10-11N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM Kelsall@nih.gov OI Staats, Herman/0000-0003-1039-1087 NR 57 TC 52 Z9 53 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 1998 VL 66 IS 12 BP 5876 EP 5881 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 142BG UT WOS:000077179600038 PM 9826368 ER PT J AU Pastrana, DV Raghavan, N Fitzgerald, P Eisinger, SW Metz, C Bucala, R Schleimer, RP Bickel, C Scott, AL AF Pastrana, DV Raghavan, N Fitzgerald, P Eisinger, SW Metz, C Bucala, R Schleimer, RP Bickel, C Scott, AL TI Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor SO INFECTION AND IMMUNITY LA English DT Article ID HUMAN LYMPHATIC FILARIASIS; T-CELL ACTIVATION; FACTOR MIF; MOLECULAR-CLONING; BRUGIA-MALAYI; PROTEINASE-INHIBITOR; CRYSTAL-STRUCTURE; IMMUNE-RESPONSE; REGULATORY ROLE; GROWTH-FACTOR AB Filarial nematode parasites establish long-term chronic infections in the context of an antiparasite immunity that is strongly biased toward a Th2 response. The mechanisms that lead to this Th2 bias toward filarial antigens are not clear, but one possibility is that the parasites produce molecules that have the capacity to proactively modify their immunological environment. Here we report that filarial parasites of humans secrete a homologue of the human proinflammatory cytokine macrophage migration inhibitory factor (MIF) that has the capability of modifying the activity of human monocytes/macrophages. A cDNA clone isolated from a Brugia malayi infective-stage larva expression library encoded a 12.5-kDa protein product (Bm-MIF) with 42% identity to human and murine MIF. MIF homologues were also found to be expressed in the related filarial species Wuchereria bancrofti and Onchocerca volvulus. Bm-mif was transcribed by adult and larval parasites, and the protein product,vas found in somatic extracts and in the parasite's excretory-secretory products. Immunohistocytochemistry revealed that Bm-MIF was localized to cells of the hypodermis/lateral chord, the uterine wall, and larvae developing in utero. Unexpectedly, the activities of recombinant Bm-MIF and human MIF on human monocytes/macrophages were found to be similar. When placed with monocytes/macrophages in a cell migration assay, Bm-MIP inhibited random migration. When placed away from cells, Bm-MIF induced an increase in monocyte/macrophage migration that was specifically inhibited by neutralizing anti-Bm MIF antibodies. Bm-MIF is the first demonstration that helminth parasites produce cytokine homologues that have the potential to modify host immune responses to promote parasite survival. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. NIH, Div Comp Res & Technol, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Ctr Asthma & Allergy, Dept Clin Immunol, Baltimore, MD 21224 USA. Picower Inst Med Res, Manhasset, NY 11030 USA. RP Scott, AL (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol & Immunol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM ascott@jhsph.edu FU NIAID NIH HHS [AI-02642, AI-29411, T32 AI007417] NR 72 TC 144 Z9 159 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 1998 VL 66 IS 12 BP 5955 EP 5963 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 142BG UT WOS:000077179600048 PM 9826378 ER PT J AU Roilides, E Dimitriadou-Georgiadou, A Sein, T Kadiltsoglou, I Walsh, TJ AF Roilides, E Dimitriadou-Georgiadou, A Sein, T Kadiltsoglou, I Walsh, TJ TI Tumor necrosis factor alpha enhances antifungal activities of polymorphonuclear and mononuclear phagocytes against Aspergillus fumigatus SO INFECTION AND IMMUNITY LA English DT Article ID COLONY-STIMULATING FACTOR; CANDIDA-ALBICANS; INTERFERON-GAMMA; INVASIVE ASPERGILLOSIS; HUMAN-NEUTROPHILS; CRYPTOCOCCUS-NEOFORMANS; BACTERIAL-MENINGITIS; CEREBROSPINAL-FLUID; FUNGAL-INFECTIONS; RESPIRATORY BURST AB Invasive aspergillosis is a serious complication in immunocompromised patients. The effects of recombinant human tumor necrosis factor alpha (TNF-alpha) on antifungal activities of human neutrophils (polymorphonuclear leukocytes [PMNs]), human monocytes (MNCs), and rabbit pulmonary alveolar macrophages (PAMs) against Aspergillus fumigatus were studied. The percentage of PMN-induced hyphal damage was increased after 30 min of incubation of PMNs with 0.1 ng of TNF-alpha per ml at 37 degrees C (P = 0.043). At 0.1 to 10 ng/ml, TNF-alpha also increased superoxide anion (O-2(-)) produced by PMNs in response to phorbol myristate acetate, N-formylmethionyl leucyl phenylalanine, and unopsonized hyphae (P < 0.01) but did not exert any effect on PMN phagocytosis of conidia in the presence of serum, By comparison, TNF-alpha induced only a slight increase in O-2(-) production by MNCs in response to phorbol myristate acetate (P = 0.05) and no concomitant increase in the percentage of MNC-induced hyphal damage. Incubation of MNCs with TNF-alpha at 0.001 to 10 ng/ml for 2 days had no effect on phagocytosis or conidiocidal activity. By contrast, incubation of PAMs with TNF-alpha at 0.1 to 10 ng/ml for 2 days increased phagocytosis of conidia (P = 0.03). Thus, TNF-alpha augments the capacity of PMNs to damage Aspergillus hyphae, possibly through enhanced oxidative mechanisms, and increases PAM phagocytic activity against conidia. As such, TNF-alpha may have an important role in host defense against aspergillosis, and neutralization of its activity may be complicated by increased susceptibility to aspergillosis. C1 NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, GR-54642 Salonika, Greece. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bldg 10,Rm 13N240, Bethesda, MD 20892 USA. NR 46 TC 95 Z9 101 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD DEC PY 1998 VL 66 IS 12 BP 5999 EP 6003 PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 142BG UT WOS:000077179600054 PM 9826384 ER PT J AU Holland, SM AF Holland, SM TI A chronic granulomatous disease patient with acute chest pain SO INFECTIONS IN MEDICINE LA English DT Letter C1 NIAID, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU SCP COMMUNICATIONS INC PI NEW YORK PA 134 W 29TH ST, NEW YORK, NY 10001-5304 USA SN 0749-6524 J9 INFECT MED JI Infect. Med. PD DEC PY 1998 VL 15 IS 12 BP 840 EP 840 PG 1 WC Infectious Diseases SC Infectious Diseases GA 150MY UT WOS:000077669800016 ER PT J AU Adler, WH Bender, BS Nagel, JE AF Adler, WH Bender, BS Nagel, JE TI Immune function and AIDS in the older patient SO INFECTIONS IN MEDICINE LA English DT Article DE human immunodeficiency virus (HIV); acquired immune deficiency syndrome (AIDS) protease inhibitors; immune function; aging ID IMMUNODEFICIENCY-VIRUS INFECTION; HIV-INFECTION; AGE; SURVIVAL; CELLS; INTERLEUKIN-6; EPIDEMIOLOGY; HEMOPHILIA; EXPRESSION; DISEASES AB Many infectious diseases result in increased rates of morbidity and mortality in the elderly. This is true for HIV, in which advancing age is related to a shorter time from Infection to the development of AIDS and early death. The effect of age in promoting HIV disease progression is unclear at present, but it may he related to the physiologic loss of immune capacity associated with aging. The adverse effects of this process are compounded by HIV-mediated injury to the immune system. C1 NIA, NIH, Baltimore, MD 21224 USA. RP Adler, WH (reprint author), NIA, NIH, Baltimore, MD 21224 USA. NR 35 TC 0 Z9 0 U1 0 U2 0 PU SCP COMMUNICATIONS INC PI NEW YORK PA 134 W 29TH ST, NEW YORK, NY 10001-5304 USA SN 0749-6524 J9 INFECT MED JI Infect. Med. PD DEC PY 1998 VL 15 IS 12 BP 842 EP + PG 6 WC Infectious Diseases SC Infectious Diseases GA 150MY UT WOS:000077669800019 ER PT J AU Soto, NE Vaghjimal, A Niazi, M Protic, JR Hardy, DJ Chapnick, EK Lutwick, LI AF Soto, NE Vaghjimal, A Niazi, M Protic, JR Hardy, DJ Chapnick, EK Lutwick, LI TI Port-a-cath-related bacteremia due to Lactobacillus casei: A case report SO INFECTIOUS DISEASES IN CLINICAL PRACTICE LA English DT Article ID ENDOCARDITIS; CATHETERS C1 Maimonides Med Ctr, Dept Pathol, Div Microbiol, Brooklyn, NY 11219 USA. Maimonides Med Ctr, Dept Internal Med, Div Infect Dis, Brooklyn, NY 11219 USA. Univ Rochester, Sch Med, Dept Microbiol & Immunol, Rochester, NY USA. RP Soto, NE (reprint author), NIH, Bldg 10,Room 11C408,10 Ctr Dr, Bethesda, MD 20892 USA. EM nsoto@atlas.niaid.nih.gov NR 13 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1056-9103 J9 INFECT DIS CLIN PRAC JI Infect. Dis. Clin. Pract. PD DEC PY 1998 VL 7 IS 9 BP 475 EP 477 DI 10.1097/00019048-199812000-00009 PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 144TH UT WOS:000077330800010 ER PT J AU Murray, CK Hospenthal, DR Grimberg, BT Gasser, RA AF Murray, CK Hospenthal, DR Grimberg, BT Gasser, RA TI Gemella morbillorum brain abscess presenting as acute meningitis SO INFECTIOUS DISEASES IN CLINICAL PRACTICE LA English DT Article ID TRICUSPID-VALVE ENDOCARDITIS; STREPTOCOCCUS-MORBILLORUM; VIRIDANS STREPTOCOCCI; INFECTION; SURGERY; COLON; SHOCK C1 Walter Reed Army Med Ctr, Dept Med, Washington, DC 20307 USA. NIH, Clin Invest Lab, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Immunol, Washington, DC 20307 USA. RP Murray, CK (reprint author), Walter Reed Army Med Ctr, Dept Med, Washington, DC 20307 USA. RI Grimberg, Brian/I-1251-2013 OI Grimberg, Brian/0000-0002-6015-4912 NR 30 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1056-9103 J9 INFECT DIS CLIN PRAC JI Infect. Dis. Clin. Pract. PD DEC PY 1998 VL 7 IS 9 BP 477 EP 480 DI 10.1097/00019048-199812000-00010 PG 4 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 144TH UT WOS:000077330800011 ER PT J AU Ribeiro, JMC AF Ribeiro, JMC TI Rhodnius prolixus salivary nitrophorins display heme-peroxidase activity SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE hematophagy; insect; platelet; hemostasis; saliva; blood-feeding; nitrophorin ID NITRIC-OXIDE; BLOODSUCKING BUG; OXYGENASE SYSTEM; PURIFICATION; DEGRADATION; BINDING; PROTEIN; ANTICOAGULANT; HEMOPROTEINS; CATABOLISM AB Rhodnius prolixus is a blood feeding triatomine bug that contains salivary nitric oxide bound to hemoproteins previously named nitrophorins. Nitrophorins, in addition to storing and transporting NO, have two other functions such as anti-histaminic and anticlotting (displayed by nitrophorin 2 only). Additionally, nitrophorins display a thiol oxidase reaction, where cysteine is oxidized to cystine with the production of hydrogen peroxide. In this paper the heme-peroxidase reaction of nitrophorins is described. The heme moiety of nitrophorins is destroyed by addition of cysteine or hydrogen peroxide. No biliverdin is produced during this reaction. We have also found that during the thiol oxidase reaction, nitrophorins can destroy norepinephrine, conferring an additional vasodilatory competence for this class of salivary molecules. Published by Elsevier Science Ltd. All rights reserved. C1 NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Ribeiro, JMC (reprint author), NIAID, Parasit Dis Lab, Bldg 4,Room 126,4 Ctr Dr,MSC-425, Bethesda, MD 20892 USA. OI Ribeiro, Jose/0000-0002-9107-0818 NR 33 TC 9 Z9 10 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD DEC PY 1998 VL 28 IS 12 BP 1051 EP 1057 DI 10.1016/S0965-1748(98)00096-4 PG 7 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 154CR UT WOS:000077871400015 ER PT J AU Marcin, JP Pollack, MM Patel, KM Ruttimann, UE AF Marcin, JP Pollack, MM Patel, KM Ruttimann, UE TI Decision support issues using a physiology based score SO INTENSIVE CARE MEDICINE LA English DT Article DE severity of illness; pediatric intensive care; intensive care units; PRISM; prediction; certainty ID INTENSIVE-CARE UNITS; ILL HOSPITALIZED ADULTS; MORTALITY; PREDICTION; MANAGEMENT; SURVIVAL; MULTICENTER; PERFORMANCE; ACTUARIAL; FUTILITY AB Objective: As physiology based assessments of mortality risk become more accurate, their potential utility in clinical decision support and resource rationing decisions increases. Before these prediction models can be used, however, their performance must be statistically evaluated and interpreted in a clinical context. We examine the issues of confidence intervals (as estimates of survival ranges) and confidence levels (as estimates of clinical certainty) by applying Pediatric Risk of Mortality III (PRISM III) in two scenarios: (1) survival prediction for individual patients and (2) resource rationing. Design: A non-concurrent cohort study. Setting: 32 pediatric intensive care units (PICUs). Patients: 10608 consecutive patients (571 deaths). Interventions: None. Measurements and results: For the individual patient application, we investigated the observed survival rates for patients with low survival predictions and the confidence intervals associated with these predictions. For the resource rationing application, we investigated the maximum error rate of a policy which would limit therapy for patients with scores exceeding a very high threshold. For both applications, we also investigated how the confidence intervals change as the confidence levels change. The observed survival in the PRISM III groups > 28, > 35, and > 42 were 6.3, 5.3, and 0 %, with 95 % upper confidence interval bounds of 10.5, 13.0, and 13.3 %, respectively. Changing the confidence level altered the survival range by more than 300 % in the highest risk group, indicating the importance of clinical certainty provisions in prognostic estimates. The maximum error rates for resource allocation decisions were low (e. g., 29 per 100 000 at a 95 % certainty level), equivalent to many of the risks of daily living. Changes in confidence level had relatively little effect on this result. Conclusions: Predictions for an individual patient's risk of death with a high PRISM score are statistically not precise by virtue of the small number of patients in these groups and the resulting wide confidence intervals. Clinical certainty (confidence level) issues substantially influence outcome ranges for individual patients, directly affecting the utility of scores for individual patient use. However, sample sizes are sufficient for rationing decisions for many groups with higher certainty levels. Before there can be widespread acceptance of this type of decision support, physicians and families must confront what they believe is adequate certainty. C1 George Washington Univ, Childrens Natl Med Ctr, Sch Med, Dept Crit Care Med, Washington, DC 20010 USA. George Washington Univ, Childrens Natl Med Ctr, Sch Med, Ctr Hlth Serv & Clin Res,Childrens Res Inst, Washington, DC 20010 USA. George Washington Univ, Sch Med, NIAAA, NIH, Bethesda, MD USA. RP Pollack, MM (reprint author), George Washington Univ, Childrens Natl Med Ctr, Sch Med, Dept Crit Care Med, 111 Michigan Ave NW, Washington, DC 20010 USA. EM mpollack@cnmc.org FU PHS HHS [MCH-110584] NR 35 TC 21 Z9 21 U1 2 U2 2 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0342-4642 J9 INTENS CARE MED JI Intensive Care Med. PD DEC PY 1998 VL 24 IS 12 BP 1299 EP 1304 DI 10.1007/s001340050766 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 150MU UT WOS:000077669300012 PM 9885884 ER PT J AU Jeong, MC Izikson, L Uccelli, A Brocke, S Oksenberg, JR AF Jeong, MC Izikson, L Uccelli, A Brocke, S Oksenberg, JR TI Differential display analysis of murine encephalitogenic mRNA SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE autoimmunity; central nervous system; experimental allergic encephalomyelitis; IL-3 ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; FACTOR-ALPHA PRODUCTION; MULTIPLE-SCLEROSIS; MESSENGER-RNA; TH2 CELLS; T-CELLS; MICE; INTERLEUKIN-3; IL-3 AB Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease which can be induced by inoculation with activated CD4(+) T lymphocytes specific for myelin proteins. It has been postulated that autoreactive T(h)1-type CD4(+) cells are responsible for the lesions, whereas autoreactive T(h)2-type cells suppress or modulate the disease. However, the mechanisms involved in the development of inflammatory lesions and neurologic deficits in EAE have not been fully described, and probably involve a complex array of mediators and alternative or redundant pathways. To identify additional factors associated with the pathological role of T cells in EAE, we adapted the differential mRNA display technique to fingerprint the transcripts expressed by encephalitogenic and non-encephalitogenic T cells. Using 60 primer combinations, 21 differentially expressed cDNAs were identified. Among them 13 are known sequences, including IL-3 in non-encephalitogenic lymphocytes. Their relevance for the disease process is discussed. C1 Univ Calif San Francisco, Sch Med, Dept Neurol, San Francisco, CA 94143 USA. NINDS, Neurol Dis Sect, NIB, NIH, Bethesda, MD 20892 USA. Univ Genoa, Dept Neurol Sci, I-16132 Genoa, Italy. RP Oksenberg, JR (reprint author), Univ Calif San Francisco, Sch Med, Dept Neurol, 513 Parnassus Ave, San Francisco, CA 94143 USA. NR 37 TC 2 Z9 3 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 DEC PY 1998 VL 10 IS 12 BP 1819 EP 1823 DI 10.1093/intimm/10.12.1819 PG 5 WC Immunology SC Immunology GA 153LM UT WOS:000077834600007 PM 9885902 ER PT J AU Prolo, P Wong, ML Licinio, J AF Prolo, P Wong, ML Licinio, J TI Leptin SO INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY LA English DT Article DE leptin; metabolism; body weight; reproduction; cortisol ID ANOREXIA-NERVOSA; RESISTANCE; HUMANS; EXPRESSION; OBESITY; CLONING; MICE AB Leptin is an adipocyte hormone that signals nutritional status to the central nervous system (CNS) and peripheral organs. Leptin is also synthetized in the placenta and in gastrointestinal tract, although its role in these tissues is not yet clear. Circulating concentrations of leptin exhibit pulsatility and circadian rhythmicity. The levels of plasma leptin vary directly with body mass index and percentage body fat, and leptin contributes to the regulation of body weight. Leptin plasma concentrations are also influenced by metabolic hormones, sex, and body energy requirements. Defects in the leptin signaling pathway result in obesity in animal models. Only a few obese humans have been identified with mutations in the leptin gene or in the leptin receptor; however, most cases of obesity in humans are associated with high leptin levels. Thus, in humans obesity may represent a state of leptin resistance. Minute-to-minute fluctuations in peripheral leptin concentrations influence the activity of the hypothalamic-pituitary-ovarian and hypothalamic-pituitary-adrenal axes, indicating that leptin may be a modulator of reproduction, stress-related endocrine function, and behavior. This suggests potential roles for leptin or its antagonists in the diagnosis, pathophysiology and treatment of several human diseases. (C) 1998 Elsevier Science Ltd. All rights reserved. C1 NIMH, Clin Neuroendocrinol Branch, NIH, Unit Clin Res, Bethesda, MD 20892 USA. RP Licinio, J (reprint author), NIMH, Clin Neuroendocrinol Branch, NIH, Unit Clin Res, NIH Bldg 10-2D46,10 Ctr Dr MSC 1284, Bethesda, MD 20892 USA. RI Wong, Ma-Li/D-7903-2011; OI Licinio, Julio/0000-0001-6905-5884 NR 18 TC 112 Z9 119 U1 3 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 1357-2725 J9 INT J BIOCHEM CELL B JI Int J. Biochem. Cell Biol. PD DEC PY 1998 VL 30 IS 12 BP 1285 EP 1290 DI 10.1016/S1357-2725(98)00094-6 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 153PE UT WOS:000077840800002 PM 9924798 ER PT J AU You, WC Zhang, L Gail, MH Ma, JL Chang, YS Blot, WJ Li, JY Zhao, CL Liu, WD Li, HQ Hu, YR Bravo, JC Correa, P Xu, GW Fraumeni, JF AF You, WC Zhang, L Gail, MH Ma, JL Chang, YS Blot, WJ Li, JY Zhao, CL Liu, WD Li, HQ Hu, YR Bravo, JC Correa, P Xu, GW Fraumeni, JF TI Helicobacter pylori infection, garlic intake and precancerous lesions in a Chinese population at low risk of gastric cancer SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE precancerous gastric lesions; high and low risk; Helicobacter pylori; alcohol; garlic ID DIALLYL SULFIDE; STOMACH-CANCER; DIET AB Background Cangshan County of Shandong Province has one of the lowest rates of gastric cancer (GC) in China. While intestinal metaplasia (IM) and dysplasia (DYS) are less common in Cangshan than in areas of Shandong at high risk of GC, these precursor lesions nevertheless affect about 20% of adults age greater than or equal to 55. Subjects and Setting In order to evaluate determinants of IM and DYS in Cangshan County, a low risk area of GC a survey was conducted among 214 adults who participated in a gastroscopic screening survey in Cangshan County in 1994. Method A dietary interview and measurement of serum Helicobacter pylori antibodies were performed. Reults The prevalence of H. pylori was lowest (19%) among those with normal gastric mucosa, rising steadily to 35% for superficial gastritis (SG), 56% for chronic atrophic gastritis (CAG), 80% for LM, and 100% for DYS. The prevalence odds of precancerous lesions were compared with the odds of normal histology or SG. The odds ratio (OR) or CAG associated with H. pylori positivity was 4.2 (95% confidence interval [CI] : 1.7-10.0), while the OR of IM/DYS associated with H. pylori positivity was 31.5 (95% CI : 5.2-187). After adjusting for H. pylori infection, drinking alcohol was a risk factor for CAG (OR = 3.2, 95% CI: 1.1-9.2) and IM/DYS (OR = 7.8, 95% CT:1.3-47.7). On the other hand, consumption of garlic showed non-significant protective effects and an inverse association with H. pylori infection. Conclusions The findings of this study suggest that infection with H. pylori is a risk factor and garlic may be protective, in the development and progression of advanced precancerous gastric lesions in an area of China at relatively low risk of GC. C1 NCI, Bethesda, MD 20892 USA. Beijing Med Univ, Beijing Inst Canc Res, Beijing 100034, Peoples R China. Beijing Med Univ, Sch Oncol, Beijing 100034, Peoples R China. Weifang Blood Ctr, Shandong 261041, Peoples R China. Int Epidemiol Inst Ltd, Rockville, MD 20850 USA. Cangshan Publ Hlth Bur, Shandong 277700, Peoples R China. Linqu Publ Hlth Bur, Shandong 262600, Peoples R China. Shandong Acad Med Sci, Shandong 250000, Peoples R China. Westat Inc, Rockville, MD 20850 USA. Louisiana State Univ, Med Ctr, New Orleans, LA 70112 USA. RP You, WC (reprint author), NCI, EPN Room 431, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-95660, N01-CP-15620, N01-CP-05631] NR 26 TC 62 Z9 70 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD DEC PY 1998 VL 27 IS 6 BP 941 EP 944 DI 10.1093/ije/27.6.941 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 166XJ UT WOS:000078602900003 PM 10024185 ER PT J AU You, WC Zhang, L Gail, MH Li, JY Chang, YS Blot, WJ Zhao, CL Liu, WD Li, HQ Ma, JL Hu, YR Bravo, JC Correa, P Xu, GW Fraumeni, JF AF You, WC Zhang, L Gail, MH Li, JY Chang, YS Blot, WJ Zhao, CL Liu, WD Li, HQ Ma, JL Hu, YR Bravo, JC Correa, P Xu, GW Fraumeni, JF TI Precancerous lesions in two counties of China with contrasting gastric cancer risk SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE precancerous gastric lesions; gastric cancer; high and low risk; population ID STOMACH-CANCER; POPULATION; CARCINOMA AB Background Gastric cancer (GC) is one of the most common cancers worldwide and shows remarkable geographical variation even within countries such as China. Linqu County in Shandong Province of northeast China has a GC rate that is 15 times higher than that of Cangshan County in Shandong, even though these counties are within 200 miles of each other. Method In order to evaluate the frequency of precancerous gastric lesions in Linqu and Cangshan Counties we examined 3400 adults in Linqu County and 224 adults in Cangshan County. An endoscopic examination with four biopsies was performed in each individual of the two populations. Results The prevalence of intestinal metaplasia (IM) and dysplasia (DYS) was 30% and 15.1%, respectively, in Linqu compared to 7.9% and 5.6% in Cangshan (P < 0.01). Within these histological categories, advanced grades were found more often in Linqu than in Cangshan. The prevalences of IM and DYS were more common at each biopsy site in Linqu, where the lesions also tended to affect multiple sites. Conclusions The findings of this study support the concept that LM and DYS are closely correlated with risks of GC and represent late stages in the multistep process of gastric carcinogenesis. C1 NCI, Bethesda, MD 20892 USA. Beijing Med Univ, Beijing Inst Canc Res, Beijing 100034, Peoples R China. Beijing Med Univ, Sch Oncol, Beijing 100034, Peoples R China. Weifang Blood Ctr, Shandong 261041, Peoples R China. Int Epidemiol Inst Ltd, Rockville, MD 20850 USA. Cangshan Publ Hlth Bur, Shandong 277700, Peoples R China. Linqu Publ Hlth Buyr, Shandong 262600, Peoples R China. Shandong Acad Med Sci, Shandong 250000, Peoples R China. Westat Inc, Rockville, MD 20850 USA. Louisiana State Univ, Med Ctr, New Orleans, LA 70112 USA. RP You, WC (reprint author), NCI, EPN Room 431, Bethesda, MD 20892 USA. FU NCI NIH HHS [N01-CP-05631, N01-CP-95660, N01-CP-15620] NR 20 TC 46 Z9 55 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD DEC PY 1998 VL 27 IS 6 BP 945 EP 948 DI 10.1093/ije/27.6.945 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 166XJ UT WOS:000078602900004 PM 10024186 ER PT J AU Pajak, A Broda, G Manolio, TA Kawalec, E Rywik, S Davis, CE Pikon, J Pytlak, A Thomas, RP AF Pajak, A Broda, G Manolio, TA Kawalec, E Rywik, S Davis, CE Pikon, J Pytlak, A Thomas, RP TI Constitutional, biochemical and lifestyle correlates of fibrinogen and factor VII activity in Polish urban and rural populations SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE fibrinogen; factor VII activity risk; coronary disease; population study ID CARDIOVASCULAR RISK-FACTORS; ISCHEMIC-HEART-DISEASE; PERIPHERAL ARTERIAL-DISEASE; PLASMA-FIBRINOGEN; HEMOSTATIC FACTORS; SEASONAL-VARIATIONS; PHYSICAL-ACTIVITY; ELDERLY PEOPLE; CORONARY RISK; BLOOD-LIPIDS AB Background Fibrinogen and factor VII activity are known to be related to atherosclerosis and coronary heart disease, but population differences in clotting factors and modifiable characteristics that influence their levels have not been widely explored. Methods This paper examines correlates of plasma fibrinogen concentration and factor VII activity in 2443 men and women aged 35-64 in random samples selected from the residents in two districts in urban Warsaw (618 men and 651 women) and from rural Tarnobrzeg Province (556 men and 618 women) screened in 1987-1988, and assesses which characteristics might explain urban-rural differences. Fibrinogen and factor VII activity were determined using coagulation methods. Results Fibrinogen was 12.9 mg/dl higher in men and 14.1 mg/dl higher in women in Tarnobrzeg compared to Warsaw. Factor VII activity was higher in Warsaw (9.2% in men and 15.3% in women). After adjustment for selected characteristics, fibrinogen was higher in smokers compared to non-smokers by 28 mg/dl in men and 22 mg/dl in women. In women, a 15 mg/dl increase in HDL-cholesterol was associated with a 10 mg/dl decrease in fibrinogen (P < 0.01). After adjustment for other variables, a higher factor VII activity in Warsaw remained significant (a difference of 9.4% in men and 14.8% in women). Lower fibrinogen in Warsaw remained significant only in women (15.4 mg/dl difference). Conclusion The study confirmed that sex, age, BMI, smoking and blood lipids are related to clotting factors. However, with the exception of gender differences and smoking, associations between clotting factors and other variables were small and of questionable practical importance. C1 Jagiellonian Univ, Collegium Medicum, Sch Publ Hlth, Unit Clin Epidemiol & Populat Studies, Krakow, Poland. Stefan Cardinal Wyszynski Natl Inst Cardiol, Dept CVD Epidemiol & Prevent, Warsaw, Poland. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. RP Pajak, A (reprint author), Univ N Carolina, Collaborat Studies Coordinating Ctr, Suite 203,137 E Franklin St, Chapel Hill, NC 27514 USA. FU NHLBI NIH HHS [N01-HV-1-2243, N01-HV-1-98112, N01-HV-59224] NR 61 TC 5 Z9 5 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD DEC PY 1998 VL 27 IS 6 BP 953 EP 961 DI 10.1093/ije/27.6.953 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 166XJ UT WOS:000078602900006 PM 10024188 ER PT J AU Kim, HS Lee, BL Bae, SI Kim, YI Park, JG Kleinman, HK Kim, WH AF Kim, HS Lee, BL Bae, SI Kim, YI Park, JG Kleinman, HK Kim, WH TI Differentiation of a colon cancer cell line on a reconstituted basement membrane in vitro SO INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY LA English DT Article DE Matrigel; extracellular matrix; colon; carcinoma; differentiation; polyhydroxyethyl methacrylate; electron microscopy; carcinoembryonic antigen; CD44 ID CAPILLARY-LIKE STRUCTURES; HUMAN-ENDOTHELIAL CELLS; FUNCTIONAL-DIFFERENTIATION; CARCINOEMBRYONIC ANTIGEN; EXTRACELLULAR-MATRIX; EPITHELIAL-CELLS; GENE-EXPRESSION; LAMININ; INDUCTION; INVITRO AB Basement membrane, a thin extracellular matrix, functions as a tissue stabilizer that promotes tissue integrity and differentiated phenotype. We studied a human colon cancer cell line, SNU 61, to evaluate its ability to differentiate on basement membrane. Cells were cultured on plastic, reconstituted basement membrane (Matrigel) or polyhydroxyethyl methacrylate (poly HEMA) for 72 h and evaluated by light and electron microscopy. On Matrigel, the cells showed gland formation with highly polarized cells containing basal nuclei and well developed brush border microvilli on the luminal surface. Apoptosis was noted mainly at the luminal side. On electron microscopic examination, numerous long microvilli, abundant cytoplasmic organelles and intercellular junctions were noted in the Matrigel-cultured cells. intermediate cytoskeletons were scattered in the cytoplasm and existed on the axes of microvilli. Junctional complexes and desmosomes were frequently formed along intercellular spaces. The cells cultured on poly HEMA, on the other hand, were poorly differentiated and contained a few glandular structures with small lumens. Brush border microvilli, characteristic of enterocytic differentiation, were few in number and were developed on the basal surface. Intermediate filaments and microtubules were fewer than in the Matrigel-cultured cells. Carcinoembryonic antigen was expressed on the luminal surface of the Matrigel-cultured cells and in the cytoplasm of the poly HEMA cultured cells. CD44 stained the basolateral surface in the Matrigel-cultured cells, but the basal side was not stained in the poly HEMA cultured cells. These results are consistent with the different localization of microvilli in the Matrigel and in the poly HEMA cultured cells. Our observations suggest that human colon cancer cells on basement membrane can undergo glandular differentiation and that extracellular matrix is an important factor in morphogenesis. C1 Seoul Natl Univ, Coll Med, Dept Pathol, Seoul 110799, South Korea. Seoul Natl Univ, Coll Med, Dept Anat, Seoul 110799, South Korea. Seoul Natl Univ, Coll Med, Dept Surg, Seoul 110799, South Korea. Seoul Natl Univ, Coll Med, Ctr Canc Res, Seoul 110799, South Korea. NIDR, NIH, Bethesda, MD 20892 USA. RP Kim, WH (reprint author), Seoul Natl Univ, Coll Med, Dept Pathol, 28 Yongondong, Seoul 110799, South Korea. RI Kim, Wooho/G-3703-2011; Seoul National University, Pathology/B-6702-2012; Lee, Byung Lan/J-5577-2012; Park, Jae-Gahb/J-5494-2012 NR 31 TC 2 Z9 2 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0959-9673 J9 INT J EXP PATHOL JI Int. J. Exp. Pathol. PD DEC PY 1998 VL 79 IS 6 BP 443 EP 451 DI 10.1046/j.1365-2613.1998.00090.x PG 9 WC Pathology SC Pathology GA 153LN UT WOS:000077834700011 PM 10319025 ER PT J AU Benjamin, J Ebstein, RP Lesch, KP AF Benjamin, J Ebstein, RP Lesch, KP TI Genes for personality traits: implications for psychopathology SO INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY LA English DT Review DE anxiety; depression; dopamine; genetics; personality; serotonin ID SEROTONIN TRANSPORTER GENE; D4 RECEPTOR D4DR; BIPOLAR AFFECTIVE-DISORDER; REGULATORY REGION POLYMORPHISM; III REPEAT POLYMORPHISM; ANXIETY-RELATED TRAITS; TWINS REARED APART; NOVELTY-SEEKING; MAJOR DEPRESSION; NO ASSOCIATION AB Although 30-60 % of the variance in many personality traits is inherited, until recently, little was known about the genes responsible. Preliminary studies of family history in bipolar disorder and of X-linkage of personality traits in colour-blindness suggested a 'quantitative trait locus' (QTL) approach to the genetics of normal personality. In methodically similar but independent studies of 124 Israeli and 315 American normal volunteers, an association was found between the dopamine D4 receptor gene (D4DR) and the personality trait of novelty-seeking. In the Israeli sample there was preliminary evidence for an interaction between the D4DR gene and the serotonin 2C receptor gene (5-HT-2C), with a marked effect on the trait of reward dependence. In addition to receptors, monoamine uptake mechanisms, such as the serotonin transporter (5-HTT), are candidate genes for personality traits. 5-HTT gene transcription is modulated by a frequent polymorphism in its promoter region, with resulting effects on 5-HTT expression and 5-HT uptake. In an extended American sample totalling 505 subjects, the 5-HTT polymorphism was associated with anxiety- and depression-related personality traits. The allelic variation in functional expression of the 5-HTT may also be a susceptibility factor for disorders of the affective spectrum. Further investigation of genes for personality traits may provide additional links between normal personality and psychiatric illness. C1 Soroka Med Ctr, Dept Psychiat, IL-84101 Beer Sheva, Israel. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Ben Gurion Univ Negev, IL-84105 Beer Sheva, Israel. S Herzog Mem Hosp, Res Lab, Jerusalem, Israel. Univ Wurzburg, Dept Psychiat, D-97070 Wurzburg, Germany. RP Benjamin, J (reprint author), Soroka Med Ctr, Dept Psychiat, POB 151, IL-84101 Beer Sheva, Israel. EM yonatan@bgumail.bgu.ac.il RI Lesch, Klaus-Peter/J-4906-2013; OI Lesch, Klaus-Peter/0000-0001-8348-153X; Ebstein, Richard/0000-0002-3626-541X NR 106 TC 31 Z9 31 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 1461-1457 J9 INT J NEUROPSYCHOPH JI Int. J. Neuropsychopharmacol. PD DEC PY 1998 VL 1 IS 2 BP 153 EP 168 DI 10.1017/S1461145798001205 PG 16 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 368RG UT WOS:000090130900008 PM 11281959 ER PT J AU Inamdar, N Kumar, SA Banavali, SD Advani, S Magrath, I Bhatia, K AF Inamdar, N Kumar, SA Banavali, SD Advani, S Magrath, I Bhatia, K TI Comparative incidence of the rearrangements of TEL/AML1 and ALL1 genes in pediatric precursor B acute lymphoblastic leukemias in India SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE TEL/AML1; ALL1/MLL; pediatric leukemia; developing countries; molecular epidemiology ID POOR-PROGNOSIS; CELL; CHILDREN; THERAPY; MLL; ABNORMALITIES; EMPHASIS; BIOLOGY; CANCER; AGE AB The TEL/AML1 translocation, which is specific for pre B-cell leukemias is predictive of a favorable treatment outcome. In contrast, translocations involving the ALL1 locus which are associated with both B and non B leukemias predict a poor outcome. To determine the relative distribution of high and low risk molecular subtypes of ALL in India, we analyzed the relative frequencies of these two translocations. The study included a random selection of 46 newly diagnosed patients of childhood ALL from the Tata Memorial Hospital, Bombay, India. Similar to the frequency observed in other world regions, we found an ALL1 rearrangement in less than 7% (3/46) of pre B-ALL patients. In contrast to the 25% frequency reported for other regions the low risk molecular subtype characterized by the TEL/AML1 translocation represented a comparatively smaller fraction (4/46) in this study. These results provide a preliminary support for a lower frequency of molecular subgroup of leukemias with a potential for favorable clinical outcome in precursor B-ALL from India. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Tata Mem Hosp, Bombay 400012, Maharashtra, India. RP Bhatia, K (reprint author), NCI, Pediat Oncol Branch, NIH, Bldg 10,RM 13N240, Bethesda, MD 20892 USA. NR 31 TC 30 Z9 30 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD DEC PY 1998 VL 13 IS 6 BP 1319 EP 1322 PG 4 WC Oncology SC Oncology GA 143YF UT WOS:000077284600035 PM 9824651 ER PT J AU Zadnik, K Barr, JR Edrington, TB Everett, DF Jameson, M McMahon, TT Shin, JA Sterling, JL Wagner, H Gordon, MO AF Zadnik, K Barr, JR Edrington, TB Everett, DF Jameson, M McMahon, TT Shin, JA Sterling, JL Wagner, H Gordon, MO CA Collaborative Longitudinal Evaluation Keratocon TI Baseline findings in the collaborative longitudinal evaluation of keratoconus (CLEK) study SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID CORNEAL TOPOGRAPHY; CONTACT-LENS AB Purpose. To describe the baseline findings in patients enrolled in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study. METHODS. This is a longitudinal observational study of 1209 patients with keratoconus enrolled at 16 clinical centers. Its main outcome measures are corneal scarring, visual acuity, keratometry, and quality of life. RESULTS. The CLEK Study patients had a mean age of 33.29 +/- 10.90 years with moderate to severe disease, assessed by a keratometric-based criterion (95.4% of patients had steep keratometric readings of at least 45 D) and relatively good visual acuity (77.9% had best corrected visual acuity of at least 20/40 in both eyes). Sixty-five percent of the patients wore rigid gas-permeable contact lens, and most of those (73%) reported that their lenses were comfortable. Only 13.5% of patients reported a family history of keratoconus. None reported serious systemic diseases that had been previously reported to be associated with keratoconus. Many (53%) reported a history of atopy. Fifty-three percent had corneal, scarring in one or both eyes. CONCLUSIONS. Baseline findings suggest that keratoconus is not associated with increased risk of connective tissue disease and that most patients in the CLEK Study sample represent mild to moderate keratoconus. Additional follow-up of at least 3 years will provide new information about the progression of keratoconus, identify factors associated with progression, and assess its impact on quality of life. C1 Ohio State Univ, Coll Optometry, Columbus, OH 43210 USA. So Calif Coll Optometry, Fullerton, CA USA. NEI, Bethesda, MD 20892 USA. Penn Coll Optometry, Philadelphia, PA 19141 USA. Univ Illinois, Dept Ophthalmol, Chicago, IL 60680 USA. Gundersen Lutheran, Lacrosse, WI USA. Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. Nova SE Univ, Coll Optometry, St Louis, MO USA. Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. RP Zadnik, K (reprint author), Ohio State Univ, Coll Optometry, 338 W 10th Ave, Columbus, OH 43210 USA. RI Wagner, Heidi/H-1422-2016 FU NEI NIH HHS [U10-EY10069, U10-EY10077, U10-EY10419] NR 34 TC 205 Z9 210 U1 4 U2 12 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 DEC PY 1998 VL 39 IS 13 BP 2537 EP 2546 PG 10 WC Ophthalmology SC Ophthalmology GA 146AP UT WOS:000077405300007 PM 9856763 ER PT J AU Lizak, MJ Secchi, EF Lee, JW Sato, S Kubo, E Akagi, Y Kador, PF AF Lizak, MJ Secchi, EF Lee, JW Sato, S Kubo, E Akagi, Y Kador, PF TI 3-FG as substrate for investigating flux through the polyol pathway in dog lens by F-19-NMR spectroscopy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ALDOSE REDUCTASE INHIBITORS; SUGAR CATARACT FORMATION; SORBITOL DEHYDROGENASE; DIABETIC COMPLICATIONS; INVIVO METABOLISM; RATS; PREVENTION; 3-DEOXY-3-FLUORO-D-GLUCOSE; 2-FLUORO-2-DEOXY-D-GLUCOSE; QUANTITATION AB PURPOSE. TO investigate nux through the polyol pathway in the dog lens by F-19-nuclear magnetic resonance (F-19-NMR) spectroscopy, using 3-fluoro-3-deoxyl-D-glucose (3-FG) as a substrate. METHODs. 3-FG metabolism was monitored by F-19-NMR analysis. Dog lenses were incubated in Dulbecco's modified Eagle's medium containing 10 mM 3-FG. Enzymatic reductase and dehydrogenase activities were spectrophotometrically determined, whereas the analyses of 3-FG metabolites were conducted by F-19-NMR analysis. Aldose reductase (AR) was immunohistochemically localized in dog lens with antibodies raised against dog kidney AR. RESULTS. F-19-NMR spectra indicate that incubation of purified dog lenses AR with 3-FG results in the formation of 3-fluoro-3-deoxy-D-sorbitol (3-FS) and that incubation of dog liver sorbitol dehydrogenase (SDH) with 3-FS results in the formation of 3-fluoro-3-deoxy-D-fructose (3-FF). This confirms that 3-FG is metabolized to 3-FF by the polyol pathway enzymes. The affinity (K-m) of AR for 3-FG is similar to 20-fold better than that for D-glucose, whereas the K-m of SDH for 3-FS was fourfold less than for D-sorbitol. 3-FG in cultured dog lenses is metabolized primarily to 3-FS; however, small amounts of 3-FF and 3-fluoro-3-deoxy-D-gluconic acid (3-FGA) are also formed. 3-FS formation was reduced by the AR inhibitor AL 1576, and 3-FF formation was eliminated by the SDH inhibitor CP-166,572. In dog lens epithelial cells cultured with 3-FG, only 3-FS is formed. Similarly, only 3-FS is formed when lens capsule containing primarily epithelial lens contaminated with superficial epithelial cells was incubated in 3-FG. Similar incubation of the remaining cortex resulted primarily in the formation of 3-FS and 3-FGA. This enzymatic distribution was confirmed by spectrophotometric activity analysis and the immunohistochemical localization of AR. CONCLUSIONS. The data confirm that flux through the polyol pathway primarily results in sorbitol accumulation. The absence of fructose and gluconic acid from cultured lens epithelium suggests that the epithelial cells primarily contain AR, whereas differentiated fiber cells also contain SDH and glucose dehydrogenase. C1 NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. Fukui Med Sch, Dept Ophthalmol, Fukui 91011, Japan. RP Lizak, MJ (reprint author), NEI, Lab Ocular Therapeut, NIH, 10-10b11,10 Ctr Dr,MSC 1850, Bethesda, MD 20892 USA. NR 36 TC 9 Z9 9 U1 0 U2 0 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 1998 VL 39 IS 13 BP 2688 EP 2695 PG 8 WC Ophthalmology SC Ophthalmology GA 146AP UT WOS:000077405300023 PM 9856779 ER PT J AU Henry, K Erice, A Tierney, C Balfour, HH Fischl, MA Kmack, A Liou, SH Kenton, A Hirsch, MS Phair, J Martinez, A Kahn, JO AF Henry, K Erice, A Tierney, C Balfour, HH Fischl, MA Kmack, A Liou, SH Kenton, A Hirsch, MS Phair, J Martinez, A Kahn, JO CA AIDS Clinical Trial Grp 193A Study Team TI A randomized, controlled, double-blind study comparing the survival benefit of four different reverse transcriptase inhibitor therapies (three-drug, two-drug, and alternating drug) for the treatment of advanced AIDS SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Article DE AIDS; antiretroviral therapy; CD4 lymphocyte count; didanosine; HIV-1 RNA; nevirapine; reverse transcriptase inhibitors survival; zalcitabine; zidovudine ID IMMUNODEFICIENCY-VIRUS INFECTION; PLACEBO-CONTROLLED TRIAL; CD4 CELL COUNTS; CUBIC MILLIMETER; ANTIRETROVIRAL THERAPY; COMBINATION THERAPY; HIV-1 INFECTION; CLINICAL-TRIALS; ZIDOVUDINE; DIDANOSINE AB Objective: The primary objective was to compare the effects of dual or triple combinations of HN-I reverse transcriptase inhibitors with respect to survival. The time to new HIV disease progression or death, toxicities, the change in CD4 cells, and plasma HIV-1 RNA concentrations in a subset of study subjects were evaluated. Design: This was a multicenter randomized, double-blind: placebo-controlled study. Setting: The study was conducted among 42 adult AIDS Clinical Trials Group sites and 7 National Hemophilia Foundation centers. Patients: 1313 HIV-infected patients with CD4 counts less than or equal to 50 cells/mm(3) participated in this study, which was conducted from June 1993 to June 1996. Intervention: Patients were randomized to one of four daily regimens containing 600 mg of zidovudine: zidovudine alternating monthly with 400 mg didanosine; zidovudine plus 2.25 mg of zalcitabine; zidovudine plus 400 mg of didanosine; or zidovudine plus 400 mg of didanosine plus 400 mg of nevirapine (triple therapy). Main Outcome Measures: The main outcome was survival (i.e., time to death). Results: A significant difference in survival time was found between the four treatment groups, favoring those assigned to triple therapy (p = .02). A significant difference was also found in the delay of disease progression or death among the four treatment arms favoring the group assigned to triple therapy(p = .002). Baseline CD4 cell counts and plasma HIV-1 RNA concentrations as well as changes of CD4 counts at week 8 predicted survival for subjects in the virology substudy. Conclusions: In the pre-protease inhibitor era, a combination of triple reverse transcriptase inhibitors prolonged life and delayed disease progression in AIDS patients with advanced immune suppression. C1 Univ Minnesota, Minneapolis, MN 55455 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Miami Univ, Sch Med, Miami, FL USA. Frontier Sci Data Management Ctr, Amherst, NY USA. AIDS Clin Trials Grp, Operat Ctr, Rockville, MD USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Northwestern Univ, Sch Med, Chicago, IL USA. NIAID, Div Aids, Rockville, MD USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Henry, K (reprint author), Reg Hosp, HIV Program, 640 Jackson,Suite 125, St Paul, MN 55101 USA. EM henry02@karloff.fstrf.org NR 40 TC 44 Z9 47 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. PD DEC 1 PY 1998 VL 19 IS 4 BP 339 EP 349 PG 11 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 140CZ UT WOS:000077070300004 PM 9833742 ER PT J AU Hendel, H Henon, N Lebuanec, H Lachgar, A Poncelet, H Caillat-Zucman, S Winkler, CA Smith, MW Kenefic, L O'Brien, S Lu, W Andrieu, JM Zagury, D Schachter, F Rappaport, J Zagury, JF AF Hendel, H Henon, N Lebuanec, H Lachgar, A Poncelet, H Caillat-Zucman, S Winkler, CA Smith, MW Kenefic, L O'Brien, S Lu, W Andrieu, JM Zagury, D Schachter, F Rappaport, J Zagury, JF TI Distinctive effects of CCR5, CCR2, and SSDF1 genetic polymorphisms in AIDS progression SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Article DE CCR5; CCR2; SDF1; genetic polymorphisms; progression to AIDS ID HIV-1 INFECTION; DISEASE PROGRESSION; CHEMOKINE RECEPTOR; DELETION ALLELE; TRANSMISSION; CCR5-DELTA-32; PHENOTYPE AB The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represents 200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progressor (Fastprog) HIV-1-infected patients. Using this unique assembly, we performed genetic studies on three recently discovered polymorphisms of CCR5, CCR2, and SDF1, which have been shown to slow the rate of disease progression. The increased prevalence of mutant alleles among Slowprogs from the GRIV cohort was significant for CCR5 (p < .0001) but not for CCR2 (p = .09) or SDF1 (p = .12), emphasizing the predominant role of CCR5 as the major HIV-1 coreceptor. However, the prevalence of the CCR2 mutant allele (641) was significantly increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .04). The prevalence of double mutants SDF1-3'A/3'A genotypes was also increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .05). The effects of the CCR2 and SDF1 mutations are overshadowed by the protective effects of the CCR5 deletion. Predictive biologic markers such as CD4 cell counts or viral load in the Slowprog population did not show significant differences between Slowprog groups with wild-type or mutant alleles for the three genes. Thus, our data suggest that the effects of these genes are exerted earlier in infection and no longer evident in the Slowprog of the GRIV cohort whose average duration of HIV infection is 12 years. We conclude that these genes, whose products serve as viral coreceptors or their ligands, may play a role early in infection and delay the onset of disease. However, among Slowprogs, whose duration of infection is >8 years, they are no longer influential for maintenance of their longterm nonprogression status. Other genetic determinants may be responsible for late protective effects. C1 Univ Paris 06, Physiol Cellulare Lab, F-75005 Paris, France. Hop Pasteur, Nice, France. Hosp Necker, Serv Immunol Clin, Paris, France. NCI, FCRDC, Sci Applicat Int Co, Bethesda, MD 20892 USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. Hop Laennec, Serv Hematol Oncol, F-75340 Paris, France. Allegheny Univ Hlth Sci, Ctr Neurovirol & Neurooncol, Philadelphia, PA 19102 USA. RP Zagury, JF (reprint author), Univ Paris 06, Physiol Cellulare Lab, 4 Pl Jussieu, F-75005 Paris, France. RI Smith, Michael/B-5341-2012 NR 22 TC 84 Z9 84 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. PD DEC 1 PY 1998 VL 19 IS 4 BP 381 EP 386 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 140CZ UT WOS:000077070300009 PM 9833747 ER PT J AU Martin, MP Carrington, M Dean, M O'Brien, SJ Sheppard, HW Wegner, SA Michael, NL AF Martin, MP Carrington, M Dean, M O'Brien, SJ Sheppard, HW Wegner, SA Michael, NL TI CXCR4 polymorphisms and HIV-1 pathogenesis SO JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES AND HUMAN RETROVIROLOGY LA English DT Letter C1 NCI, Lab Genome Divers, Frederick, MD 21701 USA. Calif Dept Hlth Serv, Berkeley, CA 94704 USA. Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD USA. RP Martin, MP (reprint author), NCI, Lab Genome Divers, Frederick, MD 21701 USA. OI Dean, Michael/0000-0003-2234-0631 NR 5 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 1077-9450 J9 J ACQ IMMUN DEF SYND JI J. Acquir. Immune Defic. Syndr. Hum. Retrovirol. PD DEC 1 PY 1998 VL 19 IS 4 BP 430 EP 430 PG 1 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 140CZ UT WOS:000077070300017 PM 9833755 ER PT J AU Rantanen, T Masaki, K Foley, D Izmirlian, G White, L Guralnik, JM AF Rantanen, T Masaki, K Foley, D Izmirlian, G White, L Guralnik, JM TI Grip strength changes over 27 yr in Japanese-American men SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE aging; muscle strength; prospective study; body composition; chronic diseases ID MAXIMAL ISOMETRIC STRENGTH; CARDIOVASCULAR-DISEASE; HANDGRIP STRENGTH; WOMEN; MUSCLE; AGE; PERFORMANCE; HEALTH; ASSOCIATIONS; EXTREMITIES AB The aim of this study was to describe changes in grip strength over a follow-up period of similar to 27 yr and to study the associations of rate of strength decline with weight change and chronic conditions. The data are from the Honolulu Heart Program, a prospective population-based study established in 1965. Participants at exam 1 were 8,006 men (ages 45-68 yr) who were of Japanese ancestry and living in Hawaii. At follow-up, 3,741 men (age range, 71-96 yr) participated. Those who died before the follow-up showed significantly lower grip-strength values at baseline than did the survivors. The average annualized strength change among the survivors was -1.0%. Steeper decline (>1.5%/yr) was associated with older age at baseline, greater weight decrease, and chronic conditions such as stroke, diabetes, arthritis, coronary heart disease, and chronic obstructive pulmonary disease. The risk factors for having very low hand-grip strength at follow-up, here termed grip-strength disability (less than or equal to 21 kg, the lowest 10th percentile), were largely same as those for steep strength decline. However, the age-adjusted correlation between baseline and follow-up strength was strong (r = 0.557, P < 0.001); i.e., those who showed greater grip strength at baseline were also likely to do so 27 yr later. Consequently, those in the lowest grip-strength tertile at baseline had about eight times greater risk of grip-strength disability than those in the highest tertile because of their lower reserve of strength. In old age, maintenance of optimal body mass may help prevent steep strength decrease and poor absolute strength. C1 NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. Kuakini Med Ctr, Honolulu Asia Aging Study, Honolulu Heart Program, Honolulu, HI 96813 USA. RP Rantanen, T (reprint author), NIA, Epidemiol Demog & Biometry Program, NIH, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. EM Rantanet@gw.nia.nih.gov RI Rantanen, Taina/O-6579-2016 OI Rantanen, Taina/0000-0002-1604-1945 NR 36 TC 187 Z9 191 U1 2 U2 8 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 DEC PY 1998 VL 85 IS 6 BP 2047 EP 2053 PG 7 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 145WZ UT WOS:000077396500008 PM 9843525 ER PT J AU Ferrara, CM Reynolds, TH Zarnowski, MJ Brozinick, JT Cushman, SW AF Ferrara, CM Reynolds, TH Zarnowski, MJ Brozinick, JT Cushman, SW TI Short-term exercise enhances insulin-stimulated GLUT-4 translocation and glucose transport in adipose cells SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE adipose cells; exercise; glucose metabolism ID RAT ADIPOCYTES; TRAINING INCREASES; GENE-EXPRESSION; SYSTEMS; NUMBER; PHOTOLABEL; RESISTANT; ADENOSINE; PROTEIN; ISOFORM AB This investigation examined the effects of short-term exercise training on ea insulin-stimulated GLUT-4 glucose transporter translocation and glucose transport activity in rat adipose cells. Male Wistar rats were randomly assigned to a sedentary (Sed) or swim training group (Sw, 4 days; final 3 days: 2 x 3 h/day). Adipose cell size decreased significantly but minimally (similar to 20%), whereas total GLUT-4 increased by 30% in Sw vs. Sed rats. Basal 3-O-methyl-D-[C-14]glucose transport was reduced by 62%, whereas maximally insulin-stimulated (MIS) glucose transport was increased by 36% in Sw vs. Sed rats. MIS cell surface GLUT-4 photolabeling was 44% higher in the Sw vs. Sed animals, similar to the increases observed in MIS glucose transport activity and total GLUT-4. These results suggest that increases in total GLUT-4 and GLUT-4 translocation to the cell surface contribute to the increase in MIS glucose transport with short-term exercise training. In addition, the results suggest that the exercise training-induced adaptations in glucose transport occur more rapidly than previously thought and with minimal changes in adipose cell size. C1 NIDDK, Diabet Branch, Expt Diabet Metab & Nutr Sect, Bethesda, MD 20892 USA. RP Ferrara, CM (reprint author), Univ Maryland, Vet Affairs Med Ctr, GRECC BT 18 GR, 10 N Greene St, Baltimore, MD 21201 USA. NR 26 TC 5 Z9 5 U1 0 U2 0 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 DEC PY 1998 VL 85 IS 6 BP 2106 EP 2111 PG 6 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 145WZ UT WOS:000077396500015 PM 9843532 ER PT J AU Pascualvaca, DM Fantie, BD Papageorgiou, M Mirsky, AF AF Pascualvaca, DM Fantie, BD Papageorgiou, M Mirsky, AF TI Attentional capacities in children with autism: Is there a general deficit in shifting focus? SO JOURNAL OF AUTISM AND DEVELOPMENTAL DISORDERS LA English DT Article DE attention deficit; autism; shifting focus ID CARD SORTING TEST; PERVASIVE DEVELOPMENTAL DISORDERS; EXECUTIVE FUNCTION; SCHIZOPHRENIA; COMPREHENSION; REMEDIATION; PERFORMANCE; MIND AB Twenty-three children with autism and two control groups completed an attention battery comprising three versions of the continuous performance test (CPT), a digit cancellation task, the Wisconsin Card Sorting Test (WCST), and two novel, computerized tests of shifting attention (i.e., the Same-Different Computerized Task and the Computerized Matching Task). Children with autism could focus on a particular stimulus and sustain this focus as indicated by their performance on the digit cancellation task and the CPT Their performance on the WCST suggested problems in some aspects of shifting attention (i.e., disengaging attention). The autism group performed as well as controls on the Same-Different Computerized Task, however, that required successive comparisons between stimuli. This implies that they could, in fact, shift their attention continuously. In addition, they did not differ from controls on the Computerized Matching Task, an analog of the WCST, suggesting that they do not have a general deficit in shifting attention. C1 NIMH, Lab Brain & Cognit, Sect Clin & Expt Neuropsychol, Bethesda, MD 20892 USA. American Univ, Dept Psychol, Human Neuropsychol Lab, Washington, DC 20016 USA. RP Pascualvaca, DM (reprint author), NIMH, Lab Brain & Cognit, Sect Clin & Expt Neuropsychol, Bldg 15K,Room 103, Bethesda, MD 20892 USA. NR 41 TC 90 Z9 91 U1 1 U2 8 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0162-3257 J9 J AUTISM DEV DISORD JI J. Autism Dev. Disord. PD DEC PY 1998 VL 28 IS 6 BP 467 EP 478 DI 10.1023/A:1026091809650 PG 12 WC Psychology, Developmental SC Psychology GA 162UD UT WOS:000078364400002 PM 9932233 ER PT J AU Navaneetham, D Penn, AS Howard, AF Conti-Fine, BM AF Navaneetham, D Penn, AS Howard, AF Conti-Fine, BM TI TCR-V beta usage in the thymus and blood of myasthenia gravis patients SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE autoimmunity; myasthenia gravis; PCR; TCR-V beta usage; thymus ID NICOTINIC ACETYLCHOLINE-RECEPTOR; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; T-CELL REPERTOIRE; STAPHYLOCOCCAL ENTEROTOXIN-B; RHEUMATOID-ARTHRITIS; AUTOIMMUNE ENCEPHALOMYELITIS; MULTIPLE-SCLEROSIS; GENE SEGMENTS; ALPHA-SUBUNIT; SUPERANTIGEN AB In myasthenia gravis (MG) the muscle acetylcholine receptor (AChR) is the target of an autoimmune response. The anti-AChR response may originate in the thymus, which is abnormal in most MG patients and contains anti-AChR T and B cells. Microbial superantigens (sAg) may trigger autoimmune responses and in this study we sought clues as to whether sAg play a role in the pathogenesis of MG. We investigated the frequency of use of the different TCR V beta families by the thymus and blood T cells in MG patients and in control subjects, using a multi-primer PCR assay. Identical TCR-V beta usage was found in the thymi of MG patients and controls, except V beta 2, which showed a small increase in MG patients' thymi. Blood T cells of MG patients used V beta 4, V beta 6, V beta 15; V beta 16 and V beta 24 significantly more than those of the controls. V beta 4 and V beta 6 are the gene families most frequently used by anti-AChR CD4(+) cells in MG patients. Blood T cells from MG patients used V beta 12, V beta 14, V beta 17 and V beta 18 significantly less than controls. MG patients used V beta 4 and V beta 6 significantly more in the blood than in the thymus, while the opposite occurred for V beta 7, V beta 21 and V beta 14. Controls used V beta 17 more and V beta 24 less in the blood than in the thymus. The preferential expansion of V beta 4 and V beta 6 in MG patients might reflect the immunodominance of certain AChR epitopes, or the action of a sAg outside the thymus. The minimal differences in the TCR-V beta usage in the blood and thymus of control subjects might be due to expansion of T cell clones specific for common antigens. Identical V beta usage in the thymi of MG patients and controls does not support an important role of the thymus as the location of anti-AChR sensitization when MG is clinically evident. The differences observed in the V beta usage in blood and thymi of MG patients are likely to be due to preferential V beta usage by the anti-AChR T cells in the blood. (C) 1998 Academic Press. C1 Univ Minnesota, Dept Biochem, Coll Biol Sci, St Paul, MN 55108 USA. Univ Minnesota, Sch Med, Dept Pharmacol, Minneapolis, MN 55455 USA. NINDS, NIH, Off Director, Bethesda, MD 20892 USA. Univ N Carolina, Dept Neurol, Chapel Hill, NC 27599 USA. RP Conti-Fine, BM (reprint author), Univ Minnesota, Dept Biochem, Coll Biol Sci, CBS,1479 Gortner Ave, St Paul, MN 55108 USA. EM conti@biosci.cbs.umn.edu FU NINDS NIH HHS [NS 17904, NS 23919] NR 68 TC 10 Z9 12 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 1998 VL 11 IS 6 BP 621 EP 633 DI 10.1006/jaut.1998.0246 PG 13 WC Immunology SC Immunology GA 154ZF UT WOS:000077920500005 PM 9878084 ER PT J AU Magnuson, R Yarmolinsky, MB AF Magnuson, R Yarmolinsky, MB TI Corepression of the P1 addiction operon by Phd and Doc SO JOURNAL OF BACTERIOLOGY LA English DT Article ID PARD STABILITY SYSTEM; RANGE PLASMID RK2; ESCHERICHIA-COLI; RECEPTOR PROTEIN; CLONING VECTORS; TERNARY COMPLEX; CCD OPERON; CELL-DEATH; F-PLASMID; CAMP-CRP AB The P1 plasmid addiction operon encodes Doc, a toxin that kills plasmid-free segregants, and Phd, an unstable antidote that neutralizes the toxin, Additionally, these products repress transcription of the operon. The antidote binds to two adjacent sites in the promoter. Here we present evidence concerning the regulatory role of the toxin, which we studied with the aid of a mutation, docH66Y. The DocH66Y protein retained the regulatory properties of the wild-type protein, but not its toxicity, In vivo, DocH66Y enhanced repression by Phd but failed to affect repression in the absence of Phd, suggesting that DocH66Y contacts Phd. In vitro, a MalE-DocH66Y fusion protein was found to bind Phd. Binding of toxin to antidote may be the physical basis for the neutralization of toxin. DocH66Y failed to hind DNA in vitro yet enhanced the affinity, cooperativity, and specificity with which Phd hound the operator, Although DocH66Y enhanced the binding of Phd to two adjacent Phd-binding sites, DocH66Y had relatively little effect on the binding of Phd to a single Phd-binding site, indicating that DocH66Y mediates cooperative interactions between adjacent Phd-binding sites. Several electrophoretically distinct protein-DNA complexes were observed with different amounts of DocH66Y relative to Phd. Maximal repression and specificity of DNA binding were observed with subsaturating amounts of DocH66Y relative to Phd. Analogous antidote-toxin pairs appear to have similar autoregulatory circuits. Autoregulation, by dampening fluctuations in the levels of toxin and antidote, may prevent the inappropriate activation of the toxin. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Magnuson, R (reprint author), Bldg 37,Room 4D15,37 Convent Dr, Bethesda, MD 20892 USA. NR 62 TC 74 Z9 76 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD DEC PY 1998 VL 180 IS 23 BP 6342 EP 6351 PG 10 WC Microbiology SC Microbiology GA 142TZ UT WOS:000077217600033 PM 9829946 ER PT J AU Ortega, JM DePamphilis, ML AF Ortega, JM DePamphilis, ML TI Nucleoskeleton and initiation of DNA replication in metazoan cells SO JOURNAL OF CELL SCIENCE LA English DT Article DE nucleoskeleton; nuclear matrix; nuclear scaffold; origin of DNA replication; DNA replication; mammalian cell; Xenopus egg ID MATRIX ATTACHMENT REGIONS; XENOPUS EGG EXTRACT; NUCLEAR MATRIX; DIHYDROFOLATE-REDUCTASE; CHROMATIN STRUCTURE; HELA-CELLS; IN-VITRO; ORIGIN; PROTEINS; OCCURS AB To determine whether or not initiation sites for DNA replication in mammalian cells are defined by association with nuclear structure, attachments between the nucleoskeleton and the hamster DHFR gene initiation zone were examined. Nucleoskeletons were prepared by encapsulating cells in agarose and then extracting them with a nonionic detergent in a physiological buffer. The fraction of DNA that remained following endonuclease digestion was resistant to salt, sensitive to Sarkosyl, and essentially unchanged by glutaraldehyde crosslinking, Although newly replicated DNA was preferentially attached to the nucleoskeleton, no specific sequence was preferentially attached within a 65 kb locus containing the DHFR gene, two origins of bi-directional replication and at least one nuclear matrix attachment region. Instead, the entire region went from preferentially unattached to preferentially attached as cells progressed from G(1) to late S-phase, Thus, initiation sites in mammalian chromosomes are not defined by attachments to the nucleoskeleton. To further assess the relationship between the nucleoskeleton and DNA replication, plasmid DNA containing the DHFR initiation region was replicated in a Xenopus egg extract. All of the DNA associated with the nucleoskeleton prior to S-phase without preference for a particular sequence and was released upon mitosis, However, about half of this DNA was trapped rather than bound to the nucleoskeleton, Thus, attachments to the nncleoskeleton can form in the absence of either DNA replication or transcription, but if they are required for replication, they are not maintained once replication is completed. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, BR-31270010 Belo Horizonte, MG, Brazil. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bldg 6,Room 416, Bethesda, MD 20892 USA. EM depamphm@box-d.nih.gov NR 53 TC 19 Z9 19 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE, CAMBS, ENGLAND CB4 4DL SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD DEC PY 1998 VL 111 BP 3663 EP 3673 PN 24 PG 11 WC Cell Biology SC Cell Biology GA 155KR UT WOS:000077946300009 PM 9819357 ER PT J AU Satomura, K Derubeis, AR Fedarko, NS Ibaraki-O'Connor, K Kuznetsov, SA Rowe, DW Young, MF Robey, PG AF Satomura, K Derubeis, AR Fedarko, NS Ibaraki-O'Connor, K Kuznetsov, SA Rowe, DW Young, MF Robey, PG TI Receptor tyrosine kinase expression in human bone marrow stromal cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID EPIDERMAL GROWTH-FACTOR; K-DEPENDENT PROTEIN; SIGNAL-TRANSDUCTION; IN-VITRO; OSTEOGENIC PRECURSORS; CFU-F; FIBROBLASTS; AXL; MOUSE; VIVO AB Bone marrow stromal cells (BMSCs) are a heterogeneous population of cells derived from colony-forming units-fibroblastic (CFU-Fs. These cells reside in the bone marrow cavity and are capable of differentiating into several cell phenotypes including osteoblasts, chondroblasts, hematopoiesis-supporting stromal cells, and adipocytes. However, the factors that regulate the proliferation and differentiation of the BMSC population are for the most part unknown. Since many members of the receptor tyrosine kinase (RTK) family have been shown to participate in growth control of various mesenchymal cell populations, in this study we examined the expression and function of RTKs in the BMSC population. Degenerate oligonucleotides corresponding to two conserved catalytic domains of the RTK family and RT-PCR were used initially to determine which RTKs are expressed in the human BMSC (hBMSC) system. After subcloning the amplification product generated from mRNA of a multicolony-derived hBMSC strain, PDGF receptor (beta), EGF receptor, FGF receptor 1,and Axl were identified by DNA sequencing of 26 bacterial colonies. Furthermore, PDGF and EGF were found to enhance BMSC growth in a dose-dependent manner and to induce tyrosine phosphorylation of intracellular molecules, including the PDGF and EGF receptors themselves, demonstrating the functionality of these receptors. On the other hand, bFGF was found to have little effect on proliferation or tyrosine phosphorylation. Since single colony-derived hBMSC strains are known to vary from one colon), to another in colony habit (growth rate and colony structure) and the ability to form bone in vivo, the expression levels of these RTKs were determined in 18 hBMSC clonal strains by semiquantitative RT-PCR and were found to vary from one clonal strain to another. While not absolutely predictive of the osteogenic capacity of individual clonal strains, on average, relatively high levels of PDGF-receptor were found in bone-forming strains, while on average, nonbone-forming strains had relatively high levels of EGF-receptor. Taken together, these results indicate that RTKs play a role in the control of hBMSC proliferation, and that the differential pattern of RTK expression may be useful in correlating the biochemical properties of individual clonal strains with their ability to produce bone in vivo. (C) 1998 Wiley-Liss, Inc.dagger. C1 NIDR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Connecticut, Ctr Hlth, Dept Pediat, Farmington, CT USA. RP Robey, PG (reprint author), NIDR, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 106, Bethesda, MD 20892 USA. EM probey@goda.nidr.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 37 TC 70 Z9 80 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD DEC PY 1998 VL 177 IS 3 BP 426 EP 438 DI 10.1002/(SICI)1097-4652(199812)177:3<426::AID-JCP6>3.0.CO;2-F PG 13 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 134TL UT WOS:000076759300006 PM 9808151 ER PT J AU Zheng, CY Hoffman, MP McMillan, T Kleinman, HK O'Connell, BC AF Zheng, CY Hoffman, MP McMillan, T Kleinman, HK O'Connell, BC TI Growth factor regulation of the amylase promoter in a differentiating salivary acinar cell line SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID TISSUE-SPECIFIC EXPRESSION; SUBMANDIBULAR-GLAND; EXTRACELLULAR-MATRIX; MEDIATED TRANSFER; EPITHELIAL-CELLS; LUNG EPITHELIUM; KALLIKREIN GENE; DUCT CELLS; ADENOVIRUS; SEQUENCES AB Salivary glands contain two major epithelial cell types: acinar cells which produce the primary salivary secretion, including amylase, and ductal cells which reabsorb electrolytes but also secrete kallikrein. Here we investigated salivary acinar cell differentiation in vitro using the activity of the salivary amylase and tissue kallikrein promoters as markers of acinar cell and ductal cell differentiation, respectively. Each of the promoter sequences was cloned into a replication-deficient adenoviral vector containing the luciferase reporter gene. Previous studies showed that a human submandibular gland cell line (HSG) differentiated into acinar cells when cultured on a reconstituted basement membrane matrix (Matrigel). The luciferase activity of the amylase promoter vector (AdAMY-luc) was low in HSG cells cultured on plastic, where they grow as an epithelial monolayer. The promoter activity increased approximately tenfold when HSG cells were cultured on Matrigel and developed an acinar phenotype. Under the same conditions, the luciferase activity of the kallikrein promoter (AdKALL-luc) was not induced. Because HSG cells demonstrate acinar cell morphology, but not amylase gene expression, when cultured on laminin-1, certain soluble components of Matrigel were tested for their ability to induce the amylase promoter during in vitro differentiation of acinar cells. We find that epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha), which are present in the basement membrane, and hepatocyte growth factor (HGF) increase activity of the amylase promoter. Other basement membrane-derived growth factors such as TGF-beta, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PGDF), as well as tumor necrosis factor (TNF-alpha), keratinocyte growth factor (KGH), nerve growth factor (NGF) and interferon gamma (IFN-gamma) were inactive. This system will be further exploited to study the mechanisms by which extracellular matrix molecules and growth factors regulate salivary acinar cell differentiation. I Cell Physiol 777.628-635, 1998. (C) 1998 Wiley-Liss, Inc.dagger. C1 NIDR, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. NIDR, Cranofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP O'Connell, BC (reprint author), NIDR, Gene Therapy & Therapeut Branch, NIH, Bldg 10-1N113,10 Ctr Dr, Bethesda, MD 20892 USA. OI O'Connell, Brian/0000-0003-4529-7664 NR 27 TC 36 Z9 39 U1 0 U2 1 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD DEC PY 1998 VL 177 IS 4 BP 628 EP 635 DI 10.1002/(SICI)1097-4652(199812)177:4<628::AID-JCP13>3.0.CO;2-L PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 144DZ UT WOS:000077299700013 PM 10092215 ER PT J AU Langlois, JA Rosen, CJ Visser, M Hannan, MT Harris, T Wilson, PWF Kiel, DP AF Langlois, JA Rosen, CJ Visser, M Hannan, MT Harris, T Wilson, PWF Kiel, DP TI Association between insulin-like growth factor I and bone mineral density in older women and men: The Framingham Heart Study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID IGF-I; BODY-COMPOSITION; ELDERLY-MEN; IDIOPATHIC OSTEOPOROSIS; SERUM-LEVELS; POTENTIAL IMPLICATIONS; PHYSICAL-ACTIVITY; RANCHO-BERNARDO; BINDING-PROTEIN; HORMONE AB Few studies of the GH axis and bone have focused specifically on elderly people. The objective of this study was to determine the association between insulin-like growth factor I (IGF-I) and bone mineral density (BMD) in 425 women and 257 men aged 72-94 who participated in the Framingham Osteoporosis Study component of the Framingham Heart Study in 1992-1993. Serum IGF-I level was determined by RIA. BMD at three femoral sites and the lumbar spine was determined by dual x-ray absorptiometry, and at the radius by single-photon absorptiometry. IGF-I level was positively associated with BMD at all five sites (Ward's area, femoral neck, trochanter, radius, and lumbar spine) in women after adjustment for weight loss and other factors (P less than or equal to 0.01) and protein intake in a subset of participants (0.006 < P < 0.07). A threshold effect of higher BMD was evident at each of the 3 femoral sites and the spine (P < 0.03) but not at the radius for women in the highest quintile of IGF-I (greater than or equal to 179 g/liter) vs, those in the lowest four quintiles. IGF-I was not significantly associated with BMD in men. These results indicate that higher IGF-I levels are associated with greater BMD in very old women, and suggest that future clinical trials employing GH may have a role in the development of treatments for older women with osteoporosis. C1 NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. St Joseph Hosp, Bangor, ME 04401 USA. Harvard Univ, Sch Med, Hebrew Rehabil Ctr Aged, Res & Training Inst, Boston, MA 02131 USA. Harvard Univ, Sch Med, Div Aging, Boston, MA 02131 USA. NHLBI, Framingham Heart Study, NIH, Bethesda, MD 20892 USA. RP Langlois, JA (reprint author), Ctr Dis Control & Prevent, Div Acute Care Rehabil Res & Disabil Prevent, Natl Ctr Injury Prevent & Control, 4770 Buford Highway NE,MS F-41, Atlanta, GA 30341 USA. EM JAL7@CDC.GOV OI Kiel, Douglas/0000-0001-8474-0310 FU NIA NIH HHS [AG41398]; NIAMS NIH HHS [AR41398]; NIMHD NIH HHS [263-MD-247269] NR 56 TC 174 Z9 179 U1 1 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 1998 VL 83 IS 12 BP 4257 EP 4262 DI 10.1210/jc.83.12.4257 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 145FB UT WOS:000077359400015 PM 9851760 ER PT J AU Glasow, A Haidan, A Hilbers, U Breidert, M Gillespie, J Scherbaum, WA Chrousos, GP Bornstein, SR AF Glasow, A Haidan, A Hilbers, U Breidert, M Gillespie, J Scherbaum, WA Chrousos, GP Bornstein, SR TI Expression of Ob receptor in normal human adrenals: Differential regulation of adrenocortical and adrenomedullary function by leptin SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID PANCREATIC BETA-CELLS; LASER CAPTURE MICRODISSECTION; TUMOR-NECROSIS-FACTOR; GENE-EXPRESSION; PLASMA LEPTIN; ADIPOSE-TISSUE; INSULIN-RESISTANCE; MESSENGER-RNA; FOOD-INTAKE; OBESE GENE AB The major effects of leptin, an adipostatic hormone produced in fat tissue, are exerted through the hypothalamic-pituitary-adrenal axis and the systemic sympathetic/adrenomedullary system at the level of the central nervous system. Here, we examined the direct effects of leptin on the adrenal gland, a peripheral end organ of both the hypothalamic-pituitary-adrenal axis and the sympathetic/adrenomedullary system. As cortical and chromaffin tissues are intermingled in the human adrenal, we employed the novel technique of laser capture microdissection to analyze these systems separately. Functional full-length leptin receptor messenger ribonucleic acid and all human isoforms Ob219.1-3 were demonstrated by RT-PCR in both cortical and medullary tissue. Immunohistochemical staining of leptin receptor protein, however, demonstrated a strong signal only in the adrenal cortex, whereas there was weak positive staining in the medulla. Corticotropin (ACTH)-induced adrenal aldosterone, cortisol, and dehydroepiandrosterone secretion was inhibited by leptin in a concentration-dependent manner, whereas this hormone had no significant effect on catecholamine release by primary cultures of human adrenal chromaffin cells. Leptin itself was not expressed in human adrenal tissue, excluding a local paracrine or autocrine function of this peptide. In conclusion, this is the first report identifying functional leptin receptor in human adrenal tissue and showing a differential action of leptin on human adrenocortical and chromaffin hormone production. This peripheral action of leptin on the adrenal gland provides an additional important link between the human stress response and body weight regulation. C1 Univ Leipzig, Dept Internal Med 3, D-04103 Leipzig, Germany. Carl Gustav Carus TU Dresden, Fac Med, Dresden, Germany. Univ Dusseldorf, Diabet Res Inst, Dusseldorf, Germany. NCI, Dept Pathol, NIH, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Glasow, A (reprint author), Univ Leipzig, Med Klin & Poliklin 3, Philipp Rosenthal Str 27, D-04103 Leipzig, Germany. EM ges90apg@studserv.uni-leipzig.de NR 85 TC 141 Z9 147 U1 0 U2 3 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 DEC PY 1998 VL 83 IS 12 BP 4459 EP 4466 DI 10.1210/jc.83.12.4459 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 145FB UT WOS:000077359400049 PM 9851794 ER PT J AU Lebrethon, MC Avallet, O Reznik, Y Archambeaud, F Combes, J Usdin, TB Narboni, G Mahoudeau, J Saez, JM AF Lebrethon, MC Avallet, O Reznik, Y Archambeaud, F Combes, J Usdin, TB Narboni, G Mahoudeau, J Saez, JM TI Food-dependent Cushing's syndrome: Characterization and functional role of gastric inhibitory polypeptide receptor in the adrenals of three patients SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID SIDE-CHAIN CLEAVAGE; ANGIOTENSIN-II; STEROIDOGENIC RESPONSIVENESS; ADENYLATE-CYCLASE; CELLS; RNA; CORTICOTROPIN; FASCICULATA; EXPRESSION; ENDOCRINE AB In the present work, the presence of gastric inhibitory polypeptide (GTP) receptors and their functional role in the adrenal cells of three patients with food-dependent Cushing's syndrome were studied. RT-PCR and in situ hybridization studies demonstrated the presence of GIP receptor in the adrenals of the three patients. The presence of this receptor was also demonstrated in two human fetal adrenals, but not in two normal adult human adrenals or in the adrenals of one patient with nonfood-dependent Cushing's syndrome. Freshly isolated cells from patient adrenals responded in a dose-dependent manner to the steroidogenic action of both ACTH and GIP, whereas cells from normal adrenals responded only to ACTH. Treatment of cultured normal adrenal cells with ACTH, but not with GIP, increased the messenger ribonucleic acid (mRNA) levels of cholesterol side-chain cleavage cytochrome P-450, P450(c17), and 3 beta-hydroxysteroid dehydrogenase, whereas bath hormones enhanced these mRNAs in patients' adrenal cells, although the effects of ACTH were greater than those of GIP. Moreover, pretreatment with ACTH enhanced the steroidogenic responsiveness of both normal and patient adrenal cells, whereas GIP caused homologous desensitization, and this was associated with a marked reduction of GIP receptor mRNA levels, as demonstrated by RT-PCR and in situ hybridization. Finally, both ACTH and GIP inhibited DNA synthesis in one patient's adrenal cells, whereas in normal adrenal cells only ACTH had this effect. In conclusion, the present data demonstrate that ectopic expression of functional GIP receptors is the main cause of food-dependent Cushing's syndrome. C1 Hop Debrousse, INRA, INSERM, U418, F-69322 Lyon 05, France. Hop Debrousse, Inst Fed Rech Endocrinol Lyon, F-69322 Lyon 05, France. CHU Caen, Dept Endocrinol, F-14000 Caen, France. CHU Besancon, F-25030 Besancon, France. NIH, Cell Biol Lab, Bethesda, MD 20892 USA. RP Saez, JM (reprint author), Hop Debrousse, INRA, INSERM, U418, F-69322 Lyon 05, France. EM saez@lyon151.inserm.fr NR 27 TC 55 Z9 56 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD DEC PY 1998 VL 83 IS 12 BP 4514 EP 4519 DI 10.1210/jc.83.12.4514 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 145FB UT WOS:000077359400057 PM 9851802 ER PT J AU Hiraoka, W Vazquez, N Nieves-Neira, W Chanock, SJ Pommier, Y AF Hiraoka, W Vazquez, N Nieves-Neira, W Chanock, SJ Pommier, Y TI Role of oxygen radicals generated by NADPH oxidase in apoptosis induced in human leukemia cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE NADPH oxidase; chronic granulomatous disease; reactive oxygen intermediates; apoptosis; camptothecin ID CHRONIC GRANULOMATOUS-DISEASE; RESPIRATORY BURST OXIDASE; TUMOR-NECROSIS-FACTOR; HUMAN COLON-CARCINOMA; NF-KAPPA-B; TOPOISOMERASE-I; GENE-EXPRESSION; DNA FRAGMENTATION; ACTIVATION; CAMPTOTHECIN AB We have used a human leukemia cell line that, after homologous recombination knockout of the gp91-phox subunit of the phagocyte respiratory-burst oxidase cytochrome b-558, mimics chronic granulomatous disease (X-CGD) to study the role of oxygen radicals in apoptosis. Camptothecin (CPT), a topoisomerase I inhibitor, induced significantly more apoptosis in PLB-985 cells than in X-CGD cells. Sensitivity to CPT was enhanced after neutrophilic differentiation, but was lost after monocytic differentiation. No difference between the two cell lines was observed after treatment with other apoptosis inducers, including etoposide, ultraviolet radiation, ionizing radiation, hydrogen peroxide, or 7-hydroxystaurosporine. After granulocytic differentiation of both cell lines, CPT still induced apoptosis, suggesting independence from replication in fully differentiated and growth-arrested cells. Pyrrolidine dithiocarbamate (an antioxidant inhibitor of NF-kappa B) and catalase partially inhibited CPT-induced DNA fragmentation in granulocytic-differentiated PLB-985 cells, but had no effect in X-CGD cells. Flow cytometry analysis revealed that reactive oxygen intermediates were generated in CPT-treated PLB-985 cells. These data indicate that oxygen radicals generated by NADPH oxidase may contribute directly or indirectly to CPT-induced apoptosis in human leukemia and in neutrophilic-differentiated cells. C1 NCI, Mol Pharmacol Lab, Div Basic Sci, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, Bldg 37,Room 5D02, Bethesda, MD 20892 USA. NR 47 TC 82 Z9 83 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC 1 PY 1998 VL 102 IS 11 BP 1961 EP 1968 DI 10.1172/JCI3437 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 146PY UT WOS:000077440600009 PM 9835621 ER PT J AU Guedez, L Stetler-Stevenson, WG Wolff, L Wang, J Fukushima, P Mansoor, A Stetler-Stevenson, M AF Guedez, L Stetler-Stevenson, WG Wolff, L Wang, J Fukushima, P Mansoor, A Stetler-Stevenson, M TI In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1 SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE Bcl-X; Bcl-2; extracellular matrix; Burkitt's lymphoma; metalloproteinases ID GROWTH-PROMOTING ACTIVITY; NF-KAPPA-B; BURKITT-LYMPHOMA; DISTANT METASTASES; IMMUNE-SYSTEM; APOPTOSIS; BCL-2; ACTIVATION; TIMP-2; EXPRESSION AB Cellular pathways for induction of programmed cell death (PCD) have been identified, but little is known about spe chic extracellular matrix processes that may affect apoptosis along those pathways. In this study, a series of Burkitt's lymphoma (BL) cell lines were assayed for their expression of tissue inhibitor of metalloproteinases (TIMP)-1. Results indicate that TIMP-1-positive BL lines show resistance to cold-shock-induced apoptosis, Furthermore, recombinant TIMP-1, but not TIMP-2 or a synthetic metalloproteinase inhibitor (BB-94), confers resistance to apoptosis induced by both CD95-dependent and -independent (cold shock, serum deprivation, and gamma-radiation) pathways in TIMP-1-negative BL lines. TIMP-1 suppression of PCD is not due to metalloproteinase inhibition, as reduction and alkylation of the TIMP-1 did not abolish this activity, Retroviral induction of TIMP-1 not only resulted in cell survival but also in continued DNA synthesis for up to 5 d in the absence of serum, while controls underwent apoptosis. This resistance to apoptosis is reversed by anti-TIMP1 antibodies, demonstrating that secreted TIMP-1 is active in blocking apoptosis, Furthermore, TIMP-1 upregulation induced expression of Bcl-X-L but not Bcl-2 as well as decreased NF-kappa B activity as compared with controls. These results demonstrate that TIMP-1 suppresses apoptosis in B cells and suggests a novel activity for TIMP-1 in tissue homeostasis. C1 NCI, Flow Cytometry Unit, Hematopathol Sect, Pathol Lab,DCS, Bethesda, MD 20892 USA. NCI, Extracellular Matrix Pathol Sect, Pathol Lab, Div Clin Sci, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Hematopathol Sect, Pathol Lab,DCS, Bldg 10,Room 2A33,MSC 1500,10 Ctr Dr, Bethesda, MD 20892 USA. EM stetler@box-s.nih.gov RI Stetler-Stevenson, William/H-6956-2012; Guedez, Liliana/H-4951-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808; NR 49 TC 305 Z9 312 U1 0 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD DEC 1 PY 1998 VL 102 IS 11 BP 2002 EP 2010 DI 10.1172/JCI2881 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 146PY UT WOS:000077440600014 PM 9835626 ER PT J AU Banerjee, SN Banerjee, M Fernando, K Burgdorfer, W Schwan, TG AF Banerjee, SN Banerjee, M Fernando, K Burgdorfer, W Schwan, TG TI Tick-borne relapsing fever in British Columbia, Canada: First isolation of Borrelia hermsii SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID LYME-DISEASE; BURGDORFERI; CULTIVATION; ANTIBODY AB The spirochete that causes tick-borne relapsing fever, Borrelia hennsii, was isolated in pure culture during 1995 and 1996 from three acutely ill human patients infected in southern British Columbia, Canada. The geographic area of exposure is a known focus of this disease dating back to 1930 when the first case was recognized in a human. Analyses of plasmid DNG protein profiles, and reactivity with a species-specific monoclonal antibody identified the new isolates of spirochetes as B, hermsii, all of which were most similar to an isolate of this spirochete from northern California described previously. These are the first reported isolates of B. hennsii from Canada. C1 NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. BC Ctr Dis Control Soc, Vector Borne Dis Lab, Vancouver, BC V5Z 4R4, Canada. RP Schwan, TG (reprint author), NIAID, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM tom_schwan@nih.gov NR 25 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 1998 VL 36 IS 12 BP 3505 EP 3508 PG 4 WC Microbiology SC Microbiology GA 140CP UT WOS:000077069400011 PM 9817862 ER PT J AU Kacena, KA Quinn, SB Hartman, SC Quinn, TC Gaydos, CA AF Kacena, KA Quinn, SB Hartman, SC Quinn, TC Gaydos, CA TI Pooling of urine samples for screening for Neisseria gonorrhoeae by ligase chain reaction: Accuracy and application SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID TRANSMISSION; HIV-1 AB The accuracy of detection of genital Neisseria gonorrhoeae infection in pooled urine samples by ligase chain reaction (LCR) was examined in three populations, Firstly, urine specimens from 300 female military recruits (FMR) were tested by LCR individually and in pools of four and six. Secondly, 300 urine specimens from middle-school students (MSS) were tested individually by LCR, and then the processed specimens were stored frozen for subsequent testing in pools of 4 and 10, Thirdly, 600 frozen urine specimens from high-school students (HSS) were tested by using the LCR pooling algorithm, i.e., testing processed specimens in pools of four in one test unit dose, and retesting individual specimens front positive pools. Finally, the pooling algorithm results were compared to culture results for a subset of 344 students from the original 600 IISS from whom cervical or urethral samples were taken at the discretion of the school nurse practitioners. Compared to individual testing of specimens by LCR in the FMR population, the pooling-by-four algorithm was 100% sensitive (5 of 5) and 100% pool specific (70 of 70), and the pool-by-six algorithm was 100% sensitive (5 of 5) and 100% pool specific (45 of 45). In the MSS population, the pool-by-4 algorithm was 95.8% sensitive (23 of 24) and 100% (52 of 52) pool specific, and the pool-by-10 algorithm was 95.8% sensitive (23 of 23) and 100% (17 of 17) pool specific. In the subset of 344 IISS from whom endocervical or urethral specimens were collected for culture, 31 were positive by LCR in urine and 26 were positive by culture. After results discrepant between culture and LCR were adjudicated by a confirmatory LCR test, the pooling algorithm was 93.8% (30 of 32) sensitive and 99.7% (311 of 312) specific. Culture from these 344 IISS was 81.3% (26 of 32) sensitive, The pooling algorithm reduced the cost of the N. gonorrhoeae LCR assay by 60% compared to individual testing of the HSS specimens and was both sensitive and specific. C1 Johns Hopkins Univ, Div Infect Dis, Sch Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Div Dis Control, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Gaydos, CA (reprint author), Johns Hopkins Univ, Div Infect Dis, Sch Med, Ross Res Bldg,Room 1159,720 Rutland Ave, Baltimore, MD 21205 USA. RI Gaydos, Charlotte/E-9937-2010 NR 15 TC 21 Z9 22 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 1998 VL 36 IS 12 BP 3624 EP 3628 PG 5 WC Microbiology SC Microbiology GA 140CP UT WOS:000077069400034 PM 9817885 ER PT J AU Lyles, CM Vlahov, D Farzadegan, H Astemborski, J Margolick, JB Masters, BA Schroeder, J Quinn, TC AF Lyles, CM Vlahov, D Farzadegan, H Astemborski, J Margolick, JB Masters, BA Schroeder, J Quinn, TC TI Comparison of two measures of human immunodeficiency virus (HIV) type 1 load in HIV risk groups SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID MULTICENTER AIDS COHORT; TRANSMISSION CATEGORY; DRUG-USERS; RNA LEVELS; PROGRESSION; SEROCONVERSION; INFECTION; PLASMA; AGE; LYMPHOCYTES AB Levels of viral burden were compared across risk group and gender populations among 485 human immunodeficiency virus type 1 (HIV-1)-infected participants consisting of 190 male injection drug users (IDUs), 92 female IDUs, and 203 homosexual men. Viral burden was quantified by a microculture technique to determine cell-associated infectious units per 10(6) peripheral blood mononuclear cells (IUPM) and by reverse transcriptase PCR (Amplicor) to determine plasma HIV RNA levels. Adjusting for CD4(+) cell count, females had a lower infectious HIV load than all males combined (0.33 log(10) lower; P = 0.004), and homosexual men had a 0.29 log(10) higher infectious viral load than all IDUs combined (P = 0.001), For HN RNA levels, females had lower levels than males (0.19 log(10) lower; P = 0.04), but no differences were observed by risk group. After controlling for percent CD lt cells, no differences were found by risk group for either assay, but females still had a 0.25 log,, lower infectious viral load than males (P = 0.04) and a viral RNA load similar to that of males (P = 0.25), The correlation between infectious viral load and HIV RNA load was 0.58 overall, which did not differ by gender or risk group, Our data suggest that differences in viral load may exist by gender and that any differences observed by risk group are driven predominantly by gender or percent CD4+ cell differences. These data also confirm a moderate correlation between cell-associated infectious viral load and plasma HIV RNA load, which appears to be similar by gender and across risk groups. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NIAID, Bethesda, MD 20892 USA. RP Lyles, CM (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, 615 N Wolfe St,E6003, Baltimore, MD 21205 USA. FU NCRR NIH HHS [M01 RR000722, RR-00722]; NIAID NIH HHS [AI-35042, U01 AI035042]; NIDA NIH HHS [R56 DA004334, DA04334, R01 DA004334, R37 DA004334] NR 26 TC 14 Z9 14 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1325 MASSACHUSETTS AVENUE, NW, WASHINGTON, DC 20005-4171 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD DEC PY 1998 VL 36 IS 12 BP 3647 EP 3652 PG 6 WC Microbiology SC Microbiology GA 140CP UT WOS:000077069400038 PM 9817889 ER PT J AU Frye, MA Kimbrell, TA Dunn, RT Piscitelli, S Grothe, D Vanderham, E Cora-Locatelli, G Post, RM Ketter, TA AF Frye, MA Kimbrell, TA Dunn, RT Piscitelli, S Grothe, D Vanderham, E Cora-Locatelli, G Post, RM Ketter, TA TI Gabapentin does not alter single-dose lithium pharmacokinetics SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID BIPOLAR DISORDER; CARBAMAZEPINE; EFFICACY; DEPRESSION; MANIA; SODIUM AB Lithium (Li) and gabapentin are both exclusively eliminated by renal excretion. When used in combination, a competitive drug-drug interaction could possibly alter Li renal excretion with important clinical implications considering the rather narrow therapeutic index of Li. This study examined the single-dose pharmacokinetic profiles of Li in 13 patients receiving placebo and then steady-state gabapentin (mean daily dose: 3,646.15 mg). During both phases, a single 600-mg dose of Li was orally administered with serial Li levels obtained at time zero and at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48, and 72 hours. The pharmacokinetic parameters assessed were the following: area under the concentration time curve (AUC) for Li, maximal concentration of Li (Li C-max), and time to reach peak Li concentration (Li T-max). For patients receiving gabapentin, the mean Li AUC at 72 hours was 9.91 +/- 3.54 mmol x hr/mL and did not differ significantly from the mean Li AUC of 10.19 +/- 2.89 mmol x hr/mL for patients receiving placebo. The mean Li C-max was 0.69 +/- 0.13 mmol/L for gabapentin patients and did not differ from the mean Li C-max of 0.72 +/- 0.15 mmol/L for placebo patients. The mean serum Li T-max was 1.38 +/- 0.62 hours for gabapentin patients and did not differ significantly from the mean serum Li T-max of 1.5 +/- 0.91 hours for placebo patients. These data indicate that gabapentin treatment at this high therapeutic dose does not cause clinically significant alterations in short-term Li pharmacokinetics in patients with normal renal function. These preliminary data warrant further controlled study in a larger, more heterogenous patient sample and a longer duration of assessment, but they do suggest that these two medications may be administered in combination for the management of bipolar disorder. C1 NIMH, Dept Psychiat, Bethesda, MD 20892 USA. Natl Inst, Ctr Clin, Dept Clin Pharm, Bethesda, MD USA. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. RP Frye, MA (reprint author), NIMH, Dept Psychiat, Bldg 10,Room 3N 212, Bethesda, MD 20892 USA. EM maf@helix.nih.gov NR 22 TC 14 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 227 EAST WASHINGTON SQ, PHILADELPHIA, PA 19106 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD DEC PY 1998 VL 18 IS 6 BP 461 EP 464 DI 10.1097/00004714-199812000-00008 PG 4 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 146JJ UT WOS:000077425300007 PM 9864078 ER PT J AU Sandak, B Nussinov, R Wolfson, HJ AF Sandak, B Nussinov, R Wolfson, HJ TI A method for biomolecular structural recognition and docking allowing conformational flexibility SO JOURNAL OF COMPUTATIONAL BIOLOGY LA English DT Article DE flexible molecular docking and molecular recognition; induced fit; structure-based drug design; object recognition; Hough transform; Geometric Hashing ID MALTODEXTRIN-BINDING-PROTEIN; MOLECULAR-SURFACE; FLEXIBLE LIGANDS; AUTOMATED DOCKING; GENETIC ALGORITHM; ACTIVE-TRANSPORT; HOUGH TRANSFORM; COMPUTER VISION; RECEPTOR-SITES; DRUG DESIGN AB In this work, we present an algorithm developed to handle biomolecular structural recognition problems, as part of an interdisciplinary research endeavor of the Computer Vision and Molecular Biology fields. A key problem in rational drug design and in biomolecular structural recognition is the generation of binding modes between two molecules, also known as molecular docking, Geometrical fitness is a necessary condition for molecular interaction. Hence, docking a ligand (e.g., a drug molecule or a protein molecule), to a protein receptor (e.g., enzyme), involves recognition of molecular surfaces. Conformational transitions by "hinge-bending" involves rotational movements of relatively rigid parts with respect to each other. The generation of docked binding modes between two associating molecules depends on their three dimensional structures (3-D) and their conformational flexibility In comparison to the particular case of rigid-body docking, the computational difficulty grows considerably when taking into account the additional degrees of freedom intrinsic to the flexible molecular docking problem. Previous docking techniques have enabled hinge movements only within small ligands. Partial flexibility in the receptor molecule is enabled by a few techniques, Hinge-bending motions of protein receptors domains are not addressed by these methods, although these types of transitions are significant, e.g., in enzymes activity. Our approach allows hinge induced motions to exist in either the receptor or the ligand molecules of diverse sizes. We allow domains/subdomains/group of atoms movements in either of the associating molecules. We achieve this by adapting a technique developed in Computer Vision and Robotics for the efficient recognition of partially occluded articulated objects, These types of objects consist of rigid parts which are connected by rotary joints (hinges). Our method is based on an extension and generalization of the Hough transform and the Geometric Hashing paradigms for rigid object recognition, We show experimental results obtained by the successful application of the algorithm to cases of bound and unbound molecular complexes, yielding fast matching times. While the "correct" molecular conformations of the known complexes are obtained with small RMS distances, additional, predictive good-fitting binding modes are generated as well. We conclude by discussing the algorithm's implications and extensions, as well as its application to investigations of protein structures in Molecular Biology and recognition problems in Computer Vision. C1 Weizmann Inst Sci, Dept Appl Math & Comp Sci, IL-76100 Rehovot, Israel. NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, SAIC, Frederick, MD USA. Tel Aviv Univ, Fac Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, Sackler Fac Exact Sci, Dept Comp Sci, IL-69978 Tel Aviv, Israel. RP Sandak, B (reprint author), Weizmann Inst Sci, Dept Appl Math & Comp Sci, IL-76100 Rehovot, Israel. EM billie@wisdom.weizmann.ac.il RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [1-CO-74102] NR 47 TC 51 Z9 53 U1 0 U2 2 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1066-5277 EI 1557-8666 J9 J COMPUT BIOL JI J. Comput. Biol. PD WIN PY 1998 VL 5 IS 4 BP 631 EP 654 DI 10.1089/cmb.1998.5.631 PG 24 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 168NJ UT WOS:000078698900002 PM 10072081 ER PT J AU Medin, DL Brown, DT Wesley, R Cunnion, RE Ognibene, FP AF Medin, DL Brown, DT Wesley, R Cunnion, RE Ognibene, FP TI Validation of continuous thermodilution cardiac output in critically ill patients with analysis of systematic errors SO JOURNAL OF CRITICAL CARE LA English DT Article ID CARDIOPULMONARY BYPASS; MECHANICAL VENTILATION; TEMPERATURE; ACCURACY; LIMITATIONS; CATHETER AB Purpose: Bolus thermodilution cardiac output (BCO) measurements are affected by variations in injectate volume, rate, and temperature. These variations are eliminated when CO is measured by a continuous automated thermal technique (CCO). Further, CCO eliminates the need for fluid boluses, reduces contamination risk, requires no operator, and provides a continuous CO trend. We prospectively evaluated CCO versus BCO in a population of critically ill adults with low, normal, and high CO states. We sought to discern any systematic effects of temperature fluctuations or signal-to-noise-ratios (SMR) on disparities between BCO and CCO measurements and also sought to assess the relative cost effectiveness of the CCO system. Materials and Methods: Pulmonary artery catheterizations were performed in a convenience sample of 20 patients over 6 months. BCO data were obtained using a standardized protocol. Three bolus injections of 5% dextrose were given when each CO was within 10% of the median before averaging; otherwise five boluses were given, with the high and low values eliminated before averaging. Injectates were administered randomly through the respiratory cycle and at 1-minute intervals. CCO measurements were recorded from a Vigilance monitor pre and post BCO measurements, yielding an average CCO value, Also recorded were pre- and post-core temperatures and SNR during the first CCO measurement. Cost data included estimates of operator time for BCO determinations as well as costs of Intellicath (Baxter-Edwards, Irvine, CA) pulmonary artery catheters, Vigilance (Baxter-Edwards, Irvine, CA) monitors, conventional catheters,and injectates. Results: Of the 20 patients, 15 were mechanically ventilated. A total of 306 paired CO values were obtained for analysis. CCO ranged from 2.5 to 14.4 L/min and BCO from 2.4 to 13.3 L/min. Absolute differences between CCO and BCO measurements increased with increasing CO, but percentage differences did not. Of the paired values, 77% were within 1 L/min of one another. Temperature instability and SNR independently had weak correlations with CCO/ BCO disparities. The Vigilance system had a slightly higher net cost than conventional BCO, although no economical value was assigned to the clinical usefulness of continuous, as opposed to intermittent, CO monitoring. Conclusions: Continuous CO is a reliable and cost-effective alternative to bolus thermodilution CO for critically ill patients in low, normal, and high CO states. This is a US government work. There are no restrictions on ifs use. C1 NCI, Dept Crit Care Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. RP Ognibene, FP (reprint author), NCI, Dept Crit Care Med, Warren G Magnuson Clin Ctr, NIH, Bldg 10,Room 7D43, Bethesda, MD 20892 USA. NR 35 TC 21 Z9 22 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0883-9441 J9 J CRIT CARE JI J. Crit. Care PD DEC PY 1998 VL 13 IS 4 BP 184 EP 189 DI 10.1016/S0883-9441(98)90004-1 PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 147GY UT WOS:000077481900005 PM 9869545 ER PT J AU Hubel, A Stroncek, D Pan, D Whitley, CB McCullough, J AF Hubel, A Stroncek, D Pan, D Whitley, CB McCullough, J TI Mobilization and transduction of peripheral blood progenitor cells in patients with mucopolysaccharidosis I SO JOURNAL OF HEMATOTHERAPY LA English DT Article ID ADENOSINE-DEAMINASE DEFICIENCY; COLONY-STIMULATING FACTOR; HEMATOPOIETIC STEM-CELLS; ALPHA-L-IDURONIDASE; BONE-MARROW; RETROVIRAL VECTOR; GAUCHER DISEASE; GENE-THERAPY; CORD-BLOOD; GLUCOCEREBROSIDASE GENE AB Mucopolysaccharidosis type I (MPS I) results from a deficiency of alpha-L-iduronidase enzyme (IDUA), an enzyme responsible for the catabolism of glycosaminoglycans, Genetically modified progenitor cells may permit a therapeutic effect similar to that obtained from allogeneic BMT without the associated risks. To that end, CD34+ peripheral blood hematopoietic progenitor cells from patients with MPS I were mobilized using G-CSF, collected by apheresis, and enriched using avidin-biotin separation techniques. These cells were cultured in a hollow fiber bioreactor and transduced with a retroviral vector (LP1CD) containing the cDNA for human IDUA and a murine dihydrofolate reductase (DHFR) enzyme. Approximately 4%-16% of the colonies expressed methotrexate drug resistance. Expression of the IDUA enzyme in the progenitor cells was initially high and declined after approximately 10 days of culture. These results indicate that PBPC from patients with MPS I can be mobilized, isolated, enriched, and transduced with a therapeutic gene. C1 Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Univ Minnesota, Inst Human Genet, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. RP Hubel, A (reprint author), Univ Minnesota, Dept Lab Med & Pathol, 420 Delaware St SE,Box 609, Minneapolis, MN 55455 USA. FU NICHD NIH HHS [NI PO1-HD32652] NR 27 TC 1 Z9 1 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1061-6128 J9 J HEMATOTHER JI J. Hematother. PD DEC PY 1998 VL 7 IS 6 BP 505 EP 514 DI 10.1089/scd.1.1998.7.505 PG 10 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 157VT UT WOS:000078082900005 PM 9919944 ER PT J AU Fraser, JK Cairo, MS Wagner, EL McCurdy, PR Baxter-Lowe, LA Carter, SL Kernan, NA Lill, MC Slone, V Wagner, JE Wallas, CH Kurtzberg, J AF Fraser, JK Cairo, MS Wagner, EL McCurdy, PR Baxter-Lowe, LA Carter, SL Kernan, NA Lill, MC Slone, V Wagner, JE Wallas, CH Kurtzberg, J TI Cord blood transplantation study (COBLT): Cord blood bank standard operating procedures SO JOURNAL OF HEMATOTHERAPY LA English DT Article ID BONE-MARROW RECONSTITUTION; UNRELATED DONORS; PLACENTAL BLOOD AB In 1995, the National Heart Lung and Blood Institute (NHLBI) solicited requests for a proposal (RFP) entitled "Transplant Centers for Clinical Research on Transplantation of Umbilical Cord Stem and Progenitor Cells." Three banks, six transplant centers, and one medical coordinating center (MCC) (Table 1) were funded with the overall goal of banking cord blood units (CBU) using a single manual of operations, Furthermore, the clinical protocols to evaluate the transplant outcome for adult and pediatric recipients of these well-characterized CBU would be analyzed in a uniform fashion. Because of the intense interest of the transplantation community in the policies and procedures for cord blood collection and processing, the principal investigators of the cord blood banks (CBB) and NHLBI elected to submit for publication the rationale and an abridged, but detailed, version of the standard operating procedures (SOP) developed between October 1996 and July 1998 prior to the initiation of the clinical protocols to be performed with these CBU, As the SOP will be refined over time, the complete SOP and subsequent amendments will be published and continually updated on the websites from the MCC-The EMMES Corporation (www.EMMES.com). All forms referred to in this document may be obtained from the EMMES website, It is hoped that the publication of this document will lay down a framework that will not only facilitate the development of other CBB but also help us more rapidly define what constitutes an "acceptable" CBU product. C1 EMMES Corp, Potomac, MD 20854 USA. Univ Calif Los Angeles, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. NHLBI, Bethesda, MD 20892 USA. Univ S Carolina, Dept Mol Genet, Columbia, SC 29203 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Childrens Hosp Orange Cty, Orange, CA 92868 USA. Univ Minnesota, Div Bone Marrow Transplantat, Minneapolis, MN 55455 USA. Amer Red Cross, Carolinas Cord Blood Bank, Charlotte, NC 28203 USA. Duke Univ, Med Ctr, Dept Pediat, Div Hematol Oncol, Durham, NC 27710 USA. RP Carter, SL (reprint author), EMMES Corp, 11325 7 Locks Rd,Suite 214, Potomac, MD 20854 USA. RI Fraser, John/I-7309-2013 FU NHLBI NIH HHS [N01-HB-67132, N01-HB-76141, N01-HB-67142] NR 20 TC 75 Z9 78 U1 0 U2 4 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1061-6128 J9 J HEMATOTHER JI J. Hematother. PD DEC PY 1998 VL 7 IS 6 BP 521 EP 561 DI 10.1089/scd.1.1998.7.521 PG 41 WC Hematology; Medicine, Research & Experimental; Transplantation SC Hematology; Research & Experimental Medicine; Transplantation GA 157VT UT WOS:000078082900007 PM 9919946 ER PT J AU Bagrov, AY Fedorova, OV AF Bagrov, AY Fedorova, OV TI Effects of two putative endogenous digitalis-like factors, marinobufagenin and ouabain, on the Na+,K+-pump in human mesenteric arteries SO JOURNAL OF HYPERTENSION LA English DT Article; Proceedings Paper CT 17th Scientific Meeting of the International-Society-of-Hypertension CY JUN 07-11, 1998 CL AMSTERDAM, NETHERLANDS SP Int Soc Hypertens DE Na+,K+-ATPase; isoforms; inhibitors; vascular smooth muscle; ouabain; bufodienolides; marinobufagenin ID NA+-K+-ATPASE; ALPHA-SUBUNIT; VENTRICULAR ARRHYTHMIAS; PUMP ACTIVITY; RAT AORTA; NA/K PUMP; NA+,K+-ATPASE; NA,K-ATPASE; INHIBITION; ISCHEMIA AB Objectives Recently, in rat aortae, two putative digitalislike factors, marinobufagenin and ouabain, were shown to interact with alpha-1 (sarcolemma) and alpha-3 (nerve endings) subunits of the sodium pump, respectively, and elicit vasoconstriction via inhibition of the Na+,K+-pump in vascular smooth muscle or norepinephrine release. The purpose of the present study was to investigate the effects of ouabain and marinobufagenin on vascular tone, activity of Na+,K+-pump, and the expression of isoforms of the Na+,K+-ATPase alpha-subunit in human mesenteric arteries. Design and methods Arteries were obtained from male patients undergoing surgery due to intestinal adenocarcinoma, Vasoconstrictor effects of both inhibitors were studied in isolated vascular rings. Na+,K+-pump activity was measured using the Rb-86 technique. Membrane fractions of sarcolemma and nerve endings plasmalemma were prepared via differential centrifugation of membranes in a sucrose density gradient. Specific antibodies to the alpha-1 and alpha-3 subunits of Na+,K+-ATPase were used to detect alpha-1 and alpha-3 isoforms in the membrane fractions by Western blotting. Results Marinobufagenin (EC50 = 88 +/- 15 nmoles/l) and ouabain (EC50 = 320 +/- 50 nmoles/l) elicited vasoconstriction in mesenteric artery rings. At a concentration of 1 nmol/l, both compounds stimulated the Na+,K+-pump, but inhibited its activity at 10-1000 nmoles/l. No stimulation of the Na+,K+-pump was observed in the presence of 5 mu mol/l phentolamine; rather 1 nmol/l of marinobufagenin and ouabain inhibited the Na+,K+-pump by 30% and 13%, respectively. The alpha-1 polyclonal antibody detected alpha-1 isoform in membrane fractions from both sarcolemma and nerve endings. A monoclonal alpha-1 antibody detected the material in sarcolemmal membranes only. The alpha-3 isoform was detected in both membrane fractions by both antibodies, but staining for alpha-3 was more pronounced in the nerve endings. Conclusions These results demonstrate that, in physiologically 'realistic' concentrations, marinobufagenin and ouabain can significantly affect the Na+,K+-pump in human mesenteric artery, and illustrate the importance of interaction of digitalis-like Na+,K+-pump inhibitors with the Na+,K+-ATPase localized to the intravascular adrenergic terminals. Present observations are in accord with the previous data suggesting that marinobufagenin and ouabain display greater affinity to alpha-1 and alpha-3 isoforms of the Na+,K+-pump, respectively, and support the view that the differential responsiveness to endogenous digitalis-like inhibitors is one of the features of alpha-isoforms of Na+,K+-ATPase. J Hypertens 1998, 16:1953-1958 (C) 1998 Lippincott Williams & Wilkins. C1 NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. IM Sechenov Evolutionary Physiol & Biochem Inst, Pharmacol Lab, St Petersburg 194223, Russia. RP Bagrov, AY (reprint author), NIA, Cardiovasc Sci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 35 TC 51 Z9 52 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD DEC PY 1998 VL 16 IS 12 BP 1953 EP 1958 DI 10.1097/00004872-199816121-00015 PN 2 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 152RW UT WOS:000077791400015 PM 9886882 ER PT J AU Fogler, WE Volker, K Watanabe, M Wigginton, JM Roessler, P Brunda, MJ Ortaldo, JR Wiltrout, RH AF Fogler, WE Volker, K Watanabe, M Wigginton, JM Roessler, P Brunda, MJ Ortaldo, JR Wiltrout, RH TI Recruitment of hepatic NK cells by IL-12 is dependent on IFN-gamma and VCAM-1 and is rapidly down-regulated by a mechanism involving T cells and expression of fas SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; LARGE GRANULAR LYMPHOCYTES; INTERFERON-GAMMA; STIMULATORY FACTOR; IN-VIVO; RESPONSE MODIFIERS; VIRAL-INFECTIONS; IMMUNE PRIVILEGE; INTERLEUKIN-12; LIGAND AB NK cells have been shown to be important antitumor or antiviral effector cells in the liver. In the present study we have examined the factors that regulate the initial recruitment and subsequent fate of hepatic NK and T cells in mice treated with IL-12 or IL-2. Daily administration of IL-12 caused a rapid initial increase in NK cells followed by a subsequent decrease that coincided with an accumulation of T cells, The recruitment of hepatic Mt cells by IL-12, but not the subsequent T cell infiltrate, was abrogated in IFN-gamma(-/-) mice. In contrast, daily administration of IL-2 caused a sustained increase in liver-associated NK cells that was not diminished in IFN-gamma(-/-) mice, The IL-12-induced recruitment in both hepatic NK and T cells was abrogated by in vivo treatment with anti-VCAM-1 mAbs, while treatment with anti-ICAM-1 Abs decreased only the recruitment of T cells in the IL-12-treated mice, The rapid loss of newly recruited hepatic NK cells in IL-12-treated mice did not occur in SCID mice or in B.MRL-Fas(lpr) (Fas(-)) and B6Smn.C3H-Fasl(gld) (FasL(-)) mutant mice, suggesting that T cells can actively eliminate hepatic Mt cells through a Fas-dependent mechanism, These Endings also imply that during the endogenous innate immune response to infectious agents or tumors or in the host response induced by cytokine therapies, the biologic effects of NK cells may be limited by T cell-mediated effects. C1 NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. Hoffmann La Roche Inc, Dept Oncol, Nutley, NJ 07110 USA. RP Wiltrout, RH (reprint author), NCI, Expt Immunol Lab, Div Basic Sci, Frederick Canc Res & Dev Ctr, Bldg 560,Room 31-93, Frederick, MD 21702 USA. EM wiltroutr@mail.ncifcrf.gov NR 61 TC 45 Z9 45 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 1 PY 1998 VL 161 IS 11 BP 6014 EP 6021 PG 8 WC Immunology SC Immunology GA 142NQ UT WOS:000077206900032 PM 9834083 ER PT J AU Chen, WJ Jin, WW Cook, M Weiner, HL Wahl, SM AF Chen, WJ Jin, WW Cook, M Weiner, HL Wahl, SM TI Oral delivery of group a streptococcal cell walls augments circulating TGF-beta and suppresses streptococcal cell wall arthritis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MYELIN BASIC-PROTEIN; CD4(+) T-CELLS; DENDRITIC CELLS; IMMUNE-RESPONSE; TOLERANCE; EXPRESSION; CYTOKINES; IL-4 AB Oral administration of autoantigens can influence the outcome of experimental autoimmune diseases, yet little is known about nonself Ag-induced tolerance. In this study, we administered group A streptococcal cell wall (SCW) peptidoglycan-polysaccharide complexes orally and monitored the impact on SCW-induced erosive polyarthritis, Oral administration of low dose SCW (3 mu g/day), initiated 7 days before an arthritogenic dose of systemic SCW, virtually eliminated the joint swelling and destruction typically observed during both the acute and chronic phases of the arthritis. High (300 mu g), but not intermediate (30 mu g), dose regimens also profoundly inhibited the disease. Most previous studies have demonstrated that prior feeding is required for efficacy, yet oral feeding of low dose SCW suppressed the evolution of arthritis even when administration was begun 10-15 days after induction of the arthritis. While the synovial inflammatory cell infiltration and expression of proinflammatory cytokines were markedly suppressed, no local enhancement of the regulatory cytokines IL-4, IL-10, and TGF-beta was detected. Oral administration of low dose SCW, however, up-regulated circulating levels of TGF-beta, concomitant with decreased circulating TNF-alpha and suppression of chronic arthritis. Moreover, IL-10 was increased in tolerized spleen lymphocytes, and unexpectedly, this SCW-specific IL-10 production was TGF-beta dependent. These data support a pivotal role for TGF-beta, although not necessarily in the joint, in the regulation of specific immune tolerance responsible for suppressed synovial inflammation and matrix destruction. The distant induction and up-regulation of regulatory cytokines and/or cells may contribute to the inhibition of the immune response through blunted infiltration of inflammatory cells to the joint. C1 Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. RP Wahl, SM (reprint author), NIDR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. EM smwahl@yoda.nidr.nih.gov NR 33 TC 48 Z9 50 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 DEC 1 PY 1998 VL 161 IS 11 BP 6297 EP 6304 PG 8 WC Immunology SC Immunology GA 142NQ UT WOS:000077206900068 PM 9834119 ER PT J AU Sulkowski, MS Chaisson, RE Karp, CL Moore, RD Margolick, JB Quinn, TC AF Sulkowski, MS Chaisson, RE Karp, CL Moore, RD Margolick, JB Quinn, TC TI The effect of acute infectious illnesses on plasma human immunodeficiency virus (HIV) type 1 load and the expression of serologic markers of immune activation among HIV-infected adults SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the Infectious-Diseases-Society-of-America CY SEP 07-16, 1997 CL SAN FRANCISCO, CA SP Infect Dis Soc Amer ID TUMOR-NECROSIS-FACTOR; FACTOR RECEPTORS; FACTOR-ALPHA; PROTEASE INHIBITOR; SOLUBLE RECEPTORS; AIDS; RNA; REPLICATION; INDUCTION; PROGRESSION AB The effect of acute coinfections on plasma human immunodeficiency virus (HIV) load and immune activation markers was evaluated. Thirty-two HIV-infected persons were prospectively enrolled; 18 had pre-illness, acute, and follow-up specimens. Plasma HIV RNA levels were determined by reverse transcriptase-polymerase chain reaction, and serum levels of activation markers, including tumor necrosis factor (TNF)-alpha, soluble (s) TNF receptors (R)-I and -II, interleukin (IL)-2, IL-6, IL-10, sIL-2R, sCD4, and sCD8, were assessed by commercial ELISAs. Median plasma HIV load increased 7.8-fold during illness (P =.001) and decreased 1.5-fold (P =.01) during convalescence (median, 15 days), Significant virus load reductions were limited to subjects with clinical recovery. By regression analysis, changes in plasma HIV RNA were significantly associated with changes in sTNFR-I, sTNFR-II, and sIL-2R. Increased HIV replication during acute coinfections is associated with in vivo immune activation, which underscores the need to prevent and promptly treat intercurrent illnesses. C1 Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Div Gen Internal Med, Baltimore, MD USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Quinn, TC (reprint author), 720 Rutland Ave,Richard Starr Ross Res Bldg,Room, Baltimore, MD 21205 USA. FU NIAID NIH HHS [AI-07451] NR 37 TC 88 Z9 89 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC PY 1998 VL 178 IS 6 BP 1642 EP 1648 DI 10.1086/314491 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 147AU UT WOS:000077466700014 PM 9815216 ER PT J AU Montali, RJ Bush, M Cromie, R Holland, SM Maslow, JN Worley, M Witebsky, FG Phillips, TM AF Montali, RJ Bush, M Cromie, R Holland, SM Maslow, JN Worley, M Witebsky, FG Phillips, TM TI Primary Mycobacterium avium complex infections correlate with lowered cellular immune reactivity in Matschie's tree kangaroos (Dendrolagus matschiei) SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Meeting of the American-Association-of-Zoo-Veterinarians CY 1995 CL E LANSING, MICHIGAN SP Amer Assoc Zoo Vet ID RESPONSES; AIDS; TUBERCULOSIS; STRESS; BLOOD; GAMMA; CELLS AB The National Zoological Park has maintained a breeding colony of Matschie's tree kangaroos (Dendrolagus matschiei) since 1975 with a documented history and continued prevalence of Mycobacterium avium complex (MAC) infections. No evidence of immunosuppressive retrovirus infections or loss of heterozygosity that may have led to an immune dysfunction in these animals was found. Isolates of MAC organisms from affected tree kangaroos and from their environment had no common restriction fragment DNA types. Cellular immune reactivity in apparently healthy tree kangaroos was 3- to 6-fold lower than in humans and other marsupial and eutherian mammals, as determined by lymphocyte proliferative assays. Thus, while MAC infections are typically opportunistic in humans and other mammals, tree kangaroos commonly develop primary progressive disease with MAC from random sources. Comparative information derived from this study should benefit both the endangered tree kangaroo and humans with immunosuppressive disorders that lead to mycobacterial infections. C1 Smithsonian Inst, Natl Zool Pk, Dept Pathol, Washington, DC 20008 USA. George Washington Univ, Med Ctr, Immunochem Lab, Washington, DC 20037 USA. Smithsonian Inst, Natl Zool Pk, Conservat & Res Ctr, Vet Serv, Front Royal, VA USA. NIAID, Host Def Lab, Bethesda, MD 20892 USA. NIH, Microbiol Serv, Dept Clin Pathol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. VA Med Ctr, Dept Med, Boston, MA USA. San Diego Zoo, Ctr Reprod Endangered Species, San Diego, CA USA. RP Montali, RJ (reprint author), Smithsonian Inst, Natl Zool Pk, Dept Pathol, 3001 Connecticut Ave NW, Washington, DC 20008 USA. NR 38 TC 21 Z9 21 U1 0 U2 4 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC PY 1998 VL 178 IS 6 BP 1719 EP 1725 DI 10.1086/314517 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 147AU UT WOS:000077466700024 PM 9815225 ER PT J AU Roilides, E Anastasiou-Katsiardani, A Dimitriadou-Georgiadou, A Kadiltsoglou, I Tsaparidou, S Panteliadis, C Walsh, TJ AF Roilides, E Anastasiou-Katsiardani, A Dimitriadou-Georgiadou, A Kadiltsoglou, I Tsaparidou, S Panteliadis, C Walsh, TJ TI Suppressive effects of interleukin-10 on human mononuclear phagocyte function against Candida albicans and Staphylococcus aureus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT IHS 9th International Symposium on Infections in the Immunocompromised Host CY JUN 23-26, 1996 CL ASSISI, ITALY ID TUMOR-NECROSIS-FACTOR; HUMAN POLYMORPHONUCLEAR NEUTROPHILS; COLONY-STIMULATING FACTOR; T-CELL PROLIFERATION; GROWTH-FACTOR-BETA; INTERFERON-GAMMA; IFN-GAMMA; MYCOBACTERIUM-AVIUM; ANTIFUNGAL ACTIVITY; FUNGAL-INFECTIONS AB The effects of interleukin (IL)-10, a potent antiinflammatory cytokine, on human monocyte functions against two medically important pathogens, Candida albicans and Staphylococcus aureus, were studied. Incubation with 20-100 ng/mL IL-10 for 2-3 days decreased the fungicidal activity of monocytes against serum-opsonized C. albicans blastoconidia (P less than or equal to.04), reduced their capacity to damage unopsonized hyphae (P less than or equal to.006), and suppressed superoxide anion production in response to phorbol myristate acetate (P=.019) and N-FMLP (P=.04) but not to serum-opsonized blastoconidia. Paradoxically, IL-IO enhanced phagocytic activity of monocytes against serum-opsonized blastoconidia (P<.01). In addition, IL-10-treated monocytes demonstrated decreased bactericidal activity (P=.046) but no change in bacterial phagocytosis. These findings demonstrate an overall suppressive role of IL-10 on human monocyte function against C. albicans and S. aureus and may have important implications in the use of this cytokine. C1 NCI, Immunocompromised Hosp Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Univ Thessaloniki, Hippokration Hosp, Dept Pediat 3, GR-54006 Salonika, Greece. RP Walsh, TJ (reprint author), NCI, Immunocompromised Hosp Sect, Pediat Oncol Branch, Bldg 10,Room 13N240, Bethesda, MD 20892 USA. NR 59 TC 29 Z9 30 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC PY 1998 VL 178 IS 6 BP 1734 EP 1742 DI 10.1086/314479 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 147AU UT WOS:000077466700026 PM 9815227 ER PT J AU Neva, FA Oliveira, J Gam, AA Thompson, R Freitas, V Melo, A Carvalho, EM AF Neva, FA Oliveira, J Gam, AA Thompson, R Freitas, V Melo, A Carvalho, EM TI Interferon-gamma and interleukin-4 responses in relation to serum IgE levels in persons infected with human T lymphotropic virus type I and Strongyloides stercoralis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HTLV-I; SCHISTOSOMA-MANSONI; CARRIERS; HOST AB Possible immunologic interaction between infection with human T lymphotropic virus type 1 (HTLV-1), a retrovirus, and the intestinal parasite Strongyloides stercoralis was investigated in persons infected with one or both agents. This was done by examining the cytokine responses of peripheral blood mononuclear cells (PBMC) to mitogens and Strongyloides antigen, PBMC of subjects infected with HTLV-1 spontaneously produced interferon (IFN)-gamma with levels that correlated inversely with serum IgE levels. HTLV-1-infected subjects also had poor interleukin (IL)-4 responses to mitogenic stimulation, unlike persons without HTLV-1 infection. It is postulated that the IFN-gamma produced by activated T cells in some HTLV-l-infected persons acts to down-regulate IL-4 with consequent reduction of serum IgE levels, The impaired IgE responses and other effects of IL-4 down-regulation may be contributing factors to more severe disease and impaired response to treatment of strongyloidiasis in some HTLV-1-infected persons. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Fed Bahia, Serv Imunol, Salvador, BA, Brazil. Univ Fed Bahia, Hosp Univ Prof Edgard Santos, Salvador, BA, Brazil. RP Neva, FA (reprint author), NIAID, Parasit Dis Lab, NIH, Bldg 4,Room 413,4 Ctr Dr, Bethesda, MD 20892 USA. NR 17 TC 45 Z9 48 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 5801 S ELLIS AVENUE, CHICAGO, IL 60637 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD DEC PY 1998 VL 178 IS 6 BP 1856 EP 1859 DI 10.1086/314507 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 147AU UT WOS:000077466700050 PM 9815251 ER PT J AU Tint, GS Pentchev, P Xu, G Batta, AK Shefer, S Salen, G Honda, A AF Tint, GS Pentchev, P Xu, G Batta, AK Shefer, S Salen, G Honda, A TI Cholesterol and oxygenated cholesterol concentrations are markedly elevated in peripheral tissue but not in brain from mice with the Niemann-Pick type C phenotype SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; DISEASE TYPE-C; CHROMATOGRAPHY MASS-SPECTROMETRY; OXIDATION-PRODUCTS; STORAGE DISORDER; REGULATORY OXYSTEROLS; STEROL SYNTHESIS; HUMAN PLASMA; BALB/C MICE; ESTERIFICATION AB Niemann-Pick disease type C (NP-C) is a rare genetic disorder characterized by progressive neurodegeneration, frequent developmental delay and early death. Tissues of affected individuals accumulate large quantities of free cholesterol in lysosomes. Because cytotoxic oxygenated derivatives of cholesterol are known to form readily when cholesterol concentrations are elevated, we searched for these compounds in liver, kidney, spleen and brain from mice with the NP-C phenotype. In order of abundance, we identified 7 alpha- and 7 beta-hydroxycholesterol, 5 alpha,6 alpha-epoxycholestan-3 beta-o1, 4 beta-hydroxycholesterol, cholest-4-en-3 beta,7 alpha-diol and cholest-4-en-3 beta,6 beta-diol in most tissue samples. Cholesterol concentrations in affected mice were increased 3-fold in kidney and 7- to 8-fold in spleen and liver compared to controls (all p < 0.001) but were unchanged in brain. Although oxysterol levels were markedly elevated in non-brain tissue, the oxysterol and cholesterol concentrations increased proportionally so that oxysterols expressed as percentage of total sterols were the same for all animals (0.34 +/- 0.19% averaged over all organs in affected animals vs 0.40 +/- 0.42% in control mice). In contrast to peripheral tissue, we could not detect any increase in either absolute or relative oxysterol levels in the brains of affected and control mice (49 +/- 61 vs 53 +/- 43 mu g/g wet weight and 0.45 +/- 0.52 vs 0.47 +/- 0.37%, respectively). Thus, brain sterols are normal in NP-C mice and it is unlikely that an accumulation of cytotoxic oxygenated derivatives of cholesterol could account for the progressive neuropathology seen in the disease. C1 Dept Vet Affairs New Jersey Hlth Care Syst, E Orange, NJ USA. UMDNJ, New Jersey Med Sch, Dept Med, Newark, NJ USA. UMDNJ, New Jersey Med Sch, Ctr Liver, Newark, NJ USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Tint, GS (reprint author), Vet Adm Med Ctr, 385 Tremont Ave, E Orange, NJ 07018 USA. FU NICHD NIH HHS [HD/HL-31932] NR 61 TC 44 Z9 44 U1 1 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD DEC PY 1998 VL 21 IS 8 BP 853 EP 863 DI 10.1023/A:1005474803278 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 153HV UT WOS:000077828300009 PM 9870211 ER PT J AU Ichiki, AT Langenberg, M Baker, EJ Hodge, JW Bamberger, EG Gerard, DA Lozzio, CB AF Ichiki, AT Langenberg, M Baker, EJ Hodge, JW Bamberger, EG Gerard, DA Lozzio, CB TI Differential regulation of interleukin-1 alpha and interleukin-1 beta in K-562 cells SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID COLONY-STIMULATING FACTORS; K562 LEUKEMIA-CELLS; MEGAKARYOBLASTIC DIFFERENTIATION; EXPRESSION; LINES; MACROPHAGE; ACTIVATION; BETA; IL-1 AB Interleukin (IL)-1 alpha and IL-1 beta are encoded by two separate genes, but both function as comitogens for lymphocyte activation. In this study, we observed K-562 cells to express constitutively mRNA for IL-1 alpha, although IL-1 alpha was not detected in the growth-conditioned medium (GCM). However, IL-1 beta mRNA was not expressed unless the cells had been treated with phorbol myristate acetate (PMA), Both IL-1 alpha and IL-1 beta were detected in the GCM after the cells had been cultured with PMA, suggesting that IL-1 elaboration required PMA treatment. The K-562 cells treated with PMA differentiated to the myeloblastic stage, as observed by nuclear morphologic properties by electron microscopy, PMA treatment induced de novo expression of CD61 or gpIIIa, a marker associated with megakaryoblasts. These results showed that although K-562 cells constitutively expressed IL-1 alpha mRNA, PMA treatment was required for secretion. On the other hand, both the expression and secretion of LL-1 beta required treatment with PMA, This study showed that K-562 cells treated with PMA differentiated to the myeloblastic stage and expressed and secreted IL-1 alpha and IL-1 beta. C1 Univ Tennessee, Med Ctr, Grad Sch Med, Knoxville, TN 37920 USA. Univ Tennessee, Coll Med, Memphis, TN 38163 USA. NCI, NIH, Bethesda, MD 20879 USA. RP Ichiki, AT (reprint author), Univ Tennessee, Med Ctr, Grad Sch Med, 1924 Alcoa Highway, Knoxville, TN 37920 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 32 TC 4 Z9 4 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD DEC PY 1998 VL 18 IS 12 BP 1045 EP 1050 DI 10.1089/jir.1998.18.1045 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 152AK UT WOS:000077752900006 PM 9877448 ER PT J AU Falanga, V Greenberg, AS Zhou, L Ochoa, SM Roberts, AB Falabella, A Yamaguchi, Y AF Falanga, V Greenberg, AS Zhou, L Ochoa, SM Roberts, AB Falabella, A Yamaguchi, Y TI Stimulation of collagen synthesis by the anabolic steroid stanozolol SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE fibroblasts; transforming growth factor-beta; wound healing ID GROWTH FACTOR-BETA; HUMAN DERMAL FIBROBLASTS; III COLLAGEN; CRYOFIBRINOGENEMIA; EXPRESSION; INCREASE; CULTURES; INVITRO; ULCERS; SKIN AB There is evidence that anabolic steroids, which are derived from testosterone and have markedly less androgenic activity, promote tissue growth and enhance tissue repair; however, the mechanisms involved in their anabolic activities remain unclear. In this report, we measured the effect of the anabolic steroid stanozolol on cell replication and collagen synthesis in cultures of adult human dermal fibroblasts. Stanozolol (0.625-5 mu g per ml) had no effect on fibroblast replication and cell viability (p = 0.764) but enhanced collagen synthesis (p < 0.01) in a dose-dependent manner (r = 0.907). Stanozolol also increased (by 2-fold) the mRNA levels of alpha 1(I) and alpha 1(III) procollagen and, to a similar extent, upregulated transforming growth factor-beta 1 (TGF-beta 1) mRNA and peptide levels (p < 0.001). There was no stimulation of collagen synthesis by testosterone, The stimulatory effects of stanozolol on collagen synthesis were blocked by a TGF-beta 1 anti-sense oligonucleotide, by antibodies to TGF-beta, and in dermal fibroblast cultures derived from TGF-beta 1 knockout mice. We conclude that collagen synthesis is increased by the anabolic steroid stanozolol and that, for the most part, this effect is due to TGF-beta 1. These findings point to a novel mechanism of action of anabolic steroids. C1 Univ Miami, Sch Med, Dept Dermatol, Miami, FL 33152 USA. Vet Affairs Med Ctr, Miami, FL 33125 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Falanga, V (reprint author), Boston Univ, Roger Williams Med Ctr, Elmhurst Bldg 50, Providence, RI 02908 USA. RI Yamaguchi, Yuji/B-9312-2008 FU NIA NIH HHS [AG10998]; NIAMS NIH HHS [AR42936] NR 29 TC 43 Z9 46 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 DEC PY 1998 VL 111 IS 6 BP 1193 EP 1197 DI 10.1046/j.1523-1747.1998.00431.x PG 5 WC Dermatology SC Dermatology GA 145PT UT WOS:000077381000044 PM 9856839 ER PT J AU Kertesz, I Balboni, G Salvadori, S Lazarus, LH Toth, G AF Kertesz, I Balboni, G Salvadori, S Lazarus, LH Toth, G TI Synthesis of 2 ',6 '-dimethyltyrosine containing tritiated delta opioid-receptor selective antagonist dipeptide ligands with extraordinary affinity SO JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS LA English DT Article DE delta opioid antagonist; dipeptide; tritium ID PHARMACOPHORE; PEPTIDES AB A new class of delta opioid antagonists was recently discovered in which the sequence Tyr-Tic was used as a message domain. The substitution of Tyr(1) by Dmt enhanced the delta selectivity and antagonist activity. The excellent properties of these ligands stimulated us to prepare the corresponding tritiated derivatives. Peptides containing Tic at position 2 undergo spontaneous diketopiperazine formation in some solvents, with a reduction in opioid activity. To avoid this side-reaction we synthesised the N,N-dimethylated analogue (N,N(Me)(2)-Dmt-Tic-OH), which was found to be stable. On the basis of this result, we prepared diiodinated analogues of H-Dmt-Tic-OH and N,N(Me)(2)-Dmt-Tic-OH to undergo catalytic dehalotritiation. Products of high specific radioactivity were obtained: 44.67 Ci/mmol for [H-3]Dmt-Tic-OH and 59.88 Ci/mmol for [H-3]N,N(Me)(2)-Dmt-Tic-OH. C1 Hungarian Acad Sci, Biol Res Ctr, Inst Biochem, H-6701 Szeged, Hungary. Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. NIEHS, LCBRA, Res Triangle Pk, NC 27709 USA. RP Toth, G (reprint author), Hungarian Acad Sci, Biol Res Ctr, Inst Biochem, POB 521, H-6701 Szeged, Hungary. EM geza@everx.szbk.u-szeged.hu OI SALVADORI, Severo/0000-0002-8224-2358 NR 11 TC 10 Z9 10 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0362-4803 J9 J LABELLED COMPD RAD JI J. Label. Compd. Radiopharm. PD DEC PY 1998 VL 41 IS 12 BP 1083 EP 1091 DI 10.1002/(SICI)1099-1344(199812)41:12<1083::AID-JLCR155>3.0.CO;2-5 PG 9 WC Biochemical Research Methods; Chemistry, Medicinal; Chemistry, Analytical SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 143PL UT WOS:000077264500001 ER PT J AU Amar, MJA Dugi, KA Haudenschild, CC Shamburek, RD Foger, B Chase, M Bensadoun, A Hoyt, RF Brewer, HB Santamarina-Fojo, S AF Amar, MJA Dugi, KA Haudenschild, CC Shamburek, RD Foger, B Chase, M Bensadoun, A Hoyt, RF Brewer, HB Santamarina-Fojo, S TI Hepatic lipase facilitates the selective uptake of cholesteryl esters from remnant lipoproteins in apoE-deficient mice SO JOURNAL OF LIPID RESEARCH LA English DT Article DE intermediate density lipoprotein metabolism; catalytically inactive HL; recombinant adenovirus; kinetic analysis ID LOW-DENSITY LIPOPROTEINS; RECEPTOR-RELATED PROTEIN; HEPARAN-SULFATE PROTEOGLYCANS; CELL-SURFACE PROTEOGLYCANS; HUMAN ADENOVIRUS TYPE-5; RAT-LIVER; SR-BI; CHYLOMICRON REMNANTS; SCAVENGER RECEPTOR; APOLIPOPROTEIN-E AB We have investigated the role of hepatic lipase (HL) in remnant lipoprotein metabolism independent of lipolysis by using recombinant adenovirus to express native and catalytically inactive HL (HL-145G) in apolipoprotein (apo)E-deficient mice characterized by increased plasma concentrations of apoB-48-containing remnants. In the absence of apoE, the mechanisms by which apoB-48-containing remnants are taken up by either low density lipoprotein (LDL)-receptor or LDC-receptor-related protein (LRP) remain unclear. Overexpression of either native or catalytically inactive HL in apoE-deficient mice led to similar reductions (P > 0.5) in the plasma concentrations of cholesterol (41% and 53%) and non high density lipoprotein (HDL)-cholesterol (41% and 56%) indicating that even in the absence of lipolysis, HL can partially compensate for the absence of apoE in this animal model, Although the clearance of [H-3]cholesteryl ether from VLDL was significantly increased (approximately 2-fold; P < 0.02) in mice expressing native or inactive HL compared to luciferase controls, the fractional catabolic rates (FCR) of [I-125-labeled] apoB- very low density lipoprotein (VLDL) in all three groups of mice were similar (P > 0.4, all) indicating selective cholesterol uptake. Hepatic uptake of [3H]cholesteryl ether from VLDL was greater in mice expressing either native HL (87%) or inactive HL-145G (72%) compared to luciferase controls (56%), Our combined findings are consistent with a role for HL in mediating the selective uptake of cholesterol from remnant lipoproteins in apoE-deficient mice, independent of lipolysis. These studies support the concept that hepatic lipase (HL) may serve as a ligand that mediates the interaction between remnant lipoproteins and cell surface receptors and/or proteoglycans, We hypothesize that one of these pathways may involve the interaction of HL with cell surface receptors, such as scavenger receptor (SR)-BI, that mediate the selective uptake of cholesteryl esters. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. RP Amar, MJA (reprint author), NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. NR 53 TC 52 Z9 52 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 DEC PY 1998 VL 39 IS 12 BP 2436 EP 2442 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148GK UT WOS:000077496700014 PM 9831632 ER PT J AU Caffrey, M Kaufman, J Stahl, SJ Wingfield, PT Gronenborn, AM Clore, GM AF Caffrey, M Kaufman, J Stahl, SJ Wingfield, PT Gronenborn, AM Clore, GM TI 3D NMR experiments for measuring N-15 relaxation data of large proteins: Application to the 44 kDa ectodomain of SIV gp41 SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE N-15 relaxation; 3D NMR; large proteins; gp41 ID MODEL-FREE APPROACH; BACKBONE DYNAMICS; SPECTROSCOPY AB A suite of 3D NMR experiments for measuring N-15-{H-1} NOE, N-15 T-1, and N-15 T-1 rho values in large proteins, uniformly labeled with N-15 and C-13, is presented. These experiments are designed for proteins that exhibit extensive spectral overlap in the 2D H-1-N-15 HSQC spectrum. The pulse sequences are readily applicable to perdeuterated samples, which increases the spectral resolution and signal-to-noise ratio, thereby permitting the characterization of protein dynamics to be extended to larger protein systems. Application of the pulse sequences is demonstrated on a perdeuterated C-13/N-15-labeled sample of the 44 kDa ectodomain of SIV gp41. C1 NIDDKD, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. NIAMSD, NIH, Prot Express Lab, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, NIH, Chem Phys Lab, Bldg 5, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 19 TC 17 Z9 17 U1 1 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD DEC PY 1998 VL 135 IS 2 BP 368 EP 372 DI 10.1006/jmre.1998.1583 PG 5 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 151MZ UT WOS:000077725400009 PM 9878465 ER PT J AU He, LP Mears, D Atwater, I Kitasato, H AF He, LP Mears, D Atwater, I Kitasato, H TI Glucagon induces suppression of ATP-sensitive K+ channel activity through a Ca2+/calmodulin-dependent pathway in mouse pancreatic beta-cells SO JOURNAL OF MEMBRANE BIOLOGY LA English DT Article DE cAMP; calmodulin antagonist; caged Ca2+; islet of Langerhans; glycogenolysis ID SINGLE POTASSIUM CHANNELS; INSULIN-SECRETING CELLS; ELECTRICAL-ACTIVITY; INTRACELLULAR ATP; B-CELLS; RELEASE; GLUCOSE; ISLETS; CAMP; OSCILLATIONS AB Glucagon is known to increase intracellular cAMP levels and enhance glucose-induced electrical activity and insulin secretion in pancreatic beta-cell perfused with Krebs-Ringer bicarbonate solution. The present experiments were aimed at evaluation of the hypothesis that changes in beta-cells ATP-sensitive K+ (K-(ATP)) channel activity are involved in the glucagon-induced enhancement of electrical activity. Channel activity was recorded using the cell-attached configuration of the patch-clamp technique. Addition of glucagon (2.9 x 10(-7) M) in the presence of 11.1 mM glucose caused closure of K-(ATP) channels followed by an increase in the frequency of biphasic current transients (action currents) due to action potential generation in the cell. Three calmodulin-antagonists (W-7, chlorpromazine, and trifluoperazine) restored with similar efficacy K-(ATP) channel activity in cells being exposed to glucagon. At 2.8 mM glucose, glucagon did not affect K-(ATP) channel activity until Ca2+ was released from Nitr-5 by flash photolysis, at which point channel activity was transiently suppressed. Similar effects were seen when db-cAMP was used instead of glucagon. These results support the view that glucagon and other cAMP-generating agonists enhance glucose-induced beta-cell electrical activity through a Ca2+/calmodulin dependent-closure of K-(ATP) channels. C1 NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. Shiga Univ Med Sci, Dept Physiol, Ohtsu, Shiga 52021, Japan. RP He, LP (reprint author), NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. NR 34 TC 10 Z9 11 U1 0 U2 0 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0022-2631 J9 J MEMBRANE BIOL JI J. Membr. Biol. PD DEC 1 PY 1998 VL 166 IS 3 BP 237 EP 244 DI 10.1007/s002329900465 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Physiology SC Biochemistry & Molecular Biology; Cell Biology; Physiology GA 143XK UT WOS:000077282700009 PM 9843597 ER PT J AU Boateng, SY Seymour, AML Bhutta, NS Dunn, MJ Yacoub, MH Boheler, KR AF Boateng, SY Seymour, AML Bhutta, NS Dunn, MJ Yacoub, MH Boheler, KR TI Sub-antihypertensive doses of ramipril normalize sarcoplasmic reticulum calcium ATPase expression and function following cardiac hypertrophy in rats SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE SR CaATPase; phospholamban; cardiac hypertrophy; regression; RNA; protein ID ANGIOTENSIN-CONVERTING ENZYME; PRESSURE-OVERLOAD HYPERTROPHY; LEFT-VENTRICULAR HYPERTROPHY; EXPERIMENTAL HEART-FAILURE; GENE-EXPRESSION; MESSENGER-RNA; II RECEPTOR; DILATED CARDIOMYOPATHY; PHOSPHOLAMBAN GENE; HYPERTENSIVE RATS AB We examined the hypothesis that the angiotensin converting enzyme inhibitor ramipril at subantihypertensive concentrations could improve sarcoplasmic reticulum (SR) CaATPase expression and function in compensated hypertrophied rat hearts. Five weeks after abdominal aortic constriction, rats received a daily dose (50 mu g/kg/day) of ramipril or Vehicle for 4 weeks. Cardiac angiotensin-converting enzyme (ACE) activity increased with cardiac hypertrophy (CH) but returned to normal following ramipril treatment. SR CaATPase protein levels and activity decreased with CH (P<0.05) and were normalized following ramipril treatment (P<0.05 for protein and activity). No change in phospholamban (PLB) protein levels could be demonstrated between any of the groups. In contrast, ramipril treatment specifically increased control SR CaATPase and PLB mRNA. levels by >60% (P<0.01) and >30%, respectively. In the hypertrophied group, SR CaATPase increased by 35% (P<0.05 n=6) after ramipril treatment. Calsequestrin mRNA levels were unaffected by ramipril administration, In conclusion, ramipril normalizes SR CaATPase protein expression and function in pressure-overloaded and compensated CH. The effects of ramipril are however multifaceted, affecting RNA and protein expression differentially. (C) 1998 Academic Press. C1 NIA, GRC, LCS, NIH, Baltimore, MD 21224 USA. Univ Hull, Dept Sci Biol, Kingston Upon Hull HU6 7RX, N Humberside, England. Univ London Imperial Coll Sci Technol & Med, Dept Cardiothorac Surg, Natl Heart & Lung Inst, London SW3 6LY, England. RP NIA, GRC, LCS, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 48 TC 20 Z9 20 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD DEC PY 1998 VL 30 IS 12 BP 2683 EP 2694 DI 10.1006/jmcc.1998.0830 PG 12 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 155LC UT WOS:000077947500018 PM 9990539 ER PT J AU Panchision, DM Martin-DeLeon, PA Takeshima, T Johnston, JM Shimoda, K Tsoulfas, P McKay, RDG Commissiong, JW AF Panchision, DM Martin-DeLeon, PA Takeshima, T Johnston, JM Shimoda, K Tsoulfas, P McKay, RDG Commissiong, JW TI An immortalized, type-1 astrocyte of mesencephalic origin source of a dopaminergic neurotrophic factor SO JOURNAL OF MOLECULAR NEUROSCIENCE LA English DT Article DE conditioned medium; dopaminergic neurons; gene expression analysis; immunocytochemistry; karotype; neurodegenerative diseases; neuroprotection; Parkinson's disease; tissue culture; ventral mescencephalon ID FIBROBLAST GROWTH-FACTOR; SYMPATHETIC NEURONS; NEUROTRANSMITTER PHENOTYPE; CEREBELLAR DEVELOPMENT; INT-1 PROTOONCOGENE; SPINAL MOTONEURONS; PARKINSONS-DISEASE; SERUM DEPRIVATION; TROPHIC SUPPORT; NERVOUS-SYSTEM AB Rat embryonic d 14 (E14) mesencephalic cells, 2.5% of which are glioblasts, were incubated in medium containing 10% of fetal bovine serum for 12 h and subsequently expanded in a serum-free medium using basic fibroblast growth factor (bFGF) as the mitogen. On a single occasion, after more than 15 d in culture, several islets of proliferating, glial-like cells were observed in one dish. The cells, when isolated and passaged, proliferated rapidly in either a serum-free or serum-containing growth medium. Subsequent immunocytochemical analysis showed that they stained positive for GFAP and vimentin, and negative for A2B5, O4, GalC, and MAP2. Serum-free conditioned medium (CM) prepared from these cells caused a fivefold increase in survival and promoted neuritic expansion of E14 mesencephalic dopaminergic neurons in culture. These actions are similar to those exerted by CM derived from primary, mesencephalic type-1 astrocytes. The pattern of expression of the region-selective genes; wnt-1, en-1, sis showed that 70% of the cells were heteroploid, and of these, 50% were tetraploid. No apparent decline in proliferative capacity has been observed after 25 passages. The properties of this cell line, named ventral mesencephalic cell line one (VMCL1), are consistent with those of an immortalized, type-1 astrocyte. The mesencephalic origin of the cell line, and the pattern and potency of the neurotrophic activity exerted by the CM, strongly suggest that the neurotrophic factor(s) identified are novel, and will likely be strong candidates with clinical utility for the treatment of Parkinson's disease. C1 Univ Delaware, Dept Sci Biol, Div Mol Biol, Newark, DE 19716 USA. Tottori Univ, Sch Med, Inst Neurol Sci, Div Neurol, Yonago, Tottori 683, Japan. Univ Hosp, Albert Einstein Coll Med, Montefiore Med Ctr, Henry & Lucy Moses Div,Dept Neurol Sci, Bronx, NY 10467 USA. Natl Nishi Tottori Hosp, Div Neurol, Tottori 68902, Japan. RP Commissiong, JW (reprint author), NINDS, NIH, Bldg 36-3D02,36 Convent Dr MSC 4092, Bethesda, MD 20892 USA. OI Tsoulfas, Pantelis/0000-0003-1974-6366 NR 66 TC 20 Z9 20 U1 0 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0895-8696 J9 J MOL NEUROSCI JI J. Mol. Neurosci. PD DEC PY 1998 VL 11 IS 3 BP 209 EP 221 DI 10.1385/JMN:11:3:209 PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 197AL UT WOS:000080342400004 PM 10344791 ER PT J AU Beutler, JA Shoemaker, RH Johnson, T Boyd, MR AF Beutler, JA Shoemaker, RH Johnson, T Boyd, MR TI Cytotoxic geranyl stilbenes from Macaranga schweinfurthii SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID PHORBOL ESTER BIOACTIVITY; TUMOR-CELL-LINES; NEW-CALEDONIA; EUPHORBIACEAE; VEDELIANA; PLANTS; LEAVES AB Three novel geranyl stilbenes, schweinfurthins A, B, and C (1, 2, and 3), were isolated from the Cameroonian plant Macaranga schweinfurthii (Euphorbiaceae) and their structures determined by NMR and mass spectral methods. The cytotoxicity profile of the schweinfurthins tested in the NCI 60-cell screen was similar to that of the stelletins and cephalostatins, suggesting that these structurally diverse natural products may share similar mechanisms of cytotoxicity. C1 NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program,Div Canc Treatment & Diag, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 NR 16 TC 69 Z9 72 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD DEC PY 1998 VL 61 IS 12 BP 1509 EP 1512 DI 10.1021/np980208m PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 154GD UT WOS:000077879700011 PM 9868152 ER EF