FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Kelberman, D Tyson, J McInerney, AM Malcolm, S Winter, RM Bitner-Glindzicz, M AF Kelberman, D Tyson, J McInerney, AM Malcolm, S Winter, RM Bitner-Glindzicz, M TI Mapping of a locus for autosomal dominant Hemifacial Microsomia SO JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Inst Child Hlth, Clin & Mol Genet Unit, London WC1N 1EH, England. NIH, NHGRI, Bethesda, MD 20892 USA. RI Kelberman, Daniel/K-3411-2013 OI Kelberman, Daniel/0000-0003-0583-5237 NR 0 TC 1 Z9 1 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-2593 J9 J MED GENET JI J. Med. Genet. PD SEP PY 2000 VL 37 SU 1 MA 618 BP S76 EP S76 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 355GW UT WOS:000089378800213 ER PT J AU Olson, TM Doan, TP Kishimoto, NY Whitby, FG Ackerman, MJ Fananapazir, L AF Olson, TM Doan, TP Kishimoto, NY Whitby, FG Ackerman, MJ Fananapazir, L TI Inherited and de novo mutations in the cardiac actin gene cause hypertrophic cardiomyopathy SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Article DE cardiomyopathy; genetics; mutation; molecular biology; actin ID LINKED DILATED CARDIOMYOPATHY; SKELETAL-MUSCLE; ALPHA-ACTININ; ATOMIC MODEL; BETA-MYOSIN; DYSTROPHIN; MUTAGENESIS; EXPRESSION; FILAMENT; PROGRAM AB Mutations in genes encoding sarcomeric proteins cause hypertrophic cardiomyopathy (HCM). The sarcomeric protein actin plays a central, dual role in cardiac myocytes, generating contractile force by interacting with myosin and also transmitting force within and between cells. Two missense mutations in the cardiac actin gene (ACTC), postulated to impair force transmission, have been associated with familial dilated cardiomyopathy (DCM), Recently, a missense mutation in ACTC was found to cosegregate with familial HCM. To further test the hypothesis that mutations within functionally distinct domains of ACTC cause either DCM or HCM, we performed mutational analyses in 368 unrelated patients with familial or sporadic HCM. Single strand conformation polymorphism and sequence analyses of genomic DNA were performed, De novo mutations in ACTC were identified in two patients with sporadic HCM who presented with syncope in early childhood. Patients were heterozygous for missense mutations resulting in Pro164Ala and Ala331Pro amino acid substitutions, adjacent to regions of actin-actin and actin-myosin interaction, respectively A mutation that cosegregated with familial HCM was also found, causing a Glu99Lys substitution in a weak actomyosin binding domain. The cardiac phenotype in many affected patients was characterized by an apical form of HCM. These Endings support the hypothesis that a single amino acid substitution in actin causes either congestive heart failure or maladaptive cardiac hypertrophy, depending on its effect on actin structure and function. (C) 2000 Academic Press. C1 Mayo Clin, Dept Pediat & Adolescent Med, Div Pediat Cardiol, Rochester, MN 55905 USA. Univ Utah, Dept Pediat, Div Pediat Cardiol, Salt Lake City, UT 84113 USA. Univ Utah, Dept Biochem, Salt Lake City, UT 84113 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Olson, TM (reprint author), Mayo Clin, Dept Pediat & Adolescent Med, Div Pediat Cardiol, 200 1st St SW, Rochester, MN 55905 USA. EM olson.timothy@mayo.edu NR 32 TC 124 Z9 132 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD SEP PY 2000 VL 32 IS 9 BP 1687 EP 1694 DI 10.1006/jmcc.2000.1204 PG 8 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 357CT UT WOS:000089481500009 PM 10966831 ER PT J AU Deng, JZ Newman, DJ Hecht, SM AF Deng, JZ Newman, DJ Hecht, SM TI Use of COMPARE analysis to discover functional analogues of bleomycin SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID DNA STRAND-SCISSION; CYCLIC-AMP PHOSPHODIESTERASE; NATURAL-PRODUCTS; CLEAVE DNA; INHIBITION; AGENTS; PROANTHOCYANIDINS; IDENTIFICATION; CONSTITUENTS; PLANTS AB Bleomycin was used as the reference compound in a COMPARE analysis to identify extracts in the National Cancer Institute's Natural Products Repository exhibiting cytotoxicity profiles similar to this antitumor agent. One of the extracts so identified was a CH2Cl2-methanol extract prepared from Gymnosporia trigyna, which effected relaxation of supercoiled pSP64 DNA in the presence of Cu2+. Bioassay-guided fractionation using DNA strand-scission activity as an end point resulted in the isolation of four active principles. These were identified as syringaldehyde (1), (-)-syringaresinol (2), (+)-catechin (3), and (+)-epicatechin (4). Compounds 1 and 2 represent a new type of DNA strand-scission agent. C1 Univ Virginia, Dept Chem, Charlottesville, VA 22901 USA. Univ Virginia, Dept Biol, Charlottesville, VA 22901 USA. NCI, Frederick Canc Res & Dev Ctr, Nat Prod Branch, Frederick, MD 21702 USA. RP Hecht, SM (reprint author), Univ Virginia, Dept Chem, Charlottesville, VA 22901 USA. FU NCI NIH HHS [CA50771] NR 35 TC 28 Z9 30 U1 0 U2 0 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 SEP PY 2000 VL 63 IS 9 BP 1269 EP 1272 DI 10.1021/np000084p PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 358CR UT WOS:000089540100020 PM 11000034 ER PT J AU Zhou, BN Hoch, JM Johnson, RK Mattern, MR Eng, WK Ma, J Hecht, SM Newman, DJ Kingston, DGI AF Zhou, BN Hoch, JM Johnson, RK Mattern, MR Eng, WK Ma, J Hecht, SM Newman, DJ Kingston, DGI TI Use of COMPARE analysis to discover new natural product drugs: Isolation of camptothecin and 9-methoxycamptothecin from a new source SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID DNA TOPOISOMERASE-I; NOTHAPODYTES-FOETIDA; CONSTITUENTS; AGENTS; FUTURE AB Analysis of cytotoxicity data of extracts from the National Cancer Institute's Active Repository by the COMPARE protocol was carried out using camptothecin as a reference point. Extracts identified by this process were further characterized by a selective yeast bioassay for inhibitors of topoisomerase I and by a biochemical assay for compounds that stabilize the topoisomerase I-DNA covalent binary complex. Five of the extracts were positive in the yeast bioassay, and eight extracts showed activity on the assay that monitors stabilization of the topoisomerase I-DNA complex. Four of the latter extracts were inactive in the yeast bioassay, and thus would not, have been identified as hits without the COMPARE preselection process. One of the extracts, from Pyrenacantha klaineana, was selected for detailed investigation, and fractionation of this extract yielded camptothecin and 9-methoxycamptothecin as the bioactive constituents. C1 Virginia Polytech Inst & State Univ, Dept Chem, Blacksburg, VA 24061 USA. SmithKline Beecham Pharmaceut, King Of Prussia, PA 19406 USA. Univ Virginia, Dept Chem, Charlottesville, VA 22901 USA. NCI, Frederick Canc Res & Dev Ctr, Nat Prod Branch, Frederick, MD 21701 USA. RP Kingston, DGI (reprint author), Virginia Polytech Inst & State Univ, Dept Chem, Blacksburg, VA 24061 USA. EM dkingston@vt.edu OI Kingston, David/0000-0001-8944-246X FU NCI NIH HHS [U19CA50771] NR 28 TC 35 Z9 39 U1 1 U2 6 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 SEP PY 2000 VL 63 IS 9 BP 1273 EP 1276 DI 10.1021/np000058r PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 358CR UT WOS:000089540100021 PM 11000035 ER PT J AU Lindquist, N Shigematsu, N Pannell, L AF Lindquist, N Shigematsu, N Pannell, L TI Corydendramines A and B, defensive natural products of the marine hydroid Corydendrium parasiticum SO JOURNAL OF NATURAL PRODUCTS LA English DT Article AB Two novel piperidinol metabolites, corydendramines A (1) and B (2), have been isolated from the marine hydroid Corydendrium parasiticum. The structures of these compounds, which deter feeding by a potential hydroid predator, were determined by interpretation of their spectral data. C1 Univ N Carolina, Marine Sci Program, Morehead City, NC 28557 USA. NIDDK, Bioorgan Chem Lab, Struct Mass Spect Grp, NIH, Bethesda, MD 20892 USA. RP Lindquist, N (reprint author), Univ N Carolina, Marine Sci Program, Morehead City, NC 28557 USA. RI Shigematsu, Naoyuki/B-9374-2014 NR 11 TC 7 Z9 8 U1 1 U2 1 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 SEP PY 2000 VL 63 IS 9 BP 1290 EP 1291 DI 10.1021/np000050h PG 2 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 358CR UT WOS:000089540100027 PM 11000041 ER PT J AU Favit, A Grimaldi, M Alkon, DL AF Favit, A Grimaldi, M Alkon, DL TI Prevention of beta-amyloid neurotoxicity by blockade of the ubiquitin-proteasome proteolytic pathway SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE neuron; neurotoxicity; beta-amyloid; proteasome; protection; Alzheimer's disease ID ALZHEIMERS-DISEASE; CORTICAL-NEURONS; PC12 CELLS; DEGRADATION; DERIVATIVES; MECHANISMS; SUBSTRATE; PROTEINS AB In many neurodegenerative disorders, such as Alzheimer's disease, inclusions containing ubiquitinated proteins have been found in the brain, suggesting a pathophysiological role for ubiquitin-mediated proteasomal degradation of neuronal proteins. Here we show for the first time that the beta-amyloid fragment 1-40, which in micromolar levels causes the death of cortical neurons, also induces the ubiquitination of several neuronal proteins. Prevention of ubiquitination and inhibition of proteasome activity block the neurotoxic effect of beta-amyloid. These data suggest that beta-amyloid neurotoxicity may cause toxicity through the activation of protein degradation via the ubiquitin-proteasome pathway. These findings suggest possible new pharmacological targets for the prophylaxis and/or treatment of Alzheimer's disease and possibly for other related neurodegenerative disorders. C1 NINDS, Lab Adapt Syst, NIH, Bethesda, MD 20817 USA. RP Alkon, DL (reprint author), NINDS, Lab Adapt Syst, NIH, Bldg 36,Room 4A24,36 Convent Dr, Bethesda, MD 20817 USA. OI Grimaldi, Maurizio/0000-0002-7331-7055 NR 22 TC 30 Z9 30 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2000 VL 75 IS 3 BP 1258 EP 1263 DI 10.1046/j.1471-4159.2000.0751258.x PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 346JY UT WOS:000088868500041 PM 10936209 ER PT J AU Arima, H Aguilera, G AF Arima, H Aguilera, G TI Vasopressin and oxytocin neurones of hypothalamic supraoptic and paraventricular nuclei co-express mRNA for type-1 andType-2 corticotropin-releasing hormone receptors SO JOURNAL OF NEUROENDOCRINOLOGY LA English DT Article DE vasopressin; oxytocin; corticotropin-releasing hormone receptor; supraoptic nucleus; paraventricular nucleus ID FACTOR MESSENGER-RNA; UROCORTIN-LIKE IMMUNOREACTIVITY; HYPERTONIC SALINE INJECTION; CENTRAL-NERVOUS-SYSTEM; FACTOR CRF RECEPTOR; RAT-BRAIN; STRESS; SECRETION; IDENTIFICATION; RESPONSES AB The presence of corticotropin-releasing hormone (CRH) receptors type-1 (CRHR-1) and type-2 (CRHR-2 alpha) in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei, and the effects of i.c.v. injection of CRH and urocortin on arginine vasopressin (AVP) and oxytocin release, have suggested that CRH ligands have a role in osmoregulation. In this study, double labelling in situ hybridization using (35)S-labelled CRHR-1 or CRHR-2 alpha and digoxigenin-labelled AVP, oxytocin or CRH riboprobes was employed to examine the localization of CRHR-1 or CRHR-2 alpha mRNA in the SON and PVN of control and osmotically stimulated rats. Rats received an i.p. hypertonic saline (1.5 M) injection or isotonic saline injection (controls), or 2% NaCl intake (salt loading) or tap water (controls) for 12 days. While CRHR-1 mRNA was undetectable in the SON and PVN in control rats, its expression was increased markedly at 4 h after i.p. hypertonic saline injection or after 12 days salt loading. Of the cells labelled with digoxigenin-AVP, 53% in the SON and 90% in the PVN coexpressed CRHR-1 mRNA after i.p. hypertonic saline injection. In oxytocinergic neurones, 73% in the SON and 91% in the PVN showed CRHR-1 autoradiographic grains higher than background levels after i.p. hypertonic saline injection. In addition, i.p. hypertonic saline induced CRHR-1 mRNA expression in digoxigenin-CRH stained cells in the parvocellular PVN. CRHR-2 alpha transcripts were present in both the SON and PVN under basal conditions, and salt loading, but not acute i.p. hypertonic saline injection, further stimulated this expression. Double labelling in situ hybridization showed colocalization of CRHR-2 alpha mRNA with AVP and oxytocin mRNA in the SON. These studies support a role for CRH and urocortin regulating the hypothalamo-neurohypophyseal system, and suggest a direct action of the peptides in the magnocellular neurones. C1 NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Arima, H (reprint author), NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hiroshia@exchange.nih.gov RI chen, xuanlan/H-4158-2011; Arima, Hiroshi/I-7383-2014 OI Arima, Hiroshi/0000-0003-3746-1997 NR 39 TC 46 Z9 46 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-8194 J9 J NEUROENDOCRINOL JI J. Neuroendocrinol. PD SEP PY 2000 VL 12 IS 9 BP 833 EP 842 DI 10.1046/j.1365-2826.2000.00528.x PG 10 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 349PH UT WOS:000089054500003 PM 10971808 ER PT J AU Richards, SM Murphy, WJ AF Richards, SM Murphy, WJ TI Use of human prolactin as a therapeutic protein to potentiate immunohematopoietic function SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE prolactin; therapeutic protein; immune function; hematopoietic function; cell function defects ID NEUROENDOCRINE HORMONES; GROWTH-HORMONE; LYMPHOCYTE-T; TGF-BETA; CELLS; PROLIFERATION; INTERLEUKIN-2; PROGRESSION; SUPPRESSION; EXPRESSION AB The conclusion that prolactin plays a role in immune and hematopoietic function was initially based upon observations in hormone deficient animals. The multiple cell function defects associated with hypophysectomy or bromocriptine treatment were reversed by administration of prolactin. Since these initial observations, an increasing body of literature supports prolactin having a role in the immune and hematopoietic system. A recombinant form of human prolactin (r-hPRL) has been produced and evaluated in a wide variety of preclinical models. Both in vitro and in vivo studies suggest that r-hPRL can enhance cell function, accelerate lymphoid and myeloid reconstitution and promote hematopoiesis. The multi-lineage effect of r-hPRL makes it an attractive candidate for clinical situations presenting with immune deficiency or myelosuppression. (C) 2000 Published by Elsevier Science B.V. C1 Genzyme Corp, Dept Cell & Prot Therapeut, Boston, MA USA. NCI, Frederick Canc Res & Dev Ctr, IRSP, SAIC Frederick, Frederick, MD USA. RP Richards, SM (reprint author), Genzyme Corp, Dept Cell & Prot Therapeut, Boston, MA USA. NR 36 TC 37 Z9 39 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD SEP 1 PY 2000 VL 109 IS 1 BP 56 EP 62 DI 10.1016/S0165-5728(00)00303-9 PG 7 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 354GU UT WOS:000089322000010 PM 10969182 ER PT J AU Liu, QY Schaffner, AE Chang, YH Maric, D Barker, JL AF Liu, QY Schaffner, AE Chang, YH Maric, D Barker, JL TI Persistent activation of GABA(A) receptor/Cl- channels by astrocyte-derived GABA in cultured embryonic rat hippocampal neurons SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID SYMPATHETIC NEURONS; NONNEURONAL CELLS; THALAMIC NEURONS; DORSAL HORN; BRAIN-STEM; IN-VITRO; EXPRESSION; GLYCINE; RELEASE; BICUCULLINE AB Whole cell patch-clamp recordings using Cl--filled pipettes revealed more negative levels of baseline current and associated current variance in embryonic rat hippocampal neurons co-cultured on a monolayer of astrocytes than those cultured on poly-D-lysine. These effects were mimicked by culturing neurons on poly-D-lysine in astrocyte-conditioned medium (ACM). The baseline current and variance decreased immediately in all cells after either local perfusion with saline or exposure to bicuculline, an antagonist of GABA at GABA(A) receptor/Cl- channels. Baseline current and variance in all cells reached a nadir at similar to 0 mV, the calculated equilibrium potential for Cl-. Perfusion of ACM rapidly induced a sustained current in neurons, which also reversed polarity at similar to 0 mV. Bicuculline attenuated or eliminated the ACM-induced current at a concentration that completely blocked micromolar GABA-induced current. Quantitative analyses of spontaneously occurring fluctuations superimposed on the ACM-induced current revealed estimated unitary properties of the underlying channel activity similar to those calculated for GABA's activation of GABA(A) receptor/Cl- channels. Bicuculline-sensitive synaptic-like transients, which reversed at similar to 0 mV, were also detected in neurons cultured in ACM, and these were immediately eliminated along with the negative baseline current and superimposed current fluctuations by perfusion. Furthermore bicuculline-sensitive synaptic-like transients were rapidly and reversibly triggered when ACM was acutely applied. ACM induced an increase in cytoplasmic Ca2+ in cultured embryonic hippocampal neurons that was completely blocked by bicuculline and strychnine. We conclude that astrocytes release diffusible substances, most likely GABA, that persistently activate GABAA receptor/Cl- channels in co-cultured neurons. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Barker, JL (reprint author), NINDS, Neurophysiol Lab, NIH, Bldg 36,Rm 2C-02,36 Convent Dr, Bethesda, MD 20892 USA. NR 37 TC 42 Z9 44 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD SEP PY 2000 VL 84 IS 3 BP 1392 EP 1403 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 351XP UT WOS:000089185200025 PM 10980012 ER PT J AU Quan, N He, LL Lai, WM Shen, TS Herkenham, M AF Quan, N He, LL Lai, WM Shen, TS Herkenham, M TI Induction of I kappa B alpha mRNA expression in the brain by glucocorticoids: A negative feedback mechanism for immune-to-brain signaling SO JOURNAL OF NEUROSCIENCE LA English DT Article DE glucocorticoid; I kappa B alpha; lipopolysaccharide; brain; inflammatory cytokines; interleukin-1 ID INTERLEUKIN-1-BETA MESSENGER-RNA; CENTRAL-NERVOUS-SYSTEM; IL-1 RECEPTOR ANTAGONIST; PERIPHERAL LIPOPOLYSACCHARIDE; RAT-BRAIN; ACTIVATION; PITUITARY; VIVO; IMMUNOSUPPRESSION; HYPOTHALAMUS AB Peripheral injection of bacterial endotoxin lipopolysaccharide (LPS) induces brain mRNA expression of the proinflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha and the cytokine-responsive immediate-early gene I kappa B alpha. Peripheral LPS also increases levels of plasma glucocorticoids. Whether the induction of I kappa B alpha mRNA in the brain after peripheral LPS injection is caused by the feedback action of glucocorticoids has not been determined. In this study, we examined the mRNA expression of I kappa B alpha and IL-1 beta in the rat brain by in situ hybridization histochemistry. Injection of the glucocorticoid agonist dexamethasone induced I kappa B alpha mRNA expression in the brain in a pattern identical to that of LPS injection. LPS but not dexamethasone also induced IL-1 beta mRNA expression. Pretreatment with dexamethasone 30 min before LPS injection enhanced the expression of I kappa B alpha mRNA in the brain in a dose-dependent manner. Immobilization of rats for 2 hr (which raises glucocorticoid levels) also induced I kappa B alpha mRNA expression without inducing the expression of IL-1 beta. Brain I kappa B alpha expression induced by peripheral LPS injection was attenuated by pretreatment of rats with the glucocorticoid antagonist RU-486. Finally, increased expression of IL-1 beta mRNA in the brain was observed at 4 hr after peripheral LPS injection in adrenalectomized rats compared with sham-operated rats. These results reveal that in the brain glucocorticoids selectively induce I kappa B alpha mRNA expression, which serves as a negative feedback mechanism for peripheral LPS-induced synthesis of proinflammatory cytokines. Such an inhibitory control mechanism may be important for preventing prolonged expression of proinflammatory cytokines in the brain after peripheral immune challenge. C1 Ohio State Univ, Dept Oral Biol, Columbus, OH 43210 USA. NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. RP Quan, N (reprint author), Ohio State Univ, Dept Oral Biol, 2214 Postle Hall,305 W 12th Ave, Columbus, OH 43210 USA. OI Herkenham, Miles/0000-0003-2228-4238 NR 27 TC 37 Z9 41 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 1 PY 2000 VL 20 IS 17 BP 6473 EP 6477 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 348VJ UT WOS:000089006900020 PM 10964953 ER PT J AU Max, MB AF Max, MB TI Is mechanism-based pain treatment attainable? Clinical trial issues SO JOURNAL OF PAIN LA English DT Article; Proceedings Paper CT Neurobiology Working Group Conference on Pain - New Targets-New Treatments CY OCT 21, 1999 CL BOCA RATON, FLORIDA DE chronic pain; analgesics; pain measurement ID NEUROPATHIC PAIN; POSTHERPETIC NEURALGIA; DOUBLE-BLIND; PLACEBO; CLASSIFICATION; ANTAGONIST; INFUSION; EFFICACY; SYMPTOMS AB Woolf et al have recently called for the development of a mechanism-based pain taxonomy to guide the individualization of treatment based on each patient's pain mechanisms. Although any scientific physician could endorse this ideal, small academic clinical trials so far have failed to identify obvious differences in the response of different pain symptoms in the same condition to various drugs. In contrast, there are clear differences in the analgesic responses of patient groups distinguished on the basis of etiology or tissue origin of pain, factors which tend to be associated with groups of mechanisms. The few tests to diagnose pain mechanisms remain too delicate, time-consuming, or uncomfortable for general clinical use. To understand how best to exploit new mechanistic insights to assign treatments, one must scrutinize the relative value of diagnostic classifications based on etiology, tissue, and individual patients' pain characteristics in large clinical trials. Research priorities should include developing simple methods for assessing pain mechanisms in the clinic and increasing the efficiency of pain assessment methods in clinical trials. I describe a collaborative research agenda for academic pain researchers and funding agencies, the pharmaceutical industry, and regulatory bodies. C1 Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. RP Max, MB (reprint author), Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mechanisms Branch, NIH, Bldg 10,3C-405, Bethesda, MD 20892 USA. NR 37 TC 32 Z9 32 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 1526-5900 J9 J PAIN JI J. Pain PD FAL PY 2000 VL 1 IS 3 SU 1 BP 2 EP 9 DI 10.1054/jpai.2000.9819 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 358BU UT WOS:000089538000002 PM 14622836 ER PT J AU Farrell, MJ Gibson, SJ McMeeken, JM Helme, RD AF Farrell, MJ Gibson, SJ McMeeken, JM Helme, RD TI Increased movement pain in osteoarthritis of the hands is associated with A beta-mediated cutaneous mechanical sensitivity SO JOURNAL OF PAIN LA English DT Article DE hyperalgesia; osteoarthritis; musculoskeletal pain ID DORSAL-ROOT REFLEXES; CURRENT PERCEPTION THRESHOLDS; LUMBAR EPIDURAL-ANESTHESIA; C FIBER RESPONSES; HUMAN SKIN NERVES; CEREBRAL POTENTIALS; OSTEO-ARTHRITIS; SENSORY BLOCK; RADIANT-HEAT; STIMULATION AB The relationship between joint pain and hyperalgesia has been explored in animal models of articular inflammation, but is yet to be shown in the most common rheumatologic condition: osteoarthritis. In this study, cutaneous thermal and mechanical pain thresholds were measured over the thumb of patients with osteoarthritis of the hands. In symptomatic patients, pain was manipulated through resisted active movement of the thumb. Provocation of movement pain (MP) was associated with a sustained fall in mechanical pain thresholds. Thermal pain thresholds remained stable during increases in joint pain. Increased mechanical sensitivity after exacerbation of MP was alleviated by A beta fiber blockade. It appears that superficial tenderness over the osteoarthritic thumb fluctuates with pain arising from movement of the joint. It is concluded that dorsal horn mechanisms contribute to MP-related hyperalgesia in osteoarthritis of the hands. C1 Natl Ageing Res Inst, Parkville, Vic, Australia. Univ Melbourne, Melbourne, Vic, Australia. RP Farrell, MJ (reprint author), NIH, Bldg 10,Rm 1N-103, Bethesda, MD 20892 USA. OI Farrell, Michael/0000-0003-4126-8911 NR 50 TC 17 Z9 17 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD FAL PY 2000 VL 1 IS 3 BP 229 EP 242 DI 10.1054/jpai.2000.8279 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 357VF UT WOS:000089520900009 PM 14622622 ER PT J AU Shousha, S Hovey, RC Peston, D Vonderhaar, BK AF Shousha, S Hovey, RC Peston, D Vonderhaar, BK TI Overexpression of prolactin receptors in mammary duct ectasia SO JOURNAL OF PATHOLOGY LA English DT Meeting Abstract C1 Charing Cross Hosp, Dept Histopathol, London, England. Univ London Imperial Coll Sci Technol & Med, Sch Med, London, England. Natl Canc Inst, Tumor Immunol & Biol Lab, Mol & Cellular Endocrinol Sect, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD SEP PY 2000 VL 192 SU S BP 21A EP 21A PG 1 WC Oncology; Pathology SC Oncology; Pathology GA 351KB UT WOS:000089155400084 ER PT J AU Stratakis, CA Rusovici, DE Kulin, HE Finkelstein, JW AF Stratakis, CA Rusovici, DE Kulin, HE Finkelstein, JW TI Dysregulation of the hypothalamic-pituitary-adrenal axis in short children with and without growth hormone deficiency SO JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM LA English DT Article DE short stature; dopamine; cortisol; adrenocorticotropin; insulin; hypoglycemia ID STRESS SYSTEM DISORDERS; CORTISOL SECRETION; DEPRESSION; ACTH AB The effects of L-dopamine (LD) administration and insulin-induced hypoglycemia in adrenocorticotropin (ACTH) and cortisol secretion were studied in 14 short boys. LD caused moderate changes in both hormones. The four boys with isolated, idiopathic growth hormone (GH) deficiency (IGD) demonstrated a greater cortisol increase in response to hypoglycemia than the 10 boys with normal GH secretion. In at least some short children with IGD, abnormal regulation of the hypothalamic-pituitary-adrenal axis may be present. C1 NICHD, UGEN, DEB, NIH,Unit Genet & Endocrinol, Bethesda, MD 20892 USA. Penn State Univ, Coll Hlth & Human Dev, Dept Biobehav Hlth, Hershey, PA USA. Penn State Univ, Coll Med, Dept Pediat, Hershey, PA USA. RP Stratakis, CA (reprint author), NICHD, UGEN, DEB, NIH,Unit Genet & Endocrinol, Bldg 10,Room 10N262,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. NR 24 TC 2 Z9 2 U1 0 U2 1 PU FREUND PUBLISHING HOUSE LTD PI LONDON PA STE 500, CHESHAM HOUSE, 150 REGENT ST, LONDON W1R 5FA, ENGLAND SN 0334-018X J9 J PEDIATR ENDOCR MET JI J. Pediatr. Endocrinol. Metab. PD SEP-OCT PY 2000 VL 13 IS 8 BP 1095 EP 1100 PG 6 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 367NY UT WOS:000090069400008 PM 11085187 ER PT J AU Singleton, R Bulkow, LR Levine, OS Butler, JC Hennessy, TW Parkinson, A AF Singleton, R Bulkow, LR Levine, OS Butler, JC Hennessy, TW Parkinson, A TI Experience with the prevention of invasive Haemophilus influenzae type b disease by vaccination in Alaska: The impact of persistent oropharyngeal carriage SO JOURNAL OF PEDIATRICS LA English DT Article ID CONJUGATE VACCINE; NATIVE INFANTS; HIGH-RISK; CHILDREN; IMMUNOGENICITY; IMMUNIZATION; POPULATION; ANTIBODY; EFFICACY; POLYSACCHARIDE AB Objectives: To report the epidemiology of invasive Haemophilus influenzae type b (Hib) disease in high-risk Alaska Native infants before and after universal infant Hib vaccination and evaluate an increase in invasive Hib disease in 1996 after changing Hib vaccine type. Study design: Statewide laboratory surveillance for invasive Hib disease has been conducted since 1980. Three cross-sectional Hib carriage studies were conducted in 1997 and 1998. Results: The invasive Hib disease rate in Alaska Natives decreased from 332 cases per 100,000 children <5 years old in 1980-1991 to 17:100,000 in 1992-1995 but increased primarily in rural areas to 57.9:100,000 after a switch in Hib vaccine types; Carriage studies in 5 rural Alaska Native villages showed oropharyngeal Hib carriage as high as 9.3% in children aged 1 to 5 years; in contrast, carriage in urban Alaska Native children was <1%. Conclusions: Although Hib disease has decreased in Alaska, the rate of Hib disease and carriage in rural Alaska Natives did not decrease to the same extent as in non-Natives and urban Alaska Natives. Use of polyribosylribitol phosphate-outer-membrane protein conjugate vaccine for the first vaccine dose is critical to disease control in this population with continued transmission in infants <6 months of age. The ability to eliminate Hib carriage and disease may be affected by population characteristics, vaccination coverage, and Hib vaccine type used. This may pose a challenge to global elimination of Hib. C1 Ctr Dis Control & Prevent, Arctic Invest Program, Natl Ctr Infect Dis, Anchorage, AK 99508 USA. Alaska Native Tribal Hlth Consortium, Anchorage, AK USA. NIAID, Resp Dis Branch, Bethesda, MD 20892 USA. RP Singleton, R (reprint author), Ctr Dis Control & Prevent, Arctic Invest Program, Natl Ctr Infect Dis, 4055 Tudor Ctr Dr, Anchorage, AK 99508 USA. NR 29 TC 38 Z9 40 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD SEP PY 2000 VL 137 IS 3 BP 313 EP 320 DI 10.1067/mpd.2000.107843 PG 8 WC Pediatrics SC Pediatrics GA 353ZQ UT WOS:000089305700006 PM 10969253 ER PT J AU Robey, FA AF Robey, FA TI Selective and facile cyclization of N-chloroacetylated peptides from the C-4 domain of HIV Gp120 in LiCl/DMF solvent systems SO JOURNAL OF PEPTIDE RESEARCH LA English DT Article DE cyclization; HIVC4 peptide; LiCl/DMF solvent system; N-chloroacetyl peptide; unprotected peptides ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN; SYNTHETIC PEPTIDES; CYCLIC-PEPTIDES; CD4 RECEPTOR; LIBRARIES; PEPTOMERS; LIGANDS AB Lithium salts have been reported to mediate the solubilization of peptides in organic solvents in 1989 (Seebach, D., Thaler, A. & Beck. A. K. Helv. Chim. Acta 1989; 72, 857-867). The use of Li salts in an organic solvent to influence cyclization of a reactive peptide that only polymerizes in an aqueous solvent, has not been reported. Here, the selective and facile cyclization of N-chloroacetylated, C-cysteine amide peptides from the C4 domain of HIV-1 gp120 in LiCl/DMF solvent systems is demonstrated. The addition of stoichiometric amounts of Tris base to 1 mg/mL peptide in LiCl/DMF solutions was sufficient to drive the cyclization to completion within 3 h at ambient temperatures. Cyclic peptides were the only detectable reaction products and these were confirmed using reversed-phase HPLC and mass spectrometric analyses of the final products. In aqueous solutions at pH 7.4, only polymers were obtained as judged by HPLC and SDS-PAGE. The method of using Li salts in an organic solvent to enhance the cyclization of unprotected amphipathic peptides may be useful in many situations beyond those described here. C1 NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Robey, FA (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bldg 30,Room 211,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 22 TC 11 Z9 11 U1 1 U2 3 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1397-002X J9 J PEPT RES JI J. Pept. Res. PD SEP PY 2000 VL 56 IS 3 BP 115 EP 120 DI 10.1034/j.1399-3011.2000.00734.x PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 355DV UT WOS:000089371300001 PM 11007268 ER PT J AU Yang, J McCrae, RR Costa, PT Yao, SQ Dai, XY Cai, TS Gao, BL AF Yang, J McCrae, RR Costa, PT Yao, SQ Dai, XY Cai, TS Gao, BL TI The cross-cultural generalizability of axis-II constructs: An evaluation of two personality disorder assessment instruments in the People's Republic of China SO JOURNAL OF PERSONALITY DISORDERS LA English DT Article ID SELF-REPORT; VALIDITY; QUESTIONNAIRE; INVENTORIES; INTERVIEWS; SAMPLE AB We examined the reliability, cross-instrument validity, and factor structure of Chinese adaptations of the Personality Diagnostic Questionnaire (PDQ-4+; N = 1,926) and Personality Disorders Interview (PDI-IV; N = 525) in psychiatric patients. Comparisons with data from Western countries suggest that the psychometric properties of these two instruments are comparable across cultures. Low to modest agreement between the PDQ-4+ and PDI-IV was observed for both dimensional and categorical personality disorder evaluations, When the PDI-IV was used as the diagnostic standard, the PDQ-4+ showed higher sensitivity than specificity, and higher negative predictive power than positive predictive power. Factor analyses of both instruments replicated the four-factor structure O'Connor and Dyce (1998) found in Western samples. Results suggested that conceptions and measures of DSM-IV personality disorders are cross-culturally generalizable to Chinese psychiatric populations. C1 NIA, Ctr Gerontol Res, Personal Stress & Coping Sect, Baltimore, MD 21224 USA. Hunan Med Univ, Affiliated Hosp 2, Clin Psychol Res Ctr, Hunan, Peoples R China. RP McCrae, RR (reprint author), NIA, Ctr Gerontol Res, Personal Stress & Coping Sect, Box 03,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Costa, Paul/0000-0003-4375-1712 NR 32 TC 46 Z9 61 U1 0 U2 7 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0885-579X J9 J PERS DISORD JI J. Pers. Disord. PD FAL PY 2000 VL 14 IS 3 BP 249 EP 263 PG 15 WC Psychiatry SC Psychiatry GA 356YT UT WOS:000089472300006 PM 11019748 ER PT J AU Widemann, BC Sung, E Anderson, L Salzer, WL Balis, FM Monitjo, KS McCully, C Hawkins, M Adamson, PC AF Widemann, BC Sung, E Anderson, L Salzer, WL Balis, FM Monitjo, KS McCully, C Hawkins, M Adamson, PC TI Pharmacokinetics and metabolism of the methotrexate metabolite 2,4-diamino-N-10-methylpteroic acid SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HIGH-DOSE METHOTREXATE; LEUCOVORIN RESCUE; RHESUS-MONKEYS; CARBOXYPEPTIDASE-G(2); THYMIDINE; TOXICITY; ASSAY; DRUG AB The novel methotrexate (MTX) rescue agent carboxypeptidase-G(2)(CPDG(2)) converts >98% of plasma MTX to 2,4-diamino-N-10-methylpteroic acid (DAMPA) and glutamate in patients with MTX-induced renal failure and delayed MTX excretion. DAMPA is eliminated more rapidly than MTX in these patients, suggesting nonrenal elimination. The pharmacokinetics and metabolism of DAMPA were studied in four nonhuman primates with reverse-phase HPLC with UV, photodiode array detection, and mass spectroscopy. The mean peak plasma DAMPA concentration was 51 mu M and the plasma disposition was described by a three-compartment open model with first order elimination. The mean clearance of DAMPA was 1.9 l/kg/h and the mean terminal half-life was 51 min. Forty-six percent of the dose was excreted in the urine as parent compound. Three DAMPA metabolites, hydroxy-DAMPA, DAMPA-glucuronide, and hydroxy-DAMPA-glucuronide, were identified in plasma and urine. These metabolites also were identified in plasma from patients who received CPDG(2) as an MTX rescue agent. The cytotoxicity of DAMPA and its effect on MTX cytotoxicity were assessed in the Molt-4 human leukemic cell line. DAMPA was not cytotoxic and did not significantly alter the cytotoxicity of MTX. In nonhuman primates metabolism of DAM PA is a major route of DAM PA elimination, and metabolism underlies the more rapid elimination of DAMPA versus MTX in patients with MTX-induced renal dysfunction after administration of CPDG(2). C1 NCI, Pharmacol & Expt Therapeut Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. US FDA, Rockville, MD 20857 USA. RP Widemann, BC (reprint author), NCI, Pharmacol & Expt Therapeut Sect, Pediat Oncol Branch, NIH, Bldg 10,Room 13N240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 23 TC 36 Z9 43 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD SEP PY 2000 VL 294 IS 3 BP 894 EP 901 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 347QH UT WOS:000088940300013 PM 10945838 ER PT J AU Reddy, DS Rogawski, MA AF Reddy, DS Rogawski, MA TI Enhanced anticonvulsant activity of ganaxolone after neurosteroid withdrawal in a rat model of catamenial epilepsy SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID GAMMA-AMINOBUTYRIC-ACID; NEUROACTIVE STEROIDS; PREMENSTRUAL-SYNDROME; ESTRUS CYCLE; RECEPTOR; BENZODIAZEPINE; PROGESTERONE; FINASTERIDE; SENSITIVITY; ETHANOL AB Perimenstrual catamenial epilepsy, the exacerbation of seizures in association with menstruation, may in part be due to withdrawal of the progesterone metabolite allopregnanolone (3 alpha-hydroxy-5 alpha-pregnan-20-one), an endogenous anticonvulsant neurosteroid that is a positive allosteric modulator of gamma-aminobutyric acid(A) receptors. Neurosteroid replacement is a potential approach to therapy, but natural neurosteroids have poor bioavailability and may be converted to metabolites with undesired progestational activity. The synthetic neuroactive steroid ganaxolone (3 alpha-hydroxy-3 beta-methyl-5 alpha-pregnane-20-one) is an orally active analog of allopregnanolone that is not converted to the hormonally active 3-keto form. To assess the potential of ganaxolone in the treatment of catamenial seizure exacerbations, a state of persistently high serum progesterone (pseudopregnancy) was induced in 28-day-old female rats with gonadotropins, and neurosteroids were withdrawn on postnatal day 39 with finasteride, a 5 alpha-reductase inhibitor that blocks the conversion of progesterone to allopregnanolone. Finasteride treatment during pseudopregnancy results in a reduction in the threshold for pentylenetetrazol seizures. During this state of enhanced seizure susceptibility, there was a 3-fold increase in the anticonvulsant potency of ganaxolone (control ED50 = 3.5 mg/kg; withdrawn = 1.2 mg/kg) without a change in the potency for induction of motor toxicity in the rotarod test. The plasma concentrations of ganaxolone did not differ significantly in control and withdrawn animals; the estimated plasma concentrations of ganaxolone producing 50% seizure protection were similar to 500 and similar to 225 ng/ml in control and withdrawn rats, respectively. Unlike ganaxolone, neurosteroid withdrawal was associated with a decrease in the anticonvulsant potency of diazepam (control ED50 = 1.9 mg/kg; withdrawn = 4.1 mg/kg) and valproate (control ED50 = 279 mg/kg; withdrawn = 460 mg/kg). The enhanced anticonvulsant potency of ganaxolone after neurosteroid withdrawal supports the use of ganaxolone as a specific treatment for perimenstrual catamenial epilepsy. C1 NINDS, Neuronal Excitabil Sect, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. RP Rogawski, MA (reprint author), NINDS, Neuronal Excitabil Sect, Epilepsy Res Branch, NIH, 10 Ctr Dr,Room 5N-250,MSC 1408, Bethesda, MD 20892 USA. RI Rogawski, Michael/B-6353-2009; OI Rogawski, Michael/0000-0002-3296-8193; Reddy, Samba/0000-0003-2735-9550 NR 36 TC 74 Z9 74 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD SEP PY 2000 VL 294 IS 3 BP 909 EP 915 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 347QH UT WOS:000088940300015 PM 10945840 ER PT J AU Lin, YM Jian, XY Lin, ZL Kroog, GS Mantey, S Jensen, RT Battey, J Northup, J AF Lin, YM Jian, XY Lin, ZL Kroog, GS Mantey, S Jensen, RT Battey, J Northup, J TI Two amino acids in the sixth transmembrane segment of the mouse gastrin-releasing peptide receptor are important for receptor activation SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID PROTEIN-COUPLED RECEPTORS; BOMBESIN STIMULATES GROWTH; S49 LYMPHOMA-CELLS; SWISS 3T3 CELLS; HIGH-AFFINITY; CONFORMATIONAL-CHANGES; ADRENERGIC-RECEPTOR; SIGNAL-TRANSDUCTION; ADENYLATE-CYCLASE; AGONIST BINDING AB The gastrin-releasing peptide receptor (GRP-R) is a G protein-coupled receptor that mediates a variety of cellular responses, including cell growth and modulation of neuronal activity by activation of heterotrimeric GTP-binding proteins in the Gq family. To understand the regulation of GRP-R signaling we have substituted alanine for each of 10 amino acid residues within the transmembrane (TM) helices of the GRP-R predicted to project into the binding pocket of the receptor and analyzed the importance of each of these residues for receptor function. Two mutations showed selective loss of either agonist (Y285A) or antagonist (F313A) affinity for the GRP-R. In addition, we identified two amino acid residues, Phe(270) and Asn(281), in the sixth TM segment, which are important for receptor-G protein interaction. In a competition-binding assay with an antagonist radioligand, bombesin showed a 20- to 100-fold decreased affinity for the N281A and F270A mutant GRP-R compared with wild-type GRP-R. The saturation-binding isotherms are best fit by a two-state model, indicating that the receptors are in either a low-affinity (K-D2) or a high-affinity (K-D1) state. The ratio of the two affinities (K-D2/K-D1) was significantly increased for both mutants compared with wild-type GRP-R, whereas the fraction of mutant receptors in the high-affinity state (R-1) was decreased. GDP/guanosine-5'-O-(3-thio)triphosphate exchange catalyzed by the N281A mutant was lower than that observed for the wild-type GRP-R. However, for both mutants, bombesin was still able to stimulate 1,4,5-inositol triphosphate in transfected cells albeit with reduced activity. We conclude that these two TM residues are important for receptor-G protein coupling, and postulate that each mutation may affect GRP-R conformational change to the high-affinity, G protein-coupled state. C1 NIDCD, Mol Biol Lab, NIH, Rockville, MD USA. NIDCD, Lab Cellular Biol, NIH, Rockville, MD USA. NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Struct Biol Lab, Bethesda, MD USA. RP Battey, J (reprint author), NIDCD, NIH, Bldg 31,Room 3C02,31 Ctr Dr,MSC 2320, Bethesda, MD 20892 USA. NR 46 TC 8 Z9 8 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD SEP PY 2000 VL 294 IS 3 BP 1053 EP 1062 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 347QH UT WOS:000088940300034 PM 10945859 ER PT J AU Roberts, JE Hu, DN Martinez, L Chignell, CF AF Roberts, JE Hu, DN Martinez, L Chignell, CF TI Photophysical studies on melatonin and its receptor agonists SO JOURNAL OF PINEAL RESEARCH LA English DT Article DE chloromelatonin; melanoma; melatonin; Mel(1a), Mel(1b) and Mel(2) receptor agonists; reactive oxygen species; singlet oxygen ID PINEAL HORMONE MELATONIN; UVEAL MELANOMA-CELLS; BREAST-CANCER-CELLS; MALIGNANT-MELANOMA; ANTIOXIDANT ACTIVITY; FLASH-PHOTOLYSIS; RETINA; GROWTH; PROLIFERATION; CULTURE AB Previous work has demonstrated that melatonin inhibits the growth of both dermal and uveal melanoma cells. Recent clinical trials have found that melatonin is an efficacious treatment for metastatic dermal melanoma. The goal of this study was to provide further insight into the oncostatic mechanism(s) of melatonin. The inhibition of the growth of uveal melanoma cells is dose-dependent (0.1-10 nM) within the range of endogenous melatonin concentrations (2 nM) found in the human aqueous humor. We know that this inhibition of growth is receptor-mediated, at least in part, because uveal melanoma cell growth was also blocked by the agonists of melatonin receptors. There are two known membrane receptors for melatonin (Mel(1a) and Mel(1b)) and one known nuclear receptor (Mel(2)). To determine if singlet oxygen production and/or quenching contributed to the growth inhibition of melatonin, we examined the photophysical properties of melatonin and its agonists. Using flash photolysis, we determined that melatonin and its membrane receptor agonist 6-chloromelatonin (Mel(1a-b), Lilly, Indianapolis, IN) produced very little singlet oxygen (phi(Delta) = 0.073 and phi(Delta) = 0.01, respectively). There was no detectable singlet oxygen phosphorescence at 1,270 nm for the nuclear receptor agonist CG-52608 (Mel(2), Novartis, Basel, Switzerland). In contrast, the agonist of the Mel(1b), receptor, S-20098 (Servier, Paris, France), produced singlet oxygen with a quantum efficiency of phi(Delta) = 0.34. Singlet oxygen was quenched by melatonin and 6-chloromelatonin at approximately the same rate (6.1 x 10(7) M-1 s(-1) and 6.0 x 10(7) M-1 s(-1) in CD3OD), while the rate of quenching for the nuclear receptor agonist CG-52608 and membrane receptor agonist S-20098 was less (2.2 x 10(7) M-1 s(-1) and 1.5 x 10(7) M-1 s(-1), respectively). It appears that the production of singlet oxygen by melatonin would not be sufficient to directly block the proliferation of melanoma cells, but may activate gene products that could contribute to the oncostatic effect. C1 Fordham Univ, New York, NY 10023 USA. New York Eye & Ear Infirm, Tissue Culture Ctr, New York, NY 10003 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Roberts, JE (reprint author), Fordham Univ, 113 West 60th St, New York, NY 10023 USA. NR 54 TC 14 Z9 15 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0742-3098 J9 J PINEAL RES JI J. Pineal Res. PD SEP PY 2000 VL 29 IS 2 BP 94 EP 99 DI 10.1034/j.1600-079X.2000.290205.x PG 6 WC Endocrinology & Metabolism; Neurosciences; Physiology SC Endocrinology & Metabolism; Neurosciences & Neurology; Physiology GA 349QZ UT WOS:000089058200005 PM 10981822 ER PT J AU Barmes, DE AF Barmes, DE TI Public policy on oral health and old age: a global view SO JOURNAL OF PUBLIC HEALTH DENTISTRY LA English DT Article; Proceedings Paper CT Satellite Symposium of the Geriatric-Oral-Research-Group of the International-Association-of-Dental-Research CY MAR 14-16, 1999 CL VANCOUVER ISL, CANADA SP Int Assoc Dental Res, Geriatr Oral Res Grp DE demographic trends; epidemiologic trends; health policy; elderly AB This paper reviews major trends in the global demography and oral health status of populations, the challenges faced in ensuring successful aging because of these trends, and basic principles to guide public policy responses. Virtually all populations in which the dental caries prevalence reached high levels in the first half of the 20th century have experienced large reductions A feared increase of the disease in the developing world has been far less than expected. Some countries that did suffer large increases dating from the 1960s already have managed to return to their former low levels because of timely use of preventive measures. Improving oral hygiene and a consequent reduction in the occurrence and severity of periodontal diseases further bolster the mainly positive trend in global oral health. Only in the former socialist economies is oral health status worsening. These positive changes have brought the expectation that an intact and well-functioning dentition should last for life, no matter how extended the lifespan becomes. But these changes take us into "uncharted waters" and the most appropriate strategies for preserving health in old age are unknown because they have never been tried. However, public policies to support community awareness and acceptance of broad-based preventive behaviors to preserve oral health in old age are essential. Policies also must provide guidance on how to proceed when disabling disease occurs, provide for regular research and updating of information, and ensure access to cost-effective and high-quality services for all. C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Barmes, DE (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Natcher Bldg 45,Room 4AS13,45 Ctr Dr,MSC 6401, Bethesda, MD 20892 USA. NR 2 TC 3 Z9 4 U1 0 U2 3 PU AAPHD NATIONAL OFFICE PI PORTLAND PA 3760 SW LYLE COURT, PORTLAND, OR 97221 USA SN 0022-4006 J9 J PUBLIC HEALTH DENT JI J. Public Health Dent. PD FAL PY 2000 VL 60 IS 4 BP 335 EP 337 DI 10.1111/j.1752-7325.2000.tb03345.x PG 3 WC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health SC Dentistry, Oral Surgery & Medicine; Public, Environmental & Occupational Health GA 407BB UT WOS:000167250600012 PM 11243057 ER PT J AU McKenzie, R Reynolds, JC O'Fallon, A Dale, J Deloria, M Blackwelder, W Straus, SE AF McKenzie, R Reynolds, JC O'Fallon, A Dale, J Deloria, M Blackwelder, W Straus, SE TI Decreased bone mineral density during low dose glucocorticoid administration in a randomized, placebo controlled trial SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE bone density; absorptiometry; glucocorticoids; osteoporosis ID CHRONIC-FATIGUE-SYNDROME; X-RAY ABSORPTIOMETRY; RHEUMATOID-ARTHRITIS; INDUCED OSTEOPOROSIS; INHALED CORTICOSTEROIDS; PREVENTION; THERAPY; SPINE; MASS; PATHOGENESIS AB Objective. While osteoporosis and bone fractures are clearly recognized side effects of high dose glucocorticoids, the effect of low dose glucocorticoids remains controversial. We investigated the effect of 3 months of low dose hydrocortisone on bone mineral density (BMD). Methods. Subjects, 18 to 55 years old with chronic fatigue syndrome and no medical or psychiatric illness requiring medication, were randomized in a double blind, placebo controlled trial to receive oral hydrocortisone, 13 mg/m(2) body surface area every morning and 3 mg/m(2) every afternoon (25 to 35 mg/day, equivalent to about 7.5 mg prednisone/day) or placebo for 12 weeks. Before and after treatment BMD of the lumbar spine was measured by dual energy x-ray absorptiometry. Results. We studied 23 subjects (19 women, 4 men). For the 11 hydrocortisone recipients there was a mean decrease in BMD: mean change from baseline of the lateral spine was -2.0% (95% CI -3.5 to -0.6, p = 0.03) and mean change of the anteroposterior spine was -0.8% (95% CI -1.5 to -0.1, p = 0.06). Corresponding changes for the 12 placebo recipients were +1.0% (95% CI -1.0 to 3.0, p = 0.34) and +0.2% (95% CI -1.4 to 1.5, p = 0.76). Conclusion. A 12 week course of low dose glucocorticoids given to ambulatory subjects with chronic fatigue syndrome was associated with a decrease in BMD of the lumbar spine. This decrease was statistically significant in lateral spine measurements and nearly so in anteroposterior spine measurements. C1 NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD USA. RP Straus, SE (reprint author), NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. NR 35 TC 23 Z9 29 U1 0 U2 2 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD SEP PY 2000 VL 27 IS 9 BP 2222 EP 2226 PG 5 WC Rheumatology SC Rheumatology GA 351FB UT WOS:000089146200026 PM 10990237 ER PT J AU Dawson, DA AF Dawson, DA TI The link between family history and early onset alcoholism: Earlier initiation of drinking or more rapid development of dependence? SO JOURNAL OF STUDIES ON ALCOHOL LA English DT Article ID D2-DOPAMINE RECEPTOR GENE; SUBSTANCE USE DISORDERS; NOVELTY SEEKING; NO ASSOCIATION; UNITED-STATES; PERSONALITY; ADOLESCENT; SAMPLE; ABUSE; PSYCHOPATHOLOGY AB Objective: This study examine!; the association between early onset alcoholism and family history to determine whether family history of alcoholism is predictive of earlier initiation of drinking, more rapid onset of dependence once drinking has begun, or both. Method: Using cross-sectional, retrospective data from a large, nationally representative sample of U.S. adults, discrete time proportional hazards models were used to assess the effects of family history saturation (% of alcoholic first- and second-degree relatives) on: (1) the risk of initiating drinking among all adults (N = 42,862; 58.4 %, female) and (2) the risk of progressing from initiation of drinking to onset of dependence among lifetime drinkers (n = 27,616; 50.7 % male). Models were estimated for different time periods, to see if the effect of family history saturation varied over time in a manner suggestive of a stronger association with early onset dependence. Results: The positive effect of family history saturation on the risk of initiating drinking was strongest prior to age 15 and declined steadily with increasing age. It was slightly weaker for men than women. After controlling for early initiation of drinking, the direct positive effect of family history saturation on the risk of progressing to dependence increased over time and was slightly reduced among individuals who starred drinking before age 18. The indirect effect of family history on the risk of developing dependence, via its effect on early drinking as a risk factor for dependence, was strongest in the interval from 3 to 9 years after initiation of drinking. Conclusions: The association between family history and early onset alcoholism appears to be driven most clearly by family history predicting earlier initiation of drinking. The weak effect of family history on the development of dependence within the first 3 years after initiation of drinking may reflect the preponderance of developmentally limited dependence during this time period. The data are consistent with the links established between novelty seeking, impulsivity and early onset alcoholism. While supporting the possibility of genetic effects via dopaminergic and serotonergic function, these findings also suggest that environmental factors may play an important part in helping to explain the association between family history and early onset alcoholism. C1 NIAAA, Div Biometry & Epidemiol, NIH, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, Div Biometry & Epidemiol, NIH, Willco Bldg,Suite 514,6000 Execut Blvd,MSC 7003, Bethesda, MD 20892 USA. NR 55 TC 59 Z9 59 U1 1 U2 5 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 0096-882X J9 J STUD ALCOHOL JI J. Stud. Alcohol PD SEP PY 2000 VL 61 IS 5 BP 637 EP 646 PG 10 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 358KU UT WOS:000089557900001 PM 11022800 ER PT J AU Lougee, L Perlmutter, SJ Nicolson, R Garvey, MA Swedo, SE AF Lougee, L Perlmutter, SJ Nicolson, R Garvey, MA Swedo, SE TI Psychiatric disorders in first-degree relatives of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE obsessive-compulsive disorder; Tourette's disorder; family history; pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections ID OBSESSIVE-COMPULSIVE DISORDER; TOURETTES-SYNDROME; RHEUMATIC-FEVER; TIC DISORDERS; ADOLESCENTS; FAMILY; SCALE; CHILDHOOD; VALIDITY; RELIABILITY AB Objective: To determine the rates of psychiatric disorders in the first-degree relatives of children with infection-triggered obsessive-compulsive disorder (OCD) and/or ties (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; PANDAS). Method: The probands of this study were 54 children with PANDAS (n = 24 with a primary diagnosis of OCD; n = 30 with a primary diagnosis of a tic disorder). One hundred fifty-seven first-degree relatives (100 parents [93%] and 57 siblings [100%]) were evaluated for the presence of a tic disorder. One hundred thirty-nine first-degree relatives (100 parents [93%] and 39 of 41 siblings over the age of 6 [95%]) were evaluated with clinical and structured psychiatric interviews to determine the presence of subclinical OCD, OCD, and other DSM-IV Axis I disorders. Results: Twenty-one probands (39%) had at least one first-degree relative with a history of a motor or vocal tie; 6 mothers (11%), 9 fathers (19%), and 8 siblings (16%) received this diagnosis. Fourteen probands (26%) had at least one first-degree relative with OCD; 10 mothers (19%), 5 fathers (11%), and 2 siblings (5%), received this diagnosis. An additional 8 parents (8%) and 3 siblings (8%) met criteria for subclinical OCD. Eleven parents (11%) had obsessive-compulsive personality disorder. Conclusions: The rates of tic disorders and OCD in first-degree relatives of pediatric probands with PANDAS are higher than those reported in the general population and are similar to those reported previously for tic disorders and OCD. Further study is warranted to determine the nature of the relationship between genetic and environmental factors In PANDAS. C1 NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. RP Lougee, L (reprint author), NIMH, Pediat & Dev Neuropsychiat Branch, Bldg 10,Room 4N208,10 Ctr Dr MSC 1255, Bethesda, MD 20892 USA. RI Nicolson, Robert/E-4797-2011 NR 43 TC 70 Z9 76 U1 7 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2000 VL 39 IS 9 BP 1120 EP 1126 DI 10.1097/00004583-200009000-00011 PG 7 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 348UK UT WOS:000089004700011 PM 10986808 ER PT J AU Bird, HR Davies, M Fisher, P Narrow, WE Jensen, PS Hoven, C Cohen, P Dulcan, MK AF Bird, HR Davies, M Fisher, P Narrow, WE Jensen, PS Hoven, C Cohen, P Dulcan, MK TI How specific is specific impairment? SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Article DE impairment; measurement; epidemiology; classification ID CHILDREN; ADOLESCENTS; DIAGNOSIS; SCALE AB Objective: To describe the usefulness of impairment items placed at the end of each diagnostic section of a structured instrument (the Diagnostic Interview Schedule for Children Version 2.3) in an attempt to link impairment to specific diagnoses. Method: Data from 3 sites of the Methods for the Epidemiology of Child and Adolescent Mental Disorders Study were used to assess the reliability of the specific impairment measures by diagnosis, the extent to which global and specific measures of impairment impact on prevalence rates, the concordance between global and specific impairment, and the degree to which there may be a "halo effect" among specific impairment ratings. Results: Test-retest reliability was better for parent than youth ratings. Fewer children were rated as impaired on well-validated global scales than on specific impairment ratings, suggesting that the threshold for specific ratings needs to be reevaluated. Agreement between specific and global ratings was poor. Most subjects with 2 or more diagnoses for which impairment was attributed to one diagnosis also had impairment attributed to other diagnoses for which they met symptom criteria, suggesting a halo effect in these ratings of specific impairment. Conclusions: Impairment measures are important in diagnostic assessments to distinguish those individuals whose psychopathology is of clinical significance. Specific impairment ratings used in structured instruments could be improved by including parameters of impairment that are diagnosis-specific. C1 Columbia Univ, Div Child & Adolescent Psychiat, Unit 78, New York State Psychiat Inst,Dept Psychiat, New York, NY 10032 USA. NIMH, Rockville, MD 20857 USA. Northwestern Univ, Sch Med, Chicago, IL USA. Childrens Mem Hosp, Chicago, IL 60614 USA. RP Bird, HR (reprint author), Columbia Univ, Div Child & Adolescent Psychiat, Unit 78, New York State Psychiat Inst,Dept Psychiat, 1051 Riverside Dr, New York, NY 10032 USA. OI Hoven, Christina/0000-0003-1274-2936; Jensen, Peter/0000-0003-2387-0650 FU NIMH NIH HHS [UO1 MH46718, UO1 MH 46717, UO1 MH46725] NR 19 TC 25 Z9 26 U1 4 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD SEP PY 2000 VL 39 IS 9 BP 1182 EP 1189 DI 10.1097/00004583-200009000-00019 PG 8 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 348UK UT WOS:000089004700019 PM 10986816 ER PT J AU Albert, MR AF Albert, MR TI Nineteenth-century patent medicines for the skin and hair SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Albert, MR (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 33 TC 2 Z9 2 U1 2 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD SEP PY 2000 VL 43 IS 3 BP 519 EP 526 DI 10.1067/mjd.2000.107479 PG 8 WC Dermatology SC Dermatology GA 349AX UT WOS:000089022600015 PM 10954667 ER PT J AU Qin, JX Jones, M Shiota, T Greenberg, NL Tsujino, H Firstenberg, MS Gupta, PC Zetts, AD Xu, Y Sun, JP Cardon, LA Odabashian, JA Flamm, SD White, RD Panza, JA Thomas, JD AF Qin, JX Jones, M Shiota, T Greenberg, NL Tsujino, H Firstenberg, MS Gupta, PC Zetts, AD Xu, Y Sun, JP Cardon, LA Odabashian, JA Flamm, SD White, RD Panza, JA Thomas, JD TI Validation of real-time three-dimensional echocardiography for quantifying left ventricular volumes in the presence of a left ventricular aneurysm: In vitro and in vivo studies SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; 3-DIMENSIONAL ECHOCARDIOGRAPHY; EJECTION FRACTION; IN-VITRO; SIZE; QUANTIFICATION; RECONSTRUCTION AB OBJECTIVES To validate the accuracy of real-time three-dimensional echocardiography (RT3DE) for quantifying aneurysmal left ventricular (LV) volumes. BACKGROUNDS Conventional two-dimensional echocardiography (2DE) has limitations when applied for quantification of LV volumes in patients with LV aneurysms. METHODS Seven aneurysmal balloons, IS sheep (5 with chronic LV aneurysms and 10 without LV aneurysms) during 60 different hemodynamic conditions and 29 patients (13 with chronic LV aneurysms and 16 with normal LV) underwent RT3DE and 2DE. Electromagnetic flow meters and magnetic resonance imaging (MRI) served as reference standards in the animals and in the patients, respectively. Rotated apical six-plane method with multiplanar Simpson's rule and apical biplane Simpson's rule were used to determine LV volumes by RT3DE and 2DE, respectively. RESULTS Both RT3DE and 2DE correlated well with actual volumes for aneurysmal balloons. However, a significantly smaller mean difference (MD) was found between RT3DE and actual volumes (-7 ml for RT3DE vs. 22 ml for 2DE, p = 0.0002). Excellent correlation and agreement between RT3DE and electromagnetic flow meters for LV stroke volumes for animals with aneurysms were observed, while 2DE showed lesser correlation and agreement (r = 0.97, MD = -1.0 ml vs. r = 0.76, MD = 4.4 ml). In patients with LV aneurysms, better correlation and agreement between RT3DE and MRI for LV volumes were obtained (r = 0.99, MD = -28 ml) than between 2DE and MRI (r = 0.91, MD = -49 ml). CONCLUSIONS For geometrically asymmetric LVs associated with ventricular aneurysms, RT3DE can accurately quantify LV volumes. (C) 2000 by the American College of Cardiology. C1 Cleveland Clin Fdn, Dept Cardiol, Cardiovasc Imaging Ctr, Cleveland, OH 44195 USA. NHLBI, Lab Anim Surg & Med, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Shiota, T (reprint author), Cleveland Clin Fdn, Dept Cardiol, Cardiovasc Imaging Ctr, 9500 Euclid Ave,Desk F 15, Cleveland, OH 44195 USA. OI White, Richard D./0000-0002-1133-7819 FU NHLBI NIH HHS [R0I-HL 56688-01A1] NR 25 TC 96 Z9 114 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD SEP PY 2000 VL 36 IS 3 BP 900 EP 907 DI 10.1016/S0735-1097(00)00793-2 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 351HQ UT WOS:000089152100038 PM 10987618 ER PT J AU Pratley, RE Hagberg, JM Dengel, DR Rogus, EM Muller, DC Goldberg, AP AF Pratley, RE Hagberg, JM Dengel, DR Rogus, EM Muller, DC Goldberg, AP TI Aerobic exercise training-induced reductions in abdominal fat and glucose-stimulated insulin responses in middle-aged and older men SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; aerobic exercise training; glucose tolerance; insulin action; body fat distribution ID 70-YEAR-OLD MEN; TOLERANCE; RESISTANCE; WOMEN; METABOLISM; OBESITY; SECRETION; SENSITIVITY; HEALTHY; YOUNG AB OBJECTIVE: To rest the effects of aerobic exercise training on glucose-stimulated insulin responses in middle-aged and older individuals. DESIGN: A 9-month moderate-intensity aerobic exercise training trial in 17 men. SETTING: An academic medical center. INTERVENTION: Subjects walked, jogged, or cycled at 50 to 60% heart rate reserve (HRR) three times per week for 30 to 45 minutes and progressed over 6 to 9 months until subjects were training at 80 to 85% of HRR for 45 to 60 minutes three to four times per week. Training intensity was stabilized for 2 weeks before retesting. Diets were stabilized on American Heart Association Step I diets before training, and calories increased to prevent weight loss. MEASUREMENTS: At baseline and after training, subjects underwent measurement of body fat (hydrodensitometry), regional fat distribution (waist-to-hip ratio (WHR)), VO2 max (maximal treadmill testing), diet intake (7-day food records), and glucose and insulin responses during 75 g, 2-hour oral glucose tolerance tests (OGTT) and 2-hour hyperglycemic (+7.9 mmol/L) glucose clamps. RESULTS: Aerobic exercise training increased VO2 max by 15% and decreased body fat from 22.8 +/- 1.6 to 20.8 +/- 1.5% (P < .0001), waist circumference by 2% (P = .038), and WHR by 1% (P = .035). Easting glucose and insulin levels, and glucose responses during the OGTT did not change, but insulin responses during the OGTT decreased 16% (P = .027) after training. Training reduced early (0-10 minutes) and late (20-120 minutes) phase insulin responses by 14% (P = .017 and .042, respectively), but did not significantly change glucose disposal (+8%, P = .398). Multiple regression analyses showed that changes in waist circumference (r(2) = 0.68, P < .0001) and percent body fat (r(2) = 0.08, P = .049) were independent predictors of the reductions in the late phase insulin responses with exercise training, however, changes in VO2 max were not (P = .199). CONCLUSIONS: The decrease in glucose-stimulated insulin secretion with aerobic exercise training in middle-aged and older men appears to be mediated, at least in part, by reductions in the amount of abdominal fat. Regular physical exercise may prevent or ameliorate conditions associated with hyperinsulinemia including dyslipidemia, hypertension, and atherosclerosis in this group. C1 Univ Maryland, Sch Med, Dept Med, Div Gerontol, Baltimore, MD 21201 USA. Baltimore Vet Adm Med Ctr, Geriatr Serv, GRECC, Baltimore, MD USA. NIA, Gerontol Res Ctr, Clin Invest Lab, Metab Sect, Baltimore, MD 21224 USA. RP Pratley, RE (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. FU NIA NIH HHS [K08-AG00494, KO7 AG00608, R01-AG07660] NR 41 TC 49 Z9 53 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2000 VL 48 IS 9 BP 1055 EP 1061 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 351PR UT WOS:000089167800004 PM 10983904 ER PT J AU Blazer, D Hybels, C Simonsick, E Hanlon, JT AF Blazer, D Hybels, C Simonsick, E Hanlon, JT TI Sedative, hypnotic, and antianxiety medication use in an aging cohort over ten years: A racial comparison SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE antianxiety agents; benzodiazepines; black race; older adults; community sample ID BENZODIAZEPINE USE; DRUG-USE; COMMUNITY; PREVALENCE; RISK; PRESCRIPTION; POPULATION; PATTERNS; OLDER; BLACK AB OBJECTIVES: Prescriptions of sedatives, hypnotics, and antianxiety medications have decreased over the past 15 years. However, racial differences have not been well investigated in controlled analyses. DESIGN: A prospective cohort study. SETTINGS AND PARTICIPANTS: The authors analyzed data from a community-based, biracial cohort of older adults (n = 4000 at baseline) followed for 10 years to determine sociodemographic and health characteristics associated with the use of these medications between 1986 and 1996. MAIN OUTCOME MEASURES: Information about sedative, hypnotic, and antianxiety medication use and demographic and health characteristics was obtained from a race-stratified, probability-based sample of black and white community-dwelling older adults in the Piedmont region of North Carolina during four in-person interviews spanning 10 years. Descriptive statistics were calculated. Logistic regression was used for the final models. RESULTS: A total of 13.3% of the subjects were taking these medications in 1986, with the frequency of use declining only to 11.8% in 1996 despite the cohort aging 10 years. Correlates of use at baseline were female gender, white race, depressive symptoms, poor self-rated health, impaired physical function, and health services use. These correlates persisted for each of the three follow-up waves of the survey. In 1996, the odds for being white and using these medications was 4.70 in controlled analyses. CONCLUSIONS: Despite the overall decline in the use of sedative, hypnotics, and antianxiety agents in the general population in recent years, over the 10 years of this survey, an aging cohort continued to use these medications at a frequency greater than the general population and did not demonstrate a significant decline in use. Factors unrelated to health status, specifically being white, were among the strongest correlates of use throughout the years of follow-up. C1 Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Ctr Study Aging, Durham, NC 27710 USA. NIA, Bethesda, MD 20892 USA. Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN 55455 USA. RP Blazer, D (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Ctr Study Aging, Box 3003, Durham, NC 27710 USA. FU NIA NIH HHS [N01 AG 12102, 1RO1 AG12765, AG15432] NR 40 TC 54 Z9 56 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2000 VL 48 IS 9 BP 1073 EP 1079 PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 351PR UT WOS:000089167800006 PM 10983906 ER PT J AU Ferrucci, L Penninx, BWJH Leveille, SG Corti, MC Pahor, M Wallace, R Harris, TB Havlik, RJ Guralnik, JM AF Ferrucci, L Penninx, BWJH Leveille, SG Corti, MC Pahor, M Wallace, R Harris, TB Havlik, RJ Guralnik, JM TI Characteristics of nondisabled older persons who perform poorly in objective tests of lower extremity function SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE lower extremity; physical performance; aging; disability; prevention of disability ID NURSING-HOME ADMISSION; PHYSICAL PERFORMANCE; SUBSEQUENT DISABILITY; MEXICAN-AMERICANS; WOMENS HEALTH; HIP FRACTURE; DEPENDENCE; COMMUNITY; RISK; ASSOCIATION AB OBJECTIVEs: It has been suggested that nondisabled older persons with poor performance of lower extremity function are ideal targets for interventions of disability prevention. However, health-related factors associated with poor performance are largely unknown. Using data from a representative sample of nondisabled older persons, this study identifies the diseases and biological markers that characterize this group of the population. DESIGN AND PARTICIPANTS: A total of 3381 persons aged 71 or older, interviewed and administered a battery of physical performance tests at the sixth annual follow-up of the Established Populations for Epidemiologic Studies of the Elderly (EPESE), who reported no need for help in walking 1/4 mile or climbing stairs. MEASUREMENTS: Lower extremity performance was measured using a short battery of tests including assessment of standing balance, a rimed 2.4-m walk, and timed test of rising 5 times from a chair. Chronic conditions were ascertained as self-report of a physician diagnosis. Data on previous hospitalizations were obtained from the Medicare database. Nonfasting blood samples were obtained and processed with standard methods. RESULTS: In a multivariate analysis, older age, female gender, higher BMI, history of hip fracture and diabetes, one or more hospital admissions for acute infection in the last 3 years, lower levels of hemoglobin and albumin, and higher leukocytes and gamma-glutamyl transferase were all associated independently with poor performance. CONCLUSIONS: Screening for older patients who are not disabled but have poor lower extremity performance selects a subgroup of the population with a high percentage of women, high prevalence of diabetes and hip fracture, and high levels of biological markers of inflammation. This group represents about 10% of the US population 70 to 90 years old. These findings should be considered in planning specifically tailored interventions for disability prevention in this subgroup. C1 NIA, Epidemiol Demog & Biometry Program, NIH, Bethesda, MD 20892 USA. INRCA, Geriatr Dept I Fraticini, Florence, Italy. Vrije Univ Amsterdam, Inst Res Extramural Med, Amsterdam, Netherlands. Osped Camposampiero, Dept Geriatr, Local Hlth Unit 15, Padua, Italy. Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. Univ Iowa, Coll Med, Iowa City, IA USA. RP Ferrucci, L (reprint author), NIA, Epidemiol Demog & Biometry Program, NIH, 7201 Wisconsihn Ave,Gateway Bldg,Suite 3C-309, Bethesda, MD 20892 USA. NR 45 TC 94 Z9 99 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2000 VL 48 IS 9 BP 1102 EP 1110 PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 351PR UT WOS:000089167800011 PM 10983911 ER PT J AU Ostchega, Y Harris, TB Hirsch, R Parsons, VL Kington, R AF Ostchega, Y Harris, TB Hirsch, R Parsons, VL Kington, R TI The prevalence of functional limitations and disability in older persons in the US: Data from the National Health and Nutrition Examination Survey III SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE disability; prevalence; US population; elderly; NHANES III ID SOCIOECONOMIC-STATUS; AGE; IMPACT; ADULTS; RISK AB OBJECTIVE: To provide estimates by sex and age and by sex and race/ethnicity of the proportion of older Americans who have difficulty with functional limitations and daily activities. SETTING: The Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994. DESIGN: A cross-sectional nationally representative survey. PARTICIPANTS: All persons aged 60 and older who completed a household interview (N = 6866) during NHANES III (conducted 1988-1994). MEASUREMENTS: The self-reported physical and functional disability questions from NHANES III included: lower-extremity function, instrumental activities of daily living, basic activities of daily living, needing help with personal and routine daily activities, and use of assistive devices for walking. RESULTS: Non-Hispanic black and Mexican-American men and women generally reported significantly (P < .01) more disability than did non-Hispanic white men and women. Disability was greater for minority women than for men. For both men and women, the prevalence in disability increased significantly (P < .01) with age for each measure. CONCLUSIONS: These sex-age and sex-race/ethnicity national estimates of disability indicate that minority women may represent a vulnerable subpopulation. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Hyattsville, MD 20782 USA. NIA, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Off Res Methodol, Hyattsville, MD 20782 USA. RP Ostchega, Y (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Room 900,6525 Belcrest Rd, Hyattsville, MD 20782 USA. NR 28 TC 90 Z9 96 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2000 VL 48 IS 9 BP 1132 EP 1135 PG 4 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 351PR UT WOS:000089167800015 PM 10983915 ER PT J AU Ostchega, Y Harris, TB Hirsch, R Parsons, VL Kington, R Katzoff, M AF Ostchega, Y Harris, TB Hirsch, R Parsons, VL Kington, R Katzoff, M TI Reliability and prevalence of physical performance examination assessing mobility and balance in older persons in the US: Data from the Third National Health and Nutrition Examination Survey SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE physical performance; prevalence; US population; elderly; NHANES III ID FUNCTIONAL STATUS; DISABILITY AB OBJECTIVE: This report provides reliability and prevalence estimates by sex, age, and race/ethnicity of an observed physical performance examination (PPE) assessing mobility and balance. SETTING: The Third National Health and Nutrition Examination Survey (NHANES III) 1988-1994. DESIGN: A cross-sectional nationally representative survey. PARTICIPANTS: All persons aged 60 and older (n = 5403) who performed the PPE either in the mobile examination center (MEC) or in the home during NHANES III (conducted 1988-1994). MEASUREMENTS: The PPE included timed chair stand, full tandem stand, and timed 8-foot walk. RESULTS: Timed chair stand and 8-foot timed walk were reliable measurements (Intraclass Correlations > 0.5). Women were significantly slower (P < .001) than men for both timed chair stands and timed walk. Non-Hispanic white men and women did the maneuvers in significantly less time than non-Hispanic black men and women and Mexican Americans women (P < .001). CONCLUSIONS: Lower extremity functions measured by timed chair stand and walk are reliable. Women at every age group were more physically limited than men. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Hyattsville, MD 20782 USA. NIA, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Off Res Methodol, Hyattsville, MD 20782 USA. RP Ostchega, Y (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Room 900,6525 Belcrest Rd, Hyattsville, MD 20782 USA. NR 20 TC 52 Z9 55 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD SEP PY 2000 VL 48 IS 9 BP 1136 EP 1141 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 351PR UT WOS:000089167800016 PM 10983916 ER PT J AU Humphreys, BL AF Humphreys, BL TI Electronic health record meets digital library: A new environment for achieving an old goal SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Editorial Material ID INFORMATION; SYSTEM; IAIMS AB Linking the electronic health record to the digital library is a Web-era reformulation of the long-standing informatics goal of seamless integration of automated clinical data and relevant knowledge-based information to support informed decisions. The spread of the Internet, the development of the World Wide Web, and converging format standards for electronic health data and digital publications make effective linking increasingly feasible. Some existing systems link electronic health data and knowledge-based information in limited settings or limited ways. Yet many challenging informatics research problems remain to be solved before flexible and seamless linking becomes a reality and before systems become capable of delivering the specific piece of information needed at the time and place a decision must be made. Connecting the electronic health record to the digital library also requires positive resolution of important policy issues, including health data privacy, government encouragement of high-speed communications, electronic intellectual property rights, and standards for health data and for digital libraries. Both the research problems and the policy issues should be important priorities for the field of medical informatics. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Humphreys, BL (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 35 TC 11 Z9 12 U1 0 U2 3 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP-OCT PY 2000 VL 7 IS 5 BP 444 EP 452 PG 9 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 356EW UT WOS:000089431900003 PM 10984463 ER PT J AU Kim, W Wilbur, WJ AF Kim, W Wilbur, WJ TI Corpus-based statistical screening for phrase identification SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Article ID MEDICAL-LANGUAGE-SYSTEM; DOCUMENT-RETRIEVAL; ACCESS; WORDS; TEXT AB Purpose: The authors study the extraction of useful phrases from a natural language database by statistical methods. The aim is to leverage human effort by providing preprocessed phrase lists with a high percentage of useful material. Method: The approach is to develop six different scoring-methods that are based on different aspects of phrase occurrence. The emphasis here is not on lexical information or syntactic structure but rather on the statistical properties of word pairs and triples that can be obtained from a large database. Measurements: The Unified Medical Language System (UMLS) incorporates a large list of humanly acceptable phrases in the medical field as a part of its structure. The authors use this list of phrases as a gold standard for validating their methods. A good method is one that ranks the UMLS phrases high among all phrases studied. Measurements are 11-point average precision values and precision-recall curves based on the rankings Results: The authors find six different scoring methods that each proves effective in identifying UMLS quality phrases in a large subset of MEDLINE. These methods are applicable both to word pairs and word triples. All six methods are optimally combined to produce composite scoring methods that are more effective than any single method. The quality of the composite methods appears sufficient to support the automatic placement of hyperlinks in text at the site of highly ranked phrases. Conclusion: Statistical scoring methods provide a promising approach to the extraction of useful phrases from a natural language database for the purpose of indexing or providing hyperlinks in text. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Natl Lib Med, Bldg 38A,Room 8S806,8600 Rockville Pike, Bethesda, MD 20894 USA. EM wonkim@ncbi.nlm.nih.gov NR 47 TC 3 Z9 3 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1067-5027 EI 1527-974X J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD SEP-OCT PY 2000 VL 7 IS 5 BP 499 EP 511 PG 13 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics SC Computer Science; Health Care Sciences & Services; Information Science & Library Science; Medical Informatics GA 356EW UT WOS:000089431900009 PM 10984469 ER PT J AU Tamura, M Yanagihara, N Tanaka, H Osajima, A Hirano, T Higashi, K Yamada, KM Nakashima, Y Hirano, H AF Tamura, M Yanagihara, N Tanaka, H Osajima, A Hirano, T Higashi, K Yamada, KM Nakashima, Y Hirano, H TI Activation of DNA synthesis and AP-1 by profilin, an actin-binding protein, via binding to a cell surface receptor in cultured rat mesangial cells SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID TUMOR-SUPPRESSOR PTEN; C-JUN; MESSENGER-RNA; FOCAL ADHESION; GENE; EXPRESSION; GROWTH; PHOSPHORYLATION; INCREASE; KINASE AB Profilin is known to bind to actin monomers (to regulate actin polymerization) and to phosphatidylinositol-4,5-bisphosphate (to inhibit hydrolysis by unphosphorylated phospholipase C-gamma 1). It was recently reported that profilin is overexpressed in glomerular mesangial cells (MC) of rats with anti-Thy-1.1-induced glomerulonephritis and is accumulated in the extracellular space around MC. In this study, the biologic activities of extracellular profilin were examined. Scatchard analysis indicated the existence of a single class of cell surface binding sites, with similar equilibrium dissociation constants for purified splenic profilin and recombinant profilin, in cultured rat MC. Profilin increased [H-3]thymidine incorporation in a dose-dependent manner and produced additive effects on platelet-derived growth factor-induced [H-3]thymidine incorporation. Profilin increased AP-1 DNA-binding activity in a concentration-dependent (ED50 = 30 nM) and time-dependent manner after transient c-jun gene expression, as measured using gel-shift assays and competitive reverse transcription-PCR. Pretreatment of profilin with an anti-profilin inhibitory antibody suppressed profilin-induced AP-1 activation and [H-3]thymidine incorporation Furthermore, profilin induced rapid transient activation of protein kinase C, and staurosporine and H-7 reduced the profilin-induced activation of AP-1, suggesting protein kinase C-dependent activation of AP-1. These findings indicate that profilin in the extracellular space can bind to cell surface receptors of MC and act as an inducer of signal transduction. These results suggest that extracellular profilin may be involved in the progression of glomerular diseases, by affecting cell growth. C1 Univ Occupat & Environm Hlth, Sch Med, Dept Internal Med 2, Kitakyushu, Fukuoka 8078555, Japan. Univ Occupat & Environm Hlth, Sch Med, Dept Biochem, Kitakyushu, Fukuoka 8078555, Japan. Univ Occupat & Environm Hlth, Sch Med, Dept Pharmacol, Kitakyushu, Fukuoka 8078555, Japan. Univ Occupat & Environm Hlth, Inst Ind Ecol, Dept Environm Oncol, Kitakyushu, Fukuoka 8078555, Japan. Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD USA. RP Tamura, M (reprint author), Univ Occupat & Environm Hlth, Sch Med, Dept Internal Med 2, 1-1 Iseigaoka, Kitakyushu, Fukuoka 8078555, Japan. OI Yamada, Kenneth/0000-0003-1512-6805 NR 50 TC 14 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD SEP PY 2000 VL 11 IS 9 BP 1620 EP 1630 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 350LL UT WOS:000089102400005 PM 10966486 ER PT J AU Eldridge, MW Peden, DB AF Eldridge, MW Peden, DB TI Airway response to concomitant exposure with endotoxin and allergen in atopic asthmatics SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A LA English DT Article; Proceedings Paper CT International Symposium on Respiratory Immunology CY OCT 10-13, 1999 CL SANTA FE, NEW MEXICO SP Lovelace Respiratory Res Inst ID INHALED ENDOTOXIN; INFLAMMATORY RESPONSE; HEALTHY-SUBJECTS; INDUCED SPUTUM; INHALATION; LIPOPOLYSACCHARIDE; SYMPTOMS; OZONE; RESPONSIVENESS; CHALLENGE AB Epidemiological and in vivo studies suggest that inhaled endotoxin may be an important environmental factor associated with the increases in asthma-related morbidity and mortality. Recent studies by our group and others provide a rationale for the hypothesis that airway exposure of atopic asthmatics to both allergen and endotoxin might result in greater inflammatory responses than those observed with either stimulus alone. Moreover, these studies may provide further evidence that concomitant exposure to allergen and endotoxin is an important factor in asthma pathogenesis. C1 Univ N Carolina, Ctr Environm Med & Lung Biol, Sch Med, Chapel Hill, NC USA. Univ N Carolina, Dept Pediat, Div Pulm Med & Allergy, Sch Med, Chapel Hill, NC USA. Univ N Carolina, Gen Clin Res Ctr, Sch Med, Chapel Hill, NC USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Eldridge, MW (reprint author), H4 468 Clin Sci Ctr, Dept Pediat, 600 Highland Ave, Madison, WI 53792 USA. FU NHLBI NIH HHS [1RO1HL62624-01]; NIEHS NIH HHS [N01-ES-35356] NR 39 TC 16 Z9 16 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI LONDON PA 11 NEW FETTER LANE, LONDON EC4P 4EE, ENGLAND SN 1528-7394 J9 J TOXICOL ENV HEAL A JI J. TOXICOL. ENV. HEALTH PT A PD SEP PY 2000 VL 61 IS 1 BP 27 EP 37 DI 10.1080/00984100050116762 PG 11 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 347JV UT WOS:000088926600004 PM 10990161 ER PT J AU Murphy, CG Lucas, WT Means, RE Czajak, S Hale, CL Lifson, JD Kaur, A Johnson, RP Knipe, DM Desrosiers, RC AF Murphy, CG Lucas, WT Means, RE Czajak, S Hale, CL Lifson, JD Kaur, A Johnson, RP Knipe, DM Desrosiers, RC TI Vaccine protection against simian immunodeficiency virus by recombinant strains of herpes simplex virus SO JOURNAL OF VIROLOGY LA English DT Article ID REPLICATION-DEFECTIVE MUTANTS; TRIGEMINAL GANGLION; NEUTRALIZING ANTIBODIES; VIRAL REPLICATION; ENVELOPE PROTEIN; GENETIC-EVIDENCE; RHESUS MACAQUES; TYPE-1; CHALLENGE; INFECTION AB An effective vaccine for AIDS may require development of novel vectors capable of eliciting long-lasting immune responses. Here we report the development and use of replication-competent and replication-defective strains of recombinant herpes simplex virus (HSV) that express envelope and Nef antigens of simian immunodeficiency virus (SIV). The HSV recombinants induced antienvelope antibody responses that persisted at relatively stable levels for months after the last administration, Two of seven rhesus monkeys vaccinated with recombinant HSV were solidly protected, and another showed a sustained reduction in viral load following rectal challenge with pathogenic SIVmac239 at 22 weeks following the last vaccine administration. HSV vectors thus show great promise for being able to elicit persistent immune responses and to provide durable protection against AIDS. C1 Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. Harvard Univ, New England Reg Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. NCI, AIDS Vaccine Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Ft Detrick, MD 21702 USA. RP Knipe, DM (reprint author), Harvard Univ, Sch Med, Dept Microbiol & Mol Genet, Boston, MA 02115 USA. FU NCRR NIH HHS [K26 RR000168, RR00168, P51 RR000168]; NIAID NIH HHS [AI46006, AI38131, P01 AI046006] NR 50 TC 92 Z9 93 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2000 VL 74 IS 17 BP 7745 EP 7754 DI 10.1128/JVI.74.17.7745-7754.2000 PG 10 WC Virology SC Virology GA 346JD UT WOS:000088866500006 PM 10933680 ER PT J AU Grivel, JC Malkevitch, N Margolis, L AF Grivel, JC Malkevitch, N Margolis, L TI Human immunodeficiency virus type 1 induces apoptosis in CD4(+) but not in CD8(+) T cells in ex vivo-infected human lymphoid tissue SO JOURNAL OF VIROLOGY LA English DT Article ID THYMIC ORGAN-CULTURE; HIV-1 INFECTION; IN-VIVO; DISEASE PROGRESSION; PROGRAMMED DEATH; TELOMERE LENGTH; RAPID TURNOVER; HOST FACTORS; LYMPHOCYTES; ACTIVATION AB Progression of human immunodeficiency virus (HIV disease is associated with massive death of CD4(+) T cells along with death and/or dysfunction of CD8(+) T cells. In vivo, both HIV infection per se and host factors mag contribute to the death and/or dysfunction of CD4(+) and CD8(+) T cells. Progression of HIV disease is often characterized by a switch from R5 to X4 HIV type 1 (HIV-1) variants. In human lymphoid tissues ex vivo, it was shown that HIV infection is sufficient for CD4(+) T-cell depletion. Here we address the question of whether infection of human lymphoid tissue ex vivo with prototypic R5 or X4 HIV variants also depletes or impairs CD8(+) T cells. We report that whereas productive infection of lymphoid tissue ex vivo with R5 and X4 HIV-1 isolates induced apoptosis in CD4(+) T cells, neither viral isolate induced apoptosis in CD8(+) T cells. Moreover, in both infected and control tissues we found similar numbers of CD8(+) T cells and similar production of cytokines by these cells in response to phorbol myristate acetate or anti-CD3-anti-CD28 stimulation. Thus, whereas HIV-1 infection per se in human lymphoid tissue is sufficient to trigger apoptosis in CD4(+) T cells, the death of CD8(+) T cells apparently requires additional factors. C1 NICHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Margolis, L (reprint author), NICHD, Lab Cellular & Mol Biophys, NIH, Bldg 10,Rm 10D14, Bethesda, MD 20892 USA. NR 69 TC 35 Z9 36 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2000 VL 74 IS 17 BP 8077 EP 8084 DI 10.1128/JVI.74.17.8077-8084.2000 PG 8 WC Virology SC Virology GA 346JD UT WOS:000088866500043 PM 10933717 ER PT J AU Arthos, J Rubbert, A Rabin, RL Cicala, C Machado, E Wildt, K Hanback, M Steenbeke, TD Swofford, R Farber, JM Fauci, AS AF Arthos, J Rubbert, A Rabin, RL Cicala, C Machado, E Wildt, K Hanback, M Steenbeke, TD Swofford, R Farber, JM Fauci, AS TI CCR5 signal transduction in macrophages by human immunodeficiency virus and simian immunodeficiency virus envelopes (vol 74, pg 6418, 2000) SO JOURNAL OF VIROLOGY LA English DT Correction C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIAID, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Arthos, J (reprint author), NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2000 VL 74 IS 17 BP 8218 EP 8218 PG 1 WC Virology SC Virology GA 346JD UT WOS:000088866500063 ER PT J AU Muszynski, KW Thompson, D Hanson, C Lyons, R Spadaccini, A Ruscetti, SK AF Muszynski, KW Thompson, D Hanson, C Lyons, R Spadaccini, A Ruscetti, SK TI Growth factor-independent proliferation of erythroid cells infected with friend spleen focus-forming virus is protein kinase C dependent but does not require Ras-GTP SO JOURNAL OF VIROLOGY LA English DT Article ID ERYTHROPOIETIN RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; TYROSINE PHOSPHORYLATION; HEMATOPOIETIC-CELLS; DNA-BINDING; ERYTHROLEUKEMIA-CELLS; SIGNAL-TRANSDUCTION; DISTINCT PATHWAYS; ACTIVATES RAF-1; PLASMA-MEMBRANE AB Interaction of erythropoietin (Epo) with its cell surface receptor activates signal transduction pathways which result in the proliferation and differentiation of erythroid cells. Infection of erythroid cells with the Friend spleen focus-forming virus (SFFV) leads to the interaction of the viral envelope glycoprotein with the Epo receptor and renders these cells Epo independent. We previously reported that SFFV induces Epo independence by constitutively activating components of several Epo signal transduction pathways, including the Jak-Stat and the Raf-1/mitogen-activated protein kinase (MAPK) pathways. To Further evaluate the mechanism by which SFFV activates the Raf-1/MAPK pathway, me investigated the effects of SFFV on upstream components of this pathway, and our results indicate that SFEV activates Shc and Grb2 and that this leads to Ras activation. While studies with a dominant-negative Ras indicated that Ras was required for Epo-induced proliferation of normal erythroid cells, the Epo-independent growth of SFFV-infected cells can still occur in the absence of Ras, although at reduced levels. In contrast, protein kinase C (PKC) was shown to be required for the Epo-independent proliferation of SFFV-infected cells. Further studies indicated that PKC, which is thought to be involved in the activation of both Raf-1 and MAPK, was required only for the activation of MAPK, not Raf-1, in SFFV-infected cells. Our results indicate that Ras and PKC define two distinct signals converging on MAPK in both Epo-stimulated and SFFV-infected erythroid cells and that activation of only PKC is sufficient for the Epo-independent proliferation of SFFV-infected cells. C1 NCI, Basic Res Labs, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Ruscetti, SK (reprint author), NCI, Basic Res Labs, Frederick Canc Res & Dev Ctr, Bldg 469,Room 205, Frederick, MD 21702 USA. NR 68 TC 24 Z9 25 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2000 VL 74 IS 18 BP 8444 EP 8451 DI 10.1128/JVI.74.18.8444-8451.2000 PG 8 WC Virology SC Virology GA 347ML UT WOS:000088933700027 PM 10954544 ER PT J AU Kuroda, MJ Schmitz, JE Lekutis, C Nickerson, CE Lifton, MA Franchini, G Harouse, JM Cheng-Mayer, C Letvin, NL AF Kuroda, MJ Schmitz, JE Lekutis, C Nickerson, CE Lifton, MA Franchini, G Harouse, JM Cheng-Mayer, C Letvin, NL TI Human immunodeficiency virus type 1 envelope epitope-specific CD4(+) T lymphocytes in simian/human immunodeficiency virus-infected and vaccinated rhesus monkeys detected using a peptide-major histocompatibility complex class II tetramer SO JOURNAL OF VIROLOGY LA English DT Article ID AIDS-LIKE DISEASE; CELL RESPONSES; HELPER CELLS; IN-VIVO; CYTOMEGALOVIRUS; INTERFERON; MECHANISM; MACAQUES; GAMMA AB A tetrameric recombinant major histocompatibility complex (MHC) class II-peptide complex was used to quantitate human immunodeficiency virus type 1 (HIV-1) envelope (Env)-specific CD4(+) T cells in vaccinated and in simian/human immunodeficiency virus (SHIV)-infected rhesus monkeys. A rhesus monkey MHC class II DR molecule, Mamu-DR*W201, and an HIV-1 Env peptide (p46) were employed to construct this tetrameric complex. A p46 specific proliferative response was seen in sorted, tetramer-binding, but not nonbinding, CD4(+) T cells, directly demonstrating that this response was mediated by the epitope-specific lymphocytes. Although staining of whole blood from 10 SHIV-infected Mamu-DR*W201(+) rhesus monkeys failed to demonstrate tetramer-binding CD4(+) T cells (<0.02%), p46-stimulated peripheral blood mononuclear cells (PBMCs) from 9 of these 10 monkeys had detectable p46 tetramer-binding cells, comprising 0.5 to 15.2% of the CD4(+) T cells. p46-stimulated PBMCs from 7 of 10 Mamu-DR*W201(+) monkeys vaccinated with a recombinant canarypox virus-HIV-1 env construct also demonstrated p46 tetramer-binding cells, comprising 0.9 to 7.2% of the CD4(+) T cells. Thus, Env p46-specific CD4(+) T cells can be detected by tetrameric Mamu-DR*W201-p46 complex staining of PBMCs in both SHIV-infected and vaccinated rhesus monkeys. These epitope-specific cell populations appear to be present in peripheral blood at a very low frequency. C1 Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis,Dept Med, Boston, MA 02215 USA. NCI, Basic Res Labs, Bethesda, MD 20892 USA. Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. RP Kuroda, MJ (reprint author), Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Viral Pathogenesis,Dept Med, RE-102,POB 15732, Boston, MA 02215 USA. FU NIAID NIH HHS [AI20729, AI85343, R01 AI020729, R37 AI020729] NR 33 TC 25 Z9 26 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD SEP PY 2000 VL 74 IS 18 BP 8751 EP 8756 DI 10.1128/JVI.74.18.8751-8756.2000 PG 6 WC Virology SC Virology GA 347ML UT WOS:000088933700061 PM 10954578 ER PT J AU Merz, CNB Olson, M McGorray, S Pakstis, DL Zell, K Rickens, CR Kelsey, SF Bittner, V Sharaf, BL Sopko, G AF Merz, CNB Olson, M McGorray, S Pakstis, DL Zell, K Rickens, CR Kelsey, SF Bittner, V Sharaf, BL Sopko, G CA WISE Study Grp TI Physical activity and functional capacity measurement in women: A report from the NHLBI-sponsored WISE study SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Article ID CORONARY HEART-DISEASE; ISCHEMIA PILOT ACIP; QUESTIONNAIRE; PREVENTION; DESIGN; RISK AB Physical activity and functional capacity have not been assessed by questionnaire for criterion validity in women. We wished to evaluate the ability of a physical activity and a functional capacity assessment questionnaire to predict functional capacity measured by treadmill exercise stress testing, as well as correlate with cardiac risk factors and angiographic coronary artery disease (CAD) in women. In a National Heart, Lung and Blood Institute (NHLBI)-sponsored cross-sectional population study involving four academic medical centers, 476 women with cardiac risk factors undergoing coronary angiography for evaluation for suspected myocardial ischemia were enrolled in the Women's Ischemia Syndrome Evaluation (WISE). The main outcome measures were functional capacity measured during: symptom-limited exercise treadmill testing, cardiac risk factors, and CAD, using core laboratory-determined measures. Physical activity measured by the Postmenopausal Estrogen and Progesterone Intervention physical activity questionnaire (PEPI-Q) and functional capacity measured by the Duke Activity Status Index (DASI) questionnaire, correlated with functional capacity measured in metabolic equivalents (METS), as estimated during: symptom-limited exercise treadmill testing ( r = 0.27, p = 0.001 and r = 0.31, p = 0.0002, respectively). The DASI was a significant independent predictor of functional capacity even after adjustment for cardiac risk factors, and the PEFI-Q was not. The DASI and PEPI-Q scores were inversely associated with higher numbers and levels of cardiac risk factors, as well as angiographic CAD. The DASI questionnaire is a reasonable correlate of functional capacity achieved during symptom-limited treadmill exercise testing in women with suspected myocardial ischemia. Lower functional capacity or physical activity measured by the DASI and PEPI-Q, respectively, is associated with more prevalent cardiac risk factors and angiographic CAD. These findings suggest that the DASI and, to a lesser extent, the PEPI-Q have criterion validity for use in health-related research in women. C1 Univ Pittsburgh, WISE Coordinating Ctr, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Cedars Sinai Med Ctr, Cedars Sinai Res Inst, Dept Med, Div Cardiol, Pittsburgh, PA USA. Univ Florida, Dept Med, Div Cardiol, Gainesville, FL USA. Allegheny Gen Hosp, Dept Med, Div Cardiol, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Dept Med, Div Cardiol, Pittsburgh, PA 15261 USA. Univ Alabama, Dept Med, Div Cardiol, Birmingham, AL 35294 USA. Rhode Isl Hosp, Providence, RI USA. NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. RP Merz, CNB (reprint author), Univ Pittsburgh, WISE Coordinating Ctr, Grad Sch Publ Hlth, Dept Epidemiol, 127 Parran Hall,130 Desoto St, Pittsburgh, PA 15261 USA. NR 18 TC 26 Z9 27 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD SEP PY 2000 VL 9 IS 7 BP 769 EP 777 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 359AW UT WOS:000089590200010 ER PT J AU Frank, E Rimer, BK Brogan, D Elon, L AF Frank, E Rimer, BK Brogan, D Elon, L TI US women physicians' personal and clinical breast cancer screening practices SO JOURNAL OF WOMENS HEALTH & GENDER-BASED MEDICINE LA English DT Article ID COUNSELING PRACTICES; PREVENTION; INTERNISTS; CARE; BEHAVIORS AB Little is known about predictors of physicians' personal or clinical compliance with breast cancer screening recommendations. We explored this in 4501 respondents to the Women Physicians' Health Study, a questionnaire-based study of a representative sample of U.S. women M.D.s. Overall, 21% of women physicians performed breast self-examination (BSE) at least monthly, about two thirds had received a clinical breast examination (CBE) within the last year, and 85% had received one within the last 2 years. Of those <40 years old, 14% had received a mammogram in the past year, as had 42% of those 40-49 and 59% of those 50-70 years old. Being a primary care practitioners or obstetrician/gynecologist was a significant predictor of counseling or screening for CBE and mammography. Only 46% of all women physicians reported discussing or performing mammograms at least once a year for those greater than or equal to 50-less than or equal to 75 years old, and 53% reported doing so for CBE. Also associated with performing CBE was examining one's own breasts at least once a year. Associated with mammography were having had a mammogram oneself in the past year and having a personal history of breast cancer. Other parameters, including age, ethnicity, region, practice type, practice site, control of work environment, work hours, amount of general continuing medical education (CME), career satisfaction, general health status, other breast disorders, personally having a recent CBE, or family histories of breast cancer or any other breast disorder, were not multivariately significantly associated with our counseling frequency outcomes. Women physicians may be especially efficient targets for breast cancer screening education. C1 Emory Univ, Sch Med, Dept Family & Prevent Med, Atlanta, GA 30306 USA. NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30306 USA. RP Frank, E (reprint author), Emory Univ, Sch Med, Dept Family & Prevent Med, 69 Butler St, Atlanta, GA 30306 USA. FU NCI NIH HHS [1R03CA71434-01A2]; NHLBI NIH HHS [5T32HL07034] NR 24 TC 21 Z9 22 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1524-6094 J9 J WOMEN HEALTH GEN-B JI J. WOMENS HEALTH GENDER-BASED MED. PD SEP PY 2000 VL 9 IS 7 BP 791 EP 801 DI 10.1089/15246090050147763 PG 11 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 359AW UT WOS:000089590200012 PM 11025871 ER PT J AU Kajiyama, W Kopp, JB Marinos, NJ Klotman, PE Dickie, P AF Kajiyama, W Kopp, JB Marinos, NJ Klotman, PE Dickie, P TI Glomerulosclerosis and viral gene expression in HIV-transgenic mice: Role of nef SO KIDNEY INTERNATIONAL LA English DT Article DE focal segmental glomerulosclerosis; renal failure; envelope protein; gp120; apoptosis ID HUMAN-IMMUNODEFICIENCY-VIRUS; EPITHELIAL-CELLS; NEPHROPATHY; APOPTOSIS; PROTEIN; TAT; ACTIVATION; TISSUE; RNA AB Background. Human immunodeficiency virus (HIV)-associated nephropathy is characterized by focal segmental glomerulosclerosis and microcystic tubular dilation. We have previously described a mouse transgenic for a Delta gag-pol HIV-1 genome, which develops glomerulosclerosis, cutaneous papillomas, and cataracts. Methods. We developed mice transgenic for a Delta gag-pol-nef HIV genome in order to investigate the role of the nef gene in these phenotypes. Results. One transgenic line, X5, expressed HIV mRNA in kidney and consistently manifested focal segmental glomerulosclerosis and tubular dilation by six weeks of age. Northern analysis indicated that renal transgene expression was higher in the Delta gag-pol-nef mice compared with the Delta gag-pol mice. In situ hybridization and immunostaining demonstrated HIV RNA and protein expression within the glomerular epithelial cells and tubular epithelial cells. These cell types showed histologic evidence of toxicity, including vacuolation and detachment from basement membrane, and exhibited increased rates of apoptosis. These data suggest that the renal disease seen in the Delta gag-pol-nef transgenic mouse may be caused by the expression of HIV genes within renal epithelial cells, that this expression may induce cellular toxicity, including apoptosis, and that nef is not required for the induction of renal disease. We have previously described mice bearing the nef gene, which do not manifest renal disease. In further experiments, Delta gag-pol-nef mice were bred with nef mice; these dual-transgenic mice developed renal disease that generally resembled that seen in Delta gag-pol-nef mice, but with somewhat more severe glomerulosclerosis and less severe tubulointerstitial injury. Results. The results of these transgenic studies suggest that the role of nef is complex and may act both to reduce transgene expression and to potentiate glomerular injury induced by other HIV-1 gene products. C1 NIDDK, Metab Dis Branch, Kidney Dis Sect, NIH, Bethesda, MD 20892 USA. NIDR, Imaging Facil, NIH, Bethesda, MD 20892 USA. Mt Sinai Sch Med, Dept Med, New York, NY USA. Univ Alberta, Edmonton, AB, Canada. RP Kopp, JB (reprint author), NIDDK, Metab Dis Branch, Kidney Dis Sect, NIH, 10-3N116, Bethesda, MD 20892 USA. NR 30 TC 46 Z9 48 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2000 VL 58 IS 3 BP 1148 EP 1159 DI 10.1046/j.1523-1755.2000.00271.x PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 351KE UT WOS:000089155700022 PM 10972678 ER PT J AU Lemley, KV Abdullah, I Myers, BD Meyer, TW Blouch, K Smith, WE Bennett, PH Nelson, RG AF Lemley, KV Abdullah, I Myers, BD Meyer, TW Blouch, K Smith, WE Bennett, PH Nelson, RG TI Evolution of incipient nephropathy in type 2 diabetes mellitus SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT 31st Annual Meeting of the American-Society-of-Nephrology CY OCT 17-20, 1998 CL PHILADELPHIA, PENNSYLVANIA SP Amer Soc Nephrol DE microalbuminuria; glomerular morphometry; filtration dynamics; ultrafiltration coefficient; Pima Indians ID GLOMERULAR-FILTRATION RATE; PIMA-INDIANS; IDDM PATIENTS; PROGRESSION; MICROALBUMINURIA; HYPERTROPHY; DISEASE; INJURY; HYPERTENSION; ALBUMINURIA AB Background. We examined the course of glomerular injury in 12 Pima Indians with long-standing (>8 years) type 2 diabetes mellitus, normal serum creatinine, and microalbuminuria. They were compared with a group of 10 Pima Indians in Arizona with new-onset (<5 years) type 2 diabetes, normal renal function, and normoalbuminuria (<30 mg albumin/g creatinine on random urine specimens). Methods. A combination of physiological and morphological techniques was used to evaluate glomerular function and structure serially on two occasions separated by a 48-month interval. Clearances of iothalamate and p-aminohippuric acid were used to determine glomerular filtration rate (GFR) and renal plasma Row, respectively. Afferent oncotic pressure was determined by membrane osmometry. The single nephron ultrafiltration coefficient (K-t) was determined by morphometric analysis of glomeruli and mathematical modeling. Results. The urinary albumin-to-creatinine ratio (median + range) increased from 84 (28 to 415) to 260 (31 to 2232) mg/g between the two examinations (P = 0.01), and 6 of 12 patients advanced from incipient (ratio = 30 to 299 mg/g) to overt nephropathy (greater than or equal to 300 mg/g). A 17% decline in GFR between the two examinations from 186 +/- 41 to 155 +/- 50 mi/min (mean +/- SD: P = 0.06) was accompanied by a 17% decline in renal plasma how (P = 0.003) and a 6% increase in plasma oncotic pressure (P = 0.02). Computed glomerular hydraulic permeability was depressed by 13% below control values at both examinations, a result of a widened basement membrane and a reduction in frequency of epithelial filtration slits. The filtration surface area declined significantly, however, from 6.96 +/- 2.53 to 5.51 +/- 1.62 x 10(5) mm(2) (P = 0.01), a change that was accompanied by a significant decline in the number of mesangial cells (P = 0.001), endothelial cells (P = 0.038), and podocytes (P = 0.0005). These changes lowered single nephron K-f by 20% from 16.5 +/- 6.0 to 13.2 +/- 3.6 nL/(minutes + mm Hg) between the two examinations (P = 0.02). Multiple linear regression analysis revealed that among the determinants of GFR, only the change in single nephron K-f was related to the corresponding change in GFR. Conclusion. We conclude that a reduction in K-t is the major determinant of a decline in GFR from an elevated toward a normal range as nephropathy in type 2 diabetes advances from an incipient to an overt stage. C1 Stanford Univ, Sch Med, Med Ctr, Div Nephrol, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Sch Med, Div Pediat Nephrol, Stanford, CA 94305 USA. Good Samaritan Hosp, Phoenix, AZ USA. NIDDK, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. RP Myers, BD (reprint author), Stanford Univ, Sch Med, Med Ctr, Div Nephrol, S201, Stanford, CA 94305 USA. RI Nelson, Robert/B-1470-2012 FU NCRR NIH HHS [M01-RR00070]; NIDDK NIH HHS [DK54600] NR 37 TC 54 Z9 55 U1 0 U2 0 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2000 VL 58 IS 3 BP 1228 EP 1237 DI 10.1046/j.1523-1755.2000.00223.x PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 351KE UT WOS:000089155700029 PM 10972685 ER PT J AU Murakami, H Liotta, L Star, RA AF Murakami, H Liotta, L Star, RA TI IF-LCM: Laser capture microdissection of immunofluorescently defined cells for mRNA analysis Rapid Communication SO KIDNEY INTERNATIONAL LA English DT Article DE microdissection; immunofluorescence; thick ascending limb; acridine orange; RNA preservation; video-microscopy ID MOLECULAR ANALYSIS; EXPRESSION; RNA; KIDNEY; POPULATIONS; SECTIONS; CLONING; TISSUE AB Background The next phase of the molecular revolution will bring functional genomics down to the level of individual cells in a tissue. Laser capture microdissection (LCM) coupled with reverse transcription-polymerase chain reaction (RT-PCR) can measure gene expression in normal, cancerous, injured, or fibrotic tissue. Nevertheless. targeting of specific cells may be difficult using routine morphologic stains. Immunohistochemistry can identify cells with specific antigens; however, exposure to aqueous solutions destroys 99% of the mRNA. Consequently, there is an overwhelming need to identify specific tissue cells for LCM without mRNA loss. We report on a rapid immunofluorescent LCM (IF-LCM) procedure that allows targeted analysis of gene expression. Methods. A LCM microscope was outfitted for epifluorescence and light level video microscopy. Heat filters were added to shield the image intensifier from the laser. Frozen sections were fluorescently labeled by a rapid one minute incubation with anti-Tamm-Horsfall antibody and an ALEXA-linked secondary antibody. Fluorescently labeled thick ascending limb (TAL) cells were detected by low light level video microscopy, captured by LCM, and mRNA was analyzed by RT PCR for basic amino acid transporter, Tamm-Horsfall protein, and aquaporin-2. Results. The immunofluorescently identified TAL could be cleanly microdissected without contamination from surrounding tubules. The recovery of RNA following rapid immunofluorescence staining was similar to that obtained following hematoxylin and eosin staining, as assessed by RT-PCR for malate dehydrogenase. Conclusions. We conclude that the new apparatus and method for the immunofluorescent labeling of tissue cells targeted for LCM call isolate pure populations of targeted cells from a sea of surrounding cells with highly acceptable preservation of mRNA. Since the TAL is minimally injured following ischemia, identification of the different responses between TAL and surrounding tissue in damaged kidneys may provide new therapeutic targets or agents for the treatment of acute renal failure. C1 NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. NIH, Pathol Lab, Bethesda, MD 20892 USA. RP Star, RA (reprint author), NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bldg 10,Room 3N108,10 Ctr Dr MSC 1268, Bethesda, MD 20892 USA. NR 23 TC 62 Z9 69 U1 0 U2 1 PU BLACKWELL SCIENCE INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD SEP PY 2000 VL 58 IS 3 BP 1346 EP 1353 DI 10.1046/j.1523-1755.2000.00295.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 351KE UT WOS:000089155700044 PM 10972700 ER PT J AU Hampshire, V McNickle, C Davis, J AF Hampshire, V McNickle, C Davis, J TI Technical team approaches to rodent care: Cost savings, reduced risk, and improved stewardship SO LAB ANIMAL LA English DT Article AB With the increasing decentralization of animal care operations, lack of training and higher density animal rooms make achieving humane assurances difficult. To offset these problems, some facilities have developed centralized animal care programs, including dispersed teams of qualified animal care specialists. C1 Adv Vet Applicat, Bethesda, MD 20817 USA. NIH, Anim Care Sect, Div Intramural Res, Bethesda, MD 20892 USA. RP Hampshire, V (reprint author), Adv Vet Applicat, 7307 Nevis Rd, Bethesda, MD 20817 USA. NR 5 TC 2 Z9 2 U1 0 U2 0 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0093-7355 J9 LAB ANIMAL JI Lab Anim. PD SEP PY 2000 VL 29 IS 8 BP 35 EP 40 PG 6 WC Veterinary Sciences SC Veterinary Sciences GA 350UF UT WOS:000089119000009 ER PT J AU Virta, A Patronas, N Raman, R Dwyer, A Barnett, A Bonavita, S Tedeschi, G Lundbom, N AF Virta, A Patronas, N Raman, R Dwyer, A Barnett, A Bonavita, S Tedeschi, G Lundbom, N TI Spectroscopic imaging of radiation-induced effects in the white matter of glioma patients SO MAGNETIC RESONANCE IMAGING LA English DT Article DE spectroscopic imaging; radiation; white matter; glioma ID MAGNETIC-RESONANCE SPECTROSCOPY; CENTRAL-NERVOUS-SYSTEM; PROTON SPECTROSCOPY; BRAIN-TUMORS; IN-VIVO; H-1 MRS; DISEASE; IRRADIATION; CHILDREN; LESIONS AB External radiation therapy of brain tumors may cause adverse effects on normal brain tissue, resulting in severe neuropsychological and cognitive impairment. We investigated the late delayed radiation effects in the white matter (WM) using H-1 magnetic resonance spectroscopic imaging ((HMRSI)-H-1). Nine glioma patients with local radiation-induced signal abnormalities in the T-2-weighted MR images were studied with nine age- and sex-matched controls. The metabolite ratios in the radiation-induced hyper intensity area (RIHA) and in the normal appealing white matter (NAWM) of the patients were compared with respective WM areas of the controls. In RIHA, choline/creatine (Cho/Cr) was 17% decreased (1.22 +/- 0.13 vs 1.47 +/- 0.16, p = 0.0027, significant (s), unpaired Student's t test with Bonferroni correction) in the patients compared to the controls, while there was no difference in N-acetyl aspartate/Cr (NAA/Cr) (2.49 +/- 0.57 vs 2.98 +/- 0.32, p = 0.039) or NAA/Cho (2.03 +/- 0.40 vs 2.04 +/- 0.17, p = 0.95), In NAWM, Cho/Cr was 24% decreased (1.21 +/- 0.15 vs 1.59 +/- 0.13, p < 0.0001, s) and NAA/Cho was 20% increased (2.49 +/- 0.49 vs 1.98 +/- 0.15, p = 0.0082, s) in the patients compared to the controls, while there was no difference in NAA/Cr (2.99 +/- 0.46 vs 3.16 +/- 0.32, p = 0.38). NAA(RIHA)/TAA(NAWM) was 25% decreased (0.75 +/- 0.20 vs 1.00 +/- 0.12, p = 0.0043, s) and Cr-RIHA/Cho(NAWM) was 16% decreased (0.89 +/- 0.15 vs 1.06 +/- 0.10, p = 0.013, s) in the patients compared to the controls, while there was no difference in Cho(RIHA)/Cho(NAWM) (0.92 +/- 0.23 vs 0.98 +/- 0.10, p = 0.47). (HMRSI)-H-1 reveals widespread chemical changes in the WM after radiation therapy. In RIHA, there is loss of NAA, Cho, and Cr implying axonal and membrane damage and in NAWM, there is loss of Cho, reflecting membrane damage. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NINDS, Neuroimaging Branch, Ctr Clin, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Virta, A (reprint author), NINDS, Neuroimaging Branch, Ctr Clin, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 32 TC 20 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0730-725X J9 MAGN RESON IMAGING JI Magn. Reson. Imaging PD SEP PY 2000 VL 18 IS 7 BP 851 EP 857 DI 10.1016/S0730-725X(00)00164-8 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 360XK UT WOS:000089692500011 PM 11027879 ER PT J AU Petersen, EF Fishbein, KW McFarland, EW Spencer, RGS AF Petersen, EF Fishbein, KW McFarland, EW Spencer, RGS TI P-31 NMR spectroscopy of developing cartilage produced from chick chondrocytes in a hollow-fiber bioreactor SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE tissue engineering; cartilage; P-31-NMR; bioreactor; development ID MAGNETIC-RESONANCE; ARTICULAR-CARTILAGE; GROWTH PLATE; CALCIFICATION; METABOLISM; SYSTEM; STATE AB P-31 NMR was used to measure the concentrations and spin-lattice relaxation times of phosphorus-containing metabolites in neocartilage developing in an NMR-compatible hollow-fiber bioreactor over four weeks. Separate studies were performed for tissue developing from chondrocytes taken from the proximal and the distal sternum of the chick embryo. The metabolite ratio beta-ATP/Pi did not change significantly with development (proximal: beta-ATP/Pi = 0.38 +/- 0.12 at one week, beta-ATP/Pi = 0.44 +/- 0.07 at four weeks, P < 0.63; distal: beta-ATP/Pi = 0.39 +/- 0.05 at one week, beta-ATP/Pi = 0.66 +/- 0.26 at four weeks, P < 0.28). ATP spin-lattice relaxation times were found to be comparable to those in muscle and brain tissue (proximal: T-1(beta-ATP) = 0.5 +/- 0.06 sec at one week, T-1(beta-ATP) = 0.4 +/- 0.01 sec at four weeks; distal: T-1(beta-ATP) = 0.3 +/- 0.12 sec at one week, T-1(beta-ATP) = 0.4 +/- 0.04 sec at four weeks). A large increase in the spin-lattice relaxation time of inorganic phosphate, from 1.2 +/- 0.13 sec to 3.8 +/- 0.04 sec (P < 0.0001) over four weeks of growth, was observed in tissue developing from chondrocytes harvested from the proximal sternum. No comparable increase in T-1(PI) was found in tissue developing from chondrocytes harvested from the distal portion of the sternum, which ossifies later in vivo. Published 2000 Wiley-Liss, Inc. C1 NIA, NMR Unit, NIH, Intramural Res Program, Baltimore, MD 21224 USA. Univ Calif Santa Barbara, Dept Chem Engn, Santa Barbara, CA 93106 USA. RP Spencer, RGS (reprint author), NIA, NMR Unit, NIH, Intramural Res Program, GRC 4D-08,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI McFarland, Eric/G-1763-2014; OI Fishbein, Kenneth/0000-0002-6353-4603 NR 27 TC 11 Z9 11 U1 0 U2 6 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD SEP PY 2000 VL 44 IS 3 BP 367 EP 372 DI 10.1002/1522-2594(200009)44:3<367::AID-MRM4>3.0.CO;2-H PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 350GT UT WOS:000089093200004 PM 10975886 ER PT J AU St Lawrence, KS Frank, JA McLaughlin, AC AF St Lawrence, KS Frank, JA McLaughlin, AC TI Effect of restricted water exchange on cerebral blood flow values calculated with arterial spin tagging: A theoretical investigation SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE arterial spin tagging; cerebral blood flow; tracer kinetic models; water exchange; MRI ID TRANSIT-TIME; PERFUSION; BRAIN; MODEL; VALIDATION; INVERSION; VOLUME; MICROVESSELS; RELAXATION; VELOCITY AB Arterial spin tagging techniques originally used the one-compartment Kety model to describe the dynamics of tagged water in the brain. The work presented here develops a more realistic model that includes the contribution of tagged water in the capillary bed and accounts for the finite time required for water to diffuse across the blood-brain barrier. The new model was used to evaluate potential errors in cerebral blood flow values calculated using the one-compartment Kety model. The results predict that if the one-compartment Kety model is used to analyze arterial spin tagging data the observed grey matter cerebral blood flow values should be relatively insensitive to restricted diffusion of water across the capillary bed. For instance, the observed grey matter cerebral blood flow should closely approximate the true cerebral blood flow and not the product of the extraction fraction and the cerebral blood flow. This prediction is in agreement with recent experimental arterial spin tagging results. Published 2000 Wiley-Liss, Inc.dagger. C1 NIH, CC, Lab Diagost Radiol Res, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP St Lawrence, KS (reprint author), NIH, CC, Lab Diagost Radiol Res, Bldg 10,Room B1N 256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. RI St. Lawrence, Keith/B-5726-2015 NR 40 TC 53 Z9 54 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD SEP PY 2000 VL 44 IS 3 BP 440 EP 449 DI 10.1002/1522-2594(200009)44:3<440::AID-MRM15>3.0.CO;2-6 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 350GT UT WOS:000089093200015 PM 10975897 ER PT J AU Ye, FQ Berman, KF Ellmore, T Esposito, G van Horn, JD Yang, YH Duyn, J Smith, AM Frank, JA Weinberger, DR McLaughlin, AC AF Ye, FQ Berman, KF Ellmore, T Esposito, G van Horn, JD Yang, YH Duyn, J Smith, AM Frank, JA Weinberger, DR McLaughlin, AC TI (H2O)-O-15 PET validation of steady-state arterial spin tagging cerebral blood flow measurements in humans SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE PET; arterial spin tagging; CBF; (H2O)-O-15; MRI ID POSITRON EMISSION TOMOGRAPHY; INTRAVENOUS (H2O)-O-15; MOTOR ACTIVATION; BRAIN PERFUSION; ERROR ANALYSIS; TRANSIT-TIME; WATER; QUANTITATION; INVERSION; INCREASES AB Steady-state arterial spin tagging approaches can provide quantitative images of CBF, but have not been validated in humans. The work presented here compared CBF values measured using steady-state arterial spin tagging with CBF values measured in the same group of human subjects using the (H2O)-O-15 IV bolus PET method. Blood flow values determined by (H2O)-O-15 PET were corrected for the known effects of incomplete extraction of water across the blood brain barrier. For a cortical strip ROI, blood flow values determined using arterial spin tagging (64 +/- 12 cc/100g/min) were not statistically different from corrected blood flow values determined using (H2O)-O-15 PET (67 +/- 13 cc/100g/min). However, for a central white matter ROI, blood flow values determined using arterial spin tagging were significantly underestimated compared to corrected blood flow values determined using (H2O)-O-15 PET, This underestimation could be caused by an underestimation of the arterial transit time for white matter regions. Published 2000 Wiley-Liss, Inc.(+). C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP McLaughlin, AC (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room B1D-69,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Duyn, Jozef/F-2483-2010; OI Ellmore, Timothy/0000-0001-6125-0044 NR 34 TC 196 Z9 201 U1 0 U2 2 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD SEP PY 2000 VL 44 IS 3 BP 450 EP 456 DI 10.1002/1522-2594(200009)44:3<450::AID-MRM16>3.0.CO;2-0 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 350GT UT WOS:000089093200016 PM 10975898 ER PT J AU Marquet, S Lepage, P Hudson, TJ Musser, JM Schurr, E AF Marquet, S Lepage, P Hudson, TJ Musser, JM Schurr, E TI Complete nucleotide sequence and genomic structure of the human NRAMP1 gene region on Chromosome region 2q35 SO MAMMALIAN GENOME LA English DT Article ID MACROPHAGE PROTEIN GENE; NATURAL-RESISTANCE; INTRACELLULAR PARASITES; SUSCEPTIBILITY; IDENTIFICATION; INFECTION; CLONING; ORGANIZATION; CONSTRUCTION; POLYMORPHISM AB Several lines of independent evidence suggest that human Natural Resistance Associated Macrophage Protein I gene (NRAMP1) is an important regulator of susceptibility to infectious diseases caused by certain intracellular pathogens. Here, we report the nucleotide sequence of 32198 bp of genomic DNA overlapping NRAMP1 on chromosomal region 2q35. The NRAMP1 gene spans 13604 bp. The gene and its 5' genomic region are highly enriched for DNA repeat sequences. A second gene was identified in the immediate vicinity of NRAMP1 and was tentatively named Nuclear LIM Interactor-Interacting Factor (NLI-IF) by analogy to its closest ortholog. The human NLI-IF gene begins 4721 bp downstream of the NRAMP1 stop codon and is composed of seven exons varying in size from 57 bp to 1644 bp. The gene gives rise to a 2655-bp, mRNA transcript that contains a 783-bp open leading frame. The predicted molecular weight of the 261-amino acid NLI-IF protein is 29.2 kDa. Several putative gene regulatory elements were identified in the 5' upstream region of NLI-IF, including consensus binding sequences fur Sp]. AP-2, NF-kappa B, and PU 1. The NLI-IF amino acid sequence has homology to proteins that have a high degree of homology with the NLI-interacting factor from Gallus gallus and are found in divergent species ranging from yeast to plants. NLI-IF is part of a human gene family encoding foul related proteins of unknown function. Northern blot analysis of 15 different human tissues revealed a 2.6-kb NLI-IF mRNA that was ubiquitously expressed, but at varying levels. A second transcript with estimated size of 7 kb was expressed only in the placenta. Our data provide new sequence information about the NRAMP1 gene region that will be useful in the search for genetic variants causally involved in altered susceptibility to infectious diseases. C1 McGill Univ, Ctr Hlth, McGill Ctr Study Host Resistance, Montreal, PQ, Canada. McGill Univ, Dept Human Genet, Montreal, PQ, Canada. McGill Univ, Montreal Genome Ctr, Ctr Hlth, Montreal, PQ, Canada. NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Schurr, E (reprint author), Montreal Gen Hosp, Res Inst, Rm L11-521,1650 Cedar Ave, Montreal, PQ H3G 1A4, Canada. RI MARQUET, Sandrine/B-2843-2008; MARQUET, Sandrine/I-6566-2016 FU NIAID NIH HHS [1RO1AI41168-01] NR 27 TC 21 Z9 27 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD SEP PY 2000 VL 11 IS 9 BP 755 EP 762 DI 10.1007/s003350010151 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 348UA UT WOS:000089003800008 PM 10967134 ER PT J AU Clancy, CM Lipscomb, J AF Clancy, CM Lipscomb, J TI From the sponsors SO MEDICAL CARE LA English DT Editorial Material C1 Agcy Healthcare Res & Qual, Ctr Outcomes & Effectiveness Res, Rockville, MD 20852 USA. NCI, Outcomes Res Sect, Bethesda, MD 20892 USA. RP Clancy, CM (reprint author), Agcy Healthcare Res & Qual, Ctr Outcomes & Effectiveness Res, Rockville, MD 20852 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 0025-7079 J9 MED CARE JI Med. Care PD SEP PY 2000 VL 38 IS 9 SU S BP 2 EP 2 PG 1 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 349FM UT WOS:000089033000001 ER PT J AU Ingram, DK AF Ingram, DK TI Age-related decline in physical activity: generalization to nonhumans SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Article DE locomotion; exploration; motivation; dopamine; striatum; nucleus accumbens ID MOTOR-PERFORMANCE; DOPAMINERGIC FUNCTION; BEHAVIORAL-ASSESSMENT; LOCOMOTOR-ACTIVITY; FISCHER-344 RATS; WISTAR RATS; AGING RATS; OPEN-FIELD; EXERCISE; EXPLORATION AB The question of whether the age-related decline in physical activity reported in humans has a biological basis is addressed by reviewing gerontological studies that have used nonhuman subjects. From at least three separate arguments, this review provides strong support for a biological basis of this phenomenon. First, age-related decline in activity measured in many different ways is observed across a wide range of nonhuman species. Second, the activity decline appears predictive of lifespan. Increased levels of activity predict longevity, and increasing activity through exercise increases median lifespan. Third, activity declines appear related to altered neurotransmission involving the central dopamine system. Reduced dopamine release or loss of dopamine receptors appears to underlie age-related activity decline, and interventions that enhance dopamine function can increase activity levers in aged animals. C1 NIA, Gerontol Res Ctr, Neurosci Lab, Behav Neurosci Sect,NIH, Baltimore, MD 21224 USA. RP Ingram, DK (reprint author), NIA, Gerontol Res Ctr, Neurosci Lab, Behav Neurosci Sect,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. NR 51 TC 120 Z9 125 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD SEP PY 2000 VL 32 IS 9 BP 1623 EP 1629 PG 7 WC Sport Sciences SC Sport Sciences GA 352TR UT WOS:000089234400016 PM 10994915 ER PT J AU Moon, YW Weil, RJ Pack, SD Park, WS Pak, E Pham, T Karkera, JD Kim, HK Vortmeyer, AO Fuller, BG Zhuang, ZP AF Moon, YW Weil, RJ Pack, SD Park, WS Pak, E Pham, T Karkera, JD Kim, HK Vortmeyer, AO Fuller, BG Zhuang, ZP TI Missense mutation of the MET gene detected in human glioma SO MODERN PATHOLOGY LA English DT Article DE fluorescence in situ hybridization; glioma; MET gene; single strand conformation polymorphism analysis ID PAPILLARY RENAL CARCINOMAS; SCATTER FACTOR EXPRESSION; TUMOR-SUPPRESSOR GENE; GROWTH-FACTOR; NONRANDOM DUPLICATION; MALIGNANT GLIOMAS; RECEPTOR; HETEROZYGOSITY; AMPLIFICATION; PROTOONCOGENE AB Multiple mechanisms, such as gene mutations, amplifications, and rearrangements, as well as perturbed mitogen and receptor function, are likely to contribute to glioma formation. The MET (also known as c-met) proto-oncogene located at 7q31-34 has been shown to be amplified in human gliomas, and activating mutations within the tyrosine kinase domain of MET have been causally related to tumorigenesis in hereditary papillary renal cell carcinoma To elucidate the role of MET gene in glioma formation, sporadic gliomas from 11 patients were examined for MET gene mutations and allelic duplications or deletions by polyermase chain reaction-single strand conformational polymorphism analysis and fluorescence in situ hybridization, Three of 11 sporadic gliomas showed a deletion of one copy of the MET gene, and a specific MET gene missense mutation in the remaining gene copy was detected in one of those tumors. The corresponding sequence in non-tumor DNA was normal in all cases. Three of 11 sporadic gliomas showed duplication of one copy of the MET gene, but none of them contained mutations. One tumor showed MET amplification without mutation. Three showed neither allelic change nor mutation. These data suggest that somatic MET gene mutation may play a role in the development of a subgroup of sporadic gliomas, However, MET mutations appear to be absent in the majority of sporadic gliomas. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Catholic Univ Korea, St Vincents Hosp, Dept Internal Med, Seoul, South Korea. RP Zhuang, ZP (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37 9000,Rockville Pike, Bethesda, MD 20892 USA. RI Pack, Svetlana/C-2020-2014 NR 33 TC 14 Z9 14 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD SEP PY 2000 VL 13 IS 9 BP 973 EP 977 DI 10.1038/modpathol.3880177 PG 5 WC Pathology SC Pathology GA 356UL UT WOS:000089461200007 PM 11007037 ER PT J AU Kumar, S Perlman, E Harris, CA Raffeld, M Tsokos, M AF Kumar, S Perlman, E Harris, CA Raffeld, M Tsokos, M TI Myogenin is a specific marker for rhabdomyosarcoma: An immunohistochemical study in paraffin-embedded tissues SO MODERN PATHOLOGY LA English DT Article DE myogenin; rhabdomyosarcoma; parraffin-embedded tissue; immunohistochemistry ID SKELETAL-MUSCLE DIFFERENTIATION; REGULATORY PROTEIN EXPRESSION; DIAGNOSTIC UTILITY; CHILDHOOD; MYOD1; SARCOMAS; ANTIBODIES; TUMORS; GENE; DESMIN AB Myogenin belongs to a group of myogenic regulatory proteins whose expression determines commitment and differentiation of primitive mesenchymal cells into skeletal muscle. The expression of myogenin has been demonstrated to be extremely specific for rhabdomyoblastic differentiation, which makes it a useful marker in the differential diagnosis of rhabdomyosarcomas (RMS) from other malignant small round cell tumors of childhood. Commercially available antibodies capable of detecting myogenin in routinely processed formalin-fixed paraffin-embedded (FFPE) tissue are now available. In this study, we evaluated myogenin expression using the monoclonal myf-4 antibody (Novocastra Labs) on FFPE in a large number of pediatric tumors in order to define the clinical utility of this marker. A total of 119 tumors were studied. These included 48 alveolar RMS (ARMS), 20 embryonal RMS (ERMS), one spindle cell RMS, 16 Ewing's sarcomas (ES), six nephroblastomas, two ectomesenchymomas, seven precursor hematopoietic neoplasms, five olfactory neuroblastomas, three neuroblastomas, six desmoplastic small round cell tumors, and five rhabdoid tumors. Distinct nuclear staining for myogenin was noted in all 69 RMS. Notably, the number of positive tumor cells differed between the ARMS and ERMS. In ARMS, the majority of tumor cells (75 to 100%) were positive, in contrast to ERMS, in which the positivity ranged from rare + to 25% in all but three tumors. Additionally, myogenin positivity was seen in two of two ectomesenchymomas and in two nephroblastomas with myogenous differentiation. All other tumors were clearly negative. Our results indicate that staining for myogenin is an extremely reliable and specific marker for rhabdomyoblastic differentiation. It gives consistent and easily interpretable results in routinely fixed tissues. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Hosp, Baltimore, MD 21287 USA. RP Kumar, S (reprint author), Childrens Natl Med Ctr, 111 Michigan Ave NW, Washington, DC 20010 USA. NR 21 TC 114 Z9 119 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD SEP PY 2000 VL 13 IS 9 BP 988 EP 993 DI 10.1038/modpathol.3880179 PG 6 WC Pathology SC Pathology GA 356UL UT WOS:000089461200009 PM 11007039 ER PT J AU Fidock, DA Nomura, T Cooper, RA Su, XZ Talley, AK Wellems, TE AF Fidock, DA Nomura, T Cooper, RA Su, XZ Talley, AK Wellems, TE TI Allelic modifications of the cg2 and cg1 genes do not alter the chloroquine response of drug-resistant Plasmodium falciparum SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE drug resistance; linkage; malaria; transfection ID HUMAN DIHYDROFOLATE-REDUCTASE; MALARIA PARASITES; TRANSFECTION; REVERSAL; AFRICA; TRANSFORMATION; RECOMBINATION; POLYMORPHISMS; PROGUANIL; PROTEIN AB The determinant of chloroquine resistance (CQR) in a Plasmodium falciparum cross was previously mapped by linkage analysis to a 36 kb segment of chromosome 7. Candidate genes within this segment have been previously shown to include two genes, cg2 and cg1, that have complex polymorphisms linked to the CQR phenotype. Using DNA transfection and allelic exchange, we have replaced these polymorphisms in CQR parasites with cg2 and cg1 sequences From chloroquine sensitive parasites. Drug assays of the allelically-modified lines show no change in the degree of CQR, providing evidence against the hypothesis that these polymorphisms are important to the CQR phenotype. Similarly, no change was found in the degree to which verapamil or other chloroquine sensitizers reverse CQR in the transformants. These results and the high though not complete degree of association of CQR with cg2 and cg1 polymorphisms in field isolates suggest involvement of another nearby gene in the P. falciparum CQR mechanism. (C) 2000 Published by Elsevier Science B.V. C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Wellems, TE (reprint author), NIAID, NIH, 4 Ctr Dr MSC 0425, Bethesda, MD 20892 USA. OI Fidock, David/0000-0001-6753-8938; Su, Xinzhuan/0000-0003-3246-3248 FU NIAID NIH HHS [R01 AI050234] NR 31 TC 65 Z9 66 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD SEP PY 2000 VL 110 IS 1 BP 1 EP 10 DI 10.1016/S0166-6851(00)00249-8 PG 10 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 357HW UT WOS:000089493300001 PM 10989140 ER PT J AU Kaneko, O Fidock, DA Schwartz, OM Miller, LH AF Kaneko, O Fidock, DA Schwartz, OM Miller, LH TI Disruption of the C-terminal region of EBA-175 in the Dd2/Nm clone of Plasmodium falciparum does not affect erythrocyte invasion SO MOLECULAR AND BIOCHEMICAL PARASITOLOGY LA English DT Article DE EBA-175; erythrocyte; invasion; malaria; merozoite; transformation ID MALARIA PARASITES; BINDING-PROTEINS; DUFFY RECEPTOR; GLYCOPHORIN-B; KNOWLESI; MEROZOITES; ANTIGEN; DOMAINS; VIVAX; IDENTIFICATION AB EBA-175 is a Plasmodium falciparum micronemal protein that binds to sialic acid in the context of the peptide backbone of glycophorin A and has been implicated in sialic acid-dependent invasion of erythrocytes. The existence of an alternative invasion pathway has been suggested by the finding that the P. falciparum clone Dd2/Nm can invade sialic acid-depleted erythrocytes. To study the role of EBA-175 in this alternative pathway, we have generated Dd2/Nm clones expressing a truncated form of EBA-175 that lacks region 6 and the cytoplasmic domain. The protein still appears to be localized to the apical end in the vicinity of the micronemes, suggesting that region 6 and the cytoplasmic domain are not involved in EBA-175 trafficking to the micronemes. In these genetically modified clones, the level of truncated EBA-175 protein expression was greatly reduced. EBA-175-disrupted clones displayed normal rates of invasion of untreated and enzyme-treated human and animal erythrocytes, suggesting a lack of involvement of EBA-175 in this alternative invasion pathway. (C) 2000 Published by Elsevier Science B.V. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Confocal Opt Imaging Facil, NIH, Bethesda, MD 20892 USA. Ehime Univ, Sch Med, Dept Mol Parasitol, Shigenobu, Ehime 7910295, Japan. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. RP Miller, LH (reprint author), NIAID, Parasit Dis Lab, NIH, Room 126,4 Ctr Dr, Bethesda, MD 20892 USA. OI Fidock, David/0000-0001-6753-8938 NR 22 TC 43 Z9 44 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-6851 J9 MOL BIOCHEM PARASIT JI Mol. Biochem. Parasitol. PD SEP PY 2000 VL 110 IS 1 BP 135 EP 146 DI 10.1016/S0166-6851(00)00263-2 PG 12 WC Biochemistry & Molecular Biology; Parasitology SC Biochemistry & Molecular Biology; Parasitology GA 357HW UT WOS:000089493300012 PM 10989151 ER PT J AU Cho-Chung, YS Park, YG Nesterova, M Lee, YN Cho, YS AF Cho-Chung, YS Park, YG Nesterova, M Lee, YN Cho, YS TI CRE-decoy oligonucleotide-inhibition of gene expression and tumor growth SO MOLECULAR AND CELLULAR BIOCHEMISTRY LA English DT Article DE cAMP; transcription factor-decoy oligonucleotides; CRE; Ap-1; p53; tumor growth; gene expression ID AMP RESPONSE ELEMENT; TRANSCRIPTION FACTOR DECOY; BREAST-CANCER CELLS; VIRUS TYPE-I; CYCLIC-AMP; SOMATOSTATIN GENE; NUCLEAR-PROTEIN; DIFFERENTIAL ACTIVATION; HAIRPIN FORMATION; BINDING-PROTEINS AB Nucleic acid molecules with high affinities for a target transcription factor can be introduced into cells as decoy cis-elements to bind these factors and alter gene expression. This review discusses a synthetic single-stranded palindromic oligonucleotide, which self-hybridizes to form a duplex/hairpin and competes with cAMP response element (CRE) enhancers for binding transcription factors. This oligonucleotide inhibits CRE- and Ap-1-directed gene transcription and promotes growth inhibition in vitro and in vivo in a broad spectrum of cancer cells, without adversely affecting normal cell growth. Evidence presented here suggests that the CRE-decoy oligonucleotide can provide a powerful new means of combating cancers, viral diseases, and other pathological conditions by regulating the expression of cAMP-responsive genes. C1 NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cho-Chung, YS (reprint author), NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bldg 10,Room 5B05, Bethesda, MD 20892 USA. NR 54 TC 31 Z9 32 U1 0 U2 1 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA SPUIBOULEVARD 50, PO BOX 17, 3300 AA DORDRECHT, NETHERLANDS SN 0300-8177 J9 MOL CELL BIOCHEM JI Mol. Cell. Biochem. PD SEP PY 2000 VL 212 IS 1-2 BP 29 EP 34 DI 10.1023/A:1007144618589 PG 6 WC Cell Biology SC Cell Biology GA 372ZV UT WOS:000165264700005 PM 11108133 ER PT J AU Shintani, S Ohyama, H Zhang, X McBride, J Matsuo, K Tsuji, T Hu, MG Hu, GF Kohno, Y Lerman, M Todd, R Wong, DTW AF Shintani, S Ohyama, H Zhang, X McBride, J Matsuo, K Tsuji, T Hu, MG Hu, GF Kohno, Y Lerman, M Todd, R Wong, DTW TI p12(DOC-1) is a novel cyclin-dependent kinase 2-associated protein SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TUMOR-SUPPRESSOR GENE; CELL-CYCLE; MUTATION ANALYSIS; DOC-1; INHIBITOR; HAMSTER; CANCER; P21 AB Regulated cyclin-dependent kinase (CDK) levels and activities are critical for the proper progression of the cell division cycle, p12(DOC-1) is a growth suppressor isolated from normal keratinocytes. We report that p(12DOC-1) associates with CDK2. More specifically, p12(DOC-1) associates with the monomeric nonphosphorylated form of CDK2 (p33CDK2). Ectopic expression of p12(DOC-1) resulted in decreased cellular CDK2 and reduced CDK2-associated kinase activities and was accompanied by a shift in the cell cycle positions of p12(DOC-1) transfectants ( up arrow G(I) and down arrow S), The p12(DOC-1)-mediated decrease of CDK2 was prevented if the p12(DOC-1\) transfectants were grown in the presence of the proteosome inhibitor clasto-lactacystin beta-lactone, suggesting that p12(DOC-1) may target CDK2 for proteolysis. A CDK2 binding mutant was created and was found to revert p12(DOC-1)-mediated, CDK2-associated cell cycle phenotypes. These data support p12(DOC-1) as a specific CDK2-associated protein that negatively regulates CDK2 activities by sequestering the monomeric pool of CDK2, and/or targets CDK2 for proteolysis, reducing the active pool of CDK2. C1 Harvard Univ, Sch Dent Med, Lab Mol Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Dent Med, Lab Oral & Maxillofacial Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Ctr Biochem & Biophys Sci & Med, Boston, MA 02115 USA. China Med Univ, Dept Cell Biol, Shenyang, Peoples R China. NCI, Frederick Canc Res & Dev Ctr, SAIC Fredrick, Intramural Res Support Program, Ft Detrick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, DBS, Immunobiol Lab, Ft Detrick, MD 21702 USA. RP Wong, DTW (reprint author), Harvard Univ, Sch Dent Med, Lab Mol Pathol, 188 Longwood Ave, Boston, MA 02115 USA. FU NIDCR NIH HHS [R01 DE08680, P01 DE012467, P01 DE12467, R29 DE 11983] NR 15 TC 57 Z9 65 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2000 VL 20 IS 17 BP 6300 EP 6307 DI 10.1128/MCB.20.17.6300-6307.2000 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 343RZ UT WOS:000088716500012 PM 10938106 ER PT J AU Esteban, LM Fernandez-Medarde, A Lopez, E Yienger, K Guerrero, C Ward, JM Tessarollo, L Santos, E AF Esteban, LM Fernandez-Medarde, A Lopez, E Yienger, K Guerrero, C Ward, JM Tessarollo, L Santos, E TI Ras-guanine nucleotide exchange factor Sos2 is dispensable for mouse growth and development SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; SEVENLESS GENE; CDC25 GENE; ACTIVATORS; PROTEINS; MUTATION; CLONING; BINDING; IDENTIFICATION; RAS-GRF2 AB The mammalian sos1 and sos2 genes encode highly homologous members of the Son of-sevenless family of guanine nucleotide exchange factors. They are ubiquitously expressed and play key roles in transmission of signals initiated by surface protein tyrosine kinases that are transduced into the cell through the action of membrane-associated Ras proteins. Recent reports showed that targeted disruption of the sos1 locus results in embryonic lethality. To gain insight into the in vivo function of sos2, we disrupted its catalytic CDC25-H domain by means of gene targeting techniques. Mating among heterozygous sos2(+/-) mice produced viable sos2(-/-) offspring with a normal Mendelian pattern of inheritance, indicating that the loss of sos2 does not interfere with embryo viability in the uterus. Adult homozygous mutant sos2(-/-) mice reached sexual maturity at the same age as their wild-type littermates, and bath male and female null mutants were fertile. Histopathological analysis showed no observable differences between mutant and wild-type mice. Our results show that unlike the case for sos1, sos2 gene function is dispensable for normal mouse development, growth, and fertility. C1 Univ Salamanca, USAL CSIC, IBMCC, Ctr Invest Canc, Salamanca 37007, Spain. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Ft Detrick, MD 21702 USA. NCI, Mammalian Genet Lab, Ft Detrick, MD 21702 USA. RP Santos, E (reprint author), Univ Salamanca, USAL CSIC, IBMCC, Ctr Invest Canc, Campus Unamuno, Salamanca 37007, Spain. RI Guerrero, Carmen/F-1776-2010 OI Guerrero, Carmen/0000-0002-8747-6831 NR 25 TC 28 Z9 29 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2000 VL 20 IS 17 BP 6410 EP 6413 DI 10.1128/MCB.20.17.6410-6413.2000 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 343RZ UT WOS:000088716500024 PM 10938118 ER PT J AU Fletcher, TM Ryu, BW Baumann, CT Warren, BS Fragoso, G John, S Hager, GL AF Fletcher, TM Ryu, BW Baumann, CT Warren, BS Fragoso, G John, S Hager, GL TI Structure and dynamic properties of a glucocorticoid receptor-induced chromatin transition SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MAMMARY-TUMOR VIRUS; LONG TERMINAL REPEAT; DNA-BINDING DOMAIN; MMTV PROMOTER; IN-VIVO; TRANSCRIPTION FACTORS; NEGATIVE REGULATION; REMODELING FACTOR; NUCLEAR FACTOR-1; MOUSE AB Activation of the mouse mammary tumor virus (MMTV) promoter by the glucocorticoid receptor (GR) is associated with a chromatin structural transition in the B nucleosome region of the viral long terminal repeat (LTR), Recent evidence indicates that this transition extends upstream of the B nucleosome, encompassing a region larger than a single nucleosome (G. Fragoso, W, D, Pennie, S, John, and G, L, Eager, Mol. Cell. Biol, 18:3633-3644). We have reconstituted MMTV LTR DNA into a polynucleosome array using Drosophila embryo extracts. We show binding of purified GR to specific GR elements within a large, multinucleosome array and describe a GR-induced nucleoprotein transition that is dependent on ATP and a HeLa nuclear extract. Previously uncharacterized GR binding sites in the upstream C nucleosome region are involved in the extended region of chromatin remodeling. We also show that GR-dependent chromatin remodeling is a multistep process; in the absence of ATP, GR binds to multiple sites on the chromatin array end prevents restriction enzyme access to recognition sites. Upon addition of ATP, GR induces remodeling and a large increase in access to enzymes sites within the transition region. These findings suggest a dynamic model in which CR first binds to chromatin after ligand activation, recruits a remodeling activity, and is then lost from the template. This model is consistent with the recent description of a "hit-and-run" mechanism for GR action in living cells (J, G, McNally, W, G. Muller, D, Walker, and G, L, Hager, Science 287:1262-1264, 2000). C1 NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,B602,41 Lib Dr, Bethesda, MD 20892 USA. NR 52 TC 73 Z9 76 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2000 VL 20 IS 17 BP 6466 EP 6475 DI 10.1128/MCB.20.17.6466-6475.2000 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 343RZ UT WOS:000088716500029 PM 10938123 ER PT J AU Chi, HB Yang, XN Kingsley, PD O'Keefe, RJ Puzas, JE Rosier, RN Shears, SB Reynolds, PR AF Chi, HB Yang, XN Kingsley, PD O'Keefe, RJ Puzas, JE Rosier, RN Shears, SB Reynolds, PR TI Targeted deletion of Minpp1 provides new insight into the activity of multiple inositol polyphosphate phosphatase in vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ENDOPLASMIC-RETICULUM; 1,3,4,5-TETRAKISPHOSPHATE 3-PHOSPHATASE; RAT-LIVER; PROTEIN; CELLS; HEXAKISPHOSPHATE; BIP; 1,3,4,5,6-PENTAKISPHOSPHATE; ACTIVATION; MATURATION AB Multiple inositol polyphosphate phosphatase (Minpp1) metabolizes inositol 1,3,4,5,6-pentakisphosphate (InsP(5)) and inositol hexakisphosphate (InsP(6)) with high affinity in vitro. However, Minpp1 is compartmentalized in the endoplasmic reticulum (ER) lumen, where access of enzyme to these predominantly cytosolic substrates in vivo has not previously been demonstrated. To gain insight into the physiological activity of Minpp1, Minpp1-deficient mice were generated by homologous recombination. Tissue extracts from Minpp1-deficient mice lacked detectable Minpp1 mRNA expression and Minpp1 enzyme activity. Unexpectedly, Minpp1-deficient mice were viable, fertile, and without obvious defects. Although Minpp1 expression is upregulated during chondrocyte hypertrophy, normal chondrocyte differentiation and bone development were observed in Minpp1-deficient mice. Biochemical analyses demonstrate that InsP(5) and InsP(6) are in vivo substrates for ER-based Minpp1, as levels of these polyphosphates in Minpp1-deficient embryonic fibroblasts were 30 to 45% higher than in wild-type cells. This increase was reversed by reintroducing exogenous Minpp1 into the ER. Thus, ER-based Minpp1 plays a significant role in the maintenance of steady state levels of InsP(5) and InsP(6). These polyphosphates could be reduced below their natural levels by aberrant expression in the cytosol of a truncated Minpp1 lacking its ER-targeting N terminus. This was accompanied by slowed cellular proliferation, indicating that maintenance of cellular InsP(5) and InsP(6) is essential to normal cell growth. Yet, depletion of cellular inositol polyphosphates during erythropoiesis emerges as an additional physiological activity of Minpp1; loss of this enzyme activity in erythrocytes from Minpp1-deficient mice was accompanied by upregulation of a novel, substitutive inositol polyphosphate phosphatase. C1 Univ Rochester, Med Ctr, Ctr Oral Biol, Aab Inst Biomed Sci,Sch Med & Dent,Dept Orthopaed, Rochester, NY 14642 USA. Univ Rochester, Sch Med, Dept Pediat, Rochester, NY 14642 USA. Univ Rochester, Sch Med, Dept Pathol & Lab Med, Rochester, NY 14642 USA. NIEHS, Inositide Signaling Sect, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Reynolds, PR (reprint author), Univ Rochester, Med Ctr, Ctr Oral Biol, Aab Inst Biomed Sci,Sch Med & Dent,Dept Orthopaed, 601 Elmwood Ave,Box 611, Rochester, NY 14642 USA. FU NIAMS NIH HHS [R01 AR038945, AR44091, AR38945] NR 37 TC 36 Z9 38 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2000 VL 20 IS 17 BP 6496 EP 6507 DI 10.1128/MCB.20.17.6496-6507.2000 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 343RZ UT WOS:000088716500032 PM 10938126 ER PT J AU Dey, A Ellenberg, J Farina, A Coleman, AE Maruyama, T Sciortino, S Lippincott-Schwartz, J Ozato, K AF Dey, A Ellenberg, J Farina, A Coleman, AE Maruyama, T Sciortino, S Lippincott-Schwartz, J Ozato, K TI A bromodomain protein, MCAP, associates with mitotic chromosomes and effects, G(2)-to-M transition SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EFFECT HOMEOTIC GENE; HISTONE H3; CELL-CYCLE; RING3 GENE; PERICENTROMERIC HETEROCHROMATIN; DROSOPHILA-FSH; LIVING CELLS; TRANSCRIPTION; CHROMATIN; PHOSPHORYLATION AB We describe a novel nuclear factor called mitotic chromosome-associated protein (MCAP), which belongs to the poorly understood BET subgroup of the bromodomain superfamily. Expression of the 200-kDa MCAP was linked to cell division, as it was induced by growth stimulation and repressed by growth inhibition. The most notable feature of MCAP was its association with chromosomes during mitosis, observed at a time when the majority of nuclear regulatory factors were released into the cytoplasm, coinciding with global cessation of transcription. Indicative of its predominant interaction with euchromatin, MCAP localized on mitotic chromosomes with exquisite specificity: (i) MCAP-chromosome association became evident subsequent to the initiation of histone H3 phosphorylation and early chromosomal condensation; and (ii) MCAP was absent from centromeres, the sites of heterochromatin. Supporting a role for MCAP in G(2)/M transition, microinjection of anti-MCAP antibody into HeLa cell nuclei completely inhibited the entry into mitosis, without abrogating the ongoing DNA replication. These results suggest that MCAP plays a role in a process governing chromosomal dynamics during mitosis. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bldg 6,Rm 2A01, Bethesda, MD 20892 USA. RI Ellenberg, Jan/I-4688-2014 OI Ellenberg, Jan/0000-0001-5909-701X NR 58 TC 160 Z9 162 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2000 VL 20 IS 17 BP 6537 EP 6549 DI 10.1128/MCB.20.17.6537-6549.2000 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 343RZ UT WOS:000088716500035 PM 10938129 ER PT J AU Lin, Y Devin, A Cook, A Keane, MM Kelliher, M Lipkowitz, S Liu, ZG AF Lin, Y Devin, A Cook, A Keane, MM Kelliher, M Lipkowitz, S Liu, ZG TI The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of I kappa B kinase and c-Jun N-terminal kinase SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; FADD-DEPENDENT APOPTOSIS; CYTOTOXIC LIGAND TRAIL; INDUCED CELL-DEATH; TNF RECEPTOR-1; MEDIATED APOPTOSIS; JNK ACTIVATION; APO-2 LIGAND; COMPLEX; FAMILY AB Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) (Apo2 Ligand [Apo2L]) is a member of the TNF superfamily and has been shown to have selective antitumor activity. Although it is known that TRAIL (Apo2L) induces apoptosis and activates NF-kappa B and Jun N-terminal kinase (JNK) through receptors such as TRAIL-R1 (DR4) and TRAIL-R2 (DR5), the components of its signaling cascade have not been well defined. In this report, we demonstrated that the death domain kinase RIP is essential for TRAIL-induced I kappa B kinase (IKK) and JNK activation. We found that ectopic expression of the dominant negative mutant RIP, RIP(559-671), blocks TRAIL-induced IKK and JNK activation. In the RIP null fibroblasts, TRAIL failed to activate IKK and only partially activated JNK. The endogenous RIP protein was detected by immunoprecipitation in the TRAIL-R1 complex after TRAIL treatment. More importantly, we found that RIP is not involved in TRAIL-induced apoptosis. In addition, we also demonstrated that the TNF receptor-associated factor 2 (TRAF2) plays little role in TRAIL-induced IKK activation although it is required for TRAIL-mediated JNK activation. These results indicated that the death domain kinase RIP, a key factor in TNF signaling, also plays a pivotal role in TRAIL-induced IKK and JNK activation. C1 NCI, Med Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NCI, Dept Cell & Canc Biol, NIH, Bethesda, MD 20892 USA. NCI, Dept Genet, NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Med Ctr, Worcester, MA 01605 USA. RP Liu, ZG (reprint author), NCI, Med Branch, Div Clin Sci, NIH, Bldg 10,Rm 6N105,9000 Rockville Pike, Bethesda, MD 20892 USA. FU NIGMS NIH HHS [R01 GM061298] NR 53 TC 172 Z9 176 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2000 VL 20 IS 18 BP 6638 EP 6645 DI 10.1128/MCB.20.18.6638-6645.2000 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 348HH UT WOS:000088979100002 PM 10958661 ER PT J AU Shan, XC Czar, MJ Bunnell, SC Liu, PH Liu, YS Schwartzberg, PL Wange, RL AF Shan, XC Czar, MJ Bunnell, SC Liu, PH Liu, YS Schwartzberg, PL Wange, RL TI Deficiency of PTEN in Jurkat T cells causes constitutive localization of Itk to the plasma membrane and hyperresponsiveness to CD3 stimulation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID PROTEIN-KINASE-B; PLECKSTRIN HOMOLOGY DOMAIN; BRUTON TYROSINE KINASE; PHOSPHATIDYLINOSITOL 3-KINASE ACTIVATION; TUMOR-SUPPRESSOR; PHOSPHOINOSITIDE 3-KINASE; CROSS-LINKING; PHOSPHATASE-ACTIVITY; SIGNAL-TRANSDUCTION; SELECTIVE INHIBITOR AB Pleckstrin homology (PH) domain binding to D3-phosphorylated phosphatidylinositides (PI) provides a reversible means of recruiting proteins to the plasma membrane, with the resultant change in subcellular localization playing a key role in the activation of multiple intracellular signaling pathways. Previously we found that the T-cell-specific PH domain-containing kinase Itk is constitutively membrane associated in Jurkat T cells. This distribution was unexpected given that the closely related B-cell kinase, Btk, is almost exclusively cytosolic. In addition to constitutive membrane association of Itk, unstimulated JTAg T cells also exhibited constitutive phosphorylation of Akt on Ser-473, an indication of elevated basal levels of the phosphatidylinositol 3-kinase (PI3K) products PI-3,4-P-2 and PI-3,4,5-P-3 in the plasma membrane. Here we describe a defect in expression of the D3 phosphoinositide phosphatase, PTEN, in Jurkat and JTAg T cells that leads to unregulated PH domain interactions with the plasma membrane. Inhibition of D3 phosphorylation by PI3K inhibitors, or by expression of PTEN, blocked constitutive phosphorylation of Akt on Ser-473 and caused Itk to redistribute to the cytosol. The PTEN-deficient cells were also hyperresponsive to T-cell receptor (TCR) stimulation, as measured by Itk kinase activity, tyrosine phosphorylation of phospholipase C-gamma 1, and activation of Erk compared to those in PTEN-replete cells. These data support the idea that PH domain-mediated association with the plasma membrane is required for Itk activation, provide evidence for a negative regulatory role of PTEN in TCR stimulation, and suggest that signaling models based on results from Jurkat T-cell lines may underestimate the role of PI3K in TCR signaling. C1 NIA, Gerontol Res Ctr, NIH, Biol Chem Lab, Baltimore, MD 21224 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wange, RL (reprint author), NIA, Gerontol Res Ctr, NIH, Biol Chem Lab, MSC-12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Liu, Yusen/E-3527-2011 NR 78 TC 241 Z9 243 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2000 VL 20 IS 18 BP 6945 EP 6957 DI 10.1128/MCB.20.18.6945-6957.2000 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 348HH UT WOS:000088979100031 PM 10958690 ER PT J AU Zhang, JZ Nei, M AF Zhang, JZ Nei, M TI Positive selection in the evolution of mammalian interleukin-2 genes SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Letter DE interleukin-2; positive selection; artiodactyls; substitution pattern ID NUCLEOTIDE-SEQUENCES; SUBSTITUTIONS; COMPLEX; REGION; TREE C1 Penn State Univ, Inst Mol Evolutionary Genet, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. RP Zhang, JZ (reprint author), NIAID, NIH, Bldg 10,Room 11N104,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 20 TC 17 Z9 18 U1 0 U2 1 PU SOC MOLECULAR BIOLOGY EVOLUTION PI LAWRENCE PA PO BOX 1897, LAWRENCE, KS 66044-8897 USA SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD SEP PY 2000 VL 17 IS 9 BP 1413 EP 1416 PG 4 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 350MA UT WOS:000089104100015 PM 10958857 ER PT J AU Chandrasekaran, L He, CZ Al-Barazi, H Krutzsch, HC Iruela-Arispe, ML Roberts, DD AF Chandrasekaran, L He, CZ Al-Barazi, H Krutzsch, HC Iruela-Arispe, ML Roberts, DD TI Cell contact-dependent activation of alpha 3 beta 1 integrin modulates endothelial cell responses to thrombospondin-1 SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID HEPARIN-BINDING PEPTIDES; FIBROBLAST GROWTH-FACTOR; ALPHA(3)BETA(1) INTEGRIN; PLATELET THROMBOSPONDIN; REPEAT PEPTIDES; PROTEIN-KINASE; TUMOR-GROWTH; I REPEATS; ANGIOGENESIS; ADHESION AB Thrombospondin-1 (TSP1) can inhibit angiogenesis by interacting with endothelial cell CD36 or proteoglycan receptors. We have now identified alpha 3 beta 1 integrin as an additional receptor for TSP1 that modulates angiogenesis and the in vitro behavior of endothelial cells. Recognition of TSP1. and an alpha 3 beta 1 integrin-binding peptide from TSP1 by normal endothelial cells is induced after loss of cell-cell contact or ligation of CD98. Although confluent endothelial cells do not spread on a TSP1 substrate, alpha 3 beta 1 integrin mediates efficient spreading on TSP1 substrates of endothelial cells deprived of cell-cell contact or vascular endothelial cadherin signaling. Activation of this integrin is independent of proliferation, but ligation of the alpha 3 beta 1 integrin modulates endothelial cell proliferation. In solution, both intact TSP1 and the alpha 3 beta 1 integrin-binding peptide from TSP1 inhibit proliferation of sparse endothelial cell cultures independent of their CD36 expression. However, TSP1 or the same peptide immobilized on the substratum promotes their proliferation. The TSP1 peptide, when added in solution, specifically inhibits endothelial cell migration and inhibits angiogenesis in the chick chorioallantoic membrane, whereas a fragment of TSP1 containing this sequence stimulates angiogenesis. Therefore, recognition of immobilized TSP1 by alpha 3 beta 1 integrin may stimulate endothelial cell proliferation and angiogenesis. Peptides that inhibit this interaction are a novel class of angiogenesis inhibitors. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90025 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NCI NIH HHS [CA63356-01] NR 82 TC 99 Z9 105 U1 1 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3992 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP PY 2000 VL 11 IS 9 BP 2885 EP 2900 PG 16 WC Cell Biology SC Cell Biology GA 355LU UT WOS:000089387800005 PM 10982388 ER PT J AU Low, SH Miura, M Roche, PA Valdez, AC Mostov, KE Weimbs, T AF Low, SH Miura, M Roche, PA Valdez, AC Mostov, KE Weimbs, T TI Intracellular redirection of plasma membrane trafficking after loss of epithelial cell polarity SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID CANINE KIDNEY-CELLS; POLYMERIC IMMUNOGLOBULIN RECEPTOR; APICAL COMPARTMENT VAC; MDCK CELLS; SNARE COMPLEXES; CYTOPLASMIC DOMAIN; SURFACE POLARITY; SYNTAXIN FAMILY; PROTEINS; TRANSPORT AB In polarized Madin-Darby canine kidney epithelial cells, components of the plasma membrane fusion machinery, the t-SNAREs syntaxin 2, 3, and 4 and SNAP-23, are differentially localized at the apical and/or basolatoral plasma membrane domains. Here we identify syntaxin 11 as a novel apical and basolateral plasma membrane t-SNARE. Surprisingly, all of these t-SNAREs redistribute to intracellular locations when Madin-Darby canine kidney cells lose their cellular polarity. Apical SNAREs relocalize to the previously characterized vacuolar apical compartment, whereas basolateral SNAREs redistribute to a novel organelle that appears to be the basolateral equivalent of the vacuolar apical compartment. Both intracellular plasma membrane compartments have an associated prominent actin cytoskeleton and receive membrane traffic from cognate apical or basolateral pathways, respectively. These findings demonstrate a fundamental shift in plasma membrane traffic toward intracellular compartments while protein sorting is preserved when epithelial cells lose their cell polarity. C1 Cleveland Clin Fdn, Dept Cell Biol, Lerner Res Inst, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Inst Urol, Cleveland, OH 44195 USA. Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biochem & Biophys, Cardiovasc Res Inst, San Francisco, CA 94143 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Weimbs, T (reprint author), Cleveland Clin Fdn, Dept Cell Biol, Lerner Res Inst, Cleveland, OH 44195 USA. EM weimbst@ccf.org FU NIAID NIH HHS [R01AI25144, R01 AI025144] NR 67 TC 44 Z9 45 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP PY 2000 VL 11 IS 9 BP 3045 EP 3060 PG 16 WC Cell Biology SC Cell Biology GA 355LU UT WOS:000089387800016 PM 10982399 ER PT J AU Sullivan, BM Harrison-Lavoie, KJ Marshansky, V Lin, HY Kehrl, JH Ausiello, DA Brown, D Druey, KM AF Sullivan, BM Harrison-Lavoie, KJ Marshansky, V Lin, HY Kehrl, JH Ausiello, DA Brown, D Druey, KM TI RGS4 and RGS2 bind coatomer and inhibit COPI association with Golgi membranes and intracellular transport SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID HETEROTRIMERIC G-PROTEINS; ADP-RIBOSYLATION FACTOR; GTPASE-ACTIVATING PROTEIN; DILYSINE RETRIEVAL MOTIFS; LLC-PK1 EPITHELIAL-CELLS; TRIMERIC G-PROTEINS; ENDOPLASMIC-RETICULUM; ALPHA-SUBUNITS; COATED VESICLES; WD-REPEAT AB COPI, a protein complex consisting of coatomer and the small GTPase ARF1, is an integral component of some intracellular transport carriers. The association of COPI with secretory membranes has been implicated in the maintenance of Golgi integrity and the normal functioning of intracellular transport in eukaryotes. The regulator of G protein signaling, RGS4, interacted with the COPI subunit beta'-COP in a yeast two-hybrid screen. Both recombinant RGS4 and RGS2 bound purified recombinant beta'-COP in vitro. Endogenous cytosolic RGS4 from NG108 cells and RGS2 from HEK293T cells cofractionated with the COPI complex by gel filtration. Binding of beta'-COP to RGS4 occurred through two dilysine motifs in RGS4, similar to those contained in some aminoglycoside antibiotics that are known to bind coatomer. RGS4 inhibited COPI binding to Golgi membranes independently of its GTPase-accelerating activity on G(i alpha). In RCS4-transfected LLC-PK1 cells, the amount of COPI in the Golgi region was considerably reduced compared with that in wild-type cells, but there was no detectable difference in the amount of either Golgi-associated ARF1 or the integral Golgi membrane protein giantin, indicating that Golgi integrity was preserved. In addition, RGS4 expression inhibited trafficking of aquaporin 1 to the plasma membrane in LLC-PK1 cells and impaired secretion of placental alkaline phosphatase from HEK293T cells. The inhibitory effect of RGS4 in these assays was independent of GTPase-accelerating activity but correlated with its ability to bind COPI. Thus, these data support the hypothesis that these RGS proteins sequester coatomer in the cytoplasm and inhibit its recruitment onto Golgi membranes, which may in turn modulate Golgi-plasma membrane or intra-Golgi transport. C1 NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Program Membrane Biol, Renal Unit, Charlestown, MA 02129 USA. Inst Canc Res, Chester Beatty Labs, London SW3 6JB, England. NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Druey, KM (reprint author), NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. OI Kehrl, John/0000-0002-6526-159X FU NIDDK NIH HHS [P01 DK038452, DK38452] NR 68 TC 21 Z9 23 U1 0 U2 1 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3992 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD SEP PY 2000 VL 11 IS 9 BP 3155 EP 3168 PG 14 WC Cell Biology SC Cell Biology GA 355LU UT WOS:000089387800024 PM 10982407 ER PT J AU Hodge, DR Clausen, PA AF Hodge, DR Clausen, PA TI Transcriptional activation analysis using bioluminescent reporter assays SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE bioluminescent reporter vectors; luciferase; promoters and enhancers ID ACETYL TRANSFERASE CAT; GENE-TRANSCRIPTION; TRANSFECTION; ELECTROPORATION; EFFICIENCY; EXPRESSION; PROMOTERS; VECTOR AB Analysis of promoter and enhancer DNA sequences provides the researcher with valuable information regarding the expression patterns of genes. Insertion of small DNA fragments containing the regulatory sequence of interest into vectors carrying reporter genes allows for the accurate quantitative analysis of the gene's expression patterns and responses to various stimuli. The use of bioluminescent reporter genes provides a simple, rapid, and inexpensive system that generates virtually no toxic or radioactive waste products. In addition, bioluminescent reporter vectors are more sensitive than previous methods such as the chloramphenicol acetyl transferase (CAT) systems, that require the use of hazardous chemicals and isotopically labeled reagents. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Cytokine Mol Mech Sect,NIH, Frederick, MD USA. NR 20 TC 3 Z9 3 U1 0 U2 3 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD SEP PY 2000 VL 16 IS 1 BP 67 EP 76 DI 10.1385/MB:16:1:67 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 366NE UT WOS:000090010800006 PM 11098469 ER PT J AU Watanabe, Y Haugen-Strano, A Umar, A Yamada, K Hemmi, H Kikuchi, Y Takano, S Shibata, Y Barrett, JC Kunkel, TA Koi, M AF Watanabe, Y Haugen-Strano, A Umar, A Yamada, K Hemmi, H Kikuchi, Y Takano, S Shibata, Y Barrett, JC Kunkel, TA Koi, M TI Complementation of an hMSH2 defect in human colorectal carcinoma cells by human chromosome 2 transfer SO MOLECULAR CARCINOGENESIS LA English DT Article DE hMSH2; mismatch repair; alkylating agent; G2 cell cycle; gene targeting ID DNA MISMATCH REPAIR; NONPOLYPOSIS COLON-CANCER; HUMAN MICROCELL HYBRIDS; MICROSATELLITE INSTABILITY; TUMOR-CELLS; HETERODUPLEX REPAIR; ENDOMETRIAL CANCER; HELA-CELLS; MUTATION; DAMAGE AB The human colorectal tumor cell line LoVo has a homozygous deletion in the hMSH2 gene from exon 3 to exon 8. is deficient in mismatch repair (MMR) activity, and exhibits microsatellite instability. To determine whether the introduction of a wild type hMSH2 into LoVo restores MMR activity and stabilizes microsatellite loci, we transferred a chromosome 2 fragment containing hMSH2 into a homologous recombination-proficient chicken DT40/human hybrid (DT40 2C) and a human chromosome 2 in a mouse A9 hybrid to LoVo. Transfers of these chromosomes into LoVo resulted in LoVo both with and without a wild-type hMSH2. Complete correlation was found between the presence of the wild-type hMSH2 and hMSH2 expression, an increased stability in microsatellite loci, and competency in MMR. The hMSH2-positive LoVo hybrids also showed an increased sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine. This enhanced toxicity is associated with G(2) cell-cycle arrest followed by premature mitosis and cell death. These results suggest that hMSH2 may be responsible for complementing mutator and drug-resistant phenotypes in chromosome 2-transferred LoVo cells. To test whether the hMSH2 in DT40 2C cells can be modified by homologous recombination, we transfected DT40 2C with a targeting vector containing an hMSH2 exon 4 disrupted by the zeocin-resistant gene. The results showed that the hMSH2 locus in DT40 2C was efficiently targeted by an exogeneously transfected homologous sequence, suggesting that transfer of a modified hMSH2 from DT40 2C to LoVo via chromosome transfer could be used to determine the function of hMSH2. Mel. Carcinog. 29:37-49 2000. dagger published 2000 Wiley-Liss, Inc. C1 NIEHS, Mol Carcinogenesis Lab, Gene Mapping & Cloning Grp, Res Triangle Pk, NC 27709 USA. NIEHS, Genet Mol Lab, Res Triangle Pk, NC 27709 USA. Toho Univ, Sch Med, Dept Mol Biol, Tokyo, Japan. RP Koi, M (reprint author), NIEHS, Mol Carcinogenesis Lab, Gene Mapping & Cloning Grp, Res Triangle Pk, NC 27709 USA. RI Koi, Minoru/C-3489-2012; Koi, Minoru/G-9197-2014 NR 41 TC 28 Z9 30 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 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD SEP PY 2000 VL 29 IS 1 BP 37 EP 49 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 360WT UT WOS:000089690900005 PM 11020245 ER PT J AU Gahl, WA Kuehl, EM Iwata, F Lindblad, A Kaiser-Kupfer, MI AF Gahl, WA Kuehl, EM Iwata, F Lindblad, A Kaiser-Kupfer, MI TI Corneal crystals in nephropathic cystinosis: Natural history and treatment with cysteamine eyedrops SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE cystinosis; cysteamine; cornea; crystals; photophobia; ocular; deletion ID TOPICAL CYSTEAMINE; CTNS MUTATIONS; GENE; THERAPY; TRANSPORT; COMPLICATIONS; INSUFFICIENCY; FIBROBLASTS; FRACTIONS; DEPLETION AB Although renal disease is the most prominent feature of the lysosomal storage disease cystinosis, corneal cystine crystal formation remains a major complication, leading to photophobia, corneal erosions, and keratopathies. Moreover, the extent of corneal crystal accumulation reflects the course and severity of the disease itself, and the cornea is accessible to direct examination. Therefore, we employed a scoring system, based on a library of slit-lamp photographs of corneas with increasing crystal densities (0.00-3.00), to assess the degree of crystal accumulation in 170 patients with nephropathic cystinosis examined at the National Institutes of Health between 1976 and 2000. None of the patients had received topical cystine-depleting therapy at the time of the evaluation. In this natural history study, infants in the first year of life had absent or minimal corneal crystals, i.e., a corneal cystine crystal score (CCCS) of 0 or 0.25. However, the CCCS increased linearly with age, such that every patient had visible crystals by 16 months of age, and plateaued at approximately 3.00 by early adolescence. Longitudinal studies in representative patients support the cross-sectional results. Individuals homozygous for the common 57-kb deletion involving the cystinosis gene (CTNS) displayed the same course of corneal crystal accumulation as did individuals not bearing the large deletion. Patients with ocular or nonnephropathic cystinosis had CCCSs that were, in general, half those expected for patients with nephropathic cystinosis of the same age. Administration of 0.55% cysteamine eyedrops, given 6 to 12 times per day, dissolved corneal cystine crystals in 10 representative patients with nephropathic cystinosis aged 1 to 32 years within 8 to 41 months. (C) 2000 Academic Press. C1 NICHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NEI, Ophthalm Genet & Clin Serv Branch, NIH, Bethesda, MD 20892 USA. EMMES Corp, Potomac, MD 20854 USA. RP Gahl, WA (reprint author), NICHD, Sect Human Biochem Genet, Heritable Disorders Branch, NIH, 10 Ctr Dr,MSC 1830,Bldg 10,Room 9S-241, Bethesda, MD 20892 USA. NR 51 TC 68 Z9 72 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2000 VL 71 IS 1-2 BP 100 EP 120 DI 10.1006/mgme.2000.3062 PG 21 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 360XQ UT WOS:000089693000014 PM 11001803 ER PT J AU Porter, FD AF Porter, FD TI RSH/Smith-Lemli-Opitz syndrome: A multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis SO MOLECULAR GENETICS AND METABOLISM LA English DT Review ID CULTURED SKIN FIBROBLASTS; SONIC-HEDGEHOG; PRENATAL-DIAGNOSIS; AMNIOTIC-FLUID; CHONDRODYSPLASIA PUNCTATA; DELTA-7-STEROL REDUCTASE; RENAL HYPOPLASIA; LIVER-MICROSOMES; 7-DEHYDROCHOLESTEROL; GENE AB The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation syndrome caused by an inborn error of cholesterol biosynthesis. The RSH/SLOS phenotypic spectrum is broad; however, typical features include microcephaly, ptosis, a small upturned nose, micrognathia, postaxial polydactaly, second and third toe syndactaly, genital. anomalies, growth failure, and mental retardation. RSH/SLOS is due to a deficiency of the SP-hydroxysterol Delta(7)-reductase, which catalyzes the reduction of 7-dehydrocholesterol (7-DHC) to cholesterol. This inborn error of cholesterol biosynthesis results in elevated serum and tissue 7-DHC levels. The 3 beta-hydroxysterol Delta(7)-reductase gene (DHCR7) maps to chromosome 11q12-13, and to date 66 different mutations of this gene have been identified in RSH/SLOS patients. Identification of the biochemical basis of RSH/SLOS has led to development of therapeutic regimens based on dietary cholesterol supplementation and has increased our understanding of the role cholesterol plays during embryonic development. (C) 2000 Academic Press. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Porter, FD (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. NR 89 TC 59 Z9 59 U1 1 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2000 VL 71 IS 1-2 BP 163 EP 174 DI 10.1006/mgme.2000.3069 PG 12 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 360XQ UT WOS:000089693000018 PM 11001807 ER PT J AU Forlino, A Marini, JC AF Forlino, A Marini, JC TI Osteogenesis imperfecta: Prospects for molecular therapeutics SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Osteogenesis Imperfecta; collagen; Brittle mouse; ribozymes ID I COLLAGEN; TRANSGENIC MICE; PARENTAL MOSAICISM; MUTATIONS; GENE; HETEROGENEITY; PHENOTYPE; DISEASES; THERAPY; MARROW AB Osteogenesis Imperfects (OI) is a dominant negative disorder of connective tissue. OI patients present with bone fragility and skeletal deformity within a broad phenotypic range. Defects in the COL1A1 or COL1A2 genes, coding, respectively, for the alpha 1 and alpha 2 chains of type I collagen, are the causative mutations. Over 150 mutations have been characterized. Both quantitative defects, such as null COL1A1 alleles, and qualitative defects, such as glycine substitutions, exon skipping, deletions, and insertions, have been described in type I collagen. Quantitative and structural mutations are associated with the milder and more severe forms of OI, respectively. A more detailed relationship between genotype and phenotype is still incompletely understood; several models have been proposed and are being tested. Transgenic and knock-out murine models for OI have previously been created. We have recently generated a knock-in murine model (the Brittle mouse) carrying a typical glycine substitution in type I collagen. This mouse will permit a better understanding of OI pathophysiology and phenotypic variability. It will also be used for gene therapeutic approaches to OI, especially mutation suppression by hammerhead ribozymes, The present review will provide an update of OI clinical and molecular data and outline gene therapeutic approaches being tested on OI murine models for this disorder. (C) 2000 Academic Press. C1 NICHHD, Sect Connect Tissue Disorders, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Marini, JC (reprint author), NICHHD, Sect Connect Tissue Disorders, Heritable Disorders Branch, NIH, 10 Ctr Dr,MSC 1830,Bldg 10,Rm 9S-241, Bethesda, MD 20892 USA. RI Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 NR 42 TC 39 Z9 39 U1 0 U2 6 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2000 VL 71 IS 1-2 BP 225 EP 232 DI 10.1006/mgme.2000.3039 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 360XQ UT WOS:000089693000025 PM 11001814 ER PT J AU Koch, R Hanley, W Levy, H Matalon, R Rouse, B Trefz, F Guttler, F Azen, C Friedman, E Platt, L de la Cruz, F AF Koch, R Hanley, W Levy, H Matalon, R Rouse, B Trefz, F Guttler, F Azen, C Friedman, E Platt, L de la Cruz, F TI Maternal phenylketonuria: An international study SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE phenylketonuria; phenylalanine; pregnancy; microcephaly; congenital heart disease; nutrition; congenital anomalies; dietary treatment ID PHENYLALANINE-HYDROXYLASE DEFICIENCY; MOLECULAR-BASIS; PHENOTYPE; GENOTYPE AB Maternal phenylketonuria (PKU) syndrome results in multiple congenital anomalies in the offspring, usually consisting of microcephaly, intrauterine growth retardation, dysmorphology, and congenital heart disease. Pregnancies treated preconceptionally with a phenylalanine-restricted diet and control of maternal blood phenylalanine levels within the recommended range result in normal offspring. However, in this 15-year study, several significant factors resulted in microcephaly in 27% of the offspring, and 7% exhibited serious congenital heart disease. These results occurred chiefly in women with mean IQ scores of 83 associated with low socioeconomic status and decreased educational achievement, Another important factor associated with suboptimal control of blood phenylalanine levels during pregnancy was the fact that most pregnancies were not carefully planned and occurred in women off dietary treatment with phenylalanine-restricted products. These results indicate that greater effort must be developed to assist women with PKU in remaining on diet during their reproductive years. It appears that continued adherence to the diet, resulting in normal maternal intelligence, is an important contribution to improved fetal development. (C) 2000 Academic Press. C1 Univ So Calif, Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Univ So Calif, Dept Pediat, Los Angeles, CA 90027 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Childrens Hosp & Med Ctr, Boston, MA USA. Univ Texas, Med Branch, Child Dev & Genet Div, Galveston, TX 77550 USA. Univ Teubingen, Reutlingen, Germany. John Kennedy Inst, Glostrup, Denmark. Univ Calif Los Angeles, Med Ctr, Cedars Sinai Med Ctr, Dept Obstet & Gynecol, Los Angeles, CA 90024 USA. NICHHD, Bethesda, MD 20892 USA. RP Koch, R (reprint author), Univ So Calif, Childrens Hosp Los Angeles, 4650 Sunset Blvd,Mail Stop 73, Los Angeles, CA 90027 USA. FU NICHD NIH HHS [N01-HD-2-3148] NR 17 TC 26 Z9 27 U1 1 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2000 VL 71 IS 1-2 BP 233 EP 239 DI 10.1006/mgme.2000.3038 PG 7 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 360XQ UT WOS:000089693000026 PM 11001815 ER PT J AU DeLuca, JG Doebber, TW Kelly, LJ Kemp, RK Molon-Noblot, S Sahoo, SP Ventre, J Wu, MS Peters, JM Gonzalez, FJ Moller, DE AF DeLuca, JG Doebber, TW Kelly, LJ Kemp, RK Molon-Noblot, S Sahoo, SP Ventre, J Wu, MS Peters, JM Gonzalez, FJ Moller, DE TI Evidence for peroxisome proliferator-activated receptor (PPAR)alpha-independent peroxisome proliferation: Effects of PPAR gamma/delta-specific agonists in PPAR alpha-Null mice SO MOLECULAR PHARMACOLOGY LA English DT Article ID GAMMA; EXPRESSION; LIGANDS; PRODUCE; BINDING; ISOFORM AB Peroxisome proliferators are a diverse group of compounds that cause hepatic hypertrophy and hyperplasia, increase peroxisome number, and on chronic high-dose administration, lead to rodent liver tumorigenesis. Various lines of evidence have led to the conclusion that these agents induce their pleiotropic effects exclusively via agonism of peroxisome proliferator-activated receptor (PPAR)alpha, a member of the steroid receptor superfamily involved in the regulation of fatty acid metabolism. Recently, agonists of two other members of this receptor family have been identified. PPAR gamma is predominantly expressed in adipocytes where it mediates differentiation; PPAR delta is a widely expressed orphan receptor with yet unresolved physiologic functions. In the course of characterizing newer PPAR ligands, we noted that highly selective PPAR gamma agonists or dual PPAR gamma/PPAR delta agonists, lacking apparent murine PPAR alpha agonist activity, cause peroxisome proliferation in CD-1 mice. We therefore made use of PPAR alpha knockout mice to investigate whether these effects resulted from agonism of PPAR alpha by these agents at very high dose levels or whether PPAR gamma (or PPAR delta) agonism alone can result in peroxisome proliferation. We report here that several parameters linked to the hepatic peroxisome proliferation response in mice that were seen with these agents resulted from PPAR alpha-independent effects. C1 Merck Res Labs, Dept Safety Assessment Genet & Cellular Toxicol, W Point, PA 19438 USA. Merck Res Labs, Dept Mol Endocrinol, Rahway, NJ USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP DeLuca, JG (reprint author), Merck Res Labs, Dept Safety Assessment Genet & Cellular Toxicol, WP45-302, W Point, PA 19438 USA. RI Peters, Jeffrey/D-8847-2011 NR 22 TC 41 Z9 42 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD SEP PY 2000 VL 58 IS 3 BP 470 EP 476 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 346KA UT WOS:000088868800002 PM 10953038 ER PT J AU Kim, SY Adachi, H Koo, JS Jetten, AM AF Kim, SY Adachi, H Koo, JS Jetten, AM TI Induction of the cytochrome P450 gene CYP26 during mucous cell differentiation of normal human tracheobronchial epithelial cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID LUNG-CARCINOMA CELLS; RECEPTOR-SELECTIVE RETINOIDS; ACID TREATMENT; VITAMIN-A; EXPRESSION; CANCER; IDENTIFICATION; PROLIFERATION; 4-HYDROXYLASE; METABOLISM AB In this study, the expression of CYP26 is examined in relation to retinoid-induced mucosecretory differentiation in human tracheobronchial epithelial (HTBE) cells and compared with that in human lung carcinoma cell lines. In HTBE cells, retinoic acid (RA) inhibits squamous differentiation and induces mucous cell differentiation as indicated by the suppression of transglutaminase I and increased expression of the mucin gene MUC2. The latter is accompanied by increased expression of CYP26 mRNA. RA is required but not sufficient to induce RAR beta, CYP26, and MUC2 mRNA because induction is only observed in confluent but not in logarithmic cultures, suggesting that additional factors are critical in their regulation. CYP26 mRNA can be induced by the RAR-selective retinoid 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid (TTAB) but not by the RXR-selective retinoid SR11217 or the anti-activator-protein 1-selective retinoid SR11302. RAR alpha-, beta-, and gamma-selective retinoids are able to induce CYP26; this induction is inhibited by the RAR alpha-selective antagonist Ro41-5253. TTAB is able to induce CYP26 mRNA expression in only a few of the lung carcinoma cell lines tested. The lack of CYP26 induction in many carcinoma cell lines may relate to previously reported defects in the retinoid-signaling pathway. The induction of CYP26 correlated with increased metabolism of RA into 18-hydroxy-, 4-oxo-, and 4-hydroxy-RA. The latter metabolite was shown to be able to induce MUC2 and MUC5AC expression in HTBE cells. Our results demonstrate that in normal HTBE cells, CYP26 expression is closely associated with mucous cell differentiation and that many lung carcinoma cells exhibit increased RA metabolism and a defective regulation of CYP26. C1 NIEHS, Cell Biol Sect, Pulm Pathobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Pulm Pathobiol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. OI Jetten, Anton/0000-0003-0954-4445 NR 39 TC 11 Z9 11 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD SEP PY 2000 VL 58 IS 3 BP 483 EP 490 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 346KA UT WOS:000088868800004 PM 10953040 ER PT J AU Soh, YJ Jeong, KS Lee, IJ Bae, MA Kim, YC Song, BJ AF Soh, YJ Jeong, KS Lee, IJ Bae, MA Kim, YC Song, BJ TI Selective activation of the c-Jun N-terminal protein kinase pathway during 4-hydroxynonenal-induced apoptosis of PC12 cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID LIPID-PEROXIDATION; JNK ACTIVATION; SYMPATHETIC NEURONS; SIGNALING PATHWAYS; OXIDATIVE STRESS; DEATH; INDUCTION; SURVIVAL; PHOSPHORYLATION; LIVER AB The by-product of lipid peroxidation, 4-hydroxynonenal (HNE), was shown to cause apoptosis in PC12 cells. In this study, we investigated the molecular mechanism of HNE-induced apoptosis in these cells. Specifically, we determined the effect of HNE on the activities of mitogen-activated protein (MAP) kinases involved in early signal transduction. Within 15 to 30 min after HNE treatment, c-Jun N-terminal protein kinase (JNK) was maximally activated, before it returned to control level at 1 h post-treatment. In contrast, activities of extracellular signal-regulated kinase and p38 MAP kinase remained unchanged from their baseline levels. Stress-activated protein kinase kinase (SEK1), an upstream kinase of JNK, was also activated within 5 min after HNE treatment and remained activated for up to 60 min. Marked activation of the JNK pathway through SEK1 and apoptosis signal-regulating kinase 1 (ASK1), an upstream kinase of SEK1, was demonstrated by the transient transfection of cDNA for wild-type SEK1 or ASK1 together with JNK into COS-7 cells. Furthermore, significant reductions in JNK activation and HNE-induced cell death were observed when either of the dominant negative mutant of SEK1 or ASK1 was cotransfected with JNK. Pretreatment of PC12 cells with a survival-promoting agent, 8-(4-chlorophenylthio)-cAMP, prevented both the HNE-induced JNK activation and apoptosis. Nonaldehyde, a nontoxic aldehyde, neither caused apoptosis nor JNK activation. Pretreatment of PC12 cells with SB203580, a specific inhibitor of p38 MAP kinase, had no effect on HNE-induced apoptosis. All these data suggest that the selective JNK activation by HNE is critical for the apoptosis of PC12 cells and that the HNE-mediated apoptosis is likely to be mediated through the activation of the ASK1-SEK1-JNK pathway without activation of extracellular signal-regulated kinase or p38 MAP kinase. C1 NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Song, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, 12420 Parklawn Dr,Rm 425, Rockville, MD 20852 USA. NR 40 TC 107 Z9 107 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD SEP PY 2000 VL 58 IS 3 BP 535 EP 541 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 346KA UT WOS:000088868800010 PM 10953046 ER PT J AU Cho, H Kozasa, T Takekoshi, K De Gunzburg, J Kehrl, JH AF Cho, H Kozasa, T Takekoshi, K De Gunzburg, J Kehrl, JH TI RGS14, a GTPase-activating protein for Gi alpha, attenuates Gi alpha- and G13 alpha-mediated signaling pathways SO MOLECULAR PHARMACOLOGY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; SERUM RESPONSE FACTOR; ADENYLYL-CYCLASE; PHOSPHOLIPASE-C; P115 RHOGEF; RECEPTORS; REGULATOR; SUBUNITS; INHIBITION; GAIP AB Regulator of G protein signaling (RGS) proteins are a family of approximately 20 proteins that negatively regulate signaling through heterotrimeric G protein-coupled receptors. The RGS proteins act as GTPase-activating proteins (GAPs) for certain Ga subunits and as effector antagonists for Gq alpha. Mouse RGS14 encodes a 547-amino-acid protein with an N-terminal RGS domain, which is highly expressed in lymphoid tissues. In this study, we demonstrate that RGS14 is a GAP for Gi alpha subfamily members and it attenuates interleukin-8 receptor-mediated mitogen-activated protein kinase activation. However, RGS14 does not exhibit GAP activity toward Gs alpha or Gq alpha nor does it regulate Gs alpha- or Gq alpha-mediated signaling pathways. Although RGS14 does not act as a GAP for G12/13 alpha, it impairs c-fos serum response element activation induced by either a constitutively active mutant of G13 alpha (G13 alpha Q226L) or by carbachol stimulation of muscarinic type 1 receptors. An RGS14 mutant (EN92/93AA), which does not block Gi alpha-linked signaling, also inhibits serum response element activation. RGS14 localizes predominantly in the cytosol, but it can be recruited to membranes by expression of G13 alpha Q226L. Although RGS14 is constitutively expressed in lymphoid cells, agents that activate B or T lymphocytes further enhance its levels. Taken together, our results suggest that signals generated after lymphocyte activation may via RGS14 directly impinge on Gi alpha- or G13 alpha-mediated cellular processes in lymphocytes, such as adhesion and migration. C1 NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Inst Curie, Sect Rech, Paris, France. Univ Illinois, Dept Pharmacol, Chicago, IL USA. RP Kehrl, JH (reprint author), NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, NIH, Bldg 10,Rm 11B-13,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. NR 34 TC 62 Z9 62 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD SEP PY 2000 VL 58 IS 3 BP 569 EP 576 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 346KA UT WOS:000088868800014 PM 10953050 ER PT J AU Pluymers, W Neamati, N Pannecouque, C Fikkert, V Marchand, C Burke, TR Pommier, Y Schols, D De Clercq, E Debyser, Z Witvrouw, M AF Pluymers, W Neamati, N Pannecouque, C Fikkert, V Marchand, C Burke, TR Pommier, Y Schols, D De Clercq, E Debyser, Z Witvrouw, M TI Viral entry as the primary target for the anti-HIV activity of chicoric acid and its tetra-acetyl esters SO MOLECULAR PHARMACOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; IN-VITRO; DICAFFEOYLTARTARIC ACIDS; INTEGRASE INHIBITORS; POTENT INHIBITORS; ENVELOPE GP120; REPLICATION; INFECTION; ANALOGS; ASSAY AB The antiviral activity of L-chicoric acid against HIV-1 has been attributed previously to the inhibition of HIV-1 integration. This conclusion was based on the inhibition of integrase activity in enzymatic assays and the isolation of a resistant HIV strain with a mutation (G140S) in the integrase gene. Here we show that the primary antiviral target of L-CA and its analogs in cell culture is viral entry. L- and D-chicoric acid (L-CA and D-CA) and their respective tetra-acetyl esters inhibit the replication of HIV-1 (IIIB and NL4.3) and HIV-2 (ROD) in MT-4 cells at a 50% effective concentration (EC50) ranging from 1.7 to 70.6 mu M. In a time-of-addition experiment, L-CA, D-CA, L-CATA, and D-CATA were found to interfere with an early event in the viral replication cycle. Moreover, L-CA, D-CA, and their analogs did not inhibit the replication of virus strains that were resistant toward polyanionic and polycationic compounds at subtoxic concentrations. Furthermore, HIV-1 strains resistant to L-CA and D-CA were selected in the presence of L-CA and D-CA, respectively. Mutations were found in the V2, V3, and V4 loop region of the envelope glycoprotein gp120 of the L-CA and D-CA-resistant NL4.3 strains that were not present in the wild-type NL4.3 strain. Recombination of the gp120 gene of the L-CA and D-CA resistant strain in a NL4.3 wild-type molecular clone fully rescued the phenotypic resistance toward L-CA and D-CA. No significant mutations were detected in the integrase gene of the drug-resistant virus strains. Although inhibition of HIV integrase activity by L-CA and its derivatives was confirmed in an oligonucleotide-driven assay, integrase carrying the G140S mutation was inhibited to the same extent as the wild-type integrase. C1 Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. NCI, Mol Pharmacol Lab, Div Basic Sci, Bethesda, MD 20892 USA. RP Witvrouw, M (reprint author), Katholieke Univ Leuven, Rega Inst Med Res, Minderbroedersstr 10, B-3000 Louvain, Belgium. RI Burke, Terrence/N-2601-2014; Marchand, Christophe/D-8559-2016 NR 41 TC 95 Z9 101 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD SEP PY 2000 VL 58 IS 3 BP 641 EP 648 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 346KA UT WOS:000088868800023 PM 10953059 ER PT J AU Toyota, T Watanabe, A Shibuya, H Nankai, M Hattori, E Yamada, K Kurumaji, A Karkera, JD Detera-Wadleigh, SD Yoshikawa, T AF Toyota, T Watanabe, A Shibuya, H Nankai, M Hattori, E Yamada, K Kurumaji, A Karkera, JD Detera-Wadleigh, SD Yoshikawa, T TI Association study on the DUSP6 gene, an affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis on the LightCycler SO MOLECULAR PSYCHIATRY LA English DT Article DE chromosome 12q; genotyping; single nucleotide polymorphism (SNP); biallelic polymorphism; unipolar; bipolar ID DARIERS-DISEASE; PANCREATIC-CANCER; BIPOLAR DISORDER; GENOMIC ANALYSIS; IDENTIFICATION; MUTATIONS; LINKAGE; POLYMORPHISM; LOCALIZATION; PHOSPHATASE AB We introduced a new genotyping method, fluorescence resonance energy transfer-based melting curve analysis on the LightCycler, for the analysis of the gene, DUSP6(dual specificity MAP kinase phosphatase 6), in affective disorder patients. The DUSP6 gene is located on chromosome 12q22-23, which overlaps one of the reported bipolar disorder susceptibility loci. Because of its role in intracellular signalling pathways, the gene may be involved in the pathogenesis of affective disorders not only on the basis of its position but also of its function. We performed association analysis using a T>G polymorphism that gives rise to a missense mutation (Leu114Val), No evidence for a significant disease-causing effect was found in Japanese unipolars (n = 732) and bipolars (n = 122), when compared with controls (n = 299). More importantly, this study demonstrates that melting curve analysis on the LightCycler is an accurate, rapid and robust method for discriminating genotypes from biallelic markers. This strategy has the potential for use in high throughput scanning for and genotyping of single nucleotide polymorphisms (SNPs). C1 RIKEN, Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama 3510198, Japan. Tokyo Med & Dent Univ, Dept Neuropsychiat, Tokyo, Japan. Natl Sanatorium Minami Hanamaki Hosp, Hanamaki, Iwate, Japan. Tokyo Metropolitan Police Hosp, Dept Neuropsychiat, Tokyo, Japan. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. RP Yoshikawa, T (reprint author), RIKEN, Brain Sci Inst, Lab Mol Psychiat, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. NR 24 TC 27 Z9 29 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2000 VL 5 IS 5 BP 489 EP 494 DI 10.1038/sj.mp.4000748 PG 6 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 353PL UT WOS:000089284600007 ER PT J AU Chen, H Huo, Y Patel, S Zhu, X Swift-Scanlan, T Reeves, RH DePaulo, R Ross, CA McInnis, MG AF Chen, H Huo, Y Patel, S Zhu, X Swift-Scanlan, T Reeves, RH DePaulo, R Ross, CA McInnis, MG TI Gene identification using exon amplification on human chromosome 18q21: implications for bipolar disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE exons; exon trapping; chromosome 18; bipolar disorder ID MANIC-DEPRESSIVE ILLNESS; DNA MARKERS; LINKAGE; ASSOCIATION; CLONING AB We previously reported linkage between bipolar disorder and a region on human chromosome (HC) 18q21. To identify genes in this region, exon trapping was performed on cosmids isolated from an HC18-specific cosmid library (LL18NC02) using 47 sequence tagged site (STS) markers from 18q21 as hybridization probes. A total of 285 unique sequences (exons) were obtained from 850 sequenced clones. Homology searching of the databases using NCBI's BLAST algorithms revealed that 31 exons have identity to known genes and/or ESTs, seven are identical to regions of finished genomic sequences in the 18q21 region, 20 have significant similarity (>30% sequence identity) to genes from human and/or other species, 19 were repetitive sequences, and 208 sequences (72%) are novel. Seventy per cent of the trapped sequences were predicted to be derived from genes using library screening and RT-PCR analyses. This represents an initial stage in characterizing genes in a susceptibility region for further study in bipolar disorder or other diseases that map to this region. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21287 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Ross, CA (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat, 600 N Wolfe St, Baltimore, MD 21287 USA. RI McInnis, Melvin/F-6963-2012 OI McInnis, Melvin/0000-0002-0375-6247 FU NIMH NIH HHS [MH01088, MH42243, MH50763] NR 18 TC 3 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2000 VL 5 IS 5 BP 502 EP 509 DI 10.1038/sj.mp.4000780 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 353PL UT WOS:000089284600009 PM 11032383 ER PT J AU Thrasher, JB Deeths, J Bennett, C Iyer, P Dineen, MK Zhai, SP Figg, WD McLeod, DG AF Thrasher, JB Deeths, J Bennett, C Iyer, P Dineen, MK Zhai, SP Figg, WD McLeod, DG TI Comparative study of the clinical efficacy of two dosing regimens of flutamide SO MOLECULAR UROLOGY LA English DT Article; Proceedings Paper CT 5th International Conference on Neoadjuvant Hormonal Therapy for Prostate Cancer CY MAR 17-18, 2000 CL CAMBRIDGE, MASSACHUSETTS AB Purpose: We performed a randomized trial to compare the efficacy and toxicity of a new dose of flutamide (500 mg QD) with the currently recommended dose (250 mg q8h) in the treatment of advanced prostate cancer, The primary endpoints were percent of patients having normalization of prostate specific antigen (PSA), time to normalization, and percent change from baseline. Secondary endpoints were quality of life and toxicity. Patients: Altogether, 440 men aged 46 to 94 years (mean 71 years) with confirmed stage M-1 disease, documented PSA rise >0.2 ng/mL, ECOG status 0 to 2, Ilo second neoplasm, no liver function tests greater than or equal to 1.5-fold normal values, and no previous treatment for metastatic disease were entered in the trial. Results: The PSA normalized by week 12 in 71% of the patients receiving 500-mg dose and 75% of those receiving the standard dose. The percent change in PSA was 89% and 96%, respectively. The treatment groups were not significantly different with respect to the incidence of adverse events: 71% v 68% in the 500-mg and 250-mg arms, respectively (P = 0.337), Conclusions: When combined with castration, 500 mg of flutamide appears to be equally effective in lowering serum PSA and is not significantly more toxic than conventional dosing, The use of 500 mg QD instead of the standard 250 mg q8h would result in a cost savings of 30%. C1 Univ Kansas, Med Ctr, Urol Sect, Kansas City, KS 66160 USA. Nebraska Clin Res Ctr, Omaha, NE USA. Northwestern Univ, Div Hematol Oncol, Chicago, IL 60611 USA. Long Beach VA Med Ctr, Sect Haematol Oncol, Long Beach, CA USA. Atlantic Urol Assoc, Daytona Beach, FL USA. NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. RP Thrasher, JB (reprint author), Univ Kansas, Med Ctr, Urol Sect, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. RI Figg Sr, William/M-2411-2016 NR 3 TC 7 Z9 8 U1 0 U2 2 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1091-5362 J9 MOL UROL JI Mol. Urol. PD FAL PY 2000 VL 4 IS 3 BP 259 EP 263 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 364UY UT WOS:000089912400040 PM 11062382 ER PT J AU Slavotinek, AM Stone, EM Mykytyn, K Heckenlively, JR Green, JS Heon, E Musarella, MA Parfrey, PS Sheffield, VC Biesecker, LG AF Slavotinek, AM Stone, EM Mykytyn, K Heckenlively, JR Green, JS Heon, E Musarella, MA Parfrey, PS Sheffield, VC Biesecker, LG TI Mutations in MKKS cause Bardet-Biedl syndrome SO NATURE GENETICS LA English DT Article ID SYNDROME LOCUS; LINKAGE C1 Univ Iowa, Howard Hughes Med Inst, Iowa City, IA 52242 USA. Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Univ Iowa, Dept Ophthalmol, Iowa City, IA 52242 USA. Harbor UCLA Med Ctr, Dept Ophthalmol, Torrance, CA 90509 USA. Mem Univ St Johns, Fac Med, St Johns, NF, Canada. Univ Toronto, Dept Ophthalmol, Toronto, ON M5S 1A1, Canada. Univ Toronto, Vis Sci Res Program, Toronto, ON M5S 1A1, Canada. Long Isl Coll Hosp, Brooklyn, NY 11201 USA. RP Sheffield, VC (reprint author), Univ Iowa, Howard Hughes Med Inst, Iowa City, IA 52242 USA. FU NEI NIH HHS [EY11298] NR 14 TC 182 Z9 185 U1 0 U2 8 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2000 VL 26 IS 1 BP 15 EP 16 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 350AK UT WOS:000089078000008 PM 10973238 ER PT J AU Grady, WM Willis, J Guilford, PJ Dunbier, AK Toro, TT Lynch, H Wiesner, G Ferguson, K Eng, C Park, JG Kim, SJ Markowitz, S AF Grady, WM Willis, J Guilford, PJ Dunbier, AK Toro, TT Lynch, H Wiesner, G Ferguson, K Eng, C Park, JG Kim, SJ Markowitz, S TI Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer SO NATURE GENETICS LA English DT Article ID CADHERIN GERMLINE MUTATIONS; CPG ISLAND METHYLATION; DNA METHYLATION; COLORECTAL-CANCER; HYPERMETHYLATION; TUMORS; CELLS C1 Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Human Genet, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Ireland Canc Ctr, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. Univ Otago, Dept Biochem, Canc Genet Lab, Dunedin, New Zealand. Creighton Univ, Sch Med, Dept Prevent Med, Omaha, NE 68178 USA. Ohio State Univ, Sch Med, Clin Canc Genet Program, Ctr Comprehens Canc, Columbus, OH 43210 USA. Ohio State Univ, Sch Med, Human Canc Genet Program, Ctr Comprehens Canc, Columbus, OH 43210 USA. Ohio State Univ, Sch Med, Div Human Genet, Dept Internal Med, Columbus, OH 43210 USA. Seoul Natl Univ Hosp, Dept Surg, Seoul 110744, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Cleveland, OH USA. RP Markowitz, S (reprint author), Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. RI Park, Jae-Gahb/J-5494-2012; OI Eng, Charis/0000-0002-3693-5145 FU NCI NIH HHS [R01 CA67409, R01 CA72160, KO8 CA77676] NR 15 TC 264 Z9 277 U1 0 U2 15 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2000 VL 26 IS 1 BP 16 EP 17 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 350AK UT WOS:000089078000009 PM 10973239 ER PT J AU Kirschner, LS Carney, JA Pack, SD Taymans, SE Giatzakis, C Cho, YS Cho-Chung, YS Stratakis, CA AF Kirschner, LS Carney, JA Pack, SD Taymans, SE Giatzakis, C Cho, YS Cho-Chung, YS Stratakis, CA TI Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex SO NATURE GENETICS LA English DT Article ID SPOTTY SKIN PIGMENTATION; ENDOCRINE OVERACTIVITY; ACTIVATING MUTATIONS; CARDIAC MYXOMAS; RI-ALPHA; SCHWANNOMAS; DIAGNOSIS; DISEASE; TUMORS; MICE AB Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas(1-5). CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22-24 (refs 6,7). Because of its similarities to the McCune-Albright syndrome(5,8) and other features, such as paradoxical responses to endocrine signals(9), genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q. we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (Rl alpha), including a polymorphic site within its 5' region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours, We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease. C1 NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Cellular Biochem Sect, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. Mayo Clin, Emeritus Staff, Dept Lab Med & Pathol, Rochester, MN USA. RP Stratakis, CA (reprint author), NICHHD, Unit Genet & Endocrinol, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RI Pack, Svetlana/C-2020-2014 NR 28 TC 566 Z9 582 U1 0 U2 4 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2000 VL 26 IS 1 BP 89 EP 92 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 350AK UT WOS:000089078000025 PM 10973256 ER PT J AU Meffre, E Davis, E Schiff, C Cunningham-Rundles, C Ivashkiv, LB Staudt, LM Young, JW Nussenzweig, MC AF Meffre, E Davis, E Schiff, C Cunningham-Rundles, C Ivashkiv, LB Staudt, LM Young, JW Nussenzweig, MC TI Circulating human B cells that express surrogate light chains and edited receptors SO NATURE IMMUNOLOGY LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; HUMAN BONE-MARROW; IMMUNOGLOBULIN HEAVY; SOMATIC MUTATION; VARIABLE REGION; V(D)J RECOMBINATION; SURFACE EXPRESSION; RHEUMATOID FACTORS; ESCAPE TOLERANCE; GERMINAL-CENTERS AB Immunoglobulin gene recombination can result in the assembly of self-reactive antibodies. Deletion, anergy or receptor editing normally silence B cells that produce these autoantibodies. Receptor editing is highly efficient in mouse B cells that carry pre-recombined autoantibody transgenes or gene "knock-ins". However, it has been difficult to identify cells that have edited receptors in unmanipulated mice and humans. To try to identify such cells we isolated and characterized B cells that coexpress surrogate and conventional light chains (V-preB(+)L(+)) from the blood of normal human donors. V-preB(+)L(+) B cells express RAG mRNA, display an unusual heavy and light chain antibody repertoire consistent with antiself reactivity, and show evidence of receptor editing. These cells accumulate in the joints of patients with rheumatoid arthritis, consistent with a role for V-preB(+)L(+) B cells and receptor editing in autoimmune disease. C1 Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. Howard Hughes Med Inst, New York, NY 10021 USA. NCI, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Ctr Immunol Marseille Luminy, F-13288 Marseille 09, France. Mt Sinai Med Ctr, Dept Med & Pediat, New York, NY 10029 USA. Hosp Special Surg, Dept Med, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Mem Sloan Kettering Canc Ctr, Dept Med,Allogen Bone Marrow Transplant Serv, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Mem Sloan Kettering Canc Ctr, Dept Med,Clin Immunol Serv, New York, NY 10021 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, 1230 York Ave, New York, NY 10021 USA. NR 63 TC 95 Z9 96 U1 0 U2 3 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD SEP PY 2000 VL 1 IS 3 BP 207 EP 213 DI 10.1038/79739 PG 7 WC Immunology SC Immunology GA 363BY UT WOS:000089815100018 PM 10973277 ER PT J AU Karp, CL Grupe, A Schadt, E Ewart, SL Keane-Moore, M Cuomo, PJ Kohl, J Wahl, L Kuperman, D Germer, S Aud, D Peltz, G Wills-Karp, M AF Karp, CL Grupe, A Schadt, E Ewart, SL Keane-Moore, M Cuomo, PJ Kohl, J Wahl, L Kuperman, D Germer, S Aud, D Peltz, G Wills-Karp, M TI Identification of complement factor 5 as a susceptibility locus for experimental allergic asthma SO NATURE IMMUNOLOGY LA English DT Article ID INDUCED AIRWAY HYPERRESPONSIVENESS; TUMOR-NECROSIS-FACTOR; GENOME-WIDE SEARCH; HEMOLYTICALLY INACTIVE C5B67; POLYMORPHONUCLEAR LEUKOCYTES; INFLAMMATORY RESPONSES; COMPONENT C5; IL-12; ACTIVATION; RECEPTOR AB The prevalence and severity of allergic asthma continue to rise, lending urgency to the search for environmental triggers and genetic substrates. Using microarray analysis of pulmonary gene expression and single nucleotide polymorphism-based genotyping, combined with quantitative trait locus analysis, we identified the gene encoding complement factor 5 (CS) as a susceptibility locus for allergen-induced airway hyperresponsiveness in a murine model of asthma. A deletion in the coding sequence of CS leads to C5-deficiency and susceptibility. Interleukin 12 (IL-12) is able to prevent or reverse experimental allergic asthma. Blockade of the C5a receptor rendered human monocytes unable to produce IL-12, mimicking blunted IL-12 production by macrophages from C5-deficient mice and providing a mechanism for the regulation of susceptibility to asthma by C5. The role of complement in modulating susceptibility to asthma highlights the importance of immunoregulatory events at the interface of innate and adaptive immunity in disease pathogenesis. C1 Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Roche Biosci, Palo Alto, CA 94304 USA. Michigan State Univ, Dept Large Anim Sci, E Lansing, MI 48824 USA. Med Hsch Hannover, Inst Med Microbiol, D-30625 Hannover, Germany. Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. Roche Mol Syst Inc, Alameda, CA 94501 USA. RP Wills-Karp, M (reprint author), Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Environm Hlth Sci, 615 N Wolfe St, Baltimore, MD 21205 USA. RI Koehl, Joerg/C-8531-2011 OI Koehl, Joerg/0000-0003-1121-3178 FU NCRR NIH HHS [RR00097]; NHLBI NIH HHS [HL58527]; NIAID NIH HHS [AI40507]; NIDCR NIH HHS [DE12167]; NIEHS NIH HHS [ES09606] NR 42 TC 276 Z9 290 U1 0 U2 4 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD SEP PY 2000 VL 1 IS 3 BP 221 EP 226 DI 10.1038/79759 PG 6 WC Immunology SC Immunology GA 363BY UT WOS:000089815100020 PM 10973279 ER PT J AU Biragyn, A Kwak, LW AF Biragyn, A Kwak, LW TI Designer cancer vaccines are still in fashion SO NATURE MEDICINE LA English DT Editorial Material ID TELOMERASE ACTIVITY; CELLS; EXPRESSION C1 NCI, Dept Expt Transplantat & Immunol, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. RP Biragyn, A (reprint author), NCI, Dept Expt Transplantat & Immunol, Med Branch, Div Clin Sci, Bethesda, MD 20892 USA. NR 12 TC 18 Z9 19 U1 0 U2 3 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2000 VL 6 IS 9 BP 966 EP 968 DI 10.1038/79649 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 351ZR UT WOS:000089190500019 PM 10973307 ER PT J AU Grossman, Z Paul, WE AF Grossman, Z Paul, WE TI The impact of HIV on naive T-cell homeostasis SO NATURE MEDICINE LA English DT Editorial Material ID ACTIVATION; INFECTION; COUNTS; MEMORY C1 Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Grossman, Z (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. RI Grossman, Zvi/A-9643-2008 NR 15 TC 43 Z9 43 U1 0 U2 2 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2000 VL 6 IS 9 BP 976 EP 977 DI 10.1038/79667 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 351ZR UT WOS:000089190500025 PM 10973313 ER PT J AU Koslow, SH AF Koslow, SH TI Should the neuroscience community make a paradigm shift to sharing primary data? SO NATURE NEUROSCIENCE LA English DT Editorial Material ID TASTE RECEPTORS; FAMILY AB The author outlines the pros and cons of data shaving for neuroscientists and argues that continued progress in the field will depend on a cultural shift toward making primary data freely available. He argues in favor of distributed databases to maximize the efficient use of data. C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Koslow, SH (reprint author), NIMH, NIH, 6001 Execut Blvd,Room 6167, Bethesda, MD 20892 USA. NR 7 TC 50 Z9 51 U1 0 U2 3 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD SEP PY 2000 VL 3 IS 9 BP 863 EP 865 DI 10.1038/78760 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 405TV UT WOS:000167177400011 PM 10966615 ER PT J AU Ishima, R Torchia, DA AF Ishima, R Torchia, DA TI Protein dynamics from NMR SO NATURE STRUCTURAL BIOLOGY LA English DT Review ID CHEMICAL-SHIFT ANISOTROPY; MODEL-FREE APPROACH; MAGNETIC-RESONANCE RELAXATION; DNA-BINDING DOMAIN; BACKBONE DYNAMICS; ROTATIONAL DIFFUSION; ORDER PARAMETERS; TIME-SCALE; CONFORMATIONAL ENTROPY; TRANSVERSE RELAXATION AB This review surveys recent investigations of conformational fluctuations of proteins in solution using NMR techniques. Advances in experimental methods have provided more accurate means of characterizing fast and slow internal motions as well as overall diffusion. The information obtained from NMR dynamics experiments provides insights into specific structural changes or configurational energetics associated with function. A variety of applications illustrate that studies of protein dynamics provide insights into protein-protein interactions, target recognition, ligand binding, and enzyme function. C1 Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. RP Ishima, R (reprint author), Natl Inst Dent & Craniofacial Res, Struct Mol Biol Unit, NIH, Bethesda, MD 20892 USA. NR 66 TC 355 Z9 360 U1 7 U2 77 PU NATURE AMERICA INC PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1072-8368 J9 NAT STRUCT BIOL JI Nat. Struct. Biol. PD SEP PY 2000 VL 7 IS 9 BP 740 EP 743 DI 10.1038/78963 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 350AQ UT WOS:000089078500013 PM 10966641 ER PT J AU Murphy, DD Segal, M AF Murphy, DD Segal, M TI Progesterone prevents estradiol-induced dendritic spine formation in cultured hippocampal neurons SO NEUROENDOCRINOLOGY LA English DT Article DE gonadal steroids; hippocampus; dendritic spines; ontogeny; nerve growth factors; glutamic acid decarboxylase; cyclic AMP; GABA; electrophysiology; CREB ID GABA(A) RECEPTOR; NEUROTROPHIC FACTOR; STEROID-HORMONES; FEMALE RATS; DENSITY; BRAIN; PLASTICITY; CELLS; ACTIVATION; RU486 AB Estradiol has been shown to cause an increase in dendritic spine density in cultured hippocampal neurons, an effect mediated by downregulation of brain-derived neurotrophic factor (BDNF) and glutamic acid decarboxylase (GAD), and the subsequent phosphorylation of cAMP response element binding protein (CREB) in response to enhanced activity levels. Interestingly, progesterone was shown to counteract the effects of estradiol on dendritic spine density in vivo and in vitro. The present study examined how progesterone may act to block the effects of estradiol in the molecular cascade of cellular events leading to formation of dendritic spines. Progesterone did not affect the estradiol-induced downregulation of BDNF or GAD, but it did block the effect of estradiol on CREB phosphorylation. The latter effects of progesterone on the pCREB response and spine formation were reversed by indomethacin, which prevents the conversion of progesterone to the neurosteroid tetrahydroprogesterone (THP). We therefore examined if the progesterone effects were caused by its active metabolite THP. Progesterone treatment caused a 60-fold increase in THP in the cu Itu re medium. THP itself enhanced spontaneous GABAergic activity in patch-clamped cultured neurons. Finally, THP blocked the estradiol-induced increase in spine density. These results suggest that progesterone, through conversion to THP, blocks the effects of estradiol on dendritic spines not via a direct nuclear receptor interaction but by counteracting the enhanced excitability produced by estradiol in the cultured network. Copyright (C) 2000 S. Karger AG, Basel. C1 Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. NINDS, NIH, Bethesda, MD USA. RP Segal, M (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. NR 32 TC 48 Z9 48 U1 0 U2 1 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 0028-3835 J9 NEUROENDOCRINOLOGY JI Neuroendocrinology PD SEP PY 2000 VL 72 IS 3 BP 133 EP 143 DI 10.1159/000054580 PG 11 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 364CZ UT WOS:000089875600001 PM 11025407 ER PT J AU Blair, IP Bennett, CL Abel, A Rabin, BA Griffin, JW Fischbeck, KH Cornblath, DR Chance, PF AF Blair, IP Bennett, CL Abel, A Rabin, BA Griffin, JW Fischbeck, KH Cornblath, DR Chance, PF TI A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34 SO NEUROGENETICS LA English DT Article DE amyotrophic lateral sclerosis; ALS4 locus; fine mapping of ALS4 ID HUMAN GENOME; LINKAGE; MAP; CANDIDATE; CELLS; LOCUS; TSC1; RAS AB Amyotrophic lateral sclerosis (ALS) denotes a heterogeneous group of neurodegenerative disorders affecting upper and lower motor neurons, ALS4 is a juvenile-onset, autosomal dominant form of ALS that is characterized by slow progression, distal limb weakness and amyotrophy, and pyramidal signs associated with severe loss of motor neurons in the brain and spinal cord. The ALS4 locus was recently mapped by linkage analysis to a large genetic interval on chromosome 9q34. By undertaking extensive genetic linkage analysis, we have significantly refined the ALS4 locus to a critical interval of less than 3 cM, flanked by D9S149 and D9S1198. Previous physical mapping in this region has indicated that this critical interval spans approximately 500 kb. Seventeen putative transcripts have been localized within this interval including 7 characterized genes, 2 partially characterized genes, and 8 "anonymous" expressed sequence tags, These are therefore positional candidate genes for the ALS4 locus. We have also undertaken mutation analysis and genetic mapping to investigate and exclude candidate genes, including RING3L/ORFX and RALGDS, from a pathogenic role in ALS4. C1 Univ Washington, Sch Med, Dept Pediat, Div Genet & Dev, Seattle, WA 98195 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. RP Chance, PF (reprint author), Univ Washington, Sch Med, Dept Pediat, Div Genet & Dev, Box 356320, Seattle, WA 98195 USA. NR 27 TC 30 Z9 30 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD SEP PY 2000 VL 3 IS 1 BP 1 EP 6 PG 6 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 362BP UT WOS:000089759000001 PM 11085590 ER PT J AU Kluwe, L Mautner, V Parry, DM Jacoby, LB Baser, M Gusella, J Davis, K Stavrou, D MacCollin, M AF Kluwe, L Mautner, V Parry, DM Jacoby, LB Baser, M Gusella, J Davis, K Stavrou, D MacCollin, M TI The parental origin of new mutations in neurofibromatosis 2 SO NEUROGENETICS LA English DT Article DE parental origin; neurofibromatosis 2; allele loss; mosaicism ID GERM-LINE MUTATIONS; NF2 GENE; TYPE-2 NEUROFIBROMATOSIS; SPORADIC MENINGIOMAS; DINUCLEOTIDE REPEAT; RETINOBLASTOMA GENE; SOMATIC MUTATIONS; TUMOR-SUPPRESSOR; PATERNAL ORIGIN; SCHWANNOMAS AB Neurofibromatosis 2 (NF2) is an autosomal dominant disorder characterized by schwannomas and meningiomas that develop after inactivation of both copies of the NF2 gene. Approximately half of all patients with NF2 have unaffected parents and the disease results from new mutations at the NF2 locus. Loss of heterozygosity (LOH) in tumor specimens due to deletions covering the normal NF2 allele can be used to infer the haplotypes surrounding underlying mutations and determine the allelic origin of new mutations. We studied 71 sporadic NF2 patients using both LOH and pedigree analysis and compared the parental origin of the new mutation with the underlying molecular change. In the 45 informative individuals, 31 mutations (69%) mere of paternal and 14 (31%) were of maternal origin (P=0.016). Comparison with corresponding constitutional mutations revealed no correlation between parental origin and the type or location of the mutations. However, in 4 of 6 patients with somatic mosaicism the NF2 mutation was of maternal origin. A slight parent of origin effect on severity of disease was found. Further clinical and molecular studies are needed to determine the basis of these unexpected observations. C1 Univ Hamburg, Hosp Eppendorf, Dept Neurosurg, Lab Brain Tumor Biol, D-20246 Hamburg, Germany. Gen Hosp Ochsnezoll, Dept Neurol, Hamburg, Germany. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Mol Neurogenet Unit, Charlestown, MA USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Univ Hamburg, Hosp Eppendorf, Dept Neuropathol, D-20246 Hamburg, Germany. RP Kluwe, L (reprint author), Univ Hamburg, Hosp Eppendorf, Dept Neurosurg, Lab Brain Tumor Biol, Martinistr 52, D-20246 Hamburg, Germany. FU NCI NIH HHS [CA51410] NR 48 TC 19 Z9 20 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1364-6745 J9 NEUROGENETICS JI Neurogenetics PD SEP PY 2000 VL 3 IS 1 BP 17 EP 24 DI 10.1007/s100480000088 PG 8 WC Genetics & Heredity; Clinical Neurology SC Genetics & Heredity; Neurosciences & Neurology GA 362BP UT WOS:000089759000003 PM 11085592 ER PT J AU Mattay, VS Callicott, JH Bertolino, A Heaton, I Frank, JA Coppola, R Berman, KF Goldberg, TE Weinberger, DR AF Mattay, VS Callicott, JH Bertolino, A Heaton, I Frank, JA Coppola, R Berman, KF Goldberg, TE Weinberger, DR TI Effects of dextroamphetamine on cognitive performance and cortical activation SO NEUROIMAGE LA English DT Article DE catecholamines; dopamine; dextroamphetamine; BOLD fMRI; cognition; cortical activation; working memory ID POSITRON-EMISSION TOMOGRAPHY; AUTOMATED IMAGE REGISTRATION; PREFRONTAL CORTEX; WORKING-MEMORY; FUNCTIONAL MRI; EXTRASTRIATE CORTEX; NEURONAL-ACTIVITY; MODULATION; DOPAMINE; SCHIZOPHRENIA AB Monoaminergic neurotransmitters are known to have modulatory effects on cognition and on neurophysiological function in the cortex. The current study was performed with BOLD fMRI to examine physiological correlates of the effects of dextroamphetamine on working-memory performance in healthy controls. In a group analysis dextroamphetamine increased BOLD signal in the right prefrontal cortex during a task with increasing working-memory load that approached working-memory capacity. However, the effect of dextroamphetamine on performance and on signal change varied across individuals. Dextroamphetamine improved performance only in those subjects who had relatively low working-memory capacity at baseline, whereas in the subjects who had high working-memory capacity at baseline, it worsened performance. In subjects whose performance deteriorated, signal change was greater than that in subjects who had an improvement in performance, and these variations were correlated (Spearman rho = 0.89, P < 0.02). These data shed light on the manner in which monoaminergic tone, working memory, and prefrontal function interact and, moreover, demonstrate that even in normal subjects the behavioral and neurophysiologic effects of dextroamphetamine are not homogeneous. These heterogeneic effects of dextroamphetamine may be explained by genetic variations that interact with the effects of dextroamphetamine. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, Off Intramural Res, Bethesda, MD 20892 USA. RP Mattay, VS (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Callicott, Joseph/C-9102-2009; Bertolino, Alessandro/O-6352-2016 OI Callicott, Joseph/0000-0003-1298-3334; Bertolino, Alessandro/0000-0002-1251-1380 NR 43 TC 197 Z9 200 U1 2 U2 12 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD SEP PY 2000 VL 12 IS 3 BP 268 EP 275 DI 10.1006/nimg.2000.0610 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 350AX UT WOS:000089079300003 PM 10944409 ER PT J AU Karp, BI Laureno, R AF Karp, BI Laureno, R TI Central pontine and extrapontine myelinolysis after correction of hyponatremia SO NEUROLOGIST LA English DT Review DE myelinolysis; hyponatremia ID OSMOTIC DEMYELINATION SYNDROME; CENTRAL-NERVOUS-SYSTEM; ELECTROLYTE-INDUCED DEMYELINATION; MAGNETIC-RESONANCE SPECTROSCOPY; LIVER-TRANSPLANT RECIPIENTS; RAPID CORRECTION; ORGANIC OSMOLYTES; BRAIN-DAMAGE; SERUM SODIUM; NEUROLOGICAL COMPLICATIONS AB BACKGROUND- Central pontine myelinolysis can cause pseudobulbar palsy, quadriplegia, and death attributable to symmetric myelin damage in the center of the basis pontis. Extrapontine myelinolysis symmetrically affects thalamocapsular regions, neostriatum, and other territories. Myelinolysis usually results from the rapid correction of hyponatremia. REVIEW SUMMARY- The clinical spectrum of myelinolysis includes seemingly asymptomatic cases, transient encephalopathies, mutism, behavioral changes, stupor, and coma in addition to the classic syndrome of spastic quadriparesis and pseudobulbar palsy. As paralysis resolves, movement disorders or ataxia may become evident. Magnetic resonance imaging is the best diagnostic test, but the lesions may not be visible until 1 to 2 weeks after the onset of the illness. Myelinolysis can follow a rapid (greater than or equal to 10 mEq/L/d) rise in sodium regardless of the cause of hyponatremia and method of therapy. It is more to occur after correction of chronic hyponatremia (greater than or equal to 48-hour duration) than acute hyponatremia. CONCLUSIONS- To minimize the incidence of myelinolysis, the therapeutic rise in sodium associated with the management of hyponatremia should be less than 10 mEq/L on the first day of treatment whenever possible. An even slower rate of correction is adequate after hyponatremic symptoms are controlled. Because the rise in sodium is unpredictable in a given individual, frequent monitoring of the sodium level is necessary. Should the sodium rise more quickly than anticipated, relowering of the sodium level may help minimize morbidity. The administration of dilute fluid and deamino-8-D-arginine vasopressin has been used for this purpose in the initial days of myelinolytic symptoms. When severe symptoms of myelinolysis are established despite all efforts, supportive care may allow good recovery over the following months. C1 Washington Hosp Ctr, Dept Neurol, Washington, DC 20010 USA. NINDS, NIH, Bethesda, MD 20892 USA. George Washington Univ, Sch Med, Dept Neurol, Washington, DC USA. NR 137 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1074-7931 J9 NEUROLOGIST JI Neurologist PD SEP PY 2000 VL 6 IS 5 BP 255 EP 266 DI 10.1097/00127893-200006050-00002 PG 12 WC Clinical Neurology SC Neurosciences & Neurology GA 356CK UT WOS:000089426500002 ER PT J AU Putney, JW AF Putney, JW TI Presenilins, Alzheimer's disease, and capacitative calcium entry SO NEURON LA English DT Editorial Material ID CA2+ C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 13 TC 18 Z9 19 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP PY 2000 VL 27 IS 3 BP 411 EP 412 DI 10.1016/S0896-6273(00)00048-9 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 359FR UT WOS:000089601300002 PM 11055420 ER PT J AU Webster, HD AF Webster, HD TI Section on Cellular Neuropathology, NINDS, National Institutes of Health, Bethesda, Maryland SO NEUROPATHOLOGY LA English DT Article ID MYELIN-ASSOCIATED GLYCOPROTEIN; MULTIPLE-SCLEROSIS LESIONS; ALLERGIC ENCEPHALOMYELITIS EAE; ACIDIC PROTEIN GFAP; BASIC-PROTEIN; FIBER REGENERATION; DEVELOPING RAT; SCHWANN-CELLS; AGING MICE; OLIGODENDROGLIA C1 NIH, Bethesda, MD 20892 USA. NR 26 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0919-6544 J9 NEUROPATHOLOGY JI Neuropathology PD SEP PY 2000 VL 20 SU S BP S105 EP S107 PG 3 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 375PA UT WOS:000165409400027 ER PT J AU Lipska, BK Weinberger, DR AF Lipska, BK Weinberger, DR TI To model a psychiatric disorder in animals: Schizophrenia as a reality test SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE schizophrenia; animal models; neurodevelopment; glutamate; genetic models ID NEONATAL HIPPOCAMPAL-LESIONS; MEDIAL TEMPORAL-LOBE; BORNA-DISEASE VIRUS; INTRACEREBROVENTRICULAR KAINIC ACID; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; PRENATAL PROTEIN-MALNUTRITION; ACCUMBENS DOPAMINE RESPONSE; PYRAMIDAL CELL DISARRAY; PREFRONTAL CORTEX; PREPULSE INHIBITION AB Animal modeling has been instrumental in dissecting pathophysiological mechanisms and designing more effective therapies in many areas of medicine but not so in psychiatry. The critical obstacle in modeling psychiatric disorders has been limited information about their origin and underlying neural mechanisms. Recently, with rapidly growing knowledge about the neurobiology and genetics of psychiatric disorders, animal models of these diseases are gaining popularity in psychiatric research. New models of schizophrenia mimic biological phenomena associated with the clinical condition, particularly developmental changes in the cortex, abnormalities of glutamate neurotransmission, and genetic characteristics of selected behavioral traits. The biological fidelity of some aspects of these new models suggests that they will be useful in the development of new therapies, in identifying candidate genes, and in providing new insights about pathophysiology and etiology. (C) 2000 American College of Neuropsychopharmacology. Published by Elsevier Science Inc. All right reserved. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Lipska, BK (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RI Lipska, Barbara/E-4569-2017 NR 185 TC 421 Z9 438 U1 3 U2 27 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2000 VL 23 IS 3 BP 223 EP 239 DI 10.1016/S0893-133X(00)00137-8 PG 17 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 347BA UT WOS:000088905300002 PM 10942847 ER PT J AU Funabashi, T Kleopoulos, SP Brooks, PJ Kimura, F Pfaff, DW Shinohara, K Mobbs, CV AF Funabashi, T Kleopoulos, SP Brooks, PJ Kimura, F Pfaff, DW Shinohara, K Mobbs, CV TI Changes in estrogenic regulation of estrogen receptor alpha mRNA and progesterone receptor mRNA in the female rat hypothalamus during aging: an in situ hybridization study SO NEUROSCIENCE RESEARCH LA English DT Article DE estrogen; estrogen receptor alpha mRNA; progesterone receptor mRNA; aging; ventromedial hypothalamus; preoptic area; in situ hybridization; senescence ID MESSENGER-RIBONUCLEIC-ACID; MEDIAL PREOPTIC NUCLEUS; AGE-RELATED-CHANGES; INSITU HYBRIDIZATION; LUTEINIZING-HORMONE; GENE-EXPRESSION; MEDIOBASAL HYPOTHALAMUS; C57BL/6J MICE; BRAIN; ESTRADIOL AB We examined two molecular responses to estrogen: reduction in estrogen receptor alpha (ER alpha) mRNA and increase in progesterone receptor (PR) mRNA, in the hypothalamus of 3- (young) and 10-month-old (middle-aged) cycling, and 15-month-old (old) acyclic, Fischer 344 female rats. The rats were ovariectomized and then given silastic capsules containing 5% 17 beta-estradiol: or empty implants. and killed 4 days after implantation. By means of in situ hybridization, we found that. in young rats, estrogen reduced ER alpha mRNA in both the ventromedial hypothalamus (VMH) and arcuate nucleus (ARC) but not in the preoptic area (POA). In contrast, the effect of estrogen on ER alpha mRNA in the VMH and ARC of middle-aged and old rats was not statistically significant. On the other hand in all regions the induction of PR mRNA by estrogen was at least as strong in middle-aged and old as in young rats. The present study revealed that the induction of PR mRNA by estrogen in the hypothalamus was not impaired with age but ER alpha mRNA in the VMH and ARC was significantly impaired with age: but not in the POA. (C) 2000 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved. C1 Rockefeller Univ, Neurobiol & Behav Lab, New York, NY 10021 USA. Mt Sinai Sch Med, New York, NY 10128 USA. VA Med Ctr, Fishberg Ctr Neurobiol, Bronx, NY USA. Yokohama City Univ, Sch Med, Dept Physiol, Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan. NIAAA, Neurogenet Lab, Mol Neurobiol Sect, NIH, Rockville, MD 20852 USA. RP Funabashi, T (reprint author), Rockefeller Univ, Neurobiol & Behav Lab, 1230 York Ave, New York, NY 10021 USA. NR 37 TC 47 Z9 49 U1 0 U2 2 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0168-0102 J9 NEUROSCI RES JI Neurosci. Res. PD SEP PY 2000 VL 38 IS 1 BP 85 EP 92 DI 10.1016/S0168-0102(00)00150-4 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 350BC UT WOS:000089080000010 PM 10997581 ER PT J AU Koch, CA Heiss, JD Pacak, K Krakoff, J Winer, KK Wassermann, EM AF Koch, CA Heiss, JD Pacak, K Krakoff, J Winer, KK Wassermann, EM TI Chiari malformation type 1 and osteoporosis SO NEUROSURGICAL REVIEW LA English DT Letter ID POSTERIOR CRANIAL FOSSA; I MALFORMATION; PATHOGENESIS; MANAGEMENT; RICKETS; MR C1 NICHD, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Koch, CA (reprint author), NICHD, NIH, Bldg 10,Room 10N262, Bethesda, MD 20892 USA. RI Koch, Christian/A-4699-2008; OI Koch, Christian/0000-0003-3127-5739; Koch, Christian/0000-0003-0678-1242 NR 12 TC 2 Z9 2 U1 0 U2 0 PU WALTER DE GRUYTER & CO PI BERLIN PA GENTHINER STRASSE 13, D-10785 BERLIN, GERMANY SN 0344-5607 J9 NEUROSURG REV JI Neurosurg. Rev. PD SEP PY 2000 VL 23 IS 3 BP 171 EP 172 DI 10.1007/PL00011952 PG 2 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 372QT UT WOS:000165245900013 PM 11086745 ER PT J AU Paule, MG Rowland, AS Ferguson, SA Chelonis, JJ Tannock, R Swanson, JM Castellanos, FX AF Paule, MG Rowland, AS Ferguson, SA Chelonis, JJ Tannock, R Swanson, JM Castellanos, FX TI Attention deficit/hyperactivity disorder: characteristics, interventions, and models SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Review DE attention deficit disorder; epidemiology; prevalence; rodent models; cerebellar stunting; short-term memory; cognitive markers; treatment; stimulant medication; multimodal interventions; neuroimaging; prefrontal cortex; dopaminergic dysfunction ID DEFICIT-HYPERACTIVITY DISORDER; SPONTANEOUSLY HYPERTENSIVE RATS; OPERANT TEST BATTERY; IV FIELD TRIALS; CEREBRAL GLUCOSE-METABOLISM; CORPUS-CALLOSUM MORPHOLOGY; OF-ONSET CRITERION; WISTAR-KYOTO RAT; MAGNETIC-RESONANCE; INHIBITORY CONTROL AB An epidemiological study of Attention Deficit/Hyperactivity Disorder (ADHD) suggests that the prevalence may be two to three times higher than the figure of 3-5% often cited. In addition, the data suggest that both underdiagnosis and overdiagnosis occur frequently. Rodent animal models of ADHD, like the Spontaneously Hypertensive Rat (SHR) and other rat models such as those with chemical and radiation-induced brain lesions and cerebellar stunting, and the Coloboma mouse model exhibit clear similarities with several aspects of the human disorder and should prove useful in studying specific traits. Operant behavioral tasks that model learning, short-term memory and simple discriminations are sensitive to ADHD and methylphenidate has been shown to normalize ADHD performance in a short-term memory task. Recent findings challenge not only the current postulate that response inhibition is a unique deficit in ADHD, but also the concepts of ADHD and its treatment, which presume intact perceptual abilities. Time perception deficits may account, in part, for the excessive variability in motor response times on speeded reaction time tasks, motor control problems and motor clumsiness associated with ADHD. The Multimodality Treatment Study of ADHD (MTA) provided data suggesting that pharmacological interventions that included systematic and frequent follow-up with parents and teachers, with or without psychosocial interventions, are superior to psychosocial interventions or standard community care alone. Additionally, the MTA was one of the first studies to demonstrate benefits of multimodal and pharmacological interventions lasting longer than 1 year. Imaging studies have demonstrated differences in brain areas in children with ADHD: anterior corpus callosum, right anterior white matter, and cerebellar volumes are all decreased in children with ADHD and there is less brain asymmetry in ADHD subjects. Additionally, functional imaging studies, coupled with pharmacological manipulations, suggest decreased blood flow and energy utilization in prefrontal cortex and striatum, and the dysregulation of catecholamine systems in persons with ADHD. (C) 2000 Elsevier Science Inc. All rights reserved. C1 Natl Ctr Toxicol Res, Div Neurotoxicol, Beh Toxicol Lab, Jefferson, AR 72079 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ Arkansas, Dept Psychol, Little Rock, AR 72204 USA. Hosp Sick Children, Res Inst, Brain & Behav Res Programme Psychiat Res, Toronto, ON M5G 1X8, Canada. Univ Calif Irvine, Child Dev Ctr, Irvine, CA 92612 USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Paule, MG (reprint author), Natl Ctr Toxicol Res, Div Neurotoxicol, Beh Toxicol Lab, HFT-132,3900 NCTR Rd, Jefferson, AR 72079 USA. NR 240 TC 71 Z9 74 U1 9 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD SEP-OCT PY 2000 VL 22 IS 5 BP 631 EP 651 DI 10.1016/S0892-0362(00)00095-7 PG 21 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 381NR UT WOS:000165769900003 PM 11106857 ER PT J AU Davis, J Krasnewich, D Puck, JM AF Davis, J Krasnewich, D Puck, JM TI Genetic testing and screening in pediatric populations SO NURSING CLINICS OF NORTH AMERICA LA English DT Article ID CHILDREN; IMMUNODEFICIENCY AB It is conceivable that in the near future a family could present themselves to their health care provider and request to be tested for diseases X, Y, and Z, equipped only with a web page listing of disease-causing genes. The testing of children suggests subtle and controversial inherent conflicts, however. Decisions about whether to provide genetic testing become increasingly murky for a health care professional as the requests advance from testing a child for carrier status for an autosomal recessive disorder, to testing a girl for a sex-linked mutation, to testing an asymptomatic child for a susceptibility to a particular disorder. Although no single case can exemplify every variable and circumstance confronting health care professionals today, this case-based discussion of x-linked severe combined immune deficiency can serve as a framework to examine some of the potential dilemmas surrounding the testing of children for genetic disorders. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Nursing, Baltimore, MD USA. RP Davis, J (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bldg 10,Room 3C710,MSC 1253,10 Ctr Dr, Bethesda, MD 20892 USA. NR 14 TC 1 Z9 1 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0029-6465 J9 NURS CLIN N AM JI Nurs. Clin. North Am. PD SEP PY 2000 VL 35 IS 3 BP 643 EP + PG 10 WC Nursing SC Nursing GA 357XX UT WOS:000089528300006 PM 10957679 ER PT J AU Fibison, WJ AF Fibison, WJ TI Gene therapy SO NURSING CLINICS OF NORTH AMERICA LA English DT Article ID ADENOSINE-DEAMINASE DEFICIENCY; SEVERE COMBINED IMMUNODEFICIENCY; BONE-MARROW TRANSPLANTATION; LYMPHOCYTES; DISEASES; CELLS; GANCICLOVIR; RETROVIRUS; EXPRESSION; SEQUENCES AB Gene therapy represents a fundamentally new way to treat disease. Originally conceived as an approach to hereditary disease, it is now being applied to a broad range of acquired conditions such as infections, cancers, and degenerative disorders. A current overview of gene therapy is presented in this article, including descriptions of two clinical protocols and perspectives for new directions. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Fibison, WJ (reprint author), NHGRI, Clin Gene Therapy Branch, NIH, Bldg 10,10C103, Bethesda, MD 20892 USA. NR 57 TC 5 Z9 5 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 0029-6465 J9 NURS CLIN N AM JI Nurs. Clin. North Am. PD SEP PY 2000 VL 35 IS 3 BP 757 EP + PG 17 WC Nursing SC Nursing GA 357XX UT WOS:000089528300015 PM 10957688 ER PT J AU McCarthy, NJ Swain, SM AF McCarthy, NJ Swain, SM TI Update on adjuvant chemotherapy for early breast cancer SO ONCOLOGY-NEW YORK LA English DT Article ID HIGH-DOSE CHEMOTHERAPY; RANDOMIZED TRIAL; DOXORUBICIN-CYCLOPHOSPHAMIDE; PREMENOPAUSAL WOMEN; STAGE-II; C-ERBB-2 EXPRESSION; THERAPY; FLUOROURACIL; METHOTREXATE; TAMOXIFEN AB Adjuvant chemotherapy represents a significant advance in the management of early-stage breast cancer and, as such, has saved many lives, Worldwide, adjuvant chemotherapy has benefitted all groups tested, including pre- and postmenopausal women, those with node-negative and node-positive disease, and those with estrogen-receptor (ER)-positive and ER-negative disease. However, the significant number of women who relapse despite adjuvant therapy provides the impetus to develop more efficacious regimens. Results from large randomized clinical trials, which will mature over the next few years, will clarify the potential benefits of the taxanes in the adjuvant setting, provide answers as to the efficacy of a dose-dense approach, and define a role, if any, for high-dose chemotherapy. A shift toward targeted therapies has also begun, with the incorporation of trastuzumab (Herceptin) into the adjuvant setting. Minimizing the long-term toxicity of adjuvant therapy for the large number of women who survive their disease is paramount. This article highlights the need to develop predictive factors to help tailor individual therapy. C1 NCI, Div Clin Sci, Med Branch, NIH, Bethesda, MD 20892 USA. RP Swain, SM (reprint author), NCI, Div Clin Sci, Med Branch, NIH, 10 Ctr Dr,Bldg 10 Room 12N 226, Bethesda, MD 20892 USA. RI McCarthy, Nicole/A-3468-2013 NR 68 TC 9 Z9 9 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD SEP PY 2000 VL 14 IS 9 BP 1267 EP + PG 12 WC Oncology SC Oncology GA 368QU UT WOS:000090129700005 PM 11033824 ER PT J AU Reed, E Dabholkar, M Thornton, K Thompson, C Yu, JJ Bostick-Bruton, F AF Reed, E Dabholkar, M Thornton, K Thompson, C Yu, JJ Bostick-Bruton, F TI Evidence for 'order' in the appearance of mRNAs of nucleotide excision repair genes, in human ovarian cancer tissues SO ONCOLOGY REPORTS LA English DT Article DE nucleotide excision repair; ovarian cancer; ERCC1; XPB; CSB; XPA ID INTERSTRAND CROSS-LINKS; A XERODERMA-PIGMENTOSUM; YEAST DNA-REPAIR; ERCC1; EXPRESSION; CELLS; HELICASES; MUTATION; PROTEINS; NUCLEASE AB Nucleotide excision repair (NER) is the DNA repair pathway through which cisplatin-DNA intrastrand adduct is repaired. Clinical studies have shown that increased mRNA expression of selected genes involved in the rate-limiting step of NER, appear to be closely associated with clinical resistance to platinum agents. These specific studies have led to the possibility of an assessment of the order in which, the appearance of mRNAs of selected NER genes may occur. Included in this assessment are ERCC1, XPB, CSB, and XPA, studied in 28 ovarian cancer tumor tissue specimens. The study of these four genes, in pairs, from 28 ovarian cancer specimens, results in 168 separate observations. Based on the mRNA expression patterns of these genes in these tissues, it is suggested that ERCC1 mRNA may appear before the mRNA of any of the other genes, in an obligate fashion. This is followed by XPB mRNA; which appears before the mRNA of XPA; which in turn, may appear before CSB. This pattern is consistent with what we have reported previously, in non-malignant human bone marrow specimens from a cohort of 52 patients. C1 NCI, Med Ovarian Canc Sect, Med Branch, NIH, Bethesda, MD 20892 USA. RP Reed, E (reprint author), NCI, Med Ovarian Canc Sect, Med Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 12N226, Bethesda, MD 20892 USA. EM reed92@helix.nih.gov NR 35 TC 22 Z9 26 U1 0 U2 0 PU SPANDIDOS PUBL LTD PI ATHENS PA POB 18179, ATHENS, 116 10, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD SEP-OCT PY 2000 VL 7 IS 5 BP 1123 EP 1128 PG 6 WC Oncology SC Oncology GA 342LC UT WOS:000088645200035 PM 10948350 ER PT J AU Baccaglini, L Pillemer, SR Baum, BJ AF Baccaglini, L Pillemer, SR Baum, BJ TI Sjogren's syndrome: a possible pathogenetic mechanism involving somatostatin SO ORAL DISEASES LA English DT Article DE Sjogren's syndrome; somatostatin; salivary glands; autoimmunity; hormones ID CYCLIC-AMP; CELL-LINE; MODULATION; EXPRESSION; SECRETION; AXIS; GENE AB Sjogren's syndrome is a chronic systemic disease that primarily affects the salivary and lacrimal glands, The pathogenesis of Sjogren's syndrome is unknown. We hypothesize that reduced somatostatin activity is an important factor in promoting immune dysregulation in patients affected by Sjogren's syndrome. Somatostatin is a multifunctional peptide with potent immunomodulatory properties. Its effects include reduced lymphocytic activity, reduced gastric and intestinal secretions, activation of the hypothalamic-pituitary axis, and anti-inflammatory action, all opposite to the general presentation in Sjogren's syndrome, We suggest that the activity of somatostatin is low in patients affected by this disease, and this contributes significantly to the pathology observed. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, Sjogrens Syndrome Clin, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, Sjogrens Syndrome Clin, NIH, Bldg 10,1N113,MSC-1190, Bethesda, MD 20892 USA. NR 22 TC 0 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1354-523X J9 ORAL DIS JI Oral Dis. PD SEP PY 2000 VL 6 IS 5 BP 264 EP 266 PG 3 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 358YU UT WOS:000089585400002 PM 11002406 ER PT J AU Horowitz, AM Drury, TF Canto, MT AF Horowitz, AM Drury, TF Canto, MT TI Practices of Maryland dentists: oral cancer prevention and early detection - baseline data from 1995 SO ORAL DISEASES LA English DT Article DE dentists, oral cancer; prevention; examinations; health history ID KNOWLEDGE; OPINIONS; TOBACCO AB OBJECTIVES: To investigate practices and opinions of general dentists in Maryland, USA, related to oral and pharyngeal cancer prevention and early detection. DESIGN AND METHODS: A pre-tested, 34-item questionnaire, cover letter and addressed, stamped envelope were mailed in the summer, 1995, to a simple random sample of 800 members and non-members of the American Dental Association practicing in Maryland. A reminder postcard was sent 3 weeks after initial mailing; a second complete mailing to all non-respondents 6 weeks after first mailing, RESULTS: Over 90% of dentists asked about patient's current use of tobacco but only 77% assessed patient's history of tobacco use and types and amounts used. Fewer (66%) asked about present use of alcohol. Ninety percent reported providing an oral cancer examination at the initial appointment for patients 40 years of age or older; only 6% provided the examination for edentulous patients and only 40% reported palpating lymph nodes of patients 80% or more of the time. CONCLUSIONS: Dentists' reporting on providing oral cancer examinations and taking appropriate health histories are disappointing. These results call for comprehensive educational interventions in terms of changes in dental curricula and as continuing education courses especially since most dentists were interested in continuing education courses on oral cancer prevention and early detection. C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NCI, NIH, Bethesda, MD 20892 USA. RP Horowitz, AM (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 14 TC 29 Z9 30 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1354-523X J9 ORAL DIS JI Oral Dis. PD SEP PY 2000 VL 6 IS 5 BP 282 EP 288 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 358YU UT WOS:000089585400006 PM 11002410 ER PT J AU Reid, BC Winn, DM Morse, DE Pendrys, DG AF Reid, BC Winn, DM Morse, DE Pendrys, DG TI Head and neck in situ carcinoma: incidence, trends, and survival SO ORAL ONCOLOGY LA English DT Article DE carcinoma in situ; epidemiology; head and neck neoplasms; SEER program ID UPPER AERODIGESTIVE TRACT; MALIGNANT TRANSFORMATION; INSITU; LEUKOPLAKIA; DYSPLASIA; CANCER AB This analysis describes the epidemiology of in situ head and neck carcinomas (anatomic sites of lip, oral cavity, pharynx, larynx) about which there is limited knowledge. Data were derived from nine population-based cancer registries participating in the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program. SEER annual age-adjusted incidence rates for in situ head and neck carcinomas increased from 6.33/1,000,000 person-years (PY) in 1976 to 8.04/1,000,000 PY in 1995 [percent change (PC) = 35%, P < 0.001]. From 1976 to 1995 age-adjusted changes in incidence by anatomic site ranged from 53% PC (larynx) to -11% PC (lip) (both P < 0.005). Incidence and survival associated with in situ head and neck carcinomas varied by anatomic site, age, sex, and race and did so in a pattern similar to that seen for invasive carcinomas of this region. However, the climbing incidence of in situ carcinoma, which may be related to increased surveillance, contrasts sharply with the declining incidence of invasive carcinoma. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 NIDCR, Craniofacial Genet & Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ Connecticut, Sch Dent Med, Oral Epidemiol Training Program, Farmington, CT 06032 USA. Univ Connecticut, Sch Dent Med, Dept Behav Sci, Farmington, CT 06032 USA. RP Reid, BC (reprint author), NIDCR, Craniofacial Genet & Epidemiol Branch, NIH, Bldg 45,Room 4AS-43C,Ctr Dr, Bethesda, MD 20892 USA. FU NIDCR NIH HHS [DE-T255] NR 19 TC 31 Z9 31 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0964-1955 J9 ORAL ONCOL JI Oral Oncol. PD SEP PY 2000 VL 36 IS 5 BP 414 EP 420 DI 10.1016/S1368-8375(00)00028-2 PG 7 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 347YC UT WOS:000088955900003 PM 10964047 ER PT J AU Leethanakul, C Patel, V Gillespie, J Shillitoe, E Kellman, RM Ensley, JF Limwongse, V Emmert-Buck, MR Krizman, DB Gutkind, JS AF Leethanakul, C Patel, V Gillespie, J Shillitoe, E Kellman, RM Ensley, JF Limwongse, V Emmert-Buck, MR Krizman, DB Gutkind, JS TI Gene expression profiles in squamous cell carcinomas of the oral cavity: use of laser capture microdissection for the construction and analysis of stage-specific cDNA libraries SO ORAL ONCOLOGY LA English DT Article DE oral cancer; gene expression; CGAP; tumor progression ID CANCER STATISTICS; NECK-CANCER; PROTEINS; TISSUES; LESIONS; CLONING; MCP-3; HEAD AB Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer among men in the developed world affecting the oral cavity, salivary glands, larynx and pharynx. Utilizing tissue from patients with HNSCC, we sought to systematically identify and catalog genes expressed in HNSCC progression, Here, we demonstrate the successful use of laser capture microdissection for procuring pure populations of cells from patient tissue sets comprised of oral squamous cell carcinomas (OSCCs) and matching normal tissue. From the estimated 5000 cells procured for each sample, we were able to extract total RNA (14.7-18.6 ng) of sufficient quality to transcribe GAPDH by reverse transcriptase-polymerase chain reaction (RT-PCR). The RNA was used for the synthesis of blunt-ended, double-strand complementary DNAs (cDNAs) by oligo (dT)-mediated reverse transcription, followed by addition of linkers. Primers specific for these linkers with uracil deglycosylase-compatible ends were used to amplify these cDNAs by PCR and the product was subcloned into the pAMP10 cloning vector. Ninety-six clones from each of six libraries were randomly sequenced and results indicated that 76-96% of the inserts represent either anonymous expressed sequence tags (ESTs) (25-48%), known genes (9-29%) or novel sequences (27-51%), respectively, with very little redundancy. These results demonstrate that high quality, representative cDNA libraries can be generated from microdissected OSCC tissue. Furthermore, these finding suggest the existence of at least 132 novel genes expressed in our cDNA libraries, which may have a role in the pathogenesis of HNSCC, and may represent novel markers for early detection as well as targets for pharmacological intervention in this disease. Published by Elsevier Science Ltd. C1 NCI, Canc Genome Anat Project, Off Director, NIH,Adv Technol Ctr, Gaithersburg, MD 20877 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathogenet Unit, Pathol Lab, Canc Genome Anat Project,NIH, Bethesda, MD 20892 USA. SUNY Upstate Med Univ, Dept Microbiol & Immunol, Syracuse, NY 13210 USA. SUNY Upstate Univ, Dept Commun Sci, Syracuse, NY 13210 USA. Wayne State Univ, Div Hematol Oncol, Detroit, MI 48201 USA. Chulalongkorn Univ, Fac Dent, Bangkok 10330, Thailand. RP Krizman, DB (reprint author), NCI, Canc Genome Anat Project, Off Director, NIH,Adv Technol Ctr, 8717 Grovemont Circle,134F, Gaithersburg, MD 20877 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 28 TC 54 Z9 59 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0964-1955 J9 ORAL ONCOL JI Oral Oncol. PD SEP PY 2000 VL 36 IS 5 BP 474 EP 483 DI 10.1016/S1368-8375(00)00039-7 PG 10 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 347YC UT WOS:000088955900013 PM 10964057 ER PT J AU Kearns, GL Bradley, JS Jacobs, RF Capparelli, EV James, LP Johnson, KM Abdel-Rahman, SM AF Kearns, GL Bradley, JS Jacobs, RF Capparelli, EV James, LP Johnson, KM Abdel-Rahman, SM CA Pediat Pharmacology Res Unit Netw TI Single dose pharmacokinetics of pleconaril in neonates SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article; Proceedings Paper CT 100th Annual Meeting of the American-Society-of-Clinical-Pharmacology-and-Therapeutics CY MAR 18-20, 1999 CL SAN ANTONIO, TEXAS SP Amer Soc Clin Pharmacol & Therapeut DE pleconaril; neonates; pharmacokinetics; enterovirus ID VP63843 ORAL SOLUTION; ENTEROVIRUS INFECTION; PREMATURE-INFANTS; FAT-ABSORPTION; EPIDEMIOLOGY; MENINGITIS; BACTERIAL; PATHOGENS; CHILDREN; LIPASE AB Background. Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection, Methods, Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years). Results. Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (C-max 686.7 vs. 617.1 ng/ml), elimination half-life (t(1/2); 4.6 us. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V-dss/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg), In addition, no correlation was observed between postconceptional age and AUG, V-dss/F, t(1/2) or Cl/F for pleconaril, Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V-dss/F (9.3 vs, 4.7 liters/kg), dose-normalized C-max (686.7 vs. 1272.5 ng/ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t(1/2) between neonates and children was not appreciably different. Conclusions. The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates, Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection. C1 Childrens Mercy Hosp, Sect Pediat Clin Pharmacol & Expt Therapeut, Kansas City, MO 64108 USA. Univ Missouri, Dept Pediat, Kansas City, MO 64110 USA. Univ Missouri, Dept Pharmacol, Kansas City, MO 64110 USA. Univ Missouri, Dept Pharm Practice, Kansas City, MO 64110 USA. Univ Calif San Diego, Childrens Hosp & Hlth Ctr, Div Infect Dis, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. Univ Arkansas Med Sci, Dept Pediat, Little Rock, AR 72205 USA. Arkansas Childrens Hosp, Div Pediat Infect Dis, Little Rock, AR 72202 USA. Arkansas Childrens Hosp, Div Clin Pharmacol & Toxicol, Little Rock, AR 72202 USA. NICHHD, Pediat Pharmacol Res Unit Network, Bethesda, MD 20892 USA. RP Kearns, GL (reprint author), Childrens Mercy Hosp, Sect Pediat Clin Pharmacol & Expt Therapeut, 2401 Gillham Rd, Kansas City, MO 64108 USA. FU NICHD NIH HHS [1U10 HD31313-06] NR 28 TC 23 Z9 24 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD SEP PY 2000 VL 19 IS 9 BP 833 EP 839 DI 10.1097/00006454-200009000-00005 PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 356EV UT WOS:000089431800004 PM 11001105 ER PT J AU Smith, R Malee, K Charurat, M Magder, L Mellins, C MacMillan, C Hittleman, J Lasky, T Llorente, A Moye, J AF Smith, R Malee, K Charurat, M Magder, L Mellins, C MacMillan, C Hittleman, J Lasky, T Llorente, A Moye, J CA Women Infant Transmission Study G TI Timing of perinatal human immunodeficiency virus type 1 infection and rate of neurodevelopment SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE pediatric human immunodeficiency virus type 1; infection; developmental outcome; early vs. late infant infection ID INFUSION ZIDOVUDINE THERAPY; SYMPTOMATIC HIV-INFECTION; DISEASE PROGRESSION; INFANTS TRANSMISSION; CLINICAL-TRIALS; CHILDREN; WOMEN; INTRAUTERINE; REPLICATION; PREDICTORS AB Background. Identifying HIV-1-infected children who are at greatest risk for disease-related morbidities is critical for optimal therapeutic as well as preventive care. Several factors have been implicated in HIV-1 disease onset and severity, including maternal and infant host characteristics, viral phenotype and timing of HIV-1 infection. Early HIV-1 culture positivity, i.e. intrauterine infection, has been associated with poor immunologic, virologic and clinical outcomes in children of HIV-infected women. However, a direct effect of timing of infection on neurodevelopmental outcome in infancy has not yet been identified. Methods. Serial neurodevelopmental assessments were performed with 114 infants vertically infected with HIV-1 in a multicenter natural history, longitudinal study. Median mental and motor scores were compared at three time points. Longitudinal regression analyses were used to evaluate the neurodevelopmental functioning of children with early positive cultures and those with late positive cultures. Results. Early infected infants scored significantly lower than late infected infants by 24 months of age and beyond on both mental (P = 0.05) and motor (P = 0.03) measures. Early HIV-1 infection was associated with a decline in estimated motor scores of 1 standard score point per month compared with 0.28 point in the late infected group (P < 0.02). Estimated mental. scores of the early infected group declined 0.72 point/month, whereas the average decline of the late infected group was 0.30 point/month (P < 0.13). Conclusion. Early HIV-1 infection increases a child's risk for poor neurodevelopmental functioning within the first 30 months of life. C1 Univ Illinois, Chicago, IL 60612 USA. Northwestern Univ, Childrens Mem Hosp, Chicago, IL 60614 USA. Inst Human Virol, Baltimore, MD USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Baylor Coll Med, Houston, TX 77030 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Smith, R (reprint author), Univ Illinois, 840 S Wood St,M-C 856, Chicago, IL 60612 USA. OI moye, john/0000-0001-9976-8586 FU NIAID NIH HHS [U01 AI 34856, U01 AI 34842, U01 AI 34858] NR 45 TC 40 Z9 41 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD SEP PY 2000 VL 19 IS 9 BP 862 EP 871 DI 10.1097/00006454-200009000-00010 PG 10 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 356EV UT WOS:000089431800009 PM 11001110 ER PT J AU Howland, LC Gortmaker, SL Mofenson, LM Spino, C Gardner, JD Gorski, H Fowler, MG Oleske, J AF Howland, LC Gortmaker, SL Mofenson, LM Spino, C Gardner, JD Gorski, H Fowler, MG Oleske, J TI Effects of negative life events on immune suppression in children and youth infected with human immunodeficiency virus type 1 SO PEDIATRICS LA English DT Article DE CD4 percentile; life events; pediatric human immunodeficiency virus disease ID HIV-INFECTION; UNITED-STATES; STRESS; BORN; TRANSMISSION; ZIDOVUDINE; PARENTS; PLASMA; AIDS; RNA AB Objectives. To evaluate the association of negative stressful life events experienced over 12 months and the risk of moderate to severe immune suppression among children and youth infected with human immunodeficiency virus type 1 (HIV-1). Methods. Longitudinal study of 618 HIV-1-infected children, baseline ages 1 to 20 years (mean age: 6.4 years), who completed 52 weeks of participation in the Pediatric Late Outcomes Study (Pediatric AIDS Clinical Trials Group Protocol 219). Severity of immune suppression was indicated by the Centers for Disease Control and Prevention Pediatric HIV Disease Classification System, based on CD4 percentages. The total number of negative life events-categorized as none, 1, or >1 life event reported as having occurred in the previous 12 months (previous 6 months for children <3 years of age)-was the predictor variable. Multiple logistic regressions were estimated to assess the relationship of negative life events and immune suppression at outcome, controlling for baseline measures of immune suppression, continuous CD4%, negative life events, age, race/ethnicity, gender, primary caretaker, education level of caretaker, and acquired immunodeficiency syndrome status. Results. At week 52, 379 subjects (61% of total study population) had moderate to severe immune suppression. Of 275 children with normal immune function at baseline, 68 (24.7%) subsequently developed moderate to severe suppression levels by week 52 of follow-up. Of 343 children with immune suppression at baseline, 32 (9.2%) had recovered to normal CD4% levels by week 52. More than 1 negative life event was associated with an increased risk (prevalence) of immune suppression (odds ratio [OR]: 2.76; 95% confidence interval [CI]: 1.44,5.31), controlling for baseline CD4%, total life events, and other covariates. Children without immune suppression at baseline who experienced >1 negative life event had an increased incidence of immune suppression (OR: 2.93; 95% CI: 1.34,6.39), controlling for baseline covariates. Conclusions. Results indicate that negative stressful life events increase the risk of children with HIV-1 infection having impaired immune function. Further research is needed to identify potential mechanisms of the relationship between stressful life events and impaired immune function. These mechanisms include psychoneuroendocrinologic response and difficulties in adherence to therapy after exposure of a child to major negative life events. C1 Harvard Univ, Sch Publ Hlth, Dept Maternal & Child Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. NIAID, Efficacy Trials Branch, Div AIDS, NIH, Bethesda, MD 20892 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pediat, Newark, NJ 07103 USA. RP Howland, LC (reprint author), Univ Massachusetts, Grad Sch Nursing, 55 Lake Ave N, Worcester, MA 01655 USA. OI Mofenson, Lynne/0000-0002-2818-9808 NR 37 TC 33 Z9 35 U1 2 U2 5 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD SEP PY 2000 VL 106 IS 3 BP 540 EP 546 DI 10.1542/peds.106.3.540 PG 7 WC Pediatrics SC Pediatrics GA 350WP UT WOS:000089124900026 PM 10969100 ER PT J AU Persico, AM Mengual, E Moessner, R Revay, RS Sora, I Arellano, J DeFelipe, J Gimenez-Amaya, JM Conciatori, M Marino, R Baldi, A Cabib, S Pascucci, T Uhl, GR Murphy, DL Lesch, KP Keller, F AF Persico, AM Mengual, E Moessner, R Revay, RS Sora, I Arellano, J DeFelipe, J Gimenez-Amaya, JM Conciatori, M Marino, R Baldi, A Cabib, S Pascucci, T Uhl, GR Murphy, DL Lesch, KP Keller, F TI Barrel pattern formation requires serotonin uptake by thalamocortical afferents, while vesicular monoamine release is necessary for development of supragranular layers SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Meeting Abstract C1 Libera Univ, Neurosci Lab, I-00155 Rome, Italy. Univ Navarra, Fac Med, Dept Anat, E-31080 Pamplona, Spain. Univ Wurzburg, Dept Psychiat, Wurzburg, Germany. NIDA, ARC, Mol Neurobiol Branch, NIH, Baltimore, MD USA. CSIC, Inst Cajal, E-28002 Madrid, Spain. Univ Rome La Sapienza, Dept Psychol, I-00100 Rome, Italy. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD SEP PY 2000 VL 440 IS 5 MA 60 BP R34 EP R34 PG 1 WC Physiology SC Physiology GA 352GZ UT WOS:000089208200080 ER PT J AU Yang, YW Kotin, RM AF Yang, YW Kotin, RM TI Glucose-responsive gene delivery in pancreatic islet cells via recombinant adeno-associated viral vectors SO PHARMACEUTICAL RESEARCH LA English DT Article DE recombinant adeno-associated virus; insulin gene promoter; pancreatic islet cells; glucose-responsive gene delivery ID HUMAN FACTOR-IX; ADENOASSOCIATED VIRUS; BETA-CELLS; INSULIN REPLACEMENT; IN-VITRO; EXPRESSION; LINES; EFFICIENT; THERAPY; TUMORIGENESIS AB Purpose. Recent progress in genetic engineering presents the possibility of providing physiologically regulated glucose metabolism in individuals with diabetes. The objective of this study is to explore the feasibility of obtaining glucose dependent gene expression in the pan creatic beta -cell lines via recombinant adeno-associated virus type 2 (rAAV) mediated gene transfer. Methods, Two transcription cassettes containing the luciferase gene under the control of the rat insulin I gene promoter and the enhanced green fluorescent protein (EGFP) open reading frame under the control of the immediate early gene promoter of human cytomegalovirus (CMV) were placed in series between the inverted terminal repeats (ITRs) of AAV. The rAAV vectors produced were used to transduce pancreatic beta -cell line grown in the absence or presence of various concentrations of glucose. Luciferase activity assays were performed at 72 hr post-transduction. Results, Glucose-responsive reporter gene expression was obtained in both calcium phosphate transfected HIT-T15 and beta HC-9 cells, demonstrating regulated luciferase gene expression under control of the insulin gene promoter. At MOI of 100, rAAV-transduced beta HC-9 cells exhibited glucose-dependent luciferase activities, which were approximately 4.3 fold higher than those transfected by the calcium phosphate coprecipitation method at 20 mM glucose. Conclusions. Delivery of the insulin gene promoter via rAAV was shown in this study to result in glucose-dependent control of the reporter gene expression. The results suggest that rAAV is an efficient viral vector for gene transfer into the pancreatic islet cells. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. Natl Taiwan Univ, Taipei 10764, Taiwan. RP Kotin, RM (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10,Rm 7D18,10 Ctr Dr, Bethesda, MD 20892 USA. RI kotin, robert/B-8954-2008 NR 26 TC 23 Z9 23 U1 0 U2 1 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARMACEUT RES JI Pharm. Res. PD SEP PY 2000 VL 17 IS 9 BP 1056 EP 1061 DI 10.1023/A:1026445426982 PG 6 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 368ZP UT WOS:000090147600003 PM 11087036 ER PT J AU de Gasparo, M Catt, KJ Inagami, T Wright, JW Unger, T AF de Gasparo, M Catt, KJ Inagami, T Wright, JW Unger, T TI International union of pharmacology. XXIII. The angiotensin II receptors SO PHARMACOLOGICAL REVIEWS LA English DT Review ID VASCULAR-SMOOTH-MUSCLE; ACTIVATED PROTEIN-KINASE; ADRENAL GLOMERULOSA CELLS; TYPE-2 AT(2) RECEPTOR; NEUROBLASTOMA N1E-115 CELLS; GUANINE-NUCLEOTIDE-BINDING; RAT CARDIAC FIBROBLASTS; CONVERTING ENZYME-INHIBITION; SIGNAL-TRANSDUCTION PATHWAYS; LEFT-VENTRICULAR HYPERTROPHY AB The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system. C1 Novartis Pharma AG, Metab & Cardiovasc Dis, Basel, Switzerland. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37212 USA. Washington State Univ, Dept Psychol, Pullman, WA 99164 USA. Univ Kiel, Inst Pharmacol, Kiel, Germany. RP de Gasparo, M (reprint author), Novartis Pharma AG, Metab & Cardiovasc Dis, WKL 121-210,POB 4200, Basel, Switzerland. NR 737 TC 1400 Z9 1425 U1 9 U2 63 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD SEP PY 2000 VL 52 IS 3 BP 415 EP 472 PG 58 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 351VX UT WOS:000089180000004 PM 10977869 ER PT J AU Winterer, G Hermann, WM AF Winterer, G Hermann, WM TI Valproate and the symptomatic treatment of schizophrenia spectrum patients SO PHARMACOPSYCHIATRY LA English DT Review ID NEURONAL MEMBRANE ORDER; SODIUM VALPROATE; DIVALPROEX SODIUM; DRUG VALPROATE; GABA AMINOTRANSFERASE; PSYCHIATRIC-DISORDERS; PERSONALITY-DISORDER; CYCLOID PSYCHOSIS; ELDERLY PATIENTS; AMINO-ACIDS AB Valproate is currently one of the most frequently prescribed drugs in schizophrenia spectrum disorders. However, surprisingly little is known from controlled studies. Also, no review articles are available. Here, we summarize basic and clinical research on valproate and its application for treatment in schizophrenia spectrum disorders. The molecular and physiological effects of valproate are outlined. It is discussed how the effects of valproate on the cellular level involving serotonin, GABA, glutamate, sodium-channels, membrane fluidity and RNA-expression may account for its clinical effect in schizophrenia spectrum patients. The target symptoms are a reduction of psychomotor agitation and aggression, possibly reflecting a drug effect on temporal robe pathology, which is considered to be involved in the etiology of schizophrenic illness. C1 NIMH, NIH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. Free Univ Berlin, Dept Psychiat, Hosp Benjamin Franklin, D-1000 Berlin, Germany. RP Winterer, G (reprint author), NIMH, NIH, Clin Brain Disorders Branch, 10 Ctr Dr,Room 4S235 MSC 1379, Bethesda, MD 20892 USA. NR 114 TC 24 Z9 25 U1 3 U2 5 PU GEORG THIEME VERLAG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0176-3679 J9 PHARMACOPSYCHIATRY JI Pharmacopsychiatry PD SEP PY 2000 VL 33 IS 5 BP 182 EP 188 DI 10.1055/s-2000-12981 PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 358ET UT WOS:000089545100005 PM 11071020 ER PT J AU Boguna, M Masoliver, J Weiss, GH AF Boguna, M Masoliver, J Weiss, GH TI The asymptotic form of the probability density of sojourn times in randomly changing multistate systems SO PHYSICA A LA English DT Article ID MOLECULE FLUORESCENCE SPECTROSCOPY; SINGLE MOLECULES; TEMPERATURE AB Recent investigations, motivated by applications to the interpretation of kinetic records of single molecules that randomly change their states, have shown that if the data is from a single state only, the asymptotic form of the probability density for the residence time in that state is Gaussian. In this paper we extend the formalism to show that when data is available from several states the joint density for any subset of them is a multivariate Gaussian. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Univ Barcelona, Dept Fis Fonamental, E-08028 Barcelona, Spain. RP Weiss, GH (reprint author), NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RI Boguna, Marian/B-7795-2011; Masoliver, Jaume/F-7198-2016 OI Boguna, Marian/0000-0001-7833-3487; Masoliver, Jaume/0000-0002-5810-879X NR 18 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 J9 PHYSICA A JI Physica A PD SEP 1 PY 2000 VL 284 IS 1-4 BP 13 EP 22 DI 10.1016/S0378-4371(00)00208-9 PG 10 WC Physics, Multidisciplinary SC Physics GA 346XX UT WOS:000088897300002 ER PT J AU Boguna, M Berezhkovskii, AM Weiss, GH AF Boguna, M Berezhkovskii, AM Weiss, GH TI Occupancy of a single site by many random walkers SO PHYSICAL REVIEW E LA English DT Article ID SPHERICAL BROWNIAN PARTICLES; N LEVY FLIGHTS; DIMENSIONAL LATTICE; NUMBER; VOLUME; TIMES AB We consider an infinite number of noninteracting lattice random walkers with the goal of determining statistical properties of the time, out of a total time T, that a single site has been occupied by it random walkers. Initially the random walkers are assumed uniformly distributed on the lattice except for the target site at the origin, which is unoccupied. The random-walk model is taken to be a continuous-time random walk and the pausing-time density at the target site is allowed to differ from the pausing-time density at other sites. We calculate the dependence of the mean time of occupancy by n random walkers as a function of n and the observation time T. We also find the variance for the cumulative time during which the site is unoccupied. The large-T behavior of the variance differs according as the random walk is transient or recurrent. It is shown that the variance is proportional to T at large T in three or more dimensions, it is proportional to T-3/2 in one dimension and to T ln T in two dimensions. C1 Ctr Informat Technol, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Ctr Informat Technol, Bethesda, MD 20892 USA. RI Boguna, Marian/B-7795-2011 OI Boguna, Marian/0000-0001-7833-3487 NR 24 TC 5 Z9 5 U1 0 U2 2 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 2470-0045 EI 2470-0053 J9 PHYS REV E JI Phys. Rev. E PD SEP PY 2000 VL 62 IS 3 BP 3250 EP 3256 DI 10.1103/PhysRevE.62.3250 PN A PG 7 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 356MK UT WOS:000089446900037 ER PT J AU Gelbart, WM Bruinsma, RF Pincus, PA Parsegian, VA AF Gelbart, WM Bruinsma, RF Pincus, PA Parsegian, VA TI DNA-inspired electrostatics SO PHYSICS TODAY LA English DT Article ID LIPID COMPLEXES; MACROION; ATTRACTION; POLYELECTROLYTES; CHARGE; FORCES; IONS C1 Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Univ Calif Santa Barbara, Santa Barbara, CA 93106 USA. NIH, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. RP Gelbart, WM (reprint author), Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NR 20 TC 365 Z9 367 U1 2 U2 44 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0031-9228 J9 PHYS TODAY JI Phys. Today PD SEP PY 2000 VL 53 IS 9 BP 38 EP 44 DI 10.1063/1.1325230 PG 7 WC Physics, Multidisciplinary SC Physics GA 348JZ UT WOS:000088982900012 ER PT J AU Boice, JD Persson, I Brinton, LA Hober, M McLaughlin, JK Blot, WJ Fraumeni, JF Nyren, O AF Boice, JD Persson, I Brinton, LA Hober, M McLaughlin, JK Blot, WJ Fraumeni, JF Nyren, O TI Breast cancer following breast reduction surgery in Sweden SO PLASTIC AND RECONSTRUCTIVE SURGERY LA English DT Article ID PROPHYLACTIC MASTECTOMY; WOMEN; RISK; COHORT; BRCA1 AB Women undergoing breast reduction surgery have been reported to be at low subsequent risk of breast cancer, especially when the surgery is performed after age 40. To evaluate the ago and time-related patterns of cancer risk following surgical removal of breast tissue, we identified 31,910 women who underwent br-cast reduction surgery from 1965 to 1993 in Sweden using hospital discharge register data. There were 19,975 women (63 percent) under age 40 at surgery. Linkages with Swedish registries for cancer, death, and emigration were based on unique national registration numbers assigned to each Swedish resident. Cancer incidence was contrasted with that expected in the general population based on age- and calendar year-specific data from the nationwide cancer registry. Overall, 161 incident breast cancers were identified during 238,765 person-years of observation (mean, 7.5 years) compared with 223.9 expected (standardized incidence ratio = 0.72; 95 percent confidence interval = 0.61 to 0.84). The reduction in risk of breast cancer was most pronounced for women whose operations were performed after age 50 (SIR = 0.57) and for those followed for more than,5 years (SIR = 0.68). Among women operated on before age 40, risk was nonsignificantly elevated within the first 5 years after surgery (SIR = 1.47; 95 percent CI = 0.89 to 2.30) but tended to br reduced thereafter (SIR = 0.80; 95 percent CI = 0.55 to 1.13). The magnitude of tilt: reduction in risk thus appears directly related to age at surgery. Women followed for an average of 7.5 years after bilateral breast reduction surgery were at a statistically significant 28 percent decreased risk of breast cancer. The current study is thus consistent with a protective effect following partial removal of breast glandular tissue. C1 Int Epidemiol Inst, Rockville, MD 20850 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Karolinska Inst, Stockholm, Sweden. RP Boice, JD (reprint author), Int Epidemiol Inst, 1455 Res Blvd,Suite 550, Rockville, MD 20850 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 27 TC 53 Z9 53 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0032-1052 J9 PLAST RECONSTR SURG JI Plast. Reconstr. Surg. PD SEP PY 2000 VL 106 IS 4 BP 755 EP 762 DI 10.1097/00006534-200009040-00001 PG 8 WC Surgery SC Surgery GA 350CY UT WOS:000089084200001 PM 11007385 ER PT J AU Finnegan, JR Meischke, H Zapka, JG Leviton, L Meshack, A Benjamin-Garner, R Estabrook, B Hall, NJ Schaeffer, S Smith, C Weitzman, ER Raczynski, J Stone, E AF Finnegan, JR Meischke, H Zapka, JG Leviton, L Meshack, A Benjamin-Garner, R Estabrook, B Hall, NJ Schaeffer, S Smith, C Weitzman, ER Raczynski, J Stone, E TI Patient delay in seeking care for heart attack symptoms: Findings from focus groups conducted in five US regions SO PREVENTIVE MEDICINE LA English DT Article DE acute myocardial infarction; heart attack; community trials; community campaigns; focus groups; formative evaluation; emergency medical care ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY DISEASE; RAPID-EARLY-ACTION; THROMBOLYTIC THERAPY; CHEST PAIN; PREHOSPITAL DELAY; HOSPITAL ARRIVAL; MEDICAL-CARE; TIME; PERSPECTIVE AB Background. Patient delay in seeking health care for heart attack symptoms is a continuuing problem in the United States. Methods. Investigators conducted focus groups (N = 34; 207 participants) in major U.S. regions (NE, NW, SE, SW, MW) as formative evaluation to develop a multicenter randomized community trial (the REACT Project). Target groups included adults with previous heart attacks, those at higher risk for heart attack, and bystanders to heart attacks. There were also subgroups reflecting gender and ethnicity (African-American, Hispanic-American, White). Findings. Patients, bystanders, and those at higher risk expected heart attack symptoms to present as often portrayed in the movies, that is, as sharp, crushing chest pain rather than the more common onset of initially ambiguous but gradually increasing discomfort. Patients and those at higher risk also unrealistically judge their personal risk as low, understand little about the benefits of rapid action, are generally unaware of the benefits of using EMS/9-1-1 over alternative transport, and appear to need the "permission" of health care providers or family to act. Moreover, participants reported rarely discussing heart attack symptoms and appropriate responses in advance with health care providers, spouses, or family members. Women often described heart attack as "male problem," an important aspect of their underestimation of personal risk. African-American participants were more likely to describe negative feelings about EMS/9-1-1, particularly whether they would be transported to their hospital of choice. Conclusions. Interventions to reduce patient delay need to address expectations about heart attack symptoms, educate about benefits and appropriate actions, and provide legitimacy for taking specific health care-seeking actions. In addition, strategy development must emphasize the role of health care providers in legitimizing the need and importance of taking rapid action in the first place. (C) 2000 American Health Foundation and Academic Press. C1 Univ Minnesota, Sch Publ Hlth, Minneapolis, MN 55455 USA. King Cty Dept Emergency Serv, Seattle, WA USA. Univ Massachusetts, Worcester, MA 01605 USA. Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. Harvard Univ, Cambridge, MA 02138 USA. Univ Alabama, Birmingham, AL USA. NHLBI, Bethesda, MD 20892 USA. RP Finnegan, JR (reprint author), Univ Minnesota, Sch Publ Hlth, A-302,Box 197,420 Delaware St SE, Minneapolis, MN 55455 USA. FU NHLBI NIH HHS [U01HL53142, U01HL53211, U01HL54517] NR 47 TC 97 Z9 100 U1 0 U2 5 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD SEP PY 2000 VL 31 IS 3 BP 205 EP 213 DI 10.1006/pmed.2000.0702 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 354AP UT WOS:000089307900003 PM 10964634 ER PT J AU Simopoulos, AP Leaf, A Salem, N AF Simopoulos, AP Leaf, A Salem, N TI Workshop Statement on the Essentiality of and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article; Proceedings Paper CT Workshop on the Essentiality of and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids CY APR 07-09, 1999 CL BETHESDA, MARYLAND SP NIAAA, NIH, Off Dietary Supplements, Ctr Genet Nutrit & Hlth, Int Soc Study Fatty Acids & Lipids C1 Ctr Genet Nutr & Hlth, Washington, DC USA. Massachusetts Gen Hosp, Charlestown, MA USA. NIAAA, NIH, Rockville, MD 20852 USA. RP Simopoulos, AP (reprint author), Ctr Genet Nutr & Hlth, Washington, DC USA. NR 0 TC 135 Z9 145 U1 1 U2 21 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD SEP PY 2000 VL 63 IS 3 BP 119 EP 121 DI 10.1054/plef.2000.0176 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 369GV UT WOS:000165058300002 PM 10991764 ER PT J AU Lands, WEM AF Lands, WEM TI Workshop Statement on the Essentiality of and Recommended Dietary Intakes for Omega-6 and Omega-3 Fatty Acids - Commentary on the workshop statement SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Editorial Material ID PLASMA C1 NIAAA, Bethesda, MD 20892 USA. RP Lands, WEM (reprint author), NIAAA, 6000 Execut Blvd,Suite 400, Bethesda, MD 20892 USA. NR 13 TC 4 Z9 4 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 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD SEP PY 2000 VL 63 IS 3 BP 125 EP 126 DI 10.1054/plef.2000.0178 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 369GV UT WOS:000165058300004 PM 10991766 ER PT J AU Ma, BY Tsai, CJ Nussinov, R AF Ma, BY Tsai, CJ Nussinov, R TI Binding and folding: in search of intramolecular chaperone-like building block fragments SO PROTEIN ENGINEERING LA English DT Article DE amino-terminus; chaperones; energy landscape; folding funnels; proregions; prosequences; protein binding; protein folding ID ALPHA-LYTIC PROTEASE; DIHYDROFOLATE-REDUCTASE; IN-VIVO; ENERGY LANDSCAPES; PRO-DOMAIN; MECHANISMS; SEQUENCES; PROTEINS; FUNNELS; GROEL AB We propose an intramolecular chaperone which catalyzes folding and neither dissociates nor is cleaved. This uncleaved foldase is an intramolecular chain-linked chaperone, which constitutes a critical building block of the structure. Macroscopically, all molecular chaperones facilitate folding reactions and manifest similar energy landscapes. However, microscopically they differ. While intermolecular chaperones catalyze folding by unfolding misfolded conformations or prevent misfolding, the chain-linked cleaved (proregion) and uncleaved intramolecular chaperone-like building blocks suggested here, catalyze folding by binding to, stabilizing and increasing the populations of native conformations of adjacent building block fragments. In both, the more stable the intramolecular chaperone fragment region, the faster is the folding rate. Hence, mechanistically, intramolecular chaperones and chaperone-like segments are similar. Both play a dual role, in folding and in protein function. However, while the functional role of the proregions is inhibitory, necessitating their cleavage, the function of the uncleaved intramolecular chaperone-like building blocks does not require their subsequent removal. On the contrary, it requires that they remain in the structure. This may lead to the difference in the type of control they are under: proteins folding with the assistance of the proregion have been shown to be under kinetic control. It has been suggested that kinetically controlled folding reactions, with the proregion catalyst removed, lend longevity under harsh conditions. On the other hand, proteins with uncleaved intramolecular chaperone-like building blocks, with their /foldases' still attached, are largely under thermodynamic control, consistent with the control observed in most protein folding reactions. We propose that an uncleaved intramolecular chaperone-like fragment occurs frequently in proteins. We further propose that such proteins would be prone to changing conditions and in particular, to mutations in this critical building block region. We describe the features qualifying it for its proposed chaperone-like role, compare it with inter- and intramolecular chaperones and review current literature in this light. We further propose a mechanism showing how it lowers the barrier heights, leading to faster folding reaction rates, Since these fragments constitute an intergal part of the protein structure, we call these critical building blocks intramolecular, chaperone-like fragments, to clarify, distinguish and adhere to the definition of the transiently associating chaperones. The new mechanism presented here differs from the concept of 'folding nuclei'. While the concept of folding nuclei focuses on a non-sequential distribution of the folding information along the entire protein chain, the chaperone-like building block fragments proposition focuses on a segmental distribution of the folding information. This segmental distribution controls the distributions of the populations throughout the hierarchical folding processes. C1 NCI, Intramural Res Support Program, SAIC, Lab Expt & Computat Biol,FCRDC, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Intramural Res Support Program, SAIC, Lab Expt & Computat Biol,FCRDC, Bldg 469,Rm 151, Frederick, MD 21702 USA. RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-56000] NR 64 TC 37 Z9 39 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0269-2139 J9 PROTEIN ENG JI Protein Eng. PD SEP PY 2000 VL 13 IS 9 BP 617 EP 627 DI 10.1093/protein/13.9.617 PG 11 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 373JW UT WOS:000165286700004 PM 11054456 ER PT J AU Greenberg, BD Murphy, DL Rasmussen, SA AF Greenberg, BD Murphy, DL Rasmussen, SA TI Neuroanatomically based approaches to obsessive-compulsive disorder - Neurosurgery and transcranial magnetic stimulation SO PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article ID GLUCOSE METABOLIC RATES; POSITRON EMISSION TOMOGRAPHY; CEREBRAL BLOOD-FLOW; HUMAN MOTOR CORTEX; PARKINSONS-DISEASE; SYMPTOM PROVOCATION; COMPUTED-TOMOGRAPHY; CAUDATE-NUCLEUS; BASAL GANGLIA; RESONANCE AB Obsessive-compulsive disorder is a severe condition. Unfortunately, current medication and behavior therapies fail to adequately benefit some patients most severely affected. Advancing knowledge of brain circuit involvement has potential treatment implications. The neurosurgical techniques most often used in the United States for crippling, treatment-refractory obsessive-compulsive disorder are reviewed in the context of anatomic models of the illness. The use of transcranial magnetic stimulation to probe possible neuroanatomic and neurophysiologic substrates of this disorder is considered, and how the knowledge gained from such studies might advance treatment is presented. C1 Brown Univ, Butler Hosp, Dept Psychiat & Human Behav, Providence, RI 02906 USA. Brown Univ, Sch Med, Dept Psychiat & Human Behav, Providence, RI 02912 USA. NIMH, Clin Sci Lab, Adult Obsess Compuls Disorder Res Unit, Bethesda, MD 20892 USA. RP Greenberg, BD (reprint author), Brown Univ, Butler Hosp, Dept Psychiat & Human Behav, 345 Blackstone Blvd, Providence, RI 02906 USA. EM bdg@butler.org NR 89 TC 32 Z9 32 U1 3 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0193-953X J9 PSYCHIAT CLIN N AM JI Psychiatr. Clin. North Amer. PD SEP PY 2000 VL 23 IS 3 BP 671 EP + DI 10.1016/S0193-953X(05)70188-X PG 17 WC Psychiatry SC Psychiatry GA 349UN UT WOS:000089064100015 PM 10986735 ER PT J AU Sher, L Greenberg, BD Murphy, DL Rosenthal, NE Sirota, LA Hamer, DH AF Sher, L Greenberg, BD Murphy, DL Rosenthal, NE Sirota, LA Hamer, DH TI Pleiotropy of the serotonin transporter gene for seasonality and neuroticism SO PSYCHIATRIC GENETICS LA English DT Article DE seasonal affective disorder; seasonality; neuroticism; serotonin transporter; pleiotropy ID REPEAT LENGTH POLYMORPHISM; AFFECTIVE-DISORDER; MOOD CHANGE; META-CHLOROPHENYLPIPERAZINE; BEHAVIORAL-RESPONSES; READING DEFICITS; BINDING-SITES; PERSONALITY; ETIOLOGY; ASSOCIATION AB Pleiotropy refers to the ability of a single gene to influence multiple traits. A polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) has previously been found to be associated both with the personality trait of neuroticism and with seasonal changes in mood and behavior, or seasonality. Hypothesizing that the contribution of the serotonin transporter gene to seasonality is specific, i.e. independent of neuroticism, we measured 5-HTTLPR genotypes and both psychological traits in 236 healthy volunteers. The results indicated that the 5-HTTLPR contributions to variation in the two traits are largely independent; approximately three-quarters of the effect of the gene on seasonality are not related to its effects on neuroticism. Moreover, the gene has a larger effect on the covariation between neuroticism and seasonality than it does on either trait alone. Sibling-pair analysis confirmed that the effects of the 5-HTTLPR are due to genetic pleiotropy rather than population stratification. Psychiatr Genet 10:125-130 (C) 2000 Lippincott Williams & Wilkins. C1 NIMH, Sect Biol Rhythms, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. NCI, Biochem Lab, Bethesda, MD 20892 USA. NR 41 TC 19 Z9 19 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIATR GENET JI Psychiatr. Genet. PD SEP PY 2000 VL 10 IS 3 BP 125 EP 130 DI 10.1097/00041444-200010030-00004 PG 6 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 392HP UT WOS:000166405900004 PM 11204348 ER PT J AU Lipkus, IM Halabi, S Strigo, TS Rimer, BK AF Lipkus, IM Halabi, S Strigo, TS Rimer, BK TI The impact of abnormal mammograms on psychosocial outcomes and subsequent screening SO PSYCHO-ONCOLOGY LA English DT Article ID FALSE-POSITIVE MAMMOGRAM; BREAST-CANCER; FOLLOW-UP; WOMEN AB Few studies have examined the impact of abnormal mammograms on subsequent mammography screening and psychosocial outcomes specifically as a function of the length of time that has passed since the abnormal test result. This cross-sectional report compared breast cancer screening practices and psychosocial outcomes among three groups of women. These groups were women who (1) never had an abnormal mammogram, (2) had an abnormal mammogram 2 or more years prior to the study's baseline interview, and (3) had an abnormal mammogram within 2 years prior to the study's baseline interview. Women who had an abnormal mammogram at least 2 years prior to the baseline interview expressed greater 10-year and lifetime risks of getting breast cancer than women who never had an abnormal mammogram. Women who had abnormal mammograms, independent of when they occurred, were substantially more worried about getting boast cancer than were women who never had abnormal mammograms. Women who had an abnormal mammogram within 2 years prior to the baseline interview were more likely to be on schedule for mammography, compared with women who never had an abnormal mammogram. These results suggest that (1) few differences exist in perceived breast cancer risk and worry as a function of when an abnormal mammogram occurred, and (2) subsequent screening behavior is most affected by whether an abnormal mammogram occurred within 2 years from the interview. Not surprisingly, more recent experiences of abnormal mammograms had a greater influence on behavior. Copyright (C) 2000 John Wiley & Sons. C1 Duke Univ, Med Ctr, Canc Prevent Detect & Control Res Program, Durham, NC 27701 USA. Duke Univ, Med Ctr, Div Biometry Community & Family Med, Durham, NC USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Lipkus, IM (reprint author), Duke Univ, Med Ctr, Canc Prevent Detect & Control Res Program, 905 W Main St,Box 34, Durham, NC 27701 USA. FU NCI NIH HHS [5U19-CA-72009-03] NR 23 TC 50 Z9 51 U1 2 U2 4 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD SEP-OCT PY 2000 VL 9 IS 5 BP 402 EP 410 DI 10.1002/1099-1611(200009/10)9:5<402::AID-PON475>3.0.CO;2-U PG 9 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 362LP UT WOS:000089779700005 PM 11038478 ER PT J AU Grimm, JW Kruzich, PJ See, RE AF Grimm, JW Kruzich, PJ See, RE TI Contingent access to stimuli associated with cocaine self-administration is required for reinstatement of drug-seeking behavior SO PSYCHOBIOLOGY LA English DT Article ID ADMINISTERED COCAINE; 2ND-ORDER SCHEDULE; AMYGDALA; RATS; WITHDRAWAL; REINFORCEMENT; ACQUISITION; ACTIVATION; EXTINCTION; RELAPSE AB In this study, we examined the importance of contingent access to a cocaine-related stimulus in the production of cocaine seeking following extinction of lever responding for cocaine. Rats self-administered cocaine for 2 weeks in daily 3-h sessions under a fixed-ratio 1 schedule. A compound stimulus (tone + light) was presented with each infusion. Following seven daily 3-h extinction sessions, rats were reintroduced to the compound stimulus alone. This stimulus was presented in three ways: (1) contingent on lever pressing, (2) noncontingent, and (3) both contingent and noncontingent. Following 3 more extinction days, rats were again reintroduced to the compound stimulus, yet with contingent access to cocaine. Only the two groups with contingent presentation increased lever responding on the Ist day, while all groups increased responding for cocaine on the 2nd day. The need for contingent access to drug-associated stimuli in the absence of drug to produce drug-seeking behavior may be relevant for studies of neural substrates of relapse. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Grimm, JW (reprint author), NIDA, Intramural Res Program, POB 5180, Baltimore, MD 21224 USA. NR 18 TC 39 Z9 39 U1 0 U2 0 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 0889-6313 J9 PSYCHOBIOLOGY JI Psychobiology PD SEP PY 2000 VL 28 IS 3 BP 383 EP 386 PG 4 WC Psychology; Psychology, Multidisciplinary SC Psychology GA 373XV UT WOS:000165316100010 ER PT J AU Goldberg, TE Dodge, M Aloia, M Egan, MF Weinberger, DR AF Goldberg, TE Dodge, M Aloia, M Egan, MF Weinberger, DR TI Effects of neuroleptic medications on speech disorganization in schizophrenia: biasing associative networks towards meaning SO PSYCHOLOGICAL MEDICINE LA English DT Article ID LEXICAL DECISION TASK; THOUGHT-DISORDER; SEMANTIC NETWORK; WORKING-MEMORY; CORTEX; ATTENTION; LANGUAGE AB Background. While some cognitive accounts of disorganized speech, or thought disorder, in schizophrenia have emphasized failures in working memory/discourse planning or selective attention, we have suggested that thought disorder resides in the semantic system. In this study we assessed the effect of neuroleptic medication on thought disorder and semantic processing. Methods. Seventeen patients with schizophrenia were assessed while receiving neuroleptic medications and in crossover fashion, placebo. A number of measures were obtained: clinically rated thought disorder (using the Thought, Language and Communication Scale); working memory (letter number span); lexical integrity (naming and receptive vocabulary); and, semantic priming of intracategorical word pairs. Results. Semantic priming measures improved with neuroleptic medication, as did clinically rated thought disorder. No other measure changed significantly. Priming selectively covaried with changes in thought disorder. Conclusion. Changes in spreading semantic activation, measured in a semantic priming paradigm and presumably brought about by neuroleptics' influence on dopaminergic neuromodulatory systems, might reflect changes in the biases of pre-existing associative networks that favour or increase the accessibility of representations related by shared features. This study also has implications for the architecture of normal language in that a dissociation between the lexical and semantic levels was observed, due to the selective compromise of tasks demanding semantic processing. C1 NIMH, IRP, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Goldberg, TE (reprint author), NIMH, IRP, Clin Brain Disorders Branch, 10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. NR 41 TC 29 Z9 29 U1 5 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD SEP PY 2000 VL 30 IS 5 BP 1123 EP 1130 DI 10.1017/S0033291799002639 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 353ZR UT WOS:000089305800012 PM 12027048 ER PT J AU Shippenberg, TS Funada, M Schutz, CG AF Shippenberg, TS Funada, M Schutz, CG TI Dynorphin A (2-17) attenuates the unconditioned but not the conditioned effects of opiate withdrawal in the rat SO PSYCHOPHARMACOLOGY LA English DT Article DE DYN 2-17; opiate withdrawal; opiate dependence; place preference conditioning; naloxone; morphine ID KAPPA-OPIOID RECEPTOR; NMDA RECEPTOR; MORPHINE-WITHDRAWAL; EXPRESSION; TOLERANCE; PEPTIDES; MICE; BIOTRANSFORMATION; SENSITIZATION; SENSITIVITY AB Objectives: An unbiased place preference conditioning procedure was used to examine the influence of the non-opioid peptide, dynorphin A 2-17 (DYN 2-17), upon the conditioned and unconditioned effects of opiate withdrawal in the rat. Methods: Rats were implanted SC with two pellets containing 75 mg morphine or placebo. Single-trial place conditioning sessions with saline and the opioid receptor antagonist naloxone (0.1-1.0 mg/kg; SC) commenced 4 days later. Ten minutes before SC injections, animals received an IV infusion of saline or DYN 2-17 (0.1-5.0 mg/kg). Additional groups of placebo- and morphine-pelleted animals were conditioned with saline and DYN 2-17. During each 30-min conditioning session, somatic signs of withdrawal were quantified. Tests of place conditioning were conducted in pelleted animals 24 h later. Results: Naloxone produced wet-dog shakes, body weight loss, ptosis and diarrhea in morphine-pelleted animals. Morphine-pelleted animals also exhibited significant aversions for an environment previously associated with the administration of naloxone. These effects were not observed in placebo-pelleted animals. DYN 2-17 pretreatment resulted in a dose-related attenuation of somatic withdrawal signs. However, conditioned place aversions were still observed in morphine-pelleted animals that had received DYN 2-17 in combination with naloxone. Furthermore, the magnitude of this effect did not differ from control animals. Conclusions: These data demonstrate that the administration of DYN 2-17 attenuates the somatic, but not the conditioned aversive effects of antagonist-precipitated withdrawal from morphine in the rat. Differential effects of this peptide in modulating the conditioned and unconditioned effects of opiate withdrawal are suggested. C1 NIDA, Integrat Neurosci Unit, Behav Pharmacol Branch, NIH, Baltimore, MD 21224 USA. Daiichi Pharmaceut Univ, Minami Ku, Fukuoka 815, Japan. Univ Munich, Munich, Germany. RP Shippenberg, TS (reprint author), NIDA, Integrat Neurosci Unit, Behav Pharmacol Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU PHS HHS [P01 11470-01A1] NR 33 TC 12 Z9 12 U1 1 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2000 VL 151 IS 4 BP 351 EP 358 DI 10.1007/s002130000475 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 357EZ UT WOS:000089486700008 PM 11026742 ER PT J AU Panyutin, IG Winters, TA Feinendegen, LE Neumann, RD AF Panyutin, IG Winters, TA Feinendegen, LE Neumann, RD TI Development of DNA-based radiopharmaceuticals carrying Auger-electron emitters for anti-gene radiotherapy SO QUARTERLY JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE nucleic acids; radiotherapy; gene therapy; radiopharmaceuticals; nucleic acid conformation; radionuclide imaging ID TRIPLEX-FORMING-OLIGONUCLEOTIDES; I-125 LABELED OLIGONUCLEOTIDES; DOUBLE-STRAND BREAKS; INDUCED SINGLE-STRAND; EXCISION-REPAIR; POLYMERASE-BETA; MAMMALIAN-CELLS; XRCC1 PROTEIN; LIGASE-III; DAMAGE AB Targeting of radiation damage to specific DNA sequences is the essence of antigene radiotherapy. This technique also provides a tool to study molecular mechanisms of DNA repair on a defined, single radiodamaged site, We achieved such sequence-specific radiodamage by combining the highly localized DNA damage produced by the decay of Auger-electron-emitters such as I-125 With the sequence-specific action of tripler-forming oligonucleotides (TFO), TFO complementary to polypurine-polypyrimidine regions of human genes were synthesized and labeled with I-125-dCTP by the primer extension method. I-125-TFO were delivered into cells with several delivery systems. In addition, human enzymes capable of supporting DNA single-strand-break repair were isolated and assessed for their role in the repair of this lesion. Also, the mutagenicity and repairability of I-125-TFO-induced double strand breaks (DSB) were assessed by repair of a plasmid possessing a site-specific DSB lesion. Using plasmids containing target polypurine-polypyrimidine tracts, we obtained the fine structure of sequence-specific DNA breaks produced by decay of I-125 With single-nucleotide resolution. We showed that the designed I-125-TFO in nanomolar concentrations could bind to and introduce double-strand breaks into the target sequences in situ, i.e., within isolated nuclei and intact digitonin-permeabilized cells. We also showed I-125-TFO-induced DSB to be highly mutagenic lesions resulting in a mutation frequency of nearly 80%, with deletions com prising the majority of mutations, The results obtained demonstrate the ability of 125I-TFO to target specific sequences in their natural environment - within eucaryotic nucleus. Repair of I-125-TFO-induced DNA damage should typically result in mutagenic gene Inactivation. C1 NIH, Dept Nucl Med, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIH, Dept Nucl Med, Bldg 10 Room 1C-401,10 Ctr Dr,MSC 1180, Bethesda, MD 20892 USA. NR 65 TC 27 Z9 30 U1 1 U2 3 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 1125-0135 J9 Q J NUCL MED JI Q. J. Nucl. Med. PD SEP PY 2000 VL 44 IS 3 BP 256 EP 267 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 339GX UT WOS:000088470200005 PM 11105589 ER PT J AU Koshurnikova, NA Gilbert, ES Sokolnikov, M Khokhryakov, VF Miller, S Preston, DL Romanov, SA Shilnikova, NS Suslova, KG Vostrotin, VV AF Koshurnikova, NA Gilbert, ES Sokolnikov, M Khokhryakov, VF Miller, S Preston, DL Romanov, SA Shilnikova, NS Suslova, KG Vostrotin, VV TI Bone cancers in Mayak workers SO RADIATION RESEARCH LA English DT Article ID PLUTONIUM; MORTALITY; EXPOSURES; RADIATION; RISK AB Bone cancer mortality risks were evaluated in 11,000 workers who started working at the "Mayak" Production Association in 1948-1958 and who were exposed to both internally deposited plutonium and external gamma radiation. Comparisons with Russian and U.S, general population rates indicate excess mortality, especially among females, plutonium plant workers, and workers with external doses exceeding 1 Sv. Comparisons within the Mayak worker cohort, which evaluate the role of plutonium body burden with adjustment for cumulative external dose, indicate excess mortality among workers with burdens estimated to exceed 7.4 kBq (relative risk = 7.9; 95% CI = 1.6-32) and among workers in the plutonium plant who did not have routine plutonium monitoring data based on urine measurements (relative risk = 4.1; 95% CI = 1.2-14), In addition, analyses treating the estimated plutonium body burden as a continuous variable indicate increasing risk with increasing burden (P < 0.001). Because of limitations In current plutonium dosimetry, no attempt was made to quantify bone cancer risks from plutonium in terms of organ dose, and risk from external dose could not be reliably evaluated. (C) 2000 by Radiation Research Society. C1 State Sci Ctr Biophys Inst, Branch 1, Ozyorsk, Chelyabinsk Reg, Russia. NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Univ Utah, Div Radiobiol, Salt Lake City, UT 84112 USA. Radiat Effects Res Fdn, Dept Stat, Hiroshima, Japan. RP Gilbert, ES (reprint author), Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, 6120 Execut Blvd,MS 7238, Rockville, MD 20852 USA. FU NCI NIH HHS [CA66749, N01-CP-51025, N01-CP-81034] NR 29 TC 64 Z9 66 U1 0 U2 2 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD SEP PY 2000 VL 154 IS 3 BP 237 EP 245 DI 10.1667/0033-7587(2000)154[0237:BCIMW]2.0.CO;2 PG 9 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 352LA UT WOS:000089215800002 PM 10956428 ER PT J AU Gilbert, ES Koshurnikova, NA Sokolnikov, M Khokhryakov, VF Miller, S Preston, DL Romanov, SA Shilnikova, NS Suslova, KG Vostrotin, VV AF Gilbert, ES Koshurnikova, NA Sokolnikov, M Khokhryakov, VF Miller, S Preston, DL Romanov, SA Shilnikova, NS Suslova, KG Vostrotin, VV TI Liver cancers in Mayak workers SO RADIATION RESEARCH LA English DT Article ID ATOMIC-BOMB SURVIVORS; PLUTONIUM; RADIATION; MORTALITY AB Liver cancer mortality risks were evaluated in 11,000 workers who started working at the "Mayak" Production Association in 1948-1958 and who were exposed to both internally deposited plutonium and external gamma radiation. Comparisons with Russian liver cancer incidence rates indicate excess risk, especially among those with detectable plutonium body burdens and among female workers in the plutonium plant. Comparisons within the Mayak worker cohort which evaluate the role of plutonium body burden with adjustment for cumulative external dose indicate excess risk among workers with burdens estimated to exceed 7.4 kBq (relative risk = 17; 95% CI = 8.0-36) and among workers in the plutonium plant who did not have routine plutonium monitoring data based on urine measurements (relative risk = 2.8; 95% CI = 1.3-6.2). In addition, analyses treating the estimated plutonium body burden as a continuous variable indicate increasing risk with increasing burden (P < .001). Relative risks tended to be higher for females than for males, probably because of the lower baseline risk and the higher levels of plutonium measured in females. Because of limitations in current plutonium dosimetry, no attempt was made to quantify liver cancer risks from plutonium in terms of organ dose, and risk from external dose could not be reliably evaluated, (C) 2000 by Radiation Research Society. C1 NCI, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. State Sci Ctr Biophys Inst, Branch 1, Ozyorsk, Chelyabinsk Reg, Russia. Univ Utah, Div Radiobiol, Salt Lake City, UT 84112 USA. Radiat Effects Res Fdn, Dept Stat, Hiroshima, Japan. RP Gilbert, ES (reprint author), Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, 6120 Execut Blvd,MS 7238, Rockville, MD 20852 USA. FU NCI NIH HHS [N01-CP-81034, CA66749, N01-CP-51025] NR 24 TC 64 Z9 69 U1 0 U2 3 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD SEP PY 2000 VL 154 IS 3 BP 246 EP 252 DI 10.1667/0033-7587(2000)154[0246:LCIMW]2.0.CO;2 PG 7 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 352LA UT WOS:000089215800003 PM 10956429 ER PT J AU Amundson, SA Do, KT Shahab, S Bittner, M Meltzer, P Trent, J Fornace, AJ AF Amundson, SA Do, KT Shahab, S Bittner, M Meltzer, P Trent, J Fornace, AJ TI Identification of potential mRNA biomarkers in peripheral blood lymphocytes for human exposure to ionizing radiation SO RADIATION RESEARCH LA English DT Article ID ACCIDENT VICTIMS; CDNA MICROARRAY; RNA; HYBRIDIZATION; INDUCTION AB Since early in the Atomic Age, biological indicators of radiation exposure have been sought, but currently available methods are not entirely satisfactory. Using cDNA microarray hybridization to discover new potential biomarkers, we have identified genes expressed at increased levels in human peripheral blood lymphocytes after ex vivo irradiation. We recently used this technique to identify a large set of ionizing radiation-responsive genes in a human cell line (Oncogene 18, 3666-3672, 1999). The present set of radiation markers in peripheral blood lymphocytes was identified 24 h after treatment, and while the magnitude of mRNA induction generally decreased over time, many markers were still significantly elevated up to 72 h after irradiation. In all donors, the most highly responsive gene identified was DDB2, which codes for the p48 subunit of XPE, a protein known to play a crucial role in repair of ultraviolet (UV) radiation damage in DNA. Induction of DDB2, CDKN1A (also known as CIP1/WAF1) and XPC showed a linear dose-response relationship between 0.2 and 2 Gy at 24 and 48 h after irradiation, with less linearity at earlier or later times. These results suggest that relative levels of gene expression in peripheral blood cells may provide estimates of environmental radiation exposures. (C) 2000 by Radiation Research Society. C1 NCI, NIH, Div Basic Sci, Bethesda, MD 20892 USA. NHGRI, Bethesda, MD 20892 USA. RP Amundson, SA (reprint author), NCI, NIH, Div Basic Sci, 37 Convent Dr,Bldg 37,Rm 5C09, Bethesda, MD 20892 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 16 TC 190 Z9 206 U1 1 U2 12 PU RADIATION RESEARCH SOC PI OAK BROOK PA 2021 SPRING RD, STE 600, OAK BROOK, IL 60521 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD SEP PY 2000 VL 154 IS 3 BP 342 EP 346 DI 10.1667/0033-7587(2000)154[0342:IOPMBI]2.0.CO;2 PG 5 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 352LA UT WOS:000089215800016 PM 11012342 ER PT J AU Doppman, JL Chrousos, GP Papanicolaou, DA Stratakis, CA Alexander, HR Nieman, LK AF Doppman, JL Chrousos, GP Papanicolaou, DA Stratakis, CA Alexander, HR Nieman, LK TI Adrenocorticotropin-independent macronodular adrenal hyperplasia: An uncommon cause of primary adrenal hypercortisolism SO RADIOLOGY LA English DT Article DE adrenal gland, CT; adrenal gland, diseases; adrenal gland, hyperplasia; adrenal gland, MR; pituitary, MR ID GASTRIC-INHIBITORY POLYPEPTIDE; DEPENDENT CUSHINGS-SYNDROME; ADENOMA CELLS; ACTH; DISEASE; RESPONSIVENESS; RECEPTORS; SUBTYPE; PATIENT AB PURPOSE: To describe the imaging findings in the adrenal glands of 12 patients with adrenocorticotropin (ACTH)-independent macronodular adrenocortical hyperplasia (AIMAH). MATERIALS AND METHODS: Computed tomographic (CT) and magnetic resonance (MR) imaging findings in the adrenal glands were reviewed retrospectively in 12 patients (three men, nine women) with ACTH-independent Cushing syndrome and with bilateral nonpigmented multinodular adrenal hyperplasia. The results of pituitary MR imaging, adrenal scintigraphy, and petrosal sampling were available in nine, five, and six patients, respectively. Eleven patients underwent bilateral and one patient underwent unilateral adrenalectomy. RESULTS: Eleven patients had enlarged multinodular adrenal glands: Nodules were 0.1-5.5 cm. The combined weight of both adrenal specimens for the 11 bilateral adrenalectomy specimens was 28-297 g, with a mean weight of 122 g. Glands were hypointense compared with the liver on T1-weighted images and were hyperintense on T2-weighted images. Pituitary MR imaging findings were negative in nine of nine patients. Iodomethylnorcholesterol scintigraphy showed bilateral uptake in four of five patients. Petrosal sinus sampling revealed no petrosal-to-peripheral ACTH gradients before corticotropin-releasing hormone (CRH) stimulation in six of six patients, but three patients had gradients after CRH stimulation. After undergoing bilateral or unilateral adrenalectomy, all patients were cured. CONCLUSION: AIMAH is a rare cause of ACTH-independent Cushing syndrome, with characteristic CT findings of massively enlarged multinodular adrenal glands. Bilateral adrenalectomy is indicated on the basis of clinical and CT findings. C1 NICHHD, Dept Diagnost Radiol, Imaging Sci Program, Warren Grant Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Doppman, JL (reprint author), NICHHD, Dept Diagnost Radiol, Imaging Sci Program, Warren Grant Magnuson Clin Ctr,NIH, 10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 33 TC 36 Z9 41 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMER PI EASTON PA 20TH AND NORTHAMPTON STS, EASTON, PA 18042 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD SEP PY 2000 VL 216 IS 3 BP 797 EP 802 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 348BT UT WOS:000088964900028 PM 10966714 ER PT J AU Smith, JC Butera, RJ Koshiya, N Del Negro, C Wilson, CG Johnson, SM AF Smith, JC Butera, RJ Koshiya, N Del Negro, C Wilson, CG Johnson, SM TI Respiratory rhythm generation in neonatal and adult mammals: the hybrid pacemaker-network model SO RESPIRATION PHYSIOLOGY LA English DT Article DE respiratory rhythm generation; neonatal mammals; adult mammals; hybrid pacemaker-network model ID PRE-BOTZINGER COMPLEX; RAT-BRAIN-STEM; NEURAL MECHANISMS; IN-VITRO; PREBOTZINGER COMPLEX; SYNAPTIC INHIBITION; MEMBRANE-PROPERTIES; MEDULLARY SLICES; MOTOR OUTPUT; AMINO-ACIDS AB We review a new unified model of respiratory rhythm generation - the hybrid pacemaker-network model. This model represents a comprehensive synthesis of cellular and network mechanisms that can theoretically account for rhythm generation in different functional states, from the most reduced states in the neonatal nervous system in vitro to the intact adult system in vivo. The model incorporates a critical neuronal kernel consisting of a network of excitatory neurons with state-dependent, oscillatory bursting or pacemaker properties. This kernel: located in the pre-Botzinger complex of the ventrolateral medulla, provides a rudimentary pacemaker network mechanism for generating an inspiratory rhythm, revealed predominately in functionally reduced states in vitro. In vivo the kernel is embedded in a larger network that interacts with the kernel via inhibitory synaptic connections that provide the dynamic control required for the evolution of the complete pattern of inspiratory and expiratory network activity. The resulting hybrid of cellular pacemaker and network properties functionally endows the system with multiple mechanisms of rhythm generation. New biophysically realistic mathematical models of the hybrid pacemaker-network have been developed that illustrate these concepts and provide a computational framework for investigating interactions of cellular and network processes that must be analyzed to understand rhythm generation. (C) 2000 Elsevier Science B.V, All rights reserved. C1 NINDS, Cellular & Syst Neurobiol Sect, Neural Control Lab, NIH, Bethesda, MD 20892 USA. Georgia Inst Technol, Inst Bioengn & Biosci, Sch Elect & Comp Engn, Atlanta, GA 30332 USA. RP Smith, JC (reprint author), NINDS, Cellular & Syst Neurobiol Sect, Neural Control Lab, NIH, Bldg 49,Room 3A50,49 Convent Dr,MSC 4455, Bethesda, MD 20892 USA. EM jsmith@helix.nih.gov OI Butera, Robert/0000-0002-1806-0621 NR 65 TC 182 Z9 182 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0034-5687 J9 RESP PHYSIOL JI Respir. Physiol. PD SEP PY 2000 VL 122 IS 2-3 BP 131 EP 147 DI 10.1016/S0034-5687(00)00155-9 PG 17 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 350TE UT WOS:000089116600005 PM 10967340 ER PT J AU Kim, LK Matsufuji, T Matsufuji, S Carlson, BA Kim, SS Hatfield, DL Lee, BJ AF Kim, LK Matsufuji, T Matsufuji, S Carlson, BA Kim, SS Hatfield, DL Lee, BJ TI Methylation of the ribosyl moiety at position 34 of selenocysteine tRNA([Ser]Sec) is governed by both primary and tertiary structure SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE 1-methyladenine; 2 '-O-ribose methylation; 5-methylcarboxymethyluridine; 5-methylcarboxymethyluridine-2 '-O-methylribose; N-6-isopentenyladenosine; pseudouridine; selenocysteine; tRNA modification ID TRANSFER-RNA; TRANSFER RNASEC; ENZYMATIC FORMATION; WOBBLE NUCLEOSIDE; SELENIUM; SYNTHETASE; EXPRESSION; POPULATION; EUKARYOTES; TRNA(SEC) AB The selenocysteine (Sec) tRNA([Ser]Sec) population in higher vertebrates consists of two major isoacceptors that differ from each other by a single nucleoside modification in the wobble position of the anticodon (position 34), One isoacceptor contains 5-methylcarboxymethyluridine (mcmU) in this position, whereas the other contains 5-methylcarboxymethyluridine-2'-O-methylribose (mcmUm), The other modifications in these tRNAs are N-6-isopentenyladenosine (i(6)A), pseudouridine (psi), and 1-methyladenosine (m(1)A) at positions 37, 55, and 58, respectively, As methylation of the ribose at position 34 is influenced by the intracellular selenium status and the presence of this methyl group dramatically alters tertiary structure, we investigated the effect of the modifications at other positions as well as tertiary structure on its formation, Mutations were introduced within a synthetic gene encoded in an expression vector, transcripts generated and microinjected into Xenopus oocytes, and the resulting tRNA products analyzed for the presence of modified bases, The results suggest that efficient methylation of mcmU to yield mcmUm requires the prior formation of each modified base and an intact tertiary structure, whereas formation of modified bases at other positions, including mcmU, is not as stringently connected to precise primary and tertiary structure, These results, along with the observations that methylation of mcmU is enhanced in the presence of selenium and that this methyl group affects tertiary structure, further suggest that the mcmUm isoacceptor must have a role in selenoprotein synthesis different from that of the mcmU isoacceptor. C1 Seoul Natl Univ, Mol Genet Lab, Inst Mol Biol & Genet, Seoul 151742, South Korea. Jikei Univ, Daisan Hosp, Sch Med, Dept Internal Med, Tokyo 1058461, Japan. Jikei Univ, Dept Biochem 2, Sch Med, Tokyo 1058461, Japan. NCI, Basic Res Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Lee, BJ (reprint author), Seoul Natl Univ, Mol Genet Lab, Inst Mol Biol & Genet, Seoul 151742, South Korea. NR 31 TC 32 Z9 32 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH STREET, NEW YORK, NY 10011-4211 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD SEP PY 2000 VL 6 IS 9 BP 1306 EP 1315 DI 10.1017/S1355838200000388 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 353VA UT WOS:000089295100010 PM 10999607 ER PT J AU Varis, K Sipponen, P Laxen, F Samloff, IM Huttunen, JK Taylor, PR Heinonen, OP Albanes, D Sande, N Virtamo, J Harkonen, M AF Varis, K Sipponen, P Laxen, F Samloff, IM Huttunen, JK Taylor, PR Heinonen, OP Albanes, D Sande, N Virtamo, J Harkonen, M CA Helsinki Gastritis Study Grp TI Implications of serum pepsinogen I in early endoscopic diagnosis of gastric cancer and dysplasia SO SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY LA English DT Article DE atrophic gastritis; cancer prevention; dysplasia; gastric cancer; pepsinogen ID ATROPHIC GASTRITIS; FOLLOW-UP; CARCINOMA; RISK; MUCOSA; POPULATION; CRITERIA; JAPANESE; STOMACH; MARKER AB Background and Aims: The risk of gastric cancer (GCA) is increased in atrophic gastritis. A low serum pepsinogen group I (SPGI) level is a good serologic indicator of atrophic gastritis of the gastric corpus and fundus, and can be used for diagnosis of subjects with atrophic gastritis and of increased risk for GCA. The present study was undertaken to investigate whether SPGI assay and a diagnostic gastroscopy could enable the diagnosis of GCA at an early stage. Material and Methods: The study was carried out as part of the Alpha-Tocopherol, Beta-Carotene Cancer prevention study (ATBC study) in Finland, in which 22,436 male smokers aged 50-69 years were screened by SPGI. Low SPGI levels (< 25 mu g/l) were found in 2196 (9.8%) men. Upper GI endoscopy (gastroscopy) was performed in 1344 men (61%) and 78% of these had moderate or severe atrophic corpus gastritis in endoscopic biopsies. A control series of 136 men from the ATBC study cohort with abdominal symptoms, but with SPGI greater than or equal to 50 mu g/l were similarly endoscopied, and 2.2% of these had corpus atrophy. Results: Neoplastic alterations were found in 63 (4.7%; 95% CI: 3.6%-5.8%) of the 1344 endoscopied men with low SPGI levels. Of these, 42 were definite dysplasias of low grade, 7 dysplasias of high grade, 11 invasive carcinomas, of which 7 were 'early' cancers, and 3 carcinoid tumors. In the control series, 1 man (0.7%) of the 136 men had a definite low-grade dysplasia. Thus, 18 (1.3%; 95% CI 0.7%-2.0%) cases with 'severe' neoplastic lesions (4 advanced cancers, 7 early cancers and 7 dysplasias of high grade) were found in the low SPGI group, but there were none in the control group. All four patients with advanced cancer died from the malignancy within 5 years (mean survival time 2.5 years), whereas surgical treatment in all those with early cancer or high-grade dysplasia was curative. One of the seven patients with early cancer and two of the seven with high-grade dysplasia died within 5 years, but none died from the gastric cancer. Thus, curative treatment was given to 14 of 18 men in whom a malignant lesion was found in gastroscopy. This is about 15% of all gastric cancer cases (92 cases) which were diagnosed within 5 years after SPGI screening in the 22,436 men. Among the gastric cancer cases of the main ATBC study, the 5-year survival rate was 33% (85% of the non-survivors died from gastric cancer). Conclusions: We conclude that assay of SPGI followed by endoscopy is an approach which can enable the early diagnosis of gastric cancer at a curable stage. C1 Jorvi Hosp, Dept Pathol, FI-02740 Espoo, Finland. Natl Publ Hlth Inst, Helsinki, Finland. Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Clin Chem, Helsinki, Finland. Vet Adm Med Ctr, Sepulveda, CA 91343 USA. NCI, Bethesda, MD 20892 USA. RP Sipponen, P (reprint author), Jorvi Hosp, Dept Pathol, FI-02740 Espoo, Finland. RI Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [N01-CN-45165] NR 37 TC 71 Z9 79 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0036-5521 J9 SCAND J GASTROENTERO JI Scand. J. Gastroenterol. PD SEP PY 2000 VL 35 IS 9 BP 950 EP 956 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 359JZ UT WOS:000089608900010 PM 11063155 ER PT J AU Thayer, JF Johnsen, BH AF Thayer, JF Johnsen, BH TI Sex differences in judgement of facial affect: A multivariate analysis of recognition errors SO SCANDINAVIAN JOURNAL OF PSYCHOLOGY LA English DT Article DE Ekman faces; gender differences; emotional recognition errors ID EMOTIONAL EXPRESSIONS AB The present paper investigated recognition errors in affective judgement of facial emotional expressions. Twenty-eight females and sixteen males participated in the study. The results showed that in both males and females emotional displays could be correctly classified, but females had a higher rate of correct classification; males were more likely to have difficulty distinguishing one emotion from another. Females rated emotions identically regardless of whether the emotion was displayed by a male or female face. Furthermore, the two-factor structure of emotion, based on a valence and an arousal dimension, was only present for female subjects. These results further extend our knowledge about gender differences in affective information processing. C1 Univ Bergen, Dept Clin Psychol, N-5015 Bergen, Norway. NIA, Baltimore, MD 21224 USA. RP Johnsen, BH (reprint author), Univ Bergen, Dept Clin Psychol, Chriestiesgt 12, N-5015 Bergen, Norway. NR 16 TC 126 Z9 133 U1 2 U2 22 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0036-5564 J9 SCAND J PSYCHOL JI Scand. J. Psychol. PD SEP PY 2000 VL 41 IS 3 BP 243 EP 246 DI 10.1111/1467-9450.00193 PG 4 WC Psychology, Multidisciplinary SC Psychology GA 353CJ UT WOS:000089255900008 PM 11041306 ER PT J AU Miles, EW Davies, DR AF Miles, EW Davies, DR TI Protein evolution - On the ancestry of barrels SO SCIENCE LA English DT Editorial Material ID TRYPTOPHAN SYNTHASE; SEQUENCE-ANALYSIS C1 NIH, Bethesda, MD 20892 USA. RP Miles, EW (reprint author), NIH, Bethesda, MD 20892 USA. NR 12 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD SEP 1 PY 2000 VL 289 IS 5484 BP 1490 EP 1490 DI 10.1126/science.289.5484.1490 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349XW UT WOS:000089071700032 PM 10991737 ER PT J AU Marcos, HB Choyke, PL AF Marcos, HB Choyke, PL TI Magnetic resonance angiography of the kidney SO SEMINARS IN NEPHROLOGY LA English DT Review ID RENAL-ARTERY STENOSIS; 3-DIMENSIONAL MR-ANGIOGRAPHY; SINGLE-BREATH HOLD; TIME-OF-FLIGHT; CONTRAST; HYPERTENSION; OPTIMIZATION; FEASIBILITY; DIAGNOSIS; AORTA C1 NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bldg 10,Room 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. NR 29 TC 28 Z9 29 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0270-9295 J9 SEMIN NEPHROL JI Semin. Nephrol. PD SEP PY 2000 VL 20 IS 5 BP 450 EP 455 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 353WA UT WOS:000089297400010 PM 11022898 ER PT J AU Bartlett, DL AF Bartlett, DL TI Gallbladder cancer SO SEMINARS IN SURGICAL ONCOLOGY LA English DT Review DE gallbladder neoplasms/diagnosis/epidemiology/pathology/surgery; cholecystectomy; neoplasm staging; incidence; lymph node metastasis; neoplasm metastasis; prognosis; risk factors; morbidity; mortality; postoperative complications; laparoscopy; lymph node excision; adjuvant chemotherapy; adjuvant radiotherapy; palliative care ID POTENTIALLY RESECTABLE TUMORS; SURGICAL-TREATMENT; RADICAL OPERATIONS; BILIARY-TRACT; BILE-DUCTS; ADVANCED-CARCINOMA; POLYPOID LESIONS; RISK-FACTORS; DIAGNOSIS; RESECTION AB Gallbladder cancer has a reputation for being aggressive and incurable. Single institution series, however, have defined successful management strategies in which the extent of resection is based on the stage of the tumor at presentation. Careful ultrasound screening for abnormalities in the gallbladder wall, and CA19-9 serum determination prior to routine cholecystectomy may heighten awareness for cancer in this population. For tumors confined to the muscular layer of the gallbladder a simple cholecystectomy is associated with an almost 100% cure rate. Tumors invading through the muscle wall (Stage II) should be managed with extended cholecystectomy, including resection of hepatic segments IVb and V, and an extensive lymph node dissection of the porta hepatis, posterior pancreaticoduodenal, and interaortocaval lymph nodes. This operation for Stage II gallbladder cancer is associated with a 90% to 100% 3-year survival rate. Simple cholecystectomy fails in the majority of Stage II patients. Patients with Stage III and IV tumors may also benefit from an extended cholecystectomy. Patients with bulky primary tumors without lymph node metastases (T4N0) seem to have a better prognosis than those with distant lymph node metastases, and should be treated aggressively when possible. It is advantageous to perform the appropriate extent of surgery for gallbladder cancer at the initial operation. Heightened awareness of the presence of cancer and the knowledge of appropriate management are important. For patients whose cancer is an incidental finding on pathologic review, re-resection is indicated for all disease except Stage I. This review will discuss the epidemiology, pathology, and staging of gallbladder cancer and describe the appropriate surgical management based on the stage of the cancer. Semin. Surg. Oncol. 19:145-155, 2000. Published 2000 Wiley-Liss, Inc. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Bartlett, DL (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B07, Bethesda, MD 20892 USA. NR 81 TC 54 Z9 57 U1 0 U2 5 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 8756-0437 J9 SEMIN SURG ONCOL JI Semin. Surg. Oncol. PD SEP-OCT PY 2000 VL 19 IS 2 BP 145 EP 155 DI 10.1002/1098-2388(200009)19:2<145::AID-SSU7>3.0.CO;2-6 PG 11 WC Oncology; Surgery SC Oncology; Surgery GA 371QC UT WOS:000165188800007 PM 11126379 ER PT J AU Meteyer, CU Loeffler, IK Fallon, JF Converse, KA Green, E Helgen, JC Kersten, S Levey, R Eaton-Poole, L Burkhart, JG AF Meteyer, CU Loeffler, IK Fallon, JF Converse, KA Green, E Helgen, JC Kersten, S Levey, R Eaton-Poole, L Burkhart, JG TI Hind limb malformations in free-living northern leopard frogs (Rana pipiens) from Maine, Minnesota, and Vermont suggest multiple etiologies SO TERATOLOGY LA English DT Article ID XENOPUS-LAEVIS; SEDIMENT EXTRACTS; VERTEBRATE LIMB; POND WATER; DEFORMITIES; EXPRESSION; GLI3; GENE; USA AB Background: Reports of malformed frogs have increased throughout the North American continent in recent years. Most of the observed malformations have involved the hind limbs. The goal of this study was to accurately characterize the hind limb malformations in wild frogs as an important step toward understanding the possible etiologies. Methods: During 1997 and 1998, 182 recently metamorphosed northern leopard frogs (Rana pipiens] were collected from Minnesota, Vermont, and Maine. Malformed hind limbs were present in 157 (86%) of these frogs, which underwent: necropsy and radiographic evaluation at the National Wildlife Health Center. These malformations are described in detail and classified into four major categories: (1) no limb (amelia); (2) multiple limbs or limb elements (polymelia, polydactyly, polyphalangy); (3) reduced limb segments or elements (phocomelia, ectromelia, ectrodactyly, and brachydactyly; and (4) distally complete but malformed limb (bone rotations, bridging, skin webbing, and micromelia). Results: Amelia and reduced segments and/or elements were the most common finding. Frogs with bilateral hind limb malformations were not common, and in only eight of these 22 frogs were the malformations symmetrical. Malformations of a given type tended to occur in frogs collected from the same site, but the types of malformations varied widely among all three states, and between study sites within Minnesota. Conclusions: Clustering of malformation type suggests that developmental events may produce a variety of phenotypes depending on the timing, sequence, and severity of the environmental insult. Hind limb malformations. in free-living frogs transcend current mechanistic explanations of tetrapod limb development. Published 2000 Wiley-Liss, Inc.(dagger) C1 US Geol Survey, Biol Resource Div, Natl Wildlife Hlth Ctr, Madison, WI 53711 USA. Univ Wisconsin, Sch Med, Dept Anat, Madison, WI 53706 USA. Natl Inst Environm Hlth Sci, Ctr Dev & Mol Toxicol, Madison, WI 53706 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Univ Wisconsin, Sch Vet Med, Madison, WI 53706 USA. Minnesota Pollut Control Agcy, St Paul, MN 55155 USA. Vermont Agcy Nat Resources, Waterbury, VT 05671 USA. US Fish & Wildlife Serv, Ecol Serv, Concord, NH 03301 USA. RP Meteyer, CU (reprint author), US Fish & Wildlife Serv, Natl Wildlife Hlth Res Ctr, 6006 Schroeder Rd, Madison, WI 53711 USA. FU NICHD NIH HHS [HD32551]; NIEHS NIH HHS [ES09090-02] NR 37 TC 59 Z9 66 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0040-3709 J9 TERATOLOGY JI Teratology PD SEP PY 2000 VL 62 IS 3 BP 151 EP 171 DI 10.1002/1096-9926(200009)62:3<151::AID-TERA3>3.0.CO;2-2 PG 21 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 346EJ UT WOS:000088857600003 PM 10935979 ER PT J AU Watzl, C Peterson, M Long, EO AF Watzl, C Peterson, M Long, EO TI Homogenous expression of killer cell immunoglobulin-like receptors (KIR) on polyclonal natural killer cells detected by a monoclonal antibody to KIR2D SO TISSUE ANTIGENS LA English DT Article DE immunoglobulin superfamily; killer cell immunoglobulin-like receptors; monoclonal antibodies; natural killer cells ID MHC CLASS-I; INHIBITORY RECEPTOR; HLA-C; NK CELLS; FUNCTIONAL TRANSFER; DIRECT BINDING; T-LYMPHOCYTES; RECOGNITION; MOLECULES; CLONES AB The activity of human natural killer (NK) cells is in part regulated by the expression of killer cell immunoglobulin (Ig)-like receptors (KIR) that recognize major histocompatibility complex (MHC) class I and can inhibit NK cell cytotoxicity. A monoclonal anti-KIR antibody was established and designated Lig1. Lig1 was shown to be specific for KIR in cell-surface staining and to react with all KIR2D except KIR2DL4 which lacks a D1 domain, but not with KIR3D molecules in an enzyme-linked immunoadsorbent assay (ELISA) and Western blotting. Unlike other anti-KIR antibodies, Lig1 did not inhibit binding of KIR-Ig-fusion proteins to MHC-class I expressing cells nor did it interfere with KIR-mediated inhibition of NK cell cytotoxicity in a functional assay. Lig1 reacted with all NK cells in polyclonal NK populations from different donors, demonstrating that all NK cells express at least one KIR2D receptor. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. RI Long, Eric/G-5475-2011; Watzl, Carsten/B-4911-2013 OI Long, Eric/0000-0002-7793-3728; Watzl, Carsten/0000-0001-5195-0995 NR 26 TC 4 Z9 4 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD SEP PY 2000 VL 56 IS 3 BP 240 EP 247 DI 10.1034/j.1399-0039.2000.560306.x PG 8 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 357WF UT WOS:000089523200006 PM 11034560 ER PT J AU Thompson, SA White, CC Krejsa, CM Eaton, DL Kavanagh, TJ AF Thompson, SA White, CC Krejsa, CM Eaton, DL Kavanagh, TJ TI Modulation of glutathione and glutamate-L-cysteine ligase by methylmercury during mouse development SO TOXICOLOGICAL SCIENCES LA English DT Article DE glutamate-cysteine ligase; gamma-glutamylcysteine synthetase; glutathione; methylmercury; mouse development ID GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; EMBRYONIC-DEVELOPMENT INVITRO; POSTIMPLANTATION RAT EMBRYOS; MESSENGER-RNA EXPRESSION; VISCERAL YOLK SACS; BUTHIONINE SULFOXIMINE; MOLECULAR-CLONING; METHYL MERCURY; DEPLETION; TOXICITY AB The antioxidant tripeptide glutathione has been proposed to be important in defense against oxidative stress and heavy metal toxicity. We evaluated alterations in glutathione regulation and synthesis associated with low-level chronic methylmercury (MeHg) exposure in the developing mouse fetus. Female C57Bl/6 mice were given 0, 3, or 10 ppm MeHg in the drinking water for 2 weeks prior to breeding and throughout pregnancy. Fetuses were collected on gestational days (gd) 12 and 16. Total glutathione, reduced glutathione (GSH), oxidized glutathione (GSSR), and glutamate-l-cysteine ligase (Glcl) activity were assessed in yolk sacs and fetuses at gd 16. Western and Northern blots for Glcl-catalytic (Glclc) and Glcl-regulatory (Glclr) subunits were performed on gd 12 and gd 16 fetuses. There were no changes in total glutathione in gd 16 mouse fetuses with exposure, but there were dose-related decreases in GSH and increases in GSSR. In contrast, visceral yolk sacs exhibited an increase in total glutathione in the low-dose groups, but no changes in the high-dose group. There were no changes in Glcl activity in fetuses, but there was a 2-fold increase in Glcl activity in yolk sacs from both low-dose and high-dose groups, There was a 2-fold induction in Glclc mRNA and protein in the gd 16 yolk sacs at both 3 and 10 ppm MeHg. No treatment-related changes in Glclr protein in either gd 12 or gd 16 yolk sacs or fetuses were found. Thus, the yolk sac is capable of up-regulating Glclc and GSH synthetic capacity in response to MeHg exposure. This increase appears to be sufficient to resist MeHg-induced GSH depletion in the yolk sac; however fetal glutathione redox status is compromised with exposure to 10 ppm MeHg. C1 Univ Washington, Dept Environm Hlth, Seattle, WA 98195 USA. Univ Washington, Dept Comparat Med, Seattle, WA 98195 USA. Univ Washington, NIEHS, Ctr Ecogenet & Environm Hlth, Seattle, WA 98195 USA. RP Kavanagh, TJ (reprint author), Univ Washington, Dept Environm Hlth, Mail Box 354695, Seattle, WA 98195 USA. FU NIEHS NIH HHS [P30-ES04696, P50-ES07033, T32-ES07032] NR 30 TC 25 Z9 27 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2000 VL 57 IS 1 BP 141 EP 146 DI 10.1093/toxsci/57.1.141 PG 6 WC Toxicology SC Toxicology GA 377BU UT WOS:000165492700017 PM 10966520 ER PT J AU Liu, YP Liu, J Habeebu, SM Waalkes, MP Klaassen, CD AF Liu, YP Liu, J Habeebu, SM Waalkes, MP Klaassen, CD TI Metallothionein-I/II null mice are sensitive to chronic oval cadmium-induced nephrotoxicity SO TOXICOLOGICAL SCIENCES LA English DT Article DE cadmium; chronic oral exposure; nephrotoxicity, metallothionein-I/II null mice; histopathology; apoptosis; immunohistochemistry ID INDUCED HEPATOTOXICITY; OXIDATIVE STRESS; TRANSGENIC MICE; CDMT EXPOSURE; RENAL INJURY; II GENES; RATS; APOPTOSIS; NEPHROPATHY; ABSORPTION AB Chronic exposure to cadmium (Cd) via food and drinking water is a major human health concern. We have previously shown that metallothionein (MT), a metal-binding protein, plays an important role in protecting against Cd toxicity produced by repeated sc injections. However, it is unclear whether MT protects against Cd-induced nephrotoxicity following chronic oral exposure, a route with obvious human relevance. To clarify this issue, MT-I/II knockout (MT-null) and background-matched wild-type (WT) mice were allowed free access to drinking water containing CdCl2 (30, 100, and 300 ppm Cd), or feed containing CdCl2 (100 ppm Cd) for 6 months, and the resultant nephrotoxicity was examined. Chronic oral Cd exposure produced a dose-dependent accumulation of Cd in liver and kidney of WT mice, reaching levels up to 50 mug Cd/g tissue. Immunohistological localization of renal MT indicated that chronic oral Cd exposure in WT mice greatly increased MT in the proximal tubules and the medulla, with cellular localization in both the cytoplasm and nuclei. As expected, no MT was detected in kidneys of MT-null mice. After 6 months of Cd exposure, tissue Cd concentrations in MT-null mice were only about one-fifth of that in WT mice. Even though the renal Cd concentrations were much lower in the MT-null mice, they were more sensitive than WT mice to Cd-induced renal injury, as evidenced by more severe nephropathic lesions, increased urinary excretion of gamma -glutamyl-transferase and glucose, and elevated blood urea nitrogen. Six months of Cd exposure to MT-null animals resulted in greater increases in renal caspase-3 activity, an indicator of apoptosis, than to WT mice. In conclusion, this study demonstrates that lack of MT renders MT-null mice vulnerable to Cd-induced nephrotoxicity after chronic oral exposure, the primary route of human Cd exposure. C1 Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. NCI, Comparat Carcinogenesis Lab, NIEHS, Res Triangle Pk, NC USA. RP Klaassen, CD (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. NR 47 TC 51 Z9 54 U1 2 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2000 VL 57 IS 1 BP 167 EP 176 DI 10.1093/toxsci/57.1.167 PG 10 WC Toxicology SC Toxicology GA 377BU UT WOS:000165492700020 PM 10966523 ER PT J AU Huff, J Tomatis, L AF Huff, J Tomatis, L TI Letter to the editor SO TOXICOLOGICAL SCIENCES LA English DT Letter C1 NIEHS, Res Triangle Pk, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. NR 3 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2000 VL 57 IS 1 BP 186 EP 186 DI 10.1093/toxsci/57.1.186 PG 1 WC Toxicology SC Toxicology GA 377BU UT WOS:000165492700022 PM 10966525 ER PT J AU Lightfoot, T Leitman, SF Stroncek, DF AF Lightfoot, T Leitman, SF Stroncek, DF TI Storage of G-CSF-mobilized granulocyte concentrates SO TRANSFUSION LA English DT Article ID COLONY-STIMULATING FACTOR; TRANSFUSION REACTIONS; DONORS; NEUTROPHILS; COLLECTION; DEXAMETHASONE; CYTOKINES; PLASMA AB BACKGROUND: Current standards limit granulocyte storage to 24 hours. Since G-CSF inhibits granulocyte apoptosis, it may be possible to store G-CSF-mobilized granulocytes for longer periods while maintaining cell viability and function. However, G-CSF mobilization increases the yield of granulocytes several times, and the resulting higher cell concentrations may diminish viability during storage and significant levels of pyrogenic cytokines may be produced. STUDY DESIGN: Ten granulocyte donors were given dexamethasone (8 mg PO), G-CSF (5 mu g/kg SQ), or both and on the next day granulocyte concentrates were collected using a blood cell separator. Component cell counts, cell viablilities, pH, and IL-1 beta, IL-6, IL-8 and TNF levels were measured at 2 to 4 (2), 20 to 28 (24), and 44 to 52 hours (48 hours). RESULTS: Significantly more granulocytes were collected when donors were given G-CSF (4.2 +/- 2.3 x 10(10)) or G-CSF plus dexamethasone (6.4 +/- 2.5 x 10(10)) compared with that collected with dexamethasone alone (2.2 +/- 1.2 x 10(10)); p = 0.03 and p = 0.002, respectively. Storage had little effect on WBC count. Slight but significant increases in IL-1 beta and IL-8 occurred after 24 and 48 hours as compared to the levels at 2 hours' storage. Levels of IL-6 and TNF did not change. The pH dropped significantly with time in granulocytes mobilized with each regimen. Granulocytes mobilized with G-CSF plus dexamethasone were acidic immediately after collection, and pH was below 6.0 after 24 hours. To assess the effect of cell concentrations on pH, serial dilutions were performed on 13 granulocyte concentrates in autologous plasma prior to storage. The pH remained above 7.0 only when dexamethasone-mobilized granulocytes were diluted 1-in-8 and when the G-CSF plus dexamethasone-mobilized granulocytes were diluted 1-in-16. CONCLUSIONS: To optimize storage pH, mobilized granulocyte concentrates require a 1-in-8 to 1-in-16 dilution, which is operationally impractical. Clinical-grade granulocyte preservative solutions are needed to maintain pH during storage. C1 NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C711,10 Ctr,Dr MSC 1184, Bethesda, MD 20892 USA. NR 25 TC 14 Z9 14 U1 0 U2 0 PU AMER ASSOC BLOOD BANKS PI BETHESDA PA 8101 GLENBROOK RD, BETHESDA, MD 20814-2749 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2000 VL 40 IS 9 BP 1104 EP 1110 DI 10.1046/j.1537-2995.2000.40091104.x PG 7 WC Hematology SC Hematology GA 352RX UT WOS:000089232600014 PM 10988314 ER PT J AU Aravind, L AF Aravind, L TI The BED finger, a novel DNA-binding domain in chromatin-boundary-element-binding proteins and transposases SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Article ID DROSOPHILA; INTERACTS; PROMOTER; GENES; HOBO; TAM3; DREF C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 21 TC 88 Z9 92 U1 1 U2 4 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 SEP PY 2000 VL 25 IS 9 BP 421 EP 423 DI 10.1016/S0968-0004(00)01620-0 PG 3 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 357ZB UT WOS:000089531800005 PM 10973053 ER PT J AU Rogawski, MA AF Rogawski, MA TI KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy SO TRENDS IN NEUROSCIENCES LA English DT Article ID FAMILIAL NEONATAL CONVULSIONS; LONG-QT SYNDROME; POTASSIUM CHANNEL; DE-POINTES; MUTATION; GENE; MECHANISMS; MICE; SEIZURES; KCNQ2 AB In 1998, the discovery of two novel genes KCNQ2 and KCNQ3, mutated in a rare inherited form of epilepsy known as benign familial neonatal convulsions, for the first time enabled insight into the molecular etiology of a human idiopathic generalized epilepsy syndrome,These disease genes encode subunits of neuronal M-type K+ channels, key regulators of brain excitability, Analogies between benign familial neonatal convulsions and other channelopathies of skeletal and cardiac. muscle, including periodic paralysis, myotonia and the long QT syndrome, provide clues about the nature of epilepsy-susceptibility genes and about the fundamental basis of epilepsy as an episodic disorder. It now appears that the KCNQ2/KCNQ3 K+ channels that are mutated in benign familial neonatal convulsions represent an important new target for anti-epileptic drugs. In the future, the identification of ion channel defects as predisposing factors in the common epilepsies could herald a new era of genotype-specific therapies. C1 NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. RP Rogawski, MA (reprint author), NINDS, Epilepsy Res Branch, NIH, Bethesda, MD 20892 USA. RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 NR 56 TC 105 Z9 110 U1 1 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD SEP PY 2000 VL 23 IS 9 BP 393 EP 398 DI 10.1016/S0166-2236(00)01629-5 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 350AD UT WOS:000089077100002 PM 10941184 ER PT J AU Gussio, R Fojo, T Giannakakou, P AF Gussio, R Fojo, T Giannakakou, P TI Mutants yield a pharmacophore model for the tubulin-paclitaxel binding site - Reply SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material C1 NCI, Target Struct Based Drug Discovery Grp, Informat Technol Branch, Dev Therapeut Program,NIH, Frederick, MD 21702 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Gussio, R (reprint author), NCI, Target Struct Based Drug Discovery Grp, Informat Technol Branch, Dev Therapeut Program,NIH, Frederick, MD 21702 USA. NR 3 TC 1 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD SEP PY 2000 VL 21 IS 9 BP 323 EP 324 DI 10.1016/S0165-6147(00)01522-4 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 356LB UT WOS:000089443800002 ER PT J AU Lee, W Kirk, JS Shaheen, KW Romero, R Hodges, AN Comstock, CH AF Lee, W Kirk, JS Shaheen, KW Romero, R Hodges, AN Comstock, CH TI Fetal cleft lip and palate detection by three-dimensional ultrasonography SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE 3D ultrasonography; cleft lip; cleft palate; prenatal diagnosis; ultrasound ID 3-DIMENSIONAL ULTRASONOGRAPHY; FACIAL CLEFTS; FACE; VISUALIZATION; ABNORMALITIES; ULTRASOUND AB Objectives To demonstrate a standardized approach for the evaluation of cleft lip and palate by three-dimensional (3D) ultrasonography. Design This was a retrospective study of seven fetuses with confirmed facial cleft anomalies. Post-natal findings were compared to a blinded review of 3D volume data from abnormal fetuses with seven other normal fetuses that were matched for gestational age. Upper lip integrity was examined by 3D multiplanar imaging. Sequential axial views were used to evaluate the maxillary tooth-bearing alveolar ridge contour and anterior tooth socket alignment. Alveolar ridge disruption suggested cleft palate. Premaxillary protrusion, either by multiplanar imaging or surface rendering, indicated bilateral cleft lip and palate. Results Post-natal findings confirmed bilateral cleft lip and palate (four cases), unilateral cleft lip and palate (one case), and unilateral cleft lip (two cases). Multiplanar review identified all three fetuses with unilateral cleft lip, three of four fetuses with bilateral cleft lip, one fetus with unilateral cleft palate, and three of four fetuses with bilateral cleft palate. Surface rendering correctly identified all cleft lips, with the exception of one fetus, who was thought to have a unilateral cleft lip and palate, despite the actual presence of a bilateral lesion. One cleft palate defect was directly visualized by 3D surface rendering. No false-positives occurred. Conclusion Interactive review of standardized 3D multiplanar images allows one to evaluate labial defects, abnormalities of the maxillary tooth-bearing alveolar ridge, and presence of premaxillary protrusion for detecting cleft lip and palate anomalies. Surface rendering may increase diagnostic confidence for normal or abnormal studies. This technology provides an array of visualization tools that may improve the prenatal characterization of facial clefts, particularly of the palate. C1 William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48073 USA. William Beaumont Hosp, Dept Plast Surg, Royal Oak, MI 48073 USA. NICHD, Perinatol Res Branch, Bethesda, MD USA. RP Lee, W (reprint author), William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. NR 15 TC 40 Z9 47 U1 1 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD SEP PY 2000 VL 16 IS 4 BP 314 EP 320 DI 10.1046/j.1469-0705.2000.00181.x PG 7 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 401DX UT WOS:000166913000005 PM 11169306 ER PT J AU Lee, W Kirk, JS Comstock, CH Romero, R AF Lee, W Kirk, JS Comstock, CH Romero, R TI Vasa previa: prenatal detection by three-dimensional ultrasonography SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE prenatal diagnosis; three-dimensional ultrasonography; vasa previa ID ANTENATAL DIAGNOSIS; COLOR; INSERTION; CORD AB Objective To describe three-dimensional (3D) ultrasonography (US) for the antepartum diagnosis of vasa previa. Design This was a descriptive study of two pregnant women who were suspected to have vasa previa by conventional gray-scale ultrasonography. Three-dimensional studies were also performed during the early third trimester to further investigate the possibility of this condition. Results In the first case, 3D US provided gray-scale multiplanar and surface-rendered views of an aberrant vessel over the internal cervical os. For the second case, a 'flight-path' technique allowed the examiner to follow axial views of the endocervical canal toward the internal os until an aberrant vessel was verified. The 'niche-mode' analysis, with and without color power Doppler ultrasonography, was also used to confirm the diagnosis. Conclusion Three-dimensional ultrasonography offers several additional imaging tools that are not currently provided by more conventional ultrasonography for the detection of vasa previa. It represents an important adjunct to two-dimensional (2D) studies, especially when this diagnosis is questionable. C1 William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48073 USA. NICHD, Perinatol Res Branch, Bethesda, MD USA. RP Lee, W (reprint author), William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. NR 8 TC 25 Z9 25 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD SEP PY 2000 VL 16 IS 4 BP 384 EP 387 DI 10.1046/j.1469-0705.2000.00188.x PG 4 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 401DX UT WOS:000166913000016 PM 11169317 ER PT J AU Orenstein, JM Ciufo, DM Zoeteweij, JP Blauvelt, A Hayward, GS AF Orenstein, JM Ciufo, DM Zoeteweij, JP Blauvelt, A Hayward, GS TI Morphogenesis of HHV8 in primary human dermal microvascular endothelium and primary effusion lymphomas SO ULTRASTRUCTURAL PATHOLOGY LA English DT Article DE endothelium; HHV8; KSHV; lymphoma; morphogenesis; TEM ID SARCOMA-ASSOCIATED HERPESVIRUS; MULTICENTRIC CASTLEMANS-DISEASE; AIDS-RELATED LYMPHOMAS; CAVITY-BASED LYMPHOMA; EPSTEIN-BARR-VIRUS; KAPOSIS-SARCOMA; DNA-SEQUENCES; ULTRASTRUCTURAL DEMONSTRATION; MULTIPLE-MYELOMA; CELLS AB This study elucidates the morphology of HHV8 replication in human dermal endothelial cells and primary effusion lymphomas (PEL) and compares it to that seen in Kaposi sarcoma. Primary human dermal microvascular endothelial cells (DMVEC) exposed to the cell-filtered supernatant of the PEL JSC1 and PEL cell lines (KS-1, BCBL-1, BC-1, BC-3) were cultured in the presence or absence of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or butyrate. Cells were fixed in neutral-buffered glutaraldehyde, gelled in cooled agar, and processed for TEM. There was a quantitative, but not a qualitative difference in Viral expression associated with no treatment or exposure to TPA or butyrate of HHV8 in DMVEC and PEL. Two types of viral-induced intranuclear inclusions (INI) were visible at the light and ultrastructural levels. The more common INI had lighter staining material filling the nucleus, except for a rim of dense chromatin, and could be seen even before viral nucleocapsids (NC) were visible. The second type of INI resembled a target formed by condensation of electron-dense material surrounded by a lighter halo and marginated heterochromatin and containing NC. Collections of coalescing electron-dense granules resembling starbursts were often present in nuclei containing either type of INI. Next to appear in productively infected cells were mature enveloped particles that formed mostly by the budding of NC into cytoplasmic vacuoles. Mature particles were also seen free on the plasma membrane. Tufts of electron-dense intermediate filaments were associated with maturing particles. Mature virions lacked an electron-dense tegument. Viral production was ultimately associated with cell lysis. It appears that HHV8 propagate in DMVEC. with and without stimulation, and have a similar morphogenesis to that seen in PEL cell lines and Kaposi sarcoma lesions. Several unique features characterize cells productively infected by HHV8. C1 George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. Johns Hopkins Sch Med, Dept Pharmacol, Baltimore, MD USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Orenstein, JM (reprint author), George Washington Univ, Med Ctr, Dept Pathol, Ross 502,2300 Eye Str NW, Washington, DC 20037 USA. NR 34 TC 7 Z9 8 U1 0 U2 0 PU HEMISPHERE PUBL CORP PI BRISTOL PA 1900 FROST ROAD, SUITE 101, BRISTOL, PA 19007-1598 USA SN 0191-3123 J9 ULTRASTRUCT PATHOL JI Ultrastruct. Pathol. PD SEP-OCT PY 2000 VL 24 IS 5 BP 291 EP 300 PG 10 WC Microscopy; Pathology SC Microscopy; Pathology GA 369RQ UT WOS:000165081100002 PM 11071567 ER PT J AU Taube, SE Freiberg, GP AF Taube, SE Freiberg, GP TI Regulatory issues related to marker development SO UROLOGIC ONCOLOGY LA English DT Article; Proceedings Paper CT 2nd International Workshop on Diagnostic and Prognostic Markers in Bladder Cancer CY OCT, 1998 CL BARCELONA, SPAIN DE FDA; in vitro devices; regulatory issues; safety and effectiveness; marker development AB Development of clinical laboratory tests (described in this article as "markers" and in vitro devices) is guided by governmental regulation both in the U.S. and abroad. The purpose of the regulation is to assure that products used in medical cars are safe, perform reliably, and are effective. This article presents a brief overview of the U.S. regulations and how they affect the clinical studies that must be performed to bring a new test to market. The FDA's definitions of safety and effectiveness are provided. The three regulatory classes and the regulatory requirements that are associated with each class are described. An attempt is made to compare the U.S. system with those of Europe and Japan. (C) 2000 Elsevier Science Inc. All rights reserved. C1 NCI, Div Canc Treatment & Diag, Canc Diag Program, Rockville, MD 20852 USA. Gen Probe Inc, Regulatory Affairs, San Diego, CA 92121 USA. RP Taube, SE (reprint author), NCI, Div Canc Treatment & Diag, Canc Diag Program, Execut Plaza N,Room 700,6130 Execut Blvd, Rockville, MD 20852 USA. NR 0 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1078-1439 J9 UROL ONCOL JI Urol. Oncol. PD SEP-OCT PY 2000 VL 5 IS 5 BP 214 EP 216 DI 10.1016/S1078-1439(00)00076-4 PG 3 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 390NH UT WOS:000166302300006 ER PT J AU Poggi, MM Johnstone, PAS Conner, RJ AF Poggi, MM Johnstone, PAS Conner, RJ TI Glycosaminoglycan content of human bladders: a method of analysis using cold-cup biopsies SO UROLOGIC ONCOLOGY LA English DT Article; Proceedings Paper CT 2nd International Workshop on Diagnostic and Prognostic Markers in Bladder Cancer CY OCT, 1998 CL BARCELONA, SPAIN DE bladder; glycosaminoglycan; assay ID INTERSTITIAL CYSTITIS; URINARY-BLADDER; PENTOSANPOLYSULFATE; SURFACE; LAYER; MECHANISM; HEPARIN AB A glycocalyx layer composed of glycosaminoglycans (GAGs) and ether molecules lines the transitional epithelium of the urinary bladder. This laver forms a barrier between the transitional cells and urinary bladder environment and is believed to help prevent the adherence of bacteria, minerals and carcinogens. Investigators postulate that quantitative and/or qualitative defects in the GAG component may be responsible for a spectrum of acute and chronic disease processes ranging from urinary tract infections to cancer. While the presence of epithelium GAGs has been confirmed biochemically and histochemically, few rigorous characterizations have been performed. This study establishes the methodology and feasibility of using routine cold-cup biopsies from cadaveric human bladders for GAG analysis and establishes baseline contents of the sulfated and non-sulfated GAGs in the urinary bladder glycocalyx. Using detergent extraction, the GAGs from cold-cup biopsies (n = 34) from four cadaveric bladders were isolated. The isolates were subjected to two colorimetric assays to quantify both sulfated and non-sulfated GAGs. The nonsulfated GAG content of the bladder epithelium ranged from 2.15 x 10(-4) to 5.50 x 10(-4) mmol/kg of dry, defatted bladder. The sulfated GAG content ranged from 2.00 x 10(-1) to 7.40 x 10(-1) mmol/kg of dry, defatted bladder. These values are consistent with reports found in the literature using electrophoresis on full-thickness human bladder specimens. The GAG content of human bladder epithelium can be readily and accurately characterized from cold-cup biopsy samples. Our future plans involve using this routinely used technique to analyze samples from live control and disease-state bladders thereby demonstrating any quantitative and/or qualitative differences in GAG constituents. (C) 2000 Elsevier Science Inc. All rights reserved. C1 USN, Med Ctr, Div Radiat Oncol, San Diego, CA 92134 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. USN, Med Ctr, Dept Urol, San Diego, CA 92134 USA. Univ Calif San Diego, Div Radiat Oncol, San Diego, CA 92103 USA. RP Johnstone, PAS (reprint author), USN, Med Ctr, Div Radiat Oncol, San Diego, CA 92134 USA. NR 22 TC 17 Z9 18 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1078-1439 J9 UROL ONCOL JI Urol. Oncol. PD SEP-OCT PY 2000 VL 5 IS 5 BP 234 EP 237 DI 10.1016/S1078-1439(00)00074-0 PG 4 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 390NH UT WOS:000166302300010 ER PT J AU Wallace, M Pyzalski, R Horejsh, D Brown, C Djavani, M Lu, YC Hanson, JM Mitchen, JL Perlman, SB Pauza, CD AF Wallace, M Pyzalski, R Horejsh, D Brown, C Djavani, M Lu, YC Hanson, JM Mitchen, JL Perlman, SB Pauza, CD TI Whole body positron emission tomography imaging of activated lymphoid tissues during acute simian-human immunodeficiency virus 89.6PD infection in rhesus macaques SO VIROLOGY LA English DT Article DE simian-human immunodeficiency virus; acute infection; pathogenesis; AIDS; positron emission tomography imaging ID PRIMARY HIV-INFECTION; KAPPA-B ACTIVATION; T-CELL RESPONSES; TAT PROTEIN; DISEASE PROGRESSION; HOST RESPONSES; FDG-PET; AIDS; EXPRESSION; ORGANS AB Mechanisms of acute retroviral pathogenesis have been examined during primary infection of rhesus macaques with simian-human immunodeficiency virus 89.6PD (SHIV89.6PD). During acute infection. between initial exposure and establishment of antigen-specific immune responses that stabilize the Virus burden, rapid immune system changes influence the viral set-point and dictate subsequent steps in disease progression. In a previous study, we described specific patterns of lymphocyte activation during acute SHIV89.6PD infection. We now extend these studies to describe lymphoid tissue activation, using whole body positron emission tomography (PET) and the radioactive tracer 2-[F-18]fluorodeoxyglucose (FDG). Within a few days after primary infection by intravenous, intrarectal, or intravaginal routes, PET-FDG imaging revealed a distinct pattern of lymphoid tissue activation centered on axillary, cervical, and mediastinum lymph nodes. Increased tissue FDG uptake preceded fulminant virus replication at these sites, suggesting that a diffusible factor of host or viral origin was responsible for lymphoid tissue changes. These data show that activation of lymphoid tissues in the upper body is an early response to virus infection and that diffusible mediators of activation might be important targets for vaccine or therapeutic intervention strategies. (C) 2000 Academic Press. C1 Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53705 USA. Univ Wisconsin, Dept Radiol, Madison, WI 53705 USA. Univ Wisconsin, PET Imaging Ctr, Madison, WI 53705 USA. Univ Wisconsin, Wisconsin Reg Primate Res Ctr, Madison, WI 53705 USA. NIH, Immunodeficiency Viruses Sect, Infect Dis Lab, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Pauza, CD (reprint author), Univ Maryland, Inst Biotechnol, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. FU NCRR NIH HHS [RR00167]; NIAID NIH HHS [AI38491, AI41977] NR 38 TC 22 Z9 22 U1 0 U2 0 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 SEP 1 PY 2000 VL 274 IS 2 BP 255 EP 261 DI 10.1006/viro.2000.0479 PG 7 WC Virology SC Virology GA 353TE UT WOS:000089290900003 PM 10964769 ER PT J AU Cunliffe, NA Gentsch, JR Kirkwood, CD Gondwe, JS Dove, W Nakagomi, O Nakagomi, T Hoshino, Y Bresee, JS Glass, RI Molyneux, ME Hart, CA AF Cunliffe, NA Gentsch, JR Kirkwood, CD Gondwe, JS Dove, W Nakagomi, O Nakagomi, T Hoshino, Y Bresee, JS Glass, RI Molyneux, ME Hart, CA TI Molecular and serologic characterization of novel serotype G8 human rotavirus strains detected in Blantyre, Malawi SO VIROLOGY LA English DT Article ID POLYMERASE CHAIN-REACTION; RNA-RNA HYBRIDIZATION; MONOCLONAL-ANTIBODIES; SEQUENCE-ANALYSIS; P-TYPE; UNITED-STATES; SUBGROUP-I; BOVINE ROTAVIRUSES; BRAZILIAN CHILDREN; YOUNG-CHILDREN AB During a 2-year study of diarrhea among children in Blantyre, Malawi, greater than 50% of rotavirus strains genotyped by using reverse transcription-polymerase chain reaction possessed previously unrecognized combinations of the neutralization proteins VP7 and VP4. Serotype G8 rotaviruses, which have been identified recently in several African countries, were found to possess P[4] or P[6] VP4 genotype specificity Two of these short electropherotype rotaviruses were further investigated: these comprised a P[6], G8 representative strain (MW23) and a P[4], G8 representative strain (MW333). The VP7 gene sequences of both strains exhibited greatest homology to human and animal serotype G8 rotaviruses. Sequence analysis of the VP4 gene of MW23 indicated closest identity to the P2A[6], G9 strain US1205 from the United States, The VP4 gene of MW333 was most closely related to the P[4], G12 strain L26 isolated in the Philippines and the Australian P[4], G2 strain RV-5. The NSP4 gene sequences of both strains were classified in NSP4 genetic group I, RNA-RNA hybridization demonstrated that each of these two strains is related to the DS-1 genogroup of human rotaviruses. Subgroup analysis and virus neutralization confirmed complete antigenic characterization of MW23 as subgroup I, P2A[6], G8 and MW333 as subgroup I, P1B[4], G8. The similarity of the VP7 gene sequences of the prototype strains described in this report to bovine serotype G8 rotaviruses suggests that they may represent human/bovine reassortant viruses. (C) 2000 Academic Press. C1 Wellcome Trust Res Labs, Blantyre, Malawi. Univ Malawi, Coll Med, Dept Paediat, Zomba, Malawi. Ctr Dis Control & Prevent, Viral Gastroenteritis Unit, Atlanta, GA 30333 USA. Akita Univ, Sch Med, Dept Microbiol, Akita 010, Japan. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Liverpool, Sch Trop Med, Liverpool, Merseyside, England. Univ Liverpool, Dept Med Microbiol & Genitourinary Med, Liverpool L69 3BX, Merseyside, England. RP Hart, CA (reprint author), Univ Liverpool, Dept Med Microbiol & Genitourinary Med, Duncan Bldg,Daulby St, Liverpool L69 3BX, Merseyside, England. OI Cunliffe, Nigel/0000-0002-5449-4988 NR 66 TC 55 Z9 56 U1 0 U2 0 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 SEP 1 PY 2000 VL 274 IS 2 BP 309 EP 320 DI 10.1006/viro.2000.0456 PG 12 WC Virology SC Virology GA 353TE UT WOS:000089290900008 PM 10964774 ER PT J AU Waldvogel, D van Gelderen, P Muellbacher, W Ziemann, U Immisch, I Hallett, M AF Waldvogel, D van Gelderen, P Muellbacher, W Ziemann, U Immisch, I Hallett, M TI The relative metabolic demand of inhibition and excitation SO NATURE LA English DT Article ID CEREBRAL BLOOD-FLOW; POSITRON EMISSION TOMOGRAPHY; PRESUPPLEMENTARY MOTOR AREA; FINGER MOVEMENTS; NORMAL VALUES; STIMULATION; BRAIN; CORTEX; ACTIVATION; CELLS AB By using the (C-14)2-deoxyglucose method(1), inhibition has been shown to be a metabolically active process at the level of the synapse(2,3). This is supported by recent results from magnetic resonance spectroscopy that related the changes in neuroenergetics occurring with functional activation to neurotransmitter cycling(4). However, inhibitory synapses are less numerous and strategically better located than excitatory synapses, indicating that inhibition may be more efficient, and therefore less energy-consuming, than excitation. Here we test this hypothesis using event-related functional magnetic resonance imaging in volunteers whose motor cortex was inhibited during the no-go condition of a go/no-go task, as demonstrated by transcranial magnetic stimulation. Unlike excitation, inhibition evoked no measurable change in the blood-oxygenation-level-dependent signal in the motor cortex, indicating that inhibition is less metabolically demanding. Therefore, the 'activation' seen in functional imaging studies probably results from excitation rather than inhibition. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NINDS, In Vivo NMR Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. NR 30 TC 191 Z9 193 U1 1 U2 10 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 31 PY 2000 VL 406 IS 6799 BP 995 EP 998 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 348ZW UT WOS:000089020200045 PM 10984053 ER PT J AU Desai, SA Bezrukov, SM Zimmerberg, J AF Desai, SA Bezrukov, SM Zimmerberg, J TI A voltage-dependent channel involved in nutrient uptake by red blood cells infected with the malaria parasite SO NATURE LA English DT Article ID PLASMODIUM-FALCIPARUM; TRANSPORT; MEMBRANE; ERYTHROCYTES; PERMEATION; CULTURE AB Growth of the malaria parasite in human red blood cells (RBCs) is accompanied by an increased uptake of many solutes including anions(1), sugars(2), purines(3), amino acids(4) and organic cations(5). Although the pharmacological properties and selectivity of this uptake suggest that a chloride channel is involved, the precise mechanism has not been identified. Moreover, the location of this uptake in the infected RBC is unknown because tracer studies are complicated by possible uptake through fluid-phase pinocytosis(6) or membranous ducts(7). Here we have studied the permeability of infected RBCs using the whole-cell voltage-clamp method. With this method, uninfected RBCs had ohmic whole-cell conductances of less than 100 pS, consistent with their low tracer permeabilities(8). In contrast, trophozoite-infected RBCs exhibited voltage-dependent, non-saturating currents that were 150-fold larger, predominantly carried by anions and abruptly abolished by channel blockers. Patch-clamp measurements and spectral analysis confirmed that a small (<10 pS) ion channel on the infected RBC surface, present at about 1,000 copies per cell, is responsible for these currents. Because its pharmacological properties and substrate selectivities match those seen with tracer studies, this channel accounts for the increased uptake of small solutes in infected RBCs. The surface location of this new channel and its permeability to organic solutes needed for parasite growth indicate that it may have a primary role in a sequential diffusive pathway for parasite nutrient acquisition. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. NICHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Desai, SA (reprint author), NIAID, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Desai, Sanjay/B-7110-2009 FU Intramural NIH HHS [Z01 AI000882-07] NR 27 TC 175 Z9 183 U1 1 U2 11 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 31 PY 2000 VL 406 IS 6799 BP 1001 EP 1005 DI 10.1038/35023000 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 348ZW UT WOS:000089020200047 PM 10984055 ER PT J AU Verselis, SJ Rheinwald, JG Fraumeni, JF Li, FP AF Verselis, SJ Rheinwald, JG Fraumeni, JF Li, FP TI Novel p53 splice site mutations in three families with Li-Fraumeni syndrome SO ONCOGENE LA English DT Article DE p53; germline mutation; Li-Fraumeni syndrome; alternate splicing ID CANCER-PRONE FAMILY; CELL-LINES; GENE; TP53; DATABASE; PATIENT; POLYMORPHISM; DEFICIENCY; PROTEIN; TUMORS AB Germline mutations in the p53 tumor suppressor gene predispose to a variety of cancers in families with Li-Fraumeni syndrome. Most germline p53 mutations observed to date cause amino acid substitutions in the protein's central sequence-specific DNA binding domain. Outside this conserved core region, however, we found novel alterations in sequences that regulate precursor mRNA splicing in three Li-Fraumeni syndrome families. Two splice site mutations affected the consensus sequence at the splice donor sites of introns 1 and 9, and produced unstable variant transcripts in normal cells. A third mutation at the splice acceptor site of intron 9 generated splicing at a cryptic acceptor site in intron 9, These splice site alterations emphasize the need to examine both noncoding and untranslated regions of the p53 gene for germline mutations in Li-Fraumeni syndrome families. C1 Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Skin Dis Res Ctr, Boston, MA 02115 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Li, FP (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA. NR 33 TC 19 Z9 21 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 31 PY 2000 VL 19 IS 37 BP 4230 EP 4235 DI 10.1038/sj.onc.1203758 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 349FL UT WOS:000089032900005 PM 10980596 ER PT J AU Nakano, K Balint, E Ashcroft, M Vousden, KH AF Nakano, K Balint, E Ashcroft, M Vousden, KH TI A ribonucleotide reductase gene is a transcriptional target of p53 and p73 SO ONCOGENE LA English DT Article DE p53; p73; DNA damage; ribonucleotide reductase; p53R2 ID CELL-CYCLE ARREST; KINASE C-ABL; DNA-DAMAGE; APOPTOTIC RESPONSE; TUMOR SUPPRESSION; INDUCE APOPTOSIS; ENDOREDUPLICATION; PROLIFERATION; MUTANTS; CANCER AB Many p53-inducible genes have been identified that might play a role in mediating the various downstream activities of p53, We have identified a close relative of ribonucleotide reductase, recently named p53R2, as a p53-inducible gene, and show that this gene is activated by several stress signals that activate a p53 response, including DNA damaging agents and p14(ARF), p53R2 expression was induced by p53 mutants that are defective for the activation of apoptosis, but retain cell cycle arrest function, although no induction of p53R2 was seen in response to p21(WAF1/CIP1)-mediated cell cycle arrest. Several isoforms of the p53 family member p73 were also shown to induce p53R2 expression. Transient ectopic expression of either wild type p53R2 or p53R2 targeted to the nucleus, did not significantly alter cell cycle progression in unstressed cells, The identification of this gene as a p53 target supports a direct role for p53 in DNA repair, in addition to inhibition of growth of damaged cells. C1 NCI, Frederick Canc Res & Dev Ctr, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RP Vousden, KH (reprint author), NCI, Frederick Canc Res & Dev Ctr, Regulat Cell Growth Lab, Bldg 560,Room 22-96,W 7th St, Frederick, MD 21702 USA. RI Balint, Eva/B-8695-2008 NR 32 TC 169 Z9 172 U1 0 U2 10 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 31 PY 2000 VL 19 IS 37 BP 4283 EP 4289 DI 10.1038/sj.onc.1203774 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 349FL UT WOS:000089032900011 PM 10980602 ER PT J AU Subramaniam, S Henderson, R AF Subramaniam, S Henderson, R TI Crystallographic analysis of protein conformational changes in the bacteriorhodopsin photocycle SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOENERGETICS LA English DT Review DE electron microscopy; time-resolved crystallography ID X-RAY-DIFFRACTION; STRUCTURAL-CHANGES; ELECTRON-DIFFRACTION; REPROTONATION SWITCH; NEUTRON-DIFFRACTION; N-INTERMEDIATE; TRANSITION; TEMPERATURE; RESOLUTION; HYDRATION AB A variety of neutron, X-ray and electron diffraction experiments have established that the transmembrane regions of bacteriorhodopsin undergo significant light-induced changes in conformation during the course of the photocycle. A recent comprehensive electron crystallographic analysis of light-driven structural changes in wild-type bacteriorhodopsin and a number of mutants has established that a single, large protein conformational change occurs within 1 ms after illumination, roughly coincident with the time scale of formation of the M-2 intermediate in the photocycle of wild-type bacteriorhodopsin. Minor differences in structural changes that are observed in mutants that display long-lived M-2, N or O intermediates are best described as variations of one fundamental type of conformational change, rather than representing structural changes that are unique to the optical intermediate that is accumulated. These observations support a model for the photocycle of wild-type bacteriorhodopsin in which the structures of the initial state and the early intermediates (K, L and M-1) are well approximated by one protein conformation in which the Schiff base has extracellular accessibility, while the structures of the later inter-mediates (M-2, N and O) are well approximated by the other protein conformation in which the Schiff base has cytoplasmic accessibility. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NCI, Biochem Lab, Bethesda, MD 20892 USA. MRC, Mol Biol Lab, Cambridge CB2 2QH, England. RP Subramaniam, S (reprint author), NCI, Biochem Lab, Bethesda, MD 20892 USA. NR 21 TC 37 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2728 J9 BBA-BIOENERGETICS JI Biochim. Biophys. Acta-Bioenerg. PD AUG 30 PY 2000 VL 1460 IS 1 SI SI BP 157 EP 165 DI 10.1016/S0005-2728(00)00136-5 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 353TG UT WOS:000089291100013 PM 10984597 ER PT J AU Felsenfeld, G Clark, D Studitsky, V AF Felsenfeld, G Clark, D Studitsky, V TI Transcription through nucleosomes SO BIOPHYSICAL CHEMISTRY LA English DT Article ID TRANSCRIBING POLYMERASE; MECHANISM; TEMPLATE; BARRIER; DNA AB Transcriptionally active genes in eukaryotes still retain most of the Chromatin packaging that is characteristic of eukaryotic DNA. Nucleosomes and even some higher order structure are present, although the histones may be chemically modified, for example by acetylation or phosphorylation, as part of the activation process. The presence of nucleosomes on the coding region of active genes raises the question: How does an RNA polymerase transcribe such a template? We have attempted to answer this question with relatively simple model systems involving a template carrying a single positioned nucleosome. We have shown that when a phage polymerase, SP6, transcribes such a template, the histone octamer of the nucleosome is not released into solution. Instead it is retained on the same DNA molecule, but displaced from its original binding site. Further studies have allowed us to propose a detailed model, which appears to hold not only for SP6 but also for transcription by the much larger RNA polymerase III from yeast. Our most recent results, obtained by electron cryomicroscopy, confirm and refine this model. (C) 2000 Published by Elsevier Science B.V. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Sch Med, Dept Biochem, Detroit, MI 48021 USA. RP Felsenfeld, G (reprint author), NIDDKD, Mol Biol Lab, NIH, Bldg 5,Room 212, Bethesda, MD 20892 USA. RI Studitsky, Vasily/A-9382-2014 NR 9 TC 21 Z9 21 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD AUG 30 PY 2000 VL 86 IS 2-3 BP 231 EP 237 DI 10.1016/S0301-4622(00)00134-4 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 352CZ UT WOS:000089198100015 PM 11026687 ER PT J AU Minton, AP AF Minton, AP TI Effects of excluded surface area and adsorbate clustering on surface adsorption of proteins I. Equilibrium models SO BIOPHYSICAL CHEMISTRY LA English DT Article DE protein adsorption; excluded volume; protein assembly ID LOCALLY PLANAR SURFACES; LARGE-LIGAND ADSORPTION; PHOSPHOLIPID-MEMBRANES; GLOBULAR-PROTEINS; BINDING; KINETICS; PROTHROMBIN; SYSTEMS; LENGTH AB Statistical-thermodynamic models for the equilibrium adsorption of proteins onto homogeneous, locally planar surfaces are presented. An extension of earlier work [R.C. Chatelier, AP. Minton, Biophys. J. 71 (1996) 2367], the models presented here allow for the formation of a broadly heterogeneous population of adsorbate clusters in addition to excluded volume interactions between all adsorbate species. Calculations are carried out for three simple models for the structure of adsorbate, illustrating similarities and differences in the equilibrium properties of maximally compact clusters, minimally compact clusters and isomerizing clusters. Depending upon the strength of attractive interactions between adsorbate molecules, the resulting equilibrium isotherms may exhibit negative cooperativity, positive cooperativity, essentially no apparent cooperativity, or a mixture of positive cooperativity at low surface density and negative cooperativity at high surface density of adsorbate. The condition of apparent lack of cooperativity, which might naively be interpreted as evidence of a lack of interaction between adsorbate molecules, actually conceals a balance between attractive and repulsive interactions and extensive clustering of adsorbate. (C) Published by Elsevier Science B.V. C1 NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NR 20 TC 46 Z9 46 U1 0 U2 16 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD AUG 30 PY 2000 VL 86 IS 2-3 BP 239 EP 247 DI 10.1016/S0301-4622(00)00151-4 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 352CZ UT WOS:000089198100016 PM 11026688 ER PT J AU Davenport, RW Lanuza, M Kim, S Jia, M Snyder, E Nelson, PG AF Davenport, RW Lanuza, M Kim, S Jia, M Snyder, E Nelson, PG TI Thrombin action decreases acetylcholine receptor aggregate number and stability in cultured mouse myotubes SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE myotube; protease inhibitor; thrombin; acetylcholine receptor; aggregate; cell culture ID SYNAPSE REDUCTION; MUSCLE-CELLS; ACTIVATION; ELIMINATION; MECHANISM AB Neurons develop and make very stable, long-term synaptic connections with other nerve cells and with muscle. Synaptic stability at the neuromuscular junction changes over development in that a proliferation of synaptic input are made to individual myotubes and synapses from all but one neuron are lost during development. In an established co-culture paradigm in which spinal motoneurons synaptically contact myotubes, thrombin and associated protease inhibitors have been shown to affect the loss of functional synaptic contacts [6]. Evidence has not been provided which clearly demonstrate whether protease/protrease inhibitors affect either the pre- or postsynaptic terminal, or both. In an effort to determine whether these reagents directly affect postsynaptic receptors on myotubes, myotubes were cultured in the absence of neurons and the spontaneous presence and stability of aggregates of acetylcholine receptors (AChR) in control and thrombin-containing media were evaluated. In dishes fixed after treatment and in dishes in which individual aggregates were observed live, thrombin action appeared to increase loss of AChR aggregates over time. Hirudin, a specific inhibitor of the thrombin protease, diminished this loss. Neither reagent affected the overall incorporation or degradation of AChR; therefore, it appears these protease/protease inhibitors affect the state of AChR aggregation. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Maryland, Dept Biol, College Pk, MD 20742 USA. NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Univ Rovira & Virgili, Fac Med, Unitat Histol Neurobiol 1, Reus 4320, Spain. RP Davenport, RW (reprint author), Univ Maryland, Dept Biol, 1210 Biol Psych Bldg, College Pk, MD 20742 USA. NR 13 TC 3 Z9 3 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 AUG 30 PY 2000 VL 122 IS 2 BP 119 EP 123 DI 10.1016/S0165-3806(00)00062-6 PG 5 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 350NE UT WOS:000089107200002 ER PT J AU Peng, S Rapoport, SI Pearce, RJ Galdzicki, Z AF Peng, S Rapoport, SI Pearce, RJ Galdzicki, Z TI Abnormal chloride and potassium conductances in cultured embryonic tongue muscle from trisomy 16 mouse SO DEVELOPMENTAL BRAIN RESEARCH LA English DT Article DE muscle; tongue; hypotonia; Down syndrome; Ts16 mouse; potassium conductance; chloride conductance ID ROOT GANGLION NEURONS; SKELETAL-MUSCLE; DOWN-SYNDROME; SODIUM CURRENT; CHANNELS; FIBERS; MYOTONIA; STRENGTH; FETUS; MODEL AB Trisomy 16 (Ts16) mouse is considered an animal model of Down syndrome (human trisomy 21). Whole-cell patch-clamp was used to evaluate potassium and chloride currents of cultured tongue muscle cells from fetal Ts16 and diploid mice. No difference was found in membrane capacitance between the two groups. K+ and Cl- currents were pharmacologically isolated. K+ conductance was reduced by 31% in Ts16 cells (373 pS/pF) compared with diploid cells (539 pS/pF). Cl- conductance was 51% larger in Ts16 cells (103 pS/pF) compared with diploid cells (68 pS/pF). However kinetics for K+ and Cl- currents did not differ between the cell types. An increase in Cl- conductance and a decrease in K+ conductance in Ts16 muscle cells, if present in muscle of Down syndrome subjects, might account for the observed hypotonia in these subjects. (C) 2000 Elsevier Science BN. All rights reserved. C1 NIA, Neurosci Lab, NIH, Bethesda, MD 20892 USA. RP Galdzicki, Z (reprint author), NIA, Neurosci Lab, NIH, Room 6C-103,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 32 TC 1 Z9 1 U1 0 U2 1 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 AUG 30 PY 2000 VL 122 IS 2 BP 193 EP 197 DI 10.1016/S0165-3806(00)00058-4 PG 5 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 350NE UT WOS:000089107200010 ER PT J AU Beard, WA Wilson, SH AF Beard, WA Wilson, SH TI Structural design of a eukaryotic DNA repair polymerase: DNA polymerase beta SO MUTATION RESEARCH-DNA REPAIR LA English DT Article DE base excision repair; DNA polymerase; lyase; gap-filling; fidelity; endogenous DNA damage ID BASE-EXCISION-REPAIR; CRYSTAL-STRUCTURE; NUCLEOTIDE INCORPORATION; ANGSTROM RESOLUTION; ESCHERICHIA-COLI; MAMMALIAN-CELLS; ACTIVE-SITE; REVERSE-TRANSCRIPTASE; CATALYTIC MECHANISM; TERNARY COMPLEXES AB DNA polymerase beta, the smallest eukaryotic DNA polymerase, is designed to synthesize DNA in short DNA gaps during DNA repair. It is composed of two specialized domains that contribute essential enzymatic activities to base excision repair (BER). Its amino-terminal domain possesses a lyase activity necessary to remove the 5'-deoxyribose phosphate (dRP) intermediate generated during BER. Removal of the dRP moiety is often the rate-limiting step during BER. Failure to remove this group may initiate alternate BER pathways. The larger polymerase domain has nucleotidyl transferase activity. This domain has a modular organization with sub-domains that bind duplex DNA, catalytic metals, and the correct nucleoside triphosphate in a template-dependent manner. X-ray crystal structures of DNA polymerase beta, with and without bound substrates, has inferred that domain, sub-domain, and substrate conformational changes occur upon ligand binding. Many of these conformational changes are distinct from those observed in structures of other DNA polymerases. This review will examine the structural aspects of DNA polymerase beta that facilitate its role in BER. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 90 TC 115 Z9 118 U1 0 U2 2 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 AUG 30 PY 2000 VL 460 IS 3-4 BP 231 EP 244 DI 10.1016/S0921-8777(00)00029-X PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 352NF UT WOS:000089224200008 PM 10946231 ER PT J AU Yang, W AF Yang, W TI Structure and function of mismatch repair proteins SO MUTATION RESEARCH-DNA REPAIR LA English DT Article DE MutH; MutL; endonuclease; ATPase; mismatch repair; molecular switch ID NONPOLYPOSIS COLORECTAL-CANCER; II RESTRICTION ENDONUCLEASES; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; SACCHAROMYCES-CEREVISIAE; REPLICATION FIDELITY; PVUII ENDONUCLEASE; DNA HETERODUPLEXES; GENE-PRODUCT; ATP BINDING AB DNA mismatch repair is required for maintaining genomic stability and is highly conserved from prokaryotes to eukaryotes. Errors made during DNA replication, such as deletions, insertions and mismatched basepairs, are substrates for mismatch repair. Mismatch repair is strand-specific and targets only the newly synthesized daughter strand. To initiate mismatch repair in Escherichia coli, three proteins are essential, MutS, for mismatch recognition, MutH, for introduction of a nick in the target strand, and MutL, for mediating the interactions between MutH and MutS. Homologues of MutS and MutL important for mismatch repair have been found in nearly all organisms. Mutations in MutS and MutL homologues have been linked to increased cancer susceptibility in both mice and humans. Here, we review the crystal structures of the MutH endonuclease, a conserved ATPase fragment of MutL (LN40), and complexes of LN40 with various nucleotides. Based on the crystal structure, the active site of MutH has been identified and an evolutionary relationship between MutH and type II restriction endonucleases established. Recent crystallographic and biochemical studies have revealed that MutL operates as a molecular switch with its interactions with MutH and MutS regulated by ATP binding and hydrolysis. These crystal structures also shed light on the general mechanism of mismatch repair and the roles of Mut proteins in preventing mutagenesis. (C) 2000 Published by Elsevier Science B.V. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 NR 56 TC 67 Z9 69 U1 3 U2 13 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 AUG 30 PY 2000 VL 460 IS 3-4 BP 245 EP 256 DI 10.1016/S0921-8777(00)00030-6 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 352NF UT WOS:000089224200009 PM 10946232 ER PT J AU Theis, K Skorvaga, M Machius, M Nakagawa, N Van Houten, B Kisker, C AF Theis, K Skorvaga, M Machius, M Nakagawa, N Van Houten, B Kisker, C TI The nucleotide excision repair protein UvrB, a helicase-like enzyme with a catch SO MUTATION RESEARCH-DNA REPAIR LA English DT Article DE DNA damage; nucleotide excision repair; helicase; domain motion; ATPase; UvrB ID ESCHERICHIA-COLI UVRB; DNA-POLYMERASE-I; C-TERMINAL REGION; THERMUS-THERMOPHILUS; (A)BC EXCINUCLEASE; CRYSTAL-STRUCTURE; DAMAGED DNA; ACTIVE-SITE; UVRABC ENDONUCLEASE; PREINCISION COMPLEX AB Nucleotide excision repair (NER) is a universal DNA repair mechanism found in all three kingdoms of life. Its ability to repair a broad range of DNA lesions sets NER apart From other repair mechanisms. NER systems recognize the damaged DNA strand and cleave it 3', then 5' to the lesion. After the oligonucleotide containing the lesion is removed, repair synthesis fills the resulting gap. UvrB is the central component of bacterial NER. It is directly involved in distinguishing damaged from undamaged DNA and guides the DNA from recognition to repair synthesis. Recently solved structures of UvrB from different organisms represent the first high-resolution view into bacterial NER. The structures provide detailed insight into the domain architecture of UvrB and, through comparison, suggest possible domain movements. The structure of UvrB consists of five domains. Domains la and 3 bind ATP at the inter-domain interface and share high structural similarity to helicases of superfamilies I and II. Not related to helicase structures, domains 2 and 4 are involved in interactions with either UvrA or UvrC, whereas domain Ib was implicated for DNA binding. The structures indicate that ATP binding and hydrolysis is associated with domain motions. UvrB's ATPase activity, however, is not coupled to the separation of long DNA duplexes as in helicases, but rather leads to the formation of the preincision complex with the damaged DNA substrate. The location of conserved residues and structural comparisons with helicase-DNA structures suggest how UvrB might bind to DNA. A model of the UvrB-DNA interaction in which a beta-hairpin of UvrB inserts between the DNA double strand has been proposed recently. This padlock model is developed further to suggest two distinct consequences of domain motion: in the UvrA(2)B-DNA complex, domain motions lead to translocation along the DNA, whereas in the tight UvrB-DNA pre-incision complex, they lead to distortion of the 3' incision site. (C) 2000 Elsevier Science B.V. All rights reserved. C1 SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. Slovak Acad Sci, Canc Res Inst, Dept Mol Genet, Bratislava 83391, Slovakia. Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75235 USA. Osaka Univ, Grad Sch Sci, Dept Biol, Osaka 5600043, Japan. RP Kisker, C (reprint author), SUNY Stony Brook, Dept Pharmacol Sci, Stony Brook, NY 11794 USA. NR 72 TC 48 Z9 48 U1 0 U2 7 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 AUG 30 PY 2000 VL 460 IS 3-4 BP 277 EP 300 DI 10.1016/S0921-8777(00)00032-X PG 24 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 352NF UT WOS:000089224200011 PM 10946234 ER PT J AU Hauptmann, M Lubin, JH Rosenberg, P Wellmann, J Kreienbrock, L AF Hauptmann, M Lubin, JH Rosenberg, P Wellmann, J Kreienbrock, L TI The use of sliding time windows for the exploratory analysis of temporal effects of smoking histories on lung cancer risk SO STATISTICS IN MEDICINE LA English DT Article ID INTERVALS AB To examine the time-dependent effects of exposure histories on disease we use sliding time windows as an exploratory alternative to the analysis of variables like time since last exposure and duration of exposure. The method fits a series of risk models which contain total cumulative exposure and an additional covariate for exposures received during fixed time intervals. Characteristics of the fitted models provide insight into the influence of exposure increments at different times on disease risk. A simulation study is performed to check the validity of the approach. We apply the method to data from a recent German case-control study on smoking and lung cancer risk with about 4300 lung cancer cases and a similiar number of controls. The sliding time window approach indicates that the amount of cigarettes smoked from two to 11 years before disease incidence is most predicitive of lung cancer incidence. Among different smoking profiles that result in the same lifelong cumulative number of cigarettes smoked, those with a concentration of smoked cigarettes within 20 years before interview bear substantially larger risk than others. Copyright (C) 2000 John Wiley & Sons, Ltd. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Hannover Vet Sch, Inst Epidemiol & Biometry, D-30559 Hannover, Germany. Univ Munster, Inst Epidemiol & Social Med, D-48129 Munster, Germany. GSF Forschungszentrum Umwelt & Gesundheit, Inst Epidemiol, Neuherberg, Germany. RP Hauptmann, M (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-7089, Bethesda, MD 20892 USA. NR 9 TC 15 Z9 16 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD AUG 30 PY 2000 VL 19 IS 16 BP 2185 EP 2194 DI 10.1002/1097-0258(20000830)19:16<2185::AID-SIM528>3.0.CO;2-I PG 10 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 344NG UT WOS:000088765300008 PM 10931519 ER PT J AU Jhee, KH McPhie, P Miles, EW AF Jhee, KH McPhie, P Miles, EW TI Domain architecture of the heme-independent yeast cystathionine beta-synthase provides insights into mechanisms of catalysis and regulation SO BIOCHEMISTRY LA English DT Article ID O-ACETYLSERINE SULFHYDRYLASE; SACCHAROMYCES-CEREVISIAE; SALMONELLA-TYPHIMURIUM; ESCHERICHIA-COLI; 3-DIMENSIONAL STRUCTURE; PYRIDOXAL 5'-PHOSPHATE; THREONINE DEAMINASE; TRYPTOPHAN SYNTHASE; CULTURED-CELLS; PROTEIN AB Cystathionine beta-synthase from yeast (Saccharomyces cerevisiae) provides a model system for understanding some of the effects of disease-causing mutations in the human enzyme. The mutations, which lead to accumulation of L-homocysteine, are linked to homocystinuria and cardiovascular diseases. Here we characterize the domain architecture of the heme-independent yeast cystathionine beta-synthase. Our finding that the homogeneous recombinant truncated enzyme (residues 1-353) is catalytically active and binds pyridoxal phosphate stoichiometrically establishes that the N-terminal residues 1-353 compose a catalytic domain. Removal of the C-terminal residues 354-507 increases the specific activity and alters the steady-state kinetic parameters including the K-d for pyridoxal phosphate, suggesting that the C-terminal residues 354-507 compose a regulatory domain, The yeast enzyme, unlike the human enzyme, is not activated by S-adenosyl-L-methionine. The truncated yeast enzyme is a dimer, whereas the full-length enzyme is a mixture of tetramer and octamer, suggesting that the C-terminal domain plays a role in the interaction of the subunits to form higher oligomeric structures, The N-terminal catalytic domain is more stable and less prone to aggregate than full-length enzyme and is thus potentially more suitable for structure determination by X-ray crystallography. Comparisons of the yeast and human enzymes reveal significant differences in catalytic and regulatory properties. C1 NIDDKD, Sect Enzyme Struct & Funct, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Miles, EW (reprint author), NIDDKD, Sect Enzyme Struct & Funct, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. NR 48 TC 57 Z9 58 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 29 PY 2000 VL 39 IS 34 BP 10548 EP 10556 DI 10.1021/bi001020g PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 349VQ UT WOS:000089066600023 PM 10956046 ER PT J AU Wodarz, D Arnaout, RA Nowak, MA Lifson, JD AF Wodarz, D Arnaout, RA Nowak, MA Lifson, JD TI Transient antiretroviral treatment during acute simian immunodeficiency virus infection facilitates long-term control of the virus SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article DE simian immunodeficiency virus; treatment lymphoproliferation; helper cell; memory; immune control ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; CYTOTOXIC T-LYMPHOCYTES; CD40 LIGAND; CTL MEMORY; VIREMIA; MICE; RESPONSES; CELLS; LOAD; REPLICATION AB Experimental evidence and mathematical models indicate that CD4(+) T-cell help is required to generate memory cytotoxic T-lymphocyte precursors (CTLp) that are capable of persisting without ongoing antigenic stimulation, and that such responses are necessary to clear an infection or to control it in the long term. Here we analyse mathematical models of simian immunodefiiency virus (SIV) replication in macaques, assuming that SIV impairs specific CD4(+) T-cell responses. According to the models, fast viral replication during the initial stages of primary infection can result in failure to generate sufficient long-lived memory CTLp required to control the infection in the long term. Modelling of drug therapy during the acute phase of the infection indicates that transient treatment can minimize the amount of virus-induced immune impairment, allowing a more effective initial immune sensitization. The result is the development of high levels of memory CTLp that are capable of controlling SIV replication in the long term, in the absence of continuous treament. In the model, the success of treatment depends crucially on the timing and duration of antiretroviral therapy. Data on SIV-infected macaques receiving transient drug therapy during acute infection support these theoretical predictions. The data and modelling suggest that among subjects controlling SIV replication most efficiently after treatment, there is a positive correlation between cellular immune responses and virus load in the post-acute stage of infection. Among subjects showing less-efficient virus control, the correlation is negative. We discuss our findings in relation to previously published data on HIV infection. C1 NCI, Frederick Canc Res & Dev Ctr, Lab Retroviral Pathogenesis,AIDS Vaccine Program, Sci Applicat Int Corp Frederick, Frederick, MD 21702 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Inst Adv Study, Princeton, NJ 08540 USA. RP Lifson, JD (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Retroviral Pathogenesis,AIDS Vaccine Program, Sci Applicat Int Corp Frederick, Bldg 535,5th Floor, Frederick, MD 21702 USA. RI Nowak, Martin/A-6977-2008 FU NCI NIH HHS [N01-CO-56000] NR 23 TC 22 Z9 23 U1 0 U2 1 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD AUG 29 PY 2000 VL 355 IS 1400 BP 1021 EP 1029 PG 9 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 354WV UT WOS:000089354600004 PM 11186303 ER PT J AU Gladwin, MT Ognibene, FP Pannell, LK Nichols, JS Pease-Fye, ME Shelhamer, JH Schechter, AN AF Gladwin, MT Ognibene, FP Pannell, LK Nichols, JS Pease-Fye, ME Shelhamer, JH Schechter, AN TI Relative role of heme nitrosylation and beta-cysteine 93 nitrosation in the transport and metabolism of nitric oxide by hemoglobin in the human circulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SICKLE-CELL HEMOGLOBIN; S-NITROSOHEMOGLOBIN; OXYGEN-BINDING; BIOCHEMICAL-CHARACTERIZATION; BIOLOGICAL-SYSTEMS; INHALED NO; BLOOD-FLOW; KINETICS; MECHANISMS; REDUCTION AB To quantify the reactions of nitric oxide (NO) with hemoglobin under physiological conditions and to test models of NO transport on hemoglobin, we have developed an assay to measure NO-hemoglobin reaction products in normal volunteers, under basal conditions and during NO inhalation. NO inhalation markedly raised total nitrosylated hemoglobin levels, with a significant arterial-venous gradient, supporting a role for hemoglobin in the transport and delivery of NO. The predominant species accounting for this arterial-venous gradient is nitrosyl(heme)hemoglobin. NO breathing increases S-nitrosation of hemoglobin beta-chain cysteine 93, however only to a fraction of the level of nitrosyl(heme)hemoglobin and without a detectable arterial-venous gradient. A strong correlation between methemoglobin and plasma nitrate formation was observed, suggesting that NO metabolism is a primary physiological cause of hemoglobin oxidation, Our results demonstrate that NO-heme reaction pathways predominate in vivo, NO binding to heme groups is a rapidly reversible process, and S-nitrosohemoglobin formation is probably not a primary transport mechanism for NO but may facilitate NO release from heme. C1 NIH, Warren G Magnuson Clin Ctr, Crit Care Med Dept, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Struct Mass Spectrometry Grp, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIH, Warren G Magnuson Clin Ctr, Crit Care Med Dept, Bldg 10,Room 7D43,10 Ctr Dr,MSC 1662, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408 NR 39 TC 200 Z9 207 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 AUG 29 PY 2000 VL 97 IS 18 BP 9943 EP 9948 DI 10.1073/pnas.180155397 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349WA UT WOS:000089067500026 PM 10954746 ER PT J AU Dunn, KJ Williams, BO Li, Y Pavan, WJ AF Dunn, KJ Williams, BO Li, Y Pavan, WJ TI Neural crest-directed gene transfer demonstrates Wnt1 role in melanocyte expansion and differentiation during mouse development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TYROSINASE-RELATED PROTEIN; RETROVIRAL VECTORS; BETA-CATENIN; IN-VITRO; DOPACHROME TAUTOMERASE; EPIDERMAL MELANOCYTES; CELL FATE; RECEPTOR; PROLIFERATION; VIRUS AB Wnt1 signaling has been implicated as one factor involved in neural crest-derived melanocyte (NC-M) development. Mice deficient for both Wnt1 and Wnt3a have a marked deficiency in trunk neural crest derivatives including NC-Ms, We have used cell lineage-directed gene targeting of Wnt signaling genes to examine the effects of Wnt signaling in mouse neural crest development. Gene expression was directed to cell lineages by infection with subgroup A avian leukosis virus vectors in lines of transgenic mice that express the retrovirus receptor tv-a. Transgenic mice with tva in either nestin-expressing neural precursor cells (line Ntva) or dopachrome tautomerase (DCT)-expressing melanoblasts (line DCTtva) were analyzed, We overstimulated Wnt signaling in two ways: directed gene transfer of Wnt1 to Ntva(+) cells and transfer of beta-catenin to DCTtva(+) NC-M precursor cells, In both methods, NC-M expansion and differentiation were effected. Significant increases were observed in the number of NC-Ms [melanin(+) and tyrosinase-related protein 1 (TYRP1)(+) cells], the differentiation of melanin-TYRP1(+) cells to melanin(+) TYRP1(+) NC-Ms, and the intensity of pigmentation per NC-M. These data are consistent with Wnt1 signaling being involved in both expansion and differentiation of migrating NC-Ms in the developing mouse embryo, The use of lineage-directed gene targeting will allow the dissection of signaling molecules involved in NC development and is adaptable to other mammalian developmental systems. C1 NHGRI, Gent Dis Res Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Pavan, WJ (reprint author), NHGRI, Gent Dis Res Branch, NIH, 49-4A82,49 Convent Dr, Bethesda, MD 20892 USA. RI Williams, Bart/A-3539-2013 OI Williams, Bart/0000-0002-5261-5301 NR 38 TC 110 Z9 114 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 29 PY 2000 VL 97 IS 18 BP 10050 EP 10055 DI 10.1073/pnas.97.18.10050 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349WA UT WOS:000089067500044 PM 10963668 ER PT J AU Kurebayashi, S Ueda, E Sakaue, M Patel, DD Medvedev, A Zhang, F Jetten, AM AF Kurebayashi, S Ueda, E Sakaue, M Patel, DD Medvedev, A Zhang, F Jetten, AM TI Retinoid-related orphan receptor gamma (ROR gamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID T-CELL DEVELOPMENT; NUCLEAR RECEPTOR; DEFICIENT MICE; TRANSGENIC MICE; DNA-BINDING; FAMILY; ALPHA; GENE; IDENTIFICATION; LYMPHOTOXIN AB To identify the physiological functions of the retinoid-related orphan receptor gamma (ROR gamma), a member of the nuclear receptor superfamily. mice deficient in ROR gamma function were generated by targeted disruption. ROR gamma(-/-) mice lack peripheral and mesenteric lymph nodes and Peyer's patches, indicating that ROR gamma expression is indispensable for lymph node organogenesis. Although the spleen is enlarged, its architecture is normal. The number of peripheral blood CD3(+) and CD4(+) lymphocytes is reduced 6- and 10-fold, respectively, whereas the number of circulating a cells is normal. The thymus of ROR gamma(-/-) mice contains 74.4% +/- 8.9% fewer thymocytes than that of wild-type mice. Flow cytometric analysis showed a decrease in the CD4(+)CD8(+) subpopulation. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining demonstrated a 4-fold increase in apoptotic cells in the cortex of the thymus of ROR gamma(-/-) mice. The latter was supported by the observed increase in annexin V-positive cells. ROR gamma(-/-) thymocytes placed in culture exhibit a dramatic increase in the rate of "spontaneous" apoptosis. This increase is largely associated with CD4(+)CD8(+) thymocytes and may, at least in part, be related to the greatly reduced level of expression of the anti-apoptotic gene Bcl-X-L. Flow cytometric analysis demonstrated a C-fold rise in the percentage of cells in the 5 phase of the cell cycle among thymocytes from ROR gamma(-/-) mice. Our observations indicate that ROR gamma is essential for lymphoid organogenesis and plays an important regulatory role in thymopoiesis. Our findings support a model in which ROR gamma negatively controls apoptosis in thymocytes. C1 NIEHS, Lab Pulm Pathol, Cell Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Jetten, AM (reprint author), NIEHS, Lab Pulm Pathol, Cell Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. OI Jetten, Anton/0000-0003-0954-4445 FU NIAID NIH HHS [R01 AI47604] NR 39 TC 197 Z9 201 U1 1 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 AUG 29 PY 2000 VL 97 IS 18 BP 10132 EP 10137 DI 10.1073/pnas.97.18.10132 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349WA UT WOS:000089067500058 PM 10963675 ER PT J AU Parchi, P Zou, WQ Wang, W Brown, P Capellari, S Ghetti, B Kopp, N Schulz-Schaeffer, WJ Kretzschmar, HA Head, MW Ironside, JW Gambetti, P Chen, SG AF Parchi, P Zou, WQ Wang, W Brown, P Capellari, S Ghetti, B Kopp, N Schulz-Schaeffer, WJ Kretzschmar, HA Head, MW Ironside, JW Gambetti, P Chen, SG TI Genetic influence on the structural variations of the abnormal prion protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CREUTZFELDT-JAKOB-DISEASE; FATAL FAMILIAL INSOMNIA; DNA POLYMORPHISM; VARIANT CJD; SCRAPIE; AGENT; STRAINS; CONFORMATIONS; ISOFORM; CLONING AB Prion diseases are characterized by the presence of the abnormal prion protein PrPSc, which is believed to be generated by the conversion of the alpha-helical structure that predominates in the normal PrP isoform into a beta-sheet structure resistant to proteinase K (PK). In human prion diseases, two major types of PrPSc, type 1 and 2, can be distinguished based on the difference in electrophoretic migration of the PK-resistant core fragment. In this study, protein sequencing was used to identify the PK cleavage sites of PrPSc in 36 cases of prion diseases. We demonstrated two primary cleavage sites at residue 82 and residue 97 for type 1 and type 2 PrPSc, respectively, and numerous secondary cleavages distributed along the region spanning residues 74-102. Accordingly, we identify three regions in PrPSc: one N-terminal (residues 23-73) that is invariably PK-sensitive, one C-terminal (residues 103-231) that is invariably PK-resistant, and a third variable region (residues 74-102) where the site of the PK cleavage, likely reflecting the extent of the beta-sheet structure, varies mostly as a function of the PrP genotype at codon 129. C1 Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. NINDS, Cent Nervous Syst Studies Lab, Bethesda, MD 20892 USA. Indiana Univ, Med Ctr, Dept Pathol, Indianapolis, IN 46202 USA. Hop Neurol Pierre Wertheimer, F-69003 Lyon, France. Univ Gottingen, Inst Neuropathol, D-37075 Gottingen, Germany. Western Gen Hosp, Creutzfeldt Jakob Dis Surveillance Unit, Edinburgh EH4 2XU, Midlothian, Scotland. RP Gambetti, P (reprint author), Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. RI capellari, sabina/F-5545-2012; Chen, Shu/O-4750-2014; Parchi, Piero/L-9833-2015 OI Chen, Shu/0000-0001-7180-3001; Parchi, Piero/0000-0002-9444-9524 FU NIA NIH HHS [P01 AG014359, P01 AG014359-010003, P01 AG014359-020003, P01 AG014359-030003, P01 AG014359-040003, P01 AG014359-050003, P01 AG014359-060003] NR 29 TC 196 Z9 199 U1 0 U2 4 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 AUG 29 PY 2000 VL 97 IS 18 BP 10168 EP 10172 DI 10.1073/pnas.97.18.10168 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349WA UT WOS:000089067500064 PM 10963679 ER PT J AU Lossos, IS Alizadeh, AA Eisen, MB Chan, WC Brown, PO Botstein, D Staudt, LM Levy, R AF Lossos, IS Alizadeh, AA Eisen, MB Chan, WC Brown, PO Botstein, D Staudt, LM Levy, R TI Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; V-H GENES; FOLLICULAR LYMPHOMA; ANTIGEN SELECTION; EXPRESSION; HYPERMUTATION; REGION; DISEASE; CD5(+); SYSTEM AB B cell diffuse large cell lymphoma (B-DLCL) is a heterogeneous group of tumors, based on significant variations in morphology. clinical presentation, and response to treatment. Gene expression profiling has revealed two distinct tumor subtypes of B-DLCL: germinal center B cell-like DLCL and activated B cell-like DLCL. In a separate study, we determined that B-DLCL can also be subdivided Into two groups based on the presence or absence of ongoing Ig gene hypermutation, Here, we evaluated the correlation between these B-DLCL subtypes established by the two different methods. Fourteen primary B-DLCL cases were studied by gene expression profiling using DNA microarrays and for the presence of ongoing mutations in their Ig heavy chain gene. All seven cases classified as germinal center B cell-like DLCL by gene expression showed the presence of ongoing mutations in the Ig genes. Five of the seven cases classified by gene expression as activated B cell-like DLCL had no ongoing somatic mutations, whereas, in the remaining two cases, a single point mutation was observed in only 2 of 15 and 21 examined molecular clones of variable heavy (V-H) chain gene, respectively. These two cases were distantly related to the rest of the activated B cell-like DLCL tumors by gene expression. Our findings validate the concept that lymphoid malignancies are derived from cells at discrete stages of normal lymphocyte maturation and that the malignant cells retain the genetic program of those normal cells. C1 Stanford Univ, Med Ctr, Dept Med, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Dept Biochem, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Dept Genet, Div Oncol, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Howard Hughes Med Inst, Stanford, CA 94305 USA. Univ Nebraska, Med Ctr, Dept Pathol, Omaha, NE 68198 USA. NCI, Div Clin Sci, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Levy, R (reprint author), Stanford Univ, Med Ctr, Dept Med, Stanford, CA 94305 USA. OI Eisen, Michael/0000-0002-7528-738X; Alizadeh, Arash Ash/0000-0002-5153-5625 FU NCI NIH HHS [CA34233, CA33399, P01 CA034233, R37 CA033399, U01 CA084967, UO1 CA84967] NR 34 TC 162 Z9 170 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 AUG 29 PY 2000 VL 97 IS 18 BP 10209 EP 10213 DI 10.1073/pnas.180316097 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349WA UT WOS:000089067500071 PM 10954754 ER PT J AU Cheng, CM Reinhardt, RR Lee, WH Joncas, G Patel, SC Bondy, CA AF Cheng, CM Reinhardt, RR Lee, WH Joncas, G Patel, SC Bondy, CA TI Insulin-like growth factor 1 regulates developing brain glucose metabolism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mental retardation; glycogen synthase kinase; glucose transporter; GLUT4; Akt ID RECEPTOR GENE-EXPRESSION; CENTRAL-NERVOUS-SYSTEM; I IGF-I; RAT-BRAIN; CELLULAR-PATTERN; MESSENGER-RNA; LOCALIZATION; NEURONS; MATURATION; KINASE AB The brain has enormous anabolic needs during early postnatal development, This study presents multiple lines of evidence showing that endogenous brain insulin-like growth factor 1 (Igf1) serves an essential, insulin-like role in promoting neuronal glucose utilization and growth during this period. Brain 2-deoxy-D-[1-C-14]glucose uptake parallels Igf1 expression in wild-type mice and is profoundly reduced in Igf1-/- mice, particularly in those structures where Igf1 is normally most highly expressed. 2-Deoxy-D-[1-C-14]glucose is significantly reduced in synaptosomes prepared from Igf1-/- brains, and the deficit is corrected by inclusion of Igf1 in the incubation medium. The serine/threonine kinase Akt/PKB is a major target of insulin-signaling in the regulation of glucose transport via the facilitative glucose transporter (GLUT4) and glycogen synthesis in peripheral tissues. Phosphorylation of Akt and GLUT4 expression are reduced in Igf1-/- neurons. Phosphorylation of glycogen synthase kinase 3 beta and glycogen accumulation also are reduced in Igf1-/- neurons. These data support the hypothesis that endogenous brain Igf1 serves an anabolic, insulin-like role in developing brain metabolism. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bldg 10-10N262,10 Ctr Dr, Bethesda, MD 20892 USA. NR 39 TC 113 Z9 116 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 AUG 29 PY 2000 VL 97 IS 18 BP 10236 EP 10241 DI 10.1073/pnas.170008497 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349WA UT WOS:000089067500076 PM 10954733 ER PT J AU King, AA DeBaun, RR Riccardi, VM Gutmann, DH AF King, AA DeBaun, RR Riccardi, VM Gutmann, DH TI Malignant peripheral nerve sheath tumors in neurofibromatosis 1 SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE neurofibromatosis; neurofibroma; cancer; sarcoma ID VONRECKLINGHAUSEN NEUROFIBROMATOSIS; TYPE-1; CANCER; RISK; NF1 AB One of the most clinically aggressive cancers associated with neurofibromatosis 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST). To determine the incidence and relative risk (RR) of MPNSTs in individuals with NF1, 1,475 individuals with NF1 were included from a cohort of patients examined by a single experienced geneticist from 1977 to 1996, The end points were incidence of MPNST, relative risk of MPNST, and relative risk associated with specific NF1 physical findings. Thirty-four individuals were identified with MPNST (2%), The relative risk of MPNST was higher than expected with an RR value of 113 (95% confidence interval [CI] = 78-158), The average 10-year annual incidence of MPNST between the second and fifth decade of life was roughly the same with a range of 0.0013 and 0.0068 MPNST per patient year, Most lesions occurred in the limbs (n = 18; 53%), and those with limb lesions survived longer than those with nonlimb MPNSTs. Pain associated with a mass was the greatest risk factor associated with MPNST development (RR = 31.4; 95% CI = 13,2-75,1), Further biological and epidemiological studies are needed to determine other factors that influence the risk of MPNST development in individuals affected with NF1, Published 2000 Wiley-Liss, Inc. C1 NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Pediat, Div Pediat Hematol Oncol, St Louis, MO 63110 USA. Amer Med Consumers Inc, La Crescenta, CA USA. Washington Univ, St Louis Childrens Hosp, Sch Med, Dept Neurol,Neurofibromatosis Program, St Louis, MO 63110 USA. RP DeBaun, RR (reprint author), NCI, Genet Epidemiol Branch, NIH, EPN 400,6130 Execut Blvd, Bethesda, MD 20892 USA. OI King, Allison/0000-0002-1951-6176 NR 23 TC 77 Z9 78 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 AUG 28 PY 2000 VL 93 IS 5 BP 388 EP 392 DI 10.1002/1096-8628(20000828)93:5<388::AID-AJMG8>3.0.CO;2-# PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 339WW UT WOS:000088501700008 PM 10951462 ER PT J AU Borkowf, CB AF Borkowf, CB TI A new nonparametric method for variance estimation and confidence interval construction for Spearman's rank correlation SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article DE bootstrap; empirical bivariate quantile-partitioned (EBQP) distribution; jackknife; nonparametric statistics; Spearman's rank correlation AB Spearman's rank correlation, rho(s), has become one of the most widely used nonparametric statistical techniques. However, explicit formulas for the finite sample variance of its point estimate, <(rho)over cap>(s), are generally not available, except under special conditions, and the estimation of this variance from observed data remains a challenging statistical problem. In this paper, we show that <(rho)over cap>(s) can be calculated from a two-way contingency table with categories defined by the bivariate ranks. We note that this table has the "empirical bivariate quantile-partitioned" (EBQP) distribution (Borkowf et al., 1997), and hence <(rho)over cap>(s) belongs to the class of statistics with distributions derived from the EBQP distribution. The study of <(rho)over cap>(s) provides an opportunity to extend large sample EBQP methods to handle the special challenges posed by statistics calculated from EBQP tables defined by bivariate ranks. We present extensive simulations to study the estimation of the sample variance of <(rho)over cap>(s) and the coverage of confidence intervals for this measure. We compare these results for the EBQP method with those for the bootstrap and jackknife algorithms. We illustrate the use of these nonparametric methods on two data sets, Spearman's original data set and an example from nutritional epidemiology. These results demonstrate that standard EBQP methods can be successfully adapted for the estimation of the sample variance of <(rho)over cap>(s). They also suggest that EBQP methods should be used to estimate the sample variances of other nonparametric statistics calculated from bivariate ranks, such as Kendall's tau. (C) 2000 Published by Elsevier Science B.V. All rights reserved. C1 NHLBI, Div Epidemiol & Clin Applicat, OBR, Rockledge Ctr 2, Bethesda, MD 20892 USA. NR 20 TC 7 Z9 7 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD AUG 28 PY 2000 VL 34 IS 2 BP 219 EP 241 DI 10.1016/S0167-9473(99)00077-8 PG 23 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 350LZ UT WOS:000089104000005 ER PT J AU Cole, LK Le Roux, I Nunes, F Laufer, E Lewis, J Wu, DK AF Cole, LK Le Roux, I Nunes, F Laufer, E Lewis, J Wu, DK TI Sensory organ generation in the chicken inner ear: Contributions of bone morphogenetic protein 4, Serrate1, and Lunatic Fringe SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE Notch genes; crista ampullaris; basilar papilla; macula ID CELL FATE CHOICES; SONIC-HEDGEHOG; GUINEA-PIG; NOTCH; EXPRESSION; DELTA; DROSOPHILA; PATHWAY; GENES; MOUSE AB The chicken inner ear is a remarkably complex structure consisting of eight morphologically distinct sensory organs. Unraveling how these sensory organs are specified during development is key to understanding how such a complex structure is generated. Previously, we have shown that each sensory organ in the chicken inner ear arises independently in the rudimentary otocyst based on Bone morphogenetic protein 4 (Bmp4) expression. Here, we compare the expression of Bmp4 with two other putative sensory organ markers, Lunatic Fringe (L-fng) and chicken Serrate1 (Ser1), both of which are components of the Notch signaling pathway. L-fng and Ser1 expression domains were asymmetrically distributed in the otic cup. At this early stage, expression of L-fng is similar to Delta1 (Dl1), in an anteroventral domain apparently corresponding to the neurogenic region, while Ser1 is expressed at both the anterior and posterior poles. By the otocyst stage, the expression of both L-fng and Ser1 largely coincided in the medial region. All presumptive sensory organs, as identified by Bmp4 expression, arose within the broad L-fng- and Sari-positive domain, indicating the existence of a sensory-competent region in the rudimentary otocyst. In addition, there is a qualitative difference in the levels of expression between L-fng and Ser1 such that L-fng expression was stronger in the ventral anterior, whereas Ser1 was stronger in the dorsal posterior region of this broad domain. This early difference in expression may presage the differences among sensory organs as they arise from this sensory competent zone. Published 2000 Wiley-Liss, Inc.dagger C1 Natl Inst Deafness & Other Commun Disorders, Rockville, MD 20850 USA. Imperial Canc Res Fund, London WC2A 3PX, England. Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA. RP Wu, DK (reprint author), Natl Inst Deafness & Other Commun Disorders, 5 Res Court,Rm 2B84, Rockville, MD 20850 USA. RI Lewis, Julian/E-8733-2010; Nunes, Fabio/B-4543-2011; OI Nunes, Fabio/0000-0002-7785-6785; Laufer, Edward/0000-0002-4933-1017 NR 44 TC 96 Z9 101 U1 0 U2 5 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 AUG 28 PY 2000 VL 424 IS 3 BP 509 EP 520 DI 10.1002/1096-9861(20000828)424:3<509::AID-CNE8>3.0.CO;2-Q PG 12 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 339RW UT WOS:000088492500008 PM 10906716 ER PT J AU London, SJ Yuan, JM Chung, FL Gao, YT Coetzee, GA Ross, RK Yu, MC AF London, SJ Yuan, JM Chung, FL Gao, YT Coetzee, GA Ross, RK Yu, MC TI Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China SO LANCET LA English DT Article ID DIETARY ISOTHIOCYANATES; GSTT1 POLYMORPHISMS; CIGARETTE-SMOKING; NULL GENOTYPE; GSTM1; VEGETABLES; METABOLISM; SINGAPORE; BROCCOLI; SPROUTS AB Background Dietary isothiocyanates inhibit lung carcinogenesis in laboratory animals but human data are limited. Glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) conjugate isothiocyanates leading to more rapid elimination, Common deletion polymorphisms of GSTM1 and GSTT1 abolish enzyme activity. We hypothesised that chemopreventive effects of isothiocyanates might be heightened when enzymes that enhance their elimination are lacking. Methods We examined the relation between total isothiocyanate concentrations in urine, collected before diagnosis, and the subsequent risk of lung cancer among 232 incident cases of lung cancer and 710 matched controls from a cohort of 18 244 men in Shanghai, China, followed from 1986 to 1997. Homozygous deletion of the GSTM1 and GSTT1 genes were determined by PCR. Findings Individuals with detectable isothiocyanates in the urine were at decreased risk of lung cancer (smoking-adjusted relative risk for lung cancer=0.65 [95% CI 0.43-0.97]). This protective effect of isothiocyanates was seen primarily among individuals with homozygous deletion of GSTT1 (0.36 [0.20-0.63]) and particularly with deletion of both GSTM1 and GSTT1 (0.28 [0.13-0.57]). Interpretation Isothiocyanates appeared to reduce lung-cancer risk in this cohort of Chinese men. Reduction in risk was strongest among persons genetically deficient in enzymes that rapidly eliminate these chemopreventive compounds. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA USA. Amer Hlth Fdn, Div Carcinogenesis & Mol Epidemiol, Valhalla, NY 10595 USA. Shanghai Canc Inst, Shanghai, Peoples R China. RP London, SJ (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. OI Yuan, Jian-Min/0000-0002-4620-3108; London, Stephanie/0000-0003-4911-5290 FU NCI NIH HHS [R01 CA043092, R01 CA43092, R01 CA043092-20, R35 CA53890]; NIEHS NIH HHS [5P30 ES07048] NR 33 TC 300 Z9 311 U1 0 U2 9 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 26 PY 2000 VL 356 IS 9231 BP 724 EP 729 DI 10.1016/S0140-6736(00)02631-3 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 347UU UT WOS:000088948200012 PM 11085692 ER PT J AU Purcell, RH AF Purcell, RH TI Hepatitis B virus mutants and efficacy of vaccination SO LANCET LA English DT Letter C1 NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Purcell, RH (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 16 Z9 16 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 26 PY 2000 VL 356 IS 9231 BP 769 EP 769 DI 10.1016/S0140-6736(05)73670-9 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 347UU UT WOS:000088948200050 PM 11085716 ER PT J AU Smith, AE Sherman, ME Scott, DR Tabbara, SO Dworkin, L Olson, J Thompson, J Faser, C Snell, J Schiffman, M AF Smith, AE Sherman, ME Scott, DR Tabbara, SO Dworkin, L Olson, J Thompson, J Faser, C Snell, J Schiffman, M TI Review of the Bethesda System atlas does not improve reproducibility or accuracy in the classification of atypical squamous cells of undetermined significance smears SO CANCER CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT 87th Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology CY FEB 28-MAR 08, 1998 CL BOSTON, MASSACHUSETTS SP US & Canadian Acad Pathol DE atypical squamous cells of undetermined significance; Bethesda System; Papanicolau; cervicovaginal; cytopathology; interobserver agreement; reproducibility; accuracy ID HUMAN-PAPILLOMAVIRUS DNA; QUALITY ASSURANCE; FOLLOW-UP; NEOPLASIA; CYTOLOGY; WOMEN AB BACKGROUND. The Bethesda System (TBS) and its accompanying atlas were developed to promote uniform diagnosis and reporting of cervical and vaginal cytology, especially with respect to borderline abnormal smears. The authors assessed whether group study of TBS atlas improves the reproducibility and accuracy of the cytopathologic diagnosis of equivocal Papanicolaou smears. METHODS. One hundred "atypical" smears were divided into pretest and posttest sets containing equal numbers of negative, atypical squamous cells of undetermined significance (ASCUS), and squamous intraepithelial lesion (SIL) diagnoses based on a five-member panel review. Two comparable teams of four pathologists from George Washington University Medical Center (Washington, DC) and Kaiser Permanente (Portland, OR), each comprised of two more experienced cytopathologists and two less experienced pathologists, independently reviewed the 50 pretest slides and classified the slides according to TBS as negative, ASCUS, or SIL. The teams then conducted group study sessions using TBS atlas. After the review, the pathologists independently classified the 50 posttest slides in a similar manner. RESULTS. Pretest, pair-wise interobserver agreement ranged from 30% to 66% compared with 34-62% for posttest agreement. Absolute percent agreement of reviewers' diagnoses with a previously developed consensus diagnosis based on opinions of a five-expert panel (cytopathologic certainty scale) ranged from 44% to 62% for the pretest set and from 40% to 60% for the posttest set. Comparison of the detection of oncogenic human papilloma virus (HPV) DNA by hybrid capture tube test with smears classified as negative, ASCUS, or SIL revealed that seven of eight reviewers did not demonstrate a stronger association between HPV detection and cytologic diagnosis in the posttest set. CONCLUSIONS. Review of TBS atlas by itself does not appear to improve the reproducibility or accuracy of cytologic diagnoses. The lack of improvement was similar among the pathologists involved regardless of experience level or whether they had a close working relation. Cancer (Cancer Cytopathol) 2000;90:201-6. (C) 2000 American Cancer Society. C1 Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. Kaiser Fdn Hlth Plan NW, Reg Lab, Clackamas, OR 97015 USA. George Washington Univ, Med Ctr, Dept Pathol, Washington, DC 20037 USA. Portland Providence Med Ctr, Dept Pathol, Portland, OR USA. Pathol Labs, Muskegon, MI USA. Comanche Cty Mem Hosp, Dept Pathol, Lawton, OK USA. NCI, Bethesda, MD 20892 USA. RP Smith, AE (reprint author), Johns Hopkins Med Inst, Dept Pathol, Carnegie 400,600 N Wolfe St, Baltimore, MD 21287 USA. NR 20 TC 21 Z9 24 U1 0 U2 1 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD AUG 25 PY 2000 VL 90 IS 4 BP 201 EP 206 DI 10.1002/1097-0142(20000825)90:4<201::AID-CNCR1>3.0.CO;2-Q PG 6 WC Oncology; Pathology SC Oncology; Pathology GA 346HY UT WOS:000088866000001 PM 10966559 ER PT J AU Fetsch, PA Riker, AI Marincola, FM Abati, A AF Fetsch, PA Riker, AI Marincola, FM Abati, A TI Tyrosinase immunoreactivity in fine-needle aspiration samples of metastatic malignant melanoma - Fixation methods yield variable results SO CANCER CYTOPATHOLOGY LA English DT Article; Proceedings Paper CT 90th Annual Meeting of the United-States-and-Canadian-Academy-of-Patholog CY MAR 10-17, 2000 CL NEW ORLEANS, LOUISIANA SP US & Canadian Acad Pathol DE melanoma; immunocytochemistry; immunotherapy; tyrosinase; fine-needle aspiration ID MELANOSOMAL PROTEINS; CELL-LINES; IMMUNOTHERAPY; EXPRESSION; LESIONS; MART-1; GP100; OXIDATION; SECTIONS; DOPA AB BACKGROUND. Tyrosinase, the rate-limiting enzyme in melanin synthesis, is a melanoma associated antigen that is recognized by both CD4+ and CD8+ T-ceIls in an HLA-restricted fashion. Peptides derived from the tyrosinase antigen currently are being utilized as a target for T-ceIls in several immunotherapy protocols for metastatic malignant melanoma (MMM) at the National Institutes of Health/ National Cancer Institute. Serial fine-needle aspirations of metastatic lesions are performed to monitor the antigen expression of tyrosinase during treatment by immunostaining cytologic preparations with the monoclonal antibody T311. METHODS. In the current study, 62 samples of MMM were evaluated for tyrosinase immunoreactivity on air-dried, acetone fixed cytospins and the corresponding formalin fixed, paraffin embedded cell block using an avidin-biotin immunoperoxidase method. RESULTS. Positive immunoreactivity revealed a granular cytoplasmic staining in melanocytic cells. The current study results showed that 92% of samples (57 of 62) were T311 immunoreactive on cell block preparations, whereas only 61% (38 of 62) were immunoreactive on cytospin preparations. In 66% of samples (41 of 62) immunoreactivity for T311 was greater in the cell block sample than in the corresponding cytospin, whereas in only 3% of samples (2 of 62) was it greater in the cytospins. In 31% of samples (19 of 62) there was no significant difference in immunoreactivity between the 2 sample types. CONCLUSIONS. The results of the current study show that tyrosinase is a sensitive marker for the detection of MMM; however, the optimal method of sample preparation for immunoperoxidase staining appears to be formalin fixation and paraffin embedding as tyrosinase immunoreactivity is diminished significantly in air-dried cytospin samples despite subsequent acetone fixation. Cancer (Cancer Cytopathol) 2000;90:252-7, (C) 2000 American Cancer Society. C1 NCI, Cytopathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NCI, Cytopathol Sect, Pathol Lab, NIH, Bldg 10,Room 2A19,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. RI Riker, Adam/A-6065-2011 NR 20 TC 12 Z9 12 U1 0 U2 0 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0008-543X J9 CANCER CYTOPATHOL JI Cancer Cytopathol. PD AUG 25 PY 2000 VL 90 IS 4 BP 252 EP 257 DI 10.1002/1097-0142(20000825)90:4<252::AID-CNCR9>3.0.CO;2-N PG 6 WC Oncology; Pathology SC Oncology; Pathology GA 346HY UT WOS:000088866000009 PM 10966567 ER PT J AU Virador, VM Santis, C Furumura, M Kalbacher, H Hearing, VJ AF Virador, VM Santis, C Furumura, M Kalbacher, H Hearing, VJ TI Bioactive motifs of agouti signal protein SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE agouti; melanocortin; receptor; G protein; antagonist ID MELANOCYTE-STIMULATING-HORMONE; MELANOCORTIN RECEPTORS; IN-VITRO; TRANSCRIPTION FACTOR; ALPHA-MELANOTROPIN; COUPLED RECEPTORS; LOCUS PROTEIN; MSH RECEPTOR; RED HAIR; PIGMENTATION AB The switch between the synthesis of eu- and pheomelanins is modulated by the interaction of two paracrine signaling molecules, a-melanocyte stimulating hormone (MSH) and agouti signal protein (ASP), which interact with melanocytes via the MSH receptor (MC1R). Comparison of the primary sequence of ASP with the known MSH pharmacophore provides no suggestion about the putative bioactive domain(s) of ASP. To identify such bioactive motif(s), we synthesized 15-mer peptides that spanned the primary sequence of ASP and determined their effects on the melanogenic activities of murine melanocytes. Northern and Western blotting were used, together with chemical analysis of melanins and enzymatic assays, to identify three distinct bioactive regions of ASP that down-regulate eumelanogenesis. The decrease in eumelanin production was mediated by down-regulation of mRNA levels for tyrosinase and other melanogenic enzymes, as occurs in vivo, and these effects were comparable to those elicited by intact recombinant ASP. Shorter peptides in those motifs were synthesized and their effects on melanogenesis were further investigated. The amino acid arginine, which is present in the MSH peptide pharmacophore (HFRW), is also in the most active domain of ASP (KVARP). Our data suggest that lysines and an arginine tin motifs such as KxxxxKxxR or KxxRxxxxK) are important for the bioactivity of ASP. Identification of the specific ASP epitope that interacts with the MC1R has potential pharmacological applications in treating dysfunctions of skin pigmentation. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Tubingen, Med & Nat Sci Res Ctr, D-72074 Tubingen, Germany. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 1B25, Bethesda, MD 20892 USA. NR 63 TC 9 Z9 13 U1 0 U2 1 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD AUG 25 PY 2000 VL 259 IS 1 BP 54 EP 63 DI 10.1006/excr.2000.4975 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 350GE UT WOS:000089091900005 PM 10942578 ER PT J AU Watari, H Blanchette-Mackie, EJ Dwyer, NK Watari, M Burd, CG Patel, S Pentchev, PG Strauss, JF AF Watari, H Blanchette-Mackie, EJ Dwyer, NK Watari, M Burd, CG Patel, S Pentchev, PG Strauss, JF TI Determinants of NPC1 expression and action: Key promoter regions, posttranscriptional control, and the importance of a "cysteine-rich" loop SO EXPERIMENTAL CELL RESEARCH LA English DT Article ID NIEMANN-PICK C1; INTRACELLULAR CHOLESTEROL TRANSPORT; LIPOPROTEIN-DERIVED CHOLESTEROL; HAMSTER OVARY CELLS; ZINC-FINGER; PROTEIN; DISEASE; DOMAIN; GENE; 3-BETA-<2-(DIETHYLAMINO)ETHOXY>ANDROST-5-EN-17-ONE AB Mutations in the NPC1 gene cause Niemann-Pick type C disease, which is characterized by the accumulation of free cholesterol and other lipids in lysosomes, The NPC1 glycoprotein is located in a late endosomal compartment that transiently interacts with lysosomes. To identify factors regulating NPC1 expression and action, we analyzed the function of the human NPC1 promoter in human-derived ovarian, hepatic, and neuronal cells. A fragment containing the first 208 base pairs upstream from the major transcription initiation site was sufficient to drive near maximal NPC1 promoter activity. Deletion analysis revealed that sequences between base pairs -111 and -37 play an important role in controlling NPCI transcription. Treatment of proliferating granulosa cells with 30 mu M progesterone, which induces a reversible phenocopy of the cholesterol trafficking defect of Niemann-Pick type C disease, increased NPC1 mRNA levels threefold. The protein synthesis inhibitor, cycloheximide, also increased NPC1 mRNA levels, augmenting the progesterone-induced increase in NPC1 mRNA abundance. Progesterone treatment was shown to increase the mRNA half-life, but did not affect NPCI promoter activity. Cysteine residues in a "cysteine-rich" loop predicted to reside in the intralumenal compartment of vesicles containing NPCI were mutated, resulting in proteins that were incapable of correcting the cholesterol trafficking defect in CT60 cells, a Chinese hamster cell line in which the endogenous NPCI gene is inactivated. Converting isoleucine 1061, also predicted to lie within the cysteine-rich loop, to a threonine residue inactivated the protein as well. The I1061T mutation is one of the most common mutations in Niemann-Pick type C disease. All of the cysteine-rich loop mutants were localized to cholesterol-engorged lysosomes in a pattern mimicking the distribution of NPCI in progesterone-treated cells. A recombinant protein representing the cysteine-rich loop was shown to bind to a zinc-NTA agarose column. We conclude:(1) that cis elements residing in the first 111 base pairs upstream from the transcription start site are critical for transcription of the NPCI gene;(2) that NPCI expression is subject to posttranscriptional regulation in response to treatments that disrupt NPC1 function; and (3) that an intralumenal cysteinerich loop with zinc-binding activity is critical to NPC1's ability to unload lysosomal cargo. (C) 2000 Academic Press. C1 Univ Penn, Med Ctr, Dept Obstet & Gynecol, Ctr Res Reprod Womens Hlth, Philadelphia, PA 19104 USA. NIDDKD, Sect Lipid Cell Biol, NIH, Bethesda, MD 20892 USA. Univ Penn, Med Ctr, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. Vet Adm Connecticut Healthcare Syst, Neurol Res Lab, Newington, CT 06111 USA. NINDS, Cellular & Mol Pathophysiol Sect, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Strauss, JF (reprint author), 1354 BRB 2-3,421 Curie Blvd, Philadelphia, PA 19104 USA. OI Burd, Christopher/0000-0003-1831-8706 FU NICHD NIH HHS [HD06274]; NINDS NIH HHS [NS34339] NR 36 TC 36 Z9 36 U1 0 U2 3 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD AUG 25 PY 2000 VL 259 IS 1 BP 247 EP 256 DI 10.1006/excr.2000.4976 PG 10 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 350GE UT WOS:000089091900023 PM 10942596 ER PT J AU Nika, J Yang, WM Pavitt, GD Hinnebusch, AG Hannig, EM AF Nika, J Yang, WM Pavitt, GD Hinnebusch, AG Hannig, EM TI Purification and kinetic analysis of eIF2B from Saccharomyces cerevisiae SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GUANINE-NUCLEOTIDE-EXCHANGE; INITIATION FACTOR-II; POLYPEPTIDE-CHAIN INITIATION; TRANSLATION INITIATION; PROTEIN-SYNTHESIS; EUKARYOTIC INITIATION-FACTOR-2; ALPHA-SUBUNIT; GAMMA-SUBUNIT; DROSOPHILA-MELANOGASTER; RABBIT RETICULOCYTES AB Eukaryotic translation initiation factor 2B (eIF2B) is the heteropentameric guanine nucleotide exchange factor for translation initiation factor 2 (eIF2). Recent studies in the yeast Saccharomyces cerevisiae have served to characterize genetically the exchange factor. However, enzyme kinetic studies of the yeast enzyme have been hindered by the lack of sufficient quantities of protein suitable for biochemical analysis. We have purified yeast eIF2B and characterized its catalytic properties in vitro. Values for K-m and V-max were determined to be 12.2 nM and 250.7 fmol/min, respectively, at 0 degrees C. The calculated turnover number (K-cat) of 43.2 pmol of GDP released per min/pmol of eIF2B at 30 degrees C is approximately 1 order of magnitude lower than values previously reported for the mammalian factor. Reciprocal plots at varying fixed concentrations of the second substrate were linear and intersected to the left of the gamma axis. This is consistent with a sequential catalytic mechanism and argues against a ping-pong mechanism similar to that proposed for EF-Tu/EF-Ts. In support of this model, our yeast eIF2B preparations bind guanine nucleotides, with an apparent dissociation constant for GTP in the low micromolar range. C1 Univ Texas, Dept Mol & Cell Biol, Richardson, TX 75083 USA. NICHHD, Lab Eukaryot Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Univ Texas, Dept Mol & Cell Biol, Mail Stn FO 3-1,POB 8306888, Richardson, TX 75083 USA. EM hannig@utdallas.edu RI Pavitt, Graham/A-1363-2010 OI Pavitt, Graham/0000-0002-8593-2418 NR 65 TC 26 Z9 28 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 25 PY 2000 VL 275 IS 34 BP 26011 EP 26017 DI 10.1074/jbc.M003718200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 348RF UT WOS:000088999700019 PM 10852917 ER PT J AU Caterina, JJ Yamada, S Caterina, NCM Longenecker, G Holmback, K Shi, J Yermovsky, AE Engler, JA Birkedal-Hansen, H AF Caterina, JJ Yamada, S Caterina, NCM Longenecker, G Holmback, K Shi, J Yermovsky, AE Engler, JA Birkedal-Hansen, H TI Inactivating mutation of the mouse tissue inhibitor of metalloproteinases-2(Timp-2) gene alters proMMP-2 activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MATRIX METALLOPROTEINASES; GELATINASE-A; 72-KDA GELATINASE; PROGELATINASE-A; TERMINAL DOMAIN; IV COLLAGENASE; TIMP-2; COMPLEX; FIBROBLASTS; EXPRESSION AB To understand the biologic function of TIMP-2, a member of the tissue inhibitors of metalloproteinases family, an inactivating mutation was introduced in the mouse Timp-2 gene by homologous recombination, Outbred homozygous mutants developed and procreated indistinguishably from wild type littermates, suggesting that fertility, development, and growth are not critically dependent on TIMP-2, Lack of functional TIMP-2, however, dramatically altered the activation of proMMP-2 both in vivo and in vitro. Fully functional TIMP-2 is essential for efficient activation of proMMP-2 in vivo, No evidence of successful functional compensation was observed. The results illustrate the duality of TIMP-2 function, i.e. at low concentrations, TIMP-2 exerts a "catalytic" or enhancing effect on cell-mediated proMMP-2 activation, whereas at higher concentrations, TIMP-2 inhibits the activation and/or activity of MMP-2. C1 NIDCR, Matrix Metalloprot Unit, NIH, Bethesda, MD 20892 USA. NIDCR, Gene Targeting Res & Core Facil, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA. RP Caterina, JJ (reprint author), 30 Convent Dr,MSC 4380, Bethesda, MD 20892 USA. FU NCI NIH HHS [CA13148]; NIDCR NIH HHS [DE10631, DE08228] NR 30 TC 98 Z9 102 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 AUG 25 PY 2000 VL 275 IS 34 BP 26416 EP 26422 DI 10.1074/jbc.M001271200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 348RF UT WOS:000088999700074 PM 10827176 ER PT J AU Arozarena, I Aaronson, DS Matallanas, D Sanz, V Ajenjo, N Tenbaum, SP Teramoto, H Ighishi, T Zabala, JC Gutkind, JS Crespo, P AF Arozarena, I Aaronson, DS Matallanas, D Sanz, V Ajenjo, N Tenbaum, SP Teramoto, H Ighishi, T Zabala, JC Gutkind, JS Crespo, P TI The Rho family GTPase Cdc42 regulates the activation of Ras/MAP kinase by the exchange factor Ras-GRF SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-MEDIATED SIGNALS; DBL HOMOLOGY DOMAIN; SACCHAROMYCES-CEREVISIAE; DEPENDENT ACTIVATION; BINDING PROTEINS; PH DOMAIN; CALCIUM; VAV; TRANSFORMATION; PATHWAYS AB The Ras guanine-nucleotide exchange factor Ras-GRF/Cdc25(Mn) harbors a complex array of structural motifs that include a Dbl-homology (DH) domain, usually found in proteins that interact functionally with the Rho family GTPases, and the role of which is not yet fully understood. Here, we present evidence that Ras-GRF requires its DH domain to translocate to the membrane, to stimulate exchange on Ras, and to activate mitogen-activated protein kinase (MAPK), In an unprecedented fashion, we have found that these processes are regulated by the Rho family GTPase Cdc42. We show that GDP- but not GTP-bound Cdc42 prevents Ras-GRF recruitment to the membrane and activation of Ras/MAPK, although no direct association of Ras-GrRF with Cdc42 was detected, We also demonstrate that catalyzing GDP/GTP exchange on Cdc42 facilitates Ras-GRF-induced MAPK activation. Moreover, we show that the potentiating effect of ionomycin on Ras-GRF-mediated MAPK stimulation is also regulated by Cdc42. These results provide the first evidence for the involvement of a Rho family G protein in the control of the activity of a Ras exchange factor. C1 CSIC, Inst Invest Biomed, E-28029 Madrid, Spain. Univ Cantabria, Dept Mol Biol, Santander 39011, Spain. NIDR, Cell Growth Regulat Sect, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Crespo, P (reprint author), CSIC, Inst Invest Biomed, Arturo Duperier 4, E-28029 Madrid, Spain. RI Gutkind, J. Silvio/A-1053-2009; Zabala, Juan Carlos/K-5163-2014; Crespo, Piero/M-3273-2014 OI Zabala, Juan Carlos/0000-0003-2679-5473; Crespo, Piero/0000-0003-2825-7783 NR 47 TC 30 Z9 31 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 AUG 25 PY 2000 VL 275 IS 34 BP 26441 EP 26448 DI 10.1074/jbc.M002992200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 348RF UT WOS:000088999700078 PM 10840034 ER PT J AU Baer, M Johnson, PF AF Baer, M Johnson, PF TI Generation of truncated C/EBP beta isoforms by in vitro proteolysis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENHANCER-BINDING-PROTEIN; TRANSCRIPTIONAL ACTIVATOR PROTEIN; NF-KAPPA-B; CELL-PROLIFERATION; LEUCINE-ZIPPER; POSTTRANSCRIPTIONAL REGULATION; ADIPOCYTE DIFFERENTIATION; MESSENGER-RNA; MAMMARY-GLAND; DNA-BINDING AB Multiple forms of the transcriptional regulator CCAAT/enhancer-binding protein beta (C/EBP beta) with molecular masses of approximately 38, 34, 20, and 14 kDa have been observed in cell extracts. It has been proposed that these proteins arise by alternative initiation at in-frame AUG codons. The truncated C/EBP beta isoforms (p14 and p20/LIP) lack transactivation domains but retain DNA-binding and dimerization sequences and are therefore assumed to function as competitive inhibitors of C/EBP-mediated transcription in vivo. By comparing various extraction procedures to analyze endogenous and overexpressed C/EBP beta proteins, we determined that p20-C/EBP beta is generated predominantly by in vitro proteolytic cleavage during isolation from cells and that p14-C/EBP beta is produced exclusively by this mechanism. In transfected cells, the full-length (p34 and p38) isoforms but not the truncated proteins were detectable in the cytoplasm, indicating that the latter are not primary translation products. In addition, the C/EBP beta leucine zipper dimerization domain was essential for the appearance of the truncated species, demonstrating that protein folding or dimerization are critical determinants of proteolytic sensitivity. Our findings suggest that the presence of truncated C/EBP beta proteins in cell extracts must be interpreted with caution and that assumptions about the in vivo relevance of these isoforms should be re-evaluated. C1 NCI, Frederick Canc Res & Dev Ctr, Eukaryot Transcript Regulat Sect, Adv BioSci Labs,Basic Res Program, Frederick, MD 21702 USA. RP Johnson, PF (reprint author), NCI, Frederick Canc Res & Dev Ctr, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 NR 37 TC 65 Z9 67 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 AUG 25 PY 2000 VL 275 IS 34 BP 26582 EP 26590 DI 10.1074/jbc.M004268200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 348RF UT WOS:000088999700096 PM 10856306 ER PT J AU Yang, YH Jiang, L Zhu, LQ Wu, YJ Yang, SL AF Yang, YH Jiang, L Zhu, LQ Wu, YJ Yang, SL TI Thermal stable and oxidation-resistant variant of subtilisin E SO JOURNAL OF BIOTECHNOLOGY LA English DT Article DE oxidation-resistant; random mutagenesis; subtilisin E; thermal stability ID DIRECTED EVOLUTION; RANDOM MUTAGENESIS; BACILLUS-SUBTILIS; CRYSTAL-STRUCTURE; SERINE-PROTEASE; DISULFIDE BOND; STABILITY; DIMETHYLFORMAMIDE; THERMOSTABILITY; CONSTRUCTION AB A remarkable thermal stable and oxidation-resistant mutant was obtained using the random mutagenesis PCR technique on the mutant M222A gene of subtilisin E. Sequencing analysis revealed an A was replaced by G at nucleotide 671 of the subtilisin E gene, converting the asparagine codon (AAT) to serine codon (AGT) at position 118. The half-life of M222A/N118S enzyme activity, when heated at 65 degrees C, was approximately 80 min while the half-life of M222A and wild-type subtilisin E were 13 min and 15 min, respectively. This suggested the stability of the M222A/N118S mutant was five times greater than that of the wild-type enzyme. The mutant was also as oxidation resistant as the mutant M222A of subtilisin E. These results indicated the M222A/N118S mutant is both an oxidation-resistant and a heat-stable variant of subtilisin E. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China. Chinese Acad Sci, Shanghai Res Ctr Biotechnol, Shanghai 200233, Peoples R China. RP Yang, YH (reprint author), NIEHS, LPC, C3-01,POB 12233, Res Triangle Pk, NC 27709 USA. NR 19 TC 16 Z9 16 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1656 J9 J BIOTECHNOL JI J. Biotechnol. PD AUG 25 PY 2000 VL 81 IS 2-3 BP 113 EP 118 DI 10.1016/S0168-1656(00)00272-8 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 354NJ UT WOS:000089336300003 PM 10989170 ER PT J AU Kliger, Y Peisajovich, SG Blumenthal, R Shai, Y AF Kliger, Y Peisajovich, SG Blumenthal, R Shai, Y TI Membrane-induced conformational change during the activation of HIV-1 gp41 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1 gp41; membrane fusion; helix-helix interaction ID IMMUNODEFICIENCY-VIRUS TYPE-1; FLUORESCENCE ENERGY-TRANSFER; TERMINAL FUSION PEPTIDE; ENVELOPE GLYCOPROTEIN; INFLUENZA HEMAGGLUTININ; PHOSPHOLIPID-MEMBRANES; LIPID BILAYERS; STRUCTURAL CHARACTERIZATION; TRANSMEMBRANE GLYCOPROTEIN; MONOCLONAL-ANTIBODY AB The human immunodeficiency virus type 1 gp41 ectodomain forms a three-hairpin protease-resistant core in the absence of membranes, namely, the putative gp41 fusion-active state. Here, we show that recombinant proteins corresponding to the ectodomain of gp41, but lacking the fusion peptide, bind membranes and consequently undergo a major conformational change. As a result, the protease-resistant core becomes susceptible to proteolytic digestion. Accordingly, synthetic peptides corresponding to the segments that construct this core bind the membrane. It is remarkable that the hetero-oligomer formed by these peptides dissociates upon binding to the membrane. These results are consistent with a model in which, after the three-hairpin conformation is formed, membrane binding induces opening of the gp41 core complex. We speculate that binding of the segments that constructed the core to the viral and cellular membranes could bring the membranes closer together and facilitate their merging. (C) 2000 Academic Press. C1 Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. NIH, Lab Expt & Computat Biol, Frederick, MD 21702 USA. RP Shai, Y (reprint author), Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. RI Peisajovich, Sergio/C-6641-2011 NR 68 TC 52 Z9 52 U1 0 U2 8 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 AUG 25 PY 2000 VL 301 IS 4 BP 905 EP 914 DI 10.1006/jmbi.2000.4004 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 354WC UT WOS:000089351800015 PM 10966795 ER PT J AU Hagen, SJ Eaton, WA AF Hagen, SJ Eaton, WA TI Two-state expansion and collapse of a polypeptide SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE cytochrome c; molten globule; collapse; temperature-jump; denatured states ID PROTEIN-FOLDING KINETICS; UNFOLDED CYTOCHROME-C; MOLTEN GLOBULE; FLEXIBLE COIL; HOMOPOLYMER; DIFFUSION; TRANSITION; DYNAMICS; MODEL; THERMODYNAMICS AB The initial phase of folding for many proteins is presumed to be the collapse of the polypeptide chain from expanded to compact but still denatured, conformations. Theory and simulations suggest that this collapse may be a two-state transition, characterized by barrier-crossing kinetics, while the collapse of homopolymers is continuous and multiphasic. We have used laser temperature-jump with fluorescence spectroscopy to measure the complete time-course of the collapse of denatured cytochrome c with nanosecond time resolution. We find the process to be exponential in time and thermally activated, with an apparent activation energy similar to 9 k(B)T (after correction for solvent viscosity). These results indicate that polypeptide collapse is kinetically a two-state transition. Because of the observed free energy barrier, the time scale of polypeptide collapse is dramatically slower than is predicted by Langevin models for homopolymer collapse. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Eaton, WA (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. RI Hagen, Stephen/E-9737-2015 OI Hagen, Stephen/0000-0002-3373-5033 NR 45 TC 67 Z9 67 U1 3 U2 14 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 AUG 25 PY 2000 VL 301 IS 4 BP 1019 EP 1027 DI 10.1006/jmbi.2000.3969 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 354WC UT WOS:000089351800022 PM 10966803 ER PT J AU Childs, S Weinstein, BM Mohideen, MAPK Donohue, S Bonkovsky, H Fishman, MC AF Childs, S Weinstein, BM Mohideen, MAPK Donohue, S Bonkovsky, H Fishman, MC TI Zebrafish dracula encodes ferrochelatase and its mutation provides a model for erythropoietic protoporphyria SO CURRENT BIOLOGY LA English DT Article ID GENE AB Exposure to light precipitates the symptoms of several genetic disorders that affect both skin and internal organs. It is presumed that damage to non-cutaneous organs is initiated indirectly by light, but this is difficult to study in mammals. Zebrafish have an essentially transparent periderm for the first days of development. In a previous large-scale genetic screen we isolated a mutation, dracula (drc), which manifested as a light-dependent lysis of red blood cells [1]. We report here that protoporphyrin IX accumulates in the mutant embryos, suggesting a deficiency in the activity of ferrochelatase, the terminal enzyme in the pathway for heme biosynthesis. We find that homozygous drc(m248) mutant embryos have a G-->T transversion at a splice donor site in the ferrochelatase gene, creating a premature stop codon. The mutant phenotype, which shows light-dependent hemolysis and liver disease, is similar to that seen in humans with erythropoietic protoporphyria, a disorder of ferrochelatase. C1 Massachusetts Gen Hosp E, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. RP Fishman, MC (reprint author), NICHHD, Genet Mol Lab, Bethesda, MD 20892 USA. FU NCRR NIH HHS [R01RR0888]; NHLBI NIH HHS [R01HL49579]; NIDDK NIH HHS [R01DK55383] NR 18 TC 71 Z9 71 U1 3 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 24 PY 2000 VL 10 IS 16 BP 1001 EP 1004 DI 10.1016/S0960-9822(00)00653-9 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 350VC UT WOS:000089121000022 PM 10985389 ER PT J AU Tamamura, H Bienfait, B Nacro, K Lewin, NE Blumberg, PM Marquez, VE AF Tamamura, H Bienfait, B Nacro, K Lewin, NE Blumberg, PM Marquez, VE TI Conformationally constrained analogues of diacylglycerol (DAG). 17. Contrast between sn-1 and sn-2 DAG lactones in binding to protein kinase C SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID 5-DISUBSTITUTED TETRAHYDRO-2-FURANONE TEMPLATE; PHORBOL ESTER BINDING; LIGANDS; ISOZYMES; PHARMACOPHORE; RECEPTOR; DELTA AB In previous work, we have obtained potent protein kinase C (PK-C) ligands with low-namomolar binding affinities by constructing diacylglycerol (DAG) mimetics in which the sn-2 carbonyl of DAG was constrained into a lactone ring. An additional structural element that helped achieve high binding affinity was the presence of branched acyl or alpha-alkylidene chains. In the present study, the effects of similarly branched chains on a different lactone system, where the lactone carbonyl is now equivalent to the sn-l carbonyl of DAG, are investigated. In this new lactone template, the two chiral centers must have the S-configuration for enzyme recognition. As with the sn-2 DAG lactones, the branched chains were designed to optimize van der Waals contacts with a group of conserved hydrophobic amino acids located on the rim of the C1 domain of PK-C. The acyl and alpha-alkylidene chains were also designed to be lipophilically equivalent (8 carbons each). Eight new compounds (7-14) representing all possible combinations of linear and branched acyl and alpha-alkylidene were synthesized and evaluated. The sn-1 DAG lactones were less effective as PK-C ligands than the sn-2 DAG lactones despite having a similar array of linear or branched acyl and alpha-alkylidene chains. 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, Bldg 37,Rm 5C-02,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. NR 25 TC 13 Z9 13 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 AUG 24 PY 2000 VL 43 IS 17 BP 3209 EP 3217 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 349BJ UT WOS:000089023700003 PM 10966739 ER PT J AU Nabel, EG AF Nabel, EG TI Coronary heart disease in women - An ounce of prevention SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ESTROGEN; HORMONE; THERAPY; HEALTH C1 NHLBI, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 12 TC 31 Z9 31 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 AUG 24 PY 2000 VL 343 IS 8 BP 572 EP 574 DI 10.1056/NEJM200008243430809 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 346QM UT WOS:000088882600009 PM 10954767 ER PT J AU Ge, NL Rudikoff, S AF Ge, NL Rudikoff, S TI Expression of PTEN in PTEN-deficient multiple mgeloma cells abolishes tumor growth in vivo SO ONCOGENE LA English DT Article DE multiple myeloma; PTEN; AKT; OPM-2 cells ID SUPPRESSOR GENE; FACTOR-I; GERMLINE MUTATIONS; CARCINOMA-CELLS; MYELOMA; INSULIN; BREAST; CANCER; APOPTOSIS; LINES AB Biochemical abnormalities associated with the development of multiple myeloma hale been difficult to define especially in terms of demonstrating an irt vivo effect of suspected lesions. Herein, we have identified such a defect associated with lack of expression of PTEN, a cellular phosphatase involved in the regulation of phosphatidylinositol phosphates (PIP's), In myeloma cells, PIP's are required for phosphorylation of Akt, a key event leading to inhibition of apoptosis, Loss of PTEN results in a failure to de-phosphorylate PIP's and a corresponding increase in Akt phosphorylation. OPM-2 cells lacking PTEN expression have the highest level of Akt phosphorylation of eight lines examined. Loss of PTEN was found to be associated with a 630 bp deletion corresponding to amino acids 56-267, Ectopic expression of wild type PTEN in OPM-2 cells inhibited Akt phosphorylation which was correlated with an increase in apoptosis, The in vivo relevance of loss of PTEN expression was demonstrated by injecting control and wild type PTEN transfected OPM-2 cells into SCID mice. Tumors arose at an incidence of 100% in controls, but only 50% (and of smaller size and longer latency) in lon PTEN expressing clones. Importantly, clones expressing high le,els of PTEN failed to produce tumors even at five times the latency period of controls. These results demonstrate that PTEN deletion/mutation is responsible for in vivo growth of this tumor and suggests that PTEN regulation may play an important role in turner development in a subset of multiple myeloma patients. C1 NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rudikoff, S (reprint author), NCI, Cellular & Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. NR 32 TC 41 Z9 42 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 24 PY 2000 VL 19 IS 36 BP 4091 EP 4095 DI 10.1038/sj.onc.1203801 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 347XU UT WOS:000088955100002 PM 10962569 ER PT J AU Cannon, RO AF Cannon, RO TI Cardiovascular benefit of cholesterol-lowering therapy - Does improved endothelial vasodilator function matter? SO CIRCULATION LA English DT Editorial Material DE editorials; cholesterol; vasodilation; endothelium; statins ID CORONARY-ARTERY DISEASE; MYOCARDIAL-ISCHEMIA; POSTMENOPAUSAL WOMEN; PRAVASTATIN; REDUCTION; ACETYLCHOLINE; ANTIOXIDANT; VASOMOTION; RELAXATION; INFARCTION C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,Room 7B15,10 Ctr Dr MSC-1650, Bethesda, MD 20892 USA. NR 22 TC 16 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 22 PY 2000 VL 102 IS 8 BP 820 EP 822 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 346GT UT WOS:000088863200001 PM 10952945 ER PT J AU Laks, MM Arzbaecher, R Geselowitz, D Bailey, JJ Berson, A AF Laks, MM Arzbaecher, R Geselowitz, D Bailey, JJ Berson, A TI Revisiting the question - Will relaxing safe current limits for electromedical equipment increase hazards to patients? SO CIRCULATION LA English DT Editorial Material DE editorials; electrical stimulation; electrocardiography ID AMERICAN-HEART-ASSOCIATION; ELECTROCARDIOGRAPHY; RECOMMENDATIONS; COMMITTEE C1 NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. Harbor UCLA Med Ctr, Los Angeles, CA USA. IIT, Pritzker Inst Technol, Chicago, IL 60616 USA. Penn State Univ, Pittsburgh, PA USA. RP Berson, A (reprint author), NHLBI, Div Heart & Vasc Dis, NIH, 6701 Rockledge Dr,Suite 9044,MSC 7940, Bethesda, MD 20892 USA. NR 13 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 22 PY 2000 VL 102 IS 8 BP 823 EP 825 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 346GT UT WOS:000088863200002 PM 10952946 ER PT J AU Appel, LJ Miller, ER Jee, SH Stolzenberg-Solomon, R Lin, PH Erlinger, T Nadeau, MR Selhub, J AF Appel, LJ Miller, ER Jee, SH Stolzenberg-Solomon, R Lin, PH Erlinger, T Nadeau, MR Selhub, J TI Effect of dietary patterns on serum homocysteine - Results of a randomized, controlled feeding study SO CIRCULATION LA English DT Article DE nutrition; risk factors; metabolism ID PLASMA HOMOCYSTEINE; FOLIC-ACID; FOLATE; RISK; VITAMIN-B12; ASSOCIATION; POPULATION; DISEASE; HEALTH AB Background-Elevated blood levels of homocysteine are associated with an increased risk of atherosclerotic cardiovascular disease. Although numerous studies have assessed the impact of vitamin supplements on homocysteine, the effect of dietary patterns on homocysteine has not been well studied. Methods and Results-During a 3-week run-in, 118 participants were fed a control diet, low in fruits, vegetables, and dairy products, with a fat content typical of US consumption. During an 8-week intervention phase, participants were then fed 1 of 3 randomly assigned diets: the control diet, a diet rich in fruits and vegetables but otherwise similar to control, or a combination diet rich in fruits, vegetables, and low-fat dairy products and reduced in saturated and total fat. Between the end of run-in and intervention periods, mean change in homocysteine was +0.46 mu mol/L in the control diet, +0.21 mu mol/L in the fruits and vegetables diet (P=0.47 compared with control), and -0.34 mu mol/L in the combination diet (P=0.03 compared with control, P=0.12 compared with the fruits and vegetables diet), In multivariable regression models, change in homocysteine was significantly and inversely associated with change in serum folate (P=0.03) but not with change in serum vitamin B-12 (P=0.64) or pyridoxal 5' phosphate, the coenzyme form of vitamin B-6 (P=0.83). Conclusions-Modification of dietary patterns can have substantial effects on fasting levels of total serum homocysteine. These results provide additional insights into the mechanisms by which diet might influence the occurrence of atherosclerotic cardiovascular disease. C1 Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. Yonsei Univ, Grad Sch Hlth Sci & Management, Dept Epidemiol & Dis Control, Seoul 120749, South Korea. NCI, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Sarah W Stedman Ctr Nutr Studies, Durham, NC USA. Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. RP Appel, LJ (reprint author), Johns Hopkins Univ, 2024 E Monument St,Suite 2-645, Baltimore, MD 21205 USA. FU NCRR NIH HHS [RR-00722]; NHLBI NIH HHS [HL-02642, HL-50981] NR 29 TC 103 Z9 110 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 22 PY 2000 VL 102 IS 8 BP 852 EP 857 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 346GT UT WOS:000088863200008 PM 10952952 ER PT J AU Butefisch, CM Gambetti, P Cervenakova, L Park, KY Hallett, M Goldfarb, LG AF Butefisch, CM Gambetti, P Cervenakova, L Park, KY Hallett, M Goldfarb, LG TI Inherited prion encephalopathy associated with the novel PRNP H187R mutation - A clinical study SO NEUROLOGY LA English DT Article ID STRAUSSLER-SCHEINKER-DISEASE; CREUTZFELDT-JAKOB-DISEASE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES; PHENOTYPIC VARIABILITY; CEREBROSPINAL-FLUID; PROTEIN GENE; POLYMORPHISM; HETEROGENEITY; VARIANT; FAMILY AB Objective: To describe a variant of prion encephalopathy associated with the recently identified H187R mutation in the prion protein (PRNP) gene. Methods: The authors studied a multigenerational American family with nine affected individuals. Clinical examination included imaging, EEG, and CSF analysis with 14-3-3 protein testing. Histopathology was characterized by examination of a brain biopsy from an H187R mutation-positive patient. Results: The disease in this family is caused by the PRNP H187R mutation and characterized by autosomal dominant inheritance, median age at disease onset of 42 years (range 33 to 50 years), and median duration of illness of 12 years (range 8 to 19 years). Clinical signs include progressive dementia, ataxia, myoclonus, and seizures. Histopathologic features consist of distinctive "curly" prion protein deposits with a strictly laminar distribution in the cerebral cortex and minimal astrogliosis in the absence of amyloid plaques or spongiosis. Conclusion: A Variant of prion encephalopathy associated with the novel H187R mutation in the PRNP gene displays distinctive clinical and immunostaining characteristics that further expand the boundaries of human prion disease. C1 NINDS, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD USA. Case Western Reserve Univ, Sch Med, Dept Pathol, Cleveland, OH 44106 USA. RP Goldfarb, LG (reprint author), NINDS, NIH, 10 Ctr Dr,MSC 1361,Bldg 10,Rm 4B37, Bethesda, MD 20892 USA. NR 20 TC 24 Z9 25 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 22 PY 2000 VL 55 IS 4 BP 517 EP 522 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 346DG UT WOS:000088855000011 PM 10953183 ER PT J AU Terrence, K Pavlovich, CP Matechak, EO Fowlkes, BJ AF Terrence, K Pavlovich, CP Matechak, EO Fowlkes, BJ TI Premature expression of T cell receptor (TCR)alpha beta suppresses TCR gamma delta gene rearrangement but permits development of gamma delta lineage T cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE lineage commitment; TCR transgenic mice; thymus; differentiation; positive selection ID ALPHA-BETA; TRANSGENIC MICE; ANTIGEN RECEPTOR; IMMATURE THYMOCYTES; POSITIVE SELECTION; CLONAL DELETION; COMMITMENT; REPERTOIRE; MATURATION; PRECURSOR AB The T cell receptor (TCR)gamma delta and the pre-TCR promote survival and maturation of early thymocyte precursors. Whether these receptors also influence gamma delta versus alpha beta lineage determination is less clear. We show here that TCR gamma delta gene rearrangements are suppressed in TCR alpha beta transgenic mice when the TCR alpha beta is expressed early in T cell development. This situation offers the opportunity to examine the outcome of gamma delta versus alpha beta T lineage commitment when only the TCR alpha beta is expressed. We find that precursor thymocytes expressing TCR alpha beta not only mature in the alpha beta pathway as expected, but also as CD4(-)CD8(-) T cells with properties of gamma delta lineage cells. In TCR alpha beta transgenic mice, in which the transgenic receptor is expressed relatively late, TCR gamma delta rearrangements occur normally such that TCR alpha beta(+)CD4(-)CD8(-) cells co-express TCR gamma delta. The results support the notion that TCR alpha beta can substitute for TCR gamma delta to permit a gamma delta lineage choice and maturation in the gamma delta lineage. The findings could fit a model in which lineage commitment is determined before or independent of TCR gene rearrangement. However, these results could be compatible with a model in which distinct signals bias lineage choice and these signaling differences are not absolute or intrinsic to the specific TCR structure. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Fowlkes, BJ (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bldg 4,Rm 111, Bethesda, MD 20892 USA. NR 69 TC 94 Z9 94 U1 1 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 21 PY 2000 VL 192 IS 4 BP 537 EP 548 DI 10.1084/jem.192.4.537 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 349WB UT WOS:000089067600009 PM 10952723 ER PT J AU Russell, LB Hunsicker, PR Kerley, MK Johnson, DK Shelby, MD AF Russell, LB Hunsicker, PR Kerley, MK Johnson, DK Shelby, MD TI Bleomycin, unlike other male-mouse mutagens, is most effective in spermatogonia, inducing primarily deletions SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE germ-cell stage; spermatogonial mutations; deletions; specific-locus test; dominant-lethal test ID DOMINANT LETHAL MUTATIONS; INDUCED SPECIFIC-LOCUS; GERM-LINE MUTATIONS; DILUTION P LOCUS; MALE-MICE; COMPLEMENTATION ANALYSES; MOLECULAR ANALYSIS; FEMALE MICE; CELL STAGES; INDUCTION AB Dominant-lethal tests [P.D. Sudman, J,C. Rutledge, J.B. Bishop, W.M. Generoso, Bleomycin: female-specific dominant lethal effects in mice, Mutat. Res. 296 (1992) 205-217] had suggested that Bleomycin sulfate (Blenoxane), BLM, might be a female-specific mutagen. While confirming that BLM is indeed a powerful inducer of dominant-lethal mutations in females that fails to induce such mutations in postspermatogonial stages of males, we have shown in a specific-locus test that BLM is, in fact, mutagenic in males. This mutagenicity, however, is restricted to spermatogonia (stem-cell and differentiating stages), fur which the specific-locus mutation rate differed significantly (P < 0.008) from the historical control rate. In treated groups, dominant mutations, also, originated only in spermatogonia. With regard to mutation frequencies, this germ-cell-stage pattern is different from that for radiation and fur any other chemical studied to date, except ethylnitrosourea (ENU). However, the nature of the spermatogonial specific-locus mutations differentiates BLM from ENU as well, because BLM induced primarily (or, perhaps, exclusively) multilocus deletions. Heretofore, no chemical that induced specific-locus mutations in spermatogonia did not also induce specific-locus as well as dominant-lethal mutations in postspermatogonial stages, making the dominant lethal test, up till now, predictive of male mutagenicity in general. The BLM results now demonstrate that there are chemicals that can induce specific-locus mutations in spermatogonia without testing positive in postspermatogonial stages. Thus, BLM, while not female-specific, is unique, (a) in its germ-cell-stage specificity in males, and (b) in inducing a type of mutation (deletions) that is atypical for the responding germ-cell stages (spermatogonia). (C) 2000 Elsevier Science B.V. All rights reserved. C1 Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Russell, LB (reprint author), Oak Ridge Natl Lab, Div Life Sci, Bldg 9210,POB 2009,MS 8077, Oak Ridge, TN 37831 USA. EM russelllb@ornl.gov FU NIEHS NIH HHS [Y1-ES-8048/O524-I119-AI] NR 41 TC 12 Z9 12 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD AUG 21 PY 2000 VL 469 IS 1 BP 95 EP 105 DI 10.1016/S1383-5718(00)00060-7 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 350FY UT WOS:000089091300010 PM 10946246 ER PT J AU Alisky, JM Hughes, SM Sauter, SL Jolly, D Dubensky, TW Staber, PD Chiorini, JA Davidson, BL AF Alisky, JM Hughes, SM Sauter, SL Jolly, D Dubensky, TW Staber, PD Chiorini, JA Davidson, BL TI Transduction of murine cerebellar neurons with recombinant FIV and AAV5 vectors SO NEUROREPORT LA English DT Article DE axonal transport; gene therapy; Purkinje cells ID MEDIATED GENE-TRANSFER; EFFICIENT TRANSDUCTION; NONDIVIDING CELLS; LENTIVIRAL VECTOR; PURKINJE-CELLS; VIRUS VECTORS; IN-VIVO; BRAIN; EXPRESSION; DELIVERY AB Our data demonstrate that vectors derived from recombinant feline immunodeficiency virus (rFIV) and adeno-associated virus type 5 (rAAV5) transduce cerebellar cells following direct injection into the cerebellar lobules of mice. Both recombinant viruses mediated gene transfer predominantly to neurons, with up to 2500 and 1500 Purkinje cells transduced for rAAV5 or rFIV-based vectors, respectively. The vectors also transduced stellate, basket and Golgi neurons, with occasional transduction of granule cells and deep cerebellar nuclei. rAAV5 also spread outside the cerebellum to the inferior colliculus and ventricular epithelium, while rFIV demonstrated the ability to undergo retrograde transport to the physically close lateral vestibular nuclei. Thus, AAV5 and FIV-based vectors show promise for targeting neurons affected in the hereditary spinocerebellar ataxias. These vectors could be important tools for unraveling the pathophysiology of these disorders, or in testing factors which may promote neuronal survival. (C) 2000 Lippincott Williams & Wilkins. C1 Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA. Univ Iowa, Coll Med, Dept Neurol, Program Gene Therapy, Iowa City, IA 52242 USA. Chiron Corp, Ctr Gene Therapy, San Diego, CA 92121 USA. NIDCR, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. RP Davidson, BL (reprint author), Univ Iowa, Coll Med, Dept Internal Med, Program Gene Therapy, Iowa City, IA 52242 USA. FU NICHD NIH HHS [HD33531]; NINDS NIH HHS [NS34568] NR 28 TC 101 Z9 103 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 21 PY 2000 VL 11 IS 12 BP 2669 EP 2673 DI 10.1097/00001756-200008210-00013 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 348TV UT WOS:000089003300021 PM 10976941 ER PT J AU Adah, SA Jacobson, AE Rice, KC Dersch, CM Horel, R Rothman, RB AF Adah, SA Jacobson, AE Rice, KC Dersch, CM Horel, R Rothman, RB TI Development of analogs of N-phenethylphenylmorphan as potential narcotic antagonists. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NIDA, Addict Res Ctr, Clin Psychopharmacol Sect, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 236-MEDI BP U578 EP U578 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203143 ER PT J AU Adejare, A Ogunbadeniyi, A Bowen, W Mattson, M AF Adejare, A Ogunbadeniyi, A Bowen, W Mattson, M TI Ligands for characterizing PCP binding sites on the NMDA receptor complex. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Idaho State Univ, Dept Pharmaceut Sci, Pocatello, ID 83209 USA. NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 214-MEDI BP U574 EP U574 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203121 ER PT J AU Ananthan, S Saini, SK Davis, P Porreca, F Dersch, CM Rothman, RB AF Ananthan, S Saini, SK Davis, P Porreca, F Dersch, CM Rothman, RB TI Synthesis and opioid receptor binding profiles of pyrimidothienoepoxymorphinans. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 So Res Inst, Dept Organ Chem, Birmingham, AL 35255 USA. Univ Arizona, Dept Pharmacol, Tucson, AZ USA. NIDA, Clin Psychopharmacol Sect, Addict Res Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 235-MEDI BP U578 EP U578 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203142 ER PT J AU Arnold, EV Hrabie, JA Keefer, LK AF Arnold, EV Hrabie, JA Keefer, LK TI Surprising reactivity of C-based diazeniumdiolates: Conversion of a nitrile to an imidate and its decomposition to yield nitric oxide. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Frederick Canc Res & Dev Ctr, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick, Analyt Chem Lab, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 111-INOR BP U471 EP U471 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202477 ER PT J AU Banavali, NK Wang, PY Marquez, VE Brank, A Christman, JK MacKerell, AD AF Banavali, NK Wang, PY Marquez, VE Brank, A Christman, JK MacKerell, AD TI Computational study of inhibition of the Hha I cytosine-C5-methyltransferase by conformationally constrained abasic oligonucleotides. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Maryland, Dept Pharmaceut Sci, Sch Pharm, Baltimore, MD 21201 USA. NCI, Med Chem Lab, DBS, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Dept Biochem & Mol Biol, Lincoln, NE USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 312-PHYS BP U202 EP U202 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091301130 ER PT J AU Barchi, JJ Anderson, L Siddiqui, MA Marquez, VE AF Barchi, JJ Anderson, L Siddiqui, MA Marquez, VE TI NMR analysis of conformationally biased anti-HIV and anticancer nucleoside analogues. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 73-CARB BP U120 EP U120 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200583 ER PT J AU Brechbiel, MW Mandler, R Dadachova, E Brechbiel, JK Waldmann, TA AF Brechbiel, MW Mandler, R Dadachova, E Brechbiel, JK Waldmann, TA TI Synthesis and evaluation of anti-proliferative activity of a geldanamycin-herceptin immunoconjugate. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, NIH, Radiat Oncol Branch, Inorgan & Radioimmune Chem Sect, Bethesda, MD 20892 USA. NCI, NIH, Metab Branch, Bethesda, MD 20892 USA. RI Dadachova, Ekaterina/I-7838-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 71-MEDI BP U549 EP + PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202979 ER PT J AU Brinton, LA AF Brinton, LA TI Relationship of cigarette smoking to risk of breast cancer. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Natl Canc Inst, Rockville, MD 20852 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 25-CHAS BP U191 EP U191 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200978 ER PT J AU Brooks, BR AF Brooks, BR TI QM/MM techniques for examining enzyme mechanism. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 166-PHYS BP U180 EP U180 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300984 ER PT J AU Bryant, LH Dadachova, E Brechbiel, MW Frank, JA AF Bryant, LH Dadachova, E Brechbiel, MW Frank, JA TI Synthesis and kinetic stability of Ga(III) and Cu(II) 18-membered hexaazamacrocyclic complexes: Ga-67(pyan) and Cu-67(pyan). SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. NIH, Radioimmune & Inorgan Chem Sect, Bethesda, MD 20892 USA. RI Dadachova, Ekaterina/I-7838-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 180-INOR BP U481 EP U481 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202546 ER PT J AU Bryant, SH AF Bryant, SH TI Information system for structural genomics. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Computat Biol Branch, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 117-PHYS BP U172 EP U173 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300935 ER PT J AU Caldwell, TM Rice, KC Howlett, AC AF Caldwell, TM Rice, KC Howlett, AC TI Synthesis of new chiral analogs of PF460 as potential cannabinoid ligands. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, NIDDK, Med Chem Lab, Bethesda, MD 20892 USA. St Louis Univ, Sch Med, Dept Pharmacol, St Louis, MO 63104 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 243-MEDI BP U579 EP U580 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203150 ER PT J AU Cassatt, JC AF Cassatt, JC TI Biology at the level of the cell. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Natl Inst Gen Med Sci, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 141-ANYL BP U99 EP U99 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200468 ER PT J AU Cook, AB Davies, KM Saavedra, JE Hrabie, JA AF Cook, AB Davies, KM Saavedra, JE Hrabie, JA TI Micellar catalysis of nitric oxide dissociation from diazeniumdiolates. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 175-COLL BP U252 EP U252 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091201311 ER PT J AU Das, D Billings, EM Brooks, BR AF Das, D Billings, EM Brooks, BR TI Quantum mechanical/molecular mechanical study using density functionals and the double link atom method. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, NHLBI, Biophys Chem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 108-COMP BP U292 EP U293 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091201559 ER PT J AU Davies, KM Wink, DA Saavedra, JE Keefer, LK AF Davies, KM Wink, DA Saavedra, JE Keefer, LK TI Kinetics and mechanisms of nitric oxide dissociation from diazeniumdiolates. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. NCI, Radiat Biol Branch, Bethesda, MD USA. NCI, Frederick Canc Res & Dev Ctr, IRSP, SAIC, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 381-ORGN BP U93 EP U93 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300546 ER PT J AU Gao, Y Voigt, JH Kelley, J Yang, DJ Burke, TR AF Gao, Y Voigt, JH Kelley, J Yang, DJ Burke, TR TI Design and synthesis of conformationally constrained Grb2 SH2 domain inhibitors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 249-MEDI BP U580 EP U580 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203156 ER PT J AU Garmestani, K Plascjak, PS Brechbiel, MW Yao, ZS Carrasquillo, J AF Garmestani, K Plascjak, PS Brechbiel, MW Yao, ZS Carrasquillo, J TI Synthesis and in vivo evaluation of a new bifunctional macrocyclic ligand as a potential chelating agent for bismuth-212/213. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, NIH, Radioimmune & Inorgan Chem Sect, ROB,DCS, Bethesda, MD 20892 USA. NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. RI Carrasquillo, Jorge/E-7120-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 72-MEDI BP U549 EP U549 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202980 ER PT J AU Gussio, R McGrath, CF Zaharevitz, DW Kellogg, GE Schultz, C Kunick, C Leost, M Meijer, L Sausville, EA AF Gussio, R McGrath, CF Zaharevitz, DW Kellogg, GE Schultz, C Kunick, C Leost, M Meijer, L Sausville, EA TI Structure-based, 3D, quantitative structure activity relationship between paullones and CDK5/p25. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, FCRDC, Dev Therapeut Program, Frederick, MD 21702 USA. Virginia Commonwealth Univ, Dept Med Chem, Richmond, VA 23298 USA. Univ Hamburg, Dept Pharmaceut Chem, Hamburg, Germany. CNRS, Biol Stn, F-75700 Paris, France. RI Kellogg, Glen/A-8008-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 97-COMP BP U291 EP U291 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091201548 ER PT J AU Hazard, GF Hudson, VW Liwanag, PM AF Hazard, GF Hudson, VW Liwanag, PM TI Chemical and environmental health information at the National Library of Medicine. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Natl Lib Med, Specialized Informat Serv, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 82-CINF BP U206 EP U206 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091201060 ER PT J AU Henry, SH Bosch, FX Bowers, JC Portier, CJ AF Henry, SH Bosch, FX Bowers, JC Portier, CJ TI Aflatoxin, hepatitis, and worldwide liver cancer risks. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 US FDA, Ctr Food Safety & Appl Nutr, Washington, DC 20204 USA. Inst Oncol, Lhospitalet De Llobregat, Spain. NIEHS, Res Triangle Pk, NC 27709 USA. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 105-AGFD BP U36 EP U37 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200106 ER PT J AU Hernandez, S Nicklaus, MC Russ, P Rodgriguez, JB Habte, K Ford, H Marquez, VE AF Hernandez, S Nicklaus, MC Russ, P Rodgriguez, JB Habte, K Ford, H Marquez, VE TI Synthesis and evaluation of adenosine deaminase mediated hydrolysis of conformationally restricted bicyclo[3.1.0]hexane carbocyclic nucleosides: Efforts to improve the critical hydration step of the base. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 70-MEDI BP U548 EP U549 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202978 ER PT J AU Horkay, F Hecht, AM Geissler, E AF Horkay, F Hecht, AM Geissler, E TI Investigation of nanosize heterogeneities in polymer gels by small angle neutron scattering. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, CNRS, Spectrometrie Phys Lab, UMR 5588, Grenoble, France. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 132-COLL BP U245 EP U246 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091201268 ER PT J AU Horkay, F Tasaki, I Basser, PJ AF Horkay, F Tasaki, I Basser, PJ TI Volume transition of polyacrylate hydrogels induced by monovalent-divalent cation exchange in physiological salt solutions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NICHD, NIH, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 256-PMSE BP U366 EP U366 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091302121 ER PT J AU Jacobson, KA Li, AH Kim, HS Ji, XD AF Jacobson, KA Li, AH Kim, HS Ji, XD TI Pyran template approach to the design of G protein-coupled receptor antagonists. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDKD, Bioorgan Chem Lab, Ctr Mol Recognit, NIH, Bethesda, MD 20892 USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 263-MEDI BP U583 EP + PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203170 ER PT J AU Jacobson, KA King, BF Burnstock, G Harden, TK Boyer, JL AF Jacobson, KA King, BF Burnstock, G Harden, TK Boyer, JL TI Probing the binding sites of P2X and P2Y receptors: Selective antagonists and receptor structure. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. UCL Royal Free & Univ Coll, Sch Med, London, England. Univ N Carolina, Sch Med, Chapel Hill, NC USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 187-MEDI BP U569 EP U569 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203095 ER PT J AU Kim, YC Ji, XD Linden, J Jacobson, KA AF Kim, YC Ji, XD Linden, J Jacobson, KA TI Anilide derivatives of an 8-phenylxanthine carboxylic congener (XCC) are highly potent and selective antagonists at human A(2B) adenosine receptors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Univ Virginia, Dept Internal Med & Mol Physiol & Biol Phys, Charlottesville, VA USA. RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 128-MEDI BP U559 EP U559 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203036 ER PT J AU Lee, JW Lee, JY Marquez, VE Beheshti, M Szabo, T Blumberg, PM AF Lee, JW Lee, JY Marquez, VE Beheshti, M Szabo, T Blumberg, PM TI 3-Acyloxy-2-benzyl-propyl thiourea analogs of tetrahydrobenzazepine and tetrahydroisoquinoline as vanilloid receptor ligands. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Seoul Natl Univ, Coll Pharm, Med Chem Lab, Kwanak Ku, Seoul 151742, South Korea. NIH, Natl Canc Inst, Med Chem Lab, Bethesda, MD USA. NIH, Natl Canc Inst, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 244-MEDI BP U580 EP U580 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203151 ER PT J AU Levin, IW AF Levin, IW TI High fidelity vibrational spectroscopic imaging microscopy: Biological applications. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDKD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 282-CHED BP U174 EP U174 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200876 ER PT J AU Liu, DG Gao, Y Voigt, J Zhang, ZY Burke, TR AF Liu, DG Gao, Y Voigt, J Zhang, ZY Burke, TR TI Focused library approach to PTP inhibitor discovery predicated on the X-ray structure of PTP1B-bound lead compound. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 42-MEDI BP U544 EP U544 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202950 ER PT J AU Luo, HY Eberly, N Rogers, RD Brechbiel, MW AF Luo, HY Eberly, N Rogers, RD Brechbiel, MW TI Cis,cis-1,3,5-triaminocyclohexane-N,N ',N ''-triacetic acid (H3tachta) and its metal complexes. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Natl Canc Ctr, Chem Sect, Bethesda, MD 20892 USA. Univ Alabama, Ctr Green Manufacturing, Tuscaloosa, AL 35487 USA. RI Rogers, Robin/C-8265-2013 OI Rogers, Robin/0000-0001-9843-7494 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 387-INOR BP U510 EP U510 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202751 ER PT J AU Luzzio, FA Thomas, EM Figg, WD AF Luzzio, FA Thomas, EM Figg, WD TI Thalidomide analogs and metabolites: Cyclic and acyclic derivatives of 2S, 3S-2-N-phthalimido(3-hydroxy)ornithine. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Louisville, Louisville, KY 40292 USA. NCI, Med Branch, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 401-ORGN BP U96 EP U96 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300566 ER PT J AU Ma, JY Ziffer, H Kyle, DE AF Ma, JY Ziffer, H Kyle, DE TI Synthesis and antimalarial activities of 10-substituted deoxoartemisinin. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, NIDDK, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Div Expt Therapeut, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 92-MEDI BP U553 EP U553 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203000 ER PT J AU Maeda, DY Williams, W Kim, WE Bowen, WD Coop, A AF Maeda, DY Williams, W Kim, WE Bowen, WD Coop, A TI N-arylalkylpiperidines: High affinity sigma-1 and sigma-2 receptor ligands. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. NIDDK, Med Chem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 213-MEDI BP U574 EP U574 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203120 ER PT J AU Marquez, VE AF Marquez, VE TI Discovery of tiazole-4-carboxamide adenine dinucleotide (TAD) and recent synthetic approaches used in the construction of hydrolytically-resistant surrogates. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 20-CARB BP U111 EP U112 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200530 ER PT J AU McGrath, CF Gussio, R Zaharevitz, DW Sausville, EA AF McGrath, CF Gussio, R Zaharevitz, DW Sausville, EA TI Homology model for CDK5/p25. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Frederick Canc Res & Dev Ctr, NCI, SAIC, DTPCC, Ft Detrick, MD 21702 USA. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Informat Technol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 100-COMP BP U291 EP U291 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091201551 ER PT J AU Mirzadeh, S Kennel, SJ Brechbiel, MW AF Mirzadeh, S Kennel, SJ Brechbiel, MW TI In vivo radionuclide generators: Pb-212/Bi-212 and Ac-225/Bi-213 systems. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. NIH, Chem Sect, Radiat Oncol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 164-NUCL BP U27 EP U27 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300164 ER PT J AU Moon, HR Marquez, VE AF Moon, HR Marquez, VE TI Intramolecular cyclopropanation approach to chiral methanocarbocyclic adenine nucleosides. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Natl Canc Inst, Div Basic Sci, Med Chem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 111-ORGN BP U50 EP U50 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300277 ER PT J AU Moon, HR Habte, K Ford, H Marquez, VE AF Moon, HR Habte, K Ford, H Marquez, VE TI Intramolecular cyclopropanation approach to racemic methanocarbocyclic adenine nucleosides: Enzymatic resolution by adenosine deaminase. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Natl Canc Inst, Div Basic Sci, Med Chem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 110-ORGN BP U49 EP U50 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300276 ER PT J AU Mu, L Nicklaus, MC Marquez, VE AF Mu, L Nicklaus, MC Marquez, VE TI Ribose ring conformations: A 3D descriptor for the estimation of inhibition and catalytic activity of nucleosides and nucleotides. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Med Chem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 89-MEDI BP U552 EP U552 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202997 ER PT J AU Nicklaus, MC Oellien, F Ihlenfeldt, WD AF Nicklaus, MC Oellien, F Ihlenfeldt, WD TI Large chemical databases on the web: Enhanced CACTVS browser of the open NCI database. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Natl Canc Inst, Div Basic Sci, Med Chem Lab, Bethesda, MD 20892 USA. Univ Erlangen Nurnberg, Inst Organ Chem, Comp Chem Ctr, D-8520 Erlangen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 57-CINF BP U203 EP U203 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091201036 ER PT J AU O'Rourke, P AF O'Rourke, P TI Molecular medicine: A view of the future. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Off Sci Policy, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 10-CHAL BP U217 EP U217 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091201100 ER PT J AU Pais, GCG Neamati, N Pommier, Y Burke, TR AF Pais, GCG Neamati, N Pommier, Y Burke, TR TI 1,3-Diketo analogs as HIV integrase inhibitors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 82-MEDI BP U551 EP U551 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202990 ER PT J AU Peters, JM Park, Y Gonzalez, FJ Pariza, MW AF Peters, JM Park, Y Gonzalez, FJ Pariza, MW TI Influence of conjugated linoleic acid (CLA) in peroxisome proliferator-activated receptor alpha-null mice. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Penn State Univ, Dept Vet Sci, Ctr Mol Toxicol, University Pk, PA 16802 USA. Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. NCI, Met Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 24-AGFD BP U24 EP U25 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200025 ER PT J AU Rajendran, GR Ji, XD Melman, N Siddiqui, MA Li, AH Shin, KJ Marquez, VE Jocobson, KA AF Rajendran, GR Ji, XD Melman, N Siddiqui, MA Li, AH Shin, KJ Marquez, VE Jocobson, KA TI Methanocarba analogs of purine nucleosides as potent and selective adenosine receptor agonists. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, LBC, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 315-MEDI BP U592 EP U592 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203222 ER PT J AU Rodriguez, JB Comin, MJ Russ, P Marquez, VE AF Rodriguez, JB Comin, MJ Russ, P Marquez, VE TI Synthesis of 2 '-deoxyneplanocin C. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Quim Organ, RA-1428 Buenos Aires, DF, Argentina. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 276-MEDI BP U585 EP U585 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203183 ER PT J AU Russ, P Marquez, VE AF Russ, P Marquez, VE TI 5-Substituted derivatives of the potent antiherpes agent (North)methanocarba thymine. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Natl Canc Inst, Div Basic Sci, Med Chem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 91-MEDI BP U552 EP U553 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202999 ER PT J AU Sethi, ML Ford, H Roth, JS Agbaria, R Johns, DG Kelley, JA AF Sethi, ML Ford, H Roth, JS Agbaria, R Johns, DG Kelley, JA TI Analytical evaluation of a trace, bioactive constituent in lodenosine, a new anti-AIDS drug. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Ben Gurion Univ Negev, Dept Clin Pharmacol, IL-84105 Beer Sheva, Israel. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 31-ANYL BP U83 EP U83 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200358 ER PT J AU Sigano, DM Nacro, K Lewin, NE Blumberg, PM Marquez, VA AF Sigano, DM Nacro, K Lewin, NE Blumberg, PM Marquez, VA TI Effects of smaller, non-equivalent branched acyl chains in diacylglycerols (DAGs) on their log P and binding affinity for protein kinase C (PK-C). SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RI Sigano, Dina/M-6144-2014 OI Sigano, Dina/0000-0001-7489-9555 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 57-MEDI BP U546 EP U546 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091202965 ER PT J AU Spirtas, R AF Spirtas, R TI Harmonization of carcinogenicity classifications. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, NICHHD, Bethesda, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 22-CHAS BP U190 EP U190 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200975 ER PT J AU Tcherkasskaya, O Gronenborn, AM AF Tcherkasskaya, O Gronenborn, AM TI Modification of natural amino acids for the study of protein folding: Multi-site fluorescence energy transfer in protein GB1. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, LECB, NIH, Bethesda, MD 20892 USA. NIDDK, LCP, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 169-ORGN BP U58 EP U58 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300335 ER PT J AU Thomas, KW Sheldon, LS Steen, WC Sandler, DP Blair, A Dosemeci, M Alavanja, MCR AF Thomas, KW Sheldon, LS Steen, WC Sandler, DP Blair, A Dosemeci, M Alavanja, MCR TI Agricultural Health Study/pesticide exposure study design. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 US EPA, Natl Exposure Res Lab, Res Triangle Pk, NC 27711 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 53-AGRO BP U55 EP U55 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200206 ER PT J AU Ullrich, T Rice, KC AF Ullrich, T Rice, KC TI Practical synthesis of the serotonin 5-HT2A receptor antagonist MDL 100907 and MDL 105725, its precursor for [C-11]labeled PET ligands, based on optical resolution via formation of diastereomeric salts. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIDDK, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 111-MEDI BP U556 EP U556 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203019 ER PT J AU Voigt, JH Gao, Y Zhao, H Ford, H Nicklaus, MC Zhang, ZY Burke, TR AF Voigt, JH Gao, Y Zhao, H Ford, H Nicklaus, MC Zhang, ZY Burke, TR TI Exploration of novel ligand binding modes leading to potent small molecule bis-carboxy naphthalene PTP1B-inhibitors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 305-MEDI BP U590 EP U590 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203212 ER PT J AU Walters, D AF Walters, D TI Laboratory hoods, quo vadis? Past, present and future. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27607 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 8-CHAS BP U189 EP U189 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091200962 ER PT J AU Yordanov, AT Brechbiel, MW Yamada, K Krishna, MC Mitchell, JB AF Yordanov, AT Brechbiel, MW Yamada, K Krishna, MC Mitchell, JB TI Synthesis of TEMPO-functionalized G-6-PAMAM(TM)-dendrimers for in vivo EPR imaging. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Radioimmune & Inorgan Chem Sect, ROB,DCS, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 279-MEDI BP U585 EP U585 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203186 ER PT J AU Yordanov, AT Garmestani, K Nguyen, TT Pannu, YS Sung, C Dedrick, R Beitzel, MP Smith, AM Gansow, OA Oldfield, EH Brechbiel, MW AF Yordanov, AT Garmestani, K Nguyen, TT Pannu, YS Sung, C Dedrick, R Beitzel, MP Smith, AM Gansow, OA Oldfield, EH Brechbiel, MW TI Synthesis of novel BSA-iodopanoic acid conjugate as a computed tomography (CT) agent. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Radioimmune & Inorgan Chem Sect, ROB,DCS, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, Bethesda, MD USA. ORS, Bioengn & Phys Sci Program, Bethesda, MD USA. Lab Diagnost Radiol & Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 278-MEDI BP U585 EP U585 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203185 ER PT J AU Yordanov, AT Bryant, LH Linnoila, JJ Brechbiel, MW Frank, JA AF Yordanov, AT Bryant, LH Linnoila, JJ Brechbiel, MW Frank, JA TI First noncovalent calix[4]arene-Gd-albumin complex. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Radioimmune & Inorgan Chem Sect, ROB,DCS, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 252-MEDI BP U581 EP U581 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091203159 ER PT J AU Yuan, P King, BA Miller, MP Robinson, MR Grimes, GJ Daniels, CE Potti, GK AF Yuan, P King, BA Miller, MP Robinson, MR Grimes, GJ Daniels, CE Potti, GK TI Sustained release implants of triamcinolone acetonide for use in rat models of experimental uveitis and neovascularization. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIH, Bioengn & Phys Sci Program, OD, Bethesda, MD 20892 USA. NEI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 197-PMSE BP U357 EP U357 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091302062 ER PT J AU Zaharevitz, DW Holbeck, SL Bowerman, C Svetlik, PA AF Zaharevitz, DW Holbeck, SL Bowerman, C Svetlik, PA TI Compare: A web accessible tool for investigating mechanisms of cell growth inhibition. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, EPN, Dev Therapeut Program, Informat Technol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 23-COMP BP U280 EP U280 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XU UT WOS:000166091201474 ER PT J AU Zhang, XC Lee, YK Neamati, N Pommier, Y Burke, TR AF Zhang, XC Lee, YK Neamati, N Pommier, Y Burke, TR TI New, "indirect approach" to arylisothiocyanates and its application to the synthesis of potential irreversible HIV integrase inhibitors. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 81-ORGN BP U45 EP U45 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300247 ER PT J AU Zhurkin, VB Olson, WK Tolstorukov, MY Jernigan, RL AF Zhurkin, VB Olson, WK Tolstorukov, MY Jernigan, RL TI Dna-centric view of protein-DNA interactions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 NIH, NCI, Bethesda, MD 20892 USA. Rutgers State Univ, Dept Chem, Piscataway, NJ USA. RI Jernigan, Robert/A-5421-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 20 PY 2000 VL 220 MA 84-PHYS BP U168 EP U168 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 386XV UT WOS:000166091300903 ER PT J AU Orenstein, JM Bhat, N Yoder, C Fox, C Polis, MA Metcalf, JA Kovacs, JA Falloon, J Walker, RE Masur, H Lane, HC Davey, RT AF Orenstein, JM Bhat, N Yoder, C Fox, C Polis, MA Metcalf, JA Kovacs, JA Falloon, J Walker, RE Masur, H Lane, HC Davey, RT TI Rapid activation of lymph nodes and mononuclear cell HIV expression upon interrupting highly active antiretroviral therapy in patients after prolonged viral suppression SO AIDS LA English DT Article DE AIDS; HAART; HIV; immunohistochemistry; in-situ hybridization; lymph nodes ID IMMUNODEFICIENCY VIRUS-INFECTION; NUCLEOSIDE ANALOG THERAPY; INSITU HYBRIDIZATION; COMBINATION THERAPY; ANTIVIRAL THERAPY; T-CELLS; REPLICATION; PLASMA; RNA; DISCONTINUATION AB Objective: To compare the architecture and HIV-1 RNA and Gag p24 protein expression in lymph nodes (LN) excised from individuals during chronic highly active antiretroviral therapy (HAART) with LN removed from the same patient after plasma vi rus rebound following the interruption of HAART. Materials and methods: Six HIV-1-infected patients on HAART, with CD4 cell counts greater than 350 cells/mu l, and plasma HIV-1 RNA less than 50 copies/ml, underwent inguinal LN excision upon discontinuation of HAART, and again after rebound of plasma virus. Lymph nodes were evaluated by immunohistochemical staining for Gag p24 antigen and Ki67, in-situ hybridization for HIV-1 RNA and H3-histone, and transmission electron microscopy (TEM). Results: LN at baseline were quiescent to mildly hyperplastic and generally contained more primary than secondary follicles. Only one LN had detectable follicular dendritic cell (FDC)-associated p24 antigen, none had HIV RNA. Few mononuclear cells (MNC) expressed RNA or p24 antigen. Plasma virus at the second biopsy ranged from 329 to 3.2 x 10(6) copies/ml. CD4 cell count. decline ranged from 5 to 51% during drug hiatus, and was greatest in patients with highest viral rebound. Four of six of the second LN were more hyperplastic than the initial LN, two showed paracortical hyperplasia. MNC expression of HIV RNA in the second LN paralleled the level of plasma viremia. Increased Ki67 and H3-histone signal occurred in the second LN. Conclusion: Quiescent LN from individuals on HAART rapidly become hyperplastic and activated within 1-2 months after treatment interruption. As in acute HIV infection, virus expression by LN MNC parallels the rebound in plasma viremia and fall in CD4 cell count. (C) 2000 Lippincott Williams & Wilkins. C1 George Washington Univ Hosp, Dept Pathol, Washington, DC USA. NIAID, Lab Immunoregulat, Bethesda, MD 20892 USA. Warren G Magnuson Clin Ctr, Dept Crit Care Med, NIH, Bethesda, MD USA. Mol Histol Inc, Gaithersburg, MD USA. RP Orenstein, JM (reprint author), George Washington Univ, Dept Pathol, Med Ctr, Ross 502,2300 Eye St NW, Washington, DC 20037 USA. OI Polis, Michael/0000-0002-9151-2268 NR 39 TC 33 Z9 35 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 AUG 18 PY 2000 VL 14 IS 12 BP 1709 EP 1715 DI 10.1097/00002030-200008180-00004 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 348RN UT WOS:000089000400004 PM 10985306 ER PT J AU Bauer, H Mayer, H Marchler-Bauer, A Salzer, U Prohaska, R AF Bauer, H Mayer, H Marchler-Bauer, A Salzer, U Prohaska, R TI Characterization of p40/GPR69A as a peripheral membrane protein related to the lantibiotic synthetase component C SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE erythrocyte; G-protein-coupled receptor; GPR69A; lanthionine synthetase; lantibiotic; peptide antibody; peripheral membrane protein; proteolysis; red blood cell ID HUMAN ERYTHROCYTE-MEMBRANE; TISSUE-SPECIFIC EXPRESSION; MOLECULAR CHARACTERIZATION; COUPLED RECEPTOR; BIOSYNTHESIS; ALIGNMENT; PEPTIDES; COMPLEX AB The 40 kDa erythrocyte membrane protein p40/GPR69A, previously assigned to the G-protein-coupled receptor superfamily, was now identified by peptide-antibodies and characterized as a loosely associated peripheral membrane protein. This result is in striking contrast to the proposed seven-transmembrane protein structure and function and therefore we wish to correct our previous proposal. p40 is located at the cytoplasmic side of the membrane and is neither associated with the cytoskeleton nor lipid rafts. Refined sequence analysis revealed that p40 is related to the LanC family of bacterial membrane-associated proteins which are involved in the biosynthesis of antimicrobial peptides. Therefore, we rename p40 to LanC-like protein 1 (LANCL1) and suggest that it may play a similar role as a peptide-modifying enzyme component in eukaryotic cells, (C) 2000 Academic Press. C1 Univ Vienna, Inst Med Biochem, Dept Biochem, Vienna Bioctr, A-1030 Vienna, Austria. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Prohaska, R (reprint author), Univ Vienna, Inst Med Biochem, Dept Biochem, Vienna Bioctr, Dr Bohr Gasse 9-3, A-1030 Vienna, Austria. RI Marchler-Bauer, Aron/A-9681-2009; OI Marchler-Bauer, Aron/0000-0003-1516-0712 NR 19 TC 28 Z9 32 U1 1 U2 3 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 AUG 18 PY 2000 VL 275 IS 1 BP 69 EP 74 DI 10.1006/bbrc.2000.3260 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 347TU UT WOS:000088945900014 PM 10944443 ER PT J AU Ikura, T Ogryzko, VV Grigoriev, M Groisman, R Wang, J Horikoshi, M Scully, R Qin, J Nakatani, Y AF Ikura, T Ogryzko, VV Grigoriev, M Groisman, R Wang, J Horikoshi, M Scully, R Qin, J Nakatani, Y TI Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis SO CELL LA English DT Article ID GCN5-RELATED N-ACETYLTRANSFERASE; STRAND BREAK REPAIR; RUVB-LIKE PROTEIN; COENZYME-A; CRYSTAL-STRUCTURE; SUPERFAMILY; CHROMATIN; SWI/SNF; COACTIVATOR; COMPONENTS AB It is well known that histone acetylases are important chromatin modifiers and that they play a central role in chromatin transcription. Here, we present evidence for novel roles of histone acetylases. The TIP60 histone acetylase purifies as a multimeric protein complex. Besides histone acetylase activity on chromatin, the TIP60 complex possesses ATPase, DNA helicase, and structural DNA binding activities. Ectopic expression of mutated TIP60 lacking histone acetylase activity results in cells with defective double-strand DNA break repair. Importantly, the resulting cells lose their apoptotic competence, suggesting a defect in the cells' ability to signal the existence of DNA damage to the apoptotic machinery. These results indicate that the histone acetylase TIP60-containing complex plays a role in DNA repair and apoptosis. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Baylor Coll Med, Dept Biochem, Houston, TX 77030 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo 1130032, Japan. Japan Sci & Technol Corp, Exploratory Res Adv Technol, Horikoshi Gene Selector Project, Tsukuba, Ibaraki 3002635, Japan. RP Nakatani, Y (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. RI Scully, Ralph/F-5008-2013; Ogryzko, Vasily/M-6665-2015 OI Ogryzko, Vasily/0000-0002-8548-1389 FU NCI NIH HHS [K01 CA079576] NR 47 TC 704 Z9 730 U1 3 U2 33 PU CELL PRESS PI CAMBRIDGE PA 1050 MASSACHUSETTES AVE, CIRCULATION DEPT, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 18 PY 2000 VL 102 IS 4 BP 463 EP 473 DI 10.1016/S0092-8674(00)00051-9 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 347BX UT WOS:000088908000008 PM 10966108 ER PT J AU Johansson, J Balsalobre, C Wang, SY Urbonaviciene, J Jin, DJ Sonden, B Uhlin, BE AF Johansson, J Balsalobre, C Wang, SY Urbonaviciene, J Jin, DJ Sonden, B Uhlin, BE TI Nucleoid proteins stimulate stringently controlled bacterial promoters: A link between the cAMP-CRP and the (p)ppGpp regulons in Escherichia coli SO CELL LA English DT Article ID HISTONE-LIKE PROTEINS; GUANOSINE 5'-DIPHOSPHATE 3'-DIPHOSPHATE; H-NS; STATIONARY PHASE; GENE-EXPRESSION; PPGPP SYNTHESIS; RNA-POLYMERASE; DNA TOPOLOGY; INVITRO; COMPLEXES AB We report that the H-NS nucleoid protein plays a positive role in the expression of stringently regulated genes in Escherichia coli. Bacteria lacking both H-NS and the paralog StpA show reduced growth rate. Colonies displaying an increased growth rate were isolated, and mapping of a suppressor mutation revealed a base pair substitution in the spoT gene. The spoT(A404E) mutant showed low ppGpp synthesizing ability. The crp gene, which encodes the global regulator CRP, was subject to negative stringent regulation. The stable RNA/protein ratio in an hns, stpA strain was decreased, whereas it was restored in the suppressor strain. Our findings provide evidence of a direct link between the cAMP-CRP modulon and the stringent response. C1 Umea Univ, Dept Microbiol, S-90187 Umea, Sweden. NCI, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Umea Univ, Dept Microbiol, S-90187 Umea, Sweden. EM bernt.eric.uhlin@micro.umu.se RI Balsalobre, Carlos/E-4213-2016 OI Balsalobre, Carlos/0000-0002-4147-219X NR 53 TC 57 Z9 57 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 EI 1097-4172 J9 CELL JI Cell PD AUG 18 PY 2000 VL 102 IS 4 BP 475 EP 485 DI 10.1016/S0092-8674(00)00052-0 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 347BX UT WOS:000088908000009 PM 10966109 ER PT J AU Tong, HY Chen, WN Steenbergen, C Murphy, E AF Tong, HY Chen, WN Steenbergen, C Murphy, E TI Ischemic preconditioning activates phosphatidylinositol-3-kinase upstream of protein kinase C SO CIRCULATION RESEARCH LA English DT Article DE phosphatidylinositol 3-kinase; protein kinase C; nitric oxide; ischemic preconditioning ID RABBIT HEART; RAT-HEART; 3-KINASE; PROTECTION; INHIBITION; MECHANISM; CHANNELS; INSULIN; AKT; CARDIOPROTECTION AB The present study is designed to test whether phosphatidylinositol 3-kinase (PU-kinase) has a role in the signaling pathway in ischemic preconditioning (PC) and whether it is proximal or distal to protein kinase C (PKC). Before 20 minutes of global ischemia, Langendorff-perfuse rat hearts were perfused for 20 minutes (control); preconditioned with 4 cycles of ti-minute ischemia and 5-minute reflow (PC); treated with either wortmannin (WM) or LY 294002, (LY), each of which is a PU-kinase inhibitor, for 5 minutes before and throughout PC; treated with 1,2-dioctanoyl-sn-glycerol (DOG), an activator of PKC for 10 minutes (DOG); treated identically to the DOG group except with WM added 10 minutes before and during perfusion with DOG; or treated with either WM or LY for 25 minutes. Recovery of left ventricular developed pressure (LVDP; percentage of initial preischemic LVDP), measured after 30 minutes of reflow, was improved by PC (72+/-2% versus 36+/-4% in control; P<0.001), and this was blocked by WM and LY (41+/-4% and 33+/-5%, respectively; P<0.05 compared with PC). DOG addition improved postischemic LVDP (67+/-6%; P<0.001 compared with control), but in contrast to its effect on PC, WM did not completely eliminate the protective effect of DOG (52+/-4%; P>0.05 compared with DOG; P<0.05 compared with control). PC induced phosphorylation of ptotein kinase B and translocation of PKC epsilon, and it increased NO production, and these effects were blocked by WM, which suggests a role for P13-kinase in PC upstream of PKC and NO. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC USA. RP Tong, HY (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Mail Drop D2-03, Res Triangle Pk, NC 27709 USA. EM tong@niehs.nih.gov FU NHLBI NIH HHS [R01 HL039752, R01-HL-39752] NR 37 TC 252 Z9 263 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 18 PY 2000 VL 87 IS 4 BP 309 EP 315 PG 7 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 347WA UT WOS:000088951100010 PM 10948065 ER PT J AU Chen, Y McCarron, RM Ohara, Y Bembry, J Azzam, N Lenz, FA Shohami, E Mechoulam, R Spatz, M AF Chen, Y McCarron, RM Ohara, Y Bembry, J Azzam, N Lenz, FA Shohami, E Mechoulam, R Spatz, M TI Human brain capillary endothelium - 2-arachidonoglycerol (endocannabinoid) interacts with endothelin-1 SO CIRCULATION RESEARCH LA English DT Article DE brain endothelial function; 2-arachidonoglycerol; endothelin-1; endothelium; cannabinoids ID VASODILATOR-STIMULATED PHOSPHOPROTEIN; NITRIC-OXIDE; SIGNAL-TRANSDUCTION; ACTIN-FILAMENTS; CELLS; CA2+; 2-ARACHIDONOYLGLYCEROL; MOBILIZATION; INHIBITION; RECEPTORS AB In brain, the regulatory mechanism of the endothelial reactivity to nitric oxide and endothelin-l may involve Ca2+, cytoskeleton, and vasodilator-stimulated phosphoprotein changes mediated by the cGMP/cGMP kinase system.(1) Endothelium of human brain capillaries or microvessels is used to examine the interplay of endothelin-1 with the putative vasorelaxant 2-arachidonoyl glycerol, an endogenous cannabimimetic derivative of arachidonic acid. This study demonstrates that 2-arachidonoyl glycerol counteracts Ca2+ mobilization and cytoskeleton rearrangement induced by endothelin-1. This event is independent of nitric oxide, cyclooxygenase, and lipoxygenase and is mediated in part by cannabimimetic CB1 receptor, G protein, phosphoinositol signal transduction pathway, and Ca2+-activated K+ channels. The induced rearrangements of cellular cytoskeleton (actin or vimentin) are partly prevented by inhibition of protein kinase C or high levels of potassium chloride, The 2-arachidonoyl glycerol-induced phosphorylation of vasodilator-stimulated phosphoprotein is mediated by cAMP, These findings suggest that 2-arachidonoyl glycerol may contribute to the regulation of cerebral capillary and microvascular function. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. USN, Med Res Ctr, Bethesda, MD 20084 USA. Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD USA. Hebrew Univ Jerusalem, Jerusalem, Israel. RP Spatz, M (reprint author), NINDS, Stroke Branch, NIH, 36 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. EM spatzm@ninds.nih.gov FU NIDA NIH HHS [DA-09789] NR 28 TC 41 Z9 40 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 18 PY 2000 VL 87 IS 4 BP 323 EP 327 PG 5 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 347WA UT WOS:000088951100012 PM 10948067 ER PT J AU Weijer, C Emanuel, EJ AF Weijer, C Emanuel, EJ TI Ethics - Protecting communities in biomedical research SO SCIENCE LA English DT Article ID GUIDELINES C1 Dalhousie Univ, Dept Bioeth, Halifax, NS B3H 4H7, Canada. NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Weijer, C (reprint author), Dalhousie Univ, Dept Bioeth, Halifax, NS B3H 4H7, Canada. NR 17 TC 138 Z9 139 U1 1 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 AUG 18 PY 2000 VL 289 IS 5482 BP 1142 EP 1144 DI 10.1126/science.289.5482.1142 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 346JE UT WOS:000088866600020 PM 10970227 ER PT J AU Seder, RA Hill, AVS AF Seder, RA Hill, AVS TI Vaccines against intracellular infections requiring cellular immunity SO NATURE LA English DT Article ID MEMORY T-CELLS; IMMUNODEFICIENCY VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; IN-VIVO; PROTECTIVE IMMUNITY; INTERFERON-GAMMA; DNA VACCINATION; CPG MOTIFS; ANTIGEN; LYMPHOCYTES AB Vaccines against a variety of infectious diseases represent one of the great triumphs of medicine. The immune correlates of protection induced by most current vaccines seem to be mediated by long-lived humoral immune responses. By contrast, there are no currently available vaccines that are uniformly effective for diseases such as HIV, malaria and tuberculosis, in which the cellular immune response might be crucial in mediating protection. Here we examine the mechanisms by which long-lived cellular immune responses are generated and maintained in vivo. We then discuss current approaches for vaccination against diseases in which cellular immune responses are important for protection. C1 NIAID, Clin Immunol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Univ Oxford, John Radcliffe Hosp, Nuffield Dept Med, Inst Mol Med,Mol Immunol Grp, Oxford OX3 9DU, England. RP Seder, RA (reprint author), NIAID, Clin Immunol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RI HILL, Adrian/C-1306-2008 NR 47 TC 216 Z9 230 U1 1 U2 10 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 17 PY 2000 VL 406 IS 6797 BP 793 EP 798 DI 10.1038/35021239 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 344PH UT WOS:000088767700057 PM 10963610 ER PT J AU Cohen, JI AF Cohen, JI TI Epstein-Barr virus infection. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE; HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL-NERVOUS-SYSTEM; NON-HODGKINS-LYMPHOMA; ORGAN TRANSPLANT RECIPIENTS; ORAL HAIRY LEUKOPLAKIA; CYTOTOXIC T-CELLS; NASOPHARYNGEAL CARCINOMA; EPITHELIAL-CELLS; ACQUIRED IMMUNODEFICIENCY C1 NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIAID, Med Virol Sect, Clin Invest Lab, NIH, Bldg 10,Rm 11N214,10 Ctr Dr, Bethesda, MD 20892 USA. NR 103 TC 724 Z9 764 U1 6 U2 57 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 17 PY 2000 VL 343 IS 7 BP 481 EP 492 DI 10.1056/NEJM200008173430707 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 344FC UT WOS:000088747700007 PM 10944566 ER PT J AU Jin, SQ Zhao, HC Fan, FY Blanck, P Fan, WH Colchagie, AB Fornace, AJ Zhan, QM AF Jin, SQ Zhao, HC Fan, FY Blanck, P Fan, WH Colchagie, AB Fornace, AJ Zhan, QM TI BRCA1 activation of the GADD45 promoter SO ONCOGENE LA English DT Article DE GADD45; BRCA1; p53; gene regulation ID P53-REGULATED PROTEIN GADD45; MAMMARY EPITHELIAL-CELLS; DNA-DAMAGE; OVARIAN-CANCER; CYCLE CHECKPOINT; GENE-EXPRESSION; BREAST; P53; INDUCTION; GROWTH AB Breast cancer susceptibility gene BRCA1 has been implicated in the control of gene regulation and such regulated genes are thought to mediate the biological role of BRCA1. Overexpression of BRCA1 induces GADD45, a p53-regulated and stress-inducible gene. However, the molecular mechanism by which BRCA1 induces the expression GADD45 remains unclear. In this report, we have shown that the GADD45 promoter is strongly activated following expression of wild-type BRCA1, In contrast, both the tumor-derived BRCA1 mutants (p1749R and Y1853insA) and truncated BRCA1 mutant protein (Delta 500-1863 BRCA1), which lack transactivation activity, were unable to activate the GADD45 promoter, indicating that the BRCA1-mediated activation of the GADD45 promoter requires normal transcriptional properties of BRCA1. BRCA1 did not induce the c-Jun and c-fos promoters, which rules out a general effect of BRCA1 on other immediate-responsive genes. Expression of the human papillomavirus E6 and the dominant-negative mutant p53 proteins had no effect on the induction of the GADD45 promoter by BRCA1, suggesting that activation of the GADD45 promoter by BRCA1 is independent of cellular p53 function. With the 5'-deletion analysis, the BRCA1-responsive element of the GADD45 promoter was mapped at the region from -121 to -75. Disruption of this region resulted in the abrogation of BRCA1 activation of the GADD45 promoter. Taken together, these results demonstrate that the mechanism by which BRCA1 induces GADD45 is mainly through the transactivation of the GADD45 promoter, further demonstrating the evidence that GADD45 acts as one of the BRCA1-regulated genes. C1 Univ Pittsburgh, Sch Med, Inst Canc, Dept Radiat Oncol, Pittsburgh, PA 15213 USA. NCI, Gene Response Sect, DBS, NIH, Bethesda, MD 20892 USA. RP Zhan, QM (reprint author), Univ Pittsburgh, Sch Med, Inst Canc, Dept Radiat Oncol, BST W-945,200 Lothrop St, Pittsburgh, PA 15213 USA. RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 38 TC 76 Z9 80 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 17 PY 2000 VL 19 IS 35 BP 4050 EP 4057 DI 10.1038/sj.onc.1203759 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 345PX UT WOS:000088825300011 PM 10962562 ER PT J AU Marcus, PM Bergstralh, EJ Fagerstrom, RM Williams, DE Fontana, R Taylor, WF Prorok, PC AF Marcus, PM Bergstralh, EJ Fagerstrom, RM Williams, DE Fontana, R Taylor, WF Prorok, PC TI Lung cancer mortality in the Mayo Lung Project: Impact of extended follow-up SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ISSUES; TRIALS; DESIGN AB Background: The Mayo Lung Project (MLP) was a randomized, controlled clinical trial of lung cancer screening that was conducted in 9211 male smokers between 1971 and 1983. The intervention arm was offered chest x-ray and sputum cytology every 4 months for 6 years; the usual-care arm was advised at trial entry to receive the same tests annually. No lung cancer mortality benefit was evident at the end of the study. We have extended follow-up through 1996, Methods: A National Death Index-PLUS search was used to assign vital status and date and cause of death for 6523 participants with unknown information. The median survival for lung cancer patients diagnosed before July 1, 1983, was calculated by use of Kaplan-Meier estimates. Survival curves were compared with the log-rank test. Results: The median followup time was 20.5 years. Lung cancer mortality was 4.4 (95% confidence interval [CI] = 3.9-4.9) deaths per 1000 person-years in the intervention arm and 3.9 (95% CI = 3.5-4.4) in the usual-care arm (two-sided P for difference = .09), For participants diagnosed with lung cancer before July 1, 1983, survival was better in the intervention arm (two-sided P = .0039). The median survival for patients with resected early-stage disease was 16.0 years in the intervention arm versus 5.0 years in the usual-care arm. Conclusions: Extended follow-up of MLP participants did not reveal a lung cancer mortality reduction for the intervention arm. Similar mortality but better survival for individuals in the intervention arm indicates that some lesions with limited clinical relevance may have been identified in the intervention arm. C1 NIH, Bethesda, MD 20892 USA. RP Marcus, PM (reprint author), NIH, 6130 Execut Blvd,MSC 7345,Suite 344, Bethesda, MD 20892 USA. NR 31 TC 330 Z9 340 U1 3 U2 12 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 AUG 16 PY 2000 VL 92 IS 16 BP 1308 EP 1316 DI 10.1093/jnci/92.16.1308 PG 9 WC Oncology SC Oncology GA 345CD UT WOS:000088797100010 PM 10944552 ER PT J AU Kammula, US Marincola, FM Rosenberg, SA AF Kammula, US Marincola, FM Rosenberg, SA TI Real-time quantitative polymerase chain reaction assessment of immune reactivity in melanoma patients after tumor peptide vaccination SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CANCER REGRESSION ANTIGENS; IN-VITRO STIMULATION; CD8(+) T-CELLS; PERIPHERAL-BLOOD; INFILTRATING LYMPHOCYTES; SYNTHETIC PEPTIDES; ELISPOT ASSAY; FREQUENCY; IDENTIFICATION; IMMUNIZATION AB Background: Monitoring the immune response to epitope-specific vaccination in cancer patients is important for vaccine development. The traditional method, in which the in vitro sensitization of peripheral blood mononuclear cells (PBMCs) with epitope is compared before and after vaccination, is time-consuming and allows only a qualitative assessment of the response, We used a rapid, quantitative, realtime polymerase chain reaction (PCR) assay to directly measure the immune reactivity of patients' PBMCs to the vaccine epitope, Methods: PBMCs were obtained from melanoma patients before and after two rounds of vaccination with either g209-2M, a peptide derived from melanoma protein gp100 (n = 24), or ESg209-2M, a modified version of this peptide (n = 20), PBMCs were tested for immune reactivity by assaying interferon gamma (IFN gamma) protein release after in vitro sensitization with the epitope or for IFN gamma messenger RNA expression by real-time PCR, A twofold or more increase in IFN gamma protein release or a 1.5-fold or more increase in IFN gamma transcript accumulation in PBMCs after vaccination was considered to be evidence of a specific response. Correlation between the two methods was tested by use of the Spearman correlation coefficient after the results were ranked as positive or negative. All statistical tests were two-sided. Results: The results obtained with the two methods were strongly correlated (Spearman's rho = 0.72; P = .0006). The g209-2M and Esg209-2M peptides resulted in similar percentages of vaccine-specific reactivity in PBMCs after in vitro sensitization (63% and 65% of patients, respectively; Fisher's exact test P = .6 for comparison of the two groups). The PCR method could detect vaccine-specific reactivity in a subset of patients (38% and 35% of patients, respectively; Fisher's exact test P = .7 for comparison of the two groups). Conclusion: Vaccination induces circulating antitumor lymphocytes, albeit in low frequencies, capable of directly reacting with tumor antigen. PBMCs of vaccinated individuals can respond to a vaccine-specific stimulus in a direct assay that does not require prolonged irt vitro manipulations. C1 NCI, Div Clin Sci, Surg Branch, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Bldg 10,Rm R-2B56,10 Ctr Dr, Bethesda, MD 20892 USA. NR 25 TC 81 Z9 84 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 AUG 16 PY 2000 VL 92 IS 16 BP 1336 EP 1344 DI 10.1093/jnci/92.16.1336 PG 9 WC Oncology SC Oncology GA 345CD UT WOS:000088797100014 PM 10944556 ER PT J AU Sinha, R Gustafson, DR Kulldorff, M Wen, WQ Cerhan, JR Zheng, W AF Sinha, R Gustafson, DR Kulldorff, M Wen, WQ Cerhan, JR Zheng, W TI 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, a carcinogen in high-temperature-cooked meat, and breast cancer risk SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HETEROCYCLIC AMINE CONTENT; MAMMARY CARCINOMAS; VARYING DEGREES; FRIED MEAT; WELL-DONE; COOKING; MUTAGEN; FOODS; BEEF; INDUCTION C1 NCI, Nutrit Epidemiol Branch, Div Canc Epidemiol, Bethesda, MD 20892 USA. Utah State Univ, Dept Nutr & Food Sci, Logan, UT 84322 USA. Univ Connecticut, Sch Med, Div Biostat, Dept Community Med & Hlth Care, Farmington, CT USA. Univ S Carolina, Sch Publ Hlth, S Carolina Sch, Ctr Canc, Columbia, SC 29208 USA. Mayo Clin, Rochester, MN USA. RP Sinha, R (reprint author), NIH, 6120 Execut Blvd,Rm 7028, 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 21 TC 132 Z9 134 U1 0 U2 7 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 AUG 16 PY 2000 VL 92 IS 16 BP 1352 EP 1354 DI 10.1093/jnci/92.16.1352 PG 3 WC Oncology SC Oncology GA 345CD UT WOS:000088797100016 PM 10944558 ER PT J AU Austin, MA Rodriguez, BL McKnight, B McNeely, MJ Edwards, KL Curb, JD Sharp, DS AF Austin, MA Rodriguez, BL McKnight, B McNeely, MJ Edwards, KL Curb, JD Sharp, DS TI Low-density lipoprotein particle size, triglycerides, and high-density lipoprotein cholesterol as risk factors for coronary heart disease in older Japanese-American men SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID INSULIN-RESISTANCE SYNDROME; LDL SUBCLASS PHENOTYPES; MYOCARDIAL-INFARCTION; ELDERLY MEN; WOMEN; PLASMA; ASCERTAINMENT; PROGRAM AB Decreased low-density lipoprotein (LDL) particle size is associated with coronary heart disease (CHD) risk among middle-aged Caucasian populations, and has been consistently correlated with increased plasma levels of triglyceride and decreased levels of high-density lipoprotein (HDL) cholesterol. This study examines whether these risk factors predict CHD among older Japanese-American men. With use of the Honolulu Heart Program Lipoprotein from 3 (1980 to 1982) as baseline, and 12-year follow-up for CHD events, a nested, case-control study was designed. One hundred forty-five incident CHD cases were identified and matched to 2 controls each. LDL particle diameter (size) was determined by gradient gel electrophoresis, A 10-angstrom (Angstrom) decrease in LDL size at baseline was associated with increased risk of incident CHD (relative risk 1.28, 95% confidence interval 1.01 to 1.63), After adjustment for baseline risk factors, the LDL size association was no longer statistically significant (relative risk 1.13, 95% confidence interval 0.86 to 1.49). When principal components analysis was used to define a composite variable for LDL size, triglycerides, and HDL cholesterol, this component predicted CHD independent of smoking, alcohol consumption, physical activity, body mass index, hypertension, diabetes, and beta-blocker use (p <0.01), Therefore, this prospective analysis of data from older, Japanese-American men demonstrated that decreased LDL size is a univariate predictor of incident CHD, and that a composite risk factor of LDL size, triglyceride, and HDL cholesterol was a risk factor for CHD independent of other risk factors. (C)2000 by Excerpta Medico, Inc. C1 Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA. Univ Hawaii Manoa, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Biostat, Seattle, WA 98195 USA. Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. NHLBI, Epidemiol & Biometry Branch, NIH, Bethesda, MD 20892 USA. RP Austin, MA (reprint author), Univ Washington, Sch Publ Hlth & Community Med, Box 357236,1959 NE Pacific Ave, Seattle, WA 98195 USA. FU NHLBI NIH HHS [R01 HL50268] NR 30 TC 81 Z9 85 U1 1 U2 5 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 15 PY 2000 VL 86 IS 4 BP 412 EP 416 DI 10.1016/S0002-9149(00)00956-5 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 344FP UT WOS:000088748800009 PM 10946034 ER PT J AU Carney, PA Geller, BM Moffett, H Ganger, M Sewell, M Barlow, WE Stalnaker, N Teplin, SH Sisk, C Ernster, VL Wilkie, HA Yankaskas, B Poplack, SP Urban, N West, MM Rosenberg, RD Michael, S Mercurio, TD Ballard-Barbash, R AF Carney, PA Geller, BM Moffett, H Ganger, M Sewell, M Barlow, WE Stalnaker, N Teplin, SH Sisk, C Ernster, VL Wilkie, HA Yankaskas, B Poplack, SP Urban, N West, MM Rosenberg, RD Michael, S Mercurio, TD Ballard-Barbash, R TI Current medicolegal and confidentiality issues in large, multicenter research programs SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE confidentiality; liability, legal; privacy ID BREAST-CANCER; INFORMATION AGE; PRIVACY; POPULATION; PROTECTION; OUTCOMES; DATABASE; LAW AB The convenience of fast computers and the Internet have encouraged large collaborative research efforts by allowing transfers of data from multiple sites to a single data repository; however, standards for managing data security are needed to protect the confidentiality of participants. Through Dartmouth Medical School, in 1996-1998, the authors conducted a medicolegal analysis of federal laws, state statutes, and institutional policies in eight states and three different types of health care settings, which are part of a breast cancer surveillance consortium contributing data electronically to a centralized data repository. They learned that a variety of state and federal laws are available to protect confidentiality of professional and lay research participants. The strongest protection available is the Federal Certificate of Confidentiality, which supersedes state statutory protection, has been tested in court, and extends protection from forced disclosure (in litigation) to health care providers as well as patients. This paper describes the careful planning necessary to ensure adequate legal protection and data security, which must include a comprehensive understanding of state and federal protections applicable to medical research. Researchers must also develop rules or guidelines to ensure appropriate collection, use, and sharing of data. Finally, systems for the storage of both paper and electronic records must be as secure as possible. C1 Dartmouth Med Sch, Norris Cotton Canc Ctr, Dartmouth Hitchcock Med Ctr, Dept Community & Family Med, Lebanon, NH 03756 USA. Univ Vermont, Coll Med, Off Hlth Promot Res, Burlington, VT USA. Orr & Reno Profess Assoc, Concord, NH USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. Univ Vermont, Off Sponsored Programs, Burlington, VT USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Iowa, Coll Med, Dept Prevent Med, Iowa City, IA USA. Univ New Mexico, Dept Radiol, Albuquerque, NM 87131 USA. Colorado Dept Publ Hlth & Environm, Canc Prevent & Control Program, Denver, CO USA. NCI, Appl Res Branch, Canc Control Program, Bethesda, MD 20892 USA. RP Carney, PA (reprint author), Dartmouth Med Sch, Norris Cotton Canc Ctr, Dartmouth Hitchcock Med Ctr, Dept Community & Family Med, 1 Med Ctr Dr,HB 7925, Lebanon, NH 03756 USA. NR 21 TC 61 Z9 61 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2000 VL 152 IS 4 BP 371 EP 378 DI 10.1093/aje/152.4.371 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 345RV UT WOS:000088829700009 PM 10968382 ER PT J AU Arioglu, E Duncan-Morin, J Sebring, N Rother, KI Gottlieb, N Lieberman, J Herion, D Kleiner, DE Reynolds, J Premkumar, A Sumner, AE Hoofnagle, J Reitman, ML Taylor, SI AF Arioglu, E Duncan-Morin, J Sebring, N Rother, KI Gottlieb, N Lieberman, J Herion, D Kleiner, DE Reynolds, J Premkumar, A Sumner, AE Hoofnagle, J Reitman, ML Taylor, SI TI Efficacy and safety of troglitazone in the treatment of lipodystrophy syndromes SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CONGENITAL GENERALIZED LIPODYSTROPHY; TYPE-2 DIABETES-MELLITUS; BODY-FAT DISTRIBUTION; ADIPOSE-TISSUE MASS; INSULIN-RESISTANCE; INDIRECT CALORIMETRY; OBESITY; GENE; THIAZOLIDINEDIONES; TRIGLYCERIDE AB Background: Troglitazone promotes adipocyte differentiation in vitro and increases insulin sensitivity in vivo. Therefore, troglitazone may have therapeutic benefit in lipoatrophic diabetes. Objective: To determine whether troglitazone ameliorates hyperglycemia and hypertriglyceridemia or increases fat mass in lipoatrophic patients. Design: Open-labeled prospective study. Setting: United States and Canada. Patients: 20 patients with various syndromes associated with lipoatrophy or lipodystrophy. Intervention: 6 months of therapy with troglitazone, 200 to 600 mg/d. Measurements: Levels of hemoglobin A(1c), triglycerides, free fatty acids, and insulin; respiratory quotient; percentage of body fat; liver volume; and regional fat mass. Results: In the 13 patients with diabetes who completed 6 months of troglitazone therapy, hemoglobin A(1c) levels decreased by a mean of 2.8% (95% CI, 1.9% to 3.7%; P < 0.001). In all 19 study patients, fasting triglyceride levels decreased by 2.6 mmol/L (230 mg/dL) (CI, 0.7 to 4.5 mmol/L [62 to 398 mg/dL] P = 0.019) and free fatty acid levels decreased by 325 mu mol/L (CI, 135 to 515 mu mol/L; P = 0.035). The respiratory quotient decreased by a mean of 0.12 (CI, 0.08 to 0.16; P < 0.001), suggesting that troglitazone promoted oxidation of fat. Body fat increased by a mean of 2.4 percentage points (CI, 1.3 to 4.5 percentage points; P = 0.044). Magnetic resonance imaging showed an increase in subcutaneous adipose tissue but not in visceral fat. In one patient, the serum alanine aminotransferase level increased eightfold during the 10th months of troglitazone treatment but normalized 3 months after discontinuation of treatment. Liver biopsy revealed an eosinophilic infiltrate, suggesting hypersensitivity reaction as a cause of hepatotoxicity. Conclusion: Troglitazone therapy improved metabolic control and increased body fat in patients with lipoatrophic diabetes. The substantial benefits of troglitazone must be balanced against the risk for hepatotoxicity, which can occur relatively late in the treatment course. C1 NIH, Ctr Clin, Bethesda, MD 20892 USA. NIDDKD, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. RP Arioglu, E (reprint author), NIH, Ctr Clin, Bldg 10,Room 9S213, Bethesda, MD 20892 USA. RI Reitman, Marc/B-4448-2013; OI Reitman, Marc/0000-0002-0426-9475; Oral, Elif/0000-0002-9171-1144; Kleiner, David/0000-0003-3442-4453 NR 54 TC 197 Z9 202 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 15 PY 2000 VL 133 IS 4 BP 263 EP 274 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 346NG UT WOS:000088877500003 PM 10929166 ER PT J AU Abraham, J Fojo, T Wood, BJ AF Abraham, J Fojo, T Wood, BJ TI Radiofrequency ablation of metastatic lesions in adrenocortical cancer SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID LIVER METASTASES; TISSUE ABLATION; EXPERIENCE; CARCINOMA C1 NIH, Bethesda, MD 20892 USA. RP Abraham, J (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 24 Z9 25 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 AUG 15 PY 2000 VL 133 IS 4 BP 312 EP 313 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 346NG UT WOS:000088877500021 PM 10929185 ER PT J AU Mansur, DB Hao, HL Gladyshev, VN Korotkov, KV Hu, YJ Moustafa, ME El-Saadani, MA Carlson, BA Hatfield, DL Diamond, AM AF Mansur, DB Hao, HL Gladyshev, VN Korotkov, KV Hu, YJ Moustafa, ME El-Saadani, MA Carlson, BA Hatfield, DL Diamond, AM TI Multiple levels of regulation of selenoprotein biosynthesis revealed from the analysis of human glioma cell lines SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE glioma; glutathione peroxidase; selenium; selenocysteine; selenoprotein; tRNA ID SELENOCYSTEINE TRANSFER RNASEC; GLUTATHIONE-PEROXIDASE EXPRESSION; THIOREDOXIN REDUCTASE-ACTIVITY; HAMSTER OVARY CELLS; DIETARY SELENIUM; CANCER MORTALITY; SERUM SELENIUM; TRANSFER-RNA; RISK; RAT AB To gain a better understanding of the biological consequences of the exposure of tumor cells to selenium, we evaluated the selenium-dependent responses of two selenoproteins (glutathione peroxidase and the recently characterized 15-kDa selenoprotein) in three human glioma cell lines. Protein levels, mRNA levels, and the relative distribution of the two selenocysteine tRNA isoacceptors (designated mcm(5)U and mcm(5)Um) were determined for standard as well as selenium-supplemented conditions. The human malignant glioma cell lines D54, U251, and U87 were maintained in normal or selenium-supplemented (30 nM sodium selenite) conditions. Northern blot analysis demonstrated only minor increases in steady-state GSHPx-1 mRNA in response to selenium addition. Baseline glutathione peroxidase activity was 10.7 +/- 0.7, 7.6 +/- 0.7, and 4.1 +/- 0.7 nmol NADPH oxidized/min/mg protein for D54, U251, and U87, respectively, as determined by the standard coupled spectrophotometric assay. Glutathione peroxidase activity increased in a cell line-specific manner to 19.7 +/- 1.4, 15.6 +/- 2.1, and 6.7 +/- 0.5 nmol NADPH oxidized/min/mg protein, respectively, as did a proportional increase in cellular resistance to H2O2, in response to added selenium. The 15-kDa selenoprotein mRNA levels likewise remained constant despite selenium supplementation. The selenium-dependent change in distribution between the two selenocysteine tRNA isoacceptors also occurred in a cell line-specific manner. The percentage of the methylated isoacceptor, mcm(5)Um, changed from 35.5 to 47.2 for D54, from 38.1 to 47.3 for U251, and from 49.0 to 47.6 for U87. These data represent the first time that selenium-dependent changes in selenoprotein mRNA and protein levels, as well as selenocysteine tRNA distribution, were examined in human glioma cell lines. BIOCHEM PHARMACOL 60;4:489-497, 2000. (C) 2000 Elsevier Science Inc. C1 Univ Illinois, Dept Human Nutr & Dietet, Chicago, IL 60612 USA. Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. NCI, Sect Mol Biol Selenium, Basic Res Lab, NIH, Bethesda, MD 20892 USA. Univ Alexandria, Fac Sci, Dept Biochem, Alexandria, Egypt. RP Diamond, AM (reprint author), Univ Illinois, Dept Human Nutr & Dietet, 1919 W Taylor St,MC 517, Chicago, IL 60612 USA. RI Gladyshev, Vadim/A-9894-2013 FU NCI NIH HHS [R01CA81153] NR 43 TC 10 Z9 10 U1 0 U2 1 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 AUG 15 PY 2000 VL 60 IS 4 BP 489 EP 497 DI 10.1016/S0006-2952(00)00366-X PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 335GE UT WOS:000088235100004 PM 10874123 ER PT J AU Kamal, MA Greig, NH Alhomida, AS Al-Jafari, AA AF Kamal, MA Greig, NH Alhomida, AS Al-Jafari, AA TI Kinetics of human acetylcholinesterase inhibition by the novel experimental Alzheimer therapeutic agent, tolserine SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE acetylcholinesterase; Alzheimer's disease; inhibition; kinetics; novel; tolserine ID HUMAN ERYTHROCYTE ACETYLCHOLINESTERASE; 14-UNIT T-MAZE; CHOLINERGIC SYSTEM; DISEASE; PHYSOSTIGMINE; PHENSERINE; TACRINE; RATS; CHOLINESTERASE; IMPAIRMENT AB Characterization of the: kinetic parameters of tolserine, a novel acetylcholinesterase (AChE) inhibitor of potential in the therapy of Alzheimer's disease, to inhibit purified human erythrocyte AChE was undertaken for the first time. An IC50 value was estimated by three methods. Its mean value was found to be 8.13 nM, whereas the IC100 was observed to be 25.5 nM as calculated by single graphical method. The Michaelis-Menten constant (K-m) for the hydrolysis of the substrate acetylthiocholine iodide was found to be 0.08 mM. Dixon as well as Lineweaver-Burk plots and their secondary replots indicated that the nature of the inhibition was of the partial non-competitive type. The value of K-i was estimated as 4.69 nM by the primary and secondary replots of the Dixon as well as secondary replots of the Lineweaver-Burk plot. Four new kinetic constants were also investigated by polynomial regression analysis of the relationship between the apparent K-i (K-Iapp) and substrate concentration, which may open new avenues for the kinetic study of the inhibition of several enzymes by a wide variety of inhibitors in vitro. Tolserine proved to be a highly potent inhibitor of human AChE compared to its structural analogues physostigmine and phenserine. BIOCHEM PHARMACOL 60;41:561-570, 2000. (C) 2000 Elsevier Science Inc. C1 King Saud Univ, Coll Sci, Dept Biochem, Riyadh 11451, Saudi Arabia. NIA, NIH, Baltimore, MD 21224 USA. RP Al-Jafari, AA (reprint author), King Saud Univ, Coll Sci, Dept Biochem, POB 2455, Riyadh 11451, Saudi Arabia. RI Kamal, Mohammad/H-9643-2012; Kamal, Mohammad/J-4622-2013; OI Kamal, Mohammad/0000-0003-1862-173X; Kamal, Mohammad Amjad/0000-0003-0088-0565 NR 48 TC 28 Z9 30 U1 2 U2 11 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 AUG 15 PY 2000 VL 60 IS 4 BP 561 EP 570 DI 10.1016/S0006-2952(00)00330-0 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 335GE UT WOS:000088235100012 PM 10874131 ER PT J AU Akin, C Schwartz, LB Kitoh, T Obayashi, H Worobec, AS Scott, LM Metcalfe, DD AF Akin, C Schwartz, LB Kitoh, T Obayashi, H Worobec, AS Scott, LM Metcalfe, DD TI Soluble stem cell factor receptor (CD117) and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mastocytosis: relationships to disease severity and bone marrow pathology SO BLOOD LA English DT Article ID SYSTEMIC LUPUS-ERYTHEMATOSUS; BLOOD MONONUCLEAR-CELLS; C-KIT RECEPTOR; INTERLEUKIN-2 RECEPTOR; SERUM LEVELS; RHEUMATOID-ARTHRITIS; CATALYTIC DOMAIN; APLASTIC-ANEMIA; MESSENGER-RNA; TAC PEPTIDE AB Systemic mastocytosis is a disease of mast cell proliferation that may be associated with hematologic disorders, There are no features on examination that allow the diagnosis of systemic disease, and mast cell-derived mediators, which may be elevated in urine or blood, may also be elevated in individuals with severe allergic disorders. Thus, the diagnosis usually depends on results of bone marrow biopsy. To facilitate evaluation, surrogate markers of the extent and severity of the disease are needed. Because of the association of mastocytosis with hematologic disease, plasma levels were measured for soluble KIT (sKIT) and soluble interleukin-2 receptor alpha chain (sCD25), which are known to be cleaved in part from the mast cell surface and are elevated in some hematologic malignancies, Results revealed that levels of both soluble receptors are increased in systemic mastocytosis. Median plasma sKIT concentrations as expressed by AU/mL (1 AU =1.4 ng/ mt) were as follows: controls, 176 (n = 60); urticaria pigmentosa without systemic involvement, 194 (n = 8); systemic indolent mastocytosis, 511 (n = 30); systemic mastocytosis with an associated hematologic disorder, 1320 (n = 7); aggressive mastocytosis, 3390 (n = 3), Plasma sCD25 levels were elevated in systemic mastocytosis; the highest revels were associated with extensive bone marrow involvement. Levels of sKIT correlated with total tryptase levels, sCD25 levels, and bone marrow pathology These results demonstrate that sKIT and sCD25 are useful surrogate markers of disease severity in patients with mastocytosis and should aid in diagnosis, in the selection of those needing a bone marrow biopsy, and in the documentation of disease progression. (Blood. 2000;96: 1267-1273) (C) 2000 by The American Society of Hematology. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Richmond, VA USA. Nichirei Corp, Tokyo, Japan. RP Akin, C (reprint author), NIAID, Lab Allerg Dis, NIH, Room 11C205,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. NR 45 TC 46 Z9 49 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2000 VL 96 IS 4 BP 1267 EP 1273 PG 7 WC Hematology SC Hematology GA 358VQ UT WOS:000089578200010 PM 10942367 ER PT J AU Chinnasamy, D Chinnasamy, N Enriquez, MJ Otsu, M Morgan, RA Candotti, F AF Chinnasamy, D Chinnasamy, N Enriquez, MJ Otsu, M Morgan, RA Candotti, F TI Lentiviral-mediated gene transfer into human lymphocytes: role of HIV-1 accessory proteins SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROVIRAL DNA-SYNTHESIS; PERIPHERAL-BLOOD LYMPHOCYTES; CD4(+) T-CELLS; IN-VIVO; NUCLEAR-LOCALIZATION; MONONUCLEAR-CELLS; RETROVIRAL VECTOR; NONDIVIDING CELLS; TYPE-1 PARTICLES AB Resting lymphocytes are refractory to gene transfer using Moloney murine leukemia virus (MMLV)-based retroviral vectors because of their quiescent status, Recently, it has been shown that lentiviral Vectors are capable of transferring genes into nondividing and terminally differentiated cells, We used human immunodeficiency virus type-1 (HIV-1)-based vectors expressing enhanced green fluorescent protein (EGFP) driven by different promoters (CMV, MPSV, or PGK) and investigated their ability to transduce human T- and B-cell lines, as well as resting or activated primary peripheral and umbilical cord blood lymphocytes, The effects of the presence or the absence of HIV-I accessory proteins (Vif, Vpr, Vpu, and Nef) in the vector system were also assessed, Flow cytometry analysis showed no differences in the ability of these vectors of transferring the reporter gene into lymphocytic lines and mitogen-stimulated primary lymphocytes in the presence or the absence of HIV-1 accessory proteins (APs), Similarly, viral supernatants generated in the presence of accessory genes could efficiently transduce various subsets of resting lymphocytes and provide long-term expression of the transgene, No significant transduction-induced changes in cell activation or cycling status were observed and Alu-HIV-1 long terminal repeat polymerase chain reaction (LTR PCR) analysis demonstrated integration of the vector sequences at the molecular level. In contrast, in the absence of HIV-1 APs, lentiviral vectors failed to integrate and express the transgene in resting lymphocytes, These results show that transduction of primary resting lymphocytes with HIV-1-based vectors requires the presence of viral accessory proteins.(Blood. 2000;96:1309-1316) (C) 2000 by The American Society of Hematology. C1 NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Candotti, F (reprint author), NHGRI, Clin Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. OI Otsu, Makoto/0000-0002-9769-0217 NR 53 TC 71 Z9 74 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2000 VL 96 IS 4 BP 1309 EP 1316 PG 8 WC Hematology SC Hematology GA 358VQ UT WOS:000089578200016 PM 10942372 ER PT J AU Aoki, Y Yarchoan, R Braun, J Iwamoto, A Tosato, G AF Aoki, Y Yarchoan, R Braun, J Iwamoto, A Tosato, G TI Viral and cellular cytokines in AIDS-related malignant lymphomatous effusions SO BLOOD LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; INTERLEUKIN-6; VIRUS; GROWTH; CELLS; HEMATOPOIESIS; EXPRESSION; RECEPTOR; HOMOLOG; ENCODES AB Kaposi sarcoma-associated herpesvirus encodes Viral IL-6 (vIL-6). To investigate the potential role of vIL-6 in the pathogenesis of human immunodeficiency virus (HIV)related primary effusion lymphomas (PEL), a sensitive enzyme-linked immunosorbent assay was developed for vIL-6 and applied to the study of PEL. Whereas vIL-6 was detectable in 6 of 8 PEL effusions (range, 1390-66 630 pg/mL), it was not detectable in any of the control effusions, As expected, all PEL effusions contained human IL-6 (range, 957-37 494 pg/mL), and 7 of 8 contained detectable human IL-10 (range, 66-2,521,297 pg/mL), Human and vIL-6 have previously been shown to induce vascular endothelial growth factor, which in turn can increase vascular permeability. The results of the current study suggest that these cytokines play a central role in the pathogenesis and manifestations of PEL. (Blood. 2000;96: 1599-1601) (C) 2000 by The American Society of Hematology. C1 NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. St Vincents Hosp & Med Ctr, Dept Med, New York, NY 10011 USA. Univ Tokyo, Inst Med Sci, Dept Infect Dis, Tokyo, Japan. RP Aoki, Y (reprint author), NCI, Med Branch, NIH, Bldg 10,Room 12C207,8800 Rockville Pike, Bethesda, MD 20892 USA. OI Braun, Jonathan/0000-0003-1646-2974 NR 22 TC 67 Z9 67 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2000 VL 96 IS 4 BP 1599 EP 1601 PG 3 WC Hematology SC Hematology GA 358VQ UT WOS:000089578200059 PM 10942415 ER PT J AU Gatta, G Capocaccia, R Coleman, MP Ries, LAG Hakulinen, T Micheli, A Sant, M Verdecchia, A Berrino, F AF Gatta, G Capocaccia, R Coleman, MP Ries, LAG Hakulinen, T Micheli, A Sant, M Verdecchia, A Berrino, F TI Toward a comparison of survival in American and European cancer patients SO CANCER LA English DT Article; Proceedings Paper CT XXI Annual Conference on the International-Association-of-Cancer-Registries CY SEP 29-OCT 01, 1999 CL LISBON, PORTUGAL SP Int Assoc Canc Registries DE cancer; relative survival; population-based cancer registries; Europe; United States ID PROSTATE-CANCER; UNITED-STATES AB BACKGROUND. Only recently have extensive population-based cancer survival data become available in Europe, providing an opportunity to compare survival in Europe and the United States. METHODS, The authors considered 12 cancers: lung, breast, stomach, colon, rectum, melanoma, cervix uteri, corpus uteri, ovary prostate, Hodgkin disease, and non-Hodgkin lymphoma. The authors analyzed 738,076 European and 282,398 U.S. patients, whose disease was diagnosed in 1985-1989, obtained from 41 EUROCARE cancer registries in 17 countries and 9 U.S. SEER registries. Relative survival was estimated to correct for competing causes of mortality. RESULTS, Europeans had significantly lower survival rates than U.S. patients for most cancers. Differences in 5-year relative survival rates were higher for prostate (56% vs. 81%), skin melanoma (76% vs. 86%), colon (47% vs. 60%), rectum (43% vs. 57%), breast (73% vs. 82%), and corpus uteri (73% vs. 83%). Survival declined with increasing age at diagnosis for most cancers in both the U.S. and Europe but was more marked in Europe. CONCLUSIONS. Survival for most major cancers was worse in Europe than the U.S. especially for older patients. Differences in data collection, analysis, and quality apparently had only marginal influences on survival rate differences. Further research is required to clarify the reasons for the survival rate differences. (C) 2000 American Cancer Society. C1 Ist Nazl Studio & Cura Tumori, Dept Epidemiol, I-20133 Milan, Italy. Ist Super Sanita, I-00161 Rome, Italy. London Sch Hyg & Trop Med, London WC1, England. NCI, Bethesda, MD 20892 USA. Finnish Canc Registry, FIN-00170 Helsinki, Finland. RP Gatta, G (reprint author), Ist Nazl Studio & Cura Tumori, Dept Epidemiol, Via Venezian 1, I-20133 Milan, Italy. RI Gatta, Gemma/B-8627-2017; Sant, Milena/D-2362-2017; OI Gatta, Gemma/0000-0003-4160-6458; Sant, Milena/0000-0002-4148-8597; Coleman, Michel/0000-0001-8940-3807; Micheli, Andrea/0000-0002-4558-4754 NR 25 TC 105 Z9 108 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 AUG 15 PY 2000 VL 89 IS 4 BP 893 EP 900 DI 10.1002/1097-0142(20000815)89:4<893::AID-CNCR24>3.0.CO;2-9 PG 8 WC Oncology SC Oncology GA 344HQ UT WOS:000088753500024 PM 10951355 ER PT J AU Yokoyama, Y Green, JE Sukhatme, VP Ramakrishnan, S AF Yokoyama, Y Green, JE Sukhatme, VP Ramakrishnan, S TI Effect of endostatin on spontaneous tumorigenesis of mammary adenocarcinomas in a transgenic mouse model SO CANCER RESEARCH LA English DT Article ID LARGE T-ANTIGEN; LARGE-TUMOR-ANTIGEN; GROWTH; MICE; ANGIOGENESIS; CARCINOMA; PROGRESSION; INHIBITOR; ANGIOSTATIN; SUPPRESSION AB A transgenic mouse model was used to evaluate the effect of endostatin treatment on spontaneous turnorigenesis, In this model system, female mice develop multiple mammary adenocarcinomas and male mice develop prostate cancer. Female mice treated with mouse endostatin during a 12-15-week period showed delayed tumor development by 4-6 weeks and significantly decreased tumor burden. Furthermore, endostatin treatment reduced the number of malignant lesions per mouse. In a separate set of experiments. male mice treated with endostatin showed a survival advantage, and their life spans were prolonged by 10.5 weeks over control animals. These data demonstrate that mouse endostatin is effective in delaying spontaneous tumor development and growth. C1 Univ Minnesota, Dept Pharmacol, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Obstet & Gynecol, Minneapolis, MN 55455 USA. Univ Minnesota, Ctr Comprehens Canc, Minneapolis, MN 55455 USA. NCI, Div Basic Sci, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Renal, Boston, MA 02215 USA. RP Ramakrishnan, S (reprint author), Univ Minnesota, Dept Pharmacol, 6-120 Jackson Hall,Church St SE, Minneapolis, MN 55455 USA. FU NCI NIH HHS [R01 CA073871] NR 21 TC 50 Z9 57 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 AUG 15 PY 2000 VL 60 IS 16 BP 4362 EP 4365 PG 4 WC Oncology SC Oncology GA 348AG UT WOS:000088961100015 PM 10969778 ER PT J AU Woodworth, CD Gaiotti, D Michael, E Hansen, L Nees, H AF Woodworth, CD Gaiotti, D Michael, E Hansen, L Nees, H TI Targeted disruption of the epidermal growth factor receptor inhibits development of papillomas and carcinomas from human papillomavirus-immortalized keratinocytes SO CANCER RESEARCH LA English DT Article ID 16-IMMORTALIZED HUMAN KERATINOCYTES; SQUAMOUS-CELL CARCINOMA; SKIN TUMOR PROMOTERS; TRANSGENIC MICE; CERVICAL-CARCINOMA; EPITHELIAL-CELLS; FACTOR-ALPHA; UTERINE CERVIX; EGF RECEPTOR; SENCAR MICE AB The epidermal growth factor receptor (EGF-R) is frequently overexpressed in human papillomavirus (HPV)-associated dysplasias and carcinomas, implying that it is important for the progression of keratinocytes to malignancy. We used mice with a targeted disruption of the EGF-R gene to directly examine its role in cell immortalization and tumor development. Epidermal keratinocytes were cultured from EGF-R knockout, heterozygous, and wild-type mice, infected with retroviruses encoding HPV-16 E6 and E7 oncogenes, and grafted to nude mice. E6/E7 induced immortalization of EGF-R wild-type cells 5-fold more efficiently than null cells. Immortal EGF-R null cells grew more slowly, achieved a lower saturation density, and were more sensitive to apoptosis than the immortalized wild-type or heterozygous cells. Analyses using cDNA expression arrays showed that EGF-R null cells expressed increased levels of RNAs encoding p21(waf) and insulin-like growth factor-binding protein-2, EGFR-positive immortal keratinocytes formed papillomas in 17% (15 of 90) of skin grafts, and seven grafts progressed to squamous carcinoma after 6-12 months. EGF-R null keratinocytes did not form papillomas. but 1 of 96 grafts progressed to a squamous carcinoma after 1 gear. However, treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate inducted tumors in 18 and 35% of grafts containing EGF-R null or EGF-R-positive cells, respectively. Transduction with an activated v-Ha-ras gene, which signals downstream of the EGF-R, induced rapidly growing carcinomas in all grafts regardless of EGF-R genotype, These results directly show that the EGF-R is important, but not essential, for immortalization by HPV and for progression of immortal cells to papillomas and carcinomas. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. RP Woodworth, CD (reprint author), Clarkson Univ, Dept Biol, Potsdam, NY 13699 USA. NR 44 TC 21 Z9 23 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 AUG 15 PY 2000 VL 60 IS 16 BP 4397 EP 4402 PG 6 WC Oncology SC Oncology GA 348AG UT WOS:000088961100021 PM 10969784 ER PT J AU Nava, VE Cuvillier, O Edsall, LC Kimura, K Milstien, S Gelmann, EP Spiegel, S AF Nava, VE Cuvillier, O Edsall, LC Kimura, K Milstien, S Gelmann, EP Spiegel, S TI Sphingosine enhances apoptosis of radiation-resistant prostate cancer cells SO CANCER RESEARCH LA English DT Article ID NECROSIS-FACTOR-ALPHA; PROTEIN-KINASE-C; CERAMIDE SYNTHASE; ACID SPHINGOMYELINASE; IONIZING-RADIATION; SIGNALING PATHWAYS; LNCAP CELLS; LINE LNCAP; ACTIVATION; DEATH AB Ceramide has been implicated as an important component of radiation-induced apoptosis of human prostate cancer tells. We examined the role of the sphingolipid metabolites-ceramide, sphingosine, and sphingosine-1-phosphate-in susceptibility to radiation-induced apoptosis in prostate cancer cell lines with different sensitivities to gamma-irradiation, Exposure of radiation-sensitive TSU-Prl cells to 8-Gy irradiation led to a sustained increase in ceramide, beginning after 12 h of treatment and increasing to 2.5- to 3-fold within 18 h. Moreover, irradiation of TSU-Pr1 cells also produced a marked and rapid 50% decrease in the activity of sphingosine kinase, the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate, In contrast, the radiation-insensitive cell line, LNCaP, had sustained sphingosine kinase activity and did not produce elevated ceramide levels on 8-Gy irradiation. Although LNCaP cells are highly resistant to gamma-irradiation-induced apoptosis. they are sensitive to the death-inducing effects of tumor necrosis factor alpha, which also increases ceramide levels in these cells (K. Kimura et al., Cancer Res., 59: 1606-1614, 1999), Moreover, we found that although irradiation alone did not increase sphingosine levels in LNCaP cells, tumor necrosis factor alpha plus irradiation induced significantly higher sphingosine levels and markedly reduced intracellular levels of sphingosine-1-phosphate. The elevation of sphingosine levels either by exogenous sphingosine or by treatment with the sphingosine kinase inhibitor N,N-dimethylsphingosine induced apoptosis and also sensitized LNCaP cells to gamma-irradiation-induced apoptosis. Our data suggest that the relative levels of sphingolipid metabolites may play a role in determining the radiosensitivity of prostate cancer cells, and that the enhancement of ceramide and sphingosine generation could be of therapeutic value. C1 Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Div Hematol Oncol, Dept Med, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Lombardi Canc Ctr, Washington, DC 20007 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, 353 Basic Sci Bldg,3900 Reservoir Rd NW, Washington, DC 20007 USA. RI CUVILLIER, Olivier/B-2567-2009 OI CUVILLIER, Olivier/0000-0003-3346-375X FU NCI NIH HHS [CA/AG79912, CA61774] NR 54 TC 109 Z9 111 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2000 VL 60 IS 16 BP 4468 EP 4474 PG 7 WC Oncology SC Oncology GA 348AG UT WOS:000088961100031 PM 10969794 ER PT J AU Forozan, F Mahlamaki, EH Monni, O Chen, YD Veldman, R Jiang, Y Gooden, GC Ethier, SP Kallioniemi, A Kallioniemi, OP AF Forozan, F Mahlamaki, EH Monni, O Chen, YD Veldman, R Jiang, Y Gooden, GC Ethier, SP Kallioniemi, A Kallioniemi, OP TI Comparative genomic hybridization analysis of 38 breast cancer cell lines: A basis for interpreting complementary DNA microarray data SO CANCER RESEARCH LA English DT Article ID CARCINOMA IN-SITU; GENETIC ABERRATIONS; DIFFERENT PATTERNS; CHROMOSOME 20Q13; CDNA MICROARRAYS; AMPLIFICATION; TUMORS; CGH; ONCOGENE; REVEALS AB Breast cancer cell lines provide a useful starting point for the discovery and functional analysis of genes involved in breast cancer. Here, we studied 38 established breast cancer cell lines by comparative genomic hybridization (CGH) to determine recurrent genetic alterations and the extent to which these cell lines resemble uncultured tumors. The following chromosomal gains were observed: 8q (75%), 1q (61%), 20q (55%), 7p (44%), 3q (39%), 5p (39%), 7q (39%), 17q (33%), 1p (30%), and 20p (30%), and the most common losses were: 8p (58%), 18q (58%), 1p (42%), Xp (42%),,Xq (42%), 4p (36%), 11q (36%), 18p (33%), 10q (30%), and 19p (28%). Furthermore, 35 recurrent high-level amplification sites were identified, most often involving 8q23 (37%), 20q13 (29%), 3q25-q26 (24%), 17q22-q23 (16%), 17q23-q24 (16%), 1p13 (11%), 1q32 (11%), 5p13 (11%), 5p14 (11%), 11q13 (11%), 17q12-q21(11%), and 7q21-q22 (11%). A comparison of DNA copy number changes found in the cell lines with those reported in 17 published studies (698 tumors) of uncultured tumors revealed a substantial degree of overlap. CGH copy number profiles may facilitate identification of important new genes located at the hotspots of such chromosomal alterations. This was illustrated by analyzing expression levels of 1236 genes using cDNA microarrays in four of the cell lines. Several highly overexpressed genes (such as RCH1 at 17q23, TOPO II at 17q21-q22, as well as CAS and MYBL2 at 20q13) were involved in these recurrent DNA amplifications. In conclusion, DNA copy number profiles were generated by CGH for most of the publicly available breast cancer cell lines and mere made available on a web site (http://www.nhgri.nih.gov/DIR/CGB/CR2000). This should facilitate the correlative analysis of gene expression and copy number as illustrated here by the finding by cDNA microarrays of several overexpressed genes that were amplified. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Tampere Univ, Inst Med Technol, Canc Genet Lab, FIN-33521 Tampere, Finland. Tampere Univ Hosp, FIN-33521 Tampere, Finland. Univ Michigan, Sch Med, Dept Radiat Oncol, Div Radiat & Canc Biol, Ann Arbor, MI 48109 USA. RP Kallioniemi, OP (reprint author), NHGRI, Canc Genet Branch, NIH, Bldg 49,Room 4A24,49 Convent Dr,MSC 4470, Bethesda, MD 20892 USA. RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Anne/0000-0003-3552-8158 NR 32 TC 209 Z9 216 U1 1 U2 6 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 AUG 15 PY 2000 VL 60 IS 16 BP 4519 EP 4525 PG 7 WC Oncology SC Oncology GA 348AG UT WOS:000088961100038 PM 10969801 ER PT J AU Bouzahzah, B Fu, MF Iavarone, A Factor, VM Thorgeirsson, SS Pestell, RG AF Bouzahzah, B Fu, MF Iavarone, A Factor, VM Thorgeirsson, SS Pestell, RG TI Transforming growth factor-beta 1 recruits histone deacetylase 1 to a p130 repressor complex in transgenic mice in vivo SO CANCER RESEARCH LA English DT Article ID CELL-CYCLE ARREST; TGF-BETA; RETINOBLASTOMA PROTEIN; TRANSCRIPTIONAL REPRESSION; C-MYC; E2F; GENE; CDC25A; D1; GROWTH-FACTOR-BETA-1 AB Transforming growth factor (TGF)-beta 1 functions as a tumor suppressor in vivo. Using transgenic mice, we show that hepatic TGF-beta 1 overexpression inhibits abundance of the cyclin-dependent kinase activating tyrosine phosphatase cdc25A protein. The reduction in cdc25A protein levels was associated with increased binding of histone deacetylase 1 to p130 in the hepatic extracts, In cultured cells, HDAC1/p130 overexpression inhibited activity of the cdc25A promoter through an E2F site. TGF-beta 1 treatment enhanced p130 binding to the cdc25A promoter E2F site assessed in chromatin immunoprecipitation assays. Hepatic proliferation induced by partial hepatectomy was associated with a decrease in the amount of HDAC1 bound to p130, without a significant decrease in p130 abundance, suggesting that HDAC1 binding to p130 may be regulated by proliferative stimuli. The induction of cdc25A abundance induced by partial hepatectomy correlated with the induction of DNA synthesis. These studies suggest that TGF-beta 1 may enhance HDAC1 binding to p130 irt vivo, thereby inhibiting cdc25A gene expression, TGF-beta 1 regulation of HDAC1/pocket protein associations may provide a link between chromatin remodeling proteins and cdk inhibition through induction of cdc25A in vivo. C1 Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Med, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Dev & Mol Biol, Bronx, NY 10461 USA. Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Neurol, Bronx, NY 10461 USA. NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Pestell, RG (reprint author), Yeshiva Univ Albert Einstein Coll Med, Albert Einstein Canc Ctr, Dept Med, Chanin 302,1300 Morris Pk Ave, Bronx, NY 10461 USA. FU NCI NIH HHS [R01CA77552-01, R01CA70897]; NIDDK NIH HHS [R01DK53446] NR 43 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 AUG 15 PY 2000 VL 60 IS 16 BP 4531 EP 4537 PG 7 WC Oncology SC Oncology GA 348AG UT WOS:000088961100040 PM 10969803 ER PT J AU Hummer, G Garde, S Garcia, AE Pratt, LR AF Hummer, G Garde, S Garcia, AE Pratt, LR TI New perspectives on hydrophobic effects SO CHEMICAL PHYSICS LA English DT Review ID TEMPERATURE-DEPENDENCE; COMPUTER-SIMULATION; WATER-STRUCTURE; PROTEIN STABILITY; SURFACE-TENSION; CONFORMATIONAL EQUILIBRIA; SOLVATION THERMODYNAMICS; PRESSURE DENATURATION; MOLECULAR-DYNAMICS; DISORDERED WATER AB Recent breakthroughs in the theory of hydrophobic effects permit new analyses of several characteristics of hydrophobic hydration and interaction. Heat capacities of non-polar solvation, and their temperature dependences, are analyzed within an information theory approach, using experimental information available from bulk liquid water. Non-polar solvation in aqueous electrolytes is studied by computer simulations, and interpreted within the information theory, We also study the preferential solvation of small non-polar molecules in heavy water (D2O) relative to light water (H2O) and find that this revealing difference can be explained by the higher compressibility of D2O. We develop a quasi-chemical description of hydrophobic hydration that incorporates the hydration structure and permits quantum-mechanical treatment of the solute. Finally, these new results are discussed in the context of hydrophobic effects in protein stability and folding, and of mesoscopic hydrophobic effects such as dewetting. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Rensselaer Polytech Inst, Dept Chem Engn, Troy, NY 12180 USA. Los Alamos Natl Lab, Div Theoret, Los Alamos, NM 87545 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Rm 132, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov RI Garde, Shekhar/C-3060-2008; Pratt, Lawrence/H-7955-2012; Hummer, Gerhard/A-2546-2013 OI Pratt, Lawrence/0000-0003-2351-7451; Hummer, Gerhard/0000-0001-7768-746X NR 134 TC 229 Z9 232 U1 8 U2 75 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0104 EI 1873-4421 J9 CHEM PHYS JI Chem. Phys. PD AUG 15 PY 2000 VL 258 IS 2-3 BP 349 EP 370 DI 10.1016/S0301-0104(00)00115-4 PG 22 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 347WV UT WOS:000088952900022 ER PT J AU Incardona, JP Gaffield, W Lange, Y Cooney, A Pentchev, PG Liu, S Watson, JA Kapur, RP Roelink, H AF Incardona, JP Gaffield, W Lange, Y Cooney, A Pentchev, PG Liu, S Watson, JA Kapur, RP Roelink, H TI Cyclopamine inhibition of sonic hedgehog signal transduction is not mediated through effects on cholesterol transport SO DEVELOPMENTAL BIOLOGY LA English DT Article DE neural development; holoprosencephaly; teratogen; U18666A; progesterone; membrane trafficking ID LEMLI-OPITZ-SYNDROME; NIEMANN-PICK DISEASE; KINESIN-RELATED PROTEIN; MOTOR-NEURON INDUCTION; COENZYME-A REDUCTASE; FLOOR PLATE; C-DISEASE; 7-DEHYDROCHOLESTEROL REDUCTASE; CRANIOFACIAL MALFORMATIONS; PRENATAL-DIAGNOSIS AB Cyclopamine is a teratogenic steroidal alkaloid that causes cyclopia by blocking Sonic hedgehog (Shh) signal transduction. We have tested whether this activity of cyclopamine is related to disruption of cellular cholesterol transport and putative secondary effects on the Shh receptor, Patched (Ptc). First, we report that the potent antagonism of Shh signaling by cyclopamine is not a general property of steroidal alkaloids with similar structure. The structural features of steroidal alkaloids previously associated with the induction of holoprosencephaly in whole animals are also associated with inhibition of Shh signaling in vitro. Second, by comparing the effects of cyclopamine on Shh signaling with those of compounds known to block cholesterol transport, we show that the action of cyclopamine cannot be explained by inhibition of intracellular cholesterol transport. However, compounds that block cholesterol transport by affecting the vesicular trafficking of the Niemann-Pick C1 protein (NPC1), which is structurally similar to Ptc, are weak Shh antagonists. Rather than supporting a direct link between cholesterol homeostasis and Shh signaling, our findings suggest that the functions of both NPC1 and Ptc involve a common vesicular transport pathway. Consistent with this model, we find that Ptc and NPC1 colocalize extensively in a vesicular compartment in cotransfected cells. (C) 2000 Academic Press. C1 Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. Univ Washington, Ctr Dev Biol, Seattle, WA 98195 USA. Univ Washington, Dept Pathol, Seattle, WA 98195 USA. ARS, Western Reg Res Ctr, USDA, Albany, CA 94710 USA. Rush Presbyterian St Lukes Med Ctr, Dept Pathol, Chicago, IL 60612 USA. NINDS, Dev & Metab Neurobiol Branch, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94143 USA. RP Roelink, H (reprint author), Univ Washington, Dept Biol Struct, Box 357420,HSB G527, Seattle, WA 98195 USA. FU NHLBI NIH HHS [HL28448]; NIEHS NIH HHS [ES07033, ES09210] NR 77 TC 77 Z9 84 U1 1 U2 8 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 AUG 15 PY 2000 VL 224 IS 2 BP 440 EP 452 DI 10.1006/dbio.2000.9775 PG 13 WC Developmental Biology SC Developmental Biology GA 347XY UT WOS:000088955500027 PM 10926779 ER PT J AU Mochizuki, T Karavanov, AA Curtiss, PE Ault, KT Sugimoto, N Watabe, T Shiokawa, K Jamrich, M Cho, KWY Dawid, IB Taira, M AF Mochizuki, T Karavanov, AA Curtiss, PE Ault, KT Sugimoto, N Watabe, T Shiokawa, K Jamrich, M Cho, KWY Dawid, IB Taira, M TI Xlim-1 and LIM domain binding protein 1 cooperate with various transcription factors in the regulation of the goosecoid promoter SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Xenopus; head organizer; homeobox gene; goosecoid promoter; Xlim-1; Ldb1; Otx2; Gsc; PV.1; Xvent-1; Xbra; LIM domain ID ANTERIOR PRIMITIVE ENDODERM; HOMEOBOX GENE; XENOPUS-EMBRYOS; SPEMANNS ORGANIZER; HOMEODOMAIN PROTEINS; MOUSE GASTRULA; RETINOIC ACID; MESODERM; HEAD; DROSOPHILA AB The homeobox genes Xlim-1 and goosecoid (gsc) are coexpressed in the Spemann organizer and later in the prechordal plate that acts as head organizer. Based on our previous finding that gsc is a possible target gene for Xlim-1, we studied the regulation of gsc transcription by Xlim-1 and other regulatory genes expressed at gastrula stages, by using gsc-luciferase reporter constructs injected into animal explants. A 492-bp upstream region of the gsc promoter responds to Xlim-1/3m, an activated form of Xlim-1, and to a combination of wild-type Xlim-1 and Ldb1, a LIM domain binding protein, supporting the view that gsc is a direct target of Xlim-1. Footprint and electrophoretic mobility shift assays with GST-homeodomain fusion proteins and embryo extracts overexpressing FLAG-tagged full-length proteins showed that the Xlim-1 homeodomain or Xlim-1/Ldb1 complex recognize several TAATXY core elements in the 492-bp upstream region, where XY is TA, TG, CA, or GG. Some of these elements are also bound by the ventral factor PV.1, whereas a TAATCT element did not bind Xlim-1 or PV.1 but did bind the anterior factors Otx2 and Gsc. These proteins modulate the activity of the gsc reporter in animal caps: Otx2 activates the reporter synergistically with Xlim-1 plus Ldb1, whereas Gsc and PV.1 strongly repress reporter activity. We show further, using animal cap assays, that the endogenous gsc gene was synergistically activated by Xlim-1, Ldb1, and Otx2 and that the endogenous otx2 gene was activated by Xlim-1/3m, and this activation was suppressed by the posterior factor Xbra. Based on these data, we propose a model for gene interactions in the specification of dorsoventral and anteroposterior differences in the mesoderm during gastrulation. (C) 2000 Academic Press. C1 Univ Tokyo, Dept Biol Sci, Grad Sch Sci, Mol Embryol Lab,Bunkyo Ku, Tokyo 1130033, Japan. CREST, Japanese Sci & Technol Corp, Tokyo, Japan. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. US FDA, Dev Biol Lab, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. Univ Calif Irvine, Dept Dev & Cell Biol, Ctr Dev Biol, Irvine, CA 92717 USA. RP Taira, M (reprint author), Univ Tokyo, Dept Biol Sci, Grad Sch Sci, Mol Embryol Lab,Bunkyo Ku, Tokyo 1130033, Japan. NR 56 TC 48 Z9 52 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 15 PY 2000 VL 224 IS 2 BP 470 EP 485 DI 10.1006/dbio.2000.9778 PG 16 WC Developmental Biology SC Developmental Biology GA 347XY UT WOS:000088955500029 PM 10926781 ER PT J AU Agarwala, R Biesecker, LG Schaffer, AA AF Agarwala, R Biesecker, LG Schaffer, AA TI Inverse inbreeding coefficient problems with an application to linkage analysis of recessive diseases in inbred populations SO DISCRETE APPLIED MATHEMATICS LA English DT Article DE pedigree; linkage analysis; inbreeding coefficient; recessive diseases; cycles; graphs ID COMPLEX PEDIGREES; TRAITS; HUMANS AB Medical geneticists connect relatives having the same disease into a family structure called a pedigree. Genetic linkage analysis uses pedigrees to find the approximate chromosomal locations of disease-causing genes. The problem of choosing a pedigree is particularly interesting for diseases inherited in an autosomal recessive pattern in inbred populations because there are many possible paths of inheritance to choose from. A variety of shortcuts are taken to produce plausible pedigrees from inbred populations. We lay the mathematical foundations for a shortcut that was recently used in a pedigree-disease study of an inbred Mennonite population. Recessive disease genes can be localized using the shortcut of homozygosity mapping by finding regions of the genome where affected persons are homozygous. An important quantity in homozygosity mapping is the inbreeding coefficient of a person, which is the prior probability that the person inherited the same piece of DNA on both copies of the chromosome from a single ancestor. Software packages are ill-suited to handle large pedigrees with many inbreeding loops. Therefore, we consider the problem of generating small pedigrees that match the inbreeding coefficient of one or more affected persons in the larger pedigree. We call such a problem an inverse inbreeding coefficient problem, We focus on the case where there is one sibship with one or more affected persons, and consider the problem of constructing a pedigree so that it is "simpler" and gives the sibship a specified inbreeding coefficient. First, we give a construction that yields small pedigrees for any inbreeding coefficient. Second, we add the constraint that ancestor-descendant matings are not allowed, and we give another more complicated construction to match any inbreeding coefficient. Third, we show some examples of how to use the one-sibship construction to do pedigree replacement on real pedigrees with multiple affected sibships. Fourth, we give a different construction to match the inbreeding coefficient of one sibship, while attempting to minimize a measure of the inbreeding loop complexity. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIH, IDRB, NHGRI, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NIH, GDRB, NHGRI, Bethesda, MD 20892 USA. RP Schaffer, AA (reprint author), NIH, IDRB, NHGRI, Natl Ctr Biotechnol Informat, Bldg 38A,Room 8N-805,8600 Rockville Pike, Bethesda, MD 20894 USA. RI Schaffer, Alejandro/F-2902-2012 NR 24 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-218X J9 DISCRETE APPL MATH JI Discret Appl. Math. PD AUG 15 PY 2000 VL 104 IS 1-3 BP 3 EP 44 DI 10.1016/S0166-218X(00)00193-1 PG 42 WC Mathematics, Applied SC Mathematics GA 345KD UT WOS:000088814400002 ER PT J AU Li, JW Wang, J Wang, JX Nawaz, Z Liu, JM Qin, J Wong, JM AF Li, JW Wang, J Wang, JX Nawaz, Z Liu, JM Qin, J Wong, JM TI Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3 SO EMBO JOURNAL LA English DT Article DE HDAC3; repression; SMRT and N-CoR corepressor complexes; TBL1 ID THYROID-HORMONE RECEPTOR; HISTONE DEACETYLASE; TRANSCRIPTIONAL REPRESSION; ACETYLATION; GENE; ACTIVATION; CHROMATIN; BINDING; OSCILLATIONS; SUPERFAMILY AB We present evidence that both corepressors SMRT and N-CoR exist in large protein complexes with estimated sizes of 1.5-2 MDa in HeLa nuclear extracts. Using a combination of conventional and immunoaffinity chromatography, we have successfully isolated a SMRT complex and identified histone deacetylase 3 (HDAC3) and transducin (beta)-like I (TBL1), a WD-40 repeat-containing protein, as the subunits of the purified SMRT complex. We show that the HDAC3-containing SMRT and N-CoR complexes can bind to unliganded thyroid hormone receptors (TRs) in vitro. We demonstrate further that in Xenopus oocytes, both SMRT and N-CoR also associate with HDAC3 in large protein complexes and that injection of antibodies against HDAC3 or SMRT/N-CoR led to a partial relief of repression by unliganded TR/RXR. These findings thus establish both SMRT and N-CoR complexes as bona fide HDAC-containing complexes and shed new light on the molecular pathways by which N-CoR and SMRT function in transcriptional repression. C1 Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Baylor Coll Med, Dept Biochem, Houston, TX 77030 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Wong, JM (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza, Houston, TX 77030 USA. FU NIDDK NIH HHS [DK 56324, R01 DK056324] NR 45 TC 399 Z9 409 U1 1 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 15 PY 2000 VL 19 IS 16 BP 4342 EP 4350 DI 10.1093/emboj/19.16.4342 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 346CM UT WOS:000088853000016 PM 10944117 ER PT J AU Nicholson, RH Pantano, S Eliason, JF Galy, A Weiler, S Kaplan, J Hughes, MR Ko, MSH AF Nicholson, RH Pantano, S Eliason, JF Galy, A Weiler, S Kaplan, J Hughes, MR Ko, MSH TI Phemx, a novel mouse gene expressed in hematopoietic cells maps to the imprinted cluster on distal chromosome 7 SO GENOMICS LA English DT Article ID IN-SITU HYBRIDIZATION; PROGENITOR CELLS; ANTIPROLIFERATIVE ANTIBODY-1; MAMMALS; TISSUE; CD81; DIFFERENTIATION; TRANSCRIPTS; ENRICHMENT; COMPLEX AB Phemx (Pan hematopoietic expression) is a novel murine gene expressed in developmentally regulated sites of hematopoiesis from early in embryogenesis through adulthood. Phemx is expressed in hematopoietic progenitors and mature cells of the three main hematopoietic lineages. Conceptual translation of the murine Phemx cDNA predicts a 25-kDa polypeptide with four hydrophobic regions and several potential phosphorylation sites, suggestive of a transmembrane protein involved in cell signaling. The PHEMX protein is structurally similar to tetraspanin CD81 (TAPA-1), a transmembrane protein involved in leukocyte activation, adhesion, and proliferation. Phemx maps to the distal region of chromosome 7, a segment of the mouse genome that contains a cluster of genes that exhibit genomic imprinting, However, imprinting analysis of Phemx at the whole organ level shows that it is biallelically expressed, suggesting that mechanisms leading to monoallelic expression are not imposed at this locus. The human PHEMX ortholog is specifically expressed in hematopoietic organs and tissues and, in contrast to murine Phemx, undergoes alternative splicing. The unique mode and range of Phemx expression suggest that it plays a role in hematopoietic cell function. (C) 2000 Academic Press. C1 NIA, Dev Genomics & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Barbara Ann Karmanos Canc Inst, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. RP Ko, MSH (reprint author), NIA, Dev Genomics & Aging Sect, Genet Lab, NIH, 333 Cassell Dr,Suite 4000, Baltimore, MD 21224 USA. RI Ko, Minoru/B-7969-2009; Galy, Anne/J-4439-2013 OI Ko, Minoru/0000-0002-3530-3015; Galy, Anne/0000-0002-0153-4392 FU NICHD NIH HHS [HD32248] NR 39 TC 17 Z9 19 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 AUG 15 PY 2000 VL 68 IS 1 BP 13 EP 21 DI 10.1006/geno.2000.6277 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 349EM UT WOS:000089030700002 PM 10950922 ER PT J AU Boissy, RJ Watson, MA Umbach, DM Deakin, M Elder, J Strange, RC Bell, DA AF Boissy, RJ Watson, MA Umbach, DM Deakin, M Elder, J Strange, RC Bell, DA TI A pilot study investigating the role of NAT1 and NAT2 polymorphisms in gastric adenocarcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID ARYLAMINE N-ACETYLTRANSFERASE; POLYADENYLATION POLYMORPHISM; N-ACETYLTRANSFERASE-1 NAT1; COLORECTAL ADENOMAS; STOMACH-CANCER; BLADDER-CANCER; RISK; ACETYLATION; SMOKING; GENE AB In humans, aromatic and heterocyclic amine carcinogens may be acetylated by the expression products of either of the N-acetyltransferase genes, NAT1 or NAT2. This conjugation reaction can result in either activation or detoxication of these carcinogens depending on the tissue involved. Recent studies suggest that polymorphisms in NAT1 or NAT2 may modulate cancer risk. To determine if genetic differences in NAT1 and NAT2 could alter risk of gastric cancer, we tested for the presence of polymorphic N-acetyltransferase alleles (both NAT1 and NAT2) in a preliminary study of 94 gastric adenocarcinoma patients and 112 control subjects from North Staffordshire, England. We used established PCR protocols to genotype for NAT2 and NAT1 alleles (NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*14; NAT1*3, NAT1*4, NAT1*10, and NAT1*11), and implemented an oligonucleotide ligation assay (OLA) to test for low-activity NAT1 alleles [NAT1*14 (G560A), NAT1*15 (C559T), and NAT1*17 (C190T)]. No significant increased risk was observed for NAT2 acetylation genotypes. However, among all cases, we found that individuals inheriting a variant NAT1 allele, NAT1*10, have a significantly elevated risk for gastric cancer (OR = 2.2, 95% CI 1.2-3.9, P < 0.01). Interestingly, the risk observed for NAT1*10 appears to be solely associated with advanced-stage tumors (OR = 4.8, P < 0.001), suggesting a possible role in progression to advanced disease. This preliminary finding needs confirmation in a larger, detailed epidemiological study. Int. J. Cancer 87:507-511, 2000. Published 2000 Wiley-Liss, Inc.dagger C1 NIEHS, Lab Computat Biol & Risk Anal, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. Keele Univ, Stoke On Trent, Staffs, England. RP Bell, DA (reprint author), NIEHS, Lab Computat Biol & Risk Anal, NIH, MD C3-03,POB 12233, Res Triangle Pk, NC 27709 USA. NR 30 TC 29 Z9 33 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 15 PY 2000 VL 87 IS 4 BP 507 EP 511 DI 10.1002/1097-0215(20000815)87:4<507::AID-IJC7>3.3.CO;2-9 PG 5 WC Oncology SC Oncology GA 339GK UT WOS:000088469100007 PM 10918189 ER PT J AU Grigorenko, BL Nemukhin, AV Topol, IA Burt, SK AF Grigorenko, BL Nemukhin, AV Topol, IA Burt, SK TI Hydrogen bonding at the diatomics-in-molecules level: Water clusters SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID POTENTIAL-ENERGY SURFACES; MANY-BODY POTENTIALS; DER-WAALS COMPLEXES; AB-INITIO; IONIC-SYSTEMS; STATIONARY-POINTS; BINDING-ENERGIES; HF DIMER; SIMULATIONS; STATES AB Further developments of the intermolecular diatomics-in-molecules (DIM) theory towards construction of potential energy surfaces of hydrogen-bonded molecular aggregates are presented. Compared to the previously studied hydrogen fluoride clusters (HF)(n) [J. Chem. Phys. 111, 4442 (1999)], considerably more complicated and challenging systems, namely, water clusters (H2O)(n) (n = 2-6) have been analyzed in this work. The present DIM, or more precisely, diatomics-in-ionic-systems, scheme is based on the balanced treatment of neutral and ionic contributions to the electronic properties of polyatomic species, and in this case takes into account the mixing of the OH and O-H+ electronic states within the valence bond description of water molecules. The potential curves of diatomic molecules required for the present application, including ionic species O-H, OH+, O-2(-), have been computed by ab initio quantum chemistry tools. The results of DIM calculations of equilibrium geometry configurations, binding energies, and relative energies for the low-lying isomers of (H2O)(n) (n = 2-6) are compared to the reference data showing a good predictive power of this method. (C) 2000 American Institute of Physics. [S0021-9606(00)30527-X]. C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Grigorenko, BL (reprint author), Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119899, Russia. RI Nemukhin, Alexander/P-9662-2015 NR 51 TC 14 Z9 15 U1 0 U2 3 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 15 PY 2000 VL 113 IS 7 BP 2638 EP 2647 AR PII [S0021-9606(00)30527-X] DI 10.1063/1.1303850 PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 344XY UT WOS:000088787400012 ER PT J AU Gopich, IV Burshtein, AI AF Gopich, IV Burshtein, AI TI Comment on "Statistical theory of time-dependent diffusion-controlled reactions in fluids and solids" [J. Chem. Phys. 103, 10201 (1995)] SO JOURNAL OF CHEMICAL PHYSICS LA English DT Letter ID ENERGY-TRANSFER C1 RAS, Inst Chem Kinet & Combust, Novosibirsk 630090, Russia. Weizmann Inst Sci, IL-76100 Rehovot, Israel. RP Gopich, IV (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 8 TC 2 Z9 2 U1 15 U2 16 PU AMER INST PHYSICS PI MELVILLE PA 2 HUNTINGTON QUADRANGLE, STE 1NO1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD AUG 15 PY 2000 VL 113 IS 7 BP 2932 EP 2934 DI 10.1063/1.1303743 PG 3 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 344XY UT WOS:000088787400044 ER PT J AU Lucas, B Germain, RN AF Lucas, B Germain, RN TI Opening a window on thymic positive selection: Developmental changes in the influence of cosignaling by integrins and CD28 on selection events induced by TCR engagement SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; INTERCELLULAR-ADHESION MOLECULE-1; NEGATIVE SELECTION; ANTIGEN RECEPTOR; CD4(+)CD8(+) THYMOCYTES; IMMATURE THYMOCYTES; CD4+8+ THYMOCYTES; CLONAL DELETION; TRANSGENIC MICE; SINGLE PEPTIDE AB How TCR and non-TCR signals are integrated by thymocytes to generate a decision to undergo either positive or negative selection remains incompletely understood, Recent evidence suggests that TCR signal transduction changes its quality during thymocyte maturation, but whether the contributions of various cosignaling or costimulatory pathways to thymocyte selection also are modified during development is unclear. Questions also remain about the possible selective roles of specific costimulatory pathways in induction of differentiation vs death among thymocytes at any given stage of maturity. To address these issues, a quantitative in vitro analysis of initiation of CD4(+)CD8(+) thymocyte differentiation as measured by CD69 up-regulation/coreceptor downmodulation was conducted in parallel with an analysis of induction of death. Using transfected cells varying in their surface display of ICAM-1 or B7.1 along with antibody blocking experiments, we demonstrate here that ICAM-1 provides a selective boost to signaling for differentiation without substantially affecting induction of death among CD4(+)CD8(+) cells, a property that is lost as thymocytes mature further. In contrast, B7 engagement enhances both cell activation and death in parallel. Based on these data, we propose that the high level of ICAM-1 on cortical epithelial cells plays a special role in opening a window between TCR signaling for differentiation vs death, permitting efficient initiation of positive selection on epithelial ligands, In contrast, late CD28-dependent cosignaling on hemopoietic cells in the medulla would help enforce negative selection by augmenting the effects of TCR engagement by low levels of high affinity ligands. C1 NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bethesda, MD 20892 USA. Inst Necker, INSERM, U345, Paris, France. RP Germain, RN (reprint author), NIAID, Immunol Lab, Lymphocyte Biol Sect, NIH, Bldg 10,Room 11N-311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. NR 61 TC 37 Z9 38 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2000 VL 165 IS 4 BP 1889 EP 1895 PG 7 WC Immunology SC Immunology GA 342BW UT WOS:000088626200023 PM 10925269 ER PT J AU Charest, H Sedegah, M Yap, GS Gazzinelli, RT Caspar, P Hoffman, SL Sher, A AF Charest, H Sedegah, M Yap, GS Gazzinelli, RT Caspar, P Hoffman, SL Sher, A TI Recombinant attenuated Toxoplasma gondii expressing the Plasmodium yoelii circumsporozoite protein provides highly effective priming for CD8(+) T cell-dependent protective immunity against malarial SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IFN-GAMMA; INTERFERON-GAMMA; MEDIATED CYTOLYSIS; SELECTABLE MARKER; GENE REPLACEMENT; MICE; INFECTION; IMMUNIZATION; RESISTANCE; VACCINE AB The protozoan parasite Toxoplasma gondii elicits strong cell-mediated immunity against itself as well as nonspecific resistance against other pathogens and tumors, For this reason, we asked whether recombinant Toxoplasma could be utilized as an effective vaccine vehicle for inducing immunity against heterologous microbial infections. The circumsporozoite protein (PyCSP) of Plasmodium yoelii was engineered into a T. gondii temperature-sensitive strain (ts-4), a mutant that induces complete protection against virulent Toxoplasma challenge. When administered to mice in a single dose, a recombinant ts-4 (CSC3) that both secretes and expresses surface PyCSP induced strong anti-CSP Ab responses, with an isotype distribution pattern similar to that stimulated by the T. gondii carrier. When challenged with P, yoelii sporozoites during the first month after CSC3 vaccination, these animals displayed substantial levels of nonspecific resistance attributable entirely to the T. gondii carrier, Nevertheless, after the nonspecific protection had waned, high levels (up to 79%) of specific immunity against sporozoite challenge were achieved by boosting the animals with recombinant vaccinia virus expressing PyCSP. These CSC3-primed PyCSP-vaccinia-boosted mice displayed high frequencies of splenic PyCSP-specific IFN-gamma-producing cells, as well as CD8(+) T cell-dependent cytolytic activity. In vivo depletion of CD8(+) lymphocytes at the time of challenge completely ablated protective immunity in the T, gondii-primed/vaccinia-boosted animals, while neutralization of IFN-gamma or IL-12 caused a partial but significant reduction In resistance. Together these findings establish the efficacy of recombinant attenuated Toxoplasma as a vaccine vehicle for priming CD8(+)-dependent cell-mediated immunity. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. USN, Malaria Program, Med Res Ctr, Silver Spring, MD 20910 USA. Univ Maryland, Sch Med, Dept Microbiol, Baltimore, MD 21201 USA. Univ Fed Minas Gerais, Dept Biochem & Immunol, Belo Horizonte, MG, Brazil. RP Sher, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 4,Room 126,4 Ctr Dr, Bethesda, MD 20892 USA. EM Alan_Sher@nih.gov NR 52 TC 28 Z9 32 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2000 VL 165 IS 4 BP 2084 EP 2092 PG 9 WC Immunology SC Immunology GA 342BW UT WOS:000088626200047 PM 10925293 ER PT J AU Junn, E Lee, KN Ju, HR Han, SH Im, JY Kang, HS Lee, TH Bae, YS Ha, KS Lee, ZW Rhee, SG Choi, I AF Junn, E Lee, KN Ju, HR Han, SH Im, JY Kang, HS Lee, TH Bae, YS Ha, KS Lee, ZW Rhee, SG Choi, I TI Requirement of hydrogen peroxide generation in TGF-beta 1 signal transduction in human lung fibroblast cells: Involvement of hydrogen peroxide and Ca2+ in TGF-beta 1-induced IL-6 expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; ACTIVATED PROTEIN-KINASE; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; TRANSFORMING GROWTH-FACTOR-BETA-1; TYROSINE PHOSPHORYLATION; TRANSCRIPTION FACTOR; OSTEOBLASTIC CELLS; GENE-EXPRESSION; PHOSPHOLIPASE-D AB Stimulation of human lung fibroblast cells with TGF-beta 1 resulted in a transient burst of reactive oxygen species with maximal increase at 5 min after treatment. This reactive oxygen species increase was inhibited by the antioxidant, N-acetyl-L-cysteine (NAC), TGF-beta 1 treatment stimulated IL-6 gene expression and protein synthesis in human lung fibroblast cells. Antioxidants including NAC, glutathione, and catalase reduced TGF-beta 1-induced IL-6 gene expression, and direct H2O2 treatment induced IL-6 expression in a dose-dependent manner. NAC also reduced TGF-beta 1-induced AP-1 binding activity, which is involved in IL-6 gene expression. It has been reported that Ca2+ influx is stimulated by TGF-beta 1 treatment. EGTA suppressed TGF-beta 1- or H2O2-induced IL-6 expression, and ionomycin increased IL-6 expression, with simultaneously modulating AP-1 activity in the same pattern. PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase/extracellular signal-related kinase kinase 1, suppressed TGF-beta 1- or H2O2-induced IL-6 and AP-1 activation. In addition, TGF-beta 1 or H2O2 increased MAPK activity which was reduced by EGTA and NAG, suggesting that MAPK is involved in TGF-beta 1-induced IL-6 expression. Taken together, these results indicate that TGF-beta 1 induces a transient increase of intracellular H2O2 production, which regulates downstream events such as Ca2+ influx, MAPK, and AP-1 activation and IL-6 gene expression. C1 Korea Res Inst Biosci & Biotechnol, Immunol Lab, Taejon 305333, South Korea. Yonsei Univ, Dept Biol, Seoul 120749, South Korea. Ewha Womans Univ, Dept Biol Sci, Seoul, South Korea. Korea Basic Sci Inst, Biomol Res Team, Taejon, South Korea. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Choi, I (reprint author), Korea Res Inst Biosci & Biotechnol, Immunol Lab, Taejon 305333, South Korea. NR 44 TC 104 Z9 111 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2000 VL 165 IS 4 BP 2190 EP 2197 PG 8 WC Immunology SC Immunology GA 342BW UT WOS:000088626200060 PM 10925306 ER PT J AU Nielsen, MB Monsurro, V Migueles, SA Wang, E Perez-Diez, A Lee, KH Kammula, U Rosenberg, SA Marincola, FM AF Nielsen, MB Monsurro, V Migueles, SA Wang, E Perez-Diez, A Lee, KH Kammula, U Rosenberg, SA Marincola, FM TI Status of activation of circulating vaccine-elicited CD8(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MELANOMA PATIENTS; PEPTIDE VACCINATION; IMMUNE-RESPONSE; PERIPHERAL-BLOOD; IN-VIVO; LYMPHOCYTES; ANTIGEN; FREQUENCY; CTL; AVIDITY AB Selective blunting of the status of activation of circulating tumor-specific T cells was invoked to explain their paradoxical coexistence with unhampered tumor growth. By analogy, lack of tumor regression in the face of observable melanoma vaccine-induced T cell responses might be attributed to their status of activation. We enumerated with HLA-A*0201/peptide tetramers (tHLA) vaccine-elicited T cell precursor frequency directly in PBMC of patients with melanoma undergoing vaccination with the HLA-A*0201-associated gp100:209-217(210 M) epitope (g209-2 M), Furthermore, we tested by intracellular (IC)-FACS analysis and quantitative real-time PCR (qRT-PCR) the ability of postvaccination PBMC to produce cytokine in response to challenge with vaccine-related epitopes or vaccine-matched (HLA-A*0201) melanoma cells. Vaccine-induced enhancement of T cell precursor frequency could be detected with tHLA in PBMC from six of eight patients studied at frequencies ranging between 0.3 and 2.3% of the total CD8(+) population, Stimulation with vaccine-related epitopes induced IFN-gamma expression detectable by IC-FACS or qRT-PCR, respectively, in five and six of these patients. Furthermore, down-regulation of tHLA staining was noted upon cognate stimulation that could be utilized as an additional marker of T cell responsiveness. Finally, we observed in six patients an enhancement of reactivity against vaccine-matched tumor targets that was partly independent of documented vaccine-specific immune responses. A strong correlation was noted between tHLA staining of postvaccination PBMC and IFN-gamma expression by the same samples upon vaccine-relevant stimulation and assessed either by IC-FACS or qRT-PCR, Thus, blunting of the status of T cell activation on itself cannot easily explain the lack of clinical responses observed with vaccination. C1 NCI, Surg Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. NIAID, Dept Transfus Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NCI, Surg Branch, Div Clin Sci, NIH, Bldg 10,Room 2B42,10 Ctr Dr MSC 1502, Bethesda, MD 20892 USA. NR 41 TC 99 Z9 101 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2000 VL 165 IS 4 BP 2287 EP 2296 PG 10 WC Immunology SC Immunology GA 342BW UT WOS:000088626200072 PM 10925318 ER PT J AU Frolenkov, GI Mammano, F Belyantseva, IA Coling, D Kachar, B AF Frolenkov, GI Mammano, F Belyantseva, IA Coling, D Kachar, B TI Two distinct Ca2+-dependent signaling pathways regulate the motor output of cochlear outer hair cells SO JOURNAL OF NEUROSCIENCE LA English DT Article DE sensory transduction; electromotility; voltage-dependent capacitance; cochlea; endoplasmic reticulum; patch clamp; organ of Corti ID GUINEA-PIG COCHLEA; ELECTROKINETIC SHAPE CHANGES; IMMUNOHISTOCHEMICAL LOCALIZATION; ELECTRICAL AMPUTATION; GATING CHARGE; ACETYLCHOLINE; CALCIUM; MOTILITY; CURRENTS; CAPACITANCE AB The outer hair cells (OHCs) of the cochlea have an electromotility mechanism, based on conformational changes of voltage-sensitive "motor" proteins in the lateral plasma membrane. The translocation of electrical charges across the membrane that accompanies electromotility imparts a voltage dependency to the membrane capacitance. We used capacitance measurements to investigate whether electromotility may be influenced by different manipulations known to affect intracellular Ca2+ or Ca2+-dependent protein phosphorylation. Application of acetylcholine (ACh) to the synaptic pole of isolated OHCs evoked a Ca2+-activated apamin-sensitive outward K+ current. It also enhanced electromotility, probably because of a phosphorylation-dependent decrease of the cell's axial stiffness. However, ACh did not change the voltage-dependent capacitance either in conventional whole-cell experiments or under perforated-patch conditions. The effects produced by the Ca2+ ionophore ionomycin mimicked those produced by ACh. Hyperpolarizing shifts of the voltage dependence of capacitance and electromotility were induced by okadaic acid, a promoter of protein phosphorylation, whereas trifluoperazine and W-7, antagonists of calmodulin, caused opposite depolarizing shifts. Components of the protein phosphorylation cascade-IP3 receptors and calmodulin-dependent protein kinase type IV-were immunolocalized to the lateral wall of the OHC. Our results suggest that two different Ca2+-dependent pathways may control the OHC motor output. The first pathway modulates cytoskeletal stiffness and can be activated by ACh. The second pathway shifts the voltage sensitivity of the OHC electromotile mechanism and may be activated by the release of Ca2+ from intracellular stores located in the proximity of the lateral plasma membrane. C1 Natl Inst Deafness & Other Commun Disorders, Sect Struct Cell Biol, Nihon Univ, Bethesda, MD 20892 USA. Int Sch Adv Studies, Ist Nazl Fis Mat, I-34014 Trieste, Italy. RP Kachar, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Struct Cell Biol, Nihon Univ, Bldg 36,Room 5D15, Bethesda, MD 20892 USA. RI Mammano, Fabio/I-5064-2012; OI Mammano, Fabio/0000-0003-3751-1691; Coling, Donald/0000-0001-6285-5336 NR 51 TC 70 Z9 74 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 AUG 15 PY 2000 VL 20 IS 16 BP 5940 EP 5948 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 342ZC UT WOS:000088676400008 PM 10934241 ER PT J AU Li, BS Zhang, L Gu, JG Amin, ND Pant, HC AF Li, BS Zhang, L Gu, JG Amin, ND Pant, HC TI Integrin alpha(1)beta(1)-mediated activation of cyclin-dependent kinase 5 activity is involved in neurite outgrowth and human neurofilament protein H Lys-Ser-Pro tail domain phosphorylation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cdk5; p35; neurofilament; integrin; matrix; laminin; retinoic acid ID AMYOTROPHIC LATERAL SCLEROSIS; PERIPHERAL-NERVE REGENERATION; PHEOCHROMOCYTOMA PC12 CELLS; PAIRED HELICAL FILAMENTS; EXTRACELLULAR-MATRIX; AXONAL-TRANSPORT; RETINOIC ACID; MAMMALIAN NEUROFILAMENTS; NEUROBLASTOMA-CELLS; LAMININ RECEPTOR AB Cellular adhesion to the extracellular matrix is mediated by a diverse class of alpha/beta heterodimeric receptors known as integrins, which transduce signals to activate multiple intracellular signal transduction pathways within the cells. The signaling pathway linking integrins to mediate neuronal process outgrowth is not well understood. Here, we have provided evidence that intracellular signaling by the alpha(1)beta(1) integrin-induced activation of cyclin-dependent kinase 5 (cdk5) is involved in neurite outgrowth and human neurofilament protein H (hNF-H) Lys-Ser-Pro (KSP) tail domain phosphorylation in differentiated human SH-SY5Y cells. The integrin alpha(1) and beta(1) monoclonal antibodies and BL-1, a specific cdk5 inhibitor, inhibited these effects. We also demonstrated that cdk5 activity and hNF-H KSP tail domain phosphorylation were increased in cdk5/p35 and hNF-H tail domain co-transfected HEK293 cells grown on laminin. This increased hNF-H tail domain phosphorylation was triggered by cdk5 activation. Taken together, these results indicated that cdk5 may play an important role in promoting neurite outgrowth and hNF-H tail KSP domain phosphorylation through the integrin alpha(1)beta(1) signaling pathway. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NIMH, Behav & Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Room 4D20,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 84 TC 83 Z9 86 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 15 PY 2000 VL 20 IS 16 BP 6055 EP 6062 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 342ZC UT WOS:000088676400022 PM 10934255 ER PT J AU Kim, WG Mohney, RP Wilson, B Jeohn, GH Liu, B Hong, JS AF Kim, WG Mohney, RP Wilson, B Jeohn, GH Liu, B Hong, JS TI Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: Role of microglia SO JOURNAL OF NEUROSCIENCE LA English DT Article DE endotoxin; lipopolysaccharide; inflammation; gliamediated neurotoxicity; midbrain; microglia; Parkinson's disease ID CENTRAL-NERVOUS-SYSTEM; ACTIVATED HUMAN MICROGLIA; NITRIC-OXIDE; ALZHEIMERS-DISEASE; CULTURES; EXPRESSION; CONSEQUENCES; ASTROCYTES; CYTOKINES; INDUCTION AB Inflammation in the brain has been increasingly associated with the development of a number of neurological diseases. The hallmark of neuroinflammation is the activation of microglia, the resident brain immune cells. Injection of bacterial endotoxin lipopolysaccharide (LPS) into the hippocampus, cortex, or substantia nigra of adult rats produced neurodegeneration only in the substantia nigra. Although LPS appeared to impact upon mesencephalic neurons in general, an extensive loss of dopaminergic neurons was observed. Analysis of the abundance of microglia revealed that the substantia nigra had the highest density of microglia. When mixed neuron-glia cultures derived from the rat hippocampus, cortex, or mesencephalon were treated with LPS, mesencephalic cultures became sensitive to LPS at a concentration as low as 10 ng/ml and responded in a dose-dependent manner with the production of inflammatory factors and a loss of dopaminergic and other neurons. In contrast, hippocampal or cortical cultures remained insensitive to LPS treatment at concentrations as high as 10 mg/ml. Consistent with in vivo observations, mesencephalic cultures had fourfold to eightfold more microglia than cultures from other regions. The positive correlation between abundance of microglia and sensitivity to LPS-induced neurotoxicity was further supported by the observation that supplementation with enriched microglia derived from mesencephalon or cortex rendered LPS-insensitive cortical neuron-glia cultures sensitive to LPS-induced neurotoxicity. These data indicate that the region-specific differential susceptibility of neurons to LPS is attributable to differences in the number of microglia present within the system and may reflect levels of inflammation-related factors produced by these cells. C1 NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Hong, JS (reprint author), NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, POB 12233,MD Fl-01, Res Triangle Pk, NC 27709 USA. RI liu, Bin/A-7695-2009 NR 35 TC 538 Z9 568 U1 4 U2 42 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 AUG 15 PY 2000 VL 20 IS 16 BP 6309 EP 6316 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 342ZC UT WOS:000088676400050 PM 10934283 ER PT J AU Phillips, LR Malspeis, L Tubbs, EK Supko, JG AF Phillips, LR Malspeis, L Tubbs, EK Supko, JG TI Characterization of a novel degradation product of 2,2 '-dithiobis[N-isoleucylbenzamide], an inhibitor of HIV nucleocapsid protein zinc fingers SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE 2,2 '-dithiobis[N-isoleucylbenzamide]; benzisothiazolone; antiviral agents; liquid chromatography; mass spectrometry; nuclear magnetic resonance spectroscopy ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTI-HIV; DISULFIDE BENZAMIDES; BINDING DOMAINS; EJECTION; AGENTS; BENZISOTHIAZOLONES; AIDS AB Zinc finger motifs have been found to be important in a variety of protein structures including transcription factors and viral nucleocapsid proteins. Recently, it was demonstrated that various aromatic disulfides effectively remove the metal ion from the zinc finger, resulting in an alteration of tertiary structure in this region of the protein, thereby inhibiting transcription. Among these compounds, 2,2'-dithiobis[N-isoleucylbenzamide] exhibits activity against human immunodeficiency virus (HIV)-type 1 in vitro and has been selected for preclinical development as an anti-HIV agent. Analysis of this agent by reversed-phase high-performance liquid chromatography (HPLC) indicated a significant quantity of two additional compounds. Identifying the parent disulfide was accomplished by scanning eluting peaks with positive ion thermospray ionization (TSP) mass spectrometry (RIS). Solution-induced disproportionation of the disulfide into its sulfydryl monomer was demonstrated by treating the drug with dithiothreitol (DTT) prior to HPLC analysis. TSP-MS analysis of the remaining chromatographic peak suggested a molecular weight of 265, which, with H-1-nuclear magnetic resonance (NMR) data of the isolated material, allowed us to elucidate the chemical structure as N-isoleucyl-benzisothiazolone. Contact with stainless steel, such as that employed in an HPLC system, was found to accelerate degradation of the parent disulfide to the benzisothiazolone. (C) Published by Elsevier Science B.V. C1 NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Lab Drug Discovery Res & Dev, Frederick, MD 21701 USA. Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21701 USA. RP Phillips, LR (reprint author), NCI, Div Canc Treatment & Diag, Dev Therapeut Program, Lab Drug Discovery Res & Dev, Frederick, MD 21701 USA. FU NCI NIH HHS [N01-CO-56000] NR 16 TC 8 Z9 9 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD AUG 15 PY 2000 VL 23 IS 2-3 BP 395 EP 402 DI 10.1016/S0731-7085(00)00311-3 PG 8 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 337YU UT WOS:000088391700017 PM 10933532 ER PT J AU Cervenakova, L Protas, II Hirano, A Votiakov, VI Nedzved, MK Kolomiets, ND Taller, I Park, KY Sambuughin, N Gajdusek, DC Brown, P Goldfarb, LG AF Cervenakova, L Protas, II Hirano, A Votiakov, VI Nedzved, MK Kolomiets, ND Taller, I Park, KY Sambuughin, N Gajdusek, DC Brown, P Goldfarb, LG TI Progressive muscular atrophy variant of familial amyotrophic lateral sclerosis (PMA/ALS) SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article DE familial amyotrophic lateral sclerosis; SOD1 gene; D101N mutation; Belarus ID CU/ZN SUPEROXIDE-DISMUTASE; MOTOR NEURON DISEASE; MOLECULAR PATHOLOGY; SOD1 MUTATION; GENE; EXON-4; IDENTIFICATION; INVOLVEMENT; PATIENT AB Twelve cases of adult-onset progressive muscular atrophy variant of amyotrophic lateral sclerosis (PMA/ALS) were studied in a small rural population of 1500 in the Republic of Belarus (former Soviet Union). The patients were members of three apparently related kindreds, each showing autosomal dominant pattern of disease inheritance. The average age at clinical onset ranged from 26 to 57 years (mean, 40 years). Each patient suffered from skeletal muscle weakness and wasting, starting in the limbs and spreading to the trunk and neck, with very limited bulbar and no upper motor neuron involvement. Death from respiratory failure occurred from 13 to 48 months (mean, 28 months) after first symptoms. Dramatically decreased number of spinal motor neurons was the most characteristic neuropathologic feature in two autopsied cases. Most of the remaining degenerating neurons contained intracytoplasmic hyaline inclusion bodies. A D101N mutation in exon 4 of the SOD1 gene was identified in a PMA/ALS patient and in one of her three unaffected children. Our data support the view that some subtypes of familial ALS associated with SOD1 mutations may present as PMA. Diagnostic criteria of ALS should be accordingly modified to include the PMA variant of familial ALS. (C) 2000 Published by Elsevier Science B.V. C1 NINDS, NIH, Bethesda, MD 20892 USA. Amer Red Cross, Jerome H Holland Lab, Rockville, MD 20855 USA. Belarussian Inst Epidemiol & Microbiol, Minsk, Byelarus. Montefiore Med Ctr, Bronx, NY 10467 USA. Barrow Neurol Inst, Phoenix, AZ 85013 USA. Univ Amsterdam, Dept Human Virol, NL-1105 AZ Amsterdam, Netherlands. RP Goldfarb, LG (reprint author), NIH, Bldg 10,Room 4B37,10 Convent Dr,MSC 1361, Bethesda, MD 20892 USA. NR 30 TC 15 Z9 15 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD AUG 15 PY 2000 VL 177 IS 2 BP 124 EP 130 DI 10.1016/S0022-510X(00)00350-6 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 357NE UT WOS:000089507100005 PM 10980308 ER PT J AU Sunesen, M Selzer, RR Brosh, RM Balajee, AS Stevnsner, T Bohr, VA AF Sunesen, M Selzer, RR Brosh, RM Balajee, AS Stevnsner, T Bohr, VA TI Molecular characterization of an acidic region deletion mutant of Cockayne syndrome group B protein SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; TRANSCRIPTION-COUPLED REPAIR; PCNA COMPLEX-FORMATION; TATA-BINDING PROTEIN; DNA-DAMAGING AGENTS; PIGMENTOSUM GROUP-A; XERODERMA-PIGMENTOSUM; SYNDROME CELLS; ACTIVE GENES; ELONGATION COMPLEXES AB Cockayne syndrome (CS) is a human genetic disorder characterized by post-natal growth failure, neurological abnormalities and premature aging. CS cells exhibit high sensitivity to UV light, delayed RNA synthesis recovery after UV irradiation and defective transcription-coupled repair (TCR). Two genetic complementation groups of CS have been identified, designated CS-A and CS-B, The CSB gene encodes a helicase domain and a highly acidic region N-terminal to the helicase domain. This study describes the genetic characterization of a CSB mutant allele encoding a full deletion of the acidic region, We have tested its ability to complement the sensitivity of UV61, the hamster homolog of human CS-B cells, to UV and the genotoxic agent N-acetoxy-2-acetylaminofluorene (NA-AAF), Deleting 39 consecutive amino acids, of which similar to 60% are negatively charged, did not impact on the ability of the protein to complement the sensitive phenotype of UV61 cells to either UV or NA-AAF, Our data indicate that the highly acidic region of CSB is not essential for the TCR and general genome repair pathways of UV- and NA-AAF-induced DNA lesions. C1 Univ Aarhus, Dept Biol Mol & Struct, DK-8000 Aarhus C, Denmark. NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. RP Univ Aarhus, Dept Biol Mol & Struct, DK-8000 Aarhus C, Denmark. EM vbohr@nih.gov NR 62 TC 16 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG 15 PY 2000 VL 28 IS 16 BP 3151 EP 3159 DI 10.1093/nar/28.16.3151 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 346DC UT WOS:000088854600019 PM 10931931 ER PT J AU Straus, SE AF Straus, SE TI Immunoactive cannabinoids: therapeutic prospects for marijuana constituents SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID RECEPTOR C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Straus, SE (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Bldg 10, Bethesda, MD 20892 USA. NR 20 TC 16 Z9 17 U1 2 U2 4 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 AUG 15 PY 2000 VL 97 IS 17 BP 9363 EP 9364 DI 10.1073/pnas.180314297 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 345XM UT WOS:000088840500006 PM 10931962 ER PT J AU Vogel, JL Kristie, TM AF Vogel, JL Kristie, TM TI Autocatalytic proteolysis of the transcription factor-coactivator C1 (HCF): A potential role for proteolytic regulation of coactivator function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protease; enhancer; trans-cleavage; transport ID HERPES-SIMPLEX VIRUS; HOST-CELL FACTOR; INTRACELLULAR DOMAIN; PRECURSOR PROTEIN; NUCLEAR ACCESS; IN-VIVO; VP16; COMPLEX; PATHWAY; NOTCH AB Site-specific proteolysis is an important biological mechanism for the regulation of cellular processes such as gene expression, cell signaling, development, and apoptosis. In transcriptional regulation, specific proteolysis regulates the localization and activity of many regulatory factors. The C1 factor (HCF), a cellular transcription factor and coactivator, undergoes site-specific proteolytic processing at a series of unusual amino acid reiterations to generate a family of amino- and carboxyl-terminal polypeptides that remain tightly associated. Expression and purification of bacterially expressed domains of the CI factor identifies an autocatalytic activity that is responsible for the specific cleavage of the reiterations. In addition, coexpression of the autocatalytic domain with a heterologous protein containing a target cleavage site demonstrates that the C1 protease may also function in trans. C1 NIH, Viral Dis Lab, Bethesda, MD 20892 USA. RP Kristie, TM (reprint author), NIH, Viral Dis Lab, Bldg 4,Room 133,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 42 TC 23 Z9 26 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 AUG 15 PY 2000 VL 97 IS 17 BP 9425 EP 9430 DI 10.1073/pnas.160266697 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 345XM UT WOS:000088840500018 PM 10920196 ER PT J AU Wolfgang, CD Essand, M Vincent, JJ Lee, B Pastan, I AF Wolfgang, CD Essand, M Vincent, JJ Lee, B Pastan, I TI TARP: A nuclear protein expressed in prostate and breast cancer cells derived from an alternate reading frame of the T cell receptor gamma chain locus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE expressed sequence tag; leucine zipper; nucleus ID GENE-EXPRESSION; CARCINOMA; RNA; DATABASE; COMPLEX; LINES; TUP1 AB previously, we identified the expression of a prostate-specific form of T cell receptor gamma chain (TCR gamma) mRNA in the human prostate and demonstrated that it originates from epithelial cells and not from infiltrating T lymphocytes. Here, we show that this prostate-specific transcript is also expressed in three breast cancer cell lines and breast cancer tissues. Analysis of the cDNA sequence predicts that this transcript can encode two protein products of 7 and 13 kDa, and in vitro translation experiments showed that both proteins were made. The longer ORF encodes a 13-kDa truncated version of TCR gamma, whereas the shorter alternative reading frame encodes a 7-kDa protein with five leucine residues in heptad repeats followed by a basic region. Studies with specific antibodies against each protein product revealed that both prostate and breast cancer cells contain only the 7-kDa protein, which is located in the nucleus. We have named this protein TCR gamma alternate reading frame protein (TARP). These results demonstrate that an alternative protein product is encoded by the TCR gamma locus in cells other than T lymphocytes. 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, Bethesda, MD 20892 USA. NR 26 TC 50 Z9 50 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 AUG 15 PY 2000 VL 97 IS 17 BP 9437 EP 9442 DI 10.1073/pnas.160270597 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 345XM UT WOS:000088840500020 PM 10931945 ER PT J AU Goldman, ASH Lichten, M AF Goldman, ASH Lichten, M TI Restriction of ectopic recombination by interhomolog interactions during Saccharomyces cerevisiae meiosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE homolog pairing; sequence divergence; NDJ1 ID SYNAPTONEMAL COMPLEX-FORMATION; MEIOTIC GENE CONVERSION; DOUBLE-STRAND BREAKS; CHROMOSOME SYNAPSIS; BUDDING YEAST; DROSOPHILA-MELANOGASTER; HOMOLOGOUS CHROMOSOMES; CHECKPOINT GENES; CELLS; CARLSBERGENSIS AB In Saccharomyces cerevisiae meiosis, recombination occurs frequently between sequences at the same location on homologs (allelic recombination) and can take place between dispersed homologous sequences (ectopic recombination). Ectopic recombination occurs less often than does allelic, especially when homologous sequences are on heterologous chromosomes. To account for this, it has been suggested that homolog pairing (homolog colocalization and alignment) either promotes allelic recombination or restricts ectopic recombination. The latter suggestion was tested by examining ectopic recombination in two cases where normal interhomolog relationships are disrupted. In the first case, one member of a homolog pair was replaced by a homoeologous (related but not identical) chromosome that has diverged sufficiently to prevent allelic recombination. In the second case, ndj1 mutants were used to delay homolog pairing and synapsis. Both circumstances resulted in a substantial increase in the frequency of ectopic recombination between arg4-containing plasmid inserts located on heterologous chromosomes. These findings suggest that, during normal yeast meiosis, progressive homolog colocalization, alignment, synapsis, and allelic recombination restrict the ability of ectopically located sequences to find each other and recombine. In the absence of such restrictions, the meiotic homology search may encompass the entire genome. C1 Univ Sheffield, Dept Mol Biol & Biotechnol, Sheffield S10 2TN, S Yorkshire, England. NCI, Div Basic Sci, Biochem Lab, Bethesda, MD 20892 USA. RP Lichten, M (reprint author), NIH, Bldg 37,Room 4C03,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. RI Lichten, Michael/C-5795-2013 OI Lichten, Michael/0000-0001-9707-2956 NR 51 TC 62 Z9 63 U1 1 U2 4 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 AUG 15 PY 2000 VL 97 IS 17 BP 9537 EP 9542 DI 10.1073/pnas.97.17.9537 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 345XM UT WOS:000088840500038 PM 10944222 ER PT J AU Kainu, T Juo, SHH Desper, R Schaffer, AA Gillanders, E Rozenblum, E Freas-Lutz, D Weaver, D Stephan, D Bailey-Wilson, J Kallioniemi, OP Tirkkonen, M Syrjakoski, K Kuukasjarvi, T Koivisto, P Karhu, R Holli, K Arason, A Johannesdottir, G Bergthorsson, JT Johannsdottir, H Egilsson, V Barkardottir, RB Johannsson, O Haraldsson, K Sandberg, T Holmberg, E Gronberg, H Olsson, H Borg, A Vehmanen, P Eerola, H Heikkila, P Pyrhonen, S Nevanlinna, H AF Kainu, T Juo, SHH Desper, R Schaffer, AA Gillanders, E Rozenblum, E Freas-Lutz, D Weaver, D Stephan, D Bailey-Wilson, J Kallioniemi, OP Tirkkonen, M Syrjakoski, K Kuukasjarvi, T Koivisto, P Karhu, R Holli, K Arason, A Johannesdottir, G Bergthorsson, JT Johannsdottir, H Egilsson, V Barkardottir, RB Johannsson, O Haraldsson, K Sandberg, T Holmberg, E Gronberg, H Olsson, H Borg, A Vehmanen, P Eerola, H Heikkila, P Pyrhonen, S Nevanlinna, H TI Somatic deletions in hereditary breast cancers implicate 13q21 as a putative novel breast cancer susceptibility locus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; PEUTZ-JEGHERS-SYNDROME; GERM-LINE MUTATIONS; LINKAGE ANALYSIS; TUMOR PROGRESSION; DISTINCT REGIONS; FAMILIAL BREAST; PROSTATE-CANCER; CHROMOSOME 13Q; ALLELIC LOSS AB A significant proportion of familial breast cancers cannot be explained by mutations in the BRCA1 or BRCA2 genes. We applied a strategy to identify predisposition loci for breast cancer by using mathematical models to identify early somatic genetic deletions in tumor tissues followed by targeted linkage analysis. Comparative genomic hybridization was used to study 61 breast tumors from 37 breast cancer families with no identified BRCA1 or BRCA2 mutations. Branching and phylogenetic tree models predicted that loss of 13q was one of the earliest genetic events in hereditary cancers. In a Swedish family with five breast cancer cases, all analyzed tumors showed distinct 13q deletions, with the minimal region of loss at 13q21-q22. Genotyping revealed segregation of a shared 13q21 germ-line haplotype in the family. Targeted linkage analysis was carried out in a set of 77 Finnish, Icelandic, and Swedish breast cancer families with no detected BRCA1 and BRCA2 mutations. A maximum parametric two-point logarithm of odds score of 2.76 was obtained for a marker at 13q21 (D13S1308, theta = 0.10). The multipoint logarithm of odds score under heterogeneity was 3.46. The results were further evaluated by simulation to assess the probability of obtaining significant evidence in favor of linkage by chance as well as to take into account the possible influence of the BRCA2 locus, located at a recombination fraction of 0.25 from the new locus. The simulation substantiated the evidence of linkage at D13S1308 (P < 0.0017). The results warrant studies of this putative breast cancer predisposition locus in other populations. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Inherited Dis Res Branch, NIH, Bethesda, MD 20892 USA. Natl Ctr Biotechnol Informat, Computat Biol Branch, NIH, Bethesda, MD 20892 USA. Deutsch Krebsforschungszentrum, Abt Theroet Bioinformat, D-69120 Heidelberg, Germany. Tampere Univ, Canc Genet Lab, FIN-33520 Tampere, Finland. Tampere Univ, Dept Pathol, FIN-33520 Tampere, Finland. Tampere Univ, Dept Oncol, FIN-33520 Tampere, Finland. Tampere Univ Hosp, FIN-33520 Tampere, Finland. Univ Hosp Iceland, Dept Pathol, IS-101 Reykjavik, Iceland. Univ Hosp Iceland, Cell Biol Lab, IS-101 Reykjavik, Iceland. Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden. Univ Lund Hosp, Dept Oncol, SE-22185 Lund, Sweden. Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00029 Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Oncol, FIN-00029 Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Pathol, FIN-00029 Helsinki, Finland. Turku Univ Hosp, Dept Radiotherapy & Oncol, FIN-20520 Turku, Finland. RP Kallioniemi, OP (reprint author), NHGRI, Canc Genet Branch, NIH, 49 Convent Dr,MSC 4470,Room 4A24, Bethesda, MD 20892 USA. RI Juo, Suh-Hang/A-1765-2010; Kallioniemi, Olli/H-5111-2011; Schaffer, Alejandro/F-2902-2012; Juo, Suh-Hang/C-9545-2009; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Bailey-Wilson, Joan/0000-0002-9153-2920 NR 37 TC 132 Z9 134 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 AUG 15 PY 2000 VL 97 IS 17 BP 9603 EP 9608 DI 10.1073/pnas.97.17.9603 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 345XM UT WOS:000088840500049 PM 10944226 ER PT J AU DeBarber, AE Mdluli, K Bosman, M Bekker, LG Barry, CE AF DeBarber, AE Mdluli, K Bosman, M Bekker, LG Barry, CE TI Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CATALASE PEROXIDASE; GENOME SEQUENCE; TARGET; INHA; GENE; IDENTIFICATION; AGENT AB Ethionamide (ETA) is an important component of second-line therapy for the treatment of multidrug-resistant tuberculosis. Synthesis of radiolabeled ETA and an examination of drug metabolites formed by whole cells of Mycobacterium tuberculosis (MTb) have allowed us to demonstrate that ETA is activated by S-oxidation before interacting with its cellular target. ETA is metabolized by MTb to a 4-pyridylmethanol product remarkably similar in structure to that formed by the activation of isoniazid by the catalase-peroxidase KatG, We have demonstrated that overproduction of Rv3855 (EtaR), a putative regulatory protein from MTb, confers ETA resistance whereas overproduction of an adjacent, clustered monooxygenase (Rv3854c, EtaA) confers ETA hypersensitivity, Production of EtaA appears to be negatively regulated by EtaR and correlates directly with [C-14]ETA metabolism, suggesting that EtaA is the activating enzyme responsible for thioamide oxidation and subsequent toxicity. Coding sequence mutations in EtaA were found in 11 of 11 multidrug-resistant MTb patient isolates from Cape Town, South Africa. These isolates showed broad cross-resistance to thiocarbonyl containing drugs including ETA, thiacetazone, and thiocarbide. C1 NIAID, Host Def Lab, Tuberculosis Res Sect, NIH, Rockville, MD 20852 USA. Univ Cape Town, S African Inst Med Res, ZA-7937 Cape Town, South Africa. Univ Cape Town, Clin Infect Dis Res Unit, Dept Med, ZA-7937 Cape Town, South Africa. RP Barry, CE (reprint author), NIAID, Host Def Lab, Tuberculosis Res Sect, NIH, Twinbrook 2,Room 239,12441 Parklawn Dr, Rockville, MD 20852 USA. RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11] NR 45 TC 186 Z9 201 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 15 PY 2000 VL 97 IS 17 BP 9677 EP 9682 DI 10.1073/pnas.97.17.9677 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 345XM UT WOS:000088840500062 PM 10944230 ER PT J AU Doody, MM Lonstein, JE Stovall, M Hacker, DG Luckyanov, N Land, CE AF Doody, MM Lonstein, JE Stovall, M Hacker, DG Luckyanov, N Land, CE CA US Scoliosis Cohort Study Collab TI Breast cancer mortality after diagnostic radiography - Findings from the US Scoliosis Cohort Study SO SPINE LA English DT Article DE breast neoplasms; radiation-induced; cohort study; epidemiology; mortality; radiation; radiography; scoliosis ID ATOMIC-BOMB SURVIVORS; ADOLESCENT IDIOPATHIC SCOLIOSIS; SPINAL RADIOGRAPHS; LIFETIME RISK; RADIATION; TUBERCULOSIS; FLUOROSCOPY; IRRADIATION; DISEASE; INFANCY AB Study Design. A retrospective cohort study was conducted in 5573 female patients with scoliosis who were referred for treatment at 14 orthopedic medical centers in the United States, Patients were less than 20 years of age at diagnosis which occurred between 1912 and 1965. Objectives. To evaluate patterns in breast cancer mortality among women with scoliosis, with special emphasis on risk associated with diagnostic radiograph exposures. Summary of Background Data. A pilot study of 1030 women with scoliosis revealed a nearly twofold statistically significant increased risk for incident breast cancer. Although based on only 11 cases, findings were consistent with radiation as a causative factor. Methods. Medical records were reviewed for information on personal characteristics and scoliosis history. Diagnostic radiographic exposures were tabulated based on review of radiographs, radiology reports in the medical records, radiograph jackets, and radiology log books. Radiation doses were estimated for individual examinations. The mortality rate of the cohort through January 1, 1997, was determined by using state and national vital statistics records and was compared with that of women in the general U.S. population. Results. Nearly 138,000 radiographic examinations 'average number of examinations per patient was 24.7 (range, 0-618); mean estimated cumulative radiation dose to the breast was 10.8 cGy (range, 0-170). After excluding patients with missing information, 5466 patients were included in breast cancer mortality analyses. Their mean age at diagnosis was 10.6 years and average length of follow-up was 40.1 years. There were 77 breast cancer deaths observed compared with the 45.6 deaths expected on the basis of U.S. mortality rates (standardized mortality ratio [SMR] = 1.69; 95% confidence interval [CI] = 1.3-2.1). Risk increased significantly with increasing number of radiograph exposures cumulative radiation dose. The unadjusted excess relative risk per Gy was 5.4 (95% CI = 1.2-14.1); when analyses were restricted to patients who had undergone at least one radiographic examination, the risk estimate was 2.7 (95% CI = -0.2-9.3). Conclusions. These data suggest that exposure to multiple diagnostic radiographic examination during childhood and adolescence may increase the risk of breast cancer among women with scoliosis; however, potential confounding between radiation dose and severity of disease and thus wit reproductive history may explain some of the increased risk observed. C1 NCI, Radiat Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Twin Cities Spine Ctr, Minneapolis, MN USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Doody, MM (reprint author), NCI, Radiat Epidemiol Branch, NIH, Execut Plaza S,Room 7088, Bethesda, MD 20892 USA. RI Hacker, David/D-5134-2011; OI Hacker, David/0000-0002-0762-9667 FU NCI NIH HHS [N01-CP-40535, N01-CP-85651, N02-CP-33013] NR 37 TC 235 Z9 247 U1 2 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-2436 J9 SPINE JI SPINE PD AUG 15 PY 2000 VL 25 IS 16 BP 2052 EP 2063 PG 12 WC Clinical Neurology; Orthopedics SC Neurosciences & Neurology; Orthopedics GA 345XA UT WOS:000088839400010 PM 10954636 ER PT J AU Pletnev, AG Karganova, GG Dzhivanyan, TI Lashkevich, VA Bray, M AF Pletnev, AG Karganova, GG Dzhivanyan, TI Lashkevich, VA Bray, M TI Chimeric Langat/Dengue viruses protect mice from heterologous challenge with the highly virulent strains of tick-borne encephalitis virus SO VIROLOGY LA English DT Article ID DENGUE TYPE-4 VIRUSES; SEQUENCE AB Langat virus (LGT), a tick-borne flavivirus, is naturally attenuated for humans but it is very virulent in SCID mice. In contrast, viable recombinant chimeras of LGT (preM and E genes) and dengue type 4 virus (all other sequences) recovered in mosquito cell culture were completely attenuated in SCID mice but still capable of providing protection against LGT. To develop the chimeras into Vaccine candidates, we adapted them to replicate efficiently in simian Vero cells, a satisfactory substrate for human vaccines. The adapted chimeras remained completely attenuated for SCID mice and, significantly provided protection in immunocompetent mice against tick-borne encephalitis virus, the most virulent of the tick-borne flaviviruses. (C) 2000 Academic Press. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Russian Acad Med Sci, Chumakovs Inst Poliomyelitis & Viral Encephalitis, Moscow 142782, Russia. USA, Med Res Inst Infect Dis, Div Virol, Ft Detrick, MD 21702 USA. RP Pletnev, AG (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 7,Room 236,7 Ctr Dr,MSC 0740, Bethesda, MD 20892 USA. RI Karganova, Galina/D-8601-2014 NR 18 TC 26 Z9 31 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 AUG 15 PY 2000 VL 274 IS 1 BP 26 EP 31 DI 10.1006/viro.2000.0426 PG 6 WC Virology SC Virology GA 347YW UT WOS:000088957600005 PM 10936085 ER PT J AU Forns, X Allander, T Rohwer-Nutter, P Bukh, J AF Forns, X Allander, T Rohwer-Nutter, P Bukh, J TI Characterization of modified hepatitis C virus E2 proteins expressed on the cell surface SO VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODIES; GLYCOPROTEIN COMPLEXES; HYPERVARIABLE REGION-1; ENDOPLASMIC-RETICULUM; TRANSMEMBRANE DOMAIN; RECOMBINANT VACCINIA; HYPERIMMUNE SERUM; DNA IMMUNIZATION; IMMUNE-RESPONSES; INFECTION AB The envelope proteins of hepatitis C virus (HCV) are the likely targets of neutralizing antibodies and their molecular and functional characterization is relevant for vaccine development. We previously showed that surface-expressed E2 is a better immunogen than intracellular E2 and, therefore, we were interested in exploring more efficient ways to present E2 protein on the cell surface. We found that E2 targeted to the cell surface by replacement of its transmembrane domain did not bring El to the surface although El could be expressed independently on the cell surface if its transmembrane domain was similarly replaced. FAGS analysis suggested that E2 expressed on the cell surface acquired its native conformation more efficiently when truncated at aa 661 than when truncated at aa 715. The shorter form of truncated E2 better retained the ability to bind the second extracellular loop (EC2) of CD81, the putative HCV receptor. Interestingly, deletion of the hypervariable region 1 (HVR1) did not perceptibly alter E2 structure; cell-surface forms of E2 lacking the HVR1 remained reactive with conformation-sensitive MAbs and were able to bind recombinant EC2 of CD81, (C) 2000 Academic Press. C1 NIAID, Infect Dis Lab, Hepatitis Viruses Sect, NIH, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, Mol Hepatitis Sect, NIH, Bethesda, MD 20892 USA. RP Forns, X (reprint author), Hosp Clin Barcelona, Liver Unit, Villarroel 170, E-08036 Barcelona, Spain. FU NCI NIH HHS [CO-56000] NR 37 TC 32 Z9 35 U1 2 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 AUG 15 PY 2000 VL 274 IS 1 BP 75 EP 85 DI 10.1006/viro.2000.0419 PG 11 WC Virology SC Virology GA 347YW UT WOS:000088957600010 PM 10936090 ER PT J AU Dekaban, GA Peters, AA Mulloy, JC Johnson, JM Trovato, R Rivadeneira, E Franchini, G AF Dekaban, GA Peters, AA Mulloy, JC Johnson, JM Trovato, R Rivadeneira, E Franchini, G TI The HTLV-I orfl protein is recognized by serum antibodies from naturally infected humans and experimentally infected rabbits SO VIROLOGY LA English DT Article ID VIRUS TYPE-I; CELL LEUKEMIA-VIRUS; OPEN READING FRAMES; BOVINE PAPILLOMAVIRUS; IMMORTALIZATION; LYMPHOCYTES; EXPRESSION; BINDS AB The mechanism of T-cell transformation by human T-cell lymphotropic virus type I (HTLV-I), though not completely understood, appears to involve the interactions of several viral and cellular proteins. One of these viral proteins, p12(1), encoded by HTLV-I orfl, is a weak oncogene that binds the 16-kDa subunit of the vacuolar ATPase and interacts with the immature beta and gamma(c) chains of the IL-2 receptor. We have expressed the singly spliced om cDNA in the baculovirus system a nd used the recombinant protein as a tool to assess the presence of antibodies in naturally or experimentally infected hosts In addition, rabbit antisera were raised against Various p12(1) synthetic peptides and used to identify three antigenic regions within p12(1), one between the two putative transmembrane regions of p12(1) and two at the carboxy-terminus of the protein. Mote importantly, sera from a naturally infected human (1 of 32) and experimentally infected rabbits (9 of 20) recognized the rp12(1), demonstrating orfl expression and immunogenicity in vivo. Taken together these data provide the first evidence of orfl expression during HTLV-I infections, (C) 2000 Academic Press. C1 NCI, Div Basic Sci, Sect Anim Models & Retroviral Vaccines, Basic Res Lab,NIH, Bethesda, MD 20892 USA. Univ Western Ontario, John P Robarts Res Inst, Gene Therapy & Mol Virol Grp, London, ON N6A 5K8, Canada. Univ Western Ontario, Dept Immunol & Microbiol, London, ON N6A 5K8, Canada. RP Franchini, G (reprint author), NCI, Div Basic Sci, Sect Anim Models & Retroviral Vaccines, Basic Res Lab,NIH, 41 Lib Dr,41-D804, Bethesda, MD 20892 USA. RI Dekaban, Gregory/L-1987-2013 OI Dekaban, Gregory/0000-0002-3087-4660 NR 22 TC 29 Z9 29 U1 0 U2 0 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 AUG 15 PY 2000 VL 274 IS 1 BP 86 EP 93 DI 10.1006/viro.2000.0406 PG 8 WC Virology SC Virology GA 347YW UT WOS:000088957600011 PM 10936091 ER PT J AU Kumar, A Lifson, JD Silverstein, PS Jia, F Sheffer, D Li, Z Narayan, O AF Kumar, A Lifson, JD Silverstein, PS Jia, F Sheffer, D Li, Z Narayan, O TI Evaluation of immune responses induced by HIV-1 gp120 in rhesus macaques: Effect of vaccination on challenge with pathogenic strains of homologous and heterologous simian human immunodeficiency viruses SO VIROLOGY LA English DT Article ID RECOMBINANT VACCINIA VIRUS; T-LYMPHOCYTE RESPONSES; PIG-TAILED MACAQUES; ENVELOPE GLYCOPROTEIN; ANTIBODY-RESPONSES; NEUTRALIZING ANTIBODIES; SUBUNIT VACCINES; TYPE-1 ISOLATE; PROTECTIVE IMMUNITY; MONOCLONAL-ANTIBODY AB The simian human immunodeficiency virus (SHIV) macaque model of AIDS has provided a very useful system for evaluation of envelope-based candidate vaccines against HIV-I. Eight rhesus macaques were immunized with monomeric recombinant gp120 of HIV-1(LA1) (rgp120) and used to evaluate whether this vaccine conferred protection against challenge with pathogenic SHIVs (SHIVKU-2 and SHIV89.6P). The vaccinated macaques developed high titers of antibodies against rgp120 that reacted efficiently with the envelope proteins of homologous SHIV (SHIVKU-2) and poorly with the SHIV89.6P envelope, a heterologous strain of SHIV. This vaccine also induced neutralizing antibodies but only against SHIVKU-2. Vaccine-induced antibodies were of high avidity and predominantly against linear epitopes on the protein. Vaccinated macaques developed gp120-specific T-helper cells but no consistent cytotoxic T lymphocytes. However, cellular immune responses were short-lived in all eight vaccinates. At week 22 postimmunization, four vaccinates were challenged with SHIVKU-2 and the other four with SHIV89.6P. Four unvaccinated control macaques were also infected: two with SHIVKU-2 and two with SHIV89.6P. Vaccinated macaques generally showed anamnestic antibody and T-helper cell responses. However, T-helper responses were again short-lived. Upon challenge, the level of productive virus replication was indistinguishable between vaccine and control groups, suggesting that rgp120 did not confer protection against virus replication when animals were challenged with homologous or heterologous SHIV viruses. (C) 2000 Academic Press. C1 Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Lab Viral Pathogenesis, Kansas City, KS 66160 USA. NCI, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Kumar, A (reprint author), Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Lab Viral Pathogenesis, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. FU NCRR NIH HHS [RR-06753]; NIAID NIH HHS [AI-29382]; NINDS NIH HHS [NS-32203] NR 73 TC 23 Z9 24 U1 0 U2 0 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 AUG 15 PY 2000 VL 274 IS 1 BP 149 EP 164 DI 10.1006/viro.2000.0444 PG 16 WC Virology SC Virology GA 347YW UT WOS:000088957600016 PM 10936096 ER PT J AU Biesecker, BB Ishibe, N Hadley, DW Giambarresi, TR Kase, RG Lerman, C Struewing, JP AF Biesecker, BB Ishibe, N Hadley, DW Giambarresi, TR Kase, RG Lerman, C Struewing, JP TI Psychosocial factors predicting BRCA1/BRCA2 testing decisions in members of hereditary breast and ovarian cancer families SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Article DE BRCA1/2 testing; hereditary cancer families; breast cancer; ovarian cancer; genetics education; genetic counseling; predisposition testing predictors ID HUNTINGTONS-DISEASE; SUSCEPTIBILITY; OPTIMISM; BRCA1; PESSIMISM; MOTIVATION; STRATEGIES; ATTITUDES; BEHAVIOR; QUALITY AB Although BRCA1/2 testing has increasingly entered clinical practice, much is to be learned about the most effective ways to provide counseling to persons potentially interested in receiving test results. The purpose of this study was to identify factors affecting genetic testing decisions in a cohort of hereditary breast and ovarian cancer (HBOC) families presented with the choice to undergo testing. Relatives in these families are known to carry BRCA1 or BRCA2 mutations, Sociodemographics, personality traits, and family functioning were self-assessed using validated psychometric instruments at baseline. Among 172 individuals who participated in pretest education and counseling, 135 (78%) chose to undergo genetic testing and 37 (22%) chose not to be tested. Individuals who chose to undergo genetic testing were more likely to be older (greater than or equal to 40 years), to have lower levels of optimism, and to report higher levels of cohesiveness in their families. A better understanding of factors that influence interest in predictive testing may help to inform the counseling that occurs prior to genetic testing. Published 2000 Wiley-Liss, Inc.dagger C1 Natl Human Genome Res Inst, Med Genet Branch, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Bethesda, MD 20892 USA. Westat Res Inc, Rockville, MD USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NCI, Lab Populat Genet, Bethesda, MD 20892 USA. RP Biesecker, BB (reprint author), Natl Human Genome Res Inst, Med Genet Branch, Bldg 10,Room 10C101,10 Ctr Dr,MSC 1852, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 NR 35 TC 78 Z9 78 U1 1 U2 10 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 AUG 14 PY 2000 VL 93 IS 4 BP 257 EP 263 DI 10.1002/1096-8628(20000814)93:4<257::AID-AJMG1>3.0.CO;2-8 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 335RH UT WOS:000088258100001 PM 10946349 ER PT J AU Guidry, G Landis, SC AF Guidry, G Landis, SC TI Absence of cholinergic sympathetic innervation from limb muscle vasculature in rats and mice SO AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL LA English DT Article DE limb muscle; vasculature; vasodilation; innervation; sympathetic; VAChT; cholinergic; peptide; rat ID VESICULAR ACETYLCHOLINE TRANSPORTER; VASOACTIVE INTESTINAL PEPTIDE; SKELETAL-MUSCLE; POSTGANGLIONIC NEURONS; DEFENSE REACTION; SWEAT GLANDS; GUINEA-PIG; NITROSYL FACTORS; NERVOUS-SYSTEM; CAT AB Although the existence of cholinergic sympathetic vasodilatory innervation in Limb muscle vasculature is well established for some species, previous pharmacological studies have failed to reveal the presence of such innervation in rats. Recently, Schafer and colleagues [Schafer, M.K., Eiden, L.E., Weihe, E., 1998. Cholinergic neurons and terminal fields revealed by immunohistochemistry for the vesicular acetylcholine transporter. II. The peripheral nervous system. Neuroscience 84(2), 361-376] reported that vesicular acetylcholine transporter immunoreactivity (VAChT-IR), a marker for cholinergic terminals, is present in the innervation of the microvasculature of rat hindlimb skeletal muscle and concluded that rats possess cholinergic sympathetic innervation of limb muscle vasculature. Because of our interest in identifying targets of cholinergic sympathetic neurons, we have analyzed the transmitter properties of the innervation of muscle vessels in rat and mouse limbs. We found that the innervation of vasculature in muscle is noradrenergic, exhibiting robust catecholamine histofluorescence and immunoreactivity for tyrosine hydroxylase (TH) and the peptide transmitters, neuropeptide Y (NPY) and occasionally vasoactive intestinal peptide (VIP). In contrast, cholinergic phenotypic markers,VAChT-IR and acetylcholinesterase (AChE) activity, are absent. Neuron cell bodies in sympathetic ganglia, retrogradely labeled with injections of tracer into limb muscles, also lacked VAChT but contained TH-IR. The innervation of large extramuscular feed arteries in hindlimbs was also devoid of cholinergic markers, as were the cell bodies of sympathetic neurons innervating extramuscular femoral arteries. These results, like those of previous physiological studies, provide no evidence for the presence of cholinergic sympathetic innervation of muscle vasculature in rats or mice. (C) 2000 Published by Elsevier Science B.V. All rights reserved. C1 NINDS, Neural Dev Sect, NIH, Bethesda, MD 20892 USA. RP Guidry, G (reprint author), NINDS, Neural Dev Sect, NIH, Bldg 36 Room 2B08,36 Convent Dr, Bethesda, MD 20892 USA. NR 57 TC 25 Z9 26 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1566-0702 J9 AUTON NEUROSCI-BASIC JI Auton. Neurosci-Basic Clin. PD AUG 14 PY 2000 VL 82 IS 3 BP 97 EP 108 DI 10.1016/S0165-1838(00)00094-1 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 352BY UT WOS:000089195700002 PM 11023615 ER PT J AU Veeranna Shetty, KT Takahashi, M Grant, P Pant, HC AF Veeranna Shetty, KT Takahashi, M Grant, P Pant, HC TI Cdk5 and MAPK are associated with complexes of cytoskeletal proteins in rat brain (vol 76, pg 229, 2000) SO MOLECULAR BRAIN RESEARCH LA English DT Correction C1 NINCDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NIMHANS, Bangalore, Karnataka, India. Yokohama Univ, Sch Med, Dept Psychiat, Yokohama, Kanagawa, Japan. RP Pant, HC (reprint author), NINCDS, Neurochem Lab, NIH, Bldg 36,Rm 4D20, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD AUG 14 PY 2000 VL 80 IS 1 BP 109 EP 109 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 349DA UT WOS:000089027500012 ER PT J AU Zhou, YX Xu, XL Chen, L Li, CL Brodie, SG Deng, CX AF Zhou, YX Xu, XL Chen, L Li, CL Brodie, SG Deng, CX TI A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures SO HUMAN MOLECULAR GENETICS LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; FACTOR RECEPTOR 3; CLEIDOCRANIAL DYSPLASIA; THANATOPHORIC DYSPLASIA; TARGETED DISRUPTION; BONE-DEVELOPMENT; OSTEOBLAST DIFFERENTIATION; TRANSMEMBRANE DOMAIN; PFEIFFER-SYNDROME; DEVELOPING SKULL AB Pfeiffer syndrome is a classic form of craniosynostosis that is caused by a proline-->arginine substitution at amino acid 252 (Pro252Arg) in fibroblast growth factor receptor 1 (FGFR1). Here we show that mice carrying a Pro250Arg mutation in Fgfr1, which is orthologous to the Pfeiffer syndrome mutation in humans, exhibit anterio-posteriorly shortened, laterally widened and vertically heightened neurocraniums, Analysis of the posterior and anterior frontal, sagittal and coronal sutures of early post-natal mutant mice revealed premature fusion, The sutures of mutant mice had accelerated osteoblast proliferation and increased expression of genes related to osteoblast differentiation, suggesting that bone formation at the sutures is locally increased in Pfeiffer syndrome. Of note, dramatically increased expression of core-binding transcription factor a subunit type 1 (Cbfa1) accompanied premature fusion, suggesting that Cbfa1 may be a downstream target of Fgf/Fgfr1 signals. This was confirmed in vitro, where we demonstrate that transfection with wild-type or mutant Fgfr1 induces Cbfa1 expression. The induced expression was also observed using Fgf ligands (Fgf2 and Fgf8), These studies provide direct genetic evidence that the Pro252Arg mutation in FGFR1 causes human Pfeiffer syndrome and uncovers a molecular mechanism in which Fgf/Fgfr1 signals regulate intramembraneous bone formation by modulating Cbfa1 expression. C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 64 TC 149 Z9 156 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 12 PY 2000 VL 9 IS 13 BP 2001 EP 2008 DI 10.1093/hmg/9.13.2001 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 346KX UT WOS:000088871200012 PM 10942429 ER PT J AU Bokesch, HR Pannell, LK McKee, TC Boyd, MR AF Bokesch, HR Pannell, LK McKee, TC Boyd, MR TI Coscinamides A, B and C, three new bis indole alkaloids from the marine sponge Coscinoderma sp. SO TETRAHEDRON LETTERS LA English DT Article DE bis indole alkaloid; marine natural product; Coscinoderma ID SESTERTERPENE; SPONGOSORITES; INHIBITORS AB Three novel bis indole alkaloids, coscinamides A-C have been isolated from an extract of the marine sponge Coscinoderma sp., and their structures determined on the basis of spectral data, These compounds contain an unusual alpha-keto enamide functionality and are the first reported alkaloids from this genus, Published by Elsevier Science Ltd. C1 NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diag,Fraderick Canc Res & De, Frederick, MD 21702 USA. FCRDC, SAIC Frederick, Frederick, MD 21702 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Boyd, MR (reprint author), NCI, Lab Drug Discovery Res & Dev, Dev Therapeut Program, Div Canc Treatment & Diag,Fraderick Canc Res & De, Frederick, MD 21702 USA. NR 16 TC 49 Z9 51 U1 3 U2 6 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 AUG 12 PY 2000 VL 41 IS 33 BP 6305 EP 6308 DI 10.1016/S0040-4039(00)01062-5 PG 4 WC Chemistry, Organic SC Chemistry GA 348LE UT WOS:000088985600011 ER PT J AU Zheng, CY Goldsmith, CM O'Connell, BC Baum, BJ AF Zheng, CY Goldsmith, CM O'Connell, BC Baum, BJ TI Adenoviral vector cytotoxicity depends in part on the transgene encoded SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE adenovirus; first-generation vectors; G(2)/M arrest; transgene product; epithelial cells ID MEDIATED GENE-TRANSFER; SALIVARY-GLANDS; CELL-LINE; IN-VIVO; RECOMBINANT; EXPRESSION; INFECTION; DELIVERY; THERAPY; ARREST AB First-generation adenoviral vectors induce G(2)/M arrest and cell death at high multiplicities of infection (m.o.i.'s) in vitro. It is unclear whether this cytotoxicity is entirely adenoviral gene related or influenced in part by the encoded transgene. We examined this question in epithelial cells using seven vectors at relatively low (50) or higher (200) m.o.i.'s. The vectors contained no transgene (+/-promoter), transgenes encoding a cytoplasmic reporter protein (two luciferase constructs; P-galactosidase), or transgenes encoding a secretory protein (alpha 1-antitrypsin; growth hormone). After 24 h with a m.o.i. of 50, vectors encoding cytoplasmic reporter proteins led to greatest cytotoxicity (similar to 35-40% cells in G(2)/M). Vectors without a transgene resulted in lower cytotoxicity (similar to 15%, minus, or 23%, plus promoter, cells in G(2)/M). Vectors encoding secretory proteins led to similar to 22-25% cells in G(2)/RI. A similar pattern resulted when cell number was measured. Results were unrelated to the steady-state levels of transgene product. At the higher m.o.i., all vectors caused substantial growth retardation, This is the first demonstration that adenoviral vector-induced cytotoxic effects are in part related to the transgene encoded. (C) 2000 Academic Press. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Room 1N113,MSC-1190, Bethesda, MD 20892 USA. OI O'Connell, Brian/0000-0003-4529-7664 NR 21 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 AUG 11 PY 2000 VL 274 IS 3 BP 767 EP 771 DI 10.1006/bbrc.2000.3213 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 345LQ UT WOS:000088817800034 PM 10924352 ER PT J AU Sang, QXA Jia, MC Schwartz, MA Jaye, MC Kleinman, HK Ghaffari, MA Luo, YL AF Sang, QXA Jia, MC Schwartz, MA Jaye, MC Kleinman, HK Ghaffari, MA Luo, YL TI New thiol and sulfodiimine metalloproteinase inhibitors and their effect on human microvascular endothelial cell growth SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE synthetic metalloproteinase inhibitors; matrix metalloproteinases; endothelial proliferation; migration and invasion; angiogenesis; extracellular matrix; basement membrane ID COMPUTATIONAL SEQUENCE-ANALYSIS; MATRIX METALLOPROTEINASES; INTERSTITIAL COLLAGENASE; BASEMENT-MEMBRANE; IN-VITRO; ANGIOGENESIS; PURIFICATION; PROCOLLAGENASE; METASTASIS; ACTIVATION AB Matrix metalloproteinases (MMPs, matrixins) are a family of homologous zinc endopeptidases that may play a very important role in many physiological and pathological processes, e.g., the initiation of angiogenesis, Two new matrixin inhibitors were synthesized and characterized. A thiol inhibitor MAG-283 had IC50 values of 480, 3, 280, 14, 1.1, and 2.3 nM against human interstitial collagenase (MMP-1), gelatinase A (MMP-2), stromelysin (MMP-3), matrilysin (MMP-7), neutrophil collagenase (MMP-8), and gelatinase B (MMP-9), respectively. A sulfodiimine inhibitor YLL-224 had IC50 values of 180, 63, 4500, 210, 5.9, and 44 nM against MMP-1, -2, -3, -7, -8, and -9, respectively. Human skin microvascular endothelial cells were treated with these two compounds in culture. These inhibitors at very low micromolar concentrations suppressed proliferation of the endothelial cells stimulated by acidic fibroblast growth factor and vascular endothelial growth factor. They also partially blocked cell invasion through type IV collagen. These results suggested a correlation between the anti-metalloenzyme activity and the effects of these inhibitors on the growth and invasion of endothelial cells. (C) 2000 Academic Press. C1 Florida State Univ, Dept Chem, Dittmer Lab 203, Tallahassee, FL 32306 USA. Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. Rhone Poulenc Rorer, Dept Cardiovasc Biol, Collegeville, PA 19426 USA. NIDR, NIH, Bethesda, MD 20892 USA. RP Sang, QXA (reprint author), Florida State Univ, Dept Chem, Dittmer Lab 203, Tallahassee, FL 32306 USA. FU NCI NIH HHS [CA78646] NR 33 TC 13 Z9 13 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 AUG 11 PY 2000 VL 274 IS 3 BP 780 EP 786 DI 10.1006/bbrc.2000.3212 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 345LQ UT WOS:000088817800036 PM 10924354 ER PT J AU Thiruchelvam, M Brockel, BJ Richfield, EK Baggs, RB Cory-Slechta, DA AF Thiruchelvam, M Brockel, BJ Richfield, EK Baggs, RB Cory-Slechta, DA TI Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson's disease? SO BRAIN RESEARCH LA English DT Article DE Parkinson's disease; dopamine; striatum; substantia nigra; tyrosine hydroxylase; locomotor activity; immunohistochemistry ID ETHYLENE-BIS-DITHIOCARBAMATE; SUBSTANTIA-NIGRA; CHRONIC EXPOSURE; FUNGICIDE MANEB; CELL LOSS; BRAIN; RAT; TOXICITY; TRIADIMEFON; NEURONS AB The absence of any compelling basis for a heritable basis of idiopathic Parkinson's disease (PD) has focused attention on environmental exposures as causative agents. While the herbicide paraquat has repeatedly been implicated, its impact on dopamine systems following systemic exposures is equivocal. The restricted focus on paraquat also ignores the extensive geographical overlap of its use with other agrichemicals known to adversely impact dopamine systems, including ethylenebisdithiocarbamate fungicides such as maneb. The present study sought to determine whether combined exposures to paraquat and maneb would produce additive effects and support a multiple-hit environmental contribution to PD. C57BL/6 mice were exposed to either paraquat (5-10 mg/kg) or maneb (15-30 mg/kg) i.p. alone or in combination once a week for 4 weeks. Sustained decreases in motor activity immediately following injections were consistently observed only with combined exposures, with activity levels returning to control values 24 h later. Concurrently, levels of dopamine and metabolites and dopamine turnover were increased immediately post-injection only by combined exposures, and returned to control levels or below within 48 h. Reductions in tyrosine hydroxylase immunoreactivity, measured 3 days after the last injection, resulted only from combined exposure and were detected in dorsal striatum, but not in the nucleus accumbens. The fact that combined exposures resulted in potentiated effects that appear to target nigrostriatal dopamine systems suggests that these combinations may be important environmental risk factors for Parkinsonism. These findings also raise questions about the adequacy of current risk assessment guidelines for these chemicals which are based on effect levels derived from exposures to single agents. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Univ Rochester, Sch Med, Dept Environm Med, Rochester, NY 14642 USA. Univ Rochester, Sch Med, Dept Pathol & Lab Med, Rochester, NY 14642 USA. Univ Rochester, Sch Med, Dept Lab Anim Med, Rochester, NY 14642 USA. Univ Rochester, Sch Med, NIEHS, Environm Hlth Sci Ctr, Rochester, NY 14642 USA. RP Cory-Slechta, DA (reprint author), Univ Rochester, Sch Med, Dept Environm Med, Rochester, NY 14642 USA. FU NIEHS NIH HHS [ES01247, ES05017, ES05903] NR 60 TC 188 Z9 200 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD AUG 11 PY 2000 VL 873 IS 2 BP 225 EP 234 DI 10.1016/S0006-8993(00)02496-3 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 344TN UT WOS:000088775100006 PM 10930548 ER PT J AU Shi, CS Sinnarajah, S Cho, H Kozasa, T Kehrl, JH AF Shi, CS Sinnarajah, S Cho, H Kozasa, T Kehrl, JH TI G(13)alpha-mediated PYK2 activation - PYK2 is a mediator of G(13)alpha-induced serum response element-dependent transcription SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; TYROSINE KINASE PYK2; TERNARY COMPLEX FACTORS; N-TERMINAL KINASE; NEURITE RETRACTION; LYSOPHOSPHATIDIC ACID; ANGIOTENSIN-II; P115 RHOGEF; G-ALPHA(12); PATHWAYS AB G(12)alpha/G(13)alpha transduces signals from G-protein-coupled receptors to stimulate growth-promoting pathways and the early response gene c-fos, Within the c-fos promoter lies a key regulatory site, the serum response element (SRE). Here we show a critical role for the tyrosine kinase PYK2 in muscarinic receptor type 1 and G12 alpha/G(13)alpha signaling to an SRE reporter gene. A kinase-inactivate form of PYK2 (PYR2 KD) inhibits muscarinic receptor type 1 signaling to the SRE and PYK2 itself triggers SRE reporter gene activation through a RhoA-dependent pathway. Placing PYK2 downstseam of G-protein activation but upstream of RhoA, the expression of PYK2 KD blocks the activation of an SRE reporter gene by GTPase-deficient forms of G(12)alpha or G(13)alpha but not by RhoA The GTPase-deficient form of G(13)alpha triggers PYK2 kinase activity and PYK2 tyrosine phosphorylation, and co-expression of the RGS domain of p115 Rho-GEF inhibits both responses. Finally, we show that in vivo G(13)alpha, although not G(12)alpha, readily associates with PYK2. Thus, G-protein-coupled receptors via G(13)alpha activation can use PYR2 to link to SRE-dependent gene expression. C1 NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Illinois, Dept Pharmacol, Chicago, IL 60612 USA. RP Kehrl, JH (reprint author), NIAID, Cell Mol Immunol Sect B, Immunoregulat Lab, NIH, Bldg 10,Rm 11B08,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. NR 34 TC 68 Z9 70 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 AUG 11 PY 2000 VL 275 IS 32 BP 24470 EP 24476 DI 10.1074/jbc.M908449199 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300032 PM 10821841 ER PT J AU Xu, YS Kantorow, M Davis, J Piatigorsky, J AF Xu, YS Kantorow, M Davis, J Piatigorsky, J TI Evidence for gelsolin as a corneal crystallin in zebrafish SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIN-REGULATORY PROTEIN; MAJOR SOLUBLE-PROTEIN; ALDEHYDE DEHYDROGENASE; BOVINE CORNEA; F-ACTIN; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; SEVERING PROTEINS; LENS CRYSTALLINS; PLASMA GELSOLIN; BINDING DOMAIN AB We have shown that gelsolin is one of the most prevalent water-soluble proteins in the transparent cornea of zebrafish. There are also significant amounts of actin. In contrast to actin, gelsolin is barely detectable in other eye tissues (iris, lens, and remaining eye) of the zebrafish, Gelsolin cDNA hybridized intensely in Northern blots to RNA from the cornea but not from the lens, brain, or headless body. The deduced zebrafish gelsolin is similar to 60% identical to mammalian cytosolic gelsolin and has the characteristic six segmental repeats as well as the binding sites for actin, calcium, and phosphatidylinositides. In situ hybridization tests showed that gelsolin mRNA is concentrated in the zebrafish corneal epithelium. The zebrafish corneal epithelium stains very weakly with rhodamine-phalloidin, indicating little F-actin in the cytoplasm, In contrast, the mouse corneal epithelium contains relatively little gelsolin and stains intensely with rhodamine-phalloidin, as does the zebrafish extraocular muscle. We propose, by analogy with the diverse crystallins of the eye lens and with the putative enzyme-crystallins (aldehyde dehydrogenase class 3 and other enzymes) of the mammalian cornea, that gelsolin and actin-gelsolin complexes act as water-soluble crystallins in the zebrafish cornea and contribute to its optical properties. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NEI, Mol & Dev Biol Lab, NIH, 6 Ctr Dr,MSC 2730,Bldg 6,Rm 201, Bethesda, MD 20892 USA. NR 85 TC 40 Z9 41 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 AUG 11 PY 2000 VL 275 IS 32 BP 24645 EP 24652 DI 10.1074/jbc.M001159200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300057 PM 10818094 ER PT J AU Saiardi, A Caffrey, JJ Snyder, SH Shears, SB AF Saiardi, A Caffrey, JJ Snyder, SH Shears, SB TI The inositol hexakisphosphate kinase family - Catalytic flexibility and function in yeast vacuole biogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DIPHOSPHOINOSITOL POLYPHOSPHATE PHOSPHOHYDROLASE; SACCHAROMYCES-CEREVISIAE; PROTEIN; TETRAKISPHOSPHATE; PENTAKISPHOSPHATE; CELLS; METABOLISM; TURNOVER; 1,3,4,5,6-PENTAKISPHOSPHATE; 1,3,4,6-TETRAKISPHOSPHATE AB Saiardi et al. (Saiardi, A., Erdjument-Bromage, H., Snowman, A., Tempst, P., and Snyder, S. H. (1999) Curr. Biol. 9, 1323-1326) previously described the cloning of a kinase from yeast and two kinases from mammals (types 1 and 2), which phosphorylate inositol hexakisphosphate (InsP(6)) to diphosphoinositol pentakisphosphate, a "high energy" candidate regulator of cellular trafficking. We have now studied the significance of InsP(6) kinase activity in Saccharomyces cerevisiae by disrupting the kinase gene. These ip6k Delta cells grew more slowly their levels of diphosphoinositol polyphosphates were 60-80% lower than wild-type cells, and the cells contained abnormally small and fragmented vacuoles. Novel activities of the mammalian and yeast InsP(6) kinases mere identified; inositol pentakisphosphate (InsP(5)) was phosphorylated to diphosphoinositol tetrakisphosphate (PP-InsP(4)), which was further metabolized to a novel compound, tentatively identified as bis-diphosphoinositol trisphosphate, The latter is a new substrate for human diphosphoinositol polyphosphate phosphohydrolase. Kinetic parameters for the mammalian type 1 kinase indicate that InsP(5) (K-m = 1.2 mu M) and InsP(6) (K-m = 6.7 mu M) compete for phosphorylation in vivo. This is the first time a PP-InsP(4) synthase has been identified. The mammalian type 2 kinase and the yeast kinase are more specialized for the phosphorylation of InsP(6). Synthesis of the diphosphorylated inositol phosphates is thus revealed to be more complex and interdependent than previously envisaged. C1 NIEHS, Inositide Signaling Grp, Inositide Signaling Sect, Lab Signal Transduct,NIH, Res Triangle Pk, NC 27709 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. RP NIEHS, Inositide Signaling Grp, Inositide Signaling Sect, Lab Signal Transduct,NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Shears@niehs.nih.gov FU NIDA NIH HHS [DA00074]; NIMH NIH HHS [MH18501] NR 37 TC 115 Z9 118 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 11 PY 2000 VL 275 IS 32 BP 24686 EP 24692 DI 10.1074/jbc.M002750200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300062 PM 10827188 ER PT J AU Potapova, O Gorospe, M Bost, F Dean, NM Gaarde, WA Mercola, D Holbrook, NJ AF Potapova, O Gorospe, M Bost, F Dean, NM Gaarde, WA Mercola, D Holbrook, NJ TI c-Jun N-terminal kinase is essential for growth of human T98G glioblastoma cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAY; LUNG-CARCINOMA CELLS; PROTEIN-KINASE; HA-RAS; ACTIVATION DOMAIN; DNA-SYNTHESIS; G(1) ARREST; MAP KINASES; INDUCTION; JNK AB The c-Jun N-terminal kinase/stress-activated protein kinase (JNR/SAPK) pathway is activated by numerous cellular stresses. Although it has been implicated in me diating apoptosis and growth factor signaling, its role in regulating cell growth is not yet clear. Here, the influence of JNK on basal (unstimulated) growth of human tumor glioblastoma T98G cells was investigated using highly specific JNK antisense oligonucleotides to inhibit JNK expression. Transient depletion of either JNK1 or JNK2 suppressed cell growth associated with an inhibition of DNA synthesis and cell cycle arrest in S phase. The growth-inhibitory potency of JNK2 antisense ((JNK)2 IC50 = 0.14 mu M) was greater than that of JNK1 antisense ((JNK)1 IC50 = 0.37 mu M), suggesting that JNK2 plays a dominant role in regulating growth of T98G cells. Indeed, JNK2 antisense-treated populations exhibited greater inhibition of DNA synthesis and accumulation of S-phase cells than did the JNK1 antisense-treated cultures, with a significant proportion of these cells detaching from the tissue culture plate. JNK2 (but not JNK1) antisense-treated cultures exhibited marked elevation in the expression of the cyclin-dependent kinase inhibitor p21(cip1/waf1) accompanied by inhibition of Cdk2/Cdc2 kinase activities. Taken together, these results indicate that JNK is required for growth of T98G cells in nonstress conditions and that p21(cip1/waf1) may contribute to the sustained growth arrest of JNK2-depleted T98G cultures. C1 NIA, Ctr Gerontol Res, Biol Chem Lab, Cell Stress & Aging Sect,NIH, Baltimore, MD 21224 USA. Sidney Kimmel Canc Ctr, San Diego, CA 91212 USA. ISIS Pharmaceut Inc, Carlsbad, CA 92008 USA. RP Holbrook, NJ (reprint author), NIA, Ctr Gerontol Res, Biol Chem Lab, Cell Stress & Aging Sect,NIH, 5600 Nathan Shock Dr,Box 12, Baltimore, MD 21224 USA. FU NCI NIH HHS [CA76173, CA63783] NR 53 TC 92 Z9 94 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 AUG 11 PY 2000 VL 275 IS 32 BP 24767 EP 24775 DI 10.1074/jbc.M904591199 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300073 PM 10825181 ER PT J AU Liu, X Brzeska, H Korn, ED AF Liu, X Brzeska, H Korn, ED TI Functional analysis of tail domains of Acanthamoeba myosin IC by characterization of truncation and deletion mutants SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAVY-CHAIN KINASE; ACTIN-BINDING SITE; ACTIVATED ATPASE ACTIVITY; SH3 DOMAIN; IN-VIVO; PHOSPHORYLATION SITE; 3RD ISOFORM; LIGHT-CHAIN; AMINO-ACID; TEDS RULE AB Acanthamoeba myosin IC has a single 129-kDa heavy chain and a single l7-kDa light chain. The heavy chain comprises a 75-kDa catalytic head domain with an ATP-sensitive F-actin-binding site, a 3-kDa neck domain, which binds a single 17-kDa light chain, and a 50-kDa tail domain, which binds F-actin in the presence or absence of ATP. The actin-activated MgATPase activity of myosin IC exhibits triphasic actin dependence, apparently as a consequence of the two actin-binding sites, and is regulated by phosphorylation of Ser-329 in the head. The 50-kDa tail consists of a basic domain, a glycine/proline/alanine-rich (GPA) domain, and a Src homology 3 (SH3) domain, often referred to as tail homology (TH)-1, -2, and -3 domains, respectively. The SH3 domain divides the TH-3 domain into GPA-1 and GPA-2. To define the functions of the tail domains more precisely, we determined the properties of expressed wild type and six mutant myosins, an SH3 deletion mutant and five mutants truncated at the C terminus of the SH3, GPA-2, TH-1, neck and head domains, respectively. We found that both the TH-1 and GPA-2 domains bind F-actin in the presence of ATP, Only the mutants that retained an actin-binding site in the tail exhibited triphasic actin-dependent MgATPase activity, in agreement with the F-actin-cross-linking model, but truncation reduced the MgATPase activity at both low and high actin concentrations. Deletion of the SH3 domain had no effect. Also, none of the tail domains, including the SH3 domain, affected either the K-m or V-max for the phosphorylation of Ser-329 by myosin I heavy chain kinase. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Korn, ED (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 3,Rm B1-22, Bethesda, MD 20892 USA. RI Korn, Edward/F-9929-2012 NR 52 TC 14 Z9 14 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 AUG 11 PY 2000 VL 275 IS 32 BP 24886 EP 24892 DI 10.1074/jbc.M004287200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343CC UT WOS:000088683300087 PM 10840041 ER PT J AU Andrus, MB Turner, TM Sauna, ZE Ambudkar, SV AF Andrus, MB Turner, TM Sauna, ZE Ambudkar, SV TI The synthesis and evaluation of a solution phase indexed combinatorial library of non-natural polyenes for reversal of p-glycoprotein mediated multidrug resistance SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ASYMMETRIC ALDOL REACTION; PURE ANTI-ALDOLS; ACYCLIC STEREOSELECTION; SYN-ALDOLS; STIPIAMIDE; ACETYLCHOLINESTERASE; DIHYDROXYLATION; TRANSPORTER; REAGENT; KETONES AB A combinatorial library of polyenes, based on (-)-stipiamide, has been constructed and evaluated for the discovery of new multidrug resistance reversal agents. A palladium coupling was used to react each individual vinyl iodide with a mixture of the seven acetylenes at near 1:1 stoichiometry. The coupling was also used to react each individual acetylene with the mixture of six vinyl iodides to create 13 pools indexed in two dimensions for a total of 42 compounds. Individual compounds were detected at equimolar concentration. The vinyl iodides, made initially using a crotylborane addition to generate the anti1,2-hydroxylmethyl products, were now made using a more efficient norephedrine propionate boron enolate aldol reaction. The indexed approach, ideally suited for cellular assays that involve membrane-bound targets, allowed for the rapid identification of reversal agents using assays with drug-resistant human breast cancer MCF7-adrR cells. Intersections of potent pools identified new compounds with promising activity. Aryl dimension pools showed R = ph and naphthyl as the most potent. The acetylene dimension had R' = phenylalaninol and alaninol as the most potent. Isolated individual compounds, both active and nonpotent, were assayed to confirm the library results. The most potent new compound was 4ek (R = naphthyl, R' = phenylaninol) at 1.45 mu M. Other nonnatural individual naphthyl-amide compounds showed potent MDR reversal including the morpholino-amide 4ej (1.69 mu M). Synergistic activities attributed to the two ends of the molecule were also identified. Direct interaction with Pgp was established by ATPase and photoaffinity displacement assays. The results indicate that both ends of the polyene reversal agent are involved in Pgp interaction and can be further modified for increased potency. C1 Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. Natl Canc Inst, Cell Biol Lab, NIH, Bethesda, MD 20878 USA. RP Andrus, MB (reprint author), Brigham Young Univ, Dept Chem & Biochem, C100 BNSN, Provo, UT 84602 USA. RI Ambudkar, Suresh/B-5964-2008 FU NIGMS NIH HHS [GM57275] NR 57 TC 28 Z9 28 U1 1 U2 7 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 AUG 11 PY 2000 VL 65 IS 16 BP 4973 EP 4983 DI 10.1021/jo000453m PG 11 WC Chemistry, Organic SC Chemistry GA 345JK UT WOS:000088812700029 PM 10956480 ER PT J AU Hessol, NA Anastos, K Levine, AM Ameli, N Cohen, M Young, M Augenbraun, M Miotti, P Gange, SJ AF Hessol, NA Anastos, K Levine, AM Ameli, N Cohen, M Young, M Augenbraun, M Miotti, P Gange, SJ CA WIHS Collaborative Study Grp TI Factors associated with incident self-reported AIDS among women enrolled in the Women's Interagency HIV Study (WIHS) SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID NEW-YORK-CITY; IMMUNODEFICIENCY-VIRUS-INFECTION; HOMOSEXUAL MEN; PROSPECTIVE COHORT; CIGARETTE-SMOKING; RISK-FACTORS; DRUG-USE; PROGRESSION; DISEASE; OUTCOMES AB We evaluated factors associated with incident self-reported AIDS diagnoses among HIV-infected women in the Women's Interagency HIV Study (WIHS), Baseline information included age, race/ethnicity, HIV risk category, site of enrollment, years of education, cigarette smoking, CD4 cell count, and HIV viral load. Baseline and follow-up data on self-reported AIDS were analyzed using chi-square, Kaplan-Meier, and Cox proportional hazard models. Among the 1397 HIV-infected women who reported being free of clinical AIDS at baseline, 335 women (24%) reported an incident AIDS diagnosis during follow-up. In stratified Kaplan-Meier analyses, the development of self-reported AIDS was significantly associated with baseline CD4 cell count and viral load (p < 0.01). In multivariate Cox proportional hazard analyses, women were statistically more likely to report AIDS if they had CD4 cell counts below 195 cells/mm(3) (p < 0.01), HIV RNA >4000 copies/ml (p < 0.01), were current smokers (p < 0.01), and had "no identifiable risk" for acquisition of EW (p = 0.03). Self-reports of a clinical AIDS diagnosis may not always be accurate, but laboratory markers of HIV disease indicate that those women who self-report such diagnoses have greater immunodeficiency and a higher viral load when compared with those who report no AIDS-defining diagnoses. C1 Univ Calif San Francisco, Dept Med, San Francisco, CA 94122 USA. Catholic Med Ctr Brooklyn, Jamaica, NY 11432 USA. Catholic Med Ctr Queens, Jamaica, NY 11432 USA. Univ So Calif, Los Angeles, CA 90033 USA. Cook Cty Hosp, Chicago, IL 60612 USA. George Washington Univ, Washington, DC 20007 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. NIAID, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. RP Hessol, NA (reprint author), Univ Calif San Francisco, Dept Med, 405 Irving St,2nd Floor, San Francisco, CA 94122 USA. OI Gange, Stephen/0000-0001-7842-512X FU NIAID NIH HHS [U01-AI-31834, U01-AI-35004, U01-AI-34994] NR 37 TC 10 Z9 10 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG 10 PY 2000 VL 16 IS 12 BP 1105 EP 1111 DI 10.1089/088922200414947 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 345FU UT WOS:000088806600002 PM 10954885 ER PT J AU Wiznia, A Stanley, K Krogstad, P Johnson, G Lee, S McNamara, J Moye, J Jackson, JB Mendez, H Aguayo, R Dieudonne, A Kovacs, A Bamji, M Abrams, E Rana, S Sever, J Nachman, S AF Wiznia, A Stanley, K Krogstad, P Johnson, G Lee, S McNamara, J Moye, J Jackson, JB Mendez, H Aguayo, R Dieudonne, A Kovacs, A Bamji, M Abrams, E Rana, S Sever, J Nachman, S CA Pediat AIDS Clin Trial Grp 377 Study TI Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children: Week 24 results of a randomized controlled trial - PACTG 377 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNODEFICIENCY-VIRUS INFECTION; TYPE-1 RNA; QUANTITATION; INDINAVIR; PROGRAM; PLASMA AB One hundred eighty-one antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children between 4 months and 17 years of age were randomly assigned to receive one of four combination regimens to evaluate the change in plasma HIV RNA, safety, and tolerance when changing antiretroviral therapy to a protease inhibitor-containing combination regimen, All four regimens contained stavudine; in addition children received nevirapine plus ritonavir, lamivudine plus nelfinavir, nevirapine plus nelfinavir, or lamivudine plus nevirapine plus nelfinavir. Twelve additional children chose to receive stavudine plus lamivudine plus nelfinavir, with nelfinavir given bid, rather than tid as for the main regimens, Overall, 51% (89/176; 95% CI 43-58%) of the children on the randomized portion of the study had an HIV RNA response (less than or equal to 400 copies/ml) on at least two of the three HIV RNA determinations taken at Weeks 8, 12, and 16. At Week 24 the proportion of children with an HIV RNA response still on initial therapy was 47% (83/176; 95% CI 40-55%) and ranged from 41 to 61% for the four randomized treatment arms. Rash was frequently seen (27%) on the treatment arms containing nevirapine. At Week 24 64% (7/11, 95% CI 31-89%) of the children on the bid nelfinavir combination regimen were still on initial therapy with an HN RNA response as compared with 46% (23/50; 95% CI 32-61%) on the corresponding tid nelfinavir combination regimen. A change in antiretroviral therapy to a protease inhibitor-containing regimen was associated with a virological response rate of approximately 50% for this patient population. C1 Jacobi Med Ctr, Pediat HIV Serv, Bronx, NY 10461 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90095 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NIAID, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD 21287 USA. Childrens Med Ctr, Brooklyn, NY 11203 USA. Ramon Ruiz Aranu Univ Hosp, Bayamon, PR 00956 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Univ So Calif, Sch Med, Los Angeles, CA 90033 USA. Metropolitan Hosp Ctr, New York, NY 10029 USA. Harlem Hosp Med Ctr, New York, NY 10037 USA. Howard Univ Hosp, Washington, DC 20060 USA. George Washington Univ, Sch Med, Washington, DC 20010 USA. SUNY Stony Brook, Hlth Sci Ctr, Stony Brook, NY 11794 USA. RP Wiznia, A (reprint author), Jacobi Med Ctr, Pediat HIV Serv, JACP-518,1440 Pelham Pkwy S, Bronx, NY 10461 USA. OI moye, john/0000-0001-9976-8586 FU NIAID NIH HHS [AI-41110] NR 14 TC 62 Z9 63 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG 10 PY 2000 VL 16 IS 12 BP 1113 EP 1121 DI 10.1089/088922200414956 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 345FU UT WOS:000088806600003 PM 10954886 ER PT J AU Furness, MS Zhang, XY Coop, A Jacobson, AE Rothman, RB Dersch, CM Xu, H Porreca, F Rice, KC AF Furness, MS Zhang, XY Coop, A Jacobson, AE Rothman, RB Dersch, CM Xu, H Porreca, F Rice, KC TI Probes for narcotic receptor-mediated phenomena. 27. Synthesis and pharmacological evaluation of selective delta-opioid receptor agonists from 4-[(alpha R)-alpha-(2S,5R)-4-substituted-2,5-dimethyl-1-piperazinyl-3-methoxybenzy l]-N,N-diethylbenzamides and their enantiomers SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID (+)-4-<(ALPHA-R)-ALPHA-((2S,5R)-4-ALLYL-2,5-DIMETHYL-1-PIPERAZINYL)-3-ME THOXYBE.; (+)-BW373U86; BINDING; SNC80 AB Potent, selective, and efficacious delta-opioid receptor agonists such as (+)-4-[(alpha R)-alpha-(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamide [SNC80, (+)-2] have been found to be useful tools for exploring the structural requirements which are necessary for ligands which interact with the delta-receptor. To determine the necessity for the 4-allyl moiety in (+)-2, this substituent was replaced with a variety of 4-alkyl, 4-arylalkyl, and 4-alkenyl substituents. The corresponding enantiomers of these compounds were also synthesized. The binding affinities for the mu-, delta-, and kappa-opioid receptors and efficacies in the functional GTP gamma S binding assay were determined for the (+)-2 related compounds and their enantiomers. The 4-crotyl analogue was found to have similar delta-receptor affinity and efficacy as (+)-2, but the 4-cyclopropylmethyl analogue, in the functional assay, appeared to be a partial agonist with little antagonist activity. C1 NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. NIDA, Clin Psychopharmacol Sect, Addict Res Ctr, Baltimore, MD 21224 USA. Univ Arizona, Hlth Sci Ctr, Dept Pharmacol, Tucson, AZ 85724 USA. RP Rice, KC (reprint author), NIDDK, LMC, NIH, Bldg 8,Rm B1-23,8 Ctr Dr,MSC 0815, Bethesda, MD 20902 USA. NR 15 TC 17 Z9 17 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 10 PY 2000 VL 43 IS 16 BP 3193 EP 3196 DI 10.1021/jm0001222 PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 343ZU UT WOS:000088733800024 PM 10956228 ER PT J AU Subramaniam, S Henderson, R AF Subramaniam, S Henderson, R TI Molecular mechanism of vectorial proton translocation by bacteriorhodopsin SO NATURE LA English DT Article ID X-RAY-DIFFRACTION; STRUCTURAL-CHANGES; CRYSTAL-STRUCTURE; PHOTOCYCLE; CHROMOPHORE; INTERMEDIATE; RESOLUTION; MODEL; NMR AB Bacteriorhodopsin, a membrane protein with a relative molecular mass of 27,000, is a light driven pump which transports protons across the cell membrane of the halophilic organism Halobacterium salinarum. The chromophore retinal is covalently attached to the protein via a protonated Schiff base. Upon illumination, retinal is isomerized. The Schiff base then releases a proton to the extracellular medium, and is subsequently reprotonated from the cytoplasm. An atomic model for bacteriorhodopsin was first determined by Henderson et al(1), and has been confirmed and extended by work in a number of laboratories in the last few years(2). Here we present an atomic model for structural changes involved in the vectorial, light-driven transport of protons by bacteriorhodopsin. A 'switch' mechanism ensures the vectorial nature of pumping. First, retinal unbends, triggered by loss of the Schiff base proton, and second, a protein conformational change occurs. This conformational change, which we have determined by electron crystallography at atomic (3.2 Angstrom in-plane and 3.6 Angstrom vertical) resolution, is largely localized to helices F and G, and provides an 'opening' of the protein to protons on the cytoplasmic side of the membrane. C1 MRC, Mol Biol Lab, Cambridge CB2 2QH, England. NCI, Biochem Lab, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 2QH, England. NR 28 TC 340 Z9 349 U1 7 U2 50 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 10 PY 2000 VL 406 IS 6796 BP 653 EP 657 DI 10.1038/35020614 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 342PF UT WOS:000088653800054 PM 10949309 ER PT J AU Manoussaki, D Chadwick, RS AF Manoussaki, D Chadwick, RS TI Effects of geometry on fluid loading in a coiled cochlea SO SIAM JOURNAL ON APPLIED MATHEMATICS LA English DT Article DE cochlear coiling; helical geometry; helicoidal coordinates; mathematical biology; biomathematics; added mass calculation ID BASILAR-MEMBRANE; MAMMALS AB Despite its snail-shaped geometry, theoretical studies of the mammalian cochlea generally modeled it as a straight fluid-filled duct. Most people support the idea that the purpose of coiling is to pack the cochlea into a small space. However, attempts by researchers to establish the functional significance of the complex shape of the cochlea have been inconclusive. We study the effects of geometry on fluid loading in the cochlea and introduce helicoidal coordinates in order to describe cochlear geometry and fluid motion. The geometrical description takes into account curvature, partition width, basilar membrane (BM) width, and the height of the modiolus of a guinea pig cochlea. We assume a given mode, wavelength, and amplitude for the BM. We study the fluid equations within the WKB framework and numerically simulate the pressure in a plane containing the modiolar axis. We then compare numerical results for different geometrical parameters. We find that pressure on the BM increases with increasing BM width and decreasing cross-sectional area of the cochlear ducts. We also find that the net effect of curvature is to decrease the fluid pressure on the BM. When the cochlea spirals out of the plane, fluid loading is greater compared with the in-plane coiled case but smaller than in a straightened cochlea. These results suggest that the coiling helps to lower the fluid impedance, particularly at the apex, where BM curvature is greatest. C1 NIDCD, Sect Auditory Mech, LCB, NIH, Bethesda, MD 20892 USA. RP Manoussaki, D (reprint author), NIDCD, Sect Auditory Mech, LCB, NIH, Bldg 9 Rm 1E-116,9 Ctr Dr,MSC 0922, Bethesda, MD 20892 USA. NR 28 TC 21 Z9 21 U1 0 U2 5 PU SIAM PUBLICATIONS PI PHILADELPHIA PA 3600 UNIV CITY SCIENCE CENTER, PHILADELPHIA, PA 19104-2688 USA SN 0036-1399 J9 SIAM J APPL MATH JI SIAM J. Appl. Math. PD AUG 10 PY 2000 VL 61 IS 2 BP 369 EP 386 DI 10.1137/S0036139999358404 PG 18 WC Mathematics, Applied SC Mathematics GA 348WC UT WOS:000089008600001 ER PT J AU Roca, CA Schmidt, PJ Daly, RC Rubinow, DR AF Roca, CA Schmidt, PJ Daly, RC Rubinow, DR TI Estrogen-progestin replacement and risk of breast cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIMH, Bethesda, MD 20892 USA. RP Roca, CA (reprint author), NIMH, Bethesda, MD 20892 USA. NR 5 TC 1 Z9 1 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 AUG 9 PY 2000 VL 284 IS 6 BP 693 EP 693 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 341JM UT WOS:000088587300019 PM 10927770 ER PT J AU Schairer, C Lubin, J Troisi, R Sturgeon, S Brinton, L Hoover, R AF Schairer, C Lubin, J Troisi, R Sturgeon, S Brinton, L Hoover, R TI Estrogen-progestin replacement and risk of breast cancer - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Schairer, C (reprint author), NCI, Bethesda, MD 20892 USA. RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 NR 5 TC 1 Z9 1 U1 0 U2 1 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 AUG 9 PY 2000 VL 284 IS 6 BP 693 EP 694 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 341JM UT WOS:000088587300020 ER PT J AU Baker, F Ainsworth, SR Dye, JT Crammer, C Thun, MJ Hoffmann, D Repace, JL Henningfield, JE Slade, J Pinney, J Shanks, T Burns, DM Connolly, GN Shopland, DR AF Baker, F Ainsworth, SR Dye, JT Crammer, C Thun, MJ Hoffmann, D Repace, JL Henningfield, JE Slade, J Pinney, J Shanks, T Burns, DM Connolly, GN Shopland, DR TI Health risks associated with cigar smoking SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CANCER; DISEASE; MEN AB This article summarizes principal findings from a conference convened by the American Cancer Society in June 1998 to examine the health risks of cigar smoking. State-of-the-science reports were presented and 120 attendees (representing government and private agencies, academia, health educators, and tobacco control experts) participated in panels and summary development discussions, The following conclusions were reached by consensus: (1) rates of cigar smoking am rising among both adults and adolescents; (2) smoking cigars instead of cigarettes does not reduce the risk of nicotine addiction; (3) as the number of cigars smoked and the amount of smoke inhaled increases, the risk of death related to cigar smoking approaches that of cigarette smoking; (4) cigar smoke contains higher concentrations of toxic and carcinogenic compounds than cigarettes and is a major source of fine-particle and carbon monoxide indoor air pollution; and (5) cigar smoking is known to cause cancers of the lung and upper aerodigestive tract. C1 Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30329 USA. Amer Hlth Fdn, Valhalla, NY 10595 USA. Repace Associates Inc, Bowie, MD USA. NCI, Smoking & Tobacco Control Program, Bethesda, MD 20892 USA. Piney Associates Inc, Bethesda, MD USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ 08903 USA. Univ Calif San Diego, Tobacco Control Policies Project, San Diego, CA 92103 USA. Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. Massachusetts Dept Publ Hlth, Boston, MA USA. RP Baker, F (reprint author), Amer Canc Soc, Behav Res Ctr, 1599 Clifton Rd NE, Atlanta, GA 30329 USA. NR 32 TC 91 Z9 93 U1 0 U2 11 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 AUG 9 PY 2000 VL 284 IS 6 BP 735 EP 740 DI 10.1001/jama.284.6.735 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 341JM UT WOS:000088587300033 PM 10927783 ER PT J AU Johnson, PE Turner, RB Wu, ZR Hairston, L Guo, JH Levin, JG Summers, MF AF Johnson, PE Turner, RB Wu, ZR Hairston, L Guo, JH Levin, JG Summers, MF TI A mechanism for plus-strand transfer enhancement by the HIV-1 nucleocapsid protein during reverse transcription SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PRIMER-BINDING-SITE; ACID-CHAPERONE ACTIVITY; MURINE LEUKEMIA-VIRUS; TERMINAL ZINC-FINGER; TRANSFER-RNA; IN-VITRO; NMR-SPECTROSCOPY; POSTTRANSLATIONAL MODIFICATIONS; ANNEALING ACTIVITIES AB The HIV-1 nucleocapsid protein (NC) functions as a nucleic acid chaperone during the plus-strand transfer step in reverse transcription by facilitating annealing of the primer binding site (PBS) sequence in the short plus-strand strong-stop DNA fragment [(+) SSDNA] to a complementary site located near the 3' end of the minus-strand DNA [(-) PBS DNA]. To investigate the mechanism by which NC performs this function, we have prepared an 1s-nucleotide (-) PBS DNA for nuclear magnetic resonance (NMR) based structural and NC binding studies. The (-) PBS DNA forms a stable hairpin (T-m similar to 42 +/- 5 degrees C) that contains a five-residue loop and a bulged thymine in a guanosine-cytosine-rich stem. Addition of substoichiometric amounts of NC results in significant broadening and reductions in NMR signal intensities of the Watson-Crick base-paired imino protons and a reduction by 20 degrees C in the upper temperature at which the imino proton signals are detectable, consistent with destabilization of the structure. The results suggest that inefficient annealing in the absence of NC may be due to the intrinsic stability of an internal (-) PBS DNA hairpin and that NC facilitates strand transfer by destabilizing the hairpin and exposing stem nucleotides for base pairing with the PBS sequence in (+) SSDNA. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Baltimore, MD 21250 USA. Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. RP Levin, JG (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RI Johnson, Philip/D-3621-2012 OI Johnson, Philip/0000-0002-5573-4891 FU NIGMS NIH HHS [R25GM55036] NR 81 TC 76 Z9 77 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 AUG 8 PY 2000 VL 39 IS 31 BP 9084 EP 9091 DI 10.1021/bi000841i PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 341MC UT WOS:000088593300004 PM 10924101 ER PT J AU Umland, TC Wei, SQ Craigie, R Davies, DR AF Umland, TC Wei, SQ Craigie, R Davies, DR TI Structural basis of DNA bridging by barrier-to-autointegration factor SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ESCHERICHIA-COLI RUVA; RETROVIRAL DNA; HOLLIDAY JUNCTION; CRYSTAL-STRUCTURE; POLYMERASE-BETA; REPAIR ENZYME; CELLULAR FACTOR; BINDING MOTIFS; PROTEIN RUVA AB Barrier-to-autointegration factor (BAF) is a host cell protein that plays a crucial role in retroviral integration. Preintegration complexes (PICs) stripped of BAF lose their normal integration activity, which can be restored by incubation with purified BAF. BAF bridges double-stranded DNA both intra- and intermolecularly in a non-sequence-specific manner, leading to the formation of a nucleoprotein network. BAF also binds to the nuclear protein lamina-associated polypeptide 2 (LAP2), and is localized with chromatin during interphase and mitosis. The crystal structure of homodimeric human BAF has been determined to 1.9 Angstrom resolution. The fold of the BAF monomer resembles that of the second domain of RuvA. This comparison revealed the presence of the helix-hairpin-helix (HhH) nonspecific DNA binding motif within BAF. A novel feature of BAF's HhH motif is the occupation of the metal binding site by the epsilon-amino group of Lys 6, providing an alternative means of sequestering positive charge. Mutational analysis corroborates the HhH motif's prominent role in DNA binding and argues against a previously proposed helix-turn-helix (HTH) binding site located in another region of the monomer. A model of BAF bridging DNA via the HhH motif is proposed. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Davies, DR (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. OI Umland, Timothy/0000-0002-0772-9510 NR 45 TC 52 Z9 53 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 8 PY 2000 VL 39 IS 31 BP 9130 EP 9138 DI 10.1021/bi000572w PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 341MC UT WOS:000088593300009 PM 10924106 ER PT J AU Grollman, EF Philp, NJ McPhie, P Ward, RD Sauer, B AF Grollman, EF Philp, NJ McPhie, P Ward, RD Sauer, B TI Determination of transport kinetics of chick MCT3 monocarboxylate transporter from retinal pigment epithelium by expression in genetically modified yeast SO BIOCHEMISTRY LA English DT Article ID SKELETAL-MUSCLE; SACCHAROMYCES-CEREVISIAE; DEVELOPMENTAL EXPRESSION; LACTATE TRANSPORT; PROTON SYMPORT; GENE; MITOCHONDRIA; COTRANSPORT; CARRIER; PROTEIN AB Monocarboxylate transporters (MCTs) comprise a group of highly homologous proteins that reside in the plasma membrane of almost all cells and which mediate the 1:I electroneutral transport of a proton and a lactate ion. The isoform MCT3 is restricted to the basal membrane of the retinal pigment epithelium where it regulates lactate levels in the neural retina. Kinetic analysis of this transporter poses formidable difficulties due to the presence of multiple lactate transporters and their complex interaction with MCTs in adjacent cells. To circumvent these problems, we expressed both the MCT3 gene and a green fluorescent protein-tagged MCT3 construct in Saccharomyces cerevisiae. Since L-lactate metabolism in yeast depends on the CYB2 gene, we disrupted CYB2 to study the MCT3 transporter activity free from the complications of metabolism. Under these conditions L-lactate uptake varied inversely with pH, greater uptake being associated with lower pH. Whereas the V-max was invariant, the K-m increased severalfold as the pH rose from 6 to 8. In addition, MCT3 was highly resistant to a number of "classical" inhibitors of lactate transport. Last, studies with diethyl pyrocarbonate and p-chforomercuribenzenesulfonate set limitations on the locus of potential residues involved in the critical site of lactate translocation. C1 Oklahoma Med Res Fdn, Dev Biol Program, Oklahoma City, OK 73104 USA. NIDDK, Biochem Pharmacol Lab, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. RP Sauer, B (reprint author), Oklahoma Med Res Fdn, Dev Biol Program, 825 NE 13th St,MS 49, Oklahoma City, OK 73104 USA. NR 33 TC 48 Z9 49 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 8 PY 2000 VL 39 IS 31 BP 9351 EP 9357 DI 10.1021/bi000464+ PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 341MC UT WOS:000088593300032 PM 10924129 ER PT J AU Prota, A Vogt, J Pilger, B Perozzo, R Wurth, C Marquez, VE Russ, P Schulz, GE Folkers, G Scapozza, L AF Prota, A Vogt, J Pilger, B Perozzo, R Wurth, C Marquez, VE Russ, P Schulz, GE Folkers, G Scapozza, L TI Kinetics and crystal structure of the wild-type and the engineered Y101F mutant of Herpes simplex virus type 1 thymidine kinase interacting with (North)-methanocarba-thymidine SO BIOCHEMISTRY LA English DT Article ID VARICELLA-ZOSTER VIRUS; SITE-DIRECTED MUTAGENESIS; SUICIDE GENE-THERAPY; NUCLEOSIDE ANALOGS; BICYCLO<3.1.0>HEXANE TEMPLATE; CONFORMATIONAL-ANALYSIS; CARBOCYCLIC THYMIDINE; BIOLOGICAL-ACTIVITY; ANTIVIRAL ACTIVITY; ACYCLOVIR AB Kinetic and crystallographic analyses of wild-type Herpes simplex virus type 1 thymidine kinase (TKHSV1) and its Y101F-mutant [TKHSV1(Y101F)] acting on the potent antiviral drug 2'-exo-methanocarba-thymidine (MCT) have been performed. The kinetic study reveals a 12-fold K-M increase for thymidine processed with Y101F as compared to the wild-type TKHSV1 Furthermore, MCT is a substrate for both wild-type and mutant TKHSV1 Its binding affinity for TKHSV1 and TKHSV1(Y101F), expressed as K-i, is 11 mu M and 51 mu M, respectively, whereas the K-i for human cytosolic thymidine kinase is as high as 1.6 mM, rendering TKHSV1 a selectivity filter for antiviral activity. Moreover, TKHSV1(Y101F) shows a decrease in the quotient of the catalytic efficiency (k(cat)/K-M) of dT over MCT corresponding to an increased specificity for MCT when compared to the wild-type enzyme. Crystal structures of wild-type and mutant TKHSV1 in complex with MCT have been determined to resolutions of 1.7 and 2.4 Angstrom, respectively. The thymine moiety of MCT binds Like the base of dT while the conformationally restricted bicyclo[3.1.0]-hexane, mimicking the sugar moiety, assumes a 2'-exo envelope conformation that is flatter than the one observed for the free compound. The hydrogen bond pattern around the sugar-like moiety differs from that of thymidine, revealing the importance of the rigid conformation of MCT with respect to hydrogen bonds. These findings make MCT a lead compound in the design of resistance-repellent drugs for antiviral therapy, and mutant Y101F, in combination with MCT, opens new possibilities for gene therapy. C1 Swiss Fed Inst Technol, Dept Appl BioSci, CH-8057 Zurich, Switzerland. Univ Freiburg, Inst Organ Chem & Biochem, D-79104 Freiburg, Germany. NCI, Med Chem Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. RP Scapozza, L (reprint author), Swiss Fed Inst Technol, Dept Appl BioSci, Winterthurerstr 190, CH-8057 Zurich, Switzerland. NR 61 TC 40 Z9 42 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 8 PY 2000 VL 39 IS 31 BP 9597 EP 9603 DI 10.1021/bi000668q PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 341MC UT WOS:000088593300060 PM 10924157 ER PT J AU Maillard, L Ishii, K Bushara, K Waldvogel, D Schulman, AE Hallett, M AF Maillard, L Ishii, K Bushara, K Waldvogel, D Schulman, AE Hallett, M TI Mapping the basal ganglia - fMRI evidence for somatotopic representation of face, hand, and foot SO NEUROLOGY LA English DT Article ID STRIATAL MICROEXCITABLE ZONES; PRIMATE NEOSTRIATUM; PARKINSONS-DISEASE; ORGANIZATION; CORTEX; MONKEY; MICROSTIMULATION; PROJECTIONS; ACTIVATION; CEREBELLUM AB Objective: To noninvasively investigate the somatotopy of the basal ganglia in humans. Methods: Functional MRI, 1.5-T, was performed on six normal right-handed volunteers during simple acoustically paced motor tasks involving the right hand, foot, and face. Results: In a single-subject analysis, statistical parametric maps showed overlapping activation extending along the anteroposterior extent of the left lentiform nucleus (LLN) for the hand, foot, and face representations, Within the LLN, the centers of gravity of each body part, reflecting both the extent and gradient of activation, were all located in the retrocommissural portion of the putamen. Their spatial relationship followed a similar pattern across subjects-face was medial to toes and fingers, toes were dorsal and rostral to fingers. Conclusions: The somatotopic organization of hand, face, and foot representation in the human lentiform nucleus suggests a triangular pattern, rather than the linear pattern seen in primate studies. The overlap observed between the distinct body parts differs from the cortical sensorimotor representation, indicating a different organizational concept of the basal ganglia. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NINDS, Med Neurol Branch, Biometry & Field Studies Branch, NIH, Bethesda, MD 20892 USA. Hop Cent, Serv Neurol, Nancy, France. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC1428, Bethesda, MD 20892 USA. NR 22 TC 42 Z9 42 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 8 PY 2000 VL 55 IS 3 BP 377 EP 383 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 342ED UT WOS:000088631500011 PM 10932271 ER PT J AU Long, JC Brooks, J Bergen, AW Kittles, RA Goldman, D AF Long, JC Brooks, J Bergen, AW Kittles, RA Goldman, D TI Population genetics of complex alcoholism. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 NIAAA, Neurogenet Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 AUG 7 PY 2000 VL 96 IS 4 MA S22 BP 457 EP 458 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900017 ER PT J AU Adams, LJ Badenhop, RF Morris, JA Moses, MJ Scimone, A Ma, L Jones, AM Mathavan, K Donald, JA Hewitt, JE Detera-Wadleigh, SD Mitchell, PB Austin, CP Schofield, PR AF Adams, LJ Badenhop, RF Morris, JA Moses, MJ Scimone, A Ma, L Jones, AM Mathavan, K Donald, JA Hewitt, JE Detera-Wadleigh, SD Mitchell, PB Austin, CP Schofield, PR TI Analysis of a bipolar affective disorder susceptibility locus on chromosome 4q35. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Garvan Inst Med Res, Program Med Neurobiol, Sydney, NSW, Australia. Univ New S Wales, Sch Psychiat, Sydney, NSW 2036, Australia. Prince Henry Hosp, Mood Disorders Unit, Sydney, NSW, Australia. Merck Res Labs, W Point, PA USA. Macquarie Univ, Sch Biol Sci, Sydney, NSW 2109, Australia. Univ Nottingham, Div Genet, Nottingham NG7 2RD, England. NIMH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA O36 BP 469 EP 469 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900056 ER PT J AU Liu, CY Badner, JA Christian, S Guroff, JJ Detera-Wadleigh, SD Gershon, ES AF Liu, CY Badner, JA Christian, S Guroff, JJ Detera-Wadleigh, SD Gershon, ES TI Fine mapping provides further linkage evidence for a bipolar disorder susceptibility locus on 13q32. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. NIMH, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Hunan Med Univ, Nat Lab Med Genet China, Changsha, Peoples R China. RI Liu, Chunyu/G-7561-2012 OI Liu, Chunyu/0000-0002-5986-4415 NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA O38 BP 469 EP 469 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900058 ER PT J AU Kikuchi, M Saito, K Watanabe, A Yamada, K Shibuya, M Nankai, M Kurumaji, A Hattori, E Ishiguro, H Shimizu, H Okubo, Y Toru, M Detera-Wadleigh, SD Yoshikawa, T AF Kikuchi, M Saito, K Watanabe, A Yamada, K Shibuya, M Nankai, M Kurumaji, A Hattori, E Ishiguro, H Shimizu, H Okubo, Y Toru, M Detera-Wadleigh, SD Yoshikawa, T TI Evidence for association of the myo-inositol monophosphatase 2 (IMPA2) gene with schizophrenia in Japanese samples. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 RIKEN, Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama 3510198, Japan. Minami Hanamaki Hosp, Natl Sanat, Iwate, Japan. Tokyo Metropolitan Police Hosp, Dept Neuropsychiat, Tokyo, Japan. Tokyo Med & Dent Univ, Dept Neuropsychiat, Tokyo, Japan. Hokushin Gen Hosp, Dept Neuropsychiat, Nagano, Japan. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA O66 BP 477 EP 477 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900086 ER PT J AU Basu, S Ashley-Koch, A Wolpert, CM Menold, MM Matsumoto, N Greenblatt, DM Powell, CM Qumsiyeh, MB Cuccaro, ML Ledbetter, DH Green, ED Vance, JM Pericak-Vance, MA Gilbert, JR AF Basu, S Ashley-Koch, A Wolpert, CM Menold, MM Matsumoto, N Greenblatt, DM Powell, CM Qumsiyeh, MB Cuccaro, ML Ledbetter, DH Green, ED Vance, JM Pericak-Vance, MA Gilbert, JR TI Identification of autism susceptibility candidates on 7q. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. Univ N Carolina, Dept Pediat, Chapel Hill, NC USA. Univ S Carolina, W S Hall Inst Psychiat, Columbia, SC 29208 USA. Natl Inst Hlth, NHGRI, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA O73 BP 479 EP 479 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900092 ER PT J AU Sommer, SS Feng, J Craddock, N Cook, E Goldman, D Heston, LL AF Sommer, SS Feng, J Craddock, N Cook, E Goldman, D Heston, LL TI Scanning of steroid hormone receptor genes with DOVAM-S in patients with psychiatric diseases. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 City Hope Natl Med Ctr, Dept Mol Genet, Duarte, CA 91010 USA. Univ Birmingham, Dept Psychiat, Birmingham, W Midlands, England. Univ Chicago, Dept Psychiat, Chicago, IL USA. NIAAA, Dept Psychiat, NIH, Bethesda, MD USA. Univ Washington, Dept Psychiat, Seattle, WA USA. NR 0 TC 0 Z9 0 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA O84 BP 481 EP 482 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900101 ER PT J AU Detera-Wadleigh, SD Badner, JA Yoshikawa, T Gershon, ES Sanders, AR Berrettini, WH Goldin, LR Nurnberger, JI Moses, TY Turner, G Rollins, DY AF Detera-Wadleigh, SD Badner, JA Yoshikawa, T Gershon, ES Sanders, AR Berrettini, WH Goldin, LR Nurnberger, JI Moses, TY Turner, G Rollins, DY TI Linkage disequilibrium analysis unveils evidence for a chromosome 11q23 bipolar disorder susceptibility locus. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 NIMH, Intramural Res Program, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA O93 BP 483 EP 483 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900108 ER PT J AU Rotondo, A Mazzanti, CM Gemignani, A Pfanner, C Presta, S Milanfranchi, A Doria, MR Gonnelli, C Goldman, D Dell'Osso, L Cassano, GB AF Rotondo, A Mazzanti, CM Gemignani, A Pfanner, C Presta, S Milanfranchi, A Doria, MR Gonnelli, C Goldman, D Dell'Osso, L Cassano, GB TI Obsessive-compulsive spectrum and serotonin: A genetic association study. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 Univ Pisa, Dept Psychiat Pharmacol Neurobiol & Biotechnol, Pisa, Italy. NIAAA, NIH, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA P185 BP 525 EP 525 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900258 ER PT J AU Rudolph, JG Mazzanti, CM McManaman, C Rho, J Berezdivin, BD Sokolsky, C Bozak, D Marko, A Lipsky, RH Goldman, D AF Rudolph, JG Mazzanti, CM McManaman, C Rho, J Berezdivin, BD Sokolsky, C Bozak, D Marko, A Lipsky, RH Goldman, D TI Nucleotide sequence diversity in human NMDA receptor genes. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 NIAAA, NIH, Neurogenet Lab, Rockville, MD 20852 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA P394 BP 562 EP 562 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900395 ER PT J AU Syagailo, YV Grassle, M Bennett, A Higley, JD Lesch, KP AF Syagailo, YV Grassle, M Bennett, A Higley, JD Lesch, KP TI A monoamine oxidase A promoter-associated polymorphic region in evolutionary perspective. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 NIAAA, NIH, Clin Studies Lab, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA P400 BP 562 EP 562 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900397 ER PT J AU Lipsky, RP Xu, K Kelly, C Terhakopian, A Marini, AM AF Lipsky, RP Xu, K Kelly, C Terhakopian, A Marini, AM TI NF kappa B is a critical determinant in NMDA receptor mediated neuroprotection. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 NIAAA, NIH, Neurogenet Lab, Rockville, MD USA. NR 0 TC 0 Z9 0 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA P402 BP 563 EP 563 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900399 ER PT J AU Myakishev, MV Khripin, Y Hu, S Lueders, S Trachtenberg, B Sirota, L Hamer, D AF Myakishev, MV Khripin, Y Hu, S Lueders, S Trachtenberg, B Sirota, L Hamer, D TI A new method for SNP genotyping and its application to candidate genes for nicotine addiction and personality traits. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. Intergen Discovery Products, Gaithersburg, MD USA. NCI, NIH, Biochem Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA P446 BP 570 EP 570 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900426 ER PT J AU Toyota, T Watanabe, A Shibuya, H Nankai, M Hattori, E Yamada, K Kurumaji Karkera, JD Detera-Wadleigh, SD Yoshikawa, T AF Toyota, T Watanabe, A Shibuya, H Nankai, M Hattori, E Yamada, K Kurumaji Karkera, JD Detera-Wadleigh, SD Yoshikawa, T TI Association study on the DUSP6 gene: An affective disorder candidate gene on 12q23, performed by using fluorescence resonance energy transfer-based melting curve analysis. SO AMERICAN JOURNAL OF MEDICAL GENETICS LA English DT Meeting Abstract C1 RIKEN, Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama 3510198, Japan. Natl Sanat Minami Hanamaki Hosp, Iwate, Japan. Tokyo Metropolitan Police Hosp, Dept Neuropsychiat, Tokyo, Japan. Tokyo Med & Dent Uni, Dept Neuropsychiat, Tokyo, Japan. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 0148-7299 J9 AM J MED GENET JI Am. J. Med. Genet. PD AUG 7 PY 2000 VL 96 IS 4 MA P445 BP 570 EP 570 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 340ZE UT WOS:000088565900425 ER PT J AU Dundr, M Misteli, T Olson, MOJ AF Dundr, M Misteli, T Olson, MOJ TI The dynamics of postmitotic reassembly of the nucleolus SO JOURNAL OF CELL BIOLOGY LA English DT Article DE mitosis; nucleolus; prenucleolar body; pre-rRNA processing; rDNA transcription ID PRE-RIBOSOMAL-RNA; RDNA TRANSCRIPTION MACHINERY; POLYMERASE-I TRANSCRIPTION; PRENUCLEOLAR BODIES; CHROMOSOME PERIPHERY; GENE-TRANSCRIPTION; PROTEIN B23; FACTOR SL1; FACTOR UBF; U3 SNRNA AB Mammalian cell nucleoli disassemble at the onset of M-phase and reassemble during telophase, Recent studies showed that partially processed preribosomal RNA (pre-rRNA) is preserved in association with processing components in the perichromosomal regions (PRs) and in particles called nucleolus-derived foci (NDF) during mitosis. Here, the dynamics of nucleolar reassembly were examined for the first time in living cells expressing fusions of the processing-related proteins fibrillarin, nucleolin, or B23 with green fluorescent protein (GFP), During telophase the NDF disappeared with a concomitant appearance of material in the reforming nuclei. Prenucleolar bodies (PNBs) appeared in nuclei in early telophase and gradually disappeared as nucleoli formed, strongly suggesting the transfer of PNB components to newly forming nucleoli. Fluorescence recovery after photobleaching (FRAP) showed that fibrillarin-GFP reassociates with the NDF and PNBs at rapid and similar rates. The reentry of processing complexes into telophase nuclei is suggested by the presence of pre-rRNA sequences in PNBs. Entry of specific proteins into the nucleolus approximately correlated with the timing of processing events. The mitotically preserved processing complexes may be essential for regulating the distribution of components to reassembling daughter cell nucleoli. C1 Univ Mississippi, Med Ctr, Dept Biochem, Jackson, MS 39216 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Olson, MOJ (reprint author), 2500 N State St, Jackson, MS 39216 USA. NR 47 TC 176 Z9 183 U1 1 U2 8 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 AUG 7 PY 2000 VL 150 IS 3 BP 433 EP 446 DI 10.1083/jcb.150.3.433 PG 14 WC Cell Biology SC Cell Biology GA 343XM UT WOS:000088727800005 PM 10931858 ER PT J AU Wanant, S Quon, MJ AF Wanant, S Quon, MJ TI Insulin receptor binding kinetics: Modeling and simulation studies SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article ID SITE-SITE INTERACTIONS; FACTOR-I RECEPTOR; WHITE FAT-CELLS; NEGATIVE COOPERATIVITY; CRYSTAL-STRUCTURE; TYROSINE KINASE; HUMAN-PLACENTA; AGGREGATION; HORMONE; 15-DEGREES-C AB Biological actions of insulin regulate glucose metabolism and other essential physiological functions. Binding of insulin to its cell surface receptor initiates signal transduction pathways that mediate cellular responses. Thus, it is of great interest to understand the mechanisms underlying insulin receptor binding kinetics. Interestingly, negative cooperative interactions are observed at high insulin concentrations while positive cooperativity may be present at low insulin concentrations. Clearly, insulin receptor binding kinetics cannot be simply explained by a classical bimolecular reaction. Mature insulin receptors have a dimeric structure capable of binding two molecules of insulin. The binding affinity of the receptor for the second insulin molecule is significantly lower than for the first bound insulin molecule. In addition, insulin receptor aggregation occurs in response to ligand binding and aggregation may also influence binding kinetics. In this study, we develop a mathematical model for insulin receptor binding kinetics that explicitly represents the divalent nature of the insulin receptor and incorporates receptor aggregation into the kinetic model. Model parameters are based upon published data. where available. Computer simulations with our model are capable of reproducing both negative and positive cooperativity at the appropriate insulin concentrations. This model may be a useful tool for helping to understand the mechanisms underlying insulin receptor binding and the coupling of receptor binding to downstream signaling events. (C) 2000 Academic Press. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Quon, MJ (reprint author), NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 51 TC 22 Z9 23 U1 2 U2 7 PU ACADEMIC PRESS LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD AUG 7 PY 2000 VL 205 IS 3 BP 355 EP 364 DI 10.1006/jtbi.2000.2069 PG 10 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 334DT UT WOS:000088171000002 PM 10882558 ER PT J AU O'Shea, MS Rosen, JB Post, RM Weiss, SRB AF O'Shea, MS Rosen, JB Post, RM Weiss, SRB TI Specific amygdaloid nuclei are involved in suppression or propagation of epileptiform activity during transition stage between oral automatisms and generalized clonic seizures SO BRAIN RESEARCH LA English DT Article DE kindling; amygdala; seizures; claustrum; rat; mRNA expression ID FOS MESSENGER-RNA; CENTRAL EXTENDED AMYGDALA; LIMBIC STATUS EPILEPTICUS; DEEP PREPIRIFORM CORTEX; IMMEDIATE-EARLY GENES; LONG-LASTING CHANGES; C-FOS; PERIRHINAL CORTEX; BASOLATERAL AMYGDALA; PIRIFORM CORTEX AB Kindling is a model of the neural plasticity that occurs following stimulation to the brain, which can result in epileptogenesis. The amygdala (Am), one of the most sensitive structures from which to induce electrical kindling, is comprised of distinct nuclei that possess differences in threshold for seizure initiation, unique cellular and molecular morphology, and specific neuroanatomical connections within the amygdala and, to other cortical and subcortical brain structures. The aim of this study was to map the spread of epileptiform activity throughout the ipsilateral and contralateral hemispheres during the transition stage between oral automatisms and generalized clonic seizures, by measuring changes in mRNA expression for c-Sos, NGFI-A, and BDNF. The stimulating electrode was implanted in either the basolateral (BL) or the lateral (CeL) or medial (CeM) subdivisions of the central nucleus of the amygdala. The rats were kindled once daily using afterdischarge-threshold electrical stimulation until the first forelimb clonic seizure was induced. They were sacrificed 30 min later, and their brains were prepared for in situ hybridization to measure mRNA expression of c-Sos, NGFI-A and BDNF. The results demonstrate that: (1) the threshold to elicit an afterdischarge from the BL was lower than that of either the medial (CeM) or lateral (CeL) subdivisions of the Ce, which did not differ from each other; (2) the patterns of mRNA expression for c-Sos, NGFI-A and BDNF were highly similar to each other when the stimulation site was the BL or the CeL, and included mainly limbic cortical and subcortical areas ipsilateral to the electrode: (3) c-fos was the only probe to be expressed in the contralateral hemisphere following the first motor seizure, and the pattern of its expression reflected a subset of structures recruited in the ipsilateral hemisphere including the claustrum, insular and perirhinal cortices; (4) unexpectedly, stimulation of the CeL elicited seizures and afterdischarges of shorter duration than those evoked by stimulation of the BL or CeL, and failed to increase mRNA expression for any of the probes in the hippocampus or in the contralateral hemisphere. A neuroanatomical model of Am-induced seizure propagation is proposed suggesting that the Claust-Ins-PRh play a pivotal role during the transition between oral automatisms and generalized clonic convulsions. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Univ Maryland, Dept Biol, College Pk, MD 20782 USA. Univ Delaware, Dept Psychol, Newark, DE 19716 USA. RP O'Shea, MS (reprint author), Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. NR 99 TC 9 Z9 9 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 AUG 4 PY 2000 VL 873 IS 1 BP 1 EP 17 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 341MQ UT WOS:000088594500001 ER PT J AU Rimer, BK AF Rimer, BK TI Response to Kreuter and Skinner SO HEALTH EDUCATION RESEARCH LA English DT Letter C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Rimer, BK (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 J9 HEALTH EDUC RES JI Health Educ. Res. PD AUG 4 PY 2000 VL 15 IS 4 BP 503 EP 503 DI 10.1093/her/15.4.503 PG 1 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 345HU UT WOS:000088811200012 PM 11066467 ER PT J AU Brosh, RM Li, JL Kenny, MK Karow, JK Cooper, MP Kureekattil, RP Hickson, ID Bohr, VA AF Brosh, RM Li, JL Kenny, MK Karow, JK Cooper, MP Kureekattil, RP Hickson, ID Bohr, VA TI Replication protein A physically interacts with the Bloom's syndrome protein and stimulates its helicase activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; ROTHMUND-THOMSON-SYNDROME; WERNERS-SYNDROME GENES; ESCHERICHIA-COLI; BINDING PROTEIN; SYNDROME CELLS; MOLECULAR-CLONING; RECQ FAMILY; IN-VIVO; RECOMBINATION AB Bloom's syndrome is a rare autosomal recessive disorder characterized by genomic instability and predisposition to cancer. BLM, the gene defective in Bloom's syndrome, encodes a 159-kDa protein possessing DNA-stimulated ATPase and ATP-dependent DNA helicase activities. We have examined mechanistic aspects of the catalytic functions of purified recombinant BLM protein, Through analyzing the effects of different lengths of DNA cofactor on ATPase activity, we provide evidence to suggest that BLM translocates along single-stranded DNA in a processive manner. The helicase reaction catalyzed by BLM protein was examined as a function of duplex DNA length. We show that BLM: catalyzes unwinding of short DNA duplexes (less than or equal to 71 base pairs (bp)) but is severely compromised on longer DNA duplexes (greater than or equal to 259-bp), The presence of the human single-stranded DNA-binding protein (human replication protein A (hRPA)) stimulates the BLM unwinding reaction on the 259-bp partial duplex DNA substrate. Heterologous single-stranded DNA-binding proteins fail to stimulate similarly the helicase activity of BLM protein. This is the first demonstration of a functional interaction between BLM and another protein. Consistent with a functional interaction between hRPA and the BLM helicase, we demonstrate a direct physical interaction between the two proteins mediated by the 70-kDa subunit of RPA. The interactions between BLM and hRPA suggest that the two proteins function together in vivo to unwind DNA duplexes during replication, recombination, or repair. C1 NIA, Mol Genet Lab, NIH, Baltimore, MD 21224 USA. Univ Oxford, John Radcliffe Hosp, Inst Mol Med, Imperial Canc Res Fund Labs, Oxford OX3 9DS, England. Montefiore Med Ctr, Dept Radiat Oncol, Bronx, NY 10467 USA. Montefiore Med Ctr, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. RP Bohr, VA (reprint author), NIA, Mol Genet Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NCI NIH HHS [CA71612] NR 39 TC 197 Z9 202 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 AUG 4 PY 2000 VL 275 IS 31 BP 23500 EP 23508 DI 10.1074/jbc.M001557200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 340YL UT WOS:000088564200015 PM 10825162 ER PT J AU Cavalli, A Druey, KM Milligan, G AF Cavalli, A Druey, KM Milligan, G TI The regulator of G protein signaling RGS4 selectively enhances alpha(2A)-adreoreceptor stimulation of the GTPase activity of G(o1)alpha and G(i2)alpha SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HETEROTRIMERIC G-PROTEINS; ALPHA(2A)-ADRENOCEPTOR-G(I1)ALPHA FUSION PROTEIN; ALPHA-SUBUNITS; ACTIVATING PROTEINS; PHOSPHOLIPASE C-BETA-1; G-ALPHA(I) SUBUNITS; RAT-1 FIBROBLASTS; TRANSITION-STATE; POINT-MUTATION; FAMILY MEMBERS AB Agonist-stimulated high affinity GTPase activity of fusion proteins between the alpha(2A)-adrenoreceptor and the alpha subunits of forms of the G proteins G(i1), G(i2), G(i3), and G(o1), modified to render them insensitive to the action of pertussis toxin, was measured following transient expression in COS-7 cells. Addition of a recombinant regulator of G protein signaling protein, RGS4, did not significantly affect basal GTPase activity nor agonist stimulation of the fusion proteins containing G alpha(i1) and G alpha(i3) but markedly enhanced agonist-stimulation of the proteins containing G alpha(i2) and G alpha(o1). The effect of RGS4 on the alpha(2A)-adrenoreceptor-G alpha(o1) fusion protein was concentration-dependent with EC50 of 30 +/- 3 nM and the potency of the receptor agonist UK14304 was reduced 3-fold by 100 nM RGS4. Equivalent reconstitution with Asn(88)-Ser RGS4 failed to enhance agonist function on the alpha(2A)-adrenoreceptor-G alpha(o1) or alpha(2A)-adrenoreceptor-G alpha(i2) fusion proteins. Enzyme kinetic analysis of the GTPase activity of the alpha(2A)-adrenoreceptor-G alpha(o1) and alpha(2A)-adrenoreceptor-G alpha(i2) fusion proteins demonstrated that RGS4 both substantially increased GTPase V-max and significantly increased K-m of the fusion proteins for GTP. The increase in K-m for GTP was dependent upon RGS4 amount and is consistent with previously proposed mechanisms of RGS function. Agonist-stimulated GTPase turnover number in the presence of 100 nM RGS4 was substantially higher for alpha(2A)-adrenoreceptor-G alpha(o1) than for alpha(2A)-adrenoreceptor-G alpha(i2). These studies demonstrate that although RGS4 has been described as a generic stimulator of the GTPase activity of G(i)-family G proteins, selectivity of this interaction and quantitative variation in its function can be monitored in the presence of receptor activation of the G proteins. C1 Univ Glasgow, Inst Biomed & Life Sci, Div Biochem & Mol Biol, Mol Pharmacol Grp, Glasgow G12 8QQ, Lanark, Scotland. NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Rockville, MD 20852 USA. RP Milligan, G (reprint author), Univ Glasgow, Inst Biomed & Life Sci, Div Biochem & Mol Biol, Mol Pharmacol Grp, Davidson Bldg, Glasgow G12 8QQ, Lanark, Scotland. RI Milligan, Graeme/F-9426-2011 OI Milligan, Graeme/0000-0002-6946-3519 NR 57 TC 54 Z9 54 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 AUG 4 PY 2000 VL 275 IS 31 BP 23693 EP 23699 DI 10.1074/jbc.M910395199 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 340YL UT WOS:000088564200041 PM 10807934 ER PT J AU Fan, QR Long, EO Wiley, DC AF Fan, QR Long, EO Wiley, DC TI Cobalt-mediated dimerization of the human natural killer cell inhibitory receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HLA-C; DIRECT BINDING; NK CELLS; ZINC; MOLECULES; P58; SPECIFICITIES; RECOGNITION; PROLACTIN; ALLOTYPES AB Upon engagement of specific class I major histocompatibility complex (MHC) molecules on target cells, inhibitory receptors on natural killer (NK) cells deliver a negative signal that prevents the target cell lysis by NK cells. In humans, killer cell immunoglobulin-related receptors (KIR) with two immunoglobulin-like domains (KIR2D) modulate the lysis of target cells bearing specific HLA-C alleles (Moretta, A., Vitale, M., Bottino, C., Orengo, A. M., Morelli, L., Augugliaro, R., Barbaresi, M., Ciccone, E., and Moretta, L. (1993) J. Exp. Med. 178, 597-604). The transduction of inhibitory signals by KIR2D molecules is impaired by the zinc chelator, 1,10-phenanthroline, and mutation of a putative zinc-binding site (Rajagopalan, S., and Long, E. O. (1998) J. Immunol. 161, 1299-1305), but the mechanism by which zinc may affect the function of KIR remains unknown. In this study, the inhibitory NK receptor KIR2DL1 was discovered to dimerize in the presence of Co2+ as observed on native gel electrophoresis and by gel filtration column chromatography. Furthermore, Co2+-mediated KIR2DL1 dimer binds to HLA-Cw4 with higher affinity than the wild type KIR2DL1 monomer. Replacement of the amino-terminal His residue by Ala abolishes the ability of KIR2DL1 to bind Co2+, indicating that Co2+-mediated KIR2DL1 dimerization involves pairing of the D1 domain. Although not observed on native gels, the inhibitory receptor KIR2DL1 can be chemically cross-linked into dimers in the presence of Zn2+ and its related divalent metal ions, suggesting that Co2+-mediated dimerization of KIR2DL1 may mimic a weaker interaction between KIR2DL1 and zinc in vivo. C1 Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA. Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Wiley, DC (reprint author), Harvard Univ, Dept Mol & Cellular Biol, 7 Divin Ave, Cambridge, MA 02138 USA. RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 NR 29 TC 21 Z9 21 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 4 PY 2000 VL 275 IS 31 BP 23700 EP 23706 DI 10.1074/jbc.M003318200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 340YL UT WOS:000088564200042 PM 10816589 ER PT J AU Lacourciere, GM Mihara, H Kurihara, T Esaki, N Stadtman, TC AF Lacourciere, GM Mihara, H Kurihara, T Esaki, N Stadtman, TC TI Escherichia coli NifS-like proteins provide selenium in the pathway for the biosynthesis of selenophosphate SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SELENOCYSTEINE LYASE; HAEMOPHILUS-INFLUENZAE; NUCLEOTIDE-SEQUENCE; GENE-PRODUCT; PURIFICATION; ENZYME; SYNTHETASE; CLONING; MECHANISM; CLUSTER AB Selenophosphate synthetase (SPS), the selD gene product from Escherichia coli, catalyzes the biosynthesis of monoselenophosphate, AMP, and orthophosphate in a 1:1:1 ratio from selenide and ATP. Kinetic characterization revealed the K-m value for selenide approached levels that; are toxic to the cell, Our previous demonstration that a Se-0-generating system consisting of L-selenocysteine and the Azotobacter vinelandii NifS protein can replace selenide for selenophosphate biosynthesis in vitro suggested a mechanism whereby cells can overcome selenide toxicity. Recently, three E. coli NifS-like proteins, CsdB, CSD, and IscS, have been overexpressed and characterized. All three enzymes act on selenocysteine and cysteine to produce Se-0 and S-0, respectively. In the present study, we demonstrate the ability of each E. coli NifS-like protein to function as a selenium delivery protein for the in vitro biosynthesis of selenophosphate by E. coli wild-type SPS. Significantly, the SPS (C17S) mutant, which is inactive in the standard in vitro assay with selenide as substrate, was found to exhibit detectable activity in the presence of CsdB, CSD, or IscS and L-selenocysteine. Taken together the ability of the NifS-like proteins to generate a selenium substrate for SPS and the activation of the SPS (C17S) mutant suggest a selenium delivery function for the proteins in vivo. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Chem Res Inst, Kyoto 6110011, Japan. RP Lacourciere, GM (reprint author), NHLBI, Biochem Lab, NIH, Bldg 3 Rm 103,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Mihara, Hisaaki/F-2172-2010 OI Mihara, Hisaaki/0000-0002-5153-4403 NR 39 TC 45 Z9 51 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 AUG 4 PY 2000 VL 275 IS 31 BP 23769 EP 23773 DI 10.1074/jbc.M000926200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 340YL UT WOS:000088564200051 PM 10829016 ER PT J AU Bittner, M Meitzer, P Chen, Y Jiang, Y Seftor, E Hendrix, M Radmacher, M Simon, R Yakhini, Z Ben-Dor, A Sampas, N Dougherty, E Wang, E Marincola, F Gooden, C Lueders, J Glatfelter, A Pollock, P Carpten, J Gillanders, E Leja, D Dietrich, K Beaudry, C Berens, M Alberts, D Sondak, V Hayward, N Trent, J AF Bittner, M Meitzer, P Chen, Y Jiang, Y Seftor, E Hendrix, M Radmacher, M Simon, R Yakhini, Z Ben-Dor, A Sampas, N Dougherty, E Wang, E Marincola, F Gooden, C Lueders, J Glatfelter, A Pollock, P Carpten, J Gillanders, E Leja, D Dietrich, K Beaudry, C Berens, M Alberts, D Sondak, V Hayward, N Trent, J TI Molecular classification of cutaneous malignant melanoma by gene expression profiling SO NATURE LA English DT Article ID EXTRACELLULAR-MATRIX; CDNA MICROARRAYS; CELL-ADHESION; IN-VITRO; MIGRATION; PATTERNS; MOTILITY; INTEGRIN; CANCER; ASSAY AB The most common human cancers are malignant neoplasms of the skin(1,2). Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease(3,4). Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm(2,3). Accordingly, though melanoma is thought to present with different 'taxonomic' forms, these are considered part of a continuous spectrum rather than discrete entities(2). Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas(5). Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression. C1 Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Iowa, Ctr Canc, Dept Anat & Cell Biol, Iowa City, IA 52242 USA. NCI, DCTDC, NIH, Bethesda, MD 20852 USA. Agilent Labs, Chem & Biol Syst Dept, Palo Alto, CA 94304 USA. Univ Washington, Dept Comp Sci & Engn, Seattle, WA 98105 USA. Texas A&M Univ, Dept Elect Engn, College Stn, TX 77843 USA. NCI, Surg Branch, NIH, Bethesda, MD 20850 USA. Queensland Inst Med Res, Herston, Qld 4029, Australia. Barrow Neurol Inst, Neurooncol Lab, Phoenix, AZ 85013 USA. Univ Arizona, Arizona Canc Ctr, Tucson, AZ 85724 USA. Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA. RP Bittner, M (reprint author), Natl Human Genome Res Inst, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RI hayward, nicholas/C-1367-2015 OI hayward, nicholas/0000-0003-4760-1033 NR 30 TC 1362 Z9 1407 U1 10 U2 76 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 3 PY 2000 VL 406 IS 6795 BP 536 EP 540 DI 10.1038/35020115 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 340ML UT WOS:000088538000051 PM 10952317 ER PT J AU Shen, XT Mizuguchi, G Hamiche, A Wu, C AF Shen, XT Mizuguchi, G Hamiche, A Wu, C TI A chromatin remodelling complex involved in transcription and DNA processing SO NATURE LA English DT Article ID SACCHAROMYCES-CEREVISIAE; NUCLEOSOME; BINDING; PROTEIN; SWI/SNF; RUVB; RECOMBINATION; HELICASE; SUBUNIT; FAMILY AB The packaging of the eukaryotic genome in chromatin presents barriers that restrict the access of enzymes that process DNA(1,2). To overcome these barriers, cells possess a number of multi-protein, ATP-dependent chromatin remodelling complexes, each containing an ATPase subunit from the SNF2/SWI2 superfamily(3,4). Chromatin remodelling complexes function by increasing nucleosome mobility and are clearly implicated in transcription(5-7). Here we have analysed SNF2/SWI2- and ISWI-related proteins to identify remodelling complexes that potentially assist other DNA transactions. We purified a complex from Saccharomyces cerevisiae that contains the Ino80 ATPase(8). The INO80 complex contains about 12 polypeptides including two proteins related to the bacterial RuvB DNA helicase(9-11), which catalyses branch migration of Holliday junctions. The purified complex remodels chromatin, facilitates transcription in vitro and displays 3' to 5' DNA helicase activity. Mutants of ino80 show hypersensitivity to agents that cause DNA damage, in addition to defects in transcription(8). These results indicate that chromatin remodelling driven by the Ino80 ATPase may be connected to transcription as well as DNA damage repair. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Biostudies, Sakyo Ku, Kyoto 6068502, Japan. RP Wu, C (reprint author), NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NR 30 TC 499 Z9 516 U1 12 U2 38 PU MACMILLAN PUBLISHERS LTD PI LONDON PA PORTERS SOUTH, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 3 PY 2000 VL 406 IS 6795 BP 541 EP 544 DI 10.1038/35020123 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 340ML UT WOS:000088538000052 PM 10952318 ER PT J AU Corthout, E Uttl, B Juan, CH Hallett, M Cowey, A AF Corthout, E Uttl, B Juan, CH Hallett, M Cowey, A TI Suppression of vision by transcranial magnetic stimulation: a third mechanism SO NEUROREPORT LA English DT Article DE transcranial magnetic stimulation (TMS); visual cortex; visual perception ID VISUAL-PERCEPTION; FACIAL-NERVE; CORTICAL STIMULATION; OCCIPITAL CORTEX; COIL; HUMANS; FIELD AB We recently reported three periods when single-pulse transcranial magnetic stimulation (TMS) of the occipital pole impaired performance on a forced-choice visual letter-identification task. TMS-induced suppression during these periods is best explained by a blink-associated covering of the pupils and by a direct interference with letter-processing neural activity. We now report TMS-induced suppression at times that seem too late for the suppression to be explained by the first mechanism and too early for the suppression to be explained by the second mechanism. The most likely explanation is a blink-associated interference with letter-processing neural activity. NeuroReport 11:2345-2349 (C) 2000 Lippincott Williams & Wilkins. C1 Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. Oregon State Univ, Dept Psychol, Corvallis, OR 97331 USA. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Corthout, E (reprint author), Univ Oxford, Dept Expt Psychol, S Parks Rd, Oxford OX1 3UD, England. NR 25 TC 32 Z9 32 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 3 PY 2000 VL 11 IS 11 BP 2345 EP 2349 DI 10.1097/00001756-200008030-00003 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 340ZY UT WOS:000088567600005 PM 10943683 ER PT J AU Carta, AR Gerfen, CR Steiner, H AF Carta, AR Gerfen, CR Steiner, H TI Cocaine effects on gene regulation in the striatum and behavior: increased sensitivity in D3 dopamine receptor-deficient mice SO NEUROREPORT LA English DT Article DE basal ganglia; c-fos; cocaine; dopamine; dynorphin; D3 receptor; psychostimulant ID IMMEDIATE-EARLY GENE; FOS MESSENGER-RNA; NUCLEUS-ACCUMBENS; MUTANT MICE; D-3 RECEPTOR; EXPRESSION; AMPHETAMINE; DYNORPHIN; RAT; D1 AB Central effects of psychostimulants such as cocaine are predominantly mediated by dopamine receptors. We have used mice with a targeted deletion of the D3 dopamine receptor subtype to investigate the role of this receptor in the regulation of gene expression in striatal neurons and behavior by acute and repeated treatment with cocaine (25 mg/kg). In mice lacking D3 receptors, acute administration of cocaine has more pronounced stimulatory effects on c-fos and dynorphin expression in the dorsal and ventral striatum. The behavioral response to cocaine is also increased in these mice. These findings indicate that the D3 receptor plays an inhibitory role in the action of cocaine on behavior and gene regulation in the striatum. NeuroReport 11:2395-2399 (C) 2000 Lippincott Williams & Wilkins. C1 NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. Univ Tennessee, Coll Med, Dept Anat & Neurobiol, Memphis, TN 38163 USA. RP Steiner, H (reprint author), Finch Univ Hlth Sci Chicago Med Sch, Dept Mol & Cellular Pharmacol, 3333 Green Bay Rd, N Chicago, IL 60064 USA. FU NIDA NIH HHS [DA11261] NR 32 TC 31 Z9 32 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 3 PY 2000 VL 11 IS 11 BP 2395 EP 2399 DI 10.1097/00001756-200008030-00012 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 340ZY UT WOS:000088567600014 PM 10943692 ER PT J AU Gray, RH Quinn, TC Serwadda, D Sewankambo, NK Wabwire-Mangen, F Wawer, MJ AF Gray, RH Quinn, TC Serwadda, D Sewankambo, NK Wabwire-Mangen, F Wawer, MJ TI The ethics of research in developing countries. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Johns Hopkins Univ, Baltimore, MD 21205 USA. NIAID, Bethesda, MD 20892 USA. Makerere Univ, Kampala, Uganda. Columbia Univ, New York, NY 10032 USA. RP Gray, RH (reprint author), Johns Hopkins Univ, Baltimore, MD 21205 USA. NR 10 TC 6 Z9 6 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 AUG 3 PY 2000 VL 343 IS 5 BP 361 EP 362 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 340GR UT WOS:000088525200010 PM 10928888 ER PT J AU Quinn, TC Wawer, MJ Sewankambo, NK AF Quinn, TC Wawer, MJ Sewankambo, NK TI A study in rural Uganda of heterosexual transmission of human immunodeficiency virus. Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID TYPE-1 C1 NIAID, Baltimore, MD 21205 USA. Columbia Univ, New York, NY 10032 USA. Makerere Univ, Kampala, Uganda. RP Quinn, TC (reprint author), NIAID, Baltimore, MD 21205 USA. NR 6 TC 7 Z9 7 U1 1 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 3 PY 2000 VL 343 IS 5 BP 364 EP 365 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 340GR UT WOS:000088525200019 ER PT J AU Vaughn, J Wolford, JK Prochazka, M Permana, PA AF Vaughn, J Wolford, JK Prochazka, M Permana, PA TI Genomic structure and expression of human KCNJ9 (Kir3.3/GIRK3) SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID RECTIFYING K+ CHANNELS; POTASSIUM CHANNEL; PIMA-INDIANS; INWARD RECTIFIER; XENOPUS-OOCYTES; GENE-EXPRESSION; PROTEIN; SUBUNITS; BINDING; CLONING AB The human KCNJ9 (Kir 3.3, GIR-K3) is a member of the G-protein-activated inwardly rectifying potassium (GIRK) channel family. Here we describe the genomic organization of the KCNJ9 locus on chromosome 1q21-23 as a candidate gene for Type Il diabetes mellitus in the Pima Indian population. The gene spans similar to 7.6 kb and contains one noncoding and two coding exons separated by similar to 2.2 and similar to 2.6 kb introns, respectively. We identified 14 single nucleotide polymorphisms (SNPs), including one that predicts a Val366Ala substitution, and an 8 base-pair (bp) insertion/deletion. Our expression studies revealed the presence of the transcript in various human tissues including pancreas, and two major insulin-responsive tissues: fat and skeletal muscle. The characterization of the KCNJ9 gene should facilitate further studies on the function of the KCNJ9 protein and allow evaluation of the potential role of the locus in Type II diabetes. (C) 2000 Academic Press. C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Permana, PA (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16th St, Phoenix, AZ 85016 USA. NR 35 TC 14 Z9 15 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 AUG 2 PY 2000 VL 274 IS 2 BP 302 EP 309 DI 10.1006/bbrc.2000.3136 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 341LU UT WOS:000088592500006 PM 10913335 ER PT J AU Hodge, JW Rad, AN Grosenbach, DW Sabzevari, H Yafal, AG Gritz, L Schlom, J AF Hodge, JW Rad, AN Grosenbach, DW Sabzevari, H Yafal, AG Gritz, L Schlom, J TI Enhanced activation of T cells by dendritic cells engineered to hyperexpress a triad of costimulatory molecules SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ANTITUMOR IMMUNE-RESPONSES; RECOMBINANT VACCINIA VIRUS; BONE-MARROW; ANTIGEN GENE; MAMMALIAN-CELLS; TUMOR-IMMUNITY; LYMPHOCYTES-T; FOWLPOX VIRUS; IN-VITRO; EXPRESSION AB Background: Activation and proliferation of T cells are essential for a successful cellular immune response to an antigen, Antigen-presenting cells (APCs) activate T cells through a two-signal mechanism. The first signal is antigen specific and causes T cells to enter the cell cycle. The second signal involves a costimulatory molecule that interacts with a ligand on the T-cell surface and leads to T-cell cytokine production and their proliferation. Dendritic cells express several costimulatory molecules and are believed to be the most potent APCs, Two recombinant poxvirus vectors (replication-defective avipox [fowlpox; rF] and a replication-competent vaccinia [rV]) have been engineered to express a triad of costimulatory molecules (B7-1, intercellular adhesion molecule-1, and leukocyte function-associated antigen-3; designated TRICOM), This study was designed to determine if dendritic cells infected with these vectors would have an enhanced capacity to stimulate T-cell responses. Methods: Murine dendritic cells (of both intermediate maturity and full maturity) were infected with rF-TRICOM or rV-TRICOM I and were used in vitro to stimulate naive T cells with the use of a pharmacologic agent as signal 1, to stimulate T cells in allospecific mixed lymphocyte cultures, and to stimulate CD8(+) T cells specific for a peptide from the ovalbumin (OVA) protein, In addition, dendritic cells infected with TRICOM vectors were pulsed with OVA peptide and used to vaccinate mice to examine T-cell responses in vivo. All statistical tests were two-sided, Results: Dendritic cells infected with either rF-TRICOM or rV-TRICOM were found to greatly enhance naive T-cell activation (P<.001), allogeneic responses of T cells (P<.001), and peptide-specific T-cell stimulation in vitro (P<.001), Peptide-pulsed dendritic cells infected with rF-TRICOM or rV-TRICOM induced cytotoxic T-lymphocyte activity in vivo to a markedly greater extent than peptide-pulsed dendritic cells (P = .001 in both). Conclusions: The ability of dendritic cells to activate both naive and effector T cells in vitro and in vivo can be enhanced with the use of poxvirus vectors that potentiate the hyperexpression of a triad of costimulatory molecules. Use of either rF-TRICOM or rV-TRICOM vectors significantly improved the efficacy of dendritic cells in priming specific immune responses. These studies have implications in vaccine strategies for both cancer and infectious diseases. C1 NCI, Tumor Immunol & Biol Lab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. Therion Biol Corp, Cambridge, MA USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Div Basic Sci, NIH, 10 Ctr Dr,Rm 8B09, Bethesda, MD 20892 USA. RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 NR 67 TC 76 Z9 76 U1 0 U2 2 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 AUG 2 PY 2000 VL 92 IS 15 BP 1228 EP 1239 DI 10.1093/jnci/92.15.1228 PG 12 WC Oncology SC Oncology GA 340FA UT WOS:000088521400011 PM 10922408 ER PT J AU Groves, FD Linet, MS Travis, LB Devesa, SS AF Groves, FD Linet, MS Travis, LB Devesa, SS TI Cancer surveillance series: Non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID T-LYMPHOTROPIC-VIRUS; SYSTEMIC LUPUS-ERYTHEMATOSUS; FRANCISCO BAY AREA; T(14-18) CHROMOSOMAL TRANSLOCATION; SOLAR ULTRAVIOLET-RADIATION; BONE-MARROW TRANSPLANTATION; INTRAVENOUS-DRUG-USERS; HAIR DYE USE; RHEUMATOID-ARTHRITIS; LYMPHOPROLIFERATIVE DISORDERS AB Background: Clinical investigations have shown prognostic heterogeneity within the non-Hodgkin's lymphomas (NHLs) according to histology, but few descriptive studies have considered NHLs by subgroup. Our purpose is to assess the demographic patterns and any notable increases in population-based rates of different histologic subgroups of NHL, Methods: Using data collected by the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, we calculated incidence rates for the major clinicopathologic categories of NHL by age, race, sex, geographic area, and time period. Results: Among the 60 057 NHL cases diagnosed during the period from 1978 through 1995, total incidence (per 100 000 person-years) was 17.1 and 11.5 among white males and females, respectively, and 12.6 and 7.4 among black males and females, respectively. However, rates for follicular NHLs mere two to three times greater among whites than among blacks, with little sex variation. Blacks demonstrated much higher incidence than whites for peripheral T-cell NHL, with the incidence rates higher in males than in females. For other NHL subgroups, the incidence rates for persons less than 60 years of age were generally higher among males than among females, with little racial difference; at older ages, the rates mere higher among whites than among blacks, with little sex difference. High-grade NHL was the most rapidly rising subtype, particularly among males. Follicular NHL increased more rapidly in black males than in the other three race/sex groups. Overall, the broad categories of small lymphocytic, follicular, diffuse, high-grade, and peripheral T-cell NHL emerged as distinct entities with specific age, sex, racial, temporal, and geographic variations in rates, Conclusions: Findings from our large, population-based study reveal differing demographic patterns and incidence trends according to histologic group. Future descriptive and analytic investigations should evaluate NHL risks according to subtype, as defined by histology and new classification criteria. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Devesa, SS (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Execut Plaza S,Rm 8048,6120 Execut Blvd,MSC 7244, Bethesda, MD 20892 USA. NR 125 TC 310 Z9 323 U1 1 U2 6 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 AUG 2 PY 2000 VL 92 IS 15 BP 1240 EP 1251 DI 10.1093/jnci/92.15.1240 PG 12 WC Oncology SC Oncology GA 340FA UT WOS:000088521400012 PM 10922409 ER PT J AU Barlund, M Forozan, F Kononen, J Bubendorf, L Chen, YD Bittner, ML Torhorst, J Haas, P Bucher, C Sauter, G Kallioniemi, OP Kallioniemi, A AF Barlund, M Forozan, F Kononen, J Bubendorf, L Chen, YD Bittner, ML Torhorst, J Haas, P Bucher, C Sauter, G Kallioniemi, OP Kallioniemi, A TI Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; HUMAN BREAST-CANCER; GENE-EXPRESSION; CHROMOSOME 20Q13; CDNA MICROARRAYS; COPY NUMBER; CELL-LINES; AMPLIFICATION; APOPTOSIS; P70(S6K) AB Background: Studies by comparative genomic hybridization (CGH) have shown that chromosomal region 17q23 is amplified in up to 20% of primary breast cancers. We used microarray analyses to measure the expression levels of genes in this region and to explore their prognostic importance. Methods: A microarray that contained 4209 complementary DNA (cDNA) clones was used to identify genes that are overexpressed in the MCF-7 breast cancer cell line as compared with normal mammary tissue. Fluorescence in situ hybridization was used to analyze the copy number of one overexpressed gene, ribosomal protein S6 kinase (S6K), and to localize it to the 17q23 region. Northern and western blot analyses were used to measure S6K gene and protein expression, and an enzymatic assay was used to measure S6K activity. Tumor tissue microarray analysis was used to study amplification of S6K and the HER-2 oncogene, another 17q-linked gene, and the relationship between amplification and prognosis was analyzed, The Kaplan-Meier method was used for data analysis, and the log-rank test was used for statistical analysis. All P values are two-sided. Results: S6K was amplified and highly overexpressed in MCF-7 cells relative to normal mammary epithelium, and protein expression and enzyme activity were increased. S6K was amplified in 59 (8.8%) of 668 primary breast tumors, and a statistically significant association between amplification and poor prognosis (P = .0021) was observed. Amplification of both S6K and HER-2 implied particularly poor survival (P = .0001). Conclusions: The combination of CGH information with cDNA and tissue microarray analysts can be used to identify amplified and overexpressed genes and to evaluate the clinical implications of such genes and genomic rearrangements. S6K is likely to be one of the genes at 17q23 that is amplified during oncogenesis and may adversely affect the prognosis of patients with this amplification. C1 NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Tampere Univ, Inst Med Technol, Canc Genet Lab, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Tampere, Finland. Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. RP Kallioniemi, A (reprint author), NHGRI, Canc Genet Branch, NIH, 49 Convent Dr,Rm 4B24, Bethesda, MD 20892 USA. RI bucher, christoph/A-2520-2008; Kallioniemi, Olli/H-5111-2011; Bubendorfl, Lukas/H-5880-2011; Kallioniemi, Olli/H-4738-2012; OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Anne/0000-0003-3552-8158 NR 38 TC 207 Z9 227 U1 1 U2 5 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 AUG 2 PY 2000 VL 92 IS 15 BP 1252 EP 1259 DI 10.1093/jnci/92.15.1252 PG 8 WC Oncology SC Oncology GA 340FA UT WOS:000088521400013 PM 10922410 ER PT J AU Hedges, JR Feldman, HA Bittner, V Goldberg, RJ Zapka, J Osganian, SK Murray, DM Simons-Morton, DG Linares, A Williams, J Luepker, RV Eisenberg, MS AF Hedges, JR Feldman, HA Bittner, V Goldberg, RJ Zapka, J Osganian, SK Murray, DM Simons-Morton, DG Linares, A Williams, J Luepker, RV Eisenberg, MS CA REACT Study Grp TI Impact of community intervention to reduce patient delay time on use of reperfusion therapy for acute myocardial infarction: Rapid early action for coronary treatment (REACT) trial SO ACADEMIC EMERGENCY MEDICINE LA English DT Article DE acute myocardial infarction; reperfusion therapy; thrombolysis; angioplasty; public health; community education ID CHEST PAIN; THROMBOLYTIC THERAPY; PREHOSPITAL DELAY; UNITED-STATES; EMERGENCY; CAMPAIGN; DESIGN; ONSET AB Background: Reperfusion therapy for acute myocardial infarction (AMI) id a time-dependent intervention that can reduce infarct-related morbidity and mortality. Out-of-hospital patient delay from symptom onset until emergency department (ED) presentation may reduce the expected benefit of reperfusion therapy. Objective: To determine the impact of a community educational intervention to reduce patient delay time on the use of reperfusion therapy for AMI. Methods: This was a randomized, controlled community-based trial to enhance patient recognition of AMI symptoms and encourage early ED presentation with resultant increased reperfusion therapy rates for AMI. The study took place in 44 hospitals in 20 pair-matched communities in five U.S. geographic regions. Eligible study subjects were noninstitutionalized patients without chest injury (aged greater than or equal to 30 years) who were admitted to participating hospitals and who received a hospital discharge diagnosis of AMI (ICD 410); n = 4,885. For outcome assessment, patients were excluded if they were without survival data (n = 402), enrolled in thrombolytic trials (n = 61), receiving reperfusion therapy >12 hours after ED arrival (n = 628), or missing symptom onset or reperfusion times (n = 781). The applied intervention was an educational program targeting community organizations and the general public, high-risk patients, and health professionals in target communities. The primary outcome was a change in the proportion of AMI patients receiving early reperfusion therapy (i.e., within one hour of ED arrival or within six hours of symptom onset). Trends in reperfusion therapy rates were determined after adjustment for patient demographics, presenting blood pressure, cardiac history, and insurance status. Four-month baseline was compared with the 18-month intervention period. Results: Of 3,013 selected AMI patients, 40% received reperfusion therapy. Eighteen percent received therapy within one hour of ED arrival (46% of treated patients), and 32% within six hours of symptom onset (80% of treated patients). No significant difference in the trends in reperfusion therapy rates was attributable to the intervention, although increases in early reperfusion therapy rates were noted during the first six months of the intervention. A significant association of early reperfusion therapy use with ambulance use was identified. Conclusions: Community-wide educational efforts to enhance patient response to AMI symptoms may not translate into sustained changes in reperfusion practices. However, an increased odds for early reperfusion therapy use during the initiation of the intervention and the association of early therapy with ambulance use suggest that reperfusion therapy rates can be enhanced. C1 Oregon Hlth Sci Univ, Dept Emergency Med, Sch Med, Portland, OR 97201 USA. New England Res Inst, Watertown, MA 02172 USA. Univ Alabama, Birmingham, AL USA. Univ Massachusetts, Sch Med, Worcester, MA USA. Univ Minnesota, Minneapolis, MN USA. Univ Memphis, Memphis, TN 38152 USA. NHLBI, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. Univ Washington, Seattle, WA 98195 USA. King Co, EMS, Seattle, WA USA. RP Hedges, JR (reprint author), Oregon Hlth Sci Univ, Dept Emergency Med, Sch Med, 3181 SW Sam Jackson Pk Rd,MP-54, Portland, OR 97201 USA. FU NHLBI NIH HHS [U01-HL-53141, U01-HL-53149, U01-HL-53412] NR 24 TC 37 Z9 38 U1 2 U2 3 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1069-6563 J9 ACAD EMERG MED JI Acad. Emerg. Med. PD AUG PY 2000 VL 7 IS 8 BP 862 EP 872 DI 10.1111/j.1553-2712.2000.tb02063.x PG 11 WC Emergency Medicine SC Emergency Medicine GA 347CQ UT WOS:000088910200003 PM 10958125 ER PT J AU Hoffman, JM Staab, EV Begg, L Croft, BY Menkens, AE Sullivan, DC AF Hoffman, JM Staab, EV Begg, L Croft, BY Menkens, AE Sullivan, DC TI Training the next generation of imaging scientists and clinicians SO ACADEMIC RADIOLOGY LA English DT Article C1 NCI, Biomed Imaging Program, Div Canc Treatment & Diag, DIP, Bethesda, MD 20892 USA. NCI, Training Branch, Off Ctr Training & Resources, Bethesda, MD 20892 USA. RP Hoffman, JM (reprint author), NCI, Biomed Imaging Program, Div Canc Treatment & Diag, DIP, EPN-800,6130 Execut Blvd,MSC 7440, Bethesda, MD 20892 USA. RI Croft, Barbara/D-1248-2013 OI Croft, Barbara/0000-0003-2544-150X NR 0 TC 5 Z9 5 U1 0 U2 1 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD AUG PY 2000 VL 7 IS 8 BP 678 EP + DI 10.1016/S1076-6332(00)80621-2 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 340YM UT WOS:000088564300016 PM 10952118 ER PT J AU Yang, F Dauter, Z Wlodawer, A AF Yang, F Dauter, Z Wlodawer, A TI Effects of crystal twinning on the ability to solve a macromolecular structure using multiwavelength anomalous diffraction SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID MOLECULAR-REPLACEMENT; ANGSTROM-RESOLUTION AB The crystal structure of gpD, the capsid-stabilizing protein of bacteriophage lambda, was solved by multiwavelength anomalous diffraction (MAD) for a selenomethionine (SeMet) derivative of the protein at 1.8 Angstrom resolution, using crystals in space group P2(1) [Yang et al. (2000), Nature Struct. Biol. 7, 230-237]. Subsequent analysis showed that the crystals of both the original protein and the SeMet derivative were pseudomerohedrally twinned with a twinning fraction similar or equal to 0.36, owing to the near-identity of the a and c axes. An analysis of the crystal structure solution is presented and the utility of twinned crystals for solving the structure using MAD and of different phasing strategies is discussed; the results obtained with several software packages are compared. C1 NCI, Prot Struct Sec, Macromol Crystallog Lab, Program Struct Biol,FCRDC, Frederick, MD 21702 USA. Brookhaven Natl Lab, NSLS, Upton, NY 11973 USA. NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Program Struct Biol, Upton, NY 11973 USA. RP Wlodawer, A (reprint author), NCI, Prot Struct Sec, Macromol Crystallog Lab, Program Struct Biol,FCRDC, Frederick, MD 21702 USA. NR 21 TC 28 Z9 28 U1 0 U2 1 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD AUG PY 2000 VL 56 BP 959 EP 964 DI 10.1107/S0907444900007162 PN 8 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 337WD UT WOS:000088384200004 PM 10944332 ER PT J AU Liberski, PP Bratosiewicz, J Barcikowska, M Cervenakova, L Marczewska, M Brown, P Gajdusek, DC AF Liberski, PP Bratosiewicz, J Barcikowska, M Cervenakova, L Marczewska, M Brown, P Gajdusek, DC TI A case of sporadic Creutzfeldt-Jakob disease with a Gerstmann-Straussler-Scheinker phenotype but no alterations in the PRNP gene SO ACTA NEUROPATHOLOGICA LA English DT Letter ID MUTATIONS AB In 1998, we published a case of "sporadic Creutzfeld-Jakob disease with a Gerstmann-Straussler-Scheinker phenotype but with no alterations in the PRNP gene" [3]. Our molecular analysis at that time covered codons 8-221; subsequently, we extended our analysis to include the entire C-terminal end of the translated exon and found an ATG to ACG mutation at codon 232 (methionine to threonine). This mutation was absent from 40 healthy Polish controls and from 16 other Polish Creutzfeldt-Jakob disease (CJD) cases, and we therefore believe that 232(Thr) is a new pathogenic mutation and not a benign polymorphism. DNA was extracted twice from formalin-fixed and paraffin-embedded brain tissue. The tissue was cut and transferred to 1.5-ml tubes and washed twice with xylene followed by washing with 95% ethanol twice and with 70% ethanol once. The pellet was dried and resuspended in 50 mu l of extraction buffer (1% SDS, 10 mM EDTA, 0.2 M TRIS pH 8.0) and digested with proteinase K (5 mg/ml) overnight at 56 degrees C. DNA was then isolated by phenol:chloroform extraction and salt-ethanol precipitation. C1 Med Acad Lodz, Chair Oncol, Dept Mol Biol, Lab Neuropathol & ELect Microscopy, PL-92216 Lodz, Poland. Med Res Ctr, Dept Neuropathol, Warsaw, Poland. NINDS, Cent Nervous Syst Studies Lab, Bethesda, MD 20892 USA. Med Acad Warsaw, Dept Anat Pathol, Warsaw, Poland. RP Liberski, PP (reprint author), Med Acad Lodz, Chair Oncol, Dept Mol Biol, Lab Neuropathol & ELect Microscopy, Czechoslowacka 8-10, PL-92216 Lodz, Poland. NR 4 TC 5 Z9 5 U1 1 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD AUG PY 2000 VL 100 IS 2 BP 233 EP 234 PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 336MV UT WOS:000088307600018 PM 10963373 ER PT J AU Drummond, DC Litten, RZ Lowman, C Hunt, WA AF Drummond, DC Litten, RZ Lowman, C Hunt, WA TI Craving research: future directions SO ADDICTION LA English DT Article ID ALCOHOLICS AB Many prospective clinical studies have concluded that craving does not reliably predict relapse and that the concept is of little or no clinical utility. Contrary to earlier more simplistic clinical models of addiction, more recent models do not require that craving be present for relapse to occur. New approaches to study human craving may enhance its predictive validity and yield more knowledge of its nature, course, behavioural sequelae and regulatory function in alcohol/drug consumption. These approaches include empirical research that focuses on: (1) the elucidation of the domains of craving (i.e. subjective experience, physiological responses, behavioural sequelae and their inter-relationships); (2) the temporal dynamics of craving (i.e. its course over minutes or days, as well as its natural history over the course of a drinking career); (3) the factors that may mediate/moderate/determine the development and resolution of craving; (4) studies of the predictive validity of craving measures; and (5) the development of valid methods of measuring the different domains of craving. The conclusions are that future craving research should: (1) incorporate more sophisticated general theories of behaviour (conditioning, cognitive social learning, neurobiological, and genetic); (2) apply more sophisticated and standardized measurement methods and experimental paradigms, including studies in which alcohol is made available to human subjects; and (3) effective development of new pharmacological and behavioural therapies for relapse prevention depend on greater understanding of the nature and measurement of craving. C1 Univ London St Georges Hosp, Sch Med, Dept Addict Behav & Psychol Med, London SW17 0RE, England. NIAAA, Div Clin & Prevent Res, Treatment Res Branch, NIH, Bethesda, MD USA. NIAAA, Div Basic Res, NIH, Bethesda, MD USA. RP Drummond, DC (reprint author), Univ London St Georges Hosp, Sch Med, Dept Addict Behav & Psychol Med, Cranmer Terrace, London SW17 0RE, England. RI Drummond, Colin/H-5459-2011 NR 37 TC 40 Z9 42 U1 1 U2 3 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2000 VL 95 IS 8 SU 2 BP S247 EP S255 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 346FT UT WOS:000088860700019 PM 11002919 ER PT J AU Lowman, C Hunt, WA Litten, RZ Drummond, DC AF Lowman, C Hunt, WA Litten, RZ Drummond, DC TI Research perspectives on alcohol craving: an overview - Introduction SO ADDICTION LA English DT Editorial Material ID INITIAL VALIDATION; URGES; ADDICTION AB This overview of the Addiction supplement on 'Research Perspectives on Alcohol Craving' has three objectives. The first is to familiarize readers with the variety of theoretical models relevant to craving and the definitions of craving generated by them that are discussed in the supplement. These include phenomenological models, classical and operant conditioning models, the incentive-sensitization theory, a tonic-phasic model of dopamine system regulation, cognitive social learning theory and the cognitive processing theory of craving. The second objective is to provide a brief summary of the methodological articles which focus as a whole more on what can be done than on what has been done in alcohol craving research. The final objective is to emphasize the potential importance of transdisciplinary research-research that integrates components of different theoretical models-for delineating the role of alcohol and drug craving in the complex biobehavioral process known as addiction. It is the hope of the guest editors (the authors of this overview) that the Addiction supplement and this introduction to it will contribute to development of a framework for future transdisciplinary research on alcohol craving. C1 NIAAA, NIH, DCPR, Bethesda, MD 20892 USA. NIAAA, Div Basic Res, Bethesda, MD 20892 USA. Univ London St Georges Hosp, Sch Med, London, England. RP Lowman, C (reprint author), NIAAA, NIH, DCPR, Willco Bldg,Suite 505,6000 Execut Blvd, Bethesda, MD 20892 USA. RI Drummond, Colin/H-5459-2011 NR 36 TC 35 Z9 38 U1 0 U2 10 PU CARFAX PUBLISHING PI BASINGSTOKE PA RANKINE RD, BASINGSTOKE RG24 8PR, HANTS, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD AUG PY 2000 VL 95 IS 8 SU 2 BP S45 EP S54 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 346FT UT WOS:000088860700001 PM 11002901 ER PT J AU Simonsick, EM Gardner, AW Poehlman, ET AF Simonsick, EM Gardner, AW Poehlman, ET TI Assessment of physical function and exercise tolerance in older adults: Reproducibility and comparability of five measures SO AGING-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE aging; exercise tolerance; fitness assessment; physical function; walking tests ID CHRONIC HEART-FAILURE; 6-MINUTE WALK TEST; TREADMILL WALKING; ELDERLY SUBJECTS; DISEASE; PERFORMANCE; CAPACITY; FITNESS; RELIABILITY; VALIDITY AB This study examined the reproducibility and comparability of five measures of Junction and exercise tolerance. The test battery and questionnaire on Junction and physical activity were administered twice, 7-10 days apart to 38 men and 12 women aged 54-80 years at the Baltimore Veterans Affairs Medical Center. Tests included fast pace 4 and 20-meter walks, B-minute and graded treadmill walks, and a seated step test. All tests demonstrated good reproducibility with Pearson and intraclass correlation coefficients ranging from 0.84 to 0.98, and percent differences on retest ranging from 4 to 11%. Although correlations between different tests were all significant (range 0.34-0.89), comparison of performance ranks and linear regression analyses indicated that the short fast walks and seated step test may not be suitable substitutes for treadmill or long self-paced corridor walks. Only 28% had the same quintile performance ranking on the step test as on the treadmill walk, and 36% had rankings 2 or more points apart. The fast 20 m walk shows the most promise as a low-level alternative to the B-minute walk; performances had a correlation of 0.73, 82% of ranks were within one point, and 20 m speed explained 42% of the variance in distance covered. More development is needed for comprehensive assessment of exercise tolerance in older adults; the 6-minute walk did not adequately discriminate fitness level in persons who walk regularly, and the treadmill posed problems for those with walking difficulty. (Aging Clin. Exp. Res. 12: 274-280, 2000) (C) 2000, Editrice Kurtis. C1 NIA, Epidemiol Demog & Biometry Program, Bethesda, MD 20892 USA. RP Simonsick, EM (reprint author), NIA, Epidemiol Demog & Biometry Program, 7201 Wisconsin Ave,Suite 3C-309, Bethesda, MD 20892 USA. NR 31 TC 44 Z9 44 U1 1 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 AUG PY 2000 VL 12 IS 4 BP 274 EP 280 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 362RT UT WOS:000089792600005 PM 11073346 ER PT J AU Evans, MS Li, Y Faingold, C AF Evans, MS Li, Y Faingold, C TI Inferior colliculus intracellular response abnormalities in vitro associated with susceptibility to ethanol withdrawal seizures SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE inferior colliculus; ethanol withdrawal; audiogenic seizures; intracellular ID EPILEPSY-PRONE RATS; AUDIOGENIC-SEIZURES; MEDIATED INHIBITION; IDENTIFIED NEURONS; LATERAL LEMNISCUS; CENTRAL NUCLEUS; DORSAL NUCLEUS; MESSENGER-RNA; BRAIN SLICE; IN-VIVO AB During ethanol withdrawal (ETX), rats become susceptible to audiogenic seizures in which the inferior colliculus (IC) is known to play a critical role. The present study examined changes in membrane properties that occurred in IC dorsal cortex (ICd) neurons in brain slices from rats after 4 days of three times daily intragastric ethanol, which is proposed to be an analog of binge drinking. Compared with neurons from control animals, ICd neurons during ETX had action potentials (APs) with lower thresholds, a greater incidence of spontaneous APs, a reduced degree of spike Firing adaptation, and an increased incidence of anode-break firing. With synaptic stimulation, epileptiform firing was seen in nearly 50% of ICd neurons during ETX but never was seen in normal ICd neurons except after perfusion of the gamma-aminobutyric acid type A (GABA(A)) antagonist bicuculline. Paired pulse responses of ICd neurons were also abnormal during ETX. Thus, in 75% of normal rats, paired synaptic stimuli inhibited the second response, but during ETX all neurons tested showed paired pulse facilitation. These aberrant membrane and synaptic properties provide direct evidence for the hyperexcitability of IC neurons during ETX. They may be due, in part, to changes in GABAergic and glutamatergic neurotransmission known to be produced during withdrawal after continued ethanol administration. C1 So Illinois Univ, Sch Med, Dept Pharmacol, Springfield, IL 62794 USA. So Illinois Univ, Sch Med, Dept Neurol, Springfield, IL 62794 USA. NIH, Lab Cellular Mol Neurophysiol, Bethesda, MD USA. RP Faingold, C (reprint author), So Illinois Univ, Sch Med, Dept Pharmacol, POB 19629, Springfield, IL 62794 USA. FU NIAAA NIH HHS [AA11628] NR 69 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2000 VL 24 IS 8 BP 1180 EP 1186 DI 10.1111/j.1530-0277.2000.tb02081.x PG 7 WC Substance Abuse SC Substance Abuse GA 345TQ UT WOS:000088831600007 PM 10968655 ER PT J AU Smith, WB Weisner, C AF Smith, WB Weisner, C TI Women and alcohol problems: A critical analysis of the literature and unanswered questions SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article C1 NIAAA, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. RP Smith, WB (reprint author), NIAAA, NIH, 6000 Execut Blvd,Suite 505, Bethesda, MD 20892 USA. NR 1 TC 20 Z9 21 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2000 VL 24 IS 8 BP 1320 EP 1321 DI 10.1111/j.1530-0277.2000.tb02098.x PG 2 WC Substance Abuse SC Substance Abuse GA 345TQ UT WOS:000088831600024 PM 10968672 ER PT J AU Singh, JP Larson, MG O'Donnell, CJ Wilson, PF Tsuji, H Lloyd-Jones, DM Levy, D AF Singh, JP Larson, MG O'Donnell, CJ Wilson, PF Tsuji, H Lloyd-Jones, DM Levy, D TI Association of hyperglycemia with reduced heart rate variability (The Framingham Heart Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID DEPENDENT DIABETES-MELLITUS; MYOCARDIAL-INFARCTION; AUTONOMIC NEUROPATHY; INSULIN; MORTALITY; GLUCOSE; EVENTS; RISK AB This study was designed to examine the association of heart rate variability (HRV) with blood glucose levels in a large community-based population. Previous reports have shown HRV to be reduced in diabetics, suggesting the presence of abnormalities in neural regulatory mechanisms. There is scant information about HRV across the spectrum of blood glucose levels in a population-based cohort. One thousand nine hundred nineteen men and women from the Framingham Offspring Study, who underwent ambulatory electrocardiographic recordings at a routine examination, were eligible. HRV variables included the SD of normal RR intervals (SDNN), high-frequency (HF, 0.15 to 0.40 Hz) and low-frequency (LF, 0.04 to 0.15 Hz) power, and LF/HF ratio. Pasting plasma glucose levels were used to classify subjects as normal (<110 mg/dl; n = 1,779), as having impaired fasting glucose levels (110 to 125 mg/dl; n = 56), and as having diabetes mellitus (DM greater than or equal to 126 mg/dl or receiving therapy; n = 84). SDNN, LF and HF power, and LF/HF ratio were inversely related to plasma glucose levels (p <0.0001). SDNN and LF and HF powers were reduced in DM subjects (4.28 +/- 0.03, 6.03 +/- 0.08, and 4.95 +/- 0.09) and in subjects with impaired fasting glucose levels (4.37 +/- 0.04, 6.26 +/- 0.10, and 5.06 +/- 0.11) compared with those with normal fasting glucose (4.51 +/- 0.01, 6.77 +/- 0.02, and 5.55 +/- 0.02, all p <0.005), respectively. After adjusting for covariates (age, sex, heart rate, body mass index, antihypertensive and cardiac medications, systolic and diastolic blood pressures, smoking, and alcohol and coffee consumption), LF power and LF/HF ratio were lower in DM subjects than in those with normal fasting glucose (p <0.005). HRV is inversely associated with plasma glucose levels and is reduced in diabetics as well as in subjects with impaired fasting glucose levels. Additional research is needed to determine if low HRV contributes to the increased cardiovascular morbidity and mortality described in subjects with hyperglycemia. (C) 2000 by Excerpta Medica, Inc. C1 NHLBI, Framingham Heart Study, Framingham, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Div Epidemiol & Prevent Med, Boston, MA 02118 USA. Beth Israel Hosp, Div Cardiol, Boston, MA 02215 USA. Beth Israel Hosp, Div Clin Epidemiol, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. Kansai Med Univ, Osaka, Japan. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 5 Thurber St, Framingham, MA USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 28 TC 190 Z9 199 U1 0 U2 9 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 1 PY 2000 VL 86 IS 3 BP 309 EP 312 DI 10.1016/S0002-9149(00)00920-6 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 338MM UT WOS:000088423900011 PM 10922439 ER PT J AU Marriott, BM Kanter, MM AF Marriott, BM Kanter, MM TI National Institutes of Health Workshop on the Role of Dietary Supplements for Physically Active People - Proceedings of a Workshop held in Bethesda, MD - June 3-4, 1996 - Preface SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material C1 Quaker Oats Co, Barrington, IL 60010 USA. NIH, Off Dietary Supplements, Bethesda, MD 20735 USA. RP Marriott, BM (reprint author), NIH, Off Dietary Supplements, 9000 Rockville Pike,Bldg 31,Room 1B25, Bethesda, MD 20735 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 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 AUG PY 2000 VL 72 IS 2 SU S BP 504S EP 506S PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 342FH UT WOS:000088634200002 ER PT J AU Guarner, J Shieh, WJ Dawson, J Subbarao, K Shaw, M Ferebee, T Morken, T Nolte, KB Freifeld, A Cox, N Zaki, SR AF Guarner, J Shieh, WJ Dawson, J Subbarao, K Shaw, M Ferebee, T Morken, T Nolte, KB Freifeld, A Cox, N Zaki, SR TI Immunohistochemical and in situ hybridization studies of influenza A virus infection in human lungs SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE immunohistochemistry; in situ hybridization; pathology; influenza A virus; lungs ID MONOCLONAL-ANTIBODIES; PNEUMONIA; ENCEPHALITIS; IMMUNITY; BIOPSY AB Influenza viruses are responsible for acute febrile respiratory disease. When deaths occur, definitive diagnosis requires viral isolation because no characteristic viral inclusions are seen. We examined the distribution of influenza A virus in tissues from 8 patients with fatal infection using 2 immunohistochemical assays (monoclonal antibodies to nucleoprotein [NP] and hemagglutinin [HA]) and 2 in situ hybridization (ISH) assays (digoxigenin-labeled probes that hybridized to HA and NP genes). Five patients had prominent bronchitis; by immunohistochemical assay, influenza A staining was present focally in the epithelium of larger bronchi (intact and detached necrotic cells) and in rare interstitial cells. The anti-NP antibody stained primarily cell nuclei, and the anti-HA antibody stained mainly the cytoplasm. In 4 of these cases, nucleic acids (ISH) were identified in the same areas. Three patients had lymphohistiocytic alveolitis and showed no immunohistochemical or ISH staining. Both techniques were useful for detection of influenza virus antigens and nucleic acids in formalin-fixed paraffin-embedded tissues and can enable further understanding of fatal influenza A virus infections in humans. C1 Ctr Dis Control & Prevent, Div Viral & Rickettsial Dis, Influenza Branch, Atlanta, GA 30333 USA. Univ New Mexico, Sch Med, Off Med Investigator, Albuquerque, NM 87131 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Guarner, J (reprint author), Ctr Dis Control & Prevent, Div Viral & Rickettsial Dis, Influenza Branch, Mailstop G32,1600 Clifton Rd NE, Atlanta, GA 30333 USA. RI Guarner, Jeannette/B-8273-2013 NR 23 TC 48 Z9 50 U1 0 U2 2 PU AMER SOC CLIN PATHOLOGISTS PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2000 VL 114 IS 2 BP 227 EP 233 PG 7 WC Pathology SC Pathology GA 339CU UT WOS:000088460700009 PM 10941338 ER PT J AU Weinberg, CR Umbach, DM AF Weinberg, CR Umbach, DM TI Choosing a retrospective design to assess joint genetic and environmental contributions to risk SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE bias; causality; epidemiologic research design; genetics; linkage disequilibrium; logistic models; polymorphism (genetics); sampling ID CASE-PARENT TRIADS; CANDIDATE GENES; SIBSHIP TEST; DISEQUILIBRIUM; ASSOCIATION; LINKAGE; GENOTYPE; MODELS AB The authors consider issues that should be weighed when designing a retrospective study in which a focus of interest is the joint role of genetic and environmental factors in causing a disease. In place of the classical case-control design, in which controls are sampled from the same population that gives rise to the cases, one could study cases only The case-only approach can be usefully extended by genotyping the two biologic parents of each case and in effect letting the parental genotype data provide the genetic control. Alternatively, one could carry out a case-control study in which the controls are siblings or cousins of the cases and inference is based on within-family parameters. The authors compare and contrast the parameters that can be estimated and the assumptions that must be made when each of these designs is used. The investigator must also consider certain practical issues, such as the availability of parents or sibling controls. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat Branch, POB 12233,A3-03, Res Triangle Pk, NC 27709 USA. NR 32 TC 72 Z9 75 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2000 VL 152 IS 3 BP 197 EP 203 DI 10.1093/aje/152.3.197 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 339XC UT WOS:000088502300001 PM 10933265 ER PT J AU Hsieh, YH Bobo, LD Quinn, TC West, SK AF Hsieh, YH Bobo, LD Quinn, TC West, SK TI Risk factors for trachoma: 6-year follow-up of children aged 1 and 2 years SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE child; Chlamydia trachomatis; hygiene; mortality; risk factors; trachoma ID POLYMERASE CHAIN-REACTION; CHLAMYDIAL INFECTION; ENZYME-IMMUNOASSAY; HYPERENDEMIC AREA; GAMBIAN VILLAGE; TANZANIA; EPIDEMIOLOGY; PATHOGENESIS; REINFECTION; DIAGNOSIS AB The authors investigated the long-term stability of risk factors in predicting the presence of active trachoma and severe inflammatory trachoma in 176 children in Kongwa, Tanzania, who were aged 1 and 2 years in 1989 and were available for follow-up in 1995. Familial cattle ownership, living more than 2 hours away from a water source, and facial cleanliness at both time points were associated with the presence of active trachoma at both time points (odds ratio (OR) = 2.58, 95% confidence interval (Cl): 1.15, 5.79; OR = 3.07, 95% Cl. 1.23, 7.64; and OR = 0.52, 95% Cl: 0.26, 1.03, respectively). An association of familial cattle ownership with facial cleanliness and water accessibility was observed. Having a clean face at both time points was associated with lower odds of active trachoma at both time points for children in non-cattle-herding families (OR = 0.40, 95% Cl: 0.18, 0.87). Living more than 2 hours away from a water source at both time points increased the odds of active trachoma at both time points in children of cattle-herding families (OR = 8.00, 95% Cl: 1.99, 32.10). Noticeably, severe inflammatory trachoma at baseline predicted mortality in children from villages in which trachoma was less common (OR = 3.75, 95% Cl: 1.09, 12.98). The results suggest that risk factor reduction could diminish persistent disease. C1 Johns Hopkins Univ, Sch Med, Div Infect Dis, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Infect Dis, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dana Ctr Invest Ophthalmol, Baltimore, MD USA. RP Hsieh, YH (reprint author), Johns Hopkins Univ, Sch Med, Div Infect Dis, Dept Med, Ross 1155B,720 Rutland Ave, Baltimore, MD 21205 USA. NR 26 TC 31 Z9 32 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2000 VL 152 IS 3 BP 204 EP 211 DI 10.1093/aje/152.3.204 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 339XC UT WOS:000088502300002 PM 10933266 ER PT J AU Subar, AF Midthune, D Kulldorff, M Brown, CC Thompson, FE Kipnis, V Schatzkin, A AF Subar, AF Midthune, D Kulldorff, M Brown, CC Thompson, FE Kipnis, V Schatzkin, A TI Evaluation of alternative approaches to assign nutrient values to food groups in food frequency questionnaires SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diet; epidemiologic methods; food habits; nutrition assessment; nutrition surveys; questionnaires ID NHANES-II SURVEY; QUANTITATIVE DATA; AMERICAN DIET; FAT; MACRONUTRIENTS; ENERGY; FIBER; WOMEN AB Although every food frequency questionnaire (FFQ) requires a nutrient database to produce nutrient intake estimates, it is often unclear how a particular database has been generated. Moreover, alternative methods for constructing a database have not been rigorously evaluated. Using 24-hour recalls from the 1994-1996 Continuing Survey of Food Intake by Individuals, the authors categorized 5,261 individual foods reported by 10,019 adults into 170 food groups consistent with line items on an FFQ. These food groups were used to generate 10 potential nutrient databases for a FFQ that varied by whether the authors 1) used means or medians, 2) did or did not consider age, 3) incorporated collapsing strategies for small age-gender-portion size cells, 4) excluded outliers in a regression, and 5) used weighted median nutrient density x age-gender-portion size-specific median gram weights (Block method). Mean error, mean squared error, and mean absolute error were calculated and compared across methods, with error being the difference in total observed (from recalls for each individual) and total estimated intake (from each of the 10 methods) for seven nutrients. Mean method's for assigning nutrients to food groups were superior to median approaches for all measurements. Among the mean methods, no single variation was consistently better. C1 NCI, Bethesda, MD 20892 USA. Univ Connecticut, Sch Med, Farmington, CT USA. RP Subar, AF (reprint author), NCI, 6130 Execut Blvd,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. RI Kulldorff, Martin/H-4282-2011; OI Kulldorff, Martin/0000-0002-5284-2993 NR 21 TC 172 Z9 172 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2000 VL 152 IS 3 BP 279 EP 286 DI 10.1093/aje/152.3.279 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 339XC UT WOS:000088502300011 PM 10933275 ER PT J AU Lubin, JH Fraumeni, JF AF Lubin, JH Fraumeni, JF TI Re: "Does arsenic exposure increase the risk for circulatory disease?" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID DIABETES-MELLITUS; MORTALITY; CANCERS; WATER C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Lubin, JH (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 11 TC 8 Z9 8 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2000 VL 152 IS 3 BP 290 EP 293 DI 10.1093/aje/152.3.290 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 339XC UT WOS:000088502300015 PM 10933278 ER PT J AU Ciotti, P Struewing, JP Mantelli, M Chompret, A Avril, MF Santi, PL Tucker, MA Bianchi-Scarra, G Bressac-de Paillerets, B Goldstein, AM AF Ciotti, P Struewing, JP Mantelli, M Chompret, A Avril, MF Santi, PL Tucker, MA Bianchi-Scarra, G Bressac-de Paillerets, B Goldstein, AM TI A single genetic origin for the G101W CDKN2A mutation in 20 melanoma-prone families SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GERMLINE MUTATIONS; MALIGNANT-MELANOMA; PHENOTYPE ANALYSIS; PANCREATIC-CANCER; P16 GENE; KINDREDS; P16(INK4); HAPLOTYPE; INHIBITION; NEOPLASIA AB Germline mutations within the coding region of CDKN2A have been observed in affected members of melanoma-prone families. G101W is the most common CDKN2A missense mutation identified to date. It has been reported in several families from around the world, with a particularly high occurrence in France and Italy. Given the frequency of this mutation, we were interested in determining whether the mutation resulted from a single origin or represented a mutational hotspot in the CDKN2A gene. rn addition, given the geographical distribution of the mutation, we examined the date of origination of the mutation and its migratory spread. We examined 10 families from Italy, 4 families from the United States, and 6 families from France with the G101W mutation. The following eight markers were employed for the haplotype analysis: IFNA, D9S736, D9S1749, D9S942, D9S1748, D9S1604, D9S171, and D9S126. Our findings showed no significant evidence for mutational heterogeneity, suggesting that all studied families derived from a single ancestral haplotype on which the mutation arose. Using maximum-likelihood methods, we estimated the mutation to have arisen 97 generations ago (1-LOD-unit support interval 70-133 generations) providing some explanation for the wide geographical spread of this common mutation, particularly in southwestern Europe. The presence of a founder mutation in a defined geographic area can facilitate carrier detection and genetic counseling and can provide an opportunity to study disease penetrance and the effect of environmental factors on the background of a common genetic susceptibility. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. Ist Nazl Ric Canc, Genoa, Italy. Inst Gustave Roussy, Unite Marqueurs Genet Canc, Villejuif, France. RP Goldstein, AM (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. RI Struewing, Jeffery/C-3221-2008; Bianchi Scarra, Giovanna/G-8933-2014; Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013 OI Bianchi Scarra, Giovanna/0000-0002-6127-1192; Struewing, Jeffery/0000-0002-4848-3334 NR 38 TC 63 Z9 64 U1 0 U2 0 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 AUG PY 2000 VL 67 IS 2 BP 311 EP 319 DI 10.1086/303001 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 354YA UT WOS:000089357800008 PM 10869234 ER PT J AU Lai, CSL Fisher, SE Hurst, JA Levy, ER Hodgson, S Fox, M Jeremiah, S Povey, S Jamison, DC Green, ED Vargha-Khadem, F Monaco, AP AF Lai, CSL Fisher, SE Hurst, JA Levy, ER Hodgson, S Fox, M Jeremiah, S Povey, S Jamison, DC Green, ED Vargha-Khadem, F Monaco, AP TI The SPCH1 region on human 7q31: Genomic characterization of the critical interval and localization of translocations associated with speech and language disorder SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENE; MAP; CHROMOSOME; DISEASE; AUTISM AB The KE family is a large three-generation pedigree in which half the members are affected with a severe speech and language disorder that is transmitted as an autosomal dominant monogenic trait. In previously published work, we localized the gene responsible (SPCH1) to a 5.6-cM region of 7q31 between D7S2459 and D7S643. In the present study, we have employed bioinformatic analyses to assemble a derailed BAC-/PAC-based sequence map of this interval, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 Mb of completed genomic sequence. We screened the affected chromosome 7 from the KE family with 120 of these STSs (average spacing <100 kb), but we did not detect any evidence of a microdeletion. Novel polymorphic markers were generated from the sequence and were used to further localize critical recombination breakpoints in the KE family. This allowed refinement of the SPCH1 interval to a region between new markers 013A and 330B, containing similar to 6.1 Mb of completed sequence. In addition, we have studied two unrelated patients with a similar speech and language disorder, who have de novo translocations involving 7q31. Fluorescence in situ hybridization analyses with BACs/PACs from the sequence map localized the t(5;7)(q22;q31.2) breakpoint in the first patient (CS) to a single clone within the newly refined SPCH1 interval. This clone contains the CAGH44 gene, which encodes a brain-expressed protein containing a large polyglutamine stretch. However, we found that the t(2;7)(p23;q31.3) breakpoint in the second patient (BRD) resides within a BAC clone mapping >3.7 Mb distal to this, outside the current SPCH1 critical interval. Finally, we investigated the CAGH44 gene in affected individuals of the KE family, but we found no mutations in the currently known coding sequence. These studies represent further steps toward the isolation of the first gene to be implicated in the development of speech and language. C1 Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. Oxford Radcliffe Hosp, Dept Clin Genet, Oxford, England. UCL, Guys Hosp, Genet Ctr, London WC1E 6BT, England. UCL, MRC, Human Biochem Genet Unit, London WC1E 6BT, England. Inst Child Hlth, Cognit Neurosci Unit, London, England. NHGRI, NIH, Bethesda, MD 20892 USA. RP Monaco, AP (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. EM anthony.monaco@well.ox.ac.uk RI Vargha-Khadem, Faraneh/C-2558-2008; Monaco, Anthony/A-4495-2010; Fisher, Simon/E-9130-2012 OI Monaco, Anthony/0000-0001-7480-3197; Fisher, Simon/0000-0002-3132-1996 NR 24 TC 119 Z9 124 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2000 VL 67 IS 2 BP 357 EP 368 DI 10.1086/303011 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 354YA UT WOS:000089357800012 PM 10880297 ER PT J AU Goldberg, EK Glendening, JM Karanjawala, Z Sridhar, A Walker, GJ Hayward, NK Rice, AJ Kurera, D Tebha, Y Fountain, JW AF Goldberg, EK Glendening, JM Karanjawala, Z Sridhar, A Walker, GJ Hayward, NK Rice, AJ Kurera, D Tebha, Y Fountain, JW TI Localization of multiple melanoma tumor-suppressor genes on chromosome 11 by use of homozygosity mapping-of-deletions analysis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; HUMAN PROSTATE-CANCER; CELL-LINES; ATAXIA-TELANGIECTASIA; OVARIAN-CANCER; BREAST-CANCER; PHYSICAL MAP; COLON-CANCER; LONG ARM; GENOMIC ORGANIZATION AB Loss-of-heterozygosity (LOH) studies have implicated one or more chromosome 11 tumor-suppressor gene(s) in the development of cutaneous melanoma as well as a variety of other forms of human cancer. In the present study, we have identified multiple independent critical regions on this chromosome by use of homozygosity mapping of deletions (HOMOD) analysis. This method of analysis involved the use of highly polymorphic microsatellite markers and statistics to identify regions of hemizygous deletion in unmatched melanoma cell line DNAs. Regions of loss were defined by the presence of an extended region of homozygosity (ERH) at greater than or equal to 5 adjacent markers and having a statistical probability of less than or equal to.001. Significant ERHs were similar in nature to deletions identified by LOH analyses performed on uncultured melanomas, although a higher frequency of loss (24 [60%] of 40 vs. 16 [34%] of 47) was observed in the cell lines. Overall, six small regions of overlapping deletions (SROs) were identified on chromosome 11 flanked by the markers D11S1338/D11S907 (11p13-15.5 [SRO1]), D11S1344/D11S11385 (11p11.2 [SRO2]), D11S917/D11S1886 (11q21-22.3 [SRO3]), D11S927/D11S4094 (11q23 [SRO4]),AFM210ve3/D11S990 (11q24 [SR05]), and D11S1351/D11S4123 (11q24-25 [SRO6]). We propose that HOMOD analysis can be used as an adjunct to LOH analysis in the localization of tumor-suppressor genes. C1 Univ So Calif, Inst Med Genet, Dept Biochem & Mol Biol, Los Angeles, CA USA. Queensland Inst Med Res, Joint Expt Oncol Program, Queensland Canc Fund Res Unit, Herston, Qld 4006, Australia. Univ Queensland, Royal Brisbane Hosp, Herston, Qld, Australia. RP Fountain, JW (reprint author), NCI, Organ Syst Branch, 6116 Execut Blvd,Suite 7008,MSC 8347, Rockville, MD 20852 USA. RI Walker, Graeme/C-2548-2012; hayward, nicholas/C-1367-2015 OI Walker, Graeme/0000-0002-9392-8769; hayward, nicholas/0000-0003-4760-1033 FU NCI NIH HHS [CA66021] NR 91 TC 39 Z9 39 U1 0 U2 0 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 AUG PY 2000 VL 67 IS 2 BP 417 EP 431 DI 10.1086/302999 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 354YA UT WOS:000089357800017 PM 10877980 ER PT J AU Troisi, RJ Cowie, CC Harris, MI AF Troisi, RJ Cowie, CC Harris, MI TI Oral contraceptive use and glucose metabolism in a national sample of women in the United States SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE C-peptide; epidemiology; glucose; hemoglobin A(1c); insulin; oral contraceptives ID CARBOHYDRATE-METABOLISM; DIABETES-MELLITUS; TOLERANCE AB OBJECTIVE: This study was undertaken to determine whether users of oral contraceptives in a nationally representative population of US women had elevated levels of measures of glucose metabolism. STUDY DESIGN: Cross-sectional data from the Third National Health and Nutrition Examination Survey (1988-1994) included hemoglobin A(1c) levels and fasting glucose, insulin, and C-peptide levels. Means were compared among those who had never used oral contraceptives, current users of oral contraceptives, and former users of oral contraceptives, with and without adjustment for potential confounders. RESULTS: The vast majority of current users of oral contraceptives were using low-dose estrogen formulations. The two most common preparations were a triphasic formulation containing 0.035 mg ethinyl estradiol and 0.5, 0.75, and 1 mg norethindrone (23.9%) and a monophasic formulation containing 0.035 ethinyl estradiol and 1 mg norethindrone (20.7%). Current users of oral contraceptives did not have elevated values for any of the four measures of glucose metabolism. Hemoglobin A(1c) level and fasting glucose, insulin, and C-peptide levels were not related to duration of current use, age at which use began, or major formulation type. Among women who were former users of oral contraceptives there was no evidence of higher values among those who had recently ceased use. CONCLUSION: Oral contraceptive formulations currently available in the United States are not associated with an adverse glucose metabolic profile. C1 NIDDKD, Bethesda, MD 20892 USA. Social & Sci Syst Inc, Bethesda, MD USA. RP Harris, MI (reprint author), NIDDKD, 6707 Democracy Blvd,Rm 695, Bethesda, MD 20892 USA. NR 20 TC 20 Z9 21 U1 0 U2 0 PU MOSBY, 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 AUG PY 2000 VL 183 IS 2 BP 389 EP 395 DI 10.1067/mob.2000.105909 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 346NL UT WOS:000088877900047 PM 10942475 ER PT J AU Schmidt, PJ Nieman, L Danaceau, MA Tobin, MB Roca, CA Murphy, JH Rubinow, DR AF Schmidt, PJ Nieman, L Danaceau, MA Tobin, MB Roca, CA Murphy, JH Rubinow, DR TI Estrogen replacement in perimenopause-related depression: A preliminary report SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE perimenopause; estrogen replacement therapy; depression; antidepressants ID PREMENSTRUAL-SYNDROME; POSTMENOPAUSAL WOMEN; MENOPAUSAL WOMEN; DOUBLE-BLIND; THERAPY; MOOD AB OBJECTIVES: We examined the efficacy of estrogen in the treatment of depression in perimenopausal women with and without hot flushes. STUDY DESIGN: Women with perimenopause-related depression were randomized in a double-blind parallel design to receive either 17 beta-estradiol or placebo for 3 weeks. Subsequently, women receiving estradiol during the first 3 weeks continued receiving estradiol for an additional 3 weeks, whereas women who had received placebo crossed over to estradiol for 3 weeks. Outcome measures included standardized mood rating scales and a visual analog scale self-report instrument. RESULTS: Of 34 female subjects, 16 received estradiol first and 18 received placebo first. After 3 weeks of estradiol, standardized mood rating scale scores and visual analog scale symptom scores (eg, sadness, anhedonia, and social isolation) were significantly decreased compared with baseline scores (P < .01) and were significantly lower than scores in women receiving placebo (P < .01), who showed no significant improvement. Neither the presence of hot flushes nor the duration of treatment (3 weeks vs 6 weeks) influenced outcome. A full or partial therapeutic response was seen in 80% of subjects receiving estradiol and 22% of those receiving placebo. CONCLUSION: In this preliminary study estradiol replacement effectively treats perimenopausal depression independent of its salutary effects on vasomotor symptoms. C1 NIMH, Behav Endocrinol Branch, Bethesda, MD 20892 USA. NICHHD, Bethesda, MD 20892 USA. NIH, Clin Ctr Nursing Dept, Bethesda, MD 20892 USA. RP Schmidt, PJ (reprint author), NIMH, Behav Endocrinol Branch, Bldg 10,Rm 3N238,10 Ctr Dr,MSC 1276, Bethesda, MD 20892 USA. NR 25 TC 337 Z9 352 U1 1 U2 5 PU MOSBY, 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 AUG PY 2000 VL 183 IS 2 BP 414 EP 420 DI 10.1067/mob.2000.106004 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 346NL UT WOS:000088877900051 PM 10942479 ER PT J AU Leondires, MP Ernst, SD Miller, BT Scott, RT AF Leondires, MP Ernst, SD Miller, BT Scott, RT TI Triplets: Outcomes of expectant management versus multifetal reduction for 127 pregnancies SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 62nd Annual Meeting of the South-Atlantic-Association-of-Obstetricians-and-Gynecologists CY JAN 22-25, 2000 CL ST PETERSBURG, FLORIDA SP S Atlantic Assoc Obstetricians & Gynecologists DE triplets; multifetal pregnancy reduction; spontaneous abortion; perinatal mortality ID LOW-BIRTH-WEIGHT; SELECTIVE REDUCTION; QUADRUPLET PREGNANCIES; MULTIPLE GESTATIONS; TWINS AB OBJECTIVE: Our purpose was to compare outcomes of women with triplet gestations conceived via assisted reproductive technology who chose expectant management or multifetal pregnancy reduction. STUDY DESIGN: We performed a retrospective review of all women who initiated assisted reproductive technology cycles from August 1995 through July 1997 with ultrasonographic documentation of triplets exhibiting fetal heart tones at 9 weeks of gestation (N = 127). Patients were then uniformly referred to a maternal-fetal medicine specialist and to 3 centers offering multifetal pregnancy reduction. RESULTS: Thirty-six percent of patients (46/127) chose multifetal pregnancy reduction with 95% undergoing reduction to twins. In the expectant management group, 13.6% of pregnancies were reduced spontaneously after 9 weeks of gestation. The "take home" infant per delivery rates for the multifetal pregnancy reduction and expectant management groups were 87% and 90.1%, respectively (P=.66). The mean gestational ages at delivery (+/-SE) for the multifetal pregnancy reduction and expectant management groups were 33.25 +/- 1.03 weeks and 32.04 +/- 0.58 weeks (P=.23), and the mean birth weights of infants delivered at >24 weeks of gestation were 2226 +/- 79 and 1796 +/- 44, respectively (P<.0001). There were no significant differences in perinatal mortality, gestational age at delivery, or "take home" infant per delivery rates between these groups. CONCLUSIONS: These data suggest that multifetal pregnancy reduction does not have a significant impact on the probability of live birth or on gestational age at delivery for women with triplets conceived with assisted reproductive technology. C1 Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Washington, DC 20307 USA. Natl Naval Med Ctr, Dept Obstet & Gynecol, Bethesda, MD USA. NICHHD, NIH, Bethesda, MD 20892 USA. St Barnabas Med Ctr, Inst Reprod Med & Sci, Livingston, NJ USA. RP Leondires, MP (reprint author), Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Rm 2J06,Bldg 2,6825 16th St NW, Washington, DC 20307 USA. NR 24 TC 23 Z9 25 U1 0 U2 0 PU MOSBY, 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 AUG PY 2000 VL 183 IS 2 BP 454 EP 459 DI 10.1067/mob.2000.105546 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 346NL UT WOS:000088877900058 PM 10942486 ER PT J AU Goldenberg, RL Klebanoff, M Carey, JC MacPherson, C Leveno, KJ Moawad, AH Sibai, B Heine, RP Ernest, JM Dombrowski, MP Miodovnik, M Wapner, RJ Iams, JD Langer, O O'Sullivan, MJ Roberts, JM AF Goldenberg, RL Klebanoff, M Carey, JC MacPherson, C Leveno, KJ Moawad, AH Sibai, B Heine, RP Ernest, JM Dombrowski, MP Miodovnik, M Wapner, RJ Iams, JD Langer, O O'Sullivan, MJ Roberts, JM TI Vaginal fetal fibronectin measurements from 8 to 22 weeks' gestation and subsequent spontaneous preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE preterm birth; fetal fibronectin; bacterial vaginosis; Trichomonas vaginalis ID BACTERIAL VAGINOSIS; GENITAL-TRACT; PREDICTION; DELIVERY; INFECTIONS AB OBJECTIVE: We sought to determine the range of fetal fibronectin Values in the vagina from 8 to 22 weeks' gestation, the factors associated with both low and high values, and whether high values are associated with gestational age at birth. STUDY DESIGN: Vaginal fetal fibronectin was quantitatively determined in a prospective cohort study of 13,360 women being evaluated for participation in the National Institute of Child Health and Human Development Maternal-Fetal Medicine Unit treatment trials for bacterial vaginosis and Trichomonas vaginalis. Fetal fibronectin values were correlated with gestational age at screening, race, the presence of bacterial vaginosis and Trichomonas vaginalis, and gestational age at delivery. RESULTS: Vaginal fetal fibronectin values at each gestational age ranged from unmeasurable to >1000 ng/mL, with median values always being <10 ng/mL. Fetal fibronectin values declined progressively with increasing gestational age at sampling. Bacterial vaginosis and black race were associated with higher values, whereas nulliparity was associated with lower values. High values after 13 weeks' gestation were associated with a 2- to 3-fold increased risk of subsequent spontaneous preterm birth overall and a 4-fold increased risk of very early preterm birth. CONCLUSION: Elevated vaginal fetal fibronectin levels from 13 to 22 weeks' gestation are associated with a significantly increased risk of spontaneous preterm birth. C1 Natl Inst Child Hlth & Human Dev, Maternal Fetal Med Units Network, Bethesda, MD USA. RP Goldenberg, RL (reprint author), Univ Alabama, Dept Obstet & Gynecol, 619 19th S S,OHB 560, Birmingham, AL 35249 USA. FU NICHD NIH HHS [U10 HD27869, U10 HD21410, U10 HD21414] NR 19 TC 34 Z9 36 U1 0 U2 4 PU MOSBY, 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 AUG PY 2000 VL 183 IS 2 BP 469 EP 475 DI 10.1067/mob.2000.106073 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 346NL UT WOS:000088877900061 PM 10942489 ER PT J AU Horska, A Fishbein, KW Fleg, JL Spencer, RGS AF Horska, A Fishbein, KW Fleg, JL Spencer, RGS TI The relationship between creatine kinase kinetics and exercise intensity in human forearm is unchanged by age SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE skeletal muscle; P-31 magnetic resonance spectroscopy; reaction rate; magnetization transfer ID NMR SATURATION-TRANSFER; HUMAN SKELETAL-MUSCLE; MAGNETIC-RESONANCE SPECTROSCOPY; LATTICE RELAXATION-TIMES; RAT; METABOLISM; PH; PHOSPHOCREATINE; SPILLOVER; TISSUES AB Using P-31 magnetic resonance spectroscopy, creatine kinase (CK) reaction kinetics was assessed in the forearm flexor digitorum profundus muscle of healthy young (n = 11, age 34.7 +/- 5 yr) and older (n = 20, age 73.5 +/- 8 yr) subjects at rest, intermittent exercise at 20% maximum voluntary contraction (MVC), and 40% MVC. Exercise resulted in a significant increase in the average ratio of inorganic phosphate (P-i) to phosphocreatine (PCr) from resting values of 0.073 +/- 0.031 (young) and 0.082 +/- 0.037 (older) to 0.268 +/- 0.140 (young, P < 0.01) and 0.452 +/- 0.387 (older, P < 0.01) at 40% MVC. At 40% MVC, intracellular pH decreased significantly, from resting values of 7.08 +/- 0.08 (young) and 7.08 +/- 0.11 (older) to 6.84 +/- 0.19 (young, P < 0.05) and to 6.75 +/- 0.25 (older, P < 0.05). Average values of the pseudo-first-order reaction rate k((PCr-->ATP)) at rest were 0.07 +/- 0.04 s(-1) in the young and 0.07 +/- 0.03 s(-1) in the older group. At both exercise levels, the reaction rate constant increased compared with the resting value, but only the difference between the resting value and the 20% MVC value, which showed an 86% higher reaction rate constant in both groups, reached statistical significance (P < 0.05). No difference in the reaction rate constant between the young and older groups was observed at either exercise level. As with k((PCr-->ATP)), the average phosphorus flux through the CK reaction increased during exercise at 20% MVC (P, 0.05 in the older group) but decreased toward resting values at 40% MVC in both groups. The data in our study suggest that normal aging does not significantly affect the metabolic processes associated with the CK reaction. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. NIA, Nucl Magnet Resonance Unit, NIH, Baltimore, MD 21224 USA. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Horska, A (reprint author), Johns Hopkins Univ, Dept Radiol, 217 Traylor Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. NR 41 TC 19 Z9 19 U1 0 U2 3 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 AUG PY 2000 VL 279 IS 2 BP E333 EP E339 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 338EM UT WOS:000088405200013 PM 10913033 ER PT J AU Promeneur, D Kwon, TH Frokiaer, J Knepper, MA Nielsen, S AF Promeneur, D Kwon, TH Frokiaer, J Knepper, MA Nielsen, S TI Vasopressin V(2)-receptor-dependent regulation of AQP2 expression in Brattleboro rats SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE arginine vasopressin; aquaporin; collecting duct; urinary concentrating mechanism; water transport ID NEPHROGENIC DIABETES-INSIPIDUS; WATER CHANNEL EXPRESSION; COLLECTING DUCT; V-2 RECEPTOR; RENAL AQUAPORINS; KIDNEY; OXYTOCIN; GENE; PATHOGENESIS; ANTIDIURESIS AB The role of AVP-V(2) receptor (AVP-V(2)R)dependent regulation of aquaporin-2 (AQP2) expression was evaluated in vasopressin-deficient Brattleboro (BB) rats. AQP2 levels were relatively high in BB rats (52 +/- 8% of levels in Wistar rats), and treatment with the AVP-V(2)R antagonist SR-121463A (0.8 mg/day) for 48 h was associated with 1) increased urine output (170 +/- 9%), 2), reduced AQP2 protein levels (42 +/- 10% in whole kidney and 53 +/- 8% in inner medulla), and 3) reduced AQP2 mRNA levels (36 +/- 7%). In addition, the levels of AQP2 phosphorylated in the protein kinase A (PKA) consensus site (Ser(256) of AQP2) was reduced to 3 +/- 1% of control levels. Lithium (Li) treatment of BB rats for 1 mo, known to reduce adenylyl cyclase (AC) activity, downregulated AQP2 protein levels (15 +/- 6%) and increased urine output (220%). Downregulation of AQP2 expression in response to SR-121463A or Li treatment indicates that AQP2 expression in BB rats depends in part on activation of AVP-V(2)Rs and that the signaling cascade(s) involves AC and hence cAMP. Complete water restriction of BB rats produced only a small increase in AQP2 mRNA (235 +/- 33%) and AQP2 protein (156 +/- 22%) levels. Immunoelectron microscopy confirmed the increase in AQP2 abundance but revealed no change in AQP2 apical plasma membrane labeling in response to thirsting. In conclusion, the expression and phosphorylation of AQP2 in BB rats are in part dependent on AVP-V(2)R signaling, and AVP-V(2)-mediated regulation of AQP2 trafficking and expression is effectively decoupled in BB rats, indicating differences in AVP-V(2)R-mediated regulation of AQP2 trafficking and expression. C1 Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus C, Denmark. Aarhus Univ Hosp, Dept Clin Physiol, DK-8200 Aarhus, Denmark. Inst Expt Clin Res, DK-8200 Aarhus N, Denmark. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Aarhus Univ, Inst Anat, Dept Cell Biol, DK-8000 Aarhus C, Denmark. EM sn@ana.au.dk RI chen, xuanlan/H-4158-2011 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 46 TC 44 Z9 44 U1 1 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 AUG PY 2000 VL 279 IS 2 BP F370 EP F382 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 339RE UT WOS:000088491100020 PM 10919858 ER PT J AU Herbst, JH Zonderman, AB McCrae, RR Costa, PT AF Herbst, JH Zonderman, AB McCrae, RR Costa, PT TI Do the dimensions of the temperament and character inventory map a simple genetic architecture? Evidence from molecular genetics and factor analysis SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID SEROTONIN TRANSPORTER GENE; DOPAMINE-RECEPTOR GENE; ANXIETY-RELATED TRAITS; EXON-III POLYMORPHISM; REGULATORY REGION POLYMORPHISM; HUMAN PERSONALITY-TRAIT; NOVELTY-SEEKING; PROMOTER POLYMORPHISM; REPEAT POLYMORPHISM; NO ASSOCIATION AB Objective: It has been reported that the human temperament dimensions of novelty seeking and harm avoidance are associated with polymorphisms in the D-4 dopamine receptor gene (D4DR) and the serotonin-transporter-linked promoter region (5-HTTLPR), respectively. Although these findings are consistent with Cloninger's hypothesized psychobiological model of temperament and character, many studies failed to replicate these findings. In the present study the authors tested whether the psychobiological model taps the genetic architecture of personality by exploring associations between these candidate genes and the dimensions of the Temperament and Character Inventory and by examining its phenotypic structure. Method: Of the 946 male and female participants in the Baltimore Longitudinal Study of Aging to whom the Temperament and Character Inventory was administered, 587 were genotyped for a polymorphism with a 48-base-pair repeat in the D4DR gene and 425 were genotyped for a 44-base-pair insertion or deletion in the 5-HTTLPR polymorphism. Results: There was no significant association between D4DR polymorphisms and novelty seeking. The authors also failed to find an association between 5-HTTLPR polymorphisms and harm avoidance. The factor structure of the Temperament and Character Inventory did not reveal the hypothesized phenotypic structure. Conclusions: This investigation produced no support for the temperament-character model at either the biological or psychological level. C1 NIA, Ctr Gerontol Res, Lab Personal & Cognit,Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Costa, PT (reprint author), NIA, Ctr Gerontol Res, Lab Personal & Cognit,Intramural Res Program, NIH, Box 03,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Costa, Paul/0000-0003-4375-1712; Zonderman, Alan B/0000-0002-6523-4778 NR 32 TC 103 Z9 104 U1 2 U2 8 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2000 VL 157 IS 8 BP 1285 EP 1290 DI 10.1176/appi.ajp.157.8.1285 PG 6 WC Psychiatry SC Psychiatry GA 340EL UT WOS:000088520100017 PM 10910792 ER PT J AU Egan, MF Goldberg, TE Gscheidle, T Weirich, M Bigelow, LB Weinberger, DR AF Egan, MF Goldberg, TE Gscheidle, T Weirich, M Bigelow, LB Weinberger, DR TI Relative risk of attention deficits in siblings of patients with schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Society-for-Biological-Psychiatry CY MAY 13-16, 1999 CL WASHINGTON, D.C. SP Soc Biol Psychiat ID GENETICALLY COMPLEX TRAITS; DISCORDANT SIB PAIRS; NONPSYCHOTIC RELATIVES; SUSTAINED ATTENTION; COGNITIVE-ABILITIES; VULNERABILITY LOCUS; LINKAGE STRATEGIES; ROSCOMMON FAMILY; EYE TRACKING; PERFORMANCE AB Objective: Impaired attention has frequently been observed in studies of unaffected siblings of patients with schizophrenia. To assess the suitability of impaired attention for use as an intermediate phenotype in genetic studies, the authors estimated the relative risk of impaired attention in a large group of siblings. Method: The authors used the Continuous Performance Test. 1-9 version, with and without a distraction condition, to study 147 patients with schizophrenia, 193 of their siblings, and 47 normal comparison subjects. Relative risk (a) was estimated by using cutoff scores that were one, two, and three standard deviations below the mean sensitivity index value (d') of the normal comparison group in both Continuous Performance Test conditions. Results: Patients but not their siblings performed worse than the normal comparison subjects in both conditions. Fifty percent of the patients, 24% of their siblings, and 18% of the normal comparison subjects scored one standard deviation below the mean score of the comparison group for the more difficult distraction version of the Continuous Performance Test. The patients with Continuous Performance Test scores one standard deviation below the mean score of the comparison group had a total of 97 siblings. Compared with the comparison group, this subgroup of siblings had significantly lower Continuous Performance Test scores. Relative risk was also significantly higher for the siblings of patients whose scores were one standard deviation (lambda=2.1) and two standard deviations (lambda=3.3) below the mean of comparison subjects. Attempts to assess ascertainment bias suggest that this may be an underestimate. Conclusions: Poor performance on the Continuous Performance Test appears to be familiar and, possibly, genetic. Relative risk estimates were in the moderate range. Given the ease of administering the Continuous Performance Test, the use of impaired attention as an intermediate phenotype could increase the power of genetic studies of schizophrenia. C1 NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bethesda, MD 20814 USA. NIMH, St Elizabeths Hosp, Ctr Res Neurosci, Washington, DC 20032 USA. RP Egan, MF (reprint author), NIMH, Intramural Res Program, Clin Brain Disorders Branch, NIH, Bldg 10,Ctr Dr,Rm 4S-241,MSC1377, Bethesda, MD 20814 USA. NR 50 TC 134 Z9 141 U1 5 U2 5 PU AMER PSYCHIATRIC PRESS, INC PI WASHINGTON PA 1400 K ST, N W, STE 1101, WASHINGTON, DC 20005 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2000 VL 157 IS 8 BP 1309 EP 1316 DI 10.1176/appi.ajp.157.8.1309 PG 8 WC Psychiatry SC Psychiatry GA 340EL UT WOS:000088520100021 PM 10910796 ER PT J AU Helfand, WH Lazarus, J Theerman, P AF Helfand, WH Lazarus, J Theerman, P TI Demonstrating pelvic measurement to midwives SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article C1 Natl Lib Med, Hist Med Div, Bethesda, MD 20894 USA. Natl Lib Med, New York, NY USA. RP Theerman, P (reprint author), Natl Lib Med, Hist Med Div, 8600 Rockville Pike, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2000 VL 90 IS 8 BP 1196 EP 1196 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 338BR UT WOS:000088398700005 ER PT J AU Galanis, DJ Joseph, C Masaki, KH Petrovitch, H Ross, GW White, L AF Galanis, DJ Joseph, C Masaki, KH Petrovitch, H Ross, GW White, L TI A longitudinal study of drinking and cognitive performance in elderly Japanese American men: The Honolulu-Asia Aging Study SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID COMMUNITY POPULATION; ALCOHOL-CONSUMPTION; ALZHEIMERS-DISEASE; PREVALENCE; DEMENTIA; HAWAII; STATE; RISK; SMOKING; STROKE AB Objectives. This study prospectively describes the relationships between alcohol intake and subsequent cognitive performance among participants in the Honolulu Heart Pro,sram (HHP). Methods. Alcohol intake was assessed at Exam III of the HHP, and cognitive performance was measured approximately 18 years later with the Cognitive Abilities Screening Instrument (CASI). Complete information was available for 3556 participants, aged 71 to 93 years at follow-up. Results. In multivariate analyses, the relationship between drinking and later cognitive performance appeared nonlinear, as nondrinkers and heavy drinkers (more than 60 ounces of alcohol per month) had the lowest CASI scores and the highest risks of poor and intermediate CASI outcomes. Compared with nondrinkers, the risk of a poor CASI score was lowered by 22% to 40% among men who consumed 1-60 ounces of alcohol per month. Conclusions. We report a positive association between moderate alcohol intake among middle-aged men and subsequent cognitive performance in later life. However, it is possible that the health risks associated with drinking outweigh any potential benefits for many elderly persons. C1 NIA, NIH, Bethesda, MD 20892 USA. Dept Vet Affairs, Honolulu, HI USA. Univ Hawaii, John A Burns Sch Med, Dept Internal Med, Honolulu, HI 96822 USA. Kuakini Med Ctr, Honolulu Asia Aging Study, Honolulu, HI USA. NIA, NIH, Bethesda, MD 20892 USA. RP Galanis, DJ (reprint author), Hawaii Dept Hlth, Injury Prevent & Control Program, 1250 Punchbowl St,Room 213, Honolulu, HI 96813 USA. NR 37 TC 62 Z9 66 U1 1 U2 4 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2000 VL 90 IS 8 BP 1254 EP 1259 DI 10.2105/AJPH.90.8.1254 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 338BR UT WOS:000088398700017 PM 10937006 ER PT J AU Baris, D Brown, LM Silverman, DT Hayes, R Hoover, RN Swanson, GM Dosemeci, M Schwartz, AG Liff, JM Schoenberg, JB Pottern, LM Lubin, J Greenberg, RS Fraumeni, JF AF Baris, D Brown, LM Silverman, DT Hayes, R Hoover, RN Swanson, GM Dosemeci, M Schwartz, AG Liff, JM Schoenberg, JB Pottern, LM Lubin, J Greenberg, RS Fraumeni, JF TI Socioeconomic status and multiple myeloma among US Blacks and Whites SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; UNITED-STATES; MONOCLONAL GAMMOPATHY; UNDETERMINED SIGNIFICANCE; ATTRIBUTABLE RISK; CANCER SITES; MEN; HISTORY; POPULATION; EXPOSURES AB Objective. This study examined the relation between socioeconomic status (SES) and risk of multiple myeloma among Blacks and Whites in the United States. Methods. This population-based case-control study included 573 cases (206 Blacks and 367 Whites) with new diagnoses of multiple myeloma identified between August 1, 1986, and April 30, 1989, and 2131 controls (967 Blacks and 1164 Whites) from 3 US geographic areas. Information on occupation, income, and education was obtained by personal interview. Results. Inverse gradients in risk were associated with occupation-based SES, income, and education. Risks were significantly elevated of subjects in the lowest categories of occupation-based SES (odds ratio [OR] = 1.71, 95% confidence interval [CI] = 1.16, 2.53), education (OR = 1.36, 95% CI = 1.06, 1.75), and income (OR = 1.43, 95% CI = 1.05, 1.93). Occupation-based low SES accounted for 37% of multiple myeloma in Blacks and 17% in Whites, as well as 49% of the excess incidence in Blacks Low education and low income accounted for 17% and 28% of the excess incidence in Blacks, respectively. Conclusions. Our results indicate that the measured SES-related factors account for a substantial amount of the black-White differential in multiple myeloma incidence. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Michigan State Univ, Ctr Canc, E Lansing, MI 48824 USA. Allegheny Univ Hlth Sci, Dept Human Genet, Pittsburgh, PA USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. New Jersey State Dept Hlth, Trenton, NJ 08625 USA. NHLBI, Womens Hlth Initiat, Bethesda, MD 20892 USA. Med Univ S Carolina, Charleston, SC 29425 USA. RP Baris, D (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S,Room 8122, Bethesda, MD 20892 USA. NR 47 TC 33 Z9 33 U1 1 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2000 VL 90 IS 8 BP 1277 EP 1281 DI 10.2105/AJPH.90.8.1277 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 338BR UT WOS:000088398700020 PM 10937009 ER PT J AU Vogel, DL AF Vogel, DL TI NIH funding and career development opportunities for women in reproductive immunology SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Editorial Material DE careers; grants; NIH; training; women's health AB The National Institutes of Health (NIH) has a number of mechanisms available to support research, research training and research career development. The various institutes, centers and special offices within the NIH have, as part of their missions, a diverse array of basic and clinical research goals. Much of the scientific spectrum of reproductive immunology, however, falls within the mission of the National Institute of Child Health and Human Development (NICHD). There have been a number of recent innovations in the preparation, review and funding of NIH grant applications. Specific opportunities, such as fellowships, career awards, and new investigator status, are available for investigators at different career stages. A wealth of information is available on the NIH website at www.nih.gov. NIH staff are available to answer your questions and to provide administrative guidance in preparing grant applications. C1 NICHD, Reprod Sci Branch, Populat Res Ctr, NIH, Bethesda, MD 20892 USA. RP Vogel, DL (reprint author), NICHD, Reprod Sci Branch, Populat Res Ctr, NIH, 6100 Execut Blvd,Room 8B01,MSC-7510, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MUNKSGAARD INT PUBL LTD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 8755-8920 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD AUG PY 2000 VL 44 IS 2 BP 125 EP 128 DI 10.1111/j.8755-8920.2000.440209.x PG 4 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 348FW UT WOS:000088975700009 PM 10994641 ER PT J AU Weese-Mayer, DE Corwin, MJ Peucker, MR Di Fiore, JM Hufford, DR Tinsley, LR Neuman, MR Martin, RJ Brooks, LJ Ward, SLD Lister, G Willinger, M AF Weese-Mayer, DE Corwin, MJ Peucker, MR Di Fiore, JM Hufford, DR Tinsley, LR Neuman, MR Martin, RJ Brooks, LJ Ward, SLD Lister, G Willinger, M CA CHIME Study Grp TI Comparison of apnea identified by respiratory inductance plethysmography with that detected by end-tidal CO2 or thermistor SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article ID AGREEMENT; VOLUME AB As part of the Collaborative Home Infant Monitoring Evaluation (CHIME) we compared apnea identified by a customized home monitor using respiratory inductance plethysmography (RIP) with simultaneously recorded polysomnography-acquired nasal endtidal CO2 (PETCO2) and nasal/oral thermistor in 422 infants during overnight laboratory recordings to determine concordance between techniques, sources of disagreement, and capacity of RIP to detect obstructed breaths within an apnea. Among 233 episodes of apnea identified by at least one method as greater than or equal to 16 s, 120 were observed by the CHIME monitor, 219 by PETCO2, and 163 by thermistor. The positive predictive value of the CHIME-identified apnea was 89.2% (95% CI 83, 95) and 73% (95% CI 65, 81) for PETCO2 and thermistor, respectively. However, the sensitivity of the CHIME monitor in identifying events detected by the other methods was only similar to 50%. Among 87 apnea events identified by all three techniques, no two methods showed high agreement in measurement of apnea duration: RIP and PETCO2 (ICC = 0.54), RIP and thermistor (ICC = 0.13), PETCO2 and nasal thermistor (ICC = 0.41). Among the 179 breaths identified by RIP as obstructed, 79.9% were judged to be obstructed on the PETCO2 and 80.4% were judged to be obstructed on the thermistor channel. Among 238 breaths identified on PETCO2 as obstructed, 54.2% were determined to be obstructed by RIP. Among 204 breaths identified on thermistor as obstructed, 55.4% were determined to be obstructed by RIP. Reasons for discrepancies in apnea detection among channels included body movement, partial airway obstruction, and obstructed breaths. Despite these limitations the CHIME monitor provides an opportunity to record physiological data previously unavailable in the home. C1 Rush Presbyterian St Lukes Med Ctr, Rush Childrens Hosp, Dept Pediat, Chicago, IL 60612 USA. Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Biostat & Epidemiol, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Biostat & Epidemiol, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Pediat, Boston, MA 02118 USA. Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. Med Coll Ohio, Dept Pediat, Toledo, OH 43699 USA. Toledo Hosp, Toledo, OH USA. Kapiolani Med Ctr Women & CHildren, Dept Pediat, Honolulu, HI USA. Metrohlth Med Ctr, Dept Obstet & Gynecol, Cleveland, OH USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Univ So Calif, Sch Med, Los Angeles, CA USA. Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. NICHHD, Pregnancy & Perinatol Branch, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. RP Weese-Mayer, DE (reprint author), Rush Univ, Dept Pediat, 1653 W Congress Pkwy, Chicago, IL 60612 USA. FU NICHD NIH HHS [HD 28971, HD 29067, HD 29071] NR 10 TC 24 Z9 24 U1 0 U2 0 PU AMER LUNG ASSOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG PY 2000 VL 162 IS 2 BP 471 EP 480 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 345RP UT WOS:000088829200024 PM 10934073 ER PT J AU Freidlin, B Gastwirth, JL AF Freidlin, B Gastwirth, JL TI Should the median test be retired from general use? SO AMERICAN STATISTICIAN LA English DT Article DE Kolmogorov-Smirnov test; median test; nonparametric inference; power; two-sample rank tests; Wilcoxon test ID BEHRENS-FISHER PROBLEM AB Although several authors have indicated that the median test has low power in small samples, it continues to be presented in many statistical textbooks, included in a number of popular statistical software packages, and used in a variety of application areas, We present results of a power simulation study that shows that the median test has noticeably lower power, even for the double exponential distribution for which it is asymptotically most powerful, than other readily available rank tests. We suggest that the median test be "retired" from routine use and recommend alternative rank tests that have superior power over a relatively large family of symmetric distributions. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, MSC7434, Bethesda, MD 20892 USA. NR 36 TC 25 Z9 25 U1 1 U2 10 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD AUG PY 2000 VL 54 IS 3 BP 161 EP 164 DI 10.2307/2685584 PG 4 WC Statistics & Probability SC Mathematics GA 384NR UT WOS:000165952200001 ER PT J AU Kim, JR Yoon, HW Kwon, KS Lee, SR Rhee, SG AF Kim, JR Yoon, HW Kwon, KS Lee, SR Rhee, SG TI Identification of proteins containing cysteine residues that are sensitive to oxidation by hydrogen peroxide at neutral pH SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE assay of protein cysteine oxidation; hydrogen peroxide; protein oxidation; selenocysteine oxidation ID CHROMATOGRAPHY MASS-SPECTROMETRY; EPIDERMAL GROWTH-FACTOR; DISULFIDE-ISOMERASE; CREATINE-KINASE; D-GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; TYROSINE PHOSPHORYLATION; THIOREDOXIN REDUCTASE; CELLS; H2O2; SELENOCYSTEINE AB A procedure for detecting proteins that contain H2O2-sensitive cysteine (or selenocysteine) residues was developed as a means with which to study protein oxidation by H2O2 in cells. The procedure is based on the facts that H2O2 and biotin-conjugated iodoacetamide (BIAM) selectively and competitively react with cysteine residues that exhibit a low pK(a), and that the decrease in the labeling of cell lysate proteins with BIAM caused by prior exposure of cells to H2O2 or to an agent that induces H2O2 production can be monitored by streptavidin blot analysis. This procedure was applied to rat pheochromocytoma PC12 cells directly treated with H2O2, mouse hippocampal HT22 cells in which H2O2 production was induced by glutamate, and human erythroleukemia K562 cells in which H2O2 production was induced by phorbol myristate acetate. It revealed that several cell proteins contain cysteine or selenocysteine residues that are selectively oxidized by H2O2. Three of these H2O2-sensitive proteins were identified as a member of the protein disulfide isomerase family, thioredoxin reductase, and creatine kinase, all of which were previously known to contain at least one reactive cysteine or selenocysteine at their catalytic sites. This procedure should thus prove useful for the identification of proteins that are oxidized by H2O2 generated in response to a variety of extracellular agents. (C) 2000 Academic Press. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Korea Res Inst Biosci & Biotechnol, Taejon 305606, South Korea. RP Rhee, SG (reprint author), NHLBI, Lab Cell Signaling, NIH, Bldg 3,Room 122, Bethesda, MD 20892 USA. NR 38 TC 199 Z9 203 U1 1 U2 18 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 AUG 1 PY 2000 VL 283 IS 2 BP 214 EP 221 DI 10.1006/abio.2000.4623 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 341KB UT WOS:000088588600013 PM 10906242 ER PT J AU Chen, Y Zhao, Z Code, WE Hertz, L AF Chen, Y Zhao, Z Code, WE Hertz, L TI A correlation between dexmedetomidine-induced biphasic increases in free cytosolic calcium concentration and energy metabolism in astrocytes SO ANESTHESIA AND ANALGESIA LA English DT Article ID CEREBRAL BLOOD-FLOW; AGONIST DEXMEDETOMIDINE; CULTURED ASTROCYTES; NEURONS; RATS; HALOTHANE; ALPHA(2)-ADRENOCEPTORS; RECEPTORS; ALPHA-2; POTENT AB The alpha(2)-adrenergic agonist, dexmedetomidine, increases free cytosolic calcium concentration ([Ca2+](i)) in astrocytes, but not in neurons. The present study was performed to characterize the origin of the increased Ca2+ in mouse astrocytes cultured from the cerebral cortex, the dose dependence of the effect, and its functional consequences. The increase in [Ca2+](i) was independent of extracellular Ca2+, but was inhibited by dantrolene, showing that it is derived from intracellular stores; two peaks in [Ca2+](i) were demonstrated-one around 100 nM dexmedetomidine and the other in the low micromolar range. A similar dose dependence was found for pyruvate dehydrogenation, the initial metabolic reaction of oxidative degradation of pyruvate, suggesting that the these events are interrelated. The alpha(2)-adrenergic antagonist, yohimbine, abolished the metabolic stimulation at both peaks. However, whereas the increase in [Ca2+](i) at 100 nM is abolished by yohimbine, increase in the micromolar range was partly inhibited by yohimbine and partly by idazoxan, an inhibitor at the imidazoline-preferring site. The stimulation of energy metabolism in cerebrocortical astrocytes may explain the repeated finding that dexmedetomidine does not decrease oxidative metabolism in the brain in vivo. The functional importance of the additional imidazoline receptor-mediated increase in [Ca2+](i) at large dexmedetomidine concentrations is unknown. C1 Univ Saskatchewan, Dept Pharmacol, Saskatoon, SK S7N 0W0, Canada. Univ Saskatchewan, Dept Anesthesia, Saskatoon, SK S7N 0W0, Canada. RP Chen, Y (reprint author), NINDS, Stroke Branch, NIH, 36 Convent Dr,MSC 4128, Bethesda, MD 20892 USA. NR 25 TC 22 Z9 25 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-2999 J9 ANESTH ANALG JI Anesth. Analg. PD AUG PY 2000 VL 91 IS 2 BP 353 EP 357 DI 10.1097/00000539-200008000-00022 PG 5 WC Anesthesiology SC Anesthesiology GA 338YD UT WOS:000088450100022 PM 10910847 ER PT J AU Putnam, SD Cerhan, JR Parker, AS Bianchi, GD Wallace, RB Cantor, KP Lynch, CF AF Putnam, SD Cerhan, JR Parker, AS Bianchi, GD Wallace, RB Cantor, KP Lynch, CF TI Lifestyle and anthropometric risk factors for prostate cancer in a cohort of Iowa men SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE obesity; physical activity; prostate cancer; smoking ID OCCUPATIONAL PHYSICAL-ACTIVITY; POPULATION-BASED COHORT; LIFE-STYLE FACTORS; GROWTH-FACTOR-I; CIGARETTE-SMOKING; UNITED-STATES; TOBACCO USE; FOLLOW-UP; ALCOHOL; DIET AB PURPOSE: Several lines of evidence suggest that prostate cancer has a hormonal etiology. We evaluated factors known to modulate the endocrine system, including alcohol and tobacco use, physical activity, and obesity as risk factors for prostate cancer. METHODS: Cancer-free controls (n = 1572) who participated in a population-based case control study from 1986-1989 (81% response rate) were followed through 1995 for cancer incidence by linkage to the Iowa Cancer Registry; 101 incident prostate cancers were identified. RESULTS: Compared with non-users of alcohol, men who consumed <22 grams alcohol per week (relative risk [RR] = 1.1; 95% Confidence Interval [CI] 0.6-2.1), 22-96 grams alcohol per week (RR = 2.6; 95% CI 1.4-4.6) and >96 grams alcohol per week (RR = 3.1; 95% CI 1.5-6.3) were at increased risk of prostate cancer after adjustment: for age, family history of prostate cancer, body mass index, total energy, and intake of carbohydrate, linoleic acid, lycopene, retinol, and red meat (p for trend < 0.0001). The respective RRs were similar when assessing type of alcohol consumed (beer, wine or liquor) or when well-differentiated, localized tumors were excluded. Body mass index was only weakly and positively associated with prostate cancer after adjustment for age (p for trend = 0.3), but this association strengthened after multivariate adjustment (p for trend = 0.08) and exclusion of well-differentiated, localized tumors (p for trend = 0.03). For the latter tumors, men with a BMI of 24.1-26.6 kg/m(2) (RR = 1.5; 95% CI 0.7 - 3.0) and >26.6 kg/m(2) (RR = 2.1; 95% CI 1.1-4.3) were at elevated risk compared to men with a BMI <24.1 kg/m(2). Tobacco use (cigarettes, cigar/pipe, chewing tobacco and snuff use), height, weight, and both leisure and occupational physical activity were not associated with risk of prostate cancer in this cohort. CONCLUSIONS: These data suggest that in white men obesity is a risk factor for more clinically significant prostate cancer and confirm limited previous reports showing that alcohol consumption is positively associated with prostate cancer and that this risk is not limited to any specific type of alcohol. Ann Epidemiol 2000;10:361-369. Published by Elsevier Science Inc. C1 Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, Rochester, MN 55905 USA. Univ Iowa, Coll Med, Dept Prevent Med & Environm Hlth, Iowa City, IA 52242 USA. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Cerhan, JR (reprint author), Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. FU NCI NIH HHS [N01-CP-51026, R21 CA/ES69838]; NIEHS NIH HHS [P30 ES05605] NR 54 TC 116 Z9 122 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2000 VL 10 IS 6 BP 361 EP 369 DI 10.1016/S1047-2797(00)00057-0 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 347RM UT WOS:000088943000004 PM 10964002 ER PT J AU Williams, RR Rao, DC Ellison, RC Arnett, DK Heiss, G Oberman, A Eckfeldt, JH Leppert, MF Province, MA Mokrin, SC Hunt, SC AF Williams, RR Rao, DC Ellison, RC Arnett, DK Heiss, G Oberman, A Eckfeldt, JH Leppert, MF Province, MA Mokrin, SC Hunt, SC CA HyperGEN Investigators TI NHLBI Family Blood Pressure Program: Methodology and recruitment in the HyperGEN network SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE genetics; epidemiology; pathophysiology; blood pressure; consent; recruitment ID SODIUM-LITHIUM COUNTERTRANSPORT; CARDIOVASCULAR RISK-FACTORS; FRENCH-CANADIAN POPULATION; DYSLIPIDEMIC HYPERTENSION; EXTENSIVE INFORMATION; UTAH PEDIGREES; TWINS; GENE; ANGIOTENSINOGEN; ASSOCIATIONS AB PURPOSE: Hypertension is a common precursor of serious disorders including stroke, myocardial infarction, congestive heart failure, and renal failure in whites and to a greater extent in African Americans. Large genetic-epidemiological studies of hypertension are needed to gain information that will improve future methods for diagnosis, treatment, and prevention of hypertension, a major contributor to cardiovascular morbidity and mortality. METHODS: We report successful implementation of a new structure of research collaboration involving four NHLBI "Networks," coordinated under the Family Blood Pressure Program. The Hypertension Genetic Epidemiology Network (HyperGEN) involves scientists from six universities and the NHLBI who seek to identify and characterize genes promoting hypertension. Blood samples and clinical data were projected to be collected from a sample of 2244 hypertensive siblings diagnosed before age 60 from 960 sibships (half African-American) with two or more affected persons. Nonparametric sibship linkage analysis of over one million genotype determinations (20 candidate loci and 387 anonymous marker loci) was projected to have sufficient power for detecting genetic loci promoting hypertension. For loci showing evidence for linkage in this study and for loci reported linked or associated with hypertension by other groups, genotypes are compared in hypertensive cases Versus population-based controls to identify or confirm genetic variants associated with hypertension. For some of these genetic variants associated with hypertension, detailed physiological and biochemical characterization of untreated adult offspring carriers versus non-carriers may help elucidate the pathophysiological mechanisms that promote hypertension. RESULTS: The projected sample size of 2244 hypertensive participants was surpassed, as 2407 hypertensive individuals (1262 African Americans and 1145 whites) from 917 sibships were examined. Detailed consent forms were designed to offer participants several options for DNA testing; 94% of participants gave permission for DNA testing now or in the future for any confidential medical research, with only 6% requesting restrictions for tests performed on their DNA. Since this is a family study, participants also are asked to list all first degree relatives (along with names, addresses, and phone numbers) and to indicate for each relative whether they were willing to allow study staff to make a contact. Seventy percent gave permission to contact some relatives; about 30% gave permission to contact all first degree relatives; and less than 1% asked that no relatives be contacted. Successes after the first four years of this study include: 1) productive collaboration of eight centers from six different locations; 2) early achievement of recruitment goals for study participants including African-Americans; 3) an encouraging rate of consent for DNA testing (including future testing) and relative contacting; 4) completed analyses of genetic linkage and association for several candidate gene markers and polymorphisms; 5) completed genotyping of random markers for over half of the full sample; and 6) early sharing of results among the four Family Blood Pressure Program networks for candidate and genome search analyses. CONCLUSIONS: Experience after four years of this five-year program (1995-2000) suggests that the newly initiated NHLBI Network Program mechanism is fulfilling many of the expectations for which it was designed. It may serve as a paradigm for future genetic research that can benefit from large sample sizes, frequent sharing of ideas among laboratories, and prompt independent confirmation of early findings, which are required in the search for common genes with relatively small effects such as those that predispose to human hypertension. Ann Epidemiol 2000;10:389-400. Published by Elsevier Science inc. C1 Univ Utah, Dept Internal Med, Cardiovasc Genet Res Clin, Salt Lake City, UT 84112 USA. Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ Alabama, Med Sch Birmingham, Div Prevent Med, Birmingham, AL USA. Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. Univ Utah, Dept Human Genet, Salt Lake City, UT USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Hunt, SC (reprint author), 410 Chipeta Way,Room 167, Salt Lake City, UT 84108 USA. FU NHLBI NIH HHS [HL-54473, HL54471, HL54472] NR 37 TC 113 Z9 117 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 655 AVENUE OF THE AMERICAS, NEW YORK, NY 10010 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2000 VL 10 IS 6 BP 389 EP 400 DI 10.1016/S1047-2797(00)00063-6 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 347RM UT WOS:000088943000007 PM 10964005 ER PT J AU Miller, KD Cameron, M Wood, LV Dalakas, MC Kovacs, JA AF Miller, KD Cameron, M Wood, LV Dalakas, MC Kovacs, JA TI Lactic acidosis and hepatic steatosis associated with use of stavudine: Report of four cases SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID ACQUIRED-IMMUNODEFICIENCY-SYNDROME; NUCLEOSIDE ANALOG; MITOCHONDRIAL TOXICITY; ZIDOVUDINE THERAPY; HIV-INFECTION; MYOPATHY; THIAMINE; PATIENT; FAILURE; VIRUS AB Background: An association between use of zidovudine and didanosine and a rare but life-threatening syndrome of hepatic steatosis, lactic acidosis, and myopathy has been reported. Objective: To describe the syndrome of hepatic steatosis, lactic acidosis, and myopathy in four patients taking stavudine. Design: Case series. Setting: A community hospital in Washington, D.C., and National Institutes of Health Clinical Center, Bethesda, Maryland. Patients: Two men and two women with HIV-1 infection who were taking stavudine presented with lactic acidosis and elevated levels of aminotransferases. All patients required intensive care. Measurements: Levels of lactic acid, alanine aminotransferase, aspartate aminotransferase, amylase, and lipase; computed tomography of the abdomen; liver biopsy (two patients); and muscle biopsy (two patients). Results: Histologic findings consistent with mitochondrial injury confirmed the diagnosis of hepatic or muscle abnormality. Conclusion: Because hepatic steatosis may be life-threatening, physicians should consider it as a possible cause of elevated hepatic aminotransferase levels among patients taking stavudine. C1 NIAID, Dept Crit Care Med, Warren Grant Magnuson Clin Ctr, NIH,Intramural AIDS Program, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. Kaiser Permanente Mid Atlantic & W End Med Ctr, Washington, DC USA. RP Miller, KD (reprint author), NIAID, Dept Crit Care Med, Warren Grant Magnuson Clin Ctr, NIH,Intramural AIDS Program, Bldg 10,Room 8C410, Bethesda, MD 20892 USA. RI Andrade, Hugo/M-6631-2013 OI Andrade, Hugo/0000-0001-6781-6125 NR 20 TC 142 Z9 147 U1 1 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD AUG 1 PY 2000 VL 133 IS 3 BP 192 EP 196 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 338XW UT WOS:000088449400004 PM 10906833 ER PT J AU Olivieri, I Padula, A Ciancio, G Moro, L Durante, E Gaudiano, C Masciandaro, S Pozzi, S Ferrara, GB AF Olivieri, I Padula, A Ciancio, G Moro, L Durante, E Gaudiano, C Masciandaro, S Pozzi, S Ferrara, GB TI The HLA-B*2709 subtype in a patient with undifferentiated spondarthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Letter ID ANKYLOSING-SPONDYLITIS; HLA-B27; SUSCEPTIBILITY C1 Osped S Carlo, Serv Reumatol, Rheumat Dis Unit, I-85100 Potenza, Italy. Ca Foncello Hosp, Blood Bank, Tissue Typing Lab, Treviso, Italy. Matera Hosp, HLA Typing Serv, Matera, Italy. Natl Canc Inst, Adv Biotechnol Ctr, Genoa, Italy. RP Olivieri, I (reprint author), Osped S Carlo, Serv Reumatol, Rheumat Dis Unit, I-85100 Potenza, Italy. NR 10 TC 15 Z9 16 U1 0 U2 0 PU BRITISH MED JOURNAL PUBL GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD AUG PY 2000 VL 59 IS 8 BP 654 EP 655 PG 2 WC Rheumatology SC Rheumatology GA 341HZ UT WOS:000088586100017 PM 10991760 ER PT J AU Walsh, TJ Jackson, AJ Lee, JW Amantea, M Sein, T Bacher, J Zech, L AF Walsh, TJ Jackson, AJ Lee, JW Amantea, M Sein, T Bacher, J Zech, L TI Dose-dependent pharmacokinetics of amphotericin B lipid complex in rabbits SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article AB Amphotericin B lipid complex (ABLC) was recently approved by the Food and Drug Administration for treatment of patients with invasive fungal infections who are intolerant of or refractory to conventional amphotericin B therapy. Little is known, however, about the pharmacokinetics of this new antifungal compound. We therefore investigated the pharmacokinetics of ABLC in comparison with those of conventional desoxycholate amphotericin B (DAmB) in rabbits. The pharmacokinetics of DAmB in a rabbit model were similar to those previously reported in humans. The pharmacokinetics of ABLC differed substantially from those of DAmB. Plasma amphotericin B levels following ABLC administration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DAmB model by (i) a dose- and time-dependent uptake and return between the plasma compartment and apparent cellular components of the blood-sediment compartment and (ii) time-dependent tissue uptake and return to plasma from serially connected compartments. Following infusion of ABLC, there was a nonlinear uptake into the apparent cellular components of the blood-sediment compartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The transfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution back to the plasma. The study describes a detailed model of the pharmacokinetics of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue. C1 NCI, Mycol Unit, NIH, Bethesda, MD 20892 USA. NCI, Immunocompromised Host Sect, NIH, Bethesda, MD 20892 USA. NCI, Math Biol Lab, NIH, Bethesda, MD 20892 USA. NIH, Vet Resource Program, Bethesda, MD 20892 USA. US FDA, Ctr Drug Evaluat & Res, Div Bioequivalence, Rockville, MD 20857 USA. RP Walsh, TJ (reprint author), NCI, Mycol Unit, NIH, Bldg 10,Room BN240, Bethesda, MD 20892 USA. NR 18 TC 17 Z9 17 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2000 VL 44 IS 8 BP 2068 EP 2076 DI 10.1128/AAC.44.8.2068-2076.2000 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 336NB UT WOS:000088308200010 PM 10898677 ER PT J AU Jordan, MK Polis, MA Kelly, G Narang, PK Masur, H Piscitelli, SC AF Jordan, MK Polis, MA Kelly, G Narang, PK Masur, H Piscitelli, SC TI Effects of fluconazole and clarithromycin on rifabutin and 25-O-desacetylrifabutin pharmacokinetics SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INFECTED PATIENTS; PLASMA AB Ten human immunodeficiency virus-infected patients were given rifabutin in addition to fluconazole and clarithromycin. There was a 76% increase in the area under the concentration-time curve of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together with rifabutin. Patients should be monitored for adverse effects of rifabutin administered concomitantly with clarithromycin and/or fluconazole. C1 NIAID, NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NIAID, NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. NIAID, NIH, Immunoregulat Lab, Bethesda, MD 20892 USA. Pharmacia & Upjohn Inc, Kalamazoo, MI 49001 USA. RP Piscitelli, SC (reprint author), NIAID, NIH, Ctr Clin, Dept Pharm, Bldg 10,Room 1N257, Bethesda, MD 20892 USA. OI Polis, Michael/0000-0002-9151-2268 NR 10 TC 11 Z9 12 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD AUG PY 2000 VL 44 IS 8 BP 2170 EP 2172 DI 10.1128/AAC.44.8.2170-2172.2000 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 336NB UT WOS:000088308200026 PM 10898693 ER PT J AU Hoque, ATMS Sedelnikova, OA Luu, AN Swaim, WD Panyutin, IG Baum, BJ AF Hoque, ATMS Sedelnikova, OA Luu, AN Swaim, WD Panyutin, IG Baum, BJ TI Use of polyethylenimine-adenovirus complexes to examine tripler formation in intact cells SO ANTISENSE & NUCLEIC ACID DRUG DEVELOPMENT LA English DT Article ID HELIX-FORMING OLIGONUCLEOTIDES; MAMMALIAN-CELLS; TRANSCRIPTION ELONGATION; LABELED OLIGONUCLEOTIDES; EPITHELIAL-CELLS; GENE-EXPRESSION; IN-VITRO; DNA; INHIBITION; I-125 AB Tripler-forming oligonucleotides (TFOs) show potential for sequence-specific DNA binding and inhibition of gene expression. We have applied this antigene strategy using a TFO incorporating an Auger-emitting radionucleotide, I-125, to study the production of double-strand breaks (dsb) in the rat aquaporin 5 (rAQP5) cDNA, I-125-TFO bound to the pCMVrAQP5 plasmid in vitro in a dose-dependent manner and formed stable triplexes up to 65 degrees C and in the presence of 140 mM KCl. Further, I-125-TFO resulted in a predictable dsb when analyzed by Southern hybridization. To deliver TFOs to epithelial cells, we employed I-125-TFO-polyethyleneimine-adenovirus (I-125-TFO-PEI-Ad) complexes. We hypothesized that these complexes would take advantage of adenoviral characteristics to transfer I-125-TFO to the cell nucleus. Adenovirus-containing complexes brought about greater uptake and nuclear localization of TFOs compared with delivery with I-125-TFO-PEI complexes alone. No significant degradation of I-125-TFO was found after delivery into cells using PEI-Ad complexes and freezing and thawing. We next used PEI-Ad complexes to deliver I-125-TFO and pCMVrAQP5 separately to epithelial cells to determine if triplexes can form de novo within cells, resulting in the specific dsb in the rAQP5 cDNA, After delivery, cell pellets were stored at -80 degrees C for more than 60 days. Thereafter, plasmid DNA was isolated from cells and analyzed for dsb by Southern hybridization, However, none were detected, We conclude that under the experimental conditions employed, effective triplexes, with I-125-TFO and pCMVrAQP5, do not form de novo inside cells. C1 NIDCR, GTTB, NIH, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Cellular Imaging Core Facil, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, GTTB, NIH, Bldg 10,Room 1N113,MSC-1190, Bethesda, MD 20892 USA. NR 37 TC 2 Z9 3 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1087-2906 J9 ANTISENSE NUCLEIC A JI Antisense Nucleic Acid Drug Dev. PD AUG PY 2000 VL 10 IS 4 BP 229 EP 241 DI 10.1089/108729000421411 PG 13 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 348FC UT WOS:000088974000001 PM 10984117 ER PT J AU Sawyer, LA AF Sawyer, LA TI Antibodies for the prevention and treatment of viral diseases SO ANTIVIRAL RESEARCH LA English DT Review DE antibodies; monoclonal antibodies; antiviral; immune globulin; therapy; prophylaxis ID RESPIRATORY SYNCYTIAL VIRUS; HUMANIZED MONOCLONAL-ANTIBODY; B IMMUNE GLOBULIN; HEPATITIS-C VIRUS; ORTHOTOPIC LIVER-TRANSPLANTATION; HIGH-RISK INFANTS; PASSIVE-IMMUNIZATION; INFECTIOUS-DISEASES; YOUNG-CHILDREN; MARROW TRANSPLANTATION AB This paper reviews current use and evolving role of polyclonal and monoclonal antibody products for the prevention and treatment of viral diseases. Antibodies continue to be indicated for prophylaxis either prior to an anticipated exposure especially in situations of travel, or more commonly following an exposure. The predominant indication for use of antibody products is to prevent infection. With the availability of vaccines for the prevention of chickenpox, hepatitis A, hepatitis B, measles, rabies and smallpox, the role of passive immunization is reserved for susceptible individuals and those at high risk for complications of infection. Risks of transmission of infections associated with use of human plasma-derived products have been reduced by improvements in donor screening and virus removal and inactivation procedures. An additional safety concern has been addressed by the removal of thimerosal as a preservative. Within the last 5 years, two antibodies have been licensed for a viral indication, RespiGam(TM) and Synagis(TM) both for prevention of respiratory syncytial virus infection. RespiGam(TM) is a human plasma derived antibody and Synagis(TM) is a humanized monoclonal antibody, the first such antibody to be licensed for an infectious disease indication. CytoCam(R) for prevention of cytomegalovirus infection in kidney transplant patients has recently been granted an expanded indication to include use in lung, liver, pancreas and heart transplant patients. As the use of therapeutics becomes more sophisticated, researchers may find better ways of using antibody products. (C) 2000 Published by Elsevier Science B.V. C1 NIAID, Virol Branch, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Sawyer, LA (reprint author), NIAID, Virol Branch, Div Microbiol & Infect Dis, NIH, 6700B Rockledge Dr,MSC-7630, Bethesda, MD 20892 USA. NR 116 TC 88 Z9 94 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD AUG PY 2000 VL 47 IS 2 BP 57 EP 77 DI 10.1016/S0166-3542(00)00111-X PG 21 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 354DA UT WOS:000089313500001 PM 10996394 ER PT J AU Glushakova, S Dubrovsky, L Grivel, JC Haffar, O Bukrinsky, M AF Glushakova, S Dubrovsky, L Grivel, JC Haffar, O Bukrinsky, M TI Small molecule inhibitor of HIV-1 nuclear import suppresses HIV-1 replication in human lymphoid tissue ex vivo: a potential addition to current anti-HIV drug repertoire SO ANTIVIRAL RESEARCH LA English DT Article DE nuclear import inhibitor; lymphoid tissue; histoculture; reverse transcriptase ID VIRUS-REPLICATION; T-CELLS; IN-VIVO; INFECTION; TYPE-1; HISTOCULTURES; LYMPHOCYTES; MACROPHAGES; CNI-H0294; DYNAMICS AB Despite recent progress in anti-HIV therapy, which has to do mainly with introduction of protease inhibitors into clinical practice, drug toxicity and emergence of drug-resistant isolates during the long-term treatment of the patients necessitates search for new drugs that can be added to currently used components of a multi-drug cocktail in highly active anti-retroviral therapy (HAART). Recently, we described a class of arylene bis(methylketone) compounds that inhibit nuclear import of HIV-1 pre-integration complexes and suppress viral replication in macrophages and PBMC in vitro. In this report, we demonstrate that one of these compounds, CNI-H1194, inhibited HIV-1 replication in primary lymphoid tissue ex vivo. The compound did not antagonize the activity of currently used anti-HIV drugs that inhibit viral reverse transcriptase or protease. These results suggest that arylene bis(methylketone) compounds might be a valuable addition to HAART. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Picower Inst Med Res, Manhasset, NY 11030 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Int Therapeut Inc, Seattle, WA 98122 USA. RP Bukrinsky, M (reprint author), Picower Inst Med Res, 350 Community Dr, Manhasset, NY 11030 USA. FU NIAID NIH HHS [R01 AI 40386] NR 20 TC 8 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD AUG PY 2000 VL 47 IS 2 BP 89 EP 95 DI 10.1016/S0166-3542(00)00093-0 PG 7 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 354DA UT WOS:000089313500003 PM 10996396 ER PT J AU Toro, JR Wood, LV Patel, NK Turner, ML AF Toro, JR Wood, LV Patel, NK Turner, ML TI Topical cidofovir - A novel treatment for recalcitrant molluscum contagiosum in children infected with human immunodeficiency virus 1 SO ARCHIVES OF DERMATOLOGY LA English DT Article ID CONTROLLED TRIAL; REPLICATION; METABOLISM; AIDS C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Clin, Dept Pharm, NIH, Bethesda, MD 20892 USA. RP Toro, JR (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N-238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 15 TC 50 Z9 51 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD AUG PY 2000 VL 136 IS 8 BP 983 EP 985 DI 10.1001/archderm.136.8.983 PG 3 WC Dermatology SC Dermatology GA 343MD UT WOS:000088705400001 PM 10926733 ER PT J AU Toro, JR Beaty, M Sorbara, L Turner, ML White, J Kingma, DW Raffeld, M Jaffe, ES AF Toro, JR Beaty, M Sorbara, L Turner, ML White, J Kingma, DW Raffeld, M Jaffe, ES TI gamma delta T-cell lymphoma of the skin - A clinical, microscopic, and molecular study SO ARCHIVES OF DERMATOLOGY LA English DT Article ID DISTINCT CLINICOPATHOLOGICAL ENTITY; EPSTEIN-BARR-VIRUS; GENE REARRANGEMENT; HEMOPHAGOCYTIC SYNDROME; SUBCUTANEOUS TISSUE; HODGKINS-DISEASE; RECEPTOR; EXPRESSION; LEUKEMIA; IMMUNOGLOBULIN AB Background: Only a few cases of primary gamma delta cutaneous T-cell lymphoma (CTCL) have been reported. We encountered 3 cases of this rare condition. Objectives: To characterize gamma delta CTCLby clinical, microscopic, and molecular methods and to investigate the role of Epstein-Barr virus (EBV) infection in its pathogenesis. Design: Patients were evaluated by clinical examination. and biopsy specimens of lesional skin were examined by light microscopy and immunohistochemistry. Polymerase chain reaction amplification for T-cell receptor gamma gene rearrangements and in situ hybridization for EBV were performed on 3 biopsy specimens. Setting: National Institutes of Health, a tertiary referral center. Patients: Individuals with a clinical and histologic diagnosis of primary gamma delta CTCL. Outcome Measures: Clinical, light microscopic, and immunohistochemical features, and the presence of T-cell rearrangement and EBV RNA in biopsy specimens. Results: Patients exhibited multiple plaques, tumors, and/or subcutaneous nodules primarily distributed over the extremities, Individuals exhibited an aggressive clinical course with resistance to multiagent chemotherapy and radiation. Microscopic examination revealed epidermotropism in 2 cases, a dermal infiltrate in all 3 cases, and subcutaneous involvement in 1 case. Immunohistochemical studies showed the presence of CD3(+) TCR delta(+) in 3 patients, CD8(+) in 1, and CD4(+), CD20(+), CD56(+), and beta F1(+) in none. All 3 cases exhibited an activated cytotoxic T-cell phenotype positive for T-cell intracellular antigen 1, perforin, and granzyme B. A clonal T-cell receptor gamma chain gene rearrangement was detected in all 3 cases by polymerase chain reaction. In situ hybridization was negative for EBV sequences in all 3 cases. Conclusion: gamma delta Cutaneous T-cell lymphomas are EBV-negative lymphomas that express a mature cytotoxic phenotype and have an aggressive clinical behavior. C1 NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. NCI, Hematopathol Sect, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Toro, JR (reprint author), NCI, Dermatol Branch, NIH, Bldg 10,Room 12N-238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. NR 42 TC 84 Z9 91 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD AUG PY 2000 VL 136 IS 8 BP 1024 EP 1032 DI 10.1001/archderm.136.8.1024 PG 9 WC Dermatology SC Dermatology GA 343MD UT WOS:000088705400007 PM 10926739 ER PT J AU Siegel, KL AF Siegel, KL TI Beneficial effect of bilateral pallidotomy on gait is unproven - In reply SO ARCHIVES OF NEUROLOGY LA English DT Letter C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Rehabil Med, Biomech Lab, Bethesda, MD 20892 USA. RP Siegel, KL (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Rehabil Med, Biomech Lab, Bldg 10,Room 6S235,10 Med Ctr,MSC 1604, Bethesda, MD 20892 USA. RI Siegel, Karen Lohmann/B-5898-2008 NR 5 TC 0 Z9 0 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 AUG PY 2000 VL 57 IS 8 BP 1231 EP 1232 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 342PR UT WOS:000088654800023 ER PT J AU Styblo, M Del Razo, LM Vega, L Germolec, DR LeCluyse, EL Hamilton, GA Reed, W Wang, C Cullen, WR Thomas, DJ AF Styblo, M Del Razo, LM Vega, L Germolec, DR LeCluyse, EL Hamilton, GA Reed, W Wang, C Cullen, WR Thomas, DJ TI Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells SO ARCHIVES OF TOXICOLOGY LA English DT Article DE arsenic; toxicity; methylation; cell culture; liver; skin; lung; bladder; arsenate; arsenite; methylarsonic acid; methylarsonous acid; dimethylarsinic acid; dimethylarsinous acid ID IN-VITRO METHYLATION; DRINKING-WATER; ENZYMATIC METHYLATION; HUMAN HEPATOCYTES; CELLULAR UPTAKE; RABBIT LIVER; GLUTATHIONE; METABOLISM; ARSENATE; BINDING AB Biomethylation is considered a major detoxification pathway for inorganic arsenicals (iAs). According to the postulated metabolic scheme, the methylation of iAs yields methylated metabolites in which arsenic is present in both pentavalent and trivalent forms. Pentavalent mono- and dimethylated arsenicals are less acutely toxic than iAs. However, little is known about the toxicity of trivalent methylated species. In the work reported here the toxicities of iAs and trivalent and pentavalent methylated arsenicals were examined in cultured human cells derived from tissues that are considered a major site for iAs methylation (liver) or targets for carcinogenic effects associated with exposure to iAs (skin, urinary bladder, and lung). To characterize the role of methylation in the protection against toxicity of arsenicals, the capacities of cells to produce methylated metabolites were also examined. In addition to human cells, primary rat hepatocytes were used as methylating controls. Among the arsenicals examined, trivalent monomethylated species were the most cytotoxic in all cell types. Trivalent dimethylated arsenicals were at least as cytotoxic as trivalent iAs (arsenite) for most cell types. Pentavalent arsenicals were significantly less cytotoxic than their trivalent analogs. Among the cell types examined, primary rat hepatocytes exhibited the greatest methylation capacity for iAs followed by primary human hepatocytes, epidermal keratinocytes, and bronchial epithelial cells. Cells derived from human bladder did not methylate iAs. There was no apparent correlation between susceptibility of cells to arsenic toxicity and their capacity to methylate iAs. These results suggest that (1) trivalent methylated arsenicals, intermediary products of arsenic methylation, may significantly contribute to the adverse effects associated with exposure to iAs, and (2) high methylation capacity does not protect cells from the acute toxicity of trivalent arsenicals. C1 Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27599 USA. IPN, CINVESTAV, Dept Pharmacol & Toxicol, Environm Toxicol Sect, Mexico City 07738, DF, Mexico. Natl Inst Environm Hlth Sci, Environm Immunol Lab, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Pharm, Div Drug Delivery & Disposit, Chapel Hill, NC 27599 USA. Univ N Carolina, Ctr Environm Med & Lung Biol, Chapel Hill, NC 27599 USA. Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, Canada. US EPA, NHEERL, Expt Toxicol Div, Pharmacokinet Branch, Res Triangle Pk, NC 27711 USA. RP Styblo, M (reprint author), Univ N Carolina, Sch Med, Dept Pediat, CB 7220, Chapel Hill, NC 27599 USA. RI Vega, Libia/C-3391-2013; OI Vega, Libia/0000-0002-4993-5267; LeCluyse, Edward/0000-0002-2149-8990 NR 37 TC 584 Z9 604 U1 6 U2 96 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-5761 J9 ARCH TOXICOL JI Arch. Toxicol. PD AUG PY 2000 VL 74 IS 6 BP 289 EP 299 DI 10.1007/s002040000134 PG 11 WC Toxicology SC Toxicology GA 349ZA UT WOS:000089074500001 PM 11005674 ER PT J AU Langford, CA Talar-Williams, C Sneller, MC AF Langford, CA Talar-Williams, C Sneller, MC TI Use of methotrexate and glucocorticoids in the treatment of Wegener's granulomatosis - Long-term renal outcome in patients with glomerulonephritis SO ARTHRITIS AND RHEUMATISM LA English DT Article AB Objective. To determine the long-term renal outcome in patients with Wegener's granulomatosis (WG) and active glomerulonephritis who were treated with methotrexate (MTX) and glucocorticoids. Methods. An open-label, prospective standardized trial using weekly low-dose MTX and glucocorticoids for the treatment of WG was performed. Forty-two patients were enrolled into the study, of whom 21 had active glomerulonephritis as a disease manifestation. The mean pretreatment level of serum creatinine in the patients with glomerulonephritis was 1.4 mg/dl. The extent of renal function in these patients at the time of their last followup was subsequently examined. Results. Overall, 20 of 21 patients achieved renal remission. At 1 month and 6 months following study entry, the serum creatinine level in all patients either remained stable or improved. The 20 patients have now been followed up for a median time of 76 months (range 20-108 months). Only 2 patients have had a rise of >0.2 mg/dl in their creatinine level from the time of enrollment to the most recent followup examination. Of the remaining 18 patients, 12 have had stable renal function and 6 have had improvement in their creatinine levels by more than 0.2 mg/dl. Conclusion. In this study, the use of MTX and prednisone as initial therapy for patients with WG-related glomerulonephritis and a normal or near-normal level of serum creatinine was not associated with a long-term decline in renal function. C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Langford, CA (reprint author), NIAID, NIH, 10 Ctr Dr,MSC 1876,Bldg 10,Room 11B-13, Bethesda, MD 20892 USA. NR 9 TC 72 Z9 77 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 AUG PY 2000 VL 43 IS 8 BP 1836 EP 1840 DI 10.1002/1529-0131(200008)43:8<1836::AID-ANR20>3.0.CO;2-R PG 5 WC Rheumatology SC Rheumatology GA 342RT UT WOS:000088659500020 PM 10943874 ER PT J AU Kimball, AB Summers, RM Turner, M Dugan, EM Hicks, J Miller, FW Rider, LG AF Kimball, AB Summers, RM Turner, M Dugan, EM Hicks, J Miller, FW Rider, LG TI Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile dermatomyositis - Implications for diagnosis and therapy SO ARTHRITIS AND RHEUMATISM LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; VALIDATED DISEASE-ACTIVITY; DAMAGE INDEXES; MUSCLE; PANNICULITIS; MYOSITIS; SUBCUTIS AB Objective. To assess the utility of magnetic resonance imaging (MRI) of skin, subcutaneous tissue, and fascia in evaluating disease activity in juvenile dermatomyositis (DM). Methods. Short tau inversion recovery (STIR) MRI of the proximal thighs and buttocks, cutaneous assessment, and other measures of disease activity were prospectively obtained in 26 children meeting criteria for probable or definite juvenile DM. Also undergoing STIR MRI assessment were 8 subjects who were being evaluated for muscle disorders and who were not diagnosed as having juvenile DM. Results. Skin, subcutaneous, or fascial edema of the thighs and buttocks were seen on STIR MRI in up to 85% of juvenile DM patients at baseline evaluation compared with no more than 38% of the comparison group without juvenile DM. In juvenile DM, STIR MRI skin and subcutaneous edema scores correlated (r(s) = 0.51, P = 0.008), as did fascial and muscle edema scores (r(s) = 0.58, P = 0.002). Skin global disease activity scores correlated with MRI skin edema scores (r(s) = 0.41, P = 0.04), and serum aldolase levels correlated with both MRI skin and subcutaneous edema scores (r = 0.44 and 0.40, P = 0.03 and 0.05 respectively). The extent and severity of STIR MRI changes in the skin, subcutaneous tissue, and fascia were not predicted by most other measures of juvenile DM disease activity. Five juvenile DM patients with thigh MRI subcutaneous edema developed clinically apparent calcinosis at the same location within 9 months. Conclusion. Edema or inflammation in the skin, subcutaneous tissue, and fascia, found on STIR MRI, is common in juvenile DM patients and is often undetected by standard assessments. These MRI changes can precede the development of calcinosis. STIR MRI may be a useful adjunct for assessing disease activity and guiding the treatment of juvenile DM. C1 Natl Canc Inst, NIH, Bethesda, MD USA. Washington Hosp Ctr, Washington, DC 20010 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. US FDA, Bethesda, MD 20014 USA. RP Rider, LG (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Monoclonal Antibodies, Bldg 29B,Room 2G11,HFM-561,8800 Rockville Pike, Bethesda, MD 20892 USA. OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 NR 24 TC 65 Z9 71 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 AUG PY 2000 VL 43 IS 8 BP 1866 EP 1873 DI 10.1002/1529-0131(200008)43:8<1866::AID-ANR24>3.0.CO;2-6 PG 8 WC Rheumatology SC Rheumatology GA 342RT UT WOS:000088659500024 PM 10943878 ER PT J AU Sihver, W Nordberg, A Langstrom, B Mukhin, AG Koren, AO Kimes, AS London, ED AF Sihver, W Nordberg, A Langstrom, B Mukhin, AG Koren, AO Kimes, AS London, ED TI Development of ligands for in vivo imaging of cerebral nicotinic receptors SO BEHAVIOURAL BRAIN RESEARCH LA English DT Review DE nicotinic receptor ligands; brain imaging; positron emission tomography; single photon emission computed tomography neurodegenerative disorders ID POSITRON-EMISSION-TOMOGRAPHY; RAT-BRAIN MEMBRANES; ACETYLCHOLINE-RECEPTORS; IN-VIVO; BINDING-SITES; ALZHEIMERS-DISEASE; CHOLINERGIC RECEPTORS; HIGH-AFFINITY; REGIONAL DISTRIBUTION; RHESUS-MONKEY AB Nicotinic acetylcholine receptors (nAChRs) mediate a variety of brain functions. Findings from postmortem studies and clinical investigations have implicated them in the pathophysiology and treatment of Alzheimer's and Parkinson's diseases and other CNS disorders (e.g. Tourette's syndrome, epilepsy, nicotine dependence). Therefore, it ultimately might be useful to image nAChRs noninvasively for diagnosis, for studies on how changes in nAChRs might contribute to cerebral disorders, for development of therapies targeted at nAChRs, and to monitor the effects of such treatments. To date, only (S)-(-)-nicotine, radiolabeled with C-11, has been used for external imaging of nAChRs in human subjects. Since this radiotracer presents drawbacks, new ligands, with more favorable properties, have been synthesized and tested. Three general classes of compounds, namely, nicotine and its analogs, epihatidine and related compounds, and 3-pyridyl ether compounds, including A-85380, have been evaluated. Analogs of A-85380 appear to be the most promising candidates because of their low toxicity and high selectivity for the alpha 4 beta 2 subtype of nAChRs. (C) 2000 Elsevier Science B.V. All rights reserved. C1 Huddinge Univ Hosp, Karolinska Inst, Dept Med Pharmacol, Div Mol Neuropharmacol, S-14186 Huddinge, Sweden. Huddinge Univ Hosp, Karolinska Inst, Div Mol Neuropharmacol, Dept Clin Neurosci Occupat Therapy & Elderly Care, S-14186 Huddinge, Sweden. Univ Uppsala, PET Ctr, Inst Chem, S-75185 Uppsala, Sweden. NIDA, Brain Imaging Ctr, NIH, Baltimore, MD 21224 USA. RP Sihver, W (reprint author), Huddinge Univ Hosp, Karolinska Inst, Dept Med Pharmacol, Div Mol Neuropharmacol, B84, S-14186 Huddinge, Sweden. NR 118 TC 70 Z9 70 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD AUG PY 2000 VL 113 IS 1-2 BP 143 EP 157 DI 10.1016/S0166-4328(00)00209-6 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 338VR UT WOS:000088444400016 PM 10942041 ER PT J AU Chiariello, M Gomez, E Gutkind, JS AF Chiariello, M Gomez, E Gutkind, JS TI Regulation of cyclin-dependent kinase (Cdk) 2 Thr-160 phosphorylation and activity by mitogen-activated protein kinase in late G(1) phase SO BIOCHEMICAL JOURNAL LA English DT Article DE Cdk-activating kinase; cell-cycle control; MEK inhibitors; PDGF ID CELL-CYCLE; GROWTH-FACTOR; IN-VIVO; INHIBITOR; RAS; P27(KIP1); PATHWAY; FIBROBLASTS; CAK; D1 AB Mitogen-activated protein (MAP) kinases, p42(MAPK) and p44(MAPK), are central components of growth-promoting signalling pathways. However, how stimulation of MAP kinases culminates in cell-cycle progression is still poorly understood. Here we show that mitogenic stimulation of NIH 3T3 cells causes a sustained activation of MAP kinases, which lasts until cells begin progressing through the G(1)/S boundary. Furthermore, we observed that disruption of the MAP-kinase pathway with a selective MEK (MAP kinase/extracellular-signal-regulated protein kinase kinase) inhibitor, PD98059, prevents the activation of cyclin-dependent kinase (Cdk) 2 and DNA synthesis, even when added during late G(1) phase, once the known mechanisms by which MAP kinase controls G(1) progression, accumulation of G(1) cyclins and degradation of Cdk inhibitors have already taken place. Moreover, we provide evidence indicating that MAP kinases control Cdk2 Thr-160 activating phosphorylation and function, possibly by regulating the activity of a Cdk-activating kinase, thus promoting the re-initiation of DNA synthesis. These findings suggest the existence of a novel mechanism whereby signal-transducing pathways converging on MAP kinases can affect the cell-cycle machinery and, ultimately, participate in cell-growth control. C1 Natl Inst Dental & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dental & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 9000 Rockville Pike,Bldg 30,Room 211, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009; OI Chiariello, Mario/0000-0001-8434-5177 NR 41 TC 35 Z9 35 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 1 PY 2000 VL 349 BP 869 EP 876 PN 3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343QA UT WOS:000088712000026 PM 10903150 ER PT J AU Harper, JL Daly, JW AF Harper, JL Daly, JW TI Effect of calmidazolium analogs on calcium influx in HL-60 cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE calcium influx and release; calmidazolium; miconazole; phosphodiesterase; capacitative calcium influx; calmodulin ID MUSCLE SARCOPLASMIC-RETICULUM; IN-VITRO; CALMODULIN; PHOSPHODIESTERASE; INHIBITORS; RELEASE; CHANNELS; ENZYMES AB The structure-activity relationships of calmidazolium analogs with respect to intracellular calcium levels were investigated in HL-60 cells. Quaternized derivatives of miconazole and clotrimazole, known inhibitors of store-operated calcium (SOC) channels, were synthesized. The quaternary N-methyl derivatives of miconazole (3) and clotrimazole (6) had no effect on intracellular calcium levels, alone or after elevation of calcium induced by ATP. Calmidazolium alone induced a large increase in intracellular calcium levels in HL-60 cells (EC50 3 mu M) Similar effects were observed for miconazole derivatives 1 (EC50 15 mu M) and 2 (EC50 10 mu M), wherein the diphenylmethyl group in calmidazolium was replaced by a 3,5-difluorobenzyl or cyclohexylmethyl group, respectively. The analogous clotrimazole derivatives 4 and 5 had no effect on intracellular calcium levels. The elevation of calcium levels by calmidazolium, 1, and 2 appears to be comprised of a calcium release component from inositol trisphosphate (IP3)-sensitive stores followed by a large calcium influx component. Calcium influx was greater than that normally observed due to depletion of IP3-sensitive calcium stores and activation of SOC channels. In addition, only a small component of the calmidazolium-elicited influx was inhibited by the SOC channel blocker miconazole. Thus, certain quaternized imidazoles substituted with large residues at both nitrogens of the imidazole ring caused both release and influx of calcium, the latter in part through SOC channels but mainly through an undefined cationic channel. Quaternized imidazoles, unlike the parent nonquaternary imidazole miconazole, did not block SOC channels. Inhibitory effects on calmodulin-activated phosphodiesterase did not correlate with effects on calcium release and influx. BIOCHEM PHARMACOL 60;3:317-324, 2000. (C) 2000 Elsevier Science Inc. C1 NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Bldg 8,Rm 1A17, Bethesda, MD 20892 USA. NR 20 TC 17 Z9 17 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 1 PY 2000 VL 60 IS 3 BP 317 EP 324 DI 10.1016/S0006-2952(00)00349-X PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 326BD UT WOS:000087711300003 PM 10856426 ER PT J AU Wolffe, AP Urnov, FD Guschin, D AF Wolffe, AP Urnov, FD Guschin, D TI Co-repressor complexes and remodelling chromatin for repression SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Colloquium on Steroid Receptor Co-Activators and the Remodelling of Chromatin CY APR 11-13, 2000 CL UNIV LEEDS, LEEDS, ENGLAND HO UNIV LEEDS DE histone deacetylase; nuclear hormone receptor; transcriptional repression ID THYROID-HORMONE RECEPTOR; HISTONE DEACETYLASE; TRANSCRIPTIONAL REPRESSION; NUCLEOSOMAL DNA; POSITIVE ROLE; N-COR; ACETYLATION; BINDING; METHYLATION; DISRUPTION AB Recent progress identifies targeted chromatin remodelling by co-repressor complexes as being an integral component of transcriptional silencing. Here we discuss how chromatin structure and the basal transcriptional machinery are manipulated by the co-repressor complex containing the Mi-2 nucleosomal ATPase, the histone-binding protein RbAp48 and histone deacetylase and by the corepressor complex containing SIN3, RbAp48 and histone deacetylase. Remarkably, both of these complexes also contain methyl-CpG-binding proteins. This observation provides a molecular mechanism to integrate DNA methylation fully into gene control in vertebrates. C1 NICHHD, Mol Embryol Lab, NIH, Bethesda, MD 20892 USA. RP Wolffe, AP (reprint author), NICHHD, Mol Embryol Lab, NIH, Bldg 18T,Room 106, Bethesda, MD 20892 USA. NR 51 TC 47 Z9 47 U1 0 U2 2 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2000 VL 28 BP 379 EP 386 DI 10.1042/0300-5127:0280379 PN 4 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 349VY UT WOS:000089067300013 PM 10961924 ER PT J AU Hager, GL Fletcher, TM Xiao, N Baumann, CT Muller, WG McNally, JG AF Hager, GL Fletcher, TM Xiao, N Baumann, CT Muller, WG McNally, JG TI Dynamics of gene targeting and chromatin remodelling by nuclear receptors SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Colloquium on Steroid Receptor Co-Activators and the Remodelling of Chromatin CY APR 11-13, 2000 CL UNIV LEEDS, LEEDS, ENGLAND HO UNIV LEEDS DE glucocorticoid receptor; MMTV; nucleosome ID TUMOR VIRUS PROMOTER; GLUCOCORTICOID RECEPTOR; MMTV PROMOTER; NUCLEOSOME; TRANSCRIPTION; FRAMES; ENHANCEMENT; ACTIVATION; MECHANISM; POSITIONS AB Activation of the murine-mammary-tumour virus (MMTV) promoter by the glucocorticoid receptor (GR) is associated with a chromatin structural transition in the B nucleosome region of the viral long terminal repeat (LTR). We have reconstituted this nucleoprotein transition with chromatin assembled on MMTV LTR DNA with Drosophila embryo extracts, purified GR, and HeLa nuclear extract. Chromatin remodelling in vitro is ATP-dependent and maps to a region identical with that found in vivo. We demonstrate specific, glucocorticoid response element dependent, binding of purified GR to a large, multi-nucleosome MMTV chromatin array and show that GR-dependent chromatin remodelling is a multistep process. In the absence of ATP, GR binds to multiple sites on the chromatin array and inhibits nuclease access to GR recognition sites. On the addition of ATP, GR induces remodelling resulting in a large increase in access of enzymes to their sites within the transition region. These findings are complemented by studies in living cells; using a tandem array of MMTV-Ras reporter elements and a form of GR labelled with the green fluorescent protein, we have observed direct targeting of the receptor to response elements in live mouse cells. Whereas the ligand-activated receptor is associated with the MMTV promoter for observable periods, photobleaching experiments provide direct evidence that the hormone-occupied receptor undergoes rapid exchange between chromatin and the nucleoplasmic compartment. The results both in vitro and in vivo are consistent with a dynamic model ('hit and run') in which GR first binds to chromatin after ligand activation, recruits a remodelling activity and is then lost from the template. C1 NCI, Lab Receptor Biol & Gene Express, NIH, Gaithersburg, MD 20899 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,B602,41 Lib Dr, Gaithersburg, MD 20899 USA. NR 28 TC 24 Z9 25 U1 1 U2 3 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2000 VL 28 BP 405 EP 410 DI 10.1042/0300-5127:0280405 PN 4 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 349VY UT WOS:000089067300018 PM 10961929 ER PT J AU Brenneman, DE Spong, CY Gozes, I AF Brenneman, DE Spong, CY Gozes, I TI Protective peptides derived from novel glial proteins SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Colloquium on Neuropeptides - From Gene Regulation to Protein Processing CY APR 11-13, 2000 CL UNIV LEEDS, LEEDS, ENGLAND HO UNIV LEEDS DE activity-dependent neuroprotective protein; activity-dependent neurotrophic factor; astrocytes; cell death; vasoactive intestinal peptide ID VASOACTIVE-INTESTINAL-PEPTIDE; DEPENDENT NEUROTROPHIC FACTOR; ACTING NEUROPROTECTIVE PEPTIDE; NEURONS; CELLS AB In studying the mediators of VIP neurotrophism in the central nervous system? two glial proteins have been discovered. Both of these proteins contain short peptides that exhibit femtomolar potency in preventing neuronal cell death from a wide variety of neurotoxic substances. Extension of these peptides to models of oxidative stress or neurodegeneration in vivo have indicated significant efficacy in protection. These peptides, both as individual agents and in combination, have promise as possible protective agents in the treatment of human neurodegenerative disease and in pathologies involving oxidative stress. C1 NICHHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Sch Med, Dept Clin Biochem, IL-69978 Tel Aviv, Israel. RP Brenneman, DE (reprint author), NICHHD, Sect Dev & Mol Pharmacol, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NR 16 TC 20 Z9 22 U1 0 U2 1 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD AUG PY 2000 VL 28 BP 452 EP 455 DI 10.1042/0300-5127:0280452 PN 4 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 349VY UT WOS:000089067300027 PM 10961938 ER PT J AU Deng, CX Brodie, SG AF Deng, CX Brodie, SG TI Roles of BRCA1 and its interacting proteins SO BIOESSAYS LA English DT Review ID POLYMERASE-II HOLOENZYME; DNA-DAMAGE RESPONSE; CANCER-SUSCEPTIBILITY GENES; EARLY EMBRYONIC LETHALITY; MAMMARY EPITHELIAL-CELLS; TUMOR-SUPPRESSOR GENE; CENTROSOME AMPLIFICATION; IN-VIVO; TRANSCRIPTIONAL ACTIVATION; MEIOTIC CELLS AB Germline mutations of BRCA1 predispose women to breast and ovarian cancers. BRCA1 contains several functional domains that interact directly or indirectly with a variety of molecules, including tumor suppressors (p53, RE, BRCA2 and ATM), oncogenes (c-Myc, casein kinase II and E2F), DNA damage repair proteins (RAD50 and RAD51), cell-cycle regulators (cyclins and cyclin-dependent kinases), transcriptional activators and repressors (RNA polymerase II, RHA, histone deacetylase complex and CtlP) and others. Mounting evidence indicates that these physical associations are not artifacts; rather, BRCA1 is likely to serve as an important central component in multiple biological pathways that regulate cell-cycle progression, centrosome duplication, DNA damage repair, cell growth and apoptosis, and transcriptional activation and repression. This review examines our understanding of the significance of the interactions between BRCA1 and other proteins, through which BRCA1 maintains genome integrity and represses tumor formation. Published 2000 John Wiley & Sons, Inc. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 85 TC 213 Z9 217 U1 0 U2 13 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0265-9247 J9 BIOESSAYS JI Bioessays PD AUG PY 2000 VL 22 IS 8 BP 728 EP 737 PG 10 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 339RK UT WOS:000088491600006 PM 10918303 ER PT J AU Jamison, DC Thomas, JW Green, ED AF Jamison, DC Thomas, JW Green, ED TI ComboScreen facilitates the multiplex hybridization-based screening of high-density clone arrays SO BIOINFORMATICS LA English DT Article ID HUMAN-GENOME; CHROMOSOME; MAP AB Motivation: The construction of physical maps based on bacterial clones [e.g. bacterial artificial chromosomes (BACs)] is valuable for a number of molecular genetics applications, including the high-resolution mapping of genomic regions of interest and the identification of clones suitable for systematic sequencing A common approach for large-scale screening of bacterial clone libraries involves the hybridization of high-density arrays of immobilized, lysed colonies with collections of DNA probes. The use of a multiplex hybridization screening strategy, whereby pooled probes are analysed en masse, simplifies the effort by reducing the total number of parallel experiments required. However this approach generates large amounts of hybridization-based data that must be carefully analysed, assimilated, and disambiguated in a careful but efficient manner Results: To facilitate the screening of high-density clone arrays by a multiplex hybridization approach, Me have written a program called ComboScreen. This program provides an organizational framework and analytical tools required for the high-throughput hybridization screening of clone arrays with pools of probes. We have used this program extensively for constructing mouse sequence ready BAC contig maps. C1 Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Green, ED (reprint author), Natl Human Genome Res Inst, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NR 23 TC 8 Z9 9 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG PY 2000 VL 16 IS 8 BP 678 EP 684 DI 10.1093/bioinformatics/16.8.678 PG 7 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 375AL UT WOS:000165377300003 PM 11099254 ER PT J AU Becker, KG White, SL Muller, J Engel, J AF Becker, KG White, SL Muller, J Engel, J TI BBID: the biological biochemical image database SO BIOINFORMATICS LA English DT Article ID GENE-EXPRESSION; PATTERNS AB The Biological Biochemical Image Database is a WWW accessible relational database of archived images from research articles that describe regulatory pathways of higher eukaryotes. Pathway information is annotated and can be queried in the study of complex gene expression. In this way, complex regulatory pathways can be tested empirically in an efficient manner in the context of large-scale gene-expression systems. C1 NIA, DNA Array Unit, RRB, NIH, Baltimore, MD 21224 USA. NIA, NCTS, NIH, Baltimore, MD 21224 USA. RP Becker, KG (reprint author), NIA, DNA Array Unit, RRB, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. OI Becker, Kevin/0000-0002-6794-6656 NR 9 TC 16 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG PY 2000 VL 16 IS 8 BP 745 EP 746 DI 10.1093/bioinformatics/16.8.745 PG 2 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 375AL UT WOS:000165377300012 PM 11099263 ER PT J AU Sokolov, BP Tcherepanov, AA Haroutunian, V Davis, KL AF Sokolov, BP Tcherepanov, AA Haroutunian, V Davis, KL TI Levels of mRNAs encoding synaptic vesicle and synaptic plasma membrane proteins in the temporal cortex of elderly schizophrenic patients SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the Society-of-Biological-Psychiatry CY MAY 14-18, 1997 CL SAN DIEGO, CALIFORNIA SP Soc Biol Psychiat DE Schizophrenia; temporal cortex; synaptic proteins; gene expression; synaptic organization; mRNA ID SYNAPTOSOMAL-ASSOCIATED PROTEIN; MESSENGER-RNAS; ALZHEIMERS-DISEASE; PREFRONTAL CORTEX; SEQUENCE-ANALYSIS; PLANUM TEMPORALE; RT-PCR; EXPRESSION; ABNORMALITIES; SYNAPTOPHYSIN AB Background: Electron microscopy and biochemical studies indicate that developmental abnormalities in synaptic organization may be present in brains of schizophrenic patients. This study determined whether these synaptic abnormalities are reflected in differential or uniform alterations in the expression of various synaptic protein genes in the left superior temporal gyrus of schizophrenic patients. Methods: Levels of nRNAs encoding four synaptic vesicle proteins (synaptotagmin 1 [p65], rab3a, synaptobrevin 1, and synaptobrevin 2) and two synaptic plasma membrane proteins (syntaxin 1A and SNAP-25) were measured post-mortem in the left superior temporal gyrus from elderly (58-95 years) schizophrenic patients (n = 14) and age-matched control subjects (n = 9). Results: There were significant negative correlations between age and levels of synaptotagmin 1 (p65), rab3a, synaptobrevin 1, SNAP-25 and syntaxin 1A mRNAs in schizophrenic patients (-.692 < r < -.517, .003 < p < .030) but not in control subjects. Levels of all six synaptic mRNAs studied were increased in the younger (58-79 years) subgroup of schizophrenic patients compared to control subjects and older (80-95 years) subgroup of schizophrenic patients. Conclusions: That similar abnormalities were found for mRNAs encoding different synaptic vesicle and synaptic plasma membrane proteins suggests that they reflect overall neurodevelopmental abnormalities in synaptic connectivity in the temporal cortex of schizophrenic patients rather than changes in the number of synaptic vesicles per synapse or abnormalities in a specific synaptic function. Biol Psychiatry 2000;48:184-196 (C) 2000 Society of Biological Psychiatry. C1 NIDA, Mol Neurobiol Branch, NIH, Baltimore, MD 21224 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Sokolov, BP (reprint author), NIDA, Mol Neurobiol Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. FU NIH HHS [R2NH56083] NR 65 TC 58 Z9 60 U1 1 U2 2 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 AUG 1 PY 2000 VL 48 IS 3 BP 184 EP 196 DI 10.1016/S0006-3223(00)00875-1 PG 13 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 338VK UT WOS:000088443800001 PM 10924661 ER PT J AU Bauer, KS Lush, RM Rudek, MA Shih, C Sausville, E Figg, WD AF Bauer, KS Lush, RM Rudek, MA Shih, C Sausville, E Figg, WD TI A high-performance liquid chromatography method using ultraviolet and fluorescence detection for the quantitation of UCN-01, 7-hydroxystaurosporine, from human plasma and saliva SO BIOMEDICAL CHROMATOGRAPHY LA English DT Article ID ALPHA(1)-ACID GLYCOPROTEIN; ANTICANCER DRUG; BINDING AB UCN-01, 7-hydroxystaurosporine, is an antagonist of protein kinase C, as well as causing cell cycle arrest. We developed and validated an HPLC assay method for the quantitation of UCN-01. Plasma and saliva standard curves were prepared at concentrations ranging from 0.2 to 20.0 mu g/mL and 4.0 to 200.0 ng/mL, respectively. The sample preparation consisted of acetonitrile precipitation. Separation was accomplished on a phenyl column and a C-18 precolumn insert utilizing a gradient-profile consisting of ammonium acetate and acetonitrile. UV detection was set at 295 nm for UCN-01 and 323 nm for umbelliferone, the internal standard. For fluorescence detection, excitation occurred at 290 nm, while emission was at 400 nm. The retention times were around 4 min for umbelliferone and 9.1 for UCN-01. Inter- and intra-assay errors of accuracy were less than 7.0% and 10.7%, respectively, for the plasma standard curve and less than 7.1% and 6.7%, respectively, for the saliva standard curve. The recoveries of UCN-01 and umbelliferone from saliva were 81.4 +/- 0.9% and 106.3 +/- 10.2%, respectively. The recovery of UCN-01 from plasma was 97.9 +/- 7.1% and for umbelliferone was 103.3 +/- 2.3%. This method is suitable for quantifying UCN-01 in patient samples and further characterizing the clinical pharmacology of this compound. Published in 2000 by John Wiley & Sons, Ltd. 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 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. RI Figg Sr, William/M-2411-2016 NR 9 TC 12 Z9 12 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI W SUSSEX PA BAFFINS LANE CHICHESTER, W SUSSEX PO19 1UD, ENGLAND SN 0269-3879 J9 BIOMED CHROMATOGR JI Biomed. Chromatogr. PD AUG PY 2000 VL 14 IS 5 BP 338 EP 343 DI 10.1002/1099-0801(200008)14:5<338::AID-BMC993>3.0.CO;2-6 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA 346PJ UT WOS:000088880000011 PM 10960835 ER PT J AU Inoue, J Cui, YS Sakai, O Nakamura, Y Kogiso, H Kador, PF AF Inoue, J Cui, YS Sakai, O Nakamura, Y Kogiso, H Kador, PF TI Synthesis and aldose reductase inhibitory activities of novel N-nitromethylsulfonanilide derivatives SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article ID DIABETIC COMPLICATIONS; RAT LENS; SITE AB A novel series of 14 N-nitromethylsulfonanilide derivatives were synthesized and evaluated for their ability to inhibit recombinant aldose reductase. Computational docking simulations provided a good explanation for the observed structure-activity relationships. Kinetic analysis of (2-fluoro-5-methyl-N-methyl)-N-nitromethylsulfonanilide 11, one of the most potent compounds in this series with an IC50 = 0.35 mu M, showed uncompetitive inhibition. Subsequent in vitro culture studies of rat lenses with 11 indicated that this series of aldose reductase inhibitors are effective in either preventing or retarding sugar cataract formation associated with diabetes. (C) 2000 Elsevier Science Ltd. All rights reserved. C1 Senju Pharmaceut Co Ltd, Kobe Creat Ctr, Res Lab, Nishi Ku, Kobe, Hyogo 6512241, Japan. NEI, Lab Ocular Therapeut, NIH, Bethesda, MD 20892 USA. RP Cui, YS (reprint author), Senju Pharmaceut Co Ltd, Kobe Creat Ctr, Res Lab, Nishi Ku, 1-5-4 Murotani, Kobe, Hyogo 6512241, Japan. NR 22 TC 6 Z9 6 U1 0 U2 1 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 AUG PY 2000 VL 8 IS 8 BP 2167 EP 2173 DI 10.1016/S0968-0896(00)00158-9 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 345LR UT WOS:000088817900033 PM 11003161 ER PT J AU Vargas, J Alarcon, JM Rojas, E AF Vargas, J Alarcon, JM Rojas, E TI Displacement currents associated with the insertion of Alzheimer disease amyloid beta-peptide into planar bilayer membranes SO BIOPHYSICAL JOURNAL LA English DT Article ID SQUID GIANT-AXON; PRECURSOR PROTEIN; LIPID BILAYERS; SODIUM CONDUCTANCE; PORE FORMATION; CHANNELS; VOLTAGE; NEUROTOXICITY; CAPACITANCE; ACTIVATION AB The role of endogenous amyloid beta-peptides as causal factors of neurodegenerative diseases is largely unknown. We have previously reported that interactions between Alzheimer's disease A beta P[1-40] peptide in solution and planar bilayer membranes made from anionic phospholipids lead to the formation of cation-selective channels. We now find and report here that the spontaneous insertion of free A beta P[1-40] across the bilayer can be detected as an increase in bilayer capacity. To this end we recorded the displacement currents across planar bilayers (50 mM KCI on both sides) in response to sudden displacements of the membrane potential, from -300 to 300 mV in 20-mV increments. To monitor the A beta P[1-40]-specific displacement currents, we added A beta P[1-40] (1-5 mu M) to the solution on either side of the membrane and noted that the direction of the displacement current depended on the side with A beta P[1-40], The size of the A beta P[1-40]-specific charge displaced during a pulse was always equal to the charge returning to the original configuration after the pulse, suggesting that the dipole molecules are confined to the membrane. As a rule, the steady-state distribution of the A beta P[1-40]-specific charges within the bilayer could be fit by a Boltzmann distribution. The potential at which the charges were found to be equally distributed (V-o) were similar to -135 mV (peptide added to the solution in the compartment electrically connected to earth) and 135 mV (peptide added to the solution connected to the input of the amplifier). The A beta P[1-40]-specific transfer of charge reached a maximum value (Q(max)) when the electrical potential of the side containing the amyloid beta-protein was taken to either -300 or 300 mV. For a circular membrane of 25-mu m radius (similar to 2000 mu m(2)), the total A beta P[1-40]-specific charge Q(max) was estimated as 55 fC, corresponding to some 170 e.c./mu m(2). Regardless of the side selected for the addition of A beta P[1-40], at V-o the charge displaced underwent an e-fold change for a similar to 27-mV change in potential. The effective valence (a) of the A beta P[1-40] dipole (i.e., the actual valence Z multiplied by the fraction of the electric field chi acting on the dipole) varied from 1 to 2 electronic charges. We also tested, with negative results, the amyloid peptide with the reverse sequence (A beta P[40-1]). These data demonstrate that A beta P[1-40] molecules can span the low dielectric domain of the bilayer, exposing charged residues (D-1, E-3, R-5, H-6, D-7, E-11, H-13, and H-14) to the electric field. Thus the A beta P[1-40] molecules in solution must spontaneously acquire suitable conformations (beta-pleated sheet) allowing specific interactions with charged phospholipids. Interestingly, the domain from residues 676 to 704 in the APP(751) is homologous with the consensus sequence for lipid binding found in other membrane proteins regulated by anionic phospholipids. C1 Sansum Med Res Inst, Santa Barbara, CA 93105 USA. NIDDK, Lab Biochem & Cell Biol, NIH, Bethesda, MD 20892 USA. Univ Chile, Fac Med, Inst Biomed Sci, Santiago 7, Chile. RP Rojas, E (reprint author), Sansum Med Res Inst, 2219 Bath St, Santa Barbara, CA 93105 USA. NR 43 TC 29 Z9 30 U1 0 U2 2 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 2000 VL 79 IS 2 BP 934 EP 944 PG 11 WC Biophysics SC Biophysics GA 340YF UT WOS:000088563700030 PM 10920024 ER PT J AU La Penna, G Fausti, S Perico, A Ferretti, JA AF La Penna, G Fausti, S Perico, A Ferretti, JA TI Smoluchowski dynamics of the vnd/NK-2 homeodomain from Drosophila melanogaster: Second-order maximum correlation approximation SO BIOPOLYMERS LA English DT Article DE diffusion theory; molecular dynamics; vnd/NK-2 homeodomain ID MOLECULAR-DYNAMICS; RELAXATION MEASUREMENTS; NK-2 HOMEODOMAIN; DNA; PROTEINS; SIMULATION; POLYMERS; PEPTIDE; BINDING; SYSTEM AB The mode coupling diffusion theory is applied to the derivation of local dynamics in proteins in solution. The rotational dynamics of the bonds along the protein sequence are calculated and compared to the experimentally measured nmr N-15 spin-lattice relaxation time T-1, at 36.5, 60.8, and 81.1 MHz of the vnd/NK-2 homeodomain from Drosophila melanogaster. The starting point for the calculations is the experimental three-dimensional solution structure of the homeodomain determined by multidimensional nmr spectroscopy. The higher order mode-coupling computations are compared also with the recently published first-order approximation calculations. The more accurate calculations improve substantially the first-order ORZLD calculations and show that the role of the strength of the hydrodynamic interactions becomes crucial to fix the order of magnitude of the rotational dynamics for these very compact molecules characterized by partial screening of the internal atoms to water. However, the relative mobility of the bonds along the sequence and the differential fluctuations depend only weakly on the hydrodynamic strength but strongly on the geometry of the three-dimensional structure and on the statistics incorporated into the theory. Both rigid and fluctuating dynamic models are examined, with fluctuations evaluated using molecular dynamics simulations. The comparison with nmr data shows that mode coupling diffusion accounts for the T-1 relaxation pattern at low frequency where the rotational tumbling dominates. An important contribution of internal motions in the nanosecond time scale is seen at high frequencies and is discussed in terms of diffusive concepts. (C) 2000 John Wiley & Sons, Inc. C1 Natl Res Council, Ist Studi Chim Fis Macromol Sintet & Nat, I-16149 Genoa, Italy. Univ Genoa, Dipartimento Chim & Chim Ind, I-16146 Genoa, Italy. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP La Penna, G (reprint author), Natl Res Council, Ist Studi Chim Fis Macromol Sintet & Nat, Via De Marini 6, I-16149 Genoa, Italy. RI La Penna, Giovanni/E-5241-2011; OI La Penna, Giovanni/0000-0002-8619-4867; Penna, Maria Pietronilla/0000-0002-0982-3893 NR 37 TC 20 Z9 20 U1 1 U2 4 PU JOHN WILEY & SONS INC PI NEW YORK PA 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD AUG PY 2000 VL 54 IS 2 BP 89 EP 103 DI 10.1002/1097-0282(200008)54:2<89::AID-BIP2>3.0.CO;2-C PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 323TD UT WOS:000087580300002 PM 10861370 ER PT J AU Lachtermacher, MBR Seuanez, HN Moser, HW Smith, KD AF Lachtermacher, MBR Seuanez, HN Moser, HW Smith, KD TI One-step multiplex PCR strategy for identification of mutations by SSCP and DNA sequencing SO BIOTECHNIQUES LA English DT Article ID GENE C1 Kennedy Krieger Inst, Baltimore, MD USA. Univ Fed Fluminense, Niteroi, RJ, Brazil. Inst Nacl Canc, Rio De Janeiro, Brazil. Univ Fed Rio de Janeiro, Rio De Janeiro, Brazil. Johns Hopkins Sch Med, Baltimore, MD USA. RP Lachtermacher, MBR (reprint author), NCI, Frederick Canc Res & Dev Ctr, Lab Genom Divers, Frederick, MD 21702 USA. NR 6 TC 3 Z9 3 U1 0 U2 0 PU EATON PUBLISHING CO PI NATICK PA 154 E. CENTRAL ST, NATICK, MA 01760 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 2000 VL 29 IS 2 BP 234 EP + PG 2 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343AK UT WOS:000088679400014 PM 10948421 ER PT J AU Panoskaltsis-Mortari, A Strieter, RM Hermanson, JR Fegeding, KV Murphy, WJ Farrell, CL Lacey, DL Blazar, BR AF Panoskaltsis-Mortari, A Strieter, RM Hermanson, JR Fegeding, KV Murphy, WJ Farrell, CL Lacey, DL Blazar, BR TI Induction of monocyte- and T-cell-attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation SO BLOOD LA English DT Article ID VERSUS-HOST DISEASE; HISTOCOMPATIBILITY COMPLEX BARRIER; TOTAL-BODY IRRADIATION; AIRWAY HYPERREACTIVITY; FAMILY CHEMOKINES; LYMPHOCYTES-T; BETA-FAMILY; MICE; CYCLOPHOSPHAMIDE; CHEMOATTRACTANT AB Idiopathic pneumonia syndrome (IPS) is a significant complication following bone marrow transplantation (BMT), We have developed a murine model in which severe IFS is induced by pre-BMT conditioning and allogeneic T cells and is characterized by the recruitment of host monocytes and donor T cells into the lung by day 7 post-BMT. Chemokines regulate cellular recruitment and the migration of cells into inflammatory lesions. In this study, we examined the profiles of chemokines produced locally in the lung (parenchyma and bronchoalveolar lavage fluid) and systemically (serum) during the generation of IFS in the peri-BMT period. Protein and messenger RNA (mRNA) levels of CC chemokines (monocyte/lymphocyte attractants), especially monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1 alpha, RANTES (regulated upon activation normal T-cell expressed and secreted), and C10, were preferentially induced in the lung by day 7 postallogeneic BMT. In addition, there was an increase in mRNA for IP-10 (a monocyte and Th1-cell chemoattractant). The CXC chemokines MIP-2 and KC, known neutrophil attractants, were moderately elevated. Far the most part, these increases in chemokines were dependent on the coinfusion of allogeneic T cells with the BM inoculum, Ribonuclease protection assay end in situ hybridization analyses post-BMT showed that the lung was a major producer of MCP-1, a potent inducer of monocyte chemotaxis, Increases in MCP-1 levels in the lung preceded host APC influx whereas MIP-1 alpha levels accompanied donor T-cell infiltration. In summary, we have shown that monocyte- and T-cell-attracting chemokines are associated with monocyte and T-cell recruitment during IFS. (C) 2000 by The American Society of Hematology. C1 Univ Minnesota, Dept Pediat, Div Heme Onc, Blood & Marrow Transplant Program, Minneapolis, MN 55455 USA. Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. Univ Calif Los Angeles, Sch Med, Dept Med, Div Pulm & Crit Care Med, Los Angeles, CA 90024 USA. Walter Reed Army Med Ctr, Dept Pathol, Washington, DC USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD USA. Amgen Inc, Thousand Oaks, CA 91320 USA. RP Panoskaltsis-Mortari, A (reprint author), Univ Minnesota, Dept Pediat, Div Heme Onc, Blood & Marrow Transplant Program, Box 366 Mayo,420 Delaware St SE, Minneapolis, MN 55455 USA. FU NHLBI NIH HHS [HL 55209] NR 39 TC 37 Z9 37 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2000 VL 96 IS 3 BP 834 EP 839 PG 6 WC Hematology SC Hematology GA 337ZQ UT WOS:000088394000007 PM 10910893 ER PT J AU Howard, OMZ Dong, HF Shirakawa, AK Oppenheim, JJ AF Howard, OMZ Dong, HF Shirakawa, AK Oppenheim, JJ TI LEC induces chemotaxis and adhesion by interacting with CCR1 and CCR8 SO BLOOD LA English DT Article ID BETA-CHEMOKINE TCA3; CHROMOSOME 17Q11.2; MOLECULAR-CLONING; T-LYMPHOCYTES; CUTTING EDGE; RECEPTOR; CELLS; RANTES; MIP-1-ALPHA; AGONIST AB Liver-expressed chemokine (LEC) is an unusually large CC chemokine, which is also known as LMC, HCC-4, NCC-4, and CCL16, Previously, LEC was shown to induce leukocyte migration but the responsible signaling receptors were not characterized, We report chemotaxis and competitive binding studies that show LEC binds to and activates CCR1 and CCR8 transfected HEK-293 cells, LEC induced maximal migration of CCR1 and CCR8 transfected cells at 89.3 nmol/L and cell adhesion at 5.6 nmol/L, The molar concentration of LEC required to induce maximum cell migration is 20- to 200-fold greater than that required for RANTES or 1309, respectively. All 3 chemokines induced maximal static adhesion at 5 to 7 nmol/L. A neutralizing polyclonal antibody to LEC was developed to demonstrate that the unusually high concentration of LEC required to induce chemotaxis was a property of LEC end not as a result of an irrelevant protein contamination. This study suggests that LEC may be a more effective inducer of cell adhesion than cell migration. (C) 2000 by The American Society of Hematology. C1 NCI, Frederick Canc Res & Dev Ctr, Div Basic Sci, Lab Mol Immunoregulat,Intramural Res Support Prog, Frederick, MD USA. RP Howard, OMZ (reprint author), POB B, Frederick, MD 21702 USA. RI Howard, O M Zack/B-6117-2012 OI Howard, O M Zack/0000-0002-0505-7052 FU NCI NIH HHS [N01-CO-56000] NR 38 TC 32 Z9 33 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2000 VL 96 IS 3 BP 840 EP 845 PG 6 WC Hematology SC Hematology GA 337ZQ UT WOS:000088394000008 PM 10910894 ER PT J AU Altarescu, G Schiffmann, R Parker, CC Moore, DF Kreps, C Brady, RO Barton, NW AF Altarescu, G Schiffmann, R Parker, CC Moore, DF Kreps, C Brady, RO Barton, NW TI Comparative efficacy of dose regimens in enzyme replacement therapy of type I Gaucher disease SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE Gaucher type I; enzyme replacement therapy; treatment; metabolic disease; macrophage-targeted glucocerebrosidase ID CLINICAL-FEATURES; GLUCOCEREBROSIDASE; IMIGLUCERASE; ALGLUCERASE; DIAGNOSIS AB Gaucher disease is caused by a deficiency of P-glucocerebrosidase activity. The optimum dose and frequency of enzyme replacement therapy for Gaucher patients have not been determined. We set to compare the therapeutic effects of initiating treatment with macrophage-targeted glucocerebrosidase at a high dose followed by progressive dose reductions with that produced by initial treatment at a low dose in patients with type I Gaucher disease. The study included two parts: (i) Twelve patients received every 2 weeks enzyme replacement therapy at 60 IU/kg body wt for 24 months followed by sequential dose reduction every 6 months to 30 and then to 15 IU/kg body wt. (ii) Thirty-two patients received enzyme replacement therapy at 10 IU/kg every 2 weeks for 12 months. Hematologic parameters and liver and spleen volume were monitored in all patients, All patients had intact spleens. In patients who were started on high-dose enzyme replacement therapy, hemoglobin, acid phosphatase, and organ volume improved or remained unchanged at the end of each dose reduction. Platelet count decreased significantly when the dose of enzyme was reduced from 30 to 15 IU/kg body wt. Initiation of therapy at a low dose led to a significant improvement in all measured parameters at the end of 1 year. We conclude that the minimal effective dose for the nonskeletal manifestations of Gaucher disease can be achieved either by initiating enzyme replacement therapy with a high dose followed by a stepwise dose reduction or by starting treatment at the minimal dose. High dose provides a faster clinical response and should be considered for patients with more aggressive disease. The therapeutic threshold for macrophage-targeted glucocerebrosidase appears to be 10-15 IU/kg body wt every 2 weeks. (C) 2000 Academic Press. C1 Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Schiffmann, R (reprint author), Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 30 TC 39 Z9 42 U1 0 U2 0 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD AUG PY 2000 VL 26 IS 4 BP 285 EP 290 DI 10.1006/bcmd.2000.0310 PG 6 WC Hematology SC Hematology GA 365NN UT WOS:000089957500003 PM 11042029 ER PT J AU Murata, K Dalakas, MC AF Murata, K Dalakas, MC TI Expression of the co-stimulatory molecule BB-1, the ligands CTLA-4 and CD28 and their mRNAs in chronic inflammatory demyelinating polyneuropathy SO BRAIN LA English DT Article DE co-stimulatory molecules; immunohistological study; RT-PCR; chronic inflammatory demyelinating; polyneuropathy; antigen-presenting cells ID PERIPHERAL NERVOUS-SYSTEM; MESSENGER-RNA EXPRESSION; SCHWANN-CELLS INVITRO; ANTIGEN PRESENTATION; IFN-GAMMA; TNF-ALPHA; LYMPHOCYTES; PROTEIN; GENE; B7 AB To examine whether the Schwann cells in patients with autoimmune neuropathies have the potential to behave as professional antigen-presenting cells, we investigated the expression of the co-stimulatory molecules BB-1, B7-1 (CD80) B7-2 (CD86) and their counter-receptors CD28 or CTLA-4 (CD152) at the protein and mRNA levels in sural nerve biopsies of patients with chronic inflammatory demyelinating polyneuropathy (CIDP), CIDP associated with human immunodeficiency virus infection (HIV-CIDP), IgM paraproteinaemic neuropathy and normal or non-immune axonal neuropathy, In single-and double-labelling experiments, we used the S-100 antigen as a pan-Schwann cell marker, myelin-associated glycoprotein as a marker for myelinating Schwann cells and the fibrillary acidic protein as a marker for unmyelinating Schwann cells, The expression of the B7 family of molecules was limited to BB-1 and was observed only on the Schwann cells, There was constitutive expression of BB-1 on unmyelinating Schwann cells in all nerves studied, However, in CIDP and HIV-CIDP, but not the other diseases, there was prominent upregulation of BB-1 on the myelinating Schwann cells, The endoneurial T cells in the proximity of BB-1-positive Schwann cells expressed the CD28 or CTLA-4 counterreceptors, Reverse transcription-polymerase chain reaction confirmed that these ligands were upregulated only in CIDP, Because the myelinating BB-1-positive Schwann cells expressed HLA-DR antigen, the findings indicate that, in CIDP, Schwann cells possess the necessary markers to function as antigen-presenting cells. C1 NINDS, Neuromusclar Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromusclar Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr DR MSC 1382, Bethesda, MD 20892 USA. NR 31 TC 41 Z9 44 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD AUG PY 2000 VL 123 BP 1660 EP 1666 DI 10.1093/brain/123.8.1660 PN 8 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 351EG UT WOS:000089144400011 PM 10908195 ER PT J AU Shaham, Y Erb, S Stewart, J AF Shaham, Y Erb, S Stewart, J TI Stress-induced relapse to heroin and cocaine seeking in rats: a review SO BRAIN RESEARCH REVIEWS LA English DT Review DE cocaine; heroin; reinstatement; relapse; review; stress ID CORTICOTROPIN-RELEASING-FACTOR; SELF-ADMINISTRATION BEHAVIOR; MESSENGER-RNA EXPRESSION; FACTOR-LIKE IMMUNOREACTIVITY; NUCLEUS-ACCUMBENS SHELL; ACOUSTIC STARTLE REFLEX; PITUITARY-ADRENAL AXIS; CENTRAL-NERVOUS-SYSTEM; FREELY-MOVING RATS; STRIA TERMINALIS AB Studies in humans suggest that exposure to stress increases the probability of relapse to drug use, bur until recently there has been no animal model to study the mechanisms that mediate this effect. We have developed a reinstatement procedure that allows us to study the effect of stress on relapse to drug seeking in rats. Using this procedure, we have shown that exposure to intermittent footshock stress reliably reinstates heroin and cocaine seeking after prolonged drug-free periods. In the present paper, we summarize results from several studies on stress-induced reinstatement of heroin and cocaine seeking in rats. We first assess the degree to which the phenomenon of stress-induced relapse generalizes to other stressors, to behaviors controlled by other drugs of abuse, and to behaviors controlled by non-drug reinforcers. We then review evidence from studies concerned with the neurotransmitters, the brain sites, and the neural systems involved in stress-induced reinstatement of drug seeking. Finally, we consider the mechanisms that might underlie stress-induced relapse to drug seeking and the possible implications of the findings for the treatment of relapse to drug use in humans. (C) 2000 Elsevier Science B.V. All rights reserved. C1 NIDA, Behav Neurosci Branch, IRP, NIH, Baltimore, MD 21224 USA. Concordia Univ, Dept Psychol, Ctr Studies Behav Neurobiol, Montreal, PQ H3G 1M8, Canada. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. RI shaham, yavin/G-1306-2014 NR 221 TC 449 Z9 463 U1 2 U2 19 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0173 J9 BRAIN RES REV JI Brain Res. Rev. PD AUG PY 2000 VL 33 IS 1 BP 13 EP 33 DI 10.1016/S0165-0173(00)00024-2 PG 21 WC Neurosciences SC Neurosciences & Neurology GA 346JW UT WOS:000088868300002 PM 10967352 ER PT J AU Albo, D Rothman, VL Roberts, DD Tuszynski, GP AF Albo, D Rothman, VL Roberts, DD Tuszynski, GP TI Tumour cell thrombospondin-1 regulates tumour cell adhesion and invasion through the urokinase plasminogen activator receptor SO BRITISH JOURNAL OF CANCER LA English DT Article DE urokinase plasminogen activator; plasmin; pericellular proteolysis ID GROWTH-FACTOR-BETA; BREAST-CANCER PROGRESSION; A549 LUNG-CARCINOMA; SURFACE UROKINASE; INHIBITOR TYPE-1; IN-VITRO; SYSTEM; LOCALIZATION; EXPRESSION; ANGIOGENESIS AB We have previously shown that platelet-produced thrombospondin-1 up-regulates the urokinase plasminogen activator and its receptor and promotes tumour cell invasion. Although tumour cells produce thrombospondin-l in vivo, they produce only minimal amounts of thrombospondin-1 in vitro. To determine the effect of tumour cell-produced thrombospondin-l in the regulation of the plasminogen/plasmin system and tumour cell invasion, we studied THBS-1-transfected MDA-MB-435 breast cancer cells that overexpress thrombospondin-1. The role of urokinase plasminogen receptor in thrombospondin-1-mediated adhesion and invasion was studied by antisense inhibition, enzymatic cleavage and antibody neutralization. Tumour cell adhesion to collagen and laminin was evaluated. Tumour cell invasion was studied in a modified Boyden chamber collagen invasion assay. Tumour cell thrombospondin-l induced a 2-7 fold increase in urokinase plasminogen activator receptor and cell-associated urokinase plasminogen activator expression and a 50-65% increase in cell-associated urokinase plasminogen activator and plasmin activities. Furthermore, tumour cell thrombospondin-l promoted tumour cell invasion and decreased tumour cell adhesion through up-regulation of urokinase plasminogen activator receptor-controlled urokinase plasminogen activator and plasmin activities. We conclude that tumour cell-produced thrombospondin-1 may play a critical role in the regulation of tumour cell adhesion and tumour cell invasion. (C) 2000 Cancer Research Campaign. C1 MCP Hahnemann Univ, Dept Surg, Philadelphia, PA 19102 USA. MCP Hahnemann Univ, Dept Pathol, Philadelphia, PA 19102 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Tuszynski, GP (reprint author), MCP Hahnemann Univ, Dept Surg, Philadelphia, PA 19102 USA. RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NCI NIH HHS [CA65675, CA69722] NR 64 TC 27 Z9 28 U1 2 U2 4 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 AUG PY 2000 VL 83 IS 3 BP 298 EP 306 DI 10.1054/bjoc.2000.1268 PG 9 WC Oncology SC Oncology GA 333JY UT WOS:000088128200005 PM 10917542 ER PT J AU Ciolino, HP Wang, TTY Sathyamoorthy, N AF Ciolino, HP Wang, TTY Sathyamoorthy, N TI Inhibition of aromatase activity and expression in MCF-7 cells by the chemopreventive retinoid N-(4-hydroxy-phenyl)-retinamide SO BRITISH JOURNAL OF CANCER LA English DT Article DE aromatase; 4-HPR; MCF-7; cAMP ID HUMAN-BREAST-CANCER; STROMAL CELLS; FENRETINIDE; PROMOTER; PROLIFERATION; CARCINOMA; TUMORS; SYSTEM; CYCLE; GENE AB The effect of the chemopreventive synthetic retinoid N-(4-hydroxyphenyl)-retinamide (4-HPR) on aromatase activity and expression was examined. 4-HPR caused a dose-dependent inhibition of aromatase activity in microsomes isolated from JEG-3 human placental carcinoma cells. The kinetics of inhibition were analysed by double-reciprocal plot. The Km of the substrate increased and the Vmax of the reaction decreased in the presence of 4-HPR, indicating that enzyme inhibition involved both competition for the substrate-binding site and non-competitive mechanisms. To determine whether 4-HPR would also inhibit aromatase activity in intact cells, MCF-7 human breast cancer cells were incubated with or without cAMP in the presence of 4-HPR. 4-HPR inhibited both basal and cAMP-induced aromatase activity in intact MCF-7 cells. The induction of aromatase mRNA expression in MCF-7 cells by cAMP was inhibited in cells treated with 4-HPR. These results indicate that 4-HPR inhibits both the enzymatic activity and expression of aromatase. These activities may play an important role in the known chemopreventive effect of 4-HPR towards breast cancer. (C) 2000 Cancer Research Campaign. C1 NCI, Div Basic Sci, Basic Res Lab, Cellular Def & Carcinogenesis Sect,Frederick Canc, Frederick, MD 21701 USA. USDA, Beltsville Human Nutr Res Ctr, Phytonutrients Lab, Beltsville, MD 20705 USA. NCI, Tumor Biol & Metastasis Branch, Bethesda, MD 20892 USA. RP Ciolino, HP (reprint author), NCI, Div Basic Sci, Basic Res Lab, Cellular Def & Carcinogenesis Sect,Frederick Canc, Frederick, MD 21701 USA. NR 32 TC 21 Z9 21 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG PY 2000 VL 83 IS 3 BP 333 EP 337 DI 10.1054/bjoc.2000.1269 PG 5 WC Oncology SC Oncology GA 333JY UT WOS:000088128200011 PM 10917548 ER PT J AU Cooper, GS Longnecker, MP Sandler, DP Ness, RB AF Cooper, GS Longnecker, MP Sandler, DP Ness, RB TI Risk of ovarian cancer in relation to use of phenolphthalein-containing laxatives SO BRITISH JOURNAL OF CANCER LA English DT Article DE ovarian cancer; phenolphthalein; laxatives AB We examined ovarian cancer risk in relation to use of phenolphthalein-containing laxatives in 410 epithelial ovarian cancer cases and 713 controls. Compared to women who never used a laxative, ever use of a phenolphthalein-containing laxative was not associated with an increased risk of ovarian cancer (odds ratio. OR, 1.1, 95% confidence interval, GI, 0.9-1.4). Risk was slightly, but not significantly, higher with more frequent use (OR 1.2 for 75 or more days of use). When women who used non-phenolphthalein containing laxatives was used as the reference group, the associations were slightly, but not significantly larger (OR 1.4 for any use of phenolphthalein-containing laxatives and OR 1.5 for 75 or more days of use) (C) 2000 Cancer Research Campaign. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. RP Cooper, GS (reprint author), NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. OI Longnecker, Matthew/0000-0001-6073-5322; Sandler, Dale/0000-0002-6776-0018 NR 11 TC 3 Z9 3 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG PY 2000 VL 83 IS 3 BP 404 EP 406 DI 10.1054/bjoc.2000.1250 PG 3 WC Oncology SC Oncology GA 333JY UT WOS:000088128200022 PM 10917559 ER PT J AU Hrinczenko, BW Alayash, AI Wink, DA Gladwin, MT Rodgers, GP Schechter, AN AF Hrinczenko, BW Alayash, AI Wink, DA Gladwin, MT Rodgers, GP Schechter, AN TI Effect of nitric oxide and nitric oxide donors on red blood cell oxygen transport SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE nitric oxide; haemoglobin; methaemoglobin; oxygen affinity; sickle cell anaemia ID S-NITROSOHEMOGLOBIN; COVALENT BINDING; HEMOGLOBIN-S; DISEASE; NO; HYDROXYUREA; AFFINITY; ERYTHROCYTES; GLUTATHIONE; OXIDATION AB A mechanism has been proposed in which nitric oxide (NO) may bind to cysteine beta 93 and be transported B haemoglobin from the lungs to the tissues and modify vascular tone. In addition, it has been reported that treatment of sickle cell anaemia blood with 80 p.p.m. NO gas in air shifts the oxygen affinity as measured by P-50 to the left. We exposed normal and sickle cell anaemia blood to 80 p.p.m. NO in air for 1 h in vitro and found no change in P-50 of either normal or sickle cell blood, in addition, we exposed normal and sickle cell blood in buffer to aqueous NO (NO gas dissolved in buffer) at varying concentrations and found that the induced left shift in P-50 correlates strongly and linearly with methaemoglobin formation. We also treated normal and sickle cell blood with other nitric oxide donors, such as sodium 2-(N,N-diethylamino)-diazenolate-2-oxide (DEANO), S-nitrosocysteine (CysNO) and sodium trioxodinitrate (OXINO, or Angeli's salt). In all cases, we found a dose-dependent increase in methaemoglobin that was strongly correlated with the dose-dependent P-50 reduction. Our data do not support the report that low NO concentrations call selectively increase the oxygen affinity of sickle fell blood without affecting methaemoglobin levels significantly. NO, however map have benefit in sickle cell disease by other mechanisms. C1 NIDDK, NIH, Biol Chem Lab, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Hematol, Lab Plasma Derivat, Bethesda, MD USA. NCI, NIH, Radiat Biol Branch, Div Clin Sci, Bethesda, MD USA. NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD USA. NIDDK, NIH, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. RP Schechter, AN (reprint author), NIDDK, NIH, Biol Chem Lab, Bldg 10,Rm 9N-307, Bethesda, MD 20892 USA. OI Schechter, Alan N/0000-0002-5235-9408 NR 40 TC 22 Z9 25 U1 0 U2 2 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 AUG PY 2000 VL 110 IS 2 BP 412 EP 419 DI 10.1046/j.1365-2141.2000.02203.x PG 8 WC Hematology SC Hematology GA 347PC UT WOS:000088937500022 PM 10971400 ER PT J AU Vieira, NE Goans, RE Weiss, GH Hopkins, E Marini, JC Yergey, AL AF Vieira, NE Goans, RE Weiss, GH Hopkins, E Marini, JC Yergey, AL TI Calcium kinetics in children with osteogenesis imperfecta type III and IV: Pre- and post-growth hormone therapy SO CALCIFIED TISSUE INTERNATIONAL LA English DT Article DE stable isotopes; bone-metabolism; children ID PLASMA CALCIUM; BONE; AXIS AB Children with osteogenesis imperfecta (OI) type III and type IV were studied using a Ca-42 stable isotope technique. Serum dilution kinetics of 42Ca were studied pre-and post-growth hormone (GH) treatment in 9 OI III (age range 5-9 years) and 8 OI IV patients (age range 5-12 years). Each subject was studied twice: at baseline and following GH therapy (range 1-1.5 years). Isotopic enrichments of 42Ca were followed over 7 days using thermal ionization mass spectrometry. A binding site model, which describes reversible and irreversible binding of calcium (Ca) ions to postulated short- and long-term binding sites in bone, was used to analyze the kinetic data. In type III patients, GH treatment (1) increased the fraction of short-term binding sites, theta (0.777 +/- 0.112 versus 0.877 +/- 0.05, respectively; P = 0.034); (2) increased the apparent half-life of a Ca ion attached to the long-term binding site by 76% (P = 0.009); (3) although not statistically significant (P = 0.098), a trend toward an increased growth rate was observed with increasing change in theta (Delta theta); (4) patients experienced a 75% increase in growth rate during the first 6 months of treatment. In type IV patients, GH treatment increased the apparent half-life of a Ca ion attached to the long-term binding site by 83% (P = 0.048), however, no trend toward an Increased growth rate was observed with increasing Delta theta in these patients. These significant changes in Ca binding to bone may influence growth in type III patients. C1 NICHHD, NIH, Lab Cellular & Mol Biophys, Bethesda, MD 20892 USA. Oak Ridge Associated Univ, REACTS, Oak Ridge, TN 37716 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. NICHHD, NIH, Heritable Disorders Branch, Bethesda, MD 20892 USA. RP Vieira, NE (reprint author), NICHHD, NIH, Lab Cellular & Mol Biophys, Bldg 10,Room 9D52,10 Ctr Dr,M5C 1580, Bethesda, MD 20892 USA. NR 15 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0171-967X J9 CALCIFIED TISSUE INT JI Calcif. Tissue Int. PD AUG PY 2000 VL 67 IS 2 BP 97 EP 100 DI 10.1007/s00223001110 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 337XA UT WOS:000088387400001 PM 10920211 ER PT J AU Black, SE Moffat, SD Yu, DC Parker, J Stanchev, P Bronskill, M AF Black, SE Moffat, SD Yu, DC Parker, J Stanchev, P Bronskill, M TI Callosal atrophy correlates with temporal lobe volume and mental status in Alzheimer's disease SO CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES LA English DT Article ID HUMAN CORPUS-CALLOSUM; ANTERIOR COMMISSURE; REGIONAL PATTERN; RHESUS-MONKEY; DEGENERATION; DEMENTIA; SEX; MR; METABOLISM; ASYMMETRY AB Background: Recent studies have reported significant atrophy of the corpus callosum (CC) in Alzheimer's Disease (AD), However. it is currently unknown whether CC atrophy is associated with specific cortical volume changes in AD. Moreover, possible atrophy in extra-callosal commissures has not been examined to date, The purpose of the present study was to quantify atrophy in two cerebral commissures [the CC and the anterior commissure (BC)I, to con,elate this measure with cognitive status, and to relate commissural size to independent measures of temporal lobe volume in AD patients. Methods: A sample of AD patients and of age- and education-matched normal control subjects (NCs) underwent MRI and a cognitive test battery including the Dementia Rating Scale and Mini Mental State examination. Mid-sagittal regional areas within CC and AC were measured along with superior, middle and inferior temporal lobes volumes. Results: Alzheimer's Disease patients had significantly smaller callosa than did NCs, The callosal regions most affected in AD included the midbody, isthmus and genu. The isthmus and midbody areas of the CC were positively correlated with cognitive performance and with superior temporal lobe volume in AD patients. The mid-sagittal area of the AC and the superior temporal volumes did not differ between AD patients and NCs. Conclusions: The study demonstrated that the regional morphology of the CC correlates with current cognitive status and temporal lobe atrophy in AD. As well, the lack of difference for the AC suggests that commissural atrophy in AD is regionally specific. C1 Univ Toronto, Sunnybrook Womens Coll & Hlth Sci Ctr, Dept Med, Cognit Neurol Unit, Toronto, ON, Canada. Univ Toronto, Sunnybrook Womens Coll & Hlth Sci Ctr, Res Program Aging, Toronto, ON, Canada. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. Bulgarian Acad Sci, Inst Math & Comp Sci, BG-1040 Sofia, Bulgaria. Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. RP Black, SE (reprint author), Sunnybrook Womens Coll & Hlth Sci Ctr, Cognit Neurol Unit, Div Neurol, Room A421,2075 Bayview Ave, N York, ON M4N 3M5, Canada. OI Black, Sandra/0000-0001-7093-8289 NR 34 TC 28 Z9 29 U1 0 U2 2 PU CANADIAN J NEUROL SCI INC PI CALGARY PA PO BOX 4220, STATION C EDITORIAL & SUBSCRIPTION SERV, CALGARY, AB T2T 5N1, CANADA SN 0317-1671 J9 CAN J NEUROL SCI JI Can. J. Neurol. Sci. PD AUG PY 2000 VL 27 IS 3 BP 204 EP 209 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 346JJ UT WOS:000088867000004 PM 10975532 ER PT J AU Albores-Saavedra, J Murakata, L Krueger, JE Henson, DE AF Albores-Saavedra, J Murakata, L Krueger, JE Henson, DE TI Noninvasive and minimally invasive papillary carcinomas of the extrahepatic bile ducts SO CANCER LA English DT Article DE papillary carcinoma; extrahepatic bile ducts; p53; MIB-1 ID K-RAS CODON-12; BILIARY-TRACT TUMORS; PANCREATIC DUCT; P53 PROTEIN; GALLBLADDER; MUTATIONS; PAPILLOMATOSIS; CANCER AB BACKGROUND. Adenocarcinomas of the extrahepatic bile ducts (EBD) are uncommon neoplasms that are morphologically heterogenous and associated with a poor prognosis. Papillary carcinomas of the EBD, however, appear to follow a much less aggressive clinical course. METHODS, The authors reviewed the clinical records of nine patients with papillary carcinoma of the EBD, analyzed the microscopic features, and selected immunohistochemical reactivity (p53 and MIB-1) that might correlate with patient survival. RESULTS. Six patients were male and three were female, with a mean age of 65 years (range, 48-83 years). The clinical presentation of disease in these patients was similar to that reported for conventional adenocarcinoma of EBD. According to their cell phenotypes, these papillary carcinomas were classified as biliary type (7 cases) and intestinal type (2 cases). Most were located in the common bile duct and were well differentiated (7 cases). Five showed minimal expansile invasion into the ductal wail and four were noninvasive. Five patients were treated with a Whipple operation, three underwent segmental resections, and one underwent a left hepatic lobectomy. One patient died of unrelated causes 16 years after a Whipple operation, and another died of postoperative complications. The remaining 7 patients are alive and disease free 1-13 years after surgery. CONCLUSIONS. Noninvasive and minimally invasive papillary carcinomas of the EBD are associated with excellent long term prognosis regardless of their cytologic features or their immunohistochemical reactivity to p53 and MIB-1. These tumors should be distinguished from biliary papillomatosis, intraductal papillary mucinous carcinomas of the pancreas extending into the bile ducts, papillary adenomas, and papillary hyperplasia. (C) 2000 American Cancer Society. C1 Univ Texas, SW Med Ctr, Dept Pathol, Div Anat Patol, Dallas, TX 75235 USA. Armed Forces Inst Pathol, Washington, DC USA. NCI, Bethesda, MD 20892 USA. RP Albores-Saavedra, J (reprint author), Univ Texas, SW Med Ctr, Dept Pathol, Div Anat Patol, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. NR 20 TC 64 Z9 66 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 0008-543X J9 CANCER JI Cancer PD AUG 1 PY 2000 VL 89 IS 3 BP 508 EP 515 DI 10.1002/1097-0142(20000801)89:3<508::AID-CNCR5>3.0.CO;2-D PG 8 WC Oncology SC Oncology GA 340HN UT WOS:000088527200005 PM 10931449 ER PT J AU Boffetta, P Gridley, G Gustavsson, P Brennan, P Blair, A Ekstrom, AM Fraumeni, JF AF Boffetta, P Gridley, G Gustavsson, P Brennan, P Blair, A Ekstrom, AM Fraumeni, JF TI Employment as butcher and cancer risk in a record-linkage study from Sweden SO CANCER CAUSES & CONTROL LA English DT Article DE butchers; epidemiology; lung neoplasms; occupational exposures; stomach neoplasms ID NON-HODGKINS LYMPHOMA; NESTED CASE-CONTROL; LUNG-CANCER; HELICOBACTER-PYLORI; MEAT INDUSTRY; ABATTOIR WORKERS; OCCUPATION; MORTALITY; EXPOSURE; PLANTS AB Objective: To investigate the risk of cancer among butchers and other meat workers in a large record-linkage study from Sweden. Methods: The Swedish Cancer Environment Register III contains nationwide data on cancer incidence during 1971-1989 for all residents, by occupation and industry of employment as reported at the 1960 and 1970 censuses. We identified 25,049 men classified as butchers or meat workers at either census. We used as a comparison group the remaining part of the active male population, after exclusion of workers with direct contact with animals. Results: Butchers in the meat industry had a slight increase in the risk of cancer (relative risk [RR] 1.1, 95% confidence interval [CI] 1.0-1.3), which was due to an increased risk of cancers of the oral cavity and pharynx (RR 1.6, 95% CI 1.0-2.7), stomach (RR 1.6, 95% CI 1.1-2.7), larynx (RR 1.4, 95% CI 0.6-3.4), and lung (RR 1.4, 95% CI 1.1-1.9). The risk of stomach cancer was highest during the first 5 years of the study, and among butchers from urban areas. No temporal or geographic variations were seen for lung cancer risk, with elevations restricted to squamous cell carcinoma. An increased risk of stomach, laryngeal and lung cancers was present in butchers and meat workers outside the meat industry. There was no clear indication of an increased risk of other neoplasms. Conclusions: The increased risk of oral. laryngeal, lung and stomach cancers among Swedish butchers may be at least partly due to confounding by tobacco smoking, alcohol drinking, and other lifestyle factors. However, exposures in the meat industry (e.g., viruses, nitrosamines, polycyclic aromatic hydrocarbons) may contribute the elevated cancer risks. C1 Int Agcy Res Canc, Unit Environm Canc Epidemiol, F-69008 Lyon, France. NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. Karolinska Hosp, Dept Occupat Hlth, S-10401 Stockholm, Sweden. Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden. RP Boffetta, P (reprint author), Int Agcy Res Canc, Unit Environm Canc Epidemiol, 150 Cours Albert Thomas, F-69008 Lyon, France. NR 45 TC 43 Z9 46 U1 3 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 AUG PY 2000 VL 11 IS 7 BP 627 EP 633 DI 10.1023/A:1008947531573 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 351KD UT WOS:000089155600006 PM 10977107 ER PT J AU Okamoto, K Andreola, F Chiantore, MV Dedrick, RL De Luca, LM AF Okamoto, K Andreola, F Chiantore, MV Dedrick, RL De Luca, LM TI Differences in uptake and metabolism of retinoic acid between estrogen receptor-positive and -negative human breast cancer cells SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE free diffusion; retinoic acid uptake; breast cancer cells ID GROWTH-INHIBITION; TISSUE TRANSGLUTAMINASE; IONIZATION BEHAVIOR; SERUM-ALBUMIN; DISPOSITION; RESISTANT; MICE AB Purpose: Our previous work had shown that retinoic acid (RA) inhibits cell growth and induces apoptosis in estrogen receptor-positive (ER-positive) MCF-7 and T-47D human breast carcinoma cells, but not in ER-negative human breast carcinoma cells MB-231 and MB-453, The purpose of this work was to determine whether these differences might be due to differences in uptake and metabolism of the drug between ER-positive and ER-negative cells. Methods: We measured RA uptake in cultured human breast cancer cells and determined its metabolism by high-pressure liquid chromatographic analysis, Results: The two ER positive cell lines reached maximum RA uptake at about 2 h, followed by a sharp decline, so that most RA had disappeared from the cells and from the medium by 24 h and was found as oxidation products in the culture medium. In contrast, the two ER-negative cell lines showed a pattern of lower accumulation without the sharp increase and subsequent steep decline, so that by 24 h there was more RA in these cells and their culture medium than in the RA-responsive ER-positive cells, even though at 2 h the ER-negative cells had taken up less RA than the ER-positive cells, Kinetic analysis of the uptake of RA in MCF-7 cells was consistent with rapid movement across the cell membranes and the actual rate determined by diffusion of albumin-bound retinoid to the cells. Conclusions: This study is the first to demonstrate profound differences in RA accumulation and confirms previous results on different rates of RA metabolism between ER-positive and ER-negative human breast cancer cells, The findings reported here, therefore, may introduce additional elements to be considered in the design of new drugs for cancer chemoprevention and therapy. C1 NIH, Bethesda, MD 20892 USA. NIH, Bioengn & Phys Sci Program, Off Res Serv, Bethesda, MD 20892 USA. Ist Super Sanita, I-00161 Rome, Italy. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. Toho Univ, Sch Med, Dept Surg 2, Ota Ku, Tokyo 141, Japan. RP De Luca, LM (reprint author), NIH, Bldg 37 Room 3A-17, Bethesda, MD 20892 USA. NR 18 TC 13 Z9 13 U1 1 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD AUG PY 2000 VL 46 IS 2 BP 128 EP 134 DI 10.1007/s002800000125 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 345MN UT WOS:000088819900006 PM 10972482 ER PT J AU Ishibe, N Stampfer, M Hunter, DJ Hennekens, C Kelsey, KT AF Ishibe, N Stampfer, M Hunter, DJ Hennekens, C Kelsey, KT TI A prospective study of cytochrome P450 1A1 polymorphisms and colorectal cancer risk in men SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CIGARETTE-SMOKING; LUNG-CANCER; MEAT; GENE C1 NCI, Genet Epidemiol Branch, Rockville, MD 20852 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Ishibe, N (reprint author), NCI, Genet Epidemiol Branch, MSC 7236, Rockville, MD 20852 USA. RI Kelsey, Karl/I-1252-2014 FU NCI NIH HHS [CA70817]; NIEHS NIH HHS [ES-00002, T32ES07069] NR 9 TC 21 Z9 23 U1 0 U2 0 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 AUG PY 2000 VL 9 IS 8 BP 855 EP 856 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 343UC UT WOS:000088719500014 PM 10952105 ER PT J AU Vandier, D Rixe, O Besnard, F Kim, M Rikiyama, T Goldsmith, M Brenner, M Gouyette, A Cowan, KH AF Vandier, D Rixe, O Besnard, F Kim, M Rikiyama, T Goldsmith, M Brenner, M Gouyette, A Cowan, KH TI Inhibition of glioma cells in vitro and in vivo using a recombinant adenoviral vector containing an astrocyte-specific promoter SO CANCER GENE THERAPY LA English DT Article DE gene therapy; glial fibrillary acidic protein; glioblastoma; adenovirus; herpes simplex virus thymidine kinase gene ID FIBRILLARY ACIDIC PROTEIN; THYMIDINE KINASE GENE; BRAIN-TUMORS; TRANSGENIC MICE; THERAPY; EXPRESSION; SYSTEM; GFAP; MALIGNANCIES; REGRESSION AB Gene therapy using the herpes simplex virus thymidine kinase (HSV-TK) gene in combination with the drug ganciclovir (GCV) is a promising approach for the treatment of cancer-inducing gliomas, a tumor with a poor prognosis. In an attempt to limit the toxic effects on normal tissues, we constructed a recombinant adenoviral vector, Adgfa2TK, in which the HSV-TK gene is driven by the promoter for the gene encoding glial fibrillary acidic protein, an intermediate filament protein expressed primarily in astrocytes. Infection by Adgfa2TK of a glial cell line (C6) and a non-glial cell line (MDA-MB-231) revealed markedly increased expression of HSV-TK in glial cells as determined by Western blot. In comparison, high HSV-TK protein levels were produced in both cell lines after infection with a control virus, AdCMVTK, in which the constitutive cytomegalovirus viral promoter was used to direct HSV-TK expression. infection of two glial cell lines (C6, U251) and two non-glial cell lines (HepG2, MDA-MB-231) with Adgfa2TK followed by GCV treatment revealed high toxicity in glial cell lines (50% growth inhibitory concentration: <2 mu g/mL of GCV) with little or no toxicity (50% growth inhibitory concentration: >75 mu g/mL) in the non-glial cell lines. In vivo, injection of Adgfa2TK into CG tumors grown in nude mice followed by intraperitoneal GCV treatment significantly repressed tumor growth compared with the controls. Adgfa2TK may be useful for directing expression of the HSV-TK gene to gliomas. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Eppley Canc Ctr, Omaha, NE 68198 USA. NCI, Med Branch, Bethesda, MD 20892 USA. Clin Claude Bernard, Dept Oncol, Metz, France. Sanofi Synthelabo, Rueil Malmaison, France. Univ Alabama, Dept Neurobiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Phys Med & Rehabil, Birmingham, AL 35294 USA. Inst Gustave Roussy, Dept Pharmacotoxicol & Pharmacogenet, Unite Mixte Rech 8532, CNRS, Villejuif, France. RP Cowan, KH (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Eppley Canc Ctr, Room 2016, Omaha, NE 68198 USA. NR 30 TC 25 Z9 25 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD AUG PY 2000 VL 7 IS 8 BP 1120 EP 1126 DI 10.1038/sj.cgt.7700211 PG 7 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 347VQ UT WOS:000088950200003 PM 10975672 ER PT J AU Patel, SD Moskalenko, M Tian, T Smith, D McGuinness, R Chen, LL Winslow, GA Kashmiri, S Schlom, J Stanners, CP Finer, MH McArthur, JG AF Patel, SD Moskalenko, M Tian, T Smith, D McGuinness, R Chen, LL Winslow, GA Kashmiri, S Schlom, J Stanners, CP Finer, MH McArthur, JG TI T-cell killing of heterogenous tumor or viral targets with bispecific chimeric immune receptors SO CANCER GENE THERAPY LA English DT Article DE chimeric immune receptors; bispecific immune receptors; gene therapy; T-cell receptors; immunotherapy ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; CARCINOEMBRYONIC ANTIGEN; ADOPTIVE TRANSFER; MUTATION-RATE; TYPE-1; LYMPHOCYTES; INFECTION; EVOLUTION; GENE AB We have previously described several novel chimeric immune receptors (CIRs) that redirect human T cells to kill malignant or HIV-infected cells. These CIRs comprise a cancer- or virus-specific ligand or single-chain antibody fused to the signaling domain of the T-ccll receptor CD3-zeta subunit. Binding of the ligand- or antibody-based CIR to the target antigen (Ag) triggers T-cell-mediated cytolysis of the tumor- or virus-infected cell independent of target cell major histocompatibility complex class I expression. A new type of CIR was developed to mediate the lysis of cells that expressed one or more distinct viral or tumor Ags; three bispecific CIRs (BCIRs) were generated that recognized the carcinoembryonic Ag (CEA) and TAG-72 tumor Ags or, alternatively, distinct epitopes in the HIV envelope (HIVenv). T cells expressing the antitumoral Ag BCIR lysed both CEA- and TAG-72-expressing targets and did not kill Ag-negative targets or target cells Expressing other members of the CEA family. Similarly, T cells expressing the anti-HIVenv BCIR lysed target cells expressing both the wild-type HIVenv and a mutant HIVenv that lacked the epitopes recognized by the monospecific CIRs. This approach permits the generation of T cells with a broader spectrum of activity capable of killing virus-infected cells and malignant cells and reduces the potential of progression of disease due to Ag loss variants. C1 Cell Genesys Inc, Dept Preclin Biol & Immunol, Foster City, CA 94404 USA. NCI, Bethesda, MD 20892 USA. McGill Canc Ctr, Dept Biochem, Montreal, PQ, Canada. McGill Univ, Ctr Canc, Montreal, PQ H3G 1Y6, Canada. RP McArthur, JG (reprint author), Cell Genesys Inc, Dept Preclin Biol & Immunol, 342 Lakeside Dr, Foster City, CA 94404 USA. NR 29 TC 15 Z9 15 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD AUG PY 2000 VL 7 IS 8 BP 1127 EP 1134 DI 10.1038/sj.cgt.7700213 PG 8 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 347VQ UT WOS:000088950200004 PM 10975673 ER PT J AU Athanasiou, M LeGallic, L Watson, DK Blair, DG Mavrothalassitis, G AF Athanasiou, M LeGallic, L Watson, DK Blair, DG Mavrothalassitis, G TI Suppression of the Ewing's sarcoma phenotype by FLI1/ERF repressor hybrids SO CANCER GENE THERAPY LA English DT Article DE FLI1; ERF; Ewing's sarcoma; tumor suppression ID ETS TRANSCRIPTION FACTORS; PRIMITIVE NEUROECTODERMAL TUMOR; MURINE LEUKEMIA-VIRUS; RNA-POLYMERASE-II; DNA-BINDING; EWS GENE; FUSION PROTEIN; TEL GENE; FAMILY; CELLS AB Fusion of the 5' half of the Ewing's sarcoma (ES) gene EWS with the DNA-binding domain of several transcription factors has been detected in many human tumors. The t(11;22)(q24;q12) chromosomal translocation is specifically linked to ES and primitive neuroectodermal tumors and results, in the majority of cases, in the fusion of the amino terminus of the EWS gene to the carboxyl-terminal DNA-binding domain of the Fill gene. The chimeric protein has been shown to be oncogenic, a potent transcriptional activator, and necessary for the maintenance of the Ewing's phenotype, making it an attractive target for gene therapy. In this study, we demonstrate that the ES transformed phenotype can he suppressed by chimeric transcriptional repressors containing the DNA-binding domain of FLI1 and the regulatory and repressor domain of ERF, a transcription suppressor and member of the ets gene family. The hybrid repressor is expressed at levels comparable with EWS/FLI1, does not affect EWS/FLI1 expression, and exhibits similar DNA-binding specificity but suppresses transcriptional activity. The FLI1/ERF repressor, like the wild-type ERF, is regulated by mitogen-activated protein kinase-dependent subcellular localization. Our data suggest that transformation by EWS/FLI1 may partially be due to activation of specific EWS/FLI1-regulated genes involved in cell proliferation. C1 Univ Crete, Sch Med, Heraklion 71409, Crete, Greece. Sci Applicat Int Corp, Intramural Res Support Program, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Basic Res Lab, Div Basic Sci, Frederick, MD 21702 USA. Med Univ S Carolina, Ctr Mol & Struct Biol, Hollings Canc Ctr, Charleston, SC 29425 USA. Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Hellas, Greece. RP Mavrothalassitis, G (reprint author), Univ Crete, Sch Med, Heraklion 71409, Crete, Greece. FU NCI NIH HHS [N01-CO-56000] NR 45 TC 8 Z9 9 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD AUG PY 2000 VL 7 IS 8 BP 1188 EP 1195 DI 10.1038/sj.cgt.7700220 PG 8 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 347VQ UT WOS:000088950200011 PM 10975680 ER PT J AU Zwiebel, J AF Zwiebel, J TI Second Pasman keynote lecture: Gene and oncolytic virus therapies SO CANCER GENE THERAPY LA English DT Meeting Abstract C1 NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD AUG PY 2000 VL 7 IS 8 MA 001 BP 1203 EP 1203 PG 1 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 347VQ UT WOS:000088950200014 ER PT J AU Acar, H Copeland, NG Gilbert, DJ Jenkins, NA Largaespada, DA AF Acar, H Copeland, NG Gilbert, DJ Jenkins, NA Largaespada, DA TI Detection of integrated murine leukemia viruses in a mouse model of acute myeloid leukemia by fluorescence in situ hybridization combined with tyramide signal amplification SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID GENETIC-LINKAGE MAP; LYMPHOMAS; HOMOLOGY; STRAINS; REGION; MICE; LOCI; DNA AB This study rt as undertaken to develop a reliable method to enumerate and map somatically acquired, clonal, murine leukemia virus (MuLV) proviral insertions in acute myeloid leukemia (AML) cells from the BXH-2 mouse strain. This was achieved by using fluorescence in situ hybridization combined with tyramide signal amplification (FISH-TSA) and an 8.8 kilobase pair (kb) full-length ecotropic MuLV or 2.0 kb MuLV envelope (env) gene probe. Two-color FISH was utilized combining chromosome-specific probes for regions near the telomere and/or centromere and the MuLV probes. The technique reliably detected germline and somatically acquired, tumor-specific, MuLV proviruses in BXH-2 AML cell lines. It rr as possible to readily verify homozygous insertions at endogenous ecotropic,MuLV loci, Emv1 (chromosome 5), Emv2 (chromosome 8) and a BXH-2 strain-specific locus (chromosome 11). This strategy also verified the presence of molecularly cloned proviral insertions within the mouse Nf1 gene and another locus on distal chromosome II, as well as on chromosome 7 and chromosome 9 in BXH-2 AML cell line B117. The technique rc as also used to detect several new tumor-specific, proviral insertions in BXH-2 AML cell lines. (C) 2000 Elsevier Science Inc, All rights reserved. C1 Univ Minnesota, Ctr Canc, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. Selcuk Univ, Dept Med Genet, Konya, Turkey. NCI, Frederick Canc Res & Dev Ctr, Mouse Canc Genet Program, Frederick, MD USA. RP Largaespada, DA (reprint author), Univ Minnesota, Ctr Canc, Dept Genet Cell Biol & Dev, Res Bldg,425 E River Rd, Minneapolis, MN 55455 USA. RI Largaespada, David/C-9832-2014 FU NCI NIH HHS [UO1-CA84221] NR 22 TC 7 Z9 9 U1 0 U2 3 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 AUG PY 2000 VL 121 IS 1 BP 44 EP 51 DI 10.1016/S0165-4608(00)00232-6 PG 8 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 348KE UT WOS:000088983400008 PM 10958940 ER PT J AU Roth, MJ Dawsey, SM Wang, GQ Tangrea, JA Zhou, B Ratnasinghe, D Woodson, KG Olivero, OA Poirier, MC Frye, BL Taylor, PR Weston, A AF Roth, MJ Dawsey, SM Wang, GQ Tangrea, JA Zhou, B Ratnasinghe, D Woodson, KG Olivero, OA Poirier, MC Frye, BL Taylor, PR Weston, A TI Association between GSTM1*0 and squamous dysplasia of the esophagus in the high risk region of Linxian, China SO CANCER LETTERS LA English DT Article DE esophageal cancer; cytochrome P450; glutathione-S-transferase; China ID XENOBIOTIC-METABOLIZING ENZYMES; S-TRANSFERASE M1; CELL CARCINOMA; LUNG-CANCER; GENETIC POLYMORPHISMS; BREAST-CANCER; SUSCEPTIBILITY; CYP1A1; GSTM1; GSTT1 AB Individuals with specific phase I and phase II enzyme polymorphisms may be at increased risk for squamous cell carcinoma of the esophagus. However, to our knowledge there has been only one previous report that evaluates a potential role for these polymorphisms in increasing risk for preneoplastic squamous lesions of the esophagus. To explore this further, we examined polymorphisms in CYP1A1, CYP2E1, GSTM1 and GSTT1, both independently and in combination, for potential associations with the risk of biopsy-proven squamous dysplasia of the esophagus in asymptomatic adults from Linxian, a high risk region in China. Cases consisted of 56 individuals from an esophageal cancer screening study with an endoscopic biopsy diagnosis of mild or moderate squamous dysplasia. Each case was matched on age (+/- 1 year) and gender to a control. Controls were defined as screening study participants with an endoscopic biopsy diagnosis of normal mucosa or esophagitis. DNA was extracted from frozen cell samples obtained by cytologic balloon examination and genotyped using standard methods. Individuals who were GSTM1 null (homozygous for GSTM1*0) were found to have a tendency for an increased risk of esophageal squamous dysplasia (odds ratio = 2.6, 95% CI, 0.9-7.4). No excess risks were observed for inheritance of other putative at risk genotypes CYP1A1*2B, CYP2E1*6 or GSTT1*0. The risk associated with the inheritance of combined genotypes was not significantly different than the risk estimates from the univariate analysis. These results are consistent with the notion that exposure to environmental carcinogens that are detoxified by GSTM1, such as polycyclic aromatic hydrocarbons, may contribute to the etiology of esophageal cancer in Linxian. Published by Elsevier Science Ireland Ltd. C1 NCI, Canc Prevent Studies Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Dept Endoscopy, Beijing 100021, Peoples R China. Chinese Acad Med Sci, Dept Cytol, Beijing 100021, Peoples R China. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Div Biol Sci, NIH, Bethesda, MD 20892 USA. NIOSH, Toxicol & Mol Biol Branch, Hlth Effects Lab Div, CDC, Morgantown, WV 26505 USA. RP Roth, MJ (reprint author), Suite 321,6006 Execut Blvd,MSC 7058, Bethesda, MD 20892 USA. NR 33 TC 29 Z9 30 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD AUG 1 PY 2000 VL 156 IS 1 BP 73 EP 81 DI 10.1016/S0304-3835(00)00442-0 PG 9 WC Oncology SC Oncology GA 396XC UT WOS:000166662400010 PM 10840162 ER PT J AU Linnoila, RI Zhao, BH DeMayo, JL Nelkin, BD Baylin, SB DeMayo, FJ Ball, DW AF Linnoila, RI Zhao, BH DeMayo, JL Nelkin, BD Baylin, SB DeMayo, FJ Ball, DW TI Constitutive achaete-scute homologue-1 promotes airway dysplasia and lung neuroendocrine tumors in transgenic mice SO CANCER RESEARCH LA English DT Article ID LARGE T-ANTIGEN; NEURONAL DIFFERENTIATION; PROTEIN GENE; CELLS; MARKERS; MASH1 AB The transcription factor achaete-scute homologue-1 (ASH1) is essential for neural differentiation during fetal development and is a cardinal feature of neuroendocrine (NE) tumors such as small cell lung cancer. To explore the potential of ASH1 to promote NE differentiation and tumorigenesis in the lung, we constitutively expressed the factor in nonendocrine airway epithelial cells using transgenic mice. Progressive airway hyperplasia and metaplasia developed beginning at 3 weeks of life. ASH1 potently enhanced the tumorigenic effect of SV40 large T antigen in airway epithelium. These doubly transgenic animals developed massive NE lung tumors, implying that ASH1 may cooperate with defects in p53, pRb, or related pathways in promoting NE lung carcinogenesis. C1 NCI, Cell & Canc Biol Dept, Med Branch, Div Clin Sci,NIH, Rockville, MD USA. Baylor Univ, Sch Med, Dept Mol & Cell Biol, Houston, TX 77030 USA. Johns Hopkins Univ, Sch Med, Ctr Oncol, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21231 USA. RP Ball, DW (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Baylor Plaza, Houston, TX 77030 USA. FU NCI NIH HHS [R01CA70244] NR 21 TC 83 Z9 87 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 AUG 1 PY 2000 VL 60 IS 15 BP 4005 EP 4009 PG 5 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700004 PM 10945598 ER PT J AU Mitsiades, N Poulaki, V Tseleni-Balafouta, S Koutras, DA Stamenkovic, I AF Mitsiades, N Poulaki, V Tseleni-Balafouta, S Koutras, DA Stamenkovic, I TI Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand SO CANCER RESEARCH LA English DT Article ID FLICE-INHIBITORY PROTEIN; TRAIL-INDUCED APOPTOSIS; HASHIMOTOS-THYROIDITIS; FOLLICULAR CELLS; DEATH DOMAIN; IMMUNE EVASION; IN-VIVO; RECEPTOR; EXPRESSION; FAMILY AB Fas (APO-1/CD95) is a transmembrane protein of the tumor necrosis factor (TNF)/nerve growth factor receptor superfamily that induces apoptosis in susceptible normal and neoplastic cells upon cross-linking by its ligand (FasL). TNF-related apoptosis-inducing ligand (TRAIL) is a more recently identified member of the TNF superfamily that has been shown to selectively kill neoplastic cells by engaging two cell-surface receptors, DR4 and DR5. Two additional TRAIL receptors (DcR1 and DcR2) do not transmit an apoptotic signal and have been proposed to confer protection from TRAIL-induced apoptosis. We addressed the expression of Fas, DR4, and DR5 in thyroid carcinoma cell lines and in 31 thyroid carcinoma specimens by Western blot analysis and immunohistochemistry, respectively, and tested the sensitivity of thyroid carcinoma cell lines to Fas- and TRAIL-induced apoptosis. Fas was found to be expressed in most thyroid carcinoma cell lines and tissue specimens. Although cross-linking of Fas did not induce apoptosis in thyroid carcinoma cell lines, Fas-mediated apoptosis did occur in the presence of the protein synthesis inhibitor cycloheximide, suggesting the presence of a short-hived inhibitor of the Fas pathway in these cells. Cross-linking of Pas failed to induce recruitment and activation of caspase 8, whereas transfection of a constitutively active caspase 8 construct effectively killed the SW579 papillary carcinoma cell line, arguing that the action of the putative inhibitor occurs upstream of caspase 8. By contrast, recombinant TRAIL induced apoptosis in 10 of 12 thyroid carcinoma cell lines tested, by activating caspase-10 at the receptor level and triggering a caspase-mediated apoptotic cascade. Resistance to TRAIL did not correlate with DcR1 or DcR2 protein expression and was overcome by protein synthesis inhibition in 50% of the resistant cell lines. One medullary carcinoma cell line was resistant to Fas- and TRAIL-induced apoptosis, even in the presence of cycloheximide, and to transfection of constitutively active caspase-8, suggesting a different regulation of the apoptotic pathway. Our observations indicate that TRAIL effectively kills carcinomas that originate from the follicular epithelium of the thyroid gland, by inducing caspase-mediated apoptosis, and may provide a potentially potent therapeutic reagent against thyroid cancer. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Charlestown, MA 02129 USA. Evgenid Hosp, Endocrine Unit, Athens, Greece. NCI, Sect Pediat Tumor Biol & Ultrastruct Pathol, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Athens, Dept Pathol, Athens, Greece. RP Mitsiades, N (reprint author), Dana Farber Canc Inst, Dept Adult Oncol, Mayer Bldg,Room M557,44 Binney St, Boston, MA 02115 USA. FU NIGMS NIH HHS [GM54176] NR 57 TC 84 Z9 96 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2000 VL 60 IS 15 BP 4122 EP 4129 PG 8 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700025 PM 10945619 ER PT J AU Kudoh, K Ramanna, M Ravatn, R Elkahloun, AG Bittner, ML Meltzer, PS Trent, JM Dalton, WS Chin, KV AF Kudoh, K Ramanna, M Ravatn, R Elkahloun, AG Bittner, ML Meltzer, PS Trent, JM Dalton, WS Chin, KV TI Monitoring the expression profiles of doxorubicin-induced and doxorubicin-resistant cancer cells by cDNA microarray SO CANCER RESEARCH LA English DT Article ID TRANSCRIPTIONAL PROGRAM; MULTIDRUG-RESISTANCE; GENE-EXPRESSION; BREAST-CANCER; PROTEASOME; HYBRIDIZATION; MECHANISMS; REPAIR; BCL-2 AB Drug resistance in cancer is a major obstacle to successful chemotherapy, Cancer cells exposed to antitumor drugs may be directly induced to express a subset of genes that could confer resistance, thus allowing some cells to escape killing and form the relapsed resistant tumor, Alternatively, some cancer cells may be expressing an array of genes that could confer intrinsic resistance, and exposure to cytotoxic drugs select for the survival of these cells that form the relapsed tumor. We have used cDNA microarray to monitor the expression profiles of MCF-7 cells that are either transiently treated with doxorubicin or selected for resistance to doxorubicin, Our results showed that transient treatment with doxorubicin altered the expression of a diverse group of genes in a time-dependent manner. A subset of the induced genes was also found to be constitutively overexpressed in cells selected for resistance to doxorubicin, This distinct set of overlapping genes may represent the signature profile of doxorubicin-induced gene expression and resistance in cancer cells. Our studies demonstrate the feasibility of obtaining potential molecular profile or fingerprint of anticancer drugs in cancer cells by cDNA microarray, which might yield further insights into the mechanisms of drug resistance and suggest alternative methods of treatment. C1 Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ 08901 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med, New Brunswick, NJ 08901 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pharmacol, New Brunswick, NJ 08901 USA. Natl Def Med Coll, Dept Obstet & Gynecol, Tokorozawa, Saitama 359, Japan. Res Genet Inc, Huntsville, AL 35801 USA. Natl Human Genome Res Inst, Canc Genet Lab, NIH, Bethesda, MD 20892 USA. H Lee Moffit Canc Ctr & Res Inst, Tampa, FL 33612 USA. RP Chin, KV (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, 195 Little Albany St, New Brunswick, NJ 08901 USA. RI Chin, Khew-Voon/F-2670-2013 FU NCI NIH HHS [CA67722] NR 30 TC 190 Z9 206 U1 1 U2 6 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 AUG 1 PY 2000 VL 60 IS 15 BP 4161 EP 4166 PG 6 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700030 PM 10945624 ER PT J AU Wildner, O Morris, JC AF Wildner, O Morris, JC TI The role of the E1B 55 kDa gene product in oncolytic adenoviral vectors expressing herpes simplex virus-tk: Assessment of antitumor efficacy and toxicity SO CANCER RESEARCH LA English DT Article ID HUMAN LUNG-CARCINOMA; THYMIDINE KINASE; IN-VIVO; CELL-LINES; RECOMBINANT ADENOVIRUS; OVARIAN-CANCER; P53 STATUS; INFECTED HEPATOCYTES; NUCLEOSIDE ANALOGS; DNA-POLYMERASE AB In this study, we evaluated three herpes simplex virus-1 thymidine kinase (HSV-tk) carrying replication-competent adenoviral vectors with and without the Ad5 E1B 55 kDa gene to assess whether this gene product has an influence on their antitumor efficacy, replication kinetics, and potential hepatotoxicity, Furthermore, we assessed the efficacy of these vectors in combination with ganciclovir (GCV), When compared with wild-type adenovirus, the recombinant vectors, in particular the E1B 55 kDa-deleted vector Ad.TKRC(II), generated a more efficiently cytopathic effect in proliferating cells, independently of their p53 phenotype, In a s.c. A549 lung cancer xenograft model, the cytoreductive effect of Ad.TKRC(II) was enhanced when followed by GCV treatment. In contrast, the efficacy of both E1B 55 kDa-positive vectors could not be further improved by GCV, In an i.p. MDAH 2774 ovarian cancer xenograft tumor model, the survival of animals treated with a prototypical replication-deficient adenovirus expressing HSV-tk (Ad.TK) was improved compared to controls when followed by GCV, In contrast, the cytoreductive efficacy of the replication-competent vectors was diminished when combined with the virostatic GCV, However, the antitumor effect of all replication-competent vectors was superior to combination chemotherapy with paclitaxel and carboplatin, In both tumor models, the oncolytic effect of the E1B 55 kDa-positive vectors was greater than that of Ad.TKRC(II), In an attempt to assess the toxicity of these vectors in a nonpermissive host, the viruses were administered systemically to immunocompetent and immunodeficient mice, Greater hepatotoxicity was seen with i.v. administration of the replication-competent viruses than with Ad.TK and in immunocompetent hosts, suggesting involvement of the immune system in the induction of tissue damage, The E1B 55 kDa gene had no significant influence on the liver toxicity of the vectors in this system. At therapeutic doses, intratumoral or i.p. injection of all vectors was well tolerated. Importantly, these replication-competent HSV-tk-expressing vectors were highly susceptible to GCV, representing an effective fail-safe mechanism to abolish viral replication in a clinical setting. Controllable intratumoral viral replication holds promise as a new treatment modality for cancer. C1 NCI, Metab Branch, Div Clin Sci, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Clin Gene Therapy Branch, Bethesda, MD 20892 USA. RP Wildner, O (reprint author), Max Delbruck Ctr Mol Med, Robert Rossle Klin, Charite, Labor Gentherapie, Campus Berlin-Buch,Room 0402,Lindenberger Weg 80, D-13122 Berlin, Germany. NR 67 TC 70 Z9 70 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 1 PY 2000 VL 60 IS 15 BP 4167 EP 4174 PG 8 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700031 PM 10945625 ER PT J AU Nees, M Geoghegan, JM Munson, P Prabhu, V Liu, Y Androphy, E Woodworth, CD AF Nees, M Geoghegan, JM Munson, P Prabhu, V Liu, Y Androphy, E Woodworth, CD TI Human papillomavirus type 16 E6 and E7 proteins inhibit differentiation-dependent expression of transforming growth factor-beta 2 in cervical keratinocytes SO CANCER RESEARCH LA English DT Article ID RETINOBLASTOMA GENE-PRODUCT; FACTOR-BETA; EPITHELIAL-CELLS; P53 PROTEIN; DNA; TRANSCRIPTION; CALCIUM; GROWTH-FACTOR-BETA-1; ONCOPROTEIN; APOPTOSIS AB Infection with high-risk human papillomaviruses (HPVs) represents a major risk factor for the development of cervical cancer. The HPV-16 E6 and E7 proteins are highly expressed in differentiating keratinocytes, where they inactivate the p53 and retinoblastoma (pRb) proteins, two important transcriptional regulators. We have used cDNA expression arrays to identify global alterations in gene expression induced by E6 and E7 in differentiating cultures of human cervical keratinocytes. We show that E6 and E7 decrease expression of TGF-beta 2 mRNA and alter expression of multiple TGF-beta-responsive genes involved in cell cycle regulation, apoptosis, and tissue remodeling. E6 and E7 inhibited expression of TGF-beta 2 RNA 7-fold (relative effectiveness, E6/E7 > E6 > E7 > control) and decreased secretion of biologically active TGF-beta 2 by 70-80% (reduced from 70 to 10 pg/10(6) cells/24 h), Downregulation occurred through p53- and pRb-dependent pathways. In contrast, E6 and E7 did not alter expression of TGF-beta 1 and TGF-beta 3. Down-regulation of TGP-PZ was biologically relevant because the addition of recombinant cytokine (10-200 pg/ml) to E6/E7-expressing cells restored expression of TGF-beta-responsive genes, inhibited growth of keratinocytes, and decreased immortalization by E6 and E7, These results suggest that TGF-beta 2- and TGF-beta-responsive genes are important targets for the HPV-16 E6 and E7 oncoproteins in differentiating cervical keratinocytes. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NCI, Ctr Informat Technol, Bethesda, MD 20892 USA. New England Med Ctr, Dept Dermatol, Boston, MA 02111 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. RP Woodworth, CD (reprint author), Clarkson Univ, Dept Biol, Potsdam, NY 13699 USA. OI Androphy, Elliot/0000-0002-8104-0703 NR 52 TC 42 Z9 49 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 AUG 1 PY 2000 VL 60 IS 15 BP 4289 EP 4298 PG 10 WC Oncology SC Oncology GA 342BQ UT WOS:000088625700050 PM 10945644 ER PT J AU Ramljak, D Calvert, RJ Wiesenfeld, PW Diwan, BA Catipovic, B Marasas, WFO Victor, TC Anderson, LM Gelderblom, WCA AF Ramljak, D Calvert, RJ Wiesenfeld, PW Diwan, BA Catipovic, B Marasas, WFO Victor, TC Anderson, LM Gelderblom, WCA TI A potential mechanism for fumonisin B-1-mediated hepatocarcinogenesis: cyclin D1 stabilization associated with activation of Akt and inhibition of GSK-3 beta activity SO CARCINOGENESIS LA English DT Article ID HUMAN ESOPHAGEAL CANCER; PROTEIN-KINASE-B; CELL-CYCLE; FUSARIUM-MONILIFORME; RAT-LIVER; SPHINGOLIPID BIOSYNTHESIS; INCREASED EXPRESSION; RESTRICTION POINT; MAMMARY-TUMORS; B-1 AB Fumonisin B-1 (FB1) is a worldwide corn contaminant and has been epidemiologically linked to the high incidence of human esophageal cancer in South Africa and China. FB1 is hepatocarcinogenic in rats by an unknown mechanism. Inhibition of ceramide synthase and disruption of membrane phospholipids have been shown to be mechanisms of toxicity. Here we show overexpression of cyclin D1 protein in both preneoplastic and neoplastic liver specimens obtained from a long-term feeding study of FB1 in rats. In rats fed FB1 short-term, cyclin D1 protein levels in liver were increased up to five-fold in a dose-responsive manner. Northern blot analysis demonstrated no increase in mRNA levels of cyclin D1, 2D electrophoresis of cyclin D1 protein in FB1-treated samples showed a distinct pattern of migration (presence of less negatively charged form of the protein) that differed from controls. Recently, it has been shown that phosphorylation of cyclin D1 by glycogen synthase kinase 3 beta (GSK-3 beta) on a single threonine residue (Thr-286) positively regulates proteosomal degradation of cyclin D1, In FB1-treated samples we detected GSK-3 beta phosphorylated on serine 9; activated protein kinase B (Akt) appears to be responsible for this activity-inhibiting phosphorylation, These findings suggest that overexpression of cyclin D1 results from stabilization due to a lack of phosphorylation mediated by GSK-3 beta, We also observed an increase in cyclin dependent kinase 4 (Cdk4) complexes with cyclin D1 in FB1-treated samples; additionally, elevated Cdk4 activity was shown by increased phosphorylation of the retinoblastoma protein. In summary, the activation of Akt leads to increased survival, inhibition of GSK-3 beta activity and post-translational stabilization of cyclin D1, all events responsible for disruption of the cell cycle G(1)/S restriction point in hepatocytes, This is the first report suggesting the mechanism by which FB1 acts as a carcinogen. C1 NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. US FDA, Ctr Food Safety & Appl Nutr, Off Special Nutr, Div Sci & Appl Technol, Laurel, MD 20708 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. Johns Hopkins Univ, Ctr Asthma & Allergy, Baltimore, MD 21224 USA. S African MRC, Nutr Dis Res Inst, ZA-7505 Tygerberg, South Africa. Univ Stellenbosch, MRC, Ctr Cellular & Mol Biol, ZA-7505 Tygerberg, South Africa. RP Ramljak, D (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Bldg 538,Room 205E, Frederick, MD 21702 USA. FU NCI NIH HHS [N01CO56000] NR 59 TC 47 Z9 47 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2000 VL 21 IS 8 BP 1537 EP 1546 DI 10.1093/carcin/21.8.1537 PG 10 WC Oncology SC Oncology GA 340XM UT WOS:000088561800012 PM 10910956 ER PT J AU Khan, QA Dipple, A AF Khan, QA Dipple, A TI Diverse chemical carcinogens fail to induce G(1) arrest in MCF-7 cells SO CARCINOGENESIS LA English DT Article ID WILD-TYPE P53; GENE AMPLIFICATION; CYCLE CONTROL; DNA-DAMAGE; DIHYDRODIOL EPOXIDE; PROTEIN EXPRESSION; HUMAN FIBROBLASTS; MAMMALIAN-CELLS; LUNG-CANCER; LINE MCF-7 AB The effect of three reactive potent chemical carcinogens on the passage of MCF-7 cells through the cell cycle was investigated. While these cells, which express wild-type p53, were arrested in G(1) after treatment with actinomycin D (a positive control), treatment with anti-benzo[a]pyrene dihydrodiol epoxide, N-acetoxy-N-2-fluorenylacetamide or N-methyl-N'-nitro-N-nitrosoguanidine, at doses consistent with survival of significant numbers of cells, caused the cells to accumulate in S phase, with little increase in those in G(1). This property of these three reactive potent carcinogens, of diverse chemical types, to induce evasion of G(1) arrest (the stealth property) presumably increases the likelihood of malignant change, because DNA replication continues on a damaged template. This stealth characteristic may be a major contributor to the tumorigenicity of DNA-adducting chemical carcinogens in general. C1 NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, ABL Basic Res Program, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Khan, QA (reprint author), NCI, Comparat Carcinogenesis Lab, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. NR 61 TC 50 Z9 52 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 AUG PY 2000 VL 21 IS 8 BP 1611 EP 1618 DI 10.1093/carcin/21.8.1611 PG 8 WC Oncology SC Oncology GA 340XM UT WOS:000088561800022 PM 10910966 ER PT J AU Kim, M Katayose, Y Rojanala, L Shah, S Sgagias, M Jang, L Jung, YJ Lee, SH Hwang, SG Cowan, KH AF Kim, M Katayose, Y Rojanala, L Shah, S Sgagias, M Jang, L Jung, YJ Lee, SH Hwang, SG Cowan, KH TI Induction of apoptosis in p16(INK4A) mutant cell lines by adenovirus-mediated overexpression of p16(INK4A) protein SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE adenovirus; p16(INK4A); apoptosis; gene therapy ID CDK INHIBITORS; HUMAN CANCERS; CYCLE ARREST; EXPRESSION; METHYLATION; CHECKPOINTS; DEATH; GENE AB The tumor suppressor gene p16(INK4A) is a cyclin-dependent kinase inhibitor (CDK1) and an important cell cycle regulator. We have previously constructed a recombinant adenovirus which expresses p16 (Adp16) and shown that infection in a variety of human tumor cell lines with this recombinant virus results in high levels of p16(INK4A) protein expression resulting in cell cycle arrest and loss of cyclin-cdk activity. Furthermore, adenoviral-mediated overexpression of wild-type p16(INK4A) is more toxic in cancer cells which express mutant forms of p16(INK4A) compared to cancer cell lines containing endogenous wild-type p16. TUNEL assay and DAPI staining following infection of MDA-MB 231 breast cancer cells with Adp16 indicate that p16(INK4A)-mediated cytotoxicity was associated with apoptosis. This is supported by studies demonstrating a decrease in cpp32 and cyclinB1 protein levels and induction of poly (ADP-ribose) polymerase (PARP) cleavage following infection of MDA-MB-231 cells with Adp16. These results suggest that gene therapy using Adp16 may be a promising treatment option for human cancers containing alterations in p16 expression. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Nebraska Med Ctr 986805, Omaha, NE 68198 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. NCI, Pediat Branch, NIH, Bethesda, MD 20892 USA. Silla Univ, Div New Mat & Biotechnol, Pusan, South Korea. RP Cowan, KH (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Nebraska Med Ctr 986805, Eppley Inst Rm 2016, Omaha, NE 68198 USA. NR 19 TC 23 Z9 29 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI BASINGSTOKE PA HOUNDMILLS, BASINGSTOKE RG21 6XS, HAMPSHIRE, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD AUG PY 2000 VL 7 IS 8 BP 706 EP 711 DI 10.1038/sj.cdd.4400703 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 338KP UT WOS:000088418800003 PM 10918444 ER PT J AU Shilkaitis, A Graves, J Mehta, RR Hu, L You, M Lubet, R Steele, V Kelloff, G Christov, K AF Shilkaitis, A Graves, J Mehta, RR Hu, L You, M Lubet, R Steele, V Kelloff, G Christov, K TI Bcl-2 and Bax are differentially expressed in hyperplastic, premalignant, and malignant lesions of mammary carcinogenesis SO CELL GROWTH & DIFFERENTIATION LA English DT Article ID PROGRAMMED CELL-DEATH; GLAND INVOLUTION; IN-VIVO; BREAST-CARCINOMA; TRANSGENIC MICE; GENE BAX; APOPTOSIS; PROTEIN; SURVIVAL; TISSUES AB Previously, we found that vorozole (Vz), a nonsteroidal aromatase inhibitor, suppresses the development and progression of mammary tumors in rats. Here we evaluated for the first time the expression of cell death-related proteins Bcl-2 and Bax in hyperplastic, premalignant (carcinoma in situ), or malignant (carcinoma) lesions of mammary carcinogenesis; we also assessed whether these proteins are involved in mediating Vz-induced cell death in tumors. We found that Bcl-2 and Bax were equally expressed in epithelial cells of terminal end buds, ducts, and alveoli. However, in myoepithelial cells, the level of Bax expression was much higher than the level of Bcl-2 expression. Bcl-2 and Bax levels in hyperplastic lesions were similar to those of normal mammary epithelial cells but lower in most carcinomas in situ and carcinomas. In animals with established mammary tumors, Vt induced apoptotic cell death, which was primarily associated with a decrease in Bcl-2 and, to a lesser extent, with a decrease in Bax. These data support the hypothesis that Bcl-2 loss is more potent than Bax gain in regulating apoptotic cell death in mammary tumors. C1 Univ Illinois, Dept Surg Oncol, Chicago, IL 60612 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43699 USA. NCI, Div Canc Prevent, Rockville, MD 20852 USA. RP Christov, K (reprint author), Univ Illinois, Dept Surg Oncol, 840 S Wood St,M-C 820, Chicago, IL 60612 USA. FU NCI NIH HHS [N01-CN 55179-MAO, N01-CN-65123-MAO] NR 44 TC 11 Z9 12 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1044-9523 J9 CELL GROWTH DIFFER JI Cell Growth Differ. PD AUG PY 2000 VL 11 IS 8 BP 437 EP 445 PG 9 WC Cell Biology SC Cell Biology GA 345NQ UT WOS:000088822400003 PM 10965848 ER PT J AU Nam, SW Clair, T Schiffmann, E Liotta, LA Stracke, ML AF Nam, SW Clair, T Schiffmann, E Liotta, LA Stracke, ML TI A sensitive screening assay for secreted motility-stimulating factors SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article DE motility; autotaxin; Boyden chamber; chemotaxis; autocrine motility factor ID TRANSFORMING GROWTH-FACTORS; TUMOR-CELLS; MOLECULAR-CLONING; SEQUENCE-ANALYSIS; FACTOR-II; AUTOTAXIN; EXPRESSION; PROTEIN; PURIFICATION; CDNA AB Secreted motility-stimulating factors are often expressed and secreted at low concentrations that are difficult to detect by Northern or Western blot analysis. Autotaxin (ATX) is a tumor-secreted autocrine motility-stimulating factor that has been associated with tumor invasion and metastatic potential. Although ATX has a number of enzymatic activities, it is most sensitively detected by its induced chemotactic response. After transfecting ATX cDNA into NIH3T3 fibroblasts, we developed a motility-based method to screen the resulting cloned cells for secretion of active protein. We placed the cloned and transfected cells into the bottom wells of a modified Boyden chamber and placed responding cells (A2058 human melanoma cells) into the upper wells. After overnight incubation, the membrane that separated the two chambers was removed and stained. Simple densitometry measurements were sufficiently accurate to determine which clones secreted active protein. Utilizing this method, 4 positive cell lines were chosen out of 36 tested clones. Further tests on the expanded cell lines determined that all 4 were secreting ATX. Thus, this modified Boyden chamber assay appears to provide a rapid and highly adaptable means to identify cells that secrete motility-stimulating factors. Cell Motil. Cytoskeleton 46:279-284, 2000. dagger Published 2000 Wiley-Liss, Inc. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Nam, SW (reprint author), NCI, Pathol Lab, NIH, Bldg 10 Rm 2A33,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 23 TC 12 Z9 12 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 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD AUG PY 2000 VL 46 IS 4 BP 279 EP 284 DI 10.1002/1097-0169(200008)46:4<279::AID-CM5>3.0.CO;2-P PG 6 WC Cell Biology SC Cell Biology GA 350BD UT WOS:000089080100005 PM 10962482 ER PT J AU Putney, JW Ribeiro, CMP AF Putney, JW Ribeiro, CMP TI Signaling pathways between the plasma membrane and endoplasmic reticulum calcium stores SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE calcium signaling; calcium pools; capacitative calcium entry; gene expression; apoptosis; endoplasmic reticulum structure; protein kinase C ID PROTEIN-KINASE-C; CAPACITATIVE CA2+ ENTRY; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; CYCLIC ADP-RIBOSE; CA2+-ATPASE INHIBITOR THAPSIGARGIN; GLUCOCORTICOID-INDUCED APOPTOSIS; CA2+-PERMEABLE CATION CHANNEL; GLUCOSE-REGULATED PROTEINS; VASCULAR ENDOTHELIAL-CELLS; OPERATED HTRP3 CHANNELS AB This review discusses multiple ways in which the endoplasmic reticulum participates in and is influenced by signal transduction pathways. The endoplasmic reticulum provides a Ca2+ store that can be mobilized either by calcium-induced calcium release or by the diffusible messenger inositol 1,4,5-trisphosphate. Depletion of endoplasmic reticulum Ca2+ stores provides a signal that activates surface membrane Ca2+ channels, a process known as capacitative calcium entry. Depletion of endoplasmic reticulum stores can also signal long-term cellular responses such as gene expression and programmed cell death or apoptosis. In addition to serving as a source of cellular signals, the endoplasmic reticulum is also functionally and structurally modified by the Ca2+ and protein kinase C pathways. Elevated cytoplasmic Ca2+ causes a rearrangement and fragmentation of endoplasmic reticulum membranes. Protein kinase C activation reduces the storage capacity of the endoplasmic reticulum Ca2+ pool. In some cell types. protein kinase C inhibits capacitative calcium entry. Protein kinase C activation also protects the endoplasmic reticulum from the structural effects of high cytoplasmic Ca2+. The emerging view is one of a complex network of pathways through which the endoplasmic reticulum and the Ca2+ and protein kinase C signaling pathways interact at various levels regulating cellular structure and function. C1 NIEHS, Lab Signal Transduct, Calcium Regulat Sect, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Med, Cyst Fibrosis Pulm Res & Training Ctr, Chapel Hill, NC 27599 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, Calcium Regulat Sect, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. RI Ribeiro, Carla Maria/A-6955-2009 NR 166 TC 86 Z9 91 U1 2 U2 27 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD AUG PY 2000 VL 57 IS 8-9 BP 1272 EP 1286 DI 10.1007/PL00000765 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 349YY UT WOS:000089074300012 PM 11028918 ER PT J AU Vinade, L Dosemeci, A AF Vinade, L Dosemeci, A TI Regulation of the phosphorylation state of the AMPA receptor GluR1 subunit in the postsynaptic density SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE glutamate receptors; GluR1; postsynaptic density; Ca2+/calmodulin-dependent protein kinase; cAMP-dependent protein kinase; protein phosphatase ID LONG-TERM POTENTIATION; PROTEIN-KINASE-II; GLUTAMATE RECEPTORS; DEPENDENT PHOSPHORYLATION; SYNAPTIC ACTIVITY; CALMODULIN; DEPRESSION; PHOSPHATASE; PROTEIN-PHOSPHATASE-1; CONDUCTANCE AB 1. Changes in the phosphorylation state of AMPA-type glutamate receptors are thought to underlie activity-dependent synaptic modification. It has been established that the GluR1 subunit is phosphorylated on two distinct sires, Ser-831 and Ser-845, by CaMKII and by PKA, respectively, and that phosphorylation by either kinase correlates with an increase-in the AMPA receptor-mediated current. GluR1 is concentrated in postsynaptic densities and it is expected that this particular receptor pool is involved in synaptic modification. The present study describes the regulation of the phosphorylation state of GluR1 in isolated postsynaptic densities. 2. Addition of Ca2+/calmodulin to the postsynaptic density fraction promotes phosphorylation of GluR1, and under these conditions, dephosphorylation is prevented by the inclusion of phosphatase type 1 inhibitors, microcystin-LR and Inhibitor-1. CaMKII and phosphatase type 1 are also found to be enriched in the PSD fraction compared to the parent fractions. 3. On the other hand, the addition of cAMP, either by itself or with exogenous PKA, does not change the phosphorylation slate of GluR1. Prior incubation of PSDs under dephosphorylating conditions results in only a small PKA-mediated phosphorylation of GluR1. 4. These results support the hypothesis that PSDs contain the molecular machinery to promote the phosphorylation as well as the dephosphorylation of GluR1 on Ser-831, while Ser-845, the site phosphorylated by PKA, appears to be mostly occluded. Thus, it is possible that a large pool of PSD-associated GluR1 is regulated through modification of the phosphorylation state of the Ser-831 site only. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP NINDS, Neurobiol Lab, NIH, Bldg 36-2A21, Bethesda, MD 20892 USA. EM vinade@codon.nih.gov NR 30 TC 24 Z9 27 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 EI 1573-6830 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD AUG PY 2000 VL 20 IS 4 BP 451 EP 463 DI 10.1023/A:1007019030595 PG 13 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 330PD UT WOS:000087969700003 PM 10901266 ER PT J AU Maric, D Maric, I Chang, YH Barker, JL AF Maric, D Maric, I Chang, YH Barker, JL TI Stereotypical physiological properties emerge during early neuronal and glial lineage development in the embryonic rat neocortex SO CEREBRAL CORTEX LA English DT Article ID MICROTUBULE-ASSOCIATED PROTEINS; AVIAN SPINAL-CORD; SONIC HEDGEHOG; TETANUS TOXIN; PRECURSOR CELLS; MONOCLONAL-ANTIBODIES; VENTRICULAR ZONE; NERVOUS-SYSTEM; EXPRESSION; CALCIUM AB Surface immunolabeling was used together with membrane potential and/or Ca2+ indicator dyes to characterize physiological properties emerging among precursors, neuroglial progenitors and differentiating neurons during neurogenesis of embryonic rat neocortex. Cells were immunoidentified with tetanus toxin (TnTx), which binds to gangliosides expressed by neurons, and anti-A2B5, which reacts with gangliosides expressed by neuroglial progenitors. Microdissection of the neocortex into ventricular/subventricular zone (WZ/SVZ) and cortical plate/subplate (CP/SP) regions further resolved the TnTx/A2B5-immunoidentified cells into pre- and post-migratory subpopulations. Quantitative immunocytochemistry revealed mainly proliferative (BrdU(+)) and immature (nestin(+)) elements among TnTx(-)A2B5(-) precursors and TnTx(-)A2B5(+) progenitors in the VZ/SVZ. and the appearance of neuron-specific antigens among post-mitotic TnTx(+) subpopulations of the CP/SP Flow cytometry of acutely prepared cells in suspension and dual-imaging of cells in culture revealed that ionotropic amino acid receptors and metabotropic acetylcholine receptors closely paralleled the emergence of voltage-dependent Na+ and Ca2+ channels and Na+-Ca2+ exchange activity among TnTx(+) neuronal progenitors migrating from VZ/SVZ to CP/SP. During this period, TnTx(-)A2B5(-) precursors and TnTx(-)A2B5(+) neuroglial progenitors from VZ/SVZ predominantly exhibited Ca2+ responses to ATP. Thus, stereotypical and contrasting physiologies emerge among embryonic cortical cells in vivo as they initially progress from proliferating precursors and progenitors along neuronal and glial cell lineages. C1 NINDS, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Maric, D (reprint author), NINDS, Neurophysiol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 56 TC 29 Z9 30 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD AUG PY 2000 VL 10 IS 8 BP 729 EP 747 DI 10.1093/cercor/10.8.729 PG 19 WC Neurosciences SC Neurosciences & Neurology GA 337NB UT WOS:000088366900001 PM 10920046 ER PT J AU Aposhian, HV Gurzau, ES Le, XC Gurzau, A Healy, SM Lu, XF Ma, MS Yip, L Zakharyan, RA Maiorino, RM Dart, RC Tircus, MG Gonzalez-Ramirez, D Morgan, DL Avram, D Aposhian, MM AF Aposhian, HV Gurzau, ES Le, XC Gurzau, A Healy, SM Lu, XF Ma, MS Yip, L Zakharyan, RA Maiorino, RM Dart, RC Tircus, MG Gonzalez-Ramirez, D Morgan, DL Avram, D Aposhian, MM TI Occurrence of monomethylarsonous acid in urine of humans exposed to inorganic arsenic SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID ENZYMATIC METHYLATION; RABBIT LIVER; WEST-BENGAL; METHYLTRANSFERASE; WATER; TOXICITY AB Monomethylarsonous acid (MMA(III)) has been detected for the first time in the urine of some humans exposed to inorganic arsenic in their drinking water. Our experiments have dealt with subjects in Romania who have been exposed to 2.8, 29, 84, or 161 mu g of As/L in their drinking water. In the latter two groups, MMA(III) was 11 and 7% of the urinary arsenic while the monomethylarsonic acid (MMA(V)) was 14 and 13%, respectively. Of our 58 subjects, 17% had MMA(III) in their urine. MMA(III) was not found in urine of any members of the group with the lowest level of As exposure. If the lowest-level As exposure group is excluded, 23% of our subjects had MMA(III) in their urine. Our results indicate that (a) future studies concerning urinary arsenic profiles of arsenic-exposed humans must determine MMA(III) concentrations, (b) previous studies of urinary profiles dealing with humans exposed to arsenic need to be re-examined and re-evaluated, and (c) since MMA(III) is more toxic than inorganic arsenite, a re-examination is needed of the two hypotheses which hold that methylation is a detoxication process for inorganic arsenite and that inorganic arsenite is the major cause of the toxicity and carcinogenicity of inorganic arsenic. C1 Univ Arizona, Dept Mol & Cellular Biol, Tucson, AZ 85721 USA. Ctr Environm Hlth, Cluj Napoca 3400, Romania. Univ Alberta, Fac Med & Dent, Dept Publ Hlth Sci, Edmonton, AB T6G 2G3, Canada. Rocky Mt Poison & Drug Control Ctr, Denver, CO 80220 USA. State Sanitary Inspect Arad, Arad 2900, Romania. Inst Mexicano Seguro Social, Unidad Invest Biomed Noreste, Dept Farmacol, Monterrey 64720, Nuevo Leon, Mexico. NIEHS, Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Aposhian, HV (reprint author), Univ Arizona, Dept Mol & Cellular Biol, Life Sci S Bldg,Rm 444,POB 210106, Tucson, AZ 85721 USA. RI Le, X. Chris/O-4947-2015 OI Le, X. Chris/0000-0002-7690-6701 FU NIEHS NIH HHS [ES04940, P30ES06694] NR 28 TC 210 Z9 214 U1 1 U2 12 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 AUG PY 2000 VL 13 IS 8 BP 693 EP 697 DI 10.1021/tx000114o PG 5 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 347WD UT WOS:000088951400002 PM 10956055 ER PT J AU Nicolaou, KC Scarpelli, R Bollbuck, B Werschkun, B Pereira, MMA Wartmann, M Altmann, KH Zaharevitz, D Gussio, R Giannakakou, P AF Nicolaou, KC Scarpelli, R Bollbuck, B Werschkun, B Pereira, MMA Wartmann, M Altmann, KH Zaharevitz, D Gussio, R Giannakakou, P TI Chemical synthesis and biological properties of pyridine epothilones SO CHEMISTRY & BIOLOGY LA English DT Article DE antitumor activity; chemical synthesis; epothilones; molecular modeling; pyridine epothilones ID (-)-EPOTHILONE-A; ANALOGS; ASSAY AB Background: Numerous analogs of the antitumor agents epothilones A and B have been synthesized in search of better pharmacological profiles. Insights into the structure-activity relationships within the epothilone family are still needed and more potent and selective analogs of these compounds are in demand, both as biological tools and as chemotherapeutic agents, especially against drug-resistant tumors, Results: A series of pyridine epothilone B analogs were designed, synthesized and screened. The synthesized compounds exhibited varying degrees of tubulin polymerization and cytotoxicity properties against a number of human cancer cell lines depending on the location of the nitrogen atom and the methyl substituent within the pyridine nucleus. Conclusions: The biological screening results in this study established the importance of the nitrogen atom at the ortho position as well as the beneficial effect of a methyl substituent at the 4- or 5-position of the pyridine ring. Two pyridine epothilone B analogs (i.e. compounds 3 and 4) possessing higher potencies against drug-resistant tumor cells than epothilone B, the most powerful of the naturally occurring epothilones, were identified. C1 Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. Novartis Pharma AG, TA Oncol Res, CH-4002 Basel, Switzerland. NCI, Target Struct Based Drug Discovery Grp, Informat Technol Branch, Dev Therapeut Program,NIH, Frederick, MD 21702 USA. NCI, Med Branch, NIH, Bethesda, MD 20892 USA. RP Nicolaou, KC (reprint author), Scripps Res Inst, Dept Chem, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. RI Scarpelli, Rita/A-2985-2012; Pereira, M. Manuela/C-8607-2013; Scarpelli, Rita/O-9422-2015 OI Pereira, M. Manuela/0000-0002-2358-9757; NR 25 TC 103 Z9 105 U1 1 U2 7 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD AUG PY 2000 VL 7 IS 8 BP 593 EP 599 DI 10.1016/S1074-5521(00)00006-5 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 363YX UT WOS:000089866200005 PM 11048950 ER PT J AU Gowdak, LHW Poliakova, L Wang, XT Kovesdi, I Fishbein, KW Zacheo, A Palumbo, R Straino, S Emanueli, C Marrocco-Trischitta, M Lakatta, EG Anversa, P Spencer, RGS Talan, M Capogrossi, MC AF Gowdak, LHW Poliakova, L Wang, XT Kovesdi, I Fishbein, KW Zacheo, A Palumbo, R Straino, S Emanueli, C Marrocco-Trischitta, M Lakatta, EG Anversa, P Spencer, RGS Talan, M Capogrossi, MC TI Adenovirus-mediated VEGF(121) gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia SO CIRCULATION LA English DT Article; Proceedings Paper CT 48th Annual Scientific Session of the American-College-of-Cardiology CY MAR 07-11, 1999 CL NEW ORLEANS, LOUISIANA SP Amer Coll Cardiol DE angiogenesis; endothelium-derived factors; genes; ischemia; peripheral vascular disease ID ENDOTHELIAL GROWTH-FACTOR; CORONARY-ARTERY DISEASE; THERAPEUTIC ANGIOGENESIS; LIMB ISCHEMIA; RABBIT MODEL; VEGF121 CDNA; REVASCULARIZATION; P-31-NMR; PHVEGF(165) AB Background-Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF(121)) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia. Methods and Results-Rabbits and rats received IM injections of AdCMV.VEGF(121), AdCMV.Null, or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF(121), we found 96% and 29% increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF(121), group was documented, as early as day I after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF(121)=5.69+/-0.40, AdCMV.Null=2.97+/-0.50, and saline=2.97+/-0.43 mL . min(-1) . 100 g(-1), P<0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV.VEGF(121)=50.58+/-1.48, AdCMV.Null=29.08+/-4.22, saline=11.83+/-1.90, P<0.0001), and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by P-31 NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF(121) group persisted until it was equalized by spontaneous collateral vessel development in untreated animals. Conclusions-IM administration of AdCMV.VEGF(121) stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NIA, Gene Therapy Unit, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. NIA, Nucl Magnet Resonance Unit, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. GenVec Inc, Rockville, MD USA. IRCCS, Ist Dermopat Immacolata, Lab Patol Vascolare, Rome, Italy. New York Med Coll, Dept Med, Valhalla, NY 10595 USA. RP Talan, M (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. RI Marrocco-Trischitta, Massimiliano M./A-9081-2016; Wolff Gowdak, Luis Henrique/C-4844-2012; OI Marrocco-Trischitta, Massimiliano M./0000-0003-1707-9627; Wolff Gowdak, Luis Henrique/0000-0002-6785-7506; Fishbein, Kenneth/0000-0002-6353-4603 NR 25 TC 97 Z9 103 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 1 PY 2000 VL 102 IS 5 BP 565 EP 571 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 339PB UT WOS:000088486200016 PM 10920070 ER PT J AU Okayama, Y AF Okayama, Y TI Human cultured mast cells SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Editorial Material ID FACTOR-DEPENDENT DEVELOPMENT; BLOOD MONONUCLEAR-CELLS; UMBILICAL-CORD BLOOD; RECOMBINANT HUMAN; PERIPHERAL-BLOOD; BONE-MARROW; KIT-LIGAND; GROWTH; IL-4; DIFFERENTIATION C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Okayama, Y (reprint author), NIAID, Lab Allerg Dis, NIH, 10 Ctr Dr MSC 1881, Bethesda, MD 20892 USA. NR 25 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 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD AUG PY 2000 VL 30 IS 8 BP 1053 EP 1055 PG 3 WC Allergy; Immunology SC Allergy; Immunology GA 338WE UT WOS:000088445600001 PM 10931110 ER PT J AU Zahedi, R Braun, M Wetsel, RA Ault, BH Khan, A Welch, TR Frenzke, M Davis, AE AF Zahedi, R Braun, M Wetsel, RA Ault, BH Khan, A Welch, TR Frenzke, M Davis, AE TI The C5a receptor is expressed by human renal proximal tubular epithelial cells SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE complement; renal proximal tubules; C5a receptor ID MESANGIAL CELLS; GROWTH-FACTORS; MESSENGER-RNA; HUMAN-KIDNEY; MEDIATED GLOMERULONEPHRITIS; CELLULAR EXPRESSION; UP-REGULATION; P-SELECTIN; TNF-ALPHA; IN-VIVO AB The C5a receptor is expressed by a variety of cell types. These studies demonstrate by immunohistochemistry that the receptor is present on the surface of proximal and distal tubular epithelial cells from normal kidney. In addition, the receptor was detected on transitional epithelial cells of the ureter and bladder. Primary proximal tubular cultures and a proximal tubular cell line both also expressed the C5a receptor, as demonstrated by immunofluorescence and by FACS analysis. The presence of mRNA encoding the receptor was confirmed by reverse transcriptase-polymerase chain reaction analysis. As opposed to its effect on glomerular mesangial cells, the receptor did not mediate a proliferative response by the proximal tubular cells. C5a also did not enhance the synthesis/secretion of transforming growth factor-beta 1, monocyte chemoattractant protein-1, platelet-derived growth factor-AB or tumour necrosis factor-alpha by cultured proximal tubular cells. Therefore, although the C5a receptor clearly is expressed by proximal tubular cells, clarification of its functional relevance on this cell type awaits further studies. C1 Ctr Blood Res, Boston, MA 02115 USA. NIAID, Clin Invest Lab, Mucosal Immun Sect, Inst Mol Med, Bethesda, MD 20892 USA. Univ Tennessee, Coll Med, Dept Paediat, Memphis, TN USA. Washington Univ, Sch Med, Dept Paediat, St Louis, MO USA. Childrens Hosp Res Fdn, Div Nephrol, Cincinnati, OH 45229 USA. RP Davis, AE (reprint author), Ctr Blood Res, 800 Huntington Ave, Boston, MA 02115 USA. FU NIAID NIH HHS [R01 AI025011, AI25011]; NICHD NIH HHS [R01 HD033727, HD33727, R37 HD022082, HD22082] NR 52 TC 41 Z9 45 U1 0 U2 1 PU BLACKWELL SCIENCE LTD PI OXFORD PA P O BOX 88, OSNEY MEAD, OXFORD OX2 0NE, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD AUG PY 2000 VL 121 IS 2 BP 226 EP 233 DI 10.1046/j.1365-2249.2000.01249.x PG 8 WC Immunology SC Immunology GA 336NK UT WOS:000088309000009 PM 10931135 ER PT J AU Woods, JJ Sampson, ML Ruddel, ME Remaley, AT AF Woods, JJ Sampson, ML Ruddel, ME Remaley, AT TI Rapid intraoperative cortisol assay: Design and utility for localizing adrenal tumors by venous sampling SO CLINICAL BIOCHEMISTRY LA English DT Article ID PRIMARY ALDOSTERONISM; HYPERALDOSTERONISM; DIAGNOSIS C1 NIH, Dept Clin Pathol, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NIH, Dept Clin Pathol, Bldg 10,Rm 2C-433,10 Ctr Dr, Bethesda, MD 20892 USA. NR 7 TC 15 Z9 15 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0009-9120 J9 CLIN BIOCHEM JI Clin. Biochem. PD AUG PY 2000 VL 33 IS 6 BP 501 EP 503 DI 10.1016/S0009-9120(00)00141-7 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 376MU UT WOS:000165462000010 PM 11074243 ER PT J AU Maxwell, GL Risinger, JI Hayes, KA Alvarez, AA Dodge, RK Barrett, JC Berchuck, A AF Maxwell, GL Risinger, JI Hayes, KA Alvarez, AA Dodge, RK Barrett, JC Berchuck, A TI Racial disparity in the frequency of PTEN mutations, but not microsatellite instability, in advanced endometrial cancers SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; FOCAL ADHESION KINASE; PROGNOSTIC-SIGNIFICANCE; P53 OVEREXPRESSION; CARCINOMA; WOMEN; PTEN/MMAC1; SURVIVAL; GROWTH; ADENOCARCINOMA AB Survival of African Americans with endometrial cancer is significantly worse than that of whites. Mutation of the PTEN tumor suppressor gene and microsatellite instability occur in some endometrial cancers, and they are associated with favorable prognostic features. The aim of this study was to determine whether there is a racial disparity in the frequency of these molecular alterations that contributes to differences in outcome in advanced endometrial cancer. We screened 140 stage III/IV endometrial adenocarcinomas (78 Caucasian, 62 African American) for mutations in the PTEN gene. Paired DNA samples were available in 100 cases and were analyzed for microsatellite instability using three polymorphic markers. African-American women had cancers with significantly higher stage and grade that were more often non-endometrioid, In addition, median survival of African Americans (1.0 years) was worse than that of whites (2.5 years; P = 0.02). PTEN mutation was seen in 20 of 140 (14%) cancers and was associated with endometrioid histology and more favorable survival. The frequency of PTEN mutations was significantly higher in whites (17 of 78; 22%) than in African Americans (3 of 62; 5%; P = 0.006), Microsatellite instability was found in 15% of cancers, exclusively in endometrioid cases, and was associated with favorable survival (P = 0.01). There was no racial difference in the frequency of microsatellite instability, We conclude that mutation of the PTEN tumor suppressor gene is associated with favorable survival in advanced endometrial cancer and is 4-fold more frequent in Caucasians relative to African Americans. This suggests that differences in the frequency of PTEN mutations contribute to the racial disparity in endometrial cancer survival. 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 44 TC 55 Z9 55 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI BIRMINGHAM PA PO BOX 11806, BIRMINGHAM, AL 35202 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG PY 2000 VL 6 IS 8 BP 2999 EP 3005 PG 7 WC Oncology SC Oncology GA 344HN UT WOS:000088753300009 PM 10955777 ER PT J AU Dahl, AR Grossi, IM Houchens, DP Scovell, LJ Placke, ME Imondi, AR Stoner, GD De Luca, LM Wang, DL Mulshine, JL AF Dahl, AR Grossi, IM Houchens, DP Scovell, LJ Placke, ME Imondi, AR Stoner, GD De Luca, LM Wang, DL Mulshine, JL TI Inhaled isotretinoin (13-cis retinoic acid) is an effective lung cancer chemopreventive agent in A/J mice at low doses: A pilot study SO CLINICAL CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; 2ND PRIMARY TUMORS; GROWTH-INHIBITION; VITAMIN-A; PULMONARY CARCINOGENESIS; TISSUE TRANSGLUTAMINASE; BETA-CAROTENE; MOUSE; RAS; CYCLOOXYGENASE-2 AB In previously treated head-and-neck cancer patients, p.o. administered isotretinoin (13-cis retinoic acid) reduced the occurrence of second aerodigestive tumors, including lung tumors, but side effects made chronic therapy problematic. We reasoned that inhaled isotretinoin might provide sufficient drug to the target cells for efficacy while avoiding systemic toxicity, and we proceeded with the pilot study reported here. Male A/J mice were given single i.p. doses of urethane, a common experimental lung carcinogen, or benzo[a]pyrene (BaP) or 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK), putative major carcinogens in tobacco smoke. The following day, exposures to isotretinoin aerosols for 45 min daily at 1.3, 20.7, or 481 mu g/l were initiated. After 2 weeks, the high dose caused severe toxicity on the snout skin, necessitating a reduction of dose frequency to twice a week. As a precaution, the mid dose was reduced to three exposures per week. The weekly total deposited doses after the dose frequency reductions were calculated to be 0.24, 1.6, and 24.9 mg/kg for the low, mid, and high doses, of which 16% was estimated to be deposited in the lungs. The weekly deposited pulmonary drug doses were calculated to be 0.01, 0.07, and 1.1% of a previously reported ineffective oral dose in urethane-treated A/J mice. After 10-16 weeks, mice were sacrificed to count areas of pulmonary hyperplasia and adenomas. For all, carcinogens, the mice exposed to the high isotretinoin dose showed reductions of tumor multiplicity ranging from 56 to 80% (P < 0.005). The mid dose was associated with reductions of tumor multiplicity by 67 and 88% (P < 0.005) in BaP- and NNK-treated mice, respectively, and was tolerated until similar to 12 weeks, when both these and the high-dose mice began losing weight. The low-dose mice had nonsignificant reductions of 30% (P < 0.13) and 16% (P < 0.30) for BaP- and NNK-treated mice, respectively without any evidence of side effects. For BaP- and NNK-treated mice, numbers of hyperplastic areas directly correlated to dose level and inversely to tumor number, suggesting arrested progression. Inhaled mid-dose isotretinoin caused up-regulation of lung tissue nuclear retinoic acid receptors (RARs) relative to vehicle-exposed mice, RAR alpha (3.9-fold vehicle), RAR beta (3.3-fold), and RAR gamma (3.7-fold), suggesting that these receptors may be useful biomarkers of retinoid activity in this system. The encouraging results from this pilot study suggest that inhaled isotretinoin merits evaluation in people at high risk for lung cancer. C1 Battelle Mem Inst, Columbus, OH 43201 USA. Ohio State Univ, Columbus, OH 43210 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Dahl, AR (reprint author), Battelle Mem Inst, 505 King Ave, Columbus, OH 43201 USA. EM Dahla@Battelle.org NR 52 TC 58 Z9 58 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG PY 2000 VL 6 IS 8 BP 3015 EP 3024 PG 10 WC Oncology SC Oncology GA 344HN UT WOS:000088753300011 PM 10955779 ER PT J AU Alexander, HR Libutti, SK Bartlett, DL Puhlmann, M Fraker, DL Bachenheimer, LC AF Alexander, HR Libutti, SK Bartlett, DL Puhlmann, M Fraker, DL Bachenheimer, LC TI A phase I-II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver SO CLINICAL CANCER RESEARCH LA English DT Article ID ISOLATED LIMB PERFUSION; INTERFERON-GAMMA; UVEAL MELANOMA; EXPERIENCE; CANCER; ALPHA; CHEMOEMBOLIZATION; CHEMOTHERAPY; CISPLATIN; SURVIVAL AB There are no satisfactory treatment options for patients with ocular melanoma metastatic to liver, and after liver metastases are identified, median survival is only between 2 and 7 months. Because liver metastases are the sole or life-limiting component of disease in the vast majority of patients who recur, we reasoned that complete vascular isolation and perfusion of the liver might result in clinically meaningful regression of disease. Between September 1994 and July 1999, 22 patients (13 women and 9 men; mean age, 49 years) with ocular melanoma metastatic to liver were treated with a 60-min hyperthermic isolated hepatic perfusion (IHP) using melphalan alone (1.5-25 mg/kg, n = 11) or with tumor necrosis factor (TNF, 1.0 mg, n = II). Via a laparotomy, IHP inflow was via the hepatic artery alone (n = 17) or hepatic artery and portal vein (n = 5) and outflow from an isolated segment of inferior vena cava, Most patients had advanced tumor burden with a mean percentage of hepatic replacement of 25% (range, 10-75%) and a median number of metastatic nodules of 25 (range, 5 to >50), Complete vascular isolation was confirmed in all patients using a continuous intraoperative leak monitoring technique with I-131 radiolabeled albumin. There was one treatment mortality (5%), The overall response rate in 21 patients was 62% including 2 radiographic complete responses (9.5%) and II partial responses (52%), The overall median duration of response was 9 months (range, 5-50) and was significantly longer in those treated with TNF than without (14 versus 6 months, respectively; P = 0.04), Overall median survival in 22 patients was 11 months. These data indicate that a single 60-min IHP can result in significant regression of advanced hepatic metastases from ocular melanoma, TNF appears to significantly prolong the duration of response. C1 NCI, Surg Metab Sect, Surg Branch, Div Clin Sci,Warren G Magnuson Clin Ctr,NIH, Bethesda, MD 20892 USA. NIH, Dept Anesthesia, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Metab Sect, Surg Branch, Div Clin Sci,Warren G Magnuson Clin Ctr,NIH, Bldg 10,Rom 2B07,10 Ctr Dr, Bethesda, MD 20892 USA. NR 29 TC 97 Z9 99 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 AUG PY 2000 VL 6 IS 8 BP 3062 EP 3070 PG 9 WC Oncology SC Oncology GA 344HN UT WOS:000088753300017 PM 10955785 ER PT J AU Tempero, M Leichner, P Baranowska-Kortylewicz, J Harrison, K Augustine, S Schlom, J Anderson, J Wisecarver, J Colcher, D AF Tempero, M Leichner, P Baranowska-Kortylewicz, J Harrison, K Augustine, S Schlom, J Anderson, J Wisecarver, J Colcher, D TI High-dose therapy with (90)yttrium-labeled monoclonal antibody CC49: A phase I trial SO CLINICAL CANCER RESEARCH LA English DT Article ID RADIOIMMUNOTHERAPY TRIAL; COLORECTAL-CANCER; RADIATION-THERAPY; TUMOR; GENERATION; CARCINOMA; B72.3; DOSIMETRY; ANTIGEN AB A Phase I trial of increasing administered activities of (90)yttrium (Y-90)-labeled monoclonal antibody (MAb) CC49 was conducted to determine whether extrahematopoietic toxicity occurred with this radioimmunoconjugate. Twelve patients with various gastrointestinal tract cancers were administered a tracer dose of In-111-labeled MAb CC49 for biodistribution and pharmacokinetic studies, Patients then underwent a single treatment with increasing administered activities of Y-90-labeled MAb CC49 (0.3, 0.4, and 0.5 mCi/kg), Biodistribution studies, using In-111-labeled MAb CC49 as a surrogate, were determined using planar and single photon emission computed tomography imaging. Pharmacokinetic studies were performed by measuring radioactivity in blood samples taken at intervals after radioimmunoconjugate infusions, Tissue biopsies of tumor metastases and related normal tissues (liver and bone marrow) were obtained for radioactivity measurements. Radiation dosimetry estimates were calculated using these data, Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria. No dose limiting extrahematopoietic toxicity was identified in the range of administered activities used in this study, Radioimmunolocalization based on planar and single photon emission computed tomography images In-111-labeled MAb CC49 showed heterogeneous (nonspecific) liver and splenic uptake. Liver metastases were usually photopenic, and extrahepatic metastases showed faint to moderate uptake. The alpha and beta half-lives of In-111-labeled MAb CC49 and Y-90-labeled MAb CC49 in the blood were similar. Absorbed radiation dose estimates in metastatic tumor sites ranged from 180 to 3000 cGy, The percentage of injected dose/kg of tumor ranged from 1.12 to 18.14; however, tumor:normal liver ratios were consistently <1, No objective responses were observed. Doses of up to 0.5 mCi/kg could be administered with reversible grade IV myelotoxicity, Absorbed radiation dose in tumor was suboptimal, even at the highest administered activity level, Deposition of Y-90 in liver was high, and estimates of absorbed dose in liver equaled or exceeded that which could be achieved in metastatic tumor sites. Strategies to enhance access of radioimmunoconjugates in tumor and diminish deposition in the liver need to be developed for effective treatment using MAb CC49 with cheIated radiometals. C1 Univ Calif San Francisco, Ctr Comprehens Canc, Dept Internal Med, San Francisco, CA 94115 USA. Univ Nebraska, Med Ctr, Dept Radiat Oncol, Omaha, NE 68198 USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Tempero, M (reprint author), Univ Calif San Francisco, Ctr Comprehens Canc, Dept Internal Med, 2356 Sutter St,Suite J708, San Francisco, CA 94115 USA. FU NCI NIH HHS [U01-CA58272] NR 26 TC 49 Z9 50 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 AUG PY 2000 VL 6 IS 8 BP 3095 EP 3102 PG 8 WC Oncology SC Oncology GA 344HN UT WOS:000088753300021 PM 10955789 ER PT J AU Vihinen, M Villa, A Mella, P Schumacher, RF Savoldi, G O'Shea, JJ Candotti, F Notarangelo, LD AF Vihinen, M Villa, A Mella, P Schumacher, RF Savoldi, G O'Shea, JJ Candotti, F Notarangelo, LD TI Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency SO CLINICAL IMMUNOLOGY LA English DT Article DE immunodeficiency; B cells; T cells; disease-causing mutations; structural basis of disease; structure-function relationships; JAK3base ID DEPENDENT PROTEIN-KINASE; X-LINKED AGAMMAGLOBULINEMIA; RECEPTOR-GAMMA-CHAIN; TYROSINE PHOSPHORYLATION SITES; DEFECTIVE LYMPHOID DEVELOPMENT; REFINED CRYSTAL-STRUCTURE; MICE LACKING JAK3; CATALYTIC SUBUNIT; PEPTIDE INHIBITOR; INSULIN-RECEPTOR AB Hereditary severe combined immunodeficiency (SCID) includes a heterogeneous group of diseases that profoundly affect both cellular and humoral immune responses and require treatment by bone marrow transplantation. Characterization of the cellular and molecular bases of SCID is essential to provide accurate genetic counseling and prenatal diagnosis, and it may offer the grounds for alternative forms of treatment. The Jak3 gene is mutated in most cases of autosomal recessive T-B+ SCID in humans. Jak3 belongs to the family of intracellular Janus tyrosine kinases. It is physically and functionally coupled to the common gamma chain, gamma c, shared by several cytokine receptors. We have established the JAK3base registry for disease and mutation information. In order to study the structural consequences of the Jak3 mutations, the structure of the human Jak3 kinase and pseudokinase domains was modeled. Residues involved in ATP and Mg2+ binding were highly conserved in the kinase domain whereas the substrate binding region is somewhat different compared to other kinases. We have identified the first naturally occurring mutations disrupting the function of the human Jak3 kinase domain. The structural basis of all of the known Jak3 mutations reported so far is discussed based on the modeled structure. The model of the Jak3 protein also permits us to study Jak3 phosphorylation at the structural level and may thus serve in the design of novel immune suppressive drugs. (C) 2000 Academic Press. C1 Univ Tampere, Inst Med Technol, FIN-33014 Tampere, Finland. Tampere Univ Hosp, FIN-33520 Tampere, Finland. CNR, Ist Tecnol Biomed Avanzate, I-20090 Segrate, MI, Italy. Univ Brescia, Ist Med Mol Angelo Nocivelli Clin Pediat, Brescia, Italy. NIAMSD, Arthritis & Rheumatism Branch, Lymphocyte Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP Vihinen, M (reprint author), Univ Tampere, Inst Med Technol, FIN-33014 Tampere, Finland. RI Vihinen, Mauno/A-8452-2012; Notarangelo, Luigi/F-9718-2016; OI Vihinen, Mauno/0000-0002-9614-7976; Notarangelo, Luigi/0000-0002-8335-0262; Villa, Anna/0000-0003-4428-9013 NR 68 TC 16 Z9 21 U1 0 U2 2 PU ACADEMIC PRESS INC PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD AUG PY 2000 VL 96 IS 2 BP 108 EP 118 DI 10.1006/clim.2000.4880 PG 11 WC Immunology SC Immunology GA 341XD UT WOS:000088615500007 PM 10900158 ER PT J AU Elliot, SJ Striker, LJ Connor, E Stetler-Stevenson, W McQuinn, WC Blagg, CR Striker, GE AF Elliot, SJ Striker, LJ Connor, E Stetler-Stevenson, W McQuinn, WC Blagg, CR Striker, GE TI Pentosan polysulfate decreases proliferation and extracellular matrix deposition by vascular smooth muscle cells isolated from failed hemodialysis access grafts SO CLINICAL NEPHROLOGY LA English DT Article; Proceedings Paper CT 31st Congress of the American-Society-of-Nephrology CY OCT 24-28, 1998 CL PHILADELPHIA, PENNSYLVANIA SP Amer Soc Nephrol DE PTFE grafts; stenosis PPS; hemodialysis; vascular access; extracellular matrix; metalloproteinases ID MESANGIAL CELLS; GROWTH-FACTOR; HEPARIN; METALLOPROTEINASES; EXPRESSION; MECHANISMS; ACTIVATION; INHIBITOR AB (B)ackground: Vascular access failure is a major cause of morbidity, and increased costs in patients undergoing maintenance hemodialysis. Stenosis, the most common underlying cause of loss of patency in failed grafts, appears to be caused by an obstructing mass of tissue containing proliferating smooth muscle cells and their associated extracellular matrix. Methods: To determine whether this process was amenable to pharmacologic intervention and/or prevention, we obtained samples of the material occluding vascular accesses from 7 patients undergoing revision surgery in order to characterize the cells contributing to the stenosis. In all 7 patients the outgrowth contained predominantly smooth muscle-like cells admired with fibroblasts, which produced a large amount of type IV and type I collagen. Results: Treatment with pentosan polysulfate inhibited cell proliferation and significantly reduced the accumulation of types I and type IV collagens. This was associated with increase in metalloproteinase-9 (MMP-9) and a shift of tissue inhibitor of metalloproteinase-3 (TIMP-3) from the cell layer into the medium. Conclusion: These data suggest that pentosan polysulfate (PPS) may have a favorable effect in patients with a polytetrafluoroethylene (PFTE) graft by decreasing cell proliferation and collagen deposition. C1 Univ Miami, Sch Med, Dept Med, Miami, FL 33101 USA. NCI, Extracellular Matrix Pathol Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NW Kidney Ctr, Seattle, WA USA. RP Elliot, SJ (reprint author), Univ Miami, Sch Med, Dept Med, POB 016960,R126, Miami, FL 33101 USA. RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 NR 20 TC 4 Z9 6 U1 0 U2 2 PU DUSTRI-VERLAG DR KARL FEISTLE PI MUNCHEN-DEISENHOFEN PA BAHNHOFSTRABE 9 POSTFACH 49, W-8024 MUNCHEN-DEISENHOFEN, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD AUG PY 2000 VL 54 IS 2 BP 121 EP 127 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 343DB UT WOS:000088685500005 PM 10968687 ER PT J AU Pearson, JL Brown, GK AF Pearson, JL Brown, GK TI Suicide prevention in late life: Directions for science and practice SO CLINICAL PSYCHOLOGY REVIEW LA English DT Review ID RANDOMIZED CONTROLLED TRIAL; RECURRENT MAJOR DEPRESSION; MENTAL-HEALTH SERVICES; DELIBERATE SELF-HARM; TERM CARE FACILITIES; PSYCHIATRIC OUTPATIENTS; PSYCHOLOGICAL AUTOPSY; EVENTUAL SUICIDE; FOLLOW-UP; AFFECTIVE-DISORDERS AB Suicide among the elderly is a critical public health problem, yet there remains limited information on risk factors to target due to the few, number of controlled studies that could help is isolate and focus on the most potent risk factors, We suggest that because there are no proven, effective interventions showing reduced suicidal behaviors in older adults, the best current approach is to improve detection and treatment of later-life depression. This effort may be especially effective in primary care settings, where the majority of our nation's elderly seek and receive their mental health care. We review approaches to assessment and treatment of later life depression that seem most relevant for later life suicide prevention. Testing and determining whether these treatment approaches are effective is an immediate goal on the path to advancing the science and practice of late-life suicide prevention. Published by Elsevier Science Ltd. C1 NIMH, Bethesda, MD 20892 USA. Univ Penn, Philadelphia, PA 19104 USA. RP Pearson, JL (reprint author), NIMH, 6001 Execut Blvd,Room 7160,MSC 9635, Bethesda, MD 20892 USA. NR 166 TC 64 Z9 65 U1 7 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0272-7358 J9 CLIN PSYCHOL REV JI Clin. Psychol. Rev. PD AUG PY 2000 VL 20 IS 6 BP 685 EP 705 DI 10.1016/S0272-7358(99)00066-5 PG 21 WC Psychology, Clinical SC Psychology GA 350XC UT WOS:000089126100002 PM 10983264 ER EF